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In February 2013, GlaxoSmithKline (GSK) announced a commitment to further clinical transparency through the public disclosure of GSK Clinical Study Reports (CSRs) on the GSK Clinical Study Register.
The following guiding principles have been applied to the disclosure: Information will be excluded in order to protect the privacy of patients and all namedpersons associated with the study
Patient data listings will be completely removed* to protect patient privacy. Anonymized
data from each patient may be made available subject to an approved research
proposal. For further information please see the Patient Level Data section of the GSK
Clinical Study Register.
Aggregate data will be included; with any direct reference to individual patients excluded
*Complete removal of patient data listings may mean that page numbers are no longer consecutively
numbered
CONFIDENTIAL 2014N211143_00The GlaxoSmithKline group of companies BA1116891
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Division: Worldwide DevelopmentInformation Type: Clinical Pharmacology Study Report
Title: A randomized, open label, parallel-group study to estimate bioavailability and to assess the pharmacokinetic profile, safety and tolerability of GSK933776 administered by subcutaneous or intramuscular injection relative to intravenous administration to healthy volunteers
Phase: I
Compound Number: GSK933776
Effective Date: 11-MAY-2015
Keywords: GSK933776, Pharmacokinetics, bioavailability, intravenous, subcutaneous and intramuscular administration, amyloid beta, monoclonal antibody, healthy volunteer study
Author(s): (CPSSO); (Clinical Statistics); (CPMS); (PTS); (Clinical Immunology);
(MPD); (Ophthalmology); (Ophthalmology)
Indication Studied: Healthy Volunteers supporting Geographic Atrophy secondary to Age-related Macular Degeneration
Initiation Date: 22-Jan-2014
Completion Date: 15-Jul-2014
Sponsor Signatory: (and Medical Officer)
, MDMedical Director, RD Alternative Discovery & DevelopmentGlaxoSmithKline
This study was performed in compliance with Good Clinical Practices and GlaxoSmithKline Standard Operating Procedures for all processes involved, including the archiving of essential documents. This study complies with US 21 CFR 312.120, as described in the Ethics and Good Clinical Practice section.
Copyright 2015 the group of companies. All rights reserved. Unauthorized copying or use of this information is prohibited.
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Table of Contents Page TITLE PAGE .......................................................................................................... ABBREVIATIONS .................................................................................................. ETHICS AND GOOD CLINICAL PRACTICE ......................................................... 1. CENTER INFORMATION AND STUDY ADMINISTRATION ............................. 2. OBJECTIVES & ENDPOINTS ........................................................................... 3. INVESTIGATIONAL PLAN ................................................................................
3.1. Study Rationale ............................................................................................... 3.2. Study Design Discussion ................................................................................. 3.3. Protocol Amendments ..................................................................................... 3.4. Selection of Study Population ..........................................................................
3.4.1. Inclusion/Exclusion Criteria ......................................................................... 3.4.2. Lifestyle and/or Dietary Restrictions ............................................................ 3.4.3. Withdrawal Criteria ......................................................................................
3.5. Treatments ...................................................................................................... 3.5.1. Investigational Product(s) ............................................................................ 3.5.2. Treatment Assignment ................................................................................ 3.5.3. Masking ....................................................................................................... 3.5.4. Prior and Concomitant Medications and Non-Drug Therapies .................... 3.5.5. Compliance .................................................................................................
3.6. Study Assessments and Procedures ............................................................... 3.6.1. Safety Assessments .................................................................................... 3.6.2. Physical Exams ........................................................................................... 3.6.3. Vital Signs ................................................................................................... 3.6.4. Electrocardiogram (ECG) ............................................................................ 3.6.5. Clinical Laboratory Assessments ................................................................ 3.6.6. Pharmacokinetic Assessments .................................................................... 3.6.7. Pharmacodynamic Assessments ................................................................
3.7. Biomarker(s)/Pharmacodynamic Markers ........................................................ 3.7.1. Confirmed Biomarkers/Pharmacodynamic Markers ....................................
3.8. Immunogenicity................................................................................................ 3.9. Data Quality Assurance ................................................................................... 3.10. Data Analysis Methods ..................................................................................
3.10.1. Hypotheses and Treatment Comparisons ................................................. 3.10.2. Sample size considerations ....................................................................... 3.10.3. Analysis Populations .................................................................................
3.11. Interim Analyses ............................................................................................ 3.12. Final Analyses ...............................................................................................
3.12.1. Safety Analyses ......................................................................................... 3.12.2. Pharmacokinetic Analyses ........................................................................ 3.12.3. Pharmacokinetic/Pharmacodynamic Analyses .......................................... 3.12.4. Changes in Conduct of the Study or Planned Analyses ............................
4. STUDY POPULATION RESULTS ..................................................................... 4.1. Subject Disposition ..........................................................................................
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4.2. Protocol Deviations .......................................................................................... 4.3. Populations Analyzed ...................................................................................... 4.4. Demographic and Baseline Characteristics ..................................................... 4.5. Concomitant Medications ................................................................................ 4.6. Exposure and Treatment Compliance ............................................................. 4.7. Adverse Events ............................................................................................... 4.8. Serious and Significant Adverse Events ..........................................................
4.8.1. Deaths ......................................................................................................... 4.8.2. Serious Adverse Events .............................................................................. 4.8.3. Significant Adverse Events ..........................................................................
4.9. Clinical Laboratory Evaluations ....................................................................... 4.10. Other Safety Evaluations ............................................................................... 4.11. Pregnancies ...................................................................................................
5. PHARMACOKINETIC RESULTS ...................................................................... 5.1. Drug Concentration Data ................................................................................. 5.2. Plasma Pharmacokinetic Parameters .............................................................. 5.3. Statistical Analyses of Pharmacokinetic Parameters .......................................
5.3.1. Plasma PK Parameters Statistical Assessment .......................................... 5.3.2. Statistical Analysis Details ...........................................................................
6. PHARMACODYNAMIC AND BIOMARKER RESULTS .................................... 6.1. Pharmacodynamic Results ..............................................................................
Figure 7.1: Median Plasma Free Aβ1-22 Concentration-Time Plots ..................... Figure 7.2: Median Plasma Total Aβ18-35 Concentration-Time Plot..................... Figure 7.3: Median Plasma Total Aβ Concentration-Time Plot ..............................
6.2. Immunogenicity Results ................................................................................... 7. RELATIONSHIP BETWEEN PHARMACOKINETIC AND PHARMACODYAMIC PARAMETERS ...................................................................................................... 8. DISCUSSION AND CONCLUSIONS .................................................................
8.1. Discussion ....................................................................................................... 8.2. Conclusions .....................................................................................................
9. REFERENCES ................................................................................................... 10. POST-TEXT TABLES AND FIGURES .............................................................
10.1. Time and Events Table for Treatment Arms A (200 mg IV infusion), B (200 mg SQ injection), D (200 mg IM injection) ...............................................
10.2. Time and Events Tables for Treatment Arm C (50 mg SQ injection) ............. 10.3. Treatment Arm C (50 mg SQ injection) – Weeks 2 and 3 .............................. 10.4. Treatment Arm C (50 mg SQ injection) – Week 4 through Final Follow Up ...
11. CASE NARRATIVES ....................................................................................... STUDY POPULATION DATA SOURCE TABLES ................................................
Table 9.1 Summary of Study Population (Safety Population) ................................. Table 9.2 Summary of Subject Disposition (Safety Population) .............................. Table 9.3 Summary of Protocol Deviations (Safety Population) ............................. Table 9.4 Summary of Demographic Characteristics (Safety Population) .............. Table 9.5 Summary of Race and Racial Combination Details (Safety Population) . Table 9.6 Summary of Concomitant Medications (Safety Population) ....................
SAFETY DATA SOURCE TABLES .......................................................................
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455151525354
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Table 10.1 Summary of All Adverse Events (Safety Population) ............................ Table 10.2 Summary of Adverse Events Related to Study Treatment (Safety
Population) ............................................................................................... Table 10.6 Summary of Vital Signs (Safety Population) ......................................... Table 10.7 Summary of Vital Signs Changes from Baseline (Safety Population) ... Table 10.8 Summary of ECG Findings (Safety Population) .................................... Table 10.9 Summary of ECG Values (Safety Population) ...................................... Table 10.10 Summary of Category of QTc Data by Treatment and Time (Safety
Population) ............................................................................................... Table 10.11 Summary of Category of QTc Change from Baseline by Treatment
and Time (Safety Population) .................................................................. Table 10.12 Summary of Liver Chemistry Assessments for Subjects with Liver
Signal/Event (Safety Population) ............................................................. Table 10.13 Summary of Time on Treatment Before Liver Event (Safety
Population) ............................................................................................... Table 10.14 Summary of Liver Biopsy Details (Safety Population) ......................... Table 10.15 Summary of Liver Imaging Details (Safety Population) ....................... Table 10.301 Clinical Chemistry Laboratory Summary by Visit (Safety Population)
................................................................................................................. Table 10.302 Hematology Laboratory Summary by Visit (Safety Population) ........ Table 10.401 Summary of Abnormal Chemistry Laboratory Results (Safety
Population) ............................................................................................... Table 10.402 Summary of Abnormal Hematology Laboratory Results (Safety
Population) ............................................................................................... Table 10.501 Summary of Urinalysis Data (Character Result) (Safety Population) Table 10.502 Summary of Urinalysys Data (Numerical Result) (Safety Population)
................................................................................................................. PHARMACOKINETIC DATA SOURCE FIGURES ................................................
Figure 11.1 Mean Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Pharmacokinetic Concentration Population) .........................
Figure 11.2 Mean Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated) (Pharmacokinetic Concentration Population) ......
Figure 11.3 Median Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Pharmacokinetic Concentration Population) .........................
Figure 11.4 Median Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated) (Pharmacokinetic Concentration Population) .....
Figure 11.5 Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Pharmacokinetic Concentration Population) .........................
Figure 11.6 Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated) (Pharmacokinetic Concentration Population) ......
PHARMACOKINETIC DATA SOURCE TABLES .................................................. Table 11.1 Summary of Plasma GSK933776 Pharmacokinetic Concentration-
Time Data [ng/mL] (PK Concentration Population) .................................. Table 11.2 Summary of Derived Plasma GSK933776 Pharmacokinetic
Parameters (PK Parameter Population) ...................................................
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697085
110111
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123158
200
248296
308319
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Table 11.3 Summary of the Results of the ANOVA of Log-Transformed Plasma GSK933776 Pharmacokinetic Parameters (PK parameter Population) ...
Table 11.4 Median Difference and Confidence Interval for Plasma GSK933776 Pharmacokinetic Parameters (PK Parameter Population) .......................
PHARMACODYNAMIC DATA SOURCE FIGURES .............................................. Figure 7.1 Median Plasma Free Abeta1-22 PD Concentration-Time Plot (Linear
and Semi-Log) (Pharmacodynamic Population) ...................................... Figure 7.2 Median Plasma Total Abeta18-35 PD Concentration-Time Plot (Linear
and Semi-Log) (Pharmacodynamic Population) ...................................... Figure 7.3 Median Plasma Total Abeta42 PD Concentration-Time Plot (Linear
and Semi-Log) (Pharmacodynamic Population) ...................................... Figure 12.1 Mean Plasma PD Concentration-Time Plot (Linear and Semi-Log)
(Pharmacodynamic Population) ............................................................... Figure 12.2 Mean Plasma PD Concentration Change from Baseline-Time Plot
(Linear and Semi-Log) (Pharmacodynamic Population) .......................... Figure 12.3 Mean Plasma PD Concentration-Time Plot (Linear and Semi-Log)
(Truncated) (Pharmacodynamic Population) ........................................... Figure 12.4 Mean Plasma PD Concentration Change from Baseline-Time Plot
(Linear and Semi-Log) (Truncated) (Pharmacodynamic Population) ....... Figure 12.5 Median Plasma PD Concentration-Time Plot (Linear and Semi-Log)
(Pharmacodynamic Population) ............................................................... Figure 12.6 Median Plasma PD Concentration Change from Baseline-Time Plot
(Linear and Semi-Log) (Pharmacodynamic Population) .......................... Figure 12.7 Median Plasma PD Concentration-Time Plot (Linear and Semi-Log)
(Truncated) (Pharmacodynamic Population) ........................................... Figure 12.8 Median Plasma PD Concentration Change from Baseline-Time Plot
(Linear and Semi-Log) (Truncated) (Pharmacodynamic Population) ....... Figure 12.9 Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
(Pharmacodynamic Population) ............................................................... Figure 12.10 Individual Plasma PD Concentration-Time Plot (Linear and Semi-
Log) (Truncated) (Pharmacodynamic Population) ................................... PHARMACODYNAMIC DATA SOURCE TABLES ...............................................
Table 12.1 Summary of Plasma Abeta Pharmacodynamic Concentration-Time Data [pg/mL] (Pharmacodynamic Population) .........................................
Table 12.2 Summary of Log-Transformed Plasma Abeta Pharmacodynamic Concentration-Time Data [pg/mL] (Pharmacodynamic Population) .........
Table 12.3 Summary of Plasma Abeta Pharmacodynamic Concentration Change from Baseline-Time Data (Pharmacodynamic Population) ......................
Table 12.4 Summary of Anti-GSK933776 Antibody Immunogenicity Assessment-Time Data (Pharmacodynamic Population) .............................................
PHARMACOKINETIC AND PHARMACODYNAMIC DATA SOURCE FIGURES . Figure 13.1 Mean Plasma GSK933776 Concentration and Mean Plasma Abeta
Concentration versus Nominal Time by Treatment (Pharmacokinetic/Pharmacodynamic Population) ...................................
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Figure 13.2 Mean Plasma GSK933776 Concentration and Mean Plasma Abeta Concentration Change from Baseline versus Nominal Time by Treatment (Pharmacokinetic/Pharmacodynamic Population) ..................
Figure 13.3 Mean Plasma GSK933776 Concentration and Mean Plasma Abeta Concentration versus Nominal Time by Treatment (Truncated) (Pharmacokinetic/Pharmacodynamic Population) ...................................
Figure 13.4 Mean Plasma GSK933776 Concentration and Mean Plasma Abeta Concentration Change from Baseline versus Nominal Time by Treatment (Truncated) (Pharmacokinetic/Pharmacodynamic Population) .................................................................................................................
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ABBREVIATIONS
z Terminal phase rate constant
AD Alzheimer’s diseaseADCC Antibody-dependent cellular cytotoxicityAE Adverse eventALT Alanine aminotransferase (SGPT)AMD Age-related macular degenerationANOVA Analysis of varianceAPTT/INR activated partial thromboplastin time /international normalized ratioARIA Amyloid related imaging abnormalitiesARIA-E ARIA-edema/effusionsARIA-H ARIA-hemosiderin depositsAST Aspartate aminotransferase (SGOT)AUC Area under concentration-time curve
AUC(0-) Area under the concentration-time curve over the dosing interval
AUC(0-inf) Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time
AUC(0-t) Area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration
Aβ or Abeta Amyloid betaBUN Blood urea nitrogenCDC Complement-dependent cytotoxicityCL Systemic clearance of parent drugCmax Maximum observed concentration CO2 Carbon dioxideCPK Creatine phosphokinaseCPMS Clinical Pharmacology Modelling & SimulationCP-RAP Clinical Pharmacology Reporting and Analysis PlanCPSSO Clinical Pharmacology Science and Study OperationsCRF Case Report FormCSF Cerebrospinal FluidCt Last observed quantifiable concentrationCV Coefficient of variationCVA Cerebrovascular accidentECG ElectrocardiogramECL ElectrochemiluminescentF Absolute bioavailability of drug FDA Food and Drug AdministrationFSH Follicle Stimulating HormoneGA Geographic atrophyGCP Good Clinical PracticeGCSP Global Clinical Safety and PharmacovigilenceGGT Gamma glutamyltransferaseGLP Good Laboratory PracticeGSK GlaxoSmithKline
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h/hr Hour(s)HBsAg Hepatitis B surface antigenHIV Human immunodeficiency virusIB Investigator’s BrochureICH International Conference on Harmonisation IDSL Integrated Data Standards LibraryIEC International Ethics CommitteeIM IntramuscularINR International Normalized RatioIP Investigational productIRB Institutional Review BoardIUD Intrauterine deviceIUS Intrauterine systemIV IntravenousKg KilogramL Literlbs PoundsLDH Lactate dehydrogenaseLFTs Liver function testsmAb Monoclonal antibodymg MilligrammL MillilitermmHg Millimeters of mercuryMRI Magnetic Resonance ImagingMSDS Material Safety Data Sheetmsec MillisecondsPCI Potential Clinical ImportancePD PharmacodynamicPK PharmacokineticPoC Proof of conceptQTcB QT duration corrected for heart rate by Bazett’s formulaQTcF QT duration corrected for heart rate by Fridericia’s formulaRBC Red blood cellsSAE Serious adverse event(s)SGOT Serum glutamic-oxaloacetic transaminaseSGPT Serum glutamic pyruvic transaminaseSOP Standard Operating ProcedureSPM Study Procedures ManualSQ SubcutaneousT½ Terminal phase half-lifeTmax Time of occurrence of CmaxULN Upper limit of normalVE Vasogenic edemaWBC White blood cellsτ Dosing interval
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Trademark Information
Trademarks of the GlaxoSmithKline group of companies
Trademarks not owned by the GlaxoSmithKline group of companies
NONE RandAllWinNonlin
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ETHICS AND GOOD CLINICAL PRACTICE
The study protocol, any amendments, the informed consent, and other information that required pre-approval were reviewed and approved by a institutional review board, in accordance with the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) and applicable country-specific requirements, including US 21 Code of Federal Regulations (CFR) 312.3(b) for constitution of independent ethics committees. Ethics committee or institutional review board approvals are maintained in the Sponsor’s study file.
This study was conducted in accordance with ICH GCP and all applicable subject privacy requirements, and, the ethical principles that are outlined in the Declaration of Helsinki 2008. The study was monitored in accordance with ICH E6, Section 5.18.
Investigators were trained to conduct the study in accordance with GCPs and the study protocol as defined in ICH E3, Section 9.6. Written commitments were obtained from investigators to comply with GCP and to conduct the study in accordance with the protocol.
Written informed consent was obtained from each subject prior to the performance of any study-specific procedures. The investigator agreed to provide the subject as much time as necessary to review the document, to inquire about details of the trial, and to decide whether or not to participate in the study. The informed consent was signed and dated by the study subject and by the person who conducted the informed consent discussion. (Electronic and/or paper) Case report forms were provided for each subject’s data to be recorded.
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1. CENTER INFORMATION AND STUDY ADMINISTRATION
This study was conducted at Quintiles, 6700 W. 115th Street, Overland Park, Kansas, 66211, United States. The first subject was enrolled on 22-Jan-2014 (first subject first visit) and the last subject completed on 15-Jul-2014 (last subject last visit).
Table 1 Study conduct
Name and Address Role/ResponsibilitiesInstitutional Review Board
United States
IRB Activities
Steering Committee None None
CROs/Companies and activities outsourced
Quintiles 6700 W. 115th StOverland Park, KS 66211 USA
Data Management Activities
Independent Data Monitoring Committee
None None
Monitor CCRA Site Monitoring
PK Laboratory Alliance Pharma, Inc17 Lee Boulavard, Malvern
PA 19355, USA
PK Sample Analysis
Biomarker/PD/ImmunologyLaboratory
GlaxoSmithKline709 Swedeland RoadKing of Prussia PA 19406, USA
PD/Biomarker/Immunology SampleAnalysis
Central Laboratory Quest Diagnostics26081 Avenue Hall, #150Valencia, CA 91355, USA
Liver Event Sample Analysis
Local Safety Laboratory Physicians Reference Laboratory (PRL)7800 West 110th St.Overland Park, KS 66210, USA
Hematology/Chemistry/Urinalysis Sample Analysis
Co-license or Joint Venture Agreement
None None
Contract medical writer None None
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2. OBJECTIVES & ENDPOINTS
Objectives Endpoints
Primary
To estimate the relative bioavailability of GSK933776 following single-dose IM and SQ administration and repeat-dose SQ administration as compared to IV administration
The relative bioavailability as calculated from the ratio of AUC (0-inf) following IM injection or SQ injection to IV infusion (reference arm)
Secondary
To characterize the pharmacokinetic profile of GSK933776 following single-dose IM and SQ administration and repeat-dose SQ administration as compared to IV administration
Pharmacokinetic parameters including area under the concentration-time curve from time zero to time of the last quantifiable concentration (AUC(0-t)) if AUC(0-inf) is not reportable, Cmax, time of occurrence of Cmax (Tmax), terminal phase half-life (T1/2), clearance, and volume of distribution as data permit
To evaluate the safety and tolerability of GSK933776 following IV, IM and SQ administration
Clinical safety data from adverse event reporting (including injection site reactions), clinical observations, vital signs, ECG, and clinical laboratory parameters
To further characterize the PK-PD relationship of GSK933776 based on concentrations of A as the PD marker of interest
Determination of plasma concentrations of GSK933776, total Aβ and total Aβ fragments, as well as unbound concentrations of Aβ, fragments containing the epitope 1-22, as data permit
To characterize the immunogenicity profile of GSK933776 following IV, IM and SQ administration
Presence of antibodies to GSK933776 in serum samples (if detected, characterization of neutralizing status), as data permit
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3. INVESTIGATIONAL PLAN
3.1. Study Rationale
The route of administration in clinical studies of GSK933776 prior to conduct of this study was intravenous (IV) infusion; including two completed clinical studies evaluatingGSK933776 in patients with Alzheimer’s disease (AD) and one ongoing Phase 2 study in Geographic Atrophy patients.
This study was planned and executed to support possible transition to IM or SQ administration for subsequent studies with GSK933776, by characterizing the safety, tolerability, pharmacokinetic and pharmacodynamic profiles, and immunogenicityfollowing IM and SQ administration in healthy volunteers. Such alternative routes of administration would provide more options in the selection of an efficacious dose for later development in patients with geographic atrophy.
This study was conducted in healthy adult volunteers, between ages 18-50 years. Total dose was selected as 200mg, approximating the 3 mg/kg regimen administered by IV infusion.
Previously patients had received treatment over 3 months or longer with the 3 mg/kg IV regimen, the accrued safety profile of GSK933776 in these populations suggested tolerability of single dose of 200mg or four repeat doses of 50mg of GSK933776.
3.2. Study Design Discussion
Figure 1 Study Design/Schematic
• Duration: Approximately 85 days for subjects in Treatment Arms A, B and D; approximately 106 days for subjects in Treatment Arm C
• Follow up: 84 days following last dose administration
• Sample size: Planned evaluable subjects = 24. Enrolment will account for dropouts or non-evaluable subjects via replacement
Screening 1:1:1:1
Randomization
A: Single 200 mg IV infusion of GSK933776 (n=6)
B: Single 200 mg SQ dose of GSK933776 (n=6)
C: 4 weekly 50 mg SQ doses of GSK933776 (n=6)
D: Single 200 mg IM dose of GSK933776 (n=6)
Treatment Arms
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This was a single clinical center, randomized, open-label study conducted to investigate the relative bioavailability, pharmacokinetic (PK) profile, pharmacodynamic (PD)profile, safety and tolerability, and immunogenicity profile of GSK933776 administered by IV infusion and IM and SQ routes of administration in healthy volunteers. A total of 36 subjects were enrolled for this study.
Subjects were screened to determine eligibility to participate in the study after providing informed consent. Subjects were assigned to 1 of 4 below mentioned possible treatment regimens in 1:1:1:1 ratio
Arm A (1*): Single 200 mg IV infusion of GSK933776
Arm B (2*): Single 200 mg SQ dose of GSK933776
Arm C (3*): 4 weekly 50 mg SQ dose of GSK933776
Arm D (4*): Single 200 mg IM dose of GSK933776.
*Final Treatment codes in Source Documents and Datasets are numbered 1, 2,3,4 respectively.
Subjects remained in the unit for at least 6 hours post-dose for safety and tolerability assessments and samples for pharmacokinetic and pharmacodynamic determinationswere obtained. Subjects receiving GSK933776 by IM and SQ administration were monitored for injection site tolerability and immediate post-injection reactions for at least 6 hours after injection.
Subjects in treatment arms A, B and D were followed for approximately 84 days after dose administration and subjects in treatment arm C were followed for 84-day after the final [fourth] dose. The total duration of subject participation from screening to follow-up for treatment arms A, B and D (single dose of GSK933776), was approximately 113 days and for treatment arm C (weekly SQ administration for 4 doses), was approximately 134 days. Subjects returned for periodic visits over the approximate 84-day post dosing period for monitoring of safety, tolerability and immunogenicity and samples for PK and PD assessments were obtained.
The final clinic visit was scheduled for each subject, and assessments were performed based on the Time and Events Table (Table 13)
3.3. Protocol Amendments
This study was conducted using original protocol version 1.0 dated 05 Nov 2013. There was no protocol amendment for the study.
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3.4. Selection of Study Population
3.4.1. Inclusion/Exclusion Criteria
3.4.1.1. Inclusion Criteria
A subject was eligible for inclusion in this study only if all of the following criteria applied:
1. Male or female subject 18 – 50 years of age at the time of signing the informed consent
2. In general, subjects were in good health as determined by a physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied could be included only if the Investigator and the GSK Medical Monitor agreed that the condition was unlikely to introduce additional risk factors and did not interfere with the study procedures
3. Body weight ≥ 55 kg [121 lbs (pounds)] and ≤ 85 kg (187 lbs) with a body mass index (BMI) between 18.5 and 29 (inclusively) where
BMI = (weight in kg)(height in meters)2
at the time of signing the informed consent
4. A female subject was eligible to participate if she was of:
Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea. In questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MIU/mL and estradiol < 40 pg/mL (<140 pmol/L) was confirmatory
5. Male subjects agreed to use one form of acceptable contraception methods listed in Section 3.4.2.1.1 if their partner was of childbearing potential. This criterion was to befollowed from the time of the screening visit through the follow-up visit (84 days after last dose of study medication)
6. Subjects were capable of giving written informed consent, which includedcompliance with the requirements and restrictions listed in the consent form.
3.4.1.2. Exclusion Criteria
A subject was not eligible for inclusion in this study if any of the following criteria applied:
3.4.1.2.1. Criteria Based Upon Medical Histories
1. Known risk history of:
a. Central nervous system (CNS) disorders:
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i. History and/or evidence by computerised tomography (CT) or Magnetic Resonance Imaging (MRI) scan performed within the past 12 months] of cerebral haemorrhage OR a known risk of cerebral haemorrhage, including uncontrolled hypertension, cerebrovascular malformation, coagulopathy, CNS vasculitis, degenerative or inflammatory/demyelinating CNS conditions or any other condition that the Investigator and/or the medical monitor considered a relevant risk factor for cerebral haemorrhage
ii. Transient ischemic attack (TIA)/cerebrovascular accident (CVA) in the previous year, or other uncontrolled risk factors for stroke
b. History of seizures (except febrile seizures in childhood) or recent unprovoked seizure
c. Uncontrolled type 2 diabetes mellitus [glycated haemoglobin (HbA1C) >10%], active cardiovascular disease (e.g., moderate-severe angina, unstable angina, myocardial infarction (MI) within the last 2 years, symptomatic congestive heart failure, clinically significant arrhythmia)
d. Current blood clotting or bleeding disorder or conditions that predispose to these (e.g. cancer)
e. Diagnosis of currently active, or, in remission but chronic relapsing, systemic autoimmune disease or condition (e.g. multiple sclerosis, lupus erythematosus etc) that the Investigator and/or the medical monitor considered as a relevant risk factor for concomitant administration of a therapeutic monoclonal antibody
2. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
3. Use of prescription drugs or non-prescription drugs; including vitamins, herbal and dietary supplements (including St John’s Wort) within 7 days or 5 half-lives (whichever was longer) prior to the first dose of study medication, unless in the opinion of the Investigator and GSK Medical Monitor the medication did not interfere with the study procedures or compromise subject safety
4. A positive pre-study drug/alcohol screen. Current or recent drug or alcohol abuse or dependence. History of regular alcohol consumption within 6 months of the study defined as: An average weekly intake of >14 units for males or >7 units for females. One drink was equivalent to 12 g of alcohol: 12 ounces (~360 mL) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits. Use of illegal drugs
5. History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the Investigator or GSK Medical Monitor, contraindicated their participation
3.4.1.2.2. Criteria Based Upon Diagnostic Assessments
6. Seated systolic blood pressure > 140 mmHg or seated diastolic blood pressure of > 90 mmHg
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7. QTc > 450 millisecond (msec)
8. AST and ALT ≥ 2xULN; alkaline phosphatase and bilirubin 1.5xULN (isolated bilirubin >1.5xULN was acceptable if bilirubin was fractionated and direct bilirubin <35%)
9. Significant abnormalities on hematology screen: clinically significant anemia (i.e. hemoglobin <11 g/dL for males or <10 g/dL for females), or platelet counts below 124 GI/L; INR > 2
10. A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening
11. A positive test for HIV antibody
3.4.1.2.3. Other Criteria
12. Where participation in the study resulted in donation of blood or blood products in excess of 500 mL within a 56 day period
13. Exposure to more than four new chemical entities within 12 months prior to screening
14. Prior allergic reactions to biological products (vaccines, antibodies) or known hypersensitivity to any of the components of the drug formulation
15. Prior participation in clinical investigations involving therapeutic monoclonal antibodies with a similar mode of action or proteins derived from monoclonal antibodies with any risk of cross- reactivity or any investigations of treatments or use of any other investigational medication or device within 2 months prior to screening or within 5 half-lives of use of such a medication prior to screening, whichever was longer.
3.4.2. Lifestyle and/or Dietary Restrictions
3.4.2.1. Contraception Requirements
3.4.2.1.1. Male Subjects
Male subjects with female partners of child-bearing potential were asked to use one of the following contraceptive methods after the first dose of study treatment and until the follow-up visit, 84 days after the last dose of investigational product.
• Condom (during non-vaginal intercourse with any partner - male or female) OR
• Condom and occlusive cap (diaphragm or cervical/vault caps) plus spermicidal agent (foam/gel/film/cream/suppository) (during sexual intercourse with a female)
• Abstinence, defined as sexual inactivity consistent with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
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3.4.2.2. Meals and Dietary Restrictions
3.4.2.2.1. Caffeine, Alcohol, and Tobacco
During each dosing session, subjects were asked to abstain from alcohol for 24 hours prior to the start of dosing until collection of the final PK and/or PD sample during each session. An alcohol test was given as outlined in Time and Events Table (Table 13)
3.4.2.2.2. Activity
Subjects were asked to abstain from strenuous exercise for 48 hours prior to each blood collection for clinical laboratory tests. Subjects were allowed to participate in light recreational activities during studies.
3.4.2.2.3. Other Restrictions
Subjects were asked to refrain from all recreational drugs throughout the study (screening to follow-up). Drugs of abuse tests were performed randomly throughout the study at the Investigator’s discretion. A positive result at any point may lead to exclusion from the study
One subject did test positive for Cannabis use during the study but subject was cleared to continue after approval from GSK Medical Monitor.
3.4.2.2.4. Screen and Baseline Failures
Data for screen and baseline failures was collected in source documentation at the site but was not transmitted to GSK in the study defined data capture system
3.4.3. Withdrawal Criteria
A subject could withdraw from study treatment at any time at his/her own request, or could be withdrawn at any time at the discretion of the Investigator for safety, behavioralor administrative reasons.
If a subject failed to attend the clinic for a required study visit, the site was to contact the subject and re-schedule the missed visit as soon as possible. The site also was to counsel the subject on the importance of maintaining the assigned visit schedule and ascertain whether or not the subject wished to and/or should continue in the study based on previous non-compliance. In cases where the subject did not return for the rescheduled visit or could not be reached to reschedule the missed visit, the site was to make every effort to regain contact with the subject (3 telephone calls and if necessary a certified letter to the subject’s last known mailing address) so that they could be appropriately withdrawn from the study.
These contact attempts were to be documented in the subject’s medical record. If subject continued to be unreachable, then and only then he/she was considered to have withdrawn from the study with a primary reason of “Lost to Follow-up”. For all other subjects withdrawing from the study, an alternative reason for discontinuation wasrecorded in the eCRF.
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One subject was documented as “Lost to Follow-up” after all required steps were taken to contact the subject were exhausted.
3.4.3.1. Planned Dose Adjustments
This study did not allow alteration from the outlined doses for each cohort. The maximum total dose was not to exceed 200 mg in any subject or cohort.
All subjects received the correct dosage of 200 mg in clinic as randomized.
3.4.3.2. Subject Specific Dose Adjustment/Stopping Criteria
A subject could discontinue treatment and withdraw from the study at any time at his/her own request or could be withdrawn at any time for safety or administrative reasons at the discretion of the Investigator.
Two subjects withdrew early from the study. They did receive full dosing per protocol but missed follow-up visits. One subject withdrew early due to moving out of state. Another subject was Lost to Follow-up.
3.4.3.3. Allergic Reaction
Although humanization of the GSK933776 antibody was expected to reduce the risk of acute allergic reactions, all subjects were monitored carefully for evidence of acute allergic reactions and infusion reactions (for those subjects participation in the IV arm). It was important to recognize early signs of anaphylaxis or anaphylactic reactions and to prevent progression to severe anaphylaxis should any event be noted during the study.
No subjects experienced signs of anaphylaxis or anaphylactic reactions.
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3.5. Treatments
3.5.1. Investigational Product(s)
Identity of Investigational Product
PRODUCT NAME:
GSK933776 (SQ ADMINISTRATION)
GSK933776 (IM ADMINISTRATION)
GSK933776 (IV ADMINISTRATION)
Formulation description:
Antibody solution Antibody solution Antibody solution
Dosage form: Solution for injection Solution for injection Solution for infusion
Unit dose strength(s)/Dosage level(s):
50 mg/mL (1 mL nominal volume) in a 3 mL glass vial
50 mg/mL (1 mL nominal volume) in a 3 mL glass vial
50 mg/mL (1 mL nominal volume) in a 3 mL glass vial
Route/Duration: Route: SubcutaneousDuration(Single Dose): 200 mg Duration(Repeat Dose): 50 mg weekly for 4 weeks
Route: IntramuscularDuration(Single Dose): 200 mg
Route: Intravenous Duration (Single Dose): 200 mg
Dosing instructions:
The dose was administered through a sterile disposable syringe in the subcutaneous space.Acceptable injection site was either the abdomen or the upper thigh. Injection site was documented and rotated
The dose was administered in the dorsal or ventrogluteal site (in order to achieve a 200mg dose, a 4 mL injection of the 50mg/mL product are needed)
The dose was administered through an IV catheter over approximately 1 hour
Method for individualizing dosage:
GSK933776 was drawn into a sterile disposable syringe.Study drug was then administered through a sterile needle (27GA).
GSK933776 was drawn into a sterile disposable syringe. Study drug was then administered through a sterile needle (23GA).
GSK933776 was prepared in 0.9% Sodium Chloride in infusion bags. Study drug was then administered using an IV delivery pump and a catheter.
Batch Numbers PK Lot ID: 132379262
Lot No: 091217577
PK Lot ID: 132379262
Lot No: 091217577
PK Lot ID: 132379262
Lot No: 091217577
3.5.2. Treatment Assignment
Subjects were assigned to 1 of 4 possible treatment arms in a 1:1:1:1 ratio in accordance with the randomisation schedule generated using RandAll, a web-based clinical trials system, by QSci, Clinical Statistics Department at GlaxoSmithKline (GSK).
A description of each study regimen is provided below:
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TREATMENT ARM DESCRIPTIONA (1*) 200 mg GSK933776 administered by IV infusionB (2*) 200 mg GSK933776 administered by SQ injection C (3*) 50 mg GSK933776, administered by SQ injection once weekly for 4 weeks
for a total monthly dose of 200 mg GSK933776D (4*) 200 mg GSK933776 administered by IM injection
*Final Treatment codes in Source Documents and Datasets are numbered 1, 2,3,4 respectively
3.5.3. Masking
This was an open-label study.
3.5.4. Prior and Concomitant Medications and Non-Drug Therapies
3.5.4.1. Permitted Medications:
Acetaminophen, at doses of 2 grams/day was permitted for use any time during the study. Other concomitant medication were to be considered on a case by case basis by the GSK Medical Monitor.
3.5.4.2. Prohibited Medications and Non-Drug Therapies
Subjects were asked to abstain from taking prescription or non-prescription drugs (including vitamins and dietary or herbal supplements), within 7 days (or 14 days if the drug was a potential enzyme inducer) or 5 half-lives (whichever was longer) prior to the first dose of study medication until completion of the follow-up visit, unless in the opinion of the Investigator and Sponsor the medication did not interfere with the study.
3.5.4.3. Non-Drug Therapies
Subjects were asked to abstain from taking any vitamins, herbal and dietary supplements within 7 days (or 14 days if the drug was a potential enzyme inducer) or 5 half-lives (whichever was longer) prior to the first dose of study medication until completion of the follow-up visit, unless in the opinion of the Investigator and Sponsor the medication didnot interfere with the study.
3.5.5. Compliance
When the individual dose for a subject was prepared from a bulk supply, the preparation of the dose was confirmed by a second member of the study site staff.
The subjects were dosed at the study site, they received study treatment directly from the Investigator or designee, under medical supervision. The date and time of each dose administered in the clinic was recorded in the source documents. The dose of study treatment and study participant identification was confirmed at the time of dosing by a member of the study site staff other than the person administering the study treatment.
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3.6. Study Assessments and Procedures
The planned time points for each assessment are outlined in the Time and Events Table(Table 13)
3.6.1. Safety Assessments
The safety assessments were the monitoring of adverse events (AEs), clinical laboratory tests, vital signs, ECGs, physical examinations and monitoring of allergic reactions.
Refer to Protocol Section 6.3 for full details of safety assessments.
The Investigator or site staff were responsible for detecting, documenting and reporting events that met the definition of an AE or SAE. AE information volunteered by the subject, discovered by Investigator questioning or detected by other means was collected from the start of study treatment until the follow-up contact. The following information on AEs was obtained:
Duration (start and stop dates)
Severity (mild, moderate, severe)
Causality (reasonable possibility yes/no)
Actions taken and outcome
The AE and SAE definitions are provided in the Protocol, Section 7.1.3 and Section7.1.4, respectively. The definition of laboratory and vital sign abnormalities of potential clinical importance are provided in the study RAP Section 8.6.
3.6.2. Physical Exams
A complete physical examination included assessments of the head, eyes, ears, nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and spleen), lymph nodes and extremities. Height (at screening only) and weight was also measured and recorded.
3.6.3. Vital Signs
Vital sign measurements included systolic and diastolic blood pressure and pulse rate, and were recorded whilst the subject was in a semi-supine position having rested in sameposition for at least 5 minutes.
3.6.4. Electrocardiogram (ECG)
12-lead ECGs were obtained at the screening and follow-up visits using an ECG machine that automatically calculated the heart rate and measures PR, QRS, QT, and QTcB intervals.
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3.6.5. Clinical Laboratory Assessments
Hematology, clinical chemistry, urinalysis and additional parameters were tested. Details for the preparation and shipment of samples were provided by the local laboratory.Reference ranges for all safety parameters were provided to the site by the laboratory.
3.6.6. Pharmacokinetic Assessments
Pharmacokinetic samples were collected at time-points outlined in the Time and Events (Table 13). Samples were collected at nominal times relative to the proposed time ofGSK933776 dosing.
Blood samples were taken via an indwelling cannula (or by direct venipuncture). All blood samples were taken from the opposite arm to that of drug administration. Approximately 2mL of whole blood was collected into 2mL EDTA tubes (lavender cap) and was placed on ice. Approximately 1 ml plasma was collected into storage tube.
Within 30 minutes of collection, all blood samples were centrifuged in a refrigerated centrifuge at 2000g for 15 minutes at approximately 4°C. The resultant 1 ml plasma (clear liquid on top) was transferred to uniquely labeled 1.4mL matrix -tube (clear top) and frozen immediately on dry-ice. In the absence of dry ice, the sample was immediately placed into a freezer at or below -20°C without delay.
Human plasma samples were analyzed for GSK933776 by Alliance Pharma, Malvern, PA, USA using a validated analytical immunoassay method based on sample dilution, followed by immunoassay analysis [GlaxoSmithKline Document Number: 2013N182307_00]. The LLQ for GSK933776 was 100 ng/mL, using a 100 L aliquot of eleven-fold diluted human plasma, with a higher limit of quantification (HLQ) of 5000 ng/mL.
The immunoassay utilizes 1-16 beta amyloid peptide as the means of capture and therefore measures free GSK933776 antibody which is defined as the sum of bivalent and monovalent unbound forms of the GSK933776 antibody.
For each analytical batch, quality control (QC) samples, containing GSK933776 at three different concentrations were stored with study samples and analyzed with each batch of samples against separately prepared calibration standards. For the analysis to be acceptable, no more than one-third of the total QC results and no more than one-half of the results from each concentration level were to deviate from the nominal concentration by more than 20%. The applicable analytical runs met all predefined run acceptance criteria. All data are stored in the Good Laboratory Practice Archive, Alliance Pharma, Malvern, PA, USA.
3.6.7. Pharmacodynamic Assessments
PD sampling for Aβ and related fragments is included in this study to enrich the existing PK-PD dataset and allow for specific PK-PD modeling of SQ and IM administrations. It is anticipated that these data could be useful for development of a general model
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characterizing the GSK933776 PK-PD relationship across multiple populations (AD, GA,and healthy volunteers).
3.7. Biomarker(s)/Pharmacodynamic Markers
3.7.1. Confirmed Biomarkers/Pharmacodynamic Markers
The total and free levels of beta amyloid fragments were measured in plasma for each subject. Abeta1-22, Abeta18-35 and Abeta42 were evaluated using immuno-electrochemiluminescent (ECL) assays.
Blood samples were taken from all subjects in this study according to Time and Events (Table 13).
Before collecting the PD samples, a protease inhibitor solution was prepared the morning of collection of samples, and was added to the PD collection tubes before adding the plasma.
Approximately 4mL of whole blood was collected for free and total A assays. Blood was collected into 4ml EDTA tubes (polypropylene tubes containing EDTA K2 gel, lavender cap) and the tubes were placed on ice immediately. Once collected, all blood samples were centrifuged in a refrigerated centrifuge at 2000g for 15 minutes at approximately 4°C within 30 minutes. When the sample was removed from the centrifuge, the plasma sample was mixed gently and the resultant, approximately 2 ml, plasma, was separated into 4 aliquots, each aliquots of 0.5 ml plasma was added into each tube containing 20 microliters of protease inhibitor solution and samples were frozen upright on dry ice or in a freezer at or below -70°C.
3.8. Immunogenicity
Blood samples for determination of anti-GSK933776 antibodies were taken from all subjects in this study as a safety measurement for GSK933776 at the time-points specified in the Time and Events Table (Table 13)
Samples were analysed for the presence of anti-GSK933776 antibodies by ECL screening and neutralisation assays. If sera contained anti- GSK933776 antibodies as determined by the ECL screening assay, they were further analysed for specificity, titres of antibodies and the presence of neutralising antibodies. The immunogenicity assessment report included the incidence and titres of anti-GSK933776 binding and neutralising antibodies.
Approximately 3mL of whole blood was collected into serum-separator tubes. All blood samples were maintained at ambient temperature for at least 1 hour, but no more than 4 hours. In case, clotting stimulator was added, samples were held no more than 1 hour to allow for complete clotting prior to centrifugation. Once a sample was completely clotted, it was centrifuged at 2000g for 15 minutes at approximately 4°C. Approximately 1.5 mL of serum (clear liquid on top) was equally divided into 3 aliquots and transferred to clean, uniquely labelled 1.8 ml cryotubes and frozen at -70°C immediately.
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3.9. Data Quality Assurance
Subject data was entered into GSK defined electronic case report forms (eCRFs), transmitted electronically to GSK and combined with data provided from other sources (e.g., laboratory data) in a validated data system.
Verification of data accuracy and adherence to protocol requirements was achieved through regular monitoring visits at the investigational site. Subsequent data handling and reporting processes were performed according to processes detailed in GSK’s Standard Operating Procedures (SOPs). AEs and concomitant medications were coded using company standard dictionaries, Medical Dictionary for Regulatory Activities (MedDRA) and GSKDrug.
SAEs, consistent with the data collected for other AEs, was entered into the database and quality assured, including reconciliation with the GCSP database.
Investigator(s), responsible study site staff, sponsor representative(s) and study monitor(s) attended a study site initiation meeting to review study protocol procedures, study requirements, and GCP responsibilities. Investigators and staff were given opportunity to discuss any aspect of the study protocol and GCP requirements. Training records were reviewed to ensure Investigators and staff were qualified to conduct the study and to document training in GCP.. Documentation of GCP training was confirmed prior to staff participation in the study.
The Principal Investigator signed the Investigator page of the protocol to confirm their commitment to conduct the study in accord with the protocol and GCP. The signed documents have been archived within individual Investigator study files.
Study monitor(s) contacted the site prior to the start of the study and reviewed with the site staff the protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and GSK requirements. When reviewing data collection procedures, the discussion included identification, agreement and documentation of data items for which the CRF served as the source document. The study was monitored to ensure that: (1) the data are authentic, accurate, and complete; (2) the safety and rights of subjects were protected; (3) the study was conducted in accordance with the currently approved protocol and any other study agreements, GCP and all applicable regulatory requirements.
3.10. Data Analysis Methods
3.10.1. Hypotheses and Treatment Comparisons
This study was designed to estimate the bioavailability of GSK933776 administered by SQ or IM injection relative to GSK933776 administered intravenously. No formal hypothesis was tested. For each primary pharmacokinetic endpoint, point estimates and corresponding 90% confidence intervals were constructed for the ratio of the geometric mean of the test treatment to the geometric mean of the reference treatment, (SQGSK933776)/( IV GSK933776) and (IM GSK933776)/( IV GSK933776).
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3.10.2. Sample size considerations
The sample size for this study was based on feasibility and the intention to collect safety and tolerability data from at least 6 subjects in each treatment arm of GSK933776. Variability estimates from previous studies with IV administration of GSK933776assured acceptable precision of PK parameters for the proposed sample size.
3.10.3. Analysis Populations
3.10.3.1. Safety Population
All patients enrolled in the study who received at least one dose of study drug wereincluded in the Safety Population. This population was used in the assessment of safety, and for listing and summarizing baseline/demographic and subject disposition data.
3.10.3.2. Pharmacokinetic Concentration Population
The PK Concentration Population consisted of all subjects in the Safety Population who underwent plasma PK sampling and had evaluable PK assay results. This population wasused for the concentration tables, listings, and figures.
3.10.3.3. Pharmacokinetic Parameter Population
The PK Parameter Population consisted of all subjects in the Pharmacokinetic Concentration Population for whom valid and evaluable pharmacokinetic parameters were derived. This population was used in the assessment and characterization of PK parameters. This population was also used for listing and statistical analysis of PK parameters.
3.10.3.4. Pharmacodynamic Population
The Pharmacodynamic (PD) Analysis Population consisted of all subjects in the Safety Population with at least one measurable concentration of biomarkers (including immunogenicity). This population was used for listing, summarizing and plotting of plasma concentration-time data for biomarkers.
3.10.3.5. PK/PD Analysis Population
The PK/PD Analysis Population consisted of all subjects in the Safety Population with at least one measurable concentration of biomarkers as well as one measurable concentration of GSK933776. This population was used to explore the PK/PD relationship.
3.11. Interim Analyses
No interim analyses were conducted.
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3.12. Final Analyses
3.12.1. Safety Analyses
Safety data was summarized and listed by, or under the direct auspices of, Clinical Statistics, GlaxoSmithKline. No formal statistical analysis of safety data was conducted.These tables used the “Safety” population unless otherwise specified.
3.12.2. Pharmacokinetic Analyses
Derivation of pharmacokinetic parameters was performed by, or under the direct auspices of, Clinical Pharmacology Modeling and Simulation (CPMS), GlaxoSmithKline.Statistical analysis of PK parameters was performed by, or under the direct auspices of, Clinical Statistics, GlaxoSmithKline. These tables used the PK concentration or parameter population unless otherwise specified.
The pharmacokinetic parameters were calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin 6.3 or higher. Calculations were based on the actual sampling times recorded during the study. From the plasma concentration-time data, the following pharmacokinetic parameters were determined, as data permitted area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC(0-∞)), area under the plasma concentration-time curve (AUC) AUC(0-672hrs) (for Treatment Arms A and C only), AUC(0-168hrs) (for Treatment Arms A and C only), maximum observed plasma concentration (Cmax), time to Cmax (Tmax), apparent terminal phase half-life (T1/2), apparent clearance (CL/F), apparent volume of distribution (V/F) (F=1 for Treatment Arm A). Pharmacokinetic data was presented in graphical and/or tabular form and was summarized descriptively. All pharmacokinetic data was stored in the Archives, GlaxoSmithKline Pharmaceuticals, R&D.
Following loge-transformation, the PK parameters AUC(0-∞), AUC(0-672hrs) (Treatment Arms A and C only), AUC(0-168hrs) (Treatment Arms A and C only), Cmax, CL/F and V/F of GSK933776 was separately analyzed using an analysis of variance model (ANOVA) with fixed effect terms for Regimen. Point estimates and their associated 90% confidence intervals (CIs) was constructed for the differences, B – A, C –A and D - A. For the comparison of C - A the parameter AUC(0-168hrs) was dose normalized. The point estimates and their associated 90% confidence intervals was then back-transformed to provide point estimates and 90% confidence intervals for the ratios, B:A, C:A and D:A.
Tmax of GSK933776 was separately analyzed with the non-parametric Wilcoxon rank-sum test to compute point estimates and associated 90% confidence intervals for the median differences, B – A, C - A and D - A.
3.12.3. Pharmacokinetic/Pharmacodynamic Analyses
The relationships between plasma concentration of GSK933776 and various biomarkers were explored via graphical and descriptive analyses.
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Pharmacodynamic /biomarker endpoints included plasma total Aβ and total Aβ fragments, as well as unbound concentrations of Aβ, fragments containing the amino acid sequence 1-22. PD/biomarker concentrations were listed by treatment, subject, visit, and actual plasma sampling time and summarized by treatment, visit, and nominal time. PD/biomarker concentration changes from baseline were also summarized. Standard summary statistics were calculated (i.e. mean, standard deviation, median, minimum and maximum). The immunogenicity endpoint included the measurement of antibodies to GSK933776 in serum samples. Immunogenicity data was summarized and a by-subject listing was provided.
These tables used the PD population unless otherwise specified.
3.12.4. Changes in Conduct of the Study or Planned Analyses
There were no changes in the conduct of the study but there were minor changes in planned analysis of the study as stated below.
Tmax and T1/2 of GSK933776 were originally planned to be analyzed with the non-parametric Wilcoxon rank-sum test to compute point estimates and associated 90% confidence intervals for the median differences, B - A, C - A and D - A. Wilcoxon rank-sum test, an analysis of Wilcoxon scores in the linear rank statistic for two-sample data, produces the rank sum statistic, not the median differences.
In the final analyses, non-parametric Hodges-Lehmann (HL) estimation of location shift for two-sample data was employed. Hodges-Lehmann estimate of location shift for two-sample data is the median of all possible differences in outcomes between a subject in Arm B, C, or D and a subject in Arm A. The Hodges-Lehmann estimator of location shift is associated with the Wilcoxon linear rank statistic.
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4. STUDY POPULATION RESULTS
4.1. Subject Disposition
Thirty Six (36) healthy subjects were enrolled into the study and all were randomized to one of the 4 treatment groups. Allocation of subjects was 9 subjects per treatment group. Two subjects were ultimately withdrawn from the study with one subject lost to follow-up and the other moved out of the area.
Details of subject disposition can be found in Table 2.
Table 2 Subject Disposition
Number of Subjects: Treatment A (200mg
IV)
Treatment B (200mg
SQ)
Treatment C (50mg SQ X 4)
Treatment D (200mg
IM)Number of subjects planned, [N] 6 6 6 6 Number of subjects randomized, [N] 9 9 9 9Number of subjects included in All subjects (safety) population, [n (%)]
9 (100%) 9 (100%) 9 (100%) 9 (100%)
Number of subjects included in PK population, [n (%)]
9 (100%) 9 (100%) 9 (100%) 9 (100%)
Number of subjects completed as planned, [n (%)]
9 (100%) 9 (100%) 8 (89%) 8 (89%)
Number of subjects withdrawn (any reason), [n (%)]
0 0% 1 (11%) 1 (11%)
Number of subjects withdrawn for SAE, [n (%)]
0 0 0 0
Number of subjects withdrawn for AE, [n (%)]
0 0 0 0
Reasons for subject withdrawal, [n (%)]Lost to follow-up 0 0 1 (11%) 0Adverse events 0 0 0 0Protocol violation 0 0 0 0Other1 0 0 0 1 (11%)
1Other refers to subject moving out of the area
4.2. Protocol Deviations
There were 12 subjects with reportable protocol deviations. All were considered minor in nature and all subjects were deemed eligible for analysis. None of the deviations were related to inclusion or exclusion criteria. Most were due to out of window visits or missed/out of window assessments.
4.3. Populations Analyzed
All thirty-six subjects were included in the agreed study populations defined in the RAP as in Table 3.
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Table 3 Populations analyzed
Population Definition No. of Subjects Included Displays
All SubjectsAll Subjects who received at least one dose of study treatment
36 Safety
Pharmacokinetic Concentration Population
All Subjects who have at least one evaluable GSK933776 PK Assay Result
36Pharmacokinetic Concentration
Pharmacokinetic Parameter Population
All Subjects in the PK Concentration population who have at least one evaluable PK parameterderived
36Pharmacokinetic Parameters
Pharmacodynamic Population
All Subjects in the Safety population who have at least one evaluable Biomarker Concentration (including Immunogenicity)
36Pharmacodynamic & Biomarker
PK/PD Analysis Population
All Subjects in the Safety population who have at least one evaluable Biomarker Concentration as well as one evaluable PK Concentration
36Pharmacokinetic andPharmacodynamic Relationship
4.4. Demographic and Baseline Characteristics
The demographic characteristics were well balanced except for gender.
The thirty-six subjects recruited for this study comprised 35 males and 1 female, 2 were Hispanic/Latino and the remaining 34 subjects were Non Hispanic/Latino. Subjects were between 19 and 45 years inclusive. All subject’s weights were within the agreed limits of 55kg (121 lbs) and 85kg (187 lbs) with all meeting the inclusion BMI parameter between 18.5 and 29 inclusively.
A summary of the subject demographics is in Table 4.
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Table 4 Demographics
Demographics: Treatment A (200mg
IV)
Treatment B (200mg
SQ)
Treatment C (50mg SQ X 4)
Treatment D (200mg
IM)Age in Years [Mean (SD)] 34.7 (8.86) 27.8 (7.71) 26.3 (6.18) 24.8 (6.10)
Sex [n (%)]Female 0 0 1 (11%) 0
Male 9 (100%) 9 (100%) 8 (89%) 9 (100%)BMI (kg/m2) [Mean (SD)] 25.19
(2.226)23.15
(2.068)23.72
(1.873)23.08
(2.329)Height (cm) [Mean (SD)] 176.69
(5.974))179.39 (4.739)
171.21 (7.710)
174.23 (4.224)
Weight (kg) [Mean (SD)] 78.41 (4.606)
74.37 (5.793)
69.53 (7.122)
70.02 (6.853)
Ethnicity [n (%)]Hispanic or Latino 1 (11%) 0 0 1 (11%)
Not Hispanic or Latino 8 (89%) 9 (100%) 9 (100%) 8 (89%)Race [n (%)]
African American/African Heritage 2 (22%) 4 (44%) 6 (67%) 6 (67%)American Indian or Alaskan Native 0 0 0 1 (11%)
Asian – Japanese Heritage 1 (11%) 0 0 0White – Arabic/North African Heritage 1 (11%) 0 0 0White – White/Caucasian/European
Heritage5 (56%) 5 (56%) 3 (33%) 2 (22%)
4.5. Concomitant Medications
Ten (10) subjects (28%) took concomitant medications during the study. The majority of these medications were taken for treatment emergent adverse events and were primarily antibiotics given for various infections and Tylenol given for pain.. The remaining medications were taken for prophylaxis, sleep aid, and/or for health maintenance.
One (1) subject tested positive for Cannabis use at Study Day 27 during the study. The subject admittedly self administered Cannabis one time during the study and thus it is listed as a concomitant medication. The subject was re-educated to abstain from illegal drugs while on study. It was agreed by the Primary Investigator and GSK Medical Monitor that the subject could continue in the study.
None of these medications were expected to affect the pharmacokinetic endpoints of the study.
4.6. Exposure and Treatment Compliance
Study Medication was administered by the study personnel in the Unit under the supervision of a physician. All subjects received the correct treatment as randomized and compliance with study medication was 100%.
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4.7. Adverse Events
Fifteen (15) subjects (42%) reported a total of 23 adverse events during the study – one of which was a serious adverse event. See Table 5 for a listing of all Adverse Events.
All the AEs except one were considered by the investigator to be unrelated to the investigational product . The one AE classified as having a relationship to the investigational product was Headache and started within 1 hour 11 minutes of investigational product administration and resolved the same day.None of the events were of sufficient clinical importance to warrant withdrawal from the study and all resolvedduring the study with the exception of the serious event which was not considered drug related and remained unresolved at time of study end.
Table 5 Adverse Events
Listing of all Adverse Events (Verbatim Text)
Treatment A (200mg IV)
Treatment B (200mg SQ)
Treatment C (50mg SQ x 4)
Treatment D (200mg IM)
Bruise to Lower Spine 1Cold 1Constipation 1Fatigue Feeling 1Gastroenteritis 1Generalized Itching 1Headache 2Headache/Congestion 1Hearing Voices 1Increased Urine White Blood Counts
1
Microhematuria 1Microscopic Hematuria 1Positive Chlamydia Asymptomatic Urethritis
1
Rash Penis 1Right Arm Erythema 1Slight Headache 1Strep Throat 1Swollen Mouth 1Upper Respiratory Infection 2Weight Loss 1Weight Loss Associated Increased Satiety
1
Total Number of AEs 5 10 6 2Number of Subjects Exposed 9 9 9 9Number of Subjects with AEs 4 (44%) 6 (67%) 3 (33%) 2 (22%)
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4.8. Serious and Significant Adverse Events
4.8.1. Deaths
There were no deaths in this study.
4.8.2. Serious Adverse Events
There was one serious adverse event reported on Day 27 of the study– this event was reported as Hearing Voices with a resulting diagnosis of Schizophrenia, Paranoid Type. The event was moderate in intensity and was considered not related to study treatment. The event was still ongoing at study end. The subject had a previous history of psychiatric disease, including hallucinations, as well as recently documented substance abuse.
4.8.3. Significant Adverse Events
None
4.9. Clinical Laboratory Evaluations
Clinical laboratory values were similar across the treatment groups. There were no trends or patterns identified across subjects or across groups.
Three subjects had haematology values reaching low levels of potential clinical importance [Table 6]. Three subjects had clinical chemistry values that exceeded the limits of potential clinical importance [Table 7]. There were no Urinalysis results meeting PCI criteria.
No haematology or clinical chemistry result was classified by the investigator as an adverse event and none gave cause for clinical concern.
Urinalysis results showed no clinically important changes or abnormalities overall.
Table 6 Haematology PCI Laboratory Evaluations
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Table 7 Chemistry Laboratory PCI Evaluations
4.10. Other Safety Evaluations
Vital Signs
Five (5) subjects had vital sign values exceeding the pre-set ranges of potential clinical importance [Table 8], however none were deemed clinically significant. All values returned to normal at subsequent measurements. There were no trends or changes over time noted between the treatment groups.
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Table 8 Vital Signs PCI Evaluations
ECG’s:
Three (3) subjects had abnormal findings but all were considered not clinically significant by the investigator and appear to be one-time events. These results also exceeded the pre-set ranges of potential clinical importance by GSK, however none were deemed clinically significant by the GSK Medical Monitor [Table 9]. There were also no trends or changes over time noted between the groups.
Table 9 ECG PCI Evaluations
4.11. Pregnancies
There was no pregnancy reported for the one female subject of childbearing potential or with any female partners of the 35 male subjects.
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5. PHARMACOKINETIC RESULTS
5.1. Drug Concentration Data
Individual plasma GSK933776 concentration listings and associated summary statistics are prepared. Individual plasma GSK933776 concentration-time profiles are displayed with actual time on both semi-logarithmic and linear scales (Source Data Figure 11.5) and with the actual times truncated to 1000 hours post dose (Source Data Figure 11.6).
Mean plasma GSK933776 concentration-time profiles are displayed with nominal time on both semi-logarithmic and linear scales (Source Data Figure 11.1, Figure 1) and truncated to 800 hours post-dose (Source Data Figure 11.2, Figure 2). Median plasma GSK933776 concentration-time profiles are displayed with nominal time on both semi-logarithmic and linear scales(Source Data Figure 11.3) and truncated to 800 hours post dose (Source Data Figure 11.4).
Descriptive statistics for plasma GSK933776 concentration data at each planned relative time are presented by treatment in Source Data Table 11.1.
Figure 2 Arithmetic Mean GSK933776 Plasma Concentration - Time (Linear and Semi-logarithmic Scales)
Source Data: Figure 11.1
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Figure 3 Arithmetic Mean GSK933776 Plasma Concentration - Time Truncated to 800 hours Postdose (Linear and Semi-logarithmic Scales)
Source Data: Figure 11.2
5.2. Plasma Pharmacokinetic Parameters
Plasma PK parameters following each treatment are summarized in Source Data Table 11.2 for GSK933776 and also in Table 10 .
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Table 10 Summary of Plasma GSK933776 Pharmacokinetic Parameters by Treatment
PK ParameterA
IV 200 mgN=9
BSQ 200 mg
N=9
CSQ 50 mg x 4
N=9
DIM 200 mg
N=9
AUC(0-168) (h*ug/mL) 5522 (9.23)NE
934.5 (19.48)NE
AUC(0-168)/D (h*ug/mL/mg)
27.6 (9.23)NE
18.7 (19.48)NE
AUC(0-672) (h*ug/mL) 12049 (10.66)NE
7220 (22.50)NE
AUC(0-inf) (h*ug/mL) 14899 (14.86) 12371 (20.56) 14197 (21.21) 12911 (22.69)
Cmax(ng/mL)
62.5 (14.05) 22.4 (16.61) 17.8 (27.94) 28.7 (22.56)
CL/F(mL/h)
13.42 (14.86) 16.15 (20.30) 3.53 (21.40) 15.48 (22.67)
Vz/F(mL)
5618 (10.86) 7013 (19.70) 1683 (27.49) 6425 (14.66)
t1/2(h)
286 313 320 286
(203, 357) (239, 367) (289, 424) (194, 344)
tmax(h)
2 117 599 96
(1, 3) (96, 120) (527, 601) (24, 120)
tlast(h)
1344 1343 1176 1344
(673, 1345) (697, 1346) (1010, 1849) (671, 1344)
Source Data: Table 11.2All parameter values are presented as geometric mean (%CVb) except t1/2, tmax and tlast are presented as median
(minimum and maximum). NE = not estimatedTreatment Key:A: single 200 mg dose of GSK933776 administered by IV infusion (reference arm)B: single 200 mg dose of GSK933776 administered SQC: 50 mg dose of GSK933776 administered SQ once weekly for 4 weeks (total dose = 200 mg)D: single 200 mg dose of GSK933776 administered IM
Following 200 mg IV administration, GSK933776 dose normalized geometric mean AUC(0-168) was 1.5-fold higher than after a single 50 mg SQ dose. The geometric mean AUC(0-672) for 200 mg IV GSK933776 was 1.7-fold higher than 4 weekly 50 mg SQ doses. Geometric mean AUC(0-inf) was comparable for the 200 mg IV dose and 4x50 mg SQ dose, and the 200 mg SQ dose was similar to the 200 mg IM dose. Geometric mean Cmax was 2.8-, 3.5- and 2.1-fold higher for the IV 200 mg dose compared to the 200 mg SQ, 4x50 mg SQ and 200 mg IM doses, respectively. Small to moderate between-subject variability was associated with these PK parameters.
The median t½ following the IV and IM doses were identical at 286 hours followed closely by the 200 mg SQ dose at 313 hours and the 4x50 mg SQ dose at 320 hours. The geometric mean clearance for the IV dose was 13.4 mL/hr and apparent CL/F for the 200 mg SQ dose was 16.2 mL/hr, approximately 4.6-fold higher than the 4x50 mg dose.
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Apparent CL/F for the 200 mg IM dose was 15.5 mL/hr. The Vz was 5618 mL for the 200 mg IV dose and Vz/F was 7013, 1683, and 6425 mL for the 200 mg SQ, 4x50 mg SQ and 200 mg IM doses, respectively.
Median tmax valuesof 2.0, 117, 599 and 96 hours for the 200 mg IV, 200 mg SQ, 4x50 mg SQ and 200 mg IM doses, respectively.
5.3. Statistical Analyses of Pharmacokinetic Parameters
5.3.1. Plasma PK Parameters Statistical Assessment
Statistical assessments of GSK933776 parameters are presented in Source Data Table 11.3 and Table 11.4 and are reproduced below (Table 10 and Table 11).
Comparing the mean AUC(0-inf) for the 200 mg IV dose to the 200 mg IM dose resulted in relative bioavailability of 87%. Relative bioavailability of Cmax was 46% for the comparison of IV and IM doses.
Comparing the mean AUC(0-inf) for the 200 mg IV dose to the 200 mg SQ dose resulted in relative bioavailability of 83%. Relative bioavailability of Cmax was 36% for the comparison of IV and SQ doses.
Comparing the mean dose normalized AUC(0-168)/D (i.e., 7 days) and the mean AUC(0-672) (i.e., 28 days) for the 200 mg IV dose to the 4x50 mg SQ dose resulted in relative bioavailability of 68% and 60%, respectively. Relative bioavailability of Cmax was 28% for the comparison of IV and weekly SQ doses.
Statistical assessment of t½ between the 200 mg IV, 200 mg SQ, 4x50 mg SQ and 200 mg IM doses showed the dosage forms to be comparable.
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Table 11 Summary of the Results of the ANOVA of Log-Transformed Plasma GSK933776 Pharmacokinetic Parameters
__GeoMetric LS Mean__
ParameterComparison
Test Vs Reference n Test n RefRatio (%)(Test/Ref)
90% ConfidenceInterval for Ratio
AUC(0-168)/D (h*ug/mL/mg)
SQ_50mg*4 VS IV_200mg 9 18.7 9 27.6 67.70 (59.77, 76.67)
AUC(0-672) (h*ug/mL)
SQ_50mg*4 VS IV_200mg 9 7220 9 12049 59.92 (51.92, 69.16)
AUC(0-inf) (h*ug/mL)
IM_200mg VS IV_200mg 9 12911 9 14899 86.65 (73.96, 101.53)
SQ_200mg VS IV_200mg 9 12371 9 14899 83.03 (70.87, 97.29)
SQ_50mg*4 VS IV_200mg 9 14197 9 14899 95.28 (81.32, 111.64)
Cmax (ug/mL)
IM_200mg VS IV_200mg 9 28.7 9 62.5 45.99 (38.98, 54.26)
SQ_200mg VS IV_200mg 9 22.4 9 62.5 35.82 (30.36, 42.26)
SQ_50mg*4 VS IV_200mg 9 17.8 9 62.5 28.41 (24.08, 33.52)
CL/F (mL/h)
IM_200mg VS IV_200mg 9 15.47911 9 13.42335 115.31 (98.44, 135.09)
SQ_200mg VS IV_200mg 9 16.1524 9 13.42335 120.33 (102.72, 140.96)
SQ_50mg*4 VS IV_200mg 9 3.52867 9 13.42335 26.29 (22.44, 30.80)
Vz/F (mL)
IM_200mg VS IV_200mg 9 6424.608 9 5618.401 114.35 (98.28, 133.05)
SQ_200mg VS IV_200mg 9 7013.106 9 5618.401 124.82 (107.28, 145.24)
SQ_50mg*4 VS IV_200mg 9 1683.06 9 5618.401 29.96 (25.75, 34.85)
Source Data: Table 11.3
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Table 12 Median Difference and Confidence Interval for Plasma GSK933776 Pharmacokinetic Parameters
-Median-
ParameterComparison
Test vs Referencen Test n Ref.
Difference(Test-Ref)
90% ConfidenceInterval forDifference
t1/2 (h)
SQ_200mg vs IV_200mg 9 313.20 9 286.19 7.96 (-28.99, 45.7)
SQ_50mg x 4 vs IV_200mg 9 320.00 9 286.19 31.3 (-2.46, 71.89)
IM_200mg vs IV_200mg 9 285.89 9 286.19 -3.25 (-40.27, 32.72)
tmax (h)
SQ_200mg vs IV_200mg 9 116.92 9 1.50 115.42 (94.42, 117.85)
SQ_50mg x 4 vs IV_200mg 9 598.73 9 1.50 596.8 (594.97, 598.07)
IM_200mg vs IV_200mg 9 95.63 9 1.50 93.7 (45.37, 94.42)
Source Data: Table 11.4
5.3.2. Statistical Analysis Details
Statistical analyses of pharmacokinetic data were performed under the direct auspices of Clinical Pharmacology Statistics & Programming, GlaxoSmithKline.
Data was released to CPSP by CPK via HARP. Main results of the summary statistics are presented to the accuracy of the raw data. All summary statistics were carried out using SAS 9.3 for LINUX running under the HARP environment.
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6. PHARMACODYNAMIC AND BIOMARKER RESULTS
6.1. Pharmacodynamic Results
Plasma A1-22 (free), A18–35 (total) and A42 (total) from the pharmacodynamic population were summarized, graphically presented, and listed. Individual subject plots of the plasma A parameters by time and route of administration can be seen in the source data (Source Figure 12.10) and summary overviews are presented graphically in Figure 7.1, Figure 7.2 and Figure 7.3 respectively.
As expected, free A1-22 levels decreased after dosing with GSK933776 for all routes of administration, but had the most marked effect with the 200 mg IV dose. The cohort receiving 200 mg IM also showed a reduction from baseline levels of free A1-22, and although not as significant as that of the IV dose, it was greater than that of either SQ dose. The SQ 4 x 50mg dose demonstrated the most variability and showed the greatest reduction in free amyloid beta at the end of the one month dosing interval (672 hours). Based on the present data, the likely levels of target engagement for GSK933776 based on route of administration is IV>IM>SQ. Figure 7.1 summarizes the free A1-22 concentration over time on linear and semi-log scales.
Figure 7.1: Median Plasma Free A1-22 Concentration-Time Plots
There was also an evident increase in both total A18–35 and A42 levels in plasma after the administration of GSK933776, which began immediately after the dosing. Levels of total A18–35 after the 200 mg IV administration were higher than both the 200 mg IM and SQ doses, which had similar concentration-time profiles (Figure 7.2) . The cohort receiving 4 x 50 mg GSK933776 showed a more gradual accumulation of A18-35 before a decline after the last dose.
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Figure 7.2: Median Plasma Total A18-35 Concentration-Time Plot
Levels of total A42 in plasma were on average highest after the IV dose, although both the 200 mg IM and SQ doses had similar concentration-time profiles. Subjects in the 4 X 50 mg group exhibited the lowest levels of A42 (Figure 7.3); however, all groups had lower measurements of total A in the A42 assay than seen in the A18-35 assay. This is consistent with reports in the literature (see references) that indicate A1-40, rather than the full-length A1-42, may be more relevant in the pathology of A-mediated disease.
Figure 7.3: Median Plasma Total A Concentration-Time Plot
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6.2. Immunogenicity Results
No antibodies were detected post dose against GSK933776 in serum samples collected out to 85 days following single dose administration of GSK933776 by IV, SQ and IM routes; similarly, no antibodies against GSK933776 were detected in serum samples collected out to 106 days following four weekly SQ administration of GSK933776
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7. RELATIONSHIP BETWEEN PHARMACOKINETIC AND PHARMACODYAMIC PARAMETERS
Mean plasma GSK933776 concentration-time profiles are plotted with mean Aβ1-22, Aβ18-35 or Aβ42 concentrations displayed with nominal time linear scales (Source Data Figure 13.3, Figure 3) truncated to 800 hours postdose. Mean plasma GSK933776concentration-time profiles are plotted with mean change from baseline Aβ1-22, Aβ18-35 or Aβ42 concentrations displayed with nominal time linear scales (Source Data Figure 13.4, Figure 4) truncated to 800 hours post-dose.
There appears to be an increase in plasma Aβ1-22 levels with decreasing GSK933776 concentrations. .In the SQ and IM arms, there appears to be an initial transient decrease in plasma Aβ1-22 levels that might be related to delay in drug distribution into the central compartment following SQ and IM administration. The mean Aβ18-35 or Aβ42 plasma concentrations appear to mimic the plasma GSK933776 levels. The change from baseline Aβ levels followed similar trends as un-corrected values.
Figure 4 Mean Plasma GSK933776 Concentration and Mean Plasma Abeta Concentration versus Nominal Time by Treatment (Truncated)
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Data Source: Figure 13.3
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Figure 5 Mean Plasma GSK933776 Concentration and Mean Plasma Abeta Concentration Change from Baseline versus Nominal Time by Treatment (Truncated)
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Data Source: Figure 13.4
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8. DISCUSSION AND CONCLUSIONS
8.1. Discussion
GSK933776 is a humanised, Fc-disabled IgG1 monoclonal antibody (mAb) directed against the N-terminal amino acid residues 1-5 of amyloid beta (Aβ). GSK933776 is currently being evaluated as a potential treatment for geographic atrophy (GA) secondary to age-related macular degeneration (AMD); it has also previously been studied in patients with Alzheimer’s disease (AD). To date, all studies with GSK933776 have administered the dose by intravenous (IV) infusion. This study evaluated other potential routes of administration by establishing bioavailability, pharmacokinetic (PK) and pharmacodynamic (PD) profiles, tolerability and safety assessments for GSK933776 following IM and SQ administration. An IV infusion arm was included to estimate the relative bioavailability following IM and SQ administration.
The relative bioavailability of GSK933776 as measured by AUC(0-inf) following 50 mg repeat-dose SQ administration as compared with 200 mg IV administration were similar. In general, the exposure for the first 672 hours and 168 hours (dose normalized) following the 50 mg repeat-dose SQ administration as compared with 200 mg IV administration showed approximately 40% lower exposure. The Cmax following the 50 mg repeated-dose SQ was approximately 70% lower when compared with the 200 mg IV administered dose.
The relative bioavailability of GSK933776 as measured by AUC(0-inf) following 200 mg single-dose IM and SQ administration as compared to 200 mg IV administration showed approximately 15% lower exposure. The Cmax was 55% to 65% lower for the IM and SQ dosing, respectively.
Half-life was comparable across the 200 mg IV, 200 mg SQ, 4x50 mg SQ and 200 mg IM routes of administration.
The Aβ 1-22 levels increased with decreasing GSK933776 concentrations, whereas the Aβ18-35 and Aβ42 in plasma mimicked GSK933776 concentrations.
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8.2. Conclusions
Compared to intravenous administration, the relative bioavailability of subcutaneous and intramuscular administrations of GSK933776 were 83% and 87% for AUC(0-inf) and 36% and 46% for Cmax, respectively.
Compared to intravenous administration, the relative bioavailability results indicate that 200 mg subcutaneous and intra-muscular administrations of GSK933776 produce comparable exposure profiles, with the relative bioavailability at approximately 82% and 85%, respectively, compared to IV administration.
Subcutaneous administration of GSK933776 50 mg weekly were 68% for dose normalized exposure over 7 days (i.e., AUC(0-168)/D) and 60% for exposure over 28 days (i.e., AUC(0-672), respectively. Cmax following 50 mg weekly dosing was substantially lower at 28% of that following 200 mg intravenous administration.
The median t½ was comparable across routes of administration.
Intravenous, subcutaneous and intra-muscular GSK933776 were well tolerated in this study. No significant safety findings could be attributed to investigational product. Vital signs, laboratory and electrocardiographic parameters fell within expected ranges
Plasma Abeta1-22 decreased, Abeta18-35 and Abeta42 increased followingGSK933776 dosing by all routes of administration.
No antibodies were detected post dose against GSK933776 in serum samplescollected out to 85 days following single dose administration of GSK933776 by IV, SQ and IM routes; similarly, no antibodies against GSK933776 were detected in serum samples collected out to 106 days following four weekly SQ administration of GSK933776.
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9. REFERENCES
Anderson, D.H., Talaga, K.C., Rivest, A.J., Barron, E., Hageman, G.S., Johnson, L.V., (2004). Characterization of β amyloid assemblies in drusen: the deposits associated with aging and age-related macular degeneration. Experimental Eye Research, 78(2), 243-256.
Fonseca, A.C., Ferreiro, E., Oliveira, C.R., Cardoso, S.M. & Pereira, C.F. (2013). Activation of the endoplasmic reticulum stress response by the amyloid-beta 1-40 peptide in brain endothelial cells. Biochim Biophys Acta, 1832(12):2191-203. doi: 10.1016
GlaxoSmithKline Document Number 2013N182307_00 Validation of the ELISA Method “Quantification of GSK933776 in Human Plasma (Range 100 - 5000 ng/mL) Using a Colorimetric Immunoassay” 13-Nov-2013
Howlett DR, Hortobágyi T & Francis PT (2013). Clusterin associates specifically with Aβ40 in Alzheimer's disease brain tissue, Brain Pathology, 23(6), 623-632.
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10. POST-TEXT TABLES AND FIGURES
10.1. Time and Events Table for Treatment Arms A (200 mg IV infusion), B (200 mg SQ injection), D (200 mg IM injection)
Table 13 Time and Events Tables
DayScreena Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 10
Day 15
Day 22
Day 29
Day 57
Follow Up Day 85d
AssessmentsPre-dose
0h 0.25h 0.5h 0.75h 1h 2h 4h 6h 24h 48h 72h 96h 120h 216h 336h 504h 672h 1344h 2016h
Informed Consent XDemographics X
Physical Examination X X X XMedical history (inc. family cardiovascular history) XConcomitant Medications X X X X X XDose XAE/SAE Review ----------------------------------------------------------------------------------X------------------------------------------------------------------12-lead ECG X XVital Signs X X X X X X X X X X X X XUrine Drug/Alcoholc X Xc
Follicle stimulating hormone (FSH)/estradiol if indicated XHepatitis B, Hepatitis C, HIV (human immunodeficiency virus) X
Hematology, Chemistry, Urinalysis X X X X X X XHbA1c XPK Blood Sample X Xb Xb Xb Xb X Xb X X X X X X X X X X X XPD Blood Sample X Xb Xb Xb X X X X X X X XImmunogenicity Blood Sample X X X XSubjects were screened a minimum of 7 days, but no more than 30 days, prior to Day 1 Samples were drawn only for subjects in Arm A (IV infusion).Alcohol breathalyzer test night be done instead of urine test post screening visit
The follow up visit occured 3 days
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10.2. Time and Events Tables for Treatment Arm C (50 mg SQ injection)
Screening through Week 1
Day Screena Day 1 Day 2 Day 3 Day 4 Day 5 Day 6
Assessments Pre-dose 0h 0.5h 1h 2h 4h 6h 24h 48 h 72h 96h 120hInformed Consent XDemographics XPhysical Examination X XMedical history (includingfamily cardiovascular history)
X
Concomitant Medications X XDose XAE/SAE Review ------------------------------------------------------------------------------X----------------------------------------------------------------------------12-lead ECG XVital Signs X X X X X X X X XUrine Drug/Alcoholb
X Xb
Hepatitis B, Hepatitis C, HIV XHematology, Chemistry, Urinalysis X X XFSH, estradiol (if indicated) XHbA1c XPK Blood Sample X X X X X X XPD Blood Sample X X X X XImmunogenicity Blood Sample Xa. Subjects were screened a minimum of 7 days, but no more than 30 days, prior to Day 1b. Alcohol breathalyzer test may have been done instead of urine test post screening visit
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10.3. Treatment Arm C (50 mg SQ injection) – Weeks 2 and 3
Day Day 8/15 Day 9/16
Day 10/17
Day 11/18 Day 12/19
Day 13/20
Assessments Predose 0h 0.5h 1h 2h 4h 6h 24h 48h 72h 96h 120hConcomitant Medications XDose X
AE/SAE Review------------------------------------------------------------------------------------------X--------------------------------------------------------------------------
Vital Signs X X X X X X XUrine Drug/Alcohol (breathalyzer) XHematology, Chemistry, Urinalysis XPK Blood Sample X X X X X X X
PD Blood SampleX X X X X
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10.4. Treatment Arm C (50 mg SQ injection) – Week 4 through Final Follow Up
Day Day 22Day23
Day 24
Day 25
Day 26
Day 27
Day 31
Day 36
Day 43
Day 50
Day 78
Follow Up Day 106a
Assessments
Pre-dos
e 0h 0.5h 1h 2h 4h 6h 24h 48h 72h 96h 120h 216h 336h 504h 672h1344
h 2016hPhysical Examination XConcomitant Medications X X X X XDose XAE/SAE Review ---------------------------------------------------------------------------------------------X-----------------------------------------------------------------------------------------------12-lead ECG XVital Signs X X X X X X X X X X X XUrine Drug/Alcohol (breathalyzer) XHematology, Chemistry, Urinalysis X X X X XPK Blood Sample X X X X X X X X X X X X XPD Blood Sample X X X X X X X X X XImmunogenicity Blood Sample X X X X X
Follow up occured 3 days
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This section contained patient narratives which are textual descriptions of medical history,
treatment and outcome for individual patients who experienced a clinically important adverse
event including serious adverse events during the trial. They have been excluded to protect
patient privacy. This data may be made available subject to an approved research proposal and
a determination of the ability to provide information from the specific narratives whilst protecting
the patient’s privacy. For further information please see the Patient Level Data section of
the GSK Clinical Study Register.
Protocol: BA1116891 Page 1 of 1Population: Safety Table 9.1 Summary of Study Population
IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Overall (N=9) (N=9) (N=9) (N=9) (N=36) --------------------------------------------------------------------------------------------------------- Safety Population 9 9 9 9 36 Pharmacokinetic Concentration Population 9 9 9 9 36 Pharmacokinetic Parameter Population 9 9 9 9 36 Pharmacodynamic Population 9 9 9 9 36 Pharmacokinetic/Pharmacodynamic Analysis 9 9 9 9 36 Population
Subjects are included in the Safety Population if they have taken at least one dose of study medication.Subjects are included in the Pharmacokinetic (PK) Concentration Population if they have evaluableGSK933776 concentration.Subjects are included in the PK Parameter Population if they have evaluable GSK933776 PK parameter.Subjects are included in the Pharmacodynamic (PD) Population if they have evaluable biomarker concentration.Subjects are included in the PK/PD Analysis Population if they have evaluable GSK933776 concentrationand evaluable biomarker concentration.
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Protocol: BA1116891 Page 1 of 1Population: Safety Table 9.2 Summary of Subject Disposition
IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Overall (N=9) (N=9) (N=9) (N=9) (N=36) ---------------------------------------------------------------------------------------------------- Completion Status Completed 9 (100%) 9 (100%) 8 (89%) 8 (89%) 34 (94%) Prematurely Withdrawn 0 0 1 (11%) 1 (11%) 2 (6%) Primary Reason for Withdrawal Adverse Event 0 0 0 0 0 Lost to follow-up 0 0 1 (11%) 0 1 (3%) Protocol Violation 0 0 0 0 0 Subject decided to withdraw 0 0 0 0 0 from study Other 0 0 0 1 (11%) 1 (3%)
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Protocol: BA1116891 Page 1 of 1Population: Safety Table 9.3 Summary of Protocol Deviations
IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Overall Category (N=9) (N=9) (N=9) (N=9) (N=36) ---------------------------------------------------------------------------------------------------------
Any protocol deviations 1 (11%) 5 (56%) 5 (56%) 1 (11%) 12 (33%)
Assessments and/or procedures 0 1 (11%) 0 0 1 (3%) Missed assessment or procedure 1 (11%) 0 0 1 (11%) 2 (6%) Visit and/or Assessment window 0 4 (44%) 4 (44%) 0 8 (22%) Other protocol deviation category 0 0 2 (22%) 0 2 (6%)
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Protocol: BA1116891 Page 1 of 2Population: Safety Table 9.4 Summary of Demographic Characteristics
IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Overall (N=9) (N=9) (N=9) (N=9) (N=36)------------------------------------------------------------------------------------------------------------Age (y) n 9 9 9 9 36 Mean 34.7 27.8 26.3 24.8 28.4 SD 8.86 7.71 6.18 6.10 7.97 Median 34.0 26.0 25.0 23.0 26.0 Min. 22 20 19 19 19 Max. 45 43 40 36 45
Sex n 9 9 9 9 36 Female 0 0 1 (11%) 0 1 (3%) Male 9 (100%) 9 (100%) 8 (89%) 9 (100%) 35 (97%)
Ethnicity n 9 9 9 9 36 Hispanic/ 1 (11%) 0 0 1 (11%) 2 (6%) Latino Not Hispanic/ 8 (89%) 9 (100%) 9 (100%) 8 (89%) 34 (94%) Latino
Height (cm) n 9.0 9.0 9.0 9.0 36.0 Mean 176.69 179.39 171.21 174.23 175.38 SD 5.974 4.739 7.710 4.224 6.351 Median 175.40 179.40 168.30 175.30 175.70 Min. 170.4 173.5 161.0 168.5 161.0 Max. 189.2 189.4 180.5 178.4 189.4
Weight (kg) n 9.0 9.0 9.0 9.0 36.0 Mean 78.41 74.37 69.53 70.02 73.08 SD 4.606 5.793 7.122 6.853 6.944 Median 79.20 76.20 69.10 71.40 73.80 Min. 68.0 63.5 57.5 61.7 57.5 Max. 83.3 80.6 79.5 83.5 83.5
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Protocol: BA1116891 Page 2 of 2Population: Safety Table 9.4 Summary of Demographic Characteristics
IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Overall (N=9) (N=9) (N=9) (N=9) (N=36)------------------------------------------------------------------------------------------------------------BMI (kg/m^2) n 9.0 9.0 9.0 9.0 36.0 Mean 25.19 23.15 23.72 23.08 23.78 SD 2.226 2.068 1.873 2.329 2.212 Median 25.74 23.55 23.74 22.70 23.65 Min. 21.6 19.5 20.4 20.6 19.5 Max. 27.9 25.5 27.0 27.2 27.9
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Protocol: BA1116891 Page 1 of 1Population: Safety Table 9.5 Summary of Race and Racial Combination Details
IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Overall Race (N=9) (N=9) (N=9) (N=9) (N=36) ------------------------------------------------------------------------------------------------- n 9 9 9 9 36 African American/African Heritage 2 (22%) 4 (44%) 6 (67%) 6 (67%) 18 (50%) American Indian or Alaska Native 0 0 0 1 (11%) 1 (3%) Asian - Central/South Asian Heritage 0 0 0 0 0 Asian - East Asian Heritage 0 0 0 0 0 Asian - Japanese Heritage 1 (11%) 0 0 0 1 (3%) Asian - South East Asian Heritage 0 0 0 0 0 Asian - Mixed Race 0 0 0 0 0 Native Hawaiian or other Pacific 0 0 0 0 0 Islander White - Arabic/North African 1 (11%) 0 0 0 1 (3%) Heritage White - White/Caucasian/European 5 (56%) 5 (56%) 3 (33%) 2 (22%) 15 (42%) Heritage White - Mixed Race 0 0 0 0 0 Mixed Race 0 0 0 0 0
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Protocol: BA1116891 Page 1 of 1Population: Safety Table 9.6 Summary of Concomitant Medications
IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Overall Generic Term (N=9) (N=9) (N=9) (N=9) (N=36) ---------------------------------------------------------------------------------------------------- Any Medication 2 (22%) 3 (33%) 3 (33%) 2 (22%) 10 (28%)
Tylenol 1 (11%) 0 2 (22%) 0 3 (8%) Amoxil 0 1 (11%) 0 0 1 (3%) Cannabis 0 1 (11%) 0 0 1 (3%) Clemastine Fumarate 0 1 (11%) 0 0 1 (3%) Clindamycin 0 0 1 (11%) 0 1 (3%) Decadron 0 0 1 (11%) 0 1 (3%) Estazolam 0 0 1 (11%) 0 1 (3%) Flinstone Multi-Vitamin 1 (11%) 0 0 0 1 (3%) Risperdal 0 1 (11%) 0 0 1 (3%) Zithromax 0 0 0 1 (11%) 1 (3%) Zithromycin 0 0 0 1 (11%) 1 (3%)
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Protocol: BA1116891 Page 1 of 2Population: Safety Table 10.1 Summary of All Adverse Events
System Organ Class IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Overall Preferred Term (N=9) (N=9) (N=9) (N=9) (N=36) --------------------------------------------------------------------------------------- ANY EVENT 4 (44%) 6 (67%) 3 (33%) 2 (22%) 15 (42%)
Infections and infestations Any event 0 3 (33%) 2 (22%) 1 (11%) 6 (17%) Upper respiratory tract 0 2 (22%) 1 (11%) 0 3 (8%) infection Gastroenteritis 0 1 (11%) 0 0 1 (3%) Pharyngitis streptococcal 0 0 1 (11%) 0 1 (3%) Tooth abscess 0 1 (11%) 0 0 1 (3%) Urethritis chlamydial 0 0 0 1 (11%) 1 (3%)
General disorders and administration site conditions Any event 2 (22%) 1 (11%) 0 0 3 (8%) Asthenia 1 (11%) 0 0 0 1 (3%) Catheter site erythema 1 (11%) 0 0 0 1 (3%) Early satiety 0 1 (11%) 0 0 1 (3%)
Renal and urinary disorders Any event 0 2 (22%) 0 1 (11%) 3 (8%) Haematuria 0 1 (11%) 0 1 (11%) 2 (6%) Pyuria 0 1 (11%) 0 0 1 (3%)
Nervous system disorders Any event 1 (11%) 0 1 (11%) 0 2 (6%) Headache 1 (11%) 0 1 (11%) 0 2 (6%)
Skin and subcutaneous tissue disorders Any event 1 (11%) 0 1 (11%) 0 2 (6%) Pruritus generalised 0 0 1 (11%) 0 1 (3%) Skin hypertrophy 1 (11%) 0 0 0 1 (3%)
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Protocol: BA1116891 Page 2 of 2Population: Safety Table 10.1 Summary of All Adverse Events
System Organ Class IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Overall Preferred Term (N=9) (N=9) (N=9) (N=9) (N=36) --------------------------------------------------------------------------------------- Ear and labyrinth disorders Any event 1 (11%) 0 0 0 1 (3%) External ear pain 1 (11%) 0 0 0 1 (3%)
Gastrointestinal disorders Any event 0 0 1 (11%) 0 1 (3%) Constipation 0 0 1 (11%) 0 1 (3%)
Injury, poisoning and procedural complications Any event 0 0 1 (11%) 0 1 (3%) Contusion 0 0 1 (11%) 0 1 (3%)
Investigations Any event 0 1 (11%) 0 0 1 (3%) Weight decreased 0 1 (11%) 0 0 1 (3%)
Psychiatric disorders Any event 0 1 (11%) 0 0 1 (3%) Schizophrenia, paranoid type 0 1 (11%) 0 0 1 (3%)
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CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 1 of 1Population: Safety Table 10.2 Summary of Adverse Events Related to Study Treatment
System Organclass IV_200 mg SQ_200 mg SQ_50 mg x 4 IM_200 mg Overall Preferred Term (N=9) (N=9) (N=9) (N=9) (N=36) ----------------------------------------------------------------------------------------------- ANY EVENT 1 (11%) 0 0 0 1 (3%)
Nervous system disorders 1 (11%) 0 0 0 1 (3%) Any event 1 (11%) 0 0 0 1 (3%) Headache 1 (11%) 0 0 0 1 (3%)
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Protocol: BA1116891 Page 1 of 15Population: Safety Table 10.6 Summary of Vital Signs
Planned Relative Treatment N Visit Time n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------- Diastolic Blood Pressure IV_200mg 9 DAY 1 PREDOSE 9 83.0 4.53 84.0 77 92 (mmHg) 0.5 H 9 74.9 5.06 76.0 69 82 1 H 9 74.1 5.23 76.0 65 82 2 H 9 72.3 6.28 72.0 61 82 4 H 8 74.9 4.09 75.5 70 80 6 H 9 77.8 6.63 78.0 67 86 DAY 2 24 H 9 80.4 5.17 82.0 72 90 DAY 6 120 H 9 81.2 4.55 82.0 75 88 DAY 15 336 H 9 81.8 4.89 82.0 74 88 DAY 29 672 H 9 82.4 4.25 83.0 75 89 DAY 57 1344 H 9 81.4 5.55 80.0 75 93 FOLLOW-UP 2016 H 9 83.7 4.44 83.0 78 91
SQ_200mg 9 DAY 1 PREDOSE 9 76.1 5.73 75.0 67 85 0.5 H 9 73.9 8.80 71.0 64 90 1 H 9 73.3 5.48 75.0 65 82 2 H 9 70.8 6.24 73.0 57 77 4 H 9 73.6 5.90 74.0 65 83 6 H 9 79.2 14.61 74.0 67 107 DAY 2 24 H 9 69.8 10.20 71.0 49 81 DAY 6 120 H 9 73.6 5.55 73.0 65 83 DAY 15 336 H 9 76.0 10.65 75.0 61 94 DAY 29 672 H 9 75.7 7.91 75.0 66 92 DAY 57 1344 H 9 73.8 5.83 74.0 66 81 FOLLOW-UP 2016 H 9 73.0 7.05 71.0 64 84
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Protocol: BA1116891 Page 2 of 15Population: Safety Table 10.6 Summary of Vital Signs
Planned Relative Treatment N Visit Time n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------- Diastolic Blood Pressure SQ_50mg x 4 9 DAY 1 PREDOSE 9 77.8 9.18 74.0 64 92 (mmHg) 0.5 H 9 76.9 8.95 75.0 64 94 1 H 9 71.1 8.89 71.0 60 86 2 H 9 71.2 7.10 71.0 61 85 4 H 9 68.9 7.54 72.0 58 78 6 H 9 74.4 7.26 74.0 63 84 DAY 2 24 H 9 80.2 5.36 78.0 74 90 DAY 3 48 H 9 80.0 9.70 76.0 71 96 DAY 8 PREDOSE 9 77.0 8.54 79.0 58 86 0.5 H 9 74.2 7.24 74.0 62 89 1 H 9 75.3 7.95 76.0 59 87 2 H 9 75.9 8.54 78.0 60 90 4 H 9 73.6 9.49 75.0 53 87 6 H 9 78.1 8.08 78.0 61 91 DAY 9 24 H 9 81.8 12.84 81.0 57 103 DAY 15 PREDOSE 9 77.9 5.93 78.0 71 88 0.5 H 9 69.3 3.81 69.0 63 74 1 H 9 68.7 6.73 69.0 61 80 2 H 9 71.4 7.81 69.0 57 82 4 H 9 66.9 5.58 67.0 58 76 6 H 9 74.1 3.48 75.0 69 78 DAY 16 24 H 9 77.0 8.17 76.0 63 92 DAY 22 PREDOSE 9 78.6 7.99 79.0 68 93 0.5 H 9 75.9 9.18 76.0 61 93 1 H 9 73.9 6.58 73.0 64 85 2 H 9 74.4 9.26 71.0 65 92 4 H 9 70.6 7.97 70.0 56 85 6 H 9 76.7 9.86 74.0 67 101 DAY 23 24 H 9 77.8 10.21 75.0 62 93 DAY 27 120 H 9 77.6 6.54 76.0 68 87 DAY 36 336 H 9 79.8 10.27 76.0 66 96
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Protocol: BA1116891 Page 3 of 15Population: Safety Table 10.6 Summary of Vital Signs
Planned Relative Treatment N Visit Time n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------- Diastolic Blood Pressure SQ_50mg x 4 9 DAY 50 672 H 8 79.0 9.20 80.5 62 89 (mmHg) DAY 78 1344 H 8 79.6 8.72 78.5 69 93 FOLLOW-UP 2016 H 8 76.3 7.40 77.0 65 87
IM_200mg 9 DAY 1 PREDOSE 9 78.6 14.00 77.0 49 95 0.5 H 9 77.8 11.12 78.0 57 89 1 H 9 76.6 10.64 75.0 56 89 2 H 9 73.8 10.18 76.0 55 85 4 H 9 73.9 6.64 73.0 64 85 6 H 9 79.1 7.13 83.0 66 88 DAY 2 24 H 9 78.2 14.60 78.0 46 99 DAY 6 120 H 9 78.0 8.31 76.0 65 90 DAY 15 336 H 9 81.3 10.70 80.0 69 97 DAY 29 672 H 9 80.3 11.17 77.0 63 97 DAY 57 1344 H 8 81.9 7.22 82.0 72 92 FOLLOW-UP 2016 H 8 78.6 13.19 80.5 58 97
Systolic Blood Pressure IV_200mg 9 DAY 1 PREDOSE 9 122.9 7.66 122.0 112 134 (mmHg) 0.5 H 9 118.6 7.92 119.0 108 130 1 H 9 119.2 7.05 119.0 110 131 2 H 9 120.7 10.89 116.0 108 137 4 H 8 118.4 5.97 118.0 111 127 6 H 9 120.8 4.12 119.0 116 127 DAY 2 24 H 9 126.9 6.68 127.0 116 136 DAY 6 120 H 9 123.9 6.41 123.0 114 133 DAY 15 336 H 9 124.1 7.10 121.0 115 134 DAY 29 672 H 9 124.4 6.50 128.0 115 132 DAY 57 1344 H 9 125.7 6.00 124.0 118 138 FOLLOW-UP 2016 H 9 124.4 9.03 122.0 113 137
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Protocol: BA1116891 Page 4 of 15Population: Safety Table 10.6 Summary of Vital Signs
Planned Relative Treatment N Visit Time n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------- Systolic Blood Pressure SQ_200mg 9 DAY 1 PREDOSE 9 122.4 5.27 123.0 113 129 (mmHg) 0.5 H 9 122.4 11.68 117.0 112 148 1 H 9 123.2 11.27 124.0 105 143 2 H 9 120.9 9.48 121.0 103 134 4 H 9 115.7 7.94 116.0 101 126 6 H 9 120.9 14.05 117.0 106 145 DAY 2 24 H 9 120.8 8.70 119.0 108 137 DAY 6 120 H 9 119.7 8.80 122.0 110 137 DAY 15 336 H 9 120.3 13.25 123.0 101 147 DAY 29 672 H 9 121.2 8.36 119.0 110 134 DAY 57 1344 H 9 118.1 6.92 120.0 107 128 FOLLOW-UP 2016 H 9 119.2 8.27 121.0 103 130
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Protocol: BA1116891 Page 5 of 15Population: Safety Table 10.6 Summary of Vital Signs
Planned Relative Treatment N Visit Time n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------- Systolic Blood Pressure SQ_50mg x 4 9 DAY 1 PREDOSE 9 123.7 6.18 122.0 116 134 (mmHg) 0.5 H 9 120.7 7.42 119.0 108 133 1 H 9 120.6 7.30 123.0 108 129 2 H 9 122.3 4.74 123.0 116 128 4 H 9 119.7 8.46 118.0 110 132 6 H 9 122.0 6.16 123.0 110 129 DAY 2 24 H 9 128.2 6.70 128.0 119 138 DAY 3 48 H 9 127.1 8.30 125.0 115 141 DAY 8 PREDOSE 9 120.2 7.40 120.0 106 130 0.5 H 9 118.7 10.09 121.0 96 129 1 H 9 123.0 7.89 124.0 108 132 2 H 9 121.4 6.77 124.0 111 128 4 H 9 120.9 9.77 123.0 98 129 6 H 9 122.7 8.05 120.0 113 133 DAY 9 24 H 9 130.4 6.02 130.0 122 139 DAY 15 PREDOSE 9 122.6 8.79 124.0 111 135 0.5 H 9 118.4 7.97 119.0 106 131 1 H 9 118.0 4.44 119.0 110 125 2 H 9 122.0 4.80 123.0 111 128 4 H 9 115.4 5.03 117.0 106 121 6 H 9 121.3 5.63 119.0 116 132 DAY 16 24 H 9 123.1 7.01 125.0 111 131 DAY 22 PREDOSE 9 124.9 6.64 126.0 115 133 0.5 H 9 119.8 8.21 119.0 105 130 1 H 9 122.3 6.87 123.0 112 132 2 H 9 125.1 7.94 125.0 114 139 4 H 9 120.2 8.94 121.0 106 138 6 H 9 125.4 6.98 123.0 117 136 DAY 23 24 H 9 125.7 4.42 127.0 120 132 DAY 27 120 H 9 123.9 5.51 124.0 117 131 DAY 36 336 H 9 129.1 9.14 128.0 116 149
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Protocol: BA1116891 Page 6 of 15Population: Safety Table 10.6 Summary of Vital Signs
Planned Relative Treatment N Visit Time n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------- Systolic Blood Pressure SQ_50mg x 4 9 DAY 50 672 H 8 127.5 6.74 126.0 118 138 (mmHg) DAY 78 1344 H 8 124.0 10.09 125.5 107 137 FOLLOW-UP 2016 H 8 122.9 5.99 122.0 116 133
IM_200mg 9 DAY 1 PREDOSE 9 125.2 11.27 126.0 109 140 0.5 H 9 123.9 9.74 126.0 106 135 1 H 9 124.7 8.23 123.0 113 137 2 H 9 120.9 8.91 123.0 108 132 4 H 9 119.9 8.36 118.0 109 133 6 H 9 123.9 9.62 122.0 109 137 DAY 2 24 H 9 127.4 12.91 130.0 100 147 DAY 6 120 H 9 121.1 10.87 121.0 104 136 DAY 15 336 H 9 124.6 10.25 123.0 112 138 DAY 29 672 H 9 130.7 9.82 132.0 118 144 DAY 57 1344 H 8 126.3 11.21 128.5 106 142 FOLLOW-UP 2016 H 8 121.6 11.55 122.0 107 138
Pulse Rate (BEATS/MIN) IV_200mg 9 DAY 1 PREDOSE 9 61.8 9.93 62.0 49 82 0.5 H 9 64.8 8.61 65.0 56 82 1 H 9 63.6 6.67 65.0 55 76 2 H 9 64.6 11.24 64.0 49 82 4 H 8 59.9 8.82 60.0 49 73 6 H 9 62.1 10.40 62.0 47 80 DAY 2 24 H 9 71.4 10.91 70.0 60 89 DAY 6 120 H 9 65.3 10.71 62.0 54 87 DAY 15 336 H 9 69.2 6.42 68.0 62 78 DAY 29 672 H 9 64.6 6.54 65.0 56 77 DAY 57 1344 H 9 64.8 9.27 62.0 55 77 FOLLOW-UP 2016 H 9 62.0 9.15 65.0 47 77
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Protocol: BA1116891 Page 7 of 15Population: Safety Table 10.6 Summary of Vital Signs
Planned Relative Treatment N Visit Time n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------- Pulse Rate (BEATS/MIN) SQ_200mg 9 DAY 1 PREDOSE 9 70.7 14.04 73.0 54 93 0.5 H 9 71.1 14.76 68.0 52 97 1 H 9 72.8 17.28 64.0 55 104 2 H 9 73.0 16.91 65.0 56 108 4 H 9 66.2 15.92 62.0 52 106 6 H 9 71.8 15.52 79.0 52 93 DAY 2 24 H 9 72.8 17.47 67.0 49 104 DAY 6 120 H 9 70.6 7.67 68.0 61 83 DAY 15 336 H 9 66.8 12.12 66.0 49 89 DAY 29 672 H 9 70.3 14.80 65.0 53 98 DAY 57 1344 H 9 69.7 9.58 68.0 62 94 FOLLOW-UP 2016 H 9 71.6 12.60 68.0 56 93
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Protocol: BA1116891 Page 8 of 15Population: Safety Table 10.6 Summary of Vital Signs
Planned Relative Treatment N Visit Time n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------- Pulse Rate (BEATS/MIN) SQ_50mg x 4 9 DAY 1 PREDOSE 9 65.0 10.54 66.0 51 76 0.5 H 9 58.1 4.96 59.0 53 67 1 H 9 59.7 11.05 54.0 50 86 2 H 9 63.9 9.39 62.0 54 86 4 H 9 61.1 8.84 60.0 48 79 6 H 9 59.1 9.14 55.0 52 81 DAY 2 24 H 9 73.4 11.61 73.0 58 88 DAY 3 48 H 9 70.2 13.75 67.0 53 92 DAY 8 PREDOSE 9 67.1 9.16 65.0 55 85 0.5 H 9 60.7 8.19 62.0 46 73 1 H 9 62.8 9.24 63.0 51 81 2 H 9 65.4 12.69 60.0 51 93 4 H 9 73.4 13.07 74.0 56 97 6 H 9 59.6 7.42 61.0 48 67 DAY 9 24 H 9 75.9 13.27 76.0 58 97 DAY 15 PREDOSE 9 63.9 13.82 61.0 48 93 0.5 H 9 62.1 9.89 60.0 52 85 1 H 9 60.6 5.61 61.0 54 70 2 H 9 61.4 8.31 61.0 51 79 4 H 9 67.3 13.25 63.0 52 90 6 H 9 60.9 7.17 62.0 49 74 DAY 16 24 H 9 67.4 11.46 64.0 56 92 DAY 22 PREDOSE 9 63.1 15.40 60.0 48 98 0.5 H 9 63.2 14.81 59.0 51 98 1 H 9 64.0 13.13 59.0 52 95 2 H 9 65.1 12.83 62.0 54 97 4 H 9 66.4 13.09 62.0 53 89 6 H 9 62.4 15.08 56.0 52 100 DAY 23 24 H 9 69.7 5.92 69.0 62 81 DAY 27 120 H 9 70.0 12.54 65.0 55 86 DAY 36 336 H 9 70.7 16.42 69.0 53 108 DAY 50 672 H 8 68.1 14.96 67.0 51 91
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Protocol: BA1116891 Page 9 of 15Population: Safety Table 10.6 Summary of Vital Signs
Planned Relative Treatment N Visit Time n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------- Pulse Rate (BEATS/MIN) SQ_50mg x 4 9 DAY 78 1344 H 8 64.6 6.32 63.5 56 76 FOLLOW-UP 2016 H 8 65.8 10.26 67.0 53 82
IM_200mg 9 DAY 1 PREDOSE 9 64.3 14.41 65.0 39 85 0.5 H 9 67.9 10.40 68.0 52 83 1 H 9 71.4 15.99 73.0 50 99 2 H 9 66.6 7.35 65.0 58 80 4 H 9 72.4 12.53 69.0 56 89 6 H 9 69.2 14.17 65.0 51 97 DAY 2 24 H 9 74.4 10.82 70.0 62 90 DAY 6 120 H 9 78.2 14.62 80.0 57 106 DAY 15 336 H 9 78.9 5.56 79.0 68 87 DAY 29 672 H 9 71.9 14.38 72.0 55 92 DAY 57 1344 H 8 68.1 14.12 64.5 54 92 FOLLOW-UP 2016 H 8 70.5 13.02 69.0 52 90
Respiratory Rate IV_200mg 9 DAY 1 PREDOSE 9 16.0 0.00 16.0 16 16 (BEATS/MIN) 0.5 H 9 15.3 1.41 16.0 12 16 1 H 9 15.8 0.67 16.0 14 16 2 H 9 15.8 0.67 16.0 14 16 4 H 8 15.3 1.49 16.0 12 16 6 H 9 16.4 1.33 16.0 14 18 DAY 2 24 H 9 15.8 0.67 16.0 14 16 DAY 6 120 H 9 15.6 0.88 16.0 14 16 DAY 15 336 H 9 16.0 0.00 16.0 16 16 DAY 29 672 H 9 16.0 0.00 16.0 16 16 DAY 57 1344 H 9 16.0 0.00 16.0 16 16 FOLLOW-UP 2016 H 9 16.4 1.33 16.0 16 20
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Protocol: BA1116891 Page 10 of 15Population: Safety Table 10.6 Summary of Vital Signs
Planned Relative Treatment N Visit Time n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------- Respiratory Rate SQ_200mg 9 DAY 1 PREDOSE 9 16.0 0.00 16.0 16 16 (BEATS/MIN) 0.5 H 9 15.6 1.33 16.0 14 18 1 H 9 16.2 1.56 16.0 14 20 2 H 9 16.0 1.00 16.0 14 18 4 H 9 16.2 1.86 16.0 14 20 6 H 9 16.2 1.20 16.0 14 18 DAY 2 24 H 9 16.0 0.00 16.0 16 16 DAY 6 120 H 9 16.2 1.20 16.0 14 18 DAY 15 336 H 9 16.0 0.00 16.0 16 16 DAY 29 672 H 9 16.0 0.00 16.0 16 16 DAY 57 1344 H 9 16.0 0.00 16.0 16 16 FOLLOW-UP 2016 H 9 16.0 0.00 16.0 16 16
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Protocol: BA1116891 Page 11 of 15Population: Safety Table 10.6 Summary of Vital Signs
Planned Relative Treatment N Visit Time n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------- Respiratory Rate SQ_50mg x 4 9 DAY 1 PREDOSE 9 16.0 0.00 16.0 16 16 (BEATS/MIN) 0.5 H 9 15.8 0.67 16.0 14 16 1 H 9 16.0 1.00 16.0 14 18 2 H 9 15.3 1.41 16.0 14 18 4 H 9 15.1 1.76 16.0 12 18 6 H 9 15.3 2.00 16.0 12 18 DAY 2 24 H 9 16.0 0.00 16.0 16 16 DAY 3 48 H 9 16.0 0.00 16.0 16 16 DAY 8 PREDOSE 9 16.0 0.00 16.0 16 16 0.5 H 9 15.1 1.05 16.0 14 16 1 H 9 15.1 1.05 16.0 14 16 2 H 9 15.8 0.67 16.0 14 16 4 H 9 16.4 1.67 16.0 14 18 6 H 9 16.0 1.00 16.0 14 18 DAY 9 24 H 9 16.3 1.00 16.0 16 19 DAY 15 PREDOSE 9 16.0 0.00 16.0 16 16 0.5 H 9 14.7 1.41 14.0 12 16 1 H 9 15.6 1.33 16.0 14 18 2 H 9 15.8 0.67 16.0 14 16 4 H 9 15.6 1.33 16.0 14 18 6 H 9 15.1 1.45 14.0 14 18 DAY 16 24 H 9 16.0 0.00 16.0 16 16 DAY 22 PREDOSE 9 16.0 0.00 16.0 16 16 0.5 H 9 15.6 1.67 16.0 12 18 1 H 9 14.7 1.73 16.0 12 16 2 H 9 14.9 1.76 16.0 12 16 4 H 9 14.7 2.00 14.0 12 18 6 H 9 14.9 1.76 14.0 12 18 DAY 23 24 H 9 16.0 0.00 16.0 16 16 DAY 27 120 H 9 16.0 1.00 16.0 14 18 DAY 36 336 H 9 16.0 0.00 16.0 16 16
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Protocol: BA1116891 Page 12 of 15Population: Safety Table 10.6 Summary of Vital Signs
Planned Relative Treatment N Visit Time n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------- Respiratory Rate SQ_50mg x 4 9 DAY 50 672 H 8 16.0 0.00 16.0 16 16 (BEATS/MIN) DAY 78 1344 H 8 16.0 0.00 16.0 16 16 FOLLOW-UP 2016 H 8 16.0 0.00 16.0 16 16
IM_200mg 9 DAY 1 PREDOSE 9 16.0 0.00 16.0 16 16 0.5 H 9 15.8 1.56 16.0 14 18 1 H 9 15.6 1.33 16.0 14 18 2 H 9 15.8 1.20 16.0 14 18 4 H 9 15.3 1.41 16.0 14 18 6 H 9 15.8 1.86 16.0 12 18 DAY 2 24 H 9 16.0 0.00 16.0 16 16 DAY 6 120 H 9 16.4 0.88 16.0 16 18 DAY 15 336 H 9 16.0 0.00 16.0 16 16 DAY 29 672 H 9 16.0 0.00 16.0 16 16 DAY 57 1344 H 8 16.0 0.00 16.0 16 16 FOLLOW-UP 2016 H 8 15.8 0.71 16.0 14 16
Temperature (C) IV_200mg 9 DAY 1 PREDOSE 9 36.6 0.12 36.6 36 37 0.5 H 9 36.8 0.12 36.8 37 37 1 H 9 36.8 0.20 36.8 37 37 2 H 9 36.8 0.15 36.8 37 37 4 H 8 36.7 0.17 36.7 36 37 6 H 9 36.7 0.14 36.8 36 37 DAY 2 24 H 9 36.7 0.19 36.7 36 37 DAY 6 120 H 9 36.6 0.25 36.6 36 37 DAY 15 336 H 9 36.7 0.23 36.6 36 37 DAY 29 672 H 9 36.6 0.19 36.6 36 37 DAY 57 1344 H 9 36.7 0.24 36.8 36 37 FOLLOW-UP 2016 H 9 36.7 0.18 36.7 36 37
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Protocol: BA1116891 Page 13 of 15Population: Safety Table 10.6 Summary of Vital Signs
Planned Relative Treatment N Visit Time n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------- Temperature (C) SQ_200mg 9 DAY 1 PREDOSE 9 36.7 0.18 36.7 36 37 0.5 H 9 36.9 0.29 36.9 36 37 1 H 9 36.9 0.23 36.9 37 37 2 H 9 36.9 0.17 36.9 37 37 4 H 9 36.9 0.15 36.8 37 37 6 H 9 36.9 0.23 36.9 36 37 DAY 2 24 H 9 36.8 0.20 36.9 37 37 DAY 6 120 H 9 36.8 0.12 36.8 37 37 DAY 15 336 H 9 36.7 0.30 36.7 36 37 DAY 29 672 H 9 36.7 0.22 36.7 36 37 DAY 57 1344 H 9 36.7 0.29 36.6 36 37 FOLLOW-UP 2016 H 9 36.9 0.19 36.9 37 37
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Protocol: BA1116891 Page 14 of 15Population: Safety Table 10.6 Summary of Vital Signs
Planned Relative Treatment N Visit Time n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------- Temperature (C) SQ_50mg x 4 9 DAY 1 PREDOSE 9 36.6 0.17 36.6 36 37 0.5 H 9 36.8 0.18 36.7 37 37 1 H 9 36.8 0.13 36.8 37 37 2 H 9 36.7 0.21 36.8 36 37 4 H 9 36.8 0.15 36.9 37 37 6 H 9 36.9 0.20 36.9 37 37 DAY 2 24 H 9 36.7 0.15 36.8 36 37 DAY 3 48 H 9 36.6 0.20 36.6 36 37 DAY 8 PREDOSE 9 36.6 0.16 36.6 36 37 0.5 H 9 36.9 0.24 36.8 37 37 1 H 9 36.8 0.16 36.8 37 37 2 H 9 36.8 0.25 36.9 36 37 4 H 9 36.9 0.18 36.9 37 37 6 H 9 36.9 0.21 36.8 37 37 DAY 9 24 H 9 36.7 0.23 36.7 36 37 DAY 15 PREDOSE 9 36.6 0.20 36.6 36 37 0.5 H 9 36.8 0.12 36.8 37 37 1 H 9 36.8 0.17 36.8 37 37 2 H 9 36.8 0.17 36.8 37 37 4 H 9 36.8 0.12 36.9 37 37 6 H 9 36.8 0.23 36.8 36 37 DAY 16 24 H 9 36.7 0.29 36.8 36 37 DAY 22 PREDOSE 9 36.7 0.22 36.6 36 37 0.5 H 9 36.7 0.10 36.7 37 37 1 H 9 36.7 0.09 36.7 37 37 2 H 9 36.7 0.11 36.7 37 37 4 H 9 36.8 0.13 36.8 37 37 6 H 9 36.8 0.18 36.8 37 37 DAY 23 24 H 9 36.8 0.20 36.8 36 37 DAY 27 120 H 9 36.8 0.28 36.8 36 37 DAY 36 336 H 9 36.8 0.24 36.9 37 37 DAY 50 672 H 8 36.7 0.18 36.8 37 37
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Protocol: BA1116891 Page 15 of 15Population: Safety Table 10.6 Summary of Vital Signs
Planned Relative Treatment N Visit Time n Mean SD Median Min. Max. -------------------------------------------------------------------------------------------------------- Temperature (C) SQ_50mg x 4 9 DAY 78 1344 H 8 36.8 0.24 36.8 36 37 FOLLOW-UP 2016 H 8 36.9 0.17 36.8 37 37
IM_200mg 9 DAY 1 PREDOSE 9 36.7 0.17 36.7 36 37 0.5 H 9 36.9 0.21 36.9 37 37 1 H 9 37.0 0.28 36.9 37 38 2 H 9 37.0 0.16 37.0 37 37 4 H 9 36.8 0.16 36.8 37 37 6 H 9 37.0 0.19 37.0 37 37 DAY 2 24 H 9 36.9 0.22 36.8 37 37 DAY 6 120 H 9 36.8 0.27 36.9 36 37 DAY 15 336 H 9 36.7 0.12 36.7 36 37 DAY 29 672 H 9 36.8 0.13 36.8 37 37 DAY 57 1344 H 8 36.7 0.23 36.8 36 37 FOLLOW-UP 2016 H 8 36.7 0.16 36.7 36 37
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CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 1 of 25Population: Safety Table 10.7 Summary of Vital Signs Changes from Baseline
Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Diastolic Blood IV_200mg 9 DAY 1 0.5 H 9 -8.1 4.91 -9.0 -15 1 Pressure (mmHg) 1 H 9 -8.9 6.11 -9.0 -19 1 2 H 9 -10.7 6.10 -10.0 -23 -5 4 H 8 -8.0 7.23 -9.0 -16 2 6 H 9 -5.2 8.12 0.0 -17 1
DAY 2 24 H 9 -2.6 3.94 -2.0 -7 5
DAY 6 120 H 9 -1.8 4.60 -3.0 -9 5
DAY 15 336 H 9 -1.2 7.92 1.0 -12 11
DAY 29 672 H 9 -0.6 6.33 -1.0 -8 12
DAY 57 1344 H 9 -1.6 8.66 -5.0 -11 16
FOLLOW-UP 2016 H 9 0.7 5.20 4.0 -7 6
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Protocol: BA1116891 Page 2 of 25Population: Safety Table 10.7 Summary of Vital Signs Changes from Baseline
Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Diastolic Blood SQ_200mg 9 DAY 1 0.5 H 9 -2.2 5.76 -4.0 -11 7 Pressure (mmHg) 1 H 9 -2.8 5.76 -3.0 -11 7 2 H 9 -5.3 5.61 -5.0 -16 3 4 H 9 -2.6 3.57 -2.0 -11 1 6 H 9 3.1 13.35 -1.0 -8 34
DAY 2 24 H 9 -6.3 8.41 -4.0 -27 1
DAY 6 120 H 9 -2.6 3.97 -2.0 -10 3
DAY 15 336 H 9 -0.1 6.83 -1.0 -12 9
DAY 29 672 H 9 -0.4 6.29 0.0 -9 8
DAY 57 1344 H 9 -2.3 4.15 -1.0 -9 3
FOLLOW-UP 2016 H 9 -3.1 7.36 -5.0 -14 8
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Protocol: BA1116891 Page 3 of 25Population: Safety Table 10.7 Summary of Vital Signs Changes from Baseline
Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Diastolic Blood SQ_50mg x 4 9 DAY 1 0.5 H 9 -0.9 6.13 2.0 -9 8 Pressure (mmHg) 1 H 9 -6.7 5.61 -6.0 -17 0 2 H 9 -6.6 8.57 -4.0 -27 4 4 H 9 -8.9 8.75 -7.0 -23 4 6 H 9 -3.3 7.16 -4.0 -14 8
DAY 2 24 H 9 2.4 7.30 4.0 -10 11
DAY 3 48 H 9 2.2 4.44 2.0 -8 7
DAY 8 PREDOSE 9 -0.8 7.93 1.0 -15 8 0.5 H 9 -3.6 9.33 -1.0 -16 7 1 H 9 -2.4 6.54 -2.0 -13 6 2 H 9 -1.9 12.04 4.0 -28 9 4 H 9 -4.2 10.47 -1.0 -21 9 6 H 9 0.3 7.94 3.0 -10 10
DAY 9 24 H 9 4.0 17.26 8.0 -31 33
DAY 15 PREDOSE 9 0.1 6.39 0.0 -13 8 0.5 H 9 -8.4 8.34 -7.0 -25 0 1 H 9 -9.1 11.16 -5.0 -31 6 2 H 9 -6.3 11.70 -5.0 -35 4 4 H 9 -10.9 11.85 -6.0 -34 -1 6 H 9 -3.7 8.06 -4.0 -17 5
DAY 16 24 H 9 -0.8 9.01 2.0 -20 12
DAY 22 PREDOSE 9 0.8 9.95 -1.0 -10 20 0.5 H 9 -1.9 9.74 4.0 -15 11 1 H 9 -3.9 9.03 0.0 -18 7
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Protocol: BA1116891 Page 4 of 25Population: Safety Table 10.7 Summary of Vital Signs Changes from Baseline
Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Diastolic Blood SQ_50mg x 4 9 DAY 22 2 H 9 -3.3 13.19 -4.0 -23 19 Pressure (mmHg) 4 H 9 -7.2 7.81 -8.0 -19 3 6 H 9 -1.1 12.34 3.0 -21 19
DAY 23 24 H 9 0.0 7.76 3.0 -12 9
DAY 27 120 H 9 -0.2 4.94 2.0 -9 5
DAY 36 336 H 9 2.0 8.37 2.0 -13 14
DAY 50 672 H 8 0.6 5.29 -1.5 -6 8
DAY 78 1344 H 8 1.3 8.15 4.0 -12 13
FOLLOW-UP 2016 H 8 -2.1 8.71 -0.5 -19 8
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Protocol: BA1116891 Page 5 of 25Population: Safety Table 10.7 Summary of Vital Signs Changes from Baseline
Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Diastolic Blood IM_200mg 9 DAY 1 0.5 H 9 -0.8 5.21 -2.0 -7 8 Pressure (mmHg) 1 H 9 -2.0 5.70 -1.0 -13 7 2 H 9 -4.8 8.41 -8.0 -19 8 4 H 9 -4.7 12.20 -4.0 -20 15 6 H 9 0.6 8.16 -3.0 -7 17
DAY 2 24 H 9 -0.3 4.00 1.0 -6 4
DAY 6 120 H 9 -0.6 11.49 -3.0 -16 18
DAY 15 336 H 9 2.8 9.26 1.0 -10 20
DAY 29 672 H 9 1.8 7.07 3.0 -10 14
DAY 57 1344 H 8 2.4 12.56 -3.0 -5 31
FOLLOW-UP 2016 H 8 -0.9 10.40 -4.0 -14 17
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Protocol: BA1116891 Page 6 of 25Population: Safety Table 10.7 Summary of Vital Signs Changes from Baseline
Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Systolic Blood IV_200mg 9 DAY 1 0.5 H 9 -4.3 6.32 -6.0 -12 8 Pressure (mmHg) 1 H 9 -3.7 6.56 -3.0 -14 10 2 H 9 -2.2 8.06 -3.0 -15 15 4 H 8 -3.5 4.99 -3.0 -10 4 6 H 9 -2.1 6.74 -1.0 -15 7
DAY 2 24 H 9 4.0 6.86 4.0 -5 19
DAY 6 120 H 9 1.0 6.98 1.0 -13 9
DAY 15 336 H 9 1.2 9.73 0.0 -14 18
DAY 29 672 H 9 1.6 6.67 1.0 -7 15
DAY 57 1344 H 9 2.8 6.28 1.0 -4 14
FOLLOW-UP 2016 H 9 1.6 8.72 3.0 -18 13
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Protocol: BA1116891 Page 7 of 25Population: Safety Table 10.7 Summary of Vital Signs Changes from Baseline
Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Systolic Blood SQ_200mg 9 DAY 1 0.5 H 9 0.0 11.19 -4.0 -10 24 Pressure (mmHg) 1 H 9 0.8 9.40 1.0 -16 19 2 H 9 -1.6 10.16 2.0 -25 10 4 H 9 -6.8 6.59 -7.0 -20 3 6 H 9 -1.6 10.71 -7.0 -14 16
DAY 2 24 H 9 -1.7 8.63 -4.0 -14 13
DAY 6 120 H 9 -2.8 7.36 -4.0 -11 10
DAY 15 336 H 9 -2.1 11.12 -3.0 -21 18
DAY 29 672 H 9 -1.2 6.89 -1.0 -12 7
DAY 57 1344 H 9 -4.3 5.96 -4.0 -15 4
FOLLOW-UP 2016 H 9 -3.2 9.60 -1.0 -19 10
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Protocol: BA1116891 Page 8 of 25Population: Safety Table 10.7 Summary of Vital Signs Changes from Baseline
Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Systolic Blood SQ_50mg x 4 9 DAY 1 0.5 H 9 -3.0 8.14 0.0 -16 8 Pressure (mmHg) 1 H 9 -3.1 8.12 -5.0 -13 9 2 H 9 -1.3 6.02 1.0 -11 6 4 H 9 -4.0 10.98 -7.0 -16 16 6 H 9 -1.7 7.16 -1.0 -11 7
DAY 2 24 H 9 4.6 6.88 4.0 -6 13
DAY 3 48 H 9 3.4 7.84 5.0 -13 12
DAY 8 PREDOSE 9 -3.4 6.41 -3.0 -16 4 0.5 H 9 -5.0 9.26 -5.0 -22 10 1 H 9 -0.7 8.79 -1.0 -10 11 2 H 9 -2.2 6.16 -2.0 -15 6 4 H 9 -2.8 12.19 2.0 -28 8 6 H 9 -1.0 10.94 -4.0 -15 16
DAY 9 24 H 9 6.8 5.04 6.0 -4 14
DAY 15 PREDOSE 9 -1.1 7.79 1.0 -12 9 0.5 H 9 -5.2 11.26 -6.0 -26 7 1 H 9 -5.7 7.65 -6.0 -17 9 2 H 9 -1.7 10.22 0.0 -21 12 4 H 9 -8.2 9.52 -5.0 -26 2 6 H 9 -2.3 7.78 -2.0 -13 8
DAY 16 24 H 9 -0.6 5.59 -1.0 -9 8
DAY 22 PREDOSE 9 1.2 7.07 2.0 -8 14 0.5 H 9 -3.9 9.27 -5.0 -16 8 1 H 9 -1.3 10.12 1.0 -20 10
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Protocol: BA1116891 Page 9 of 25Population: Safety Table 10.7 Summary of Vital Signs Changes from Baseline
Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Systolic Blood SQ_50mg x 4 9 DAY 22 2 H 9 1.4 11.08 3.0 -15 17 Pressure (mmHg) 4 H 9 -3.4 8.86 -5.0 -12 16 6 H 9 1.8 9.59 2.0 -15 14
DAY 23 24 H 9 2.0 5.17 5.0 -7 7
DAY 27 120 H 9 0.2 5.87 1.0 -12 9
DAY 36 336 H 9 5.4 9.61 3.0 -8 24
DAY 50 672 H 8 3.1 8.61 4.0 -9 16
DAY 78 1344 H 8 -0.4 11.86 2.5 -18 13
FOLLOW-UP 2016 H 8 -1.5 7.15 -1.5 -12 7
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Protocol: BA1116891 Page 10 of 25Population: Safety Table 10.7 Summary of Vital Signs Changes from Baseline
Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Systolic Blood IM_200mg 9 DAY 1 0.5 H 9 -1.3 9.87 -1.0 -16 15 Pressure (mmHg) 1 H 9 -0.6 10.04 -2.0 -14 22 2 H 9 -4.3 11.25 -5.0 -16 23 4 H 9 -5.3 14.08 -8.0 -27 23 6 H 9 -1.3 8.09 -2.0 -13 13
DAY 2 24 H 9 2.2 12.32 4.0 -22 20
DAY 6 120 H 9 -4.1 14.00 -6.0 -18 27
DAY 15 336 H 9 -0.7 6.16 -3.0 -7 12
DAY 29 672 H 9 5.4 6.02 7.0 -4 11
DAY 57 1344 H 8 -0.5 8.28 -1.0 -10 16
FOLLOW-UP 2016 H 8 -5.1 8.49 -9.0 -14 9
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Protocol: BA1116891 Page 11 of 25Population: Safety Table 10.7 Summary of Vital Signs Changes from Baseline
Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Pulse Rate IV_200mg 9 DAY 1 0.5 H 9 3.0 9.35 2.0 -9 24 (BEATS/MIN) 1 H 9 1.8 8.27 3.0 -14 13 2 H 9 2.8 8.64 0.0 -4 24 4 H 8 -1.8 6.27 -2.0 -9 11 6 H 9 0.3 9.18 0.0 -8 22
DAY 2 24 H 9 9.7 13.03 11.0 -12 25
DAY 6 120 H 9 3.6 9.94 3.0 -6 24
DAY 15 336 H 9 7.4 9.40 10.0 -7 23
DAY 29 672 H 9 2.8 10.13 -1.0 -14 18
DAY 57 1344 H 9 3.0 9.75 6.0 -13 19
FOLLOW-UP 2016 H 9 0.2 11.79 1.0 -17 16
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Protocol: BA1116891 Page 12 of 25Population: Safety Table 10.7 Summary of Vital Signs Changes from Baseline
Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Pulse Rate SQ_200mg 9 DAY 1 0.5 H 9 0.4 7.00 0.0 -9 11 (BEATS/MIN) 1 H 9 2.1 8.75 1.0 -9 18 2 H 9 2.3 7.68 0.0 -10 15 4 H 9 -4.4 13.19 -1.0 -33 13 6 H 9 1.1 5.69 0.0 -8 10
DAY 2 24 H 9 2.1 14.43 8.0 -24 17
DAY 6 120 H 9 -0.1 13.75 2.0 -19 21
DAY 15 336 H 9 -3.9 14.26 -1.0 -36 12
DAY 29 672 H 9 -0.3 16.99 1.0 -32 25
DAY 57 1344 H 9 -1.0 11.63 1.0 -23 14
FOLLOW-UP 2016 H 9 0.9 15.27 -3.0 -25 23
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Protocol: BA1116891 Page 13 of 25Population: Safety Table 10.7 Summary of Vital Signs Changes from Baseline
Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Pulse Rate SQ_50mg x 4 9 DAY 1 0.5 H 9 -6.9 7.37 -9.0 -16 2 (BEATS/MIN) 1 H 9 -5.3 8.06 -6.0 -15 10 2 H 9 -1.1 8.45 1.0 -13 10 4 H 9 -3.9 11.48 -3.0 -17 21 6 H 9 -5.9 8.13 -5.0 -19 5
DAY 2 24 H 9 8.4 11.13 11.0 -14 21
DAY 3 48 H 9 5.2 13.32 9.0 -20 24
DAY 8 PREDOSE 9 2.1 8.27 4.0 -12 12 0.5 H 9 -4.3 8.11 -4.0 -18 8 1 H 9 -2.2 12.05 -4.0 -15 27 2 H 9 0.4 8.47 0.0 -15 17 4 H 9 8.4 16.57 6.0 -10 43 6 H 9 -5.4 9.51 -8.0 -18 13
DAY 9 24 H 9 10.9 15.88 12.0 -9 43
DAY 15 PREDOSE 9 -1.1 15.64 -6.0 -21 18 0.5 H 9 -2.9 13.72 -7.0 -15 27 1 H 9 -4.4 8.79 -5.0 -16 7 2 H 9 -3.6 11.91 -8.0 -14 21 4 H 9 2.3 12.41 0.0 -12 32 6 H 9 -4.1 7.57 -6.0 -13 8
DAY 16 24 H 9 2.4 7.00 2.0 -7 16
DAY 22 PREDOSE 9 -1.9 11.23 0.0 -15 22 0.5 H 9 -1.8 12.74 -4.0 -16 22 1 H 9 -1.0 9.70 -2.0 -13 19
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Protocol: BA1116891 Page 14 of 25Population: Safety Table 10.7 Summary of Vital Signs Changes from Baseline
Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Pulse Rate SQ_50mg x 4 9 DAY 22 2 H 9 0.1 10.49 3.0 -13 21 (BEATS/MIN) 4 H 9 1.4 13.50 2.0 -13 31 6 H 9 -2.6 12.95 -2.0 -21 24
DAY 23 24 H 9 4.7 11.36 8.0 -11 18
DAY 27 120 H 9 5.0 19.76 4.0 -20 30
DAY 36 336 H 9 5.7 13.11 3.0 -16 32
DAY 50 672 H 8 1.9 10.99 3.5 -15 16
DAY 78 1344 H 8 -1.6 9.72 -2.5 -14 12
FOLLOW-UP 2016 H 8 -0.5 7.67 0.0 -9 11
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Protocol: BA1116891 Page 15 of 25Population: Safety Table 10.7 Summary of Vital Signs Changes from Baseline
Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Pulse Rate IM_200mg 9 DAY 1 0.5 H 9 3.6 18.17 3.0 -23 42 (BEATS/MIN) 1 H 9 7.1 19.90 0.0 -18 44 2 H 9 2.2 13.43 4.0 -20 26 4 H 9 8.1 15.50 9.0 -23 30 6 H 9 4.9 16.39 -3.0 -13 34
DAY 2 24 H 9 10.1 13.88 8.0 -4 44
DAY 6 120 H 9 13.9 19.25 13.0 -17 41
DAY 15 336 H 9 14.6 14.66 10.0 -4 41
DAY 29 672 H 9 7.6 15.44 7.0 -8 41
DAY 57 1344 H 8 6.4 17.62 1.0 -15 33
FOLLOW-UP 2016 H 8 8.8 13.74 7.5 -11 26
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Protocol: BA1116891 Page 16 of 25Population: Safety Table 10.7 Summary of Vital Signs Changes from Baseline
Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Respiratory Rate IV_200mg 9 DAY 1 0.5 H 9 -0.7 1.41 0.0 -4 0 (BEATS/MIN) 1 H 9 -0.2 0.67 0.0 -2 0 2 H 9 -0.2 0.67 0.0 -2 0 4 H 8 -0.8 1.49 0.0 -4 0 6 H 9 0.4 1.33 0.0 -2 2
DAY 2 24 H 9 -0.2 0.67 0.0 -2 0
DAY 6 120 H 9 -0.4 0.88 0.0 -2 0
DAY 15 336 H 9 0.0 0.00 0.0 0 0
DAY 29 672 H 9 0.0 0.00 0.0 0 0
DAY 57 1344 H 9 0.0 0.00 0.0 0 0
FOLLOW-UP 2016 H 9 0.4 1.33 0.0 0 4
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Protocol: BA1116891 Page 17 of 25Population: Safety Table 10.7 Summary of Vital Signs Changes from Baseline
Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Respiratory Rate SQ_200mg 9 DAY 1 0.5 H 9 -0.4 1.33 0.0 -2 2 (BEATS/MIN) 1 H 9 0.2 1.56 0.0 -2 4 2 H 9 0.0 1.00 0.0 -2 2 4 H 9 0.2 1.86 0.0 -2 4 6 H 9 0.2 1.20 0.0 -2 2
DAY 2 24 H 9 0.0 0.00 0.0 0 0
DAY 6 120 H 9 0.2 1.20 0.0 -2 2
DAY 15 336 H 9 0.0 0.00 0.0 0 0
DAY 29 672 H 9 0.0 0.00 0.0 0 0
DAY 57 1344 H 9 0.0 0.00 0.0 0 0
FOLLOW-UP 2016 H 9 0.0 0.00 0.0 0 0
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Protocol: BA1116891 Page 18 of 25Population: Safety Table 10.7 Summary of Vital Signs Changes from Baseline
Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Respiratory Rate SQ_50mg x 4 9 DAY 1 0.5 H 9 -0.2 0.67 0.0 -2 0 (BEATS/MIN) 1 H 9 0.0 1.00 0.0 -2 2 2 H 9 -0.7 1.41 0.0 -2 2 4 H 9 -0.9 1.76 0.0 -4 2 6 H 9 -0.7 2.00 0.0 -4 2
DAY 2 24 H 9 0.0 0.00 0.0 0 0
DAY 3 48 H 9 0.0 0.00 0.0 0 0
DAY 8 PREDOSE 9 0.0 0.00 0.0 0 0 0.5 H 9 -0.9 1.05 0.0 -2 0 1 H 9 -0.9 1.05 0.0 -2 0 2 H 9 -0.2 0.67 0.0 -2 0 4 H 9 0.4 1.67 0.0 -2 2 6 H 9 0.0 1.00 0.0 -2 2
DAY 9 24 H 9 0.3 1.00 0.0 0 3
DAY 15 PREDOSE 9 0.0 0.00 0.0 0 0 0.5 H 9 -1.3 1.41 -2.0 -4 0 1 H 9 -0.4 1.33 0.0 -2 2 2 H 9 -0.2 0.67 0.0 -2 0 4 H 9 -0.4 1.33 0.0 -2 2 6 H 9 -0.9 1.45 -2.0 -2 2
DAY 16 24 H 9 0.0 0.00 0.0 0 0
DAY 22 PREDOSE 9 0.0 0.00 0.0 0 0 0.5 H 9 -0.4 1.67 0.0 -4 2 1 H 9 -1.3 1.73 0.0 -4 0
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Protocol: BA1116891 Page 19 of 25Population: Safety Table 10.7 Summary of Vital Signs Changes from Baseline
Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Respiratory Rate SQ_50mg x 4 9 DAY 22 2 H 9 -1.1 1.76 0.0 -4 0 (BEATS/MIN) 4 H 9 -1.3 2.00 -2.0 -4 2 6 H 9 -1.1 1.76 -2.0 -4 2
DAY 23 24 H 9 0.0 0.00 0.0 0 0
DAY 27 120 H 9 0.0 1.00 0.0 -2 2
DAY 36 336 H 9 0.0 0.00 0.0 0 0
DAY 50 672 H 8 0.0 0.00 0.0 0 0
DAY 78 1344 H 8 0.0 0.00 0.0 0 0
FOLLOW-UP 2016 H 8 0.0 0.00 0.0 0 0
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Protocol: BA1116891 Page 20 of 25Population: Safety Table 10.7 Summary of Vital Signs Changes from Baseline
Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Respiratory Rate IM_200mg 9 DAY 1 0.5 H 9 -0.2 1.56 0.0 -2 2 (BEATS/MIN) 1 H 9 -0.4 1.33 0.0 -2 2 2 H 9 -0.2 1.20 0.0 -2 2 4 H 9 -0.7 1.41 0.0 -2 2 6 H 9 -0.2 1.86 0.0 -4 2
DAY 2 24 H 9 0.0 0.00 0.0 0 0
DAY 6 120 H 9 0.4 0.88 0.0 0 2
DAY 15 336 H 9 0.0 0.00 0.0 0 0
DAY 29 672 H 9 0.0 0.00 0.0 0 0
DAY 57 1344 H 8 0.0 0.00 0.0 0 0
FOLLOW-UP 2016 H 8 -0.3 0.71 0.0 -2 0
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Protocol: BA1116891 Page 21 of 25Population: Safety Table 10.7 Summary of Vital Signs Changes from Baseline
Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Temperature (C) IV_200mg 9 DAY 1 0.5 H 9 0.2 0.16 0.2 -0 0 1 H 9 0.2 0.20 0.2 -0 1 2 H 9 0.2 0.17 0.1 0 1 4 H 8 0.1 0.19 0.0 -0 0 6 H 9 0.1 0.15 0.0 -0 0
DAY 2 24 H 9 0.1 0.23 0.1 -0 1
DAY 6 120 H 9 0.0 0.31 0.0 -0 1
DAY 15 336 H 9 0.1 0.22 0.0 -0 1
DAY 29 672 H 9 -0.0 0.21 0.0 -0 0
DAY 57 1344 H 9 0.1 0.30 0.2 -1 1
FOLLOW-UP 2016 H 9 0.1 0.23 0.2 -0 0
105
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Protocol: BA1116891 Page 22 of 25Population: Safety Table 10.7 Summary of Vital Signs Changes from Baseline
Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Temperature (C) SQ_200mg 9 DAY 1 0.5 H 9 0.2 0.31 0.3 -0 1 1 H 9 0.2 0.14 0.2 0 0 2 H 9 0.2 0.13 0.2 0 0 4 H 9 0.2 0.12 0.2 0 0 6 H 9 0.2 0.12 0.2 0 0
DAY 2 24 H 9 0.1 0.29 0.1 -0 1
DAY 6 120 H 9 0.1 0.19 0.1 -0 0
DAY 15 336 H 9 0.0 0.34 0.1 -0 1
DAY 29 672 H 9 -0.0 0.15 0.0 -0 0
DAY 57 1344 H 9 0.0 0.33 0.0 -0 1
FOLLOW-UP 2016 H 9 0.2 0.21 0.2 -0 0
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Protocol: BA1116891 Page 23 of 25Population: Safety Table 10.7 Summary of Vital Signs Changes from Baseline
Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Temperature (C) SQ_50mg x 4 9 DAY 1 0.5 H 9 0.2 0.13 0.2 -0 0 1 H 9 0.2 0.23 0.2 -0 1 2 H 9 0.1 0.30 0.1 -0 1 4 H 9 0.2 0.23 0.2 -0 0 6 H 9 0.3 0.26 0.2 -0 1
DAY 2 24 H 9 0.1 0.27 0.1 -1 0
DAY 3 48 H 9 -0.1 0.28 0.0 -1 0
DAY 8 PREDOSE 9 -0.1 0.23 -0.1 -0 1 0.5 H 9 0.2 0.33 0.1 -0 1 1 H 9 0.2 0.22 0.2 -0 1 2 H 9 0.2 0.26 0.2 -0 1 4 H 9 0.3 0.26 0.3 -0 1 6 H 9 0.2 0.23 0.3 -0 1
DAY 9 24 H 9 0.1 0.26 0.1 -0 0
DAY 15 PREDOSE 9 -0.0 0.16 -0.1 -0 0 0.5 H 9 0.1 0.21 0.1 -0 0 1 H 9 0.1 0.28 0.1 -0 0 2 H 9 0.2 0.25 0.1 -0 1 4 H 9 0.2 0.24 0.2 -0 1 6 H 9 0.1 0.26 0.1 -0 1
DAY 16 24 H 9 0.1 0.25 0.1 -0 0
DAY 22 PREDOSE 9 0.0 0.23 0.0 -0 1 0.5 H 9 0.0 0.19 -0.1 -0 0 1 H 9 0.1 0.16 0.0 -0 0 2 H 9 0.1 0.17 0.1 -0 0
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Protocol: BA1116891 Page 24 of 25Population: Safety Table 10.7 Summary of Vital Signs Changes from Baseline
Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Temperature (C) SQ_50mg x 4 9 DAY 22 4 H 9 0.1 0.20 0.1 -0 1 6 H 9 0.2 0.19 0.2 -0 1
DAY 23 24 H 9 0.1 0.32 0.1 -1 1
DAY 27 120 H 9 0.1 0.30 0.1 -0 1
DAY 36 336 H 9 0.2 0.23 0.1 -0 1
DAY 50 672 H 8 0.1 0.18 0.0 -0 0
DAY 78 1344 H 8 0.1 0.33 0.0 -0 1
FOLLOW-UP 2016 H 8 0.2 0.22 0.2 -0 1
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Protocol: BA1116891 Page 25 of 25Population: Safety Table 10.7 Summary of Vital Signs Changes from Baseline
Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Temperature (C) IM_200mg 9 DAY 1 0.5 H 9 0.2 0.17 0.2 0 1 1 H 9 0.3 0.27 0.2 0 1 2 H 9 0.3 0.10 0.3 0 1 4 H 9 0.1 0.17 0.1 -0 0 6 H 9 0.3 0.21 0.2 0 1
DAY 2 24 H 9 0.2 0.20 0.2 -0 0
DAY 6 120 H 9 0.1 0.32 0.2 -1 0
DAY 15 336 H 9 0.0 0.14 0.0 -0 0
DAY 29 672 H 9 0.1 0.16 0.1 -0 0
DAY 57 1344 H 8 0.0 0.27 0.1 -1 0
FOLLOW-UP 2016 H 8 0.0 0.29 0.0 -1 1
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Protocol: BA1116891 Page 1 of 1Population: Safety Table 10.8 Summary of ECG Findings
IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Category (N=9) (N=9) (N=9) (N=9) -------------------------------------------------------------------------------------------- SCREENING n 9 9 9 9 Normal 2 (22.2%) 3 (33.3%) 4 (44.4%) 0 Abnormal - Not Clinically 7 (77.8%) 6 (66.7%) 5 (55.6%) 9 (100.0%) Significant Abnormal - Clinically 0 0 0 0 Significant
FOLLOW-UP n 9 9 8 8 Normal 3 (33.3%) 5 (55.6%) 2 (25.0%) 2 (25.0%) Abnormal - Not Clinically 6 (66.7%) 4 (44.4%) 6 (75.0%) 6 (75.0%) Significant Abnormal - Clinically 0 0 0 0 Significant
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Protocol: BA1116891 Page 1 of 4Population: Safety Table 10.9 Summary of ECG Values
Treatment N Visit n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------- Heart Rate IV_200mg 9 SCREENING 9 57.3 8.20 58.0 48 76 (bpm) FOLLOW-UP 9 58.8 7.79 58.0 49 71
SQ_200mg 9 SCREENING 9 64.0 9.21 64.0 51 76 FOLLOW-UP 9 67.1 11.96 63.0 53 92
SQ_50mg x 4 9 SCREENING 9 61.1 7.36 62.0 49 69 FOLLOW-UP 8 66.8 8.71 67.5 53 80
IM_200mg 9 SCREENING 9 62.0 7.02 60.0 52 73 FOLLOW-UP 8 64.8 10.02 64.5 47 78
PR Interval IV_200mg 9 SCREENING 9 167.2 16.77 163.0 143 195 (msec) FOLLOW-UP 9 167.9 14.40 164.0 151 196
SQ_200mg 9 SCREENING 9 155.2 24.57 165.0 117 183 FOLLOW-UP 9 154.8 24.98 159.0 120 186
SQ_50mg x 4 9 SCREENING 9 163.6 21.92 155.0 133 208 FOLLOW-UP 8 169.5 16.67 166.5 143 199
IM_200mg 9 SCREENING 9 165.7 34.19 150.0 130 241 FOLLOW-UP 8 168.1 30.32 154.0 138 225
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Protocol: BA1116891 Page 2 of 4Population: Safety Table 10.9 Summary of ECG Values
Treatment N Visit n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------- QRS Duration IV_200mg 9 SCREENING 9 98.6 6.97 99.0 89 109 (msec) FOLLOW-UP 9 98.0 9.76 93.0 85 114
SQ_200mg 9 SCREENING 9 93.9 6.53 93.0 85 104 FOLLOW-UP 9 94.6 9.07 92.0 82 109
SQ_50mg x 4 9 SCREENING 9 92.9 3.69 92.0 88 101 FOLLOW-UP 8 92.3 3.92 92.0 88 98
IM_200mg 9 SCREENING 9 99.3 8.76 96.0 90 114 FOLLOW-UP 8 95.4 6.65 94.5 87 109
QTcB IV_200mg 9 SCREENING 9 394.7 10.69 394.0 379 417 (msec) FOLLOW-UP 9 396.0 20.04 391.0 375 432
SQ_200mg 9 SCREENING 9 396.0 11.03 393.0 381 417 FOLLOW-UP 9 398.8 13.74 402.0 376 415
SQ_50mg x 4 9 SCREENING 9 384.8 18.41 376.0 366 420 FOLLOW-UP 8 403.8 17.66 404.5 380 436
IM_200mg 9 SCREENING 9 393.9 17.60 393.0 370 414 FOLLOW-UP 8 392.4 17.41 397.0 368 416
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Protocol: BA1116891 Page 3 of 4Population: Safety Table 10.9 Summary of ECG Values
Treatment N Visit n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------- QTcF IV_200mg 9 SCREENING 9 397.9 11.75 399.0 381 417 (msec) FOLLOW-UP 9 397.6 15.30 393.0 379 424
SQ_200mg 9 SCREENING 9 391.9 6.86 391.0 381 405 FOLLOW-UP 9 391.9 10.88 395.0 376 407
SQ_50mg x 4 9 SCREENING 9 383.4 14.28 381.0 366 410 FOLLOW-UP 8 396.8 15.98 397.5 376 428
IM_200mg 9 SCREENING 9 391.9 16.44 395.0 367 414 FOLLOW-UP 8 387.4 9.83 387.5 373 400
QT,Corrected IV_200mg 9 SCREENING 9 397.4 11.16 398.0 382 417 (msec) FOLLOW-UP 9 396.8 14.76 394.0 379 423
SQ_200mg 9 SCREENING 9 391.8 6.61 391.0 382 405 FOLLOW-UP 9 392.1 11.19 396.0 377 407
SQ_50mg x 4 9 SCREENING 9 383.4 14.06 380.0 366 410 FOLLOW-UP 8 397.0 15.71 398.5 378 428
IM_200mg 9 SCREENING 9 392.1 16.04 396.0 369 414 FOLLOW-UP 8 387.1 10.25 388.0 375 401
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Protocol: BA1116891 Page 4 of 4Population: Safety Table 10.9 Summary of ECG Values
Treatment N Visit n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------- QT Interval IV_200mg 9 SCREENING 9 405.0 24.99 417.0 355 432 (msec) FOLLOW-UP 9 401.0 19.46 398.0 375 434
SQ_200mg 9 SCREENING 9 384.6 20.59 383.0 352 412 FOLLOW-UP 9 379.7 25.23 392.0 330 400
SQ_50mg x 4 9 SCREENING 9 381.8 18.83 380.0 358 418 FOLLOW-UP 8 383.8 24.34 381.5 349 419
IM_200mg 9 SCREENING 9 388.4 23.00 382.0 359 424 FOLLOW-UP 8 378.9 18.22 381.5 354 413
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Protocol: BA1116891 Page 1 of 2Population: Safety Table 10.10 Summary of Category of QTc Data by Treatment and Time
Planned 451 to 481 to Treatment N Visit Time n <=450 <=480 <=500 >500 --------------------------------------------------------------------------------------------------------- QT, IV_200mg 9 SCREENING SCREENING 9 9 (100.0%) 0 0 0 Corrected (msec) FOLLOW-UP 2016 H 9 9 (100.0%) 0 0 0
SQ_200mg 9 SCREENING SCREENING 9 9 (100.0%) 0 0 0 FOLLOW-UP 2016 H 9 9 (100.0%) 0 0 0
SQ_50mg x 4 9 SCREENING SCREENING 9 9 (100.0%) 0 0 0 FOLLOW-UP 2016 H 8 8 (100.0%) 0 0 0
IM_200mg 9 SCREENING SCREENING 9 9 (100.0%) 0 0 0 FOLLOW-UP 2016 H 8 8 (100.0%) 0 0 0
QTcB IV_200mg 9 SCREENING SCREENING 9 9 (100.0%) 0 0 0 (msec) FOLLOW-UP 2016 H 9 9 (100.0%) 0 0 0
SQ_200mg 9 SCREENING SCREENING 9 9 (100.0%) 0 0 0 FOLLOW-UP 2016 H 9 9 (100.0%) 0 0 0
SQ_50mg x 4 9 SCREENING SCREENING 9 9 (100.0%) 0 0 0 FOLLOW-UP 2016 H 8 8 (100.0%) 0 0 0
IM_200mg 9 SCREENING SCREENING 9 9 (100.0%) 0 0 0 FOLLOW-UP 2016 H 8 8 (100.0%) 0 0 0
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Protocol: BA1116891 Page 2 of 2Population: Safety Table 10.10 Summary of Category of QTc Data by Treatment and Time
Planned 451 to 481 to Treatment N Visit Time n <=450 <=480 <=500 >500 --------------------------------------------------------------------------------------------------------- QTcF IV_200mg 9 SCREENING SCREENING 9 9 (100.0%) 0 0 0 (msec) FOLLOW-UP 2016 H 9 9 (100.0%) 0 0 0
SQ_200mg 9 SCREENING SCREENING 9 9 (100.0%) 0 0 0 FOLLOW-UP 2016 H 9 9 (100.0%) 0 0 0
SQ_50mg x 4 9 SCREENING SCREENING 9 9 (100.0%) 0 0 0 FOLLOW-UP 2016 H 8 8 (100.0%) 0 0 0
IM_200mg 9 SCREENING SCREENING 9 9 (100.0%) 0 0 0 FOLLOW-UP 2016 H 8 8 (100.0%) 0 0 0
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Protocol: BA1116891 Page 1 of 2Population: Safety Table 10.11 Summary of Category of QTc Change from Baseline by Treatment and Time
Planned Treatment N Visit Time n <=30 31 to <=60 >61 -------------------------------------------------------------------------------------------------------- QT, IV_200mg 9 FOLLOW-UP 2016 H 9 9 (100.0%) 0 0 Corrected (msec)
SQ_200mg 9 FOLLOW-UP 2016 H 9 9 (100.0%) 0 0
SQ_50mg x 4 9 FOLLOW-UP 2016 H 8 8 (100.0%) 0 0
IM_200mg 9 FOLLOW-UP 2016 H 8 8 (100.0%) 0 0
QTcB IV_200mg 9 FOLLOW-UP 2016 H 9 8 (88.9%) 1 (11.1%) 0 (msec)
SQ_200mg 9 FOLLOW-UP 2016 H 9 9 (100.0%) 0 0
SQ_50mg x 4 9 FOLLOW-UP 2016 H 8 7 (87.5%) 1 (12.5%) 0
IM_200mg 9 FOLLOW-UP 2016 H 8 8 (100.0%) 0 0
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Protocol: BA1116891 Page 2 of 2Population: Safety Table 10.11 Summary of Category of QTc Change from Baseline by Treatment and Time
Planned Treatment N Visit Time n <=30 31 to <=60 >61 -------------------------------------------------------------------------------------------------------- QTcF IV_200mg 9 FOLLOW-UP 2016 H 9 9 (100.0%) 0 0 (msec)
SQ_200mg 9 FOLLOW-UP 2016 H 9 9 (100.0%) 0 0
SQ_50mg x 4 9 FOLLOW-UP 2016 H 8 8 (100.0%) 0 0
IM_200mg 9 FOLLOW-UP 2016 H 8 8 (100.0%) 0 0
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Protocol: BA1116891 Page 1 of 1Population: Safety Table 10.12 Summary of Liver Chemistry Assessments for Subjects with Liver Signal/Event
No data to report
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Protocol: BA1116891 Page 1 of 1Population: Safety Table 10.13 Summary of Time on Treatment Before Liver Event
No data to report
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Protocol: BA1116891 Page 1 of 1Population: Safety Table 10.14 Summary of Liver Biopsy Details
No data to report
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CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 1 of 1Population: Safety Table 10.15 Summary of Liver Imaging Details
No data to report
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Protocol: BA1116891 Page 1 of 35Population: Safety Table 10.301 Clinical Chemistry Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Alanine IV_200mg 9 DAY 1 PREDOSE 9 24.1 5.80 24.0 17 33 Aminotrans ferase (U/L)
DAY 5 96 H 9 24.9 5.90 25.0 17 36
DAY 15 336 H 9 25.4 7.14 25.0 17 36
DAY 29 672 H 9 22.7 3.91 21.0 18 29
DAY 57 1344 H 9 27.7 9.01 28.0 13 42
FOLLOW-UP 2016 H 9 23.2 4.87 24.0 15 31
SQ_200mg 9 DAY 1 PREDOSE 9 21.8 5.67 20.0 14 32
DAY 5 96 H 9 21.7 7.25 19.0 11 34
DAY 15 336 H 9 20.3 6.82 19.0 8 28
DAY 29 672 H 9 18.4 3.61 18.0 15 27
DAY 57 1344 H 9 22.1 12.60 16.0 12 50
FOLLOW-UP 2016 H 9 22.1 6.85 21.0 13 36
SQ_50mg x 4 9 DAY 1 PREDOSE 9 30.7 10.81 28.0 17 49
DAY 6 120 H 9 32.0 13.77 35.0 15 56
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Protocol: BA1116891 Page 2 of 35Population: Safety Table 10.301 Clinical Chemistry Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Alanine SQ_50mg x 4 9 DAY 8 PREDOSE 9 32.0 14.36 33.0 13 57 Aminotrans ferase (U/L)
DAY 15 PREDOSE 9 29.2 14.16 31.0 12 58
DAY 22 PREDOSE 9 31.1 18.38 24.0 12 64
DAY 31 216 H 9 30.8 15.66 26.0 14 65
DAY 50 672 H 8 32.1 16.77 31.5 11 67
DAY 78 1344 H 8 29.4 13.95 26.5 12 60
FOLLOW-UP 2016 H 8 26.6 12.99 24.5 13 56
IM_200mg 9 DAY 1 PREDOSE 9 18.8 5.89 19.0 11 31
DAY 5 96 H 9 20.4 3.97 20.0 16 29
DAY 15 336 H 9 20.4 6.56 17.0 14 32
DAY 29 672 H 9 20.2 5.24 18.0 15 31
DAY 57 1344 H 8 25.5 10.43 25.5 15 48
FOLLOW-UP 2016 H 8 18.3 5.65 19.0 10 27
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Protocol: BA1116891 Page 3 of 35Population: Safety Table 10.301 Clinical Chemistry Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Albumin IV_200mg 9 DAY 1 PREDOSE 9 43.0 3.71 44.0 34 47 (g/L)
DAY 5 96 H 9 43.6 3.71 45.0 36 47
DAY 15 336 H 9 43.9 3.41 44.0 37 49
DAY 29 672 H 9 43.0 3.81 44.0 34 47
DAY 57 1344 H 9 43.3 3.50 43.0 36 47
FOLLOW-UP 2016 H 9 43.8 3.67 44.0 36 48
SQ_200mg 9 DAY 1 PREDOSE 9 41.9 2.32 41.0 38 45
DAY 5 96 H 9 44.2 1.79 44.0 42 48
DAY 15 336 H 9 43.6 2.24 44.0 40 47
DAY 29 672 H 9 44.7 2.29 45.0 42 49
DAY 57 1344 H 9 43.2 2.77 44.0 38 48
FOLLOW-UP 2016 H 9 41.7 1.94 41.0 38 45
SQ_50mg x 4 9 DAY 1 PREDOSE 9 43.7 2.00 43.0 41 47
DAY 6 120 H 9 45.6 2.83 45.0 42 51
DAY 8 PREDOSE 9 44.4 2.79 44.0 41 49
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Protocol: BA1116891 Page 4 of 35Population: Safety Table 10.301 Clinical Chemistry Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Albumin SQ_50mg x 4 9 DAY 15 PREDOSE 9 43.9 2.37 44.0 40 47 (g/L)
DAY 22 PREDOSE 9 43.9 1.76 44.0 41 47
DAY 31 216 H 9 45.6 2.40 46.0 40 49
DAY 50 672 H 8 44.9 2.23 45.0 41 48
DAY 78 1344 H 8 44.8 2.49 44.5 41 48
FOLLOW-UP 2016 H 8 43.9 2.17 43.5 40 47
IM_200mg 9 DAY 1 PREDOSE 9 43.9 2.76 45.0 39 47
DAY 5 96 H 9 45.1 3.33 45.0 40 51
DAY 15 336 H 9 44.7 3.08 45.0 38 49
DAY 29 672 H 9 44.0 3.28 44.0 39 48
DAY 57 1344 H 8 44.8 2.19 44.0 42 49
FOLLOW-UP 2016 H 8 44.5 2.98 43.5 41 50
Alkaline IV_200mg 9 DAY 1 PREDOSE 9 74.7 14.97 78.0 55 93 Phosphatas e (U/L)
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Protocol: BA1116891 Page 5 of 35Population: Safety Table 10.301 Clinical Chemistry Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Alkaline IV_200mg 9 DAY 5 96 H 9 79.8 18.71 79.0 57 116 Phosphatas e (U/L)
DAY 15 336 H 9 76.8 13.34 81.0 53 90
DAY 29 672 H 9 75.0 14.97 69.0 57 103
DAY 57 1344 H 9 75.9 12.15 74.0 61 99
FOLLOW-UP 2016 H 9 77.1 12.26 83.0 59 90
SQ_200mg 9 DAY 1 PREDOSE 9 65.2 14.32 67.0 40 89
DAY 5 96 H 9 64.2 11.91 62.0 43 80
DAY 15 336 H 9 64.7 11.92 65.0 41 78
DAY 29 672 H 9 65.9 11.25 69.0 40 77
DAY 57 1344 H 9 61.0 9.82 60.0 43 77
FOLLOW-UP 2016 H 9 61.9 11.25 64.0 46 81
SQ_50mg x 4 9 DAY 1 PREDOSE 9 64.8 18.45 61.0 40 102
DAY 6 120 H 9 68.7 15.43 70.0 47 91
DAY 8 PREDOSE 9 66.3 15.33 67.0 44 98
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Protocol: BA1116891 Page 6 of 35Population: Safety Table 10.301 Clinical Chemistry Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Alkaline SQ_50mg x 4 9 DAY 15 PREDOSE 9 62.7 14.65 61.0 43 84 Phosphatas e (U/L)
DAY 22 PREDOSE 9 62.2 14.94 62.0 38 85
DAY 31 216 H 9 65.2 15.25 64.0 42 94
DAY 50 672 H 8 64.5 16.63 60.0 44 91
DAY 78 1344 H 8 70.3 20.40 70.5 41 97
FOLLOW-UP 2016 H 8 64.4 14.20 65.5 39 79
IM_200mg 9 DAY 1 PREDOSE 9 72.1 19.60 65.0 45 107
DAY 5 96 H 9 79.0 24.79 68.0 53 126
DAY 15 336 H 9 76.7 22.62 66.0 48 112
DAY 29 672 H 9 75.2 23.40 63.0 50 111
DAY 57 1344 H 8 81.0 21.26 72.5 56 114
FOLLOW-UP 2016 H 8 80.6 20.11 77.0 56 111
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Protocol: BA1116891 Page 7 of 35Population: Safety Table 10.301 Clinical Chemistry Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Aspartate IV_200mg 9 DAY 1 PREDOSE 9 24.9 2.15 25.0 21 28 Aminotrans ferase (U/L)
DAY 5 96 H 9 25.2 4.38 23.0 21 33
DAY 15 336 H 9 26.8 2.68 27.0 21 29
DAY 29 672 H 9 24.6 3.28 25.0 19 29
DAY 57 1344 H 9 28.3 5.41 27.0 23 39
FOLLOW-UP 2016 H 9 26.3 4.09 26.0 21 34
SQ_200mg 9 DAY 1 PREDOSE 9 24.2 6.10 23.0 17 35
DAY 5 96 H 9 24.7 8.72 23.0 17 45
DAY 15 336 H 9 25.3 7.30 23.0 16 39
DAY 29 672 H 9 24.0 5.29 22.0 18 33
DAY 57 1344 H 9 27.2 11.42 23.0 18 49
FOLLOW-UP 2016 H 9 24.1 7.04 22.0 17 39
SQ_50mg x 4 9 DAY 1 PREDOSE 9 27.3 6.08 26.0 18 38
DAY 6 120 H 9 27.4 6.44 26.0 18 37
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Protocol: BA1116891 Page 8 of 35Population: Safety Table 10.301 Clinical Chemistry Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Aspartate SQ_50mg x 4 9 DAY 8 PREDOSE 9 27.1 6.97 25.0 15 35 Aminotrans ferase (U/L)
DAY 15 PREDOSE 9 27.2 7.28 31.0 16 34
DAY 22 PREDOSE 9 26.1 8.52 23.0 15 40
DAY 31 216 H 9 27.6 6.75 28.0 17 39
DAY 50 672 H 8 28.1 8.32 27.0 15 42
DAY 78 1344 H 8 26.9 8.04 26.5 15 40
FOLLOW-UP 2016 H 8 29.6 9.35 26.0 21 46
IM_200mg 9 DAY 1 PREDOSE 9 22.8 2.95 23.0 19 27
DAY 5 96 H 9 24.3 5.59 23.0 16 35
DAY 15 336 H 9 24.4 4.56 25.0 17 33
DAY 29 672 H 9 26.1 4.65 26.0 18 34
DAY 57 1344 H 8 38.1 26.01 30.5 20 100
FOLLOW-UP 2016 H 8 23.5 7.11 22.5 12 35
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Protocol: BA1116891 Page 9 of 35Population: Safety Table 10.301 Clinical Chemistry Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Bilirubin IV_200mg 9 DAY 1 PREDOSE 9 11.780 6.0121 8.550 5.13 22.23 (umol/L)
DAY 5 96 H 9 11.780 6.4802 10.260 3.42 25.65
DAY 15 336 H 9 15.200 14.5963 13.680 5.13 53.01
DAY 29 672 H 9 12.350 5.8477 10.260 6.84 25.65
DAY 57 1344 H 9 11.400 4.8366 10.260 5.13 20.52
FOLLOW-UP 2016 H 9 14.060 6.3280 13.680 5.13 25.65
SQ_200mg 9 DAY 1 PREDOSE 9 9.690 3.4200 8.550 5.13 15.39
DAY 5 96 H 9 13.300 4.2560 13.680 6.84 20.52
DAY 15 336 H 9 12.540 3.3114 11.970 8.55 18.81
DAY 29 672 H 9 11.210 3.5368 10.260 6.84 17.10
DAY 57 1344 H 9 12.730 2.4350 11.970 8.55 15.39
FOLLOW-UP 2016 H 9 12.730 4.1103 11.970 5.13 18.81
SQ_50mg x 4 9 DAY 1 PREDOSE 9 7.600 3.0959 6.840 3.42 11.97
DAY 6 120 H 9 9.310 1.9330 8.550 6.84 13.68
DAY 8 PREDOSE 9 7.790 2.7187 8.550 5.13 13.68
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Protocol: BA1116891 Page 10 of 35Population: Safety Table 10.301 Clinical Chemistry Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Bilirubin SQ_50mg x 4 9 DAY 15 PREDOSE 9 7.410 2.5650 6.840 3.42 11.97 (umol/L)
DAY 22 PREDOSE 9 7.410 1.7100 6.840 5.13 10.26
DAY 31 216 H 9 8.740 2.6276 6.840 6.84 13.68
DAY 50 672 H 8 10.474 2.6550 10.260 6.84 13.68
DAY 78 1344 H 8 8.764 1.6947 8.550 6.84 11.97
FOLLOW-UP 2016 H 8 8.550 3.1663 9.405 3.42 11.97
IM_200mg 9 DAY 1 PREDOSE 9 9.880 6.0323 8.550 5.13 22.23
DAY 5 96 H 9 9.690 4.6830 10.260 3.42 17.10
DAY 15 336 H 9 9.500 2.9755 8.550 5.13 13.68
DAY 29 672 H 9 11.020 5.4150 8.550 5.13 20.52
DAY 57 1344 H 8 11.115 4.9222 9.405 5.13 18.81
FOLLOW-UP 2016 H 8 10.688 6.0458 8.550 5.13 23.94
Blood Urea IV_200mg 9 DAY 1 PREDOSE 9 4.9583 1.06270 4.6410 3.213 7.140 Nitrogen (mmol/L)
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Protocol: BA1116891 Page 11 of 35Population: Safety Table 10.301 Clinical Chemistry Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Blood Urea IV_200mg 9 DAY 5 96 H 9 4.6410 1.07100 4.9980 3.213 6.426 Nitrogen (mmol/L)
DAY 15 336 H 9 4.4427 1.23811 4.6410 2.856 6.069
DAY 29 672 H 9 4.4427 1.01150 4.6410 2.499 6.069
DAY 57 1344 H 9 4.5617 1.48034 4.2840 2.499 6.426
FOLLOW-UP 2016 H 9 4.7997 0.82015 5.3550 3.570 5.712
SQ_200mg 9 DAY 1 PREDOSE 9 5.1963 1.32513 5.3550 2.499 6.783
DAY 5 96 H 9 4.1650 1.18404 4.6410 2.142 6.069
DAY 15 336 H 9 4.7203 1.53321 5.3550 2.499 6.426
DAY 29 672 H 9 4.5220 1.60650 4.6410 2.142 6.783
DAY 57 1344 H 9 4.2443 1.17654 4.2840 2.142 5.712
FOLLOW-UP 2016 H 9 4.6013 1.74387 4.2840 2.142 7.140
SQ_50mg x 4 9 DAY 1 PREDOSE 9 5.5533 0.83935 5.7120 3.927 6.783
DAY 6 120 H 9 5.3550 0.96125 4.9980 4.284 7.497
DAY 8 PREDOSE 9 5.7913 1.18104 5.7120 4.284 7.854
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Protocol: BA1116891 Page 12 of 35Population: Safety Table 10.301 Clinical Chemistry Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Blood Urea SQ_50mg x 4 9 DAY 15 PREDOSE 9 4.9980 0.91017 4.6410 3.927 6.426 Nitrogen (mmol/L)
DAY 22 PREDOSE 9 5.0773 1.69131 4.9980 2.142 8.211
DAY 31 216 H 9 4.9583 0.60386 4.9980 3.927 6.069
DAY 50 672 H 8 4.7749 0.83042 4.9980 3.213 5.712
DAY 78 1344 H 8 5.0426 0.90390 4.9980 3.927 6.426
FOLLOW-UP 2016 H 8 5.2658 1.09204 4.9980 3.927 7.497
IM_200mg 9 DAY 1 PREDOSE 9 5.4740 1.56633 5.3550 2.856 7.497
DAY 5 96 H 9 5.3550 0.85606 5.3550 3.927 6.783
DAY 15 336 H 9 5.1170 0.97768 4.6410 3.927 6.426
DAY 29 672 H 9 4.7600 1.54586 4.9980 2.856 8.211
DAY 57 1344 H 8 4.4625 0.80960 4.2840 3.570 5.355
FOLLOW-UP 2016 H 8 5.1765 1.09620 5.1765 3.570 7.140
Calcium IV_200mg 9 DAY 1 PREDOSE 9 2.3222 0.10929 2.3500 2.125 2.450 (mmol/L)
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Protocol: BA1116891 Page 13 of 35Population: Safety Table 10.301 Clinical Chemistry Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Calcium IV_200mg 9 DAY 5 96 H 9 2.3111 0.08580 2.3250 2.150 2.450 (mmol/L)
DAY 15 336 H 9 2.3167 0.06847 2.3000 2.225 2.450
DAY 29 672 H 9 2.2778 0.10112 2.3000 2.100 2.425
DAY 57 1344 H 9 2.2944 0.09336 2.3250 2.125 2.425
FOLLOW-UP 2016 H 9 2.2944 0.11711 2.3000 2.125 2.500
SQ_200mg 9 DAY 1 PREDOSE 9 2.3472 0.07949 2.3750 2.225 2.475
DAY 5 96 H 9 2.4111 0.05017 2.4250 2.350 2.475
DAY 15 336 H 9 2.3639 0.09610 2.3750 2.250 2.550
DAY 29 672 H 9 2.3889 0.04526 2.3750 2.325 2.450
DAY 57 1344 H 9 2.3528 0.06548 2.3500 2.275 2.475
FOLLOW-UP 2016 H 9 2.3167 0.06731 2.3250 2.225 2.425
SQ_50mg x 4 9 DAY 1 PREDOSE 9 2.3500 0.04507 2.3500 2.275 2.425
DAY 6 120 H 9 2.3889 0.06509 2.4000 2.300 2.500
DAY 8 PREDOSE 9 2.3722 0.06548 2.3750 2.250 2.475
DAY 15 PREDOSE 9 2.3417 0.06495 2.3500 2.250 2.425
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Protocol: BA1116891 Page 14 of 35Population: Safety Table 10.301 Clinical Chemistry Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Calcium SQ_50mg x 4 9 DAY 22 PREDOSE 9 2.3556 0.05559 2.3500 2.300 2.475 (mmol/L)
DAY 31 216 H 9 2.3889 0.07615 2.3750 2.225 2.475
DAY 50 672 H 8 2.3750 0.07196 2.3750 2.275 2.500
DAY 78 1344 H 8 2.3844 0.07433 2.4000 2.225 2.475
FOLLOW-UP 2016 H 8 2.3156 0.04989 2.3125 2.250 2.400
IM_200mg 9 DAY 1 PREDOSE 9 2.3806 0.07683 2.3750 2.300 2.575
DAY 5 96 H 9 2.3722 0.07336 2.3750 2.250 2.475
DAY 15 336 H 9 2.3500 0.07906 2.3500 2.200 2.475
DAY 29 672 H 9 2.3528 0.06548 2.3500 2.250 2.475
DAY 57 1344 H 8 2.3656 0.08958 2.3375 2.225 2.500
FOLLOW-UP 2016 H 8 2.3500 0.07319 2.3625 2.250 2.475
Carbon IV_200mg 9 DAY 1 PREDOSE 9 31.6 1.42 32.0 30 34 Dioxide (mmol/L)
DAY 5 96 H 9 31.4 1.67 31.0 30 35
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Protocol: BA1116891 Page 15 of 35Population: Safety Table 10.301 Clinical Chemistry Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Carbon IV_200mg 9 DAY 15 336 H 9 30.4 1.13 30.0 29 32 Dioxide (mmol/L)
DAY 29 672 H 9 30.9 1.45 31.0 28 33
DAY 57 1344 H 9 29.7 1.50 30.0 28 32
FOLLOW-UP 2016 H 9 30.4 1.88 31.0 26 32
SQ_200mg 9 DAY 1 PREDOSE 9 31.0 1.50 31.0 29 34
DAY 5 96 H 9 31.7 1.58 31.0 29 34
DAY 15 336 H 9 30.3 2.12 31.0 26 32
DAY 29 672 H 9 30.8 1.92 30.0 28 34
DAY 57 1344 H 9 29.9 1.76 30.0 28 33
FOLLOW-UP 2016 H 9 30.9 2.32 31.0 28 34
SQ_50mg x 4 9 DAY 1 PREDOSE 9 29.4 2.01 30.0 26 33
DAY 6 120 H 9 30.1 1.54 30.0 28 33
DAY 8 PREDOSE 9 30.2 2.11 30.0 26 33
DAY 15 PREDOSE 9 29.9 2.76 31.0 23 32
137
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Protocol: BA1116891 Page 16 of 35Population: Safety Table 10.301 Clinical Chemistry Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Carbon SQ_50mg x 4 9 DAY 22 PREDOSE 9 29.4 1.51 30.0 26 31 Dioxide (mmol/L)
DAY 31 216 H 9 30.6 2.40 31.0 26 34
DAY 50 672 H 8 29.0 2.83 29.5 23 32
DAY 78 1344 H 8 28.8 2.25 29.5 25 32
FOLLOW-UP 2016 H 8 29.1 2.17 29.0 26 32
IM_200mg 9 DAY 1 PREDOSE 9 31.3 1.66 31.0 29 34
DAY 5 96 H 9 31.2 0.83 31.0 30 32
DAY 15 336 H 9 30.3 1.87 30.0 27 33
DAY 29 672 H 9 30.8 1.92 30.0 28 34
DAY 57 1344 H 8 29.4 2.07 30.0 27 32
FOLLOW-UP 2016 H 8 30.5 2.07 31.0 28 34
Chloride IV_200mg 9 DAY 1 PREDOSE 9 104.2 2.44 103.0 102 109 (mmol/L)
DAY 5 96 H 9 104.7 2.50 104.0 101 108
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Protocol: BA1116891 Page 17 of 35Population: Safety Table 10.301 Clinical Chemistry Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Chloride IV_200mg 9 DAY 15 336 H 9 105.3 2.29 106.0 101 108 (mmol/L)
DAY 29 672 H 9 105.1 2.71 105.0 102 111
DAY 57 1344 H 9 105.2 1.99 105.0 102 108
FOLLOW-UP 2016 H 9 104.6 3.61 104.0 99 110
SQ_200mg 9 DAY 1 PREDOSE 9 104.3 1.50 104.0 102 106
DAY 5 96 H 9 103.8 1.79 104.0 101 106
DAY 15 336 H 9 103.9 3.10 104.0 99 108
DAY 29 672 H 9 103.7 1.73 104.0 101 106
DAY 57 1344 H 9 103.7 3.71 104.0 95 108
FOLLOW-UP 2016 H 9 105.1 2.09 106.0 102 108
SQ_50mg x 4 9 DAY 1 PREDOSE 9 105.9 1.45 106.0 103 108
DAY 6 120 H 9 105.1 1.90 105.0 102 108
DAY 8 PREDOSE 9 105.1 2.03 104.0 103 109
DAY 15 PREDOSE 9 105.9 2.47 105.0 103 111
DAY 22 PREDOSE 9 106.1 1.62 106.0 104 109
139
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Protocol: BA1116891 Page 18 of 35Population: Safety Table 10.301 Clinical Chemistry Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Chloride SQ_50mg x 4 9 DAY 31 216 H 9 105.4 2.07 105.0 102 110 (mmol/L)
DAY 50 672 H 8 105.6 2.00 106.0 102 108
DAY 78 1344 H 8 105.9 2.42 106.0 102 110
FOLLOW-UP 2016 H 8 106.3 1.91 106.5 103 109
IM_200mg 9 DAY 1 PREDOSE 9 104.3 1.22 104.0 103 107
DAY 5 96 H 9 104.8 1.48 104.0 103 108
DAY 15 336 H 9 104.7 2.40 105.0 101 109
DAY 29 672 H 9 104.8 2.59 106.0 101 108
DAY 57 1344 H 8 105.1 1.25 105.0 104 107
FOLLOW-UP 2016 H 8 104.8 2.12 105.5 102 107
Creatine SQ_200mg 9 DAY 57 1344 H 1 799.0 799.0 799 799 Kinase BB (U/L)
SQ_50mg x 4 9 DAY 22 PREDOSE 1 405.0 405.0 405 405
FOLLOW-UP 2016 H 1 974.0 974.0 974 974
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Protocol: BA1116891 Page 19 of 35Population: Safety Table 10.301 Clinical Chemistry Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Creatine SQ_200mg 9 DAY 57 1344 H 1 4.50 4.50 4.5 4.5 Kinase MB (ug/L)
SQ_50mg x 4 9 DAY 22 PREDOSE 1 1.10 1.10 1.1 1.1
FOLLOW-UP 2016 H 1 1.30 1.30 1.3 1.3
Creatine IM_200mg 9 DAY 57 1344 H 1 6462.0 6462.0 6462 6462 Kinase (U/L)
Creatinine IV_200mg 9 DAY 1 PREDOSE 9 81.52629 10.624598 79.56180 61.881 97.242 (umol/L)
DAY 5 96 H 9 78.57956 11.220826 79.56180 53.041 88.402
DAY 15 336 H 9 77.59731 14.510979 79.56180 53.041 97.242
DAY 29 672 H 9 74.65058 10.926780 79.56180 53.041 88.402
DAY 57 1344 H 9 77.59731 7.366833 79.56180 61.881 88.402
FOLLOW-UP 2016 H 9 75.63282 16.004859 79.56180 44.201 97.242
SQ_200mg 9 DAY 1 PREDOSE 9 80.54404 18.983002 79.56180 44.201 106.082
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Protocol: BA1116891 Page 20 of 35Population: Safety Table 10.301 Clinical Chemistry Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Creatinine SQ_200mg 9 DAY 5 96 H 9 79.56180 18.752896 79.56180 53.041 114.922 (umol/L)
DAY 15 336 H 9 78.57956 16.207033 79.56180 53.041 97.242
DAY 29 672 H 9 78.57956 12.844513 79.56180 53.041 97.242
DAY 57 1344 H 9 78.57956 19.490809 79.56180 44.201 114.922
FOLLOW-UP 2016 H 9 78.57956 20.468664 70.72160 53.041 106.082
SQ_50mg x 4 9 DAY 1 PREDOSE 9 81.52629 14.510979 88.40200 53.041 97.242
DAY 6 120 H 9 80.54404 19.490809 88.40200 44.201 97.242
DAY 8 PREDOSE 9 81.52629 16.406717 88.40200 44.201 97.242
DAY 15 PREDOSE 9 79.56180 17.118974 79.56180 44.201 106.082
DAY 22 PREDOSE 9 79.56180 17.118974 79.56180 44.201 97.242
DAY 31 216 H 9 80.54404 12.844513 79.56180 53.041 97.242
DAY 50 672 H 8 78.45678 14.516321 79.56180 53.041 97.242
DAY 78 1344 H 8 78.45678 17.321572 79.56180 53.041 106.082
FOLLOW-UP 2016 H 8 77.35175 18.752896 75.14170 53.041 106.082
IM_200mg 9 DAY 1 PREDOSE 9 76.61507 6.250965 79.56180 70.721 88.402
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Protocol: BA1116891 Page 21 of 35Population: Safety Table 10.301 Clinical Chemistry Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Creatinine IM_200mg 9 DAY 5 96 H 9 79.56180 7.655838 79.56180 70.721 88.402 (umol/L)
DAY 15 336 H 9 77.59731 8.591130 79.56180 61.881 88.402
DAY 29 672 H 9 78.57956 6.910702 79.56180 70.721 88.402
DAY 57 1344 H 8 77.35175 6.250965 79.56180 70.721 88.402
FOLLOW-UP 2016 H 8 75.14170 8.184435 75.14170 61.881 88.402
Direct IV_200mg 9 DAY 1 PREDOSE 9 3.800 2.0552 3.420 1.71 6.84 Bilirubin (umol/L)
DAY 5 96 H 9 4.180 1.7336 5.130 1.71 6.84
DAY 15 336 H 9 4.750 3.0563 5.130 1.71 11.97
DAY 29 672 H 9 3.990 2.2621 3.420 1.71 8.55
DAY 57 1344 H 9 3.990 2.0943 3.420 1.71 8.55
FOLLOW-UP 2016 H 9 4.940 2.3328 5.130 1.71 8.55
SQ_200mg 9 DAY 1 PREDOSE 9 3.420 1.2092 3.420 1.71 5.13
DAY 5 96 H 9 4.370 1.2423 5.130 1.71 5.13
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Protocol: BA1116891 Page 22 of 35Population: Safety Table 10.301 Clinical Chemistry Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Direct SQ_200mg 9 DAY 15 336 H 9 4.370 1.2423 3.420 3.42 6.84 Bilirubin (umol/L)
DAY 29 672 H 9 3.800 0.7540 3.420 3.42 5.13
DAY 57 1344 H 9 4.370 0.9012 5.130 3.42 5.13
FOLLOW-UP 2016 H 9 4.370 1.5081 5.130 1.71 6.84
SQ_50mg x 4 9 DAY 1 PREDOSE 9 2.850 1.4809 1.710 1.71 5.13
DAY 6 120 H 9 3.230 1.0276 3.420 1.71 5.13
DAY 8 PREDOSE 9 2.850 1.2092 3.420 1.71 5.13
DAY 15 PREDOSE 9 2.470 0.9012 1.710 1.71 3.42
DAY 22 PREDOSE 9 2.470 0.9012 1.710 1.71 3.42
DAY 31 216 H 9 2.850 1.4809 1.710 1.71 5.13
DAY 50 672 H 8 3.420 1.2926 3.420 1.71 5.13
DAY 78 1344 H 8 3.420 0.0000 3.420 3.42 3.42
FOLLOW-UP 2016 H 8 3.206 1.0959 3.420 1.71 5.13
IM_200mg 9 DAY 1 PREDOSE 9 3.610 2.3328 3.420 1.71 8.55
144
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Protocol: BA1116891 Page 23 of 35Population: Safety Table 10.301 Clinical Chemistry Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Direct IM_200mg 9 DAY 5 96 H 9 3.610 1.8025 3.420 1.71 6.84 Bilirubin (umol/L)
DAY 15 336 H 9 3.420 1.2092 3.420 1.71 5.13
DAY 29 672 H 9 3.610 1.5868 3.420 1.71 6.84
DAY 57 1344 H 8 3.848 1.7700 3.420 1.71 6.84
FOLLOW-UP 2016 H 8 3.634 1.6947 3.420 1.71 6.84
Gamma IV_200mg 9 DAY 1 PREDOSE 9 23.6 9.07 22.0 14 40 Glutamyl Transferas e (U/L)
DAY 5 96 H 9 23.4 8.79 22.0 13 37
DAY 15 336 H 9 22.7 8.31 20.0 14 37
DAY 29 672 H 9 21.0 7.07 20.0 12 29
DAY 57 1344 H 9 23.1 13.73 19.0 13 56
FOLLOW-UP 2016 H 9 24.9 16.66 16.0 12 65
SQ_200mg 9 DAY 1 PREDOSE 9 17.1 11.60 12.0 6 44
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Protocol: BA1116891 Page 24 of 35Population: Safety Table 10.301 Clinical Chemistry Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Gamma SQ_200mg 9 DAY 5 96 H 9 19.2 12.15 13.0 9 46 Glutamyl Transferas e (U/L)
DAY 15 336 H 9 17.9 12.40 11.0 8 46
DAY 29 672 H 9 17.4 12.17 13.0 4 46
DAY 57 1344 H 9 18.8 11.41 14.0 7 43
FOLLOW-UP 2016 H 9 17.6 11.02 12.0 9 43
SQ_50mg x 4 9 DAY 1 PREDOSE 9 21.7 11.57 16.0 11 43
DAY 6 120 H 9 21.7 10.63 18.0 9 43
DAY 8 PREDOSE 9 21.2 11.14 19.0 9 44
DAY 15 PREDOSE 9 18.6 12.12 16.0 6 47
DAY 22 PREDOSE 9 18.7 9.95 15.0 7 39
DAY 31 216 H 9 21.9 12.99 17.0 7 43
DAY 50 672 H 8 20.5 13.34 15.5 10 51
DAY 78 1344 H 8 21.9 14.52 19.5 6 53
FOLLOW-UP 2016 H 8 20.1 13.09 16.5 8 48
146
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Protocol: BA1116891 Page 25 of 35Population: Safety Table 10.301 Clinical Chemistry Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Gamma IM_200mg 9 DAY 1 PREDOSE 9 21.7 12.00 19.0 10 51 Glutamyl Transferas e (U/L)
DAY 5 96 H 9 22.6 10.98 21.0 11 49
DAY 15 336 H 9 22.8 10.34 23.0 11 47
DAY 29 672 H 9 22.0 10.34 20.0 11 47
DAY 57 1344 H 8 25.4 9.93 24.0 16 48
FOLLOW-UP 2016 H 8 25.3 11.30 21.5 19 53
Glucose IV_200mg 9 DAY 1 PREDOSE 9 4.93333 0.354771 4.99500 4.440 5.439 (mmol/L)
DAY 5 96 H 9 4.72983 0.359443 4.71750 4.051 5.439
DAY 15 336 H 9 4.93333 0.470479 5.05050 4.051 5.494
DAY 29 672 H 9 4.81000 0.330679 4.66200 4.495 5.439
DAY 57 1344 H 9 4.80383 0.383624 4.77300 4.162 5.494
FOLLOW-UP 2016 H 9 4.61267 0.495199 4.44000 4.107 5.605
SQ_200mg 9 DAY 1 PREDOSE 9 4.90250 0.374368 4.99500 4.384 5.494
147
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Protocol: BA1116891 Page 26 of 35Population: Safety Table 10.301 Clinical Chemistry Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Glucose SQ_200mg 9 DAY 5 96 H 9 4.67433 0.427005 4.66200 4.218 5.494 (mmol/L)
DAY 15 336 H 9 4.72983 0.415118 4.82850 3.885 5.161
DAY 29 672 H 9 4.69283 0.229019 4.66200 4.384 5.217
DAY 57 1344 H 9 4.68667 0.471024 4.71750 3.996 5.328
FOLLOW-UP 2016 H 9 4.91483 0.773081 4.66200 4.051 6.604
SQ_50mg x 4 9 DAY 1 PREDOSE 9 4.99500 0.430796 4.82850 4.551 5.883
DAY 6 120 H 9 5.11833 0.725639 4.99500 4.273 6.660
DAY 8 PREDOSE 9 4.82850 0.401177 4.93950 4.162 5.328
DAY 15 PREDOSE 9 4.91483 0.357653 4.88400 4.329 5.439
DAY 22 PREDOSE 9 5.26017 1.750402 4.71750 4.218 9.823
DAY 31 216 H 9 4.75450 0.374368 4.77300 4.162 5.272
DAY 50 672 H 8 4.65506 0.414728 4.55100 4.218 5.328
DAY 78 1344 H 8 4.73138 0.377295 4.71750 4.329 5.383
FOLLOW-UP 2016 H 8 4.87706 0.561650 4.82850 4.218 6.105
IM_200mg 9 DAY 1 PREDOSE 9 5.09367 0.446402 4.93950 4.384 5.827
148
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Protocol: BA1116891 Page 27 of 35Population: Safety Table 10.301 Clinical Chemistry Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Glucose IM_200mg 9 DAY 5 96 H 9 4.75450 0.686497 4.77300 3.663 6.216 (mmol/L)
DAY 15 336 H 9 4.85317 0.400323 4.93950 3.996 5.217
DAY 29 672 H 9 4.90250 0.383513 4.88400 4.107 5.328
DAY 57 1344 H 8 4.68281 0.342045 4.82850 4.051 5.050
FOLLOW-UP 2016 H 8 4.56488 0.261583 4.52325 4.218 4.939
Potassium IV_200mg 9 DAY 1 PREDOSE 9 4.17 0.194 4.10 4.0 4.6 (mmol/L)
DAY 5 96 H 9 4.09 0.220 4.10 3.7 4.4
DAY 15 336 H 9 4.20 0.292 4.20 3.8 4.7
DAY 29 672 H 9 4.21 0.190 4.20 3.8 4.4
DAY 57 1344 H 9 4.23 0.224 4.20 3.9 4.7
FOLLOW-UP 2016 H 9 4.33 0.265 4.40 3.9 4.7
SQ_200mg 9 DAY 1 PREDOSE 9 4.11 0.276 4.10 3.7 4.4
DAY 5 96 H 9 4.20 0.180 4.20 4.0 4.4
DAY 15 336 H 9 4.33 0.287 4.40 3.9 4.7
149
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Protocol: BA1116891 Page 28 of 35Population: Safety Table 10.301 Clinical Chemistry Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Potassium SQ_200mg 9 DAY 29 672 H 9 4.24 0.364 4.20 3.8 4.9 (mmol/L)
DAY 57 1344 H 9 4.01 0.237 3.90 3.7 4.4
FOLLOW-UP 2016 H 9 4.29 0.276 4.30 3.7 4.6
SQ_50mg x 4 9 DAY 1 PREDOSE 9 4.02 0.249 4.10 3.5 4.4
DAY 6 120 H 9 4.22 0.222 4.20 3.9 4.6
DAY 8 PREDOSE 9 4.14 0.194 4.20 3.7 4.3
DAY 15 PREDOSE 9 4.04 0.292 4.00 3.6 4.7
DAY 22 PREDOSE 9 4.10 0.250 4.00 3.8 4.6
DAY 31 216 H 9 4.17 0.173 4.10 3.9 4.4
DAY 50 672 H 8 4.21 0.309 4.30 3.7 4.6
DAY 78 1344 H 8 4.29 0.336 4.20 3.9 5.0
FOLLOW-UP 2016 H 8 4.24 0.192 4.25 4.0 4.5
IM_200mg 9 DAY 1 PREDOSE 9 4.12 0.291 4.10 3.7 4.7
DAY 5 96 H 9 4.20 0.274 4.10 3.9 4.7
DAY 15 336 H 9 4.14 0.279 4.10 3.8 4.6
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Protocol: BA1116891 Page 29 of 35Population: Safety Table 10.301 Clinical Chemistry Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Potassium IM_200mg 9 DAY 29 672 H 9 4.20 0.212 4.20 3.9 4.6 (mmol/L)
DAY 57 1344 H 8 4.21 0.280 4.30 3.8 4.6
FOLLOW-UP 2016 H 8 4.21 0.242 4.20 3.9 4.7
Protein/Cr SQ_200mg 9 DAY 5 96 H 1 0.030 0.030 0.03 0.03 eatinine (Ratio)
DAY 29 672 H 1 0.040 0.040 0.04 0.04
DAY 57 1344 H 1 0.020 0.020 0.02 0.02
IM_200mg 9 DAY 5 96 H 1 0.030 0.030 0.03 0.03
FOLLOW-UP 2016 H 2 0.185 0.2192 0.185 0.03 0.34
Protein IV_200mg 9 DAY 1 PREDOSE 9 71.0 7.16 72.0 54 80 (g/L)
DAY 5 96 H 9 71.2 6.28 72.0 57 77
DAY 15 336 H 9 71.7 6.48 72.0 57 81
DAY 29 672 H 9 70.1 6.83 72.0 53 76
151
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Protocol: BA1116891 Page 30 of 35Population: Safety Table 10.301 Clinical Chemistry Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Protein IV_200mg 9 DAY 57 1344 H 9 70.2 6.85 70.0 55 79 (g/L)
FOLLOW-UP 2016 H 9 70.9 7.91 73.0 54 79
SQ_200mg 9 DAY 1 PREDOSE 9 71.9 4.23 73.0 65 79
DAY 5 96 H 9 74.7 5.05 75.0 67 82
DAY 15 336 H 9 74.1 5.13 74.0 64 83
DAY 29 672 H 9 75.1 4.23 76.0 69 80
DAY 57 1344 H 9 72.7 5.07 75.0 65 80
FOLLOW-UP 2016 H 9 68.9 2.71 69.0 65 74
SQ_50mg x 4 9 DAY 1 PREDOSE 9 71.8 3.60 73.0 67 76
DAY 6 120 H 9 74.3 4.44 73.0 68 84
DAY 8 PREDOSE 9 72.9 5.11 74.0 64 82
DAY 15 PREDOSE 9 70.3 3.74 72.0 64 75
DAY 22 PREDOSE 9 70.7 3.28 69.0 67 75
DAY 31 216 H 9 74.7 4.58 75.0 65 80
DAY 50 672 H 8 72.5 3.30 73.0 68 77
152
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Protocol: BA1116891 Page 31 of 35Population: Safety Table 10.301 Clinical Chemistry Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Protein SQ_50mg x 4 9 DAY 78 1344 H 8 72.0 3.59 72.5 65 77 (g/L)
FOLLOW-UP 2016 H 8 70.3 4.13 71.0 63 75
IM_200mg 9 DAY 1 PREDOSE 9 72.4 5.13 71.0 64 81
DAY 5 96 H 9 73.3 5.83 73.0 63 81
DAY 15 336 H 9 73.8 6.30 74.0 61 84
DAY 29 672 H 9 72.1 6.39 72.0 61 80
DAY 57 1344 H 8 72.1 4.42 72.5 65 80
FOLLOW-UP 2016 H 8 72.3 4.71 71.5 67 81
Sodium IV_200mg 9 DAY 1 PREDOSE 9 141.6 1.24 142.0 139 143 (mmol/L)
DAY 5 96 H 9 141.3 1.80 141.0 139 145
DAY 15 336 H 9 141.6 2.13 141.0 139 145
DAY 29 672 H 9 141.1 1.96 141.0 138 145
DAY 57 1344 H 9 140.9 1.76 140.0 138 144
FOLLOW-UP 2016 H 9 140.8 2.05 141.0 136 143
153
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Protocol: BA1116891 Page 32 of 35Population: Safety Table 10.301 Clinical Chemistry Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Sodium SQ_200mg 9 DAY 1 PREDOSE 9 141.4 1.01 142.0 140 143 (mmol/L)
DAY 5 96 H 9 140.7 2.12 140.0 138 143
DAY 15 336 H 9 140.7 2.83 142.0 135 144
DAY 29 672 H 9 140.4 1.33 140.0 139 143
DAY 57 1344 H 9 140.6 2.35 141.0 135 143
FOLLOW-UP 2016 H 9 141.0 1.73 141.0 138 143
SQ_50mg x 4 9 DAY 1 PREDOSE 9 141.7 1.22 142.0 140 143
DAY 6 120 H 9 141.0 0.71 141.0 140 142
DAY 8 PREDOSE 9 141.0 1.73 141.0 138 143
DAY 15 PREDOSE 9 141.4 1.01 141.0 140 143
DAY 22 PREDOSE 9 141.9 1.17 142.0 140 144
DAY 31 216 H 9 141.8 1.09 142.0 140 143
DAY 50 672 H 8 141.4 1.06 141.5 140 143
DAY 78 1344 H 8 141.1 1.96 141.0 139 144
FOLLOW-UP 2016 H 8 142.6 1.92 143.0 139 145
154
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Protocol: BA1116891 Page 33 of 35Population: Safety Table 10.301 Clinical Chemistry Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Sodium IM_200mg 9 DAY 1 PREDOSE 9 141.9 1.05 142.0 141 144 (mmol/L)
DAY 5 96 H 9 141.8 1.79 142.0 140 145
DAY 15 336 H 9 141.4 1.94 141.0 138 144
DAY 29 672 H 9 141.1 2.09 140.0 139 144
DAY 57 1344 H 8 141.5 1.20 141.5 140 143
FOLLOW-UP 2016 H 8 141.4 1.60 141.0 139 144
Thyrotropi SQ_200mg 9 DAY 29 672 H 1 1.9400 1.9400 1.940 1.940 n (mIU/L)
Thyroxine, SQ_200mg 9 DAY 29 672 H 1 15.4440 15.4440 15.444 15.444 Free (pmol/L)
Triiodothy SQ_200mg 9 DAY 29 672 H 1 0.04620 0.04620 0.046 0.046 ronine, Free (nmol/L)
155
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Protocol: BA1116891 Page 34 of 35Population: Safety Table 10.301 Clinical Chemistry Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Urate IV_200mg 9 DAY 1 PREDOSE 9 331.878 80.4779 321.300 208.25 464.10 (umol/L)
DAY 5 96 H 9 341.794 57.5423 357.000 226.10 404.60
DAY 15 336 H 9 335.844 76.3197 362.950 238.00 452.20
DAY 29 672 H 9 329.233 55.0174 303.450 243.95 410.55
DAY 57 1344 H 9 319.978 56.4292 315.350 226.10 404.60
FOLLOW-UP 2016 H 9 331.217 93.5116 339.150 226.10 487.90
SQ_200mg 9 DAY 1 PREDOSE 9 362.289 63.1404 357.000 279.65 464.10
DAY 5 96 H 9 349.728 53.3660 333.200 279.65 440.30
DAY 15 336 H 9 349.728 60.3696 327.250 285.60 476.00
DAY 29 672 H 9 351.050 69.0687 327.250 267.75 481.95
DAY 57 1344 H 9 345.100 62.4750 321.300 285.60 458.15
FOLLOW-UP 2016 H 9 364.272 27.5533 362.950 327.25 404.60
SQ_50mg x 4 9 DAY 1 PREDOSE 9 302.789 59.0854 309.400 214.20 392.70
DAY 6 120 H 9 304.111 48.1035 315.350 202.30 368.90
DAY 8 PREDOSE 9 309.400 57.9934 327.250 184.45 392.70
156
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Protocol: BA1116891 Page 35 of 35Population: Safety Table 10.301 Clinical Chemistry Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ----------------------------------------------------------------------------------------------------- Urate SQ_50mg x 4 9 DAY 15 PREDOSE 9 277.667 51.0973 285.600 184.45 339.15 (umol/L)
DAY 22 PREDOSE 9 296.839 54.4063 297.500 196.35 368.90
DAY 31 216 H 9 289.567 57.3025 309.400 166.60 362.95
DAY 50 672 H 8 310.887 72.9937 318.325 184.45 404.60
DAY 78 1344 H 8 311.631 68.9450 327.250 220.15 380.80
FOLLOW-UP 2016 H 8 325.019 61.0056 327.250 238.00 404.60
IM_200mg 9 DAY 1 PREDOSE 9 266.428 46.9238 273.700 172.55 309.40
DAY 5 96 H 9 288.244 59.7309 273.700 202.30 398.65
DAY 15 336 H 9 288.244 51.2798 321.300 220.15 357.00
DAY 29 672 H 9 286.261 41.1631 297.500 202.30 327.25
DAY 57 1344 H 8 287.088 41.6803 288.575 220.15 345.10
FOLLOW-UP 2016 H 8 302.706 64.9798 294.525 220.15 392.70
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Protocol: BA1116891 Page 1 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Basophils IV_200mg 9 DAY 1 PREDOSE 9 0.01 0.033 0.00 0.0 0.1 (10^9/L)
DAY 5 96 H 9 0.02 0.044 0.00 0.0 0.1
DAY 15 336 H 9 0.00 0.000 0.00 0.0 0.0
DAY 29 672 H 9 0.02 0.044 0.00 0.0 0.1
DAY 57 1344 H 9 0.01 0.033 0.00 0.0 0.1
FOLLOW-UP 2016 H 9 0.01 0.033 0.00 0.0 0.1
SQ_200mg 9 DAY 1 PREDOSE 9 0.00 0.000 0.00 0.0 0.0
DAY 5 96 H 9 0.01 0.033 0.00 0.0 0.1
DAY 15 336 H 9 0.00 0.000 0.00 0.0 0.0
DAY 29 672 H 9 0.01 0.033 0.00 0.0 0.1
DAY 57 1344 H 9 0.00 0.000 0.00 0.0 0.0
FOLLOW-UP 2016 H 9 0.01 0.033 0.00 0.0 0.1
SQ_50mg x 4 9 DAY 1 PREDOSE 9 0.00 0.000 0.00 0.0 0.0
DAY 6 120 H 9 0.00 0.000 0.00 0.0 0.0
DAY 8 PREDOSE 9 0.00 0.000 0.00 0.0 0.0
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Protocol: BA1116891 Page 2 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Basophils SQ_50mg x 4 9 DAY 15 PREDOSE 9 0.00 0.000 0.00 0.0 0.0 (10^9/L)
DAY 22 PREDOSE 9 0.01 0.033 0.00 0.0 0.1
DAY 31 216 H 9 0.00 0.000 0.00 0.0 0.0
DAY 50 672 H 8 0.00 0.000 0.00 0.0 0.0
DAY 78 1344 H 8 0.00 0.000 0.00 0.0 0.0
FOLLOW-UP 2016 H 8 0.00 0.000 0.00 0.0 0.0
IM_200mg 9 DAY 1 PREDOSE 9 0.00 0.000 0.00 0.0 0.0
DAY 5 96 H 9 0.00 0.000 0.00 0.0 0.0
DAY 15 336 H 9 0.01 0.033 0.00 0.0 0.1
DAY 29 672 H 9 0.01 0.033 0.00 0.0 0.1
DAY 57 1344 H 8 0.01 0.035 0.00 0.0 0.1
FOLLOW-UP 2016 H 8 0.00 0.000 0.00 0.0 0.0
Basophils/Le IV_200mg 9 DAY 1 PREDOSE 9 0.0053 0.00187 0.0050 0.002 0.008 ukocytes (1)
DAY 5 96 H 9 0.0056 0.00296 0.0040 0.003 0.012
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Protocol: BA1116891 Page 3 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Basophils/Le IV_200mg 9 DAY 15 336 H 9 0.0044 0.00167 0.0040 0.003 0.008 ukocytes (1)
DAY 29 672 H 9 0.0068 0.00286 0.0070 0.003 0.011
DAY 57 1344 H 9 0.0061 0.00440 0.0040 0.002 0.014
FOLLOW-UP 2016 H 9 0.0053 0.00194 0.0050 0.003 0.009
SQ_200mg 9 DAY 1 PREDOSE 9 0.0046 0.00194 0.0040 0.003 0.009
DAY 5 96 H 9 0.0051 0.00276 0.0040 0.002 0.010
DAY 15 336 H 9 0.0029 0.00183 0.0030 0.000 0.005
DAY 29 672 H 9 0.0059 0.00190 0.0050 0.004 0.010
DAY 57 1344 H 9 0.0043 0.00265 0.0040 0.000 0.010
FOLLOW-UP 2016 H 9 0.0060 0.00541 0.0050 0.002 0.020
SQ_50mg x 4 9 DAY 1 PREDOSE 9 0.0059 0.00220 0.0050 0.004 0.010
DAY 6 120 H 9 0.0049 0.00196 0.0050 0.002 0.009
DAY 8 PREDOSE 9 0.0059 0.00285 0.0060 0.002 0.011
DAY 15 PREDOSE 9 0.0059 0.00310 0.0060 0.003 0.012
DAY 22 PREDOSE 9 0.0066 0.00559 0.0050 0.002 0.020
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Protocol: BA1116891 Page 4 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Basophils/Le SQ_50mg x 4 9 DAY 31 216 H 9 0.0051 0.00302 0.0040 0.002 0.012 ukocytes (1)
DAY 50 672 H 8 0.0049 0.00223 0.0045 0.003 0.010
DAY 78 1344 H 8 0.0050 0.00245 0.0045 0.002 0.010
FOLLOW-UP 2016 H 8 0.0058 0.00362 0.0050 0.002 0.013
IM_200mg 9 DAY 1 PREDOSE 9 0.0051 0.00190 0.0050 0.002 0.008
DAY 5 96 H 9 0.0043 0.00141 0.0040 0.002 0.006
DAY 15 336 H 9 0.0057 0.00474 0.0040 0.002 0.017
DAY 29 672 H 9 0.0051 0.00369 0.0040 0.001 0.014
DAY 57 1344 H 8 0.0054 0.00475 0.0050 0.001 0.016
FOLLOW-UP 2016 H 8 0.0053 0.00403 0.0040 0.002 0.014
Eosinophils IV_200mg 9 DAY 1 PREDOSE 9 0.13 0.050 0.10 0.1 0.2 (10^9/L)
DAY 5 96 H 9 0.14 0.073 0.10 0.1 0.3
DAY 15 336 H 9 0.12 0.097 0.10 0.0 0.3
DAY 29 672 H 9 0.14 0.088 0.10 0.0 0.3
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Protocol: BA1116891 Page 5 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Eosinophils IV_200mg 9 DAY 57 1344 H 9 0.14 0.101 0.10 0.0 0.3 (10^9/L)
FOLLOW-UP 2016 H 9 0.13 0.100 0.10 0.0 0.3
SQ_200mg 9 DAY 1 PREDOSE 9 0.29 0.237 0.20 0.1 0.9
DAY 5 96 H 9 0.22 0.192 0.20 0.1 0.7
DAY 15 336 H 9 0.19 0.105 0.20 0.1 0.4
DAY 29 672 H 9 0.21 0.226 0.10 0.1 0.8
DAY 57 1344 H 9 0.21 0.127 0.20 0.1 0.5
FOLLOW-UP 2016 H 9 0.23 0.166 0.20 0.1 0.6
SQ_50mg x 4 9 DAY 1 PREDOSE 9 0.20 0.122 0.20 0.0 0.4
DAY 6 120 H 9 0.14 0.101 0.10 0.0 0.3
DAY 8 PREDOSE 9 0.18 0.097 0.20 0.0 0.3
DAY 15 PREDOSE 9 0.21 0.105 0.20 0.1 0.4
DAY 22 PREDOSE 9 0.22 0.148 0.20 0.0 0.5
DAY 31 216 H 9 0.17 0.122 0.20 0.0 0.3
DAY 50 672 H 8 0.15 0.053 0.15 0.1 0.2
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Protocol: BA1116891 Page 6 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Eosinophils SQ_50mg x 4 9 DAY 78 1344 H 8 0.23 0.139 0.20 0.1 0.5 (10^9/L)
FOLLOW-UP 2016 H 8 0.15 0.120 0.15 0.0 0.3
IM_200mg 9 DAY 1 PREDOSE 9 0.18 0.083 0.20 0.1 0.3
DAY 5 96 H 9 0.14 0.113 0.10 0.0 0.4
DAY 15 336 H 9 0.17 0.141 0.10 0.0 0.5
DAY 29 672 H 9 0.12 0.083 0.10 0.0 0.2
DAY 57 1344 H 8 0.16 0.106 0.15 0.0 0.3
FOLLOW-UP 2016 H 8 0.16 0.092 0.20 0.0 0.3
Eosinophils/ IV_200mg 9 DAY 1 PREDOSE 9 0.0249 0.01159 0.0220 0.012 0.042 Leukocytes (1)
DAY 5 96 H 9 0.0261 0.01793 0.0210 0.010 0.059
DAY 15 336 H 9 0.0222 0.01660 0.0180 0.004 0.054
DAY 29 672 H 9 0.0274 0.01781 0.0210 0.010 0.065
DAY 57 1344 H 9 0.0283 0.01676 0.0240 0.007 0.063
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Protocol: BA1116891 Page 7 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Eosinophils/ IV_200mg 9 FOLLOW-UP 2016 H 9 0.0241 0.01621 0.0220 0.007 0.051 Leukocytes (1)
SQ_200mg 9 DAY 1 PREDOSE 9 0.0458 0.03713 0.0310 0.012 0.135
DAY 5 96 H 9 0.0404 0.03741 0.0360 0.008 0.135
DAY 15 336 H 9 0.0311 0.02059 0.0240 0.010 0.080
DAY 29 672 H 9 0.0347 0.03035 0.0270 0.010 0.112
DAY 57 1344 H 9 0.0369 0.03252 0.0290 0.015 0.120
FOLLOW-UP 2016 H 9 0.0389 0.03157 0.0300 0.015 0.120
SQ_50mg x 4 9 DAY 1 PREDOSE 9 0.0368 0.02607 0.0270 0.009 0.072
DAY 6 120 H 9 0.0333 0.02137 0.0370 0.007 0.071
DAY 8 PREDOSE 9 0.0374 0.02149 0.0430 0.009 0.076
DAY 15 PREDOSE 9 0.0399 0.02621 0.0430 0.009 0.091
DAY 22 PREDOSE 9 0.0367 0.02086 0.0370 0.007 0.067
DAY 31 216 H 9 0.0332 0.02126 0.0230 0.007 0.058
DAY 50 672 H 8 0.0258 0.00848 0.0265 0.012 0.040
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Protocol: BA1116891 Page 8 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Eosinophils/ SQ_50mg x 4 9 DAY 78 1344 H 8 0.0406 0.03348 0.0300 0.010 0.110 Leukocytes (1)
FOLLOW-UP 2016 H 8 0.0281 0.02461 0.0205 0.005 0.077
IM_200mg 9 DAY 1 PREDOSE 9 0.0272 0.01419 0.0300 0.010 0.046
DAY 5 96 H 9 0.0276 0.02192 0.0220 0.008 0.080
DAY 15 336 H 9 0.0313 0.03158 0.0240 0.007 0.110
DAY 29 672 H 9 0.0260 0.01547 0.0240 0.008 0.055
DAY 57 1344 H 8 0.0329 0.02114 0.0295 0.012 0.073
FOLLOW-UP 2016 H 8 0.0324 0.02025 0.0305 0.012 0.071
Hematocrit IV_200mg 9 DAY 1 PREDOSE 9 0.4454 0.03211 0.4470 0.406 0.500 (1)
DAY 5 96 H 9 0.4383 0.02165 0.4350 0.401 0.473
DAY 15 336 H 9 0.4410 0.03351 0.4400 0.398 0.504
DAY 29 672 H 9 0.4402 0.02393 0.4380 0.409 0.483
DAY 57 1344 H 9 0.4490 0.02800 0.4400 0.417 0.496
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Protocol: BA1116891 Page 9 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Hematocrit IV_200mg 9 FOLLOW-UP 2016 H 9 0.4517 0.03391 0.4530 0.407 0.525 (1)
SQ_200mg 9 DAY 1 PREDOSE 9 0.4257 0.01527 0.4220 0.396 0.447
DAY 5 96 H 9 0.4441 0.01985 0.4500 0.409 0.468
DAY 15 336 H 9 0.4366 0.02064 0.4370 0.410 0.468
DAY 29 672 H 9 0.4403 0.01728 0.4420 0.412 0.465
DAY 57 1344 H 9 0.4427 0.02354 0.4330 0.418 0.481
FOLLOW-UP 2016 H 9 0.4440 0.02978 0.4430 0.393 0.496
SQ_50mg x 4 9 DAY 1 PREDOSE 9 0.4438 0.02964 0.4510 0.383 0.495
DAY 6 120 H 9 0.4567 0.02971 0.4680 0.389 0.486
DAY 8 PREDOSE 9 0.4490 0.03012 0.4580 0.374 0.474
DAY 15 PREDOSE 9 0.4377 0.02251 0.4410 0.401 0.464
DAY 22 PREDOSE 9 0.4317 0.03206 0.4310 0.372 0.470
DAY 31 216 H 9 0.4484 0.03810 0.4590 0.387 0.498
DAY 50 672 H 8 0.4475 0.02115 0.4520 0.406 0.477
DAY 78 1344 H 8 0.4628 0.02855 0.4680 0.408 0.500
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Protocol: BA1116891 Page 10 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Hematocrit SQ_50mg x 4 9 FOLLOW-UP 2016 H 8 0.4504 0.03898 0.4610 0.373 0.498 (1)
IM_200mg 9 DAY 1 PREDOSE 9 0.4471 0.01443 0.4530 0.422 0.462
DAY 5 96 H 9 0.4416 0.02020 0.4450 0.409 0.465
DAY 15 336 H 9 0.4451 0.01608 0.4450 0.417 0.469
DAY 29 672 H 9 0.4407 0.01755 0.4380 0.422 0.483
DAY 57 1344 H 8 0.4508 0.01585 0.4470 0.432 0.474
FOLLOW-UP 2016 H 8 0.4456 0.01496 0.4515 0.420 0.461
Hemoglobin IV_200mg 9 DAY 1 PREDOSE 9 150.0 9.54 149.0 140 168 (g/L)
DAY 5 96 H 9 151.9 7.36 152.0 140 164
DAY 15 336 H 9 150.2 11.64 148.0 134 173
DAY 29 672 H 9 150.9 10.60 149.0 139 170
DAY 57 1344 H 9 153.6 10.94 154.0 138 171
FOLLOW-UP 2016 H 9 151.8 13.72 149.0 134 180
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Protocol: BA1116891 Page 11 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Hemoglobin SQ_200mg 9 DAY 1 PREDOSE 9 145.3 5.98 145.0 137 155 (g/L)
DAY 5 96 H 9 152.9 7.88 153.0 141 167
DAY 15 336 H 9 148.6 6.58 147.0 141 158
DAY 29 672 H 9 150.4 4.80 148.0 147 161
DAY 57 1344 H 9 152.2 9.11 151.0 139 167
FOLLOW-UP 2016 H 9 151.0 10.59 153.0 136 164
SQ_50mg x 4 9 DAY 1 PREDOSE 9 149.3 9.54 151.0 130 162
DAY 6 120 H 9 155.2 10.39 159.0 134 171
DAY 8 PREDOSE 9 152.0 11.34 156.0 125 164
DAY 15 PREDOSE 9 148.0 7.91 152.0 134 156
DAY 22 PREDOSE 9 146.6 11.17 149.0 127 161
DAY 31 216 H 9 151.7 12.99 154.0 130 170
DAY 50 672 H 8 151.3 8.84 154.5 135 160
DAY 78 1344 H 8 154.8 12.42 155.0 130 171
FOLLOW-UP 2016 H 8 150.4 13.39 152.0 129 170
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Protocol: BA1116891 Page 12 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Hemoglobin IM_200mg 9 DAY 1 PREDOSE 9 150.6 4.48 150.0 143 157 (g/L)
DAY 5 96 H 9 150.4 7.62 148.0 137 160
DAY 15 336 H 9 150.7 4.47 150.0 142 157
DAY 29 672 H 9 148.1 7.79 146.0 136 164
DAY 57 1344 H 8 153.4 7.67 153.5 144 164
FOLLOW-UP 2016 H 8 149.4 5.80 149.0 141 158
Lymphocytes IV_200mg 9 DAY 1 PREDOSE 9 2.04 0.425 2.00 1.5 2.8 (10^9/L)
DAY 5 96 H 9 2.02 0.552 1.80 1.6 3.3
DAY 15 336 H 9 1.87 0.505 1.70 1.2 2.7
DAY 29 672 H 9 1.86 0.461 1.80 1.3 2.7
DAY 57 1344 H 9 1.89 0.535 1.70 1.3 2.6
FOLLOW-UP 2016 H 9 1.94 0.602 1.70 1.2 2.9
SQ_200mg 9 DAY 1 PREDOSE 9 2.18 0.531 2.30 1.4 2.9
DAY 5 96 H 9 1.83 0.512 1.60 1.3 2.7
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Protocol: BA1116891 Page 13 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Lymphocytes SQ_200mg 9 DAY 15 336 H 9 1.89 0.619 1.70 1.3 3.1 (10^9/L)
DAY 29 672 H 9 1.89 0.537 1.80 1.4 2.8
DAY 57 1344 H 9 1.92 0.698 1.80 1.1 3.1
FOLLOW-UP 2016 H 9 1.83 0.656 1.70 0.8 3.2
SQ_50mg x 4 9 DAY 1 PREDOSE 9 2.22 0.531 2.10 1.4 3.1
DAY 6 120 H 9 1.79 0.426 1.90 1.3 2.4
DAY 8 PREDOSE 9 2.23 0.587 2.00 1.8 3.7
DAY 15 PREDOSE 9 2.33 0.424 2.20 1.5 2.9
DAY 22 PREDOSE 9 2.32 0.507 2.10 1.9 3.5
DAY 31 216 H 9 2.01 0.376 1.90 1.6 2.8
DAY 50 672 H 8 1.96 0.389 1.90 1.6 2.7
DAY 78 1344 H 8 2.11 0.422 2.10 1.6 2.8
FOLLOW-UP 2016 H 8 1.94 0.307 1.85 1.6 2.4
IM_200mg 9 DAY 1 PREDOSE 9 2.09 0.643 2.10 1.0 2.9
DAY 5 96 H 9 1.87 0.510 1.70 1.3 2.8
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Protocol: BA1116891 Page 14 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Lymphocytes IM_200mg 9 DAY 15 336 H 9 1.78 0.380 1.70 1.3 2.4 (10^9/L)
DAY 29 672 H 9 1.78 0.406 1.80 1.1 2.3
DAY 57 1344 H 8 1.94 0.463 1.85 1.3 2.8
FOLLOW-UP 2016 H 8 1.85 0.571 1.65 1.3 2.8
Lymphocytes SQ_200mg 9 DAY 15 336 H 1 0.0 0.0 0 0 Atypical (10^9/L)
Lymphocytes SQ_200mg 9 DAY 15 336 H 1 0.010 0.010 0.01 0.01 Atypical/Leu kocytes (1)
Lymphocytes/ IV_200mg 9 DAY 1 PREDOSE 9 0.3812 0.06778 0.3860 0.294 0.477 Leukocytes (1)
DAY 5 96 H 9 0.3710 0.06090 0.3660 0.308 0.497
DAY 15 336 H 9 0.3028 0.08745 0.3360 0.146 0.401
DAY 29 672 H 9 0.3729 0.05075 0.3620 0.327 0.484
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Protocol: BA1116891 Page 15 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Lymphocytes/ IV_200mg 9 DAY 57 1344 H 9 0.3647 0.10094 0.3560 0.193 0.586 Leukocytes (1)
FOLLOW-UP 2016 H 9 0.3303 0.07970 0.3180 0.201 0.504
SQ_200mg 9 DAY 1 PREDOSE 9 0.3363 0.07341 0.3000 0.244 0.465
DAY 5 96 H 9 0.3097 0.06941 0.2990 0.198 0.426
DAY 15 336 H 9 0.3324 0.10718 0.3020 0.194 0.510
DAY 29 672 H 9 0.3349 0.08319 0.3350 0.243 0.480
DAY 57 1344 H 9 0.3102 0.09172 0.3200 0.142 0.414
FOLLOW-UP 2016 H 9 0.2937 0.07240 0.2940 0.165 0.386
SQ_50mg x 4 9 DAY 1 PREDOSE 9 0.4034 0.08743 0.4130 0.263 0.513
DAY 6 120 H 9 0.3614 0.07518 0.3840 0.206 0.476
DAY 8 PREDOSE 9 0.3948 0.07545 0.4320 0.283 0.471
DAY 15 PREDOSE 9 0.4059 0.09263 0.3690 0.298 0.549
DAY 22 PREDOSE 9 0.3733 0.08586 0.3360 0.286 0.515
DAY 31 216 H 9 0.3958 0.07671 0.3940 0.319 0.563
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Protocol: BA1116891 Page 16 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Lymphocytes/ SQ_50mg x 4 9 DAY 50 672 H 8 0.3699 0.07672 0.3705 0.261 0.504 Leukocytes (1)
DAY 78 1344 H 8 0.3703 0.03993 0.3540 0.326 0.434
FOLLOW-UP 2016 H 8 0.3679 0.06949 0.3505 0.304 0.479
IM_200mg 9 DAY 1 PREDOSE 9 0.3703 0.11408 0.3820 0.161 0.542
DAY 5 96 H 9 0.3681 0.08418 0.3930 0.235 0.511
DAY 15 336 H 9 0.3489 0.08806 0.3230 0.216 0.494
DAY 29 672 H 9 0.3760 0.09169 0.4210 0.241 0.514
DAY 57 1344 H 8 0.3954 0.09418 0.4275 0.229 0.526
FOLLOW-UP 2016 H 8 0.3698 0.09179 0.3670 0.229 0.527
Ery. Mean IV_200mg 9 DAY 1 PREDOSE 9 29.73 1.477 29.90 26.7 31.9 Corpuscular Hemoglobin (pg)
DAY 5 96 H 9 30.51 1.346 30.60 27.4 31.9
DAY 15 336 H 9 30.18 1.620 30.70 26.4 31.9
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Protocol: BA1116891 Page 17 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Ery. Mean IV_200mg 9 DAY 29 672 H 9 30.26 1.415 30.80 27.0 31.5 Corpuscular Hemoglobin (pg)
DAY 57 1344 H 9 29.99 1.352 30.00 27.1 31.5
FOLLOW-UP 2016 H 9 30.13 1.388 30.10 27.1 31.4
SQ_200mg 9 DAY 1 PREDOSE 9 30.52 1.460 30.60 27.6 32.6
DAY 5 96 H 9 31.00 1.708 30.80 27.8 33.9
DAY 15 336 H 9 30.64 1.426 30.70 28.1 32.9
DAY 29 672 H 9 30.72 1.456 31.00 28.1 32.7
DAY 57 1344 H 9 30.98 1.527 31.30 28.2 33.3
FOLLOW-UP 2016 H 9 31.30 1.527 31.80 28.4 33.2
SQ_50mg x 4 9 DAY 1 PREDOSE 9 29.39 1.419 29.30 27.0 31.2
DAY 6 120 H 9 29.82 1.504 30.10 27.3 31.5
DAY 8 PREDOSE 9 29.66 1.599 29.80 27.1 31.7
DAY 15 PREDOSE 9 29.56 1.526 30.00 26.9 31.4
DAY 22 PREDOSE 9 29.60 1.530 30.00 27.0 31.7
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Protocol: BA1116891 Page 18 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Ery. Mean SQ_50mg x 4 9 DAY 31 216 H 9 29.67 1.309 30.10 27.1 31.1 Corpuscular Hemoglobin (pg)
DAY 50 672 H 8 29.58 1.614 30.15 26.7 31.1
DAY 78 1344 H 8 29.39 1.503 29.70 26.7 31.1
FOLLOW-UP 2016 H 8 29.71 1.678 29.90 27.1 31.9
IM_200mg 9 DAY 1 PREDOSE 9 30.39 1.697 30.20 28.1 33.0
DAY 5 96 H 9 30.84 1.913 30.50 28.6 33.6
DAY 15 336 H 9 30.57 1.551 30.20 28.6 33.3
DAY 29 672 H 9 30.49 1.472 30.30 28.6 33.0
DAY 57 1344 H 8 30.89 1.801 30.35 28.8 33.5
FOLLOW-UP 2016 H 8 30.89 1.730 30.65 28.3 33.9
Ery. Mean IV_200mg 9 DAY 1 PREDOSE 9 336.7 7.14 337.0 324 348 Corpuscular HGB Concentratio n (g/L)
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CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 19 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Ery. Mean IV_200mg 9 DAY 5 96 H 9 346.4 5.46 347.0 334 352 Corpuscular HGB Concentratio n (g/L)
DAY 15 336 H 9 340.8 9.24 344.0 320 349
DAY 29 672 H 9 342.6 7.20 342.0 331 352
DAY 57 1344 H 9 341.7 5.85 342.0 331 350
FOLLOW-UP 2016 H 9 335.8 9.52 331.0 324 354
SQ_200mg 9 DAY 1 PREDOSE 9 341.4 10.27 342.0 326 360
DAY 5 96 H 9 344.2 8.67 345.0 328 358
DAY 15 336 H 9 340.9 11.10 339.0 324 356
DAY 29 672 H 9 341.6 9.41 343.0 328 358
DAY 57 1344 H 9 343.7 8.60 342.0 332 357
FOLLOW-UP 2016 H 9 340.1 14.92 339.0 313 361
SQ_50mg x 4 9 DAY 1 PREDOSE 9 337.0 7.63 340.0 323 347
DAY 6 120 H 9 339.4 7.35 339.0 325 351
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Protocol: BA1116891 Page 20 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Ery. Mean SQ_50mg x 4 9 DAY 8 PREDOSE 9 338.1 7.11 337.0 328 352 Corpuscular HGB Concentratio n (g/L)
DAY 15 PREDOSE 9 338.4 6.19 338.0 330 351
DAY 22 PREDOSE 9 339.3 5.77 342.0 328 347
DAY 31 216 H 9 337.7 5.81 336.0 332 351
DAY 50 672 H 8 338.0 8.25 338.0 325 348
DAY 78 1344 H 8 333.5 8.57 335.0 318 343
FOLLOW-UP 2016 H 8 333.5 10.60 337.0 318 345
IM_200mg 9 DAY 1 PREDOSE 9 337.0 14.39 340.0 312 355
DAY 5 96 H 9 340.3 10.87 340.0 327 360
DAY 15 336 H 9 338.4 10.57 345.0 321 352
DAY 29 672 H 9 336.2 9.76 334.0 318 350
DAY 57 1344 H 8 340.1 12.70 337.5 324 362
FOLLOW-UP 2016 H 8 335.4 13.37 333.0 321 361
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Protocol: BA1116891 Page 21 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Ery. Mean IV_200mg 9 DAY 1 PREDOSE 9 88.21 3.146 88.80 82.4 91.6 Corpuscular Volume (fL)
DAY 5 96 H 9 88.03 3.066 89.00 81.8 91.2
DAY 15 336 H 9 88.56 3.194 89.20 82.6 92.7
DAY 29 672 H 9 88.30 3.523 89.60 81.8 92.6
DAY 57 1344 H 9 87.81 3.756 88.30 80.7 92.3
FOLLOW-UP 2016 H 9 89.80 4.619 90.90 83.7 95.3
SQ_200mg 9 DAY 1 PREDOSE 9 89.43 4.577 88.20 81.6 94.1
DAY 5 96 H 9 90.01 4.139 89.70 82.7 94.8
DAY 15 336 H 9 89.92 3.689 90.70 82.9 94.3
DAY 29 672 H 9 89.97 4.169 90.00 82.0 94.4
DAY 57 1344 H 9 90.16 4.241 91.10 82.6 96.4
FOLLOW-UP 2016 H 9 92.14 5.485 92.70 80.9 99.7
SQ_50mg x 4 9 DAY 1 PREDOSE 9 87.24 4.238 88.90 80.0 91.7
DAY 6 120 H 9 87.88 4.101 89.60 80.8 91.5
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Protocol: BA1116891 Page 22 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Ery. Mean SQ_50mg x 4 9 DAY 8 PREDOSE 9 87.66 4.374 89.20 80.5 92.0 Corpuscular Volume (fL)
DAY 15 PREDOSE 9 87.36 4.052 89.00 79.7 92.1
DAY 22 PREDOSE 9 87.27 4.168 88.80 80.6 92.7
DAY 31 216 H 9 87.92 4.314 89.50 80.3 92.8
DAY 50 672 H 8 87.45 4.518 88.85 79.5 92.3
DAY 78 1344 H 8 88.11 5.071 89.55 80.9 96.2
FOLLOW-UP 2016 H 8 89.11 5.169 90.65 80.8 95.5
IM_200mg 9 DAY 1 PREDOSE 9 90.24 4.790 90.80 82.4 96.9
DAY 5 96 H 9 90.58 4.881 90.60 83.1 99.0
DAY 15 336 H 9 90.38 4.716 91.30 82.7 96.7
DAY 29 672 H 9 90.73 4.920 90.80 83.1 97.2
DAY 57 1344 H 8 90.81 4.341 91.10 82.1 96.2
FOLLOW-UP 2016 H 8 92.10 4.334 92.40 85.7 97.6
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Protocol: BA1116891 Page 23 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Monocytes IV_200mg 9 DAY 1 PREDOSE 9 0.37 0.050 0.40 0.3 0.4 (10^9/L)
DAY 5 96 H 9 0.32 0.067 0.30 0.2 0.4
DAY 15 336 H 9 0.39 0.093 0.40 0.3 0.6
DAY 29 672 H 9 0.30 0.071 0.30 0.2 0.4
DAY 57 1344 H 9 0.33 0.112 0.30 0.2 0.6
FOLLOW-UP 2016 H 9 0.41 0.105 0.40 0.3 0.6
SQ_200mg 9 DAY 1 PREDOSE 9 0.43 0.122 0.50 0.2 0.6
DAY 5 96 H 9 0.38 0.083 0.40 0.3 0.5
DAY 15 336 H 9 0.40 0.112 0.40 0.2 0.6
DAY 29 672 H 9 0.37 0.141 0.40 0.1 0.6
DAY 57 1344 H 9 0.46 0.101 0.50 0.3 0.6
FOLLOW-UP 2016 H 9 0.36 0.124 0.30 0.2 0.5
SQ_50mg x 4 9 DAY 1 PREDOSE 9 0.33 0.071 0.30 0.2 0.4
DAY 6 120 H 9 0.27 0.100 0.30 0.1 0.4
DAY 8 PREDOSE 9 0.33 0.071 0.30 0.2 0.4
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Protocol: BA1116891 Page 24 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Monocytes SQ_50mg x 4 9 DAY 15 PREDOSE 9 0.33 0.071 0.30 0.2 0.4 (10^9/L)
DAY 22 PREDOSE 9 0.37 0.087 0.40 0.2 0.5
DAY 31 216 H 9 0.29 0.078 0.30 0.2 0.4
DAY 50 672 H 8 0.31 0.064 0.30 0.2 0.4
DAY 78 1344 H 8 0.35 0.107 0.40 0.2 0.5
FOLLOW-UP 2016 H 8 0.35 0.107 0.30 0.2 0.5
IM_200mg 9 DAY 1 PREDOSE 9 0.33 0.071 0.30 0.2 0.4
DAY 5 96 H 9 0.28 0.067 0.30 0.2 0.4
DAY 15 336 H 9 0.33 0.071 0.30 0.3 0.5
DAY 29 672 H 9 0.29 0.060 0.30 0.2 0.4
DAY 57 1344 H 8 0.29 0.083 0.30 0.2 0.4
FOLLOW-UP 2016 H 8 0.33 0.089 0.35 0.2 0.4
Monocytes/Le IV_200mg 9 DAY 1 PREDOSE 9 0.0696 0.01129 0.0690 0.055 0.090 ukocytes (1)
DAY 5 96 H 9 0.0621 0.00955 0.0640 0.045 0.074
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Protocol: BA1116891 Page 25 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Monocytes/Le IV_200mg 9 DAY 15 336 H 9 0.0606 0.01792 0.0550 0.042 0.096 ukocytes (1)
DAY 29 672 H 9 0.0647 0.01563 0.0590 0.046 0.095
DAY 57 1344 H 9 0.0668 0.01132 0.0720 0.050 0.082
FOLLOW-UP 2016 H 9 0.0678 0.01746 0.0650 0.045 0.090
SQ_200mg 9 DAY 1 PREDOSE 9 0.0644 0.01290 0.0620 0.053 0.091
DAY 5 96 H 9 0.0644 0.01318 0.0690 0.049 0.079
DAY 15 336 H 9 0.0732 0.02934 0.0650 0.041 0.140
DAY 29 672 H 9 0.0636 0.01210 0.0620 0.050 0.086
DAY 57 1344 H 9 0.0723 0.02357 0.0650 0.044 0.110
FOLLOW-UP 2016 H 9 0.0591 0.01115 0.0610 0.042 0.077
SQ_50mg x 4 9 DAY 1 PREDOSE 9 0.0584 0.01017 0.0570 0.043 0.076
DAY 6 120 H 9 0.0559 0.01737 0.0560 0.029 0.093
DAY 8 PREDOSE 9 0.0608 0.01652 0.0610 0.038 0.091
DAY 15 PREDOSE 9 0.0580 0.01638 0.0520 0.038 0.092
DAY 22 PREDOSE 9 0.0596 0.01654 0.0570 0.032 0.087
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Protocol: BA1116891 Page 26 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Monocytes/Le SQ_50mg x 4 9 DAY 31 216 H 9 0.0559 0.00872 0.0580 0.043 0.070 ukocytes (1)
DAY 50 672 H 8 0.0604 0.01384 0.0590 0.043 0.082
DAY 78 1344 H 8 0.0621 0.01424 0.0585 0.046 0.089
FOLLOW-UP 2016 H 8 0.0673 0.01618 0.0665 0.047 0.089
IM_200mg 9 DAY 1 PREDOSE 9 0.0609 0.00929 0.0630 0.045 0.071
DAY 5 96 H 9 0.0556 0.00635 0.0570 0.044 0.064
DAY 15 336 H 9 0.0653 0.01576 0.0610 0.050 0.104
DAY 29 672 H 9 0.0623 0.01044 0.0630 0.046 0.082
DAY 57 1344 H 8 0.0583 0.00969 0.0565 0.041 0.072
FOLLOW-UP 2016 H 8 0.0661 0.01152 0.0650 0.053 0.089
Neutrophils IV_200mg 9 DAY 1 PREDOSE 9 2.86 0.823 2.80 1.7 4.0 (10^9/L)
DAY 5 96 H 9 2.96 0.702 2.80 1.7 4.2
DAY 15 336 H 9 3.88 1.122 3.60 2.3 6.2
DAY 29 672 H 9 2.62 0.659 2.40 1.8 3.8
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Protocol: BA1116891 Page 27 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Neutrophils IV_200mg 9 DAY 57 1344 H 9 2.91 1.257 2.20 1.4 5.4 (10^9/L)
FOLLOW-UP 2016 H 9 3.53 1.474 2.90 2.2 5.9
SQ_200mg 9 DAY 1 PREDOSE 9 3.70 1.233 3.80 1.6 5.5
DAY 5 96 H 9 3.57 1.222 3.70 1.6 5.9
DAY 15 336 H 9 3.42 1.332 4.00 1.0 4.8
DAY 29 672 H 9 3.24 0.879 3.50 1.2 4.0
DAY 57 1344 H 9 3.92 1.950 4.10 1.4 7.3
FOLLOW-UP 2016 H 9 4.01 1.738 4.10 1.4 6.7
SQ_50mg x 4 9 DAY 1 PREDOSE 9 2.89 1.082 2.70 1.4 4.4
DAY 6 120 H 9 2.86 1.114 2.90 1.6 4.6
DAY 8 PREDOSE 9 3.00 1.168 2.60 1.6 4.5
DAY 15 PREDOSE 9 3.14 1.535 3.10 1.3 5.0
DAY 22 PREDOSE 9 3.40 1.007 3.70 1.8 4.5
DAY 31 216 H 9 2.66 0.716 2.60 1.2 3.5
DAY 50 672 H 8 2.94 0.865 2.65 2.2 4.7
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Protocol: BA1116891 Page 28 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Neutrophils SQ_50mg x 4 9 DAY 78 1344 H 8 3.05 0.823 2.90 1.6 4.3 (10^9/L)
FOLLOW-UP 2016 H 8 3.01 1.303 3.10 1.1 4.8
IM_200mg 9 DAY 1 PREDOSE 9 3.16 1.061 3.00 1.6 4.9
DAY 5 96 H 9 2.80 0.669 2.60 1.9 3.8
DAY 15 336 H 9 2.83 0.723 2.80 1.6 4.1
DAY 29 672 H 9 2.60 0.758 2.50 1.6 4.0
DAY 57 1344 H 8 2.58 0.812 2.55 1.4 3.8
FOLLOW-UP 2016 H 8 2.70 0.898 2.70 1.5 4.2
Neutrophils/ IV_200mg 9 DAY 1 PREDOSE 9 0.5191 0.06886 0.5300 0.424 0.613 Leukocytes (1)
DAY 5 96 H 9 0.5351 0.06387 0.5580 0.415 0.605
DAY 15 336 H 9 0.6094 0.09050 0.5850 0.496 0.784
DAY 29 672 H 9 0.5286 0.05857 0.5520 0.412 0.590
DAY 57 1344 H 9 0.5340 0.10116 0.5540 0.312 0.691
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Protocol: BA1116891 Page 29 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Neutrophils/ IV_200mg 9 FOLLOW-UP 2016 H 9 0.5726 0.08626 0.5860 0.387 0.691 Leukocytes (1)
SQ_200mg 9 DAY 1 PREDOSE 9 0.5488 0.07088 0.5350 0.421 0.646
DAY 5 96 H 9 0.5804 0.08659 0.5820 0.465 0.702
DAY 15 336 H 9 0.5592 0.12333 0.5980 0.350 0.714
DAY 29 672 H 9 0.5610 0.08906 0.5620 0.420 0.673
DAY 57 1344 H 9 0.5762 0.12721 0.5930 0.380 0.780
FOLLOW-UP 2016 H 9 0.6028 0.08536 0.5940 0.514 0.767
SQ_50mg x 4 9 DAY 1 PREDOSE 9 0.4960 0.09646 0.5230 0.338 0.622
DAY 6 120 H 9 0.5446 0.07694 0.5330 0.402 0.684
DAY 8 PREDOSE 9 0.5011 0.09084 0.4800 0.374 0.628
DAY 15 PREDOSE 9 0.4906 0.11792 0.5130 0.317 0.616
DAY 22 PREDOSE 9 0.5243 0.09617 0.5820 0.375 0.637
DAY 31 216 H 9 0.5099 0.08880 0.5030 0.308 0.604
DAY 50 672 H 8 0.5394 0.07790 0.5225 0.410 0.657
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Protocol: BA1116891 Page 30 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Neutrophils/ SQ_50mg x 4 9 DAY 78 1344 H 8 0.5221 0.05778 0.5345 0.389 0.582 Leukocytes (1)
FOLLOW-UP 2016 H 8 0.5311 0.10267 0.5575 0.341 0.636
IM_200mg 9 DAY 1 PREDOSE 9 0.5361 0.10968 0.5360 0.372 0.738
DAY 5 96 H 9 0.5444 0.07921 0.5280 0.418 0.692
DAY 15 336 H 9 0.5486 0.09138 0.5370 0.418 0.706
DAY 29 672 H 9 0.5306 0.09326 0.4870 0.413 0.672
DAY 57 1344 H 8 0.5081 0.09818 0.5025 0.394 0.682
FOLLOW-UP 2016 H 8 0.5264 0.08835 0.5255 0.394 0.678
Platelets IV_200mg 9 DAY 1 PREDOSE 9 204.6 42.55 200.0 146 278 (10^9/L)
DAY 5 96 H 9 214.0 37.32 211.0 148 284
DAY 15 336 H 9 217.9 42.81 209.0 161 278
DAY 29 672 H 9 210.7 49.10 214.0 127 294
DAY 57 1344 H 9 214.8 51.88 214.0 144 301
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Protocol: BA1116891 Page 31 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Platelets IV_200mg 9 FOLLOW-UP 2016 H 9 206.0 45.69 198.0 149 314 (10^9/L)
SQ_200mg 9 DAY 1 PREDOSE 9 222.2 63.97 189.0 162 333
DAY 5 96 H 9 230.7 75.97 198.0 163 386
DAY 15 336 H 9 236.9 84.25 217.0 153 408
DAY 29 672 H 9 236.2 85.60 198.0 160 422
DAY 57 1344 H 9 223.3 66.85 217.0 154 377
FOLLOW-UP 2016 H 9 214.3 70.10 195.0 134 344
SQ_50mg x 4 9 DAY 1 PREDOSE 9 197.3 38.86 187.0 151 274
DAY 6 120 H 8 187.4 32.03 177.5 159 261
DAY 8 PREDOSE 9 188.0 30.68 188.0 143 251
DAY 15 PREDOSE 9 197.9 32.98 190.0 158 272
DAY 22 PREDOSE 8 189.0 38.71 182.0 149 276
DAY 31 216 H 9 189.1 36.49 192.0 147 272
DAY 50 672 H 7 190.4 38.98 178.0 141 266
DAY 78 1344 H 8 186.5 17.66 184.0 163 216
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Protocol: BA1116891 Page 32 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Platelets SQ_50mg x 4 9 FOLLOW-UP 2016 H 7 186.1 38.43 184.0 148 267 (10^9/L)
IM_200mg 9 DAY 1 PREDOSE 9 225.1 25.21 216.0 186 268
DAY 5 96 H 9 222.4 31.06 228.0 178 268
DAY 15 336 H 9 220.8 40.41 223.0 162 281
DAY 29 672 H 9 222.3 36.43 230.0 173 271
DAY 57 1344 H 8 218.9 33.66 215.5 180 268
FOLLOW-UP 2016 H 8 209.8 39.58 191.5 171 282
Platelet SQ_50mg x 4 9 DAY 6 120 H 1 260.0 260.0 260 260 Count (Lt Blue) (10^9/L)
DAY 8 PREDOSE 1 241.0 241.0 241 241
DAY 15 PREDOSE 1 242.0 242.0 242 242
DAY 22 PREDOSE 1 252.0 252.0 252 252
DAY 31 216 H 1 227.0 227.0 227 227
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Protocol: BA1116891 Page 33 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Erythrocytes IV_200mg 9 DAY 1 PREDOSE 9 5.061 0.4550 4.960 4.44 5.70 (10^12/L)
DAY 5 96 H 9 4.990 0.3721 4.810 4.57 5.61
DAY 15 336 H 9 4.986 0.4471 4.890 4.30 5.73
DAY 29 672 H 9 4.996 0.3903 4.870 4.49 5.53
DAY 57 1344 H 9 5.126 0.4139 5.110 4.60 5.72
FOLLOW-UP 2016 H 9 5.042 0.4926 4.990 4.30 5.97
SQ_200mg 9 DAY 1 PREDOSE 9 4.770 0.2644 4.720 4.50 5.16
DAY 5 96 H 9 4.938 0.2491 4.940 4.42 5.34
DAY 15 336 H 9 4.862 0.3024 4.850 4.48 5.34
DAY 29 672 H 9 4.901 0.2358 4.910 4.60 5.31
DAY 57 1344 H 9 4.923 0.3855 4.780 4.34 5.52
FOLLOW-UP 2016 H 9 4.829 0.3519 4.820 4.35 5.51
SQ_50mg x 4 9 DAY 1 PREDOSE 9 5.100 0.4506 5.120 4.18 5.71
DAY 6 120 H 9 5.207 0.3714 5.320 4.26 5.48
DAY 8 PREDOSE 9 5.139 0.4651 5.200 4.07 5.79
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Protocol: BA1116891 Page 34 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Erythrocytes SQ_50mg x 4 9 DAY 15 PREDOSE 9 5.018 0.3517 5.030 4.36 5.68 (10^12/L)
DAY 22 PREDOSE 9 4.963 0.5022 5.020 4.01 5.84
DAY 31 216 H 9 5.119 0.5556 5.270 4.17 6.03
DAY 50 672 H 8 5.140 0.4982 5.055 4.40 6.00
DAY 78 1344 H 8 5.278 0.5496 5.255 4.24 6.04
FOLLOW-UP 2016 H 8 5.074 0.5746 5.130 4.02 5.81
IM_200mg 9 DAY 1 PREDOSE 9 4.964 0.2485 4.960 4.68 5.37
DAY 5 96 H 9 4.889 0.3670 4.750 4.53 5.60
DAY 15 336 H 9 4.930 0.2209 4.860 4.66 5.30
DAY 29 672 H 9 4.868 0.2842 4.770 4.53 5.29
DAY 57 1344 H 8 4.969 0.2503 4.865 4.76 5.49
FOLLOW-UP 2016 H 8 4.846 0.2369 4.800 4.59 5.32
Erythrocytes IV_200mg 9 DAY 1 PREDOSE 9 0.1314 0.00700 0.1310 0.123 0.147 Distribution Width (1)
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Protocol: BA1116891 Page 35 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Erythrocytes IV_200mg 9 DAY 5 96 H 9 0.1308 0.00703 0.1300 0.123 0.145 Distribution Width (1)
DAY 15 336 H 9 0.1321 0.00713 0.1300 0.125 0.149
DAY 29 672 H 9 0.1314 0.00826 0.1310 0.122 0.149
DAY 57 1344 H 9 0.1304 0.00621 0.1290 0.125 0.146
FOLLOW-UP 2016 H 9 0.1314 0.00954 0.1290 0.120 0.154
SQ_200mg 9 DAY 1 PREDOSE 9 0.1291 0.00580 0.1270 0.123 0.138
DAY 5 96 H 9 0.1292 0.00554 0.1270 0.123 0.137
DAY 15 336 H 9 0.1291 0.00558 0.1290 0.123 0.137
DAY 29 672 H 9 0.1294 0.00510 0.1290 0.121 0.137
DAY 57 1344 H 9 0.1318 0.00565 0.1340 0.122 0.139
FOLLOW-UP 2016 H 9 0.1289 0.00457 0.1310 0.120 0.134
SQ_50mg x 4 9 DAY 1 PREDOSE 9 0.1310 0.00482 0.1310 0.124 0.140
DAY 6 120 H 9 0.1312 0.00463 0.1300 0.125 0.139
DAY 8 PREDOSE 9 0.1311 0.00483 0.1310 0.123 0.139
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Protocol: BA1116891 Page 36 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Erythrocytes SQ_50mg x 4 9 DAY 15 PREDOSE 9 0.1312 0.00543 0.1310 0.124 0.140 Distribution Width (1)
DAY 22 PREDOSE 9 0.1317 0.00548 0.1300 0.125 0.141
DAY 31 216 H 9 0.1329 0.00537 0.1330 0.126 0.142
DAY 50 672 H 8 0.1336 0.00434 0.1335 0.129 0.141
DAY 78 1344 H 8 0.1343 0.00406 0.1335 0.130 0.143
FOLLOW-UP 2016 H 8 0.1328 0.00480 0.1320 0.127 0.142
IM_200mg 9 DAY 1 PREDOSE 9 0.1307 0.00548 0.1310 0.124 0.141
DAY 5 96 H 9 0.1306 0.00561 0.1300 0.122 0.142
DAY 15 336 H 9 0.1308 0.00648 0.1300 0.123 0.144
DAY 29 672 H 9 0.1321 0.00779 0.1310 0.124 0.150
DAY 57 1344 H 8 0.1306 0.00780 0.1285 0.123 0.147
FOLLOW-UP 2016 H 8 0.1316 0.00924 0.1290 0.119 0.146
Reticulocyte IV_200mg 9 DAY 1 PREDOSE 9 104.53 62.221 86.70 64.7 266.7 s (10^9/L)
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Protocol: BA1116891 Page 37 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Reticulocyte IV_200mg 9 DAY 5 96 H 9 93.41 12.979 92.00 73.6 114.6 s (10^9/L)
DAY 15 336 H 9 94.46 17.289 87.10 74.0 127.2
DAY 29 672 H 9 89.58 16.994 85.60 66.9 126.5
DAY 57 1344 H 9 89.16 17.141 93.80 64.0 110.3
FOLLOW-UP 2016 H 9 81.76 9.753 81.30 66.9 96.7
SQ_200mg 9 DAY 1 PREDOSE 9 87.99 25.247 83.10 59.7 142.1
DAY 5 96 H 9 88.00 30.477 79.20 51.3 138.6
DAY 15 336 H 9 86.01 28.025 77.20 44.2 133.9
DAY 29 672 H 9 85.54 21.980 77.20 55.6 125.9
DAY 57 1344 H 9 90.63 19.448 97.10 59.5 122.1
FOLLOW-UP 2016 H 9 74.67 23.212 75.30 39.3 118.9
SQ_50mg x 4 9 DAY 1 PREDOSE 9 75.90 19.952 79.40 44.0 98.0
DAY 6 120 H 9 77.03 17.084 71.00 52.5 107.7
DAY 8 PREDOSE 9 78.16 19.926 72.50 55.3 107.7
DAY 15 PREDOSE 9 75.78 11.978 77.20 55.4 98.7
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Protocol: BA1116891 Page 38 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Reticulocyte SQ_50mg x 4 9 DAY 22 PREDOSE 9 77.00 14.431 84.50 44.7 91.8 s (10^9/L)
DAY 31 216 H 9 86.59 17.444 86.30 64.9 121.6
DAY 50 672 H 8 81.06 15.632 79.90 51.1 98.8
DAY 78 1344 H 8 79.84 25.869 72.05 62.3 141.6
FOLLOW-UP 2016 H 8 89.84 31.863 86.40 46.4 152.6
IM_200mg 9 DAY 1 PREDOSE 9 76.81 18.176 77.80 43.9 101.7
DAY 5 96 H 9 72.99 21.806 65.60 56.2 119.6
DAY 15 336 H 9 83.37 20.142 86.10 57.1 114.2
DAY 29 672 H 9 80.52 14.741 80.90 54.9 98.4
DAY 57 1344 H 8 69.41 13.186 67.50 54.2 98.2
FOLLOW-UP 2016 H 8 75.51 13.524 72.05 60.2 96.7
Reticulocyte IV_200mg 9 DAY 1 PREDOSE 9 0.0210 0.01285 0.0170 0.012 0.054 s/Erythrocyt es (1)
DAY 5 96 H 9 0.0189 0.00302 0.0190 0.014 0.024
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Protocol: BA1116891 Page 39 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Reticulocyte IV_200mg 9 DAY 15 336 H 9 0.0191 0.00318 0.0190 0.015 0.026 s/Erythrocyt es (1)
DAY 29 672 H 9 0.0180 0.00371 0.0180 0.013 0.025
DAY 57 1344 H 9 0.0174 0.00332 0.0190 0.012 0.022
FOLLOW-UP 2016 H 9 0.0163 0.00158 0.0170 0.013 0.018
SQ_200mg 9 DAY 1 PREDOSE 9 0.0186 0.00568 0.0180 0.012 0.030
DAY 5 96 H 9 0.0179 0.00609 0.0150 0.011 0.028
DAY 15 336 H 9 0.0179 0.00607 0.0160 0.010 0.029
DAY 29 672 H 9 0.0177 0.00485 0.0160 0.011 0.026
DAY 57 1344 H 9 0.0186 0.00400 0.0200 0.013 0.023
FOLLOW-UP 2016 H 9 0.0157 0.00520 0.0150 0.008 0.025
SQ_50mg x 4 9 DAY 1 PREDOSE 9 0.0152 0.00380 0.0160 0.010 0.020
DAY 6 120 H 9 0.0149 0.00310 0.0140 0.010 0.020
DAY 8 PREDOSE 9 0.0153 0.00391 0.0150 0.010 0.021
DAY 15 PREDOSE 9 0.0152 0.00217 0.0160 0.011 0.019
196
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Protocol: BA1116891 Page 40 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Reticulocyte SQ_50mg x 4 9 DAY 22 PREDOSE 9 0.0158 0.00259 0.0170 0.011 0.019 s/Erythrocyt es (1)
DAY 31 216 H 9 0.0170 0.00287 0.0160 0.012 0.022
DAY 50 672 H 8 0.0158 0.00287 0.0160 0.012 0.020
DAY 78 1344 H 8 0.0154 0.00487 0.0140 0.011 0.027
FOLLOW-UP 2016 H 8 0.0176 0.00566 0.0175 0.010 0.028
IM_200mg 9 DAY 1 PREDOSE 9 0.0156 0.00347 0.0160 0.009 0.020
DAY 5 96 H 9 0.0147 0.00308 0.0140 0.012 0.021
DAY 15 336 H 9 0.0169 0.00408 0.0180 0.011 0.022
DAY 29 672 H 9 0.0164 0.00292 0.0150 0.012 0.021
DAY 57 1344 H 8 0.0139 0.00210 0.0140 0.011 0.018
FOLLOW-UP 2016 H 8 0.0156 0.00226 0.0155 0.013 0.019
Leukocytes IV_200mg 9 DAY 1 PREDOSE 9 5.44 1.093 4.90 4.1 7.4 (10^9/L)
DAY 5 96 H 9 5.48 1.006 5.30 3.8 6.9
197
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Protocol: BA1116891 Page 41 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Leukocytes IV_200mg 9 DAY 15 336 H 9 6.29 0.925 6.40 4.7 7.9 (10^9/L)
DAY 29 672 H 9 4.96 0.977 4.70 3.7 6.4
DAY 57 1344 H 9 5.30 1.501 4.40 3.7 7.8
FOLLOW-UP 2016 H 9 6.04 1.868 5.70 4.2 9.4
SQ_200mg 9 DAY 1 PREDOSE 9 6.62 1.595 6.50 3.9 8.8
DAY 5 96 H 9 6.03 1.503 5.80 3.3 9.1
DAY 15 336 H 9 5.89 1.563 6.40 2.9 7.8
DAY 29 672 H 9 5.72 1.324 5.60 2.9 7.1
DAY 57 1344 H 9 6.50 2.257 6.50 2.9 9.7
FOLLOW-UP 2016 H 9 6.47 2.171 6.50 2.5 9.6
SQ_50mg x 4 9 DAY 1 PREDOSE 9 5.63 1.377 5.20 4.1 7.6
DAY 6 120 H 9 5.11 1.379 5.00 3.5 7.4
DAY 8 PREDOSE 9 5.80 1.494 5.40 4.2 8.1
DAY 15 PREDOSE 9 6.08 1.823 6.10 3.9 8.2
DAY 22 PREDOSE 9 6.36 1.094 6.60 4.3 7.7
198
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Protocol: BA1116891 Page 42 of 42Population: Safety Table 10.302 Hematology Laboratory Summary by Visit
Planned Time Lab Test Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------------------- Leukocytes SQ_50mg x 4 9 DAY 31 216 H 9 5.14 0.800 5.00 4.0 6.6 (10^9/L)
DAY 50 672 H 8 5.36 0.865 5.25 4.3 7.1
DAY 78 1344 H 8 5.76 1.143 5.50 4.1 7.4
FOLLOW-UP 2016 H 8 5.48 1.651 5.20 3.3 7.8
IM_200mg 9 DAY 1 PREDOSE 9 5.80 1.161 5.90 4.2 7.6
DAY 5 96 H 9 5.11 0.821 4.80 4.1 6.8
DAY 15 336 H 9 5.12 0.646 5.20 3.8 5.8
DAY 29 672 H 9 4.84 0.806 4.90 3.9 6.0
DAY 57 1344 H 8 4.96 0.930 5.10 3.6 6.5
FOLLOW-UP 2016 H 8 5.08 1.155 4.90 3.4 6.8
199
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Protocol: BA1116891 Page 1 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Alanine Aminotransferase (U/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0
DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0
DAY 6 n 0 0 9 0 High 0 0 1 (11%) 0 Low 0 0 0 0
DAY 8 n 0 0 9 0 High 0 0 1 (11%) 0 Low 0 0 0 0
DAY 15 n 9 9 9 9 High 0 0 1 (11%) 0 Low 0 0 0 0
DAY 22 n 0 0 9 0 High 0 0 2 (22%) 0 Low 0 0 0 0
DAY 29 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0
DAY 31 n 0 0 9 0 High 0 0 1 (11%) 0 Low 0 0 0 0
200
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Protocol: BA1116891 Page 2 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Alanine Aminotransferase (U/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 1 (13%) 0 Low 0 0 0 0
DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 0 0 0
DAY 78 n 0 0 8 0 High 0 0 1 (13%) 0 Low 0 0 0 0
FOLLOW-UP n 9 9 8 8 High 0 0 1 (13%) 0 Low 0 0 0 0
201
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Protocol: BA1116891 Page 3 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Albumin (g/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0
DAY 5 n 9 9 0 9 High 0 0 0 1 (11%) Low 0 0 0 0
DAY 6 n 0 0 9 0 High 0 0 1 (11%) 0 Low 0 0 0 0
DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 15 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0
DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 29 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0
DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
202
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Protocol: BA1116891 Page 4 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Albumin (g/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 0 0 0
DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
FOLLOW-UP n 9 9 8 8 High 0 0 0 0 Low 0 0 0 0
203
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Protocol: BA1116891 Page 5 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Alkaline Phosphatase (U/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 2 (22%) 2 (22%) 3 (33%) 2 (22%)
DAY 5 n 9 9 0 9 High 0 0 0 0 Low 1 (11%) 2 (22%) 0 1 (11%)
DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 3 (33%) 0
DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 2 (22%) 0
DAY 15 n 9 9 9 9 High 0 0 0 0 Low 1 (11%) 2 (22%) 3 (33%) 2 (22%)
DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 3 (33%) 0
DAY 29 n 9 9 0 9 High 0 0 0 0 Low 1 (11%) 1 (11%) 0 2 (22%)
DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 3 (33%) 0
204
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Protocol: BA1116891 Page 6 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Alkaline Phosphatase (U/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 3 (38%) 0
DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 4 (44%) 0 1 (13%)
DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 3 (38%) 0
FOLLOW-UP n 9 9 8 8 High 0 0 0 0 Low 0 3 (33%) 3 (38%) 1 (13%)
205
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Protocol: BA1116891 Page 7 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Aspartate Aminotransferase (U/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0
DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0
DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 15 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0
DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 29 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0
DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
206
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Protocol: BA1116891 Page 8 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Aspartate Aminotransferase (U/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
DAY 57 n 9 9 0 8 High 0 1 (11%) 0 1 (13%) Low 0 0 0 0
DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
FOLLOW-UP n 9 9 8 8 High 0 0 1 (13%) 0 Low 0 0 0 0
207
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Protocol: BA1116891 Page 9 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Bilirubin (umol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 1 (11%) 0 0 1 (11%) Low 0 0 0 0
DAY 5 n 9 9 0 9 High 1 (11%) 0 0 0 Low 0 0 0 0
DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 15 n 9 9 9 9 High 1 (11%) 0 0 0 Low 0 0 0 0
DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 29 n 9 9 0 9 High 1 (11%) 0 0 0 Low 0 0 0 0
DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
208
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Protocol: BA1116891 Page 10 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Bilirubin (umol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 0 0 0
DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
FOLLOW-UP n 9 9 8 8 High 1 (11%) 0 0 1 (13%) Low 0 0 0 0
209
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Protocol: BA1116891 Page 11 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Blood Urea Nitrogen (mmol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 1 (11%) Low 1 (11%) 1 (11%) 0 1 (11%)
DAY 5 n 9 9 0 9 High 0 0 0 0 Low 2 (22%) 2 (22%) 0 0
DAY 6 n 0 0 9 0 High 0 0 1 (11%) 0 Low 0 0 0 0
DAY 8 n 0 0 9 0 High 0 0 1 (11%) 0 Low 0 0 0 0
DAY 15 n 9 9 9 9 High 0 0 0 0 Low 3 (33%) 3 (33%) 0 0
DAY 22 n 0 0 9 0 High 0 0 1 (11%) 0 Low 0 0 1 (11%) 0
DAY 29 n 9 9 0 9 High 0 0 0 1 (11%) Low 1 (11%) 3 (33%) 0 1 (11%)
DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
210
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Protocol: BA1116891 Page 12 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Blood Urea Nitrogen (mmol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 1 (13%) 0
DAY 57 n 9 9 0 8 High 0 0 0 0 Low 2 (22%) 2 (22%) 0 0
DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
FOLLOW-UP n 9 9 8 8 High 0 0 1 (13%) 0 Low 0 2 (22%) 0 0
211
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Protocol: BA1116891 Page 13 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Calcium (mmol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 2 (22%) 0 0 0
DAY 5 n 9 9 0 9 High 0 0 0 0 Low 1 (11%) 0 0 0
DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 15 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 1 (11%)
DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 29 n 9 9 0 9 High 0 0 0 0 Low 2 (22%) 0 0 0
DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
212
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Protocol: BA1116891 Page 14 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Calcium (mmol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
DAY 57 n 9 9 0 8 High 0 0 0 0 Low 2 (22%) 0 0 0
DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
FOLLOW-UP n 9 9 8 8 High 0 0 0 0 Low 2 (22%) 0 0 0
213
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Protocol: BA1116891 Page 15 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Carbon Dioxide (mmol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 5 (56%) 3 (33%) 1 (11%) 4 (44%) Low 0 0 0 0
DAY 5 n 9 9 0 9 High 3 (33%) 4 (44%) 0 4 (44%) Low 0 0 0 0
DAY 6 n 0 0 9 0 High 0 0 2 (22%) 0 Low 0 0 0 0
DAY 8 n 0 0 9 0 High 0 0 3 (33%) 0 Low 0 0 0 0
DAY 15 n 9 9 9 9 High 2 (22%) 4 (44%) 2 (22%) 3 (33%) Low 0 0 0 0
DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 29 n 9 9 0 9 High 3 (33%) 3 (33%) 0 3 (33%) Low 0 0 0 0
DAY 31 n 0 0 9 0 High 0 0 4 (44%) 0 Low 0 0 0 0
214
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Protocol: BA1116891 Page 16 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Carbon Dioxide (mmol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 1 (13%) 0 Low 0 0 0 0
DAY 57 n 9 9 0 8 High 1 (11%) 1 (11%) 0 1 (13%) Low 0 0 0 0
DAY 78 n 0 0 8 0 High 0 0 1 (13%) 0 Low 0 0 0 0
FOLLOW-UP n 9 9 8 8 High 3 (33%) 3 (33%) 1 (13%) 2 (25%) Low 0 0 0 0
215
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Protocol: BA1116891 Page 17 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Chloride (mmol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0
DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0
DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 15 n 9 9 9 9 High 0 0 1 (11%) 0 Low 0 0 0 0
DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 29 n 9 9 0 9 High 1 (11%) 0 0 0 Low 0 0 0 0
DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
216
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Protocol: BA1116891 Page 18 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Chloride (mmol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 1 (11%) 0 0
DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
FOLLOW-UP n 9 9 8 8 High 0 0 0 0 Low 0 0 0 0
217
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Protocol: BA1116891 Page 19 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Creatine Kinase (U/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 High 0 0 0 0 Low 0 0 0 0
DAY 5 High 0 0 0 0 Low 0 0 0 0
DAY 6 High 0 0 0 0 Low 0 0 0 0
DAY 8 High 0 0 0 0 Low 0 0 0 0
DAY 15 High 0 0 0 0 Low 0 0 0 0
DAY 22 High 0 0 0 0 Low 0 0 0 0
DAY 29 High 0 0 0 0 Low 0 0 0 0
DAY 31 High 0 0 0 0 Low 0 0 0 0
DAY 50 High 0 0 0 0 Low 0 0 0 0
DAY 57 n 0 0 0 1 High 0 0 0 1 (100%) Low 0 0 0 0
218
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Protocol: BA1116891 Page 20 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Creatine Kinase (U/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 78 High 0 0 0 0 Low 0 0 0 0
FOLLOW-UP High 0 0 0 0 Low 0 0 0 0
219
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Protocol: BA1116891 Page 21 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Creatine Kinase BB (U/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 High 0 0 0 0 Low 0 0 0 0
DAY 5 High 0 0 0 0 Low 0 0 0 0
DAY 6 High 0 0 0 0 Low 0 0 0 0
DAY 8 High 0 0 0 0 Low 0 0 0 0
DAY 15 High 0 0 0 0 Low 0 0 0 0
DAY 22 n 0 0 1 0 High 0 0 1 (100%) 0 Low 0 0 0 0
DAY 29 High 0 0 0 0 Low 0 0 0 0
DAY 31 High 0 0 0 0 Low 0 0 0 0
DAY 50 High 0 0 0 0 Low 0 0 0 0
DAY 57 n 0 1 0 0 High 0 1 (100%) 0 0 Low 0 0 0 0
220
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Protocol: BA1116891 Page 22 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Creatine Kinase BB (U/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 78 High 0 0 0 0 Low 0 0 0 0
FOLLOW-UP n 0 0 1 0 High 0 0 1 (100%) 0 Low 0 0 0 0
221
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Protocol: BA1116891 Page 23 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Creatine Kinase MB (ug/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 High 0 0 0 0 Low 0 0 0 0
DAY 5 High 0 0 0 0 Low 0 0 0 0
DAY 6 High 0 0 0 0 Low 0 0 0 0
DAY 8 High 0 0 0 0 Low 0 0 0 0
DAY 15 High 0 0 0 0 Low 0 0 0 0
DAY 22 n 0 0 1 0 High 0 0 0 0 Low 0 0 0 0
DAY 29 High 0 0 0 0 Low 0 0 0 0
DAY 31 High 0 0 0 0 Low 0 0 0 0
DAY 50 High 0 0 0 0 Low 0 0 0 0
DAY 57 n 0 1 0 0 High 0 1 (100%) 0 0 Low 0 0 0 0
222
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Protocol: BA1116891 Page 24 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Creatine Kinase MB (ug/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 78 High 0 0 0 0 Low 0 0 0 0
FOLLOW-UP n 0 0 1 0 High 0 0 0 0 Low 0 0 0 0
223
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Protocol: BA1116891 Page 25 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Creatinine (umol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 1 (11%) 1 (11%) 0 0
DAY 5 n 9 9 0 9 High 0 0 0 0 Low 1 (11%) 2 (22%) 0 0
DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 1 (11%) 0
DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 15 n 9 9 9 9 High 0 0 0 0 Low 2 (22%) 3 (33%) 0 1 (11%)
DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 1 (11%) 0
DAY 29 n 9 9 0 9 High 0 0 0 0 Low 2 (22%) 1 (11%) 0 0
DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
224
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Protocol: BA1116891 Page 26 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Creatinine (umol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
DAY 57 n 9 9 0 8 High 0 0 0 0 Low 1 (11%) 2 (22%) 0 0
DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 1 (13%) 0
FOLLOW-UP n 9 9 8 8 High 0 0 0 0 Low 2 (22%) 4 (44%) 3 (38%) 1 (13%)
225
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Protocol: BA1116891 Page 27 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Direct Bilirubin (umol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 1 (11%) Low 0 0 0 0
DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0
DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 15 n 9 9 9 9 High 1 (11%) 0 0 0 Low 0 0 0 0
DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 29 n 9 9 0 9 High 1 (11%) 0 0 0 Low 0 0 0 0
DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
226
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Protocol: BA1116891 Page 28 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Direct Bilirubin (umol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
DAY 57 n 9 9 0 8 High 1 (11%) 0 0 0 Low 0 0 0 0
DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
FOLLOW-UP n 9 9 8 8 High 1 (11%) 0 0 0 Low 0 0 0 0
227
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Lab Test: Gamma Glutamyl Transferase (U/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 0 2 (22%) 0 1 (11%)
DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 1 (11%) 0 0
DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 15 n 9 9 9 9 High 0 0 0 0 Low 0 4 (44%) 2 (22%) 0
DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 1 (11%) 0
DAY 29 n 9 9 0 9 High 0 0 0 0 Low 0 2 (22%) 0 0
DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 1 (11%) 0
228
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Protocol: BA1116891 Page 30 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Gamma Glutamyl Transferase (U/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 1 (13%) 0
DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 3 (33%) 0 0
DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 1 (13%) 0
FOLLOW-UP n 9 9 8 8 High 1 (11%) 0 0 0 Low 0 2 (22%) 2 (25%) 0
229
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Protocol: BA1116891 Page 31 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Glucose (mmol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0
DAY 5 n 9 9 0 9 High 0 0 0 1 (11%) Low 0 0 0 1 (11%)
DAY 6 n 0 0 9 0 High 0 0 1 (11%) 0 Low 0 0 0 0
DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 15 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0
DAY 22 n 0 0 9 0 High 0 0 1 (11%) 0 Low 0 0 0 0
DAY 29 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0
DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
230
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Lab Test: Glucose (mmol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 0 0 0
DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
FOLLOW-UP n 9 9 8 8 High 0 1 (11%) 0 0 Low 0 0 0 0
231
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Lab Test: Potassium (mmol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 0 0 1 (11%) 0
DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0
DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 15 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0
DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 29 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0
DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
232
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Lab Test: Potassium (mmol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 0 0 0
DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
FOLLOW-UP n 9 9 8 8 High 0 0 0 0 Low 0 0 0 0
233
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Protocol: BA1116891 Page 35 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Protein (g/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 1 (11%) 0 0 0
DAY 5 n 9 9 0 9 High 0 0 0 0 Low 1 (11%) 0 0 0
DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 15 n 9 9 9 9 High 0 0 0 0 Low 1 (11%) 0 0 0
DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 29 n 9 9 0 9 High 0 0 0 0 Low 1 (11%) 0 0 0
DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
234
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Protocol: BA1116891 Page 36 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Protein (g/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
DAY 57 n 9 9 0 8 High 0 0 0 0 Low 1 (11%) 0 0 0
DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
FOLLOW-UP n 9 9 8 8 High 0 0 0 0 Low 1 (11%) 0 0 0
235
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Protocol: BA1116891 Page 37 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Sodium (mmol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0
DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0
DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 15 n 9 9 9 9 High 0 0 0 0 Low 0 1 (11%) 0 0
DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 29 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0
DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
236
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Protocol: BA1116891 Page 38 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Sodium (mmol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 1 (11%) 0 0
DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
FOLLOW-UP n 9 9 8 8 High 0 0 0 0 Low 1 (11%) 0 0 0
237
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Protocol: BA1116891 Page 39 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Thyrotropin (mIU/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 High 0 0 0 0 Low 0 0 0 0
DAY 5 High 0 0 0 0 Low 0 0 0 0
DAY 6 High 0 0 0 0 Low 0 0 0 0
DAY 8 High 0 0 0 0 Low 0 0 0 0
DAY 15 High 0 0 0 0 Low 0 0 0 0
DAY 22 High 0 0 0 0 Low 0 0 0 0
DAY 29 n 0 1 0 0 High 0 0 0 0 Low 0 0 0 0
DAY 31 High 0 0 0 0 Low 0 0 0 0
DAY 50 High 0 0 0 0 Low 0 0 0 0
DAY 57 High 0 0 0 0 Low 0 0 0 0
238
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Protocol: BA1116891 Page 40 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Thyrotropin (mIU/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 78 High 0 0 0 0 Low 0 0 0 0
FOLLOW-UP High 0 0 0 0 Low 0 0 0 0
239
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Lab Test: Thyroxine, Free (pmol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 High 0 0 0 0 Low 0 0 0 0
DAY 5 High 0 0 0 0 Low 0 0 0 0
DAY 6 High 0 0 0 0 Low 0 0 0 0
DAY 8 High 0 0 0 0 Low 0 0 0 0
DAY 15 High 0 0 0 0 Low 0 0 0 0
DAY 22 High 0 0 0 0 Low 0 0 0 0
DAY 29 n 0 1 0 0 High 0 0 0 0 Low 0 0 0 0
DAY 31 High 0 0 0 0 Low 0 0 0 0
DAY 50 High 0 0 0 0 Low 0 0 0 0
DAY 57 High 0 0 0 0 Low 0 0 0 0
240
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Protocol: BA1116891 Page 42 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Thyroxine, Free (pmol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 78 High 0 0 0 0 Low 0 0 0 0
FOLLOW-UP High 0 0 0 0 Low 0 0 0 0
241
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Protocol: BA1116891 Page 43 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Triiodothyronine, Free (nmol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 High 0 0 0 0 Low 0 0 0 0
DAY 5 High 0 0 0 0 Low 0 0 0 0
DAY 6 High 0 0 0 0 Low 0 0 0 0
DAY 8 High 0 0 0 0 Low 0 0 0 0
DAY 15 High 0 0 0 0 Low 0 0 0 0
DAY 22 High 0 0 0 0 Low 0 0 0 0
DAY 29 n 0 1 0 0 High 0 0 0 0 Low 0 0 0 0
DAY 31 High 0 0 0 0 Low 0 0 0 0
DAY 50 High 0 0 0 0 Low 0 0 0 0
DAY 57 High 0 0 0 0 Low 0 0 0 0
242
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Protocol: BA1116891 Page 44 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Triiodothyronine, Free (nmol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 78 High 0 0 0 0 Low 0 0 0 0
FOLLOW-UP High 0 0 0 0 Low 0 0 0 0
243
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Protocol: BA1116891 Page 45 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Troponin I (ug/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 High 0 0 0 0 Low 0 0 0 0
DAY 5 High 0 0 0 0 Low 0 0 0 0
DAY 6 High 0 0 0 0 Low 0 0 0 0
DAY 8 High 0 0 0 0 Low 0 0 0 0
DAY 15 High 0 0 0 0 Low 0 0 0 0
DAY 22 High 0 0 0 0 Low 0 0 0 0
DAY 29 High 0 0 0 0 Low 0 0 0 0
DAY 31 High 0 0 0 0 Low 0 0 0 0
DAY 50 High 0 0 0 0 Low 0 0 0 0
DAY 57 n 0 1 0 0 High 0 0 0 0 Low 0 0 0 0
244
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Protocol: BA1116891 Page 46 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Troponin I (ug/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 78 High 0 0 0 0 Low 0 0 0 0
FOLLOW-UP High 0 0 0 0 Low 0 0 0 0
245
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Protocol: BA1116891 Page 47 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Urate (umol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0
DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0
DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 15 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0
DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 29 n 9 9 0 9 High 0 1 (11%) 0 0 Low 0 0 0 0
DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
246
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Protocol: BA1116891 Page 48 of 48Population: Safety Table 10.401 Summary of Abnormal Chemistry Laboratory Results
Lab Test: Urate (umol/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 0 0 0
DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
FOLLOW-UP n 9 9 8 8 High 1 (11%) 0 0 0 Low 0 0 0 0
247
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Protocol: BA1116891 Page 1 of 48Population: Safety Table 10.402 Summary of Abnormal Hematology Laboratory Results
Lab Test: Basophils (10^9/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0
DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0
DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 15 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0
DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 29 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0
DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
248
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Protocol: BA1116891 Page 2 of 48Population: Safety Table 10.402 Summary of Abnormal Hematology Laboratory Results
Lab Test: Basophils (10^9/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 0 0 0
DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
FOLLOW-UP n 9 9 8 8 High 0 0 0 0 Low 0 0 0 0
249
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Protocol: BA1116891 Page 3 of 48Population: Safety Table 10.402 Summary of Abnormal Hematology Laboratory Results
Lab Test: Basophils/Leukocytes (1) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0
DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0
DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 15 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0
DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 29 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0
DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
250
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Protocol: BA1116891 Page 4 of 48Population: Safety Table 10.402 Summary of Abnormal Hematology Laboratory Results
Lab Test: Basophils/Leukocytes (1) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 0 0 0
DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
FOLLOW-UP n 9 9 8 8 High 0 0 0 0 Low 0 0 0 0
251
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Protocol: BA1116891 Page 5 of 48Population: Safety Table 10.402 Summary of Abnormal Hematology Laboratory Results
Lab Test: Eosinophils (10^9/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 1 (11%) 1 (11%) 0 Low 0 0 0 0
DAY 5 n 9 9 0 9 High 0 1 (11%) 0 1 (11%) Low 0 0 0 0
DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 15 n 9 9 9 9 High 0 1 (11%) 1 (11%) 1 (11%) Low 0 0 0 0
DAY 22 n 0 0 9 0 High 0 0 2 (22%) 0 Low 0 0 0 0
DAY 29 n 9 9 0 9 High 0 1 (11%) 0 0 Low 0 0 0 0
DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
252
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Protocol: BA1116891 Page 6 of 48Population: Safety Table 10.402 Summary of Abnormal Hematology Laboratory Results
Lab Test: Eosinophils (10^9/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
DAY 57 n 9 9 0 8 High 0 1 (11%) 0 0 Low 0 0 0 0
DAY 78 n 0 0 8 0 High 0 0 1 (13%) 0 Low 0 0 0 0
FOLLOW-UP n 9 9 8 8 High 0 2 (22%) 0 0 Low 0 0 0 0
253
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Protocol: BA1116891 Page 7 of 48Population: Safety Table 10.402 Summary of Abnormal Hematology Laboratory Results
Lab Test: Eosinophils/Leukocytes (1) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 3 (33%) 5 (56%) 4 (44%) 4 (44%) Low 0 0 0 0
DAY 5 n 9 9 0 9 High 2 (22%) 5 (56%) 0 3 (33%) Low 0 0 0 0
DAY 6 n 0 0 9 0 High 0 0 5 (56%) 0 Low 0 0 0 0
DAY 8 n 0 0 9 0 High 0 0 5 (56%) 0 Low 0 0 0 0
DAY 15 n 9 9 9 9 High 3 (33%) 3 (33%) 6 (67%) 3 (33%) Low 0 0 0 0
DAY 22 n 0 0 9 0 High 0 0 6 (67%) 0 Low 0 0 0 0
DAY 29 n 9 9 0 9 High 3 (33%) 3 (33%) 0 3 (33%) Low 0 0 0 0
DAY 31 n 0 0 9 0 High 0 0 4 (44%) 0 Low 0 0 0 0
254
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Protocol: BA1116891 Page 8 of 48Population: Safety Table 10.402 Summary of Abnormal Hematology Laboratory Results
Lab Test: Eosinophils/Leukocytes (1) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 2 (25%) 0 Low 0 0 0 0
DAY 57 n 9 9 0 8 High 3 (33%) 3 (33%) 0 4 (50%) Low 0 0 0 0
DAY 78 n 0 0 8 0 High 0 0 4 (50%) 0 Low 0 0 0 0
FOLLOW-UP n 9 9 8 8 High 3 (33%) 4 (44%) 3 (38%) 4 (50%) Low 0 0 0 0
255
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Protocol: BA1116891 Page 9 of 48Population: Safety Table 10.402 Summary of Abnormal Hematology Laboratory Results
Lab Test: Ery. Mean Corpuscular HGB Concentration (g/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0
DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0
DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 15 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0
DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 29 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0
DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
256
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Protocol: BA1116891 Page 10 of 48Population: Safety Table 10.402 Summary of Abnormal Hematology Laboratory Results
Lab Test: Ery. Mean Corpuscular HGB Concentration (g/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 0 0 0
DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
FOLLOW-UP n 9 9 8 8 High 0 0 0 0 Low 0 0 0 0
257
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Protocol: BA1116891 Page 11 of 48Population: Safety Table 10.402 Summary of Abnormal Hematology Laboratory Results
Lab Test: Ery. Mean Corpuscular Hemoglobin (pg) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0
DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0
DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 15 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0
DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 29 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0
DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
258
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Protocol: BA1116891 Page 12 of 48Population: Safety Table 10.402 Summary of Abnormal Hematology Laboratory Results
Lab Test: Ery. Mean Corpuscular Hemoglobin (pg) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 0 0 0
DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
FOLLOW-UP n 9 9 8 8 High 0 0 0 0 Low 0 0 0 0
259
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Protocol: BA1116891 Page 13 of 48Population: Safety Table 10.402 Summary of Abnormal Hematology Laboratory Results
Lab Test: Ery. Mean Corpuscular Volume (fL) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0
DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0
DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 15 n 9 9 9 9 High 0 0 0 0 Low 0 0 1 (11%) 0
DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 29 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0
DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
260
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Protocol: BA1116891 Page 14 of 48Population: Safety Table 10.402 Summary of Abnormal Hematology Laboratory Results
Lab Test: Ery. Mean Corpuscular Volume (fL) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 1 (13%) 0
DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 0 0 0
DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
FOLLOW-UP n 9 9 8 8 High 0 0 0 0 Low 0 0 0 0
261
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Protocol: BA1116891 Page 15 of 48Population: Safety Table 10.402 Summary of Abnormal Hematology Laboratory Results
Lab Test: Erythrocytes (10^12/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 1 (11%) 0 1 (11%) 0
DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 1 (11%) 0 0
DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 1 (11%) 0
DAY 15 n 9 9 9 9 High 0 0 0 0 Low 1 (11%) 2 (22%) 0 0
DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 1 (11%) 0
DAY 29 n 9 9 0 9 High 0 0 0 0 Low 1 (11%) 0 0 0
DAY 31 n 0 0 9 0 High 0 0 1 (11%) 0 Low 0 0 2 (22%) 0
262
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Protocol: BA1116891 Page 16 of 48Population: Safety Table 10.402 Summary of Abnormal Hematology Laboratory Results
Lab Test: Erythrocytes (10^12/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 1 (11%) 0 0
DAY 78 n 0 0 8 0 High 0 0 1 (13%) 0 Low 0 0 0 0
FOLLOW-UP n 9 9 8 8 High 0 0 0 0 Low 1 (11%) 2 (22%) 1 (13%) 0
263
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Protocol: BA1116891 Page 17 of 48Population: Safety Table 10.402 Summary of Abnormal Hematology Laboratory Results
Lab Test: Erythrocytes Distribution Width (1) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 1 (11%) 0 0 0 Low 0 0 0 0
DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0
DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 15 n 9 9 9 9 High 1 (11%) 0 0 0 Low 0 0 0 0
DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 29 n 9 9 0 9 High 1 (11%) 0 0 1 (11%) Low 0 0 0 0
DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
264
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Protocol: BA1116891 Page 18 of 48Population: Safety Table 10.402 Summary of Abnormal Hematology Laboratory Results
Lab Test: Erythrocytes Distribution Width (1) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
DAY 57 n 9 9 0 8 High 1 (11%) 0 0 1 (13%) Low 0 0 0 0
DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
FOLLOW-UP n 9 9 8 8 High 1 (11%) 0 0 1 (13%) Low 0 0 0 0
265
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Protocol: BA1116891 Page 19 of 48Population: Safety Table 10.402 Summary of Abnormal Hematology Laboratory Results
Lab Test: Hematocrit (1) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 3 (33%) 2 (22%) 0 0
DAY 5 n 9 9 0 9 High 0 0 0 0 Low 1 (11%) 1 (11%) 0 2 (22%)
DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 15 n 9 9 9 9 High 0 0 0 0 Low 2 (22%) 3 (33%) 1 (11%) 1 (11%)
DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 2 (22%) 0
DAY 29 n 9 9 0 9 High 0 0 0 0 Low 2 (22%) 1 (11%) 0 0
DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 1 (11%) 0
266
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 20 of 48Population: Safety Table 10.402 Summary of Abnormal Hematology Laboratory Results
Lab Test: Hematocrit (1) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
DAY 57 n 9 9 0 8 High 0 0 0 0 Low 2 (22%) 1 (11%) 0 0
DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
FOLLOW-UP n 9 9 8 8 High 1 (11%) 0 0 0 Low 1 (11%) 1 (11%) 1 (13%) 0
267
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Protocol: BA1116891 Page 21 of 48Population: Safety Table 10.402 Summary of Abnormal Hematology Laboratory Results
Lab Test: Hemoglobin (g/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 0 2 (22%) 0 0
DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 1 (11%)
DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 15 n 9 9 9 9 High 0 0 0 0 Low 2 (22%) 0 1 (11%) 0
DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 2 (22%) 0
DAY 29 n 9 9 0 9 High 0 0 0 0 Low 1 (11%) 0 0 1 (11%)
DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 1 (11%) 0
268
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Lab Test: Hemoglobin (g/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
DAY 57 n 9 9 0 8 High 0 0 0 0 Low 1 (11%) 1 (11%) 0 0
DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
FOLLOW-UP n 9 9 8 8 High 0 0 0 0 Low 1 (11%) 2 (22%) 1 (13%) 0
269
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Lab Test: Leukocytes (10^9/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 0 1 (11%) 0 0
DAY 5 n 9 9 0 9 High 0 0 0 0 Low 1 (11%) 1 (11%) 0 0
DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 3 (33%) 0
DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 15 n 9 9 9 9 High 0 0 0 0 Low 0 1 (11%) 1 (11%) 1 (11%)
DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 29 n 9 9 0 9 High 0 0 0 0 Low 2 (22%) 1 (11%) 0 3 (33%)
DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
270
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Lab Test: Leukocytes (10^9/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
DAY 57 n 9 9 0 8 High 0 0 0 0 Low 2 (22%) 1 (11%) 0 1 (13%)
DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
FOLLOW-UP n 9 9 8 8 High 0 0 0 0 Low 0 1 (11%) 2 (25%) 2 (25%)
271
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Lab Test: Lymphocytes (10^9/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0
DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0
DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 15 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0
DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 29 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0
DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
272
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Lab Test: Lymphocytes (10^9/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 0 0 0
DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
FOLLOW-UP n 9 9 8 8 High 0 0 0 0 Low 0 1 (11%) 0 0
273
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Lab Test: Lymphocytes Atypical (10^9/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 High 0 0 0 0 Low 0 0 0 0
DAY 5 High 0 0 0 0 Low 0 0 0 0
DAY 6 High 0 0 0 0 Low 0 0 0 0
DAY 8 High 0 0 0 0 Low 0 0 0 0
DAY 15 High 0 0 0 0 Low 0 0 0 0 n 0 1 0 0
DAY 22 High 0 0 0 0 Low 0 0 0 0
DAY 29 High 0 0 0 0 Low 0 0 0 0
DAY 31 High 0 0 0 0 Low 0 0 0 0
DAY 50 High 0 0 0 0 Low 0 0 0 0
DAY 57 High 0 0 0 0 Low 0 0 0 0
274
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Lab Test: Lymphocytes Atypical (10^9/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 78 High 0 0 0 0 Low 0 0 0 0
FOLLOW-UP High 0 0 0 0 Low 0 0 0 0
275
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Lab Test: Lymphocytes Atypical/Leukocytes (1) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 High 0 0 0 0 Low 0 0 0 0
DAY 5 High 0 0 0 0 Low 0 0 0 0
DAY 6 High 0 0 0 0 Low 0 0 0 0
DAY 8 High 0 0 0 0 Low 0 0 0 0
DAY 15 High 0 1 (100%) 0 0 Low 0 0 0 0 n 0 1 0 0
DAY 22 High 0 0 0 0 Low 0 0 0 0
DAY 29 High 0 0 0 0 Low 0 0 0 0
DAY 31 High 0 0 0 0 Low 0 0 0 0
DAY 50 High 0 0 0 0 Low 0 0 0 0
DAY 57 High 0 0 0 0 Low 0 0 0 0
276
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Lab Test: Lymphocytes Atypical/Leukocytes (1) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 78 High 0 0 0 0 Low 0 0 0 0
FOLLOW-UP High 0 0 0 0 Low 0 0 0 0
277
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Lab Test: Lymphocytes/Leukocytes (1) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 2 (22%) 1 (11%) 3 (33%) 2 (22%) Low 0 0 0 1 (11%)
DAY 5 n 9 9 0 9 High 1 (11%) 0 0 1 (11%) Low 0 1 (11%) 0 1 (11%)
DAY 6 n 0 0 9 0 High 0 0 1 (11%) 0 Low 0 0 1 (11%) 0
DAY 8 n 0 0 9 0 High 0 0 4 (44%) 0 Low 0 0 0 0
DAY 15 n 9 9 9 9 High 0 2 (22%) 3 (33%) 2 (22%) Low 2 (22%) 2 (22%) 0 1 (11%)
DAY 22 n 0 0 9 0 High 0 0 2 (22%) 0 Low 0 0 0 0
DAY 29 n 9 9 0 9 High 1 (11%) 1 (11%) 0 2 (22%) Low 0 0 0 0
DAY 31 n 0 0 9 0 High 0 0 2 (22%) 0 Low 0 0 0 0
278
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Lab Test: Lymphocytes/Leukocytes (1) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 1 (13%) 0 Low 0 0 0 0
DAY 57 n 9 9 0 8 High 1 (11%) 0 0 2 (25%) Low 1 (11%) 3 (33%) 0 1 (13%)
DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
FOLLOW-UP n 9 9 8 8 High 1 (11%) 0 2 (25%) 2 (25%) Low 1 (11%) 2 (22%) 0 1 (13%)
279
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Lab Test: Monocytes (10^9/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0
DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0
DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 15 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0
DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 29 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0
DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
280
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Lab Test: Monocytes (10^9/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 0 0 0
DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
FOLLOW-UP n 9 9 8 8 High 0 0 0 0 Low 0 0 0 0
281
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Lab Test: Monocytes/Leukocytes (1) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 1 (11%) 1 (11%) 0 0 Low 0 0 0 0
DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0
DAY 6 n 0 0 9 0 High 0 0 1 (11%) 0 Low 0 0 0 0
DAY 8 n 0 0 9 0 High 0 0 1 (11%) 0 Low 0 0 0 0
DAY 15 n 9 9 9 9 High 1 (11%) 3 (33%) 1 (11%) 1 (11%) Low 0 0 0 0
DAY 22 n 0 0 9 0 High 0 0 1 (11%) 0 Low 0 0 0 0
DAY 29 n 9 9 0 9 High 1 (11%) 1 (11%) 0 1 (11%) Low 0 0 0 0
DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
282
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Lab Test: Monocytes/Leukocytes (1) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 1 (13%) 0 Low 0 0 0 0
DAY 57 n 9 9 0 8 High 1 (11%) 3 (33%) 0 0 Low 0 0 0 0
DAY 78 n 0 0 8 0 High 0 0 1 (13%) 0 Low 0 0 0 0
FOLLOW-UP n 9 9 8 8 High 3 (33%) 0 2 (25%) 1 (13%) Low 0 0 0 0
283
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Lab Test: Neutrophils (10^9/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 0 0 0 0
DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0
DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 15 n 9 9 9 9 High 0 0 0 0 Low 0 1 (11%) 2 (22%) 0
DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 29 n 9 9 0 9 High 0 0 0 0 Low 0 1 (11%) 0 0
DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 1 (11%) 0
284
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Lab Test: Neutrophils (10^9/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 0 0 0
DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
FOLLOW-UP n 9 9 8 8 High 0 0 0 0 Low 0 0 1 (13%) 0
285
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Protocol: BA1116891 Page 39 of 48Population: Safety Table 10.402 Summary of Abnormal Hematology Laboratory Results
Lab Test: Neutrophils/Leukocytes (1) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 0 0 1 (11%) 0
DAY 5 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0
DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 15 n 9 9 9 9 High 1 (11%) 0 0 0 Low 0 1 (11%) 2 (22%) 0
DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 29 n 9 9 0 9 High 0 0 0 0 Low 0 0 0 0
DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 1 (11%) 0
286
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Lab Test: Neutrophils/Leukocytes (1) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
DAY 57 n 9 9 0 8 High 0 1 (11%) 0 0 Low 1 (11%) 0 0 0
DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
FOLLOW-UP n 9 9 8 8 High 0 1 (11%) 0 0 Low 0 0 1 (13%) 0
287
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Lab Test: Platelet Count (Lt Blue) (10^9/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 High 0 0 0 0 Low 0 0 0 0
DAY 5 High 0 0 0 0 Low 0 0 0 0
DAY 6 High 0 0 0 0 Low 0 0 0 0 n 0 0 1 0
DAY 8 High 0 0 0 0 Low 0 0 0 0 n 0 0 1 0
DAY 15 High 0 0 0 0 Low 0 0 0 0 n 0 0 1 0
DAY 22 High 0 0 0 0 Low 0 0 0 0 n 0 0 1 0
DAY 29 High 0 0 0 0 Low 0 0 0 0
DAY 31 High 0 0 0 0 Low 0 0 0 0 n 0 0 1 0
DAY 50 High 0 0 0 0 Low 0 0 0 0
288
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Lab Test: Platelet Count (Lt Blue) (10^9/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 57 High 0 0 0 0 Low 0 0 0 0
DAY 78 High 0 0 0 0 Low 0 0 0 0
FOLLOW-UP High 0 0 0 0 Low 0 0 0 0
289
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Protocol: BA1116891 Page 43 of 48Population: Safety Table 10.402 Summary of Abnormal Hematology Laboratory Results
Lab Test: Platelets (10^9/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 0 0 0 0 Low 1 (11%) 0 0 0
DAY 5 n 9 9 0 9 High 0 0 0 0 Low 1 (11%) 0 0 0
DAY 6 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 1 (11%) 0
DAY 15 n 9 9 9 9 High 0 1 (11%) 0 0 Low 0 0 0 0
DAY 22 n 0 0 8 0 High 0 0 0 0 Low 0 0 1 (13%) 0
DAY 29 n 9 9 0 9 High 0 1 (11%) 0 0 Low 1 (11%) 0 0 0
DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 1 (11%) 0
290
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Lab Test: Platelets (10^9/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 7 0 High 0 0 0 0 Low 0 0 1 (14%) 0
DAY 57 n 9 9 0 8 High 0 0 0 0 Low 1 (11%) 0 0 0
DAY 78 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
FOLLOW-UP n 9 9 7 8 High 0 0 0 0 Low 1 (11%) 1 (11%) 1 (14%) 0
291
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Protocol: BA1116891 Page 45 of 48Population: Safety Table 10.402 Summary of Abnormal Hematology Laboratory Results
Lab Test: Reticulocytes (10^9/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 1 (11%) 1 (11%) 0 0 Low 0 0 0 0
DAY 5 n 9 9 0 9 High 0 2 (22%) 0 0 Low 0 0 0 0
DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 15 n 9 9 9 9 High 1 (11%) 1 (11%) 0 0 Low 0 0 0 0
DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 29 n 9 9 0 9 High 1 (11%) 1 (11%) 0 0 Low 0 0 0 0
DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
292
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Lab Test: Reticulocytes (10^9/L) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 0 0 0
DAY 78 n 0 0 8 0 High 0 0 1 (13%) 0 Low 0 0 0 0
FOLLOW-UP n 9 9 8 8 High 0 0 1 (13%) 0 Low 0 0 0 0
293
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Protocol: BA1116891 Page 47 of 48Population: Safety Table 10.402 Summary of Abnormal Hematology Laboratory Results
Lab Test: Reticulocytes/Erythrocytes (1) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 1 n 9 9 9 9 High 1 (11%) 1 (11%) 0 0 Low 0 0 0 0
DAY 5 n 9 9 0 9 High 0 2 (22%) 0 0 Low 0 0 0 0
DAY 6 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 8 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 15 n 9 9 9 9 High 1 (11%) 1 (11%) 0 0 Low 0 0 0 0
DAY 22 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
DAY 29 n 9 9 0 9 High 1 (11%) 1 (11%) 0 0 Low 0 0 0 0
DAY 31 n 0 0 9 0 High 0 0 0 0 Low 0 0 0 0
294
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Lab Test: Reticulocytes/Erythrocytes (1) IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg (N=9) (N=9) (N=9) (N=9) --------------------------------------------------------------------------------- DAY 50 n 0 0 8 0 High 0 0 0 0 Low 0 0 0 0
DAY 57 n 9 9 0 8 High 0 0 0 0 Low 0 0 0 0
DAY 78 n 0 0 8 0 High 0 0 1 (13%) 0 Low 0 0 0 0
FOLLOW-UP n 9 9 8 8 High 0 1 (11%) 1 (13%) 0 Low 0 0 0 0
295
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Protocol: BA1116891 Page 1 of 12Population: Safety Table 10.501 Summary of Urinalysis Data (Character Result)
Lab Test: Bacteria IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------ DAY 1 Negative 1 (11%) 1 (11%) 1 (11%) Rare 1 (11%)
DAY 5 Negative 2 (22%) 2 (22%) 2 (22%)
DAY 6 Negative 2 (22%)
DAY 8 Negative 1 (11%)
DAY 15 Negative 2 (22%) 3 (33%) 4 (44%) 4 (44%)
DAY 22 Negative 1 (11%)
DAY 29 Negative 2 (22%) 2 (22%)
DAY 31 Negative 1 (11%)
DAY 50 Negative 2 (22%)
DAY 57 Negative 2 (22%) 2 (22%) 2 (22%)
DAY 78 Negative 1 (11%)
FOLLOW-UP Negative 2 (22%) 1 (11%) 1 (11%) 4 (44%) Rare 1 (11%)
Note:Data available only for Subjects who took this test.
296
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Lab Test: Calcium Oxalate Crystals IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------ DAY 29 Rare 1 (11%)
Note:Data available only for Subjects who took this test.
297
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Lab Test: Casts IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------ DAY 1 Negative 1 (11%) 2 (22%) 1 (11%)
DAY 5 Negative 2 (22%) 2 (22%) 2 (22%)
DAY 6 Negative 2 (22%)
DAY 8 Negative 1 (11%)
DAY 15 Negative 1 (11%) 2 (22%) 4 (44%) 4 (44%)
DAY 22 Negative 1 (11%)
DAY 29 Negative 2 (22%) 2 (22%)
DAY 31 Negative 1 (11%)
DAY 50 Negative 2 (22%)
DAY 57 Negative 1 (11%) 2 (22%) 2 (22%)
DAY 78 Negative 1 (11%)
FOLLOW-UP Negative 3 (33%) 1 (11%) 1 (11%) 4 (44%)
Note:Data available only for Subjects who took this test.
298
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Lab Test: Crystals IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------ DAY 1 Negative 1 (11%) 1 (11%)
DAY 5 Negative 2 (22%) 1 (11%) 2 (22%)
DAY 6 Negative 2 (22%)
DAY 15 Negative 2 (22%) 3 (33%) 4 (44%) 2 (22%)
DAY 22 Negative 1 (11%)
DAY 29 Negative 2 (22%) 1 (11%)
DAY 50 Negative 2 (22%)
DAY 57 Negative 1 (11%) 2 (22%) 2 (22%)
DAY 78 Negative 1 (11%)
FOLLOW-UP Negative 3 (33%) 1 (11%) 1 (11%) 3 (33%)
Note:Data available only for Subjects who took this test.
299
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Lab Test: Epithelial Cells IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------ DAY 1 Negative 1 (11%) 1 (11%) 1 (11%)
DAY 5 Negative 1 (11%) 1 (11%)
DAY 6 Negative 1 (11%)
DAY 8 Negative 1 (11%)
DAY 15 Negative 1 (11%) 1 (11%) 2 (22%) 3 (33%)
DAY 22 Negative 1 (11%)
DAY 29 Negative 1 (11%) 1 (11%)
DAY 31 Negative 1 (11%)
DAY 50 Negative 1 (11%)
DAY 57 Negative 2 (22%) 2 (22%)
FOLLOW-UP Negative 2 (22%) 1 (11%) 2 (22%)
Note:Data available only for Subjects who took this test.
300
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Lab Test: Glucose IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------ DAY 1 Negative 9 (100%) 9 (100%) 9 (100%) 9 (100%)
DAY 5 Negative 9 (100%) 9 (100%) 9 (100%)
DAY 6 Negative 9 (100%)
DAY 8 Negative 9 (100%)
DAY 15 Negative 9 (100%) 9 (100%) 8 (89%) 9 (100%)
DAY 22 Negative 9 (100%)
DAY 29 Negative 9 (100%) 9 (100%) 9 (100%)
DAY 31 Negative 9 (100%)
DAY 50 Negative 8 (89%)
DAY 57 Negative 8 (89%) 9 (100%) 8 (89%)
DAY 78 Negative 8 (89%)
FOLLOW-UP Negative 9 (100%) 9 (100%) 8 (89%) 8 (89%)
Note:Data available only for Subjects who took this test.
301
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Protocol: BA1116891 Page 7 of 12Population: Safety Table 10.501 Summary of Urinalysis Data (Character Result)
Lab Test: Ketones IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------ DAY 1 Negative 9 (100%) 8 (89%) 9 (100%) 9 (100%)
DAY 5 Negative 9 (100%) 9 (100%) 9 (100%)
DAY 6 Negative 8 (89%)
DAY 8 Negative 8 (89%)
DAY 15 Negative 7 (78%) 8 (89%) 8 (89%) 9 (100%)
DAY 22 Negative 9 (100%)
DAY 29 Negative 9 (100%) 8 (89%) 9 (100%)
DAY 31 Negative 9 (100%)
DAY 50 Negative 8 (89%)
DAY 57 Negative 8 (89%) 6 (67%) 8 (89%)
DAY 78 Negative 8 (89%)
FOLLOW-UP Negative 9 (100%) 9 (100%) 8 (89%) 6 (67%)
Note:Data available only for Subjects who took this test.
302
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Protocol: BA1116891 Page 8 of 12Population: Safety Table 10.501 Summary of Urinalysis Data (Character Result)
Lab Test: Mucous Threads IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------ DAY 1 Rare 1 (11%)
DAY 5 Rare 1 (11%) 1 (11%) 1 (11%)
DAY 6 Rare 1 (11%)
DAY 15 Negative 1 (11%) 1 (11%) Rare 1 (11%) 1 (11%) 2 (22%)
DAY 29 Rare 1 (11%) 1 (11%)
DAY 31 Rare 1 (11%)
DAY 50 Rare 1 (11%)
DAY 57 Rare 2 (22%) 1 (11%)
DAY 78 Rare 1 (11%)
FOLLOW-UP Rare 2 (22%) 1 (11%) 2 (22%)
Note:Data available only for Subjects who took this test.
303
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 9 of 12Population: Safety Table 10.501 Summary of Urinalysis Data (Character Result)
Lab Test: Nitrite IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------ DAY 1 Negative 1 (11%)
DAY 29 Negative 1 (11%)
Note:Data available only for Subjects who took this test.
304
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 10 of 12Population: Safety Table 10.501 Summary of Urinalysis Data (Character Result)
Lab Test: Occult Blood IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------ DAY 1 Negative 9 (100%) 9 (100%) 9 (100%) 9 (100%)
DAY 5 Negative 9 (100%) 9 (100%) 8 (89%)
DAY 6 Negative 9 (100%)
DAY 8 Negative 9 (100%)
DAY 15 Negative 9 (100%) 9 (100%) 9 (100%) 7 (78%)
DAY 22 Negative 9 (100%)
DAY 29 Negative 9 (100%) 9 (100%) 9 (100%)
DAY 31 Negative 9 (100%)
DAY 50 Negative 7 (78%)
DAY 57 Negative 8 (89%) 8 (89%) 8 (89%)
DAY 78 Negative 7 (78%)
FOLLOW-UP Negative 7 (78%) 9 (100%) 8 (89%) 7 (78%)
Note:Data available only for Subjects who took this test.
305
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 11 of 12Population: Safety Table 10.501 Summary of Urinalysis Data (Character Result)
Lab Test: Protein IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------ DAY 1 Negative 8 (89%) 9 (100%) 7 (78%) 8 (89%)
DAY 5 Negative 7 (78%) 7 (78%) 7 (78%)
DAY 6 Negative 7 (78%)
DAY 8 Negative 8 (89%)
DAY 15 Negative 7 (78%) 6 (67%) 5 (56%) 5 (56%)
DAY 22 Negative 8 (89%)
DAY 29 Negative 7 (78%) 7 (78%) 9 (100%)
DAY 31 Negative 8 (89%)
DAY 50 Negative 7 (78%)
DAY 57 Negative 6 (67%) 7 (78%) 6 (67%)
DAY 78 Negative 7 (78%)
FOLLOW-UP Negative 7 (78%) 8 (89%) 7 (78%) 4 (44%)
Note:Data available only for Subjects who took this test.
306
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 12 of 12Population: Safety Table 10.501 Summary of Urinalysis Data (Character Result)
Lab Test: Spermatozoa IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------ DAY 6 Rare 2 (22%)
DAY 29 Rare 1 (11%)
DAY 57 Rare 1 (11%)
DAY 78 Rare 1 (11%)
Note:Data available only for Subjects who took this test.
307
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 1 of 11Population: Safety Table 10.502 Summary of Urinalysys Data (Numerical Result)
LABTEST: Erythrocytes (/HPF) Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------ IV_200mg 9 DAY 1 PREDOSE 1 0.000 0.000 0.00 0.00
DAY 5 96 H 2 0.000 0.0000 0.000 0.00 0.00
DAY 15 336 H 2 0.000 0.0000 0.000 0.00 0.00
DAY 29 672 H 1 0.000 0.000 0.00 0.00
DAY 57 1344 H 1 0.000 0.000 0.00 0.00
FOLLOW-UP 2016 H 1 0.000 0.000 0.00 0.00
SQ_200mg 9 DAY 15 336 H 2 0.500 0.7071 0.500 0.00 1.00
DAY 29 672 H 2 3.500 3.5355 3.500 1.00 6.00
DAY 57 1344 H 2 6.000 8.4853 6.000 0.00 12.00
FOLLOW-UP 2016 H 1 0.000 0.000 0.00 0.00
SQ_50mg x 4 9 DAY 1 PREDOSE 2 0.000 0.0000 0.000 0.00 0.00
DAY 6 120 H 2 1.000 0.0000 1.000 1.00 1.00
DAY 15 PREDOSE 3 1.000 1.0000 1.000 0.00 2.00
DAY 22 PREDOSE 1 1.000 1.000 1.00 1.00
DAY 50 672 H 2 0.500 0.7071 0.500 0.00 1.00
308
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 2 of 11Population: Safety Table 10.502 Summary of Urinalysys Data (Numerical Result)
LABTEST: Erythrocytes (/HPF) Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------ SQ_50mg x 4 9 DAY 78 1344 H 1 0.000 0.000 0.00 0.00
FOLLOW-UP 2016 H 1 0.000 0.000 0.00 0.00
IM_200mg 9 DAY 5 96 H 2 90.000 125.8650 90.000 1.00 179.00
DAY 15 336 H 3 14.667 25.4034 0.000 0.00 44.00
DAY 57 1344 H 1 0.000 0.000 0.00 0.00
FOLLOW-UP 2016 H 4 1.500 1.0000 1.000 1.00 3.00
309
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 3 of 11Population: Safety Table 10.502 Summary of Urinalysys Data (Numerical Result)
LABTEST: Granular Casts (/LPF) Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------ IV_200mg 9 DAY 57 1344 H 1 2.0 2.0 2 2
310
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 4 of 11Population: Safety Table 10.502 Summary of Urinalysys Data (Numerical Result)
LABTEST: Hyaline Casts (/LPF) Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------ IV_200mg 9 DAY 15 336 H 1 12.0 12.0 12 12
SQ_200mg 9 DAY 15 336 H 1 1.0 1.0 1 1
311
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 5 of 11Population: Safety Table 10.502 Summary of Urinalysys Data (Numerical Result)
LABTEST: Leukocytes (/HPF) Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------ IV_200mg 9 DAY 5 96 H 1 0.00 0.00 0.0 0.0
DAY 15 336 H 1 2.00 2.00 2.0 2.0
DAY 57 1344 H 2 1.50 0.707 1.50 1.0 2.0
FOLLOW-UP 2016 H 1 2.00 2.00 2.0 2.0
SQ_200mg 9 DAY 5 96 H 1 1.00 1.00 1.0 1.0
DAY 15 336 H 2 1.00 0.000 1.00 1.0 1.0
DAY 29 672 H 2 40.50 55.861 40.50 1.0 80.0
DAY 57 1344 H 1 2.00 2.00 2.0 2.0
SQ_50mg x 4 9 DAY 1 PREDOSE 2 3.50 3.536 3.50 1.0 6.0
DAY 6 120 H 2 2.00 1.414 2.00 1.0 3.0
DAY 8 PREDOSE 1 1.00 1.00 1.0 1.0
DAY 15 PREDOSE 3 5.00 4.583 4.00 1.0 10.0
DAY 22 PREDOSE 1 1.00 1.00 1.0 1.0
DAY 31 216 H 1 1.00 1.00 1.0 1.0
DAY 78 1344 H 1 3.00 3.00 3.0 3.0
312
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 6 of 11Population: Safety Table 10.502 Summary of Urinalysys Data (Numerical Result)
LABTEST: Leukocytes (/HPF) Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------ SQ_50mg x 4 9 FOLLOW-UP 2016 H 1 1.00 1.00 1.0 1.0
IM_200mg 9 DAY 5 96 H 2 1.00 1.414 1.00 0.0 2.0
DAY 15 336 H 1 0.00 0.00 0.0 0.0
DAY 57 1344 H 1 1.00 1.00 1.0 1.0
FOLLOW-UP 2016 H 3 2.67 2.082 2.00 1.0 5.0
313
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 7 of 11Population: Safety Table 10.502 Summary of Urinalysys Data (Numerical Result)
LABTEST: Specific Gravity Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------ IV_200mg 9 DAY 1 PREDOSE 9 1.0178 0.00455 1.0200 1.009 1.023
DAY 5 96 H 9 1.0179 0.00501 1.0190 1.010 1.025
DAY 15 336 H 9 1.0168 0.00795 1.0180 1.001 1.027
DAY 29 672 H 9 1.0137 0.00610 1.0130 1.001 1.023
DAY 57 1344 H 8 1.0173 0.00658 1.0175 1.008 1.025
FOLLOW-UP 2016 H 9 1.0170 0.00819 1.0200 1.002 1.027
SQ_200mg 9 DAY 1 PREDOSE 9 1.0111 0.00805 1.0130 1.002 1.021
DAY 5 96 H 9 1.0129 0.01022 1.0120 1.002 1.028
DAY 15 336 H 9 1.0157 0.00522 1.0160 1.009 1.023
DAY 29 672 H 9 1.0180 0.00444 1.0180 1.010 1.026
DAY 57 1344 H 9 1.0181 0.00639 1.0190 1.007 1.026
FOLLOW-UP 2016 H 9 1.0136 0.00844 1.0160 1.003 1.026
SQ_50mg x 4 9 DAY 1 PREDOSE 9 1.0178 0.00696 1.0170 1.009 1.028
DAY 6 120 H 9 1.0172 0.00356 1.0180 1.011 1.021
DAY 8 PREDOSE 9 1.0172 0.00716 1.0160 1.010 1.032
314
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 8 of 11Population: Safety Table 10.502 Summary of Urinalysys Data (Numerical Result)
LABTEST: Specific Gravity Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------ SQ_50mg x 4 9 DAY 15 PREDOSE 9 1.0220 0.00638 1.0230 1.008 1.030
DAY 22 PREDOSE 9 1.0189 0.00675 1.0180 1.009 1.027
DAY 31 216 H 9 1.0169 0.00623 1.0190 1.006 1.023
DAY 50 672 H 8 1.0136 0.00802 1.0130 1.004 1.024
DAY 78 1344 H 8 1.0155 0.00431 1.0160 1.009 1.022
FOLLOW-UP 2016 H 8 1.0128 0.00688 1.0115 1.004 1.027
IM_200mg 9 DAY 1 PREDOSE 9 1.0201 0.00754 1.0200 1.005 1.028
DAY 5 96 H 9 1.0188 0.00476 1.0200 1.011 1.026
DAY 15 336 H 9 1.0167 0.00723 1.0190 1.007 1.026
DAY 29 672 H 9 1.0163 0.00577 1.0160 1.007 1.025
DAY 57 1344 H 8 1.0184 0.00600 1.0205 1.006 1.025
FOLLOW-UP 2016 H 8 1.0228 0.00565 1.0235 1.015 1.031
315
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 9 of 11Population: Safety Table 10.502 Summary of Urinalysys Data (Numerical Result)
LABTEST: Squamous Epithelial Cells (/HPF) Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------ IV_200mg 9 DAY 29 672 H 1 1.0 1.0 1 1
FOLLOW-UP 2016 H 1 1.0 1.0 1 1
SQ_200mg 9 DAY 5 96 H 1 1.0 1.0 1 1
SQ_50mg x 4 9 FOLLOW-UP 2016 H 1 1.0 1.0 1 1
IM_200mg 9 DAY 5 96 H 1 1.0 1.0 1 1
FOLLOW-UP 2016 H 1 1.0 1.0 1 1
316
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 10 of 11Population: Safety Table 10.502 Summary of Urinalysys Data (Numerical Result)
LABTEST: pH Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------ IV_200mg 9 DAY 1 PREDOSE 9 5.67 0.559 6.00 5.0 6.5
DAY 5 96 H 9 6.44 0.950 6.50 5.0 8.0
DAY 15 336 H 9 6.17 0.750 6.00 5.5 7.5
DAY 29 672 H 9 6.33 0.829 6.50 5.0 7.5
DAY 57 1344 H 8 6.44 0.729 6.50 5.5 7.5
FOLLOW-UP 2016 H 9 5.94 0.527 6.00 5.5 7.0
SQ_200mg 9 DAY 1 PREDOSE 9 6.22 0.712 6.50 5.0 7.5
DAY 5 96 H 9 6.28 0.755 6.00 5.0 7.0
DAY 15 336 H 9 6.28 0.667 6.50 5.0 7.0
DAY 29 672 H 9 6.44 1.014 6.50 5.0 8.0
DAY 57 1344 H 9 6.06 0.391 6.00 5.5 6.5
FOLLOW-UP 2016 H 9 5.89 0.741 5.50 5.0 7.0
SQ_50mg x 4 9 DAY 1 PREDOSE 9 5.50 0.250 5.50 5.0 6.0
DAY 6 120 H 9 5.94 0.527 5.50 5.5 6.5
DAY 8 PREDOSE 9 5.61 0.333 5.50 5.0 6.0
317
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 11 of 11Population: Safety Table 10.502 Summary of Urinalysys Data (Numerical Result)
LABTEST: pH Planned Time Treatment N Visit Point n Mean SD Median Min. Max. ------------------------------------------------------------------------------------------ SQ_50mg x 4 9 DAY 15 PREDOSE 9 5.83 0.354 6.00 5.5 6.5
DAY 22 PREDOSE 9 5.89 0.417 6.00 5.5 6.5
DAY 31 216 H 9 6.11 0.601 6.00 5.5 7.0
DAY 50 672 H 8 5.88 0.791 5.75 5.0 7.0
DAY 78 1344 H 8 5.75 0.535 5.50 5.0 6.5
FOLLOW-UP 2016 H 8 6.06 0.729 6.00 5.0 7.0
IM_200mg 9 DAY 1 PREDOSE 9 5.67 0.500 5.50 5.0 6.5
DAY 5 96 H 9 6.06 0.527 6.00 5.5 7.0
DAY 15 336 H 9 6.00 0.791 6.00 5.0 7.5
DAY 29 672 H 9 6.17 0.707 6.00 5.5 7.5
DAY 57 1344 H 8 6.00 0.886 5.50 5.5 8.0
FOLLOW-UP 2016 H 8 6.06 0.496 6.00 5.5 7.0
318
CONFIDENTIAL 2014N211143_00BA1116891
Analysis Value
-999
-998
Cumulative Planned Relative Time
-999 -998
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
10000
20000
30000
40000
50000
60000
70000
Planned Relative Time (Hrs)
0 520 1040 1560 2080 2600
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Planned Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 1 of 1Page 1 of 1Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.1Mean Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Note: LLQ=100 ng/mL
Treatment IM_200mg IV_200mg SQ_200mg SQ_50mg x 4O O O
Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.1Mean Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Note: LLQ=100 ng/mL
Linear Scale
O
O
OOO
OO
O
O
O
O
O
Semi-Logarithmic Scale
O
O
OOOOO
O
O
O
O
O
319
CONFIDENTIAL 2014N211143_00BA1116891
Analysis Value
-999
-998
Cumulative Planned Relative Time
-999 -998
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
10000
20000
30000
40000
50000
60000
70000
Planned Relative Time (Hrs)
0 200 400 600 800
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Planned Relative Time (Hrs)
0 200 400 600 800
Page 1 of 1Page 1 of 1Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.2Mean Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Note: LLQ=100 ng/mL
Treatment IM_200mg IV_200mg SQ_200mg SQ_50mg x 4O O O
Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.2Mean Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Note: LLQ=100 ng/mL
Linear Scale
O
O
O O O
OO
O
O
O
O
Semi-Logarithmic Scale
O
O
O O OO O
O
O
O
O
320
CONFIDENTIAL 2014N211143_00BA1116891
Analysis Value
-999
-998
Cumulative Planned Relative Time
-999 -998
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
10000
20000
30000
40000
50000
60000
70000
Planned Relative Time (Hrs)
0 520 1040 1560 2080 2600
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Planned Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 1 of 1Page 1 of 1Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.3Median Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Note: LLQ=100 ng/mL
Treatment IM_200mg IV_200mg SQ_200mg SQ_50mg x 4O O O
Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.3Median Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Note: LLQ=100 ng/mL
Linear Scale
OO
OOO
OO
O
O
O
O
O
Semi-Logarithmic Scale
O
O
OOO
OOO
O
O
O
O
321
CONFIDENTIAL 2014N211143_00BA1116891
Analysis Value
-999
-998
Cumulative Planned Relative Time
-999 -998
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
10000
20000
30000
40000
50000
60000
70000
Planned Relative Time (Hrs)
0 200 400 600 800
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Planned Relative Time (Hrs)
0 200 400 600 800
Page 1 of 1Page 1 of 1Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.4Median Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Note: LLQ=100 ng/mL
Treatment IM_200mg IV_200mg SQ_200mg SQ_50mg x 4O O O
Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.4Median Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Note: LLQ=100 ng/mL
Linear Scale
OO
O OO
OO
O
O
O
O
Semi-Logarithmic Scale
O
O
O O O
O OO
O
O
O
322
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 1 of 36Page 1 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.5Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Note: LLQ=100 ng/mL
Subject ID: Treatment:SQ_200mg
Linear Scale
OO
O
OO
OO
O
O
O
O
O
Semi-Logarithmic Scale
O
O
O
OO
OOO
O
O
O
O
323
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 2 of 36Page 2 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.5Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Note: LLQ=100 ng/mL
Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OOOOO O
OOOO
OOOO
O
OO
OOOO
O
OO
OO
O
O
OO
O
Semi-Logarithmic Scale
O
OO
OO OOOOO
OOOOOOO
OOOOO
OO
OOO
O
O
O
O
324
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 3 of 36Page 3 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.5Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Note: LLQ=100 ng/mL
Subject ID: Treatment:IM_200mg
Linear Scale
O
O
OOO
OO
O
O
OO
O
Semi-Logarithmic Scale
O
O
OOOOOO
O
O
O
O
325
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 4 of 36Page 4 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.5Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Note: LLQ=100 ng/mL
Subject ID: Treatment:IV_200mg
Linear Scale
OOO
O
O
OO
O
O
OO
O
O
O
O
O
O
Semi-Logarithmic Scale
OOOOOOOO
O
OOOO
O
O
O
O
326
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 5 of 36Page 5 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.5Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Note: LLQ=100 ng/mL
Subject ID: Treatment:IV_200mg
Linear Scale
OOO
O
OOO
O
O
OO
O
O
O
O
O
O
Semi-Logarithmic Scale
OOOOOOOO
OOOO
O
O
O
O
O
327
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 6 of 36Page 6 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.5Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Note: LLQ=100 ng/mL
Subject ID: Treatment:IM_200mg
Linear Scale
O
O
O
OO
O
O
O
O
OO
Semi-Logarithmic Scale
O
O
OOOOO
O
O
O
O
328
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 7 of 36Page 7 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.5Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Note: LLQ=100 ng/mL
Subject ID: Treatment:SQ_200mg
Linear Scale
O
O
OOOOO
O
OO
O
O
Semi-Logarithmic Scale
O
O
OOOOO
O
OO
O
O
329
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 8 of 36Page 8 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.5Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Note: LLQ=100 ng/mL
Subject ID: Treatment:SQ_50mg x 4
Linear Scale
O
OOOOO OOOO
OOO
OOOOOOO
OO
OOO
OO
OO
OO
Semi-Logarithmic Scale
O
OOO
OO OOOOO
OOOOOOOOO
OO
OOO
OOO
O
O
O
330
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 9 of 36Page 9 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.5Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Note: LLQ=100 ng/mL
Subject ID: Treatment:IV_200mg
Linear Scale
OOOO
OOO
O
O
O
OO
O
O
OO
O
Semi-Logarithmic Scale
OOOOOOOO
OOOO
OO
O
O
O
331
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 10 of 36Page 10 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.5Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Note: LLQ=100 ng/mL
Subject ID: Treatment:SQ_200mg
Linear Scale
O
O
OOOO
O
OO
O
O
Semi-Logarithmic Scale
O
O
OOOO
O
O
O
O
O
332
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 11 of 36Page 11 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.5Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Note: LLQ=100 ng/mL
Subject ID: Treatment:IM_200mg
Linear Scale
OO
O
O
OOO
O
O
OO
O
Semi-Logarithmic Scale
O
O
OOOOO
O
O
O
O
O
333
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 12 of 36Page 12 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.5Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Note: LLQ=100 ng/mL
Subject ID: Treatment:SQ_50mg x 4
Linear Scale
O
OOOOO O
OOOOOO OO
OOOOO
OOOOO
OOO
O
OO
Semi-Logarithmic Scale
O
OOO
OOOOOOO
OO OOOOOOO OOOOO
OOO
O
O
O
334
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 13 of 36Page 13 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.5Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Note: LLQ=100 ng/mL
Subject ID: Treatment:IV_200mg
Linear Scale
O
O
OO
OOO
O
OOOO
O
O
OO
Semi-Logarithmic Scale
OOOOOOOO
OOOO
O
O
O
O
335
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 14 of 36Page 14 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.5Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Note: LLQ=100 ng/mL
Subject ID: Treatment:SQ_200mg
Linear Scale
O
O
OOOOO
O
O
OO
O
Semi-Logarithmic Scale
O
O
OOOOO
OO
O
O
O
336
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 15 of 36Page 15 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.5Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Note: LLQ=100 ng/mL
Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OOOOO O
OOOOOO
OOOOO
OOO
O
OOO
OOO
OO
O
Semi-Logarithmic Scale
OOO
OO OOOOO
OOOOOOO
OOOO
OOO
OOO
OO
O
337
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 16 of 36Page 16 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.5Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Note: LLQ=100 ng/mL
Subject ID: Treatment:IM_200mg
Linear Scale
O
O
OOO
OO
O
O
OO
O
Semi-Logarithmic Scale
O
O
OOO
OOO
O
OO
O
338
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 17 of 36Page 17 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.5Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Note: LLQ=100 ng/mL
Subject ID: Treatment:SQ_200mg
Linear Scale
O
O
OO O
O
O
O
O
Semi-Logarithmic Scale
O
O
OO OO
O
O
O
339
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 18 of 36Page 18 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.5Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Note: LLQ=100 ng/mL
Subject ID: Treatment:IV_200mg
Linear Scale
O
OOO
OO
O
O
OO
OO
O
O
O
O
O
Semi-Logarithmic Scale
OOOOOOOO
OOOO
OO
O
O
O
340
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 19 of 36Page 19 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.5Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Note: LLQ=100 ng/mL
Subject ID: Treatment:IM_200mg
Linear Scale
O
O
OO
O
O O
O
O
O
Semi-Logarithmic Scale
O
O
OO
OO O
O
O
O
341
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 20 of 36Page 20 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.5Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Note: LLQ=100 ng/mL
Subject ID: Treatment:SQ_50mg x 4
Linear Scale
O
OOOO O
O
OOOOO
OOOOO
OO OO
O
OO
OO
O
O
OO
O
Semi-Logarithmic Scale
O
OOOO O
O
OOOOO OO
OOOOO O
OOOOOO
O
O
O
O
O
342
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 21 of 36Page 21 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.5Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Note: LLQ=100 ng/mL
Subject ID: Treatment:IV_200mg
Linear Scale
OOOOOO
OO
OO
O
O
O
O
OO
Semi-Logarithmic Scale
OOOOOOOO
OOOO
O
O
O
O
343
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 22 of 36Page 22 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.5Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Note: LLQ=100 ng/mL
Subject ID: Treatment:IM_200mg
Linear Scale
OO
OOO
OO
O
O
OO
O
Semi-Logarithmic Scale
O
O
OOO
OOO
O
O
O
O
344
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 23 of 36Page 23 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.5Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Note: LLQ=100 ng/mL
Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OOOO
OO OOOOO
OO OOOOO
OO OO
OOO
OO
O
O
OO
Semi-Logarithmic Scale
O
OOO
OO OOOOO
OO OOOOO
OO OOOOO
OO O
O
O
O
345
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 24 of 36Page 24 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.5Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Note: LLQ=100 ng/mL
Subject ID: Treatment:SQ_200mg
Linear Scale
O
O
OO
OOO
O
O
O
O
Semi-Logarithmic Scale
O
O
OO
OO O
O
O
O
O
346
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 25 of 36Page 25 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.5Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Note: LLQ=100 ng/mL
Subject ID: Treatment:SQ_200mg
Linear Scale
O
O
OO
OOO
O
O
O
O
Semi-Logarithmic Scale
O
O
OO
OOO
O
O
O
O
347
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 26 of 36Page 26 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.5Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Note: LLQ=100 ng/mL
Subject ID: Treatment:IM_200mg
Linear Scale
O
OOO
OO O
OO
O
O
Semi-Logarithmic Scale
O
O
OO
OO OO
O
O
O
348
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 27 of 36Page 27 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.5Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Note: LLQ=100 ng/mL
Subject ID: Treatment:IV_200mg
Linear Scale
OO
O
OOO
O
O
O
O
O
O
O
OO
O
Semi-Logarithmic Scale
OOOOOOO
OO
OO
OO
O
O
O
349
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 28 of 36Page 28 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.5Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Note: LLQ=100 ng/mL
Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OOOOO OOOOO
OO OOOOO
OO OOOOOOO
O OO O
Semi-Logarithmic Scale
OOO
OO OOOOO
OO OO
OOO
OO OOOOO
OO
OO
OO
350
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 29 of 36Page 29 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.5Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Note: LLQ=100 ng/mL
Subject ID: Treatment:IV_200mg
Linear Scale
OOOO
OO
O
O
OOOO
O
O
OO
O
Semi-Logarithmic Scale
OOOOOOOO
OOOO
O
O
O
O
O
351
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 30 of 36Page 30 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.5Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Note: LLQ=100 ng/mL
Subject ID: Treatment:IM_200mg
Linear Scale
O
O
OO
O
O
O
O
OO
O
Semi-Logarithmic Scale
O
OOO
OO
OO
O
O
O
352
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 31 of 36Page 31 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.5Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Note: LLQ=100 ng/mL
Subject ID: Treatment:SQ_50mg x 4
Linear Scale
O
OOOOO OO
OOO
OO O
OOOOOOO
O
OOO
O
OO
O
OO
O
Semi-Logarithmic Scale
O
OOOOO OO
OOO
OO O
OOOOOO O
OOOO
O
OO
O
O
O
O
353
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 32 of 36Page 32 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.5Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Note: LLQ=100 ng/mL
Subject ID: Treatment:SQ_200mg
Linear Scale
OO
O
OO
OO
O
O
O
O
O
Semi-Logarithmic Scale
O
O
O
OO
OOO
O
O
O
O
354
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 33 of 36Page 33 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.5Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Note: LLQ=100 ng/mL
Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OOOOO O
OOOOOO OOO
OOOO
OOOOO
OO
O
OO
Semi-Logarithmic Scale
OOO
OO OOOOOOO O
OOOOOO
OOOOO
OOO
O
O
355
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 34 of 36Page 34 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.5Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Note: LLQ=100 ng/mL
Subject ID: Treatment:IV_200mg
Linear Scale
OOOOOOO
O
OO
O
O
O
O
O
O
O
Semi-Logarithmic Scale
OOOOOOOO
OO
OO
OO
O
O
O
356
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 35 of 36Page 35 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.5Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Note: LLQ=100 ng/mL
Subject ID: Treatment:SQ_200mg
Linear Scale
OO
O
OO
OO
O
OO
O
Semi-Logarithmic Scale
O
O
O
OO
OO O
O
O
O
357
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 36 of 36Page 36 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.5Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Note: LLQ=100 ng/mL
Subject ID: Treatment:IM_200mg
Linear Scale
OO
OOO
OO
O
O
OO
O
Semi-Logarithmic Scale
O
O
OOO
OOO
O
O
O
O
358
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 1 of 36Page 1 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.6Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Note: LLQ=100 ng/mL
Subject ID: Treatment:SQ_200mg
Linear Scale
OO
O
O O
O O
O
O
O
O
Semi-Logarithmic Scale
O
O
O
O O
O OO
O
O
O
359
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 2 of 36Page 2 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.6Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Note: LLQ=100 ng/mL
Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OO O
O O OOO O O
O OOO
O
O O
O OOO
O
O O
OO
O
Semi-Logarithmic Scale
O
OO
O O OOO O O
O OOOO
O O
O OOO
O
O O
O OO
360
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 3 of 36Page 3 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.6Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Note: LLQ=100 ng/mL
Subject ID: Treatment:IM_200mg
Linear Scale
O
O
OO
O
O O
O
O
OO
Semi-Logarithmic Scale
O
O
O O OO O
O
O
O
O
361
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 4 of 36Page 4 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.6Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Note: LLQ=100 ng/mL
Subject ID: Treatment:IV_200mg
Linear Scale
OOO
O
O
OO
O
O
OO
O
O
O
O
O
Semi-Logarithmic Scale
OOOOOOOO
O
O OO
OO
O
O
362
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 5 of 36Page 5 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.6Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Note: LLQ=100 ng/mL
Subject ID: Treatment:IV_200mg
Linear Scale
OOO
O
OOO
O
O
OO
O
O
O
O
O
Semi-Logarithmic Scale
OOOOOOOO
OO O
O
O
O
O
O
363
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 6 of 36Page 6 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.6Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Note: LLQ=100 ng/mL
Subject ID: Treatment:IM_200mg
Linear Scale
O
O
O
OO
O
O
O
O
OO
Semi-Logarithmic Scale
O
O
OO O
OO
O
O
O
O
364
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 7 of 36Page 7 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.6Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Note: LLQ=100 ng/mL
Subject ID: Treatment:SQ_200mg
Linear Scale
O
O
OO O O
O
O
OO
O
Semi-Logarithmic Scale
O
O
O O O O O
O
OO
O
365
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 8 of 36Page 8 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.6Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Note: LLQ=100 ng/mL
Subject ID: Treatment:SQ_50mg x 4
Linear Scale
O
O O OO
O OO O O O
O OOOO
O OO O
OO
OO
O
O O
O
Semi-Logarithmic Scale
O
O O O
OO O
OO O O
O OOOO
O OO O
OO
OO
O
O OO
366
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 9 of 36Page 9 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.6Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Note: LLQ=100 ng/mL
Subject ID: Treatment:IV_200mg
Linear Scale
OOOO
OOO
O
O
O
OO
O
O
OO
Semi-Logarithmic Scale
OOOOOOOO
O OO O
OO
O
O
367
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 10 of 36Page 10 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.6Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Note: LLQ=100 ng/mL
Subject ID: Treatment:SQ_200mg
Linear Scale
O
O
O O OO
O
OO
O
Semi-Logarithmic Scale
O
O
O O OO
O
O
O
O
368
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 11 of 36Page 11 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.6Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Note: LLQ=100 ng/mL
Subject ID: Treatment:IM_200mg
Linear Scale
OO
O
O
OO O
O
O
OO
Semi-Logarithmic Scale
O
O
OO
O O O
O
O
O
O
369
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 12 of 36Page 12 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.6Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Note: LLQ=100 ng/mL
Subject ID: Treatment:SQ_50mg x 4
Linear Scale
O
O O OO O O
O O O OO O OO
OO O
O OOO O O O
O OO
Semi-Logarithmic Scale
O
O O O
O OOO O O O
O O OOO
O OO O
OO O O OO O
O
370
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 13 of 36Page 13 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.6Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Note: LLQ=100 ng/mL
Subject ID: Treatment:IV_200mg
Linear Scale
O
O
OO
OOO
O
OO
OO
O
O
OO
Semi-Logarithmic Scale
OOOOOOOO
OO O O
O
O
O
O
371
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 14 of 36Page 14 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.6Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Note: LLQ=100 ng/mL
Subject ID: Treatment:SQ_200mg
Linear Scale
O
O
OO O
OO
O
O
OO
Semi-Logarithmic Scale
O
O
OO O
O OO
O
O
O
372
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 15 of 36Page 15 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.6Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Note: LLQ=100 ng/mL
Subject ID: Treatment:SQ_50mg x 4
Linear Scale
O O OO O O
O O O OO O
OO O O O
OO
O
O
O O O
O OO
Semi-Logarithmic Scale
O OO
O O OO O O O
O OOO O O O
OO
OO
O O O
O OO
373
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 16 of 36Page 16 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.6Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Note: LLQ=100 ng/mL
Subject ID: Treatment:IM_200mg
Linear Scale
O
O
O O O
OO
O
O
OO
Semi-Logarithmic Scale
O
O
O O O
O OO
O
OO
374
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 17 of 36Page 17 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.6Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Note: LLQ=100 ng/mL
Subject ID: Treatment:SQ_200mg
Linear Scale
O
O
O OO
O
O
O
Semi-Logarithmic Scale
O
O
O O OO
O
O
375
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 18 of 36Page 18 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.6Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Note: LLQ=100 ng/mL
Subject ID: Treatment:IV_200mg
Linear Scale
O
OOO
OO
O
O
OO
OO
O
O
O
O
Semi-Logarithmic Scale
OOOOOOOO
O OO O
OO
O
O
376
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 19 of 36Page 19 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.6Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Note: LLQ=100 ng/mL
Subject ID: Treatment:IM_200mg
Linear Scale
O
O
OO
O
O O
O
O
O
Semi-Logarithmic Scale
O
O
O O
OO O
O
O
O
377
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 20 of 36Page 20 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.6Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Note: LLQ=100 ng/mL
Subject ID: Treatment:SQ_50mg x 4
Linear Scale
O
O OO O O
O
OO O
O OOO
OO O
O O OO
O
O O
O O
O
Semi-Logarithmic Scale
O
OO
O O O
O
OO O
O O OOO
O OO O O
OO
O OO O
O
378
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 21 of 36Page 21 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.6Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Note: LLQ=100 ng/mL
Subject ID: Treatment:IV_200mg
Linear Scale
OOOOOO
OO
O O
O
O
O
O
OO
Semi-Logarithmic Scale
OOOOOOO O
O OO
O
O
O
O
O
379
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 22 of 36Page 22 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.6Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Note: LLQ=100 ng/mL
Subject ID: Treatment:IM_200mg
Linear Scale
OO
O O O
OO
O
O
OO
Semi-Logarithmic Scale
O
O
O O O
O OO
O
O
O
380
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 23 of 36Page 23 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.6Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Note: LLQ=100 ng/mL
Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OO O O
O O OO O O O
O O OO O O O
O O OO
O O O
OO
O
Semi-Logarithmic Scale
O
O OO
O O OO O O O
O O OO O O O
O O OOO O O
O O O
381
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 24 of 36Page 24 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.6Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Note: LLQ=100 ng/mL
Subject ID: Treatment:SQ_200mg
Linear Scale
O
O
OO
O OO
O
O
O
Semi-Logarithmic Scale
O
O
OO
O OO
O
O
O
382
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 25 of 36Page 25 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.6Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Note: LLQ=100 ng/mL
Subject ID: Treatment:SQ_200mg
Linear Scale
O
O
O O
O OO
O
O
O
Semi-Logarithmic Scale
O
O
O O
O OO
O
O
O
383
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 26 of 36Page 26 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.6Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Note: LLQ=100 ng/mL
Subject ID: Treatment:IM_200mg
Linear Scale
O
OO O
O O O
OO
O
Semi-Logarithmic Scale
O
O
O O
O O OO
O
O
384
CONFIDENTIAL 2014N211143_00BA1116891
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
0
20000
40000
60000
80000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
GS
K93
3776
Con
cent
ratio
n (n
g/m
L)
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 27 of 36Page 27 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.6Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Note: LLQ=100 ng/mL
Subject ID: Treatment:IV_200mg
Linear Scale
OO
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Page 28 of 36Page 28 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.6Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Note: LLQ=100 ng/mL
Subject ID: Treatment:SQ_50mg x 4
Linear Scale
O O OO O OO O O O
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Page 29 of 36Page 29 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.6Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Note: LLQ=100 ng/mL
Subject ID: Treatment:IV_200mg
Linear Scale
OOOO
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Page 30 of 36Page 30 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.6Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Note: LLQ=100 ng/mL
Subject ID: Treatment:IM_200mg
Linear Scale
O
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Page 31 of 36Page 31 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.6Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Note: LLQ=100 ng/mL
Subject ID: Treatment:SQ_50mg x 4
Linear Scale
O
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Page 32 of 36Page 32 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.6Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Note: LLQ=100 ng/mL
Subject ID: Treatment:SQ_200mg
Linear Scale
OO
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Page 33 of 36Page 33 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.6Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Note: LLQ=100 ng/mL
Subject ID: Treatment:SQ_50mg x 4
Linear Scale
O O OO O O
O O O OO O OO O
O OO O
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Page 34 of 36Page 34 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.6Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Note: LLQ=100 ng/mL
Subject ID: Treatment:IV_200mg
Linear Scale
OOOOOOO
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Page 35 of 36Page 35 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.6Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Note: LLQ=100 ng/mL
Subject ID: Treatment:SQ_200mg
Linear Scale
OO
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Page 36 of 36Page 36 of 36Protocol: BA1116891Population: Pharmacokinetic Concentration
Figure 11.6Individual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Note: LLQ=100 ng/mL
Subject ID: Treatment:IM_200mg
Linear Scale
OO
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O O
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Semi-Logarithmic Scale
O
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Protocol: BA1116891 Page 1 of 4Population: PK Concentration Table 11.1 Summary of Plasma GSK933776 Pharmacokinetic Concentration-Time Data [ng/mL]
No. Time Impu 95% CITreatment N Visit point n -ted Mean (Lower, Upper) SD Median Min. Max.-----------------------------------------------------------------------------------------------------------IV_200mg 9 DAY 1 PREDOSE 8 8 NQ NQ NQ NQ 0.25 H 9 0 59553.9 (53117.0, 65990.7) 8374.04 59298.0 48466 71858 0.5 H 9 0 60036.7 (53782.8, 66290.5) 8135.94 61059.0 46293 72412 0.75 H 9 0 60308.3 (54220.7, 66396.0) 7919.72 60505.0 45858 72690 1 H 9 0 61534.1 (54242.0, 68826.2) 9486.70 61624.0 47684 79060 2 H 9 0 57057.1 (51346.4, 62767.8) 7429.38 56904.0 47076 71858 4 H 8 0 57206.5 (50903.4, 63509.6) 7539.40 57129.5 44813 68162 6 H 9 0 55827.6 (50276.2, 61378.9) 7222.05 53904.0 47076 70103 DAY 2 24 H 9 0 47895.1 (43154.0, 52636.2) 6167.95 50158.0 38239 58690 DAY 3 48 H 9 0 32207.4 (28490.9, 35924.0) 4835.07 31443.0 25778 42170 DAY 4 72 H 9 0 28468.9 (25954.1, 30983.7) 3271.66 29227.0 22995 32520 DAY 5 96 H 9 0 31205.1 (27946.9, 34463.4) 4238.82 32547.0 23759 38187 DAY 6 120 H 9 0 27108.0 (24801.6, 29414.4) 3000.48 28313.0 21285 30676 DAY 10 216 H 9 0 19899.1 (18369.1, 21429.1) 1990.45 20196.0 16073 22657 DAY 15 336 H 9 0 14879.6 (13013.9, 16745.2) 2427.17 15646.0 11477 18340 DAY 22 504 H 9 0 10104.4 (8470.3, 11738.6) 2125.97 10260.0 6462 13116 DAY 29 672 H 9 0 6716.6 (5490.2, 7942.9) 1595.37 7296.0 3705 8735 DAY 57 1344 H 8 1 1450.0 (833.1, 2066.9) 737.84 1491.0 0 2418 FOLLOW-UP 2016 H 6 6 NQ NQ NQ NQ
Note: LLQ=100 ng/mL
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Protocol: BA1116891 Page 2 of 4Population: PK Concentration Table 11.1 Summary of Plasma GSK933776 Pharmacokinetic Concentration-Time Data [ng/mL]
No. Time Impu 95% CITreatment N Visit point n -ted Mean (Lower, Upper) SD Median Min. Max.-----------------------------------------------------------------------------------------------------------SQ_200mg 9 DAY 1 PREDOSE 9 9 NQ NQ NQ NQ 2 H 6 1 1936.5 (490.0, 3383.0) 1378.38 1722.0 0 3581 6 H 9 0 3981.8 (1769.0, 6194.6) 2878.76 2530.0 1264 10391 DAY 2 24 H 9 0 11418.7 (6800.8, 16036.5) 6007.64 10668.0 5689 24415 DAY 3 48 H 8 0 15861.9 (10940.6, 20783.2) 5886.59 15265.5 9242 27231 DAY 4 72 H 8 0 16696.0 (12240.9, 21151.1) 5328.92 16667.0 10125 26340 DAY 5 96 H 9 0 22142.3 (19102.6, 25182.0) 3954.51 22151.0 16235 27386 DAY 6 120 H 9 0 21977.6 (19087.2, 24867.9) 3760.15 22463.0 14297 26489 DAY 10 216 H 9 0 18750.7 (16509.6, 20991.8) 2915.57 18308.0 12921 22725 DAY 15 336 H 9 0 14552.8 (12495.1, 16610.5) 2676.96 14744.0 9285 18216 DAY 22 504 H 9 0 10597.2 (9120.4, 12074.0) 1921.23 10583.0 6746 13021 DAY 29 672 H 9 0 6920.4 (5672.5, 8168.4) 1623.56 7185.0 3646 8894 DAY 57 1344 H 8 0 1682.5 (1384.8, 1980.2) 356.09 1734.0 1015 2068 FOLLOW-UP 2016 H 6 6 NQ NQ NQ NQ
Note: LLQ=100 ng/mL
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Protocol: BA1116891 Page 3 of 4Population: PK Concentration Table 11.1 Summary of Plasma GSK933776 Pharmacokinetic Concentration-Time Data [ng/mL]
No. Time Impu 95% CITreatment N Visit point n -ted Mean (Lower, Upper) SD Median Min. Max.-----------------------------------------------------------------------------------------------------------SQ_50mg x 9 DAY 1 PREDOSE 9 9 NQ NQ NQ NQ4 6 H 4 0 2090.8 (588.1, 3593.4) 944.32 2127.5 1150 2958 DAY 2 24 H 9 0 4258.9 (2818.9, 5698.8) 1873.31 3920.0 2113 6773 DAY 3 48 H 9 0 4787.2 (3702.2, 5872.2) 1411.56 4749.0 2392 6336 DAY 4 72 H 9 0 5347.6 (4357.9, 6337.2) 1287.54 5469.0 3108 6971 DAY 5 96 H 9 0 7264.4 (6320.8, 8208.1) 1227.65 7575.0 4945 8546 DAY 6 120 H 9 0 7283.2 (6485.6, 8080.8) 1037.64 7545.0 5486 8405 DAY 8 PREDOSE 9 0 6786.1 (6145.4, 7426.8) 833.52 6795.0 5274 8093 6 H 9 0 7642.3 (6657.7, 8627.0) 1280.99 8196.0 5274 8927 DAY 9 24 H 9 0 8932.6 (6834.9, 11030.2) 2728.98 7754.0 4797 13988 DAY 10 48 H 9 0 9152.4 (7284.3, 11020.6) 2430.38 8456.0 4917 12488 DAY 11 72 H 9 0 9172.6 (7467.5, 10877.6) 2218.21 8384.0 5235 12260 DAY 12 96 H 9 0 12359.4 (10282.9, 14436.0) 2701.47 11749.0 8074 16505 DAY 13 120 H 9 0 11743.2 (9786.6, 13699.8) 2545.42 11537.0 7455 15614 DAY 15 PREDOSE 9 0 10580.3 (9105.2, 12055.4) 1919.01 10069.0 7550 13153 6 H 9 0 11786.4 (9927.8, 13645.1) 2417.96 11408.0 7550 15245 DAY 16 24 H 9 0 12225.3 (9304.7, 15145.9) 3799.58 11397.0 5699 18034 DAY 17 48 H 9 0 11182.2 (9372.0, 12992.4) 2354.98 11633.0 6036 13721 DAY 18 72 H 9 0 11218.8 (9294.3, 13143.2) 2503.61 10809.0 6160 14055 DAY 19 96 H 9 0 14582.6 (12323.1, 16842.0) 2939.39 13691.0 9282 19715 DAY 20 120 H 9 0 14694.6 (12450.7, 16938.4) 2919.12 14156.0 9346 19144 DAY 22 PREDOSE 9 0 13184.1 (11220.7, 15147.6) 2554.37 13529.0 8931 16802 6 H 9 0 14945.6 (12320.6, 17570.5) 3414.92 16031.0 9091 18521 DAY 23 24 H 9 0 14525.1 (10732.0, 18318.2) 4934.63 12475.0 7806 22497 DAY 24 48 H 9 0 13227.0 (10989.0, 15465.0) 2911.52 12582.0 7959 17770 DAY 25 72 H 9 0 12777.0 (10541.4, 15012.6) 2908.40 12011.0 8138 17798 DAY 26 96 H 9 0 18093.4 (14416.9, 21769.9) 4782.95 17576.0 10412 26572 DAY 27 120 H 9 0 16643.4 (13765.7, 19521.2) 3743.81 16188.0 9278 22078 DAY 31 216 H 9 0 13612.4 (11215.2, 16009.7) 3118.76 14096.0 7373 17205 DAY 36 336 H 9 0 10318.1 (8600.1, 12036.2) 2235.11 9899.0 6423 13084
Note: LLQ=100 ng/mL
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Protocol: BA1116891 Page 4 of 4Population: PK Concentration Table 11.1 Summary of Plasma GSK933776 Pharmacokinetic Concentration-Time Data [ng/mL]
No. Time Impu 95% CITreatment N Visit point n -ted Mean (Lower, Upper) SD Median Min. Max.-----------------------------------------------------------------------------------------------------------SQ_50mg x 9 DAY 43 504 H 9 0 7325.3 (6019.6, 8631.0) 1698.66 6708.0 4492 97194 DAY 50 672 H 8 0 5207.1 (4284.6, 6129.7) 1103.50 4982.0 3755 7052 DAY 78 1344 H 3 0 1720.0 (1659.8, 1780.2) 24.25 1716.0 1698 1746 FOLLOW-UP 2016 H 7 7 NQ NQ NQ NQ
IM_200mg 9 DAY 1 PREDOSE 9 9 NQ NQ NQ NQ 2 H 6 0 2026.8 (1530.1, 2523.6) 473.32 2242.5 1236 2418 6 H 9 0 5879.6 (2533.0, 9226.1) 4353.67 4637.0 1968 15609 DAY 2 24 H 9 0 19661.1 (11805.4, 27516.8) 10219.84 16522.0 7056 37535 DAY 3 48 H 9 0 20577.1 (14544.2, 26610.0) 7848.49 17621.0 10090 34413 DAY 4 72 H 9 0 20901.9 (15274.5, 26529.3) 7320.99 19075.0 10834 35732 DAY 5 96 H 9 0 26883.0 (23070.0, 30696.0) 4960.52 28265.0 16077 31901 DAY 6 120 H 9 0 25089.6 (21521.0, 28658.1) 4642.47 25674.0 16768 31631 DAY 10 216 H 9 0 20255.6 (17279.4, 23231.7) 3871.79 20875.0 13814 24536 DAY 15 336 H 9 0 15227.1 (12691.3, 17763.0) 3299.01 15600.0 8829 19141 DAY 22 504 H 9 0 9940.0 (8244.5, 11635.5) 2205.81 10355.0 5072 12381 DAY 29 672 H 9 0 7044.4 (5477.3, 8611.6) 2038.77 7295.0 2599 9356 DAY 57 1344 H 8 1 1294.0 (767.0, 1821.0) 630.37 1305.5 0 2054 FOLLOW-UP 2016 H 8 8 NQ NQ NQ NQ
Note: LLQ=100 ng/mL
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Protocol: BA1116891 Page 1 of 7Population: PK Parameter Table 11.2 Summary of Derived Plasma GSK933776 Pharmacokinetic Parameters
PK Parameter IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg------------------------------------------------------------------------------------------------------------AUC(0-168) N 9 9(h*ng/mL) n 9 9 Geom. Mean 5521998 934531 95% CI (5144565, 5927122) (805702, 1083959) SD Logs 0.0921 0.1930 %CVb 9.23 19.48 Arith. Mean 5542684 949221 95% CI (5154514, 5930855) (819983, 1078458) SD 504991.1 168131.6 Median 5613730 939194 Min. 4664059 628562 Max. 6425054 1135689
AUC(0-168)/D N 9 9(h*ng/mL/mg) n 9 9 Geom. Mean 27610 18691 95% CI (25723, 29636) (16114, 21679) SD Logs 0.0921 0.1930 %CVb 9.23 19.48 Arith. Mean 27713 18984 95% CI (25773, 29654) (16400, 21569) SD 2525.0 3362.6 Median 28069 18784 Min. 23320 12571 Max. 32125 22714
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Protocol: BA1116891 Page 2 of 7Population: PK Parameter Table 11.2 Summary of Derived Plasma GSK933776 Pharmacokinetic Parameters
PK Parameter IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg------------------------------------------------------------------------------------------------------------AUC(0-672) N 9 9(h*ng/mL) n 9 9 Geom. Mean 12049256 7220426 95% CI (11103817, 13075196) (6086594, 8565472) SD Logs 0.1063 0.2222 %CVb 10.66 22.50 Arith. Mean 12109306 7370781 95% CI (11132141, 13086471) (6215333, 8526229) SD 1271244.2 1503181.8 Median 12196400 7064426 Min. 9806847 4476404 Max. 14474115 9204480
AUC(0-inf) N 9 9 9 9(h*ng/mL) n 9 9 9 9 Geom. Mean 14899413 12371299 14196870 12911085 95% CI (13299729, 16691506) (10580158, 14465667) (12082673, 16681004) (10868391, 15337700) SD Logs 0.1478 0.2035 0.2098 0.2241 %CVb 14.86 20.56 21.21 22.69 Arith. Mean 15043184 12579102 14470250 13184376 95% CI (13356409, 16729959) (10871823, 14286381) (12212286, 16728214) (11113835, 15254917) SD 2194412.8 2221087.6 2937502.1 2693673.6 Median 15601969 12685813 13400594 13245585 Min. 11845428 7583941 9584860 8336900 Max. 18985826 15576684 18540300 16018887
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Protocol: BA1116891 Page 3 of 7Population: PK Parameter Table 11.2 Summary of Derived Plasma GSK933776 Pharmacokinetic Parameters
PK Parameter IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg------------------------------------------------------------------------------------------------------------AUC(0-t) N 9 9 9 9(h*ng/mL) n 9 9 9 9 Geom. Mean 13912995 11471735 12210968 11865187 95% CI (12105207, 15990758) (9481356, 13879946) (9756147, 15283465) (9991370, 14090426) SD Logs 0.1811 0.2479 0.2920 0.2236 %CVb 18.26 25.18 29.83 22.64 Arith. Mean 14107679 11746683 12671887 12118002 95% CI (12272912, 15942447) (9924909, 13568457) (9902696, 15441077) (10182547, 14053457) SD 2386943.9 2370039.7 3602583.3 2517933.7 Median 14931389 12270968 11456806 12309600 Min. 9811001 6189117 7287154 7610470 Max. 17786417 14629803 17712773 15535571
%AUCex (%) N 9 9 9 9 n 9 9 9 9 Geom. Mean 5.60 6.31 11.38 6.03 95% CI (3.66, 8.57) (4.27, 9.32) (6.65, 19.46) (3.63, 10.02) SD Logs 0.5534 0.5088 0.6985 0.6601 %CVb 59.87 54.36 79.30 73.90 Arith. Mean 6.52 7.17 13.69 7.77 95% CI (3.13, 9.92) (3.71, 10.62) (7.88, 19.51) (1.82, 13.72) SD 4.414 4.495 7.566 7.745 Median 5.26 6.08 14.51 5.30 Min. 2.84 2.76 4.46 3.02 Max. 17.17 18.39 23.97 27.89
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Protocol: BA1116891 Page 4 of 7Population: PK Parameter Table 11.2 Summary of Derived Plasma GSK933776 Pharmacokinetic Parameters
PK Parameter IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg------------------------------------------------------------------------------------------------------------Cmax (ng/mL) N 9 9 9 9 n 9 9 9 9 Geom. Mean 62496 22387 17755 28743 95% CI (56129, 69585) (19721, 25412) (14382, 21920) (24220, 34111) SD Logs 0.1398 0.1649 0.2741 0.2228 %CVb 14.05 16.61 27.94 22.56 Arith. Mean 63037 22651 18335 29317 95% CI (56312, 69762) (19890, 25412) (14642, 22028) (25013, 33621) SD 8749.1 3592.3 4804.8 5599.2 Median 62538 22463 17576 29665 Min. 48466 16235 10412 16768 Max. 79060 27386 26572 37535
CL/F (mL/h) N 9 9 9 9 n 9 9 9 9 Geom. Mean 13.42 16.15 3.53 15.48 95% CI (11.98, 15.04) (13.84, 18.85) (3.00, 4.15) (13.03, 18.39) SD Logs 0.1478 0.2010 0.2116 0.2239 %CVb 14.86 20.30 21.40 22.67 Arith. Mean 13.56 16.48 3.60 15.85 95% CI (11.99, 15.12) (13.51, 19.44) (2.99, 4.21) (12.88, 18.82) SD 2.032 3.857 0.792 3.864 Median 12.82 15.77 3.74 15.09 Min. 10.53 12.84 2.70 12.47 Max. 16.88 26.16 5.25 23.94
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Protocol: BA1116891 Page 5 of 7Population: PK Parameter Table 11.2 Summary of Derived Plasma GSK933776 Pharmacokinetic Parameters
PK Parameter IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg------------------------------------------------------------------------------------------------------------Vz/F (mL) N 9 9 9 9 n 9 9 9 9 Geom. Mean 5618 7013 1683 6425 95% CI (5170, 6106) (6036, 8148) (1368, 2071) (5743, 7187) SD Logs 0.1082 0.1952 0.2699 0.1458 %CVb 10.86 19.70 27.49 14.66 Arith. Mean 5648 7137 1746 6484 95% CI (5169, 6128) (6013, 8260) (1302, 2191) (5786, 7181) SD 623.7 1461.7 578.3 907.2 Median 5646 6786 1692 6445 Min. 4795 5438 1300 4792 Max. 6760 10006 3211 7812
t1/2 (h) N 9 9 9 9 n 9 9 9 9 Arith. Mean 294 303 333 292 95% CI (258, 329) (273, 333) (301, 364) (255, 329) SD 45.9 38.8 40.5 48.1 Median 286 313 320 286 Min. 203 239 289 194 Max. 357 367 424 344
tmax (h) N 9 9 9 9 n 9 9 9 9 Arith. Mean 2 109 583 79 95% CI (1, 2) (99, 118) (559, 608) (50, 109) SD 0.6 12.2 31.8 37.9 Median 2 117 599 96 Min. 1 96 527 24 Max. 3 120 601 120
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Protocol: BA1116891 Page 6 of 7Population: PK Parameter Table 11.2 Summary of Derived Plasma GSK933776 Pharmacokinetic Parameters
PK Parameter IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg------------------------------------------------------------------------------------------------------------tlast (h) N 9 9 9 9 n 9 9 9 9 Arith. Mean 1195 1272 1376 1195 95% CI (967, 1422) (1106, 1437) (1114, 1639) (967, 1422) SD 295.9 215.5 341.5 296.1 Median 1344 1343 1176 1344 Min. 673 697 1010 671 Max. 1345 1346 1849 1344
#pts N 9 9 9 9 n 9 9 9 9 Arith. Mean 4.6 3.1 4.8 4.6 95% CI (3.5, 5.6) (2.9, 3.4) (3.9, 5.7) (3.2, 5.9) SD 1.30 0.30 1.20 1.80 Median 5.0 3.0 5.0 4.0 Min. 3.0 3.0 3.0 3.0 Max. 6.0 4.0 6.0 8.0
Lambda_z N 9 9 9 9(/h) n 9 9 9 9 Arith. Mean 0.0024 0.0023 0.0021 0.0024 95% CI (0.0021, 0.0028) (0.0021, 0.0026) (0.0019, 0.0023) (0.0021, 0.0028) SD 0.000 0.000 0.000 0.000 Median 0.0024 0.0022 0.0022 0.0024 Min. 0.0019 0.0019 0.0016 0.0020 Max. 0.0034 0.0029 0.0024 0.0036
404
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 7 of 7Population: PK Parameter Table 11.2 Summary of Derived Plasma GSK933776 Pharmacokinetic Parameters
PK Parameter IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg------------------------------------------------------------------------------------------------------------Lambda_z_low N 9 9 9 9er (h) n 9 9 9 9 Arith. Mean 261 480 687 291 95% CI (143, 380) (402, 558) (580, 795) (148, 433) SD 153.8 101.5 140.3 185.3 Median 215 504 624 336 Min. 120 216 598 72 Max. 504 575 1007 504
Lambda_z_upp N 9 9 9 9er (h) n 9 9 9 9 Arith. Mean 1195 1272 1376 1195 95% CI (967, 1422) (1106, 1437) (1114, 1639) (967, 1422) SD 295.9 215.5 341.5 296.1 Median 1344 1343 1176 1344 Min. 673 697 1010 671 Max. 1345 1346 1849 1344
Rsq_adj N 9 9 9 9 n 9 9 9 9 Arith. Mean 0.9987 0.9981 0.9941 0.9982 95% CI (0.9977, 0.9997) (0.9947, 1.0015) (0.9893, 0.9988) (0.9972, 0.9992) SD 0.001 0.004 0.006 0.001 Median 0.9990 0.9996 0.9972 0.9987 Min. 0.9957 0.9865 0.9831 0.9954 Max. 0.9999 1.0000 0.9997 0.9995
405
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 1 of 1Population: PK parameter Table 11.3 Summary of the Results of the ANOVA of Log-Transformed Plasma GSK933776 Pharmacokinetic Parameters
Comparison __GeoMetric LS Mean__ Ratio (%) 90% Confidence Parameter Test Vs Reference n Test n Ref (Test/Ref) Interval for Ratio ------------------------------------------------------------------------------------------------------ AUC(0-168)/D (h*ng/mL/mg) SQ_50mg*4 VS IV_200mg 9 18690.62 9 27609.99 67.70 (59.77, 76.67)
AUC(0-672) (h*ng/mL) SQ_50mg*4 VS IV_200mg 9 7220426 9 12049256 59.92 (51.92, 69.16)
AUC(0-inf) (h*ng/mL) IM_200mg VS IV_200mg 9 12911085 9 14899413 86.65 (73.96, 101.53) SQ_200mg VS IV_200mg 9 12371299 9 14899413 83.03 (70.87, 97.29) SQ_50mg*4 VS IV_200mg 9 14196870 9 14899413 95.28 (81.32, 111.64)
AUC(0-t) (h*ng/mL) IM_200mg VS IV_200mg 9 11865187 9 13912995 85.28 (70.43, 103.26) SQ_200mg VS IV_200mg 9 11471735 9 13912995 82.45 (68.10, 99.83) SQ_50mg*4 VS IV_200mg 9 12210968 9 13912995 87.77 (72.49, 106.27)
%AUCex (%) IM_200mg VS IV_200mg 9 6.033362 9 5.598382 107.77 (66.21, 175.41) SQ_200mg VS IV_200mg 9 6.306422 9 5.598382 112.65 (69.21, 183.35) SQ_50mg*4 VS IV_200mg 9 11.37599 9 5.598382 203.20 (124.84, 330.74)
Cmax (ng/mL) IM_200mg VS IV_200mg 9 28743.29 9 62495.91 45.99 (38.98, 54.26) SQ_200mg VS IV_200mg 9 22386.53 9 62495.91 35.82 (30.36, 42.26) SQ_50mg*4 VS IV_200mg 9 17755.24 9 62495.91 28.41 (24.08, 33.52)
CL/F (mL/h) IM_200mg VS IV_200mg 9 15.47911 9 13.42335 115.31 (98.44, 135.09) SQ_200mg VS IV_200mg 9 16.1524 9 13.42335 120.33 (102.72, 140.96) SQ_50mg*4 VS IV_200mg 9 3.52867 9 13.42335 26.29 (22.44, 30.80)
Vz/F (mL) IM_200mg VS IV_200mg 9 6424.608 9 5618.401 114.35 (98.28, 133.05) SQ_200mg VS IV_200mg 9 7013.106 9 5618.401 124.82 (107.28, 145.24) SQ_50mg*4 VS IV_200mg 9 1683.06 9 5618.401 29.96 (25.75, 34.85)
406
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 1 of 1Population: PK Parameter Table 11.4 Median Difference and Confidence Interval for Plasma GSK933776 Pharmacokinetic Parameters
90% Confidence Comparison ----------Median---------- Difference Interval for Parameter Test vs Reference n Test n Ref. (Test-Ref) Difference -------------------------------------------------------------------------------------------------- t1/2 (h) SQ_200mg vs IV_200mg 9 313.20 9 286.19 7.96 (-28.99, 45.7) SQ_50mg x 4 vs IV_200mg 9 320.00 9 286.19 31.3 (-2.46, 71.89) IM_200mg vs IV_200mg 9 285.89 9 286.19 -3.25 (-40.27, 32.72)
tmax (h) SQ_200mg vs IV_200mg 9 116.92 9 1.50 115.42 (94.42, 117.85) SQ_50mg x 4 vs IV_200mg 9 598.73 9 1.50 596.8 (594.97, 598.07) IM_200mg vs IV_200mg 9 95.63 9 1.50 93.7 (45.37, 94.42)
407
CONFIDENTIAL 2014N211143_00BA1116891
Analysis Value
-999
-998
Cumulative Planned Relative Time
-999 -998
Con
cent
ratio
n (p
g/m
L)
0
200
400
600
800
1000
1200
Planned Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
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n (p
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L)
10
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Planned Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 1 of 1Page 1 of 1Protocol: BA1116891Population: Pharmacodynamic
Figure 7.1Median Plasma Free Abeta1-22 PD Concentration-Time Plot (Linear and Semi-Log)
Treatment IM_200mg IV_200mg SQ_200mg SQ_50mg x 4O O O
Protocol: BA1116891Population: Pharmacodynamic
Figure 7.1Median Plasma Free Abeta1-22 PD Concentration-Time Plot (Linear and Semi-Log)
Linear Scale
O
OO
O
OO
O
O
O
Semi-Logarithmic Scale
O
OOO
O OO
OO
408
CONFIDENTIAL 2014N211143_00BA1116891
Analysis Value
-999
-998
Cumulative Planned Relative Time
-999 -998
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
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Planned Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
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L)
10
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Planned Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 1 of 1Page 1 of 1Protocol: BA1116891Population: Pharmacodynamic
Figure 7.2Median Plasma Total Abeta18-35 PD Concentration-Time Plot (Linear and Semi-Log)
Treatment IM_200mg IV_200mg SQ_200mg SQ_50mg x 4O O O
Protocol: BA1116891Population: Pharmacodynamic
Figure 7.2Median Plasma Total Abeta18-35 PD Concentration-Time Plot (Linear and Semi-Log)
Linear Scale
O
O
O
O
O
O
O
O
O
Semi-Logarithmic Scale
O
O
OO O
O
O
O
O
409
CONFIDENTIAL 2014N211143_00BA1116891
Analysis Value
-999
-998
Cumulative Planned Relative Time
-999 -998
Con
cent
ratio
n (p
g/m
L)
0
500
1000
1500
2000
2500
Planned Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
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L)
10
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Planned Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 1 of 1Page 1 of 1Protocol: BA1116891Population: Pharmacodynamic
Figure 7.3Median Plasma Total Abeta42 PD Concentration-Time Plot (Linear and Semi-Log)
Treatment IM_200mg IV_200mg SQ_200mg SQ_50mg x 4O O O
Protocol: BA1116891Population: Pharmacodynamic
Figure 7.3Median Plasma Total Abeta42 PD Concentration-Time Plot (Linear and Semi-Log)
Linear Scale
O
O
OO
O
O
O
O
O
Semi-Logarithmic Scale
O
O
OOO
O
O
O
O
410
CONFIDENTIAL 2014N211143_00BA1116891
Analysis Value
-999
-998
Cumulative Planned Relative Time
-999 -998
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
Planned Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
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100000
Planned Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 1 of 3Page 1 of 3Protocol: BA1116891Population: Pharmacodynamic
Figure 12.1Mean Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Treatment IM_200mg IV_200mg SQ_200mg SQ_50mg x 4O O O
Protocol: BA1116891Population: Pharmacodynamic
Figure 12.1Mean Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta1-22
Linear Scale
OOOO O O O O O
Semi-Logarithmic Scale
O
OOO O
OO O O
411
CONFIDENTIAL 2014N211143_00BA1116891
Analysis Value
-999
-998
Cumulative Planned Relative Time
-999 -998
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
Planned Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
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Planned Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 2 of 3Page 2 of 3Protocol: BA1116891Population: Pharmacodynamic
Figure 12.1Mean Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Treatment IM_200mg IV_200mg SQ_200mg SQ_50mg x 4O O O
Protocol: BA1116891Population: Pharmacodynamic
Figure 12.1Mean Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta18-35
Linear Scale
O
O
O
O
O
O
O
O
O
Semi-Logarithmic Scale
O
O
OO O
O
O
O
O
412
CONFIDENTIAL 2014N211143_00BA1116891
Analysis Value
-999
-998
Cumulative Planned Relative Time
-999 -998
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
Planned Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Planned Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 3 of 3Page 3 of 3Protocol: BA1116891Population: Pharmacodynamic
Figure 12.1Mean Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Treatment IM_200mg IV_200mg SQ_200mg SQ_50mg x 4O O O
Protocol: BA1116891Population: Pharmacodynamic
Figure 12.1Mean Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta42
Linear Scale
OOOO O
O O O O
Semi-Logarithmic Scale
O
O
O
O O
O
O OO
413
CONFIDENTIAL 2014N211143_00BA1116891
Change from Baseline
-999
-998
Cumulative Planned Relative Time
-999 -998
Cha
nge
from
Bas
elin
e (f
old)
0
10
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40
50
Planned Relative Time (Hrs)
0 520 1040 1560 2080 2600
Cha
nge
from
Bas
elin
e (f
old)
0.1
1
10
100
Planned Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 1 of 3Page 1 of 3Protocol: BA1116891Population: Pharmacodynamic
Figure 12.2Mean Plasma PD Concentration Change from Baseline-Time Plot (Linear and Semi-Log)
Note: Change from baseline is calculated by dividing the baseline value from the individual post-dose value.
Treatment IM_200mg IV_200mg SQ_200mg SQ_50mg x 4O O O
Protocol: BA1116891Population: Pharmacodynamic
Figure 12.2Mean Plasma PD Concentration Change from Baseline-Time Plot (Linear and Semi-Log)
Note: Change from baseline is calculated by dividing the baseline value from the individual post-dose value.
Parameter:Abeta1-22
Linear Scale
OOOO O O O O O
Semi-Logarithmic Scale
O
OOO O
O
O OO
414
CONFIDENTIAL 2014N211143_00BA1116891
Change from Baseline
-999
-998
Cumulative Planned Relative Time
-999 -998
Cha
nge
from
Bas
elin
e (f
old)
0
10
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50
Planned Relative Time (Hrs)
0 520 1040 1560 2080 2600
Cha
nge
from
Bas
elin
e (f
old)
0.1
1
10
100
Planned Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 2 of 3Page 2 of 3Protocol: BA1116891Population: Pharmacodynamic
Figure 12.2Mean Plasma PD Concentration Change from Baseline-Time Plot (Linear and Semi-Log)
Note: Change from baseline is calculated by dividing the baseline value from the individual post-dose value.
Treatment IM_200mg IV_200mg SQ_200mg SQ_50mg x 4O O O
Protocol: BA1116891Population: Pharmacodynamic
Figure 12.2Mean Plasma PD Concentration Change from Baseline-Time Plot (Linear and Semi-Log)
Note: Change from baseline is calculated by dividing the baseline value from the individual post-dose value.
Parameter:Abeta18-35
Linear Scale
O
O
O
O
O
O
O
O
O
Semi-Logarithmic Scale
O
O
OO O
O
O
O
O
415
CONFIDENTIAL 2014N211143_00BA1116891
Change from Baseline
-999
-998
Cumulative Planned Relative Time
-999 -998
Cha
nge
from
Bas
elin
e (f
old)
0
10
20
30
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50
Planned Relative Time (Hrs)
0 520 1040 1560 2080 2600
Cha
nge
from
Bas
elin
e (f
old)
0.1
1
10
100
Planned Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 3 of 3Page 3 of 3Protocol: BA1116891Population: Pharmacodynamic
Figure 12.2Mean Plasma PD Concentration Change from Baseline-Time Plot (Linear and Semi-Log)
Note: Change from baseline is calculated by dividing the baseline value from the individual post-dose value.
Treatment IM_200mg IV_200mg SQ_200mg SQ_50mg x 4O O O
Protocol: BA1116891Population: Pharmacodynamic
Figure 12.2Mean Plasma PD Concentration Change from Baseline-Time Plot (Linear and Semi-Log)
Note: Change from baseline is calculated by dividing the baseline value from the individual post-dose value.
Parameter:Abeta42
Linear Scale
O
O
O
O
O
O
O
OO
Semi-Logarithmic Scale
O
O
OO O
O
O
O
O
416
CONFIDENTIAL 2014N211143_00BA1116891
Analysis Value
-999
-998
Cumulative Planned Relative Time
-999 -998
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
Planned Relative Time (Hrs)
0 200 400 600 800
Con
cent
ratio
n (p
g/m
L)
10
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100000
Planned Relative Time (Hrs)
0 200 400 600 800
Page 1 of 3Page 1 of 3Protocol: BA1116891Population: Pharmacodynamic
Figure 12.3Mean Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Treatment IM_200mg IV_200mg SQ_200mg SQ_50mg x 4O O O
Protocol: BA1116891Population: Pharmacodynamic
Figure 12.3Mean Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta1-22
Linear Scale
OO O O O O O
Semi-Logarithmic Scale
O
O O O OO
O
417
CONFIDENTIAL 2014N211143_00BA1116891
Analysis Value
-999
-998
Cumulative Planned Relative Time
-999 -998
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
Planned Relative Time (Hrs)
0 200 400 600 800
Con
cent
ratio
n (p
g/m
L)
10
100
1000
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100000
Planned Relative Time (Hrs)
0 200 400 600 800
Page 2 of 3Page 2 of 3Protocol: BA1116891Population: Pharmacodynamic
Figure 12.3Mean Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Treatment IM_200mg IV_200mg SQ_200mg SQ_50mg x 4O O O
Protocol: BA1116891Population: Pharmacodynamic
Figure 12.3Mean Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta18-35
Linear Scale
O
O
O
O
O
O
O
Semi-Logarithmic Scale
O
O
OO O
O
O
418
CONFIDENTIAL 2014N211143_00BA1116891
Analysis Value
-999
-998
Cumulative Planned Relative Time
-999 -998
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
Planned Relative Time (Hrs)
0 200 400 600 800
Con
cent
ratio
n (p
g/m
L)
10
100
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Planned Relative Time (Hrs)
0 200 400 600 800
Page 3 of 3Page 3 of 3Protocol: BA1116891Population: Pharmacodynamic
Figure 12.3Mean Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Treatment IM_200mg IV_200mg SQ_200mg SQ_50mg x 4O O O
Protocol: BA1116891Population: Pharmacodynamic
Figure 12.3Mean Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta42
Linear Scale
OOO
O OO O
Semi-Logarithmic Scale
O
O
O
O O
O
O
419
CONFIDENTIAL 2014N211143_00BA1116891
Change from Baseline
-999
-998
Cumulative Planned Relative Time
-999 -998
Cha
nge
from
Bas
elin
e (f
old)
0
10
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50
Planned Relative Time (Hrs)
0 200 400 600 800
Cha
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e (f
old)
0.1
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Planned Relative Time (Hrs)
0 200 400 600 800
Page 1 of 3Page 1 of 3Protocol: BA1116891Population: Pharmacodynamic
Figure 12.4Mean Plasma PD Concentration Change from Baseline-Time Plot (Linear and Semi-Log) (Truncated)
Note: Change from baseline is calculated by dividing the baseline value from the individual post-dose value.
Treatment IM_200mg IV_200mg SQ_200mg SQ_50mg x 4O O O
Protocol: BA1116891Population: Pharmacodynamic
Figure 12.4Mean Plasma PD Concentration Change from Baseline-Time Plot (Linear and Semi-Log) (Truncated)
Note: Change from baseline is calculated by dividing the baseline value from the individual post-dose value.
Parameter:Abeta1-22
Linear Scale
OO O O O O O
Semi-Logarithmic Scale
O
O OO O
O
O
420
CONFIDENTIAL 2014N211143_00BA1116891
Change from Baseline
-999
-998
Cumulative Planned Relative Time
-999 -998
Cha
nge
from
Bas
elin
e (f
old)
0
10
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50
Planned Relative Time (Hrs)
0 200 400 600 800
Cha
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Bas
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e (f
old)
0.1
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100
Planned Relative Time (Hrs)
0 200 400 600 800
Page 2 of 3Page 2 of 3Protocol: BA1116891Population: Pharmacodynamic
Figure 12.4Mean Plasma PD Concentration Change from Baseline-Time Plot (Linear and Semi-Log) (Truncated)
Note: Change from baseline is calculated by dividing the baseline value from the individual post-dose value.
Treatment IM_200mg IV_200mg SQ_200mg SQ_50mg x 4O O O
Protocol: BA1116891Population: Pharmacodynamic
Figure 12.4Mean Plasma PD Concentration Change from Baseline-Time Plot (Linear and Semi-Log) (Truncated)
Note: Change from baseline is calculated by dividing the baseline value from the individual post-dose value.
Parameter:Abeta18-35
Linear Scale
O
O
O
O
O
O
O
Semi-Logarithmic Scale
O
O
OO O
O
O
421
CONFIDENTIAL 2014N211143_00BA1116891
Change from Baseline
-999
-998
Cumulative Planned Relative Time
-999 -998
Cha
nge
from
Bas
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e (f
old)
0
10
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Planned Relative Time (Hrs)
0 200 400 600 800
Cha
nge
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Bas
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e (f
old)
0.1
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Planned Relative Time (Hrs)
0 200 400 600 800
Page 3 of 3Page 3 of 3Protocol: BA1116891Population: Pharmacodynamic
Figure 12.4Mean Plasma PD Concentration Change from Baseline-Time Plot (Linear and Semi-Log) (Truncated)
Note: Change from baseline is calculated by dividing the baseline value from the individual post-dose value.
Treatment IM_200mg IV_200mg SQ_200mg SQ_50mg x 4O O O
Protocol: BA1116891Population: Pharmacodynamic
Figure 12.4Mean Plasma PD Concentration Change from Baseline-Time Plot (Linear and Semi-Log) (Truncated)
Note: Change from baseline is calculated by dividing the baseline value from the individual post-dose value.
Parameter:Abeta42
Linear Scale
O
O
O
O
O
O
O
Semi-Logarithmic Scale
O
O
OO O
O
O
422
CONFIDENTIAL 2014N211143_00BA1116891
Analysis Value
-999
-998
Cumulative Planned Relative Time
-999 -998
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
Planned Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
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1000
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100000
Planned Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 1 of 3Page 1 of 3Protocol: BA1116891Population: Pharmacodynamic
Figure 12.5Median Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Treatment IM_200mg IV_200mg SQ_200mg SQ_50mg x 4O O O
Protocol: BA1116891Population: Pharmacodynamic
Figure 12.5Median Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta1-22
Linear Scale
OOOO O O O O O
Semi-Logarithmic Scale
OOOO
O OO
OO
423
CONFIDENTIAL 2014N211143_00BA1116891
Analysis Value
-999
-998
Cumulative Planned Relative Time
-999 -998
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
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Planned Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
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10000
100000
Planned Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 2 of 3Page 2 of 3Protocol: BA1116891Population: Pharmacodynamic
Figure 12.5Median Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Treatment IM_200mg IV_200mg SQ_200mg SQ_50mg x 4O O O
Protocol: BA1116891Population: Pharmacodynamic
Figure 12.5Median Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta18-35
Linear Scale
O
O
O
O
O
O
O
O
O
Semi-Logarithmic Scale
O
O
OO O
O
O
O
O
424
CONFIDENTIAL 2014N211143_00BA1116891
Analysis Value
-999
-998
Cumulative Planned Relative Time
-999 -998
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
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Planned Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
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1000
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100000
Planned Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 3 of 3Page 3 of 3Protocol: BA1116891Population: Pharmacodynamic
Figure 12.5Median Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Treatment IM_200mg IV_200mg SQ_200mg SQ_50mg x 4O O O
Protocol: BA1116891Population: Pharmacodynamic
Figure 12.5Median Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta42
Linear Scale
OOOO O O O O O
Semi-Logarithmic Scale
O
O
OOO
O
O
O
O
425
CONFIDENTIAL 2014N211143_00BA1116891
Change from Baseline
-999
-998
Cumulative Planned Relative Time
-999 -998
Cha
nge
from
Bas
elin
e (f
old)
0
10
20
30
40
50
Planned Relative Time (Hrs)
0 520 1040 1560 2080 2600
Cha
nge
from
Bas
elin
e (f
old)
0.01
0.1
1
10
100
Planned Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 1 of 3Page 1 of 3Protocol: BA1116891Population: Pharmacodynamic
Figure 12.6Median Plasma PD Concentration Change from Baseline-Time Plot (Linear and Semi-Log)
Note: Change from baseline is calculated by dividing the baseline value from the individual post-dose value.
Treatment IM_200mg IV_200mg SQ_200mg SQ_50mg x 4O O O
Protocol: BA1116891Population: Pharmacodynamic
Figure 12.6Median Plasma PD Concentration Change from Baseline-Time Plot (Linear and Semi-Log)
Note: Change from baseline is calculated by dividing the baseline value from the individual post-dose value.
Parameter:Abeta1-22
Linear Scale
OOOO O O O O O
Semi-Logarithmic Scale
OOOO O O
OO O
426
CONFIDENTIAL 2014N211143_00BA1116891
Change from Baseline
-999
-998
Cumulative Planned Relative Time
-999 -998
Cha
nge
from
Bas
elin
e (f
old)
0
10
20
30
40
50
Planned Relative Time (Hrs)
0 520 1040 1560 2080 2600
Cha
nge
from
Bas
elin
e (f
old)
0.01
0.1
1
10
100
Planned Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 2 of 3Page 2 of 3Protocol: BA1116891Population: Pharmacodynamic
Figure 12.6Median Plasma PD Concentration Change from Baseline-Time Plot (Linear and Semi-Log)
Note: Change from baseline is calculated by dividing the baseline value from the individual post-dose value.
Treatment IM_200mg IV_200mg SQ_200mg SQ_50mg x 4O O O
Protocol: BA1116891Population: Pharmacodynamic
Figure 12.6Median Plasma PD Concentration Change from Baseline-Time Plot (Linear and Semi-Log)
Note: Change from baseline is calculated by dividing the baseline value from the individual post-dose value.
Parameter:Abeta18-35
Linear Scale
O
O
OO
O
O
O
OO
Semi-Logarithmic Scale
O
O
OO OO
O
O
O
427
CONFIDENTIAL 2014N211143_00BA1116891
Change from Baseline
-999
-998
Cumulative Planned Relative Time
-999 -998
Cha
nge
from
Bas
elin
e (f
old)
0
10
20
30
40
50
Planned Relative Time (Hrs)
0 520 1040 1560 2080 2600
Cha
nge
from
Bas
elin
e (f
old)
0.01
0.1
1
10
100
Planned Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 3 of 3Page 3 of 3Protocol: BA1116891Population: Pharmacodynamic
Figure 12.6Median Plasma PD Concentration Change from Baseline-Time Plot (Linear and Semi-Log)
Note: Change from baseline is calculated by dividing the baseline value from the individual post-dose value.
Treatment IM_200mg IV_200mg SQ_200mg SQ_50mg x 4O O O
Protocol: BA1116891Population: Pharmacodynamic
Figure 12.6Median Plasma PD Concentration Change from Baseline-Time Plot (Linear and Semi-Log)
Note: Change from baseline is calculated by dividing the baseline value from the individual post-dose value.
Parameter:Abeta42
Linear Scale
O
O
O
OO
O
O
OO
Semi-Logarithmic Scale
O
O
OO O
O
O
O
O
428
CONFIDENTIAL 2014N211143_00BA1116891
Analysis Value
-999
-998
Cumulative Planned Relative Time
-999 -998
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
Planned Relative Time (Hrs)
0 200 400 600 800
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Planned Relative Time (Hrs)
0 200 400 600 800
Page 1 of 3Page 1 of 3Protocol: BA1116891Population: Pharmacodynamic
Figure 12.7Median Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Treatment IM_200mg IV_200mg SQ_200mg SQ_50mg x 4O O O
Protocol: BA1116891Population: Pharmacodynamic
Figure 12.7Median Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta1-22
Linear Scale
OO O O O O O
Semi-Logarithmic Scale
OO O O
O OO
429
CONFIDENTIAL 2014N211143_00BA1116891
Analysis Value
-999
-998
Cumulative Planned Relative Time
-999 -998
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
Planned Relative Time (Hrs)
0 200 400 600 800
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Planned Relative Time (Hrs)
0 200 400 600 800
Page 2 of 3Page 2 of 3Protocol: BA1116891Population: Pharmacodynamic
Figure 12.7Median Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Treatment IM_200mg IV_200mg SQ_200mg SQ_50mg x 4O O O
Protocol: BA1116891Population: Pharmacodynamic
Figure 12.7Median Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta18-35
Linear Scale
O
O
O
O
O
O
O
Semi-Logarithmic Scale
O
O
OO O
O
O
430
CONFIDENTIAL 2014N211143_00BA1116891
Analysis Value
-999
-998
Cumulative Planned Relative Time
-999 -998
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
Planned Relative Time (Hrs)
0 200 400 600 800
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Planned Relative Time (Hrs)
0 200 400 600 800
Page 3 of 3Page 3 of 3Protocol: BA1116891Population: Pharmacodynamic
Figure 12.7Median Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Treatment IM_200mg IV_200mg SQ_200mg SQ_50mg x 4O O O
Protocol: BA1116891Population: Pharmacodynamic
Figure 12.7Median Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta42
Linear Scale
OOO O O O O
Semi-Logarithmic Scale
O
O
O O OO
O
431
CONFIDENTIAL 2014N211143_00BA1116891
Change from Baseline
-999
-998
Cumulative Planned Relative Time
-999 -998
Cha
nge
from
Bas
elin
e (f
old)
0
10
20
30
40
50
Planned Relative Time (Hrs)
0 200 400 600 800
Cha
nge
from
Bas
elin
e (f
old)
0.01
0.1
1
10
100
Planned Relative Time (Hrs)
0 200 400 600 800
Page 1 of 3Page 1 of 3Protocol: BA1116891Population: Pharmacodynamic
Figure 12.8Median Plasma PD Concentration Change from Baseline-Time Plot (Linear and Semi-Log) (Truncated)
Note: Change from baseline is calculated by dividing the baseline value from the individual post-dose value.
Treatment IM_200mg IV_200mg SQ_200mg SQ_50mg x 4O O O
Protocol: BA1116891Population: Pharmacodynamic
Figure 12.8Median Plasma PD Concentration Change from Baseline-Time Plot (Linear and Semi-Log) (Truncated)
Note: Change from baseline is calculated by dividing the baseline value from the individual post-dose value.
Parameter:Abeta1-22
Linear Scale
OO O O O O O
Semi-Logarithmic Scale
OO O
O O OO
432
CONFIDENTIAL 2014N211143_00BA1116891
Change from Baseline
-999
-998
Cumulative Planned Relative Time
-999 -998
Cha
nge
from
Bas
elin
e (f
old)
0
10
20
30
40
50
Planned Relative Time (Hrs)
0 200 400 600 800
Cha
nge
from
Bas
elin
e (f
old)
0.01
0.1
1
10
100
Planned Relative Time (Hrs)
0 200 400 600 800
Page 2 of 3Page 2 of 3Protocol: BA1116891Population: Pharmacodynamic
Figure 12.8Median Plasma PD Concentration Change from Baseline-Time Plot (Linear and Semi-Log) (Truncated)
Note: Change from baseline is calculated by dividing the baseline value from the individual post-dose value.
Treatment IM_200mg IV_200mg SQ_200mg SQ_50mg x 4O O O
Protocol: BA1116891Population: Pharmacodynamic
Figure 12.8Median Plasma PD Concentration Change from Baseline-Time Plot (Linear and Semi-Log) (Truncated)
Note: Change from baseline is calculated by dividing the baseline value from the individual post-dose value.
Parameter:Abeta18-35
Linear Scale
O
O
OO
O
O
O
Semi-Logarithmic Scale
O
O
O O OO
O
433
CONFIDENTIAL 2014N211143_00BA1116891
Change from Baseline
-999
-998
Cumulative Planned Relative Time
-999 -998
Cha
nge
from
Bas
elin
e (f
old)
0
10
20
30
40
50
Planned Relative Time (Hrs)
0 200 400 600 800
Cha
nge
from
Bas
elin
e (f
old)
0.01
0.1
1
10
100
Planned Relative Time (Hrs)
0 200 400 600 800
Page 3 of 3Page 3 of 3Protocol: BA1116891Population: Pharmacodynamic
Figure 12.8Median Plasma PD Concentration Change from Baseline-Time Plot (Linear and Semi-Log) (Truncated)
Note: Change from baseline is calculated by dividing the baseline value from the individual post-dose value.
Treatment IM_200mg IV_200mg SQ_200mg SQ_50mg x 4O O O
Protocol: BA1116891Population: Pharmacodynamic
Figure 12.8Median Plasma PD Concentration Change from Baseline-Time Plot (Linear and Semi-Log) (Truncated)
Note: Change from baseline is calculated by dividing the baseline value from the individual post-dose value.
Parameter:Abeta42
Linear Scale
O
O
O
OO
O
O
Semi-Logarithmic Scale
O
O
OO O
O
O
434
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 1 of 108Page 1 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta1-22, Subject ID: Treatment:SQ_200mg
Linear Scale
OOOO O O O O O
Semi-Logarithmic Scale
OOOO O O OO
O
435
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 2 of 108Page 2 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)Parameter:Abeta1-22, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OOOO O OOOO O OOOO O OOOO O O O O O O
Semi-Logarithmic Scale
O
OOOO O
OOO O OOOO
OOOOO
OO
OO O
O
436
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 3 of 108Page 3 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta1-22, Subject ID: Treatment:IM_200mg
Linear Scale
OOOO O O O O O
Semi-Logarithmic Scale
O
OOO O
OO O
O
437
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 4 of 108Page 4 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta1-22, Subject ID: Treatment:IV_200mg
Linear Scale
OOOOOOO O O O O O
Semi-Logarithmic Scale
O
OOOOOO
O
OO
O
O
438
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 5 of 108Page 5 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta1-22, Subject ID: Treatment:IV_200mg
Linear Scale
OOOOOOO O O O O O
Semi-Logarithmic Scale
O
OOOOOO O
O O
O
O
439
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 6 of 108Page 6 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta1-22, Subject ID: Treatment:IM_200mg
Linear Scale
OOOO O O O O O
Semi-Logarithmic Scale
O
OOO O O O
O
O
440
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 7 of 108Page 7 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta1-22, Subject ID: Treatment:SQ_200mg
Linear Scale
OOOO O O O O O
Semi-Logarithmic Scale
OOOO
OO O O
O
441
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 8 of 108Page 8 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)Parameter:Abeta1-22, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OOOO O OOOO O OOOO O OOOO O O O O O O O
Semi-Logarithmic Scale
OOOO O OOOO O OOOO O OOOO O O O O
OO
O
442
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 9 of 108Page 9 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta1-22, Subject ID: Treatment:IV_200mg
Linear Scale
OOOOOOO O O O O O
Semi-Logarithmic Scale
O
OOOOOO
O OO O O
443
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 10 of 108Page 10 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta1-22, Subject ID: Treatment:SQ_200mg
Linear Scale
OOOO O O O O O
Semi-Logarithmic Scale
OOOO O
O O O O
444
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 11 of 108Page 11 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta1-22, Subject ID: Treatment:IM_200mg
Linear Scale
OOOO O O O O O
Semi-Logarithmic Scale
OOOO O O
O O O
445
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 12 of 108Page 12 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)Parameter:Abeta1-22, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OOOO O OOOO O OOOO O OOOO O O O O O O
Semi-Logarithmic Scale
O
O
OOO OOOO
O
OOOO O O
OO
OO
OO O
OO
446
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 13 of 108Page 13 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta1-22, Subject ID: Treatment:IV_200mg
Linear Scale
OOOOOOO O O O O O
Semi-Logarithmic Scale
O
OOOOOO O O
O O
O
447
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 14 of 108Page 14 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta1-22, Subject ID: Treatment:SQ_200mg
Linear Scale
OOOO O O O O O
Semi-Logarithmic Scale
O
OOO
O
O OO
O
448
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 15 of 108Page 15 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)Parameter:Abeta1-22, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OOOO O OOOO O OOOO O OOOO O O O O O O
Semi-Logarithmic Scale
O
OOO O O
OOOO O
O
OO OOOOO O O
O O
O O
449
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 16 of 108Page 16 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta1-22, Subject ID: Treatment:IM_200mg
Linear Scale
OOOO O O O O O
Semi-Logarithmic Scale
O
OOO O O
O
O
O
450
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 17 of 108Page 17 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta1-22, Subject ID: Treatment:SQ_200mg
Linear Scale
OOO O O O O O
Semi-Logarithmic Scale
O
OO O O O O
O
451
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 18 of 108Page 18 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta1-22, Subject ID: Treatment:IV_200mg
Linear Scale
OOOOOOO O O O O O
Semi-Logarithmic Scale
O
OOOO
O
OO O
OO
O
452
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 19 of 108Page 19 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta1-22, Subject ID: Treatment:IM_200mg
Linear Scale
OOOO O O O
Semi-Logarithmic Scale
OOOO
O OO
453
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 20 of 108Page 20 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)Parameter:Abeta1-22, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OOOO O OOOO O OOOO O OOOO O O O O O O
Semi-Logarithmic Scale
OOOOO OO
OO O OOOO O OOOO O O O O
O O
454
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
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L)
10
100
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 21 of 108Page 21 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta1-22, Subject ID: Treatment:IV_200mg
Linear Scale
OOOOOOO O O O O O
Semi-Logarithmic Scale
O
OOOO
O
O
OO O
OO
455
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
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L)
10
100
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 22 of 108Page 22 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta1-22, Subject ID: Treatment:IM_200mg
Linear Scale
OOOO O O O O O
Semi-Logarithmic Scale
OOOO
O OO
OO
456
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 23 of 108Page 23 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)Parameter:Abeta1-22, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OOOO O OOOO O OOOO O OOOO O O O O O O
Semi-Logarithmic Scale
OOOO O OOOO O OOOO O OOOOO O O O
O O
457
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 24 of 108Page 24 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta1-22, Subject ID: Treatment:SQ_200mg
Linear Scale
OOOO O O O O O
Semi-Logarithmic Scale
OOOO O
OO
OO
458
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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20000
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
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L)
10
100
1000
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100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 25 of 108Page 25 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta1-22, Subject ID: Treatment:SQ_200mg
Linear Scale
OOOO O O O O O
Semi-Logarithmic Scale
OOOO O
O OO
O
459
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 26 of 108Page 26 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta1-22, Subject ID: Treatment:IM_200mg
Linear Scale
OOOO O O O O O
Semi-Logarithmic Scale
OOOO
O OO
OO
460
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 27 of 108Page 27 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta1-22, Subject ID: Treatment:IV_200mg
Linear Scale
OOOOOO O O O O O
Semi-Logarithmic Scale
O
OO
O
O
OO
OO
O O
461
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 28 of 108Page 28 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)Parameter:Abeta1-22, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OOOO O OOOO O OOOO O OOOO O O O O O O
Semi-Logarithmic Scale
OOOO O OOOO O OOOO O OOOO O O O
O OO
462
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 29 of 108Page 29 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta1-22, Subject ID: Treatment:IV_200mg
Linear Scale
OOOOOOO O O O O O
Semi-Logarithmic Scale
O
OOO
O
O
OO
OO
OO
463
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 30 of 108Page 30 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta1-22, Subject ID: Treatment:IM_200mg
Linear Scale
OOOO O O O O O
Semi-Logarithmic Scale
O
OOO
O OO
OO
464
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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20000
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 31 of 108Page 31 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)Parameter:Abeta1-22, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OOOO O OOOO O OOOO O OOOO O O O O O O
Semi-Logarithmic Scale
OOOO O O
OOO O OOOO
O OOOO O OO
O OO
465
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 32 of 108Page 32 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta1-22, Subject ID: Treatment:SQ_200mg
Linear Scale
OOOO O O O O O
Semi-Logarithmic Scale
OOOO O
O O
OO
466
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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20000
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 33 of 108Page 33 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)Parameter:Abeta1-22, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OOOO O OOOO O OOOO O OOOO O O O
Semi-Logarithmic Scale
OOOO
O OOOO O OOOO O OOOO OO
O
467
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 34 of 108Page 34 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta1-22, Subject ID: Treatment:IV_200mg
Linear Scale
OOOOOOO O O O O O
Semi-Logarithmic Scale
O
OOO
O
O
O O OO
O O
468
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 35 of 108Page 35 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta1-22, Subject ID: Treatment:SQ_200mg
Linear Scale
OOOO O O O O O
Semi-Logarithmic Scale
OOOO O O
O OO
469
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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20000
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 36 of 108Page 36 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta1-22, Subject ID: Treatment:IM_200mg
Linear Scale
OOOO O O O O O
Semi-Logarithmic Scale
OOOO O
O O OO
470
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 37 of 108Page 37 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta18-35, Subject ID: Treatment:SQ_200mg
Linear Scale
O
O
O
O
O
O
O
O
O
Semi-Logarithmic Scale
O
O
O
O OO
O
O
O
471
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 38 of 108Page 38 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)Parameter:Abeta18-35, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OO
O
O
OOO
O
OO OO
OO
O OOOO
O
O
O
O
OO
Semi-Logarithmic Scale
O
O
O
O
O OO
OO O OO
OO O OOOO O O
O
O
O
O
472
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
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100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 39 of 108Page 39 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta18-35, Subject ID: Treatment:IM_200mg
Linear Scale
O
O
O
O
O
O
O
OO
Semi-Logarithmic Scale
O
O
OO
O
O
O
O
O
473
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
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L)
10
100
1000
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 40 of 108Page 40 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta18-35, Subject ID: Treatment:IV_200mg
Linear Scale
O
OO
O
O
O
O
O
O
O
O
O
Semi-Logarithmic Scale
O
OOOO
OO O
O
O
O
O
474
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
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L)
10
100
1000
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 41 of 108Page 41 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta18-35, Subject ID: Treatment:IV_200mg
Linear Scale
O
OO
O
O
O
O
O
O
O
OO
Semi-Logarithmic Scale
O
OOOO
OO O
O
O
O
O
475
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
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cent
ratio
n (p
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L)
10
100
1000
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 42 of 108Page 42 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta18-35, Subject ID: Treatment:IM_200mg
Linear Scale
O
O
O
O O
O
O
O O
Semi-Logarithmic Scale
O
O
OO O
O
O
OO
476
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
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L)
10
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1000
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0 520 1040 1560 2080 2600
Page 43 of 108Page 43 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta18-35, Subject ID: Treatment:SQ_200mg
Linear Scale
O
O
O
O
O
O
O
OO
Semi-Logarithmic Scale
O
O
OO O
O
O
O
O
477
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
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cent
ratio
n (p
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L)
10
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0 520 1040 1560 2080 2600
Page 44 of 108Page 44 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)Parameter:Abeta18-35, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
O
O
O
O
OOO
OO
O
O
O
OO O OO
O
O
O
O
O
O
OO
O
Semi-Logarithmic Scale
O
O
OO O OO
OO OOOOO O OOO
O O
O
O
O
O
O
O
478
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
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cent
ratio
n (p
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L)
10
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1000
10000
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0 520 1040 1560 2080 2600
Page 45 of 108Page 45 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta18-35, Subject ID: Treatment:IV_200mg
Linear Scale
O
OO
O
O
O
O
O
O
O
OO
Semi-Logarithmic Scale
O
OO
OO
OO OO
O
O
O
479
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
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L)
10
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1000
10000
100000
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0 520 1040 1560 2080 2600
Page 46 of 108Page 46 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta18-35, Subject ID: Treatment:SQ_200mg
Linear Scale
O
O
O
O
O
O
O
OO
Semi-Logarithmic Scale
O
O
O
OO
O
O
O
O
480
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
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cent
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n (p
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L)
10
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0 520 1040 1560 2080 2600
Page 47 of 108Page 47 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta18-35, Subject ID: Treatment:IM_200mg
Linear Scale
O
O
O
O O
O
O
OO
Semi-Logarithmic Scale
O
O
OO O
O
O
O
O
481
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
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cent
ratio
n (p
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L)
10
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0 520 1040 1560 2080 2600
Page 48 of 108Page 48 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)Parameter:Abeta18-35, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
O
O
OO O OO
OOO OO
OO O
OOOO O
O
O
O
OO
Semi-Logarithmic Scale
O
O
OO O OOOO O OO
OO O OOOO OO
OO
O
O
482
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
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cent
ratio
n (p
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L)
10
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1000
10000
100000
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0 520 1040 1560 2080 2600
Page 49 of 108Page 49 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta18-35, Subject ID: Treatment:IV_200mg
Linear Scale
O
OO
O
O
O
O
O
O
O
O
O
Semi-Logarithmic Scale
OOOOO
OO O
O
OO
O
483
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
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cent
ratio
n (p
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L)
10
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 50 of 108Page 50 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta18-35, Subject ID: Treatment:SQ_200mg
Linear Scale
O
O
O
O
O
O
O
OO
Semi-Logarithmic Scale
O
O
OO O
O
O
O
O
484
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
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cent
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L)
10
100
1000
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 51 of 108Page 51 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)Parameter:Abeta18-35, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OO
O
O
O OO
O
O O
OO
OO OOOOO
O
O
O
O
OO
Semi-Logarithmic Scale
O
O
O
OO OO
OO O
OOOO O OOO
O O O
OO
O
O
485
CONFIDENTIAL 2014N211143_00BA1116891
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cent
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n (p
g/m
L)
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Con
cent
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n (p
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L)
10
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0 520 1040 1560 2080 2600
Page 52 of 108Page 52 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta18-35, Subject ID: Treatment:IM_200mg
Linear Scale
O
O
O
O O
O
O
O
O
Semi-Logarithmic Scale
O
O
OO O
O
O
O
O
486
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
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L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
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n (p
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L)
10
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 53 of 108Page 53 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta18-35, Subject ID: Treatment:SQ_200mg
Linear Scale
O
O
O
O
O
O
O
O
Semi-Logarithmic Scale
O
O
O
O O
O
O
O
487
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
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L)
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
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n (p
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L)
10
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Page 54 of 108Page 54 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta18-35, Subject ID: Treatment:IV_200mg
Linear Scale
O
OO
OO
O
O O
O
O
OO
Semi-Logarithmic Scale
O
OOOO
OO O
O
O
O
O
488
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
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Con
cent
ratio
n (p
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L)
10
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Page 55 of 108Page 55 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta18-35, Subject ID: Treatment:IM_200mg
Linear Scale
O
O
O
O
O
O
O
Semi-Logarithmic Scale
O
O
OO O
O
O
489
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
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L)
10
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Page 56 of 108Page 56 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)Parameter:Abeta18-35, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OO
O
O
OOO
O
O O
OOOO O O
O
OOO
O
O
O
O
O
Semi-Logarithmic Scale
O
O
O
OO OO
OOOOOOO O OO
OO OO
O
O
O
O
490
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
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L)
10
100
1000
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0 520 1040 1560 2080 2600
Page 57 of 108Page 57 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta18-35, Subject ID: Treatment:IV_200mg
Linear Scale
O
O
O
O
O
O
O
O
O
O
O O
Semi-Logarithmic Scale
O
OOOO
OO O
O
O
O
O
491
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
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L)
10
100
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0 520 1040 1560 2080 2600
Page 58 of 108Page 58 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta18-35, Subject ID: Treatment:IM_200mg
Linear Scale
O
O
O
O
O
O
O
OO
Semi-Logarithmic Scale
O
O
OOO
O
O
O
O
492
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
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L)
10
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 59 of 108Page 59 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)Parameter:Abeta18-35, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
O
O
O
O O OO
OO
O OO
O
O O
OO
OO O
O
O
O
OO
Semi-Logarithmic Scale
O
O
OO O OO
OO O OOOO O OO
OO OO
OO
O
O
493
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 60 of 108Page 60 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta18-35, Subject ID: Treatment:SQ_200mg
Linear Scale
O
O
O
O
O
O
O
OO
Semi-Logarithmic Scale
O
O
OO
OO
O
O
O
494
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
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L)
10
100
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 61 of 108Page 61 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta18-35, Subject ID: Treatment:SQ_200mg
Linear Scale
O
O
O
O
O
O
O
OO
Semi-Logarithmic Scale
O
O
O
OO
O
O
O
O
495
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
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cent
ratio
n (p
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L)
10
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0 520 1040 1560 2080 2600
Page 62 of 108Page 62 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta18-35, Subject ID: Treatment:IM_200mg
Linear Scale
O
O
O
O
O
O
O
OO
Semi-Logarithmic Scale
O
O
OO
OO
O
O
O
496
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
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L)
10
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 63 of 108Page 63 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta18-35, Subject ID: Treatment:IV_200mg
Linear Scale
O
O
O
O
O
O
O
O
O
OO
Semi-Logarithmic Scale
O
OO
O
OOO
O
O
O
O
497
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
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L)
10
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0 520 1040 1560 2080 2600
Page 64 of 108Page 64 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)Parameter:Abeta18-35, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OO
O
O
O OOOO O OO
OO O
OO
O
OO
O
O
O
OO
Semi-Logarithmic Scale
O
O
O
OO OOO
O O OOOO O OO
OO O O
O
O
O
O
498
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 65 of 108Page 65 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta18-35, Subject ID: Treatment:IV_200mg
Linear Scale
O
OO
O
O
O
O O
O
O
O
O
Semi-Logarithmic Scale
O
OO
OOOO O O
O
O
O
499
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 66 of 108Page 66 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta18-35, Subject ID: Treatment:IM_200mg
Linear Scale
O
O
OO
O
O
O
O
O
Semi-Logarithmic Scale
O
O
OO OO
O
O
O
500
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
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cent
ratio
n (p
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L)
10
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0 520 1040 1560 2080 2600
Page 67 of 108Page 67 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)Parameter:Abeta18-35, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
O
O
OO
OOO
O
O
O
OOOO
O
O
O
O
O
O
O
O
O
O
O
Semi-Logarithmic Scale
O
O
OOO OO
OO O OOOO
O OOO
OO O
OO
O
O
501
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
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L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 68 of 108Page 68 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta18-35, Subject ID: Treatment:SQ_200mg
Linear Scale
O
O
O
O
O
O
O
OO
Semi-Logarithmic Scale
O
O
OO O
O
O
O
O
502
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
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cent
ratio
n (p
g/m
L)
10
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1000
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 69 of 108Page 69 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)Parameter:Abeta18-35, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OO
O
O
O OO
OO O OO
OO
O
OO
OOO
O
O
Semi-Logarithmic Scale
O
O
O
OO OO
OO O OOOO O OO
OO O O
O
503
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
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L)
10
100
1000
10000
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 70 of 108Page 70 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta18-35, Subject ID: Treatment:IV_200mg
Linear Scale
O
OO
O
O
O
OO
O
O
OO
Semi-Logarithmic Scale
O
OOOO
OO O
O
O
O
O
504
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
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L)
10
100
1000
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 71 of 108Page 71 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta18-35, Subject ID: Treatment:SQ_200mg
Linear Scale
O
O
O
O
O
O
O
OO
Semi-Logarithmic Scale
O
O
OO
O
O
O
OO
505
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
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L)
10
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 72 of 108Page 72 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta18-35, Subject ID: Treatment:IM_200mg
Linear Scale
O
O
O
O
O
O
O
O
O
Semi-Logarithmic Scale
O
O
OO O O
O
O
O
506
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
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cent
ratio
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L)
10
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0 520 1040 1560 2080 2600
Page 73 of 108Page 73 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta42, Subject ID: Treatment:SQ_200mg
Linear Scale
OOOO O O O O O
Semi-Logarithmic Scale
O
O
OO
OO
O
OO
507
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
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cent
ratio
n (p
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L)
10
100
1000
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0 520 1040 1560 2080 2600
Page 74 of 108Page 74 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta42, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OOOO O OOOO O OOOO O OOOO O O O O O O
Semi-Logarithmic Scale
O
O
O
O
O OOOO O OO
OOO OOOO O O
OO
O
O
508
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
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cent
ratio
n (p
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L)
10
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1000
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0 520 1040 1560 2080 2600
Page 75 of 108Page 75 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta42, Subject ID: Treatment:IM_200mg
Linear Scale
OOOO O O O O O
Semi-Logarithmic Scale
O
O
OO O
O
O
O
O
509
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
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cent
ratio
n (p
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L)
10
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0 520 1040 1560 2080 2600
Page 76 of 108Page 76 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta42, Subject ID: Treatment:IV_200mg
Linear Scale
OOOOOOO O O O O O
Semi-Logarithmic Scale
O
OOOOOO O O
OO
O
510
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
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cent
ratio
n (p
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L)
10
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 77 of 108Page 77 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta42, Subject ID: Treatment:IV_200mg
Linear Scale
OOOOOOO O O O O O
Semi-Logarithmic Scale
O
OO
OO
OO OO
O
O
O
511
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
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cent
ratio
n (p
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L)
10
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 78 of 108Page 78 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta42, Subject ID: Treatment:IM_200mg
Linear Scale
OOOO O O O O O
Semi-Logarithmic Scale
O
O
OOO
O
O
O
O
512
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
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cent
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n (p
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L)
10
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 79 of 108Page 79 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta42, Subject ID: Treatment:SQ_200mg
Linear Scale
OOOO O O
O O O
Semi-Logarithmic Scale
OOOO O O
O OO
513
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
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cent
ratio
n (p
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L)
10
100
1000
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Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 80 of 108Page 80 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta42, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OOOO O OOOO O OOOO O OOOO O O O O O O O
Semi-Logarithmic Scale
O
O
OO
O OOOO O OO
OO
O OOOO O O
O
O
O
O
O
514
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 81 of 108Page 81 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta42, Subject ID: Treatment:IV_200mg
Linear Scale
OOOOOOO O O O O O
Semi-Logarithmic Scale
O
OOOO
OO OO
O
O
O
515
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 82 of 108Page 82 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta42, Subject ID: Treatment:SQ_200mg
Linear Scale
OOOO O O O O O
Semi-Logarithmic Scale
O
O
OO O O
O
O
O
516
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 83 of 108Page 83 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta42, Subject ID: Treatment:IM_200mg
Linear Scale
OOOO O O O O O
Semi-Logarithmic Scale
O
O
OOO
O
O
O
O
517
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 84 of 108Page 84 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta42, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OOOO O OOOO O OOOO O OOOO O O O O O O
Semi-Logarithmic Scale
O
O
OO O OOOO O OOO
O O OOOO O O
OO
O
O
518
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 85 of 108Page 85 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta42, Subject ID: Treatment:IV_200mg
Linear Scale
OOOOOO
O O
OO
O
O
Semi-Logarithmic Scale
OOOOOO
O O
OO
O
O
519
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 86 of 108Page 86 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta42, Subject ID: Treatment:SQ_200mg
Linear Scale
OOOO O O O O O
Semi-Logarithmic Scale
O
O
OO O
O
O
O
O
520
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 87 of 108Page 87 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta42, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OOOOO OOOO O OOOO O OOOO O O O O O O
Semi-Logarithmic Scale
O
O
OO
O OOOO O OOO
O O OOOO O O
OO
O
O
521
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 88 of 108Page 88 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta42, Subject ID: Treatment:IM_200mg
Linear Scale
OOOO O O O O O
Semi-Logarithmic Scale
O
O
OO O
OO
O
O
522
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 89 of 108Page 89 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta42, Subject ID: Treatment:SQ_200mg
Linear Scale
OOO O O O O O
Semi-Logarithmic Scale
O
O
O
O O
O
O
O
523
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 90 of 108Page 90 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta42, Subject ID: Treatment:IV_200mg
Linear Scale
OOOOOOO O O O O O
Semi-Logarithmic Scale
O
OO
OO
OOO
O
O
O
O
524
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 91 of 108Page 91 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta42, Subject ID: Treatment:IM_200mg
Linear Scale
OOOO O O O
Semi-Logarithmic Scale
O
O
OO O O
O
525
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 92 of 108Page 92 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta42, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OOOOO OOOO O OOOO O OOOO O O O O O O
Semi-Logarithmic Scale
O
O
O
OO OO
OO O OOOO O OO
OO O OO
O
O
O
526
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 93 of 108Page 93 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta42, Subject ID: Treatment:IV_200mg
Linear Scale
OOOOOOO O O O O O
Semi-Logarithmic Scale
O
OO
OO
OO O
O
O
OO
527
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 94 of 108Page 94 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta42, Subject ID: Treatment:IM_200mg
Linear Scale
OOOO O O O O O
Semi-Logarithmic Scale
O
O
OOO
O
O
O
O
528
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 95 of 108Page 95 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta42, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OOOO O OOOO O OOOO O OOOO O O O O O O
Semi-Logarithmic Scale
O
O
OO O OO
OO O OOOO O O
OOO O O
OO
O
O
529
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 96 of 108Page 96 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta42, Subject ID: Treatment:SQ_200mg
Linear Scale
OOOO O O O O O
Semi-Logarithmic Scale
O
O
OO O
O
O
O
O
530
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 97 of 108Page 97 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta42, Subject ID: Treatment:SQ_200mg
Linear Scale
OOOO O O O O O
Semi-Logarithmic Scale
O
O
OO
OO
O
O
O
531
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 98 of 108Page 98 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta42, Subject ID: Treatment:IM_200mg
Linear Scale
OOO
O O
O O O
O
Semi-Logarithmic Scale
OOO
O O
OO O
O
532
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 99 of 108Page 99 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta42, Subject ID: Treatment:IV_200mg
Linear Scale
OOOOOO O O O O O
Semi-Logarithmic Scale
O
OO
O
OO O
O
O
O
O
533
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 100 of 108Page 100 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta42, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OOOO O OOOO O OOOO O OOOO O O O O O O
Semi-Logarithmic Scale
O
O
O
OO OOO
O O OOOO O OO
OO O OO
O
O
O
534
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 101 of 108Page 101 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta42, Subject ID: Treatment:IV_200mg
Linear Scale
OOOOOOO O O O O O
Semi-Logarithmic Scale
O
OOOO
OO O
O
O
O
O
535
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 102 of 108Page 102 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta42, Subject ID: Treatment:IM_200mg
Linear Scale
OOOO O O O O O
Semi-Logarithmic Scale
O
O
OOO
O
O
O
O
536
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 103 of 108Page 103 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta42, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OOOO O OOO
O O OOOO O OOOO O OO O O O
Semi-Logarithmic Scale
O
O
OO O OO
OO O OOOO
O OOOO O
O
O
O
O
O
537
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 104 of 108Page 104 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta42, Subject ID: Treatment:SQ_200mg
Linear Scale
OOOO O O O O O
Semi-Logarithmic Scale
O
O
OO O
O
O
O
O
538
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 105 of 108Page 105 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta42, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OOOO O OOOO O OOOO O OOOO O O O
Semi-Logarithmic Scale
O
O
OO
OOOOO O OO
OO O OOOO O O
O
539
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 106 of 108Page 106 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta42, Subject ID: Treatment:IV_200mg
Linear Scale
OOOOOOO O O O O O
Semi-Logarithmic Scale
O
OOOO
OO
OO
O
O
O
540
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 107 of 108Page 107 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta42, Subject ID: Treatment:SQ_200mg
Linear Scale
OOOO
OO
O O O
Semi-Logarithmic Scale
O
OOO
OO
O OO
541
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 520 1040 1560 2080 2600
Page 108 of 108Page 108 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.9Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Parameter:Abeta42, Subject ID: Treatment:IM_200mg
Linear Scale
OOOO O O
O
O
O
Semi-Logarithmic Scale
OOOO O O
O
O
O
542
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 1 of 108Page 1 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta1-22, Subject ID: Treatment:SQ_200mg
Linear Scale
OO O O O O O
Semi-Logarithmic Scale
OO O O O O O
543
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 2 of 108Page 2 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta1-22, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OO O O O OO O O O OO O O O OO O O O O
Semi-Logarithmic Scale
O
O O O O OOO
O O OO O OO
OO O OO
O
544
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 3 of 108Page 3 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta1-22, Subject ID: Treatment:IM_200mg
Linear Scale
OO O O O O O
Semi-Logarithmic Scale
O
O O O O
OO
545
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 4 of 108Page 4 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta1-22, Subject ID: Treatment:IV_200mg
Linear Scale
OOOOO O O O O O
Semi-Logarithmic Scale
O
OOOO O O
O
OO
546
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
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g/m
L)
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Actual Relative Time (Hrs)
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Con
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n (p
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L)
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Page 5 of 108Page 5 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta1-22, Subject ID: Treatment:IV_200mg
Linear Scale
OOOOO O O O O O
Semi-Logarithmic Scale
O
OOOO O O O
O O
547
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
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Actual Relative Time (Hrs)
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Con
cent
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n (p
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L)
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Page 6 of 108Page 6 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta1-22, Subject ID: Treatment:IM_200mg
Linear Scale
OO O O O O O
Semi-Logarithmic Scale
O
O O O O O O
548
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
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L)
10
100
1000
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 7 of 108Page 7 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta1-22, Subject ID: Treatment:SQ_200mg
Linear Scale
OO O O O O O
Semi-Logarithmic Scale
OO O O
OO O
549
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
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50000
60000
Actual Relative Time (Hrs)
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Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 8 of 108Page 8 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta1-22, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OO O O O OO O O O OO O O O OO O O O O
Semi-Logarithmic Scale
OO O O O OO O O O OO O O O OO O O O O
550
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 9 of 108Page 9 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta1-22, Subject ID: Treatment:IV_200mg
Linear Scale
OOOOO O O O O O
Semi-Logarithmic Scale
O
OOOOO O O O
O
551
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
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40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 10 of 108Page 10 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta1-22, Subject ID: Treatment:SQ_200mg
Linear Scale
OO O O O O O
Semi-Logarithmic Scale
OO O O OO O
552
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 11 of 108Page 11 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta1-22, Subject ID: Treatment:IM_200mg
Linear Scale
OO O O O O O
Semi-Logarithmic Scale
OOO
O O OO
553
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
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50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 12 of 108Page 12 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta1-22, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OO O O O OO O O O OO O O O OO O O O O
Semi-Logarithmic Scale
O
O
O O O OOO
OO
OO O O O O
O O
OO
O
554
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 13 of 108Page 13 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta1-22, Subject ID: Treatment:IV_200mg
Linear Scale
OOOOO O O O O O
Semi-Logarithmic Scale
O
OOOOO
O O OO
555
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 14 of 108Page 14 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta1-22, Subject ID: Treatment:SQ_200mg
Linear Scale
OO O O O O O
Semi-Logarithmic Scale
O
O O O
O
O O
556
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 15 of 108Page 15 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta1-22, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OO O O O OO O O O OO O O O OO O O O O
Semi-Logarithmic Scale
O
OO
O O OO O O
O O
O
O O OOOO
O O O
557
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 16 of 108Page 16 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta1-22, Subject ID: Treatment:IM_200mg
Linear Scale
OO O O O O O
Semi-Logarithmic Scale
O
O O O O O
O
558
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 17 of 108Page 17 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta1-22, Subject ID: Treatment:SQ_200mg
Linear Scale
OO O O O O
Semi-Logarithmic Scale
O
OO O O O
559
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 18 of 108Page 18 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta1-22, Subject ID: Treatment:IV_200mg
Linear Scale
OOOOO O O O O O
Semi-Logarithmic Scale
O
OOOO
O
OO O
O
560
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 19 of 108Page 19 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta1-22, Subject ID: Treatment:IM_200mg
Linear Scale
OO O O O O O
Semi-Logarithmic Scale
OOO O
O OO
561
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 20 of 108Page 20 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta1-22, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OO O O O OO O O O OO O O O OO O O O O
Semi-Logarithmic Scale
OO O OO OO
O O O OOO O O OO O O O O
562
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 21 of 108Page 21 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta1-22, Subject ID: Treatment:IV_200mg
Linear Scale
OOOOO O O O O O
Semi-Logarithmic Scale
O
OOOO
O
O
OO O
563
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 22 of 108Page 22 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta1-22, Subject ID: Treatment:IM_200mg
Linear Scale
OO O O O O O
Semi-Logarithmic Scale
OO O O
O OO
564
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 23 of 108Page 23 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta1-22, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OO O O O OO O O O OO O O O OO O O O O
Semi-Logarithmic Scale
OO O O O OO O O O OO O O O OO O OO O
565
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 24 of 108Page 24 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta1-22, Subject ID: Treatment:SQ_200mg
Linear Scale
OO O O O O O
Semi-Logarithmic Scale
OO O O O
OO
566
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 25 of 108Page 25 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta1-22, Subject ID: Treatment:SQ_200mg
Linear Scale
OO O O O O O
Semi-Logarithmic Scale
OO O O OO O
567
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 26 of 108Page 26 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta1-22, Subject ID: Treatment:IM_200mg
Linear Scale
OO O O O O O
Semi-Logarithmic Scale
OOO
OO O
O
568
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 27 of 108Page 27 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta1-22, Subject ID: Treatment:IV_200mg
Linear Scale
OOOO O O O O O
Semi-Logarithmic Scale
O
OO
O
O
OO
OO
569
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 28 of 108Page 28 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta1-22, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OO O O O OO O O O OO O O O OO O O O O
Semi-Logarithmic Scale
OO O O O OO O O O OO O O O OO O O O O
570
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 29 of 108Page 29 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta1-22, Subject ID: Treatment:IV_200mg
Linear Scale
OOOOO O O O O O
Semi-Logarithmic Scale
O
OOO
O
O
OO
OO
571
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 30 of 108Page 30 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta1-22, Subject ID: Treatment:IM_200mg
Linear Scale
OO O O O O O
Semi-Logarithmic Scale
O
OO O O O
O
572
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 31 of 108Page 31 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta1-22, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OO O O O OO O O O OO O O O OO O O O O
Semi-Logarithmic Scale
OO O O O OO O O O OO
O O O OO O O O O
573
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 32 of 108Page 32 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta1-22, Subject ID: Treatment:SQ_200mg
Linear Scale
OO O O O O O
Semi-Logarithmic Scale
OO O O O
O O
574
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 33 of 108Page 33 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta1-22, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OO O O O OO O O O OO O O O OO O O O O
Semi-Logarithmic Scale
OOO O O OO O O O OO O O O OO O O O
O
575
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 34 of 108Page 34 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta1-22, Subject ID: Treatment:IV_200mg
Linear Scale
OOOOO O O O O O
Semi-Logarithmic Scale
O
OOO
O
O
O O OO
576
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 35 of 108Page 35 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta1-22, Subject ID: Treatment:SQ_200mg
Linear Scale
OO O O O O O
Semi-Logarithmic Scale
OOO O O O
O
577
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 36 of 108Page 36 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta1-22, Subject ID: Treatment:IM_200mg
Linear Scale
OO O O O O O
Semi-Logarithmic Scale
OO O O O
O O
578
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 37 of 108Page 37 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta18-35, Subject ID: Treatment:SQ_200mg
Linear Scale
O
O
O
O
O
O
O
Semi-Logarithmic Scale
O
O
O
O OO
O
579
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 38 of 108Page 38 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta18-35, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OO
O
O
OOO
O
OO O
O
O O
O OO O
OO
O
Semi-Logarithmic Scale
O
O
O
O
O OO
OO O OO
O O O OO O O O O
580
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 39 of 108Page 39 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta18-35, Subject ID: Treatment:IM_200mg
Linear Scale
O
O
O
O
O
O
O
Semi-Logarithmic Scale
O
O
OO
O
O
O
581
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 40 of 108Page 40 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta18-35, Subject ID: Treatment:IV_200mg
Linear Scale
O
OO
O
O
O
O
O
O
O
Semi-Logarithmic Scale
O
OOOO
OO O
O
O
582
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 41 of 108Page 41 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta18-35, Subject ID: Treatment:IV_200mg
Linear Scale
O
OO
O
O
O
O
O
O
O
Semi-Logarithmic Scale
O
OOOO
O O O
O
O
583
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 42 of 108Page 42 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta18-35, Subject ID: Treatment:IM_200mg
Linear Scale
O
O
O
O O
O
O
Semi-Logarithmic Scale
O
O
OO O
O
O
584
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 43 of 108Page 43 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta18-35, Subject ID: Treatment:SQ_200mg
Linear Scale
O
O
O
O
O
O
O
Semi-Logarithmic Scale
O
O
OO O
O
O
585
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 44 of 108Page 44 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta18-35, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
O
O
O
O
OOO
OO
O
O
O
O O O OO
O
O
O
O
Semi-Logarithmic Scale
O
O
OO O OO
O O OOOO O O OO O
O O
O
586
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 45 of 108Page 45 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta18-35, Subject ID: Treatment:IV_200mg
Linear Scale
O
OO
O
O
O
O
O
O
O
Semi-Logarithmic Scale
O
OO
OO
O O OO
O
587
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 46 of 108Page 46 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta18-35, Subject ID: Treatment:SQ_200mg
Linear Scale
O
O
O
O
O
O
O
Semi-Logarithmic Scale
O
O
O
OO
O
O
588
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 47 of 108Page 47 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta18-35, Subject ID: Treatment:IM_200mg
Linear Scale
O
O
O
O O
O
O
Semi-Logarithmic Scale
O
O
O O O
O
O
589
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 48 of 108Page 48 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta18-35, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
O
O
OO O OO
O OO OO
OO O
OOO O O
O
Semi-Logarithmic Scale
O
O
O O O OOO O O OO
O O O OO O O OO
590
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 49 of 108Page 49 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta18-35, Subject ID: Treatment:IV_200mg
Linear Scale
O
OO
O
O
O
O
O
O
O
Semi-Logarithmic Scale
OOOOO
OO O
O
O
591
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 50 of 108Page 50 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta18-35, Subject ID: Treatment:SQ_200mg
Linear Scale
O
O
O
O
O
O
O
Semi-Logarithmic Scale
O
O
OO O
O
O
592
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 51 of 108Page 51 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta18-35, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OO
O
O
O OO
O
O O
OO
O OO
OOO
O
O
O
Semi-Logarithmic Scale
O
O
O
OO OO
OO O
OOO O O OO O O O O
593
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 52 of 108Page 52 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta18-35, Subject ID: Treatment:IM_200mg
Linear Scale
O
O
O
O O
O
O
Semi-Logarithmic Scale
O
O
OO O
O
O
594
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 53 of 108Page 53 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta18-35, Subject ID: Treatment:SQ_200mg
Linear Scale
O
O
O
O
O
O
Semi-Logarithmic Scale
O
O
O
O O
O
595
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 54 of 108Page 54 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta18-35, Subject ID: Treatment:IV_200mg
Linear Scale
O
OO
OO
O
O O
O
O
Semi-Logarithmic Scale
O
OOOO
OO O
O
O
596
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 55 of 108Page 55 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta18-35, Subject ID: Treatment:IM_200mg
Linear Scale
O
O
O
O
O
O
O
Semi-Logarithmic Scale
O
O
OO O
O
O
597
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 56 of 108Page 56 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta18-35, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OO
O
O
OOO
O
O O
OOO
O O OO
O O O
O
Semi-Logarithmic Scale
O
O
O
OO OO
O O OOO
O O O OOO O O
O
598
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 57 of 108Page 57 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta18-35, Subject ID: Treatment:IV_200mg
Linear Scale
O
O
O
O
O
O
O
O
O
O
Semi-Logarithmic Scale
O
OOOO
OO O
O
O
599
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 58 of 108Page 58 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta18-35, Subject ID: Treatment:IM_200mg
Linear Scale
O
O
O
O
O
O
O
Semi-Logarithmic Scale
O
O
O O OO
O
600
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 59 of 108Page 59 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta18-35, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
O
O
O
O O OO
OO
O OO
O
O O
OO
O O O
O
Semi-Logarithmic Scale
O
O
OO O OO
O O O OOO O O OO
O O OO
601
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
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100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 60 of 108Page 60 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta18-35, Subject ID: Treatment:SQ_200mg
Linear Scale
O
O
O
O
O
O
O
Semi-Logarithmic Scale
O
O
OO
OO
O
602
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 61 of 108Page 61 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta18-35, Subject ID: Treatment:SQ_200mg
Linear Scale
O
O
O
O
O
O
O
Semi-Logarithmic Scale
O
O
O
OO
O
O
603
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 62 of 108Page 62 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta18-35, Subject ID: Treatment:IM_200mg
Linear Scale
O
O
O
O
O
O
O
Semi-Logarithmic Scale
O
O
OO
OO
O
604
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
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Actual Relative Time (Hrs)
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Con
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n (p
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L)
10
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 63 of 108Page 63 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta18-35, Subject ID: Treatment:IV_200mg
Linear Scale
O
O
O
O
O
O
O
O
O
Semi-Logarithmic Scale
O
OO
O
O OO
O
O
605
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
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60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
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ratio
n (p
g/m
L)
10
100
1000
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 64 of 108Page 64 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta18-35, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OO
O
O
O OOO
O O OO
OO O
OO
O
OO
O
Semi-Logarithmic Scale
O
O
O
OO OO O O O OO O O O OO
O O O O
606
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
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60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 65 of 108Page 65 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta18-35, Subject ID: Treatment:IV_200mg
Linear Scale
O
OO
O
O
O
O O
O
O
Semi-Logarithmic Scale
O
OO
OOO
O O O
O
607
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 66 of 108Page 66 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta18-35, Subject ID: Treatment:IM_200mg
Linear Scale
O
O
OO
O
O
O
Semi-Logarithmic Scale
O
O
O O OO
O
608
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
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60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 67 of 108Page 67 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta18-35, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
O
O
OO
OOO
O
O
O
OO O O
O
O
O
O
O
O
O
Semi-Logarithmic Scale
O
O
O O O OOO
O O OO O OO OO O
OO O
609
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
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Con
cent
ratio
n (p
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L)
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Page 68 of 108Page 68 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta18-35, Subject ID: Treatment:SQ_200mg
Linear Scale
O
O
O
O
O
O
O
Semi-Logarithmic Scale
O
O
OO O
O
O
610
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Con
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ratio
n (p
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L)
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100
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Page 69 of 108Page 69 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta18-35, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OO
O
O
O OO
O O O OO
OO
O
OO
O OO
O
Semi-Logarithmic Scale
O
O
O
OO OO
O O O OOO O O OO
O O O O
611
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
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Actual Relative Time (Hrs)
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Con
cent
ratio
n (p
g/m
L)
10
100
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 70 of 108Page 70 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta18-35, Subject ID: Treatment:IV_200mg
Linear Scale
O
OO
O
O
O
OO
O
O
Semi-Logarithmic Scale
O
OOOO
OO O
O
O
612
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
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40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
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10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 71 of 108Page 71 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta18-35, Subject ID: Treatment:SQ_200mg
Linear Scale
O
O
O
O
O
O
O
Semi-Logarithmic Scale
O
O
OO
O
O
O
613
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 72 of 108Page 72 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta18-35, Subject ID: Treatment:IM_200mg
Linear Scale
O
O
O
O
O
O
O
Semi-Logarithmic Scale
O
O
OO O O
O
614
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
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40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 73 of 108Page 73 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta42, Subject ID: Treatment:SQ_200mg
Linear Scale
OO O O O O O
Semi-Logarithmic Scale
O
O
OO
OO
O
615
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
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50000
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 74 of 108Page 74 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta42, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OO O O O OO O O O OO O O O OO O O O O
Semi-Logarithmic Scale
O
O
O
O
O OOO
O O OOO O
O OO O O O O
616
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 75 of 108Page 75 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta42, Subject ID: Treatment:IM_200mg
Linear Scale
OOO O O O O
Semi-Logarithmic Scale
O
O
OO O
O
O
617
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 76 of 108Page 76 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta42, Subject ID: Treatment:IV_200mg
Linear Scale
OOOOOO O O O O
Semi-Logarithmic Scale
O
OOOOO
O O OO
618
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
100000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 77 of 108Page 77 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta42, Subject ID: Treatment:IV_200mg
Linear Scale
OOOOOO O O O O
Semi-Logarithmic Scale
O
OO
OO
O O OO
O
619
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 78 of 108Page 78 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta42, Subject ID: Treatment:IM_200mg
Linear Scale
OOO O O O O
Semi-Logarithmic Scale
O
O
O O O
O
O
620
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
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60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 79 of 108Page 79 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta42, Subject ID: Treatment:SQ_200mg
Linear Scale
OOO O O O
O
Semi-Logarithmic Scale
OOO O O O
O
621
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 80 of 108Page 80 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta42, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OOO O O OO O O O OO O O O OO O O O O
Semi-Logarithmic Scale
O
O
OO
O OOO O O OO
OO
O OOO O
O O
622
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
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40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 81 of 108Page 81 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta42, Subject ID: Treatment:IV_200mg
Linear Scale
OOOOOO O O O O
Semi-Logarithmic Scale
O
OOOO
O O OO
O
623
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
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40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 82 of 108Page 82 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta42, Subject ID: Treatment:SQ_200mg
Linear Scale
OOO O O O O
Semi-Logarithmic Scale
O
O
OO O O
O
624
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
10000
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 83 of 108Page 83 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta42, Subject ID: Treatment:IM_200mg
Linear Scale
OOO O O O O
Semi-Logarithmic Scale
O
O
O O OO
O
625
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 84 of 108Page 84 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta42, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OOO O O OO O O O OO O O O OO O O O O
Semi-Logarithmic Scale
O
O
O O O OOO O O OO O O O OO O O O O
626
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
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60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 85 of 108Page 85 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta42, Subject ID: Treatment:IV_200mg
Linear Scale
OOOOOO
O O
OO
Semi-Logarithmic Scale
OOOOOO
O O
OO
627
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
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60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 86 of 108Page 86 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta42, Subject ID: Treatment:SQ_200mg
Linear Scale
OOO O O O O
Semi-Logarithmic Scale
O
O
OO O
O
O
628
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 87 of 108Page 87 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta42, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OO O O O OO O O O OO O O O OO O O O O
Semi-Logarithmic Scale
O
O
OO
O OOO O O OO O O O OO
O O O O
629
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
40000
50000
60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 88 of 108Page 88 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta42, Subject ID: Treatment:IM_200mg
Linear Scale
OOO O O O O
Semi-Logarithmic Scale
O
O
OO O
OO
630
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
30000
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60000
Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 89 of 108Page 89 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta42, Subject ID: Treatment:SQ_200mg
Linear Scale
OOO O O O
Semi-Logarithmic Scale
O
O
O
O O
O
631
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
20000
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 90 of 108Page 90 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta42, Subject ID: Treatment:IV_200mg
Linear Scale
OOOOOO O O O O
Semi-Logarithmic Scale
O
OO
OO
O O OO
O
632
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 91 of 108Page 91 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta42, Subject ID: Treatment:IM_200mg
Linear Scale
OOO O O O O
Semi-Logarithmic Scale
O
O
OO O O
O
633
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
10000
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 92 of 108Page 92 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta42, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OO O O O OO O O O OO O O O OO O O O O
Semi-Logarithmic Scale
O
O
O
OO OO
O O O OO O O O OOO O O O
634
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
100
1000
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 93 of 108Page 93 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta42, Subject ID: Treatment:IV_200mg
Linear Scale
OOOOOO O O O O
Semi-Logarithmic Scale
O
OO
OO
OO O
O
O
635
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
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Con
cent
ratio
n (p
g/m
L)
10
100
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 94 of 108Page 94 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta42, Subject ID: Treatment:IM_200mg
Linear Scale
OOO O O O O
Semi-Logarithmic Scale
O
O
O O OO
O
636
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
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Con
cent
ratio
n (p
g/m
L)
10
100
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 95 of 108Page 95 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta42, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OO O O O OO O O O OO O O O OO O O O O
Semi-Logarithmic Scale
O
O
OO O OO
O O O OOO O O O
O O O O O
637
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Con
cent
ratio
n (p
g/m
L)
10
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 96 of 108Page 96 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta42, Subject ID: Treatment:SQ_200mg
Linear Scale
OOO O O O O
Semi-Logarithmic Scale
O
O
OO O
O
O
638
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
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Con
cent
ratio
n (p
g/m
L)
10
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 97 of 108Page 97 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta42, Subject ID: Treatment:SQ_200mg
Linear Scale
OOO O O O O
Semi-Logarithmic Scale
O
O
OO
OO
O
639
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
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Con
cent
ratio
n (p
g/m
L)
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Actual Relative Time (Hrs)
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Page 98 of 108Page 98 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta42, Subject ID: Treatment:IM_200mg
Linear Scale
OOO
O O
O O
Semi-Logarithmic Scale
OOO
O O
OO
640
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
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Con
cent
ratio
n (p
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L)
10
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Actual Relative Time (Hrs)
0 200 400 600 800 1000
Page 99 of 108Page 99 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta42, Subject ID: Treatment:IV_200mg
Linear Scale
OOOOO O O O O
Semi-Logarithmic Scale
O
OO
O
OO O
O
O
641
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
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Con
cent
ratio
n (p
g/m
L)
10
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Actual Relative Time (Hrs)
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Page 100 of 108Page 100 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta42, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OO O O O OO O O O OO O O O OO O O O O
Semi-Logarithmic Scale
O
O
O
OO OO O
O O OO O O O OOO O O O
642
CONFIDENTIAL 2014N211143_00BA1116891
Con
cent
ratio
n (p
g/m
L)
0
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Actual Relative Time (Hrs)
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Con
cent
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Page 101 of 108Page 101 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta42, Subject ID: Treatment:IV_200mg
Linear Scale
OOOOOO O O O O
Semi-Logarithmic Scale
O
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CONFIDENTIAL 2014N211143_00BA1116891
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Page 102 of 108Page 102 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta42, Subject ID: Treatment:IM_200mg
Linear Scale
OOO O O O O
Semi-Logarithmic Scale
O
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Page 103 of 108Page 103 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta42, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OOO O O OO O O O OO O O O OO O O O O
Semi-Logarithmic Scale
O
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Page 104 of 108Page 104 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta42, Subject ID: Treatment:SQ_200mg
Linear Scale
OOO O O O O
Semi-Logarithmic Scale
O
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Page 105 of 108Page 105 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta42, Subject ID: Treatment:SQ_50mg x 4
Linear Scale
OO O O O OO O O O OO O O O OO O O O O
Semi-Logarithmic Scale
O
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O O O OOO O O OO
O OO O
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Page 106 of 108Page 106 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta42, Subject ID: Treatment:IV_200mg
Linear Scale
OOOOOO O O O O
Semi-Logarithmic Scale
O
OOOO
OO
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Page 107 of 108Page 107 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta42, Subject ID: Treatment:SQ_200mg
Linear Scale
OO O O O
O
O
Semi-Logarithmic Scale
O
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OO
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Page 108 of 108Page 108 of 108Protocol: BA1116891Population: Pharmacodynamic
Figure 12.10Individual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Parameter:Abeta42, Subject ID: Treatment:IM_200mg
Linear Scale
OOO O O O
O
Semi-Logarithmic Scale
OOO O O O
O
650
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 1 of 9Population: Pharmacodynamic Table 12.1 Summary of Plasma Abeta Pharmacodynamic Concentration-Time Data [pg/mL]
Parameter: Abeta 1-22 No. Time Imputed 95% CI Treatment N Visit point n [1] Mean (Lower, Upper) SD Median Min. Max. ---------------------------------------------------------------------------------------------------------- IV_200mg 9 DAY 1 PREDOSE 9 0 632.6 (471.4, 793.8) 209.75 559.5 42 101 1 H 9 6 111.4 31.3 3 51 2 H 9 6 113.7 31.3 3 56 4 H 8 6 115.4 31.3 3 53 6 H 9 4 136.3 72.3 3 54 DAY 2 24 H 9 2 252.9 (100.4, 405.4) 198.42 204.8 3 69 DAY 3 48 H 9 2 361.0 (172.9, 549.1) 244.71 334.3 3 78 DAY 6 120 H 9 1 457.9 (232.6, 683.2) 293.10 487.6 3 90 DAY 15 336 H 9 0 545.2 (303.9, 786.5) 313.92 599.9 8 99 DAY 29 672 H 9 0 647.6 (354.7, 940.4) 381.02 726.9 8 118 DAY 57 1344 H 9 0 811.2 (470.5, 1151.9) 443.20 944.8 22 160 FOLLOW-UP 2016 H 9 0 964.0 (803.8, 1124.2) 208.42 930.0 73 135
SQ_200mg 9 DAY 1 PREDOSE 9 0 676.0 (516.7, 835.3) 207.26 562.7 49 109 6 H 9 1 544.5 (342.4, 746.5) 262.88 590.9 3 97 DAY 2 24 H 9 1 589.3 (366.0, 812.7) 290.56 645.2 3 102 DAY 3 48 H 8 1 614.9 (338.8, 890.9) 330.19 640.5 3 103 DAY 6 120 H 9 0 672.3 (516.8, 827.8) 202.27 673.8 43 99 DAY 15 336 H 9 0 698.6 (479.7, 917.5) 284.79 681.9 12 107 DAY 29 672 H 9 0 774.8 (529.3, 1020.4) 319.41 775.9 11 126 DAY 57 1344 H 9 0 882.9 (632.8, 1133.0) 325.38 933.3 15 131 FOLLOW-UP 2016 H 9 0 916.6 (815.5, 1017.7) 131.57 927.1 75 114
SQ_50mg x 4 9 DAY 1 PREDOSE 9 0 765.7 (368.1, 1163.4) 517.36 579.9 33 210 6 H 9 0 677.9 (257.5, 1098.4) 546.95 731.3 11 195 DAY 2 24 H 9 0 647.0 (241.6, 1052.4) 527.42 632.9 17 190 DAY 3 48 H 9 0 677.2 (272.0, 1082.4) 527.18 644.4 20 191 DAY 6 120 H 9 0 691.3 (319.7, 1062.9) 483.39 756.8 22 177
[1] No. of subjects with NQs assigned half the limit of quantification.Note: Statistics for 95% CI of Mean and SD are missing because an insufficient numberof subjects have reached the limit of quantification, making calculation of these statistics inappropriate.
651
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 2 of 9Population: Pharmacodynamic Table 12.1 Summary of Plasma Abeta Pharmacodynamic Concentration-Time Data [pg/mL]
Parameter: Abeta 1-22 No. Time Imputed 95% CI Treatment N Visit point n [1] Mean (Lower, Upper) SD Median Min. Max. ---------------------------------------------------------------------------------------------------------- SQ_50mg x 4 9 DAY 8 PREDOSE 9 0 743.5 (321.6, 1165.4) 548.88 823.3 21 200 6 H 9 0 664.0 (253.3, 1074.8) 534.34 714.0 15 190 DAY 9 24 H 9 0 627.7 (222.7, 1032.6) 526.85 653.9 16 189 DAY 10 48 H 9 0 631.7 (227.7, 1035.8) 525.66 652.3 16 189 DAY 13 120 H 9 0 633.2 (270.0, 996.5) 472.59 679.0 16 170 DAY 15 PREDOSE 9 0 674.2 (275.6, 1072.9) 518.61 704.2 23 190 6 H 9 0 642.8 (224.7, 1060.9) 543.91 663.9 15 193 DAY 16 24 H 9 0 611.2 (205.7, 1016.7) 527.52 563.0 19 191 DAY 17 48 H 9 0 613.1 (200.5, 1025.7) 536.76 639.6 18 193 DAY 20 120 H 9 0 646.3 (256.6, 1036.0) 506.96 632.5 18 185 DAY 22 PREDOSE 9 0 657.4 (259.3, 1055.5) 517.91 702.2 20 188 6 H 9 0 626.4 (224.6, 1028.3) 522.81 701.1 11 183 DAY 23 24 H 9 0 588.9 (229.0, 948.7) 468.19 637.5 10 167 DAY 24 48 H 9 0 605.3 (214.1, 996.4) 508.86 629.1 17 183 DAY 27 120 H 9 0 622.6 (238.4, 1006.8) 499.82 648.5 19 180 DAY 31 216 H 9 0 667.9 (257.4, 1078.4) 534.08 685.4 19 191 DAY 43 504 H 9 0 721.9 (341.8, 1102.0) 494.49 658.5 25 179 DAY 50 672 H 8 0 816.0 (300.6, 1331.4) 616.54 559.7 26 194 DAY 78 1344 H 8 0 966.6 (685.0, 1248.2) 336.80 1034.0 36 146 FOLLOW-UP 2016 H 9 0 867.9 (748.9, 987.0) 154.85 868.0 58 112
IM_200mg 9 DAY 1 PREDOSE 9 0 545.9 (404.6, 687.2) 183.84 549.0 31 93 6 H 9 3 360.5 (148.7, 572.3) 275.55 402.3 3 80 DAY 2 24 H 9 3 376.4 (146.7, 606.0) 298.77 413.0 3 90 DAY 3 48 H 9 3 421.8 (168.0, 675.6) 330.17 475.4 3 92 DAY 6 120 H 9 3 440.9 (187.9, 693.9) 329.15 571.7 3 92 DAY 15 336 H 9 2 545.8 (285.4, 806.2) 338.79 600.1 3 112 DAY 29 672 H 9 1 738.1 (499.0, 977.2) 311.07 775.8 3 123
[1] No. of subjects with NQs assigned half the limit of quantification.Note: Statistics for 95% CI of Mean and SD are missing because an insufficient numberof subjects have reached the limit of quantification, making calculation of these statistics inappropriate.
652
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 3 of 9Population: Pharmacodynamic Table 12.1 Summary of Plasma Abeta Pharmacodynamic Concentration-Time Data [pg/mL]
Parameter: Abeta 1-22 No. Time Imputed 95% CI Treatment N Visit point n [1] Mean (Lower, Upper) SD Median Min. Max. ---------------------------------------------------------------------------------------------------------- IM_200mg 9 DAY 57 1344 H 8 0 794.9 (465.0, 1124.9) 394.67 980.8 14 111 FOLLOW-UP 2016 H 8 0 824.8 (741.9, 907.6) 99.14 841.8 62 92
[1] No. of subjects with NQs assigned half the limit of quantification.Note: Statistics for 95% CI of Mean and SD are missing because an insufficient numberof subjects have reached the limit of quantification, making calculation of these statistics inappropriate.
653
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 4 of 9Population: Pharmacodynamic Table 12.1 Summary of Plasma Abeta Pharmacodynamic Concentration-Time Data [pg/mL]
Parameter: Abeta 18-35 No. Time Imputed 95% CI Treatment N Visit point n [1] Mean (Lower, Upper) SD Median Min. Max. ---------------------------------------------------------------------------------------------------------- IV_200mg 9 DAY 1 PREDOSE 9 0 2087.8 (-259.3, 4434.9) 3053.49 1028.0 57 1013 1 H 9 0 9555.8 (7394.2, 11717.4) 2812.15 8706.5 704 1505 2 H 9 0 11523.3 (9366.1, 13680.5) 2806.38 10815.1 871 1718 4 H 8 0 16057.6 (12254.3, 19861.0) 4549.35 14861.8 1214 2643 6 H 9 0 20278.6 (17026.6, 23530.6) 4230.71 20458.7 1487 2918 DAY 2 24 H 9 0 39008.4 (35743.2, 42273.7) 4247.93 39138.1 2975 4403 DAY 3 48 H 9 0 44999.6 (41100.0, 48899.2) 5073.19 48071.9 3557 5025 DAY 6 120 H 9 0 43699.4 (39758.3, 47640.4) 5127.11 43941.5 3517 5053 DAY 15 336 H 9 0 29084.2 (23310.1, 34858.4) 7511.92 27927.1 2217 4719 DAY 29 672 H 9 0 15268.2 (11270.9, 19265.5) 5200.35 15389.6 697 2616 DAY 57 1344 H 9 0 4963.2 (2739.8, 7186.6) 2892.49 3974.8 155 1152 FOLLOW-UP 2016 H 9 0 2640.3 (892.5, 4388.0) 2273.78 1874.2 97 857
SQ_200mg 9 DAY 1 PREDOSE 9 0 1331.3 (354.0, 2308.5) 1271.34 1113.5 43 463 6 H 9 0 7860.2 (6490.1, 9230.3) 1782.44 7343.2 483 1040 DAY 2 24 H 9 0 20097.4 (17593.9, 22601.0) 3257.01 19321.8 1474 2557 DAY 3 48 H 8 0 28603.4 (25415.4, 31791.3) 3813.28 29175.1 2302 3410 DAY 6 120 H 9 0 34359.3 (31040.7, 37677.9) 4317.31 34521.5 2839 4207 DAY 15 336 H 9 0 26299.5 (23153.4, 29445.6) 4092.90 24917.9 2209 3305 DAY 29 672 H 9 0 13241.6 (11160.7, 15322.5) 2707.14 13686.7 870 1804 DAY 57 1344 H 9 0 4128.0 (3397.1, 4859.0) 950.94 4002.0 265 578 FOLLOW-UP 2016 H 9 0 2107.2 (1296.5, 2917.8) 1054.65 1965.6 105 469
SQ_50mg x 4 9 DAY 1 PREDOSE 9 0 949.2 (651.5, 1246.9) 387.30 889.1 44 155 6 H 9 0 3901.1 (2494.7, 5307.5) 1829.69 3547.3 184 724 DAY 2 24 H 9 0 10606.7 (7295.5, 13917.9) 4307.72 8708.6 614 1653 DAY 3 48 H 9 0 14458.6 (11175.9, 17741.4) 4270.75 13169.7 952 2192 DAY 6 120 H 9 0 16502.8 (14454.7, 18550.8) 2664.39 16641.0 1197 2078
[1] No. of subjects with NQs assigned half the limit of quantification.Note: Statistics for 95% CI of Mean and SD are missing because an insufficient numberof subjects have reached the limit of quantification, making calculation of these statistics inappropriate.
654
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 5 of 9Population: Pharmacodynamic Table 12.1 Summary of Plasma Abeta Pharmacodynamic Concentration-Time Data [pg/mL]
Parameter: Abeta 18-35 No. Time Imputed 95% CI Treatment N Visit point n [1] Mean (Lower, Upper) SD Median Min. Max. ---------------------------------------------------------------------------------------------------------- SQ_50mg x 4 9 DAY 8 PREDOSE 9 0 15771.5 (13928.7, 17614.2) 2397.37 15660.9 1254 1964 6 H 9 0 15895.7 (13953.5, 17837.9) 2526.69 16186.5 1213 1938 DAY 9 24 H 9 0 20727.1 (17935.9, 23518.3) 3631.21 19286.4 1644 2687 DAY 10 48 H 9 0 23616.1 (19771.5, 27460.7) 5001.65 23012.9 1707 3408 DAY 13 120 H 9 0 22284.0 (18972.6, 25595.4) 4307.94 21826.4 1631 3036 DAY 15 PREDOSE 9 0 20081.7 (17786.5, 22376.8) 2985.90 19318.7 1568 2667 6 H 9 0 20932.7 (18549.4, 23316.0) 3100.54 20174.0 1759 2809 DAY 16 24 H 9 0 24506.8 (22460.3, 26553.4) 2662.47 23622.7 2054 2896 DAY 17 48 H 9 0 25508.1 (24054.9, 26961.2) 1890.54 25636.5 2232 2872 DAY 20 120 H 9 0 25652.0 (22673.0, 28631.1) 3875.56 25504.7 2070 3478 DAY 22 PREDOSE 9 0 23862.4 (21128.7, 26596.0) 3556.34 23117.9 1816 3105 6 H 9 0 24142.2 (22109.2, 26175.2) 2644.85 24640.1 1975 2841 DAY 23 24 H 9 0 26221.4 (24691.4, 27751.4) 1990.40 25962.3 2347 3002 DAY 24 48 H 9 0 29280.2 (25803.1, 32757.3) 4523.51 28586.5 2403 3833 DAY 27 120 H 9 0 28985.3 (25727.3, 32243.2) 4238.42 27761.3 2399 3829 DAY 31 216 H 9 0 25422.6 (22204.4, 28640.8) 4186.74 23969.5 2040 3537 DAY 43 504 H 9 0 14266.8 (12341.1, 16192.5) 2505.24 14748.8 1113 1938 DAY 50 672 H 8 0 10047.1 (7833.2, 12261.0) 2648.13 8932.4 818 1627 DAY 78 1344 H 8 0 3522.4 (2538.5, 4506.3) 1176.91 3096.0 261 608 FOLLOW-UP 2016 H 9 0 1596.1 (1139.7, 2052.4) 593.70 1390.4 79 266
IM_200mg 9 DAY 1 PREDOSE 9 0 1244.1 (352.4, 2135.8) 1160.07 1040.0 35 411 6 H 9 0 8809.3 (7284.0, 10334.7) 1984.41 8576.7 556 1250 DAY 2 24 H 9 0 27278.8 (25326.6, 29231.0) 2539.73 26578.2 2398 3232 DAY 3 48 H 9 0 33188.4 (30964.5, 35412.3) 2893.16 33275.4 2954 3900 DAY 6 120 H 9 0 36438.5 (33076.1, 39800.8) 4374.30 35470.8 2991 4299 DAY 15 336 H 9 0 26288.5 (21776.4, 30800.6) 5870.06 26445.1 1793 3909 DAY 29 672 H 9 0 13522.1 (10576.8, 16467.4) 3831.66 13462.4 612 1852
[1] No. of subjects with NQs assigned half the limit of quantification.Note: Statistics for 95% CI of Mean and SD are missing because an insufficient numberof subjects have reached the limit of quantification, making calculation of these statistics inappropriate.
655
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 6 of 9Population: Pharmacodynamic Table 12.1 Summary of Plasma Abeta Pharmacodynamic Concentration-Time Data [pg/mL]
Parameter: Abeta 18-35 No. Time Imputed 95% CI Treatment N Visit point n [1] Mean (Lower, Upper) SD Median Min. Max. ---------------------------------------------------------------------------------------------------------- IM_200mg 9 DAY 57 1344 H 8 0 3969.2 (2360.0, 5578.4) 1924.80 3885.5 128 797 FOLLOW-UP 2016 H 8 0 1961.1 (878.1, 3044.0) 1295.37 1681.7 86 497
[1] No. of subjects with NQs assigned half the limit of quantification.Note: Statistics for 95% CI of Mean and SD are missing because an insufficient numberof subjects have reached the limit of quantification, making calculation of these statistics inappropriate.
656
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 7 of 9Population: Pharmacodynamic Table 12.1 Summary of Plasma Abeta Pharmacodynamic Concentration-Time Data [pg/mL]
Parameter: Abeta 42 No. Time Imputed 95% CI Treatment N Visit point n [1] Mean (Lower, Upper) SD Median Min. Max. ---------------------------------------------------------------------------------------------------------- IV_200mg 9 DAY 1 PREDOSE 9 0 495.3 (-271.7, 1262.2) 997.82 101.8 5 310 1 H 9 0 796.5 (255.7, 1337.4) 703.58 551.0 36 260 2 H 9 0 923.1 (327.5, 1518.8) 774.92 651.2 46 293 4 H 8 0 1239.4 (463.3, 2015.5) 928.34 1004.7 66 348 6 H 9 0 1367.1 (743.8, 1990.4) 810.89 1169.1 72 345 DAY 2 24 H 9 0 2290.8 (1621.9, 2959.7) 870.21 2180.3 146 444 DAY 3 48 H 9 0 2969.5 (1581.1, 4357.9) 1806.24 2448.0 166 768 DAY 6 120 H 9 0 2868.7 (1355.4, 4382.1) 1968.78 2343.7 165 802 DAY 15 336 H 9 0 2018.7 (1236.6, 2800.8) 1017.47 1846.7 116 457 DAY 29 672 H 9 0 1282.0 (660.3, 1903.7) 808.78 1172.0 55 319 DAY 57 1344 H 9 0 1015.5 (-389.6, 2420.5) 1827.88 373.5 8 580 FOLLOW-UP 2016 H 9 0 449.3 (-62.1, 960.8) 665.40 142.6 5 200
SQ_200mg 9 DAY 1 PREDOSE 9 0 1066.4 (-539.8, 2672.7) 2089.63 76.6 5 618 6 H 9 0 1212.6 (155.8, 2269.3) 1374.75 599.4 38 411 DAY 2 24 H 9 0 2026.3 (853.3, 3199.4) 1526.07 1352.4 111 507 DAY 3 48 H 8 0 2362.9 (1273.8, 3452.0) 1302.72 1703.1 150 497 DAY 6 120 H 9 0 2633.9 (1564.3, 3703.4) 1391.40 1996.6 173 578 DAY 15 336 H 9 0 2595.2 (984.2, 4206.2) 2095.78 1667.7 143 780 DAY 29 672 H 9 0 1565.1 (645.3, 2484.9) 1196.61 1062.6 61 426 DAY 57 1344 H 9 0 1010.3 (-97.7, 2118.2) 1441.40 306.6 19 424 FOLLOW-UP 2016 H 9 0 723.8 (-196.0, 1643.6) 1196.60 113.0 8 347
SQ_50mg x 4 9 DAY 1 PREDOSE 9 0 115.4 (53.2, 177.6) 80.91 87.0 5 32 6 H 9 0 305.2 (189.0, 421.4) 151.16 268.9 12 52 DAY 2 24 H 9 0 814.2 (542.8, 1085.6) 353.08 709.8 38 131 DAY 3 48 H 9 0 1058.2 (785.3, 1331.1) 354.99 988.6 57 161 DAY 6 120 H 9 0 1200.9 (975.9, 1425.9) 292.71 1166.3 81 168
[1] No. of subjects with NQs assigned half the limit of quantification.Note: Statistics for 95% CI of Mean and SD are missing because an insufficient numberof subjects have reached the limit of quantification, making calculation of these statistics inappropriate.
657
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 8 of 9Population: Pharmacodynamic Table 12.1 Summary of Plasma Abeta Pharmacodynamic Concentration-Time Data [pg/mL]
Parameter: Abeta 42 No. Time Imputed 95% CI Treatment N Visit point n [1] Mean (Lower, Upper) SD Median Min. Max. ---------------------------------------------------------------------------------------------------------- SQ_50mg x 4 9 DAY 8 PREDOSE 9 0 1133.6 (956.8, 1310.5) 230.11 1084.7 83 156 6 H 9 0 1173.0 (974.4, 1371.7) 258.43 1162.2 77 154 DAY 9 24 H 9 0 1474.2 (1208.5, 1739.9) 345.63 1392.1 102 200 DAY 10 48 H 9 0 1570.1 (1273.0, 1867.1) 386.45 1485.9 126 251 DAY 13 120 H 9 0 1522.7 (1279.1, 1766.4) 316.95 1573.9 117 219 DAY 15 PREDOSE 9 0 1431.4 (1214.6, 1648.2) 282.01 1370.5 114 207 6 H 9 0 1453.0 (1223.7, 1682.3) 298.29 1355.9 111 202 DAY 16 24 H 9 0 1634.9 (1395.6, 1874.1) 311.29 1537.4 123 230 DAY 17 48 H 9 0 1767.8 (1500.5, 2035.1) 347.71 1652.5 138 230 DAY 20 120 H 9 0 1677.5 (1374.5, 1980.5) 394.18 1572.5 115 249 DAY 22 PREDOSE 9 0 1615.7 (1355.3, 1876.0) 338.68 1571.5 124 232 6 H 9 0 1657.7 (1412.8, 1902.6) 318.59 1687.7 119 223 DAY 23 24 H 9 0 1847.4 (1521.9, 2173.0) 423.51 1711.3 136 258 DAY 24 48 H 9 0 1905.4 (1537.6, 2273.3) 478.60 1681.9 141 269 DAY 27 120 H 9 0 1739.2 (1474.1, 2004.3) 344.85 1662.3 134 239 DAY 31 216 H 9 0 1710.3 (1322.7, 2097.9) 504.30 1474.8 124 286 DAY 43 504 H 9 0 1105.7 (868.8, 1342.5) 308.16 938.8 77 170 DAY 50 672 H 8 0 740.4 (601.8, 879.0) 165.80 662.2 57 96 DAY 78 1344 H 8 0 232.5 (162.9, 302.1) 83.29 217.6 14 41 FOLLOW-UP 2016 H 9 0 118.9 (80.4, 157.3) 49.99 99.5 4 20
IM_200mg 9 DAY 1 PREDOSE 9 0 698.4 (-263.8, 1660.6) 1251.78 98.8 3 348 6 H 9 0 1232.9 (211.6, 2254.1) 1328.62 654.4 44 411 DAY 2 24 H 9 0 2137.9 (1194.7, 3081.2) 1227.13 1775.0 121 489 DAY 3 48 H 9 0 3129.5 (599.2, 5659.8) 3291.81 1863.0 145 1171 DAY 6 120 H 9 0 3360.2 (702.8, 6017.6) 3457.18 2081.6 167 1237 DAY 15 336 H 9 0 2159.7 (1198.5, 3120.9) 1250.47 1569.5 129 478 DAY 29 672 H 9 0 1461.7 (591.2, 2332.1) 1132.44 1062.8 48 392
[1] No. of subjects with NQs assigned half the limit of quantification.Note: Statistics for 95% CI of Mean and SD are missing because an insufficient numberof subjects have reached the limit of quantification, making calculation of these statistics inappropriate.
658
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 9 of 9Population: Pharmacodynamic Table 12.1 Summary of Plasma Abeta Pharmacodynamic Concentration-Time Data [pg/mL]
Parameter: Abeta 42 No. Time Imputed 95% CI Treatment N Visit point n [1] Mean (Lower, Upper) SD Median Min. Max. ---------------------------------------------------------------------------------------------------------- IM_200mg 9 DAY 57 1344 H 8 0 1488.0 (-554.8, 3530.8) 2443.50 296.2 11 674 FOLLOW-UP 2016 H 8 0 1970.3 (-1430.3, 5370.8) 4067.56 132.1 6 1162
[1] No. of subjects with NQs assigned half the limit of quantification.Note: Statistics for 95% CI of Mean and SD are missing because an insufficient numberof subjects have reached the limit of quantification, making calculation of these statistics inappropriate.
659
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 1 of 9Population: Pharmacodynamic Table 12.2 Summary of Log-Transformed Plasma Abeta Pharmacodynamic Concentration-Time Data [pg/mL]
Parameter: Abeta 1-22 Planned No. Time Imputed Geo- SD Treatment N Visit Point n [1] Mean 95 % CI of Geo. Mean logs %CVb ---------------------------------------------------------------------------------------------- IV_200mg 9 DAY 1 PREDOSE 9 0 606.4 (482.4, 762.2) 0.297584 30.4 1 H 9 6 59.6 2 H 9 6 59.0 4 H 8 6 56.2 6 H 9 4 79.0 DAY 2 24 H 9 2 174.5 (77.7, 392.2) 1.053401 142.6 DAY 3 48 H 9 2 238.5 (94.8, 600.1) 1.200622 179.6 DAY 6 120 H 9 1 319.8 (136.1, 751.6) 1.111469 156.2 DAY 15 336 H 9 0 435.7 (234.1, 811.0) 0.808287 96.0 DAY 29 672 H 9 0 508.3 (263.1, 981.9) 0.856724 104.1 DAY 57 1344 H 9 0 688.6 (418.4, 1133.2) 0.648146 72.3 FOLLOW-UP 2016 H 9 0 944.8 (803.6, 1110.9) 0.210632 21.3
SQ_200mg 9 DAY 1 PREDOSE 9 0 651.1 (523.5, 809.7) 0.283713 29.0 6 H 9 1 421.3 (192.6, 921.8) 1.018486 135.0 DAY 2 24 H 9 1 450.2 (201.2, 1007.5) 1.047941 141.4 DAY 3 48 H 8 1 451.1 (175.5, 1159.8) 1.129439 160.7 DAY 6 120 H 9 0 647.3 (518.9, 807.6) 0.287816 29.4 DAY 15 336 H 9 0 614.3 (375.7, 1004.2) 0.639423 71.1 DAY 29 672 H 9 0 670.3 (391.8, 1146.6) 0.698431 79.3 DAY 57 1344 H 9 0 783.9 (484.4, 1268.5) 0.626187 69.3 FOLLOW-UP 2016 H 9 0 908.3 (814.2, 1013.4) 0.142421 14.3
SQ_50mg x 4 9 DAY 1 PREDOSE 9 0 672.3 (461.1, 980.2) 0.490556 52.2 6 H 9 0 510.8 (269.4, 968.6) 0.832386 100.0 DAY 2 24 H 9 0 503.2 (283.6, 892.7) 0.745916 86.3 DAY 3 48 H 9 0 538.5 (312.7, 927.2) 0.707044 80.5 DAY 6 120 H 9 0 562.4 (332.1, 952.6) 0.685549 77.5
[1] No. of subjects with NQs assigned half the limit of quantification.Note: Statistics for 95% CI of Geo. Mean, SD logs and %CVb are missing because an insufficient number ofsubjects have reached the limit of quantification, making calculation of these statistics inappropriate.
660
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 2 of 9Population: Pharmacodynamic Table 12.2 Summary of Log-Transformed Plasma Abeta Pharmacodynamic Concentration-Time Data [pg/mL]
Parameter: Abeta 1-22 Planned No. Time Imputed Geo- SD Treatment N Visit Point n [1] Mean 95 % CI of Geo. Mean logs %CVb ---------------------------------------------------------------------------------------------- SQ_50mg x 4 9 DAY 8 PREDOSE 9 0 594.8 (344.2, 1028.0) 0.711787 81.2 6 H 9 0 506.1 (274.6, 932.7) 0.795287 93.9 DAY 9 24 H 9 0 483.0 (270.0, 863.8) 0.756381 87.9 DAY 10 48 H 9 0 485.0 (268.8, 875.0) 0.767773 89.6 DAY 13 120 H 9 0 500.3 (283.5, 882.7) 0.738828 85.2 DAY 15 PREDOSE 9 0 540.5 (317.6, 919.9) 0.69169 78.3 6 H 9 0 486.7 (265.1, 893.6) 0.790377 93.1 DAY 16 24 H 9 0 476.6 (274.9, 826.1) 0.715644 81.8 DAY 17 48 H 9 0 468.8 (262.3, 837.7) 0.755165 87.7 DAY 20 120 H 9 0 510.2 (292.2, 891.1) 0.725321 83.2 DAY 22 PREDOSE 9 0 518.4 (297.7, 902.8) 0.721649 82.7 6 H 9 0 459.4 (235.3, 896.8) 0.870358 106.4 DAY 23 24 H 9 0 447.1 (238.4, 838.6) 0.81818 97.6 DAY 24 48 H 9 0 466.3 (261.3, 832.3) 0.753662 87.4 DAY 27 120 H 9 0 485.4 (274.3, 859.0) 0.742572 85.8 DAY 31 216 H 9 0 521.2 (295.3, 920.1) 0.73932 85.3 DAY 43 504 H 9 0 595.4 (360.4, 983.5) 0.652977 72.9 DAY 50 672 H 8 0 639.7 (344.3, 1188.6) 0.740918 85.5 DAY 78 1344 H 8 0 900.9 (626.4, 1295.7) 0.434723 45.6 FOLLOW-UP 2016 H 9 0 855.0 (740.4, 987.3) 0.187196 18.9
IM_200mg 9 DAY 1 PREDOSE 9 0 520.4 (404.9, 668.7) 0.326325 33.5 6 H 9 3 200.5 (67.8, 593.4) 1.411281 251.6 DAY 2 24 H 9 3 205.4 (68.3, 617.6) 1.432466 260.4 DAY 3 48 H 9 3 222.6 (70.7, 700.2) 1.491166 287.1 DAY 6 120 H 9 3 232.2 (72.5, 743.4) 1.513647 298.1 DAY 15 336 H 9 2 340.4 (118.7, 975.9) 1.370194 235.3 DAY 29 672 H 9 1 566.0 (243.0, 1318.6) 1.100123 153.4
[1] No. of subjects with NQs assigned half the limit of quantification.Note: Statistics for 95% CI of Geo. Mean, SD logs and %CVb are missing because an insufficient number ofsubjects have reached the limit of quantification, making calculation of these statistics inappropriate.
661
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 3 of 9Population: Pharmacodynamic Table 12.2 Summary of Log-Transformed Plasma Abeta Pharmacodynamic Concentration-Time Data [pg/mL]
Parameter: Abeta 1-22 Planned No. Time Imputed Geo- SD Treatment N Visit Point n [1] Mean 95 % CI of Geo. Mean logs %CVb ---------------------------------------------------------------------------------------------- IM_200mg 9 DAY 57 1344 H 8 0 649.8 (334.8, 1261.3) 0.793289 93.6 FOLLOW-UP 2016 H 8 0 819.0 (735.1, 912.6) 0.129376 13.0
[1] No. of subjects with NQs assigned half the limit of quantification.Note: Statistics for 95% CI of Geo. Mean, SD logs and %CVb are missing because an insufficient number ofsubjects have reached the limit of quantification, making calculation of these statistics inappropriate.
662
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 4 of 9Population: Pharmacodynamic Table 12.2 Summary of Log-Transformed Plasma Abeta Pharmacodynamic Concentration-Time Data [pg/mL]
Parameter: Abeta 18-35 Planned No. Time Imputed Geo- SD Treatment N Visit Point n [1] Mean 95 % CI of Geo. Mean logs %CVb ---------------------------------------------------------------------------------------------- IV_200mg 9 DAY 1 PREDOSE 9 0 1290.9 (662.8, 2514.1) 0.867233 105.9 1 H 9 0 9235.1 (7509.7, 11356.9) 0.269055 27.4 2 H 9 0 11249.5 (9444.2, 13400.0) 0.227576 23.1 4 H 8 0 15603.1 (12723.2, 19135.0) 0.244069 24.8 6 H 9 0 19915.8 (17095.6, 23201.2) 0.198646 20.1 DAY 2 24 H 9 0 38785.3 (35472.3, 42407.8) 0.116162 11.7 DAY 3 48 H 9 0 44729.8 (40844.7, 48984.4) 0.118207 11.9 DAY 6 120 H 9 0 43425.8 (39608.3, 47611.4) 0.119709 12.0 DAY 15 336 H 9 0 28372.7 (23839.9, 33767.4) 0.226452 22.9 DAY 29 672 H 9 0 14472.6 (11004.4, 19034.0) 0.35642 36.8 DAY 57 1344 H 9 0 4343.0 (2850.6, 6616.8) 0.547759 59.2 FOLLOW-UP 2016 H 9 0 2173.9 (1384.7, 3412.9) 0.586765 64.1
SQ_200mg 9 DAY 1 PREDOSE 9 0 1043.0 (625.1, 1740.4) 0.666065 74.7 6 H 9 0 7670.1 (6380.4, 9220.5) 0.239504 24.3 DAY 2 24 H 9 0 19861.7 (17513.2, 22525.0) 0.163706 16.5 DAY 3 48 H 8 0 28377.2 (25339.0, 31779.7) 0.135455 13.6 DAY 6 120 H 9 0 34118.6 (30970.4, 37586.9) 0.125948 12.6 DAY 15 336 H 9 0 26029.9 (23184.1, 29225.0) 0.150623 15.1 DAY 29 672 H 9 0 12988.8 (11044.4, 15275.5) 0.210965 21.3 DAY 57 1344 H 9 0 4029.6 (3363.2, 4828.0) 0.235183 23.8 FOLLOW-UP 2016 H 9 0 1932.4 (1397.9, 2671.2) 0.421228 44.1
SQ_50mg x 4 9 DAY 1 PREDOSE 9 0 880.1 (638.3, 1213.4) 0.417853 43.7 6 H 9 0 3551.5 (2500.2, 5044.8) 0.456626 48.1 DAY 2 24 H 9 0 9897.0 (7343.1, 13339.0) 0.38829 40.3 DAY 3 48 H 9 0 13930.8 (11176.7, 17363.6) 0.286565 29.3 DAY 6 120 H 9 0 16305.3 (14346.8, 18531.0) 0.166468 16.8
[1] No. of subjects with NQs assigned half the limit of quantification.Note: Statistics for 95% CI of Geo. Mean, SD logs and %CVb are missing because an insufficient number ofsubjects have reached the limit of quantification, making calculation of these statistics inappropriate.
663
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 5 of 9Population: Pharmacodynamic Table 12.2 Summary of Log-Transformed Plasma Abeta Pharmacodynamic Concentration-Time Data [pg/mL]
Parameter: Abeta 18-35 Planned No. Time Imputed Geo- SD Treatment N Visit Point n [1] Mean 95 % CI of Geo. Mean logs %CVb ---------------------------------------------------------------------------------------------- SQ_50mg x 4 9 DAY 8 PREDOSE 9 0 15608.7 (13874.1, 17560.1) 0.153254 15.4 6 H 9 0 15714.9 (13882.9, 17788.6) 0.161251 16.2 DAY 9 24 H 9 0 20466.5 (18019.1, 23246.3) 0.165685 16.7 DAY 10 48 H 9 0 23184.0 (19872.0, 27048.1) 0.200545 20.3 DAY 13 120 H 9 0 21922.7 (18923.3, 25397.4) 0.191403 19.3 DAY 15 PREDOSE 9 0 19896.5 (17830.1, 22202.3) 0.142656 14.3 6 H 9 0 20749.7 (18674.7, 23055.4) 0.137074 13.8 DAY 16 24 H 9 0 24379.1 (22430.6, 26496.8) 0.108366 10.9 DAY 17 48 H 9 0 25445.5 (24029.9, 26944.5) 0.074466 7.5 DAY 20 120 H 9 0 25417.4 (22814.3, 28317.6) 0.140567 14.1 DAY 22 PREDOSE 9 0 23633.4 (21111.4, 26456.7) 0.146811 14.8 6 H 9 0 24011.3 (22044.6, 26153.5) 0.111177 11.2 DAY 23 24 H 9 0 26155.4 (24689.6, 27708.3) 0.075032 7.5 DAY 24 48 H 9 0 28986.4 (25850.9, 32502.3) 0.148937 15.0 DAY 27 120 H 9 0 28731.3 (25835.3, 31951.9) 0.13822 13.9 DAY 31 216 H 9 0 25151.4 (22392.3, 28250.5) 0.151167 15.2 DAY 43 504 H 9 0 14079.4 (12342.3, 16061.0) 0.171307 17.3 DAY 50 672 H 8 0 9806.3 (8140.8, 11812.6) 0.222648 22.5 DAY 78 1344 H 8 0 3383.8 (2658.3, 4307.4) 0.28866 29.5 FOLLOW-UP 2016 H 9 0 1503.7 (1134.7, 1992.7) 0.36632 37.9
IM_200mg 9 DAY 1 PREDOSE 9 0 941.2 (529.6, 1672.9) 0.748191 86.6 6 H 9 0 8607.3 (7205.3, 10282.1) 0.231297 23.4 DAY 2 24 H 9 0 27176.7 (25335.0, 29152.3) 0.091291 9.1 DAY 3 48 H 9 0 33079.7 (30980.2, 35321.6) 0.085308 8.5 DAY 6 120 H 9 0 36208.1 (33036.5, 39684.1) 0.119258 12.0 DAY 15 336 H 9 0 25737.3 (21779.0, 30415.0) 0.217253 22.0 DAY 29 672 H 9 0 12932.2 (9977.6, 16761.8) 0.337438 34.7
[1] No. of subjects with NQs assigned half the limit of quantification.Note: Statistics for 95% CI of Geo. Mean, SD logs and %CVb are missing because an insufficient number ofsubjects have reached the limit of quantification, making calculation of these statistics inappropriate.
664
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 6 of 9Population: Pharmacodynamic Table 12.2 Summary of Log-Transformed Plasma Abeta Pharmacodynamic Concentration-Time Data [pg/mL]
Parameter: Abeta 18-35 Planned No. Time Imputed Geo- SD Treatment N Visit Point n [1] Mean 95 % CI of Geo. Mean logs %CVb ---------------------------------------------------------------------------------------------- IM_200mg 9 DAY 57 1344 H 8 0 3560.7 (2302.8, 5505.7) 0.521316 55.9 FOLLOW-UP 2016 H 8 0 1701.4 (1084.9, 2668.3) 0.538258 58.0
[1] No. of subjects with NQs assigned half the limit of quantification.Note: Statistics for 95% CI of Geo. Mean, SD logs and %CVb are missing because an insufficient number ofsubjects have reached the limit of quantification, making calculation of these statistics inappropriate.
665
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 7 of 9Population: Pharmacodynamic Table 12.2 Summary of Log-Transformed Plasma Abeta Pharmacodynamic Concentration-Time Data [pg/mL]
Parameter: Abeta 45 Planned No. Time Imputed Geo- SD Treatment N Visit Point n [1] Mean 95 % CI of Geo. Mean logs %CVb ---------------------------------------------------------------------------------------------- IV_200mg 9 DAY 1 PREDOSE 9 0 171.4 (63.5, 462.5) 1.291285 207.3 1 H 9 0 645.4 (403.7, 1031.8) 0.610447 67.2 2 H 9 0 767.2 (496.0, 1186.5) 0.56727 61.6 4 H 8 0 1061.9 (681.6, 1654.5) 0.530348 57.0 6 H 9 0 1232.8 (880.1, 1726.8) 0.438421 46.0 DAY 2 24 H 9 0 2179.8 (1710.0, 2778.7) 0.315814 32.4 DAY 3 48 H 9 0 2679.6 (1927.6, 3725.1) 0.428546 44.9 DAY 6 120 H 9 0 2531.1 (1767.6, 3624.4) 0.467069 49.4 DAY 15 336 H 9 0 1859.8 (1367.1, 2530.0) 0.400395 41.7 DAY 29 672 H 9 0 1113.9 (736.2, 1685.4) 0.538744 58.0 DAY 57 1344 H 9 0 445.6 (178.2, 1114.5) 1.192692 177.4 FOLLOW-UP 2016 H 9 0 216.2 (88.1, 530.9) 1.168409 170.8
SQ_200mg 9 DAY 1 PREDOSE 9 0 218.1 (56.6, 840.9) 1.75536 455.9 6 H 9 0 800.0 (409.6, 1562.4) 0.870926 106.5 DAY 2 24 H 9 0 1685.1 (1072.8, 2647.1) 0.587523 64.2 DAY 3 48 H 8 0 2128.9 (1452.7, 3119.7) 0.457108 48.2 DAY 6 120 H 9 0 2403.3 (1741.0, 3317.6) 0.419423 43.9 DAY 15 336 H 9 0 2164.5 (1402.0, 3341.5) 0.564947 61.3 DAY 29 672 H 9 0 1296.0 (816.5, 2057.0) 0.601031 66.0 DAY 57 1344 H 9 0 503.9 (210.7, 1205.1) 1.134237 161.9 FOLLOW-UP 2016 H 9 0 253.7 (85.5, 753.1) 1.415515 253.3
SQ_50mg x 4 9 DAY 1 PREDOSE 9 0 99.7 (66.6, 149.2) 0.525025 56.3 6 H 9 0 270.9 (180.2, 407.4) 0.530807 57.0 DAY 2 24 H 9 0 747.8 (533.0, 1049.0) 0.440338 46.3 DAY 3 48 H 9 0 1005.8 (774.1, 1306.9) 0.340626 35.1 DAY 6 120 H 9 0 1169.7 (969.6, 1411.0) 0.244029 24.8
[1] No. of subjects with NQs assigned half the limit of quantification.Note: Statistics for 95% CI of Geo. Mean, SD logs and %CVb are missing because an insufficient number ofsubjects have reached the limit of quantification, making calculation of these statistics inappropriate.
666
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 8 of 9Population: Pharmacodynamic Table 12.2 Summary of Log-Transformed Plasma Abeta Pharmacodynamic Concentration-Time Data [pg/mL]
Parameter: Abeta 45 Planned No. Time Imputed Geo- SD Treatment N Visit Point n [1] Mean 95 % CI of Geo. Mean logs %CVb ---------------------------------------------------------------------------------------------- SQ_50mg x 4 9 DAY 8 PREDOSE 9 0 1113.2 (952.9, 1300.5) 0.202284 20.4 6 H 9 0 1147.0 (963.6, 1365.5) 0.226773 23.0 DAY 9 24 H 9 0 1438.9 (1202.5, 1721.7) 0.233452 23.7 DAY 10 48 H 9 0 1535.8 (1304.2, 1808.5) 0.212683 21.5 DAY 13 120 H 9 0 1495.5 (1283.6, 1742.4) 0.198816 20.1 DAY 15 PREDOSE 9 0 1409.7 (1227.2, 1619.3) 0.18036 18.2 6 H 9 0 1427.3 (1225.7, 1662.2) 0.198131 20.0 DAY 16 24 H 9 0 1610.8 (1403.3, 1848.9) 0.179391 18.1 DAY 17 48 H 9 0 1738.8 (1501.0, 2014.3) 0.191338 19.3 DAY 20 120 H 9 0 1639.2 (1378.2, 1949.5) 0.225587 22.8 DAY 22 PREDOSE 9 0 1586.7 (1362.2, 1848.2) 0.198471 20.0 6 H 9 0 1630.6 (1405.5, 1891.7) 0.19322 19.5 DAY 23 24 H 9 0 1806.4 (1521.9, 2144.1) 0.222944 22.6 DAY 24 48 H 9 0 1855.9 (1543.5, 2231.5) 0.239747 24.3 DAY 27 120 H 9 0 1710.9 (1478.9, 1979.2) 0.189569 19.1 DAY 31 216 H 9 0 1655.7 (1356.4, 2020.9) 0.259337 26.4 DAY 43 504 H 9 0 1071.2 (876.0, 1309.8) 0.261661 26.6 DAY 50 672 H 8 0 724.9 (604.4, 869.4) 0.217411 22.0 DAY 78 1344 H 8 0 221.5 (169.0, 290.2) 0.323359 33.2 FOLLOW-UP 2016 H 9 0 109.1 (76.8, 155.0) 0.456906 48.2
IM_200mg 9 DAY 1 PREDOSE 9 0 176.9 (50.7, 616.7) 1.624973 360.8 6 H 9 0 852.6 (454.1, 1600.9) 0.81967 97.9 DAY 2 24 H 9 0 1910.5 (1329.5, 2745.5) 0.471714 49.9 DAY 3 48 H 9 0 2400.6 (1449.7, 3975.2) 0.656162 73.4 DAY 6 120 H 9 0 2601.2 (1581.6, 4278.2) 0.647267 72.1 DAY 15 336 H 9 0 1926.5 (1340.1, 2769.7) 0.472246 50.0 DAY 29 672 H 9 0 1190.4 (727.8, 1946.9) 0.640008 71.1
[1] No. of subjects with NQs assigned half the limit of quantification.Note: Statistics for 95% CI of Geo. Mean, SD logs and %CVb are missing because an insufficient number ofsubjects have reached the limit of quantification, making calculation of these statistics inappropriate.
667
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 9 of 9Population: Pharmacodynamic Table 12.2 Summary of Log-Transformed Plasma Abeta Pharmacodynamic Concentration-Time Data [pg/mL]
Parameter: Abeta 45 Planned No. Time Imputed Geo- SD Treatment N Visit Point n [1] Mean 95 % CI of Geo. Mean logs %CVb ---------------------------------------------------------------------------------------------- IM_200mg 9 DAY 57 1344 H 8 0 497.2 (145.2, 1702.2) 1.472044 278.1 FOLLOW-UP 2016 H 8 0 316.2 (64.8, 1542.4) 1.895685 594.7
[1] No. of subjects with NQs assigned half the limit of quantification.Note: Statistics for 95% CI of Geo. Mean, SD logs and %CVb are missing because an insufficient number ofsubjects have reached the limit of quantification, making calculation of these statistics inappropriate.
668
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 1 of 9Population: Pharmacodynamic Table 12.3 Summary of Plasma Abeta Pharmacodynamic Concentration Change from Baseline-Time Data
Parameter: Abeta 1-22(fold) No. Time Imputed 95% CITreatment N Visit point n [1] Mean (Lower, Upper) SD Median Min. Max.------------------------------------------------------------------------------------------------------------IV_200mg 9 DAY 1 PREDOSE 9 0 1 0 1 1 1 1 H 9 6 0.15 0.063 0.03 0.5 2 H 9 6 0.15 0.063 0.03 0.56 4 H 8 6 0.151 0.062 0.03 0.53 6 H 9 4 0.186 0.09 0.06 0.54 DAY 2 24 H 9 2 0.367 (0.208, 0.526) 0.2072 0.341 0.06 0.68 DAY 3 48 H 9 2 0.533 (0.306, 0.76) 0.2953 0.579 0.06 0.87 DAY 6 120 H 9 1 0.681 (0.409, 0.954) 0.3544 0.825 0.07 0.98 DAY 15 336 H 9 0 0.826 (0.536, 1.115) 0.3765 0.967 0.2 1.31 DAY 29 672 H 9 0 0.974 (0.634, 1.315) 0.4429 1.166 0.19 1.46 DAY 57 1344 H 9 0 1.249 (0.843, 1.654) 0.5273 1.23 0.53 1.93 FOLLOW-UP 2016 H 9 0 1.59 (1.326, 1.854) 0.3434 1.476 1.13 2.21
SQ_200mg 9 DAY 1 PREDOSE 9 0 1 0 1 1 1 6 H 9 1 0.794 (0.544, 1.045) 0.3258 0.848 0.06 1.13 DAY 2 24 H 9 1 0.851 (0.591, 1.111) 0.3386 0.876 0.06 1.22 DAY 3 48 H 8 1 0.909 (0.567, 1.25) 0.4086 0.892 0.06 1.4 DAY 6 120 H 9 0 1.02 (0.834, 1.206) 0.242 0.913 0.65 1.37 DAY 15 336 H 9 0 1.041 (0.75, 1.333) 0.3795 1.096 0.25 1.48 DAY 29 672 H 9 0 1.165 (0.807, 1.523) 0.4653 1.275 0.23 1.74 DAY 57 1344 H 9 0 1.357 (0.924, 1.79) 0.5636 1.534 0.31 2 FOLLOW-UP 2016 H 9 0 1.433 (1.182, 1.684) 0.3265 1.503 0.9 1.83
SQ_50mg x 4 9 DAY 1 PREDOSE 9 0 1 0 1 1 1 6 H 9 0 0.86 (0.575, 1.145) 0.3708 1.006 0.23 1.39 DAY 2 24 H 9 0 0.816 (0.581, 1.051) 0.3058 0.907 0.3 1.13 DAY 3 48 H 9 0 0.865 (0.616, 1.114) 0.3242 0.911 0.36 1.29
[1] No. of subjects with NQs assigned half the limit of quantification.Note: Statistics for 95% CI of Mean and SD are missing because an insufficient number of subjects havereached the limit of quantification, making calculation of these statistics inappropriate.Note: Change from baseline is calculated by dividing the baseline value from the individual post-dose value
669
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 2 of 9Population: Pharmacodynamic Table 12.3 Summary of Plasma Abeta Pharmacodynamic Concentration Change from Baseline-Time Data
Parameter: Abeta 1-22(fold) No. Time Imputed 95% CITreatment N Visit point n [1] Mean (Lower, Upper) SD Median Min. Max.------------------------------------------------------------------------------------------------------------SQ_50mg x 4 9 DAY 6 120 H 9 0 0.899 (0.643, 1.155) 0.3331 0.894 0.39 1.42 DAY 8 PREDOSE 9 0 0.954 (0.686, 1.222) 0.3488 0.954 0.37 1.47 6 H 9 0 0.834 (0.573, 1.094) 0.3387 0.905 0.27 1.27 DAY 9 24 H 9 0 0.782 (0.553, 1.01) 0.2971 0.9 0.28 1.19 DAY 10 48 H 9 0 0.79 (0.553, 1.027) 0.3081 0.888 0.28 1.23 DAY 13 120 H 9 0 0.815 (0.566, 1.063) 0.3239 0.904 0.31 1.27 DAY 15 PREDOSE 9 0 0.86 (0.626, 1.094) 0.3045 0.953 0.4 1.31 6 H 9 0 0.798 (0.554, 1.041) 0.3169 0.92 0.26 1.18 DAY 16 24 H 9 0 0.76 (0.55, 0.97) 0.273 0.87 0.37 1.18 DAY 17 48 H 9 0 0.759 (0.537, 0.981) 0.2891 0.893 0.33 1.14 DAY 20 120 H 9 0 0.824 (0.583, 1.066) 0.3141 0.888 0.36 1.32 DAY 22 PREDOSE 9 0 0.835 (0.586, 1.083) 0.3231 0.902 0.38 1.37 6 H 9 0 0.783 (0.508, 1.058) 0.3576 0.872 0.21 1.29 DAY 23 24 H 9 0 0.746 (0.508, 0.984) 0.3099 0.861 0.2 1.14 DAY 24 48 H 9 0 0.758 (0.531, 0.985) 0.295 0.883 0.33 1.13 DAY 27 120 H 9 0 0.799 (0.54, 1.057) 0.3365 0.883 0.34 1.21 DAY 31 216 H 9 0 0.854 (0.567, 1.141) 0.3734 0.934 0.34 1.55 DAY 43 504 H 9 0 0.963 (0.641, 1.285) 0.4189 0.896 0.45 1.8 DAY 50 672 H 8 0 1.027 (0.614, 1.44) 0.4941 0.956 0.46 1.99 DAY 78 1344 H 8 0 1.461 (0.968, 1.954) 0.59 1.625 0.48 2.01 FOLLOW-UP 2016 H 9 0 1.236 (0.852, 1.621) 0.5003 1.456 0.37 1.71
IM_200mg 9 DAY 1 PREDOSE 9 0 1 0 1 1 1 6 H 9 3 0.578 (0.289, 0.867) 0.3757 0.784 0.08 0.89 DAY 2 24 H 9 3 0.601 (0.292, 0.911) 0.4024 0.751 0.08 1.05 DAY 3 48 H 9 3 0.68 (0.31, 1.05) 0.4816 0.87 0.08 1.42 DAY 6 120 H 9 3 0.711 (0.348, 1.074) 0.4722 0.994 0.08 1.12
[1] No. of subjects with NQs assigned half the limit of quantification.Note: Statistics for 95% CI of Mean and SD are missing because an insufficient number of subjects havereached the limit of quantification, making calculation of these statistics inappropriate.Note: Change from baseline is calculated by dividing the baseline value from the individual post-dose value
670
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 3 of 9Population: Pharmacodynamic Table 12.3 Summary of Plasma Abeta Pharmacodynamic Concentration Change from Baseline-Time Data
Parameter: Abeta 1-22(fold) No. Time Imputed 95% CITreatment N Visit point n [1] Mean (Lower, Upper) SD Median Min. Max.------------------------------------------------------------------------------------------------------------IM_200mg 9 DAY 15 336 H 9 2 0.92 (0.549, 1.291) 0.4828 1.138 0.08 1.36 DAY 29 672 H 9 1 1.337 (0.916, 1.757) 0.5471 1.375 0.1 2.04 DAY 57 1344 H 8 0 1.448 (0.91, 1.986) 0.643 1.599 0.39 2.32 FOLLOW-UP 2016 H 8 0 1.666 (1.298, 2.034) 0.4406 1.745 0.99 2.18
[1] No. of subjects with NQs assigned half the limit of quantification.Note: Statistics for 95% CI of Mean and SD are missing because an insufficient number of subjects havereached the limit of quantification, making calculation of these statistics inappropriate.Note: Change from baseline is calculated by dividing the baseline value from the individual post-dose value
671
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 4 of 9Population: Pharmacodynamic Table 12.3 Summary of Plasma Abeta Pharmacodynamic Concentration Change from Baseline-Time Data
Parameter: Abeta 18-35(fold) No. Time Imputed 95% CITreatment N Visit point n [1] Mean (Lower, Upper) SD Median Min. Max.------------------------------------------------------------------------------------------------------------IV_200mg 9 DAY 1 PREDOSE 9 0 1 0 1 1 1 1 H 9 0 8.287 (5.605, 10.968) 3.4889 8.663 1.3 12.33 2 H 9 0 10.267 (6.776, 13.758) 4.5417 10.852 1.41 16.06 4 H 8 0 14.548 (8.837, 20.258) 6.8305 15.029 1.77 23.03 6 H 9 0 18.809 (11.869, 25.749) 9.028 19.728 2.07 30.23 DAY 2 24 H 9 0 37.726 (22.247, 53.204) 20.136 37.515 3.87 68.48 DAY 3 48 H 9 0 43.674 (24.61, 62.738) 24.801 40.205 4.76 84.12 DAY 6 120 H 9 0 41.889 (24.861, 58.917) 22.152 41.503 4.4 76.89 DAY 15 336 H 9 0 26.88 (16.512, 37.248) 13.488 26.38 2.81 52.37 DAY 29 672 H 9 0 13.63 (8.278, 18.982) 6.9626 13.607 1.57 26.93 DAY 57 1344 H 9 0 3.814 (2.197, 5.43) 2.103 3.458 1.14 8.74 FOLLOW-UP 2016 H 9 0 1.852 (1.115, 2.589) 0.9587 1.565 0.85 4.16
SQ_200mg 9 DAY 1 PREDOSE 9 0 1 0 1 1 1 6 H 9 0 8.233 (5.538, 10.929) 3.5066 7.728 2.12 12.78 DAY 2 24 H 9 0 21.437 (14.694, 28.179) 8.7719 21.553 4.55 33.9 DAY 3 48 H 8 0 31.797 (20.262, 43.331) 13.796 31.361 6.15 52.93 DAY 6 120 H 9 0 37.22 (24.526, 49.913) 16.513 36.084 7.45 66.11 DAY 15 336 H 9 0 28.93 (18.749, 39.111) 13.245 28.343 4.77 53.36 DAY 29 672 H 9 0 14.575 (8.728, 20.423) 7.6071 14.644 2.48 31.46 DAY 57 1344 H 9 0 4.245 (2.877, 5.613) 1.78 4.125 1.25 7.79 FOLLOW-UP 2016 H 9 0 1.996 (1.287, 2.704) 0.9219 1.817 1.01 4.25
SQ_50mg x 4 9 DAY 1 PREDOSE 9 0 1 0 1 1 1 6 H 9 0 4.452 (2.814, 6.09) 2.1314 3.538 2.18 8.01 DAY 2 24 H 9 0 11.97 (8.651, 15.289) 4.318 10.626 5.73 18.52 DAY 3 48 H 9 0 16.507 (12.764, 20.25) 4.8691 16.465 8.62 25.17
[1] No. of subjects with NQs assigned half the limit of quantification.Note: Statistics for 95% CI of Mean and SD are missing because an insufficient number of subjects havereached the limit of quantification, making calculation of these statistics inappropriate.Note: Change from baseline is calculated by dividing the baseline value from the individual post-dose value
672
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 5 of 9Population: Pharmacodynamic Table 12.3 Summary of Plasma Abeta Pharmacodynamic Concentration Change from Baseline-Time Data
Parameter: Abeta 18-35(fold) No. Time Imputed 95% CITreatment N Visit point n [1] Mean (Lower, Upper) SD Median Min. Max.------------------------------------------------------------------------------------------------------------SQ_50mg x 4 9 DAY 6 120 H 9 0 19.279 (15.034, 23.523) 5.5223 19.373 11.35 26.95 DAY 8 PREDOSE 9 0 18.486 (14.225, 22.747) 5.5431 18.313 11.13 28.23 6 H 9 0 18.622 (14.093, 23.151) 5.8923 18.072 11.52 31.13 DAY 9 24 H 9 0 24.643 (17.677, 31.61) 9.0634 24.226 12.69 43.3 DAY 10 48 H 9 0 28.317 (19.698, 36.935) 11.212 27.592 14.13 47.13 DAY 13 120 H 9 0 26.648 (18.921, 34.375) 10.052 28.3 13.84 41.05 DAY 15 PREDOSE 9 0 24.384 (16.719, 32.048) 9.9713 22.637 12.22 41.05 6 H 9 0 25.13 (17.89, 32.37) 9.4188 25.217 13.27 42.13 DAY 16 24 H 9 0 29.972 (20.214, 39.73) 12.695 26.997 15.07 51.79 DAY 17 48 H 9 0 31.305 (20.874, 41.735) 13.569 26.778 16.21 57.76 DAY 20 120 H 9 0 31.195 (20.99, 41.4) 13.276 30.185 16.34 58.47 DAY 22 PREDOSE 9 0 28.803 (19.982, 37.624) 11.475 28.946 15.21 50.4 6 H 9 0 29.819 (19.515, 40.123) 13.405 26.489 14.36 55.46 DAY 23 24 H 9 0 32.297 (21.263, 43.331) 14.354 26.995 16.75 61.14 DAY 24 48 H 9 0 35.276 (24.513, 46.039) 14.002 35.734 18.87 61.94 DAY 27 120 H 9 0 34.922 (24.126, 45.717) 14.044 29.205 18.1 62.48 DAY 31 216 H 9 0 30.808 (21.292, 40.324) 12.379 31.585 15.75 52.08 DAY 43 504 H 9 0 16.966 (12.366, 21.566) 5.9844 18.072 9.72 25.5 DAY 50 672 H 8 0 12.212 (8.012, 16.413) 5.0246 13.132 5.53 18.42 DAY 78 1344 H 8 0 4.268 (2.772, 5.764) 1.7892 4.94 1.71 6.03 FOLLOW-UP 2016 H 9 0 1.732 (1.225, 2.238) 0.6591 1.793 0.79 2.81
IM_200mg 9 DAY 1 PREDOSE 9 0 1 0 1 1 1 6 H 9 0 11.434 (4.869, 18) 8.5418 8.631 3.04 29.81 DAY 2 24 H 9 0 35.951 (18.222, 53.681) 23.065 31.078 7.11 78.44 DAY 3 48 H 9 0 42.899 (22.277, 63.52) 26.827 32.165 9.48 94.34 DAY 6 120 H 9 0 46.285 (25.26, 67.309) 27.351 33.698 10.42 91.65
[1] No. of subjects with NQs assigned half the limit of quantification.Note: Statistics for 95% CI of Mean and SD are missing because an insufficient number of subjects havereached the limit of quantification, making calculation of these statistics inappropriate.Note: Change from baseline is calculated by dividing the baseline value from the individual post-dose value
673
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 6 of 9Population: Pharmacodynamic Table 12.3 Summary of Plasma Abeta Pharmacodynamic Concentration Change from Baseline-Time Data
Parameter: Abeta 18-35(fold) No. Time Imputed 95% CITreatment N Visit point n [1] Mean (Lower, Upper) SD Median Min. Max.------------------------------------------------------------------------------------------------------------IM_200mg 9 DAY 15 336 H 9 0 31.136 (19.094, 43.177) 15.665 25.3 9.5 56.05 DAY 29 672 H 9 0 15.39 (10.013, 20.767) 6.9953 14.79 4.5 27.99 DAY 57 1344 H 8 0 4.211 (2.566, 5.857) 1.9685 3.653 1.94 8.36 FOLLOW-UP 2016 H 8 0 2.066 (1.223, 2.91) 1.0088 2.006 0.83 3.76
[1] No. of subjects with NQs assigned half the limit of quantification.Note: Statistics for 95% CI of Mean and SD are missing because an insufficient number of subjects havereached the limit of quantification, making calculation of these statistics inappropriate.Note: Change from baseline is calculated by dividing the baseline value from the individual post-dose value
674
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 7 of 9Population: Pharmacodynamic Table 12.3 Summary of Plasma Abeta Pharmacodynamic Concentration Change from Baseline-Time Data
Parameter: Abeta 42(fold) No. Time Imputed 95% CITreatment N Visit point n [1] Mean (Lower, Upper) SD Median Min. Max.------------------------------------------------------------------------------------------------------------IV_200mg 9 DAY 1 PREDOSE 9 0 1 0 1 1 1 1 H 9 0 4.495 (2.855, 6.134) 2.1328 5.265 0.84 6.8 2 H 9 0 5.447 (3.382, 7.512) 2.6864 6.024 0.94 8.63 4 H 8 0 7.428 (3.929, 10.926) 4.1851 8.074 1.12 12.07 6 H 9 0 9.34 (5.437, 13.243) 5.0781 11.1 1.11 16.37 DAY 2 24 H 9 0 17.606 (10.013, 25.199) 9.8784 20.129 1.43 30.19 DAY 3 48 H 9 0 20.821 (11.8, 29.842) 11.736 23.836 2.48 37.33 DAY 6 120 H 9 0 19.362 (11.488, 27.236) 10.243 23.238 2.58 30.12 DAY 15 336 H 9 0 14.218 (8.548, 19.887) 7.3761 15.332 1.47 21.72 DAY 29 672 H 9 0 8.18 (4.863, 11.496) 4.3145 9.531 1.03 13.19 DAY 57 1344 H 9 0 2.862 (1.942, 3.781) 1.1959 2.98 0.96 4.57 FOLLOW-UP 2016 H 9 0 1.396 (0.893, 1.898) 0.6535 1.362 0.65 2.61
SQ_200mg 9 DAY 1 PREDOSE 9 0 1 0 1 1 1 6 H 9 0 5.025 (2.461, 7.589) 3.3354 6.509 0.66 9.73 DAY 2 24 H 9 0 12.016 (5.594, 18.437) 8.3544 17.477 0.82 21.2 DAY 3 48 H 8 0 17.23 (6.864, 27.596) 12.399 24.04 0.8 28.79 DAY 6 120 H 9 0 18.776 (8.279, 29.274) 13.657 25.584 0.94 33.52 DAY 15 336 H 9 0 15.796 (7.171, 24.42) 11.220 20.742 1.26 28 DAY 29 672 H 9 0 9.223 (4.18, 14.266) 6.5608 9.44 0.69 17.34 DAY 57 1344 H 9 0 2.719 (1.609, 3.828) 1.4433 2.811 0.69 5.2 FOLLOW-UP 2016 H 9 0 1.239 (0.901, 1.577) 0.4396 1.258 0.56 1.92
SQ_50mg x 4 9 DAY 1 PREDOSE 9 0 1 0 1 1 1 6 H 9 0 3.026 (1.836, 4.215) 1.5476 2.442 1.58 5.52 DAY 2 24 H 9 0 8.19 (5.334, 11.045) 3.7151 7.725 4.11 15.08 DAY 3 48 H 9 0 10.769 (7.694, 13.844) 4.0008 11.309 4.9 18.65
[1] No. of subjects with NQs assigned half the limit of quantification.Note: Statistics for 95% CI of Mean and SD are missing because an insufficient number of subjects havereached the limit of quantification, making calculation of these statistics inappropriate.Note: Change from baseline is calculated by dividing the baseline value from the individual post-dose value
675
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 8 of 9Population: Pharmacodynamic Table 12.3 Summary of Plasma Abeta Pharmacodynamic Concentration Change from Baseline-Time Data
Parameter: Abeta 42(fold) No. Time Imputed 95% CITreatment N Visit point n [1] Mean (Lower, Upper) SD Median Min. Max.------------------------------------------------------------------------------------------------------------SQ_50mg x 4 9 DAY 6 120 H 9 0 12.719 (9.148, 16.289) 4.6456 12.931 4.07 19.48 DAY 8 PREDOSE 9 0 12.063 (8.786, 15.34) 4.2635 12.585 3.86 18.08 6 H 9 0 12.279 (9.172, 15.386) 4.0418 13.538 4.53 17.87 DAY 9 24 H 9 0 15.555 (11.176, 19.935) 5.6971 15.71 6.03 23.26 DAY 10 48 H 9 0 17.016 (11.399, 22.634) 7.3082 17.308 5.39 29.13 DAY 13 120 H 9 0 16.453 (11.4, 21.505) 6.5729 17.738 5.28 25.42 DAY 15 PREDOSE 9 0 15.508 (10.694, 20.321) 6.2621 15.466 5.01 24.01 6 H 9 0 15.509 (11.051, 19.967) 5.7996 15.58 5.42 23.4 DAY 16 24 H 9 0 17.8 (12.047, 23.552) 7.4834 17.333 5.82 28.81 DAY 17 48 H 9 0 18.725 (13.556, 23.894) 6.7247 18.311 7.21 27.5 DAY 20 120 H 9 0 17.813 (12.653, 22.974) 6.7134 18.068 6.17 28.84 DAY 22 PREDOSE 9 0 17.33 (12.22, 22.439) 6.6474 18.057 5.75 26.94 6 H 9 0 17.99 (12.361, 23.62) 7.324 19.392 6.03 26.54 DAY 23 24 H 9 0 19.608 (13.878, 25.338) 7.4545 18.997 7.43 29.96 DAY 24 48 H 9 0 19.999 (14.305, 25.693) 7.4078 19.117 8.11 31.18 DAY 27 120 H 9 0 18.659 (13.091, 24.226) 7.2431 19.1 6.67 28.27 DAY 31 216 H 9 0 18.305 (12.054, 24.556) 8.1325 17.178 6.57 33.15 DAY 43 504 H 9 0 11.664 (7.969, 15.359) 4.8067 10.936 4.51 19.77 DAY 50 672 H 8 0 8.251 (5.617, 10.885) 3.1505 8.489 3 12.63 DAY 78 1344 H 8 0 2.676 (1.566, 3.785) 1.3271 2.393 0.61 4.79 FOLLOW-UP 2016 H 9 0 1.182 (0.683, 1.682) 0.6497 1.123 0.3 2.16
IM_200mg 9 DAY 1 PREDOSE 9 0 1 0 1 1 1 6 H 9 0 6.45 (3.015, 9.885) 4.469 6.251 1.18 13.59 DAY 2 24 H 9 0 16.758 (7.158, 26.358) 12.488 15.408 1.4 36.86 DAY 3 48 H 9 0 19.487 (9.017, 29.958) 13.621 19.45 1.72 40.29 DAY 6 120 H 9 0 21.657 (9.543, 33.772) 15.760 21.237 1.81 46.22
[1] No. of subjects with NQs assigned half the limit of quantification.Note: Statistics for 95% CI of Mean and SD are missing because an insufficient number of subjects havereached the limit of quantification, making calculation of these statistics inappropriate.Note: Change from baseline is calculated by dividing the baseline value from the individual post-dose value
676
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 9 of 9Population: Pharmacodynamic Table 12.3 Summary of Plasma Abeta Pharmacodynamic Concentration Change from Baseline-Time Data
Parameter: Abeta 42(fold) No. Time Imputed 95% CITreatment N Visit point n [1] Mean (Lower, Upper) SD Median Min. Max.------------------------------------------------------------------------------------------------------------IM_200mg 9 DAY 15 336 H 9 0 16.373 (7.599, 25.147) 11.414 17.401 1.37 35.82 DAY 29 672 H 9 0 9.356 (4.614, 14.098) 6.1691 10.147 1.13 21.33 DAY 57 1344 H 8 0 2.944 (1.933, 3.956) 1.2101 2.963 1.06 5.29 FOLLOW-UP 2016 H 8 0 1.869 (1.156, 2.582) 0.8529 1.503 0.93 3.33
[1] No. of subjects with NQs assigned half the limit of quantification.Note: Statistics for 95% CI of Mean and SD are missing because an insufficient number of subjects havereached the limit of quantification, making calculation of these statistics inappropriate.Note: Change from baseline is calculated by dividing the baseline value from the individual post-dose value
677
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 1 of 10Population: Pharmacodynamic Table 12.4 Summary of Anti-GSK933776 Antibody Immunogenicity Assessment-Time Data
ImmunogencityTest: Binding antibody detection (TITER) Immunogencity Test IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Sub Category Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------------------------------ DAY 1 Screening n 9 9 9 9 Positive 0 1 (11%) 2 (22%) 0 Negative 9 (100%) 8 (89%) 7 (78%) 9 (100%) Not reportable 0 0 0 0 Not applicable 0 0 0 0
Confirming n 9 9 9 9 Positive 0 1 (11%) 1 (11%) 0 Negative 0 0 1 (11%) 0 Not reportable 0 0 0 0 Not applicable 9 (100%) 8 (89%) 7 (78%) 9 (100%)
Titer n 9 9 9 9 Positive 0 1 (11%) 1 (11%) 0 Negative 0 0 0 0 Not reportable 0 0 0 0 Not applicable 9 (100%) 8 (89%) 8 (89%) 9 (100%)
DAY 22 Screening n 9 Positive 2 (22%) Negative 7 (78%) Not reportable 0 Not applicable 0
Confirming n 9 Positive 1 (11%) Negative 1 (11%) Not reportable 0 Not applicable 7 (78%)
678
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 2 of 10Population: Pharmacodynamic Table 12.4 Summary of Anti-GSK933776 Antibody Immunogenicity Assessment-Time Data
ImmunogencityTest: Binding antibody detection (TITER) Immunogencity Test IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Sub Category Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------------------------------ DAY 22 Titer n 9 Positive 1 (11%) Negative 0 Not reportable 0 Not applicable 8 (89%)
DAY 27 Screening n 9 Positive 2 (22%) Negative 7 (78%) Not reportable 0 Not applicable 0
Confirming n 9 Positive 1 (11%) Negative 1 (11%) Not reportable 0 Not applicable 7 (78%)
Titer n 9 Positive 1 (11%) Negative 0 Not reportable 0 Not applicable 8 (89%)
DAY 29 Screening n 9 9 9 Positive 0 0 0 Negative 9 (100%) 9 (100%) 9 (100%) Not reportable 0 0 0 Not applicable 0 0 0
679
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 3 of 10Population: Pharmacodynamic Table 12.4 Summary of Anti-GSK933776 Antibody Immunogenicity Assessment-Time Data
ImmunogencityTest: Binding antibody detection (TITER) Immunogencity Test IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Sub Category Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------------------------------ DAY 29 Confirming n 9 9 9 Positive 0 0 0 Negative 0 0 0 Not reportable 0 0 0 Not applicable 9 (100%) 9 (100%) 9 (100%)
Titer n 9 9 9 Positive 0 0 0 Negative 0 0 0 Not reportable 0 0 0 Not applicable 9 (100%) 9 (100%) 9 (100%)
DAY 50 Screening n 8 Positive 2 (25%) Negative 6 (75%) Not reportable 0 Not applicable 0
Confirming n 8 Positive 1 (13%) Negative 1 (13%) Not reportable 0 Not applicable 6 (75%)
Titer n 8 Positive 1 (13%) Negative 0 Not reportable 0 Not applicable 7 (88%)
680
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 4 of 10Population: Pharmacodynamic Table 12.4 Summary of Anti-GSK933776 Antibody Immunogenicity Assessment-Time Data
ImmunogencityTest: Binding antibody detection (TITER) Immunogencity Test IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Sub Category Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------------------------------ DAY 57 Screening n 9 9 8 Positive 0 0 0 Negative 9 (100%) 9 (100%) 8 (100%) Not reportable 0 0 0 Not applicable 0 0 0
Confirming n 9 9 8 Positive 0 0 0 Negative 0 0 0 Not reportable 0 0 0 Not applicable 9 (100%) 9 (100%) 8 (100%)
Titer n 9 9 8 Positive 0 0 0 Negative 0 0 0 Not reportable 0 0 0 Not applicable 9 (100%) 9 (100%) 8 (100%)
DAY 78 Screening n 8 Positive 2 (25%) Negative 6 (75%) Not reportable 0 Not applicable 0
Confirming n 8 Positive 1 (13%) Negative 1 (13%) Not reportable 0 Not applicable 6 (75%)
681
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 5 of 10Population: Pharmacodynamic Table 12.4 Summary of Anti-GSK933776 Antibody Immunogenicity Assessment-Time Data
ImmunogencityTest: Binding antibody detection (TITER) Immunogencity Test IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Sub Category Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------------------------------ DAY 78 Titer n 8 Positive 1 (13%) Negative 0 Not reportable 0 Not applicable 7 (88%)
FOLLOW-UP Screening n 9 9 8 8 Positive 0 0 2 (25%) 0 Negative 9 (100%) 9 (100%) 6 (75%) 8 (100%) Not reportable 0 0 0 0 Not applicable 0 0 0 0
Confirming n 9 9 8 8 Positive 0 0 1 (13%) 0 Negative 0 0 1 (13%) 0 Not reportable 0 0 0 0 Not applicable 9 (100%) 9 (100%) 6 (75%) 8 (100%)
Titer n 9 9 8 8 Positive 0 0 1 (13%) 0 Negative 0 0 0 0 Not reportable 0 0 0 0 Not applicable 9 (100%) 9 (100%) 7 (88%) 8 (100%)
682
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 6 of 10Population: Pharmacodynamic Table 12.4 Summary of Anti-GSK933776 Antibody Immunogenicity Assessment-Time Data
ImmunogencityTest: Neutralising antibody detection (TITER) Immunogencity Test IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Sub Category Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------------------------------ DAY 1 Screening n 9 9 9 9 Positive 0 0 0 0 Negative 0 0 0 0 Not reportable 0 1 (11%) 1 (11%) 0 Not applicable 9 (100%) 8 (89%) 8 (89%) 9 (100%)
Confirming n 9 9 9 9 Positive 0 0 0 0 Negative 0 1 (11%) 1 (11%) 0 Not reportable 0 0 0 0 Not applicable 9 (100%) 8 (89%) 8 (89%) 9 (100%)
Titer n 9 9 9 9 Positive 0 0 0 0 Negative 0 1 (11%) 1 (11%) 0 Not reportable 0 0 0 0 Not applicable 9 (100%) 8 (89%) 8 (89%) 9 (100%)
DAY 22 Screening n 9 Positive 0 Negative 0 Not reportable 1 (11%) Not applicable 8 (89%)
Confirming n 9 Positive 0 Negative 1 (11%) Not reportable 0 Not applicable 8 (89%)
683
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 7 of 10Population: Pharmacodynamic Table 12.4 Summary of Anti-GSK933776 Antibody Immunogenicity Assessment-Time Data
ImmunogencityTest: Neutralising antibody detection (TITER) Immunogencity Test IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Sub Category Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------------------------------ DAY 22 Titer n 9 Positive 0 Negative 1 (11%) Not reportable 0 Not applicable 8 (89%)
DAY 27 Screening n 9 Positive 0 Negative 0 Not reportable 1 (11%) Not applicable 8 (89%)
Confirming n 9 Positive 0 Negative 1 (11%) Not reportable 0 Not applicable 8 (89%)
Titer n 9 Positive 0 Negative 1 (11%) Not reportable 0 Not applicable 8 (89%)
DAY 29 Screening n 9 9 9 Positive 0 0 0 Negative 0 0 0 Not reportable 0 0 0 Not applicable 9 (100%) 9 (100%) 9 (100%)
684
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 8 of 10Population: Pharmacodynamic Table 12.4 Summary of Anti-GSK933776 Antibody Immunogenicity Assessment-Time Data
ImmunogencityTest: Neutralising antibody detection (TITER) Immunogencity Test IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Sub Category Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------------------------------ DAY 29 Confirming n 9 9 9 Positive 0 0 0 Negative 0 0 0 Not reportable 0 0 0 Not applicable 9 (100%) 9 (100%) 9 (100%)
Titer n 9 9 9 Positive 0 0 0 Negative 0 0 0 Not reportable 0 0 0 Not applicable 9 (100%) 9 (100%) 9 (100%)
DAY 50 Screening n 8 Positive 0 Negative 0 Not reportable 1 (13%) Not applicable 7 (88%)
Confirming n 8 Positive 0 Negative 1 (13%) Not reportable 0 Not applicable 7 (88%)
Titer n 8 Positive 0 Negative 1 (13%) Not reportable 0 Not applicable 7 (88%)
685
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 9 of 10Population: Pharmacodynamic Table 12.4 Summary of Anti-GSK933776 Antibody Immunogenicity Assessment-Time Data
ImmunogencityTest: Neutralising antibody detection (TITER) Immunogencity Test IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Sub Category Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------------------------------ DAY 57 Screening n 9 9 8 Positive 0 0 0 Negative 0 0 0 Not reportable 0 0 0 Not applicable 9 (100%) 9 (100%) 8 (100%)
Confirming n 9 9 8 Positive 0 0 0 Negative 0 0 0 Not reportable 0 0 0 Not applicable 9 (100%) 9 (100%) 8 (100%)
Titer n 9 9 8 Positive 0 0 0 Negative 0 0 0 Not reportable 0 0 0 Not applicable 9 (100%) 9 (100%) 8 (100%)
DAY 78 Screening n 8 Positive 0 Negative 0 Not reportable 1 (13%) Not applicable 7 (88%)
Confirming n 8 Positive 0 Negative 1 (13%) Not reportable 0 Not applicable 7 (88%)
686
CONFIDENTIAL 2014N211143_00BA1116891
Protocol: BA1116891 Page 10 of 10Population: Pharmacodynamic Table 12.4 Summary of Anti-GSK933776 Antibody Immunogenicity Assessment-Time Data
ImmunogencityTest: Neutralising antibody detection (TITER) Immunogencity Test IV_200mg SQ_200mg SQ_50mg x 4 IM_200mg Visit Sub Category Result (N=9) (N=9) (N=9) (N=9) ------------------------------------------------------------------------------------------------ DAY 78 Titer n 8 Positive 0 Negative 1 (13%) Not reportable 0 Not applicable 7 (88%)
FOLLOW-UP Screening n 9 9 8 8 Positive 0 0 0 0 Negative 0 0 0 0 Not reportable 0 0 1 (13%) 0 Not applicable 9 (100%) 9 (100%) 7 (88%) 8 (100%)
Confirming n 9 9 8 8 Positive 0 0 0 0 Negative 0 0 1 (13%) 0 Not reportable 0 0 0 0 Not applicable 9 (100%) 9 (100%) 7 (88%) 8 (100%)
Titer n 9 9 8 8 Positive 0 0 0 0 Negative 0 0 1 (13%) 0 Not reportable 0 0 0 0 Not applicable 9 (100%) 9 (100%) 7 (88%) 8 (100%)
687
CONFIDENTIAL 2014N211143_00BA1116891
Page 1 of 4Page 1 of 4Protocol: BA1116891Population: Pharmacokinetic/Pharmacodynamic
Figure 13.1Mean Plasma GSK933776 Concentration and Mean Plasma Abeta Concentration versus Nominal Time
by Treatment
688
CONFIDENTIAL 2014N211143_00BA1116891
Page 2 of 4Page 2 of 4Protocol: BA1116891Population: Pharmacokinetic/Pharmacodynamic
Figure 13.1Mean Plasma GSK933776 Concentration and Mean Plasma Abeta Concentration versus Nominal Time
by Treatment
689
CONFIDENTIAL 2014N211143_00BA1116891
Page 3 of 4Page 3 of 4Protocol: BA1116891Population: Pharmacokinetic/Pharmacodynamic
Figure 13.1Mean Plasma GSK933776 Concentration and Mean Plasma Abeta Concentration versus Nominal Time
by Treatment
690
CONFIDENTIAL 2014N211143_00BA1116891
Page 4 of 4Page 4 of 4Protocol: BA1116891Population: Pharmacokinetic/Pharmacodynamic
Figure 13.1Mean Plasma GSK933776 Concentration and Mean Plasma Abeta Concentration versus Nominal Time
by Treatment
691
CONFIDENTIAL 2014N211143_00BA1116891
Page 1 of 4Page 1 of 4Protocol: BA1116891Population: Pharmacokinetic/Pharmacodynamic
Figure 13.2Mean Plasma GSK933776 Concentration and Mean Plasma Abeta Concentration Change from Baseline versus
Nominal Time by Treatment
692
CONFIDENTIAL 2014N211143_00BA1116891
Page 2 of 4Page 2 of 4Protocol: BA1116891Population: Pharmacokinetic/Pharmacodynamic
Figure 13.2Mean Plasma GSK933776 Concentration and Mean Plasma Abeta Concentration Change from Baseline versus
Nominal Time by Treatment
693
CONFIDENTIAL 2014N211143_00BA1116891
Page 3 of 4Page 3 of 4Protocol: BA1116891Population: Pharmacokinetic/Pharmacodynamic
Figure 13.2Mean Plasma GSK933776 Concentration and Mean Plasma Abeta Concentration Change from Baseline versus
Nominal Time by Treatment
694
CONFIDENTIAL 2014N211143_00BA1116891
Page 4 of 4Page 4 of 4Protocol: BA1116891Population: Pharmacokinetic/Pharmacodynamic
Figure 13.2Mean Plasma GSK933776 Concentration and Mean Plasma Abeta Concentration Change from Baseline versus
Nominal Time by Treatment
695
CONFIDENTIAL 2014N211143_00BA1116891
Page 1 of 4Page 1 of 4Protocol: BA1116891Population: Pharmacokinetic/Pharmacodynamic
Figure 13.3Mean Plasma GSK933776 Concentration and Mean Plasma Abeta Concentration versus Nominal Time
by Treatment (Truncated)
696
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Page 2 of 4Page 2 of 4Protocol: BA1116891Population: Pharmacokinetic/Pharmacodynamic
Figure 13.3Mean Plasma GSK933776 Concentration and Mean Plasma Abeta Concentration versus Nominal Time
by Treatment (Truncated)
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Figure 13.3Mean Plasma GSK933776 Concentration and Mean Plasma Abeta Concentration versus Nominal Time
by Treatment (Truncated)
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Figure 13.3Mean Plasma GSK933776 Concentration and Mean Plasma Abeta Concentration versus Nominal Time
by Treatment (Truncated)
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Figure 13.4Mean Plasma GSK933776 Concentration and Mean Plasma Abeta Concentration Change from Baseline versus
Nominal Time by Treatment (Truncated)
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Figure 13.4Mean Plasma GSK933776 Concentration and Mean Plasma Abeta Concentration Change from Baseline versus
Nominal Time by Treatment (Truncated)
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Figure 13.4Mean Plasma GSK933776 Concentration and Mean Plasma Abeta Concentration Change from Baseline versus
Nominal Time by Treatment (Truncated)
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Figure 13.4Mean Plasma GSK933776 Concentration and Mean Plasma Abeta Concentration Change from Baseline versus
Nominal Time by Treatment (Truncated)
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Synopsis
Study Number: BA1116891
Title: A randomized, open label, parallel-group study to estimate bioavailability and to assess the pharmacokinetic profile, safety and tolerability of GSK933776 administered by subcutaneous or intramuscular injection relative to intravenous administration to healthy volunteers
Investigator(s):
Leese Philip, MD
Study Center(s):
Quintiles, 6700 W. 115th Street, Overland Park, Kansas, 66211, United States
Publication(s):
None at the time of this report
Study Period: 22-Jan-2014 - 15-Jul-2014
Phase of development: I
Objectives and Endpoints (criteria for evaluation):
Objectives Endpoints
Primary
To estimate the relative bioavailability of GSK933776 following single-dose IM and SQ administration and repeat-dose SQ administration as compared to IV administration
The relative bioavailability as calculated from the ratio of AUC (0-inf) following IM injection or SQ injection to IV infusion
Secondary
To characterize the pharmacokinetic profile of GSK933776 following single-dose IM and SQ administration and repeat-dose SQ administration as compared to IV administration
Pharmacokinetic parameters including area under the concentration-time curve from time zero to time of the last quantifiable concentration (AUC(0-t)) if AUC(0-inf) is not reportable, Cmax, time of occurrence of Cmax (Tmax), terminal phase half-life (T1/2), clearance, and volume of distribution as data permit
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Objectives Endpoints
To evaluate the safety and tolerability of GSK933776 following IV, IM and SQ administration
Clinical safety data from adverse event reporting (including injection site reactions), clinical observations, vital signs, ECG, and clinical laboratory parameters
To further characterize the PK-PD relationship of GSK933776 based on concentrations of A as the PD marker of interest
Determination of plasma concentrations of GSK933776, total Aβ and total Aβ fragments, as well as unbound concentrations of Aβ, fragments containing the epitope 1-22
To characterize the immunogenicity profile of GSK933776 following IV, IM and SQ administration
Presence of antibodies to GSK933776 in serum samples (if detected, characterization of neutralizing status)
Methodology:
This study was conducted to evaluate the bioavailability, pharmacokinetics (PK), safety, and tolerability of GSK933776 following subcutaneous (SQ) and intramuscular (IM) administration. An intravenous (IV) infusion arm was included in this study to allow estimation of relative bioavailability following SQ and IM administration. This study was conducted in healthy adult volunteers. Subjects were assigned 1 of 4 possible treatment arms in a 1:1:1:1 ratio and received either a single administration of GSK933776 200 milligram (mg) by IV infusion (reference arm), 200 mg SQ, 200 mg IM or GSK933776 50 mg SQ once every week for 4 weeks (total dose of 200 mg). Subjects were followed for approximately 84 days after drug administration.
Diagnosis and Main Criteria for Inclusion:
Healthy male/ female subjects aged 18 – 50 years of age, body weight ≥ 55 kg [121 lbs (pounds)] and ≤ 85 kg (187 lbs) with a body mass index (BMI) between 18.5 and 29 (inclusively) were included in the study.
Number of Subjects:
36 subjects were enrolled in this study
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Treatment Administration:
PRODUCT NAME:
GSK933776 (SQ ADMINISTRATION)
GSK933776 (IM ADMINISTRATION)
GSK933776 (IV ADMINISTRATION)
Formulation description:
Antibody solution Antibody solution Antibody solution
Dosage form: Solution for injection Solution for injection Solution for infusion
Unit dose strength(s)/Dosage level(s):
50 mg/ milliliter (mL) (1 mL nominal volume) in a 3 mL glass vial
50 mg/mL (1 mL nominal volume) in a 3 mL glass vial
50 mg/mL (1 mL nominal volume) in a 3 mL glass vial
Route/Duration: Route: SubcutaneousDuration(Single Dose): 200 mg Duration(Repeat Dose): 50 mg weekly for 4 weeks
Route: IntramuscularDuration(Single Dose): 200 mg
Route: Intravenous Duration (Single Dose): 200 mg
Dosing instructions:
The dose was administered through a sterile disposable syringe in the subcutaneous space.Acceptable injection site was either the abdomen or the upper thigh. Injection site was documented and rotated
The dose was administered in the dorsal or ventrogluteal site (in order to achieve a 200mg dose, a 4 mL injection of the 50mg/mL product are needed)
The dose was administered through an IV catheter over approximately 1 hour
Method for individualizing dosage:
GSK933776 was drawn into a sterile disposable syringe.Study drug was then administered through a sterile needle (27GA).
GSK933776 was drawn into a sterile disposable syringe. Study drug was then administered through a sterile needle (23GA).
GSK933776 was prepared in 0.9% Sodium Chloride in infusion bags. Study drug was then administered using an IV delivery pump and a catheter.
Batch Numbers PK Lot ID: 132379262
Lot No: 091217577
PK Lot ID: 132379262
Lot No: 091217577
PK Lot ID: 132379262
Lot No: 091217577
Statistical Methods:
The sample size for this study was based on feasibility and the intention to collect safety and tolerability data from at least 6 subjects in each treatment arm of GSK933776.
This study was designed to estimate the bioavailability of GSK933776 administered by SQ or IM injection relative to GSK933776 administered intravenously. No formal hypothesis was tested. For each primary pharmacokinetic endpoint, point estimates and corresponding 90% confidence intervals were constructed for the ratio of the geometric mean of the test treatment to the geometric mean of the reference treatment, (SQ GSK933776)/( IV GSK933776) and (IM GSK933776)/( IV GSK933776).
Plasma concentration-time data was analyzed by non-compartmental methods with WinNonlin. Pharmacokinetic data was presented in graphical and/or tabular form and
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was summarized descriptively. Following loge-transformation, AUC (0-inf), AUC (0-t) and Cmax of GSK933776 were separately analyzed using an analysis of variance model (ANOVA) with fixed effect terms for regimen.
All subjects enrolled in the study who received at least one dose of study drug were included in the Safety Population. PK Concentration Population consisted of all subjects in the Safety Population who underwent plasma PK sampling and had evaluable PK assay results. The PK Parameter Population consisted of all subjects with valid and evaluable PK parameters. The Pharmacodynamic (PD) Analysis Population consisted of all subjects in the Safety Population with at least one measurable concentration of biomarkers (including immunogenicity). The PK/PD Analysis Population consisted of all subjects in the Safety Population with at least one measurable concentration of biomarkers as well as one measurable concentration of GSK933776.
SUMMARY
Number of Subjects: Treatment A (200mg
IV)
Treatment B (200mg
SQ)
Treatment C (50mg SQ X 4)
Treatment D (200mg
IM)Number of subjects planned, [N] 6 6 6 6Number of subjects randomized2, [N] 9 9 9 9Number of subjects included in All subjects (safety) population, [n (%)]
9 (100%) 9 (100%) 9 (100%) 9 (100%)
Number of subjects included in PK population, [n (%)]
9 (100%) 9 (100%) 9 (100%) 9 (100%)
Number of subjects completed as planned, [n (%)]
9 (100%) 9 (100%) 8 (89%) 8 (89%)
Number of subjects withdrawn (any reason), [n (%)]
0 0 1 (11%) 1 (11%)
Number of subjects withdrawn for SAE, [n (%)]
0 0 0 0
Number of subjects withdrawn for AE, [n (%)]
0 0 0 0
Reasons for subject withdrawal, [n (%)]Lost to follow-up 0 0 1 (11%) 0Adverse events 0 0 0 0Protocol violation 0 0 0 0Other1 0 0 0 1 (11%)
1. 2. Study overenrolled each arm by 3 to ensure 24 subjects
completed each arm per protocol
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Demographics Summary:
Demographics: Treatment A (200mg
IV)
Treatment B (200mg
SQ)
Treatment C (50mg SQ X 4)
Treatment D (200mg
IM)Age in Years [Mean (SD)] 34.7 (8.9) 27.8 (7.7) 26.3 (6.2) 24.8 (6.1)
Sex [n (%)]Female 0 0 1 (11%) 0Male 9 (100%) 9 (100%) 8 (89%) 9 (100%)BMI (kg/m2) [Mean (SD)] 25.2 (2.2) 23.2 (2.1) 23.7 (1.9) 23.1 (2.3)
Height (cm) [Mean (SD)] 176.7 (6.0)) 179.4 (4.7) 171.2 (7.7) 174.2 (4.2)Weight (kg) [Mean (SD)] 78.4 (4.61) 74.4 (5.8) 69.5 (7.1) 70.0 (6.9)
Ethnicity [n (%)]Hispanic or Latino 1 (11%) 0 0 1 (11%)Not Hispanic or Latino 8 (89%) 9 (100%) 9 (100%) 8 (89%)
Race [n (%)]African American/African Heritage 2 (22%) 4 (44%) 6 (67%) 6 (67%)American Indian or Alaskan Native 0 0 0 1 (11%)Asian – Japanese Heritage 1 (11%) 0 0 0White – Arabic/North African Heritage 1 (11%) 0 0 0White – White/Caucasian/European Heritage
5 (56%) 5 (56%) 3 (33%) 2 (22%)
Adverse Events:
Summary of Adverse EventsTreatment A (200mg IV)
Treatment B (200mg SQ)
Treatment C (50mg SQ x 4)
Treatment D (200mg IM)
Total Number of AEs 5 10* 6 2Number of Subjects Exposed 9 9 9 9
Number of Subjects with AEs 4 6 3 2
*including one (1) Serious Adverse Event
The overall frequency of AEs reported in this study was similar between treatment groups. All AEs were mild or moderate in intensity. There was one serious adverse event (SAE) reported during the study. There were no deaths reported.
There were no clinically significant changes in laboratory parameters, vital signs (heart rate and blood pressure) or 12-lead safety ECG parameters during the study.
Pharmacokinetic Results:
There is a typical plasma PK profile across all arms with a small to moderate between-subject variability (%CVb<30%)
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The exposure of GSK933776 as measured by AUC(0-inf) following 50 mg repeat-dose SQ administration as compared with 200 mg IV administration were similar. In general, the exposure for the first 672 hours and 168 hours (dose normalized) following the 50 mg repeat-dose SQ administration as compared with 200 mg IV administration showed approximately 40% lower exposure. The Cmax following the 50 mg repeated-dose SQ was approximately 70% lower when compared with the 200 mg IV administered dose.
The exposure of GSK933776 as measured by AUC(0-inf) following 200 mg single-dose IM and SQ administration as compared to 200 mg IV administration showed approximately 15% lower exposure. The Cmax was 55% to 65% lower for the IM and SQ dosing, respectively.
Immunogenicity Results:
No antibodies are generated against GSK933776 in serum samples.
Relationship between PK and PD Results:
There is a decrease of Abeta1-22, increase of Abeta18-35 and Abeta42 after GSK933776 administration.
Conclusions:
Compared to intravenous administration, the relative bioavailability of subcutaneous and intramuscular administrations of GSK933776 were 83% and 87% for AUC(0-inf) and 36% and 46% for Cmax, respectively.
Compared to intravenous administration, the relative bioavailability results indicate that 200 mg subcutaneous and intra-muscular administrations of GSK933776 produce comparable exposure profiles, with the relative bioavailability at approximately 82% and 85%, respectively, compared to IV administration.
Subcutaneous administration of GSK933776 50 mg weekly were 68% for dose normalized exposure over 7 days (i.e., AUC(0-168)/D) and 60% for exposure over 28 days (i.e., AUC(0-672), respectively. Cmax following 50 mg weekly dosing was substantially lower at 28% of that following 200 mg intravenous administration.
The median t½ was comparable across routes of administration.
Intravenous, subcutaneous and intra-muscular GSK933776 were well tolerated in this study. No significant safety findings could be attributed to investigational product. Vital signs, laboratory and electrocardiographic parameters fell within expected ranges
Plasma Abeta1-22 decreased, Abeta18-35 and Abeta42 increased followingGSK933776 dosing by all routes of administration.
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No antibodies were detected post dose against GSK933776 in serum samples collected out to 85 days following single dose administration of GSK933776 by IV, SQ and IM routes; similarly, no antibodies against GSK933776 were detected in serum samples collected out to 106 days following four weekly SQ administration of GSK933776.
Effective Date: 11-MAY-2015
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TITLE PAGE
Division: Worldwide DevelopmentInformation Type: Clinical Protocol
Title: A randomized, open label, parallel-group study to estimate bioavailability and to assess the pharmacokinetic profile, safety and tolerability of GSK933776 administered by subcutaneous or intramuscular injection relative to intravenous administration to healthy volunteers
Compound Number: GSK933776
Phase I
Effective Date: 05-NOV-2013
Subject: Pharmacokinetics, bioavailability, intravenous, subcutaneous and intramuscular administration, amyloid beta, monoclonal antibody
Author(s):
(CPSSO); (Clinical Statistics); (CPMS); (PTS); (Clinical Immunology); (MPD); (Ophthalmology).
Copyright 2013 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited.
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SYNOPSIS:
GSK933776 is a humanized IgG1 monoclonal antibody directed against amyloid-β (Aβ) being developed for geographic atrophy (GA) secondary to age-related macular degeneration (AMD). GSK933776 has previously been studied in patients with Alzheimer’s disease (AD). To date, all studies with GSK933776 have utilized intravenous (IV) infusion as the route of administration. This study will evaluate the bioavailability, pharmacokinetics (PK), safety, and tolerability of GSK933776 following subcutaneous (SQ) and intramuscular (IM) administration. An IV infusion arm is included in this study to allow calculation of estimated relative bioavailability following SQ and IM administration.
This study will be conducted in healthy adult volunteers. Subjects will be assigned to 1 of 4 possible treatment arms in a 1:1:1:1 ratio; subjects will receive either a single administration of GSK933776 200 mg (milligram) by IV infusion (reference arm), 200 mg SQ, 200 mg IM or GSK933776 50 mg SQ once every week for 4 weeks (total dose of 200 mg). Subjects will be followed for approximately 84 days after drug administration.
The primary endpoints of the study are the estimated relative bioavailability based on area under the concentration-time curve AUC(0-inf) and a characterization of the pharmacokinetic profile of GSK933776 with each route of administration (AUC(0-), Cmax (maximum observed concentration), Tmax (time of occurrence of Cmax), T1/2 (terminal phase half-life), clearance, and volume of distribution (as data permit). Secondary endpoints include routine safety and tolerability assessments, an evaluation of potential immunogenicity as determined by the presence of antibodies to GSK933776 in serum, and characterization of the pharmacodynamic profile as determined by the measurement of plasma concentrations of GSK933776, total Aβ and total Aβ fragmentsas data permit, as well as unbound concentrations of Aβ, if possible.
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SPONSOR/MEDICAL MONITOR INFORMATION PAGE
Medical Monitor and Sponsor Contact Information:
Role Name Day Time Phone Number
After-hours Phone/Cell/PagerNumber
Fax Number
GSK Address
Primary Medical Monitor
MD, MPH
5 Moore Drive PO Box 13398, RTP, NC 27709-3398
Secondary Medical Monitor
MD,
PhD
2301 Renaissance BlvdKing of Prussia, PA 19406
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited980 Great West RoadBrentfordMiddlesex, TW8 9GSUK
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline affiliate company (or designee). If applicable, the details of the alternative Sponsor and contact person in the territory will be provided to the relevant regulatory authority as part of the clinical trial application.
Regulatory Agency Identifying Number(s): US IND #109501
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
I confirm agreement to conduct the study in compliance with the protocol.
I acknowledge that I am responsible for overall study conduct. I agree to personally conduct or supervise the described clinical study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of the study are informed about their obligations. Mechanisms are in place to ensure that site staff receives the appropriate information throughout the study.
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature Date
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TABLE OF CONTENTS
PAGE
LIST OF ABBREVIATIONS.............................................................................................9
1. INTRODUCTION....................................................................................................121.1. Study Rationale ..........................................................................................121.2. Brief Background ........................................................................................12
1.2.1. GSK933776 Preclinical Data........................................................131.2.2. GSK933776 Clinical Experience ..................................................13
2. OBJECTIVE(S) AND ENDPOINT(S) ......................................................................14
3. STUDY DESIGN ....................................................................................................153.1. Study Schematic.........................................................................................153.2. Study Design Detail ....................................................................................153.3. Discussion of Study Design ........................................................................16
3.3.1. Dose Rationale ............................................................................163.4. Risk Management.......................................................................................19
4. STUDY POPULATION ...........................................................................................214.1. Number of Subjects ....................................................................................214.2. Eligibility Criteria .........................................................................................21
4.2.1. Inclusion Criteria ..........................................................................214.2.2. Exclusion Criteria.........................................................................22
4.2.2.1. Criteria Based Upon Medical Histories .......................224.2.2.2. Criteria Based Upon Diagnostic Assessments............234.2.2.3. Other Criteria..............................................................23
4.3. Lifestyle and/or Dietary Restrictions............................................................244.3.1. Contraception Requirements .......................................................24
4.3.1.1. Male Subjects.............................................................244.3.2. Meals and Dietary Restrictions ....................................................244.3.3. Caffeine, Alcohol, and Tobacco ...................................................244.3.4. Activity .........................................................................................244.3.5. Other Restrictions ........................................................................24
4.4. Screen and Baseline Failures .....................................................................244.5. Withdrawal Criteria and Procedures............................................................25
4.5.1. Subject Withdrawal Procedures ...................................................254.5.2. Treatment After the End of the Study...........................................25
4.6. Subject Completion.....................................................................................25
5. STUDY TREATMENT ............................................................................................265.1. Investigational Product and Other Study Treatment....................................265.2. Treatment Assignment................................................................................275.3. Planned Dose Adjustments.........................................................................275.4. Subject Specific Dose Adjustment/Stopping Criteria ...................................27
5.4.1. Liver Chemistry Stopping Criteria ................................................275.4.2. QTc Withdrawal Criteria...............................................................285.4.3. Other Dose Adjustment/Stopping Safety Criteria .........................28
5.4.3.1. Allergic Reaction ........................................................285.5. Masking ......................................................................................................28
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5.6. Packaging and Labelling.............................................................................285.7. Preparation/Handling/Storage/Accountability ..............................................295.8. Assessment of Compliance ........................................................................295.9. Treatment of Study Treatment Overdose....................................................295.10. Treatment After the End of the Study..........................................................305.11. Concomitant Medications and Non-Drug Therapies....................................30
5.11.1. Permitted Medications: ................................................................305.11.2. Prohibited Medications and Non-Drug Therapies.........................305.11.3. Non-Drug Therapies ....................................................................30
6. STUDY ASSESSMENTS AND PROCEDURES .....................................................316.1. Time and Events Table ...............................................................................32
6.1.1. Time and Events Table for Treatment Arms A (200 mg IV infusion), B (200 mg SQ injection), D (200 mg IM injection) .........32
6.2. Demographic/Medical History Assessments ...............................................366.3. Safety .........................................................................................................36
6.3.1. Physical Exams ...........................................................................366.3.2. Vital Signs....................................................................................366.3.3. Electrocardiogram (ECG).............................................................366.3.4. Clinical Laboratory Assessments .................................................37
6.4. Pharmacokinetics .......................................................................................396.4.1. Blood Sample Collection..............................................................396.4.2. Sample Analysis ..........................................................................39
6.5. Biomarker(s)/Pharmacodynamic Markers ...................................................406.5.1. Confirmed Biomarkers/Pharmacodynamic Markers .....................40
6.6. Immunogenicity...........................................................................................40
7. ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, AND PREGNANCY ..........417.1. Adverse Events (AE) and Serious Adverse Events (SAEs).........................41
7.1.1. Time period for collecting AE and SAE information......................417.1.2. Method of Detecting AEs and SAEs.............................................417.1.3. Definition of Adverse Events........................................................417.1.4. Definition of Serious Adverse Events ...........................................427.1.5. Prompt Reporting of SAEs to GSK...............................................447.1.6. Regulatory Reporting Requirements for SAEs .............................44
7.2. Pregnancy ..................................................................................................447.2.1. Time period for collecting pregnancy information .........................447.2.2. Action to be taken if pregnancy occurs ........................................447.2.3. Action to be taken if pregnancy occurs in a female partner
of a male study subject ................................................................45
8. DATA MANAGEMENT ...........................................................................................46
9. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................................469.1. Hypotheses and Treatment Comparisons...................................................469.2. Sample Size Considerations.......................................................................46
9.2.1. Sample Size Assumptions ...........................................................469.2.2. Sample Size Sensitivity................................................................479.2.3. Sample Size Re-estimation..........................................................47
9.3. Data Analysis Considerations .....................................................................479.3.1. Interim Analysis ...........................................................................479.3.2. Final Analyses .............................................................................47
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9.3.2.1. Safety Analyses..........................................................479.3.2.2. Pharmacokinetic Analyses..........................................489.3.2.3. Pharmacokinetic/Pharmacodynamic Analyses ...........489.3.2.4. Pharmacodynamic/Biomarker Analyses .....................48
10. STUDY GOVERNANCE CONSIDERATIONS........................................................4910.1. Posting of Information on Publicly Available Clinical Trial Registers............4910.2. Regulatory and Ethical Considerations, Including the Informed
Consent Process ........................................................................................4910.3. Quality Control (Study Monitoring) ..............................................................4910.4. Quality Assurance.......................................................................................5010.5. Study and Site Closure ...............................................................................5010.6. Records Retention ......................................................................................5010.7. Provision of Study Results to Investigators, Posting of Information
on Publically Available Clinical Trials Registers and Publication .................51
11. REFERENCES.......................................................................................................52
12. APPENDICES ........................................................................................................5312.1. Appendix 1: Liver Safety Process ...............................................................5312.2. Appendix 2: Drug Preparation....................................................................5712.3. Appendix 3: STUDY TREATMENT INFORMATION ...................................5912.4. Appendix 4: Assessment of Injection Site Reaction Terms .........................6112.5. Appendix 5: Procedures for Detection, Evaluation, Follow-Up and
Reporting of Adverse Events Recording of AEs and SAEs .........................62
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LIST OF ABBREVIATIONS
Aβ Amyloid betaAD Alzheimer’s diseaseADCC Antibody-dependent cellular cytotoxicityAE Adverse eventALT Alanine aminotransferase (SGPT)AMD Age-related macular degenerationANOVA Analysis of varianceARIA Amyloid related imaging abnormalitiesAPTT/INR activated partial thromboplastin time /international normalized ratioARIA-E ARIA-edema/effusionsARIA-H ARIA-hemosiderin depositsAST Aspartate aminotransferase (SGOT)AUC Area under concentration-time curveAUC(0-inf) Area under the concentration-time curve from time zero (pre-dose)
extrapolated to infinite timeAUC(0-t) Area under the concentration-time curve from time zero (pre-dose) to
last time of quantifiable concentration
AUC(0-) Area under the concentration-time curve over the dosing interval
BUN Blood urea nitrogenCDC Complement-dependent cytotoxicityCL Systemic clearance of parent drugCmax Maximum observed concentration Ct Last observed quantifiable concentrationCO2 Carbon dioxideCPK Creatine phosphokinaseCPMS Clinical Pharmacology Modelling & SimulationCP-RAP Clinical Pharmacology Reporting and Analysis PlanCPSSO Clinical Pharmacology Science and Study OperationsCRF Case Report FormCSF Cerebrospinal FluidCV Coefficient of variationCVA Cerebrovascular accidentECG ElectrocardiogramECL ElectrochemiluminescentF Absolute bioavailability of drug FDA Food and Drug AdministrationFSH Follicle Stimulating HormoneGA Geographic atrophyGCP Good Clinical PracticeGCSP Global Clinical Safety and PharmacovigilenceGGT Gamma glutamyltransferaseGLP Good Laboratory PracticeGSK GlaxoSmithKlineHBsAg Hepatitis B surface antigen
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HIV Human immunodeficiency virush/hr Hour(s)IB Investigator’s BrochureICH International Conference on Harmonisation IDSL Integrated Data Standards LibraryIEC International Ethics CommitteeIM IntramuscularINR International Normalized RatioIP Investigational productIRB Institutional Review BoardIUD Intrauterine deviceIUS Intrauterine systemIV IntravenousKg Kilogram
z Terminal phase rate constant
L Literlbs PoundsLDH Lactate dehydrogenaseLFTs Liver function testsmAb Monoclonal antibodymg MilligrammL MillilitermmHg Millimeters of mercuryMRI Magnetic Resonance ImagingMSDS Material Safety Data Sheetmsec MillisecondsNONMEM Nonlinear mixed effects modelling programPD PharmacodynamicPK PharmacokineticPoC Proof of conceptQTcB QT duration corrected for heart rate by Bazett’s formulaQTcF QT duration corrected for heart rate by Fridericia’s formulaRBC Red blood cellsSAE Serious adverse event(s)SGOT Serum glutamic-oxaloacetic transaminaseSGPT Serum glutamic pyruvic transaminaseSOP Standard Operating ProcedureSPM Study Procedures ManualSQ SubcutaneousT½ Terminal phase half-lifeτ Dosing intervalTmax Time of occurrence of CmaxULN Upper limit of normalVE Vasogenic edemaWBC White blood cells
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Trademark Information
Trademarks of the GlaxoSmithKline group of companies
Trademarks not owned by the GlaxoSmithKline group of companies
NONE WinNonlin
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1. INTRODUCTION
1.1. Study Rationale
The route of administration in clinical studies of GSK933776 to date has been intravenous (IV) infusion; this includes two completed clinical studies evaluating GSK933776 in subjects with AD, and an ongoing Phase II study in patients with GA. It may be beneficial to have an alternate route of administration as a treatment option, allowing greater flexibility for physicians, patients and caregivers. The present study is intended to enable a possible transition to IM or SQ administration for subsequent studies with GSK933776 by characterizing the safety, tolerability, pharmacokinetic and pharmacodynamic profiles, and immunogenicity of GSK933776 following IM and SQ administration in healthy volunteers. Such alternate routes of administration may provide more options in the selection of an efficacious dose for subsequent development in patients with geographic atrophy.
Although previous studies have been conducted in older patient populations, this study will be conducted in healthy adult volunteers, between ages 18-50. The total dose of 200mg selected for this study equates approximately to the 3 mg/kg regimen administered by intravenous infusion. Since patients have received treatment over 3 months or longer with the 3 mg/kg IV regimen, the accrued safety profile of GSK933776 in these populations, suggest that the administration of GSK933776 as a single dose of 200mg or four repeat doses of 50mg will be well tolerated. Appropriate monitoring is defined in this protocol to insure subject safety.
1.2. Brief Background
GSK933776 is a humanised, Fc-disabled IgG1 monoclonal antibody (mAb) directed against the N-terminal amino acid residues 1-5 of amyloid beta (A). GSK933776 is currently being evaluated as a potential treatment for geographic atrophy (GA) secondary to age-related macular degeneration (AMD); it has also previously been studied in patients with Alzheimer’s disease (AD).
To date, all studies with GSK933776 have administered the dose by intravenous (IV) infusion. This study will evaluate other potential routes of administration by establishing bioavailability, pharmacokinetic (PK) and pharmacodynamic (PD) profiles, tolerability and safety assessments for GSK933776 following IM and SQ administration. An IV infusion arm is included to estimate the relative bioavailability following IM and SQ administration.
Utilizing data from previous studies in AD patients, development of a PK-PD model describing the relationship between GSK933776 concentrations and reductions in unbound serum A is ongoing. The present study will provide additional information on serum A concentrations following GSK933776 administration in healthy volunteers. This data may be used to explore the PK-PD relationship following IM and SQ administration and may provide additional data for refinement of the PK-PD model for GSK933776.
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1.2.1. GSK933776 Preclinical Data
Details of all the preclinical investigations with GSK933776 and GSK719556A (the murine parent antibody of GSK933776) can be found in the current Clinical Investigators Brochure (CIB) and any subsequent revisions [ GlaxoSmithKline Document NumberSC2009/00016/01].
1.2.2. GSK933776 Clinical Experience
Studies in Patients with Alzheimer’s Disease
Two clinical studies with GSK933776, Study BA1106006 and Study BA1113043, in subjects with AD have been completed. BA1106006 was a two-part, single-masked, placebo-controlled, ascending-dose study in subjects with mild to moderate AD. This study evaluated the safety, tolerability, pharmacokinetic and pharmacodynamic profiles, and immunogenicity following single doses (0.001, 0.01 and 0.1 mg/kg) and 3 repeat doses (0.1, 1, 3, and 6 mg/kg) of GSK933776 administered by intravenous infusion at 1-month intervals. BA1113043 was an open-label, parallel-group study in subjects with mild AD or mild cognitive impairment. The study was designed to assess the pharmacodynamic profile of GSK933776 in plasma and cerebrospinal fluid (CSF) following administration of single doses of 1, 3 and 6 mg/kg intravenously.
In these studies, 48 individuals were administered GSK933776; 19 received a single dose and 29 received multiple infusions. The safety profile of GSK933776 in patients withAD suggests that doses up to 6 mg/kg administered intravenously for up to 3 monthlyintervals have been well tolerated with no apparent significant adverse effects. The adverse events (AEs) reported were mild to moderate in nature and mostly characterised by the Investigators as not related to the study drug. No magnetic resonance imaging (MRI) findings associated with drug administration were noted; there were no reported cases of vasogenic edema. Prior studies in the literature with monoclonal antibodies of this class directed against amyloid beta included reports of vasogenic edema in as many as 10% of patients. In Study BA1106006, a dose-dependent increase in total amyloid beta (A) and a reduction of free A was observed. Similarly, in Study BA1113043, there was an observed increase in both totals A18–35 and A28–42 concentrations in plasma after the administration of GSK933776. After administration of GSK933776 1 mg/kg, 3 mg/kg and 6 mg/kg intravenously, average decreases from baseline in CSF A1–42 (0–12 h) of 22.8 pg/mL (6.2%), 43.5 pg/mL (pg/mL) (9.2%) and 60.5 pg/mL (12.5%), respectively, were observed.
These apparent dose-dependent increases in total A28–42 and A18–35 in plasma and decreases of A1–42 in CSF support the theory of the pharmacologic activity and target engagement of GSK933776 in both plasma and CSF and may be considered initial steps of the postulated ‘peripheral sink’ mechanism. Such increases would be expected if GSK933776 is forming a complex with A in plasma, which in turn results in a shift from brain to plasma as reflected in the lowered levels in CSF.
Details of the two completed clinical studies investigating the use of GSK933776 in subjects with (AD) can be found in the current Clinical Investigators Brochure and any subsequent revisions [GlaxoSmithKline Document Number SC2009/00016/01].
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Study in Patients with Geographic Atrophy
There is currently an ongoing Phase II Study, BAM114341, which is a multi-center, randomised, double-masked, placebo-controlled, parallel-group study investigating the safety, tolerability, efficacy, PK and PD of GSK933776 in adult patients with geographic atrophy due to AMD. Following an observation period of four months, the treatment regimens being evaluated are placebo, 3mg/kg, 6 mg/kg and 15 mg/kg administered by IV infusion once-monthly for a period of 18 months.
2. OBJECTIVE(S) AND ENDPOINT(S)
Objectives Endpoints
Primary
To estimate the relative bioavailability of GSK933776 following single-dose IM and SQ administration and repeat-dose SQ administration as compared to IV administration
The relative bioavailability as calculated from the ratio of AUC (0-inf) following IM injection or SQ injection to IV infusion (reference arm)
Secondary
To characterize the pharmacokinetic profile of GSK933776 following single-dose IM and SQ administration and repeat-dose SQ administration as compared to IV administration
To evaluate the safety and tolerability of GSK933776 following IV, IM and SQ administration
To further characterize the PK-PD relationship of GSK933776 based on concentrations of A as the PD marker of interest
To characterize the immunogenicity profile of GSK933776 following IV, IM and SQ administration
Pharmacokinetic parameters including area under the concentration-time curve over the dosing interval (AUC(0-)), Cmax, time of occurrence of Cmax (Tmax), terminal phase half-life (T1/2), clearance, and volume of distribution as data permit
Clinical safety data from adverse event reporting (including injection site reactions), clinical observations, vital signs, ECG, and clinical laboratory parameters
Determination of plasma concentrations of GSK933776, total Aβ and total Aβ fragments, as well as unbound concentrations of Aβ, fragments containing the epitope 1-22, as data permit
Presence of antibodies to GSK933776 in serum samples (if detected, characterization of neutralizing status), as data permit
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3. STUDY DESIGN
3.1. Study Schematic
Figure 1:
• Duration: Approximately 85 days for subjects in Treatment Arms A, B and D; approximately 106 days for subjects in Treatment Arm C
• Follow up: 84 days following last dose administration
• Sample size: Planned evaluable subjects = 24. Enrolment will account for dropouts or non-evaluable subjects via replacement
Screening 1:1:1:1
Randomization
A: Single 200 mg IV infusion of GSK933776 (n=6)
B: Single 200 mg SQ dose of GSK933776 (n=6)
C: 4 weekly 50 mg SQ doses of GSK933776 (n=6)
D: Single 200 mg IM dose of GSK933776 (n=6)
Treatment Arms
3.2. Study Design Detail
Protocol waivers or exemptions are not allowed with the exception of immediate safety concerns. Therefore, adherence to the study design requirements, including those specified in the Time and Events Table (Section 6.1) are essential and required for study conduct. Deviations to the protocol will be noted in the electronic case report form and the final study report.
This is a randomised, open label study to investigate the relative bioavailability, pharmacokinetic profile, pharmacodynamic profile, safety and tolerability, and immunogenicity profile of GSK933776 administered by IV infusion and IM and SQ routes of administration in healthy volunteers. The study will be conducted at a single clinical center. The planned number of evaluable subjects for this study is 24 with 6 subjects completing all critical assessments in each of the four treatment arms.
Having provided informed consent, subjects will undergo screening to determine whether they are eligible to participate in the study. Subjects will be assigned to 1 of 4 possible treatment arms in a 1:1:1:1 ratio as illustrated in Figure 1. Subjects will remain in the unit for at least 6 hours post-dose to assess safety and tolerability and to obtain samples
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for pharmacokinetic and pharmacodynamic determinations. Subjects receiving GSK933776 by IM and SQ administration will be monitored for injection site tolerability and immediate post-injection reactions for at least 6 hours after injection.
During the treatment period, the assessments defined in the Time and Events Table (Section 6.1) will be performed according to protocol. Subjects will be followed for approximately 84 days after dose administration (for Treatment Arm C, this 84-day period begins after the final [fourth] dose). Subjects will return for periodic visits over the approximate 84-day post dosing period in order to monitor safety, tolerability and immunogenicity and to obtain samples for pharmacokinetic and pharmacodynamic assessments.
With respect to the IV infusion, if an infusion reaction occurs, the infusion rate may be reduced or the infusion may be halted at the discretion of the Investigator and/or medical monitor, depending on the severity of signs and symptoms. If the infusion is halted, the subject will be withdrawn from the study.
For subjects in Treatment Arm C (50 mg SQ weekly for 4 weeks), the Investigator and/or medical monitor may withdraw the subject from the remainder of the study if the subject has experienced a substantial injection site reaction or other safety/tolerability issues with a prior administration of study drug.
The final visit is to occur approximately 84 days after the final dose of study medication is administered. Each subject will have this final clinic visit scheduled, and assessments will be performed based on the Time and Events schedule (Section 6.1). The total duration of subject participation from screening to follow-up for Treatment Arms A, B and D (single dose of GSK933776), will be approximately 113 days. Total duration of subject participation from screening to follow-up for Treatment Arm C (weekly SQ administration for 4 doses), will be approximately 134 days.
3.3. Discussion of Study Design
3.3.1. Dose Rationale
The total dose selected to estimate the relative bioavailability of GSK933776 for this study is 200 mg. The dose regimens in the present study were selected based on: 1) understanding that relative bioavailability will permit final decisions on the optimal route of administration, 2) safety experience with doses utilized in previous and ongoing studies in AD and GA, and 3) feasibility.
The regimens and routes of administration to be evaluated in this study are:
A: single 200 mg dose of GSK933776 administered by IV infusion (reference arm)
B: single 200 mg dose of GSK933776 administered SQ
C: 50 mg dose of GSK933776 administered SQ once weekly for 4 weeks (total dose = 200 mg)
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D: single 200 mg dose of GSK933776 administered IM
GSK933776 is being investigated in an ongoing study in patients with GA (BAM114341). For reference, the dosages in BAM114341 are 3 mg/kg, 6 mg/kg and 15 mg/kg (administered once-monthly by intravenous infusion); these regimens are approximately equal to 200 mg, 400 mg and 1005 mg, respectively, for a subject weighing 67 kg. Therefore, the 200 mg total dose selected for the present study is approximately equal to the lower dose regimen (3 mg/kg) and ~20% of the higher dose regimen (15 mg/kg) in study BAM114341. Additionally, doses of 3 mg/kg and 6 mg/kg were previously evaluated in study BA1106006 in patients with AD. The dose regimen proposed for this study is expected to be pharmacologically relevant based on available pharmacodynamic data, where dose-dependent reductions in free A plasma concentrations have been observed in the dose range of 1 to 6 mg/kg administered monthly for up to 3 consecutive months.
The GSK933776 formulation for use in the present study has a concentration of 50 mg/mL; therefore, a 200 mg dose will require 4 SQ injections of 1 mL each. Due to the number of injections that are required, a total dose higher than 200 mg SQ was not considered feasible at this time. Intramuscular injection has the potential advantage of allowing a larger volume (5.0 mL) to be injected without causing significant discomfort in patients [Nicoll and Hesby, 2002]; thus, the 200 mg dose administered by the intramuscular route will be given as one 4 mL injection either in the dorso- or ventro-gluteal region.
Rationale for the weekly administration arm
If the efficacious dose of GSK933776 for the GA indication is ultimately shown to be 3 mg/kg administered IV once-monthly, weekly SQ administration represents a viable pathway to deliver an equivalent dose while keeping injection volume reasonable. Assuming a 65% bioavailability for GSK933776, the 50 mg/mL formulation when administered SQ once weekly for 4 weeks (0.65 x 1 mL x 50 mg/mL x 4 weekly doses) would provide an approximate 130 mg IV monthly equivalent. While a weekly SQ dosing regimen would produce a lower maximum observed plasma concentration (Cmax) compared to once-monthly IV administration, the area under the plasma drug concentration versus time curve (AUC) should be approximately equivalent under the assumptions provided. Inclusion of the weekly administration arm will allow testing ofthe expectation of AUC equivalence of 200 mg SQ once-monthly as compared to 50 mg SQ once-weekly x 4 weeks. Of note, therapeutic equivalence between these two regimens (200 mg SQ once monthly vs. 50 mg SQ once weekly) would require that AUC rather than Cmax drives efficacy. Although this assumption has not been formally tested, it is a reasonable supposition given the ‘sink-hypothesis’ of potential efficacy for anti-Atherapeutics.
Therefore, the weekly administration arm is included in the present study to provide repeat-dose tolerability information, and to evaluate the PK profile of weekly SQ administration, representing a dosing frequency that may be employed in future studies if efficacious doses of GSK933776 are on the higher end of the anticipated range.
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Rationale for fixed dosing (rather than mg/kg dosing)
Weight-based (mg/kg) administration has been utilized in all previous studies of GSK933776. However, for SQ delivery, fixed dosing schemes (e.g., 200 mg) are often preferable as they enable use of prefilled, fixed-volume syringes, which are simple and could be convenient to employ in later phase clinical studies. For the present study, fixed dosing was selected based on the consideration of the number of injections required to deliver the dose.
Body weight has been shown to influence the volume of distribution and clearance of some marketed monoclonal antibodies (mAbs), but not others (Wang DD, 2009). The influence of body weight on pharmacokinetic parameters of GSK933776 has been evaluated through simulation. Using a pharmacokinetic model developed from data obtained in study BA1106006, simulations were performed with either fixed dosing or body weight-based dosing. Body weight did not significantly affect the 95th percentile of intervals of concentration-time profiles, distribution, or variability of exposure for 1000 subjects after both dosing approaches were examined (data on file at GSK).
Pharmacokinetics:
Single doses (0.001, 0.01 and 0.1 mg/kg) and 3 repeat doses (0.1, 1, 3, and 6 mg/kg) of GSK933776 were administered to patients with AD by IV infusion at 1-month intervals in study BA1106006. Plasma concentrations of GSK933776 were well characterized over the sampling duration of up to 15 weeks at IV doses of 0.1, 1, 3 and 6 mg/kg. Pharmacokinetic profiles for doses lower than 0.1 mg/kg could not be determined. In studies with other monoclonal antibodies, bioavailability for SQ or IM administration has been reported to be between 50% and 100%, of which the majority of values reported are between 60% to 75% [Lobo, 2004]. At the proposed dose of 200 mg SQ or IM, or 50 mg SQ weekly for 4 weeks, even if bioavailability equates to the lower end of the likely range (50%), plasma concentrations of GSK933776 are expected to be quantifiable with the current assay for sufficient duration to estimate absolute bioavailability.
Pharmacodynamics:
PD sampling for Aβ and related fragments (Table 1) is included in this study to enrich the existing PK-PD dataset and allow for specific PK-PD modelling of SQ administration. It is anticipated that these data could be useful for development of a general model characterizing the GSK933776 PK-PD relationship across multiple populations (AD, GA, and healthy volunteers).
It is generally accepted that the A fragment 1-42 is neurotoxic and thus may be a culprit in Alzheimer’s disease, but whether the A fragment is most relevant to geographic atrophy is not clear. Evidence in the literature is consistent with the general conclusion that the Aβ assemblies in drusen are not the ocular equivalent of A in senile plaques in the brains of patients with AD [Anderson DH, 2004; Sperling, 2011; Westlind-Danielsson, 2001]. For the present study, bound and unbound, intact and fragments of A will be measured, if feasible, given the uncertainty regarding which form or fragment of A is most relevant for GA.
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Table 1 Assays for Detection of A and Related Fragments
ASSAY DESIGNATION
CAPTURE ANTIBODY(EPITOPE RECOGNIZED)
DETECTION ANTIBODY (EPITOPE RECOGNIZED)
Ab FRAGMENTS DETETCTED
Total (28-42) 6F6 (aa28-35) 5G5 (aa35-42)All fragments containing an intact C terminus, such as Ab1-42 and Ab3-42
Total (18-35) 6F6 (aa28-35) 4G8 (aa18-22)
All fragments containing the minimal sequence aa18-35, such as Ab 1-38, ABb1-40, and Ab 1-42
Free (1-22) GSK933776 (aa1-5) 4G8 (aa18-22)
Unbound fragments containing the minimal sequence aa1-22, such as Ab1-38, Ab 1-40, and Ab 1-42
From study BA1106006 in patients with mild to moderate AD, plasma samples for total (bound and unbound) Aβ (18-35) and Aβ (28-42) were collected following administration of GSK933776. No effects on plasma A were observed following single doses of 0.001 and 0.01 mg/kg, whereas a single dose of 0.1 mg/kg and repeat doses of 0.1 to 6 mg/kg resulted in appreciable reductions in free A concentrations in plasma. Compared to baseline, total Aβ (18-35) plasma concentrations increased approximately 5- to 30-foldand free Aβ (1-22) decreased between 40% to 90% depending on dose levels.
Circulating A and related fragments are present in subjects without AD at concentrations similar to those in subjects with AD; consequently, the doses utilized in this study are expected to result in quantifiable decreases in free A and increases in total (i.e., bound by drug) A. These data will be used to characterize the PD response in the PK-PD model.
3.4. Risk Management
Table 2 Summary of Key Issues, Their Impact and Strategy to Mitigate Risk
Potential risk Summary of data Impact-eligibility criteria
Strategy-monitoring/stopping criteria
Acute allergic reaction or potential for antibody-mediated toxicity with GSK933776
As with all antibodies, there is a risk of acute allergic reactions occurring. In contrast to antibodies with an active Fc region, amino acid substitutions in the Fc region of GSK933776 substantially reduce complement fixation and Fc receptor binding, which are responsible for immune/cell-mediated tissue damage related to complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). Therefore, the potential for antibody-mediated toxicity with GSK933776
Exclusion criteria have been incorporated to ensure the selection of subjects who are not at increased risk for such events.
All subjects will also be monitored for evidence of infusion reactions or acute allergic reactions following administration.
Subjects that have signs and symptoms of an infusion or injection based reactions will be monitored and will be withdrawn and treated
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is anticipated to be more limited as compared to IgG1 mAbs with native Fc regions.
by standard of care
GSK933776 will have a low potential for immunogenicity
This assumption is supported by data from the completed studies with IV administration in patients with AD. In the initial study, none of the 12 subjects who received a single dose developed antibodies to GSK933776. With repeat administration, two of 24 subjects developed anti-GSK933776 antibodies after receiving 2 doses of the study drug. In study BA1113043, one of 18 patients developed neutralising antibodies of low titre on day 56
None Serum samples are taken and will be tested for anti-drug antibodies
All subjects will be monitored for any evidence of an immunogenicity response.
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4. STUDY POPULATION
4.1. Number of Subjects
A sufficient number of subjects will be enrolled so that approximately 24 evaluable subjects complete this study; six subjects are targeted to complete all critical assessmentsfor each of the treatment arms.
If subjects prematurely discontinue the study, additional subjects may be enrolled as replacement subjects at the discretion of the Sponsor in consultation with the Investigatorif recruitment goals are not met.
4.2. Eligibility Criteria
Specific information regarding warnings, precautions, contraindications, adverse events, and other pertinent information on the GSK investigational product or other study treatment that may impact subject eligibility is provided in the IB.
Deviations from inclusion and exclusion criteria are not allowed because they can potentially jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
4.2.1. Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria apply:
1. Male or female subject 18 – 50 years of age at the time of signing the informed consent
2. In general good health as determined by a physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the Investigator and the GSK Medical Monitor agree that the condition is unlikely to introduce additional risk factors and will not interfere with the study procedures
3. Body weight ≥ 55 kg (121 lbs) and ≤ 85 kg [187 lbs (pounds)] with a body mass index (BMI) between 18.5 and 29 (inclusively) where
BMI = (weight in kg)(height in meters)2
at the time of signing the informed consent
4. A female subject is eligible to participate if she is of:
Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea in questionable cases a blood sample with simultaneous
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follicle stimulating hormone (FSH) > 40 MIU/mL and estradiol < 40 pg/mL (<140 pmol/L) is confirmatory
5. Male subjects must agree to use one form of acceptable contraception methods listed in this protocol (Section 4.3.1.1) if their partner is of childbearing potential. This criterion must be followed from the time of the screening visit through the follow up visit (84 days after last dose of study medication)
6. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
4.2.2. Exclusion Criteria
Deviations from exclusion criteria are not allowed because they can potentially jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
A subject will not be eligible for inclusion in this study if any of the following criteria apply:
4.2.2.1. Criteria Based Upon Medical Histories
1. Known risk history of:
a. Central nervous system (CNS) disorders:
i. History and/or evidence (CT or MRI scan performed within the past 12 months) of cerebral haemorrhage OR a known risk of cerebral haemorrhage, including uncontrolled hypertension, cerebrovascular malformation, coagulopathy, CNS vasculitis, degenerative or inflammatory/demyelinating CNS conditions or any other condition that the Investigator and/or the medical monitor considers as a relevant risk factor for cerebral haemorrhage
ii. Transient ischemic attack (TIA)/cerebrovascular accident (CVA) in the last year, or other uncontrolled risk factors for stroke
b. History of seizures (except febrile seizures in childhood) or recent unprovoked seizure
c. Uncontrolled type 2 diabetes mellitus (HbA1C >10%), active cardiovascular disease (e.g., moderate-severe angina, unstable angina, myocardial infarction (MI) within the last 2 years, symptomatic congestive heart failure, clinically significant arrhythmia)
d. Current blood clotting or bleeding disorder or conditions that predispose to these (e.g. cancer)
e. Diagnosis of currently active, or, in remission but chronic relapsing, systemic autoimmune disease or condition (e.g. multiple sclerosis, lupus erythematosus etc) that the Investigator and/or the medical monitor considers as a relevant risk factor for concomitant administration of a therapeutic monoclonal antibody
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2. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
3. Use of prescription drugs or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John’s Wort) within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety
4. A positive pre-study drug/alcohol screen. Current or recent drug or alcohol abuse or dependence. History of regular alcohol consumption within 6 months of the study defined as: An average weekly intake of >14 units for males or >7 units for females. One drink is equivalent to 12 g of alcohol: 12 ounces (~360 mL) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits. Use of illegal drugs
5. History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the Investigator or GSK Medical Monitor, contraindicates their participation
4.2.2.2. Criteria Based Upon Diagnostic Assessments
6. Seated systolic blood pressure > 140 mmHg or seated diastolic blood pressure of > 90 mmHg
7. QTc > 450 millisecond (msec)
8. AST and ALT ≥ 2xULN; alkaline phosphatase and bilirubin 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)
9. Significant abnormalities on hematology screen: clinically significant anemia (i.e. hemoglobin <11 g/dL for males or <10 g/dL for females), or platelet counts below 124 GI/L; INR > 2
10. A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening
11. A positive test for HIV antibody
4.2.2.3. Other Criteria
12. Where participation in the study would result in donation of blood or blood productsin excess of 500 mL within a 56 day period
13. Exposure to more than four new chemical entities within 12 months prior to screening
14. Prior allergic reactions to biological products (vaccines, antibodies) or known hypersensitivity to any of the components of the drug formulation
15. Prior participation in clinical investigations involving therapeutic monoclonal antibodies with a similar mode of action or proteins derived from monoclonal antibodies with any risk of cross- reactivity or any investigations of treatments or use
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of any other investigational medication or device within 2 months prior to screening or within 5 half-lives of use of such a medication prior to screening, whichever is longer.
4.3. Lifestyle and/or Dietary Restrictions
4.3.1. Contraception Requirements
4.3.1.1. Male Subjects
Male subjects with female partners of child-bearing potential must use one of the following contraceptive methods after the first dose of study treatment and until the follow-up visit, 84 days after the last dose of investigational product.
Condom (during non-vaginal intercourse with any partner - male or female) OR
Condom and occlusive cap (diaphragm or cervical/vault caps) plus spermicidal agent (foam/gel/film/cream/suppository) (during sexual intercourse with a female)
Abstinence, defined as sexual inactivity consistent with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
4.3.2. Meals and Dietary Restrictions
4.3.3. Caffeine, Alcohol, and Tobacco
During each dosing session, subjects will abstain from alcohol for 24 hours prior to the start of dosing until collection of the final pharmacokinetic and or pharmacodynamic sample during each session. An alcohol test will be given as outlined on the T&E table in Section 6.1
4.3.4. Activity
Subjects will abstain from strenuous exercise for 48 hours prior to each blood collection for clinical laboratory tests. Subjects may participate in light recreational activities during studies.
4.3.5. Other Restrictions
Subjects must refrain from all recreational drugs throughout the study (screening to follow-up). Drugs of abuse tests may be performed randomly throughout the study at the Investigator’s discretion. A positive result at any point will lead to exclusion from the study
4.4. Screen and Baseline Failures
Data for screen and baseline failures will be collected in source documentation at the site but will not be transmitted to GSK in the study defined data capture system
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4.5. Withdrawal Criteria and Procedures
A subject may withdraw from study treatment at any time at his/her own request, or may be withdrawn at any time at the discretion of the Investigator for safety, behavioural or administrative reasons.
Should a subject fail to attend the clinic for a required study visit, the site should attempt to contact the subject and re-schedule the missed visit as soon as possible. The site should also counsel the subject on the importance of maintaining the assigned visit schedule and ascertain whether or not the subject wishes to and/or should continue in the study based on previous non-compliance. In cases where the subject does not return for the rescheduled visit or cannot be reached to reschedule the missed visit, the site should make every effort to regain contact with the subject (3 telephone calls and if necessary a certified letter to the subject’s last known mailing address) so that they can appropriately be withdrawn from the study.
These contact attempts should be documented in the subject’s medical record. Should the subject continue to be unreachable, then and only then will he/she be considered to have withdrawn from the study with a primary reason of “Lost to Follow-up”. For all other subjects withdrawing from the study, an alternative reason for discontinuation should be recorded in the eCRF.
Refer to Section 5.3 for planned dose adjustment/stopping criteria and Section 5.4 for subject specific dose adaptation/stopping criteria including Liver Chemistry and QTc.
Liver Chemistry threshold stopping criteria have been designed to assure subject safety and to evaluate liver event etiology (in alignment with the FDA premarketing clinical liver safety guidance). See Section 5.4.1 for details.
4.5.1. Subject Withdrawal Procedures
A subject who is withdrawn from study medication and participation in this clinical study will complete the assessments specified in the Time and Events table (Section 6.1) for the final follow up visit. Information obtained will be included in assessments of safety and effects following withdrawal from treatment.
Before discontinuing a subject from the study, the Investigator should be in contact with the GSK Medical Monitor to discuss the specific situation. In the event that the Investigator is unable to reach the GSK medical monitor, the Investigator will make a decision at his or her discretion, until the GSK medical monitor can be informed.
4.5.2. Treatment After the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the study because only healthy volunteers are eligible for study participation.
4.6. Subject Completion
A completed subject is one who has completed all phases of the study including the follow-up visit. Subjects who are screened, but are not eligible will be considered “screen failures.”
The end of the study is defined as the last subject’s last visit.
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5. STUDY TREATMENT
5.1. Investigational Product and Other Study Treatment
PRODUCT NAME:
GSK933776 (SQ ADMINISTRATION)
GSK933776 (IM ADMINISTRATION)
GSK933776 (IV ADMINISTRATION)
Formulation description:
Antibody solution Antibody solution Antibody solution
Dosage form: Solution for injection Solution for injection Solution for infusion
Unit dose strength(s)/Dosage level(s):
50 mg/mL (1 mL nominal volume) in a 3 mL glass vial
50 mg/mL (1 mL nominal volume) in a 3 mL glass vial
50 mg/mL (1 mL nominal volume) in a 3 mL glass vial
Route/Duration: Route: SubcutaneousDuration(Single Dose): 200 mg Duration(Repeat Dose): 50 mg weekly for 4 weeks
Route: IntramuscularDuration(Single Dose): 200 mg
Route: Intravenous Duration (Single Dose): 200 mg
Dosing instructions:
The dose will be administered through a sterile disposable syringe in the subcutaneous space.Acceptable injection site is either the abdomen or the upper thigh. Injection site is to be documented and should be rotated. Detailed instructions are included in Appendix 3.
The dose will be administered in the dorsal or ventrogluteal site (in order to achieve a 200mg dose, a 4 mL injection of the 50mg/mL product are needed). Detailed instructions are included in Appendix 3.
The dose will be administered through an IV catheter over approximately 1 hour
Method for individualizing dosage:
GSK933776 will be drawn into a sterile disposable syringe. Study drug will then be administered through a sterile needle (27GA).
GSK933776 will be drawn into a sterile disposable syringe. Study drug will then be administered through a sterile needle (23GA).
GSK933776 will be prepared in 0.9% Sodium Chloride in infusion bags. Study drug will then be administered using an IV delivery pump and a catheter.
Please see the Time & Events Table (Section 6.1) for further detail on administration and study day assessments. Further information about the administration of investigational product can be found in Appendix 2, and ordering of drug supplies can be found in the Study Procedures Manual (SPM).
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5.2. Treatment Assignment
Subjects will be assigned to 1 of 4 possible treatment arms in a 1:1:1:1 ratio in accordance with the randomisation schedule generated using RandAll, a web-based clinical trials system, by QSci, Clinical Statistics Department at GlaxoSmithKline (GSK).
A description of each potential study regimen is provided below:
TREATMENT ARM DESCRIPTIONA 200 mg GSK933776 administered by IV infusionB 200 mg GSK933776 administered by SQ injection C 50 mg GSK933776, administered by SQ injection once weekly for 4 weeks D 200 mg GSK933776 administered by IM injection
5.3. Planned Dose Adjustments
This protocol does not allow for alteration from the currently outlined doses for each cohort. The maximum total dose will not exceed 200 mg in any subject or cohort.
5.4. Subject Specific Dose Adjustment/Stopping Criteria
A subject may discontinue treatment and withdraw from the study at any time at his/her own request or may be withdrawn at any time for safety or administrative reasons at the discretion of the Investigator. Additional criteria for withdrawal are provided below.
5.4.1. Liver Chemistry Stopping Criteria
Liver chemistry threshold stopping criteria have been designed to assure subject safety and to evaluate liver event etiology (in alignment with the FDA premarketing clinical liver safety guidance).
Study treatment will be stopped for a subject if any of the following liver chemistry stopping criteria is met:
1. ALT 3xULN and bilirubin 2xULN (or ALT 3xULN and INR1 > 1.5) NOTE: serum bilirubin fractionation should be performed if testing is available. If fractionation is unavailable, urinary bilirubin is to be measured via dipstick (a measurement of direct bilirubin, which would suggest liver injury)
2. ALT 5xULN
3. ALT 3xULN if associated with symptoms (new or worsening) believed to be related to hepatitis (such as fatigue, nausea, vomiting, right upper quadrant pain or
1 INR testing not required per protocol and the threshold value does not apply to subjects receiving anticoagulants
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tenderness or jaundice) or believed to be related to hypersensitivity (such as fever, rash or eosinophilia)
4. ALT 3xULN persists for 4 weeks
5. ALT 3xULN and cannot be monitored weekly for 4 weeks
Subjects with ALT 3xULN and < 5xULN and bilirubin < 2xULN, who do not exhibit hepatitis symptoms or rash, can continue study treatment as long as they can be monitored weekly for 4 weeks.
NOTE: Refer to Appendix 1, for details of the required assessments if a subject meets any of the above criteria.
5.4.2. QTc Withdrawal Criteria
A subject that meets either criterion below will be withdrawn from the study. The same QT correction formula (e.g QTcB, QTcF) should be used to determine inclusion and discontinuation for any individual subject throughout the study.
[QTcB or QTcF] > 500 msec,
Change from baseline: QTc >60 msec
Withdrawal of subjects is to be based on an average QTc value of triplicate ECGs. If an ECG demonstrates a prolonged QT interval, then obtain 2 more ECGs over a brief period of time and then use the averaged QTc values of the 3 ECGs to determine whether the subject should be discontinued from the study.
5.4.3. Other Dose Adjustment/Stopping Safety Criteria
5.4.3.1. Allergic Reaction
Although humanisation of the GSK933776 antibody is expected to reduce the risk of acute allergic reactions, all subjects will be monitored carefully for evidence of acute allergic reactions and infusion reactions (for those subjects participation in the IV arm). It is important to recognise early signs of anaphylaxis or anaphylactic reactions and to prevent progression to severe anaphylaxis.
If an anaphylactic reaction should occur, study medication should be stopped immediately, where possible, and the subject should not be re-challenged. Subjects should be followed up as specified in Section 4.5.1, Subject Withdrawal Procedures.
5.5. Masking
This will be an open-label study.
5.6. Packaging and Labelling
The contents of the label will be in accordance with all applicable regulatory requirements.
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5.7. Preparation/Handling/Storage/Accountability
A description of the methods and materials required for preparation of the GSK933776 IV, IM and SQ solution is provided in Appendix 2.
Investigational product must be dispensed or administered according to procedures described herein. Only subjects enrolled in the study may receive investigational product. Only authorised site staff may supply or administer investigational product. All investigational products must be stored in a secure area with access limited to pharmacy staff or designee. Investigational product is to be stored at 2-8C and protected from light. Maintenance of a temperature log is required.
The study pharmacist or designee is responsible for investigational product accountability, reconciliation, and record maintenance. The pharmacist staff or designee must maintain investigational product accountability records throughout the course of the study. The responsible person(s) will document the amount of investigational product received from GSK and the amount supplied and administered. The required accountability unit for this study will be individual vials. Discrepancies are to be reconciled or resolved. Procedures for final disposition of unused investigational product are listed in the SPM.
Investigational product is not expected to pose significant occupational safety risk to site staff under normal conditions of use and administration. Take adequate precautions to avoid direct eye or skin contact and the generation of aerosols or mists. In the case of unintentional occupational exposure notify the monitor, medical monitor and/or study manager. A Material Safety Data Sheet (MSDS)/equivalent document describing occupational hazards and recommended handling precautions either will be provided to the Investigator, where this is required by local laws, or is available upon request from GSK.
5.8. Assessment of Compliance
When the individual dose for a subject is prepared from a bulk supply, the preparation of the dose will be confirmed by a second member of the study site staff.
When subjects are dosed at the study site, they will receive study treatment directly from the Investigator or designee, under medical supervision. The date and time of each dose administered in the clinic will be recorded in the source documents. The dose of study treatment and study participant identification will be confirmed at the time of dosing by a member of the study site staff other than the person administering the study treatment.
5.9. Treatment of Study Treatment Overdose
For this study, any dose of GSK933776 > 200mg within a 24 hour time period +/- 1 hour will be considered an overdose.
GSK does not recommend specific treatment for an overdose. The Investigator will use clinical judgment to treat any overdose.
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5.10. Treatment After the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the study because only healthy volunteers are eligible for study participation.
5.11. Concomitant Medications and Non-Drug Therapies
5.11.1. Permitted Medications:
Acetaminophen, at doses of 2 grams/day is permitted for use any time during the study. Other concomitant medication may be considered on a case by case basis by the GSK Medical Monitor.
5.11.2. Prohibited Medications and Non-Drug Therapies
Subjects must abstain from taking prescription or non-prescription drugs (including vitamins and dietary or herbal supplements), within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication until completion of the follow-up visit, unless in the opinion of the Investigator and Sponsor the medication will not interfere with the study.
5.11.3. Non-Drug Therapies
Subjects must abstain from taking any vitamins, herbal and dietary supplements within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication until completion of the follow-up visit, unless in the opinion of the Investigator and Sponsor the medication will not interfere with the study.
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6. STUDY ASSESSMENTS AND PROCEDURES
This section lists the procedures and parameters of each planned study assessment. The exact timing of each assessment is listed in the Time and Events Table Section 6.1. Whenever vital signs, 12-lead ECGs and blood draws are scheduled for the same nominal time, the assessments should occur in the following order: 12-lead ECG, vital signs, blood draws. The timing of the assessments should allow the blood draw to occur at the exact nominal time.
Protocol waivers or exemptions are not allowed with the exception of immediate safety concerns. Therefore, adherence to the study design requirements, including those specified in the Time and Events Table, are essential and required for study conduct.
The timing and number of planned study assessments, including safety, pharmacokinetic, and pharmacodynamic, and immunogenicity assessments may be altered during the course of the study based on newly available data (e.g. to obtain data closer to the time of peak plasma concentrations) to ensure appropriate monitoring. The change in timing or addition of time points for any planned study assessments must be approved and documented by GSK in a note to file and archived in the study sponsor and site study files, but this will not constitute a protocol amendment. The Institutional review Board (IRB)/International Ethics Committee (IEC) will be informed of any safety issues that require alteration of the safety monitoring scheme. No more than 500 mL of blood will be collected over the duration of the study, including any extra assessments that may be required.
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6.1. Time and Events Table
6.1.1. Time and Events Table for Treatment Arms A (200 mg IV infusion), B (200 mg SQ injection), D (200 mg IM injection)
Day Screena
Day 1Day
2Day
3Day
4Day
5Day
6Day 10
Day 15
Day 22
Day 29
Day 57
Follow Up Day 85d
AssessmentsPre-dose
0h0.25
h0.5h
0.75h
1h 2h 4h 6h 24h 48h 72h 96h 120h 216h 336h 504h 672h 1344h 2016h
Informed Consent XDemographics X
Physical Examination X X X XMedical history (inc. family cardiovascular history) XConcomitant Medications X X X X X XDose XAE/SAE Review ----------------------------------------------------------------------------------X------------------------------------------------------------------12-lead ECG X XVital Signs X X X X X X X X X X X X XUrine Drug/Alcoholc X Xc
Follicle stimulating hormone (FSH)/estradiol if indicated XHepatitis B, Hepatitis C, HIV (human immunodeficiency virus) X
Hematology, Chemistry, Urinalysis X X X X X X XHbA1c XPK Blood Sample X Xb Xb Xb Xb X Xb X X X X X X X X X X X XPD Blood Sample X Xb Xb Xb X X X X X X X XImmunogenicity Blood Sample X X X Xa. Subjects should be screened a minimum of 7 days, but no more than 30 days, prior to Day 1 b. Samples drawn only for subjects in Arm A (IV infusion).c. Alcohol breathalyzer test may be given instead of urine test post screening visitd. The follow up visit may occur +/- 3 days
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Time and Events Tables for Treatment Arm C (50 mg SQ injection)
Screening through Week 1
Day Screena Day 1 Day 2 Day 3 Day 4 Day 5 Day 6
Assessments Pre-dose 0h 0.5h 1h 2h 4h 6h 24h 48 h 72h 96h 120hInformed Consent XDemographics XPhysical Examination X XMedical history (includingfamily cardiovascular history)
X
Concomitant Medications X XDose XAE/SAE Review ------------------------------------------------------------------------------X----------------------------------------------------------------------------12-lead ECG XVital Signs X X X X X X X X XUrine Drug/Alcoholb
X Xb
Hepatitis B, Hepatitis C, HIV XHematology, Chemistry, Urinalysis X X XFSH, estradiol (if indicated) XHbA1c XPK Blood Sample X X X X X X XPD Blood Sample X X X X XImmunogenicity Blood Sample Xa. Subjects should be screened a minimum of 7 days, but no more than 30 days, prior to Day 1b. Alcohol breathalyzer test may be given instead of urine test post screening visit
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Treatment Arm C (50 mg SQ injection) – Weeks 2 and 3
Day Day 8/15 Day 9/16
Day 10/17
Day 11/18
Day 12/19
Day 13/2
0Assessments Predose 0h 0.5h 1h 2h 4h 6h 24h 48h 72h 96h 120hConcomitant Medications XDose XAE/SAE Review ------------------------------------------------------------------------------------------X--------------------------------------------------------------------------Vital Signs X X X X X X XUrine Drug/Alcohol (breathalyzer) XHematology, Chemistry, Urinalysis XPK Blood Sample X X X X X X X
PD Blood SampleX X X X X
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Treatment Arm C (50 mg SQ injection) – Week 4 through Final Follow Up
Day Day 22Day23
Day 24
Day 25
Day 26
Day 27
Day 31
Day 36
Day 43
Day 50
Day 78
Follow Up
Day 106a
Assessments
Pre-dos
e 0h 0.5h 1h 2h 4h 6h 24h 48h 72h 96h 120h 216h 336h 504h 672h 1344h 2016hPhysical Examination XConcomitant Medications X X X X XDose XAE/SAE Review ---------------------------------------------------------------------------------------------X-----------------------------------------------------------------------------------------------12-lead ECG XVital Signs X X X X X X X X X X X XUrine Drug/Alcohol (breathalyzer) XHematology, Chemistry, Urinalysis X X X X XPK Blood Sample X X X X X X X X X X X X XPD Blood Sample X X X X X X X X X XImmunogenicity Blood Sample X X X X Xa. Follow up may occur +/- 3 days
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6.2. Demographic/Medical History Assessments
The following demographic parameters will be captured: year of birth, gender, race and ethnicity.
Medical/medication/alcohol history will be assessed as related to the eligibility criteria listed in Section 4.2.
6.3. Safety
Planned time points for all safety assessments are listed in the Time and Events Table (Section 6.1). Additional time points for safety tests such as vital signs, physical exams and laboratory safety tests may be added during the course of the study based on newly available data to ensure appropriate safety monitoring.
6.3.1. Physical Exams
A complete physical examination will include assessments of the head, eyes, ears, nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and spleen), lymph nodes and extremities. Height (at screening only) and weight will also be measured and recorded.
6.3.2. Vital Signs
Vital sign measurements will include systolic and diastolic blood pressure and pulse rate. Blood pressure, body temperature and pulse rate measurements will be recorded in the seated position at the times indicated in the Time and Events Table (Section 6.1)
Vital sign measurements to be measured in seated/ semi-supine position after 5 minutes rest will include systolic and diastolic blood pressure and pulse rate and respiratory rate.
When a vital sign measurement is scheduled at the same nominal time as a PK sample draw, the vital sign measurement should be completed first
Repeat or unscheduled measurements may be taken at the discretion of the Investigator
6.3.3. Electrocardiogram (ECG)
If the screening ECG is abnormal e.g. QTc>450, 2 additional ECGs are taken within 10 minutes and the QTc of the 3 ECGs are averaged. If the average is within the normal range, the patient can be entered into the study. If the average is abnormal, they are excluded. This same principle applies to discontinuation criteria.
12-lead ECGs will be obtained at each time point during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals
All ECGs will be recorded after at least 10 minutes rest in a supine position. Where possible, hot or cold drinks and food should be avoided 30 minutes before an ECG
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measurement. Where possible, the same machine should be used at an individual site for all assessments on an individual subject throughout the study
If a measurement deviates substantially from previous readings and the operator can see no technical reason for the deviation the measurement must be repeated immediately by obtaining triplicate readings in the same sitting then averaged. Refer to Section 5.4.2 for QTc withdrawal criteria and additional QTc readings that may be necessary
6.3.4. Clinical Laboratory Assessments
Hematology, clinical chemistry, urinalysis and additional parameters to be tested are listed below. Details for the preparation and shipment of samples will be provided by the local laboratory. Reference ranges for all safety parameters will be provided to the site by the laboratory.
If additional non-protocol specified laboratory assessments are performed at the site’s local laboratory and result in a change in subject management or are considered clinical significant by the Investigator (for example SAE or AE or dose modification) the results must be captured and sent to GSK along with other study data as defined in Appendix 5.
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HematologyPlatelet Count Red Blood Cell
(RBC) Indices:Automated White Blood Cell (WBC) Differential:
RBC Count MCV NeutrophilsWBC Count (absolute) MCH LymphocytesReticulocyte Count MCHC MonocytesHemoglobin EosinophilsHematocrit BasophilsAPTT/INR (activated partial thromboplastin time/ international normalized ratio)
Clinical ChemistryBUN (blood urea nitrogen)
Potassium AST (SGOT) (Aspartate aminotransferase ) (Serum glutamic-oxaloacetic transaminase)
Total and direct bilirubin
Creatinine Chloride ALT (SGPT) (serum glutamic pyruvic transminase)
Uric Acid
Glucose, fasting Total CO2
(carbon dioxide)
Gamma glutamyltransferase (GGT)
Albumin
Sodium Calcium Alkaline phosphatase Total Protein
NOTE: Details of Liver Chemistry Stopping Criteria and Follow-Up Procedures are given in Section 5.4.1.
Routine Urinalysis
Specific gravity
pH, glucose, protein, blood and ketones by dipstickMicroscopic examination (if blood or protein is abnormal)
Other screening testsHIVHepatitis B (HBsAg) Hepatitis B surface antigenHepatitis C (Hep C antibody -- if second generation Hepatitis C antibody positive, PCR will be performed on the same sample to confirm the result)
FSH and estradiol (as needed in women of non-child bearing potential only)Alcohol and drug screen (to include at minimum: amphetamines, barbiturates, cocaine, opiates, cannabinoids and benzodiazepines).
Monitoring of Allergic Reactions
Although humanisation of the GSK933776 antibody is known to reduce the risk of acute allergic reactions, all subjects will be monitored carefully for evidence of infusion,
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injection and other allergic reactions. Subjects will remain in the clinic for observation for at least 6 hours after dosing. It is important to recognise early signs of anaphylaxis or anaphylactic reactions and to prevent progression to severe anaphylaxis.
During dosing, subjects will be closely monitored for early signs of dyspnoea and oedema and dosing will be stopped if clinically indicated. If an infusion and/or injection reaction occurs during administration, the infusion rate may be reduced or halted at the discretion of the Investigator and/or medical monitor, depending on severity of signs and symptoms.
A study physician that is certified in Advanced Cardiac Life Support (ACLS) or local equivalent should be available to be at the clinic within 10 minutes for the time period post-dose.
If more severe clinical signs are noted, then the physician should assess the subject. Assessment of the ABC's (airway, breathing, and circulation from Basic Life Support) will be done in all suspected anaphylactic reactions.
6.4. Pharmacokinetics
6.4.1. Blood Sample Collection
Blood samples for pharmacokinetic analysis of GSK933776 will be collected at the time points indicated in Section 6.1, Time and Events Table. The actual date and time of each blood sample collection will be recorded. The timing of PK samples may be altered and/or PK samples may be obtained at additional time points to ensure thorough PK monitoring.
Blood samples for pharmacokinetic assessment of GSK933776 will be taken from all subjects in this study according to the Time and Events Schedule of the protocol. All blood samples should be taken from the opposite arm to that of drug infusion. Approximately 2mL of whole blood will be collected into 2mL EDTA tubes (lavender cap) and placed on ice. Approximately 1 ml plasma will be collected into storage tube. The storage tubes and labels for the PK samples will be provided by GSK. Specimen labels will include study number, subject number, sample identification number, nominal time and date.
6.4.2. Sample Analysis
Plasma analysis will be performed under the management of Bioanalytical Science and Toxicokinetics, DMPK, GlaxoSmithKline. Concentrations of GSK933776 will be determined in plasma using the currently approved analytical methodology. Raw data will be stored in the good laboratory practice (GLP) Archives, GlaxoSmithKline. The processing procedures, storage and shipping details are described in the SPM.
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6.5. Biomarker(s)/Pharmacodynamic Markers
6.5.1. Confirmed Biomarkers/Pharmacodynamic Markers
The total and free levels of beta amyloid fragments will be measured in plasma for each subject. Free A (1–22), total A (18–35), and total A (28-42) will be evaluated using immuno-electrochemiluminescent (ECL) assays.
Blood samples will be taken from all subjects in this study according to the Time and Events Schedule, Section 6.1 of the protocol.
Approximately 4mL of whole blood will be collected for free and total A assays. Blood will be collected into 4ml EDTA tubes (polypropylene tubes containing EDTA K2 gel, lavender cap) and the tubes placed on ice immediately. Once collected, the blood samples must be processed within 30 minutes. The processing procedures, storage and shipping details are described in the SPM.
6.6. Immunogenicity
Blood samples for determination of anti-GSK933776 antibodies will be taken from all subjects in this study as a safety measurement for GSK933776 at the time-points specified in the Time and Events Table in Section 6.1. Timing of the assessments may be adjusted based on emerging data.
Samples will be analysed for the presence of anti-GSK933776 antibodies by immuno-electrochemiluminescent (ECL) screening and neutralisation assays. If sera contain anti-GSK933776 antibodies as determined by the ECL screening assay, they will be further analysed for specificity, titres of antibodies and the presence of neutralising antibodies. The immunogenicity assessment report will include the incidence and titres of anti-GSK933776 binding and neutralising antibodies.
Approximately 3mL of whole blood will be collected into serum-separator tubes. All blood samples will be maintained at ambient temperature for at least 1 hour, but no more than 4 hours. If clotting stimulator is added, samples should be held no more than 1 hour. This allows for complete clotting prior to centrifugation. Sample processing, storage and shipping procedures are provided in the SPM.
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7. ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, AND PREGNANCY
7.1. Adverse Events (AE) and Serious Adverse Events (SAEs)
The Investigator or site staff is responsible for detecting, documenting and reporting events that meet the definition of an AE or SAE.
7.1.1. Time period for collecting AE and SAE information
AEs will be collected from the start of Study Treatment and until the follow-up contact. Medical occurrences that begin prior to the start of study treatment but after obtaining informed consent may be recorded on the Medical History/Current Medical Conditions CRF.
SAEs will be collected over the same time period as stated above for AEs. However, any SAEs assessed as related to study participation (e.g., protocol-mandated procedures, invasive tests, or change in existing therapy) or related to a GSK product will be recorded from the time a subject consents to participate in the study up to and including any follow-up contact. All SAEs will be recorded and reported to GSK within 24 hours, as indicated in Appendix 5.
Investigators are not obligated to actively seek AEs or SAEs in former study participants. However, if the Investigator learns of any SAE, including a death, at any time after a subject has been discharged from the study, and he/she considers the event reasonably related to the study treatment or study participation, the Investigator would promptly notify GSK.
NOTE: The method of, recording, evaluating and follow-up of AEs and SAEs plus procedures for completing and transmitting SAE reports to GSK are provided inAppendix 5.
7.1.2. Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-leading verbal questioning of the subject is the preferred method to inquire about AE occurrence. Appropriate questions include:
“How are you feeling?”
“Have you had any (other) medical problems since your last visit/contact?”
“Have you taken any new medicines, other than those provided in this study, since your last visit/contact?”
7.1.3. Definition of Adverse Events
An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
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NOTE: An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product.
Events meeting the definition of an AE include:
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety assessments (e.g., ECGs, radiological scans, vital signs measurements), including those that worsen from baseline, and felt to be clinically significant in the medical and scientific judgement of the Investigator.
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and/or intensity of the condition.
New conditions detected or diagnosed after study treatment administration even though it may have been present prior to the start of the study.
Signs, symptoms, or the clinical sequelae of a suspected interaction.
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment or a concomitant medication (overdose per se will not be reported as an AE/SAE unless this is an intentional overdose taken with possible suicidal/self-harming intent. This should be reported regardless of sequelae.).
Events that do not meet the definition of an AE include:
Any clinically significant abnormal laboratory findings or other abnormal safety assessments that are associated with the underlying disease, unless judged by the Investigator to be more severe than expected for the subject’s condition.
The disease/disorder being studied or expected progression, signs, or symptoms of the disease/disorder being studied, unless more severe than expected for the subject’s condition.
Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads to the procedure is an AE.
Situations where an untoward medical occurrence did not occur (social and/or convenience admission to a hospital).
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the study that do not worsen.
7.1.4. Definition of Serious Adverse Events
If an event is not an AE per Section 7.1.3, then it cannot be an SAE even if serious conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to progression of disease, etc).
An SAE is any untoward medical occurrence that, at any dose:
a. Results in death
b. Is life-threatening
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NOTE: The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject was at risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it were more severe.
c. Requires hospitalization or prolongation of existing hospitalization
NOTE: In general, hospitalization signifies that the subject has been detained (usually involving at least an overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in the physician’s office or out-patient setting. Complications that occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not considered an AE.
d. Results in disability/incapacity, or
NOTE: The term disability means a substantial disruption of a person’s ability to conduct normal life functions. This definition is not intended to include experiences of relatively minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhoea, influenza, and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday life functions but do not constitute a substantial disruption.
e. Is a congenital anomaly/birth defect
f. Medical or scientific judgment should be exercised in deciding whether reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the subject or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. These should also be considered serious. Examples of such events are invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or development of drug dependency or drug abuse.
g. Is associated with liver injury and impaired liver function defined as:
ALT 3xULN and total bilirubin* 2xULN (>35% direct), or
ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, measure urinary bilirubin via dipstick. If fractionation is unavailable and ALT 3xULN and total bilirubin 2xULN, then the event is still to be reportedas an SAE.
** INR testing not required per protocol and the threshold value does not apply to subjects receiving anticoagulants. If INR measurement is obtained, the value is to be recorded on the SAE form.
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7.1.5. Prompt Reporting of SAEs to GSK
Once the Investigator determines that an event meets the protocol definition of an SAE, the SAE will be reported to GSK within 24 hours. Any follow-up information on a previously reported SAE will also be reported to GSK within 24 hours.
If the Investigator does not have all information regarding an SAE, he/she will not wait to receive additional information before notifying GSK of the event and completing the appropriate data collection tool. The Investigator will always provide an assessment of causality at the time of the initial report as described in Appendix 5.
7.1.6. Regulatory Reporting Requirements for SAEs
Prompt notification of SAEs by the Investigator to GSK is essential so that legal obligations and ethical responsibilities towards the safety of subjects are met.
GSK has a legal responsibility to notify both the local regulatory authority and other regulatory agencies about the safety of a product under clinical investigation. GSK will comply with country specific regulatory requirements relating to safety reporting to regulatory authorities, IRBs/IECs and Investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse reactions according to local regulatory requirements and GSK policy and are forwarded to Investigators as necessary. An Investigator who receives an Investigator safety report describing an SAE(s) or other specific safety information (e.g., summary or listing of SAEs) from GSK will file it with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.2. Pregnancy
7.2.1. Time period for collecting pregnancy information
All pregnancies in female subjects and/or female partners of male subjects will be collected after the start of dosing and until 84 days after the last dose per protocol.
7.2.2. Action to be taken if pregnancy occurs
The Investigator will collect pregnancy information on any female subject, who becomes pregnant while participating in this study. The Investigator will record pregnancy information on the appropriate form and submit it to GSK within 2 weeks of learning of a subject's pregnancy. The subject will also be followed to determine the outcome of the pregnancy. Information on the status of the mother and child will be forwarded to GSK. Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. Any premature termination of the pregnancy will be reported.
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or elective termination of a pregnancy for medical reasons will be recorded as an AE or SAE.
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A spontaneous abortion is always considered to be an SAE and will be reported as such. Furthermore, any SAE occurring as a result of a post-study pregnancy and is considered reasonably related to the study treatment by the investigator, will be reported to GSK as described in Section 7.1.6. While the Investigator is not obligated to actively seek this information in former study participants, he or she may learn of an SAE through spontaneous reporting.
Any female subject who becomes pregnant while participating will be withdrawn from the study.
7.2.3. Action to be taken if pregnancy occurs in a female partner of a male study subject
The Investigator will attempt to collect pregnancy information on any female partner of a male study subject who becomes pregnant while participating in this study. This applies only to subjects who are randomized to receive study medication. After obtaining the necessary written informed consent from the female partner directly, the Investigator will record pregnancy information on the appropriate form and submit it to GSK within 2 weeks of learning of the partner’s pregnancy. The partner will also be followed to determine the outcome of the pregnancy. Information on the status of the mother and child will be forwarded to GSK. Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. Any premature termination of the pregnancy will be reported.
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8. DATA MANAGEMENT
GSK Data Management will identify and implement the most effective data acquisition and management strategy for each clinical trial protocol and deliver datasets, which support the protocol objectives. Subject data will be entered into GSK defined CRFs and combined with data provided from other sources (e.g. diary data, laboratory data) in a validated data system. Subject initials will not be transmitted to GSK for inclusion in the datasets. CRF’s should be completed for all subjects that receive at least one dose of study drug. CRF’s will not be completed for screen or baseline failures. Clinical data management will be performed in accordance with applicable GSK standards and data cleaning procedures with the objective of removing errors and inconsistencies in the data, which would otherwise impact on the analysis and reporting objectives, or the credibility of the Clinical Study Report. Adverse events and concomitant medications terms will be coded using validated dictionaries.
9. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
This study is designed to estimate the relative bioavailability of GSK933776, given as either a single 200 mg SQ dose (Treatment Arm B), four weekly 50 mg SQ doses (Treatment Arm C) or a single 200 mg IM dose (Treatment Arm D), relative to a single 200 mg IV infusion (Treatment Arm A).
No formal hypothesis will be tested. For each primary pharmacokinetic endpoint, point estimates and corresponding 90% confidence intervals will be constructed for the ratio of the geometric means of B:A, C:A, and D:A.
9.1. Hypotheses and Treatment Comparisons
This study is designed to estimate the bioavailability of GSK933776 administered by subcutaneous or intramuscular injection relative to GSK933776 administered intravenously. No formal hypothesis will be tested. For each primary pharmacokinetic endpoint, point estimates and corresponding 90% confidence intervals will be constructed for the ratio of the geometric mean of the test treatment to the geometric mean of the reference treatment, (subcutaneous GSK933776)/( intravenous GSK933776) and (intramuscular GSK933776)/( intravenous GSK933776).
9.2. Sample Size Considerations
9.2.1. Sample Size Assumptions
The sample size for this study is based on feasibility and the intention to collect safety and tolerability data from at least 6 subjects in each treatment arm of GSK933776. To assure that acceptable precision of PK parameters is expected with the sample size proposed, calculations have been performed based on variability estimates from previous studies with IV administration of GSK933776. From study BA11006006, the between-subject variability (CVb) of AUC (0-t) and Cmax of 3 mg/kg dose of GSK933776 was estimated to be between 12.7% and 16.0%. Assuming a CV of 16% and a sample size of 6 subjects per arm, the estimated precision of 90% confidence interval (i.e. half-width) is expected to be no more than 20% of the point estimate. That is for a point estimate of 0.75, the 90% confidence interval would be 0.60 to 0.94.
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9.2.2. Sample Size Sensitivity
From study BA11006006, the between-subject variability (CVb) of AUC (0-t) and Cmax of 1 mg/kg dose of GSK933776 was estimated to be between 24.5% and 38.7%. Additionally, the between-subject variability of either a SQ or IM administration may be greater than that of IV administration. The table below provides estimated precision for a range of variability from 16% to 38.7%. Assuming a CV of 38.7% and a sample size of 6 subjects per arm, the estimate precision of the 90% confidence interval is expected to be approximately 31% of the point estimates.
CVHalf-width of 90% CI
16.0% 20%
21.7% 23%
27.4% 26%
33.0% 29%
38.7% 31%
9.2.3. Sample Size Re-estimation
No sample size re-estimation is currently planned for this study. However, if during the course of the study, new information becomes available about clinically meaningful differences or variability estimates, a blinded sample size re-estimation may be conducted. Full details of the procedure used would be specified in the RAP, and any subsequent change to the target sample size would be documented in a protocol amendment.
9.3. Data Analysis Considerations
9.3.1. Interim Analysis
No interim analyses are planned
9.3.2. Final Analyses
9.3.2.1. Safety Analyses
Safety data will be presented in tabular and/or graphical format and summarized descriptively according to GSK’s Integrated Data Standards Library (IDSL) standards.
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9.3.2.2. Pharmacokinetic Analyses
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacology Modeling & Simulation department within GlaxoSmithKline. Plasma concentration-time data will be analyzed by non-compartmental methods with WinNonlin, as well as compartmental methods with NONMEM (nonlinear mixed effects modeling program). Calculations will be based on the actual sampling times recorded during the study. From the plasma concentration-time data, the following pharmacokinetic parameters will be determined, as data permit: maximum observed plasma concentration (Cmax), time to Cmax (Tmax), area under the plasma concentration-time curve [AUC(0-t) and AUC(0-∞)], apparent terminal phase half-life (t1/2), systemic clearance of parent drug (CL for IV), apparent clearance (CL/F for SQ and IM), volume of distribution (V for IV) and apparent volume of distribution (V/F for SQ and IM). To estimate the extent of accumulation after repeat dosing in Arm C, the observed accumulation ratio (Ro) may be determined.
Pharmacokinetic data will be presented in graphical and/or tabular form and will be summarized descriptively. All pharmacokinetic data will be stored in the Archives, GlaxoSmithKline Pharmaceuticals, R&D.
Statistical analyses of the pharmacokinetic parameter data will be the responsibility of Discovery Biometrics GlaxoSmithKline.
Following loge-transformation, AUC (0-t) and Cmax of GSK933776 will be separately analyzed using an analysis of variance model (ANOVA) with fixed effect terms for Regimen. Point estimates and their associated 90% confidence intervals will be constructed for the differences, B – A, C – A and D - A. The point estimates and their associated 90% confidence intervals will then be back-transformed to provide point estimates and 90% confidence intervals for the ratios, B:A, C:A and D:A.
Tmax of GSK933776 will be separately analyzed with the non-parametric Wilcoxon rank-sum test to compute point estimates and associated 90% confidence intervals for the median differences, B – A, C - A and D - A.
9.3.2.3. Pharmacokinetic/Pharmacodynamic Analyses
The relationship between plasma concentration of GSK933776 and plasma concentration of total and free amyloid beta will be explored as data permit. If an apparent concentration-effect relationship exists, a population PK/PD model will be attempted using nonlinear mixed effect modelling technique with NONMEM software. Data from the present study may also be combined with previous PK/PD data from studies in patients with AD (BA1106006 and BA1113043) and the ongoing study in patients with GA (BAM114341) to develop a general model of GSK933776 PK-PD following IV, SQ, and IM administration in patients and volunteers.
9.3.2.4. Pharmacodynamic/Biomarker Analyses
Primary and secondary pharmacodynamic/biomarker endpoints (including immunogenicity) will be presented in graphical and/or tabular form, summarized descriptively and listed as data permit.
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10. STUDY GOVERNANCE CONSIDERATIONS
10.1. Posting of Information on Publicly Available Clinical Trial Registers
Study information from this protocol will be posted on publicly available clinical trial registers before enrollment of subjects begins.
10.2. Regulatory and Ethical Considerations, Including the Informed Consent Process
The study will be conducted in accordance with all applicable regulatory requirements.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), all applicable subject privacy requirements, and, the guiding principles of the 2008Declaration of Helsinki. This includes, but is not limited to, the following:
IRB/IEC review and favorable opinion/approval to conduct the study and of any subsequent relevant amended documents
Written informed consent (and any amendments) to be obtained for each subject before participation in the study
Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations to IRB/IEC)
Written informed consent must be obtained from each subject prior to participation in the study.
10.3. Quality Control (Study Monitoring)
In accordance with applicable regulations including GCP, and GSK procedures, GSK monitors will contact the site prior to the start of the study to review with the site staff the protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and GSK requirements. When reviewing data collection procedures, the discussion will also include identification, agreement and documentation of data items for which the CRFwill serve as the source document.
GSK will monitor the study and site activity to verify that the:
Data are authentic, accurate, and complete.
Safety and rights of subjects are being protected.
Study is conducted in accordance with the currently approved protocol and any other study agreements, GCP, and all applicable regulatory requirements.
The Investigator and the head of the medical institution (where applicable) agrees to allow the monitor direct access to all relevant documents
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10.4. Quality Assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK may conduct a quality assurance assessment and/or audit of the site records, and the regulatory agencies may conduct a regulatory inspection at any time during or after completion of the study. In the event of an assessment, audit or inspection, the Investigator (and institution) must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all relevant documents and to allocate their time and the time of their staff to discuss the conduct of the study, any findings/relevant issues and to implement any corrective and/or preventative actions to address any findings/issues identified.
10.5. Study and Site Closure
Upon completion or premature discontinuation of the study, the monitor will conduct site closure activities with the Investigator or site staff, as appropriate, in accordance with applicable regulations including GCP, and GSK procedures.
In addition, GSK reserves the right to temporarily suspend or prematurely discontinue this study at any time for reasons including, but not limited to, safety or ethical issues or severe non-compliance. For multicenter studies, this can occur at one or more or at all sites. If GSK determines such action is needed, GSK will discuss this with theInvestigator or the head of the medical institution (where applicable), including the reasons for taking such action. When feasible, GSK will provide advance notification to the investigator or the head of the medical institution, where applicable, of the impending action prior to it taking effect.
If the study is suspended or prematurely discontinued for safety reasons, GSK willpromptly inform Investigators or the head of the medical institution (where applicable) and the regulatory authorities of the suspension or premature discontinuation of the study and the reason(s) for the action. If required by applicable regulations, the Investigator or the head of the medical institution (where applicable) must inform the IRB/IEC promptly and provide the reason for the suspension or premature discontinuation.
10.6. Records Retention
Following closure of the study, the Investigator or the head of the medical institution (where applicable) must maintain all site study records, except for those required by local regulations to be maintained by someone else, in a safe and secure location. The records must be maintained to allow easy and timely retrieval, when needed (e.g., audit or inspection), and, whenever feasible, to allow any subsequent review of data in conjunction with assessment of the facility, supporting systems, and staff. Where permitted by local laws/regulations or institutional policy, some or all of these records can be maintained in a format other than hard copy (e.g., microfiche, scanned, electronic); however, caution needs to be exercised before such action is taken. The Investigator must assure that all reproductions are legible and are a true and accurate copy of the original and meet accessibility and retrieval standards, including re-generating a hard copy, if required. Furthermore, the Investigator must ensure there is an
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acceptable back-up of these reproductions and that an acceptable quality control process exists for making these reproductions.
GSK will inform the Investigator of the time period for retaining these records to comply with all applicable regulatory requirements. The minimum retention time will meet the strictest standard applicable to that site for the study, as dictated by any institutional requirements or local laws or regulations, or GSK standards/procedures; otherwise, the retention period will default to 15 years.
The Investigator must notify GSK of any changes in the archival arrangements, including, but not limited to, archival at an off-site facility or transfer of ownership of the records in the event the Investigator leaves the site.
10.7. Provision of Study Results to Investigators, Posting of Information on Publically Available Clinical Trials Registers and Publication
Where required by applicable regulatory requirements, an Investigator signatory will be identified for the approval of the clinical study report. The Investigator will be provided reasonable access to statistical tables, figures, and relevant reports and will have the opportunity to review the complete study results at a GSK site or other mutually-agreeable location.
GSK will also provide the Investigator with the full summary of the study results. The investigator is encouraged to share the summary results with the study subjects, as appropriate.
The results summary will be posted to the Clinical Study Register no later than eight months after the final primary completion date, the date that the final subject was examined or received an intervention for the purposes of final collection of data for the primary outcome. In addition, a manuscript will be submitted to a peer reviewed journal for publication no later than 18 months after the last subject’s last visit (LSLV). When manuscript publication in a peer reviewed journal is not feasible, a statement will be added to the register to explain the reason for not publishing.
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11. REFERENCES
Anderson DH, Talaga KC, Rivest AJ, Barron E, Hageman GS, Johnson LV. Characterization of beta amyloid assemblies in drusen: the deposits associated with aging and age-related macular degeneration. Exp Eye Res. Feb 2004;78(2):243-256.
GlaxoSmithKline Document Number SC2009/00016/01. GSK933776 Investigator's Brochure (Version 03, Supplement 1). Effective Date: 23 Feb 2011.
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
Lobo ED, Hansen RJ, Balthasar JP. Antibody pharmacokinetics and pharmacodynamics. J Pharm Sci. Nov 2004;93(11):2645-2668
Nicoll Leslie H. Hesby, Amy. Intramuscular Injection: An Integrative Research Review and Guideline for Evidence-Based Practice. Applied Nursing Research, Vol. 16, No. 2 (August), 2002: pp 149-162.
Sperling RA. Jack CR, Black SE, Frosch MP, Greenberg SM, Hyman BT, Scheltens P, Carrillo MC, Thies W, Bednar MM, Black RS, Brashear HR, Brundman M, Siemers ER, Feldman HH, Schindler, RJ.. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimer’s & Dementia. 2011; 7: 367-385.
Wang DD, Zhang S, Zhao H, Men AY, Parivar K. Fixed dosing versus body size-based dosing of monoclonal antibodies in adult clinical trials. J Clin Pharmacol. 2009;49(9):1012-1024.
Westlind-Danielsson, A, Arnerup, G. Spontaneous in vitro formation of supramolecular beta-amyloid structures, “Betaamy balls”, by beta amyloid 1-40 peptide. Biochemistry 2001 Dec 11; 40(49): 14736-43.
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12. APPENDICES
12.1. Appendix 1: Liver Safety Process
Scenario 2 Phase II Studies
The procedures listed below are to be followed if a subject meets any of the liver chemistry stopping criteria defined in Section 5.4.1
Immediately withdraw the subject from study treatment
Notify the GSK medical monitor within 24 hours of learning of the abnormality to confirm the subject’s study treatment cessation and follow-up.
Complete the “Safety Follow-Up Procedures” listed below.
Complete the liver event case report forms. If the event also meets the criteria of an SAE (see Section 7.1.4), the SAE data collection tool will be completed separately with the relevant details.
Upon completion of the safety follow-up withdraw the subject from the study unless further safety follow up is required.
Do not re-challenge with study treatment
Safety Follow-Up Procedures for subjects with ALT 3xULN and bilirubin 2xULN (>35% direct); or ALT 3xULN and INR2 > 1.5 [Stopping Criteria #1]:
This event is considered an SAE (see Section 7.1.4). Serum bilirubin fractionation should be performed if testing is available. If fractionation is unavailable, urinary bilirubin is to be measured via dipstick (a measurement of direct bilirubin, which would suggest liver injury).
Make every reasonable attempt to have the subjects return to the clinic (within 24 hours) for repeat liver chemistries, additional testing and to be monitored closely (with specialist or hepatology consultation recommended).
Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) resolve, stabilize or return to within baseline values.
Safety Follow-Up Procedures for subjects with ALT 5xULN or ALT 3xULN who have hepatitis symptoms or rash, can’t be monitored for 4 weeks or have elevations that persist 4 weeks [Stopping Criteria #2 - #5]:
Make every reasonable attempt to have the subject return to the clinic within 24-72 hrs for repeat liver chemistries and additional testing.
2 INR testing not required per protocol and the threshold value does not apply to subjects receiving anticoagulants.
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Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) resolve, stabilize or return to within baseline values.
Safety Follow-Up Procedures for subjects with ALT 3xULN and < 5xULN and bilirubin < 2xULN, who do not exhibit hepatitis symptoms or rash:
Notify the GSK medical monitor within 24 hours of learning of the abnormality to discuss subject safety.
Subject can continue study treatment if liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) can be monitored weekly for up to 4 weeks.
If at any point these subjects meet the liver chemistry stopping criteria (outlined in Section 5.4.1), immediately withdraw study treatment, perform additional testing and continue safety follow-up until liver chemistries resolve, stabilize or return to baseline values.
After 4 weeks of monitoring, if ALT < 3xULN and bilirubin < 2xULN, subjects must be monitored twice monthly until liver chemistries normalize or return to within baseline values.
Additional Follow-Up Procedures for subjects who meet any of the stopping criteria:
Viral hepatitis serology including:
Hepatitis A IgM antibody;
Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM);
Hepatitis C RNA;
Cytomegalovirus IgM antibody;
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody or monospot testing);
Hepatitis E IgM antibody.
Blood sample for pharmacokinetic (PK) analysis, obtained within 72 hours of last dose. Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best approximation. If the date/time of the last dose can not be approximated OR a PK sample can not be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are included in the SPM.
Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).
Fractionate bilirubin, if total bilirubin 2xULN.
Assess eosinophilia
Record the appearance or worsening of clinical symptoms of hepatitis (fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or eosinophilia) as relevant on the AE CRF
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Record use of concomitant medications, acetaminophen, herbal remedies, other over the counter medications, or putative hepatotoxins on the Concomitant Medications CRF.
Record alcohol use on the Liver Events CRF.
The following are required for subjects with ALT 3xULN and bilirubin 2xULN (>35% direct) but are optional for other abnormal liver chemistries:
Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver kidney microsomal antibodies and quantitative total immunoglobulin G (IgG or gamma globulins).
Serum acetaminophen adduct HPLC assay (quantifies potential acetaminophen contribution to liver injury in subjects with definite or likely acetaminophen use in the preceding week [James, 2009]).
Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to evaluate liver disease.
The Liver Imaging and/or Liver Biopsy CRFs are also to be completed if these tests are performed.
Refer to the diagram below for a visual presentation of the procedures listed above
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ALT≥3xULN ?
Bilirubin ≥ 2xULN
(or INR > 1.5 if measured)* ?
No
No
Yes
Yes
Continue investigational product (IP)
Instruct subject to stop IP Notify GSK within 24 hrs Obtain weekly liver chemistries until resolved, stabilized or returned
to baseline values Perform liver event follow up assessments (serology, PK sample, etc
as in protocol) Complete liver event CRF Withdraw subject from study after liver chemistry monitoring
complete + do not re-challenge with IP
Instruct subject to stop IP Notify GSK and arrange clinical followup within 24 hrs Perform liver event follow up assessments (serology, PK sample etc
as in protocol) Report as SAE (excl. hepatic impairment or cirrhosis studies);
complete SAE & liver event CRF + liver imaging and biopsy CRFs (if these tests are performed)
Obtain twice weekly liver chemistries until resolved, stabilized or returned to baseline values
Consultation with hepatologist/specialist recommended Withdraw subject from study after liver chemistry monitoring
complete + do not re-challenge with IP*INR threshold does not apply to subjects receiving anticoagulants.
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12.2. Appendix 2: Drug Preparation
Investigational Product (IP) Infusion:
o IP will be dosed at 120 mL/hour until IV bag is empty
o All intravenous rates and infusion times will be documented in the subject’s source documents for review by the GSK monitor.
o The time of dosing (start of the infusion) will be designated time “0”, and all subsequent time points will be in relation to this time point. Notation of the completion of the infusion as well as the completion of the normal sterile saline for ‘flushing’ the IV pump tubing and filter will also be documented in the subject’s source documents.
Flush IV Tubing
o At the end of the infusion (after approximately 50 minutes when the bag is empty) a new 50 (or 100) mL normal sterile saline bag will be hung to flush the IV tubing and filter of remaining IP. The IV pump will again be set to deliver this new volume of normal sterile saline solution at 120 mL/hour until 10 minutes have transpired (20 mL) to ensure all IP has been administered and the IV tubing and filter have been properly flushed.
Supplies:
IV Infusion Arm
1-empty 100 mL bag (IV bag must be constructed of PVC material as sourced by site personnel)
1-50 or 100 mL IV bag for ‘flushing’ IV pump tubing once IP administration is complete
Syringe(s) and needle(s) as necessary
Intravenous infusion pump
Filter: Low binding polyether sulfone in-line 0.2 micron filter is required. There are two requirements of a filter for use in the infusion:
o The filter pore size is 0.2 micron is required
o The filter membrane material is composed of Polyether Sulfone (PES).
The brand name and order number for the 0.2 micron filter are to be recorded and kept in the site study file for future reference
It is recommended that the site continue to use the same IV infusion pump and hence tubing as well as 0.2 micron filter throughout the study
Any changes to these materials should be noted and recorded in the site’s source documents
SC or IM Arm
Syringe and needle
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Investigational Product Preparation and Administration (IV)
Remove 4 vials of GSK933776 from the temperature monitored/controlled refrigerator
Withdraw 96 mL of normal saline from a normal saline source (IV bag) and inject into a sterile empty 100 mL PVC-constructed IV bag
Withdraw the contents 4 investigation product vials (total of 4 mL of drug) and inject into the IV bag containing 96 mL of normal saline such that the total volume to be delivered is 100 mL
Make sure contents are thoroughly mixed to ensure a uniform concentration by inverting IV bag gently a few times
Store the labeled bag in the pharmacy fridge at 2-8 C and protect from light prior to dosing. Do not freeze. Note: once diluted, the investigational product is stable for 12 hours including the time required for dosing
The total volume of fluid that will be infused over 1 hour will be 100 mL at a rate of 120 mL/hour
The time of dosing (start of the infusion) will be designated time “0”, and all subsequent time points will be in relation to this time point
Administer IP using an IV pump and an administration set fitted with a 0.2 micron filter
o In-line filter to be placed closest to the patient
o In the event of filter clogging, stop IP dosing, replace the filter and resume dosing. THE ENTIRE IP DOSE MUST BE DELIVERED THROUGH THE FILTER
Dose IP at 120 mL/hour until bag is empty
All intravenous rates and infusion times will be documented in the subject’s source documents for review by the GSK monitor
At the end of the infusion (after approximately 50 minutes when the bag is empty) a new 50 (or 100) mL normal sterile saline bag will be hung and the infusion will resume at 120 mL/hour until the IV infusion pump tubing and filter is properly ‘flushed’
Investigational Product Preparation and Administration (SC and IM)
Remove the appropriate number of vials of GSK933776 from the temperature monitored/controlled refrigerator (e.g. for 200 mg SC dose, remove 4 vials and for 50 mg SC dose, remove 1 vial from cold storage)
Withdraw the entire contents of the vial(s) into a syringe fitted with a needle suitable for either SC or IM administration
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12.3. Appendix 3: STUDY TREATMENT INFORMATION
IP dosing instructions
This procedure follows the SOP PI_WI_DP001 Revision 16 from Quintiles.
General Procedures:
Injections shall be performed by Research Nurse 1 OR 2 staff members who are properly trained in injection administration, unless otherwise directed by the protocol
Don proper PPE (gloves)
Palpate site area for tenderness and mass. Do not use areas where scarring, bruising, abrasions, or inflammation are visible
Use a protocol approved needle
Per each protocol directive, prepare back-up injections in case of injection inside a blood vessel
Clean the area of the injection with a protocol approved cleansing agent
Intramuscular Injection:
IM injections should be performed at the dorso or ventrogluteal sites. A description of the procedures follows:
Dorsogluteal- this is the classic site for IM injections. Care must be taken not to damage the major blood vessels, the greater trochanter, and the sciatic nerve. Damage to this nerve can cause partial to complete paralysis of the affected leg. To locate this site, have the subject lie on his/her abdomen or on his/her side with hip and knee flexed. Palpate the top of the iliac crest. This site should NEVER be used while the subject is standing
Ventrogluteal- this site involves the gluteus medius and the gluteus minimus muscle. To locate this site, the subject receiving the injection may lie on his abdomen, side, or supine. Place the palm of one’s hand over the greater trochanter, using the right hand for the subject’s right side and the left hand for the subject’s left side. Point the thumb toward the index finger over the anterior superior iliac crest, and pull the middle finger back along the crest toward the buttocks. The top of the crest and the index middle fingers form a triangle. The center of the triangle is the injection site
Hold the syringe between the thumb and forefinger of the dominant hand, with palm down and needle bevel up
Using the thumb and first two fingers of the nondominant hand, press the tissue down firmly around the injection site, while using caution not to contaminate the injection area. Compression of the subcutaneous tissue helps ensure the needle
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has entered muscle. Moving the tissue downward assists in dispersing the medication and to seal the needle track when the tissue returns to normal position
Add an air bolus of .2-.3cc to the medication in the syringe to ensure themedication remains in the muscle
Quickly thrust the needle into the tissue at a 90 degree angle at the site
As soon as the needle is in place, use the nondominant hand to hold the syringe barrel and slowly pull back on the plunger to determine if the needle rests inside a blood vessel. If blood is observed, pull the needle back slightly and aspirate again. Muscle tissue is vascular
If blood is not present inside the syringe, inject the medication slowly, followed by the air bubble into the needle. The air pocket will force the medication through the shaft of the needle into the muscle tissue and prevent the medication from entering the subcutaneous tissue as the needle is withdrawn
Remove the needle quickly and cap by approved method
Rub the injection site with a cotton ball. Rubbing assists with distribution and absorption of the medication
Dispose of the needle in the closest sharps container. Return the syringe and label to the Pharmacy
Subcutaneous Injection:
Subcutaneous injections involve depositing a substance in the loose connective tissue beneath the dermis. Absorption is slow, as the tissue is not richly supplied with blood. Absorption is complete if the subject has normal circulation. Common sites for injection are the upper arm, abdomen, and thigh
Using the non-dominate hand, grasp the area around the injection site and hold in a cushion fashion, keeping the skin tight
Hold the syringe between the thumb and forefinger of the dominate hand (similar to throwing a dart) with the palm up. Ensure the bevel of the needle is upward
Quickly inject the needle at an angle approximate to 45 degrees
When the needle is inside of the tissue, release the grasped tissue
Hold the lower portion of the syringe barrel with the non-dominant hand, without moving the syringe, pull back on plunger to determine if the needle is inside a blood vessel
If blood is present, remove the needle from the subject
If no blood appears, inject medication slowly
Remove needle and recap using one hand. Dispose of the needle in the nearest sharps container unless the pharmacist requires the capped syringe returned to the pharmacy. Return the label, and other required supplies, back to the pharmacy
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12.4. Appendix 4: Assessment of Injection Site Reaction Terms
Term Description
Edema Swelling, fluid retention
AbscessA tender, easily pressed mass generally surrounded by a colored area from pink to deep red
Erythema Redness
HematomaLocalized collection of blood outside the blood vessels, usually in liquid form within the tissue
Induration Hardening
Necrosis Dark purplish discoloration
Pain Tenderness, discomfort
PapuleSolid, raised spot on the skin with no visible fluid, less than 1 centimeter wide (may be plural: papules)
Pruritus Itching
PustuleSmall, inflamed, pus-filled, blister-like lesion on the skin surface (may be plural: pustules)
RashA change of the skin which affects its color, appearance or texture
Ulceration
The formation of an ulcer, a patch of tissue that is discontinuous with the surrounding tissue because the tissue within the ulcer has decayed or died and been swept away
Vesiculation Blistering, the formation of vesicles (small fluid-filled blisters)
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12.5. Appendix 5: Procedures for Detection, Evaluation, Follow-Up and Reporting of Adverse Events Recording of AEs and SAEs
When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) relative to the event. The Investigator will then record all relevant information regarding an AE/SAE in the appropriate data collection tool.
It is not acceptable for the Investigator to send photocopies of the subject’s medical records to GSK in lieu of completion of the GSK, AE/SAE data collection tool. However, there may be instances when copies of medical records for certain cases are requested by GSK. In this instance, all subject identifiers, with the exception of the subject number, will be blinded on the copies of the medical records prior to submission of to GSK.
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or other clinical information. In such cases, the diagnosis will be documented as the AE/SAE and not the individual signs/symptoms.
Evaluating AEs and SAEs
Assessment of Intensity
The Investigator will make an assessment of intensity for each AE and SAE reported during the study and will assign it to one of the following categories:
Mild: An event that is easily tolerated by the subject, causing minimal discomfort andnot interfering with everyday activities.
Moderate: An event that is sufficiently discomforting to interfere with normal everyday activities.
Severe: An event that prevents normal everyday activities.
An AE that is assessed as severe will not be confused with an SAE. Severity is a category utilized for rating the intensity of an event; and both AEs and SAEs can be assessed as severe. An event is defined as ‘serious’ when it meets at least one of the pre-defined outcomes as described in the definition of an SAE.
Assessment of Causality
The Investigator is obligated to assess the relationship between study treatment and the occurrence of each AE/SAE. A "reasonable possibility" is meant to convey that there are facts/evidence or arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. The Investigator will use clinical judgment to determine the relationship. Alternative causes, such as natural history of the underlying diseases, concomitant therapy, other risk factors, and the temporal relationship of the event to the study treatment will be considered and investigated. The Investigator will also consult
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the Investigator Brochure (IB) and/or Product Information, for marketed products, in the determination of his/her assessment.
For each AE/SAE the investigator must document in the medical notes that he/she has reviewed the AE/SAE and has provided an assessment of causality.
There may be situations when an SAE has occurred and the Investigator has minimal information to include in the initial report to GSK. However, it is very important that the Investigator always make an assessment of causality for every event prior to the initial transmission of the SAE data to GSK. The Investigator may change his/her opinion of causality in light of follow-up information, amending the SAE data collection tool accordingly. The causality assessment is one of the criteria used when determining regulatory reporting requirements.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each subject at subsequent visits/contacts. All AEs and SAEs will be followed until resolution, until the condition stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up.
The Investigator is obligated to perform or arrange for the conduct of supplemental measurements and/or evaluations as may be indicated or as requested by GSK to elucidate as fully as possible the nature and/or causality of the AE or SAE. The Investigator is obligated to assist. This may include additional laboratory tests or Investigations, histopathological examinations or consultation with other health care professionals. If a subject dies during participation in the study or during a recognized follow-up period, the Investigator will provide GSK with a copy of any post-mortem findings, including histopathology.
New or updated information will be recorded in the originally completed data collection tool. The Investigator will submit any updated SAE data to GSK within the designated reporting time frames.
Reporting of SAEs to GSK
The primary mechanism for reporting SAEs to GSK will be the electronic data collection tool. If the electronic system is unavailable for greater than 24 hours, the site will use the paper SAE data collection tool and fax it to the GSK Medical Monitor . Then the site will enter the serious adverse event data into the electronic system as soon as it becomes available.
After the study is completed at a given site, the electronic data collection tool (e.g., InForm system) will be taken off-line to prevent the entry of new data or changes to existing data. If a site receives a report of a new SAE from a study participant or receives updated data on a previously reported SAE after the electronic data collection tool has been taken off-line, the site can report this information on a paper SAE form or to their GSK protocol contact by telephone.
GSK contacts for SAE receipt can be found at the beginning of this protocol on the Sponsor/Medical Monitor Contact Information page.
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Division: Worldwide DevelopmentRetention Category: GRS019Information Type: Clinical Pharmacology Reporting and Analysis Plan
Title: Clinical pharmacology reporting and analysis plan for arandomized, open label, parallel-group study to estimate bioavailability and to assess the pharmacokinetic profile, safety and tolerability of GSK933776 administered by subcutaneous or intramuscular injection relative to intravenous administration to healthy volunteers (BA1116891)
Compound Number: GSK933776
Effective Date: 24-JUL-2014
Description: The purpose of this reporting and analysis plan (RAP) is to describe the planned analyses and output to be included in the Clinical Pharmacology Study Report for Protocol BA1116891. This RAP is intended to describe the bioavailability, pharmacokinetics (PK), safety and tolerability analyses required for the study. This document will be provided to the study team members to convey the content of the Statistical Analysis Complete (SAC) deliverable.
Subject: GSK933776, Pharmacokinetics, bioavailability, intravenous, subcutaneous and intramuscular administration, amyloid beta, monoclonal antibody, healthy volunteers
Author’s Name, Title and Functional Area:
Clinical Statistics, PAREXEL
Copyright 2014 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited
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Approved by (approval captured by e-mail):
Technical approvers of the RAP should include at minimum (when applicable) representatives from the following function areas:
Ophthalmology
Clinical Pharmacology Modelling and Simulation
Clinical Pharmacology Science and Study Operations
Clinical Pharmacology Science and Study Operations
Clinical Pharmacology Science and Study Operations
Ophthalmology
Statistical Resourcing and Programming
Clinical Immunology
Clinical Programming, PAREXEL
Clinical PK/PD, PAREXEL
The Clinical Statistics Director (or designee) will give final approval
Manager, Clinical Statistics 24-Jul-2014
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TABLE OF CONTENTS
PAGE
LIST OF ABBREVIATIONS.............................................................................................5
1. INTRODUCTION......................................................................................................8
2. STUDY OBJECTIVES AND ENDPOINTS................................................................82.1. Study Objectives and Endpoints ...................................................................8
3. STUDY DESIGN ......................................................................................................93.1. Study Design ................................................................................................9
4. PLANNED ANALYSES ..........................................................................................104.1. Interim Analyses .........................................................................................104.2. Final Analyses ............................................................................................10
5. SAMPLE SIZE CONSIDERATIONS.......................................................................105.1. Sample Size Assumptions ..........................................................................105.2. Sample Size Sensitivity...............................................................................105.3. Sample Size Re-estimation.........................................................................11
6. ANALYSIS POPULATIONS ...................................................................................116.1. Safety Population (SAF) .............................................................................116.2. Pharmacokinetic Concentration Population.................................................116.3. Pharmacokinetic Parameter Population ......................................................116.4. Pharmacodynamic Population ....................................................................116.5. PK/PD Analysis Population.........................................................................11
7. TREATMENT COMPARISONS..............................................................................127.1. Treatment and Other Subgroup Descriptors for Data Display .....................12
8. GENERAL CONSIDERATIONS FOR DATA ANALYSES AND HANDLING ...........128.1. Reporting Conventions ...............................................................................128.2. Data Management ......................................................................................138.3. Premature Withdrawal and Missing Data ....................................................138.4. Baseline Definition ......................................................................................138.5. Derived and Transformed Data...................................................................14
8.5.1. Change from Baseline .................................................................148.5.2. Pharmacokinetic Parameters.......................................................148.5.3. Multiple Measurements at One Timepoint....................................14
8.6. Values of Potential Clinical Importance.......................................................15
9. STUDY POPULATION ...........................................................................................179.1. Subject Disposition .....................................................................................179.2. Demographic and Baseline Characteristics.................................................179.3. Concomitant Medications............................................................................179.4. Treatment Compliance and Protocol Deviations .........................................17
10. SAFETY ANALYSES .............................................................................................1710.1. Extent of Exposure .....................................................................................1810.2. Adverse Events...........................................................................................18
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10.3. Deaths and Serious Adverse Events...........................................................1810.4. Adverse Events Leading to Discontinuation of Investigational
Product and/or Withdrawal from the Study and Other Significant Adverse Events...........................................................................................18
10.5. Pregnancies (as applicable)........................................................................1810.6. Clinical Laboratory Evaluations...................................................................1810.7. Other Safety Measures ...............................................................................18
11. PHARMACOKINETIC ANALYSES.........................................................................1911.1. Drug Concentration Measures ....................................................................1911.2. Deriving and Summarizing Pharmacokinetic Parameters............................2011.3. Statistical Analyses.....................................................................................21
12. PHARMACODYNAMIC/BIOMARKER ANALYSES ................................................21
13. PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES ...................................21
14. REFERENCES.......................................................................................................23
15. ATTACHMENTS ....................................................................................................2415.1. Table of Contents for Data Display Specifications.......................................24
15.1.1. Study Population Tables and Listings ..........................................2515.1.2. Safety Tables and Listings...........................................................2615.1.3. Pharmacokinetic Figures, Tables and Listings .............................2915.1.4. Pharmacodynamic Figures, Tables and Listings..........................3115.1.5. Pk/PD Figures .............................................................................35
15.2. Data Display Specifications (Example Shells).............................................37
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LIST OF ABBREVIATIONS
Aβ Amyloid beta
AD Alzheimer’s disease
AE Adverse event
ALT Alanine aminotransferase (SGPT)
AMD Age-related macular degeneration
ANOVA Analysis of variance
AST Aspartate aminotransferase (SGOT)
AUC Area under concentration-time curve
AUC(0-inf) Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time
AUC(0-t) Area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration
AUC(0-) Area under the concentration-time curve over the dosing interval
BUN Blood urea nitrogen
CI Confidence Interval
CL Systemic clearance of parent drug
Cmax Maximum observed concentration
Ct Last observed quantifiable concentration
CO2 Carbon dioxide
CPK Creatine phosphokinase
CPMS Clinical Pharmacology Modelling & Simulation
CP-RAP Clinical Pharmacology Reporting and Analysis Plan
CPSR Clinical Pharmacology Study Report
CPSSO Clinical Pharmacology Science and Study Operations
CRF Case Report Form
CV Coefficient of variation
DBR Database Release
DBF Database Freeze
DMPK Drug Metabolism and Pharmacokinetics
ECG Electrocardiogram
F Absolute bioavailability of drug
GA Geographic atrophy
GCP Good Clinical Practice
GCSP Global Clinical Safety and Pharmacovigilence
GGT Gamma glutamyltransferase
GLP Good Laboratory Practice
GSK GlaxoSmithKline
HARP Harmonisation for Analysis and Reporting Program
HBsAg Hepatitis B surface antigen
HIV Human immunodeficiency virus
h/hr Hour(s)
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IB Investigator’s Brochure
ICH International Conference on Harmonisation
IDSL Integrated Data Standards Library
IEC International Ethics Committee
IM Intramuscular
INR International Normalized Ratio
IP Investigational product
IRB Institutional Review Board
IV Intravenous
Kg Kilogram
z Terminal phase rate constant
L Litre
lbs Pounds
LDH Lactate dehydrogenase
LFTs Liver function tests
LLN Lower limit of normal
mAb Monoclonal antibody
MedDRA Medical Dictionary for Regulatory Activities
mg Milligram
mL Millilitre
mmHg Millimetres of mercury
MRI Magnetic Resonance Imaging
MSDS Material Safety Data Sheet
msec Milliseconds
NA Not Available
NONMEM Nonlinear mixed effects modelling program
PCI Potential Clinical Importance
PD Pharmacodynamic
PK Pharmacokinetic
QTcB QT duration corrected for heart rate by Bazett’s formula
QTcF QT duration corrected for heart rate by Fridericia’s formula
RAP Reporting and Analysis Plan
RBC Red blood cells
SAC Statistical Analysis Complete
SAE Serious adverse event(s)
SD Standard Deviation
SDTM Study Data Tabulation Model
SGOT Serum glutamic-oxaloacetic transaminase
SGPT Serum glutamic pyruvic transaminase
SOC System Organ Class
SOP Standard Operating Procedure
SPM Study Procedures Manual
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SQ Subcutaneous
T½ Terminal phase half-life
τ Dosing interval
Tmax Time of occurrence of Cmax
ULN Upper limit of normal
WBC White blood cells
Trademark Information
Trademarks of the GlaxoSmithKline group of companies
Trademarks not owned by the GlaxoSmithKline group of
companies
NONE Phoenix WinNonlinSAS
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1. INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be included in the Clinical Pharmacology Study Report for Protocol BA1116891:
Revision Chronology:
2012N142727_00 2013-NOV-05 Original
All decisions regarding final analysis, as defined in this RAP document, have been made prior to Database Freeze of the study data.
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Study Objectives and Endpoints
Objectives Endpoints
Primary
To estimate the relative bioavailability of GSK933776 following single-dose IM and SQ administration and repeat-dose SQ administration as compared to IV administration
The relative bioavailability as calculated from the ratio of AUC (0-inf) following IM injection or SQ injection to IV infusion
Secondary
To characterize thepharmacokinetic profile of GSK933776 following single-dose IM and SQ administration and repeat-dose SQ administration as compared to IV administration
To evaluate the safety and tolerability of GSK933776 following IV, IM and SQ administration
Pharmacokinetic parameters including area under the concentration-time curve from time zero to time of the last quantifiable concentration (AUC(0-t)) if AUC(0-inf) is not reportable, Cmax, time of occurrence of Cmax (Tmax), terminal phase half-life (T1/2), clearance, and volume of distribution as data permit
Clinical safety data from adverse event reporting (including injection site reactions), clinical observations, vital signs, ECG, and clinical laboratory parameters
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Objectives Endpoints
To further characterize the PK-PD relationship of GSK933776 based on concentrations of A as the PD marker
To characterize the immunogenicity profile of GSK933776 following IV, IM and SQ administration
Determination of plasma concentrations of GSK933776, total Aβ and total Aβ fragments, as well as unbound concentrations of Aβ, fragments containing the epitope 1-22
Presence of antibodies to GSK933776 in serum samples (if detected, characterization of neutralizing status)
3. STUDY DESIGN
3.1. Study Design
This is a single-center, randomized, open-label, parallel-group study in healthy volunteers to evaluate the bioavailability, pharmacokinetics (PK), safety, and tolerability of GSK933776 following subcutaneous (SQ) and intramuscular (IM) administrationcompared to GSK933776 following IV infusion.
Protocol waivers or exemptions are not allowed. Therefore, adherence to the study design requirements, including those specified in the Time and Events Table are essential. Upon successful completion of the Screening Period, a subject will be eligible to enroll in the study. Twenty-four subjects will be enrolled and randomized to one of 4 possible treatment arms in a 1:1:1:1 ratio. The treatment arms are described in Table 1.
Subjects will be followed for approximately 84 days after dose administration (for Treatment Arm C, this 84-day period begins after the final [fourth] dose). The total duration of subject participation from screening to follow-up for Treatment Arms A, B and D (single dose of GSK933776), will be approximately 113 days. Total duration of subject participation from screening to follow-up for Treatment Arm C (weekly SQ administration for 4 doses), will be approximately 134 days. Subjects who prematurely discontinue the study may be replaced.
Table 1 Study Treatments
Study Treatment
Treatment Description
A 200 mg GSK933776 administered by IV infusionB 200 mg GSK933776 administered by SQ injection C 50 mg GSK933776, administered by SQ injection once weekly for 4
weeks D 200 mg GSK933776 administered by IM injection
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4. PLANNED ANALYSES
4.1. Interim Analyses
There is no interim analysis.
4.2. Final Analyses
The final planned analyses will be performed after all subjects have completed the study and after database freeze. See Section 9 to Section 13 for all final planned analyses for this study.
5. SAMPLE SIZE CONSIDERATIONS
5.1. Sample Size Assumptions
The sample size for this study is based on feasibility and the intention to collect safety and tolerability data from at least 6 subjects in each treatment arm of GSK933776. To assure that acceptable precision of PK parameters is expected with the sample size proposed, calculations have been performed based on variability estimates from previous studies with IV administration of GSK933776. From study BA11006006, the between-subject variability (CVb) of AUC(0-t) and Cmax of 3 mg/kg dose of GSK933776 was estimated to be between 12.7% and 16.0%. Assuming a coefficient of variation (CV) of 16% and a sample size of 6 subjects per arm, the estimated precision of 90% confidence interval (i.e. half-width) is expected to be no more than 20% of the point estimate. That is for a point estimate of 0.75, the 90% confidence interval would be 0.60 to 0.94.
5.2. Sample Size Sensitivity
From study BA11006006, the CVb of AUC(0-t) and Cmax of 1 mg/kg dose of GSK933776 was estimated to be between 24.5% and 38.7%. Additionally, the CVb of either an SQ or IM administration may be greater than that of IV administration. The table below provides estimated precision for range of variability from 16% to 38.7%. Assuming a CV of 38.7% and a sample size of 6 subjects per arm, the estimate precision of the 90% confidence interval (CI) is expected to be approximately 31% of the point estimates.
CVHalf-width of 90% CI
16.0% 20%
21.7% 23%
27.4% 26%
33.0% 29%
38.7% 31%
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5.3. Sample Size Re-estimation
If during the course of the study, new information becomes available about clinically meaningful differences or variability estimates, a blinded sample size re-estimation may be conducted. Based on the observed CV of AUC(0-t) or Cmax from the blinded data review, the sample size will be increased to allow for the corresponding half-width of 90% CI to be within the boundary set by the new clinical difference. Any subsequent change to the target sample size would be documented in a protocol amendment.
6. ANALYSIS POPULATIONS
6.1. Safety Population (SAF)
All patients enrolled in the study who receive at least one dose of study drug will be included in the Safety Population. This population will be used in the assessment of safety, and for listing and summarizing baseline/demographic and subject disposition data.
6.2. Pharmacokinetic Concentration Population
The PK Concentration Population will consist of all subjects in the Safety Population who undergo plasma PK sampling and have evaluable PK assay results. This population will be used for the concentration tables, listings, and figures.
6.3. Pharmacokinetic Parameter Population
The PK Parameter Population will consist of all subjects in the Pharmacokinetic Concentration Population for whom valid and evaluable pharmacokinetic parameters are derived. This population will be used in the assessment and characterization of PK parameters. This population will also be used for listing and statistical analysis of PK parameters.
6.4. Pharmacodynamic Population
The Pharmacodynamic (PD) Analysis Population will consist of all subjects in the Safety Population with at least one measurable concentration of biomarkers (including immunogenicity). This population will be used for listing, summarizing and plotting of plasma concentration-time data for biomarkers.
6.5. PK/PD Analysis Population
The PK/PD Analysis Population will consist of all subjects in the Safety Population with at least one measurable concentration of biomarkers as well as one measurable concentration of GSK933776. This population will be used for explore the PK/PD relationship.
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7. TREATMENT COMPARISONS
The primary comparisons will be made to estimate the relative bioavailability of GSK933776 following single-dose IM and SQ administration and repeat-dose SQ administration as compared to IV administration.
7.1. Treatment and Other Subgroup Descriptors for Data Display
Subjects will be assigned to treatment in accordance with the randomization schedulegenerated by Clinical Statistics, prior to the start of the study, using validated internalsoftware.
Randomisation Final Data Display (i.e. HARP / other)Code Treatment Description Treatment Description Column
Header
A200 mg GSK933776 administered by IV infusion
200 mg GSK933776 administered by IV infusion
IV_200mg
B200 mg GSK933776 administered by SQ injection
200 mg GSK933776 administered by SQ injection
SQ_200mg
C50 mg GSK933776, administered by SQ injection once weekly for 4 weeks
50 mg GSK933776, administered by SQ injection once weekly for 4 weeks
SQ_50mg x 4
D200 mg GSK933776 administered by IM injection
200 mg GSK933776 administered by IM injection
IM_200mg
8. GENERAL CONSIDERATIONS FOR DATA ANALYSESAND HANDLING
8.1. Reporting Conventions
All data will be reported according to the actual regimen the subject received.
Actual sampling times will be used in the derivation of PK parameters and in plotting individual concentration-time profiles. Planned sampling times will be used in the summary tables and in plotting mean/median concentration-time profiles. Concentration-time data will be listed according to actual sampling times relative to dosing time.
Data from unscheduled visits (except PK data) and Screening visits will be excluded from summary tables, summary plots and statistical analyses, unless otherwise stated. However, these data will be included in the appropriate listings.
No formal assessment windows will be defined.
Analyses will be performed using the SAS/STAT module of the SAS system, version 9.1.3 or higher (SAS and SAS/STAT are registered trademarks of the SAS Institute Inc., Cary, NC, USA). Programs will be imported into HARP (Harmonisation for Analysis and Reporting Program) and the final output will be produced by running drivers in HARP.
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Any deviations from the analyses described in this RAP will be stated with justification in Section 8.2.4 of the final clinical pharmacology study report (CPSR).
8.2. Data Management
Data Type Source Format of Data Planned Date of Final File1
Responsibility
Safety Database SDTM DBF CPDS
PK ConcSMS2000 data files
dat file DBF DMPK
ADPC (Winonlin file)
SDTM PC3 CSV file DBF + 2 Days2 DB (Prog)
PK PAR PK HARP CSV file ADPC + 5 days2 CPMS
PD CSV file CSV file DBFClinical Immunology
LAB External SAS DBR CPSSO
1. This is for study teams to determine upfront if there is a possibility of not meeting the completion of the CPSR within 6 months of LSLV (i.e. novel data that may not be available until several months after LSLV).
2. Provided source data is clean.3. PK concentration data is released via SMS2000 by DMPK and the SDTM PC dataset
contains date/times and PK sample ID.
8.3. Premature Withdrawal and Missing Data
All subjects who withdraw prematurely from the study/study drug will be documented and the reason for their withdrawal recorded in the final Clinical Pharmacology Study Report (CPSR). All available data from subjects who withdraw will be listed and all available planned data will be included in the summaries according to the populations defined in Section 6.
In the event that the study is prematurely discontinued, all available data will be listed and a review carried out by the study team to assess which statistical analyses are still considered appropriate.
8.4. Baseline Definition
Baseline assessment is the last available scheduled assessment prior to time of the first dose unless it is specified otherwise. If there are multiple assessments for a given measurement collected on the same scheduled time, the average of these assessments will be used.
The following table indicates the baseline day to be used in the study:
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Parameter Baseline Days Collected Baseline To Be Used in Analysis / SummariesScreen Pre-Dose
Day 1Safety :Laboratory X X Pre-Dose Day 1Vital Signs X X Pre-Dose Day 1ECG X Screen
If the pre-dose at day 1 assessment is not available, then assessment at screening will beused for the baseline value.
8.5. Derived and Transformed Data
8.5.1. Change from Baseline
The change from baseline will be calculated by subtracting the baseline values from the individual post-randomisation values. If either the baseline or post-randomisation value is missing, the change from baseline is set to missing as well.
Change from baseline in PD/biomarker data will be calculated by dividing the baseline values from the individual post-dose values.
8.5.2. Pharmacokinetic Parameters
For the purposes of calculating summary statistics and for statistical analysis, all PK parameters except for Tmax and T1/2 will be loge transformed.
Between subject coefficient of variation CVb(%) will be calculated according to the following methods:
Untransformed Data: 100 * (SD/Mean)
Transformed Data: 100 * (sqrt(exp(SDlog2)-1))
where SDlog is the standard deviation of the loge-transformed data.
8.5.3. Multiple Measurements at One Timepoint
Where multiple measurements are recorded for a particular assessment at the same time point, the mean of the measurements will be calculated and used in any derivation of summary statistics. However all available data will be listed.
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8.6. Values of Potential Clinical Importance
Laboratory Values of Potential Clinical Importance (Healthy Volunteers)
Hematology Analyte Effect Relative – Low
(Multipliers of LLN)
Relative – High
(Multipliers of ULN)
White Blood Cell Count 0.67 1.82
Neutrophil Count 0.83
HemoglobinMale 0.90 1.03
Female 0.90 1.13
HematocritMale 0.90 1.02
Female 0.90 1.17
Platelet Count 0.67 1.57
Lymphocytes 0.81
Chemistry Analyte Effect Relative – Low
(Multipliers of LLN)
Relative – High
(Multipliers of ULN)
Serum Creatinine mg/dL NA 1.15
Creatinine clearance–ml/min
0.8 NA
Albumin (mmol/L) 0.86
Blood Urea Nitrogen (mg/dL) (BUN)** (UREA)
NA1.13 men
1.29 women
Calcium (mmol/L) 0.91 1.06
Glucose (mmol/L) 0.71 1.41
Potassium (mmol/L) 0.86 1.10
Sodium (mmol/L) 0.96 1.03
Total CO2 (mmol/L) 0.86 1.14
Note: The relative-low and relative-high values would be used as multiples of each site’s ULN or LLN in order to obtain the PCI for that laboratory.
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Liver Function Test (Healthy Volunteers)
Liver Function Test Analyte
EffectPotential Clinical Importance (PCI) Range
Unit
ALT/SGPT High ≥ 2x ULN U/LAST/SGOT High ≥ 2x ULN U/LAlkPhos High ≥ 2x ULN U/LT. Bilirubin High ≥ 1.5x ULN mol/L
T. Bilirubin + ALT High≥ 1.5x ULN T.Billirubin
+≥ 2x ULN ALT
mol/L
U/L
ECG Values of Potential Clinical Importance (Healthy Volunteers)
ECG Parameter Potential Clinical Importance (PCI) Range Unit
Absolute QTc Interval >450 Msec
Increase from Baseline QTc >60 Msec
PR Interval <110 and >220 Msec
QRS Interval <75 and >110 Msec
Also QTc interval will be categorized as follows:
ECG Parameter Potential Clinical Importance (PCI) Range Unit
Absolute QTc Interval >450 to ≤480 msec
Absolute QTc Interval >480 to ≤500 msec
Absolute QTc Interval >500 msec
Increase from Baseline QTc ≤30 msec
Increase from Baseline QTc >30 to ≤60 msec
Increase from Baseline QTc >60 msec
Vital Sign Values of Potential Clinical Importance (Healthy Volunteers)
VS Parameter Potential Clinical Importance (PCI) Range Unit
Systolic Blood Pressure <85 and >160 mmHg
Diastolic Blood Pressure <45 and >100 mmHg
Heart Rate <40 and >110 bpm
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9. STUDY POPULATION
Study population data will be summarised by, or under the direct auspices of, Clinical Statistics, GlaxoSmithKline.
The tables will use the Safety population unless otherwise specified.
9.1. Subject Disposition
A summary table will be generated to provide the count of subjects included in eachanalysis population for the study and this table will be displayed by treatment and overall.
The end of study record will be listed and summarized by treatment. The listing will include whether subjects prematurely withdrew from the study, the reason for premature discontinuation, along with the date of study drug dosing and the date of completion or premature discontinuation from the study.
9.2. Demographic and Baseline Characteristics
Demographic data include year of birth, age, gender, race, ethnicity, height, weight and body mass index (BMI). Demographic data will be summarized and listed for the safety population. Race will be summarized and listed separately from the other demographic characteristics.
9.3. Concomitant Medications
Concomitant medication verbatim text will be coded and classified by generic code and preferred term using a standardized GSK coding system: GSK DRUG. Concomitant medications will be listed by treatment and subject. It will also be summarized by treatment if sufficient data exist to warrant a summary.
9.4. Treatment Compliance and Protocol Deviations
Information on each subject who did not receive the correct treatment during each treatment period, the reason for not receiving the correct treatment, and any other protocol deviations will be listed by treatment and subject. Subjects who did not satisfy all inclusion and exclusion criteria and corresponding criteria that were violated will be listed.
10. SAFETY ANALYSES
Safety data will be summarised and listed by, or under the direct auspices of, Clinical Statistics, GlaxoSmithKline.
No formal statistical analysis of safety data will be conducted.
The tables will use the “Safety” population unless otherwise specified.
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10.1. Extent of Exposure
A by-subject listing of data on subject exposure will be generated including dose date and time, unit and route.
10.2. Adverse Events
Adverse event verbatim text will be coded and classified by system organ class (SOC) and preferred term using a standardized GSK coding system: MedDRA. The relationship of AE system organ class, preferred term, and verbatim text will be listed. All AEs will be listed by treatment and subject, and summarized by treatment.
10.3. Deaths and Serious Adverse Events
Deaths and other serious adverse events will be listed if any of these events occur.
10.4. Adverse Events Leading to Discontinuation of Investigational Product and/or Withdrawal from the Study and Other Significant Adverse Events
Adverse events leading to discontinuation of investigational product (IP) and/or withdrawal from the study will be listed by treatment and subject. A summary by treatment will also be provided if there are sufficient data. A listing of all AEs for subjects who withdrew from the study due to AEs will be provided.
10.5. Pregnancies (as applicable)
If any female subjects became pregnant during the study, a listing of such subjects will be provided.
10.6. Clinical Laboratory Evaluations
A listing of reference ranges for clinical laboratory tests performed during the study will be generated. Hematology, urinalysis and clinical chemistry data will be listed by treatment, subject, visit, and actual date and time. The data will also be summarized by treatment and visit. If any laboratory test results are outside of the reference range, they will be flagged with high/low and/or toxicity grade in the listing.
A listing of hematology and clinical chemistry data for subjects with abnormalities of potential clinical importance will be provided.
Incidence of liver event will be summarized by treatment. Liver biopsy details and liver imaging details will also be summarized by treatment if data is available. The corresponding listing will also be provided.
10.7. Other Safety Measures
Vital sign data (BP, PR and Temperature) will be summarized by treatment, visit, and planned time and listed by treatment, subject, visit, planned time, and actual time. In
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addition, a listing of vital signs for subjects with abnormalities of potential clinical importance will be provided.
ECG values will be summarized by treatment, visit, and planned time and listed by treatment, subject, visit, planned time, and actual time. Safety ECG findings will be listed and summarized. In addition, summaries of category of safety QTc data and category of change from baseline QTc data will be generated. Clinically significant ECG abnormalities will be listed by treatment, subject, visit, planned time, and actual date and time.
11. PHARMACOKINETIC ANALYSES
The reconciliation of the PK Case Report Form (CRF) and SMS2000 data will be performed by, or under the direct auspices of, Clinical Pharmacology Data Sciences (CPDS), GlaxoSmithKline.
The merge of PK concentration data, randomisation and CRF data will be performed by, or under the direct auspices of, Clinical Statistics, GlaxoSmithKline.
Derivation of pharmacokinetic parameters will be performed by, or under the direct auspices of, Clinical Pharmacology Modelling and Simulation (CPMS), GlaxoSmithKline.
Statistical analysis of PK parameters will be performed by, or under the direct auspices of, Clinical Statistics, GlaxoSmithKline.
The tables will use the PK concentration or parameter population unless otherwise specified.
11.1. Drug Concentration Measures
Plasma GSK933776 concentrations will be listed by treatment, subject, visit, and actual plasma sampling time and summarised by treatment, visit, and nominal time. Standard summary statistics will be calculated (i.e. mean, standard deviation, median, geometric mean, CV%, minimum and maximum). Refer to the standard operating procedure, SOP-CPK-0001, for information regarding the treatment of plasma concentrations below the assay’s lower limit of quantification (BQL).
Individual subject plasma GSK933776 concentration-time profiles will be plotted for all subjects in the PK Concentration Population, and median/mean profiles for plasma GSK933776, with profiles from each treatment superimposed, will be plotted for all of the subjects in the PK Concentration Population. Each of the figures will contain one plot on the untransformed scale (i.e. a linear plot) and one plot on the log transformed scale (i.e. log-linear plot). Plots for individual and group median/mean plasma GSK933776 concentration-time profiles with the truncation of Treatment Arms A, B and D to Day 29 and Treatment Arm C to Day 31 will also be presented for clearer visualization of the absorption profile.
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11.2. Deriving and Summarizing Pharmacokinetic Parameters
The following PK parameters will be determined from the plasma concentration-time data for GSK933776: AUC(0-), AUC(0-t) if AUC(0-) is not reportable, AUC(0-672hrs) (for Treatment Arms A and C only), AUC(0-168hrs) (for Treatment Arms A and C only), Cmax, Tmax, T1/2, CL/F, V/F (F=1 for Treatment Arm A).
Additional PK parameters may be calculated. Pharmacokinetic data will be presented in graphical and/or tabular form and will be summarized descriptively. All pharmacokinetic data will be stored in the Archives, GlaxoSmithKline Pharmaceuticals, R&D.
The pharmacokinetic parameters will be calculated by standard non-compartmental analysis according to current working practices and using Phoenix WinNonlin 6.3 orhigher, and according to the standard operating procedures described in the document “Non-Compartmental Analysis of Pharmacokinetic Data” (GUI-CPK-3001). Actual elapsed time from dosing will be used in the derivation of all PK parameters. The derivation of PK parameters will be performed by, or under the auspices of CPMS.
1. The first occurrence of the maximum observed plasma concentration (Cmax) will be determined directly from the raw concentration-time data.
2. The time at which Cmax is observed (Tmax) will be determined directly from the raw concentration-time data.
3. The apparent terminal elimination half-life (T1/2) obtained as the ratio of ln2/z, where z is the terminal phase elimination rate constant estimated by linear regression analysis of the log transformed concentration-time data.
4. The area under the plasma concentration-time curve to the last quantifiable concentration (AUC(0-t)) will be determined using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations.
5. The AUC extrapolated to infinity (AUC(0-)) will be calculated, where data permit, as the sum of AUC(0-t) and Ct/λz, where Ct is the last post-dose quantifiable plasma concentration.
6. The percentage of the AUC(0-) that is extrapolated (%AUCex) will be calculated as the ratio of [AUC(0-) minus AUC(0-t)] to AUC(0-).
7. The apparent clearance (CL/F) will be calculated as CL/F = Dose/AUC
8. The volume of distribution (V/F): V/F = CL/F / λz
9. In the event that AUC(0-) cannot be derived, AUC(0-t) will be the primary end point.
All the derived parameters described above will be listed. For each of these parameters, except Tmax and T1/2, the following summary statistics will be calculated for each treatment group: n, arithmetic mean with associated 95% CI, standard deviation, median, minimum, maximum, geometric mean with associated 95% CI, standard deviation of logarithmically transformed data, and CVb(%). For Tmax and T1/2, median, maximum, minimum, arithmetic mean and standard deviation will be calculated.
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11.3. Statistical Analyses
Following loge-transformation, the PK parameters AUC(0-∞), AUC(0-t), AUC(0-672hrs) (Treatment Arms A and C only), AUC(0-168hrs) (Treatment Arms A and C only), Cmax, CL/F and V/F of GSK933776 will be separately analyzed using an analysis of variance (ANOVA) model with fixed effect terms for treatment. Point estimates and their associated 90% confidence intervals (CIs) will be constructed for the differences, B - A, C - A and D - A. For the comparison of C - A the parameter AUC(0-168hrs) will be dose normalized. The point estimates and their associated 90% CIs will then be back-transformed to provide point estimates and 90% CIs for the ratios test/reference on the original scale.
Tmax and T1/2 of GSK933776 will be separately analyzed with the non-parametric Wilcoxon rank-sum test to compute point estimates and associated 90% confidence intervals for the median differences, B - A, C - A and D - A.
Additional subgroup analyses may also be conducted.
12. PHARMACODYNAMIC/BIOMARKER ANALYSES
PD/biomarker endpoints includes plasma total Aβ and total Aβ fragments, as well as unbound concentrations of Aβ, fragments containing the epitope 1-22. PD/biomarker concentrations will be listed by treatment, subject, visit, and actual plasma sampling timeand summarised by treatment, visit, and nominal time. PD/biomarker concentration changes from baseline will also be summarized. Standard summary statistics will be calculated (i.e. mean, standard deviation, median, minimum and maximum).
Individual subject plasma concentration-time profiles will be plotted by analyte for all subjects in the PD Population, and median/mean profiles and median/mean changes from baseline profiles by analyte, with profiles from each treatment superimposed, will be plotted for all of the subjects in the PD Population. Each of the figures will contain one plot on the untransformed scale (i.e. a linear plot) and one plot on the log transformed scale (i.e. log-linear plot). Plots for individual and group median/mean, and median/mean changes from baseline plasma GSK933776 concentration-time profiles with the truncation of Treatment Arms A, B and D to Day 29 and Treatment Arm C to Day 31 will also be presented for clearer visualization of the absorption profile.
Immunogenicity endpoint includes the measurement of antibodies to GSK933776 in serum samples. Immunogenicity data will be summarized and a by-subject listing will also be provided.
The tables will use the PD population unless otherwise specified.
13. PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES
The relationship between plasma concentration of GSK933776 and plasma concentration of total and free amyloid beta (Aβ) will be explored as data permit. Exploratory plots of GSK933776 concentration-time profiles overlaid with PD/biomarker concentration-time profiles or PD/biomarker concentration change from baseline-time profiles will be
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produced where it is possible to examine the PK/PD relationship. Plots with the truncation of Treatment Arms A, B and D to Day 29 and Treatment Arm C to Day 31 will also be presented for clearer visualization of the profile.
If an apparent concentration-effect relationship exists, a population PK/PD model will be attempted using nonlinear mixed effect modelling technique with NONMEM software. Data from the present study may also be combined with previous PK/PD data from studies in patients with AD (BA1106006 and BA1113043) and the ongoing study in patients with GA (BAM114341) to develop a general model of GSK933776 PK-PD following IV, SQ, and IM administration in patients and volunteers.
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14. REFERENCES
Anderson DH, Talaga KC, Rivest AJ, Barron E, Hageman GS, Johnson LV. Characterization of beta amyloid assemblies in drusen: the deposits associated with aging and age-related macular degeneration. Exp Eye Res. Feb 2004;78(2):243-256.
GlaxoSmithKline Document Number SC2009/00016/01. GSK933776 Investigator's Brochure (Version 03, Supplement 1). Effective Date: 23-FEB-2011
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
Lobo ED, Hansen RJ, Balthasar JP. Antibody pharmacokinetics and pharmacodynamics. J Pharm Sci. Nov 2004;93(11):2645-2668
Sperling RA. Jack CR, Black SE, Frosch MP, Greenberg SM, Hyman BT, Scheltens P, Carrillo MC, Thies W, Bednar MM, Black RS, Brashear HR, Brundman M, Siemers ER, Feldman HH, Schindler, RJ.. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimer’s & Dementia. 2011; 7: 367-385
Wang DD, Zhang S, Zhao H, Men AY, Parivar K. Fixed dosing versus body size-based dosing of monoclonal antibodies in adult clinical trials. J Clin Pharmacol. 2009;49(9):1012-1024.
Westlind-Danielsson, A, Arnerup, G. Spontaneous in vitro formation of supramolecular beta-amyloid structures, “Betaamy balls”, by beta amyloid 1-40 peptide. Biochemistry 2001 Dec 11; 40(49): 14736-43
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15. ATTACHMENTS
15.1. Table of Contents for Data Display Specifications
For the Clinical Pharmacology Study Report the following section numbering will apply:
Section 9: Study Population
Section 10: Safety
Section 11: Pharmacokinetic
Section 12: Pharmacodynamic/Biomarker
Section 13: Pharmacokinetic/Pharmacodynamic
Listed below are the planned figures, tables and listings to be produced for inclusion in the BA1116891 clinical study report:
The ‘IDSL No. / Example Shell”’ column refers to the relevant example in the Integrated Data Standards Library (IDSL) database
Unless otherwise indicated, these refer to the core IDSL data standards located under: o ‘Data Standards’ ‘By Component’ in the IDSL database
‘CP’ refers to the Clinical Pharmacology (CP) modified core IDSL standards located under:
o ‘Supporting Documentation’ ’TST Use of IDSL Core Choices’ ‘Clin Pharm’ in the IDSL database
‘PD’ refer to the Clinical Pharmacology data standards located under ‘Data Standards’ ‘By Therapeutic Component’ ‘Clin Pharm’ in the IDSL database.
If there is no data for the table/listing, ‘No data to report’ will be presented
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15.1.1. Study Population Tables and Listings
Tables
Table No.
Population IDSL No. / Example Shell
Title Additional Programming Notes Responsibility Deliverable Priority
9.1 Safety
POP1or
ING114556, Table 9.1
Summary of Study Population
By treatment and combined overall.Subjects are included in the Safety Population if they have taken at least one dose of study medication.Subjects are included in the PKConcentration Population if they have evaluable GSK933776 concentration.Subjects are included in the PK Parameter Population if they have evaluable GSK933776 PK parameter.Subjects are included in the PD Population if they have evaluable biomarker concentration.Subjects are included in the PK/PD AnalysisPopulation if they have evaluable GSK933776 concentration and evaluable biomarker concentration.
Programming SAC
9.2 Safety ES1 Summary of Subject Disposition Programming SAC9.3 Safety DV1A Summary of Protocol Deviations Programming SAC
9.4 Safety DM1Summary of Demographic Characteristics
By treatment and combined overall.Remove the age group segment.
Programming SAC
9.5Safety
DM6Summary of Race and Racial Combination Details
By treatment and combined overallBe the GSK race.
Programming SAC
9.6 Safety CP_CM1 Summary of Concomitant Medications Summarize by treatment Programming SAC
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Listings
ListingNo.
Population IDSL No. / Example Shell
Title Programming Notes Responsibility Deliverable Priority
9.1 Safety CP_TA1Listing of Randomized and Actual Treatments
List by treatment, no Centre ID, no Cohort. Programming SAC
9.2 Safety See Mockups Listing of Subjects excluded from Analysis Populations
Programming SAC
9.3Safety
CP_ES10Listing of Reasons for Study Withdrawal/Completion
List by treatment.Programming SAC
9.4 Safety IE3 Listing of Protocol Deviations List by treatment. Programming SAC9.5 Safety DM2 Listing of Demographic Characteristics List by treatment. Programming SAC9.6 Safety DM9 Listing of Race List by treatment. Programming SAC
9.7Safety
CP-CM3Listing of Concomitant Medications (Including Some Optional Items)
List by treatment.Programming SAC
15.1.2. Safety Tables and Listings
Tables
Table No.
Population IDSL No. / Example Shell
Title Programming Notes Responsibility Deliverable Priority
10.1
Safety
CP_AE1p Summary of All Adverse Events
Summarize by treatment.If a subject has multiple occurrences of an AE, the subject is presented only once in the respective subject count.Table presents number and percentage of subjects (n (%)) and number of events (E). N = Total number of subjects in dose group.Percentages are based on the number of subjects in the respective dose group.
Programming SAC
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Table No.
Population IDSL No. / Example Shell
Title Programming Notes Responsibility Deliverable Priority
10.2
Safety
CP_AE1pSummary of Adverse Events Related to Study Treatment
Summarize by treatment.If a subject has multiple occurrences of an AE, the subject is presented only once in the respective subject count.Table presents number and percentage of subjects (n (%)) and number of events (E). N = Total number of subjects in dose group.Percentages are based on the number of subjects in the respective dose group.
Programming SAC
10.3 Safety LB1 Clinical Laboratory Summary by Visit Summarize by treatment. Programming SAC
10.4Safety
LB2Summary of Abnormal Laboratory Results
Summarize by treatment.Programming SAC
10.5 Safety UR3 Summary of Urinalysis Data Programming SAC10.6 Safety VS1 Summary of Vital Signs Summarize by treatment. Programming SAC
10.7Safety
VS1Summary of Vital Signs Changes from Baseline
Summarize by treatment.Programming SAC
10.8 Safety EG1 Summary of ECG Findings Summarize by treatment. Programming SAC10.9 Safety EG2 Summary of ECG Values Summarize by treatment. Programming SAC
10.10Safety ING113096,
Table 10.17Summary of Category of QTc Data by Treatment and Time
Check the original program codes of t_qtcchg_cat.sas, population definition
Programming SAC
10.11Safety ING113096,
Table 10.18Summary of Category of QTc Change from Baseline by Treatment and Time
Programming SAC
10.12Safety
OLIVER2 or See Mockups
Summary of Liver Chemistry Assessments for Subjects with Liver Signal/Event
Summarize by treatment.Programming SAC
10.13Safety
See MockupsSummary of Time on Treatment Before Liver Event
Summarize by treatment.Programming SAC
10.14 Safety See Mockups Summary of Liver Biopsy Details Summarize by treatment Programming SAC10.15 Safety See Mockups Summary of Liver Imaging Details Summarize by treatment Programming SAC
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Listings
Listing No.
Population IDSL No. / Example Shell
Title Programming Notes Responsibility Deliverable Priority
10.1 SafetyEX3, ING114556
10.1Listing of Exposure to Component Listed by treatment
Programming SAC
10.2Safety
AE2Listing of Relationship Between System Organ Class and Verbatim Text
Programming SAC
10.3Safety
CP_AE8 Listing of All Adverse EventsList by treatment, no Centre ID, no Investigator, no Onset Cycle/Cycle day.
Programming SAC
10.4Safety
CP_AE8a Listing of Serious Adverse EventsList by treatment, no Centre ID, no Investigator, no Onset Cycle/Cycle day.
Programming SAC
10.5Safety
CP_AE8Listing of Adverse Events Leading to Withdrawal from the Study
Programming SAC
10.6 Safety See Mockups Listing of Pregnancy Programming SAC
10.7Safety
LB13Listing of Laboratory Tests and Associated Reference Ranges
PCI: Potential Clinical ImportanceProgramming SAC
10.8 Safety LB5 Listing of All Laboratory Data List by treatment. Programming SAC
10.9Safety
CP_LB5Listing of Laboratory Data for Subjects with Lab Values Outside of Normal Range
List by treatment.Programming SAC
10.10Safety
CP_LB5Listing of Laboratory Data for Subjects with Lab Values of Potential Clinical Importance
List by treatment.Programming SAC
10.11 Safety CP_EG5 Listing of Abnormal ECG Findings List by treatment. Programming SAC
10.12Safety
CP_EG3Listing of All ECG Values for Subjects with any Value of Potential Clinical Importance
List by treatment.Programming SAC
10.13 Safety VS4 Listing of Vital Signs List by treatment. Programming SAC
10.14Safety
VS5Listing of Vital Signs with Values of Potential Clinical Importance
Programming SAC
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15.1.3. Pharmacokinetic Figures, Tables and Listings
Figures
Figure No.
Population IDSL No. / Example Shell
Title Programming Notes Responsibility Deliverable Priority
11.1PK
ConcentrationPK17, pkcf2
Mean Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Programming SAC
11.2PK
ConcentrationPK17, pkcf2
Mean Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Plots with the truncation of Treatment Arms A, B and D to Day 29 and Treatment Arm C to Day 31.
Programming SAC
11.3PK
Concentration PK18, pkcf3Median Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Programming SAC
11.4PK
Concentration PK18, pkcf3Median Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Plots with the truncation of Treatment Arms A, B and D to Day 29 and Treatment Arm C to Day 31.
Programming SAC
11.5PK
Concentration PK16a, pkcf1pIndividual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log)
Treatment is showing in the figuresubtitle.
Programming SAC
11.6
PK Concentration
PK16a, pkcf1pIndividual Plasma GSK933776 Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Plots with the truncation of Treatment Arms A, B and D to Day 29 and Treatment Arm C to Day 31.Treatment is showing in the figure subtitle.
Programming SAC
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Tables
Table No.
Population IDSL No. / Example Shell
Title Programming Notes Responsibility Deliverable Priority
11.1PK
ConcentrationPK01,pkct1
Summary of Plasma GSK933776 Pharmacokinetic Concentration-Time Data [ng/mL]
Summarize by treatment.Include geometric mean and CV% between Median and Min.Please follow the PK summary standard, if number of imputed>1/3 of n, then SD will be missing. If mean, median, min and max is below NQ value, they will show as ‘NQ’ instead of calculated numeric statistics.
Programming SAC
11.2PK
ParameterPK06, pkpt4
Summary of Derived Plasma GSK933776 Pharmacokinetic Parameters
Tmax and T1/2 will not have geometric mean and 95% CI, SD(log) and %CVb.Note: AUC(0-672hrs): Treatment Arms A and C only; AUC(0-168hrs): Treatment Arms A and C only.
Programming SAC
11.3PK
ParameterSee Mockups
Summary of the Results of the ANOVA of Log-Transformed Plasma GSK933776 Pharmacokinetic Parameters
Note: AUC(0-672hrs): Treatment Arms A and C only; AUC(0-168hrs): Treatment Arms A and C only.
Programming SAC
11.4 PK Parameter See MockupsMedian Difference and Confidence Interval for Plasma GSK933776 Pharmacokinetic Parameters
Note: AUC(0-672hrs): Treatment Arms A and C only; AUC(0-168hrs): Treatment Arms A and C only.
Programming SAC
Listings
ListingNo.
Population IDSL No. / Example Shell
Title Programming Notes Responsibility Deliverable Priority
11.1PK
ConcentrationPK07, pkcl1p
Listing of Plasma GSK933776 Pharmacokinetic Concentration-Time Data
List by treatment.Programming SAC
11.2 PK Parameter PK13, pkpl1pListing of Derived Plasma GSK933776 Pharmacokinetic Parameters
List by treatment.NC = Not calculableND = Not determined
Programming SAC
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15.1.4. Pharmacodynamic Figures, Tables and Listings
Figures
Figure No.
Population IDSL No. / Example Shell
Title Programming Notes Responsibility Deliverable Priority
12.1 PD PK17, pkcf2Mean Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Repeat this figure for all PD endpoints.PD endpoints are spelled out in the figure title.PD endpoints: Total Aβ, Total Aβ Fragment, Unbounded Aβ, Unbounded Aβ Fragment.
Programming SAC
12.2 PD PK17, pkcf2Mean Plasma PD Concentration Change from Baseline-Time Plot (Linear and Semi-Log)
Repeat this figure for all PD endpoints.PD endpoints are spelled out in the figure title.PD endpoints: Total Aβ, Total Aβ Fragment, Unbounded Aβ, Unbounded Aβ Fragment.Note: PD concentration change from baseline is calculated by dividing the baseline value from the individual post-dose value.
Programming SAC
12.3 PD PK17, pkcf2Mean Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Plots with the truncation of Treatment Arms A, B and D to Day 29 and Treatment Arm C to Day 31. Repeat this figure for all PD endpoints.PD endpoints are spelled out in the figure title.PD endpoints: Total Aβ, Total Aβ Fragment, Unbounded Aβ, Unbounded Aβ Fragment.
Programming SAC
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Figure No.
Population IDSL No. / Example Shell
Title Programming Notes Responsibility Deliverable Priority
12.4 PD PK17, pkcf2 Mean Plasma PD Concentration Change from Baseline-Time Plot (Linear and Semi-Log) (Truncated)
Plots with the truncation of Treatment Arms A, B and D to Day 29 and Treatment Arm C to Day 31. Repeat this figure for all PD endpoints.PD endpoints are spelled out in the figure title.PD endpoints: Total Aβ, Total Aβ Fragment, Unbounded Aβ, Unbounded Aβ Fragment.Note: PD concentration change from baseline is calculated by dividing the baseline value from the individual post-dose value.
12.2 PD
12.5 PD PK18, pkcf3Median Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Repeat this figure for all PD endpoints.PD endpoints are spelled out in the figure title.PD endpoints: Total Aβ, Total Aβ Fragment, Unbounded Aβ, Unbounded Aβ Fragment.
Programming SAC
12.6 PD PK18, pkcf3 Median Plasma PD Concentration Change from Baseline-Time Plot (Linear and Semi-Log)
Repeat this figure for all PD endpoints.PD endpoints are spelled out in the figure title.PD endpoints: Total Aβ, Total Aβ Fragment, Unbounded Aβ, Unbounded Aβ Fragment.Note: PD concentration change from baseline is calculated by dividing the baseline value from the individual post-dose value.
12.3 PD
12.7 PD PK18, pkcf3Median Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Plots with the truncation of Treatment Arms A, B and D to Day 29 and Treatment Arm C to Day 31. Repeat this figure for all PD endpoints.PD endpoints are spelled out in the figure title.PD endpoints: Total Aβ, Total Aβ Fragment, Unbounded Aβ, Unbounded Aβ Fragment.
Programming SAC
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Figure No.
Population IDSL No. / Example Shell
Title Programming Notes Responsibility Deliverable Priority
12.8 PD PK18, pkcf3 Median Plasma PD Concentration Change from Baseline-Time Plot (Linear and Semi-Log) (Truncated)
Plots with the truncation of Treatment Arms A, B and D to Day 29 and Treatment Arm C to Day 31. Repeat this figure for all PD endpoints.PD endpoints are spelled out in the figure title.PD endpoints: Total Aβ, Total Aβ Fragment, Unbounded Aβ, Unbounded Aβ Fragment.Note: PD concentration change from baseline is calculated by dividing the baseline value from the individual post-dose value.
12.4 PD
12.9 PD PK16a, pkcf1pIndividual Plasma PD Concentration-Time Plot (Linear and Semi-Log)
Repeat this figure for all PD endpoints.PD endpoints are spelled out in the figure title.PD endpoints: Total Aβ, Total Aβ Fragment, Unbounded Aβ, Unbounded Aβ Fragment.Treatment is showing in the figure subtitle.
Programming SAC
12.10 PD PK16a, pkcf1pIndividual Plasma PD Concentration-Time Plot (Linear and Semi-Log) (Truncated)
Plots with the truncation of Treatment Arms A, B and D to Day 29 and Treatment Arm C to Day 31. Repeat this figure for all PD endpoints.PD endpoints are spelled out in the figure title.PD endpoints: Total Aβ, Total Aβ Fragment, Unbounded Aβ, Unbounded Aβ Fragment.Treatment is showing in the figure subtitle.
Programming SAC
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Tables
Table No.
Population IDSL No. / Example Shell
Title Programming Notes Responsibility Deliverable Priority
12.1 PD PD1Summary of Plasma PD Concentration-Time Data [ng/mL]
Follow all PK standards for PD, including imputation and SD. Repeat this table for all PD endpoints as well as Immunogenicity endpoints. PD endpoints as well as Immunogenicity endpoints are spelled out in the table title.PD endpoints: Total Aβ, Total Aβ Fragment, Unbounded Aβ, Unbounded Aβ Fragment.Immunogenicity endpoints: refer to the data.
Programming SAC
12.2 PD PD2Summary of Log Transformed Plasma PD Concentration-Time Data [ng/mL]
Follow all PK standards for PD, including imputation and SD. Repeat this table for all PD endpoints as well as Immunogenicity endpoints. PD endpoints as well as Immunogenicity endpoints are spelled out in the table title.PD endpoints: Total Aβ, Total Aβ Fragment, Unbounded Aβ, Unbounded Aβ Fragment.Immunogenicity endpoints: refer to the data.
Programming SAC
12.3 PD PD3 Summary of Plasma PD Concentration Change from Baseline-Time Data
Follow all PK standards for PD, including imputation and SD. Repeat this table for all PD endpoints. PD endpoints are spelled out in the table title.PD endpoints: Total Aβ, Total Aβ Fragment, Unbounded Aβ, Unbounded Aβ Fragment.Note: PD concentration change from baseline is calculated by dividing the baseline value from the individual post-dose value.
Programming PD
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Listings
ListingNo.
Population IDSL No. / Example Shell
Title Programming Notes Responsibility Deliverable Priority
12.1 PD PD10Listing of Plasma PD Concentration-Time Data
List by treatment.Present all PD endpointsPD endpoints: Total Aβ, Total Aβ Fragment, Unbounded Aβ, Unbounded Aβ Fragment.
Programming SAC
12.2 PD PD10Listing of Immunogenicity Concentration-Time Data
List by treatment. NQ= Not QuantifiablePresent all immunogenicity endpoints.
Programming SAC
15.1.5. Pk/PD Figures
Figure No.
Population IDSL No. / Example Shell
Title Programming Notes Responsibility Deliverable Priority
13.1 PK/PD See MockupsMean Plasma GSK933776 Concentration and Mean PD endpoint versus Nominal Time by Treatment
Repeat this figure for all PD endpoints.PD endpoints are spelled out in the figure title.PD endpoints: Total Aβ, Total Aβ Fragment, Unbounded Aβ, Unbounded Aβ Fragment.
Programming SAC
13.2 PK/PD See Mockups 13.1
Mean Plasma GSK933776 Concentration and Mean PD Endpoint Change from Baseline versus Nominal Time by Treatment
Repeat this figure for all PD endpoints.PD endpoints are spelled out in the figure title.PD endpoints: Total Aβ, Total Aβ Fragment, Unbounded Aβ, Unbounded Aβ Fragment.Note: PD concentration change from baseline is calculated by dividing the baseline value from the individual post-dose value.
13.1 PK/PD
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Figure No.
Population IDSL No. / Example Shell
Title Programming Notes Responsibility Deliverable Priority
13.3 PK/PD See Mockups
Mean Plasma GSK933776 Concentration and Mean PD Endpoint versus Nominal Time by Treatment (Truncated)
Repeat this figure for all PD endpoints.PD endpoints are spelled out in the figure title.PD endpoints: Total Aβ, Total Aβ Fragment, Unbounded Aβ, Unbounded Aβ Fragment.Plots with the truncation of Treatment Arms A, B and D to Day 29 and Treatment Arm C to Day 31.
Programming SAC
13.4 PK/PD See Mockups13.3
Mean Plasma GSK933776 Concentration and Mean PD Endpoint Change from Baseline versus Nominal Time by Treatment (Truncated)
Repeat this figure for all PD endpoints. PD endpoints are spelled out in the figure title.PD endpoints: Total Aβ, Total Aβ Fragment, Unbounded Aβ, Unbounded Aβ Fragment.Plots with the truncation of Treatment Arms A, B and D to Day 29 and Treatment Arm C to Day 31.Note: PD endpoint change from baseline is calculated by dividing the baseline value from the individual post-dose value.
13.2 PK/PD
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37
15.2. Data Display Specifications (Example Shells)
Protocol: BA1116891 Page x of yPopulation: Safety
Table 10.12 Summary of Liver Chemistry Assessments for Subjects with Liver Signal/Event
Treatment A(N=100)
Treatment A(N=100)
Treatment C(N=100)
Treatment D(N=100)
Subjects with liver signal and/or event 33 (33%) 28 (28%) 28 (28%) 28 (28%)Subject with liver event 15 (15%) 12 (12%) 12 (12%) 12 (12%)
Subjects with liver signal/event occurring while receiving study treatment
12 (12%) 10 (10%) 10 (10%) 10 (10%)
Subject with liver signal/event occurring after stopping study treatment
3 (3%) 2 (2%) 2 (2%) 2 (2%)
Total number of Liver events 20 18 18 18
Worst Criteria typeLiver event stopping criteria 10 (10%) 5 (5%) 5 (5%) 5 (5%)Liver event interruption criteria 5 (5%) 7 (7%) 7 (7%) 7 (7%)Liver monitoring criteria 18 (18%) 16 (16%) 16 (16%) 16 (16%)
Criteria involved in liver event [1]ALT (alanine aminotransferase) 15 (15%) 12 (12%) 12 (12%) 12 (12%)Total Bilirubin 14 (14%) 10 (10%) 10 (10%) 10 (10%)INR 4 (4%) 3 (3%) 3 (3%) 3 (3%)Signs and symptoms 7 (7%) 6 (6%) 6 (6%) 6 (6%)
USER ID:/PROGRAM PATH/PROGRAM DATE TIME
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Protocol: BA1116891 Page x of yPopulation: Safety
Table 10.13 Summary of Time on Treatment Before Liver Event
TRT A TRT B TRT C (N=106) (N=113) (N=104) -------------------------------------------------------------------------------------------------- Subjects reporting at least one liver event 2 (2%) 0 0 Subject with events occurring while receiving study treatment 2 (2%) 0 0 Subject with events occurring after stopping study treatment 0 0 0 Days from first dose to start of event n 1 0 0 Mean 1.0 SD Median 1.0 Min. 1 Max. 1 Days from last dose to start of event # n 1 0 0 Mean 1.0 SD Median 1.0 Min. 1 Max. 1
[#] For events which occur during treatment, time from treatment to event is set to one day
USER ID: /directory/program.sas 31JAN2008 05:38
Note: This is only a mock-up.
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Protocol: BA1116891 Page x of yPopulation: Safety
Table 10.14 Summary of Liver Biopsy Details
TRT A TRT B TRT C (N=106) (N=113) (N=104) --------------------------------------------------------------------------------------------------------- Subjects undergoing Liver Biopsy 1 (<1%) 0 0 Biopsy size n 1 0 0 Mean 19.0 SD Median 19.0 Min. 19 Max. 19 Final diagnosis n 1 0 0 Normal 0 0 0 Alcoholic hepatic 1 (<1%) 0 0 Cirrhosis 1 (<1%) 0 0 Primary biliary cirrhosis 1 (<1%) 0 0 Liver architecture n 1 0 0 Normal 0 0 0 Interface hepatitis (periportal hepatitis 1 (<1%) 0 0 or piecemeal necrosis) Cirrhosis 1 (<1%) 0 0 Description of liver cells/hepatocytes n 1 0 0 Normal 1 (<1%) 0 0 Liver cell/hepatocyte inclusion/vacuole n 1 0 0 No inclusions 1 (<1%) 0 0 USER ID: directory/program.sas 30JAN2008 04:56Note: This is only a mock-up.
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Protocol: BA1116891 Page x of yPopulation: Safety
Table 10.15 Summary of Liver Imaging Details
TRT A TRT B TRT C (N=106) (N=113) (N=104) --------------------------------------------------------------------------------------------------------- Subjects undergoing liver imaging test 2 (2%) 1 (<1%) 0 Liver imaging method Ultrasound - transabdominal 2 (2%) 0 0 Ultrasound - endoscopic 0 0 0 Other specify 0 1 (<1%) 0 Are images technically adequate
Optimal 2 (2%) 0 0 Readable, but not optimal 0 0 0 Not readable 0 1 (<1%) 0 Other specify 0 0 0 Liver size Normal size 2 (2%) 0 0 Hypertrophy (or enlarged) 0 0 0 Atrophy (or smaller than normal) 0 0 0 Segmental hypertrophy 0 0 0 Other specify 0 0 0 Liver texture Normal 2 (2%) 0 0 Heterogeneous 0 0 0 Suggestive of fibrosis 0 0 0 Nodular or suggestive of cirrhosis 0 0 0 Other specify 0 0 0
USER ID: directory/program.sas 31JAN2008 04:23
Note: This is only a mock-up.
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Protocol: BA1116891 Page x of yPopulation: PK Parameter
Table 11.3 Summary of the Results of the ANOVA of Log-Transformed Plasma GSK933776 Pharmacokinetic Parameters
Parameter Comparison Geometric LSMean Ratio 90% ConfidenceTest vs Reference (Test/Ref) Interval for Ratio
n Test n RefAUC(0-inf)(units) [Test treatment B] vs x xx.xx x xx.xx x.xxxx (x.xxxx, x.xxxx) [Reference treatment A]AUC(0-t)(units) [Test treatment B] vs x xx.xx x xx.xx x.xxxx (x.xxxx, x.xxxx) [Reference treatment A]Cmax(units) [Test treatment B] vs x xx.xx x xx.xx x.xxxx (x.xxxx, x.xxxx)
[Reference treatment A]
USER ID:/PROGRAM PATH/PROGRAM DATE TIME
Note: This is only a mock-up.
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Protocol: BA1116891 Page x of yPopulation: PK Parameter
Table 11.4 Median Difference and Confidence Interval for Plasma GSK933776 Pharmacokinetic Parameters
Parameter Comparison Median Difference 90% ConfidenceTest vs Reference (Test-Ref) Interval for Difference
n Test n RefTmax [Test treatment B] vs x xx.xx x xx.xx x.xxxx (x.xxxx, x.xxxx)
[Reference treatment A]
USER ID:/PROGRAM PATH/PROGRAM DATE TIME
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Protocol: BA1116891 Page x of yPopulation: PK/PD
Figure 13.1 Mean Plasma GSK933776 concentration and Mean PD endpoint versus Nominal Time by Treatment
Repeat this figure for all PD endpoints.
PD endpoints are spelled out in the figure title.
PD endpoints: Total Aβ, Total Aβ Fragment, Unbounded Aβ, Unbounded Aβ Fragment.
USER ID:/PROGRAM PATH/PROGRAM DATE TIME
Note: This is only a mock-up
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Protocol: BA1116891 Page x of yPopulation: PK/PD
Figure 13.3 Mean Plasma GSK933776 concentration and Mean PD endpoint versus Nominal Time by Treatment (Truncated)
Repeat this figure for all PD endpoints.
PD endpoints are spelled out in the figure title.
PD endpoints: Total Aβ, Total Aβ Fragment, Unbounded Aβ, Unbounded Aβ Fragment.
Plots with the truncation of Treatment Arms A, B and D to Day 29 and Treatment Arm C to Day 31.
USER ID:/PROGRAM PATH/PROGRAM DATE TIME
Note: This is only a mock-up.
2014N211143_00
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CRF REPORT
GlaxoSmithKline Research & Development Limited
BA1116891
P4950-1
Site Number:
Screening Number:
Subject Number:
Principal Investigator: Dr. Leese
Sponsor: GlaxoSmithKline Research & Development Limited
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1
CONFIDENTIAL 2014N211143_00BA1116891
DEMOGRAPHICSSample ID: Date/Time: Period:
Date of Birth (YYYY):
Gender:
Ethnicity:
Race:
Child bearing Potential
Comment:
SUBJECT ASSIGNMENT (ASSIGN ENROLMENT NUMBER)Sample ID: Period:The subject is only eligible for randomization if he/she fulfills all of the Inclusion and none of the Exclusion Criteria.Assigned Number Date of Randomization Comments
SUBJECT ASSIGNMENT (ASSIGN SUBJECT NUMBER)Sample ID: Period:
The subject is only eligible for randomization if he/she fulfills all of the Inclusion and none of the Exclusion Criteria.Assigned Number Date of Randomization Comments
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3/18/2014 9:23:32 AM Page 2 of 17Version 1.0.0
Screening NumberProtocolBA1116891
Subject Number
2
CONFIDENTIAL 2014N211143_00BA1116891
INFORMED CONSENTSample ID: Period:
Did the subject agree to the consent form?
Indicate the date which the informed consent was signed by the subject.
Indicate the time which the informed consent was signed by the subject.
Informed Consent Version Date:
Comment:
SCREENING ELIGIBILITYSample ID: Period:Did the subject meet all of the inclusion criteria and none of the exclusion criteria?
Actual Date/Time of Eligibility
Comment:
INCLUSION/EXCLUSION (ADMISSION ELIGIBILITY)Sample ID: Period:
Does the subject still meet all of the inclusion criteria and none of the exclusion criteria?
Actual Date/Time of Eligibility
If subject did not comply with all inclusion/exclusion criteria, please list the criteria not met.Inclusion Criteria Not Met:
Exclusion Criteria Not Met:Comment:
PHYSICAL EXAMINATION (COMPLETE) (NOT TO BE SENT TO GSK)
Sample ID Period Actual Date/Time of Examination Comments
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Screening NumberProtocolBA1116891
Subject Number
3
CONFIDENTIAL 2014N211143_00BA1116891
PHYSICAL EXAMINATION (BRIEF) (NOT TO BE SENT TO GSK)Sample ID Period Actual Date/Time of Examination Comments
MEDICAL HISTORY (NOT TO BE SENT TO GSK)Sample ID: Date/Time: Period:
Body System Description Start date Stop date Ongoing at this Visit
HEIGHT/WEIGHT (BMI)Sample ID Period Date and Actual Time of
VitalsHeight(cm)
Weight(kg)
BMI(kg/m²)
Comments
WEIGHT (WEIGHT)Sample ID Period Date and Actual
Time of VitalsWeight
(kg)Comments
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Screening NumberProtocolBA1116891
Subject Number
4
CONFIDENTIAL 2014N211143_00BA1116891
12-LEAD ECGSample ID Period Date/
Time of ECGParameters Interpretation
VentricularHR
(bpm)
If abnormal (NCS, CS), please describe:
PR Interval(msec)
RR Interval(msec)
QRS Interval(msec)
QT Interval(msec)
QTc Interval(msec)
QTcBInterval(msec)
QTcFInterval(msec)
Comment:
BLOOD PRESSURE (SITTING VITALS BP/PULSE/TEMP/RESP)Sample ID Period Date and
ActualTime of
Vitals
SystolicBP
(mmHg)
DiastolicBP (mmHg)
PulseRate
(bpm)
Resp.Rate(bpm)
Temperature(ºC)
Comments
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3/18/2014 9:23:32 AM Page 5 of 17Version 1.0.0
Screening NumberProtocolBA1116891
Subject Number
5
CONFIDENTIAL 2014N211143_00BA1116891
BREATHALYZER (NOT TO BE SENT TO GSK)
Sample ID Period Date/Time of Exam Result Comments
INFUSION (GSK 933776 200MG IV INFUSION)Sample ID Period Start Date/Time of
InfusionEnd Date/Time of
InfusionComment
Infusion Flow Rate: Infusion Flow Rate Unit (mL/h):
Actual Quantity Infused: Dosage Unit: mL
What location was the dose given in?
Did the subject receive the correct treatment?
Was there an Infusion interruption?
Any AE’s
DOSE (GSK 933776 50MG SQ INJECTION)Sample ID Period Start Date/Time
of AdministrationActual
Quantity(mg)
What location was the dose
given in?
Did the subject
receive the correct
treatment?
Comments
DOSE (GSK 933776 50MG SQ INJECTION)Sample ID Period Start Date/Time
of AdministrationActual
Quantity(mg)
What location was the dose
given in?
Did the subject
receive the correct
treatment?
Comments
DOSE (GSK 933776 200MG IM INJECTION)Sample ID Period Start Date/Time
of AdministrationActual
Quantity(mg)
What location was the dose
given in?
Did the subject
receive the correct
treatment?
Comments
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Screening NumberProtocolBA1116891
Subject Number
6
CONFIDENTIAL 2014N211143_00BA1116891
DOSE (GSK 933776 50MG SQ INJECTION)Sample ID Period Start Date/Time
of AdministrationActual
Quantity(mg)
What location was the dose
given in?
Did the subject
receive the correct
treatment?
Comments
DOSE (GSK 933776 50MG SQ INJECTION)Sample ID Period Start Date/Time
of AdministrationActual
Quantity(mg)
What location was the dose
given in?
Did the subject
receive the correct
treatment?
Comments
DOSE (GSK 933776 50MG SQ INJECTION)Sample ID Period Start Date/Time
of AdministrationActual
Quantity(mg)
What location was the dose
given in?
Did the subject
receive the correct
treatment?
Comments
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Screening NumberProtocolBA1116891
Subject Number
7
CONFIDENTIAL 2014N211143_00BA1116891
INFUSION RECORD3Sample ID Period Date/Time Comment
Infusion Flow Rate Unit (mL/h): Dose Description:(1) Date/Time (Interruption Start) (1) Volume Infused at time of
Interruption (mL):(1) Infusion Rate (prior to Interruption):
(1) Reason for Interruption
(1) Due to AE?
(2) Date/Time (InterruptionStopped/Infusion Restart)
(2) Infusion Rate (afterInterruption):
(3) Date/Time (Interruption Start) Volume Infused at time of Interruption (mL):
(3) Infusion Rate (prior to Interruption):
(3) Reason for Interruption
(3) Due to AE?
(4) Date/Time (InterruptionStopped/Infusion Restart)
(4) Infusion Rate (afterInterruption):
BLOOD (BIOCHEMISTRY)Sample ID Period Actual Date/Time
of CollectionIs the volunteer
fasting?Comments
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Screening NumberProtocolBA1116891
Subject Number
8
CONFIDENTIAL 2014N211143_00BA1116891
BLOOD (BIOMARKERS/PHARMACODYNAMIC MARKERS)Sample ID Period Actual Date/Time of Collection Comments
BLOOD (COAGULATION)Sample ID Period Actual Date/Time of Collection Comments
BLOOD (HAEMATOLOGY)Sample ID Period Actual Date/Time of Collection Comments
BLOOD (HBA1C)Sample ID Period Actual Date/Time of Collection Comments
BLOOD (IMMUNOGENICITY)Sample ID Period Actual Date/Time of Collection Comments
BLOOD (PHARMACOKINETICS)Sample ID Period Actual Date/Time of Collection Comments
SEROLOGYSample ID Period Actual Date/Time of Collection Comments
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Screening NumberProtocolBA1116891
Subject Number
9
CONFIDENTIAL 2014N211143_00BA1116891
URINESample ID Period Date/Time Comments
URINE (URINE DRUG SCREEN)Sample ID Period Date/Time Control Positive results Result contest
Drugs:Benzodiazepines(BZO) Opiates(OPI) Ecstasy(MDMA)
Cocaine(COC) Methadone(MTD) Phencyclidines(PCP)
Marijuana(THC) TricyclicAntidepressants(TCA)
Amphetamines(AMP)
Methamphetamines(MET)
Oxycodone(OXY) Barbiturates(BAR)
Comment:
SITE REACTIONSample ID Period Date/Time of Exam Comment
Site Reaction Location SiteCatheter Leakage Swelling Measurable
Swelling Area (cm^2) Swelling ListInduration Measurable Induration Area (cm^2)Discoloration Measurable Discoloration Area (cm^2)Discoloration TendernessIntolerability Itching ReactionItchiness Burning SensationRash BruisingSwelling Diameter (mm) Erythema Diameter (mm)Erythema BurningWarm Sensation Cutaneous PainRash (severity) ItchingPhlebitis Scale
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3/18/2014 9:23:32 AM Page 10 of 17Version 1.0.0
Screening NumberProtocolBA1116891
Subject Number
10
CONFIDENTIAL 2014N211143_00BA1116891
LIVER EVENTSSample ID Period Date/Time of Exam Comment
Question #1: Is this liver event a serious adverse event?Question #2: Notification Sent?
Sender: Sample Date/TimeQuestion #3: Which liver chemistry result reached or exceeded protocol-defined investigational product stopping / interruptioncriteria? Check all that apply.
Question #4: Is the subject age 55or older?
Question #5: If Female, is the subject pregnant?
Question #6: Were any diagnostic imaging tests of the liver or hepatobiliary system performed?
Question #7: Were any liver biopsies performed?
Question #8: Does the subject use herbals, complementary or alternative medicines, food supplements (vitamins) or illicit drugs?
Question #9: Did the subject undergo significant dietary change in the past week?Question #10: When did the liver event occur?Start Day/Start Month/Start Year Stop Day/Stop Month/Stop Year
LIVER EVENT REPORTINGSample ID Period Date Liver Signal /Event
first detected in chemistry lab results
Date Liver Signal /Event resolved, as
indicated in chemistry lab
results
Comment
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Screening NumberProtocolBA1116891
Subject Number
11
CONFIDENTIAL 2014N211143_00BA1116891
PHARMACOKINETICS (LIVER)Sample ID Period Date/Time of Exam Comment
Question #1: Was a pharmacokinetic blood sample obtained?
Sample Date/Time
Question #2: If Yes, date and time of last oral GSK 1265744B dose prior to PK sample:
Sample Date/Time
Question #3: If Yes, date and time of last oral MOXIFLOXACIN dose prior to PK sample:
Sample Date/Time
LIVER MEDHXSample ID Period Date/Time of Exam Comment
Question #1: Acute Viral Hepatitis A Question #2: Chronic Hepatitis B
Question #3: Chronic Hepatitis C Question #4: CytomegalovirusHepatitis
Question #5: Epstein Barr Virus Infectious Mononucleus
Question #6: Herpes Simplex Hepatitis
Question #7: Alcoholic Liver Disease Question #8: Non-alcoholicSteatohepatitis
Question #9: Fatty Liver Question #10: Hepatic Cirrhosis
Question #11: Hemochromatosis Question #12: AutoimmuneHepatitis
Question #13: Gallbladder Disease Question #14: Drug related liver disease
Question #15: Other Liver Disease Conditions, Specify Conditions:
Status:
Question #16: Drug Allergies Question #17: Rheumatoid Arthritis
Question #18: Psoriasis Question #19: Thyroid Disease
Question #20: Inflammatory Bowel Disease
Question #21: Lupus
Question #22: Sjogren’s Syndrome Question #23: Vitiligo
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Screening NumberProtocolBA1116891
Subject Number
12
CONFIDENTIAL 2014N211143_00BA1116891
LIVER ALCOHOLSample ID Period Date/Time of Exam Does
volunteerconsumealcohol?
If Yes, average units of Alcohol Consumed Per
Week
Comment
LIVER IMAGING
Sample ID Period Date/Time of Exam Comment
Question #1: Date of hepatic or liver imaging test
Question #2: What method was used for this imaging test?
Other, Specify
Question #3: Are Images technically adequate?
Other, Specify
Question #4: Indicate the liver size Other, Specify
Question #5: Indicate the liver texture Other, Specify
Question #6: Grade the diffuse and /or geographic fatty infiltrate of the liver
Other, Specify
Question #7: Ascites present Other, Specify
Question #8: Are Focal Hepatic Lesions characterisable?
Other, Specify
Question #9: Gallstones or gallbladder lesions?
Other, Specify
Question #10: Biliary ductal lesions? Other, Specify
Question #11: Portal / Hepatic vein abnormalities?
Other, Specify
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Screening NumberProtocolBA1116891
Subject Number
13
CONFIDENTIAL 2014N211143_00BA1116891
LIVER BIOPSYSample ID Period Date/Time of Exam Comment
Question #1: Date of liver biopsy
Question #2 Approximate size of liver biopsy
Question #3 Biopsy size unit MM
Question #4: Final Diagnosis Other, Specify
Question #5: Liver Architecture Other, Specify
Question #6: Description of Liver Cells or Hepatocytes
Other, Specify
Question #7: Liver Cell or Hepatocyte Inclusions or Vacuoles
Other, Specify
Question #8: Hepatocyte or Liver Cell Nuclear Abnormalities
Other, Specify
Question #9: Liver or Lobular Infiltrates
Other, Specify
Question #10: Portal Tract Inflammation
Other, Specify
Question #11: Bile Ducts Other, Specify
Question #12: Portal Veins Other, Specify
Question #13: Liver Infections Other, Specify
Question #14: Parasites of Ova Other, Specify
Question #15: Histologic Staining or Additional Studies Obtained
Other, Specify
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Screening NumberProtocolBA1116891
Subject Number
14
CONFIDENTIAL 2014N211143_00BA1116891
ADVERSE EVENTSDiagnosis
Adverse Event number/Sample ID
Sample Date (Start Date) Sample Time (StartTime)
Unknown Start Time
Stop Date Stop Time
Unknown Stop Time
Severity
Frequency
Action Taken with Study Drug
Other Action Taken
Specify Other Action taken
Relationship to Study Drug
Outcome
Did the subject withdraw from the Study as a result of this AE?Comment
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Screening NumberProtocolBA1116891
Subject Number
15
CONFIDENTIAL 2014N211143_00BA1116891
SERIOUS ADVERSE EVENTSAdverse EventAE NoAdverse Event number/Sample IDSample Date (Start Date) Sample Time (Start Time)Stop Date Stop TimeAE Caused by Study Procedure?Date AE Met Criteria for Serious AEDate Investigator Aware of Serious AEAE is serious due to:DeathPersistent or Significant Disability/IncapacityLife ThreateningCongenital Anomaly or Birth DefectRequires or Prolongs HospitalizationOther Serious / Important Medical EventDate HospitalizedDate DischargedPrimary Cause of DeathSecondary Cause of DeathDate of DeathAutopsy PerformedCausality Assessment (to other than investigational drug):AE caused by Additional Drug 1? Additional Drug 1:AE caused by Additional Drug 2? Additional Drug 2:AE caused by Other Medication? Other Medication:AE caused by Study Procedure? Study Procedure:Description of AEInvestigator’s signatureComments
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Screening NumberProtocolBA1116891
Subject Number
16
CONFIDENTIAL 2014N211143_00BA1116891
PRIOR AND CONCOMITANT MEDICATIONSMedication (trade or generic)Medication number/Sample IDStart Day/Month/Year/TimeTreatment prior to study startEnd Day/Month/Year/TimeOngoingRouteOther RouteDose/UnitFrequencyOther Frequency
IndicationAdverse Event Adverse Event NumberComments
STUDY EXITSample ID: Date/Time: Period:Did the subject complete the study?
Date/Time of Study Exit
Date of Last Contact
Reason for Withdrawal
Other, please specify
Adverse Event Number(s):
Comment
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Screening NumberProtocolBA1116891
Subject Number
17
CONFIDENTIAL 2014N211143_00BA1116891
CONFIDENTIAL
1
LIST OF INVESTIGATORS AND IECS/IRBS FOR BA1116891
Investigator Sub-Investigator Investigator
no./Center no.
Description of Research
Facility, Hospital/ Institution,
and Address
Name of IEC/IRB Committee,
Address, Committee Chair
United States
Leese, Philip T. MD,
CPI
Craven, Kelli M. MD
Hall, Anne M. MD
Holkins, Sally L. RN, MSN,
APRN
Kelly, Christina J. PA-C
Lisbon, Eleanor A. MD, MPH,
CPI
Lomeli, Barbara K. MD
Mathews, David R. MD, CPI
Murtaugh, Thomas E. MD, CPI
Newland, William L. MD
Rasmussen, Scott C. MD
Schutz, Ralph A. MD, CPI
Quintiles Phase One Services,
LLC, 6700 West, 115th Street,
Overland Park, Kansas, 66211,
United States United States
Chairperson:
All centres participated in the study under the US IND.
2014N211143_00BA1116891
This section contained Principal Investigator’s Curriculum Vitae and has been excluded to protect Principal Investigator privacy
Version 2 Print Initials __ __ __Approved by on 11/26/13
FOR QUINTILES USE ONLY
STUDY NAME: A randomized, open label, parallel-group study to estimate bioavailability and to assess the pharmacokinetic profile, safety and tolerability of GSK933776 administered by subcutaneous or intramuscular injection relative to intravenous administration to healthy volunteers.
PROTOCOL I.D.: BA1116891STUDY I.D.: 4950PURPOSED USE: Geographic atrophy (GA) secondary to Age-related macular degeneration
(AMD)TYPE OF STUDY: Phase I – HEALTHY SUBJECTSDATE APPROVED:DATE REVISED:
INFORMED CONSENTWHAT IS INFORMED CONSENT?WHAT DO YOU NEED TO KNOW ABOUT THIS STUDY?You have been asked to take part in a clinical research study of an investigational drug. You must be informed so you can decide whether to participate. Being informed means that you understand the possible risks and that there are no direct benefits to you for taking part in this study.
Only you can decide if you want to take part in this study. You should only make your decision
after reading all of the information in this form. You may talk to your family, friends and or
your family doctor to help make your decision. You can take as much time as you like to decide.
After you have read the entire form, you will be given the chance to ask any questions that you
may have. When you have had the chance to ask any questions and they have been answered to
your satisfaction, if you decide to take part, sign the pages at the end of this form to show that
you agree to be part of the study. This is called “giving your consent”.
Even after you have signed this study consent form you can change your mind and decide not to
participate in the study. You do not have to give a reason.
This consent form has been reviewed and approved by an Independent Review Board (IRB).
This board reviews research studies to protect the rights and well-being of the people taking part.
Some of the information in this consent form is required by law.
DOCTOR IN CHARGE OF THIS STUDY Philip Leese, MD, CPIQuintiles Phase One Services6700 W. 115th StreetOverland Park, KS 66211
1
CONFIDENTIAL 2014N211143_00BA1116891
Page 2 of 16Protocol Number #BA1116891
STUDY ID #4950
Version 2 Print Initials __ __ __
Approved by on 11/26/13
Please let us know if you are not comfortable talking about this informed consent in a group of volunteers, and we can speak with you individually.
NAME OF STUDY DRUG
The Investigational or study drug that you may take in this study is named GSK933776. “Investigational” means that the drug has not been approved by the Food and Drug Administration (FDA) for sale for any indication.
USE
Animal studies have shown that GSK933776 may be effective as a potential treatment for geographic atrophy (a loss of vision in the center of the visual field) that can occur with age-related macular degeneration.
PURPOSE
This is a research study involving about 36 healthy volunteers. The purpose of the study is: To compare how much of the drug gets into the blood and how long the body takes to get
rid of it, after the drug is given in different ways and as a single dose or multiple doses To find out if the drug has any important side effects, and investigate how the drug enters
and leaves the blood and body tissues over time To investigate whether the body produces antibodies to the drug after it is given
The study medication GSK933776 is a monoclonal antibody not yet approved by regulatory authorities for doctors to treat patients with GA.
REQUIREMENTS
You cannot participate in this study if you have participated in a prior study within the past 60
days. You agree that under no circumstance will you dose with two investigational medications
during the time period of this study, because it may cause you serious physical harm.
You will need to have the following exams, tests or procedures to find out if you can be in the
study. The information and samples collected as part of these screening activities will be kept
and used like the rest of the study results. These tests are sometimes part of regular medical care.
They may be done even if you do not join the study.
Medical history: You will be asked about your health and any illnesses you may have orhad in the past. You will be asked about medicines you are taking (including over-the-counter medicine, vitamins or herbal treatments)
Physical examination: You will receive a complete physical examination
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Electrocardiogram (ECG): This will record the electrical activity of your heart. Malessubjects may need to have their chest hair shaved before the ECGs so the ECG patcheswill stick to your skin. Female subjects will not be allowed to wear bras
Vital signs: Your weight, height, blood pressure, heart rate and breathing rate will all bechecked
Blood tests: A small amount of your blood (about 4 teaspoons) will be drawn from avein for clinical lab tests
You will give a urine sample to screen for the presence of drugs
You will be tested for the presence of alcohol by a urine sample or a breath test
Testing for certain diseases such as Hepatitis B, Hepatitis C, and HIV
You will be tested for the HIV antibody. HIV is a virus that causes AIDS. You will alsobe tested for Hepatitis B and C viruses as part of the screening blood tests. All of theabove test results must be negative in order for you to qualify for the study. The positiveresults must be reported, by name, to the Health Department by Quintiles, as required bylaw. The Quintiles study doctor will inform you of this and answer any questions youmay have about this matter. If Quintiles becomes aware during your participation in thisstudy that there is any change in the HIV or Hepatitis results, or other testing during thestudy shows a change, you may be removed from the study.
These screening tests will help determine if you are qualified for the study. The studydoctor may ask you to undergo additional testing to help confirm your eligibility for thestudy. If indicated, a copy of your results from lab tests and other screening procedureswill be available for you to pick up directly, or they will be sent by U.S. mail to yourhome address on file. If any of your test results are assessed to be abnormal andmedically important by the study doctor, you will be asked to share the results with aprimary care or consulting physician who would evaluate you further.
You must read, and agree to follow, the House Rules at the study site if you want to takepart in this study. The House Rules discuss proper behavior at the study site. HouseRules are important to make sure the study results are accurate. You may be fined if youdo not follow the House Rules. You may also be removed from the study and study siteif you do not follow the House Rules.
The study staff will review all of your screening study data (including your medicalhistory, questionnaires, physical exam, electrocardiogram [ECG], vital signs, and labfindings) to make sure you meet all study criteria before you can begin the study.
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PROCEDURES
1. Approximately 36 subjects, ages 18-50, will take part in this study at Quintiles, OverlandPark Kansas. Quintiles will be the only study site. There are 4 different ways planned togive this drug to volunteers (referred to as ‘treatments’). The treatments are labeled as A,B, C and D and are as follows:
TREATMENT:A. 200 mg GSK933776 given once by IV infusion (an infusion into the vein)B. 200 mg GSK933776 given once by SQ injection (an injection into the fatty tissue
under the skin). This treatment will require 4 injections of 50 mg GSK933776 to be given at the same time to get the total dose of 200 mg
C. 50 mg GSK933776, administered by SQ injection once weekly for 4 weeks (an injection into the fatty tissue under the skin)
D. 200 mg GSK933776 administered once by IM injection (an injection into the muscle)
If you qualify for the study, you will be randomly assigned to one of these treatmentgroups. A computer will put people into treatment groups by chance. Neither you nor the study doctor can choose a group. You have a 25% chance of being placed in each group. You will remain on this treatment group for the entire study. You will only receive one of the treatments.
2. Length of Stay: The length of stay will depend on the treatment to which you arerandomly assigned. You will be assigned to the treatment group on the day you check-into Quintiles to start the study.
Treatments A, B, and D: You will stay at Quintiles for 1 day on one occasion, therewill not be any overnight stays required. You must also be available to come back toQuintiles for about 11 follow up visits.
Treatment C: You will stay at Quintiles for 1 day on four separate occasions,there willnot be any overnight stays required. You must also be available to come back for about25 follow up visits.
3. The length of the study is about 18-20 weeks, depending on the part of the study you are
assigned.
Please keep in mind how the study tests and visits described here will affect your workand family schedules. Consider if you need transporation to and from the clinic. Youmay find that these tests and visits need some planning. Some tests may beuncomfortable. Ask the study doctor if you have any questions about the tests andprocedures for the study.
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4. This is an “open-label” study. This means that you and other subjects, the Quintiles staff
members and the Quintiles Pharmacist will know what drug you are receiving and by
what route (injection in the veins, muscle or fatty tissue) you will be receiving it.
5. There is no placebo (an inactive substance like a sugar pill) planned for this study. This
means you will receive the study drug while you are on the study.
6. You will be on a standard House diet while you are at Quintiles. This means that youwill be allowed only the food and drinks that are approved by Quintiles during the study.Meal substitutions (food or drink) will not be allowed. No alcohol is allowed during thestudy for 24 hours prior to the start of dosing and until the collection of the final samplesduring each session. An alcohol test will be given prior to the start of each session.
7. For your safety, you must not:
Take any other medicines without first speaking with the study doctor (Thesemedicines include prescription or over-the-counter drugs taken by mouth; appliedto skin; taken by nose or inhaled; placed in eyes or ears; vitamins, herbal ordietary supplements)
Participate in another studyThese restrictions are to be followed during the study and for at least 85 days after the last dose of the study drug that was given to you.
8. Your blood will be taken approximately 20 times during the study if you are assigned toTreatments A, B or D. If you are assigned to Treatment C, your blood will be takenapproximately 35 times. This will be done by individual needle sticks or by intravenous(IV) catheter. An IV catheter is a small plastic tube inserted into your arm or hand veinby a needle. The needle is removed but the tube temporarily remains in your vein. Thistube allows the removal of blood without having to stick you each time. If the catheterstops working, a new one may be placed. The amount of blood that will be taken inTreatments A, B or D is about 7 ounces (210 ml) throughout the entire study. If you areassigned to Treatment C, the amount of blood that will be taken is about 12 ounces (350ml) throughout the entire study. This compares to a standard blood donation of about 2cups (500ml). It is possible that more than one try may be needed to get enough blood.
9. You will have several sets of vital signs taken during the study. Physical exams will also
be completed on days over the course of the trial.
10. Several ECGs (electrocardiograms) will be done during the study.
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RISKS
This drug has been tested in a relatively small number of humans, and there is always a possibility for side effects that we do not know about to occur. As with all study drugs, some of these unknown side effects may be life-threatening.
What side effects or risks can I expect from this study?
You may experience side effects from the study drug. Everyone in the study will be watched carefully for any side effects. Side effects may be mild or serious. If you experience a side effect, the study staff may give you medicines to help lessen these effects. Some side effects may go away as soon as you stop taking the drug. In some cases, side effects can be serious, long-lasting or may never go away.
Possible side effects and risks from GSK933776:
This drug has not yet been given to healthy volunteers. There have been 2 completed clinical trials in Alzheimer’s Disease subjects and there is 1 ongoing clinical trial in subjects with geographic atrophy secondary to age-related macular degeneration (an eye disease).
GSK933776 has been given to 36 patients in 2 Alzheimer’s Disease trials and to at least 87
subjects in the ongoing eye disease trialAdverse events so far reported have been short lived and
mostly mild to moderate in nature.
The most commonly reported adverse events (>5% incidence) were fatigue/tiredness, nausea, headache, vomiting, diarrhea, dizziness, musculoskeletal signs and symptoms such as pain and stiffness.
GSK933776 is thought to lower levels of a small protein called amyloid beta. Based on current knowledge, the human body does not need amyloid beta for its normal activities, therefore it is not expected that its elimination by the study medicine would disturb the normal functions of your body.
During the study we will collect information on your blood and urine as well as your general health. We will also be testing your blood to see if antibodies against GSK933776 are made.Usually the body makes antibodies as part of the body’s defense against infection and foreign proteins. It is possible that some people given GSK933776 might produce antibodies against this drugWe will be testing your blood to see if this happens.
Potential side effects related to the use of GSK933776 (and monoclonal antibodies in general)
might include:
Infusion/injection related reaction - When GSK933776 is given to you, the infusion needlemay cause temporary pain, bruising, swelling and/or irritation to your arm or area where thestudy drug is injected. Some people develop a reaction to protein infusions, which although
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rare, may cause fever, shivering, nausea and a general feeling of being unwell to start soon after the dose has been given.
Allergic reaction consisting of, but not limited to, nausea, facial flushing, itchy rash, difficulty breathing, fever, and muscle aches may occur.
Acute anaphylaxis - Anaphylaxis is a severe allergic reaction affecting the whole body. Subjects at particular risk are those who have been exposed to monoclonal antibodies in the past which is why subjects exposed to monoclonal antibodies in the past cannot participate in this study. We do not expect this to occur but you will be closely monitored for this. If anaphylaxis occurs, you may require emergency treatment, including additional drugs and potentially breathing assistance.
If an anaphylactic reaction should occur, study medication will be stopped immediately and you will be removed from the study. You will be asked to come back to the clinic for an early withdrawal visit.
You will be monitored for a time period after the study drug is administered. You can not leave the facility until approved by the study doctor. This is so that the study doctor can watch for any potential or possible side effects that may be caused by the study drug.
There may be other side effects that may happen that are not known now. Certain problems can become worse if not treated quickly. Call the study doctor right away if:
You feel very tired or faint You feel pain or sick in your stomach and do not want to eat You bruise easily or develop itching You have yellow eyes or skin, or dark urine You become confused
If you experience certain serious problems (such as an allergic reaction, swelling, difficulty breathing, a bad skin rash, liver or kidney damage, or changes in your heart rhythm), you may be asked to return to the clinic for more assessments, which may include more blood tests. Your doctor will explain these tests to you if they are needed. You may also need to stop taking the study drug after talking with your study doctor.
You should not take part in this study if you are pregnant or able to become pregnant.
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ADDITIONAL RISKS
1. There may be side effects of drawing blood with a needle and/or IV tubes. They may
include fainting, bruising, soreness, blood clots and tenderness at the needle site. On
rare occasions, it may cause an infection. If you experience any of these symptoms or
have any other problems, you must tell a Quintiles staff member right away. You
should tell a study nurse, study director, or you may also tell the doctor.
2. You must not give blood for 30 days after the study is over because of the amount of
blood that we will take during this study.
3. Possible side effects from the patches that are put on your skin when the ECG is
performed may be a rash, redness, or minor irritation of the skin.
4. You must clearly understand that while you are on this study, the use of other
investigational drugs, alcohol or illegal drugs (such as marijuana, cocaine, etc.) may
cause you serious harm and is strictly prohibited.
5. As with all medicines or procedures, there may be risks that we do not know about.
6. The study doctor or a member of his/her staff will tell you about any important new
information that relates to the study drug and that may affect your decision to remain
in this study. If this happens, you must decide if you want to keep taking part in this
study. You will be asked to agree, in writing, that you were told about these new
findings. You may also be given an additional form to the Informed Consent. This
will be provided if more information becomes available about side effects that have
been seen with subjects in this research study. If this happens, you will be asked to
read and sign the additional form.
You should talk with the study doctor or research staff if you have any questions about these risks. Ask your study doctor if you have any questions about side effects.
INFORMATION ON BIRTH CONTROL
Women who can get pregnant will not be allowed to participate in this study. Men with partners who can get pregnant will need to use birth control while in this study, as will their partner. Some methods may not be approved for use during this study.
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FEMALES
The treatments or procedures performed during this study may pose unknown risks
to an unborn baby. Women who are pregnant or breastfeeding must not participate
in this study. You MUST be a woman of non-child bearing potential to participate
in this trial. The following are acceptable proof of non-child bearing potential:
Surgery to prevent pregnancy (hysterectomy, which is removal of the uterus; oophorectomy, which is removal of both ovaries; tubal ligation, which is having the fallopian tubes tied; tubal occlusion, which is a procedure which results in the blockage of the fallopian tubes). You may be asked to provide proof of your surgery or procedure to participate in the study.
Confirmed as being postmenopausal by not having a menstrual cycle for at least 12 months. You may also need to provide a blood sample to test forblood hormones which would confirm this.
You must not be currently breastfeeding. If, at any time during the study, you think you may be pregnant, you must immediately contact the study doctor, Phillip Leese, MD at
MALES
The drug used in this study could harm an unborn child. The effect of the study drug on the male reproductive system is unknown. Therefore, you MUST agree to use an acceptable form of birth control throughout the study and for at least ninety (90) days after the last dose of the study drug (even if you have had a vasectomy). You must also abstain from sperm donation until 90 days after your last dose of study medication. Acceptable birth control methods are:
Condom (during non-vaginal intercourse with any partner - male or female)OR
Condom OR occlusive cap (diaphragm or cervical/vault caps) plus spermicidal agent (foam/gel/film/cream/suppository) (during sexual intercourse with a female)
Abstinence, defined as sexual inactivity consistent with your preferred and usual lifestyle
Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are NOT acceptable methods of contraception
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You must not be actively trying to father a child during the time period of the entirestudy and for 90 days after the last dose of the study drug.
If you think that your partner may be pregnant at any time during the study, you must immediately contact the study doctor, Phillip Leese, MD at
BENEFITS TO YOU AND OTHER SUBJECTS:
The goal of this research study is to provide scientific information. You and other participants will not receive any direct medical benefits.
ALTERNATE THERAPY:
This is a research study. It is not treatment or therapy. You may choose not participate in the study.
COMPENSATION RELATED TO STUDY PARTICIPATION
1. Compensation will depend on the treatment group to which you are assigned.
Treatments A, B, and D: You will be compensated a total of $3,850.00 if you are accepted
for the study and finish all the tests. You will be compensated in the following way:
Day 2: $400.00 Day 10: $900 Day 29: $850 Day 57: $800 Day 85: $900
Treatment C: You will be compensated a total of $7,000.00 if you are accepted for the
study and finish all the tests. You will be compensated in the following way:
Day 2: $400 Day 9: $1000 Day 16: $1000 Day 23: $1000 Day 43: $900 Day 50: $800 Day 78: $900 Day 106: $1000
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2. According to the IRS (Internal Revenue Service) guidelines, you will be responsible for paying taxes on any compensation that you receive from your study participation. Quintiles will send you a 1099-form for this purpose. Quintiles will also report to the IRS any compensation that you receive that totals $600.00 or more for the calendar year. You should tell Quintiles Phase One Services, LLC. of your new mailing address if you move after your participation in a study. This is to make sure you receive your 1099 for your year-end tax reporting.
3. If, for any reason you cannot finish the study, or we decide to discharge you, you will be compensated for your time during the study on a pro-rated basis. You will receive this compensation at the end of the study.
4. You do not have to pay for any study-related medicines, procedures or treatment at Quintiles during the study.
COMPENSATION FOR INJURY
1. Medical care will be given to you, at no cost, if you are injured as a result of being in this study.
2. You and your insurance company will continue to pay for your regular health care.
3. GSK will pay the costs for reasonable and necessary care if you are hurt by the study drug or a procedure that is done to you only because you are part of this study. To pay these medical expenses, GSK will need to know some information about you like your name, date of birth, and social security number. This is because GSK has to check to see if you receive Medicare, and, if you do, report the payment it makes to Medicare. GSK will not use this information for any other purpose.
4. While you are in the study, you may be injured because of your personal conduct or during activities which are not part of the study. There are no plans to pay you for these types of injuries.
5. Signing this consent form does not change any legal rights you may have.
WHO IS PAYING FOR THE STUDY AND WHAT DO THEY DO?
GlaxoSmithKline (also called “GSK”) is a company that discovers and makes vaccines, medicines and other health products. GSK pays the study doctor and Quintiles to run this study.
YOUR PARTICIPATION IN THE STUDY
1. Do I have to stay in the study? No. Your participation in this study is completely voluntary. You may choose to stop
taking part in the study at any time, without giving a reason. Tell the study staff if you
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want to stop being in the study. Your decision will not affect your medical care now or
in the future. It will not affect other benefits you receive outside of the study.
You may be asked to leave the study if: The results of certain tests show that you are not right for this study or for the study
drug. You do not follow study instructions for treatment or follow-up visits. You get new health problems during the study that might not work well with the
study set-up. You get pregnant. The study doctor thinks it is best for you to stop.
New information may become available or known that might affect your choice to stay in the study. Such information will be shared and discussed with you. This new information may include updated safety information about the study drug.GSK (the study sponsor), the regulatory authority, or the study doctor may choose to stop the study at any time. Should this occur, the reason will be provided at that time.
If you decide to leave the study, you and the study doctor will discuss the best way to do this.
2. You may be photographed during the screening or enrollment process. These
photos will not identify you, but will record physical conditions before a study
begins. These photos may be used to compare to photos taken after dosing with study
drug. If you have any side effect, photos may be taken of side effects on your body
after dosing, such as if you develop a rash during the study. These photos will not
identify you. They may be used for treatment and/or research purposes. All
photographs will be the property of Quintiles and/or the Sponsor.
3. If you have health problems, you will get medical attention. You may be
withdrawn from the study by the study doctor and/or the Sponsor of the study without
your consent, if it is in your best medical interest. It is possible that the study doctor
and/or Sponsor may think you can stay on the study. You must decide what you want
to do.
4. If you do not complete the study, for any reason, you will be asked to receive a
complete physical exam, lab tests, vital signs, and ECG before you leave. This is
needed to protect your safety.
5. All the information you gave us before you left the study will still be used for the
study.
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What happens to my personal and medical information?
It is very important that your personal and medical information stay confidential and secure. GSK will protect your information in accordance with current law.
When you sign this consent form you agree that GSK can use your personal and medical information as described here:
Your personal and medical information may be checked by GSK and others (like agencies that approve and monitor studies). This is to make sure that the study is being run properly.
Besides that, only the researchers at this study site can use information that identifies you (such as name and address) and only for the purpose of the study.
Your study information will be labelled with a code number (for example, It will not include your name or address. The study doctor will have the link between your name and the code number.
The link between your name and the code number will not be shared. Only the code number and coded information will be sent to GSK.
GSK will use your coded information for research only.
GSK may:
keep your coded information electronically, and analyse it by computer to find out what the study is telling us. This may be done by GSK or a third party, in which case GSK will ensure that the third party is required to keep your data secure,
share the information with regulatory agencies that approve new medicines,
share the information with people who check that the study is done properly (like the ethics committee or review boards),
combine the information with results from other studies to learn more about the medicine and other medicines. This may help us to assess the risks and benefits of GSK (or other) medicines, or to improve disease understanding,
publish study results for medical journals, meetings and on the internet for other researchers to use; your name will not appear in any publication,
share coded information with other companies, organisations or universities to carry out research.
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Personal and medical data collected during the study may be moved, stored and used in the
country where you live or another country where GSK or those working with GSK work.
Use of this information may take place in countries with lower data protection rules than the
country where you live. GSK will make sure that if your data are moved to another country, it
will still be treated as stated in this Informed Consent Form.
A description of this clinical study will be available on the GSK Clinical Study Register:
http://www.gsk-clinicalstudyregister.com/ and may also appear in clinical trial/study registries in
countries in which the clinical study is conducted.
CONFIDENTIALITY OF RECORDS
Quintiles will handle the medical information obtained in this study with the strictest confidence. It will be protected as required by laws and/or regulations. It will not be made publicly available. If the results of this study are published you will not be identified by name.
Some people and organizations can look at and copy your medical record and the information collected during this study. They include:
Employees of the FDA (Food and Drug Administration) or other government authorities;
The Sponsor or its agents; Quintiles, and its agents (consulting physicians or specialists); Members of the The IRB is a group of
individuals from the community responsible for the review and approval of research proposed to be conducted on human subjects.
By signing this consent, you authorize Quintiles to verify your study participation history with other businesses that conduct clinical research studies.
WHAT HAPPENS TO MY BLOOD/TISSUE SAMPLES?
If you take part in this study, you will be asked to give blood samples for safety testing and blood samples to find out information about the drug. Similar to information collected in the study, your samples may also be used by GSK or shared by GSK with other companies or universities to better understand GA, other diseases or conditions, or to further develop the study drug or other drugs.
Your blood samples will be given the same code as your other study information and kept in locked storage. Anyone who works with your samples will hold the information and results in confidence.GSK may store your tissue samples for up to 15 years after the end of the study after which time your samples will be destroyed.
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PERSONS TO CONTACT FOR QUESTIONS, CONCERNS, OR COMPLAINTS
If you have any questions, concerns or complaints about this study, you can call the study doctor Phillip Leese, MD, CPI at
If you have questions about your rights, general questions, complaints or concerns about this research, or questions about your rights as a person taking part in this study, call the
at or If, at any time during or after your participation in this research, you would like information or to offer input about your research experience, you can call the at the number above or you can go to the website at and give us your comments. Either way, you do not have to give us your name, if you do not want to.
You have the right to ask any questions concerning the potential and/or unknown hazards of this study, at any time. If you have any questions concerning your participation in this study, or if at any time you feel you have experienced a research-related injury or a reaction/side effect to the study drug, contact Philip Leese, MD, CPI at
For General questions you may contact the study director, at
LEGAL RIGHTS
You will not lose any of your legal rights to which you are otherwise entitled by signing this consent form.
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DO YOU HAVE ANY QUESTIONS?
Do you have any questions that you would like to discuss with the study doctor? ____NO ___ YES
If yes, I as an Investigator, have addressed and answered the participant’s questions.
Investigator’s Initials _________________ Date_______________
SUBJECT STATEMENT- (Subject is to read this out loud to staff)
I can speak and read the English language. I have read this Informed Consent Document. I have had enough time to read this information. I have been given a chance to ask questions. I have received answers to my questions, and I am satisfied with those answers. I understand this consent and the information given to me.
I am signing this form freely and am not being forced. If I do not take part in the study, I will not lose any benefits. I have the legal capacity to enter into contract, and no Guardian has been appointed
for me. If I leave the study, I will not lose any benefits. If I leave the study, I will not lose any legal rights. My participation in this study is completely voluntary.
I agree to cooperate with all the medical personnel. I agree to take the medicines and treatments as directed. I agree to do the actions required by as discussed in this informed consent. I understand it is my duty to tell the study doctor or Quintiles staff about all changes
in my physical or mental health during the study. I have given and will give truthful and complete information about my health and
medical history to the study physician/staff.
By signing this consent form, I am agreeing to the release of my medical records to the FDA
(Food and Drug Administration) or other government authorities, the Sponsor or its agents,
Quintiles and its agents, the and any third party required
by law. I understand that I will receive a signed and dated copy of this form to keep for my
records.
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Subject’s Printed Name Subject’s Signature
Date
:
Time
Person Obtaining Consent Form Signature Date
Printed Name of Person Obtaining Consent Form
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Final Schedule Detail ReportStudy ID: BA1116891Schedule Number: 2Schedule Version: 1.0
Study DescriptionGSK933776 PH 1 HV PK Bioavailability study to compare IM and SQ administrationwith IV administration
Schedule DescriptionBA1116891 Bioavailability Study Schedule 2
Schedule DefinitionsStrata Description Block Size Rand. No. RangeALL 4
Group Code Group Description Ratio1 200 mg GSK933776 administered by IV infusion -
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Treatment Group and Treatment Definitions
Treatment GroupTreatmentCode Treatment Description Period
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2 2 200 mg GSK933776 administered by SQ injection 1
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1
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THIS IS THE LAST PAGE OF THE REPORT.
CONFIDENTIAL 2014N211143_00BA1116891
ICH Data Listings Page
Listing 9.1 Listing of Randomized and Actual Treatments (Safety Population) ....... Listing 9.2 Listing of Subjects excluded from Analysis Populations (Safety
Population) ................................................................................................... Listing 9.3 Listing of Reasons for Study Withdrawal/Completion (Safety
Population) ................................................................................................... Listing 9.4 Listing of Protocol Deviations (Safety Population) ................................. Listing 9.5 Listing of Demographic Characteristics (Safety Population) .................. Listing 9.6 Listing of Race (safety Population) ........................................................ Listing 9.7 Listing of Concomitant Medications (Safety Population) ....................... Listing 10.1 Listing of Exposure to Component (Safety Population) ....................... Listing 10.2 Listing of Relationship Between System Organ Class and Verbatim
Text (Safety Population) .............................................................................. Listing 10.3 Listing of All Adverse Events (Safety Population) ................................ Listing 10.4 Listing of Serious Adverse Events (Safety Population) ....................... Listing 10.5 Listing of Adverse Events Leading to Withdrawal from the Study
(Safety Population) ...................................................................................... Listing 10.6 Listing of Pregnancy (Safety Population) ............................................ Listing 10.7 Listing of Laboratory Tests and Associated Reference Ranges
(Safety Population) ...................................................................................... Listing 10.11 Listing of Abnormal ECG Findings (Safety Population) ..................... Listing 10.12 Listing of All ECG values for Subjects with any Value of Potential
Clinical Importance (Safety Population) ....................................................... Listing 10.13 Listing of Vital Signs (Safety Population) ........................................... Listing 10.14 Listing of All Vital Signs for Subjects with any Value of Potential
Clinical Importance (Safety Population) ....................................................... Listing 10.101 Listing of All Clinical Chemistry Laboratory Data for Subjects with
PCI Abnormalities (Safety Population) ......................................................... Listing 10.102 Listing of All Hematology Laboratory Data for Subjects with PCI
Abnormalities (Safety Population) ................................................................ Listing 10.103 Listing of All Urinalysis Data for Subjects with PCI Abnormalities
(Safety Population) ...................................................................................... Listing 10.801 Listing of All Clinical Chemistry Laboratory Data (Safety
Population) ................................................................................................... Listing 10.802 Listing of All Hematology Laboratory Data (Safety Population) ....... Listing 10.803 Listing of All Urinalysis Laboratory Data (Safety Population) ........... Listing 10.901 Listing of Clinical Chemistry Laboratory Data for Subjects with Lab
Values Outside of Normal Range (Safety Population) ................................. Listing 10.902 Listing of Hematology Laboratory Data for Subjects with Lab
Values Outside of Normal Range (Safety Population) ................................. Listing 10.903 Listing of Urinalysis Laboratory Data for Subjects with Lab Values
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This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the GSK Clincal Study Register.
Other Data Listings Page
Listing 11.1 Listing of Plasma GSK933776 Pharmacokinetic Concentration-Time Data (Pharmacokinetic Population) ..............................................................
Listing 11.2 Listing of Derived Plasma GSK933776 Pharmacokinetic Parameters (PKParameter Population) ...........................................................................
Listing 12.1 Listing of Plasma Abeta Pharmacodynamic Concentration-Time Data (Pharmacodynamic Population) ...................................................................
Listing 12.2 Listing of Anti-GSK933776 Antibody Immunogenicity Assessment-Time Data (Pharmacodynamic Population) .................................................
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CONFIDENTIAL GlaxoSmithKline
VALIDATION REPORT
Validation of the ELISA Method
“Quantification of GSK933776 in Human Plasma (Range 100 - 5000 ng/mL) Using a Colorimetric Immunoassay”
Sponsor: GlaxoSmithKline Pharmaceuticals GSK Document No.: 2013N182307_00
Alliance Pharma Study No.: 130825
Alliance Pharma Report No.: V130825.01
Document Issued on 27 Nov 2013
Prepared by
Alliance Pharma, Inc. 17 Lee Boulevard
Malvern, PA 19355 USA
GSK Document No.: 2013N182307_00
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STUDY INFORMATION
Title Validation of the ELISA Method “Quantification of GSK933776 in Human Plasma (Range 100 - 5000 ng/mL) Using a Colorimetric Immunoassay”
Bioanalytical Principal Investigator
Ph.D. Alliance Pharma Tel: Fax: E-mail:
Sponsor GlaxoSmithKline Pharmaceuticals 709 Swedeland Road King of Prussia, PA 19406
Sponsor Reviewers E-mail:
E-mail:
Bioanalysis Facility Alliance Pharma 17 Lee Boulevard Malvern, PA 19355
GSK Document No. 2013N182307_00
Alliance Pharma Study No. 130825
Experimental Start Date 27 Aug 2013
Experimental End Date 15 Oct 2013
Document Issued 27 Nov 2013
Total Number of Pages 52
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LIST OF CONTRIBUTORS
Title: Validation of the ELISA Method “Quantification of GSK933776 in Human Plasma (Range 100 - 5000 ng/mL) Using a Colorimetric Immunoassay”
Alliance Pharma Study No.: 130825
Ph.D.
Bioanalytical Principal Investigator
M.Sc.
Analyst
M.D.
Analyst
Lin, M.Sc.
Analyst
B.Sc.
Analyst
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Report No.: V130825.0lGSK Document No.: 20l3N182307 00
SIGNATURE PAGE
Title: Validation of the ELISA Method "Quantification of GSK933 776 in HumanPlasma (Range 100 - 5000 ng/mL) Using a Colorimetric Immunoassay"
Alliance Pharma Study No.: 130825
Ph.D.
Bioanalytical Principal Investigator
Alliance Pharma
Date
13Management
Alliance Pharma
40f52
Date
2014N211143_00BA1116891
Report No.: V130825.01GSK Document No.: 2013N182307 00
COMPLIANCE STATEMENT
Title: Validation of the ELISA Method "Quantification of GSK933776 in HumanPlasma (Range 100 - 5000 ng/mL) Using a Colorimetric Immunoassay"
Alliance Pharma Study No.: 130825
I certify that the bioanalytical study was conducted in compliance with the relevant AlliancePharma Standard Operating Procedures (SOPs). The information given in this report fully andaccurately reflects the raw data generated during the study.
Ph.D.
Bioanalytical Principal Investigator
Alliance Pharma
50f52
Date
2014N211143_00BA1116891
Report No.: V130825.01aSK Document No.: 2013N182307 00
QUALITY ASSURANCE STATEMENT
Title: Validation of the ELISA Method "Quantification of GSK933776 in HumanPlasma (Range 100 - 5000 ng/mL) Using a Colorimetric Immunoassay"
Alliance Pharma Study No.: 130825
This validation report has been audited by the Quality Assurance Unit for adherence to thevalidation plan and corresponding Alliance Pharma standard operating procedures (SOPs).Within the scope of the audit, this report is considered an accurate description of the method andpresentation of the results.
Date Reported toStudy Phase Inspected Date of Inspection Bioanalytical Principal
Investigator/Management
Raw Data Audit27 Sep 2013
03 Oct 201330 Sep to 01 Oct 2013
Report Audit30 Sep to 01 Oct 2013 03 Oct 2013
21 to 22 Oct 2013 22 Oct 2013
Date
Quality Assurance Auditor
Alliance Pharma
60f52
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LIST OF ABBREVIATIONS
%Bias Difference between measured value and nominal value expressed as a percentage
%CV Coefficient of variation expressed as a percentage
D.F. Dilution factor
ELISA Enzyme-linked immunosorbent assay
HQC High quality control
hr Hour(s)
LLOQ Lower limit of quantification
LQC Low quality control
mg Milligram
µL Microliter
mL Milliliter
MQC Medium quality control
n Number of samples
n/a Not available / not applicable
ng Nanogram
PA Precision and accuracy
QC Quality control
OD Optical Density
RT Room temperature
SD Standard deviation
SOP Standard operating procedure(s)
STD Standard
ULOQ Upper limit of quantification
VS Validation sample(s)
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TABLE OF CONTENTS
STUDY INFORMATION ...............................................................................................................2
LIST OF CONTRIBUTORS ...........................................................................................................3
SIGNATURE PAGE .......................................................................................................................4
COMPLIANCE STATEMENT .......................................................................................................5
QUALITY ASSURANCE STATEMENT ......................................................................................6
LIST OF ABBREVIATIONS ..........................................................................................................7
LIST OF TABLES ...........................................................................................................................9
LIST OF FIGURES .......................................................................................................................10
LIST OF APPENDICES ................................................................................................................11
1. INTRODUCTION ..................................................................................................................12
2. METHOD VALIDATION SUMMARY ................................................................................13
3. VALIDATION PROCEDURES ............................................................................................14
3.1. Reference Standard .......................................................................................................14 3.2. Preparation of Standards and Validation Samples ........................................................14 3.3. Major Computer Systems and Data Processing ............................................................14
4. RESULTS AND DISCUSSION .............................................................................................14
4.1. Run Summary ...............................................................................................................14 4.2. Standard Curve Evaluation ...........................................................................................14 4.3. Precision and Accuracy .................................................................................................15 4.4. Dilution Linearity and Prozone Effect ..........................................................................15 4.5. Selectivity and Matrix Effect ........................................................................................15 4.6. Stability of GSK933776 ................................................................................................15
5. CONCLUSION .......................................................................................................................16
6. DEVIATION ..........................................................................................................................16
7. ARCHIVE STATEMENT ......................................................................................................16
8. REVISION HISTORY ...........................................................................................................16
9. TABLES .................................................................................................................................17
10. FIGURES ................................................................................................................................25
11. APPENDICES ........................................................................................................................26
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LIST OF TABLES
Table 1 Validation Summary for Quantification of GSK933776 in Human Plasma .................17
Table 2 Back-Calculated Concentrations of GSK933776 Calibration Standards (ng/mL) .......17
Table 3 Precision and Accuracy of GSK933776 Validation Samples .......................................18
Table 4 Precision and Accuracy of GSK933776 QC Samples ..................................................20
Table 5 Dilution Linearity and Prozone Effect of GSK933776 in Human Plasma ...................20
Table 6 Selectivity of GSK933776 in Human Plasma ...............................................................21
Table 7a Stability of GSK933776 in Human Plasma Stored at RT (Bench Top) for 24 hr ........23
Table 7b Stability of GSK933776 in Human Plasma Stored at -20ºC for 15 Days .....................23
Table 7c Stability of GSK933776 in Human Plasma after 6 Freeze-Thaw (-20ºC/RT) Cycles ..23
Table 7d Stability of GSK933776 in 11-Fold Assay Buffer-Diluted Human Plasma Stored at 4°C for 24 hr .................................................................................................................24
Table 7e Stability of GSK933776 in Human Plasma Stored at -70ºC for 15 Days .....................24
Table 7f Stability of GSK933776 in Human Plasma after 6 Freeze-Thaw (-70ºC/RT) Cycles ..24
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LIST OF FIGURES
Figure 1 A Representative Calibration Curve of GSK933776 (Curve Range: 100 to 5000 ng/mL) (Batch: PA-3, 5-Parameter Regression, 1/Y weighing) .........................25
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LIST OF APPENDICES
Appendix 1 Bioanalytical Method: 130825M.01V .....................................................................26
Appendix 2 Certificate of Analysis for GSK933776 ..................................................................35
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1. INTRODUCTION This report describes the validation of the ELISA method “Quantification of GSK933776 in Human Plasma (Range 100 - 5000 ng/mL) Using a Colorimetric Immunoassay” The method was validated based on an ELISA method originally developed by GlaxoSmithKline (GSK Method Reference No.: GSK933776HUPLVALA Version 04). GSK933776 is a humanized monoclonal antibody against beta-amyloid peptide provided by GSK. GSK933776 in calibration standards, quality controls (QCs), and human plasma samples is first bound to the amyloid peptide on the plate. This complex is then further bound to mouse anti-human IgG1 (Fc specific) antibody labeled with horseradish peroxidase (HRP), which catalyzes the chromogenic HRP substrate 3,3′,5,5′-tetramethylbenzidine (TMB). This reaction yields a blue color with a maximal absorbance at 650 nm. The blue color then changes to yellow via the addition of sulfuric acid, resulting in maximum absorbance at 450 nm for the final readout. The absorbance at 450 nm is proportional to the amount of GSK933776 in the calibration standards, QCs, and samples.
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2. METHOD VALIDATION SUMMARY Title Validation of the ELISA Method “Quantification of GSK933776 in Human
Plasma (Range 100 - 5000 ng/mL) Using a Colorimetric Immunoassay” Analyte GSK933776 Matrix Human Plasma with K2 EDTA as anticoagulant Range of Standard Curve 100 – 5000 ng/mL Lower Limit of Quantification 100 ng/mL Sample Volume 50 µL Capture Reagent Beta-amyloid peptide 1-16 Detection Reagent Mouse anti-human IgG1 labeled with horseradish peroxidase (HRP) Standards Inter-Assay Precision and Accuracy for Standards
100, 200, 400, 800, 1500, 2500, 4000 and 5000 ng/mL %CV: 1.03% to 5.18% %Bias: -1.77% to 5.16%
Validation Samples (VS) 100, 300, 1000, 3800 and 5000 ng/mL Intra-Assay Precision for VS %CV: 0.85 to 24.79% Intra-Assay Accuracy for VS %Bias: -16.55 to 20.89% Inter-Assay Precision for VS %CV: 2.83 to 8.15% Inter-Assay Accuracy for VS %Bias: -8.74 to 6.61% Dilution Integrity 7600-fold dilution VS: %CV: 4.28% and %Bias: 0.12%
600-fold dilution VS: %CV: 1.44% and %Bias: -1.85% Prozone Effect Prozone effect was not observed at 2.28 mg/mL of GSK933776 in human
plasma Selectivity No significant matrix effect was observed in ten lots of human plasma with
each lot being derived from an individual donor Stability in Matrix
Bench top: 24 hr Freeze-thaw (-20ºC/RT, 70ºC/RT): 6 cycles Assay buffer-diluted samples at 4oC: 24 hr Long term storage at -20ºC and -70 ºC: 15 days
Run Acceptance Criteria Calibration Standards • Precision (%CV): ≤ 20% (≤ 25% at LLOQ and ULOQ)
• Accuracy (%Bias): within ±20% (±25% at LLOQ and ULOQ) At least 6 non-zero calibration standards should meet the above criteria.
Quality Control/Validation Samples
• Precision (%CV): ≤ 20% (≤ 25% at LLOQ and ULOQ) • Accuracy (%Bias): within ±20% (±25% at LLOQ and ULOQ)
At least ⅔ of the QC samples and at least 50% at each level should meet the above criteria.
SOP Reference Method Validation for Ligand Binding Assays
Alliance Pharma SOP BP-001-V02
Validated Method Appendix 1. Alliance Pharma Bioanalytical Method: 130825M.01V
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3. VALIDATION PROCEDURES
3.1. Reference Standard
Analyte Lot Number Correction Factor for Free Base
Expiration Date Source Storage Conditions
GSK933776 101272093 n/a 28 Feb 20141 GSK -70°C
1Vendor extended expiration to 90 months from date of manufacture (31 Aug 2006). (Appendix 2)
3.2. Preparation of Standards and Validation Samples The reference standard, GSK933776 (50 mg/mL), was used to prepare calibration standards at nominal concentrations of 50, 100, 200, 400, 800, 1000, 1500, 2500, 4000, and 5000 ng/mL in normal human plasma. The 50 ng/mL calibration standard was used as an anchor point for curve fitting purposes. Prepared calibration standards were stored at -20°C. Validation samples (VS) at 5 concentration levels were prepared by spiking a known amount of reference standard in normal human plasma. The nominal concentrations in VS were 100 (VS1-LLOQ), 300 (VS2-LQC), 1000 (VS3-MQC), 3800 (VS4-HQC), and 5000 (VS5-ULOQ) ng/mL. Prepared validation samples were also stored at -20°C. Once VS were validated in the precision and accuracy (PA) batches, VS2-LQC, VS3-MQC, and VS4-HQC were used as the quality control samples (LQC, MQC, and HQC) in subsequent batches in this study.
3.3. Major Computer Systems and Data Processing Colorimetric data were acquired using a BioTek ELx800 microplate reader (Winooski, VT), which was controlled by a Dell PC workstation via BioTek Gen5TM software. The acquired data were processed using BioTek Gen5TM software and Microsoft® Excel. A standard curve was constructed by plotting the concentrations of standards in log scale (X-axis) versus their corresponding optical density units (OD, Y-axis), and fitted with a 5-parameter logistic algorithm using a 1/Y weighting. The concentration of analyte in samples was determined based on the standard curve.
4. RESULTS AND DISCUSSION
4.1. Run Summary A total of 11 assay batches were performed for this validation, and every batch met the acceptance criteria. All assays performed in this study are summarized in Table 1.
4.2. Standard Curve Evaluation The standard curve was evaluated in 11 individual assay batches. Results of this evaluation met the acceptance criteria (Table 2). Overall precision (%CV) and accuracy (%Bias) for standards ranged from 1.03 to 5.18% and from -1.77 to 5.16%, respectively. A representative standard curve is shown in Figure 1.
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4.3. Precision and Accuracy Five levels of validation samples at 100 (LLOQ), 300 (LQC), 1000 (MQC), 3800 (HQC), and 5000 ng/mL (ULOQ) were assayed in four replicates (n = 4) along with a standard curve in each batch, and a total of six batches were performed by three analysts on two different days. Intra-assay accuracy (%Bias) and precision (%CV) of the validation samples ranged from -16.55 to 20.89% and from 0.85 to 24.79%, respectively. Inter-assay accuracy and precision of the validation samples ranged from -8.74 to 6.61% and from 2.83 to 8.15%, respectively (Table 3). These 6 batches met the assay acceptance criteria. In 5 additional validation batches the precision and accuracy of QC samples at 300 (LQC), 1000 (MQC) and 3800 ng/mL (HQC) also met the assay acceptance criteria (Table 4).
4.4. Dilution Linearity and Prozone Effect GSK933776 was spiked in human plasma at 2.28 mg/mL, then further diluted to 3800 and 300 ng/mL using blank human plasma (D.F. 600 and 7600, respectively). Six replicates (n = 6) of the diluted and undiluted samples were assayed along with a standard curve and two sets of QC samples at low, medium, and high levels (n = 2).
The results from the evaluation of dilution linearity and prozone effect are summarized in Table 5. The accuracy of dilution of GSK933776 from 2.28 mg/mL to 3800 and 300 ng/mL was -1.85% and 0.12%, respectively, whereas the precision of the dilution was 1.44% and 4.28%, respectively. No prozone effect was observed at 2.28 mg/mL GSK933776 in human plasma.
4.5. Selectivity and Matrix Effect Selectivity of the method was evaluated by analyzing 10 plasma samples derived from 10 individual donors. The selectivity samples were prepared by spiking each donor’s plasma sample with GSK933776 to 100 ng/mL (LLOQ) (n = 3) and assayed along with a standard curve and two sets of quality control (QC) samples at low, medium, and high levels (n = 2).
Results from the evaluation of selectivity and matrix effect are summarized in Table 6. Eight out of ten individual human plasma samples spiked with GSK933776 at LLOQ had %Bias within ±20% of their respective nominal concentrations and all samples had %CV ≤ 20%, which demonstrated that 80% of the samples met acceptance criteria. Therefore, it is concluded that the method is selective for quantification of GSK933776 in human plasma matrix. Since no significant matrix effect was observed in 11-fold assay buffer-diluted human plasma, the 11-fold assay buffer-diluted human plasma is suitable as the assay matrix.
4.6. Stability of GSK933776 Stability of GSK933776 was assessed in human plasma and in 11-fold assay buffer-diluted human plasma. LQC (300 ng/mL) and HQC (3800 ng/mL) samples were stored on a bench top (RT condition) for 24 hr, at -20°C and -70°C for 15 days, as well as subjected to 6 freeze-thaw cycles (-20ºC/RT, -70ºC/RT). An additional set of stability samples was pre-diluted 11-fold in assay buffer and stored at 4ºC for 24 hr. Each sample
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was tested in triplicate (n = 3) along with a freshly prepared standard curve and two sets of QCs at low, medium, and high levels (n = 2).
The %Bias and %CV for all tested samples met acceptance criteria for stability (%Bias within ±20% and %CV ≤ 20%) as summarized in Tables 7a, b, c, d, e, and f. These results indicate that GSK933776 in human plasma is stable for at least 24 hr at RT, for 15 days at -20ºC and -70ºC, for 6 freeze/thaw cycles (-20ºC/RT and -70ºC/RT ), and for at least 24 hr after 11-fold dilution in assay buffer. The stability of GSK933776 in human plasma after storage at -20ºC for extended periods of time, such as 3, 6, 12, 18, and 24 months, will be evaluated and the results of the stability testing will be presented in addendums to this report.
5. CONCLUSION The data presented in this validation report demonstrate that the method for quantification of GSK933776 in human plasma is accurate and reproducible.
6. DEVIATION There were no protocol or SOP deviations during the validation.
7. ARCHIVE STATEMENT All raw data, records, and a copy of the original signed final report will be archived at Alliance Pharma for 5 years following the submission of the final report to the sponsor. After this time, the sponsor will be contacted for instructions regarding the necessity of continuing storage, transferring to the sponsor’s site, or disposing of the materials.
8. REVISION HISTORY 08 Nov 2013: Draft
27 Nov 2013: Final
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9. TABLES
Table 1 Validation Summary for Quantification of GSK933776 in Human Plasma
Batch ID Date Run Type Accepted/Rejected (Reason)
PA-1 28-Aug-13 Precision and Accuracy Accepted PA-2 29-Aug-13 Precision and Accuracy Accepted PA-3 29-Aug-13 Precision and Accuracy Accepted PA-4 29-Aug-13 Precision and Accuracy Accepted PA-5 29-Aug-13 Precision and Accuracy Accepted
PA-6 29-Aug-13 Precision and Accuracy Accepted
Dilution Linearity 30-Aug-13 Dilution Linearity and Prozone Effect Accepted
Selectivity-1 05-Sep-13 Selectivity Accepted Selectivity-2 05-Sep-13 Selectivity Accepted Stability-1 11-Sep-13 Stability Accepted Stability-2 15-Oct-13 Stability Accepted
Table 2 Back-Calculated Concentrations of GSK933776 Calibration Standards (ng/mL)
Batch ID STD STD STD STD STD STD STD STD
100 200 400 800 1500 2500 4000 5000
PA-1 107 195 387 836 1463 2526 3989 5005 PA-2 108 201 394 814 1480 2490 4101 4906 PA-3 106 199 391 810 1501 2500 3954 5059 PA-4 106 194 393 832 1453 2540 4002 4987 PA-5 110 194 398 810 1480 2546 3847 5200 PA-6 108 198 391 818 1481 2516 3990 5006
Dilution Linearity
107 193 389 819 1511 2460 4008 5027
Selectivity-1 91 203 402 802 1490 2510 3998 4998 Selectivity-2 101 190 394 838 1459 2530 3932 5077 Stablility-1 104 216 391 793 1497 2547 3889 5088 Stablility-2 109 201 393 808 1490 2517 3976 5017
N 11 11 11 11 11 11 11 11 Mean 105 198 393 816 1482 2517 3971 5034
SD 5.44 7.23 4.20 14.16 18.17 25.99 66.93 74.05 %CV 5.18 3.65 1.07 1.73 1.23 1.03 1.69 1.47 %Bias 5.16 -0.77 -1.77 2.05 -1.18 0.67 -0.71 0.67
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Table 3 Precision and Accuracy of GSK933776 Validation Samples
Nominal Concentrations of Validation Samples (ng/mL)
100 300 1000 3800 5000
PA-1 Analyst 1
85 302 966 3993 4914 287* 335 979 3851 4871 83 301 999 4042 5470 98 303 969 3875 4950
Mean 89 311 978 3940 5051 SD 8.07 16.40 14.71 91.79 281.01
%CV 9.08 5.28 1.50 2.33 5.56 %Bias -11.14 3.51 -2.17 3.69 1.03
n 3 4 4 4 4
PA-2 Analyst 2
85 309 999 4080 5456 125 343 970 4071 5049 81 300 1011 4251 5184 84 306 970 3800 4856
Mean 94 314 988 4050 5136 SD 20.81 19.29 20.75 186.44 252.11
%CV 22.19 6.14 2.10 4.60 4.91 %Bias -6.23 4.79 -1.23 6.59 2.73
n 4 4 4 4 4
PA-3 Analyst 2
93 303 973 4347 5682 114 319 958 4114 5050 92 312 1021 4544 5105 89 300 950 4187 5252
Mean 97 309 976 4298 5272 SD 11.44 8.57 31.96 190.64 286.37
%CV 11.82 2.77 3.28 4.44 5.43 %Bias -3.22 2.93 -2.44 13.11 5.45
n 4 4 4 4 4
PA-4 Analyst 1
82 282 915 3817 4891 124 336 914 3588 4471 79 284 936 4105 5546 86 285 906 3764 5014
Mean 93 297 918 3819 4980 SD 20.73 26.18 12.91 214.41 442.91
%CV 22.36 8.82 1.41 5.61 8.89 %Bias -7.28 -1.03 -8.21 0.49 -0.39
n 4 4 4 4 4
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Table 3 (Continued)
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Nominal Concentrations of Validation Samples (ng/mL)
100 300 1000 3800 5000
PA-5 Analyst 1
81 288 924 4292 6259 126 313 929 3964 5496 77 289 941 5041 6539 83 284 925 4086 5885
Mean 92 293 930 4346 6045 SD 22.81 13.36 7.94 482.87 453.67
%CV 24.79 4.55 0.85 11.11 7.51 %Bias -8.00 -2.26 -7.02 14.36 20.89
n 4 4 4 4 4
PA-6 Analyst 3
74 291 956 3860 5071 111 320 948 3783 4535 70 291 970 4046 5061 79 293 923 3723 4766
Mean 83 299 949 3853 4858 SD 18.71 14.13 19.70 140.54 258.12
%CV 22.43 4.73 2.07 3.65 5.31 %Bias -16.55 -0.48 -5.06 1.39 -2.84
n 4 4 4 4 4 Inter-run Mean 91 304 956 4051 5224 Inter-run SD 4.61 8.58 28.53 225.12 425.77
Inter-run %CV 5.05 2.83 2.98 5.56 8.15 Inter-run %Bias -8.74 1.24 -4.36 6.61 4.48
n 6 6 6 6 6 * Value rejected since this value was an outlier determined by Dixon Q-test per AP SOP BA-021
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Table 4 Precision and Accuracy of GSK933776 QC Samples
Batch ID LQC MQC HQC 300 1000 3800
Dilution Linearity
305 1040 4163 298 979 3741
Selectivity-1 322 1014 3952 329 1051 3829
Selectivity-2 298 990 4118 292 1006 3892
Stability-1 283 974 3991 297 952 3729
Stability-2 316 980 4011 337 1021 4276
Mean 308 1001 3970 SD 17.38 31.09 180.02
%CV 5.65 3.11 4.53 %Bias 2.60 0.07 4.48
n 10 10 10
Table 5 Dilution Linearity and Prozone Effect of GSK933776 in Human Plasma
300 ng/mL (1:7600 dilution)
3800 ng/mL (1:600 dilution)
2280000 ng/mL (Undiluted Sample)
Dilution Linearity
305 3739 >ULOQ 302 3765 >ULOQ 311 3755 >ULOQ 315 3787 >ULOQ 284 3690 >ULOQ 286 3643 >ULOQ
Mean 300 3730 >ULOQ SD 12.84 53.78 N/A
%CV 4.28 1.44 N/A %Bias 0.12 -1.85 N/A
n 6 6 6
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Table 6 Selectivity of GSK933776 in Human Plasma
Selectivity Samples Unspiked (0 ng/mL) Spiked (100 ng/mL)
S-1 < LLOQ < LLOQ < LLOQ 116 94 91 Mean n/a 100 SD n/a 13.66
%CV n/a 13.60 %Bias n/a 0.44
n 3 3 S-2 < LLOQ <LLOQ < LLOQ 104 127 126
Mean n/a 119 SD n/a 12.84
%CV n/a 10.80 %Bias n/a 18.90
n 3 3 S-3 <LLOQ < LLOQ < LLOQ 107 108 122
Mean n/a 113 SD n/a 8.42
%CV n/a 7.46 %Bias n/a 12.79
n 3 3 S-4 < LLOQ < LLOQ < LLOQ 120 125 123
Mean n/a 123 SD n/a 2.15
%CV n/a 1.76 %Bias n/a 22.57
n 3 3 S-5 < LLOQ < LLOQ < LLOQ 156 142 132
Mean n/a 143 SD n/a 12.10
%CV n/a 8.45 %Bias n/a 43.15
n 3 3 S-6 < LLOQ < LLOQ < LLOQ 118 91 87
Mean n/a 99 SD n/a 17.04
%CV n/a 17.27 %Bias n/a -1.31
n 3 3
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Table 6 (continued)
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Selectivity Samples Unspiked (0 ng/mL) Spiked (100 ng/mL)
S-7 < LLOQ < LLOQ < LLOQ 80 108 94 Mean n/a 94 SD n/a 13.78
%CV n/a 14.65 %Bias n/a -5.98
n 3 3 S-8 < LLOQ < LLOQ < LLOQ 92 99 110
Mean n/a 100 SD n/a 8.83
%CV n/a 8.80 %Bias n/a 0.30
n 3 3 S-9 < LLOQ < LLOQ < LLOQ 102 103 97
Mean n/a 100 SD n/a 3.34
%CV n/a 3.33 %Bias n/a 0.33
n 3 3 S-10 < LLOQ < LLOQ < LLOQ 128 114 114 Mean n/a 118 SD n/a 7.91
%CV n/a 6.68 %Bias n/a 18.37
n 3 3
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Table 7a Stability of GSK933776 in Human Plasma Stored at RT (Bench Top) for 24 hr
Nominal Concentration 300 ng/mL 3800 ng/mL
Stability-1 322 4227 330 4362 366 4253
Mean 339 4281 SD 23.84 71.44
%CV 7.02 1.67 %Bias 13.12 12.65
N 3 3
Table 7b Stability of GSK933776 in Human Plasma Stored at -20ºC for 15 Days
Nominal Concentration 300 ng/mL 3800 ng/mL
Stability-1 307 3813 299 4022 287 4010
Mean 298 3948 SD 10.37 117.15
%CV 3.48 2.97 %Bias -0.81 3.90
n 3 3
Table 7c Stability of GSK933776 in Human Plasma after 6 Freeze-Thaw (-20ºC/RT) Cycles
Nominal Concentration 300 ng/mL 3800 ng/mL
Stability-1 296 4211 281 4307 300 4097
Mean 292 4205 SD 9.99 105.04
%CV 3.42 2.50 %Bias -2.65 10.65
n 3 3
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Table 7d Stability of GSK933776 in 11-Fold Assay Buffer-Diluted Human Plasma Stored at 4°C for 24 hr
Nominal Concentration 300 ng/mL 3800 ng/mL
Stability-1 280 3405 267 3476 300 3454
Mean 282 3445 SD 16.72 36.60
%CV 5.93 1.06 %Bias -5.97 -9.35
n 3 3
Table 7e Stability of GSK933776 in Human Plasma Stored at -70ºC for 15 Days
Nominal Concentration 300 ng/mL 3800 ng/mL
Stability-1 316 4051 329 3869 290 3843
Mean 312 3921 SD 19.95 113.24
%CV 6.40 2.89 %Bias 3.89 3.19
n 3 3
Table 7f Stability of GSK933776 in Human Plasma after 6 Freeze-Thaw (-70ºC/RT) Cycles
Nominal Concentration 300 ng/mL 3800 ng/mL
Stability-2 321 3950 336 3899 355 4187
Mean 338 4012 SD 16.76 153.87
%CV 4.96 3.84 %Bias 12.52 5.57
n 3 3
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10. FIGURES
Figure 1 A Representative Calibration Curve of GSK933776 (Curve Range: 100 to 5000 ng/mL) (Batch: PA-3, 5-Parameter Regression, 1/Y weighing)
Curve Name Curve Formula A B C D E R²
Curve Y = (A-D)/(1+(X/C)^B)^E + D 0.086 1.22 2.69E+04 2.95 13.9 1
Calibration Curve
Conc. of GSK933776, ng/mL
OD
450
nm
1 10 100 1000 10000
0.000
0.500
1.000
1.500
2.000
2.500
3.000
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11. APPENDICES
Appendix 1 Bioanalytical Method: 130825M.01V
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CONFIDENTIAL
Bioanalytiea l Method
Quantification of GSK933776 in Human Plas ma (Range 100 - SOOOng/mL) Using a Color imetric Immunoassay
1\ldhod 11>: 13082 5M.OIV
Prepared hy
Ph.D.Alliance Pharma. Inc.
Apprund hy
Date
---M.Sc .
Directo rBiopharmaccutica l ServicesAlliance Pharma, Inc.
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1 Introduction
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This document describes the procedures to quantify GSK933776 (a humanizedmonoclonal antibody against beta-amyloid peptide from OSK) in human plasma samplesusin g a colorime tric immunoassay.
2 PrincipiI' uf Mt'thod
The beta-a myloid peptide 1·1f; is coated onto a 96-we 1l plate. and GS K9.1J7 7(' incalibration standards (STDs), qualit y controls (QCs), a nd samp les will bind 10 theam yloid pept ide 0 11 the plate . This complex will then further bind to mouse anti-humanIgGI (Fe speci fic) an tibod y labeled with horseradish peroxidase (HRP). wh ich catalyzesthe chromogenic HRP substrate 3.3 '.5,Y.telnlllldhylhenzidine (TM B). This reactionyields a b lue- co lor with a maximal absorbance- at 650 lllll . The- blu e- color the-n changes toyellow after the- addition of sulfuric ac id re-sulting in maxim um absorbance at 4 50 I1I U .
111': absorbance at either 6 50 1I1ll or 450 om is proport ional to the amount of GSK933 776ill t he- ca libra tion standards, QCs, and samples.
3 Aualyte
Th e analvtc, CiSK9]3776. is provided hy CiSK with defined concentration. 101n umber,and ex pira tion da te. '111is refe rence subs tan ce is SIOH.-d at _70 °C,
.4 Bqufpments and :\ Iat t lials
:\Iah'rials I Reegcnts Functton SUUITI'
MaxjSorp Cle-ar 96 well pla it: Sol id phase Nunc, Cat. # , 439454
Aseptic Sealing Tapes Plat e- Sealing NUllC. Cat. # . 236366
Buplln' Sodium Carbonate- Coating 'lo,,"TTI1O Scient ific, Cat. #: 2X3X2Bicarbonate Huffer Pack s Buffe r Sa lt
Beta-Amyloid-Pe ptide (1-16) Capture Bachcm . Cal. # : 11-29 5XAgent
Sodium Ch lor ide, ACS grade Salt VW R Cal. #: BDllnX6
Tris Base BuU".:r EMD ~li ll ipor.: Chemicals. Cat. #: TX 1529-5
Tween 20 Detergent Sigma . Cat. #: P1379
SuperBlock in TBS Blocking Thermo Scient ific, Cat. # : 37535Sol ution
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:'o rat t rials I Reageuts Func t ion S Oli IT('
Bovine Serum Albumin Buffer Fisher Scient ific Cat. #: ICN810034(IlSA) Protein
Hum an Plasma with K2 Assay Matrix Bioreclamation. Inc. Cal. # : m,lI'LEDTA2EDTA me; ant i-coagulant
HR P La beled Mouse anti- Repo rter Tag Invitrogen. Cal. #: /\- 1064XHuman IgGl(Fc Speci fic)
l -Skp Ultra P ..IB- ELiSi\ HR I' Thermo Scientific , Cal. #; 34029Substrate Subs trate
18 ~[Sulfuric Acid Acid Sigma . Cat . #: 25&105Concentrate
Deion ized Water Solvent In house, Milli-Q Water
ELx800 Microplate Reader Plate Reader Bio-Tck Instrum ents Inc.
EL.,,4()S Microplate Washer Plate wash...rr- Bio -Tc k.. Instrumen ts Inc.
Note: Alte rnative equivalent consumablcs and cquipm cnts may he use d as approp riate.
R('a jl('nts Function Prepurarlon
I 1\1 Tr is-CL plI 7.5 Buffer Dissolve 12 1.14 grams ofTris Base. adjust pHSo lution to 7'j with concentrated Hydroc hloride Acid.
and add deionized water to \ J.iter.
5 ~I NaCl Salt Stoc k Dissolve 292 .2 grams of Sod ium Ch loride inSo lutio n deionized water to adj ust final volume to I
Liter.
tux Tris Buffered Saline Assay/Wa Combine 100 mL of I ~I Tris-C I. p li 7.5, 300Sol utio n e m S) ( 100 m M sh Buller m l . 5 i\l NaCI and GOO m i . deionized wate r andTr is-Cl , 1.5 ~I J','"aCI, pH 7.5) mix .
50 m~1 Sodium Carbo nate - COOling Empty I pouch Bupl! Sodium Carbonate-bicarbon ate Bufl"er. pH 9.4 Butler Bicarbonate Buller Pack into a conta iner
containing 2.0 L de ionized water. Stir todissolve.
1 mg .ml. Beta-A myloid Coating Add I m L of deionized water to I mg ofbeta-Pept ide ( 1-16) Stock amy lo id peptide ( 1-\6) and vortex . Make (,() ~LI ,
Solution aliq uots and store the aliquot s at -70"C.
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R('a~('nts Funct ion Prepnrnrlon
3.0 p.g/mL beta-am yloid Coal ing Add 54 ul, lmg/ml, Beta-Amyloid Pept ide intopeptid e 1·\6 in the Coa ling Solution llU ) m L o f Coatin g Huffer. Vort ex. S IOTe a t
Bulla RT for fresh usc.
10 m~\1 I ris, 150m~I NaCI, Assay Add 900 m l, deionized wate r, 100 O1L tux IDS,O. J% lIS A, O_ l~';' Tw een 20, Buffer pll 7.5, !.Og BS A, and 1.0 ml ,Tween 20 to ap1l 7.5 (Ali ) glass container . Stir 10 dissol ve. Filter through
0.2 micron filtration unit and store at 4°C for upto 3 months.
10 111 \1 Tris. 150 lu r-.I Nae l. Wash Combine 3.6 L deionized water. 4()() 1111, lOx0.1% Twee n 20, pH 7.5 Bufl~r rns, pH 7.5, and 4.0 ml . Tween 20. !\fix .
I :\00 IIRP Working Stock IIRP Reconstitute JlRP La be led Mous e anti-HumanSolution Substrate IgOI (Fe Specific) ant ibod y acc ording to
manufacture r's instructions. Dilut e an aliquotof the I[liP -antihod y conjugate InO-fold inGua rdian Peroxidase Conjugate Stabiliz er(T herm o Scienti fic , Cat . #: 37548). Store at4<>C for up to 6 months.
HR P Labeled Mouse anti- Reporter Add 138 III of 1:100 HRP Wo rking StockHuma n IgO I Conjug ate Tag Solution to I I mL of Assay Bulle r and vortexSol ution Solution ( 1:8,000 fina l dilut ion"). Store at RT for fresh
m e.
• '111.: dilu tion ma y be adjusted based on theactivit y of the HRP.antibody.
1.8 ~ l Sulfuric Ac id H.ID Sto p Slowly add 100 IIlL I8 M Sulfuric Acid into aSol ution beake r con taini ng <JOOml deionized wa ter while
stirring with a stir bar. After the solut ion coolsdown to RT, trausfcr tc a reag ent bott le.
Note: The act ual amounts can he scaled up or down us needed .
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6. Prncedures
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6.1 Preparation of GSK9JJ776 Standa rd and Q ua lit:y Cont rol Stock Solut ions
Prep are two sets of master s tock sol utions (SS) hy acc urately measuring the required volume ofre ferenc e stan dar d GSK9.B776 into !'BS to obtain J.OOO,OOO ngsml , stock so lut ions . One isused for calibration standards (SS-S"ID - l ) and the other is used for qua lity control /va lidationsam ple s (SS-QC- l ). "111<:: tota l \'Ol11l11C prepared ma y he scaled up or down as req uired. All stock
solutions are stored at · 20"C.
Working Fina lvolume or Spiking " olu me of
T ot a l \'"Iullw inSttK'k Conccut m non Co ntl 'o l \ Iatrix
So lut iull (n~/lII l,)Solut io n :\la t rix (J.lL)
()'L)
SS-STD~2 100,000 I00 ~lI , of 88-STD-I 900 1,000
SS-STI)-3 I O,(}()(J 100 ,lLofSS~STD-2 '){ J(} l ,(JOO
SS-ST D-4 1000 100 ul . or88-sT1)-] 9()0 1,000
SS-QC· 2 J(Kl.OOO 100 ~lL of SS-QC-I '){J(} l ,OOO
SS-QC-] 10,000 100 ~lL of SS-QC·2 900 1,000
SS-QC·4 1000 !OO f.lL or SS-QC-] 900 1.000
6.2 Prepa ratlon of GSK9J3776 Sta nda rd Workin j:! Solut ions
Ca libration standards are prepared as shown in the table below and stored at · 200C. The tota lvolume prepared may be sealed up or down as required.
ST HVnhrme of\Vm'kin~ Sto('k
vefumc ofSolut ion (uJ ,' Tolnl volume
STD ID Cencenrranon l\lat l1x(ng/ mL)
SS STD-3 SS ST])-~(J.l.L)
( J.l.L)10,000 nezm l. 1,000 nefm L
8TD -50 50 50 950 WOO
STD-leX} JOO \00 900 1000
STD-200 200 200 800 1000
STD-400 400 400 (,00 1000
STD-XeX} XOO ROO 200 1000
STO- 1500 1500 150 850 1000
STD-2500 2500 250 750 1000
STD-4000 4000 400 600 1000
STD-5000 5000 "JO 500 1000
5 orR
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6.3 Prcparatlon of GSK933776 Qu ality Control Sll lll[lin
;"fcthod ID: n 01l25!\10 \V
Quality controls (QCs ) and Validation Samples (VS) are prepared as shown in the table below.The to tal volume prepared may be scale d lip or down a" required. Replicate 100 ~L.L aliq uotsshould be transfe rred to appropriate assa y tub es for storage at • 20°C.
V c/VS QC/VS ""Iu ml' nf Spikin l!: Solut ion ("...1,) ' "olulIIl' ufTotal
( 'OIU"l'lIf r.lti o ll SS-Q C-3 SS-QC-.f :\Iatrh:"O) UIII(' ( IJ,L )In (lI ~/mL) 10,00U nglm L 1.000 n glmL (",. )
1.I.oQ- 1OO100 lOll 900 1000
(V'Sl )
LQC.300)00 300 700 1000
( VS2)
),fQC·1OOO1000 100 900 1000
(VS3)
I1QC.38003800 380 620 1000
(VS4)
ULOQ- 50005000 500 500 1000
(VSS )
Note: \is I and VSS arc prepared only Ior rncahod validation.
6.-1 Prcparatton of Sa mpl e Dilution
The assa y mat rix is human plasma dilute d II -fold in assa y buffe r, which is 9.09% humanplasma(c.g. 50 1-1 1. STD. QCs, or study samples into 500 1-11. assay buffer). Unknow n study samplesmay need 10 be pre-diluted into hU1IIan plasma 10 [111 within the assay range. Alte rnat ively , theunknown study samples can be first diluted I I- fold in assay buffer. then further diluted in theass"'f maIn " \\,'h""" sampl" is ,1;1,,1,,<1 . " ,l il,,1i"n QC (IX)C) n,,,',ls I" h" ",,,,ty>,<'<1 " r"ne w ;lh
the diluted samples. f or reference. the tab le below provides an example of how a DQC at:200.000 ng'ml, is prepared. The actual concentration of'thc 1)QC can be adjusted based on thecouc cntretion of OSK933776 in the samples and the dilution factor required for them to fitwithin the calibrat ion cur ve. Replicate I00 ul. aliquot s of DQCs are stored at -2ifC.
volume of Sp iking
QC DQC Sulutioll (~ ,) v clumc ufTota l Volume
Co ncenrra n on :\IatrhIlJ (ng/ mL) SS-Q C- l
(f'L )(",. )
1,000,000 ng/IllL
DQC-200000 200.000 200 800 1000
oors
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7. Immunoassay Procedures
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St tp P rocedures for :\ 1('111011 10: 130825:\1.01 V
1 Prepare ).0 IJ.g/mJ . beta-am yloid peptide 1-16 in Coat ing Buffer as co alingso lut io n (For-example, add 5 1 ~IL 1 mg/ml., bet a- am yloid stock so lution 10 17 mLCOllling Huffer for coating Z plates)
2 Add 80 ul. coating solution per well in 96- wd l plate , seal with aseptic sealingtape , and incubate for 24 ± 12 hours at 4~C_
3 Wash the plate .5 ti mes w ith 30 0 ul, wash Duffer pe r wel l usin g a plate washer
4 Add 200 ~IL blocking buffer per well, sea l with asepti c scaling tape. and incubatefor \.3 hour at RT or 4"C for up to 11 week.
5 Dilute STDs. Qes a nd Sa mples l l x in Assay Buffer (50 ~lL Plasma Samples to500 ~ . Assay Buffer) and dilute samples and DQC if' necessar y.
(, Wash the plate vumes with 300 ul. Wash Buffer per wellusing a plate washe r
7 Add 1DO IJ-l .po.:r well of Assay Buffered-diluted standards, QCs, and samples, sealwith aseptic sealing tape, and incubate fo r 2 hours at 37"C.
x Wash the plate 5 times with 300 pl. Wash Buffer per well using a plate washe r
9 Prepare Reporter Tag Solution by di luting IIRP Working Stock Solut ion (1: 100)1':0 fold ( I :1': ,000 final dilution'"). For exa mple, add 131': p.l, HRP Working StockSolution (1:100) to 11 mL Assay Butler.
* TIle di lution may be adjusted based on the act ivity of the Hkp-conj ugatedantibody .
10 Add 100 ul , Reporter Tag Solution per well. seal with aseptic sealing tape , andincubate tor I hou r at 37°C.
11 Transfer I I rn l , I -Step Ultra T!l.1B !IRP substrate P~T plate into a tube and leave itat RT to prc-wann the substrate.
12 Wash the plate 5 t imes with 300 pL Was h Buffer per well using a plate washer
13 Add I{)O jJ.I , the pre-warmed Ultra T \ IH HRI' subs trate per well and incubatewith shaking for 8 - 20 minutes at RT.
14 Add 100 pl , T \ 111 Stop Solution per well and incubate with shaking for 5 minutesat RT.
15 Measure absorbance at 450 nm using a plate reader.
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8. Ce k ulat ton
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TIle data is acquire d using a Bio -Tek microplate reader and processed using Gen5 software orLI~IS system. Additional calculations can be performed using Microsoft Excel. A standardcurve is constru...-tcd by plotting the concentrat ions of standards in a log scale [Xvaxis) versus thecorresponding absorbance (Opt ical Density, (0) (Y-axis ), and Iitting with a s-parameter logisticalgorithm using a l lY weightin g. 1110.:: concentration of GSK933776 is determine d based 011 thestandard curve.
9. Ilul..rmeut Hi stoI1'
version :\"0. ElTt'din' Date Cu mmenrs
01 22 Aug 20 B New Document
OIV 18 Oct 2013 Validak d Method
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Appendix 2 Certificate of Analysis for GSK933776
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CONFIDENTIAL Report No.: V130825.01GSK Document No.: 2013N182307 00
Gll1xoSmithKl ine
She lf Life Justification for GSK933776 (aBAM) Reference standard, 50rngfmL,Product Code AC, Batch 101272093
COVER PAGE
Ownin g Department :Local Bu siness Unit:Bu siness Department:
Description:
Printed by :
Effect ive:
R&D BPe: Upper MerionR&D BPC Upper MerionBPM Release Stability Testu -q
Shelf uie Justifica tion for GSK933776 (aBAM) Reference Standard, 50mglml,Product Code AC, Balch 101272093
cdmsview (cdmsv iew) for cornsvew (cdmsview) on 20 Mar 2013 (G MT)
14 Feb 201313 2 9:14 GMT
APPROVAL AND AUTHORISA TIONCompletion of the fo llow ing signature bloc k has been carried out t.¥ Electron ic Signature
Cocument Appro va l :Signed ByDeci sion ApprovedDecision Date ' 13 Feb 2013 20 54 53 GMTRole : AuthorPurpose : Shell-life JustificationMeanlrg Of S ignature This document is suitable for issue
Signed By 'Deci sion ApprovedDecision Date : 13 Feb 2013 20:59:24 GMTRole : AuthorPurpose : Shelf-life JustificationMeaning Of S ignature : 'r t us document is suitable for issue
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System Number:Document Alias:Document Title :
1.
CONFIDENTIAL Report No.: V130825.0 1GSK Document No.: 2013N182307 00
GlllxoSmithKline
She lf Life Justification for GSK933776 (aBAM) Reference standard, 50rngfm L,Product Code AC, Batch 101272093
INTRODUCTION
"Ib is document pro vides the Shelf 1.ifc Justification for GSK93J 776 (aBA~I) RcfcT'-'IlCCStandard (RS). 50 mg/ml, Product Cnde AC, Hatch IOI272 0'J3.
Table 1 GSK933776 RS Balch 101272093 Details
Protect GSK933776GenericName ,BAMProduct Code ACccnet ItemCode: BS159809Fe rn SolutionSiren th SOm ImLRS Batch Number: 101272093Source OSBatch NUrrDer 061123159Manufacture Date 31Au 2006DPSrte ofManufacture Nova teooretodes ltdSta bil ~y Protocol INS_8350 (Batch 061120310)
iSTAB 3460(Balch061 12(310)iSTAS 4013 (Batch 101 272093)
Stabilrty Study' BPB_ST20053 (Batch 061120310 from Inrt ialto 42months)iSTAS8PU1011240 (Batch 061 120310from 48to54months)iSTAS 8P1.Jl11166(Batch 101272093)
Presentat ionandPackaging Asoluhon conta inmg a target of 50 mglmL 01 GSK933776 (refer10CometComponents Item 8S159809 and DPl36208 forlormulallon corcos.ton details).
1mLfilledin 2 mLdear Type-l tubular glass vial (PC102083) sealed wnh13mmHel~lo(~t FM25~1 stopper(PC102427)and13 mmAluminiumtear-cutoverseat PCl29911
Primary StoraQe Ccooton ·7rJ'C ± IlfC ambienthumid~y (AH), protected fromlighl
2. BA CKGROUND
In acco rda nce with CC_20 10_BP_UPM_0130 , the storage temperature ofGSK933776 RSwas changed from S"C ± 3"C/All to ·70"C ± W"C/AII to allow for a longer period or use .OSK933776 RS Balch ur;t 1203 1() (Product Cude AA. Comet Item Ill' I362 ( 8) wasreassigned in Comet under the new recomme nde d storage temperature of".700C with thenew Batch 1012 720 93 (Product Cod e AC, Comet Item n SI S9R09). In order to determinethe shelf life of Batch 101 272093. the dat a co llected at SOC for Batch 06 11203 10 and thedata collected at ·70"C for Batch 10 1272093 will be combined to perform stati sticalanalysis.
3. STABILITY SUMMARY
A summary of the stab ility data that arc curre ntly available for GSK 933776 RS is listed inTabl e 2. Supporti ng stability data can he found in Tables 4-8.
This is a prinled copv of the document held in CDMS and it is the respcreibuty of the user to ensure that thecorrect version is used
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Table 2
Balch'061 120310101272093
CONFIDENTIAL Report No.: V130825.01GSK Document No.: 2013N182307 00
Gll1xoSm ithKl ine
She lf Life Justifica tion for GSK933776 (aBAM) Reference standard, 50rngfmL,Product Code AC, Batch 101272093
Summary of Stability Data Cu rrent ly Ava ilable for GSK933776 RS
.7I7'C :I: l ll"C/AH ·2ll"C:I: 5"C/AH 5OC:!: 3"CIAH 25"<;/60% RH 4ll"CJ7S'4 RHNA 54 months 54months 6 months 1 month
24 months NA NA NA NA
Batch 061120310'Mls reassignedin c crret ullderthe IIBW recommended storage te~ature of ·7f1CWlththe newBatch 101272093
TIle·70ne stu dy for Batch 10 1272093 was in itiated afte r the 5"C stud y for Batch06 1120310 was completed at 54 month t ime point (Table 5). 111e 1, 3, 6,1 2, 18 and 24month time points in the -70ne study (Table 8) an: 55, 57, m , 63, ('G. 72 and 781110nlhtime points after the start ofthe 5°C study.
Stahility data indicate that the GS J..: 933776 RS Ba tch 101272093 met the acceptancecriteria set forth ill the Key Quality Attributes STD _1355X7 for all tests afte r 54 months at50C (Table 5) and 24 additional months at tile revised recommended storage temperatureof -7(JOe [Table X).
Stab ility data collected at ·20OC ± 5"C1AH. 25"C/60% RH. and 40"C175% RH re veal thatthe OSI\:93 3776 RS Batch 101272093 met the acceptance criteria for all tests after 54months at -20"e ± 5OC/AIl (Table 4). 2 months at 25°C/60~'':' RH (Table 6). and 21 days at40"C175% RII (Tabl~ 7). respectivel y.
4. STASTISTICAL ANALYSIS
1l1 ~ results of stat istica l anal ys is us ing com bined 50C and-70°C stability data with shelflife pred iction arc presen ted in Table 3 and Figures 1-6. It is a nticipated that GSK933776RS Batch 1() 1272093 will remain w ithin the ac ce ptance cri teria for at least <)0 monthswhen stored at the recommended storage conditi on of ", 70°C .
Table 3 St at ist ical Ana lysis o f GSK 933776 RS Batch 1012720931,2
Assay Acceptance Criterial PredicatedShelf Life (Months)
ELISA 050 to 150 175
SEC ~ 950% 11 5
SOS-PAGE 2: 95% 140
A280 400 10600mg1mL >312'
pH 531051 158
clEF Report results p '" O(XXX)5S'
Stab5tic~ analr-; i5W35 pedomed using Sta~s bca sollware version 8.0 Cacuanons were 00500 on sing\!batchandlineardatatransformation
2 Combined stalj ilydata includestorage coodibons oI5"C at initial, 1, 3, 6,9, 12, 18,24,36,42,48.and 54months: -7rJC al55, 57, 60, 63, 66, 72and78monlhs
Th is is a pr inted copy of the doc ument held in CDMS and it is the respc reibuty of the user 10 ens ure that thecorrect vers ion is used
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System Number:Document Alias:Document Titl e:
CONFIDENTIAL Report No.: V130825.0 1GSK Document No.: 2013N182307 00
Gll1xoSmithKl ine
She lf Life Justifica tion for GSK933776 (aBAM) Reference standard, 50rngfmL,Product Code AC, Batch 101272093
3 Acceptancecntea aceordngto Key QuaityAttributes STD_135587
4 SMl lifewas nol foundv.ithin maximumallov.ed eJ( lr~alion timepoint of312months
5 No acceptance criteriaareset for clEF, rteretc e, the p vaue ct tte s1~e is repor1ed for inforrmbonony. Thepvaueof0000055 indcales that there isastatisbcal lysignificantscoelorclEF.There isIowccreatona/themeolineas indceted bythelowR'which indicates highvariltlityin the measured resutsand sothe trendseen may nol be allriblJ ted10 prcouct degradation.
5. RECOMMENDED SHELF LIFE
GSK933776 (aDA)'I ) RS, 50 mg/mL, Product Cod.: AC, Balch 101272093 is currentlyassign ed a 72-111onlo shelf life when stored at the rec ommended sto rage condition of 70CC± to°CIAH, protected from light .
Base d O il the results of statistical analysis of stahility data curre ntly available and theproced ure ofcurrent SOP, INS_94091 , GS K93377G (aBAM) RS, 50 mg'ml., ProductCo de AC, Batch to 1272093 wi ll he assigned a shelflife of 90 months when stored at therecomme nded sto rage con dit ion of-70~C ± lO~C/AH. protected from light.
6. CHANGES AND REASONS
Ver;;ion chance Reason3.0 This document supersedes RPT_136236(2.0) Revisionforshelf
li fe extensonUpdated all sectionswith new slClbilitydata collectedat 54 Shelf life extensionmonlh time point for Balch001120310 and at9, and 12monlh time points for Balch 101272093
Updatedall sectionswithnewdataa~~~ i S results Shelf life extensionI performed on the stabllitvdata current availableProposedextension of GSK933776 RS Batch 101272093 Shelf life extensionShelf Life from 72 months to 78months
40 Updated all sections withnew data analysis results Shelf life extensionperformed on thestability datacurrently available forShelfLife from78 months \0 90 months
This is a printed copyof the document held in CDMS and it is the respcreibuty of the user 10ensurethatthecorrect version is used
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System Number:Document Alias:Document Title:
CONFIDENTIAL Report No.: V130825.01GSK Document No.: 2013N182307 00
Gll1xoSmithKline
She lf Life Justification for GSK933776 (aBAM) Reference standard, 50rngfm L,Product Code AC, Batch 101272093
APPENDIX SUPPORTING STABILITY DATA TABLES ANDSTATISTICAL ANALYSIS PLOTS
Th is is a printed copy of the document held in CDMS and it is the respcreibuty of the user 10ensure thaI thecorrect version is used
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Figure 1
CONFIDENTIAL Report No.: V130825.0 1GSK Document No.: 2013N182307 00
GlaxoSmithKl ine
Shelf Life Justification for GSK933776 (aBAM) Reference standard, 50rngfmL,Product Code AC, Batch 101272093
Statist ical Plot for ELISA
Stab ilit y Plot fo r Pooled Data wil h 95% Predicti on limits
Woncs heet GSK9 33776 (aBAM) RS Balc1l101272093
Predicted Shelf Life " 175
1.4 1-- '- -- - - - - - - - ~~==:~. --~..---
USL"'1 5
1.2
~:::.; 10w Q
Q 00
Q V -.,.
Q
Q
Q
LSL" 0 5
o 20 40 80 60 100 120 140 180 180
Timepoinl
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System Number:Document Alias:Document Title:
Figure 2
CONFIDENTIAL Report No.: V130825.0 1GSK Document No.: 2013N182307 00
GlllxoSmithKl ine
She lf Life Justification for GSK933776 (aBAM) Reference standard, 50rngfmL,Product Code AC, Batch 101272093
Statistical Plot for SEC
Stability Plot for Pooled Data with 95'" Pred ict ion LimitWorksh eet GSK933776 (aBAM) RS e aten 101212093
Predict ed Shel f Li fe · 115
SheR Life99,O r - - _ - - --_--_- , -,
98 5 ~OO
98 0
o
--------------. ~ LSL=95
I
97,5
97.0ow• 00.5
00 0
955
95,0
945o zo
00
00
''''Timepoint
This is a printed copy of the document held in CDMS and it is the resp:ms ibility of the user to ensure that thecor rect vers ion is used
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CONFIDENTIAL Report No.: V130825.0 1GSK Document No.: 2013N182307 00
System Number:Document Alias:Document Title:
GlllxoSmithKline
She lf Life Justification for GSK933776 (aBAM) Refe rence standard, 50rngfmL,Product Code AC, Batch 101272093
Figu re 3 Statistical Plot for 5DS-PAGE
Stabi lity Plot for Pooled Data with 95'" Prediction Limit
Worksheet GSK933 776 (aBAM) RS eaten 101212093
Pred icted Shelf Li fe · 140
S he ll L~..
---------------I
a
LSL=gs
'"
----- ,
00
a
a
--a
a
a
20
------
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o
a a
99.S
990
98 5
98.0
w 97,S0-c~
97 0
0• 96.5
96,0
955
95,0
945
Timepoint
This is a printed copy of the document held in CDMS and it is the resp:ms ibility of the user to ensure that thecor rect vers ion is used
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System Number:Document Alias:Document Title:
CONFIDENTIAL Report No.: V130825.0 1GSK Document No.: 2013N182307 00
GlllxoSmithKl ine
She lf Life Justification for GSK933776 (aBAM) Reference standard, 50rngfmL,Product Code AC, Batch 101272093
Figure 4 Statist ical Plot for clEF
Sta bility Piol for Poo led Data with 95% preercnen Limits
Wo rksh eet GSK933n6 (aB AM ) RS Batch 10127209366
' "
" ' "' "
0 " ,ez 0 ' " " " ,
0 00 ",00
" ,58
• 0w 56u '" 0 00 0--, 0 0
"--, 0
~ ~ ~ ~ - ~ 0
52 --,0 ' "
SO
48" ,
480 to 20 eo " SO 70
Time poinl
Effect Paramo I Std.Err I I ,95 .00% I+95.00%P CL CL
Intercept .204 448*8j 3818+f.000000_158.72?8~2J.618~Slone ,009596 0017982 0000055 ,0 13389 ,0 05802
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Figure 5
56
54
52o
~ 50
aa
44
42
CONFIDENTIAL Report No.: V130825.0 1GSK Document No.: 2013N182307 00
GlllxoSmithKl ine
She lf Life Justification for GSK933776 (aBAM) Refe rence standard, 50rngfmL,Product Code AC, Batch 101272093
Statist ical Plot for A280
Stability Plot for Pooled Data with 9'% Pred ict io n lim itsWorksh eet GSK933776 (aBAM) RS eaten 101212093
°000 ° a 0 0 0 0 0 0 a0 0 0 0
O - - - - · - - - - - -9- - - - ~ - - - - - ~ - - - - - - - - - - - - - . - - - - - . - - . - . - - - - - - - -
l SL"'40
Timepoinl
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System Number:Document Alias:Document Title:
Figure 6
CONFIDENTIAL Report No.: V130825.01GSK Document No.: 2013N182307 00
GlllxoSmithKl ine
She lf Life Justification for GSK933776 (aBAM) Reference standard, 50rngfmL,Product Code AC, Batch 101272093
Statist ical Plot for pH
Sta bility Plot for Pooled Data with 95% Pred ictio n limitswcresn eee GSK933716 (aBAM) RS Balcll l01272093
Pred icted Shelf Life - 158
She ll L ~e5.75,~~~~~~~~~~~~~~~~~_-,--,
5'0 f- .- - - - - -- - - - - - - .J-505 - ------ -- ----- ----- I------5 60 O-- ~ - - - ~ -O 0
~ ---- --_ ..---S,55
USL"57
~ 5,50
5.45
540
5 ,35
, u 0
..-- ---
0=
530 f-- .- - - - - ~~ - - - ~ - - - 1- LSL=S3
5.25 '------- - --- --- --- ---'-'o ac "0 '''' '" teo
Timep oinl
Th is is a pr inted copy of the document held in CDMS and it is the resp:ms ibi lity of the user to ensure that thecorrect vers ion is used
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Syo ! @mNu~r:
Ooc_nt A"n :Doc.......n! Trtle:
CONFIDENTIAL Report No.: V130825.0 1GSK Document No: 2013N182307 00
GIa. o Sm ilhK lin&
Sh,d u'" ..... b!'''''''.,., fo, G5K933776 (. SAIl) Rorler..""" Sl.rxlard 5(IrngIrn..P rodl.<:t r"""" AC, flo"'" 101 2 1:1rn3
Table 4 5I a bi l ; t ~ Data lo r G5 K933776 RS 50 mgIml. Ba tch 061120310 at ·20·C
Slobil;lySludy ~btr:Baldo _ be"
BPe ST2Q653061120010
31o,"9' , ..d b""looting'
·we ....bi..t H"",iclily UpOltllCoInpl""
,. " ......... C,,""'.-_.- ,
",
" "...........·r ' do. ~ ...."..,,,,,,,,,,,,,,,_ _.~- - - _. _.
......,..-.. ......_ ... _ ___ r•
.....-....................-.....,_...-....-~
_........-- ,_.~- -- - '- ,_. - --,.. .....",............. "11 ". <H ' •• I ' .X !:.(" ".~ 1111•• '....,-_..-, '" ,. .0 \ ." '" '" ". '"_.~
_>'\'c'll 0 ' ° 0 ' ° 0' 0 ' ., .,~, ......'>1_- " " " " " " " ""-"%,'''_ ".1 lOUl <0 '(1. 00 1 ""oWl "' (;.001 ""-"' 'O. <3. '11.<>0) ........001 <lJl.<ll.. .
...... .,s.:;. _'..CIIll .... _ _ ' ........ ~ ,- ,....... ,-- - ,_. ,- - -•• ---....·_cas...___ ,_.~-
c,.,._~- ,- ,- - -Cunoa'_"'_"_~,..."..cae, .. .... ... ."............. 0 • 0 ' 0 ' 0' ., 0 ' ., .,
~Ei'.."~-"''''-..._.. ,- ~- -~ ~- ,- ,_. - -""'.... '"'"' ._. .,..." .nto. ,,,' ,,,. ," , ._" u ..-~ ..... • • • , , , , ,.- ,. ,. ,. " " " ,. ",- "' ., '" ,, ' ," .1.1 .,
"-.. .. 0 ... _ . , ., ., . , •• . , ., . 1.0m_• 'J_I.l o11 _ " ;:- " ' .S " " " ~:-........ ...a;;.,. .... .ooo ... _
" • • " ,. • "•• ........" ... .......- • ,, ---._.." ......._-1 .. l< _
~ .....~_......._ .....od ~'_......__ .._~_,_ ....._ ........~ ""'__ ~ 0I) ~· 10 0"'9'<l.... -"""......
Thi$ I. a pr;nllld ropy 01thedQctrn<rrc r.eld In CDMS arJd ~ I. the 'e$JXln; b~.ly of the~, to ......ure \""1 the cc-rect "",$ion 1$ U6'!dPage 11 0/ 16
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CONFIDENTIAL Report No.: V130825.0 1GSK Document No: 2013N182307 00
GIa . o Sm llhK lin&
Sh,d u '" ..... b!'''''''.,., fo' G5K933776 (. SAIl) Rorler.. """ Slarxlard 5(IrngIrn..Prodl.<:tr"""" AC, flo"'" 10121:1rn3
Table 5 5l a bi l rt ~ Data for GSK933776 RS 50 mgIml. Batch 061120310 at IS'C
StabilityStudy Number;Bal<h Number -
BPB_ST206S3061120310
SlOrage Condrtlon:T.... i"':!"
S"C Ambient HumldllyUpflghlCompl el..
'm Acc.pllnco -Torno ._.CritlHi. hili.. , a • ,
" " " " • • •"""'r_" ......- -, -, ~, ~, -, ,~.
._..,.....- ..... .... ~K_
I ..m_- ,.-...._""-....-,,_.......-~
~.... ...... ......... ,-, ,_.~~ "...... '- " -" ,-, -" ,-, ,- , - -_. -.~ A_ -.. ....... .. ,.. .. ... "1' ... ". ". ,m •• ... .." .."--- ," '. •• .. •• w •• •• •• ,,. ,,. ..
_.~ _.........'" .. ., ., ., 0' 11.' 11.' ., '" .., ..,
~, --- " " " " " " " " " " " ""-"', .... ." ." _,.1 .. <,' .' ." ." ~ " " ~.,'-- , ro ro 00 Cl.l .., . 0'_.a ._.CSiI ... ,_. ,-, ,.~ - ,-" -",_. ,- ,_. ,_. - -•• ,........--.........-.__ea..... ,-, ,-, ~~ ~". Con. ... -"'-' -" ~~. ,-, - -_.....-_.--"_ 'CW ", '" n, . , n, n, 0' .. n, 11.1 ".g .., .. ._...............,,""..... .. " .. _ . ,- - - ","10. '-" ,- ,_. -" _._. - ---._~- ....... 0/..... "H" lIU .. 1..r'll a u '-, ./ a u ,no ,....."1 '''Ul no<......,,_. • • • • • • , , , , , ,..- ,. ,. ", •• ,. " " " .. ,. . n ..-- ", ", •• m •• •• "' '" •• ", .. ••- ....-. ........,... ._,
• • • • .. • • • • • -~..-.. "''' '- . , 1... .0) . , .. , ... •• "' •• +I.' " .r • • ...,
Thi$I. a pr;nllld ro py 01the dQctrn<rrc r.eld In CDMS arJd ~ I. the 'e6IX'n; b~,ly of the~, to e n; ure tnalln" cc-rect""..;;on 1$uoedPage 12 0116
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GIa. o Sm ilhK lin&
Sh,d u'" ..... b!'''''''.,., fo, G5K933776 (. SAIl) Rorler..""" Sl.rxlard 5(IrngIrn..Prodl.<:t r"""" AC, flo"'" 10121:1rn3
Stability StudyNumber:Batch Numbef:
BPB~ST20653
061120310Storage Condition:Tesling:
5°CAmbientHumidity Upl'ighlComplele
~ ,S....P~t<:slc;.' ."• •1" 1~_ ,," , PO'"....oIoI'....II" I .....Io.~.,_·S...p._'11 ' .,. >I .. J~_ ,..,. r>odF>rt<1o< j"'..IIIo<l_.lcLnd..... b.~ "'>ltdSOIr• • rd<>1<llJOMOth _ ponlApp,,, 'n"" """""_ "" ~, ol "",.. "" ~.. ,,... _
~ Spoook .....~ .. «IC·60_0 "'1I"noLN Q _NOIRoq",.~
P~ - P"' M'd
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'- p",,"., rt"" " • • • • .. • " " • • ..- -"",., <0-........ ,., .." , , , , ,,~ -- , - _.
~ " " ,n, ~""'bo~.. ",oopI>OI.r .oloolo_,.>oi>b l
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GIa . o Sm ilhK lin&
Sh,d u '" ..... b!'''''''.,., fo, G5K933776 (. SAIl) Rorler..""" Slarxlard 5(IrngIrn..P rodl.<:t r"""" AC, flo"'" 101 2 1:1rn3
Table S 5l a bi l rt ~ Data lor GSK933776 RS 50 mgIml. Batch 061120310 at 26"<:160'4 RH
StabilityStudy Number;Bal<h Number-
BPB_ST20653061120310
StorageCondl~on :
Testing-25°CJliOOi. RelatlYe Humidity Upl1ghtComplete
"2 Sa"ll.~~2 I di1)1$_3_I~ p(J"f
3 ROSiJt ., odoeSn::('lIee'sp&cIIClllon~ _ ~ R"'l1.Qj
'm AccepIIln<:o Crilori.~, ron. " ""tho
l'litilll , , , sAwcillll ncetlj Vi, oeI Ade-Yto Cf.des<:'1/lt Ctli"...esl topile
-~Co~~ CorIflia; """,. ~ie'
I~I,", y""" liq~d. p- i'<k"v ('<00 ~ (Jll ",;u.
::: ~:C;::~::;.': ,"lDentv
, danlJly"~ Poloocybl' 8< 1>:>,,, 1o_ " TT~ "d .nllg'" Corr l~""
I -- ~I" C<>orp'", Comp...ELISA R<vrtr80dt ..",..... ' 1~ 1 "" ~ 1 .65 •• ••Roo.;; SOO:;~ t;,;,j"nc oc:l\lJt, o. '. oss •• .nP"' ~'by SECH;> LC Mo_l~O% •• ." •• 97.' i l3
REp:rt%",!J!ljat<l .. .. .. ae "R~ "" LMWng,,... r(S ' OI ILOOI " " ca ..~~' by SOS-PAGE R_ ce~ and Sf>I.. ' lion -- C",,_ """,. (Does l et CcfIl:Iie.
Corrif>"'"t1e 10" , ,, • ..,. Sl. nd1'd c...."pl'I'Non recliJCOO CoB and51-,. ".'. -~
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1J'~' by <. I E ratl e torefn", " >bnaud ., "'- 'lrl1ie" "'~.,
R'JIM pi ,e'll" aosaec 811.ll5/ 8 »867 8.00.8 59 6 <9-865N"mbel olpeak< • • • , •pi Moon •• 85 7 ... •• ••'l(, M.. n ., ., ee s •• ••
Qul nL~'llYAWlnm ~50 :iil,OmglOl. •• ", (66 ., ••"" 5 3. 57 pl.JLnIS " " es ss ssPllo1~UIOi.. M. lef
P<rtd Oi ~ ~ ~~- ~~: t "la n... " '" '" '" seP<Wtd" H 25 m-S 500 CO'lt.:ine< , ,, s,,"lle lll$lt(I25<ll after 2 moCU$ ' me Pt' rt
Thi$ I• • pr;nllld ropy 01thedQctrn<rrc r.eld In CDMS .rJd f I. the fe<;JXlrl6 b~,ly of the~r to ensure t"" t the cc-rect .'eu;ion ' $ lJ&'!dPage 14 (1/16
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GIa . o Sm ilhK lin&
Sh,d u'" ..... b!''''''' .,., fo' G5K933776 (. SAIl) Rorler..""" Slarxlard 5(IrngIrn..Prodl.<:tr"""" AC, flo"'" 10121:1rn3
TableT 5la bi l rt ~ Data for GSK933776 RS 50 mgIml. Batch 061120310 at 26"<:160'4 RH
StabilityStudy Number; Storage Condltloo; 4O"C 75%RelativeHumidityUpnght
" "~2 R..~t on 0 <loolo not__ 11'&$,,0.,1<.,.,.,
Bal<h Number: 061120310 Te.~n O>m ••Slar ogo li mo ( Month_),., "",,Iptanct Cdl<lrla r-----l-Olillr--- . 14doys }l-ci.yt ,
Appc:lr.lncel7jViIOl:l Ade<t 10:¢o:;,en:.C<!O'l'ess I:lpjt j(lII::Yi ""',. ""'~C:.rpiC$ CorrPiOS
'_ I"" Itq-i<l, p"', 'i(o!Iy r.. f ern_ . porW",
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1
This section contained Principal Investigator’s Curriculum Vitae and has been excluded to
protect Principal Investigator privacy.