appendix e-1: study protocol - neurology · 11/29/2012 · section 3.2.1 and table 3-1: clarified...

APPENDIX E-1: STUDY PROTOCOL

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006-02

A Phase IIb, Multicenter, Randomized, Double-Blind Placebo-Controlled, 2-Period Adaptive Crossover Polysomnography Studyto Evaluate the Safety and Efficacy of MK-4305 in Patients with

Primary Insomnia

1

Product: MK-4305Protocol/Amendment No.: 006-02

4305_006-02_ProtTitle VERSION 3.1 APPROVED 03-Apr-2009Worldwide Restricted Confidential – Limited Access

THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK & CO., INC., WHITEHOUSE STATION, NJ, U.S.A.

THIS PROTOCOL REPLACES THE ORIGINAL PROTOCOL AND ANY SUBSEQUENT AMENDMENTS AND SHOULD BE SIGNED BY ALL INVESTIGATORS SIGNING THE ORIGINAL PROTOCOL.

SPONSOR:Merck & Co., Inc. (hereafter referred to as the SPONSOR)One Merck DriveP.O. Box 100Whitehouse Station, NJ, 08889-0100, U.S.A.

Protocol-specific Sponsor Contact information can be found in the Administrative Binder.

TITLE:A Phase IIb, Multicenter, Randomized, Double-Blind Placebo-Controlled, 2-Period Adaptive Crossover Polysomnography Study to Evaluate the Safety and Efficacy of MK-4305 in Patients with Primary Insomnia

INVESTIGATOR:PRIMARY:

CLINICAL PHASE: IIb

US IND NUMBER: 101,847

SITE:

INSTITUTIONAL REVIEW BOARD/ETHICS REVIEW COMMITTEE:

4305, Protocol 006-02 Issue Date: 03-Apr-2009 2

Product: MK-4305 1Protocol/Amendment No.: 006-02

4305_006-02_ProtSoC VERSION 3.0 APPROVED 03-Apr-2009Worldwide Restricted Confidential – Limited Access

SUMMARY OF CHANGES

PRIMARY REASON FOR THIS AMENDMENT:

The primary reason for this amendment is to clarify that the siDMC review of the interim analyses will involve unblinding of patient level data from the ex-Japan stratum only, e.g. all Japan stratum data will remain blinded until the final data analysis following full study completion.

Affected Sections and revised text: 1.4, 2.7, 3.5.1, 3.5.6, 3.5.9.1, 3.5.9.2

OTHER CHANGES INCLUDED IN THE AMENDMENT:

Global Clarifications were made to stratification of Japanese patients. Stratification of Japanese patients will be by geographic region (Japan vs. ex-Japan).

Affected Sections and revised text: 1.4, 1.6, 2.4.1, 2.4.2, 2.7, 3.2.3.3, 3.2.3.4.3, 3.5.1, 3.5.5.1, 3.5.6, 3.5.9.1 and 3.5.9.2

Modifications to the statistical model for the analysis of primary, secondary and exploratory efficacy endpoints:

Section 2.7: Added a term to the model for geographic region (Japan vs. ex-Japan).

Section 3.5.5.1: Specified a completely unstructured covariance matrix for the mixed effects model and removed the random subject effect; if this model does not converge then a model with a random subject effect and an unstructured covariance within patient and time will be used.

S 3 3 1 12 R yz

Cover and Title Pages: Corrected protocol title

Summary of Changes 006-01

PRIMARY REASON FOR THIS AMENDMENT (006-01):

The primary reason for this amendment is to allow for an extension of the treatment period visit window with dosing beyond 28 days.

The global revision consists of changing the original 28 days of treatment to the updated 28 ± 2 days of treatment.

Affected Sections and revised text: 1.4, 1.7, 2.4.1, 2.4.2, and 3.2.3.4.3




OTHER CHANGES INCLUDED IN THE AMENDMENT (006-01):

Global Clarifications were made to enrollment and stratification of Japanese patients.

Affected Sections and revised text: 1.4, 1.5, 1.6, 2.4.1, 2.4.2, 2.7, 3.2.3.3, 3.2.3.4.3, 3.5.1, and 3.5.7

Sections 1.6, 2.4.1, and 3.2.3.4.2: The time window of 5 to 10 minutes was added to the protocol sections where oral administration of MK-4305 is specified to occur immediately (within 5 to 10 minutes) prior to bedtime on non-PSG nights.

Section 1.7 and 3.4.1.5:

Footnote § On PSG Visits, weight should be collected at both PM and AM time points, during assessment of vitals.

Footnote : Added collection of serum βhCG samples for females of child-bearing potential at Visit 1 in addition to standard urine pregnancy test.

Revised text in 3.4.1.5, paragraph 4, Appendix 6.5-footnote †

Footnote Clarified procedure for positive alcohol breath tests at Visit 4 and post randomization

Revised text in 3.4.1.5, paragraph 5

Footnote †††† and Clarified timing of assessments is consistent for each type of visit, i.e. PSG visit or non-PSG visit.

Section 2.2, Prestudy Inclusion Criteria 1p: Changed barrier c c to effective forms of contraception," modified and added additional examples of contraception: status post-vasectomy and hormonal contraceptives; Add a statement to allow a female patient to use 2 effective forms of contraception to meet criteria, if a male partner cannot use an effective form of contraception.

Section 2.3

Prestudy Exclusion Criteria 1.h: The specific QTc interval of QTcB (Bazett’s correction), as determined by the ECG reading center, should be used to meet criteria 1.h.

Screening PSG Exclusion Criteria 2a: Added an to clarify that patient must meet either 2.a.a. or 2.a.b




Section 2.4.1, 3.2.2.2, 3.2.3.4.1, 3.2.3.4.2, and 3.3.1.4: Several statements were added to clarify site’s and patient’s responsibility in regards to eDiary reporting, monitoring, and compliance.

Section 3.2.1 and Table 3-1: Clarified use of non-prohibited concomitant medication and concurrent medication, and initiation of new medications during the course of the study -1 to be consistent with Table 2-1.

Section 3.2.3.4.2 and 3.4.1.5: Corrected the urine pregnancy test collection time point. The urine pregnancy test will not be collected at Visit 2.

Section 3.2.3.4.3 and Table 3-4: Corrected the blood sample for genetic analysis (DNA) collection time point. No genetic sample will be collected at V6.

Section 3.3.1.2b: Removed 3rd paragraph regarding the timing of PSG electrode calibrations and replaced with: For the timing of electrode calibrations and other PSG activities, refer to the PSG SOP.

Section 3.3.1.7: Clarified the scoring of the WRAT-4. A patient should receive a score of 48 out of 70 to meet criteria.

Section 3.4.1.8: Amended paragraph to clarify the use of the MCQ to assess a single episode of a patient’s spontaneously-reported cataplexy-like behavior. The MCQ must also be assessed by either the Primary Investigator (PI) or a Sub-PI.

Section 3.5.8, Table 3-13: Removed United Kingdom and Australia.

Appendix 6.10: Corrected the location to which plasma samples should be shipped.

Appendix 6.7: Clarified that blood pressure measurements are collected both in the sitting and standing positions and that the instructions provided in the Appendix are only a guide for sitting blood pressure measurements.


PROTOCOL

A Phase IIb, Multicenter, Randomized, Double-Blind Placebo-Controlled, 2-Period Adaptive Crossover Polysomnography Study toEvaluate the Safety and Efficacy of MK-4305 in Patients with Primary

Insomnia

TABLE OF CONTENTS

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Summary of Changes 3

PRIMARY REASON FOR THIS AMENDMENT: 3

OTHER CHANGES INCLUDED IN THE AMENDMENT: 3

PRIMARY REASON FOR THIS AMENDMENT (006-01): 3

OTHER CHANGES INCLUDED IN THE AMENDMENT(006-01):

4

1. SUMMARY 13

1.1 Title 13

1.2 Indication 13

1.3 Summary of Rationale 13

1.4 Summary of Study Design 13

1.5 Sample 14

1.6 Dosage/Dosage Form, Route, and Dose Regimen 14

1.7 Study Flow Chart 16

2. CORE PROTOCOL 19

2.1 Objectives and Hypotheses 19

2.1.1 Primary 19

2.1.2 Secondary 19

2.1.3 Exploratory Objectives 20

2.2 Subject/Patient Inclusion Criteria 20

2.3 Subject/Patient Exclusion Criteria 22

2.4 Study Design and Duration 27


TABLE OF CONTENTS (CONT.)

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2.4.1 Summary of Study Design 27

2.4.2 Treatment Plan 30

2.5 List of Efficacy/Pharmacokinetic/Immunogenicity, etc.,Measurements

31

2.6 List of Safety Measurements 31

2.7 Data Analysis Summary 32

3. PROTOCOL DETAILS 34

3.1 Rationale 34

3.1.1 Introduction 34

3.1.2 Rationale for Study of MK-4305 in Primary Insomnia 35

3.1.3 Rationale for Study Design, Treatment Duration, andWashout

36

3.1.4 Rationale for Doses and Regimen 36

3.1.5 Rationale for Subject/Patient Genetic Sample Collection 37

3.2 Study Procedures 38

3.2.1 Concomitant Medication(s)/Treatment(s) 38

3.2.2 Diet/Activity/Other 41

3.2.2.1 Diet 41

3.2.2.2 eDiary Completion 41

3.2.2.3 Alcohol Restrictions 42

3.2.2.4 Caffeine Restrictions 42

3.2.2.5 Smoking Restrictions 42

3.2.2.6 Activity 42

3.2.2.7 Bedtime 42

3.2.3 Procedures 43

3.2.3.1 Informed Consent 44

3.2.3.1.1 General Informed Consent 44



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3.2.3.1.2 Consent and Collection of Specimens for GeneticAnalysis

44

3.2.3.2 Assignment of Baseline Number/Screening/Washout 44

3.2.3.3 Randomization/Allocation 45

3.2.3.4 Prestudy and Treatment Periods 45

3.2.3.4.1 Prestudy (Visit 1) 45

3.2.3.4.2 Screening and Baseline PSG (Visits 2 and 3) 47

3.2.3.4.3 Treatment Periods (Visits 4-9) 51

3.2.3.5 Treatment/Evaluation/Follow-Up 53

3.2.3.6 Blinding/Unblinding 54

3.2.3.7 Discontinuation/Withdrawal from Study 54

3.3 Efficacy/Pharmacokinetic/Immunogenicity, etc. Measurements 56

3.3.1 Clinical and Laboratory Measurements for Efficacy/Pharmacokinetic/ Immunogenicity, etc.

56

3.3.1.1 Procedures for Conducting Diagnosis and EfficacyMeasures

56

3.3.1.2 PSG Measurements 56

3.3.1.3 PSG Definitions and Scoring 57

3.3.1.4 Electronic Morning and Evening Questionnaires 58

3.3.1.5 MINI International Neuropsychiatric Interview (MINI) 59

3.3.1.6 Sleep Diagnostic Interview/Sleep History 59

3.3.1.7 Reading Assessment 59

3.3.1.8 Quick Inventory of Depressive Symptomatology Scale(QIDS-SR16)

60

3.3.1.9 Digit Symbol Substitution Test (DSST) and Digit SymbolCopy Test (DSCT)

60

3.3.1.10 Sheehan Disability Scale (SDS) 60

3.3.1.11 Insomnia Severity Index (ISI) 60



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3.3.1.12 Blood Collection for Pharmacokinetic Assay (of MK-4305levels in plasma)

60

3.3.2 Medication Compliance 61

3.4 Safety Measurements 61

3.4.1 Clinical and Laboratory Measurements for Safety 61

3.4.1.1 Medical and Psychiatric History 61

3.4.1.2 Physical Examination 62

3.4.1.3 Vital Signs 62

3.4.1.4 ECG 62

3.4.1.5 Laboratory Evaluations 63

3.4.1.6 Tyrer Withdrawal Symptom Questionnaire 64

3.4.1.7 Columbia Suicide Severity Rating Scale (C-SSRS) 64

3.4.1.8 Modified Cataplexy Questionnaire 64

3.4.2 Recording Adverse Experiences 64

3.4.3 Definition of an Overdose for This Protocol 65

3.4.3.1 Reporting of Overdose to SPONSOR 65

3.4.4 Reporting of Pregnancy to SPONSOR 65

3.4.5 Immediate Reporting of Adverse Experiences to theSPONSOR

66

3.4.5.1 Serious Adverse Experiences 66

3.4.5.2 Selected Nonserious Adverse Experiences/Events ofClinical Interest

66

3.4.6 Evaluating Adverse Experiences 66

3.4.7 SPONSOR Responsibility for Reporting Adverse Experiences 69

3.5 STATISTICAL ANALYSIS PLAN 69

3.5.1 Responsibility for Analyses/In-House Blinding 69

3.5.2 Hypotheses/Estimation 70

3.5.3 Analysis Endpoints 70



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3.5.3.1 Efficacy/Immunogenicity/Pharmacokinetics Endpoints 70

3.5.3.1.1 Efficacy Endpoints 70

3.5.3.1.2 Pharmacokinetics Endpoints 73

3.5.3.2 Safety Endpoints 73

3.5.3.3 Derivations of Efficacy/Immunogenicity/PharmacokineticsEndpoints Primary and Secondary Endpoints

73

3.5.3.4 Derivations of Safety Endpoints 74

3.5.4 Analysis Populations 76

3.5.4.1 Efficacy Analysis Populations 76

3.5.4.2 Safety Analysis Populations 76

3.5.5 Statistical Methods 76

3.5.5.1 Statistical Methods for Efficacy Analyses 76

3.5.5.2 Statistical Methods for Safety Analyses 78

3.5.5.3 Summaries of Baseline Characteristics, Demographics,and Other Analyses

80

3.5.6 Multiplicity 81

3.5.7 Sample Size and Power Calculations 82

3.5.7.1 Sample Size and Power for Efficacy Analyses 82

3.5.7.2 Sample Size and Power for Safety Analyses 84

3.5.8 Subgroup Analyses and Effect of Baseline Factors 84

3.5.9 Interim Analyses 84

3.5.9.1 Efficacy Interim Analyses 84

3.5.9.2 Safety Interim Analyses 85

3.5.10 Compliance (Medication Adherence) 85

3.6 PACKAGING, LABELING, STORAGE, AND RETURN OFCLINICAL SUPPLIES

86

3.6.1 Product Descriptions 86

3.6.2 Packaging Information 87



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3.6.3 Clinical Supplies Disclosure 87

3.6.4 Storage and Handling Requirements 87

3.6.5 Standard Policies / Return of Clinical Supplies 87

3.7 Data Management 88

3.8 Biological Specimens 88

4. ADMINISTRATIVE AND REGULATORY DETAILS 89

4.1 Confidentiality 89

4.1.1 Confidentiality of Data 89

4.1.2 Confidentiality of Subject/Patient Records 89

4.1.3 Confidentiality of Investigator Information 89

4.2 Compliance with Law, Audit, and Debarment 90

4.3 Compliance with Financial Disclosure Requirements 91

4.4 Quality Control and Quality Assurance 92

4.5 Compliance with Information Program on Clinical Trials forSerious or Life Threatening Conditions

92

4.6 Publications 92

5. LIST OF REFERENCES 93

6. APPENDICES 96

6.1 List of Abbreviations and Definition of Terms 96

6.2 Glossary of Sleep Terms and Definitions 98

6.3 DSM-IV-TR Criteria for Primary Insomnia 99

6.4 List of Caffeine Products and Caffeine Content 100

6.5 Laboratory Safety Tests 101

6.6 Algorithm for Assessing Out-of-Range Laboratory Values 103

6.7 Measurement of Blood Pressure 104

6.8 Calculating Body Mass Index (BMI) 106

6.9 Electronic Patient Diary (eDiary) 107



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6.10 Standard Plasma Collection Procedure 109

6.11 Details of Futility Analysis 111

7. ATTACHMENTS 112

8. SIGNATURES 116

8.1 SPONSOR’S REPRESENTATIVE 116

8.2 INVESTIGATOR 116



4305_006-02_ProtCore VERSION 3.0 APPROVED 03-Apr-2009Worldwide Restricted Confidential – Limited Access

1. SUMMARY

1.1 TITLE

A Phase IIb, Multicenter, Randomized, Double-Blind Placebo-Controlled, 2-Period Adaptive Crossover Polysomnography Study to Evaluate the Safety and Efficacy of MK-4305 in Patients with Primary Insomnia

1.2 INDICATION

Primary Insomnia

1.3 SUMMARY OF RATIONALE

1.4 SUMMARY OF STUDY DESIGN

This is a randomized, double-blind (with in-house blinding), placebo-controlled, 2-period cross-over PSG study to assess the safety, tolerability, and efficacy of four doses of MK-4305 (10, 20, 40, and 80 mg) in the treatment of patients with primary insomnia. This design is equivalent to four separate 2-treatment 2-period crossover trials with patients in each trial receiving one of the four MK-4305 doses and placebo. The objectives of the study include demonstration of the effectiveness and dose response of MK-4305 and identification of an appropriate dose or doses for Phase III development. An interim analysis (IA) will be employed to assess: (1) preliminary effectiveness of MK-4305 (futility of doses), and (2) safety and tolerability. A second IA may be performed to aid in planning and/or acceleration of future studies. Each interim analysis will include patients from the ex-Japan stratum only.

This study will enroll ~250 randomized patients to yield ~208 completed patients in the U.S. and Worldwide, including ~ 40 patients of Japanese ancestry. Nine visits occur in the study: these include Prestudy, Screening PSG, and Baseline PSG visits, as well as 2 separate 4-week treatment periods each containing 3 visits. At the Prestudy Visit (Visit 1), patients will undergo initial safety and diagnostic assessments to determine study


Redacted



eligibility based on initial criteria. Eligible patients will then advance to the Screening PSG (Visit 2) and Baseline PSG (Visit 3) visits, approximately 1 week later, respectively, during which specific polysomnographic criteria must be met and exclusionary sleep disorders ruled out. Patients who consecutively meet Visit 2 and Visit 3 criteria will be randomized upon final confirmation of eligibility at Visit 4. The single-blind placebo run-in period will begin for eligible patients as of the evening (PM) of Visit 2 and will continue for ~1 week, provided continued patient eligibility, through Visit 3 and until study randomization at Visit 4.

Patients who meet study requirements will be randomized via an Interactive Voice Response System (IVRS) and will receive double-blind treatment with MK-4305 and placebo. During the MK-4305 treatment period, patients will receive one of four possible MK-4305 doses (10, 20, 40, or 80 mg). Assignment to dose of MK-4305 and treatment sequence (MK-4305/Placebo or Placebo/MK-4305) will be randomly determined by a computer-generated random allocation schedule. The randomization will be stratified by geographic region (Japan vs. ex-Japan).

Each 4-week treatment period consists of an overnight PSG visit on the first and last night of the treatment period, with an interim office visit at the Week-2 midpoint. Each treatment period will consist of 28 ± 2 days of treatment. A single-blind placebo washout interval of a minimum of 7 days will separate the two treatment periods. Patients completing the entire study will undergo a total of 6 sleep lab overnight PSG evaluations, inclusive of 2 per treatment period and 1 each at Visits 2 and 3.

Total time in the study for patients will be a minimum of ~12 weeks (based on target study days and minimum visit windows). This is inclusive of the prestudy visit, an ~1- to 2-week placebo run-in period (from Visits 2 and 3 and leading up to randomization), two 4-week treatment periods, and one 1-week placebo washout between each treatment period. After patients have completed final treatment, there will be a 2-week post-study follow-up.

1.5 SAMPLE

Approximately 250 men and women aged 18 to <65 years with a Diagnostic and Statistical Manual of Mental Disorder-Category IV-Text Revision (DSM-IV-TR, Appendix 6.3) diagnosis of primary insomnia will be randomized into the study to yield approximately 208 patients who complete the study, including ~ 40 patients of Japanese ancestry.

1.6 DOSAGE/DOSAGE FORM, ROUTE, AND DOSE REGIMEN

MK-4305 10-mg and 30-mg film-coated tablets and respective matching placebos will be used in the study to achieve doses of 10, 20, 40, and 80 mg per dose. In order to maintain blinding, a double dummy design will be used. Study medication will be packaged in bottles to achieve the various MK-4305 dose levels. Placebo for MK-4305 will be packaged similarly to provide a range of supplies matching the active dose levels.




Each patient will be instructed to take 1 tablet each from 4 different bottles (labeled A, B, C, and D, respectively) throughout the entire course of the study, including the single-blind placebo run-in period and the washout period.

MK-4305 or matching placebo tablets will be orally administered approximately 30 minutes before bedtime on PSG nights and immediately (within 5 to 10 minutes) prior to bedtime on non-PSG nights. On PSG nights, dosing will be witnessed by study personnel. On non-PSG nights, dosing will be captured by an electronic eDiary.

Patients will receive the first dose of single-blind placebo in the PM of the Screening Visit (Visit 2) to commence the single-blind placebo run-in period. The placebo run-in period will continue up until Visit 4, pending continued patient eligibility through Visit 3. Single-blind placebo study drug will be dispensed at Visits 2 and 3.

Randomization via IVRS will occur in the PM of Visit 4 once all study criteria have been satisfied, at which point patients will begin the first of two separate 4-week double-blind treatment periods. Dose assignments for each period will be determined by a computer-generated random allocation schedule, randomizing patients to one of 8 possible treatment sequences. The randomization will be stratified by geographic region (Japan vs. ex-Japan). Double-blind MK-4305 or placebo will be dispensed at Visit 4 for Treatment Period 1, and at Visit 7 for Treatment Period 2. At Visit 6, patients will receive single-blind placebo study drug for the washout period. Patients are to be blinded to treatment throughout the entire study, including throughout the single-blind placebo washout period of a minimum of 7 days that occurs between the two treatment periods. Investigators are not to unblind a patient to treatment without first attempting to secure approval from the Sponsor. If unblinding should inadvertently or of necessity occur (e.g., by accidental unblinding, or due to emergency unblinding because of a serious adverse experience), the investigator must promptly document the circumstances and notify the SPONSOR.




1.7 STUDY FLOW CHART

Screening Period Treatment Period 1 Washout Period Treatment Period 2

Treatment Period PrestudyScreening

PSGBaseline

PSGPeriod 1Day 1

Period 1 Day 14

Period 1 Day 28

PlaceboWashout

Period 2Day 1

Period 2 Day 14

Period 2 Day 28

DisconVisit

PSGs PSG 1 PSG 2 PSG 3 PSG 4 PSG 5 PSG 6Visit Number: 1 2 3 4 5 6 7 8 9

Target Study Day†: --21 -14 -7 1/2 14 28/29 29-35 36/37 49 63/64Allowed Visit Window‡: -3/+21 -3/+7 -3/+7 +/-2 +/-2 +8 +/-2 +/-2 +3

Procedures PM¶¶ AM PM AM PM AM PM AM PM AM PM AM

Informed Consent XMedical and Psychiatric history XDiagnostic Interview/Sleep History/DSM-IV-TR XMINI International Neuropsychiatric Interview (MINI) XReading Assessment¶¶¶ XQuick Inventory of Depressive Symptomatology (QIDS) XInclusion/Exclusion X X X X X XPrior and concomitant therapy X X X X X X X X X XPhysical examination X X X XVital signs†††† X§ X X X X X X X X X X X X X X XECG ‡‡‡‡ X X X X X X X X XHematology, chemistry, urinalysis X X X X X X X X XUrine drug screen X X X X X X X XUrine pregnancy test¶ X X X X X X XInformed consent for pharmacogenomic sample analysis‡‡‡ XBlood sample for genetic analysis (DNA)‡‡‡ XBlood sample for HLA DQB1*0602 allele (DNA)‡‡‡ XBlood sample for molecular analysis (RNA) ### X X XPharmacokinetic (PK) Sampling### X X X X X X XAlcohol breath test# X X X X X X XDispense Study Drug X X X X X§§ X## X††† X X## X§§§§

Call IVRS X X X X X X X

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Screening Period Treatment Period 1 Washout Period Treatment Period 2

Treatment Period PrestudyScreening

PSGBaseline

PSGPeriod 1Day 1

Period 1 Day 14

Period 1 Day 28

PlaceboWashout

Period 2Day 1

Period 2 Day 14

Period 2 Day 28

DisconVisit

PSGs PSG 1 PSG 2 PSG 3 PSG 4 PSG 5 PSG 6Visit Number: 1 2 3 4 5 6 7 8 9

Target Study Day†: --21 -14 -7 1/2 14 28/29 29-35 36/37 49 63/64Allowed Visit Window‡: -3/+21 -3/+7 -3/+7 +/-2 +/-2 +8 +/-2 +/-2 +3

Polysomnography (PSG) X X X X X XEvening/Morning Diary‡‡ X†† X X X X X X X X X X X X X X X X§§§§

Tyrer Withdrawal Symptom Questionnaire (evening diary) X X X§§§§

Digit Symbol Substitution Test (DSST) X X X X X X XDigit Symbol Copy Test (DSCT) (part of WAIS-III) X X X X X X XSheehan Disability Scale X X X XInsomnia Severity Index (ISI) X X X XAdverse Experiences§§§ X--------------------------------------------------------------------------------------------------------------------------------------X † Th r i D -1. Each treatment period will consist of 28 ± 2 days. ‡ Deviations from visit window permitted per protocol require consultation between the investigator and the SPONSOR and written documentation of the collaborative decision on patient management. All efforts should

be made to schedule patients using the target study days as depicted in the study flow chart or the minimum visit window allowance. Visit windows for Visits 2, 3, and 4 are relative to the prior visit. Visit windows at Visits 5, 6 and 8, 9 are relative to the beginning of each treatment period (Visits 4 and 7, respectively). Total treatment will consist of 28 ± 2 days. Please note: the -21-day window for the Screening Visit 2 (i.e., window from prestudy to screening) is to allow for washout of prohibited meds and that screening assessments for patients undergoing prohibited medication washout should be delayed until closer to the screening PSG.

§ Body Mass Index (Appendix 6.4) will be calculated only at the Prestudy Visit from weight and height. Height will only be measured at the Prestudy Visit. Weight will be measured at the specified Vital Sign time points (for PSG visits, weight is measured at both PM and AM timepoints).

The interval of time between Visits 3 and 4 should be a minimum of 3 days apart in order to allow for confirmation of PSG results from the central reader. ¶ Any female patient of child-bearing potential will undergo a urine pregnancy test and a serum pregnancy test (β-hCG) at Visit 1. At other specified time points, if a female patient has a positive urine pregnancy test, a

serum pregnancy test must be performed and sent to the central laboratory for confirmation. # Patients should have a negative alcohol breath test on the PSG visit nights. If a patient has a positive alcohol breath test at Visit 1, this should be documented and site should counsel the patient on alcohol restrictions

during the study. If a patient has a positive alcohol breath test at Visits 2 and 3, then the patient will be excluded from the study. At Visit 4 and after randomization, if a patient has a positive alcohol breath test, the test may be repeated at the investigator’s discretion with notification to SPONSOR and the repeat test must be negative prior to conducting the PSG recording session. If the repeat test is positive, the recording session visit should be rescheduled to take place within no sooner than 24 hours and no later than 48 hours.

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†† The patient will complete an evening and morning diary at home every day after satisfactory completion of Prestudy Visit 1 and up to Visit 4, pending study criteria is met at each consecutive visit, in order to determine the median habitual bedtime of the patient.

‡‡ Morning Diary should be completed by the patient after completion of normal morning routine (e.g., using the bathroom, eating breakfast), and preferably within an hour of awakening for the day during the at home period or within 1 hour following lights on during PSG days. Diary should also be performed on the morning prior to all treatment period visits. Evening diaries should be completed by the patient after completion of normal evening routine, and preferably within 30 minutes prior to lights off. Evening diary on PSG nights should be completed prior to drug administration (Appendix 6.7).

§§ First dose of randomized blinded study medication will be dispensed.Patients that complete the study or prematurely discontinue either Treatment Period will receive a 14-day (from last dose) follow-up phone call to assess for serious adverse experiences.

¶¶ Measurements that are performed in the PM, with the exception of the PSG, will be conducted prior to study drug administration. This applies to all PSG study visits.## Patients are dispensed the final dose of study drug for that specific treatment period.††† Patients will be dispensed single-blind placebo for the washout period.‡‡‡ Signing of the pharmacogenomic sample consent form and obtaining the optional genetic sample can be completed at anytime up to Visit 4 (randomization).. This is not necessary to participate in the study. The

allele sample is not optional and may be collected at anytime up to Visit 4 (randomization).§§§ Please refer to Sections 3.4.1.6, 3.4.1.7, and 3.4.5.2 for specific assessments to perform on patients reporting any of the pre-specified ECIs, which include narcolepsy or cataplexy-like events, suicidal thoughts or

ideation, and complex sleep behaviors.Tyrer Questionnaire will be completed in the evenings ONLY on the first 3 nights of the placebo-washout period (depending on duration of the treatment period [28 ± 2 days], this will occur on Days 27-29, 28-30, 29-31, 30-32, or 31-33). This will be part of the eDiary evening questionnaire (Appendix 6.7). After single-blind placebo drug is dispensed, the Study Coordinator will initiate the Tyrer in the eDiary. Please refer to specific instructions in the eDiary procedures manual.

¶¶¶ Patient must obtain a score of ≥6th grade level equivalent on a standardized reading test (such as the Reading subtest of the Wide Range Achievement Test, 4th edition (WRAT-4), if available, or a comparable measure, approved by Sponsor [see administrative binder for sample reading questions]).

# # # All RNA and PK samples should be drawn 9 hours ±15 minutes post dosing on AM portions of specified PSG treatment visits.†††† All vital signs for a given patient must be taken at the same time consistently throughout the entire study, respective to each type of visit, i.e. PSG visits and non-PSG visits.‡‡‡‡ All ECGs for a given patient must be obtained at the same time consistently throughout the entire study, respective to each type of visit, i.e. PSG visits and non-PSG visits.§§§§ These procedures will only be performed if a patient discontinues during Treatment Period 1 AND wishes to continue to Treatment Period 2, pending prior SPONSOR approval. Patient will be dispensed single-blind

placebo medication to commence the washout period prior to starting Treatment Period 2, Visit 7. The Tyrer Withdrawal Symptom questionnaire will be completed for the first 3 days of washout.

4305,P

rotocol006-02Issue

Date:

03-Apr-2009

18



2. CORE PROTOCOL

2.1 OBJECTIVES AND HYPOTHESES

Both objective and subjective measures of sleep are evaluated in this study. Since some assessments measure the same variable (e.g., total sleep time [TST]) a convention of adding ’s’ before the subjective measure is used in this document (e.g., sTST). Also, since some measures involve taking the average over time (e.g., days in Week 1) a convention of adding ’m’ after the measure is used to reflect the mean value over time for this measure (e.g., sTSTm).

2.1.1 Primary

Objectives:

1. To evaluate the efficacy of MK-4305 compared with placebo in improving sleep efficiency (SE) as measured by polysomnography (PSG) on Night 1 and at the end of 4 weeks of treatment, where SE is defined as 100 times total sleep time (minutes) divided by time in bed (minutes).

2. To evaluate the safety and tolerability of MK-4305.

Hypotheses:

1. At least one dose of MK-4305 is superior to placebo in improving SE as measured by PSG on Night 1 and at the end of 4 weeks of treatment, where SE is defined as 100 times total sleep time (minutes) divided by time in bed (minutes).

2. MK-4305 is well tolerated in patients with primary insomnia.

2.1.2 Secondary

Objectives

1. To evaluate the efficacy of MK-4305 compared with placebo in improving wake after sleep onset (WASO) as measured by PSG on Night 1 and at the end of 4 weeks of treatment.

2. To evaluate the efficacy of MK-4305 compared with placebo in improving latency to persistent sleep (LPS) as measured by PSG on Night 1 and at the end of 4 weeks of treatment.

Hypotheses

1. At least one dose of MK-4305 is superior to placebo in improving WASO, as measured by PSG on Night 1 and at the end of 4 weeks of treatment.




2. At least one dose of MK-4305 is superior to placebo in improving LPS, as measured by PSG on Night 1 and at the end of 4 weeks of treatment.

2.1.3 Exploratory Objectives

Objectives

1. To evaluate the efficacy of MK-4305 compared with placebo in improving subjective sleep measures e.g., total sleep time (sTSTm), subjective time to sleep onset (sTSOm), subjective number of awakenings (sNAWm), as reported by the patient on the Morning Diary during each week of treatment.

2. To characterize other PSG sleep parameters (e.g., TST, NAW, SWS) and the sleep architecture of MK-4305 compared with placebo as measured by: 1) minutes and percentages of Stages 1, 2, 3, 4 and REM and 2) power spectra, on Night 1 and at the end of 4 weeks of treatment.

3. To evaluate the efficacy of MK-4305 compared with placebo in improving self-reported measures of daytime functioning as measured by: the Evening Diary, Insomnia Severity Index (ISI), and Sheehan Disability Scale (SDS).

4. To evaluate the consistency of MK-4305 treatment effects compared to placebo for selected efficacy and safety endpoints with respect to the presence/absence of the HLA DQB1*0602 allele.

2.2 SUBJECT/PATIENT INCLUSION CRITERIA

Patient with screening values/findings outside ranges described in the protocol may, at the discretion of the investigator, have one repeat determination performed and if the repeat value satisfies the criterion, they may continue in the screening process. Only the specific out of range valued/finding should be repeated (not the entire panel).

A patient will be eligible to participate in this study if all of the following criteria apply:

Prestudy Inclusion (Visit 1)

1.a) Patient is male or female between 18 and <65 years of age.

1.b) Patient has a DSM-IV-TR (Appendix 6.3) diagnosis of Primary Insomnia based on the investigator’s judgment and the patient’s sleep history as assessed on the Sleep Diagnostic Interview/Sleep History.

1.c) Patient understands the study procedures, alternative treatments available, and risks involved with the study, and voluntarily agrees to participate by giving written informed consent. Patient is able to read, understand and complete questionnaires and diaries, including operation of eDiary.




1.d) Patient has completed at least 6 years of formal education; patient obtains a score ≥6th grade level on Reading Subtest of Wide Range Achievement Test Version 4 (WRAT-4) at screening, or a comparable measure approved by Sponsor. If formal reading assessments are not available, or for languages other than English, the Sponsor will specify other tests or methods of assessing reading ability at screening.

1.e) Patient is judged to be in good physical and mental health.

1.f) Patient reports a total sleep time of ≤6.5 hours on at least 3 out of 7 nights each week within the 4 weeks prior to Visit 1, when not medicated on a hypnotic agent.

1.g) Patient reports a sleep latency of ≥30 minutes on at least 3 out of 7 nights each week within the 4 weeks prior to Visit 1, when not medicated on a hypnotic agent.

1.h) Patient has ≥1 hour of wakefulness after sleep onset.

1.i) Patient spends 6.5 to 9 hours nightly in bed.

1.j) Patient is willing to stay overnight at a sleep laboratory. NOTE: The overnight stays occur on a total of 6 separate nights.

1.k) Patient is willing to stay in bed for at least 8 hours each night while at the sleep laboratory.

1.l) The patient’s regular bedtime is between 9 PM (21:00) and 12 AM (00:00).

1.m) During the study, the patient is willing to refrain from napping.

1.n) During the study, patient is willing to limit alcohol to 2 drinks a day, at least 3 hours before going to bed on non-PSG visit days, and refrains from drinking alcohol on all PSG visits and at least 24 hours prior to a PSG visit. (A drink is defined as a 12-ounce bottle/can of beer (~14 grams alcohol) or a 4-ounce glass of wine (~12 grams alcohol) or 1 ounce of liquor (80 proof or 40 % alcohol, ~9 grams alcohol).)

1.o) During the study, the patient is willing to limit caffeine consumption to ≤5 standard 6-ounce cups of caffeinated beverages a day, or ≤600 mg caffeine, avoid caffeine after 4 PM (16:00) on non-PSG nights, and avoid caffeine after 1 PM (13:00) on PSG visits. (See Appendix 6.4 for additional guidance on caffeine products and content.)

1.p) A female patient who is of reproductive potential has a serum β-hCG level consistent with the nongravid state at the prestudy visit and agrees to remain abstinent (where abstinence is a locally accepted form of contraception) or to use 2 effective forms of contraception (partner using condom with spermicide or status post vasectomy and patient using approved hormonal contraceptives (oral, implants, injections, etc), diaphragm with spermicide, contraceptive sponge, IUD, etc.) for at least 2 weeks prior to and throughout the study.




If male partner does not use an effective form of contraception, a female patient MUST use 2 effective forms of contraception to satisfy the study requirement.

1.q) A female patient that is postmenopausal or status post hysterectomy, bilateral tubal ligation, or bilateral oophorectomy is eligible without requiring the use of contraception. Postmenopausal status is defined as age ≥43 years and (1) no menses for >1 year but <3 years and confirmed by FSH levels elevated into the postmenopausal range, as defined by the designated laboratory, or (2) no menses for at least 3 years.

Screening PSG Inclusion (Visit 2)

Patient must fulfill all of the Prestudy Inclusion Criteria.

2.a) Patient has LPS >20 minutes during the Screening PSG at Visit 2. NOTE:

non-wake state.

2.b) Patient has WASO >45 minutes during the Screening PSG at Visit 2.

Baseline PSG Inclusion (Visit 3)

Patient must fulfill all of the Prestudy Inclusion Criteria.

3.a) Patient has LPS >20 minutes on both Screening and Baseline PSG nights.

3.b) Patient has a mean WASO ≥60 minutes on the combined Screening and Baseline PSG nights, where neither night is ≤45 minutes.

2.3 SUBJECT/PATIENT EXCLUSION CRITERIA

The purpose of the exclusion criteria outlined above is to screen for appropriate subjects for enrollment in this study. A patient will not be eligible to participate in this study if any of the following criteria apply:

Prestudy Exclusion (Visit 1)

1.a) If female, patient has a positive pregnancy test or is planning to conceive within the projected duration of the study, is pregnant, or breastfeeding. NOTE: If male, an wer

1.b) Patient has a history of hypersensitivity or idiosyncratic reaction to more than two (2) chemical classes of drugs, including prescriptions and over-the-counter medications.




1.c) Patient has a clinically significant abnormality (as determined by the investigator) in the following assessments:

Physical examinationECGLaboratory safety tests (Appendix 6.5)

Alanine transaminase (SGPT or ALT), aspartate transaminase (SGOT or AST) >1.5x upper limit of normal

Total bilirubin >1.5x upper limit of normal

Alkaline phosphatase >1.5 times the upper limit of normal

See Appendix 6.6 for an algorithm for assessing out-of-range laboratory values.

1.d) Patient, in the opinion of the investigator, has a history or current evidence of any condition, therapy, lab abnormality or other circumstances that might confound the results of the study, or interfere with the patient’s participation for the full duration of the study, such that it is not in the best interest of the patient to participate. Examples of excluded disorders include, but are not limited to: HIV or other relevant infections, history of acute or chronic hepatitis, history of gastric bypass or gastric banding surgery, active endocrine disorders (however, patients with well-controlled insulin-dependent diabetes, type II diabetes, or hypothyroidism are allowed if on stable doses of appropriate therapy for ≥1 month prior to Screening Visit 2).

1.e) Patient has any history of a neurological disorder, including but not limited to seizure disorder (other than single episodes of childhood febrile seizures), epilepsy, stroke, transient ischemic attack, multiple sclerosis, cognitive impairment, significant head trauma with sustained loss of consciousness, or classical migraine headaches in the last 10 years.

1.f) Patient has history within the past 6 months prior to the Screening visit or current evidence of a clinically significant cardiovascular disorder, including, but not limited to:

left ventricular hypertrophymitral valve prolapseacute coronary syndromeunstable angina, congestive heart failure (e.g., ejection fraction (EF) <40%)cardiogenic syncopesymptomatic arrhythmia




1.g) Patient at Screening Visit has by ECG clinically significant AV conduction disturbance (e.g., second or third degree AV block), sick sinus syndrome, bradycardia (resting pulse <40), accessory bypass tract (e.g., Wolff-Parkinson-White).

1.h) Patient has by ECG or physical exam a history or current evidence of long QT syndrome, Torsades de pointe, or a QTcB interval of >450 (QTcB interval (Bazett’s correction) as determined by the ECG reading center).

1.i) Patient has a screening blood pressure >160 mmHg systolic or >100 mmHg diastolic or a pulse rate >100 beats/min. Blood pressure and pulse measurements exceeding these limits, may be repeated (at the initial Prestudy visit) as warranted by the investigator, but values must be within the specified limits for the patient to be eligible for the study. (See Appendix 6.7 for guidance on Blood Pressure measurements.)

1.j) Patient is taking, or plans to take, one or more of the following medications (non-inclusive), shown in Table 2-1, within the specified washout periods prior to Screening Visit 2 and throughout the course of the study (a detailed list of the prohibited medications is provided in Section 3.2.1):

Table 2-1

Prohibited Medications and Specified Washout Period

Treatment IntervalInvestigational compounds 4 weeks or 5 t½ lives (which ever is longer)Clinically relevant CYP3A4 Inhibitors and Inducers 4 weeksCentrally acting anticholinergics or antihistamines 2 weeksMelatonin 2 weeksAntidepressants Fluoxetine

2 weeks4 weeks

Anxiolytics 2 weeksBenzodiazepines 2 weeks or 5 t½ lives (which ever is longer)Hypnotics 2 weeks or 5 t½ lives (which ever is longer)Any CNS depressants 2 weeksOver-the-counter medications that could affect sleep

[e.g., kava-kava, valerian, Benadryl (diphenhydramine) St. Johns wort]

2 weeks

Stimulants 2 weeksDiet pills 2 weeksAntihistamines (sedating) 2 weeks

NOTE: While listed here as prohibited medications, please note that some of these medications are additionally associated with excluded medical disorders, e.g. excluded cardiovascular disease, stroke, epilepsy, psychotic disorders, and relevant infections, such




as H.I.V. infection. Patients should not be withdrawn from medically necessary medications (e.g. warfarin, psychotropics, antivirals) in order to participate in this study, but rather such patients should be excluded from the study both due to their medical condition and due to the requirement for these therapies.

1.k) Patient has a positive prestudy urine drug screen. NOTE: The screen may be repeated at investigator’s discretion and as warranted by medical history. A repeat drug screen must be negative prior to randomization or it must be discussed with the SPONSOR.

1.1) Patient has an active Axis I or II disorder as defined in the DSM-IV-TR (Appendix 6.3) and as assessed by the Mini International Neuropsychiatric Interview, other than Primary Insomnia. Patient has a history of Bipolar Disorder, Psychotic Disorder, or any history of antipsychotic or depot neuroleptic use.

1.m) Patient has evidence of ongoing depression as determined by a score ≥20 on the Quick Inventory of Depressive Symptomatology – Self Report Scale (QIDS-SR16), or scores ≥2 on the QIDS-SR16 suicide item #12, or in the judgment of the investigator the patient is impaired, suicidal or otherwise in such a way as to be unable to complete the study procedures in a safe and appropriate fashion (regardless of QIDS-SR16 score).

1.n) Patient has a history of substance abuse or dependence (except if currently in sustained full remission for at least one year or meets criteria for early full remission, according to DSM-IV-TR). Substances include alcohol, marijuana, hypnotics, and drugs of abuse, but excludes nicotine dependence. A patient who fulfills DSM-IV-TR criteria for sustained remission can be included if he/she, in the investigator’s opinion, is at low risk for further drug dependence or abuse.

1.o) Patient is currently participating or has participated in a study with an investigational compound or device within 30 days of signing informed consent and is not willing to refrain from participating in another study.

1.p) Patient has a history of transmeridian travel (across >3 time zones) or shift work (defined as permanent night shift or rotating day/night shift work) within the past 2 weeks or anticipates needing to travel (across >3 time zones) at any time during the study.

1.q) Patient has donated blood products or has had phlebotomy of >300 mL within 8 weeks of signing informed consent, or intends to donate or receive blood products during participation in the study.

1.r) Patient consumes the equivalent of >15 cigarettes a day, and the Primary Investigator confirms that the patient’s sleep disturbance is in part the result of this consumption and the patient is unable to refrain from smoking during the night.




1.s) Patient has recent history (within the last 3 months) of tobacco use associated with initiation or interruption of sleep (i.e., patients who interrupt sleep to smoke or use tobacco products) or requires a cigarette within 30 minutes of waking in the morning.

1.t) Patient has a history of any of following conditions:

a. Narcolepsy

b. Cataplexy

c. Circadian rhythm sleep disorder

d. Parasomnia including nightmare disorder, sleep terror disorder, sleepwalking disorder, and REM behavior disorder

e. Sleep-related breathing disorder

f. Periodic limb movement disorder

g. Restless legs syndrome

1.u) Patient has a history of malignancy ≤5 years prior to signing informed consent, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer. Melanoma, leukemia, lymphoma and myeloproliferative disorders of any duration are excluded.

1.v) Patient has a history of uncontrolled diabetes as defined by HbA1c of greater than 8%.

1.w) Patient has difficulty sleeping due to a medical condition. NOTE: Medical Conditions include pain, cardiac disease, nocturia (>3 times/night), asthma, gastroesophageal reflux disease (GERD), or hot flashes.

1.x) The patient has a Body Mass Index (BMI) >40 kg/m2. BMI is calculated by taking the subject’s weight in kg and dividing by the subject’s height in meters, squared (see Appendix 6.8).

1.y) The patient has started a weight-loss diet in the past 30 days.

1.z) Patient is unlikely to adhere to the study procedures, keep appointments, or is planning to relocate during the study.




Screening PSG Exclusion (Visit 2)

Patient meets any of the Prestudy Exclusion Criteria.

2.a) Patient has an underlying pathology of sleep identified during the screening PSG:

a. An Apnea Hypopnea Index >10 orb. >10 periodic leg movements associated with an arousal per hour of sleep

(PLMAs).

2.b) Patient has a positive alcohol breath test as analyzed by a breathalyzer machine. NOTE: The test may be repeated at investigator’s discretion (e.g., recent use of mouthwash) and as warranted by medical history. A repeat test must be negative prior to the PSG, and these results must be discussed with the SPONSOR.

Baseline PSG Exclusion (Visits 3)


3.a) Patient has a positive alcohol breath test or urine drug screen. See NOTE in Exclusion 2.b).

Treatment Day 1 PSG Exclusion (Visit 4)


4.a) Patient has a positive alcohol breath test or urine drug screen. See NOTE in Exclusion 2.b).

2.4 STUDY DESIGN AND DURATION

2.4.1 Summary of Study Design

This will be a multi-center/multi-national, randomized, double-blind (with in-house blinding), placebo-controlled, 2-period cross-over PSG study to assess the safety, tolerability, and efficacy of various doses of MK-4305 in the treatment of adult patients with primary insomnia. This design is equivalent to four separate 2-treatment 2-period crossover trials with patients in each trial receiving one of the four MK-4305 doses and placebo. The study will enroll ~250 randomized patients to yield ~208 completed patients, including ~ 40 patients of Japanese ancestry, in the U.S. and Worldwide.

Duration of each treatment period will be 4 weeks (28 ± 2days), with a single-blind placebo run-in period at onset of Visit 2 leading up to Visit 4, pending continuing satisfaction of all study entry criteria, and a single-blind placebo washout of a minimum of 7 days between each treatment period, for a total study duration of ~12 weeks. Each treatment period includes 3 visits: occurring on Night 1, Day 14, and Night 28 of each of the 3 treatment periods. On Nights 1 and 28 (at the beginning and end of each treatment periods) patients will stay overnight for an 8-hour PSG recording and will be instructed to




take study drug 30 minutes prior to the PSG recording. On non-PSG nights, patients will be instructed to take study drug once nightly, immediately (within 5 to 10 minutes) prior to lights out, throughout the entire study. After the Prestudy Visit and throughout the rest of the study, patients will also be instructed to use an electronic device (eDiary) to complete a daily diary in the morning and evening to capture quantitative and qualitative aspects of sleep (Appendix 6.9). In event that ediaries are not available for a country, paper diaries may be used at the SPONSOR’s discretion.

Prestudy/Screening/Baseline Visits (Visits 1-3)

At the Prestudy Visit (Visit 1), patients will undergo initial safety and diagnostic assessments to determine if study eligibility criteria are met as well as additional assessments per the Study Flow Chart. Adverse experiences will be collected from the time patients sign the informed consent. The SPONSOR-approved physician or clinician will conduct the Sleep Diagnostic Interview/Sleep History and the MINI, to determine inclusionary and exclusionary diagnoses. Patients eligible for enrollment must meet DSM-IV-TR (Appendix 6.3) criteria for Primary Insomnia. All prohibited medications will be discontinued in accordance with the schedule stated in the inclusion/exclusion criteria. At the end of Visit 1, if the patient has met initial eligibility criteria, the patient will be sent home with an eDiary to establish habitual median bedtime on the days prior to the Screening PSG (Visit 2). Sites will be properly trained on the accurate use of the eDiary by an external eDiary vendor. Sites are then expected to train their patients on how to appropriately complete the eDiary, including expectation that patients report the actual times to the best of their ability (within 5-10 minutes of the actual time). Sites are expected to monitor patient data no less than weekly using the eDiary vendor’s online website. (For additional information on compliance and rigorous monitoring during the screening period (Visit 1 through Visit 2) please refer to Sections: 3.2.2.2 and 3.3.1.4.)

Patients who meet the Prestudy Visit criteria will continue to a Screening PSG Visit (Visit 2). Inclusion and exclusion criteria, safety, and other diagnostic assessments will be assessed per the Study Flow Chart. If the patient is still eligible for participation, 30 minutes before the PSG recording and the patient’s median habitual bedtime (as determined by the eDiary data collected up to Screening), the patient will be administered one dose of single-blind placebo medication and will spend the night in the sleep laboratory for an 8-hour PSG recording session to exclude other sleep and neurological disorders and to determine eligibility based on screening PSG variables. If patient satisfies all criteria, the patient will be dispensed single-blind placebo study medication to continue the placebo run-in period up to Visit 3.

If the patient continues to meet eligibility criteria, they will return for the Baseline PSG Visit (Visit 3) where similar criteria to Visit 2 will be assessed. If the patient is still eligible for participation, 30 minutes before the PSG recording and the patient’s median habitual bedtime (as determined by the cumulative eDiary data leading up to Baseline), the patient will be administered one dose of single-blind placebo medication, and the patient will spend the night in the sleep laboratory for an 8-hour PSG recording session (PSG #2). Patients successfully completing Visit 3 will be dispensed single-blind




placebo study medication again, to continue placebo run-in period up to time of randomization at Visit 4.

Patients who meet the eligibility criteria at Visits 2 and 3 will continue to complete the eDiary questionnaires every morning and evening during the at-home period leading up to Visit 4 and continue using throughout the completion of the study. Sites are expected to continue monitoring patient data no less than weekly using the eDiary vendor’s online website, through the rest of the study. Sites should retrain patients who are not compliantin reporting actual times to the best of their ability (within 5-10 minutes of the actual time).

All PSGs recorded will be forwarded to the central reader for scoring. Patients who meet all final eligibility criteria will be randomized into the study on Visit 4. Screening and Baseline PSGs will initially be reviewed at the site, by a SPONSOR-approved site scorer, to determine if the PSG entry criteria have been met. The Sponsor-approved central PSG reader will provide final confirmation of study eligibility, based on required screening/ baseline PSG criteria, prior to patient randomization to the study. The central PSG reader will score all PSGs occurring from time of randomization to study completion.

Double-Blind Treatment Period (Visits 4 to 9)

At Visit 4, after patients have met all eligibility criteria including remaining exclusion criteria, patients will be randomized via IVRS and will receive double-blind treatment with MK-4305 and placebo. Assignment to dose and to one of two treatment sequences, MK-4305/Placebo or Placebo/MK-4305, will be randomly determined by a computer-generated random allocation schedule. The randomization will be stratified by geographic region (Japan vs. ex-Japan). During the double-blind treatment period in which a patient is assigned MK-4305, patients will receive one of four possible MK-4305 doses (10, 20, 40, or 80 mg).

For Visit 4, 6, 7, and 9, patients will return to the sleep laboratory for overnight 8-hour PSG recordings (Visits 5 and 8 are interim safety visits). PSG Visits 4 and 6 should be scheduled approximately at the same time, as well as with Visits 7 and 9, to maintain consistency within each treatment period. Patients will receive a witnessed dose of medication 30 minutes before patient’s median habitual bedtime (determined at Visit 3). Evening and morning assessments for safety and efficacy will be performed per the Study Flow Chart.

A single-blind placebo washout period of a minimum of 7 days will separate Treatment Periods 1 and 2. Patients will be dispensed drug for the at-home placebo washout on the morning following the last PSG visit of Visit 6. Patients will continue to complete the morning and evening questionnaires (Appendix 6.9) via the electronic patient diary (eDiary) throughout the duration of the study, including during the washout period. In addition, the patient will complete the Tyrer Withdrawal Symptom Questionnaire (Appendix 6.9), as part of the eDiary evening questionnaire, on the evening of the first




3 days of the washout period. Depending on duration of the treatment period [Day 28, ±2-day window], this will occur on Days 27-29, 28-30, 29-31, 30-32, or 31-33.

If the patient discontinues completely from the study, before the end of either Treatment Period, a discontinuation visit should be performed per the Study Flow Chart. If a patient discontinues from Treatment Period 1, but wishes to remain in the study and move to Treatment Period 2, a discontinuation visit should be performed per the Study Flow Chart (see footnotes in Section 1.7). The patient must also complete the single-blind placebo washout period prior to Visit 7 and then continue with all the other regularly scheduled visits until completion of the study. Patients who complete the study or prematurely discontinue either Treatment Period will receive a 14-day follow-up phone call to assess for serious adverse experiences.

Safety and tolerability, including residual effects, will be carefully monitored throughout the study by the Sponsor Clinical Monitor and/or designee in accordance with standard procedures. The Sponsor may discontinue randomization to any or all dose levels(s) based on emerging safety concerns.

Visit Windows:

In order to minimize patient time on the study and to reduce drop-outs, it is highly advised to schedule visits according to the target study day or the minimum allowable visit window, as noted in the study flow chart.

2.4.2 Treatment Plan

To implement this 2-period cross-over design, patients will be centrally randomized via IVRS in a 1:1:1:1:1:1:1:1 ratio to 1 of 8 treatment sequences using a computer-generated random allocation schedule (See Table 2-2). The randomization will be stratified by geographic region (Japan vs. ex-Japan). Additional treatment sequences may be added to evaluate a 5-mg dose pending the results of an interim futility analysis when approximately 50% of the patients have completed the study.




Table 2-2

Treatment Sequences

Treatment Sequence

Sample Size (n) Period 1 Period 2

1 26 completers MK-4305 10 mg Placebo2 26 completers Placebo MK-4305 10 mg3 26 completers MK-4305 20 mg Placebo4 26 completers Placebo MK-4305 20 mg5 26 completers MK-4305 40 mg Placebo6 26 completers Placebo MK-4305 40 mg7 26 completers MK-4305 80 mg Placebo8 26 completers Placebo MK-4305 80 mg

Patients will receive single-blind placebo during the night of the Screening PSG Visit 2. Pending all study criteria is met at Visit 2, patients will continue the single-blind placebo run-in period. Single-blind placebo will be taken nightly up to and including the Baseline PSG Visit 3. Pending all study criteria has been met, placebo run-in will continue up to time of randomization at Visit 4. Randomized patients will receive double-blind treatment during Visits 4 to 6, Treatment period 1, and 7 to 9, Treatment period 2 (where each treatment period consists of 28 ± 2 days), and single-blind placebo washout for a minimum of 7 days in between treatment periods.

2.5 LIST OF EFFICACY/PHARMACOKINETIC/IMMUNOGENICITY, ETC., MEASUREMENTS

The primary efficacy endpoints in this study will be derived from polysomnographic measures. PSG values for statistical analysis will be based on standardized readings from a central lab. The following PSG parameter will be evaluated as the primary endpoint: sleep efficiency (SE) as derived from total sleep time (TST). Additional objective PSG parameters evaluated as secondary endpoints include: wake after sleep onset (WASO), and latency to persistent sleep (LPS). Exploratory subjective assessments of sleep will be collected daily via the morning and evening diaries, e.g., sWASO, sTSO, sNAW, sTST. Other assessments will include pharmacokinetic sampling of MK-4305 exposures, HLA DQB1*0602 allele status, the Sheehan Disability Scale and the Insomnia Severity Index.

2.6 LIST OF SAFETY MEASUREMENTS

Laboratory evaluations (hematology, chemistry, urinalysis, Appendix 6.5), urine drug screen, urine pregnancy test, alcohol breath test, physical examination, electrocardiogram (ECG), and vital signs will be performed throughout the study as specified in the Study Flow Chart. In addition, the following functional assessments will also be performed throughout the study per the Study Flow Chart: Tyrer Withdrawal Symptom Questionnaire via the eDiary evening questionnaire (Appendix 6.9), Digit Symbol




Substitution Test, and Digit Symbol Copy Test. Subjective adverse experiences will be collected from the time of consent through the 14-day postdose follow-up telephone call.

2.7 DATA ANALYSIS SUMMARY

The co-primary endpoints that will be used in the evaluation of the primary efficacy hypothesis are sleep efficiency (SE) measurements at Night 1 and at the end of 4 weeks of treatment. The primary hypothesis will be evaluated using a mixed effects model including terms for baseline value (pre-randomization), geographic region (Japan vs. ex-Japan), treatment, sequence, period, time (as a categorical variable), and treatment-by-time and period-by-time interactions. An unstructured covariance matrix will be used. The model will be used to provide an estimate of the treatment effect for the comparison of each MK-4305 dose with placebo. A confidence interval and p-value (based upon a normal approximation) will also be computed. This approach utilizes all placebo data for each MK-4305 versus placebo comparison. The shape of the dose-response will be explored, graphically, based upon these estimates.

The primary efficacy analysis will be based on the full analysis set (FAS). All randomized patients who take at least one dose of study medication, and have a post-dose assessment of the primary efficacy measure in either treatment period will be included in the FAS analysis. Patients will be analyzed according to the treatment sequence to which they were randomized.

Safety and tolerability will be assessed by statistical and clinical review of the data on clinical or laboratory adverse experiences, reasons for discontinuation due to adverse experiences, predefined limits of change (PDLOC) for selected laboratory values, physical/neurological exam, ECG and vital signs. The following events of clinical interest: 1) narcolepsy-like events, 2) cataplexy-like events, 3) suicidal thoughts and/or ideation, and 4) complex sleep-related behaviors, as well as next day residual effects (as measured by DSST and DSCT) will be evaluated. Safety endpoints measured at the end of Treatment Periods 1 and 2 will be assessed. Rebound (as measured by sTSO and sTST during the first three days of washout compared to baseline for patients who receive MK-4305 in Period 1 versus those who receive placebo in Period 1) and withdrawal (as measured by the Tyrer questionnaire on the first three days of the washout period as compared to the last day of treatment in Period 1 for patients who receive MK-4305 in Period 1 versus those who receive placebo in Period 1) will also be assessed.

The primary approach for all safety analyses will be the All Patients as Treated (APaT) approach. All randomized patients who receive at least one dose of study medication will be included in the safety analyses. A patient’s treatment group will be determined by his/her actual treatment received.

A total of 208 patients (i.e., 52 for each of the 4 doses) completing both periods of the study, including ~ 40 patients of Japanese ancestry, will be required to compare SE between all four MK-4305 doses and placebo. Based upon this sample size, there is approximately 95% (73%) power to detect a difference of 8.33 (6.25) in SE at both time points for a particular MK-4305 dose. (Note that a difference of 8.33 (6.25) in SE




corresponds to a 40 (30) minute difference in total sleep time (TST) when time in bed is fixed at 8 hours.)

An interim analysis for identifying futile doses will be conducted after 50% of patients have completed their two 4-week treatment periods. A standing internal data monitoring committee (siDMC) will evaluate these interim data, encompassing evaluation of efficacy data in conjunction with evaluation of other data (e.g., adverse event data), to determine what if any actions will be taken for the remainder of the study. Based upon this analysis, it is possible that a lower dose of MK-4305 (5 mg) may be added to the study; in this case, the sample size may increase by up to 52 patients (due to the addition of these lower dose sequences). A second interim analysis may be conducted when approximately 160 patients have completed both periods of the crossover study to help expedite Phase III planning. Each interim analysis will include patients from the ex-Japan stratum only.



4305_006-02_ProtDet VERSION 3.0 APPROVED 03-Apr-2009Worldwide Restricted Confidential – Limited Access

3. PROTOCOL DETAILS

3.1 RATIONALE


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3.2 STUDY PROCEDURES

3.2.1 Concomitant Medication(s)/Treatment(s)

All psychotropic and other prohibited medication must be discontinued at least 2 weeks prior to the Screening PSG (Visit 2) with exceptions as described below:

Investigational compounds, fluoxetine, and clinically relevant CYP3A4 inhibitors and inducers must be withdrawn at least 4 weeks prior to Visit 2.

Patients should not be withdrawn from medically necessary medications (e.g., warfarin, psychotropics, antivirals) in order to participate in this study, but rather the patients should be excluded from the study, both due to their medical condition and due to the requirement for these therapies. While listed as prohibited medications, please note that these medications are associated with excluded medical disorders, e.g., excluded cardiovascular disease, stroke, epilepsy, psychotic disorders, and relevant infections, such as H.I.V. infection.

Patients being withdrawn from prohibited medications such as benzodiazepines, barbiturates or other medications that are likely to precipitate a withdrawal reaction or intolerance should not be abruptly discontinued from these medications. Instead, patients should be withdrawn from these medications in a manner that is consistent with labeling recommendations and conventional medical practice. Investigators should allow sufficient time to taper patients off these agents, i.e., up to several weeks prior to entry.

Non-prohibited concomitant medications may be used freely in this study, as only prohibited medication use is restricted based on the potential for those medications to impact the study in some way. However, initiation of new medications is to be discouraged and concurrent medications should preferably not be changed during the course of the study, without first consulting the PI, except in cases of medical emergencies or other obvious exceptions (i.e. discontinuation of an allowed sinus medication when the symptoms are resolved, etc).

Table 3-1 contains concomitant medications whose use is prohibited (P), allowed (A) orlimited (L) during all phases of the study:


Redacted



Table 3-1

Concomitant Medications

Centrally Acting Anticholinergics and Antihistamines:OTC H1-Antihistamines, e.g.:Diphenyhydramine HCl (Benedryl

am ami e ( Q

D menhyr ate (Dr m minr ( f

m p m n (Chlorphemamine (Chlor-TrimatonHy V

PPPPPPPP

Clinically relevant CYP3A4 Inhibitors:HIV antivirals (delaviridine, indinavir, nelfinavir, ritonavir)AmiodaroneCimetidineClarithromycinDiltiazemErythromycinFluvoxamineItraconazoleKetoconazoleMibefradilNefazodoneTroleandomycinVerapamil

PPPPPPPPPPPPP

Clinically relevant CYP3A4 Inducers:CarbamazepineSt. John’s WortPhenobarbitalTroglitazonePhenytoinRifabutinRifampin

PPPPPPP

Psychotropics:Stimulants:AmphetaminesModafinil ( gMethylphenidate

PPP

Antihistamines:SedatingNon- n Pharmaceuticals]Note: Montelukast sodium (SINGULAIR orticosteroids may be used more than twice weekly as needed for allergic symptoms.

PLL

Antidepressants PAntipsychotics PDepot neuroleptics PAnxiolytics:LorazepamAlprazolamBuspirone

PPP

Hypnotics (e.g., Prescribed [Zolpidem] and Over the Counter [A viUnisom

P




Table 3-1 (Cont.)

Concomitant Medications

Psychotropics:All herbal preparations with possible psychotropic effects (e.g., kava-kava, valerian, S-Adenosyl Methionine [SAMe], St. Johns Wort)

P

MAOIs PMelatonin PMood stabilizers:LamotrigineGabapentinLithiumOxcarbazepineCarbamazepineValproic Acid

PPPPPP

NarcoticsNote: Use of narcotics for pain relief should be avoided if there are effective alternative therapies suchas non-steroidal anti-inflammatory agents. SPONSOR must be notified of any use exceeding 3 consecutive days.

L

Tryptophan PCentrally acting muscle relaxants with psychotropic effects (e.g., Ro nRobbins])Note: Use of centrally acting muscle relaxants should be avoided if there are effective alternative therapies such as non-steroidal anti-inflammatory agents. SPONSOR must be notified of any use exceeding 3 consecutive days.

L

Anticonvulsants:Barbiturates PBenzodiazepines PGABA Analogues PHydantoins PPhenyltriazines (e.g., Lamotrigine) PSuccinimides (e.g., Ethosuximide) PMiscellaneous Anticonvulsants (e.g., carbamazepine and valproic acid) POther:Warfarin (COUMADIN PIsotretinoin (ACCUTANE PSystemic glucocorticoids PDiet Pills (prescription and over-the-counter) PGlucose metabolizing agentsNote: Allowed only when on a stable dose for 4 weeks prior to Screening Visit 2.

A

DiureticsNote: Allowed only when taken daily in a stable dose for ≥1 month prior to Screening Visit 2.

A

Hormone replacement therapy (to relieve the symptoms of menopause)Note: Allowed only when taken daily in a stable dose for ≥3 months prior to Screening Visit 2

A

Thyroid preparationsNote: Allowed only when taken daily in a stable dose for ≥1 months prior to Screening Visit 2.

A

PseudoephedrineNote: May only be used before 2 PM, and no more than twice a week. Dosage is limited to 30 mg of active ingredient in each tablet. Extended release formulations are prohibited.

L

Over-the-Counter (OTC), combination products for pain relief (e.g., EXCEDRIN [Bristol-Myers C N

Note: Two tablets are equivalent to a caffeinated beverage and should be counted as such toward the maximum of 5 beverages per day. As with any caffeinated beverages, patients should be advised to refrain from using these medications after 4 PM.

L




Concomitant drugs that are metabolized by CYP3A4 enzymes may have increased blood levels if co-administered with MK-4305. The investigator should use his/her clinical judgment to determine if any concomitant medications (not specifically prohibited) should be discontinued, or alternatively, if careful clinical monitoring is sufficient.

Centrally-acting analgesics, taken p.r.n for pain relief, may be allowed with the documented approval of the Merck clinical monitor. However, such compounds should not be taken on the day before, or day of Visits 3 through 9.

If a patient tests positive on a urine drug screen (confirmed by the central laboratory) during the course of the study, consultation between the investigator and SPONSOR is required. Written documentation is also required concerning the outcome and course of action.

3.2.2 Diet/Activity/Other

3.2.2.1 Diet

Patients should be advised to have eaten dinner prior to arrival at the sleep lab.

A nutritionally balanced breakfast will be provided by the site to all patients the morning after a PSG recording (AM of Visits 2, 3, 4, 6, 7, and 9).

Patients should refrain from consumption of no more than 1 grapefruit or 1 glass (8 ounces) of grapefruit juices a day, throughout the entire study period.

3.2.2.2 eDiary Completion

Patients will be required to complete the Evening and Morning Questionnaires (Appendix 6.9) via the eDiary every night and morning starting with the night of Prestudy Visit 1. (In event that ediaries are not available for a country, paper diaries may be used at the SPONSOR’s discretion.) Questionnaires should be completed daily through each consecutive visit, pending consecutive satisfaction of study eligibility, and thereafter throughout the completion of the study. The Tyrer Withdrawal Symptom Questionnaire (Appendix 6.9) will be administered in conjunction with the Evening Questionnaire on specified nights as indicated in the study flow chart.

Sites will be properly trained on the accurate use of the eDiary by an external eDiaryvendor. Sites are then expected to train their patients on how to appropriately complete the eDiary, including expectation that patients report the actual times to the best of their ability (within 5-10 minutes of the actual time). To ensure ongoing patient compliance with accurate eDiary reporting throughout participation in the study, sites are requested to carefully monitor incoming eDiary data at an interval of no less than weekly using the eDiary vendor’s online website. Sites should retrain patients who are not compliant. Rigorous monitoring is especially important during the screening period (Visit 1 through Visit 2), to ascertain problems with non-compliance and to ensure that patients




experiencing difficulties are re-trained to a full understanding of eDiary data entry prior to starting the baseline period (Visit 3).

3.2.2.3 Alcohol Restrictions

Patients will be advised to limit alcohol to 2 drinks a day and at least 3 hours before going to bed on non-PSG visit days. Patients should also be willing to avoid alcohol on all PSG visit days and at least 24 hours prior to a PSG visit. (A drink is defined as a 12-ounce bottle/can of beer (~14 grams alcohol) or a 4-ounce glass of wine (~12 grams alcohol) or 1 ounce of liquor (80 proof or 40 % alcohol, ~ 9 grams alcohol).)

3.2.2.4 Caffeine Restrictions

Patients will be advised to limit caffeine consumption to ≤5 standard 6-ounce cups of caffeinated beverages a day, or ≤600 mg caffeine, and avoid caffeine after 4 PM (16:00)on non-PSG nights, and avoid caffeine after 1 PM (13:00) on PSG visits. (See Appendix 6.4 for additional guidance on caffeine products and content.)

3.2.2.5 Smoking Restrictions

Patients will be advised to not smoke during the night. In addition patients may not consume >15 cigarettes a day. (Note: per Exclusion criteria 1r the Primary Investigator must confirm that the patient’s sleep disturbance is not the result of this consumption.)

3.2.2.6 Activity

Patients should be instructed to use caution when operating hazardous machinery, including automobiles, until they determine that study medication, taken as directed immediately prior to bedtime, does not affect their ability to engage in these activities the following day.

Patients are advised to keep their exercise level generally consistent with prestudy levels, i.e., a patient’s exercise level should not be significantly increased or decreased during the study compared to the patient’s prestudy baseline.

Patients are advised to not engage in the following activities during the course of the study as per Study Inclusion and Exclusion Criteria in Sections 2.2 and 2.3, respectively.

Napping

Nighttime shift work

Weight loss program/regimen

Travel across >3 time zones

3.2.2.7 Bedtime

During the study, patients should go to bed at their usual bedtime. The patient’s usual bedtime must be between 9:00 PM (21:00 hours) and 12:00 AM (00:00) in accordance with Study Inclusion Criteria in Section 2.2. The night prior to a PSG visit, the patient




should ensure that they have an adequate time period for sleep (i.e., the time allowed for sleep should not be shortened).

On PSG nights, the patient’s bedtime will be the median habitual bedtime as determined at Visit 3 from the sleep times recorded in the eDiary during the single-blind placebo run-in period. It is recommended that the patient maintain their habitual bedtime (from Visit 3) throughout the study.

3.2.3 Procedures

All study procedures and their timings are listed in the Study Flow Chart of the protocol, in Section 1.7. All procedures on PSG visits should be performed prior to dosing.

The DSM-IV-TR diagnosis of primary insomnia (Appendix 6.3), and administration of the Sleep Diagnostic Interview/Sleep History questionnaire, and the MINI must be made by a SPONSOR-approved physician or other approved clinician based on his or her documented face-to-face clinical interview. The SPONSOR-approved physician mustalso conduct a thorough medical and psychiatric history as well as perform physical examinations. Laboratory and ECG results, reviewed and signed by the investigator or subinvestigator, will further evaluate patient eligibility for entering the study. It is the responsibility of the investigator to ensure all study inclusion and exclusion criteria are met for the study.

It must be clearly documented that clinical or laboratory adverse experiences (including determination of causality) have been obtained and reviewed for medical accuracy by the physician investigator or sub-investigator. The physician investigator or sub-investigator must sign all reviews of clinical or laboratory adverse experiences.

There will be several blood collections for several types of analyses during the study. Genomic and HLA DQB1*0602 DNA sample collections will occur one time during the study. Blood will be drawn for MK-4305 Pharmacokinetic assay (Appendix 6.10) in several visits during the study.

In addition, blood samples will also be collected in PaxGene tubes for mRNA profiling in several visits during the study. Gene-expression signatures will be used for the identification of candidate target-engagement and/or pharmacodynamic biomarkers, as well as assessment of potential treatment effects on the disease state as reflected in serum biomarkers and/or to show potential drug effects. The intended analyses do not involve use of genomic DNA and therefore will not yield any genetic information that can be linked to the patient. RNA samples collected for this study may be stored for a period of up to 25 years. Information regarding the collection, processing, and labeling of RNA samples will be provided in the administrative binder.

The study will use a centralized PSG reading center to visually score the PSGs conducted for the study. The sites will initially review the Screening and Baseline PSGs for study entry criteria prior to sending to the central reader for final confirmation. The reading




center will provide a standard operating procedure (SOP) detailing how the PSGs will be conducted. All PSGs will be forwarded to the central reader for scoring.

3.2.3.1 Informed Consent

3.2.3.1.1 General Informed Consent

The investigator must obtain written informed consent from each subject prior to any study procedures (including dosing) being performed. Consent must be documented by the subject’s dated signature on a Consent Form along with the dated signature of the person conducting the consent discussion. A copy of the signed and dated consent formmust be given to the subject before participation in the trial.

The initial informed consent form and any subsequent revised informed consent form must receive the approval from the local or central Institutional Review Board (IRB) before use. The patient should be informed in a timely manner of any new information that becomes available about the study or the study drug that would be relevant to the patient’s willingness to continue participation in the study trial. The communication of this information will be provided and documented via a revised consent form or addendum to the original consent form.

3.2.3.1.2 Consent and Collection of Specimens for Genetic Analysis

During this study, a separate informed consent will be administered for collecting a whole blood specimen for potential future genetic research. Only those subjects/patients who have consented to having this genetic sample collected may have this blood sample drawn. The investigator or designate is responsible for explaining and verifying the subject’s/patient’s consent before obtaining such blood samples. At the time of sample collection, the investigator’s staff member and a witness from the investigator’s staff should verify that the subject/patient has signed the consent and the correct subject/patient-specific label is placed on the genetic sample, and then both the investigator’s staff member and witness initial and date the left-side of the Genetic Sample Label. It should be explained to the subject/patient that giving the blood sample for genetic information is entirely optional for the subject/patient and participation in the associated clinical study is not dependent upon giving this sample. The approval of the consent form for analysis and the associated protocol procedures (e.g., collection of a blood sample) may, in some cases, proceed independently through Institutional Review Boards, Ethical Review Boards, Independent Ethical Committees, Privacy Committees, etc., from the associated clinical study. In cases where the IRB/ERC approval for the donation of a sample for genetic analysis is denied or is not accomplished prior to the completion of the clinical study, samples for genetic analysis will not be collected.

3.2.3.2 Assignment of Baseline Number/Screening/Washout

Each patient who signs a consent form to participate in the study will be assigned a unique baseline number for identification purposes. Each patient should be assigned only one baseline number. Should the patient subsequently fail to qualify for the study, his/her baseline number must not be re-used for any other patient in the study. Patients are




allowed to be re-screened for participation in the study provided consultation between the investigator and Sponsor occurs. Written documentation between the investigator and Sponsor is required concerning the reasons for the initial screen fail and the agreement to allow the patient to re-screen.

3.2.3.3 Randomization/Allocation

This study will employ a central randomization scheme using an Interactive Voice Response System (IVRS). Study personnel will have access to the IVRS for patient allocation. Patients who meet all the study inclusion/exclusion criteria and have provided written informed consent will be randomized to one of 8 treatment sequences (see Table 2-2 in Section 2.4.2). Sites will call the IVRS (interactive voice response system) to dispense drug and to report patient enrollment progress at specified visits per the study flow chart. Randomization will be stratified by geographic region (Japan vs. ex-Japan).

The allocation number (AN) is a unique number and once assigned, it will become the permanent identifier for that patient when they receive their first dose of double-blind study drug. In the event a patient is enrolled in the study but does not begin or continue double-blind treatment, that patient’s allocation number will not be reassigned. Patients who do not meet entry criteria will not be assigned an allocation number. Instructions for use of IVRS will be provided separately by the IVRS vendor.

A single patient/subject cannot be assigned more than 1 allocation number.

3.2.3.4 Prestudy and Treatment Periods

3.2.3.4.1 Prestudy (Visit 1)

At the Prestudy Visit (Visit 1), patients will undergo initial safety and diagnostic assessments to determine if study eligibility criteria are met as well as additional assessments per the Study Flow Chart (See Table 3-2 or Section 1.7). Adverse experiences will be collected from the time the patient signs informed consent. The SPONSOR-approved physician or clinician will conduct the Sleep Diagnostic Interview/ Sleep History and the MINI International Neuropsychiatric Interview (MINI,) to determine inclusionary and exclusionary diagnoses. Patients eligible for enrollment must meet DSM-IV-TR (Appendix 6.3) criteria for Primary Insomnia.

An alcohol breath test will be performed at Visit 1. If a patient has a positive alcohol breath test at Visit 1, this should be documented and site should emphasize the restrictions on alcohol to the patient. All prohibited medications will be discontinued in accordance with the schedule stated in the inclusion/exclusion criteria. Please also refer to Section 3.2.1 for patients that should not be withdrawn from medically necessary medications.

At the end of Visit 1, if the patient has met initial eligibility criteria, the patient will be sent home with an eDiary (or paper diary, in event that ediaries are not available for a country) to complete morning and evening questionnaires to establish median habitual bedtime in the ~7 days prior to the Screening PSG Visit 2 (a minimum of 4 days of




eDiary data is needed for habitual bedtime calculation). The median bedtime established during this period will be used as the bedtime ("lights out") for the Screening PSG visit. (See Section 3.2.3.4.2 and 3.3.1.2b for median habitual bedtime determination and guidance.)

Sites will be properly trained on the accurate use of the eDiary by an external eDiaryvendor. Sites are then expected to train their patients on how to appropriately complete the eDiary, including expectation that patients report the actual times to the best of their ability (within 5-10 minutes of the actual time). To ensure ongoing patient compliance with accurate eDiary reporting throughout participation in the study, sites are requested to carefully monitor incoming eDiary data at an interval of no less than weekly using the eDiary vendor’s online website. Sites should retrain patients who are not compliant. Rigorous monitoring is especially important during the screening period (Visit 1 through Visit 2), to ascertain problems with non-compliance and to ensure that patients experiencing difficulties are re-trained to a full understanding of eDiary data entry prior to starting the baseline period (Visit 3).




Table 3-2

Prestudy Assessments

Informed ConsentMedical and Psychiatric historyDiagnostic Interview/Sleep History/DSM-IV-TRMINI International Neuropsychiatric Interview (MINI)Reading Assessment¶¶¶

Quick Inventory of Depressive Symptomatology (QIDS)Inclusion/ExclusionPrior and concomitant therapyPhysical examinationVital signs§, ††††

ECG‡‡‡‡

Hematology, chemistry, urinalysisUrine drug screenInformed consent for genetic sample analysis‡‡‡

Blood sample for genetic analysis (DNA)‡‡‡

Alcohol breath test#

Dispense eDiaryeDiary practiceEvening/Morning Questionnaire††, ‡‡

Adverse Experiences§§§

Note: For details on footnotes, please refer to Study Flow chart notes, Section 1.7.

3.2.3.4.2 Screening and Baseline PSG (Visits 2 and 3)

Screening PSG Visit 2

Patients who meet the Prestudy Visit criteria will return to the clinic for a Screening PSG Visit (Visit 2), ~1 week later, to exclude other sleep and neurological disorders and to ensure the patient meets a minimal criteria for LPS and WASO. Please see Inclusion and Exclusion Criteria, Sections 2.2 and 2.3, respectively, for details.

Additional safety and other diagnostic assessments will be assessed per the Study Flow Chart (Section 1.7) and in Table 3-3.

Patients are to be instructed to arrive at the sleep lab 2 hours prior to their regular bedtime and they should bring their eDiary with them to the visit. Patients should be advised to have eaten dinner prior to arrival at the sleep lab. As per the Study Flow Chart, evening assessments will be performed. Patients should be instructed to avoid alcohol on the days of the PSG visits and at least 24 hours prior to the visit. Patients that have a positive




alcohol breath test will be excluded. A urine drug screen will be performed at the site. If urine drug screen results are positive, a sample will be sent to the central laboratory for confirmation.

Data collected from the eDiary from Prestudy to Screening will be used to establish the initial median habitual sleep time for the Screening PSG visit. The median will be the midpoint value after ordering all the data points from lowest to highest (50% of the observations will fall below the median and 50% will fall above the median). If the number of data points is even, the midpoint value will be the average of the 2 middle values. Sites are requested to carefully monitor incoming eDiary data at an interval of no less than weekly using the eDiary vendor’s online website. Sites should retrain patients who are not compliant in reporting actual times to the best of their ability (within 5-10 minutes of the actual time). Rigorous monitoring is especially important during the screening period (Visit 1 through Visit 2), to ascertain problems with non-compliance and to ensure that patients experiencing difficulties are re-trained to a full understanding of eDiary data entry prior to starting the baseline period (Visit 3).

If the patient is still eligible for participation, 30 minutes before the PSG recording and the patient’s median habitual bedtime, the patient will be administered one dose of single-blind placebo medication and will spend the night in the sleep laboratory for an 8-hour PSG recording session. The following day, the patient will be awakened (or will be allowed to get out of bed if already awake) after 8 hours of PSG recording (PSG #1) and will complete their normal morning routine followed by safety and efficacy assessments as indicated in the Study Flow Chart. The diary should be completed by the patient after completion of normal morning routine (e.g., using the bathroom, eating breakfast), and preferably within 1 hour following lights-on during PSG days.

The Screening PSG will be initially reviewed at the site, by a SPONSOR-approved site scorer, to determine if the PSG entry criteria have been met. If the patient is still deemed eligible after the site has reviewed the PSG, then the patient will be dispensed single-blind placebo run-in study drug for at-home treatment to continue the placebo run-in period, and will continue completion of the morning and evening eDiary questionnaires up until at least Visit 3. The site will forward the Screening PSG recording to the centralized PSG reader for confirmation of the patient’s eligibility. Confirmation of qualifying Screening PSG (Visit 2) variables (LPS and WASO) from the PSG reading center must be received by the site prior to conducting the Baseline PSG at Visit 3.

Baseline PSG Visit 3

If the patient continues to meet eligibility criteria, they will return to the clinic ~7 days after Visit 2 for the Baseline PSG Visit (Visit 3) where additional criteria to Visit 2 must be met. Please see Inclusion and Exclusion Criteria, Sections 2.2 and 2.3, respectively, for details.

Patients should arrive at the sleep laboratory about 2 hours prior to the patient’s median habitual bedtime. Patients should be advised to have eaten dinner prior to arrival at the




sleep lab. They should be instructed to bring their placebo run-in study medication bottles and their eDiary to the visit. Per the Study Flow Chart, evening assessments will be performed. Patients will be instructed to avoid alcohol on the days of the PSG visits and at least 24 hours prior. If a patient has a positive alcohol breath test, the patient will be excluded from the study. A urine drug screen and (for females) a urine pregnancy test, will be performed at the site. If urine drug screen results are positive, a sample will be sent to the central laboratory for confirmation. If the urine pregnancy test is positive, a serum pregnancy test (β-hCG) will be sent to the central laboratory for confirmation.

The patient’s median habitual bedtime for the Baseline PSG will be determined by the cumulative eDiary data collected from prestudy up to Baseline. This will be the median habitual bedtime used for the remainder of the study if a patient is randomized at Visit 4.

If the patient is still eligible for participation, the patient will be administered a dose of single-blind placebo medication 30 minutes prior to the patient’s median habitual bedtime and the PSG recording, and will spend the night in the sleep laboratory for an 8-hour PSG recording session (PSG #2).

The following day, the patient will be awakened after 8 hours of PSG recording and will complete their normal morning routine followed by safety and efficacy assessments as indicated in the Study Flow Chart. The diary should be completed by the patient after completion of normal morning routine (e.g., using the bathroom, eating breakfast), and preferably within 1 hour following lights-on during PSG days.

The Baseline PSG will be initially reviewed at the site, by a SPONSOR-approved site scorer, to determine if the PSG entry criteria have been met. If the patient is still deemed eligible after the site has reviewed the PSG, then the patient will be dispensed single-blind placebo run-in study medication bottles for at-home treatment to continue the placebo run-in period, and will continue completion of the morning and evening eDiaryquestionnaires up until Visit 4. The site will forward the Baseline PSG recordings to the central reader for confirmation of the patient’s eligibility. Confirmation needs to be received by the site prior to the patient being randomized in the study.




Table 3-3

Screening and Baseline PSG Assessments

Screening BaselineAssessments PM¶¶ AM PM AM

Inclusion/Exclusion X X X XPrior and concomitant therapy X XVital signs§, ††† X X X XECG ‡‡‡‡ XHematology, chemistry, urinalysis XUrine drug screen X XUrine pregnancy test¶ XAlcohol breath test# X XInformed consent for genetic sample analysis‡‡‡

Blood sample for genetic analysis (DNA)‡‡‡

Blood sample for molecular analysis (RNA)# # # XPK Sampling# # # XAlcohol Breath Test# X XDispense Study Drug X X X XCall IVRS X XPolysomnography (PSG) X XEvening/Morning Diary‡‡ X X X XDigit Symbol Substitution Test (DSST) X XDigit Symbol Copy Test (part of WAIS-III) X XSheehan Disability Scale XInsomnia Severity Scale (ISI) XAdverse Experiences§§§ X X X XNote: For details on footnotes, please refer to Study Flow chart notes, Section 1.7.

Single-Blind Placebo Run-In Period

Patients will receive a supply of single-blinded study drug, in double dummy fashion, for the placebo run-in period the AM following the screening PSG recording (pending all study criteria has been met), and will be instructed to take the study drug every night immediately prior to bedtime (within 5 to 10 minutes) while at home. During the run-in period patients will complete the eDiary questionnaires in the morning and evening. Patients will be strongly counseled on the importance of complaint eDiary use during the study.

Visit Windows:





3.2.3.4.3 Treatment Periods (Visits 4-9)

Patients whose eligibility has been confirmed by the central reader and additional exclusion criteria has been met will be randomized via IVRS at Visit 4. Assignment to dose and to one of two treatment sequences, MK-4305/Placebo or Placebo/MK-4305, will be randomly determined by a computer generated random allocation schedule. The randomization will be stratified by geographic region (Japan vs. ex-Japan). During the non-placebo treatment period in which a patient is assigned MK-4305, patients will receive one of four possible MK-4305 doses (10, 20, 40, or 80 mg).

Each treatment period consists of 2 PSGs, at Nights 1 and 28, and an interim safety visit, 2 weeks in between PSG visits. Additionally, a minimum of 7 days of a single-blind placebo washout period will separate Treatment Periods 1 and 2.

For each PSG visit, patients should arrive at the sleep laboratory about 2 hours prior to the patient’s median habitual bedtime (calculated at Visit 3) to complete the evening assessments (see Table 3-4). Patients should be advised to have eaten dinner prior to arrival at the sleep lab. They should also be instructed to bring their study medication bottles and their eDiary to the visit to check for compliance. PSG Visits 4 and 6 should be scheduled approximately at the same time of day, as well as with Visits 7 and 9, to maintain consistency in each treatment period.

Patients whose alcohol breath test is positive and for whom there are no grounds to repeat (e.g., admits recent consumption of alcoholic beverage) should not undergo the PSG recording session. The PSG visit should be rescheduled to take place no sooner than 24 hours and no later than ~48 hours after its original target date. This should be discussed with SPONSOR prior to conducting the recording session.

Patients will receive a witnessed dose of medication 30 minutes before patient’s median habitual bedtime and the PSG recording, and will spend the night in the sleep laboratory for an 8-hour PSG recording session. The following day, the patient will be awakened after 8 hours of PSG recording and will complete their normal morning routine followed by safety and efficacy assessments as indicated in the Study Flow Chart and in Table 3-4. The PSG recordings for treatment visits do not need to be scored by the site. All PSG recordings of the Treatment PSGs will be forwarded directly to the central reader for scoring.




Table 3-4

Treatment Period Assessments

Treatment Period 1 Treatment Period 2

Visit/Target Study DaysVisit 4

Day 1/2Visit 5 Day 14

Visit 6Day 28/29

Visit 7Day 36/37

Visit 8Day 49

Visit 9Day 63/64

Assessments PM¶¶ AM PM AM

Placebo Washout Period

Day 29-35 PM AM PM AMInclusion/Exclusion XPrior and concomitant therapy X X X X X XPhysical Exam X XVital signs§, †††† X X X X X X X X X XECG‡‡‡‡ X X X X X XHematology, chemistry, urinalysis X X X X X XUrine drug screen X X X XUrine pregnancy test¶ X X X XObtain informed consent for genetic sample analysis XBlood sample for genetic analysis (DNA)‡‡‡ XBlood sample for HLA DQB1*0602 allele (DNA) XBlood sample for molecular analysis (RNA)# # # X XPK Sampling# # # X X X X X XAlcohol breath test# X X X XDispense Study Drug X§§ X# # X††† X X# #

Call IVRS X X X XPolysomnography (PSG) X X X XEvening/Morning Diary‡‡ X X X X X X X X X X XTyrer Withdrawal Symptom Questionnaire X XDigit Symbol Substitution Test (DSST) X X X XDigit Symbol Copy Test (part of WAIS-III) X X X XSheehan Disability Scale X XInsomnia Severity Index (ISI) X XAdverse Experiences§§§ X-----------------------------------------------------------------------------------------------------XNote: For details on footnotes, please refer to Study Flow chart notes, Section 1.7.

4305,P

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Patients returning for the interim safety visit, in between the PSG visits of each treatment period, are instructed to bring their study medication bottles for drug compliance, as well as their eDiary.

Single-Blind Placebo Washout

Following Visit 6, patients will enter a single-blind placebo washout from their prime therapy and will be dispensed single-blind placebo study drug. The washout will begin on the AM portion of Visit 6 and will continue for a minimum of 7 days. The prohibited and limited concomitant medications indicated in Section 3.2.1 and diet and activity restrictions specified in Section 3.2.2 should be observed by the patient during the washout period.

Patients should continue completing the eDiary questionnaires as part of their daily routine during this washout period. In addition patients will complete the Tyrer Withdrawal Symptom Questionnaire (Appendix 6.9) for the first three days of the washout period (i.e. Days 27-29, 28-30, 29-31, 30-32, 31-33 relative to start of treatment period). The questionnaire will be part of the evening eDiary questionnaire.

Visit Windows:


3.2.3.5 Treatment/Evaluation/Follow-Up

Procedures not performed per protocol require consultation between the investigator and the SPONSOR and written documentation of the collaborative decision on patient management.

All patients that discontinue Treatment period 1 but continue to Treatment period 2, or discontinue completely from the study are required to return to the clinic for a discontinuation visit. Patients only continuing to Treatment period 2, will have single-blind placebo study drug dispensed to commence washout period, and will continue to complete the eDiary questionnaires. Assessments performed during the discontinuation visit are noted in the Study Flow Chart and in Table 3-5. Additional information on discontinuation can be found in Section 3.2.3.7.

All patients that discontinue or complete the study will receive a 14-day follow-up phone call to assess for serious adverse experiences.




Table 3-5

Discontinuation Visit Assessments

Prior and concomitant therapyPhysical examinationVital signs§

ECGHematology, chemistry, urinalysisUrine drug screenUrine pregnancy test¶

Dispense Study Drug §§§§

Call IVRSEvening/Morning eDiary§§§§

Tyrer Withdrawal Symptom Questionnaire§§§§

Digit Symbol Substitution Test (DSST)Digit Symbol Copy Test (part of WAIS-III)Sheehan Disability ScaleInsomnia Severity Index (ISI)Adverse Experiences§§§

Note: For details on footnotes, please refer to Study Flow chart notes, Section 1.7.

3.2.3.6 Blinding/Unblinding

Patient treatment will be blinded using a masked allocation schedule created using an in-house clinical allocation schedule system. Emergency unblinding of patients by authorized clinical site personnel will occur via the IVRS using procedures outlined in a separate manual provided to sites by the SPONSOR (or vendor). The investigator should not unblind a patient’s treatment without Merck’s approval unless it is necessary for a serious adverse experience (see Section 3.4.6). If the SPONSOR was not notified prior to the patient’s unblinding, the investigator must contact the SPONSOR immediately and inform them that the unblinding has occurred. The SPONSOR personnel involved in the review/analysis of the study data and decisions regarding the study will remain blinded to patient treatments for the duration of the study unless otherwise warranted.

Emergency unblinding by the SPONSOR will occur through NWAES or IVRS. Documentation of the unblinding and the circumstances surrounding the event will be indicated on the Clinical Study Unblinding Log Sheet in the Administrative Binder.

3.2.3.7 Discontinuation/Withdrawal from Study

Every effort should be made to ensure patients remain in the study for the full duration of the study. The patient’s commitment to complete the study should be addressed during




the informed consent process. Note: Any change in patient disposition must be preceded by consultations between the subject and investigator, and between the investigator and the SPONSOR. This must be documented with a Sponsor Consultation Form.

In the event of tolerability issues, the option to discontinue the study drug in Treatment period 1 and enter Treatment period 2 can be implemented for patients who might otherwise discontinue the trial. After SPONSOR approval to discontinue Treatment period 1 and enter Treatment period 2, the Study Coordinator will instruct the patient to:

Complete the Discontinuation Visit per the study flow chart (Section 1.7)

Complete the required single-blind placebo washout for a minimum of 7 days prior to starting Treatment period 2, Visit 7

Patients who discontinue from the study completely should complete the Discontinuation Visit before they end their participation in the study.

Patients that complete the study or prematurely discontinue any of the treatment periods will receive a 14-day follow-up phone call to assess for serious adverse experiences.

Patients who become pregnant during any Treatment Period must discontinue from the study (see Section 3.4.4).

Spontaneous AE reports of suicidal thoughts or suicidal ideation by patients must be documented as ECIs in this study, and the reporting patient is administered bythe C-SSRS instrument and referred for further evaluation (see Sections 3.4.1.7 and 3.4.5.2). Patients at risk must be discontinued from the study. If after evaluation the investigator determines that a patient is not at risk, continuation in the study must first be approved by the Merck clinical monitor and documented using the SPONSOR consultation form.

Patients who demonstrate a positive Drug Screen at any time during the study must be discontinued from the study (SPONSOR-approved exceptions for discontinuing a patient with a positive drug screen may be allowed for patients who took an acute dose of a centrally acting analgesic for pain or for patients who took an acute dose of a hypnotic. These exceptions must be approved by the Merck clinical monitor and documented using the SPONSOR consultation form). NOTE: a repeat drug screen may be permitted prior to discontinuation, with permission of SPONSOR.

Subjects/patients may withdraw at any time or be dropped from the study at the discretion of the investigator should any untoward effects occur. In addition, a subject/patient may be withdrawn by the investigator or the SPONSOR if he/she violates the study plan or for administrative and/or other safety reasons. The investigator or study coordinator must




notify the SPONSOR immediately when a subject/patient has been discontinued/ withdrawn due to an adverse experience (telephone or FAX). When a subject/patient discontinues/withdraws prior to study completion, all applicable activities scheduled for the final study visit should be performed at the time of discontinuation. Any adverse experiences which are present at the time of discontinuation/withdrawal should be followed in accordance with the safety requirements outlined in Section 3.4 SAFETY MEASUREMENTS - DETAILS.

Subjects/patients who donate a blood sample for future genetic analyses may request that their sample be removed from storage and destroyed in accordance with the terms outlined in the informed consent for genetic analyses. Subjects/patients should be informed that withdrawal from the main study does not cause the withdrawal and destruction of the genetic sample. Requests for withdrawal and destruction of the genetic sample should be made in writing to the investigator.

3.3 EFFICACY/PHARMACOKINETIC/IMMUNOGENICITY, ETC.MEASUREMENTS

3.3.1 Clinical and Laboratory Measurements for Efficacy/ Pharmacokinetic/ Immunogenicity, etc.

3.3.1.1 Procedures for Conducting Diagnosis and Efficacy Measures

In order to maintain consistency of data, the same person should, whenever possible, perform the efficacy measurements/ratings evaluations for any given patient throughout the study. Table 3-6 summarizes who should determine the DSM-IV-TR diagnosis of Primary Insomnia and administer the diagnostic or efficacy instruments.

Table 3-6

Administrators for Diagnosis and Efficacy Measures

Assessment AdministratorSleep Diagnostic Interview/Sleep History

DSM-IV-TR diagnosis of Primary Insomnia

MINI

SPONSOR-approved physician/ psychologist/clinician

PSG Recording SPONSOR-approved sitePSG Scoring SPONSOR-approved technician at the site

3.3.1.2 PSG Measurements

Efficacy measures used in this study will be completed as indicated below (see Appendix 6.2 for the glossary of sleep terms and definitions).




a. PSG Recording and Evaluation

The central PSG reader for the study will provide a standard operating procedure (SOP) detailing how screening and other PSG sessions will be conducted. The SOP will address what types of recordings will be made including instructions about the EEG electrode montage, EMG electrodes, cardiac electrodes, a thermistor device for measuring air flow, plethysmography (strain gauges) to assess respiratory effort, or other recordings to be specified in the SOP. Thus, the definitive set of recordings to be conducted during a PSG screening session will be specified in the SOP, and the SOP will detail which of the recordings will be used in subsequent PSG recording nights. For a glossary of objective and subjective PSG measures and definitions, please refer to Appendix 6.2.

b. Timing of PSG (Lights Off and Lights On)

The Lights-Off time for the screening PSG Visit 2 (PSG 2) is defined as ±10 minutes of the patient’s reported median habitual bedtime based on 4 or more days of diary data. The Lights-Off time for Baseline PSG Visit 3 (PSG 3) is defined as ±10 minutes of the patient’s reported median habitual bedtime based on all diary data leading up to Visit 3. The median habitual bedtime for both Visits 2 and 3 willbe calculated by the eDiary.

Bedtime (lights off) at PSG Visits 4, 6, 7, and 9 will be based on the patient’s habitual sleep time used at Visit 3. The entire PSG recording period from lights off to lights on will be 8 hours on the PSG Visits. Immediately prior to the Lights-Off, the patient gets into bed, room lights are turned off (i.e., the room is dark), and the technologist exits the room. The Lights-Off time marks the initiation of the PSG recording period. Lights-Off Time must be indicated on the technologist’s log.

For the timing of electrode calibrations and other PSG activites, refer to the PSG SOP.

3.3.1.3 PSG Definitions and Scoring

A polysomnogram consists of an EEG (electroencephalogram) for registration of brain activity during sleep, an EOG (electro-oculogram) for registration of the eye movements during sleep and an EMG (electromyogram) for recording chin muscle activity during sleep. Sleep stage scoring will be performed visually in 30-second epochs according to Rechtschaffen and Kales criteria and the American Academy of Sleep Medicine Manual for the Scoring of Sleep and Associated Events [23, 24]. The data will be captured electronically, in order to permit subsequent spectral analysis.

The following will be evaluated from the PSGs:

Visual scoring of records from which all night and hourly sleep variables will be derived: sleep maintenance parameters (wake after sleep onset (WASO), latency to




persistent sleep (LPS), sleep period time (SPT), total sleep time (TST), total time awake (TTA), number of awakenings (NAW), duration of slow wave sleep (SWS)

Amount of slow-wave activity (SWA) determined by spectral analysis.

Sleep architecture (duration and percentage of wake and of time spent asleep in the different sleep stages, etc.) derived from visual scoring of sleep stages.

Sleep profile parameters (number and mean onset and duration of REM/non-REM cycles, duration of slow wave sleep (SWS) during thirds of the duration from sleep onset to last sleep epoch, etc.) derived from visual scoring of sleep stages.

3.3.1.4 Electronic Morning and Evening Questionnaires

The patient will fill in an electronic patient diary (eDiary) on subjective items with regard to their sleep starting from the night of Prestudy (Visit 1). If the patient continues to meet study criteria up to Visit 4, the patient will continue entry into the eDiary until the end of the study. The electronic morning and evening questionnaires will be completed every morning and night. In event that ediaries are not available for a country, paper diaries may be used at the SPONSOR’s discretion.

Sites will be properly trained on the accurate use of the eDiary by an external eDiaryvendor. Sites are then expected to train their patients on how to appropriately complete the eDiary, including expectation that patients report the actual times to the best of their ability (within 5-10 minutes of the actual time). To ensure ongoing patient compliance with accurate eDiary reporting throughout participation in the study, sites are requested to carefully monitor incoming eDiary data at an interval of no less than weekly using the eDiary vendor’s online website. Sites should retrain patients who are not compliant. Rigorous monitoring is especially important during the screening period (Visit 1 through Visit 2), to ascertain problems with non-compliance and to ensure that patients experiencing difficulties are re-trained to a full understanding of eDiary data entry prior to starting the baseline period (Visit 3).

The morning questionnaire, adapted from the VIS-M [25], assesses the following variables with respect to the previous night: patient’s bedtime, time to sleep onset, number and duration of nocturnal awakenings, time of final awakening, presence/absence and quantification of premature awakening, time of waking in the morning, total sleep time, and time of medication intake. Quality of sleep and freshness upon waking up will be documented by the patient’s completing the Visual Analogue Scales (VAS) that are part of the questionnaire.

The morning questionnaire must be completed after completion of normal morning routine (e.g., using the bathroom, eating breakfast) and preferably within an hour of awakening for the day. On PSG visit days, the morning questionnaire should be completed prior to the DSST.




The evening questionnaire assesses the following: daytime functioning, daytime tiredness, daytime energy, and daytime relaxation as visual analogue scales. In addition, there will be a question of how many naps the patient has taken and their total duration, and a question regarding the time of their evening meal.

The evening questionnaire must be completed before bedtime prior to taking study medication. On PSG visit days, the evening questionnaire should be completed prior to drug administration.

The Tyrer Withdrawal Symptom Questionnaire will be administered as part of the evening eDiary on the first 3 nights of the single-blind placebo washout, after completion of Visit 6. For additional information please see Section 3.4.1.6.

3.3.1.5 MINI International Neuropsychiatric Interview (MINI)

A psychiatric examination will be performed at the Prestudy Visit. The following will be addressed: Major depressive episode with or without melancholic features, dysthymia, suicidality, (hypo)manic episode, panic disorder, agoraphobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, alcohol abuse and dependence, non-alcohol psychoactive substance abuse and dependence, psychotic disorders, anorexianervosa, bulimia nervosa, generalized anxiety disorder, and antisocial personality disorder [26]. The MINI Version 5.0 will be used to ascertain the psychiatric diagnoses.

3.3.1.6 Sleep Diagnostic Interview/Sleep History

The Sleep Diagnostic Interview/Sleep History will be performed by a SPONSOR-approved clinician at the Prestudy Visit to determine a diagnosis of Primary Insomnia. The Sleep Diagnostic Interview is a 30-item assessment which incorporates DSM-IV-TR Sleep Disorder criteria (See Appendix 6.3) into an interview format with the aim of confirming a diagnosis of Primary Insomnia and ruling out other sleep related disorders (e.g., Primary Hypersomnia, Breathing Related Sleep Disorder, Circadian Rhythm Sleep Disorder, Parasomnias, Dyssomnias NOS). The Sleep Diagnostic Interview also obtains information on a patient’s sleep pattern history over the prior month. Patient sleep history over the previous month is also collected as part of the Sleep Diagnostic Interview. The Sleep History collects information regarding number of nights per week of problematic sleep, hour of usual bedtime, sTST and sTSO over the previous month.

3.3.1.7 Reading Assessment

At Prestudy Visit 1, patients must obtain a score ≥6th grade level equivalent (48 out of 70)on the standardized reading subtest of the Wide Range Achievement Test, 4th edition (WRAT-4), or a comparable measure, approved by Sponsor. If formal reading assessments are not available, the Sponsor must specify other tests or methods of assessing reading ability. See administrative binder for sample reading questions. Please also refer to the WRAT-4 Manual for additional information on scoring the reading subtest.




3.3.1.8 Quick Inventory of Depressive Symptomatology Scale (QIDS-SR16)

This 16 question test assesses all the criterion symptom domains designated by the DSM-IV for diagnosis of a major depressive episode, or as a screen for depression. It has 16 items, each with 4 multiple choices [0 = symptom or behavior absent, 3 = symptom or behavior maximal] [27]. For three domains (sleep, psychomotor, appetite/weight), multiple questions are used; the highest score on any item within that domain is used to represent the domain score. The QIDS-SR16 total score is computed by adding scores for the nine criterion domains, and ranges from 0 to 27. This self-administered test will be used only at Prestudy Visit 1, to confirm study eligibility. Patients excluded due to suicidality responses are to be further evaluated using the Columbia Suicide Severity Rating Scale described below in Section 3.4.1.6.

3.3.1.9 Digit Symbol Substitution Test (DSST) and Digit Symbol Copy Test (DSCT)

Residual effects on psychomotor performance will be assessed with the DSST and DSCT. The DSST and DSCT will be performed on the AM portion of PSG visits, after the completion of the morning routine and the morning questionnaire, and within 30 minutes to 1 hour following lights on. DSST and DSCT each take <5 minutes to complete. These tests evaluate coordination and attention processes and have been used extensively in the development of hypnotics. Scoring entails evaluating the number of items completed correctly, incorrectly, and the number attempted [28; 29].

3.3.1.10 Sheehan Disability Scale (SDS)

The Sheehan Disability Scale (SDS) [30] consists of 3 questions on impairment of work, social life, and family life/home responsibilities. The SDS is a self-administered questionnaire that takes 1 to 2 minutes to complete. The recall period is 7 days. High scores indicate more impairment. Reliability ranges from 0.56 to 0.86 (Cronbach’s alpha for internal consistency) and 0.53 for 8-week test-retest reliability [31].

3.3.1.11 Insomnia Severity Index (ISI)

The Insomnia Severity Index (ISI) [32; 33] is a 7-item patient reported outcome which assesses the severity of a patient’s insomnia by assessing the severity of sleep-onset and sleep maintenance difficulties and any insomnia-related interference with daytime functioning. The assessment is on a 5-point scale (0-4), where the composite score is obtained by summing the 7 rated dimensions measuring the patient’s perception of his or her insomnia. A score of 15-21 indicates a moderate level of insomnia and a score of 22 to 28 indicates severe insomnia. An ISI total score <10 indicates that the patient’s subjectively-rated insomnia symptoms, daytime impairment, and quality of life have improved to the minimal-to-none range [34].

3.3.1.12 Blood Collection for Pharmacokinetic Assay (of MK-4305 levels in plasma)

Plasma samples for evaluation of pharmacokinetic (PK) properties of MK-4305 will be collected and analyzed. This data will be used to characterize the plasma concentration of MK-4305 in patients with Primary Insomnia. Plasma samples will be collected 3




times per treatment period in addition to a baseline sample collection, for a total of 7 times during the study; at Visits 3 to 9. At each time point, 5 milliliters of blood will be collected to yield at least 2 mL of plasma. A total of approximately 35 milliliters of blood will be collected for PK samples for each patient who completes the study. On PSG visits, sample collections should be drawn 9 hours ±15 minutes postdosing on AM portion of visit. Sample collection times should be consistent across respective visits (i.e., PSGs visits and non-PSG visits).

The final decision as to which plasma samples will be assayed will be made by the Departments of Drug Metabolism and the Clinical Monitor.

Information regarding the collection and shipping of plasma samples will be provided in the Appendix 6.10 and in the administrative binder.

3.3.2 Medication Compliance

All blinded study medication will be dispensed at the IRB/IEC–approved study-site(s) by authorized study personnel. For this study, medication compliance is considered the daily consumption of the prescribed amount of study drug (according to weekly instructions) at the about the same time each day.

At study visits, patients will be instructed to bring their study drug to the clinic. Compliance will be monitored closely and determined at each visit by patient interview and pill count. All patients will be reminded of the importance of strict compliance with taking study medication for the effectiveness of treatment and for the successful outcomeof the study. Patients will be informed that blood will be collected in this study to measure drug levels. Patients will be telephoned by site personnel the evening before Visits 5 through 9 to remind them to take the study medication and to return their study drug to the clinic. Frequency of telephone contacts for compliance will occur at the discretion of site personnel.

Interruptions of two (2) or more consecutive daily doses of study drug immediately prior to Visits 6, or 9 (end of the treatment periods) will require consultation between the investigator and the SPONSOR and written documentation of the collaborative decision on patient management. A single missed dose must be reported to the study staff at the next visit and recorded.

Substantial deviation from protocol for other reasons may also result in discontinuation from the protocol and requires consultation between the investigator and the clinical monitor and written documentation of the collaborative decision on patient management.

3.4 SAFETY MEASUREMENTS

3.4.1 Clinical and Laboratory Measurements for Safety

3.4.1.1 Medical and Psychiatric History

Medical and psychiatric histories will be obtained at the Prestudy Visit




3.4.1.2 Physical Examination

A complete physical examination will be performed by a physician per the flow chart. This examination will also be performed in the event of early discontinuation. The following body systems should be included in the physical exam:

Head, ear, nose, and throatEyesNeckCardiovascular systemRespiratory systemAbdomenSkinExtremitiesNeurological systemChestMusculoskeletal system

Examination of the breast, rectum, and urogenital system are at the investigator’s discretion (i.e., clinically indicated). If a physical or neurological abnormality is noted post-treatment, the investigator will indicate whether or not the result is clinically significant and if it constitutes an adverse experience.

3.4.1.3 Vital Signs

Sitting and standing blood pressure and pulse rate, respiratory rate, temperature, and weight will be evaluated at all visits. Vital signs will also be performed in the event of early discontinuation. One minute should be allowed between sitting and standing recordings of blood pressure and pulse. All vitals signs per patient should also be collected at the same time of day on PSG and non-PSG visits, respectively, consistently throughout the entire study. (See Appendix 6.7 for additional guidelines on blood pressure measurements.)

Height will be obtained at the Prestudy Visit only.

Body mass index (BMI) (Appendix 6.8) will be calculated using the Harris-Benedict Equation (weight[Kg]/height2[m2]) only at the Prestudy Visit from the weight and height (without shoes).

3.4.1.4 ECG

A 12-lead ECG will be obtained at Visit 1, the AM portion of PSG Visits 3, 4, 6, 7, and 9, as well as the interim safety Visits 5 and 8. An ECG will also be performed in the event of early discontinuation or at any time clinical signs or symptoms warrant. All ECGs per patient should also be collected at the same time of day on PSG and non-PSG visits, respectively, consistently throughout the entire study. ECG evaluations will be confirmed by a central laboratory, although the investigator’s judgment will be




considered primary in the event of disagreement with the central vendor. If a value is found to be outside the normal range, the investigator will indicate on the ECG report whether or not it is clinically significant. If it is considered to be clinically significant, it will be recorded in the Medical History if at Visit 1. If a clinically significant ECGabnormality is first observed (and confirmed) after Visit 1, it should be recorded as an adverse experience.

3.4.1.5 Laboratory Evaluations

All laboratory safety tests (see Appendix 6.5) will be analyzed by a central laboratory, which will arrange for the collection of laboratory samples. Central laboratory contact information will be provided by the SPONSOR maintained in the site Administrative Binder. Detailed instructions for specimen collection, packaging, and shipment will be provided in a Laboratory Manual by the Central Laboratory.

Hematology, urinalysis and blood chemistry will be performed at Visit 1, in the morning following the PSG recordings at Visits 3, 6, 7, and 9, and at interim safety Visits 5 and 8. Patients should be in a fasting state for at least 8 hours prior to all lab draws throughout the study.

Laboratory evaluations will also be performed in the event of early discontinuation. A urine drug screen will be performed at the Visit 1, and on the PM portion of PSG visits before the PSG recordings at indicated in the study flow chart. The urine drug screen performed at the Prestudy Visit (Visit 1), will be sent to the central laboratory. At Visits 2, 3, 4, 6, 7, and 9, a urine drug screen dipstick will be performed at the site. If the dipstick is positive, a confirmatory urine drug screen will be sent to the central laboratory for confirmation.

A urine and serum (β-hCG) pregnancy test will be done on all women of childbearing potential at Visit 1. A urine pregnancy test will also be done on the PM portion of PSG Visits 3, 4, 6, 7, and 9 before the PSG recordings. The urine pregnancy test performed at the Prestudy Visit (Visit 1), will be sent to the central laboratory. At Visits 3, 4, 6, 7, and 9, a urine pregnancy test will be performed at the site. Any patient who has a positive urine pregnancy test will undergo a serum pregnancy test (β-hCG) which will be send to the central laboratory for confirmation.

An alcohol breath test will be performed at Visit 1 and on the PM portion of every PSGvisit. Patients should have a negative alcohol breath test on the PSG visit nights. If a patient has a positive alcohol breath test at Visit 1, this should be documented and site should emphasize the restrictions on alcohol to the patient. If a patient has a positive alcohol breath test at Visits 2, or 3 the patient will be excluded from the study. At Visit 4 and after randomization, if a patient has a positive alcohol breath test, the test may be repeated at the investigator’s discretion (with notification to the SPONSOR) and the repeat test must be negative prior to conducting the PSG recording session. If the repeat test continues to be positive, the recording session visit should be rescheduled to take place no sooner than 24 hours and no later than 48 hours. A breathalyzer machine will be provided to each site by the SPONSOR.




Patients with screening values/findings outside ranges described in the protocol may, at the discretion of the investigator, have a repeat determination performed. If the repeatvalue satisfies the criterion, patients may continue in the screening process. Only the specific out of range value/finding should be repeated (not the entire panel). If a value is found to be outside the normal range, the investigator will indicate on the laboratory report whether or not it is clinically significant. If it is considered to be clinically significant, it will be recorded on the Medical History if at Visit 1 or if after Visit 1, it should be recorded on the Adverse Experience Workbook page. See Appendix 6.5 and 6.6 for the specific list of laboratory tests and guidance on out of range laboratory values.

3.4.1.6 Tyrer Withdrawal Symptom Questionnaire

The Tyrer Withdrawal Symptom Questionnaire [35] (Appendix 6.9) will also be completed as part of the evening diary as indicated in the Study Flow Chart. This questionnaire will ask for presence/absence and severity of those symptoms listed in the questionnaire. The symptoms will be rated from 0 (No), 1 (Yes-moderate) to 2 (Yes-severe). The symptoms reported on the withdrawal symptom questionnaire will be analyzed and presented separately from adverse experiences in the clinical study report.

3.4.1.7 Columbia Suicide Severity Rating Scale (C-SSRS)

The Columbia Suicide Severity Rating Scale (C-SSRS) is a questionnaire for detailed assessment of suicidal behavior and ideation [36]. Patients who at any time during this study spontaneously report AEs of suicidal thoughts or ideation, either as outpatient or during visit interviews, or whose responses at screening to the QIDS-SR16 are indicative of suicidality, must be assessed by the Primary Investigator, or other trained and SPONSOR-approved clinician, and complete the C-SSRS. All reports of suicidal thoughts or ideation must be recorded as an ECI. Please refer to Section 3.4.5.2 for additional information.

3.4.1.8 Modified Cataplexy Questionnaire

The Modified Cataplexy Questionnaire (MSQ) is a modified version of Part V of the Stanford Center for Narcolepsy Sleep Inventory (SCNSI), a 51-item questionnaire developed and validated for the assessment of cataplexy [22]. The MCQ is to be used to assess a single episode of a patient’s spontaneously-reported cataplexy-like behavior, in conjunction with ECI reporting of the event. The MCQ will be assessed by either the Primary Investigator or sub-Investigator. All reports of cataplexy-like events must be recorded as an ECI. Please refer to Section 3.4.5.2 for additional information.

3.4.2 Recording Adverse Experiences

An adverse experience is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR’s product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the SPONSOR’s product, is also an adverse experience.




Changes resulting from normal growth and development which do not vary significantly in frequency or severity from expected levels are not to be considered adverse experiences. Examples of this may include, but are not limited to, teething, typical crying in infants and children, and onset of menses or menopause occurring at a physiologically appropriate time.

Adverse experiences may occur in the course of the use of a Merck product in clinical studies or within the follow-up period specified by the protocol, or prescribed in clinical practice, from overdose (whether accidental or intentional), from abuse, and from withdrawal.

Adverse experiences may also occur in screened subjects/patients during any preallocation baseline period as a result of a protocol-specified intervention including washout or discontinuation of usual therapy, diet, placebo treatment, or a procedure.

Such events will be recorded at each examination on the Adverse Experience Case Report Forms/Worksheets.

3.4.3 Definition of an Overdose for This Protocol

The subject has taken, (accidentally or intentionally), a dose exceeding the dose as prescribed by the protocol. For this protocol an overdose would be any dose that exceeds the specified dose to be administered in that given treatment period.

3.4.3.1 Reporting of Overdose to SPONSOR

e p e (s s of test drug or vaccine, the adverse experience(s) is reported as a serious adverse experience, even if no other criteria for serious are met.

If a dose of test drug or vaccine meeting the protocol definition of overdose is taken without any associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-serious Event of Clinical Interest (ECI), using the terminology

All reports of overdose with and without an adverse experience must be reported within 24 hours to one of the individuals listed on the sponsor contact information page found in the Administrative Binder.

3.4.4 Reporting of Pregnancy to SPONSOR

Although not considered an adverse experience, it is the responsibility of investigators or their designees to report any pregnancy in a subject/patient (spontaneously reported to them) which occurs during the study or within 14 days of completing the study. All subjects/patients who become pregnant must be followed to the completion/termination of the pregnancy. If the pregnancy continues to term, the outcome (health of infant) must also be reported to one of the individuals listed on the SPONSOR Contact Information page found in the Administrative Binder.




3.4.5 Immediate Reporting of Adverse Experiences to the SPONSOR

3.4.5.1 Serious Adverse Experiences

Any serious adverse experience, including death due to any cause, which occurs to any subject/patient entered into this study or within 14 days following cessation of treatment or within the established off therapy follow-up period for safety described in the protocol, whether or not related to the investigational product, must be reported within 24 hours to one of the individual(s) listed on the contact information page.

Additionally, any serious adverse experience considered by an investigator who is a qualified physician to be possibly, probably, or definitely related to the investigational product that is brought to the attention of the investigator at any time outside of the timeperiod specified in the previous paragraph also must be reported immediately to one of the individuals listed on the sponsor contact information page found in the administrative binder.

All subjects/patients with serious adverse experiences must be followed up for outcome.

3.4.5.2 Selected Nonserious Adverse Experiences/Events of Clinical Interest

These selected non-serious adverse experiences are also known as Events of Clinical Interest (ECI) and must be recorded as such on the Adverse Experience Case Report Forms/Worksheets.

Narcolepsy-like events (e.g., unexpected naps, excessive daytime sleepiness, sleep attacks, hypnagogic (sleep onset) hallucinations)

Cataplexy-like events (e.g., sudden muscle atonia, wake paralysis)

Suicidal Thoughts and/or Ideation

Complex Sleep-related Behaviors falling under the category of Somnambulism (e.g., sleep walking, sleep driving, making phone calls while sleeping, preparing and eating food while sleeping)

3.4.6 Evaluating Adverse Experiences

Refer to Table 3-7 for instructions in evaluating adverse experiences.




Table 3-7

An investigator who is a qualified physician, will evaluate all adverse experiences as to:Maximum Mild awareness of sign or symptom, but easily tolerated (for pediatric studies, awareness of symptom, but easily tolerated)Intensity Moderate discomfort enough to cause interference with usual activity (for pediatric studies, definitely acting like something is wrong)

Severe incapacitating with inability to work or do usual activity (for pediatric studies, extremely distressed or unable to do usual activities)Seriousness A serious adverse experience is any adverse experience occurring at any dose that:

†Results in death; or†Is life threatening; or places the subject/patient, in the view of the investigator, at immediate risk of death from the experience as it occurred [Note: This does not include an adverse experience that, had it occurred in a more severe form, might have caused death.]; or†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the hospitalization is a precautionary measure for continued observation. (Note: Hospitalization [including hospitalization for an elective procedure] for a preexisting condition which has not worsened does not constitute a serious adverse experience.); or†Is a congenital anomaly/birth defect (in offspring of subject/patient taking the product regardless of time to diagnosis); orIs a cancer; orIs an overdose (Whether accidental or intentional.) Any overdose whether or not associated with an adverse experience must be reported within 24 hours to one of the individuals on the Contact Information Page found in the Administrative Binder.Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse experience when, based upon appropriate medical judgment, the event may jeopardize the subject/patient and may require medical or surgical intervention to prevent one of the outcomes listed previously (designated above by a †).

Duration Record the start and stop dates of the adverse experience. If less than 1 day, indicate the appropriate length of time and unitsAction taken Did the adverse experience cause the test drug to be discontinued?Relationship to test drug

Did the test drug cause the adverse experience? The determination of the likelihood that the test drug caused the adverse experience will be provided by an investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet, that supports the causality noted on the AE form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse experience based upon the available information. The following components are to be used to assess the relationship between the test drug and the AE; the greater the correlation with the components and their respective elements (in number and/or intensity), the more likely the test drug caused the adverse experience (AE):Exposure Is there evidence that the subject/patient was actually exposed to the test drug such as: reliable history, acceptable compliance assessment (pill count, diary,

etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?Time Course Did the AE follow in a reasonable temporal sequence from administration of the test drug?

Is the time of onset of the AE compatible with a drug-induced effect?Likely Cause Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors

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Relationship The following components are to be used to assess the relationship between the test drug and the AE: (continued)to test drug(continued)

Dechallenge Was the dose of test drug discontinued or reduced?If yes, did the AE resolve or improve?

If yes, this is a positive dechallenge. If no, this is a negative dechallenge.(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of the test drug; or (3) the study is a single-dose drug study.)

Rechallenge Was the subject/patient reexposed to the test drug in this study?If yes, did the AE recur or worsen?

If yes, this is a positive rechallenge. If no, this is a negative rechallenge.(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the study is a single-dose drug study.)NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN CAUSED BY THE TEST DRUG, OR IF REEXPOSURE TO THE TEST DRUG POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE SUBJECT/PATIENT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. CLINICAL MONITOR AND THE INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE.

Consistency with Study Drug Profile

Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the test drug or drug class pharmacology or toxicology?

The assessment of relationship will be reported on the case report forms/worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including consideration of the above elements.Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a drug relationship).Definitely related

There is evidence of exposure to the test drug. The temporal sequence of the AE onset relative to administration of the test drug is reasonable. The AE is more likely explained by the test drug than by another cause. Dechallenge is positive. Rechallenge (if feasible) is positive. The AE shows a pattern consistent with previous knowledge of the test drug or test drug class.

Probably related

There is evidence of exposure to the test drug. The temporal sequence of the AE onset relative to administration of the test drug is reasonable. The AE is more likely explained by the test drug than by another cause. Dechallenge (if performed) is positive.

Possibly related There is evidence of exposure to the test drug. The temporal sequence of the AE onset relative to administration of the test drug is reasonable. The AE could have been due to another equally likely cause. Dechallenge (if performed) is positive.

Probably not related

There is evidence of exposure to the test drug. There is another more likely cause of the AE. Dechallenge (if performed) is negative or ambiguous. Rechallenge (if performed) is negative or ambiguous.

Definitely not related

The subject/patient did not receive the test drug. OR Temporal sequence of the AE onset relative to administration of the test drug is not reasonable. ORThere is another obvious cause of the AE.

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3.4.7 SPONSOR Responsibility for Reporting Adverse Experiences

All adverse experiences will be reported to regulatory agencies, IRB/IECs, and investigators in accordance with all applicable global laws and regulations.

3.5 STATISTICAL ANALYSIS PLAN

This section outlines the statistical analysis strategy and procedures for this study. If, after the study has begun, but prior to any unblinding, changes are made to primary and/or key secondary hypotheses, or the statistical methods related to those hypotheses, then the protocol will be amended (consistent with ICH Guideline E-9). Changes to exploratory or other non-confirmatory analyses made after the protocol has been finalized, along with an explanation as to when and why they occurred, will be listed in the Clinical Study Report (CSR) for the study. Post hoc exploratory analyses will beclearly identified in the CSR for the study. A document describing details related to the supportive non-parametric method planned for analysis of the primary and secondary hypotheses will be finalized prior to unblinding for the interim analysis.

3.5.1 Responsibility for Analyses/In-House Blinding

The statistical analysis of the data obtained from this study will be the responsibility of the Clinical Biostatistics department of the SPONSOR.

This study will be conducted as a double-blind study under in-house blinding procedures. At the completion of data collection, the official, final database for the study will not be unblinded until medical/scientific review has been performed, and data have been declared final and complete. There may be an open-label extension period to this study, but it will be conducted as a separate protocol and reported in a separate CSR.

The Clinical Biostatistics department will generate the randomized allocation schedule(s) for study treatment sequence assignment. Randomization will be implemented in an interactive voice response system (IVRS). The randomization will be stratified by geographic region (Japan vs. ex-Japan).

Plans for interim analyses are described in Section 3.5.9. Study enrollment is likely to be ongoing at the time of the interim analysis for futility; enrollment of patients from the ex-Japan stratum is expected to be complete (or nearly complete) at the time of a possible second interim analysis (which may be conducted on patients from the ex-Japan stratum to help plan future Phase III studies). Blinding to treatment assignment will be maintained at all investigational sites. The results of interim analyses will not be shared with the investigators prior to the completion of the double-blind portion of the study. Patient-level unblinding of data for the ex-Japan stratum will be restricted to an internal unblinded statistician and scientific programmer performing the interim analyses, who are unrelated to the project and have no other responsibilities associated with the study. No data from Japan will be included in the interim analyses.

Treatment-level results (and patient-level data if requested) of the interim analyses will be provided by the unblinded statistician to a standing internal Data Monitoring




Committee (siDMC) which consists of SPONSOR personnel. Limited additional SPONSOR personnel may be unblinded to the treatment level results of the interim analyses, if required, in order to act on the recommendations of the siDMC. The extent to which individuals are unblinded with respect to results of interim analyses will be documented by the unblinded statistician.

The processes by which recommendations and decisions are reached and communicated are documented in the siDMC charter for the SPONSOR. The protocol-specific siDMC charter will be referenced in the CSR. Prior to final study unblinding, individuals who have been unblinded at any level will not be involved in any discussions regarding modifications to the protocol, statistical methods, identification of protocol violators, or data validation efforts after the interim analyses.

3.5.2 Hypotheses/Estimation

Objectives and hypotheses of the study are stated in Section 2.1.

3.5.3 Analysis Endpoints

Efficacy and safety endpoints that will be evaluated for within- and/or between-treatment differences are listed below, followed by the descriptions of the derivations of selected endpoints. Both objective and subjective measures of sleep are evaluated in this study. Since some assessments measure the same variable (e.g., total sleep time [TST]) a convention of adding ’s’ before the subjective measure is used in this document (e.g., sTST). Also, since some measures involve taking the average over time (e.g., average over days during Week 1) a convention of adding ’m’ after the measure is used to reflect the mean value over time for this measure (e.g., sTSTm).

3.5.3.1 Efficacy/Immunogenicity/Pharmacokinetics Endpoints

3.5.3.1.1 Efficacy Endpoints

Primary and Secondary Endpoints

The co-primary endpoints that will be used in the evaluation of the primary efficacy hypothesis are sleep efficiency (SE) measurements at Night 1 and at the end of 4 weeks of treatment. SE is defined as total sleep time (TST) in minutes divided by time in bed (measured from lights off to lights on; fixed at 8 hours on each PSG night) in minutes, multiplied by 100, where TST is defined as the total time (minutes) in Stages 1, 2, 3, 4 and REM.

The secondary endpoints include Night 1 and end of Week 4 measurements for: 1) wakefulness after sleep onset (WASO) and 2) latency to persistent sleep (LPS). WASO is defined as the duration of wakefulness (any epoch of Stage 0) from persistent sleep onset (first epoch of the first twenty consecutive epochs of non-wake) to lights on and LPS is defined as the duration of time from lights off to persistent sleep onset. An epoch of non-wake is defined as a 30-second interval classified as either Stage 1, 2, 3, 4 or REM according to conventional Rechtschaffen and Kales (R&K) scoring.




Exploratory Endpoints

Exploratory endpoints include:

At Night 1 and End of Week 4:

Total sleep time (TST) (minutes): defined as duration of REM + NREM (Stages 1+2+3+4) from lights off to lights on

Sleep onset latency (SOL) (minutes): defined as the duration of time from lights off to the first epoch of any stage of sleep (sleep onset)

Number of awakenings (NAW): Counted from persistent sleep onset to lights on, an awakening is defined as a PSG recording of at least two consecutive wake epochs and must be bracketed by an epoch of Stage 1, 2, 3, or 4 non-REM sleep or REM sleep.

Number of Arousals (NOA): Counted from sleep onset to lights on, an arousal is defined as a PSG recording of at least one wake epoch and must be bracketed by an epoch of Stage 1, 2, 3, or 4 non-REM sleep or REM sleep.

Number of stage shifts to wake or Stage 1 (NSS_W_1)

Number of stage shifts to lighter stages of sleep (NSSL): Counted from persistent sleep onset to lights on, a stage shift to lighter stages of sleep is defined as the going from Stages 3 or 4 to Stage 2, from Stage 2 to 1, or from REM to Stage 1.

Stage 1 duration (S1) (minutes) from lights off to lights on

Stage 1 percent (PS1): defined as S1 divided by TST







Slow wave sleep (SWS) (minutes): defined as duration of Stage 3/4 sleep from lights off to lights on

SWS percent (PSWS): defined as SWS divided by TST

Latency to SWS (LSWS): defined as the duration of time from sleep onset to the first epoch of Stage 3 or 4 sleep.

Non-REM duration (NREM) (minutes): defined as the duration of time in Stages 1+2+3+4 from lights off to lights on

Percent Non-REM (PNREM): defined as NREM divided by TST




Rapid Eye Movement sleep (REM) duration (minutes) from lights off to lights on

Latency to REM (REML) (minutes): defined as the duration of time from sleep onset to the first epoch of REM

Average Over Days by Week:

Morning Diary patient-reported total sleep time (sTSTm) (minutes)Morning Diary patient-reported time to sleep onset (sTSOm) (minutes)Morning Diary patient-reported number of awakenings (sNAWm) (minutes)Morning Diary patient-reported quality of sleep VAS score (sQUALm)Morning Diary patient-reported freshness of sleep VAS score (sFRESHm)Evening Diary patient-reported tiredness VAS score (sTIREDm)Evening Diary patient-reported energy VAS score (sENERGYm)Evening Diary patient-reported relaxation VAS score (sRELAXEDm)Evening Diary patient-reported number of naps (sNAPSm)

At end of Week 4:

Sheehan Disability Scale (SDS) total scoreSDS work scoreSDS social scoreSDS family life/home scoreInsomnia Severity Index (ISI) total scoreISI difficulty falling asleep scoreISI difficulty staying asleep scoreISI waking too early scoreISI satisfied/dissatisfied with current sleep scoreISI sleep problem interfere with daily functioning scoreISI sleep problem impair QOL scoreISI worried/distressed about sleep problem score

By Hour for Night 1 and End of Week 4:

Wakefulness after sleep onset (WASO) by Hour: Minutes of WASO (defined above) which occur within each hour (i.e., Hour 1, 2, …, 8) from lights off to lights onNumber of Awakenings (NAW) by Hour: NAW (defined above) which occur within each hour (i.e., Hour 1, 2, …, 8) from lights off to lights on

Average Over 8 Hours, by Thirds of the Night and by Hour for Night 1 and End of Week 4:

Power spectra: Each 1 Hz bin from 1 to 128 Hz and traditional bands which include: Delta, Theta, Alpha, Slow Beta, and Gamma




3.5.3.1.2 Pharmacokinetics Endpoints

Plasma concentration (Cp) will be evaluated during the study. Additional PK variables may also be evaluated.

3.5.3.2 Safety Endpoints

Safety and tolerability will be assessed by statistical and clinical review of the following data collected throughout the study: adverse experiences (AEs), laboratory values, ECGs, physical examinations, vital signs, next day residual effects, rebound insomnia and withdrawal effects.

Next day residual effects will be measured by the number correct and number attempted on the DSST and DSCT. Rebound insomnia will be evaluated using 2 indicator variables (REB_sTST and REB_sTSO) derived for each of the first 3 nights of the washout period (after Treatment Period 1); the value of each indicator variable is 1 if the measurement during the washout period day is worse than the corresponding mean at baseline and is 0 otherwise. Withdrawal effects will be measured using the Tyrer Withdrawal Symptom Questionnaire (WSQ) on each of the first 3 days of the washout period.

The primary time period for safety analyses of this study includes each 4-week treatment period. Safety endpoints measured at the end of Periods 1 and 2 will be assessed.

See section 3.4 for detailed descriptions of the endpoints.

3.5.3.3 Derivations of Efficacy/Immunogenicity/Pharmacokinetics Endpoints Primary and Secondary Endpoints

Sleep stage scoring of the PSG recordings will be performed according to R&K criteria for each 30-second epoch by a central sleep scoring laboratory. Each 30-second epoch will be scored as wake, Stage 1, 2, 3, 4 or REM. The primary, secondary and exploratory PSG endpoints for analysis will be derived from this information according to the definitions given above in Section 3.5.3.1.1.

Patients Who Do Not Fall Asleep

The total sleep time (TST and sTST) may be recorded as 0; the frequency of such cases will be summarized in the report. In this case, the patient likely did not fall asleep for a whole night. Since the at-risk time for the WASO, SWS, and NAW are 0, WASO, SWS, and NAW are undefined and will be set as missing. The best treatment effect for LPS is 0 inutes. When a patient does not fall asleep, it is the worst outcome. Since the at-risk time for LPS is the duration of time in bed (TIB), which is 8 hours for PSG nights, the LPS will be set as 8 hours if TST=0. Following the same reasoning, sWASO and sNAW will be set as missing and the sTSO will be set as the sTIB or 8 hours, whichever is smaller, for the questionnaire data. The sTIB will be derived by subtracting item 3 from item 9 of the Morning questionnaire. On a few occasions, a patient may mistakenly enter a time in item 9 earlier than the time in item 3, which leads to negative sTIB value. In this case, the sTIB will be set to missing and the sTSO will be set to missing as well.




Questionnaire Data

Questionnaire data on the nights in the sleep lab will be excluded from the analysis of exploratory endpoints since: a) the subjective endpoints may be influenced by being at the sleep lab versus in the outpatient environment; b) the time in bed is limited to 8 hours in the sleep lab. Patients must have at least 3 days of data during each week; otherwise, the mean values will be considered missing for that week.

3.5.3.4 Derivations of Safety Endpoints

Predefined limits of change from baseline will be evaluated for laboratory and vital signs data in accordance with prespecified criteria noted below in Table 3-8 and Table 3-9.

Table 3-8

Predefined Limits of Change Criteria for Laboratory Data

Laboratory TestCriteria† as a % of a Limit of

Normal RangeHematologyHematocrit (M) ≤94.9% LLNHematocrit (F) ≤94.1% LLNHemoglobin (M) ≤90.5% LLNHemoglobin (F) ≤81.9% LLNWBC ≤64.2% LLN

≥149.0% ULNNeutrophils ≤37.0% LLNEosinophils ≥147.0% ULNPlatelets ≤57.7% LLN

≥177.7%ULNHepatic FunctionBilirubin ≥166.7% ULNAlkaline Phosphatase ≥300% ULNSGOT ≥300% ULNSGPT ≥300% ULNRenal FunctionCreatinine ≥142.9% ULNClinical ChemistrySodium ≤94.7% LLN

≥105.4% ULNPotassium ≤88.2% LLN

≥111.1% ULN† A laboratory value must represent a worsening from baseline (i.e.,

be more abnormal in the direction of interest) to meet the definition.LLN=Lower limit of normal.ULN=Upper limit of normal.




Table 3-9

Predefined Limits of Change Criteria for Vital Signs,Weight, and Temperature

Measurement CriteriaSystolic blood ≥180 mm Hg and ≥20 mm Hg increase pressure ≤90 mm Hg and ≥20 mm Hg decreaseDiastolic blood ≥105 mm Hg and ≥15 mm Hg increase pressure ≤50 mm Hg and ≥15 mm Hg decreasePulse ≥120 bpm and ≥15 bpm increase

≤50 bpm and ≥15 bpm decreaseOrthostatic blood

pressure>20 mm Hg systolic sitting to standing after treatment (but not in baseline)

Weight ≥7 % increase from baseline≥7 % decrease from baseline

Temperature ≥101˚F and ≥2˚F increase from baseline (≥38.3˚C and ≥1˚C increase from baseline)

For the assessment of withdrawal effects, the WSQ evaluates the presence/absence and severity of withdrawal symptoms with 20 items. The response will be rated from 0 (No), 1 (Yes-moderate) to 2 (Yes-severe). A patient is defined to have a WSQ item signal (WSQ_SIG_i, i=1,…, 20) if the item at any of the three washout days (Days 2, 3 and 4 of the washout period) is emerging for the first time or is worsening compared to the measurement taken at the end of Treatment Period 1. Symbolically,

iitemon signalno ,0

iitemon signal ,1WSQ_i

for i=1,…,20. A total signal score WSQ_SIG_TOT summing all item signal scores will be calculated, i.e., WSQ_SIG_TOT= WSQ_1+ … + WSQ_20.

Finally, a patient is defined to have withdrawal effects if WSQ_SIG_TOT is greater than or equal to 3, i.e.,

3.TWSQ_SIG_TO ,0

3TWSQ_SIG_TO ,1FWSQ_SIG_EF




3.5.4 Analysis Populations

3.5.4.1 Efficacy Analysis Populations

The Full Analysis Set (FAS) population will serve as the primary population for the analysis of efficacy data in this study. The FAS population is a subset of all randomized patients with patients excluded for the following reasons:

failure to receive at least one dose of study treatment

lack of any post-randomization efficacy data subsequent to at least one dose of study treatment

The FAS population may vary across endpoints due to the degree of missing data for each endpoint.

Patients will be included in the treatment sequence to which they were randomized for the analysis of efficacy data. Details on the approach to handling missing data are provided in Section 3.5.5 Statistical Methods.

3.5.4.2 Safety Analysis Populations

The All Patients as Treated (APaT) population will be used for the analysis of safety data in this study. The APaT population consists of all randomized patients who received at least one dose of study treatment. Patients will be included corresponding to the study treatment they actually received for a given period for the analysis of safety data using the APaT population. For most patients this will be the treatments according to the treatment sequence to which they were randomized. Patients who took incorrect study treatment for the entire period will be included in the treatment corresponding to the study treatment they actually received in the given period.

At least one laboratory or vital sign measurement obtained subsequent to at least one dose of study treatment is required for inclusion in the analysis of each specific parameter. To assess change from baseline, a baseline measurement is also required.

Details on the approach to handling missing data for safety analyses are provided in Section 3.5.5 Statistical Methods.

3.5.5 Statistical Methods

For both the efficacy and safety analyses, unless otherwise specified, all statistical tests will be conducted at α=0.05 level (two-sided). Results that will be considered to be statistically significant (versus nominally significant) after consideration of the strategy for controlling the type-I error, are described in Section 3.5.6, Multiplicity.

3.5.5.1 Statistical Methods for Efficacy Analyses

The primary and secondary hypotheses will be evaluated using a mixed effects model including terms for baseline value, geographic region (Japan vs. ex-Japan), treatment,




sequence, period, time (as a categorical variable), and treatment-by-time and period-by-time interactions. An unstructured covariance matrix will be used. If the model does not converge then a random effect for patient will be added to the model and an unstructured 2x2 covariance matrix within patient and time will be used. Note that the baseline value is only measured prior to randomization to a treatment sequence. The model will be used to provide an estimate of the treatment effect for the comparison of each MK-4305 dose with placebo. A confidence interval and p-value (based upon a normal approximation) will also be computed. This approach utilizes all placebo data for each MK-4305 versus placebo comparison.

The mixed model with baseline value as a covariate was chosen over constrained LDA since the normality assumption for the residuals may not be met for the primary and secondary sleep endpoints without adjusting for baseline. While untransformed sleep endpoints tend to be skewed, their changes from baseline tend to be more symmetric so that the residuals for the mixed model with baseline as covariate are more likely to satisfy the normality assumption.

The mixed model assumes that data are missing at random (MAR). This is a reasonable assumption in this study for the following reasons. First, the decision to discontinue patients due to lack of efficacy will likely be based mainly on observed efficacy measurements, as opposed to future, unobserved data. Secondly, for patients who are discontinued because they move, deviate from the protocol, or have clinical or laboratory AEs, it is unlikely that the discontinuation would depend on unobserved efficacy measures because there is no clear connection between the discontinuation decision and the future, unobserved efficacy measures. Finally, the missing data mechanism for patients who are discontinued for other reasons, such as lost to follow-up or withdrawal of consent, is not clear and may or may not depend on the unobserved data. In any case, the percentage of patients who fall into this category is projected to be low, and thus the impact of the missing data (which may or may not be non-ignorable) on statistical inference is likely to be limited. Multiple imputation will be also used as a sensitivity analysis to approximate the missing value for the primary, secondary (and selected exploratory) endpoints. Additionally, individual means of Night 1 and end of Week 4 measurements for the primary and secondary variables may be analyzed to evaluate whether treatment is effective on average over 4 weeks of treatment.

The approach for handling multiplicity associated with testing multiple dose comparisons to placebo is described in Section 3.5.6 Multiplicity. The treatment difference estimates and 95% confidence intervals obtained from these analyses will be graphed to explore the dose-response relationship.

A non-parametric method appropriate for a 2-period crossover design adjusting for baseline values of the response and accounting for missing data will be used as a sensitivity analysis to evaluate the primary and secondary hypotheses. The analysis will be performed separately for each subset of data comprised of the 2 sequences which contain a given MK-4305 dose. Details of this analysis will be documented prior to unblinding for the interim analysis.




The same analyses described above will be used for the interim analysis.

The mixed model assumes that the errors are normally distributed. For endpoints that violate this assumption or have outliers which are highly influential, the non-parametric analysis will also be performed. Table 3-10 summarizes the key efficacy analyses.

Table 3-10

Analysis Strategy for Key Efficacy Variables

Endpoint/Variable(Description, Time Point)

Primary vs. Supportive Approach† Statistical Method‡

Analysis Population§

Missing Data Approach

Primary:SE at Night 1 and End of P Mixed effects model FAS Model-basedWeek 4 S Non-parametric

approachFAS DAO

Secondary:WASO at Night 1 and End P Mixed effects model FAS Model-basedof Week 4, LPS at Night 1 and End of Week 4

S Non-parametric approach

FAS DAO

Exploratory: ¶

Subjective sleep endpoints at Night 1 and End of Week 4

P Mixed effects model FAS Model-based

Other PSG sleep endpoints at Night 1 and End of Week 4


Power Spectra at Night 1 and End of Week 4


Daytime functioning, impairment and quality of life endpoints (i.e., from Evening Diary, SDS and Insomnia Severity Index), at End of Week 4


† =Primary approach; S=Supportive approach.‡ tatistical models are described in detail in Section 3.5.5.1.§ AS=Full Analysis Set.

AO = Data As Observed.¶ Representative categories of exploratory endpoints are included here.

The strategy to address multiplicity issues with regard to the multiple treatment comparisons to placebo is described in Section 3.5.6 Multiplicity and Section 3.5.9 Interim Analyses.

3.5.5.2 Statistical Methods for Safety Analyses

Safety and tolerability will be assessed by clinical review of all relevant parameters including adverse experiences (AEs), laboratory tests, vital signs, and ECG measurements.




The analysis of safety results will follow a tiered approach (Table 3-11). The tiers differ with respect to the analyses that will be performed. Safety parameters or adverse experiences of special interest that are identified a priori constitute safety endpoints that will be subject to inferential testing for statistical significance with p-values and 95% confidence intervals provided for treatment versus placebo comparisons. Other safety parameters will be considered Tier 2 or Tier 3. Tier 2 parameters will be assessed via point estimates with 95% confidence intervals provided for comparisons of treatment versus placebo; only point estimates by treatment are provided for Tier 3 safety parameters.

Adverse experiences (specific terms as well as system organ class terms) and predefined limits of change in laboratory, vital sign, and ECG parameters that are not pre-specified as endpoints of special interest will be classified as belonging to "Tier 2" or "Tier 3", based on the number of events observed. Membership in Tier 2 requires that at least 4 patients on a given treatment exhibit the event; all other adverse experiences and predefined limits of change will belong to Tier 3.

The threshold of at least 4 events on a given treatment (MK-4305 dose or PBO) after combining both periods’ data was chosen because the 95% confidence interval for the between-treatment difference in percent incidence will always include zero when treatment groups of equal size each have less than 4 events and thus would add little to the interpretation of potentially meaningful differences. Because many 95% confidence intervals may be provided without adjustment for multiplicity, the confidence intervals should be regarded as a helpful descriptive measure to be used in review, not a formal method for assessing the statistical significance of the between-treatment differences in adverse experiences and predefined limits of change.

Changes from baseline in laboratory, vital signs, and ECG parameters that are not pre-specified as endpoints of special interest will be considered Tier 3 safety parameters. Summary statistics for baseline, on-treatment, and change from baseline values will be provided in table format. These summaries will use Data As Observed.

For this protocol, the following will be considered as Tier 1 AEs: 1) narcolepsy-like events, 2) cataplexy-like events, 3) suicidal thoughts and/or ideation and 4) complex sleep-related behaviors. Residual effects as measured by the number correct and number attempted at Week 4 for the DSST and the DSCT will also be considered as Tier 1 endpoints.

In addition to the Tier 2 events described above, the broad clinical and laboratory AE categories consisting of the percentage of patients with any AE, a drug related AE, aserious AE, an AE which is both drug-related and serious, and who discontinued due to an AE will be considered Tier 2 events. Rebound insomnia (for sTST and sTSO) observed during each of the first three days of washout after Period 1 will be considered as Tier 2 events. Withdrawal effects (WSQ_SIG_EFF) observed during the first three days of washout after Period 1 will also be considered a Tier 2 endpoint. Note that only effective MK-4305 doses will be included in the analysis of rebound and withdrawal.




P-values (Tier 1 only) and 95% confidence intervals (Tier 1 and Tier 2) will be provided for between-treatment differences in the percentage of patients with events; these analyses will be performed using the Tango’s method (1998) [37]. Koch’s method (Koch’s adaptation of the Wilcoxon-Mann-Whitney rank sum test) [38] will be used to analyze the Tier 1 residual effects endpoints.

Table 3-11

Analysis Strategy for Safety Parameters

Safety Tier Safety Endpoint† p-Value

95% CI for Treatment

ComparisonDescriptive Statistics

Narcolepsy-like events X X XCataplexy-like events X X XSuicidal thoughts and/or ideation X X XComplex sleep-related behaviors X X XDSST (# correct; # attempted) X X X

Tier 1

DSCT (# correct; # attempted) X X XAny AE X XAny Serious AE X XAny Drug-Related AE X XAny Serious and Drug-Related AE X XDiscontinuation due to AE X XSpecific AEs, SOCs, or PDLCs‡

(events ≥4 patients in one of the treatment groups)

X X

Rebound X X

Tier 2

Withdrawal X XSpecific AEs, SOCs or PDLCs‡

(events <4 patients in all of the treatment groups)

XTier 3

Change from Baseline Results (Labs, ECGs, Vitals)

X† Adverse Experience references refer to both Clinical and Laboratory AEs.‡ Includes only those endpoints not pre-specified as Tier 1 endpoints.Note: SOC=System Organ Class; PDLC=Pre-Defined Limit of Change; X = results will be provided; NA=Not Applicable.

3.5.5.3 Summaries of Baseline Characteristics, Demographics, and Other Analyses

Demographic and Baseline Characteristics

The comparability of the treatment sequences for each relevant characteristic will be assessed by the use of tables and/or graphs. No statistical hypothesis tests will be performed on these characteristics. The number and percentage of patients screened, randomized, the primary reasons for screen failure, and the primary reason for discontinuation will be displayed. Demographic variables (e.g., age, gender, race, ethnicity), medical history, prior and concomitant therapies, and other sleep-related baseline data (e.g., sTST) will be summarized by treatment sequence either by descriptive statistics or categorical tables.




Population PK Analyses

Based on pharmacokinetic data obtained within this study (and substudy), a separate population Pharmacokinetics (PK) analysis may be performed if deemed appropriate and necessary. The pharmacokinetic data from previous studies may be incorporated into this analysis. The prospective details of such an analysis would be specified in a separate population PK analysis plan.

3.5.6 Multiplicity

An interim analysis for futility will be conducted when approximately 50% of the patients have completed both treatment periods for the study; this analysis will not affect the Type I error. A second interim analysis may be conducted when approximately 160 patients complete both periods of the crossover study for planning future Phase III studies. If this analysis is performed, the method of Haybittle-Peto will be used to control overall Type I error; this method uses an alpha of 0.001 at the interim and an alpha of 0.05 at the end of the study. The interim analyses will include patients from the ex-Japan stratum only.

While, nominal p-values will be computed for all comparisons of MK-4305 with placebo, statistical significance for the primary and secondary hypotheses will be based on the following multiplicity strategy. To account for the multiple dose comparisons to placebo for the primary efficacy hypothesis, a fixed sequential testing procedure will be used to assess statistical significance (for all doses not deemed futile at the interim analysis), beginning with the highest dose (i.e., 80 mg). The comparison of MK-4305 with placebofor SE has to be significant at α=0.05 at both time points (i.e., Night 1 and Week 4) in order to assess the statistical significance of the comparison of MK-4305 with placebo for the next highest dose (i.e., 40 mg), and so on. If a non-significant result is observed at either time point, the differences between MK-4305 and placebo for SE will be considered nonsignificant at this and all lower doses. This procedure will provide strong control for the multiple dose comparisons of MK-4305 with placebo for the primary efficacy endpoint. MK-4305 doses that are statistically significant for the primary hypothesis will be tested in a similar fashion for the first secondary endpoint (WASO) at the 5% level of significance. Similarly, MK-4035 doses which are statistically significantly different from placebo for SE and WASO at both time points will be tested in a similar fashion for the second secondary endpoint (LPS). This will provide control (not strong) of alpha for multiple dose comparisons of MK-4305 to placebo for multiple secondary endpoints. The multiplicity strategy covering the primary and secondary hypotheses is depicted in the following diagram below.




Primary: SE

Secondary: WASO

Secondary: LPS

Test MK-4305 80 mg vs. PBO at N1 and WK4; if both positive at

5% level, then conclude dose is effective and move to next dose

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5% level, then conclude dose is effective

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The Benjamini-Hochberg false discovery rate (FDR) procedure will be applied for meaningful groupings of exploratory endpoints (e.g., sleep maintenance measures, sleep onset measures, sleep architecture measures, spectral analysis measures, patient-reported next-day function measures) at each time point and for each MK-4305 dose separately (at the 10% level) to assess the statistical significance of MK-4305 dose comparisons with placebo. Interpretation of significance for lower doses will be conditional upon significant results for higher doses for similar measures/time points.

3.5.7 Sample Size and Power Calculations

3.5.7.1 Sample Size and Power for Efficacy Analyses

Mean improvement in SE, WASO and LPS after 1 night of treatment are available from Actelion’s orexin compound, almorexant. As reported by Actelion at WorldSleep07, treatment with almorexant in doses of 100, 200, and 400 mg, respectively, resulted in mean improvements compared to placebo of: 4.6, 8.2 and 14.4 for SE; 20.1, 34.3 and 54.0 minutes for WASO; and 10.4, 10.4 and 18.0 minutes for LPS. Estimates of variability after 1 night of treatment and after 4 weeks of treatment are available from a parallel-group Merck study evaluating a different mechanism for the treatment of insomnia (MK-0928 Protocol 004 data); estimates of the mean square error (MSE) used to power this study assume a correlation of 0.5 between treatment periods. These estimates have been used in the power and sample size calculations that follow.

Table 3-12 displays the power to detect a variety of differences (within the scope of those observed for almorexant) at Night 1, end of Week 4, and jointly (i.e., at both time points)




for the primary and secondary endpoints assuming a sample size of 52 patients completing the two-period crossover study for a particular MK-4305 dose. A total of 208 patients (i.e., 52 for each of the 4 doses) completing both periods of the study, including ~ 40 patients from Japanese ancestry, will be required to compare SE between all four MK-305 doses and placebo. Based upon this sample size, there is approximately 95% (73%) power to detect a difference of 8.33 (6.25) in SE at both time points for a particular MK-4305 dose. (Note that a difference of 8.33 (6.25) in SE corresponds to a 40 (30) minute difference in total sleep time (TST) when time in bed is fixed at 8 hours.)

Table 3-12

Power to Detect True Deltas in Primary and Secondary Sleep EndpointsWith 52 Patients Completing the Study for Each MK-4305 Dose

Power†

Endpoint

Delta = True Difference

from Placebo Night 1 Week 4 Joint‡

SE 8.33§ 98% 97% 95%6.25 85% 81% 73%4.17 51% 47% 32%

WASO (minutes) 30 96 % 96 % 93%25 88% 88% 80%20 71 % 70 % 57%

LPS (minutes) 20 76% 77% 64%15 52 % 53 % 36%10 27 % 27 % 14%

† Based upon a 2-sided, 5%-level test and variability estimates from MK-0928 Protocol 004; assumed MSE for Night 1 and Week 4, respectively, is: 110 and 122 for SE; 1590 and 1607 for WASO; and 1399 and 1362 for LPS

‡ Assumes correlation of 0.5 between two test-statistics§ SE values of 8.33, 6.25 and 4.17 correspond to TST values (in minutes) of 40, 30 and

20, respectively, assuming time in bed is fixed at 8 hours.

A futility analysis will be conducted after 50% of patients (i.e., approximately 104) have completed their two 4-week treatment periods. See Section 3.5.9 for details regarding the planned interim analyses. Based upon the futility analysis, it is possible that a lower dose of MK-4305 (5 mg) may be added to the study; in this case, the sample size may increase by up to 52 patients (due to the addition of these lower dose sequences).

It is expected that approximately 10% of the patients randomized will discontinue treatment permanently during one of the two 4-week treatment periods; therefore, approximately 250 patients will be randomized to ensure 208 with complete data. Patients will be instructed to return to participate in treatment Period 2 if they drop out during treatment Period 1.




3.5.7.2 Sample Size and Power for Safety Analyses

No sample size calculations for safety endpoints were performed for this study.

3.5.8 Subgroup Analyses and Effect of Baseline Factors

To evaluate whether the treatment effect is consistent across various subgroups, the estimate of the MK-4305 vs. placebo effect will be evaluated for the primary and secondary endpoints within each category of the following classification variables:

Age category (<median age vs. ≥median age in years)Sex (female, male)Race (white, non-white)Region: defined in Table 3-13 below; if additional countries are included in the studies, the definition of the region will be documented in the Clinical Study ReportHLA DQB1*0602 allele (present, absent)

Table 3-13

Regions and Countries for Subanalyses

Region CountriesAsia JapanNorth America United States

The consistency of the treatment differences will be assessed using the supportive analysis approach (i.e., the mixed model with additional terms for the classification variable and its interaction with treatment and treatment-by-time). More specifically, the treatment difference from placebo and nominal 95% confidence intervals will be calculated for each category of the classification variables listed above. This information will be reported as well as presented graphically. Formal statistical testing of any potential interactions will not be performed.

3.5.9 Interim Analyses

A siDMC will be used to evaluate interim data to make a determination regarding futility of the MK-4305 doses after 50% of patients have completed the study. If any doses are deemed futile at this interim analysis according to the strategy noted below, then future enrollment to the treatment sequences containing such dose(s) may be stopped; however, any patients who have been enrolled to such dose(s) prior to this interim analysis, but have not yet completed the study, will continue the study to scheduled completion.

3.5.9.1 Efficacy Interim Analyses

For the efficacy interim analyses, only data for patients who have had the opportunity to complete both 4-week treatment periods will be included in the evaluations. The interim analyses will include patients from the ex-Japan stratum only.




An interim analysis for futility will be conducted after 50% of patients have completed their two 4-week treatment periods. The following guidelines will be used by a standing internal data monitoring committee (siDMC), encompassing evaluation of efficacy data in conjunction with evaluation of other data (e.g., adverse event data), to determine what if any actions will be taken for the remainder of the study.

If the conditional probability of finding a significant difference from placebo for SE is <20% at either Night 1 or at the end of Week 4 for the lowest two doses, future enrollment may be stopped for the lower of the two doses. A similar analysis will be performed for each higher MK-4305 dose pair, in order of increasing doses. If the conditional probability of finding a significant difference for a dose is ≥20% at Night 1 and at the end of Week 4, then the study will continue with this dose pair and all higher doses unless the siDMC decides otherwise on the basis of safety and/or tolerability issues. Guidelines regarding the termination of a dose on the basis of safety and/or tolerability issues will be provided in the siDMC charter. An MK-4305 dose which has ≥20% conditional probability of a significant difference in SE at both Night 1 and at the end of Week 4 but has a poor profile for safety and/or tolerability as compared with placebo will not be continued. If, based upon the siDMC’s review, the lower dose of MK-4305 (5 mg) is recommended for evaluation (e.g., if none of the MK-4305 doses are futile and/or there is poor tolerability) this dose may be included for the remainder of the study. Such a decision could increase the total patients completing the study by 26 to 52, depending upon the siDMC’s recommendation. See Appendix 6.11 for additional details regarding the operating characteristics of the futility analysis.

These guidelines will inform the siDMC charter, which will further define the criteria for actions at this interim analysis.

A second interim analysis may be conducted when approximately 160 patients have completed both periods of the crossover study. This analysis will include patients in the ex-Japan stratum only. The purpose of this analysis would be to expedite planning for Phase III studies; therefore both efficacy and safety will be evaluated. The study will not be stopped for superior efficacy on the basis of this analysis; however, the method of Haybittle-Peto will be used to account for multiplicity related to this evaluation.

3.5.9.2 Safety Interim Analyses

All ex-Japan data available for the interim analyses will be utilized to evaluate safety and tolerability. Summary information (e.g., Tier 1, Tier 2 and Tier 3 AEs) will also be provided to the SiDMC for evaluation.

3.5.10 Compliance (Medication Adherence)

In this study, as part of the routine recording of the amount of study treatment taken by each patient, the number of tablets remaining in study packaging will be counted, reviewed, and recorded at regular intervals. These results will be used to calculate patient compliance.




A day within the treatment period will be considered an -Therapy day if the patient takes the appropriate number of units from each bottle.

For a patient who is followed for the entire treatment period, the r of Days Should be on Therapy s from the first day of dosing within that treatment period to the last scheduled day for treatment administration within the period for that patient. For a patient who discontinued from the treatment period, the of Days Should be on Therap is the total number of days from the first day of dosing within that period to the day of the last dose of study medication within that period.

For each patient, percent compliance will then be calculated for each treatment period using the following formula:

Therapyon beShouldDaysofNumber

Therapyon DaysofNumber CompliancePercent

x 100.

Summary statistics will be provided on percent compliance by treatment sequence for each period for the FAS population.

In addition, the Extent of Exposure to study treatment will be evaluated by summary statistics (N, mean, median, standard deviation) and frequencies (e.g., weekly or monthly interval for t e s on Therapy

3.6 PACKAGING, LABELING, STORAGE, AND RETURN OF CLINICAL SUPPLIES

3.6.1 Product Descriptions

Clinical supplies will be packaged according to a component schedule generated by the SPONSOR.

Investigational materials will be provided by the SPONSOR as summarized in Table 3-14.




Table 3-14

Product Descriptions

Product Name and Potency Dosage FormMK-4305 5 mg†

MK-4305 10 mgMK-4305 30 mg Placebo to match MK-4305 5 mg and 10 mg†

Placebo to match MK-4305 30 mg

Tablets

† mg strength may be added after the Interim Analysis for safety and efficacy (futility) is performed. If the 5 mg strength is added, the 5 mg placebo would match the 10 mg placebo and the 5 mg MK-4305 would match the 10 mg MK-4305.

3.6.2 Packaging Information

Patients will receive blinded 4 bottles at Visit 2, 3, 4, 6, and 7. Supplies will be affixed with a clinical label in accordance with regulatory requirements.

3.6.3 Clinical Supplies Disclosure

The IVRS should be used in order to unblind subjects/patients and to unmask drug identity. The SPONSOR will not provide disclosure envelope with the clinical supplies. Drug identification information is to be unmasked ONLY if necessary for the welfare of the subject/patient. Every effort should be made not to unblind the subject/patient unless necessary. Prior to unblinding, the investigator will attempt to contact the CRA. Any unblinding that occurs at the site must be documented.

3.6.4 Storage and Handling Requirements

Clinical supplies should be kept in a secured location at a controlled room temperature according to clinical label affixed to bottle, and protect from moisture.

The clinical supplies storage area at the site must be monitored by the site staff for temperature consistency with the acceptable storage temperature range as specified on the label or in the product label. Documentation of temperature monitoring should be maintained.

3.6.5 Standard Policies / Return of Clinical Supplies

Investigational clinical supplies must be received by a designated person at the study site, handled and stored safely and properly, and kept in a secured location to which only the investigator and designated assistants have access. Clinical supplies are to be dispensed only in accordance with the protocol. The investigator is responsible for keeping accurate records of the clinical supplies received from the SPONSOR, the amount dispensed to and returned by the subjects/patients, and the amount remaining at the conclusion of the study. In accordance with Good Pharmacy Practices, gloves should always be worn by




study personnel if directly handling tablets or capsules that are returned (i.e., when counting returns). The CRA should be contacted with any questions concerning investigational products where special or protective handling is indicated. At the end of the study, all clinical supplies including partial and empty containers must be returned as indicated on the Contact Information page(s).

U.S. sites should follow instructions for the Clinical Supplies Return Form (R464) and contact your SPONSOR representative for review of shipment and form before shipping.

For sites outside of the United States, the local country Merck personnel will provide appropriate documentation that needs to be completed for drug accountability.

The investigator or designated assistant should not open individual clinical supplycontainers and count tablets/capsules, etc., before dispensing to the subjects/patients. Any deviation from this must be discussed with the CRA.

Study personnel will have access to an Interactive Voice Response System (IVRS) to allocate patients, to assign drug to subjects/patients and to manage the distribution of clinical supplies. Each person accessing the IVRS system must be assigned an individual unique PIN. They must use only their assigned PIN to access the system and they must not share their assigned PIN with anyone.

3.7 DATA MANAGEMENT

Information regarding Data Management procedures for this protocol will be provided by the SPONSOR.

3.8 BIOLOGICAL SPECIMENS

Information regarding biological specimens for this protocol will be provided by the SPONSOR.



4305_006-02_ProtA&R VERSION 2.0 APPROVED 03-Apr-2009Worldwide Restricted Confidential – Limited Access

4. ADMINISTRATIVE AND REGULATORY DETAILS

4.1 CONFIDENTIALITY

4.1.1 Confidentiality of Data

For Studies Conducted Under the U.S. INDParticular attention is drawn to the regulations promulgated by the Food and Drug Administration under the Freedom of Information Act providing, in part, that information furnished to clinical investigators and Institutional Review Boards will be kept confidential by the Food and Drug Administration only if maintained in confidence by the clinical investigator and Institutional Review Board.

For All StudiesBy signing this protocol, the investigator affirms to the SPONSOR that information furnished to the investigator by the SPONSOR will be maintained in confidence and such information will be divulged to the Institutional Review Board, Ethics Review Committee, or similar or expert committee; affiliated institution; and employees only under an appropriate understanding of confidentiality with such board or committee, affiliated institution and employees. Data generated by this study will be considered confidential by the investigator, except to the extent that it is included in a publication as provided in the Publications section of this protocol.

4.1.2 Confidentiality of Subject/Patient Records

For All StudiesBy signing this protocol, the investigator agrees that the SPONSOR (or SPONSOR representative), Institutional Review Board/Independent Ethics Committee (IRB/IEC), or Regulatory Agency representatives may consult and/or copy study documents in order to verify worksheet/case report form data. By signing the consent form, the subject/patient agrees to this process. If study documents will be photocopied during the process of verifying worksheet/case report form information, the subject/patient will be identified by unique code only; full names/initials will be masked prior to transmission to the SPONSOR.

For Studies Conducted Under the U.S. INDBy signing this protocol, the investigator agrees to treat all patient data used and disclosed in connection with this study in accordance with all applicable privacy laws, rules and regulations, including all applicable provisions of the Health Insurance Portability and Accountability Act and its implementing regulations, as amended from

4.1.3 Confidentiality of Investigator Information

For All StudiesBy signing this protocol, the investigator recognizes that certain personal identifying information with respect to the investigator, and all subinvestigators and study site




personnel, may be used and disclosed for study management purposes, as part of a regulatory submissions, and as required by law. This information may include:

name, address, telephone number, and email address;

hospital or clinic address and telephone number;

curriculum vitae or other summary of qualifications and credentials; and

other professional documentation.

Consistent with the purposes described above, this information may be transmitted to the SPONSOR, and subsidiaries, affiliates and agents of the SPONSOR, in your country and other countries, including countries that do not have laws protecting such information. Additionally, the investigator’s name and business contact information may be included when reporting certain serious adverse events to regulatory agencies or to other investigators. By signing this protocol, the investigator expressly consents to these uses and disclosures.

For Multicenter StudiesIn order to facilitate contact between investigators, the SPONSOR may share an investigator’s name and contact information with other participating investigators upon request.

4.2 COMPLIANCE WITH LAW, AUDIT, AND DEBARMENT

By signing this protocol, the investigator agrees to conduct the study in an efficient and diligent manner and in conformance with this protocol; generally accepted standards of Good Clinical Practice; and all applicable federal, state, and local laws, rules and regulations relating to the conduct of the clinical study.

The Code of Conduct, a collection of goals and considerations that govern the ethical and scientific conduct of clinical investigations sponsored by Merck & Co., Inc., is attached.

The investigator also agrees to allow monitoring, audits, Institutional Review Board/Independent Ethics Committee review, and regulatory agency inspection of trial-related documents and procedures and provide for direct access to all study-related source data and documents.

The investigator agrees not to seek reimbursement from subjects/patients, their insurance providers, or from government programs for procedures included as part of the study reimbursed to the investigator by the SPONSOR.

The Investigator shall prepare and maintain complete and accurate study documentation in compliance with Good Clinical Practice standards and applicable federal, state, and local laws, rules and regulations; and, for each subject/patient participating in the study, provide all data, and upon completion or termination of the clinical study submit any




other reports to the SPONSOR as required by this protocol or as otherwise required pursuant to any agreement with the SPONSOR.

Study documentation will be promptly and fully disclosed to the SPONSOR by the investigator upon request and also shall be made available at the investigator’s site upon request for inspection, copying, review, and audit at reasonable times by representatives of the SPONSOR or any regulatory agencies. The investigator agrees to promptly take any reasonable steps that are requested by the SPONSOR as a result of an audit to cure deficiencies in the study documentation and worksheets/case report forms.

International Conference of Harmonization Good Clinical Practice guidelines (Section 4.3.3) recommend that the investigator inform the subject’s primary physician about the subject’s participation in the trial if the subject has a primary physician and if the subject agrees to the primary physician being informed.

According to European legislation, a SPONSOR must designate a principal or coordinating investigator (CI) to review the report (summarizing the study results) and confirm that to the best of his/her knowledge the report accurately describes conduct and results of the study. The SPONSOR may consider one or more factors in the selection of the individual to serve as the CI (e.g., thorough understanding of clinical trial methods, appropriate enrollment of subject/patient cohort, timely achievement of study milestones, availability of the CI during the anticipated review process).

The investigator will promptly inform the SPONSOR of any regulatory agency inspection conducted for this study.

Persons debarred from conducting or working on clinical studies by any court or regulatory agency will not be allowed to conduct or work on this SPONSOR’s studies. The investigator will immediately disclose in writing to the SPONSOR if any person who is involved in conducting the study is debarred, or if any proceeding for debarment is pending or, to the best of the investigator’s knowledge, threatened.

In the event the SPONSOR prematurely terminates a particular trial site, the SPONSOR will promptly notify that site’s IRB/IEC.

4.3 COMPLIANCE WITH FINANCIAL DISCLOSURE REQUIREMENTS

By signing this protocol, the investigator agrees to provide to the SPONSOR accurate financial information to allow the SPONSOR to submit complete and accurate certification and disclosure statements as required by U.S. Food and Drug Administration regulations (21 CFR Part 54). The investigator further agrees to provide this information on a Financial Disclosure/Certification Form that is provided by Merck & Co., Inc. This requirement also extends to subinvestigators. The investigator also consents to the transmission of this information to Merck & Co., Inc. in the United States for these purposes. This may involve the transmission of information to countries that do not have laws protecting personal data.




4.4 QUALITY CONTROL AND QUALITY ASSURANCE

By signing this protocol, the SPONSOR agrees to be responsible for implementing and maintaining quality control and quality assurance systems with written SOPs to ensure that trials are conducted and data are generated, documented, and reported in compliance with the protocol, accepted standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and regulations relating to the conduct of the clinical study.

4.5 COMPLIANCE WITH INFORMATION PROGRAM ON CLINICALTRIALS FOR SERIOUS OR LIFE THREATENING CONDITIONS

Under the terms of The Food and Drug Administration Modernization Act (FDAMA), the SPONSOR of the study is solely responsible for determining whether the study is subject to the requirements for submission to the Clinical Trials Data Bank, http://clinicaltrials.gov/. Merck, as SPONSOR of this study, will review this protocol and submit the information necessary to fulfill this requirement. Merck entries are not limited to FDAMA mandated trials. Merck’s voluntary listings, beyond those mandated by FDAMA, will be in the same format as for treatments for serious or life-threatening illnesses. Information posted will allow patients to identify potentially appropriate trials for their disease conditions and pursue participation by calling a central contact number for further information on appropriate study locations and site contact information.

By signing this protocol, the investigator acknowledges that the statutory obligation under FDAMA is that of the SPONSOR and agrees not to submit any information about this study to the Clinical Trials Data Bank.

4.6 PUBLICATIONS

As this study is part of a multicenter trial, publications derived from this study should include input from the investigator(s) and SPONSOR personnel. Such input should be reflected in publication authorship, and whenever possible, preliminary agreement regarding the strategy for order of authors’ names should be established before conducting the study. Subsequent to the multicenter publication, or 24 months after completion of the study, whichever comes first, an investigator and/or his/her colleagues may publish the results for their study site independently. However, the SPONSOR does not recommend separate publication of individual study site results due to scientific concerns.

The SPONSOR must have the opportunity to review all proposed abstracts, manuscripts, or presentations regarding this study 60 days prior to submission for publication/presentation. Any information identified by the SPONSOR as confidential must be deleted prior to submission. SPONSOR review can be expedited to meet publication guidelines.



4305_006-02_ProtApp VERSION 2.1 APPROVED 03-Apr-2009Worldwide Restricted Confidential – Limited Access

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appendix e-1: study protocol - neurology · 11/29/2012 · section 3.2.1 and table 3-1: clarified...

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