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numbered

Division: Worldwide Development

Information Type: Clinical Study Report

Control:

No active control placebo

Title: 201135: A randomised, double-blind, multicenter, parallel-group study to compare the efficacy and safety of fluticasone furoate (FF) 100mcg once daily with fluticasone propionate (FP) 250μg twice daily and FP 100μg twice daily in well-controlled asthmatic subjects stepped down from a maintenance therapy with Relvar®100 Ellipta® (FF/VI) 100μg once-daily in Japanese subjects.

Additional Study Design Information:

Double-Blind Treatment Period：12 weeks

Phase: III

Compound Number: GW685698

Effective Date: 7-Dec-2016

Subject: Asthma, adults, Relvar® Ellipta®, fluticasone furoate, fluticasone propionate, patients with well-controlled asthma, step-down prescription, switching prescription

Author(s):

Indication Studied: Bronchial Asthma

Initiation Date: 27-Mar-2014

Completion Date: 28-Aug-2015

Earlier CSRs:

201135: A randomised, double-blind, multicenter, parallel-group study to compare the efficacy and safety of fluticasone furoate (FF) 100mcg once daily with fluticasone propionate (FP) 250μg twice daily and FP 100μg twice daily in well-controlled asthmatic subjects stepped down from a maintenance therapy with Relvar®100 Ellipta® (FF/VI) 100μg once-daily in Japanese subjects.(Document No.: 2015N239011_00, Date of Report: Feb 2016)

Clinical Study Report Revision History:

Original: 2015N239011_00 (Effectvie Date: 05-Feb-2016)

Amendment 01: 2015N239011_01 (Effectvie Date: 7-Dec-2016)

After the approval of the original CSR, it was found that “asthma worsening/exercabation” for evaluating co-primary endpoints of proportion of subjects “well controlled” at the end of Period 2 and time to withdrawal due to “poorly-controlled (requires step-up)” during Period 2 was evaluated using only “severe asthma”, although “asthma worsening/exercabation” had to be evaluated using “severe asthma” and “worsening asthma.” Therefore, co-primary endpoints as well as two ‘other’ endpoints (proportion of subjects “well controlled” at the end of Period 1and time to withdrawal due to “ poorly-controlled (requires step-up)” during Period 1) were re-analyzed using “severe asthma” and

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“worsening asthma” for evaluating “asthma worsening/exercabation”, and the CSR was amended to reflect the results of re-analysis.

Sponsor’s Medical Expert(s):GlaxoSmithKline K.K.Head, Medicines Development

Sponsor Signatory: Kihito TakahashiGlaxoSmithKline K.K.Head, Japan Development & Medical Affairs

This clinical trial was executed in compliance with the Good Clinical Practice (GCP) of

pharmaceutical product research and Standard Operating Procedures (SOP) of GlaxoSmithKline K.K.

All documents and materials concerning the clinical trial have been stored according to methods

described in the Study Protocol.

Copyright 2016 the GlaxoSmithKline group of companies. All rights reserved.

Unauthorised copying or use of this information is prohibited.

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Table of Contents Page TITLE PAGE .......................................................................................................... LIST OF DEFINITIONS FOR ABBREVIATIONS AND TERMS ............................. ETHICS AND GCP ................................................................................................. 1. Introduction ....................................................................................................... 2. Study Objectives .............................................................................................. 3. Investigators and Clinical Trial Management .................................................

3.1. Sponsor and Representatives ......................................................................... 3.2. Study Center and the Investigators.................................................................. 3.3. Testing Facility ................................................................................................. 3.4. Study Period ....................................................................................................

4. Study Plan ......................................................................................................... 4.1. Study Design ................................................................................................... 4.2. Consideration for the Study Design ................................................................. 4.3. Revision of the Study Protocol ......................................................................... 4.4. Selection of The Analysis Set ..........................................................................

4.4.1. Inclusion/Exclusion Criteria ......................................................................... 4.4.2. Withdrawal Criteria ......................................................................................

4.5. Treatment ........................................................................................................ 4.5.1. Investigational Product and related Treatments .......................................... 4.5.2. Allocation to Treatment Groups ................................................................... 4.5.3. Blinding ........................................................................................................ 4.5.4. Pre-treatment drugs, concomitant drugs and non-drug therapies ............... 4.5.5. Compliance with Treatments .......................................................................

4.6. Study Evaluations and Procedures .................................................................. 4.6.1. Efficacy Endpoints ....................................................................................... 4.6.2. Safety Evaluations ....................................................................................... 4.6.3. Health Outcomes ......................................................................................... 4.6.4. Pharmacokinetics ........................................................................................ 4.6.5. Pharmacogenetics Research ......................................................................

4.7. Quality Assurance of Data ............................................................................... 4.7.1. Data Management ....................................................................................... 4.7.2. Quality Control ............................................................................................. 4.7.3. Quality Assurance .......................................................................................

4.8. Data Analysis Method ...................................................................................... 4.8.1. Hypotheses ................................................................................................. 4.8.2. Determination of the Sample Size ............................................................... 4.8.3. Analysis Population ..................................................................................... 4.8.4. Interim Analysis ........................................................................................... 4.8.5. Final Analysis .............................................................................................. 4.8.6. Changes to the Analysis of Study Implementation or the Analysis

Protocol .................................................................................................. 5. Analysis Results of Analysis Populations .....................................................

5.1. Breakdown of Subjects ....................................................................................

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5.2. Deviations from the Study Protocol .................................................................. 5.3. Analysis Population ......................................................................................... 5.4. Demographic and Other Baseline Characteristics ........................................... 5.5. Pre-Treatment and Concomitant Therapy ....................................................... 5.6. Exposure and Compliance with Treatment ......................................................

6. Efficacy Results ................................................................................................ 6.1. Primary Endpoints ...........................................................................................

6.1.1. Time to withdrawal due to “poorly-controlled (requires step-up)” (Period 2) ............................................................................................................

6.1.2. Proportion of Subjects with “Well-controlled Asthma” (Period 2) ................. 6.2. Secondary Endpoints .......................................................................................

6.2.1. FEV1 Trough value (Period 2) ..................................................................... 6.2.2. Daily AM and PM PEF (Period 2) ................................................................ 6.2.3. Percentage of Symptom-free 24-Hour Periods (Period 2) ........................... 6.2.4. Percentage of Rescue-free 24-Hour Periods (Period 2) .............................. 6.2.5. ACT Score (Period 2) .................................................................................. 6.2.6. Proportion of Subjects with ACT Score ≥ 20 (Period 2) ...............................

6.3. Others .............................................................................................................. 6.3.1. Proportion of Subjects with “Well-controlled Asthma” (Period 1) ................. 6.3.2. Time to Withdrawal due to “Poorly-controlled (Requires Step-up)”

(Period 1) ................................................................................................ 6.3.3. FEV1 Trough Value (Period 1) .................................................................... 6.3.4. Daily AM and PM PEF (Period 1) ................................................................ 6.3.5. Percentage of Symptom-free 24-Hour Periods (Period 1) ........................... 6.3.6. Percentage of Rescue-free 24-Hour Periods (Period 1) .............................. 6.3.7. ACT Score (Period 1) .................................................................................. 6.3.8. Proportion of Subjects with ACT Score ≥20 (Period 1) ................................ 6.3.9. Unscheduled Healthcare Visits or Utilization Due to Severe Asthma

Exacerbations or Other Treatment for Asthma (Period 1 and Period 2) . 7. Safety Results ...................................................................................................

7.1. Period 2 ........................................................................................................... 7.1.1. Adverse Events ........................................................................................... 7.1.2. Serious Adverse Events and Other Important Adverse Events ................... 7.1.3. Evaluation of Clinical Laboratory Values ..................................................... 7.1.4. Other Safety Evaluations .............................................................................

7.2. Period 1 ........................................................................................................... 7.2.1. Adverse Events ........................................................................................... 7.2.2. Serious Adverse Events and Other Important Adverse Events ................... 7.2.3. Evaluation of Clinical Laboratory Values ..................................................... 7.2.4. Other Safety Evaluations .............................................................................

7.3. Accidents and Failures of Medical Equipment and Improvement Measures .... 7.4. Pregnancy .......................................................................................................

8. Pharmacokinetics ............................................................................................. 9. Discussion and Conclusion .............................................................................

9.1. Discussion ....................................................................................................... 9.2 Conclusion (in CSR body) ................................................................................

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10. References ...................................................................................................... 11. Description of Cases ...................................................................................... STUDY POPULATION DATA SOURCE TABLES ................................................

Table 5.010 Summary of Subject Populations during Period 1 (All Subjects Enrolled Population).................................................................................

Table 5.020 Summary of Subject Populations during Period 2 (ITT Population) .... Table 5.030 Summary of Reasons for Failure at Visit 1 (All Subjects Enrolled

Population) ............................................................................................... Table 5.040 Summary of Reasons for Failure at Visit 2 (All Subjects Enrolled

Population) ............................................................................................... Table 5.050 Summary of Reasons for Failure at Visit 5 (Open Label Population) .. Table 5.060 Summary of Subject Disposition during Period 1 (Open Label

Population) ............................................................................................... Table 5.070 Summary of Subject Disposition during Period 2 (ITT Population) ..... Table 5.080 Summary of Attendance at Each Clinic Visit during Period 1 (Open

Label Population) ..................................................................................... Table 5.090 Summary of Attendance at Each Clinic Visit during Period 2 (ITT

Population) ............................................................................................... Table 5.100 Summary of Inclusion/Exclusion Criteria Deviations at Visit 1 (All

Subjects Enrolled Population) .................................................................. Table 5.101 Summary of Inclusion/Exclusion Criteria Deviations at Visit 2 (All

Subjects Enrolled Population) .................................................................. Table 5.110 Summary of Randomisation Criteria Deviations at Visit 5 (Open

Label Population) ..................................................................................... Table 5.120 Summary of Protocol Deviations during Period 1 (Open Label

Population) ............................................................................................... Table 5.130 Summary of Protocol Deviations during Period 2 (ITT Population) ..... Table 5.140 Summary of Demographic Characteristics Open Label Population

(Open Label Population) .......................................................................... Table 5.150 Summary of Demographic Characteristics Intent-to-Treat Population

(ITT Population) ....................................................................................... Table 5.160 Summary of Demographic Characteristics Per Protocol Population

(Per Protocol Population) ......................................................................... Table 5.170 Summary of Race and Racial Combination Details for Period 1

(Open Label Population) .......................................................................... Table 5.180 Summary of Race and Racial Combination Details for Period 2 (ITT

Population) ............................................................................................... Table 5.190 Summary of Current Medical Conditions for Period 1 (Open Label

Population) ............................................................................................... Table 5.200 Summary of Current Medical Conditions for Period 2 (ITT Population)

................................................................................................................. Table 5.210 Summary of Past Medical Conditions for Period 1 (Open Label

Population) ............................................................................................... Table 5.220 Summary of Past Medical Conditions for Period 2 (ITT Population) ... Table 5.230 Summary of Asthma Concomitant Medications Taken Pre-Treatment

during Period 1 (Open Label Population) .................................................

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Table 5.240 Summary of Asthma Concomitant Medications Taken On-Treatment during Period 1 (Open Label Population) .................................................

Table 5.250 Summary of Asthma Concomitant Medications Taken Post-Treatment during Period 1 (Open Label Population) ...............................

Table 5.260 Summary of Asthma Concomitant Medications Taken Pre-Treatment during Period 2 (ITT Population) ..............................................................

Table 5.270 Summary of Asthma Concomitant Medications Taken On-Treatment during Period 2 (ITT Population) ..............................................................

Table 5.280 Summary of Asthma Concomitant Medications Taken Post-Treatment during Period 2 (ITT Population) .............................................

Table 5.290 Summary of Non-Asthma Concomitant Medications Taken Pre-Treatment during Period 1 (Open Label Population) ...............................

Table 5.300 Summary of Non-Asthma Concomitant Medications Taken On-Treatment during Period 1 (Open Label Population) ...............................

Table 5.310 Summary of Non-Asthma Concomitant Medications Taken Post-Treatment during Period 1 (Open Label Population) ...............................

Table 5.320 Summary of Non-Asthma Concomitant Medications Taken Pre-Treatment during Period 2 (ITT Population) .............................................

Table 5.330 Summary of Non-Asthma Concomitant Medications Taken On-Treatment during Period 2 (ITT Population) .............................................

Table 5.340 Summary of Non-Asthma Concomitant Medications Taken Post-Treatment during Period 2 (ITT Population) .............................................

Table 5.350 Summary of Screening and Baseline Lung Function Test Results during Period 1 (Open Label Population) .................................................

Table 5.360 Summary of Screening and Baseline Lung Function Test Results during Period 2 (ITT Population) ..............................................................

Table 5.370 Summary of Exposure during Period 1 (Open Label Population) ....... Table 5.380 Summary of Exposure during Period 2 (ITT Population) .................... Table 5.390 Summary of Overall Treatment Compliance (%) during Period 1

(Open Label Population) .......................................................................... Table 5.400 Summary of Overall Treatment Compliance (%) during Period 2 (ITT

Population) ............................................................................................... EFFICACY DATA SOURCE FIGURES..................................................................

Figure 6.010 Cox Proportional Hazards Model Cumulative Incidence Curve for Time to Withdrawal Due to Poorly-Controlled during Period 2 (ITT Population) ...............................................................................................

Figure 6.020 Kaplan-Meier Cumulative Incidence Curve for Time to Withdrawal Due to Poorly-Controlled during Period 2 (ITT Population) .....................

Figure 6.030 Line Plot of % Subjects Well-Controlled during Period 1 and Period 2 (ITT Population) ....................................................................................

Figure 6.040 Line Plot of % Subjects Well-Controlled during Period 1 (Open Label Population) ...............................................................................................

Figure 6.050 Line Plot of Mean Change from Baseline in FEV1 (L) during Period 1 (Open Label Population) .......................................................................

Figure 6.060 Line Plot of Mean Change from Baseline in ACT Score during Period 1 (Open Label Population) ............................................................

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Figure 6.070 Line Plot of Mean Change from Baseline in AM PEF (L/min) during Period 1 (Open Label Population) ............................................................

Figure 6.080 Line Plot of Mean Change from Baseline in PM PEF (L/min) during Period 1 (Open Label Population) ............................................................

Figure 6.090 Line Plot of Daily AM PEF Averaged (L/min) during Period 1 (Open Label Population) .....................................................................................

Figure 6.100 Line Plot of Daily PM PEF Averaged (L/min) during Period 1 (Open Label Population) .....................................................................................

Figure 6.110 Line Plot of the Percentage of Symptom-free 24-hour during Period 1 (Open Label Population) .......................................................................

Figure 6.120 Line Plot of the Percentage of Rescue-free 24-hour during Period 1 (Open Label Population) ..........................................................................

Figure 6.130 Line Plot of Asthma Control Test (ACT) Score during Period 1 (Open Label Population) ..........................................................................

Figure 6.140 Line Plot of Trough (pre-dose of Sultanol Inhaler and investigational product) FEV1 (L) during Period 1 (Open Label Population) ...................

Figure 6.150 Line Plot of Mean Change from Baseline in FEV1 (L) during Period 2 (ITT Population) ....................................................................................

Figure 6.160 Line Plot of Mean Change from Baseline in ACT Score during Period 2 (ITT Population) .........................................................................

Figure 6.170 Line Plot of Mean Change from Baseline in AM PEF (L/min) during Period 2 (ITT Population) .........................................................................

Figure 6.180 Line Plot of Mean Change from Baseline in PM PEF (L/min) during Period 2 (ITT Population) .........................................................................

Figure 6.190 Line Plot of Daily AM PEF Averaged (L/min) during Period 2 (ITT Population) ...............................................................................................

Figure 6.200 Line Plot of Daily PM PEF Averaged (L/min) during Period 2 (ITT Population) ...............................................................................................

Figure 6.210 Line Plot of the Percentage of Symptom-free 24-hour during Period 2 (ITT Population) ....................................................................................

Figure 6.220 Line Plot of the Percentage of Rescue-free 24-hour during Period 2 (ITT Population) .......................................................................................

Figure 6.230 Line Plot of Asthma Control Test (ACT) Score during Period 2 (ITT Population) ...............................................................................................

Figure 6.240 Line Plot of Trough (pre-dose of Sultanol Inhaler and investigational product) FEV1 (L) during Period 2 (ITT Population) ................................

Figure 6.250 Box Plot of Mean Change from Baseline in Daily AM PEF Averaged (L/min) during Period 2 (ITT Population) .................................................

Figure 6.260 Box Plot of Mean Change from Baseline in Daily PM PEF Averaged (L/min) during Period 2 (ITT Population) .................................................

Figure 6.270 Box Plot of Mean Change from Baseline in the Percentage of Symptom-free 24-hour Periods during Period 2 (ITT Population) ............

Figure 6.280 Box Plot of Mean Change from Baseline in the Percentage of Rescue-free 24-hour Periods during Period 2 (ITT Population) ...............

Figure 6.290 Box Plot of Mean Change from Baseline in Asthma Control Test (ACT) Score during Period 2 (ITT Population) .........................................

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Figure 6.300 Box Plot of Mean Change from Baseline in Clinic Visit Trough (pre-dose of Sultanol Inhaler and investigational product) FEV1 (L) at Visit 11 (ITT Population) .......................................................................................

Figure 6.310 Forest Plot for LS Mean from Change from Baseline of FEV1 (L) at End of Period 2 (Intent-to-treat Population) .............................................

Figure 6.320 Forest Plot for LS Mean from Change from Baseline of Asthma Control Test (ACT) Score at End of Period 2 (Intent-to-treat Population)

Figure 6.330 Forest Plot for LS Mean from Change from Baseline of Symptom-Free 24-Hour Periods (%) and Rescue-Free 24-Hour Periods (%) at Weeks 9-20 (Intent-to-treat Population) ...................................................

Figure 6.340 Forest Plot for LS Mean from Change from Baseline of AM PEF (L/min) and PM PEF (L/min) at Weeks 9-20 (Intent-to-treat Population) ..

Figure 6.350 Cox Proportional Hazards Model Cumulative Incidence Curve for Time to Withdrawal Due to Poorly-Controlled during Period 2 including Asthma Aggravated subjects into the assessment (ITT Population) ........

Figure 6.360 Kaplan-Meier Cumulative Incidence Curve for Time to Withdrawal Due to Poorly-Controlled during Period 2 including Asthma Aggravated subjects into the assessment (ITT Population) ........................................

Figure 6.370 Line Plot of % Subjects Well-Controlled during Period 1 and Period 2 including Asthma Aggravated into the assessment (ITT Population) ...

Figure 6.380 Line Plot of % Subjects Well-Controlled during Period 1 including Asthma Aggravated into the assessment (Open Label Population) .........

EFFICACY DATA SOURCE TABLES ................................................................... Table 6.010 Cox Proportional Hazards Analysis of Time to Withdrawal Due to

Poorly-Controlled during Period 2, Intent-to Treat (ITT Population) ......... Table 6.020 Cox Proportional Hazards Analysis of Time to Withdrawal Due to

Poorly-Controlled during Period 2, Per Protocol (Per Protocol Population) ...............................................................................................

Table 6.030 Logistic Regression Analysis of Proportion of Subjects who Achieved Well-Controlled at Visit11, Intent-to Treat (ITT Population) ......................

Table 6.040 Logistic Regression Analysis of Proportion of Subjects who Achieved Well-Controlled at Visit 11, Per Protocol (Per Protocol Population) .........

Table 6.050 Analysis of Mean Change from Baseline in Clinic Visit Trough (pre-dose of Sultanol Inhaler and investigational product) FEV1 (L) at the end of Period 2 (ITT Population) .....................................................................

Table 6.060 Summary of FEV1 (L) by Visit during Period 2 (ITT Population) ......... Table 6.070 Summary of Mean Change from Baseline in Clinic Visit Trough (pre-

dose of Sultanol Inhaler and investigational product) FEV1 (L) by Visit during Period 2 (ITT Population) ..............................................................

Table 6.080 Analysis of Mean Change from Baseline in Daily AM PEF Averaged (L/min) during Period 2 (ITT Population) ..................................................

Table 6.090 Analysis of Mean Change from Baseline in Daily PM PEF Averaged (L/min) during Period 2 (ITT Population) ..................................................

Table 6.100 Summary of Daily AM PEF Averaged (L/min) during Period 2 (ITT Population) ...............................................................................................

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Table 6.120 Summary of Daily PM PEF Averaged (L/min) during Period 2 (ITT Population) ...............................................................................................

Table 6.130 Summary of Mean Change from Baseline in Daily AM PEF Averaged (L/min) by Assessment Period during Period 2 (ITT Population) .............

Table 6.140 Summary of Mean Change from Baseline in Daily PM PEF Averaged (L/min) by Assessment Period during Period 2 (ITT Population) .............

Table 6.150 Analysis of Mean Change from Baseline in the Percentage of Symptom-free 24-hour Periods during Period 2 (ITT Population) ............

Table 6.160 Summary of Symptom-free 24-hour Periods (%) by Assessment Period during Period 2 (ITT Population) ...................................................

Table 6.170 Summary of Mean Change from Baseline in the Percentage of Symptom-free 24-hour Periods by Assessment Period during Period 2 (ITT Population) .......................................................................................

Table 6.180 Analysis of Mean Change from Baseline in the Percentage of Rescue-free 24-hour Periods during Period 2 (ITT Population) ...............

Table 6.190 Summary of Rescue-free 24-hour Periods (%) by Assessment Period during Period 2 (ITT Population) ..............................................................

Table 6.200 Summary of Mean Change from Baseline in the Percentage of Rescue-free 24-hour Periods by Assessment Period during Period 2 (ITT Population) .......................................................................................

Table 6.210 Analysis of Mean Change from Baseline in Asthma Control Test (ACT) Score at the end of Period 2 (ITT Population) ...............................

Table 6.220 Summary of Asthma Control Test (ACT) Score by Visit during Period 2 (ITT Population) ....................................................................................

Table 6.230 Summary of Mean Change from Baseline in Asthma Control Test (ACT) Score by Visit during Period 2 (ITT Population) .............................

Table 6.240 Logistic Regression Analysis of ACT Score >= 20 at Visit11 (ITT Population) ...............................................................................................

Table 6.250 Summary of Categorization of ACT Score by Visit during Period 2 (ITT Population) .......................................................................................

Table 6.260 Summary of Proportion of Subjects Well-Controlled at the end of Period 1 (Open Label Population) ............................................................

Table 6.270 Summary of Time to Withdrawal Due to Poorly-Controlled during Period 1 (Open Label Population) ............................................................

Table 6.280 Summary of Mean Change from Baseline in Clinic Visit Trough (pre-dose of Sultanol Inhaler and investigational product) FEV1 (L) by Visit during Period 1 (Open Label Population) .................................................

Table 6.290 Summary of Mean Change from Baseline in Daily AM PEF Averaged (L/min) during Period 1 (Open Label Population) .....................................

Table 6.300 Summary of Mean Change from Baseline in Daily PM PEF Averaged (L/min) during Period 1 (Open Label Population) ....................

Table 6.310 Summary of Mean Change from Baseline in the Percentage of Symptom-free 24-hour Periods during Period 1 (Open Label Population)

Table 6.320 Summary of Mean Change from Baseline in the Percentage of Rescue-free 24-hour Periods during Period 1 (Open Label Population) ..

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Table 6.330 Summary of Mean Change from Baseline in Asthma Control Test (ACT) Score by Visit during Period 1 (Open Label Population) ...............

Table 6.340 Summary of Asthma Control Test (ACT) Score by Visit during Period 1 (Open Label Population) .......................................................................

Table 6.350 Summary of Categorization of ACT Score by Visit during Period 1 (Open Label Population) ..........................................................................

Table 6.360 Unscheduled Visits or Utilization of a Physician's Office associated with Severe Asthma Exacerbations or Other Asthma-Related Healthcare during Period 1 and Period 2 (Open Label Population) ............................

Table 6.370 Summary of Subjects Who Withdraw Due to Poorly-Controlled during Period 1 (Open Label Population) ............................................................

Table 6.380 Summary of Subjects Who Withdraw Due to Poorly-Controlled during Period 2 (ITT Population) .........................................................................

Table 6.390 Logistic Regression Analysis of Proportion of Subjects who Achieved Well-Controlled at Visit11, excluding Unevaluable data Intent-to Treat (Intent-to-treat Population) .......................................................................

Table 6.400 Cox Proportional Hazards Analysis of Time to Withdrawal Due to Poorly-Controlled during Period 2 including Asthma Aggravated Subjects into the assessment, Intent-to Treat (ITT Population) ...............

Table 6.410 Cox Proportional Hazards Analysis of Time to Withdrawal Due to Poorly-Controlled during Period 2 including Asthma Aggravated Subjects into the assessment, Per Protocol (Per Protocol Population) ....

Table 6.420 Logistic Regression Analysis of Proportion of Subjects who Achieved Well-Controlled at Visit11 including Asthma Aggravated into the assessment, Intent-to Treat (ITT Population) ...........................................

Table 6.430 Logistic Regression Analysis of Proportion of Subjects who Achieved Well-Controlled at Visit 11 including Asthma Aggravated into the assessment, Per Protocol (Per Protocol Population) ...............................

Table 6.440 Summary of Proportion of Subjects Well-Controlled at the end of Period 1 including Asthma Aggravated into the assessment (Open Label Population) ...............................................................................................

Table 6.450 Summary of Time to Withdrawal Due to Poorly-Controlled during Period 1 including Asthma Aggravated Subjects into the assessment (Open Label Population) ..........................................................................

Table 6.460 Summary of Subjects Who Withdraw Due to Poorly-Controlled during Period 1 including Asthma Aggravated into the assessment (Open Label Population) ...............................................................................................

Table 6.470 Summary of Subjects Who Withdraw Due to Poorly-Controlled during Period 2 including Asthma Aggravated into the assessment (ITT Population) ...............................................................................................

Table 6.480 Logistic Regression Analysis of Proportion of Subjects who Achieved Well-Controlled at Visit11 including Asthma Aggravated into the assessment, excluding Unevaluable data Intent-to Treat (ITT Population) ...............................................................................................

SAFETY DATA SOURCE FIGURES .....................................................................

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Figure 7.010 Most Frequent On-Treatment Adverse Events Sorted by Relative Risk for Period 2 (>=3% in any treatment group) for FF 100 vs. FP 100 BD (ITT Population) .................................................................................

Figure 7.011 Most Frequent On-Treatment Adverse Events Sorted by Relative Risk for Period 2 (>=3% in any treatment group) for FF 100 vs. FP 250 BD (ITT Population) .................................................................................

SAFETY DATA SOURCE TABLES ....................................................................... Table 7.010 On Treatment Adverse Event Overview during Period 1 (Open Label

Population) ............................................................................................... Table 7.020 On and Post Treatment Adverse Event Overview during Period 2

(ITT Population) ....................................................................................... Table 7.030 Summary of On-Treatment Adverse Events during Period 1 (Open

Label Population) ..................................................................................... Table 7.040 Summary of On-Treatment Adverse Events during Period 2 (ITT

Population) ............................................................................................... Table 7.050 Summary of On-Treatment Adverse Events during Period 1 for

randomized treatment groups (ITT Population) ....................................... Table 7.060 Summary of Post-Treatment Adverse Events during Period 1 (Open

Label Population) ..................................................................................... Table 7.070 Summary of Post-Treatment Adverse Events during Period 2 (ITT

Population) ............................................................................................... Table 7.080 Summary of On and Post-Treatment Adverse Events during Period 2

(ITT Population) ....................................................................................... Table 7.090 Summary of 10 Most Frequent On-Treatment Adverse Events during

Period 1 (Open Label Population) ............................................................ Table 7.100 Summary of 10 Most Frequent On-Treatment Adverse Events during

Period 2 (ITT Population) ......................................................................... Table 7.110 Summary of On-Treatment Common Adverse Events during Period 1

(>=3% in any treatment group) (Open Label Population)......................... Table 7.120 Summary of On-Treatment Common Adverse Events during Period 2

(>=3% in any treatment group) (ITT Population) ...................................... Table 7.130 Summary of On and Post-Treatment Common Adverse Events

during Period 2 (>=3% in any treatment group) (ITT Population) ............ Table 7.140 Summary of On-Treatment Adverse Events (Non-SAE>=5%) during

Period 1 and Period 2(for FDAAA) (Open Label Population) ................... Table 7.150 Summary of On-Treatment Adverse Events during Period 1 by

maximum severity (Open Label Population) ............................................ Table 7.160 Summary of Post-Treatment Adverse Events during Period 1 by

maximum severity (Open Label Population) ............................................ Table 7.170 Summary of On-Treatment Adverse Events during Period 2 by

maximum severity (ITT Population) ......................................................... Table 7.180 Summary of Post-Treatment Adverse Events during Period 2 by

maximum severity (ITT Population) ......................................................... Table 7.190 Summary of On-Treatment Drug-Related Adverse Events during

Period 1 (Open Label Population) ............................................................

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Table 7.200 Summary of On-Treatment Drug-Related Adverse Events during Period 2 (ITT Population) .........................................................................

Table 7.210 Summary of On-Treatment Drug-Related Adverse Events during Period 1 for randomized treatment groups (ITT Population) ....................

Table 7.220 Summary of Drug-Related Adverse Events for Post-Treatment Period during Period 1 (Open Label Population) .....................................

Table 7.230 Summary of Drug-Related Adverse Events for Post-Treatment Period during Period 2 (ITT Population) ...................................................

Table 7.240 Summary of Drug-Related Adverse Events for On and Post-Treatment Period during Period 2 (ITT Population) .................................

Table 7.250 Summary of On-Treatment Adverse Events Leading to Permanent Discontinuation of Study Drug or Withdrawal From the Study during Period 1 (Open Label Population) ............................................................

Table 7.260 Summary of On-Treatment Adverse Events Leading to Permanent Discontinuation of Study Drug or Withdrawal From the Study during Period 2 (ITT Population) .........................................................................

Table 7.270 Summary of On-Treatment Serious Adverse Events during Period 1 (Open Label Population) ..........................................................................

Table 7.280 Summary of Post-Treatment Serious Adverse Events during Period 1 (Open Label Population) ..........................................................................

Table 7.290 Summary of On-Treatment Serious Adverse Events during Period 2 (ITT Population) .......................................................................................

Table 7.300 Summary of Post-Treatment Serious Adverse Events during Period 2 (ITT Population) .......................................................................................

Table 7.310 Summary of On-Treatment Fatal Adverse Events during Period 1 (Open Label Population) ..........................................................................

Table 7.320 Summary of Post-Treatment Fatal Adverse Events during Period 1 (Open Label Population) ..........................................................................

Table 7.330 Summary of On-Treatment Fatal Adverse Events during Period 2 (ITT Population) .......................................................................................

Table 7.340 Summary of Post-Treatment Fatal Adverse Events during Period 2 (ITT Population) .......................................................................................

Table 7.350 Summary of On-Treatment Drug-Related Serious Adverse Events during Period 1 (Open Label Population) .................................................

Table 7.360 Summary of Post-Treatment Drug-Related Serious Adverse Events during Period 1 (Open Label Population) .................................................

Table 7.370 Summary of On-Treatment Drug-Related Serious Adverse Events during Period 2 (ITT Population) ..............................................................

Table 7.380 Summary of Post-Treatment Drug-Related Serious Adverse Events during Period 2 (ITT Population) ..............................................................

Table 7.390 Summary of On-Treatment Drug-Related Fatal Adverse Events during Period 1 (Open Label Population) .................................................

Table 7.400 Summary of On-Treatment Drug-Related Fatal Adverse Events during Period 2 (ITT Population) ..............................................................

Table 7.410 Summary of On-Treatment Fatal Serious Adverse Events during Period 1 (Open Label Population) ............................................................

406

407

408

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

425

426

427

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Table 7.420 Summary of On-Treatment Non-Fatal Serious Adverse Events during Period 1 (Open Label Population) ............................................................

Table 7.430 Summary of On-Treatment Fatal Serious Adverse Events during Period 2 (ITT Population) .........................................................................

Table 7.440 Summary of On-Treatment Non-Fatal Serious Adverse Events during Period 2 (ITT Population) .........................................................................

Table 7.450 Summary of On-Treatment and Post-Treatment Adverse Events of Special Interest during Period 1 (Open Label Population) .......................

Table 7.460 Summary of On-Treatment and Post-Treatment Adverse Events of Special Interest during Period 2 (ITT Population) ....................................

Table 7.470 Relationship of Adverse Event System Organ Class, Preferred Term and Verbatim Text (Open Label Population) ............................................

Table 7.480 Summary of Clinical Chemistry Data during Period 1 (Open Label Population) ...............................................................................................

Table 7.490 Summary of Clinical Chemistry Data during Period 2 (ITT Population) .................................................................................................................

Table 7.500 Summary of Clinical Chemistry Data Outside the Reference Range during Period 2 (ITT Population) ..............................................................

Table 7.510 Summary of Change from Baseline in Clinical Chemistry Data during Period 2 (Shift Table) (ITT Population) ....................................................

Table 7.520 Summary of On-Treatment Severe Asthma Exacerbations during Period 1 (Open Label Population) ............................................................

Table 7.530 Summary of Post-Treatment Severe Asthma Exacerbations during Period 1 (Open Label Population) ............................................................

Table 7.540 Summary of On-Treatment Severe Asthma Exacerbations during Period 2 (ITT Population) .........................................................................

Table 7.550 Summary of Post-Treatment Severe Asthma Exacerbations during Period 2 (ITT Population) .........................................................................

Table 7.560 Record of all Preferred Terms That Could Have Mapped to Special Interest Terms during Period 1 (Open Label Population) .........................

Table 7.570 Record of all Preferred Terms That Could Have Mapped to Special Interest Terms during Period 2 (ITT Population) ......................................

PHARMACOKINETIC DATA SOURCE TABLES .................................................. Table 8.010 Summary of Plasma FF Concentrations (PK Population) ...................

428

429

430

431

434

436

445

449

461

482

545

546

547

548

549

592615615

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LIST OF DEFINITIONS FOR ABBREVIATIONS AND TERMS

Abbreviations

Symbol/Abbreviation Definition / Unabbreviated Name

ACT Asthma Control Test

ALT Alanine Transaminase

ANCOVA Analysis of Covariance

AST Aspartate aminotransferase

BD Twice daily

BUN Blood Urea Nitrogen

Cmax Maximum blood plasma concentration

CPK Creatinine Phosphokinase

CT Computed Tomography

CYP Cytochrome P450

DNA Deoxyribonucleic Acid

eCRF electronic Case Report Form

EW Early Withdrawal

FEV1 Forced Expiration Volume in 1 second

FF Fluticasone Furoate

FP Fluticasone Propionate

GCP Good Clinical Practice standards

GCSP Global Clinical Safety & Pharmacovigilance

GGT γ-glutamyltranspeptidase

GINA Global Initiative for Asthma

GSK GlaxoSmithKline

hCG Human Chorionic Gonadotrophin

ICS Inhaled Corticosteroids

IgE Immunoglobulin E

IgG Immunoglobulin G

IgM Immunoglobulin M

INR International Normalized Ratio

ITT Intent-to-Treat

IUD Intrauterine Device

IVRS Interactive Voice Response System

LABA Long-Acting β2 Agonists

LDH Lactate Dehydrogenase

LLQ Lower Limit of Quantification

MAO Monoamine oxydase

MCHC Mean Corpuscular Hemoglobin Concentration

MedDRA ICH International Pharmaceutical Glossary

MRI Magnetic Resonance Imaging

NHANES National Health and Nutrition Examination Survey

NIH National Institutes of Health

NQ Not quantifiable

PEF Peak Expiratory Flowrate

PGx Pharmacogenetics

PK Pharmacokinetics

PMDA Pharmaceuticals and Medical Devices Agency

PP Per Protocol

PT Preferred Term

QTc Corrected QT Interval

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QTcF QT Interval corrected with the heart rate using Fridericia ‘s formula

RNA Ribonucleic Acid

RR RR Interval

SABA Short-Acting β2 Agonist

SCR Screening

SD Standard Deviation

SE Standard Error

SMQ Standardised MedDRA Queries

SOC System Organ Class

t1/2 Half-life

ULN Upper Limit of Normal

VI Vilanterol

Trademark Information

Non-GSK Trademarks

Xolea®

Asthma Control Test (ACT™)

GSK ‘s Trademarks

Adolair®

Relvar®

Allermist®

Nasal SpraySaltanol®

Inhaler Diskus®

Ellipta®

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ETHICS AND GCP

The Study Protocol, its revisions, Informed Consent Forms and other information requiring prior approval have been reviewed and approved by an Institutional Review Board / Independent Ethics Committee stipulated in Article 27 of “Ministerial Ordinance on Standards of Good Clinical Practice”.

A copy of the notification / approval with the date from the Institutional Review Board or the Independent Ethics Committee has been stored by the Study Sponsor.

This clinical trial was implemented while complying with Standards for Good Clinical Practice (GCP), Article 14(3) and Article 80(2) of laws related to ensuring the quality, efficacy and safety of pharmaceutical products and medical equipment, privacy protection requirements for all applicable subjects and the basic principles of the Declaration of Helsinki (2008). This clinical trial was monitored in accordance with GCP.

The Principal Investigator and Subinvestigators have received training on executing this clinical trial according to GCP and the Study Protocol. We acquired an agreement form from the Principal Investigator to conduct this study in accordance with GCP and the Study Protocol.

Prior to the Clinical Trial, the Principal Investigator and Subinvestigators have provided sufficient explanations to those considered appropriate to be subjects and/or their legal representatives using the Written Information document. During this process, sufficient time and opportunities to ask questions were provided for the subjects, and the investigators obtained consent forms that were signed and dated with the date of consent from the subject and/or their legal representatives. The Sponsor has provided CRFs to record data for each subject.

There were 3 revisions to the Informed Consent Form (sample) since the start of the clinical trial, and for those subjects who were already part of the ongoing study at the time, revised consent forms were provided and their consents were re-acquired.

Revisions to the Informed Consent Form (sample)

Version Date Created Main Content of Revision

Version 1 10-January-2014 (Initial version)

Version 2 10-June-2014 Revisions associated to safety information updates

Version 3 16-September-2014 Corrections to components in the placebo, due to false imports of the placebo for Fluticasone Furoate (FF)1

Version 4 3-October-2014 Increase in volume of blood collected during Visit 1 (2 mL increase from 7 to 9 mL); Partial addition of the primary inclusion criteria; maintaining descriptions of contraceptive methods

1. Please see “5.2 Deviations from the Study Protocol” for details of this case.

There was 1 case of GCP violation in this study.

Partial loss of source documents for study data was identified for Subject prior to unblinding, and this was reported as a GCP violation. Lost data concerned visit dates and adverse events. For details, see “5.2 Deviations from the Study Protocol”.

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PPD

1. IntroductionAsthma is a chronic disease of the lungs with characteristics of inflammation of the airways,

bronchoconstriction and increased reactivity of the airways [Global Initiative for Asthma (GINA), 2011].

Although the prevalence of asthma varies between 1 to 18% depending on the country (reason for

differences in prevalence remains unknown), there is an estimated 300 million asthma patients around the

world [Beasley, 2004; Masoli, 2004]. While the number of deaths does not necessarily correlate with the

number of patients, there is an estimated 250,000 deaths annually due to asthma [Beasley, 2004; Masoli,

2004]. The number of morbidity and deaths related to asthma represents the large economic burden that

includes direct medical expenses and indirect costs from lost productivity costs.

Inhaled corticosteroids (ICS) are the most effective anti-inflammatory drugs for persistent asthma,

regardless of its severity [Global Initiative for Asthma (GINA), 2011]. ICS treatments reduces the

frequency of asthma exacerbations and asthma severity by controlling asthma symptoms, improving

Quality of Life and lung function, suppressing increased airway reactivity and controlling airway

inflammation, as a result leading to decreased mortality rates due to asthma. Dose of ICS is selected

depending on the severity of asthma.

Fluticasone Furoate (FF) is an ICS that has been developed in 2 doses, namely 100 and 200μg, for once

daily dosing in adult asthma patients undergoing maintenance therapy, and it has been approved for the

indication of bronchial asthma since August 20, 2014 in US. In Japan, it has already been developed as the

ICS component of FF/Vilanterol (FF/VI), a once daily ICS/Long-Acting β2-Agonist (LABA) that is being

marketed for asthma patients. FF 100μg has been developed as a low to medium dose inhaled

corticosteroid for those patients that have used non-steroidal monotherapy agents [e.g. short-acting β2-

Agonist (SABA), Leukotriene antagonist] or low to medium dose ICS. FF 200μg has been developed as

an ICS for patients that have used medium to high dose ICS. For patients with whom FF 100μg does not

show sufficient effect, asthma control may improve in a dose-dependent manner by increasing to FF

200μg.

Although FF/VI has been approved in Japan for the indication of bronchial asthma since

September 2013, approval reviews by the Pharmaceuticals and Medical Devices Agency (PMDA)

indicated that while the efficacy of FF/VI 100/25μg was estimated to correspond to mild persistent to

moderate persistent asthma (treatment step 2 to 3), further information about the relationship between

FV/VI 100/25μg and mild-persistent asthma is required.

Although the early market entry of FF is desirable in order to enable step-down from FF/VI to FF, it was

pointed out that in developing FF, it is necessary to clarify the positioning of FF relative to existing

treatments, by studying the dose of FF that corresponds to existing low-dose ICS and medium-dose ICS.

Based on the above, we planned this clinical trial thinking that it is important to clarify the position of FF

100μg and FF/VI 100/25μg relative to existing therapies for Japanese asthma patients, by studying the

proportion of patients with well-controlled asthma when they switch to FF/VI 100/25μg, as well as the

effect of FF 100μg relative to existing low dose and medium dose ICS, after stepping down from FF/VI

100/25μg in Japanese asthma patients being treated with medium-dose ICS/LABA equivalent to Adoair®

Diskus® 250μg.

This report is an amendment of the original CSR to reflect the results of re-analysis of co-primary

endpoints (proportion of subjects “well controlled” at the end of Period 2 and time to withdrawal due

to “poorly-controlled (requires step-up)” during Period 2) and two ‘other’ endpoints (proportion of

subjects “well controlled” at the end of Period 1and time to withdrawal due to “ poorly-controlled

(requires step-up)” during Period 1). After the approval of the original CSR, it was found that “asthma

worsening/exercabation” for evaluating co-primary endpoints was evaluated using only “severe

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CONFIDENTIAL 2015N239011_01201135

asthma”, although “asthma worsening/exercabation” had to be evaluated using “severe asthma” and

“worsening asthma.” Therefore, co-primary endpoints and two ‘other’ endpoints were re-analyzed

using “severe asthma” and “worsening asthma” for evaluating “asthma worsening/exercabation.”

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2. Study ObjectivesPrimary Objective

To clarify the positioning of FF 100μg in medical practice by evaluating time to withdrawal due to

“poorly-controlled (requires step-up) asthma” and to evaluate the proportion of subjects “well-

controlled” in fluticasone furcate (FF) 100μg once daily (OD), fluticasone propionate (FP) 250μg twice

daily (BD), or FP 100μg BD for 12 weeks (Period-2) after stepping down in Japanese subjects with

asthma who have been well-controlled on FF/VI 100/25μg OD.

Secondary ObjectiveTo evaluate the proportion of subjects “well-controlled” after switching from the middle-dose

ICS/LABA, which is equivalent to Adoair Diskus 250μg, to once-daily FF/VI 100/25μg for 8 weeks

(Period-1) in Japanese subjects with asthma who have been well-controlled on the middle-dose Inhaled

Corticosteroid/ long-acting β2-agonist (ICS/LABA).

Other objectives To evaluate safety of FF 100μg in Japanese subjects with asthma.

To evaluate Pharmacokinetic (PK) of FF 100μg in Japanese subjects with asthma.

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3. Investigators and Clinical Trial Management

3.1. Sponsor and Representatives

Sponsor

GlaxoSmithKline K.K. (GSK)

4-6-15 Sendagaya, Shibuya-ku, Tokyo, Japan 151-8566

Chief Executive of the Study:

Chief, Development Headquarters / Pharmaceutical Product Development

Department Office of Development in the Respiratory Field

Sponsor Contact Information

Study Protocol Creation Leader:

Development Headquarters / Pharmaceutical Product Development Department Office of

Development in the Respiratory Field

Monitoring Leader:

Development Headquarters / Clinical Operations Department

Medical Monitor (Physician from Sponsor) / Specialist from Sponsor

M.D., Director, Development Headquarters / Pharmaceutical Product

Development Department GlaxoSmithKline K.K.

3.2. Study Center and the InvestigatorsThis study was a multicentre study held in a total of 34 study centers within Japan, with a total of 34

Investigators participating in it.

3.3. Testing Facility

Clinical Laboratory Testing Contract Research Organization

SRL Medisearch Inc.

Responsible person: Department Head, Clinical Trial Testing Department

6-5-1 Nishi-shinjuku, Shinjuku-ku, Tokyo, Japan 163-1310

Clinical Laboratory Testing Agency

SRL Inc.

Responsible Person: Department Head, Clinical Testing Department

2-1-1 Nishi-shinjuku, Shinjuku-ku, Tokyo, Japan 163-0409

Drug Concentration Measuring Facility

Shin Nippon Biomedical Laboratories, Ltd.

Drug Metabolism Analysis Center

Responsible Person:

16-1 Minami-akasaka, Kainan-shi, Wakayama, Japan 642-0017

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PPD

PPD

PPD

PPD

PPD

PPD

PPD

3.4. Study Period

The first subject was registered on March 27th 2014, and the last subject completed his/her final stipulated observation on August 28th, 2015.

4. Study Plan

4.1. Study Design

Figure 1 shows the study design.

Figure 1 Study design

This study was a multi-center study which comprised Period 1 conducted in an uncontrolled, open-

label manner and Period-2 conducted in a randomized, double-blind, active-controlled, parallel-group

manner. This study was comprised of a run-in period (4 weeks), an open-label treatment period

(Period-1: 8 weeks), a double-blind treatment period (Period-2: 12 weeks), and a follow-up period

(1 week). The total period was 25 weeks. Subjects complying with the inclusion/exclusion criteria at

Visit 1 were registered in the run-in period (4 weeks). Subjects whose asthma was assessed as “well-

controlled” (as defined in “4.4.1.1. Inclusion Criteria”) were switched at Visit 2 from the middle-dose

ICS/LABA equivalent dose of Adoair® Diskus® 250μg to once-daily FF/VI 100/25μg (PM) for an 8-

week treatment period (Period-1: open-label treatment period). Subjects whose asthma was assessed as

well-controlled were randomized at Visit 5 in a 1:1:1 ratio to one of FF 100μg OD, FP 250μg BD, or

FP 100μg BD and entered the 12 week double blind treatment period (Period-2: double blind period).

There was a 1-week follow-up period following completion of, or early withdrawal from, the 12-week

period in Period-2.

Subjects avoided using Sultanol® Inhaler within 6 hours prior to each visit.

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4.2. Consideration for the Study Design

This study was planned, having considered that it is important to clarify the position of FF and FF/VI 100/25μg relative to existing therapies for Japanese patients, taking into account the indications of the PMDA that information for Japanese asthma patients are lacking with regards to the corresponding relationship between FF/VI 100/25μg and each step of mild/moderate persistent asthma (in particular the mild persistent type), the relationship between FF 100μg and FP 250μg BD in subject groups requiring middle-dose ICS, as well as the relationship between FF 100μg and FP 100μg BD in patient groups requiring low-dose ICS.

As to the number of enrolled subjects, 360 subjects (120 subjects in each treatment group) were randomized in Period-2. In Period-1, in order to secure the target number of subjects for randomization (360 subjects) for Period-2, screenings were carried out while observing the proportion of “well-controlled” asthma subjects, and the clinical trial was carried on while adjusting the number of registered subjects.

As switching from middle-dose ICS/LABA equivalent to Adoair Diskus 250μg to FF/VI 100/25μg and stepping down from FF/VI 100/25μg to ICS monotherapy requires these subjects to have sufficiently stable asthma symptoms [“Asthma Prevention / Management Guideline 2012” creating committee, 2012], we setup criteria to standardize the conditions of well-controlled asthma.

It would be appropriate to use strict standards to evaluate the 3 dosing regimes FP 100μg BD, FP 250μg BD and FF 100μg OD until withdrawal due to “poorly-controlled (needing step-up)” in Period-2. Therefore, based on the fact that the Asthma Prevention / Management Guideline (2012) says “For the therapeutic measure, if asthma is not well-controlled under the current treatment step, strengthen treatment with the current treatment step if asthma symptoms do not occur every week, and step-up the content of treatment by 1 or 2 levels from the current treatment if asthma symptoms occur every week or every day”, the definition of “poorly-controlled (needing step-up)” asthma was to be evaluated using the similar items of observations as those defining “well-controlled asthma”.

In order to evaluate whether or not well-controlled asthma can be maintained after subjects with “well-controlled” asthma enters and switches from middle-dose ICS/LABA to FF/VI 100/25μg, the 8-week treatment period in Period-1 should be sufficient to demonstrate the safety and efficacy of FF/VI 100/25μg. Furthermore, according to the Asthma Prevention / Management Guideline for Adult Asthma(2012), the 12-week treatment period in Period-2 should be sufficient to study the safety and tolerability of ICS monotherapy in presumed target groups, taking into consideration the general step-down in asthma treatments after 3 to 6 months of continued good control of asthma [“[“Asthma Prevention / Management Guideline 2012” creating officers, 2012] Tokyo: Kyowa Project; 2012].

4.3. Revision of the Study Protocol

The main revisions made in the protocol of this clinical trial are shown in Table 1 Main Revisions to the Study Protocol 1.

The first version of the Study Protocol (Version 00) was created on 10-January-2014, and this clinical trial was started based on it. There were 4 revisions after the start of the study. The main revisions made the first time (Version 01_00) are shown in Table 1 Main Revisions to the Study Protocol 1. Furthermore, the study period was changed from March 2014 – June 2015 to March 2014 –October 2015 in the third revision (Version 01_02). Other revisions were about organizational changes and personnel changes.

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Table 1 Main Revisions to the Study Protocol 1Version 01_00 (revised on 18-September-2014)

Section Before After Reason for Revision

4.8 Re-screening criteria

(p.36)

Screen failure subjects that did not meet the inclusion criteria may be re-screened. However, each subject can only be re-screened once, after 30 days pass from the initial screening. During re-screening, the subject will undergo the assessments and procedures stipulated for Visit 1 on the Protocol. Subjects that can be re-screened are those who have stable asthma symptoms, but could not perform the appropriate lung function measurements on Visit 1. Subjects that dropped out after commencing the run-in period cannot be re-screened.

Subjects that failed to perform the appropriate lung function measurements during Visit 1 may be re-screened. However, each subject can only be re-screened once. Subjects that dropped out after commencing the run-in period cannot be re-screened. During re-screening, the inclusion criteria (Visit 1) stipulated in the Protocol are re-checked before performing Visit 1 assessments and procedures.

As subjects eligible for re-screening are limited to those that fit the inclusion criteria but “failed to perform the appropriate lung function measurements”, the “30 days pass”was deleted and the description was consolidated.

5.1Investigational product and rescue medications(p.37)

The Sponsor will provide investigational product and rescue medications to be used in this study, except for the middle-dose ICS/LABA equivalent Adoair® Diskus® 250μg

The Sponsor will provide investigational product and rescue medications to be used in this study, via their storage place at the Mitsubishi Logistics Co., Ltd., except for the middle-dose ICS/LABA equivalent Adoair® Diskus® 250μg

Clarified the process of providing the investigational products.

5.1.1Investigational product

(p.38)

【FF Placebo】1 inhalation per time, OD(PM)

【Front】

“Formulation”: Single-strip packing:

Contains lactose

“Dosage form”: Ellipta® containing 30 blisters (30 blisters in 1 strip, 1 strip packaged)

【FF Placebo】1 inhalation per time, OD(PM)

【Front】

“Formulation”: First strip packaging: contains lactose hydrate, second strip packaging: mixture of lactose hydrate and Magnesium stearate

“Dosage form”：Ellipta® containing 30 blisters (30 blisters in 1 strip, 2 strips packaged)

As it was discovered that the actual FF placebo formulations are two-strip packages rather than the single-strip 1 this was corrected appropriately.

5.1.1Investigational product

(p.38)

【FP 250μg, FP 100μg】1 inhalation per time, BD (AM/ PM)

【Front】

“Formulation”：−

【FP 250μg, FP 100μg】1 inhalation per time, BD (AM/ PM)

【Front】

“Formulation”：combination of pulverized FP and lactose hydrate

Formulations contained were clearly appended.

5.1.1Investigational product

(p.38)

【FP Placebo】1 inhalation per time, BD (AM/ PM)

【Front】

“Formulation”：−

【FP 250μg, FP 100μg】1 inhalation per time, BD (AM/ PM)

【Front】

“Formulation”：Contains lactose hydrate

Same as above

5.6.2 Prohibited drugs and therapies

(p.41)

Asthma treatment drugs that are prohibited for concomitant use from 12

weeks before Visit 1 to Visit 11：

�Oral or non-oral steroids including sustained (depot-type) drugs

Asthma treatment drugs that are prohibited for concomitant use from

12 weeks before Visit 1 to Visit 11：

�Oral or non-oral steroids including sustained (depot-type) drugs

(However, female hormone agents including oral contraceptives may continue to be used throughout the study period as long as the prescription is not changed.)

Appended to maintain consistency with the inclusion criteria for enrolment.

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Section Before After Reason for Revision

5.6.2 Prohibited drugs and therapies (p.41)

Non-asthma Drugs Prohibited for Concomitance between Visit 1 and Visit 11:

Anticonvulsants (Barbituric acid, hydantoin, carbamazepine)

Polycyclic antidepressants

β blockers

Phenothiazine drugs

Monoamine oxidase (MAO) inhibitors

Non-asthma Drugs Prohibited for Concomitance between Visit 1 and Visit 11:

Anticonvulsants (Barbituric acid, hydantoin, carbamazepine)

Polycyclic antidepressants

β blockers

Phenothiazine drugs

Monoamine oxidase (MAO) inhibitors

Allermist Nasal®Spray

The proviso [Non-asthma drugs prohibited for concomitant use] was made clear.

8.3.1 Analysis Population(p.66–67)

All Subjects Enrolled Populationcomprised all subjects, for whom a record existed in the study database, including screen failures and any subject who was not screened but experienced an SAE between the date of informed consent and the planned date of the Screening Visit. This population was used when reporting serious adverse events concerning reasons for withdrawal before randomization (drop-out reason), deviation from inclusion/exclusion/randomization criteria, and for subjects who were not randomized.

All Subjects Enrolled Population comprised all subjects, for whom a record existed in the study database, including screen failures and any subject who was not screened but experienced an SAE between the date of informed consent and the planned date of the Screening Visit. This population was used when reporting serious adverse events concerning reasons for withdrawal before investigational product administration (drop-out reason), deviation from inclusion/exclusion criteria, and for subjects to whom the investigational product was not administered during Period-1.

Description was clarified in association with the review of the definition of the analysis population.

8.3.1 Analysis Population(p.66–67)

N/A Open Label Population comprised all subjects who received at least one dose of study medication in Period-1. This population was used for all data analyses and results presented for Period-1. Furthermore, this population was used when reporting serious adverse events concerning reasons for withdrawal before randomization (drop-out reason), deviation from inclusion/exclusion/randomization criteria, and for subjects who were not randomized during Period-2.

Same as above

8.3.1 Analysis Population(p.66–67)

Intent-to-Treat (ITT) Population comprised all subjects randomized to treatment who received at least one dose of randomized investigational product in the treatment period. Randomized subjects were assumed to have received investigational product unless definitive evidence to the contrary exists. Results were reported based on the randomized treatment group. This was the main population for all data analysis and display of analysis results.

Intent-to-Treat (ITT) Population comprised all subjects randomized to treatment who received at least one dose of randomized investigational product in the treatment period. Randomized subjects were assumed to have received investigational product unless definitive evidence to the contrary exists. Results on efficacy were reported based on the randomized treatment group. This was the main population for all data analysis and display of analysis results for Period-2.

Same as above

1. Details concerning the erroneous delivery issue of investigational product is described in “5.2. Deviations from the Study Protocol”.

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4.4. Selection of The Analysis Set

4.4.1. Inclusion/Exclusion Criteria

4.4.1.1. Inclusion Criteria

Inclusion Criteria at Enrolment (Visit 1)

Only those who fulfil all of the following were included for enrolment in this study.

1. Consent: Possible to acquire written consent from the patient him/herself.

2. Type of subject: Outpatient subjects aged 18 years or older who had a diagnosis of asthma as

defined by the diagnostic criteria of National Institutes of Health [NIH, 2007] at least 1 year prior

to Visit 1.

3. Gender: Male or eligible female

Non-childbearing potential females of or childbearing potential females who used an acceptable

method of birth control, as shown below, consistently and correctly.

The male partner of the subject is azoospermic prior to subject’s study enrolment, and that

this is the only male partner that they have

Oral contraceptives (Estrogen / progestin mixed formulation)

Intrauterine device (IUD) with contraceptive failure rate below 1% according to literature

Double-barrier method: Spermicide + physical barrier (spermicide + condom, or spermicide

+ pessary)

Females of childbearing potential must maintain complete abstinence during the study

period and during the period until the investigational product disappears from the system

(more than 6 days after the last dose).

Pregnant women, breastfeeding women, or those women who plan on becoming pregnant

during the study period cannot be enrolled in the study. Serum pregnant tests are done on

female patients of childbearing potential on the registration visit (Visit 1) and on Visit

11/Early Withdrawal Visit. All female patients of childbearing potential must undergo urine

pregnancy tests when switching to FF/VI 100/25μg (Visit 2), randomization visit (Visit 5)

and follow-up visit (Visit 12).

4. Severity of disease: A best pre-bronchodilator FEV1 of ≥80% of the predicted normal value at

Visit 1. Predicted values were based on NHANES III [Hankinson, 1999] values adjusted for Asian

race related variations [Hankinson, 2010].

5. Stable Asthma: Subjects who had stable asthma, as judged comprehensively by the Investigator/

Subinvestigator. This included no change in asthma medication for at least 8 weeks prior to Visit 1

and an Asthma Control Test (ACT) score of ≥20 at Visit 1.

6. Current anti-Asthma Therapy: Subjects who used the middle-dose ICS/LABA which was

equivalent to twice-daily Adoair Diskus 250μg for at least 12 weeks prior to Visit 1. In addition,

the prescription of the middle-dose ICS/LABA could not be changed at least 8 weeks prior to

Visit 1.

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7. SABA: Subjects who, during the study, were able to use the Sultanol Inhaler, provided as rescue

medication on Visit 1 when needed. However, subjects were able to avoid the use of the Sultanol

Inhaler 6 hours prior to every study visit.

8. 12-Lead Electrocardiogram: Subjects had no clinically problematic abnormalities in the 12-Lead

Electrocardiogram test conducted during Visit 1, according to judgments made by the Investigator/

Subinvestigator(s). The following conditions had to be met about the QT interval.

Inclusion Criteria at Switching of Medications/Randomization (Visit 2 and Visit 5)

1. Subjects whose asthma met the criterion of “well-controlled” (as defined in “Well-controlled”) and who were allowed to be “switched” or “randomized” at the discretion of the Investigator/ Subinvestigator at Visit 2 or Visit 5 respectively.

Definition of Well-controlled Asthma (assessed in one week prior to Visits 2 and 5)

Observation item Well-controlled

Assess weekly Asthma symptom score 1)

(Day-time)Two or more of the 3 criteria*

AND

1 or greater on no more than one day

Rescue salbutamol use No more than 1 day of use

Morning PEF ≥80% the best effort value every day

At visits A best pre-bronchodilator FEV1 Meet all of the criteria*

≥80% predicted

Assess daily Asthma symptom score 1) (Night-time)

0

Asthma worsening/ exacerbation 2) No

*Both should be met for ‘well-controlled’.

1) The following will be recorded every day in the eDiary in the evening (PM) before taking any rescue or study medication and before PEF measurement:

Day-time Symptom Score:0 = No symptoms during the day1 = Symptoms for one short period during the day2 = Symptoms for two or more short periods during the day3 = Symptoms for most of the day which did not affect my normal daily activities4 = Symptoms for most of the day which did affect my normal daily activities5 = Symptoms so severe that I could not go to work or perform normal daily Activities

The following will be recorded every day in the eDiary in the morning (AM) before taking any rescue medication and before PEF measurement:

Night-time Symptom Score:0 = No symptoms during the night1 = Symptoms causing me to wake once (or wake early)2 = Symptoms causing me to wake twice or more (including waking early)3 = Symptoms causing me to be awake for most of the night4 = Symptoms so severe that I did not sleep at all

QTcF

2) See Exacerbation of Asthma Symptoms: “Asthma exacerbation” of “4.6.2.9 Other Safety Endpoints”.

2. Subjects with compliance rate >80% for use of middle-dose ICS/LABA compounding agents equivalent to Adoair Diskus 250μg (Visit 1 to 2) and FF/VI 100/25μg (Visit 2 to 5)

3. Subjects that make more than 5 days of entries into the electronic diary (“4.6.1.2 Patient Diary”) in the morning and night, during the 1 week immediately before Visit 2 and Visit 5

4.4.1.2 Exclusion Criteria

Exclusion Criteria at Enrolment (Visit 1) Subjects were not enrolled to the study if they corresponded to any of the following conditions.

1. Life-threatening history of Asthma: Subject who had a life-threatening episode of asthma.

Definition of a life-threatening episode of asthma: Asthma episodes needing endotracheal intubation and/or asthma episodes involving hypercapnia, respiratory arrest or hypoxicconvulsions within the past 10 years.

2. Respiratory tract infection: Subject who had positive or suspected positive response in culture

tests of bacterial infection or viral infection in the upper respiratory tract, lower respiratory tract,

paranasal sinus or the middle ear and had not been healed of it within 8 weeks prior to Visit 1,

which had led to make changes to asthma treatments, or these infections could affect the condition

of asthma or subject’s participation in the study, based on judgments made by the Investigator/

Subinvestigator.

3. Asthma Exacerbation: Subject who received treatments with systemic oral steroids or steroidal

injections within 12 weeks before Visit 1, or was hospitalized for more than 1 night for asthma

exacerbation that required additional treatments, within 6 months of Visit 1.

4. Complications of the respiratory tract: Subject who had pneumonia, pneumothorax, atelectasis,

pulmonary fibrosis, bronchopulmonary dysplasia, chronic bronchitis, emphysema, chronic

obstructive pulmonary disease or complications with any other respiratory disorders other than

asthma.

5. Other complications/abnormalities: Subject who had clinically significant symptoms or illnesses

that are unmanaged, and who might risk their safety by participating in the study, or should these

symptoms/illnesses worsen during the study, the interpretation of results concerning efficacy

might be interfered, based on the judgment of the Investigator/ Subinvestigator.

Other symptoms/illnesses which exclude subjects from being enrolled to this study are shown in, but not limited to the table below.

Congestive heart failure Existing aortic aneurysm

Clinically significant coronary heart disease Clinically significant arrhythmia

Stroke within 3 months before Visit 1 Unmanaged hypertension1

Recently developed, unmanaged gastric ulcer Hematological, liver, kidney diseases

Lack of immunity Malignant tumor2

Tuberculosis (active or untreated)3 Cushing’s disease

Addison’s disease Unmanaged diabetes

Unmanaged thyroid disease Recent history of drug or alcohol abuse

1. If measurements of systolic blood pressure >160mmHg or diastolic blood pressure >100mmHg were taken more than twice.

2. Subjects with history of malignant tumors were allowed to enrol as long as the cancer has been in remission for 1 year prior to Visit 1 (remission means that there are no signs of the malignant tumor 12 months prior to Visit 1, and the subject has not received any treatments for it).

3. Patients with tuberculosis were allowed for enrolment provided that they are receiving appropriate treatments with antituberculotic drugs and show no clinical signs of relapsing or active tuberculosis.

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6. Oropharyngeal Examination: Subjects who had clinically visible oral candidiasis during Visit 1,

they were not subjected to enrolment during the run-in period.

7. Investigational Product Treatments: Subject who had used the investigational product within 30

days prior to Visit 1, or 5 times the half-life (t1/2) of the investigational product had not passed

(whichever was longer of these two periods).

8. Allergy：

Drug Allergy: Subject who had a history of immediate or delayed-type sensitivity to β2

agonists, sympathomimetic agents or intranasal, inhaled, systemic steroid therapies.

Subject who had or was suspected of having sensitivities against excipients of the

investigational product (Lactose hydrate, magnesium stearate).

Allergies against milk proteins: Subject who had a history of severe allergies against milk

proteins.

9. Concomitant drugs:

Subjects who were using prescription drugs or general pharmaceutical products like

anticonvulsants (Barbituric acid, hydantoin, carbamazepine), polycyclic antidepressants

(tricyclic or tetracyclic), β-blockers (both heart-selective and non-selective), phenothiazine

drugs and monoamine oxidase (MAO) inhibitors that have large impact on the progress of

asthma, or that have risks of drug interactions with the investigational product.

Immunosuppressants：Subjects who was using immunosuppressant drugs or expected to

use immunosuppressants during the study period.

Note： Immunotherapy towards allergy treatments during the study period was

allowed as long as it had started more than 4 weeks before Visit 1 and continued

during the study period with