Conditions: Asthma
Keywords: dry powder inahler vilanerol efficacy safety fluticasone furoate quality of life
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 423
Healthy volunteers: no

Brief summary:
The combination of FF, an ICS and VI, an orally inhaled LABA has been developed as a once-daily combination therapy for the long-term maintenance treatment of asthma in adults and children \>=12 years of age. Pivotal phase III studies have demonstrated the safety and efficacy of FF/VI in asthma. However, it is increasingly acknowledged that randomised clinical trials tend to be highly controlled and enrol a more highly selected subject population than is expected to be prescribed the medication post-approval. There is a need for data in a more representative population in close to a 'real life' conditions, where physicians have the ability to choose the best treatment in their view for any individual subject and adapt treatments to subjects' characteristics and response. This multi-center, open-label, randomized, parallel group study will evaluate the efficacy and safety of FF/VI compared with two usual ICS/LABA fixed combination (fluticasone propionate/salmeterol \[FP/S\] or budesonide/formoterol \[BUD/F\]) in subjects with persistent asthma, in a "close to real life" settings. FF/VI will be administered once-daily (QD) via ELLIPTA dry powder inhaler (DPI) and FP/S or BUD/F will be administered twice daily (BID) via DISKUS™ and TURBUHALER™ DPI respectively. ELLIPTA is a new powder inhaler designed to be easy to use. The total duration of subject participation will be approximately 6 months (24 weeks). ELLIPTA and DISKUS are registered trademarks of the GSK group of companies. TURBUHALER is a registered trademark of AstraZeneca.

Detailed description:

Arms:
arm 1: Subjects will receive FF/VI 92 micrograms (mcg)/22 mcg or FF/VI 184 mcg/22 mcg as decided by the investigator QD via ELLIPTA DPI for 24 weeks. arm 2: Subjects will receive FP/S (250 mcg/50 mcg or 500 mcg/50mcg) twice daily via DISKUS or BUD /F (200 mcg/6mcg or 400 mcg/12mcg one or two inhalations) twice daily via TURBUHALER DPI as decided by the investigator for 24 weeks.

Interventions: intervention 1: Fluticasone Furoate intervention 2: Vilanterol intervention 3: Fluticasone propionate intervention 4: Salmeterol intervention 5: Budesonide intervention 6: Formoterol Fumarate
Intervention descriptions: intervention 1: FF 92 mcg or 184 mcg blended with lactose administered once daily via ELLIPTA DPI intervention 2: Vilanterol 22 mcg blended with lactose and magnesium stearate administered once daily via ELLIPTA DPI intervention 3: FP 250 mcg or 500 mcg blended with lactose administered twice daily via DISKUS DPI intervention 4: Salmeterol 50 mcg blended with lactose administered twice daily via DISKUS DPI intervention 5: Budesonide 200 mcg or 400 mcg blended with lactose administered twice daily via TURBUHALER DPI intervention 6: Formoterol Furoate 6 mcg or 12 mcg blended with lactose administered twice daily via TURBUHALER DPI

Protocol document:
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1.
PROTOCOL SYNOPSIS FOR STUDY HZA116492...............................................11
2.
INTRODUCTION....................................................................................................16
2.1.
Study Rationale ..........................................................................................16
2.2.
Brief Background ........................................................................................17
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................18
4.
STUDY DESIGN ....................................................................................................21
4.1.
Overall Design ............................................................................................21
4.2.
Treatment arms and duration......................................................................24
4.3.
Type and Number of Subjects.....................................................................24
4.4.
Design Justification.....................................................................................25
4.5.
Dose Justification........................................................................................25
4.6.
Benefit: Risk Assessment ...........................................................................25
4.6.1.
Risk Assessment .........................................................................26
4.6.1.1.
Benefit Assessment....................................................30
4.6.2.
Overall Benefit: Risk Conclusion..................................................30
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............30
5.1.
Inclusion Criteria.........................................................................................30
5.2.
Exclusion Criteria........................................................................................32
5.3.
Screening/Baseline/Failures .......................................................................33
5.4.
Withdrawal/Stopping Criteria.......................................................................34
5.4.1.
Subjects Lost to Follow-up...........................................................34
5.4.2.
Subject Withdrawal by Investigator or Self-withdrawal .................34
5.4.3.
Liver Chemistry Stopping Criteria ................................................35
5.4.3.1.
Study Treatment Restart or Rechallenge....................36
5.4.4.
QTc Stopping Criteria ..................................................................36
5.5.
Subject and Study Completion....................................................................37
6.
STUDY TREATMENT ............................................................................................37
6.1.
Investigational Product and Other Study Treatment....................................37
6.2.
Medical Devices..........................................................................................38
6.3.
Treatment Assignment................................................................................39
6.4.
Planned Dose Adjustments.........................................................................40
6.5.
Blinding.......................................................................................................40
6.6.
Packaging and Labeling..............................................................................40
6.7.
Preparation/Handling/Storage/Accountability..............................................41
6.8.
Investigational Product Malfunction.............................................................41
6.9.
Compliance with Study Treatment Administration.......................................42
6.10.
Treatment of Study Treatment Overdose....................................................42
6.11.
Treatment after the End of the Study ..........................................................43
6.12.
Concomitant Medications and Non-Drug Therapies....................................43
6.12.1.
Permitted Medications and Non-Drug Therapies..........................43
6.12.2.
Prohibited Medications and Non-Drug Therapies.........................43
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................44
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7.1.
Time and Events Table...............................................................................45
7.2.
Screening and Critical Baseline Assessments ............................................47
7.3.
Efficacy.......................................................................................................47
7.3.1.
Inhaler Correct Use Assessment .................................................47
7.3.2.
Trough (pre-dose) FEV1 assessment ..........................................50
7.3.3.
Questionnaires ............................................................................51
7.3.3.1.
Asthma Control Test (ACT) ........................................51
7.3.3.2.
Asthma Quality of Life Questionnaire (AQLQ-S).........51
7.3.3.3.
EuroQol Questionnaire (EQ-5D)-5 Level ....................51
7.3.3.4.
Medication Adherence Report Scale for 
Asthma (MARS-A)......................................................51
7.3.3.5.
Patients Satisfaction and Preference with the 
device (PASAP Questionnaire)...................................52
7.4.
Safety .........................................................................................................52
7.4.1.
Adverse Events (AE), Adverse Drug Reactions (ADRs) 
and Serious Adverse Events (SAEs)............................................52
7.4.1.1.
Time period and Frequency for collecting non 
serious ADRs and SAE information............................53
7.4.1.2.
Method of Detecting non serious ADRs and 
SAEs ..........................................................................53
7.4.1.3.
Follow-up of non serious ADRs and SAEs..................54
7.4.1.4.
Cardiovascular and Death Events ..............................54
7.4.1.5.
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ................54
7.4.1.6.
Regulatory Reporting Requirements for SAEs............54
7.4.2.
Pregnancy ...................................................................................55
7.4.3.
Medical Device Incidents (Including Malfunctions).......................55
7.4.4.
Physical Exams ...........................................................................55
7.4.5.
Vital Signs....................................................................................55
7.4.6.
Electrocardiogram (ECG).............................................................55
7.4.7.
Clinical Safety Laboratory Assessments ......................................56
7.5.
Genetics .....................................................................................................56
8.
DATA MANAGEMENT ...........................................................................................56
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................56
9.1.
Hypotheses.................................................................................................56
9.2.
Sample Size Considerations.......................................................................57
9.2.1.
Sample Size Assumptions ...........................................................57
9.2.2.
Sample Size Sensitivity................................................................57
9.2.3.
Sample Size Re-estimation or Adjustment...................................58
9.3.
Data Analysis Considerations .....................................................................58
9.3.1.
Analysis Populations....................................................................58
9.3.2.
Interim Analysis ...........................................................................58
9.4.
Key Elements of Analysis Plan ...................................................................58
9.4.1.
Primary Analyses.........................................................................60
9.4.2.
Secondary Analyses ....................................................................63
9.4.3.
Other Analyses ............................................................................64
10. STUDY GOVERNANCE CONSIDERATIONS........................................................67
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............67
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10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................67
10.3.
Quality Control (Study Monitoring) ..............................................................68
10.4.
Quality Assurance.......................................................................................68
10.5.
Study and Site Closure ...............................................................................68
10.6.
Records Retention......................................................................................69
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................69
11. REFERENCES.......................................................................................................71
12. APPENDICES........................................................................................................73
12.1.
Appendix 1: Abbreviation and Trademarks .................................................73
12.2.
Appendix 2: Study Schematic .....................................................................76
12.3.
Appendix 3: Questionnaires........................................................................77
12.4.
Appendix 4: Liver Chemistry Stopping and Follow-up Criteria.....................80
12.5.
Appendix 5: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................83
12.5.1.
Definition of Adverse Events and ADRs.......................................83
12.5.2.
Definition of Serious Adverse Events...........................................84
12.5.3.
Definition of Cardiovascular Events .............................................86
12.5.4.
Recording of AEs (ADRs) and SAEs............................................86
12.5.5.
Evaluating AEs (ADRs) and SAEs ...............................................87
12.5.6.
Reporting of SAEs to GSK...........................................................88
12.6.
Appendix 6: Genetic Research ...................................................................89
12.7.
Appendix 7: Collection of Pregnancy Information........................................92
12.8.
Appendix 8: Protocol Changes....................................................................93
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2017N339371_00


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2014N190259_02
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2014N190259_02
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2017N339371_00


2014N190259_02
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1.
PROTOCOL SYNOPSIS FOR STUDY HZA116492...............................................10
2.
INTRODUCTION....................................................................................................15
2.1.
Study Rationale ..........................................................................................15
2.2.
Brief Background ........................................................................................16
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................17
4.
STUDY DESIGN ....................................................................................................20
4.1.
Overall Design ............................................................................................20
4.2.
Treatment arms and duration......................................................................23
4.3.
Type and Number of Subjects.....................................................................23
4.4.
Design Justification.....................................................................................23
4.5.
Dose Justification........................................................................................24
4.6.
Benefit: Risk Assessment ...........................................................................24
4.6.1.
Risk Assessment .........................................................................25
4.6.1.1.
Benefit Assessment....................................................29
4.6.2.
Overall Benefit: Risk Conclusion..................................................29
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............30
5.1.
Inclusion Criteria.........................................................................................30
5.2.
Exclusion Criteria........................................................................................32
5.3.
Screening/Baseline/Failures .......................................................................33
5.4.
Withdrawal/Stopping Criteria.......................................................................33
5.4.1.
Subjects Lost to Follow-up...........................................................33
5.4.2.
Subject Withdrawal by Investigator or Self-withdrawal .................33
5.4.3.
Liver Chemistry Stopping Criteria ................................................34
5.4.3.1.
Study Treatment Restart or Rechallenge....................36
5.4.4.
QTc Stopping Criteria ..................................................................36
5.5.
Subject and Study Completion....................................................................36
6.
STUDY TREATMENT ............................................................................................37
6.1.
Investigational Product and Other Study Treatment....................................37
6.2.
Medical Devices..........................................................................................38
6.3.
Treatment Assignment................................................................................38
6.4.
Planned Dose Adjustments.........................................................................40
6.5.
Blinding.......................................................................................................40
6.6.
Packaging and Labeling..............................................................................40
6.7.
Preparation/Handling/Storage/Accountability..............................................40
6.8.
Investigational Product Malfunction.............................................................41
6.9.
Compliance with Study Treatment Administration.......................................41
6.10.
Treatment of Study Treatment Overdose....................................................41
6.11.
Treatment after the End of the Study ..........................................................42
6.12.
Concomitant Medications and Non-Drug Therapies....................................42
6.12.1.
Permitted Medications and Non-Drug Therapies..........................42
6.12.2.
Prohibited Medications and Non-Drug Therapies.........................42
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................43
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7.1.
Time and Events Table...............................................................................44
7.2.
Screening and Critical Baseline Assessments ............................................46
7.3.
Efficacy.......................................................................................................46
7.3.1.
Inhaler Correct Use Assessment .................................................46
7.3.2.
Trough (pre-dose) FEV1 assessment ..........................................49
7.3.3.
Questionnaires ............................................................................50
7.3.3.1.
Asthma Control Test (ACT) ........................................50
7.3.3.2.
Asthma Quality of Life Questionnaire (AQLQ-S).........50
7.3.3.3.
EuroQol Questionnaire (EQ-5D)-5 Level ....................50
7.3.3.4.
Medication Adherence Report Scale for 
Asthma (MARS-A)......................................................50
7.3.3.5.
Patients Satisfaction and Preference with the 
device (PASAP Questionnaire)...................................51
7.4.
Safety .........................................................................................................51
7.4.1.
Adverse Events (AE), Adverse Drug Reactions (ADRs) 
and Serious Adverse Events (SAEs)............................................51
7.4.1.1.
Time period and Frequency for collecting non 
serious ADRs and SAE information............................52
7.4.1.2.
Method of Detecting non serious ADRs and 
SAEs ..........................................................................52
7.4.1.3.
Follow-up of non serious ADRs and SAEs..................53
7.4.1.4.
Cardiovascular and Death Events ..............................53
7.4.1.5.
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ................53
7.4.1.6.
Regulatory Reporting Requirements for SAEs............53
7.4.2.
Pregnancy ...................................................................................54
7.4.3.
Medical Device Incidents (Including Malfunctions).......................54
7.4.4.
Physical Exams ...........................................................................54
7.4.5.
Vital Signs....................................................................................54
7.4.6.
Electrocardiogram (ECG).............................................................54
7.4.7.
Clinical Safety Laboratory Assessments ......................................55
7.5.
Genetics .....................................................................................................55
8.
DATA MANAGEMENT ...........................................................................................55
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................55
9.1.
Hypotheses.................................................................................................55
9.2.
Sample Size Considerations.......................................................................56
9.2.1.
Sample Size Assumptions ...........................................................56
9.2.2.
Sample Size Sensitivity................................................................56
9.2.3.
Sample Size Re-estimation or Adjustment...................................57
9.3.
Data Analysis Considerations .....................................................................57
9.3.1.
Analysis Populations....................................................................57
9.3.2.
Interim Analysis ...........................................................................57
9.4.
Key Elements of Analysis Plan ...................................................................57
9.4.1.
Primary Analyses.........................................................................59
9.4.2.
Secondary Analyses ....................................................................62
9.4.3.
Other Analyses ............................................................................63
10. STUDY GOVERNANCE CONSIDERATIONS........................................................67
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............67
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10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................67
10.3.
Quality Control (Study Monitoring) ..............................................................67
10.4.
Quality Assurance.......................................................................................68
10.5.
Study and Site Closure ...............................................................................68
10.6.
Records Retention......................................................................................68
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................69
11. REFERENCES.......................................................................................................70
12. APPENDICES........................................................................................................72
12.1.
Appendix 1: Abbreviation and Trademarks .................................................72
12.2.
Appendix 2: Study Schematic .....................................................................75
12.3.
Appendix 3: Questionnaires........................................................................76
12.4.
Appendix 4: Liver Chemistry Stopping and Follow-up Criteria.....................79
12.5.
Appendix 5: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................82
12.5.1.
Definition of Adverse Events and ADRs.......................................82
12.5.2.
Definition of Serious Adverse Events...........................................83
12.5.3.
Definition of Cardiovascular Events .............................................84
12.5.4.
Recording of AEs (ADRs) and SAEs............................................85
12.5.5.
Evaluating AEs (ADRs) and SAEs ...............................................86
12.5.6.
Reporting of SAEs to GSK...........................................................87
12.6.
Appendix 6: Genetic Research ...................................................................88
12.7.
Appendix 7: Collection of Pregnancy Information........................................91
12.8.
Appendix 8: Protocol Changes....................................................................92
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Actions
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not required in China
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$GGLWLRQDOO\LIVHUXPELOLUXELQIUDFWLRQDWLRQWHVWLQJLVXQDYDLODEOHrecord presence of detectable urinary 
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1.
PROTOCOL SYNOPSIS FOR STUDY HZA116492.................................................9
2.
INTRODUCTION....................................................................................................14
2.1.
Study Rationale ..........................................................................................14
2.2.
Brief Background ........................................................................................15
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................16
4.
STUDY DESIGN ....................................................................................................18
4.1.
Overall Design ............................................................................................18
4.2.
Treatment arms and duration......................................................................21
4.3.
Type and Number of Subjects.....................................................................22
4.4.
Design Justification.....................................................................................22
4.5.
Dose Justification........................................................................................22
4.6.
Benefit:Risk Assessment ............................................................................23
4.6.1.
Risk Assessment .........................................................................24
4.6.1.1.
Benefit Assessment....................................................28
4.6.2.
Overall Benefit: Risk Conclusion..................................................28
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............29
5.1.
Inclusion Criteria.........................................................................................29
5.2.
Exclusion Criteria........................................................................................31
5.3.
Screening/Baseline/Failures .......................................................................32
5.4.
Withdrawal/Stopping Criteria.......................................................................32
5.4.1.
Subjects Lost to Follow-up...........................................................32
5.4.2.
Subject Withdrawal by Investigator or Self-withdrawal .................32
5.4.3.
Liver Chemistry Stopping Criteria ................................................33
5.4.3.1.
Study Treatment Restart or Rechallenge....................35
5.4.4.
QTc Stopping Criteria ..................................................................35
5.5.
Subject and Study Completion....................................................................36
6.
STUDY TREATMENT ............................................................................................37
6.1.
Investigational Product and Other Study Treatment....................................37
6.2.
Medical Devices..........................................................................................38
6.3.
Treatment Assignment................................................................................38
6.4.
Planned Dose Adjustments.........................................................................39
6.5.
Blinding.......................................................................................................40
6.6.
Packaging and Labeling..............................................................................40
6.7.
Preparation/Handling/Storage/Accountability..............................................40
6.8.
Compliance with Study Treatment Administration.......................................41
6.9.
Treatment of Study Treatment Overdose....................................................41
6.10.
Treatment after the End of the Study ..........................................................41
6.11.
Concomitant Medications and Non-Drug Therapies....................................41
6.11.1.
Permitted Medications and Non-Drug Therapies..........................42
6.11.2.
Prohibited Medications and Non-Drug Therapies.........................42
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................42
7.1.
Time and Events Table...............................................................................43
7.2.
Screening and Critical Baseline Assessments ............................................44

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7.3.
Efficacy.......................................................................................................45
7.3.1.
Inhaler Correct Use Assessment .................................................45
7.3.2.
Trough (pre-dose) FEV1 assessment ..........................................47
7.3.3.
Questionnaires ............................................................................48
7.3.3.1.
Asthma Control Test (ACT) ........................................48
7.3.3.2.
Asthma Quality of Life Questionnaire (AQLQ-S).........48
7.3.3.3.
EuroQol Questionnaire (EQ-5D)-5 Level ....................48
7.3.3.4.
Medication Adherence Report Scale for 
Asthma (MARS-A)......................................................48
7.3.3.5.
Patients Satisfaction and Preference with the 
device (PASAP Questionnaire)...................................49
7.4.
Safety .........................................................................................................49
7.4.1.
Adverse Events (AE), Adverse Drug Reactions (ADRs) 
and Serious Adverse Events (SAEs)............................................49
7.4.1.1.
Time period and Frequency for collecting non 
serious ADRs and SAE information............................49
7.4.1.2.
Method of Detecting non serious ADRs and 
SAEs ..........................................................................50
7.4.1.3.
Follow-up of non serious ADRs and SAEs..................50
7.4.1.4.
Cardiovascular and Death Events ..............................51
7.4.1.5.
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ................51
7.4.1.6.
Regulatory Reporting Requirements for SAEs............51
7.4.2.
Pregnancy ...................................................................................52
7.4.3.
Medical Device Incidents (Including Malfunctions).......................52
7.4.4.
Physical Exams ...........................................................................52
7.4.5.
Vital Signs....................................................................................52
7.4.6.
Electrocardiogram (ECG).............................................................53
7.4.7.
Clinical Safety Laboratory Assessments ......................................53
7.5.
Genetics .....................................................................................................53
8.
DATA MANAGEMENT ...........................................................................................53
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................53
9.1.
Hypotheses.................................................................................................53
9.2.
Sample Size Considerations.......................................................................54
9.2.1.
Sample Size Assumptions ...........................................................54
9.2.2.
Sample Size Sensitivity................................................................54
9.2.3.
Sample Size Re-estimation or Adjustment...................................55
9.3.
Data Analysis Considerations .....................................................................55
9.3.1.
Analysis Populations....................................................................55
9.3.2.
Interim Analysis ...........................................................................55
9.4.
Key Elements of Analysis Plan ...................................................................56
9.4.1.
Primary Analyses.........................................................................58
9.4.2.
Secondary Analyses ....................................................................60
9.4.3.
Other Analyses ............................................................................61
10. STUDY GOVERNANCE CONSIDERATIONS........................................................64
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............64
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................64
10.3.
Quality Control (Study Monitoring) ..............................................................65

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10.4.
Quality Assurance.......................................................................................65
10.5.
Study and Site Closure ...............................................................................66
10.6.
Records Retention......................................................................................66
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................67
11. REFERENCES.......................................................................................................68
12. APPENDICES........................................................................................................70
12.1.
Appendix 1: Abbreviation and Trademarks .................................................70
12.2.
Appendix 2: Study Schematic .....................................................................72
12.3.
Appendix 3: Questionnaires........................................................................73
12.4.
Appendix 4: Liver Chemistry Stopping and Follow-up Criteria.....................76
12.5.
Appendix 5: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................79
12.5.1.
Definition of Adverse Events and ADRs.......................................79
12.5.2.
Definition of Serious Adverse Events...........................................80
12.5.3.
Definition of Cardiovascular Events .............................................81
12.5.4.
Recording of AEs (ADRs) and SAEs............................................82
12.5.5.
Evaluating AEs (ADRs) and SAEs ...............................................83
12.5.6.
Reporting of SAEs to GSK...........................................................84
12.6.
Appendix 6: Genetic Research ...................................................................85
12.7.
Appendix 7: Collection of Pregnancy Information........................................88

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CONFIDENTIAL 
 
 
 
HZA116492
 9
 
 
1.  
PROTOCOL SYNOPSIS FOR STUDY HZA116492 
Rationale 
The  pivotal  phase  III  studies were  key  to  demonstrate  the  safety  and  efficacy  of 
Fluticasone Furoate/ Vilanterol in asthma. However, it is increasingly acknowledged that 
randomised  clinical  trials  by  definition  tend to  be  highly  controlled  and  enrol  a  more 
highly selected patient population than is expected to be prescribed the medication post-
approval. The need for data in a more representative population in a close to ‘real world’ 
setting  is  increasingly  being recognised  as  important  to complement  pivotal  phase  III 
safety and efficacy studies in order to establish the benefits and therefore the value of a 
medication in the context of clinical practice.  
Moreover,  double-blind  comparison  of  once  daily  to  twice  daily  medicines,  while 
important for assessing efficacy, removes a potential source of difference in effectiveness 
derived from patient behaviour and experience. GlaxoSmithKline (GSK) has observed an 
increasing demand from payers who make reimbursement and policy decisions for data 
that enables the evaluation of a drug
's effectiveness and impact on the health care system 
at  launch,  e.g.  effectiveness  data  from  a  setting  close  to 
 'real  world
'  in  addition  to 
traditional randomised clinical studies. 
This open-label randomised clinical study will evaluate the efficacy and safety of FF/VI 
Inhalation  Powder  
(FF  92mcg/VI  22mcg  or  FF  184mcg/VI  22mcg)  compared  with  
two 
fixed  combinations  ICS/LABA  (Inhaled  Corticosteroids/Long  Acting  Beta  Agonists) 
inhalation powders, fluticasone propionate/salmeterol (FP/S) and budesonide/formoterol 
(BUD/F),  for  asthma  maintenance  therapy,  in a  “close  to  real  life”  manner  in  French 
primary and respiratory specialist care. FF/VI will be administered once-daily (QD) via 
Ellipta™ and FP/S or BUD/F twice daily (BID) via Diskus™ and Turbuhaler respectively. 
 
Objective(s)/Endpoint(s) 
Objectives
 Endpoints 
Primary 
• To compare the efficacy of FF/VI 
92mcg/ 22mcg or FF 184mcg/22mcg 
with usual fixed combinations 
ICS/LABA for asthma maintenance 
therapy at Week 12 (Visit 4). 
• Change from baseline in the Asthma 
Control Test (ACT) total score at Week 
12 (Visit 4). 
Secondary 
 
• To assess effect of FF/VI on asthma 
control compared with usual ICS/LABA 
fixed combination at Week 24 (Visit 6). 
• To assess ELLIPTA™ inhaler correct use 
compared with other DPI (Diskus
™ and 
Turbuhaler) at Week 12 (Visit 4) and at 
Week 24 (Visit 6) independently of the 
 
• Change from baseline in ACT score at 
Week 24 (Visit 6). 
 
• Percentage of subjects making at least 1 
Type A error (likely to be critical) and 
overall errors at Week 12 (Visit 4) and 
at Week 24 (Visit 6) independently of 
 
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Endpoints
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2017N339371_00

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
HZA116492
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for A 6-month, open label, 
randomised, efficacy study to evaluate fluticasone furoate 
(FF, GW685698)/vilanterol (VI, GW642444) Inhalation 
Powder delivered once daily via the Dry Powder Inhaler 
Ellipta™ compared with usual ICS/LABA maintenance 
therapy delivered by Dry Powder Inhaler in subjects with 
Persistent Asthma
Compound Number 
:
GW685698+GW642444
Effective Date 
:
21-AUG-2017
Description:
The purpose of this document is to describe the final planned analyses and output to be 
included in the Clinical Study Report for Protocol HZA116492.
This RAP is intended to describe the planned efficacy and safety analyses required for the 
study.
This RAP will be provided to the study team members to convey the content of the final 
Statistical Analysis Complete (SAC) deliverable.
Author’s Name and Functional Area: 
05-DEC-2016
Principal Statistician (Clinical Statistics)
16-AUG-2017
Statistics Leader (Clinical Statistics)
Approved by: 
18-AUG-2017
Director, Statistics & Programming (Clinical Statistics)
21-AUG-2017
Programming Manager (Clinical Programming)
Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved. 
Unauthorised copying or use of this information is prohibited.

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CONFIDENTIAL
HZA116492
2
TABLE OF CONTENTS
PAGE
1.
REPORTING & ANALYSIS PLAN SYNPOSIS.........................................................5
2.
RAP AMENDMENTS ...............................................................................................8
3.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................9
3.1.
Changes to the Protocol Defined Statistical Analysis Plan............................9
3.2.
Study Objectives and Endpoints .................................................................12
3.3.
Statistical Hypotheses.................................................................................16
3.4.
Sample Size Assumptions ..........................................................................16
4.
PLANNED ANALYSES ..........................................................................................17
4.1.
Interim Analyses .........................................................................................17
4.2.
Data Look ...................................................................................................17
4.3.
Final Analyses ............................................................................................17
5.
ANALYSIS POPULATIONS ...................................................................................18
5.1.
Protocol Deviations.....................................................................................19
6.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................20
7.
STUDY POPULATION ANALYSES .......................................................................21
7.1.
Overview of Planned Analyses ...................................................................21
8.
PRIMARY STATISTICAL ANALYSES....................................................................22
8.1.
Efficacy Analyses........................................................................................22
8.1.1.
Overview of Planned Efficacy Analyses .......................................22
8.1.2.
Planned Efficacy Statistical Analyses...........................................23
9.
SECONDARY STATISTICAL ANALYSES .............................................................26
9.1.
Efficacy Analyses........................................................................................26
9.1.1.
Overview of Planned Efficacy Analyses .......................................26
9.1.2.
Planned Efficacy Statistical Analyses...........................................27
9.2.
Safety Analyses..........................................................................................29
9.2.1.
Overview of Planned Analyses ....................................................29
9.2.2.
Benefit:Risk analyses...................................................................30
10. OTHER STATISTICAL ANALYSES .......................................................................32
10.1.
Other Analyses ...........................................................................................32
10.1.1.
Overview of Planned Other Analyses...........................................32
10.1.2.
Planned Other Statistical Analyses ..............................................34
11. REFERENCES.......................................................................................................37
12. APPENDICES........................................................................................................38
12.1.
Appendix 1: Protocol Deviation Management and Definitions for PP 
Population...................................................................................................39
12.1.1.
Protocol Deviations......................................................................39
12.1.2.
Exclusions from PP Population....................................................39
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12.2.
Appendix 2: Time & Events.........................................................................41
12.2.1.
Protocol Defined Time & Events ..................................................41
12.3.
Appendix 3: Assessment Windows .............................................................43
12.4.
Appendix 4: Treatment States and Phases.................................................44
12.4.1.
Treatment Phases .......................................................................44
12.4.2.
Treatment States .........................................................................44
12.4.2.1.
Treatment States for Concomitant Medications ..........44
12.4.2.2.
Treatment States for Efficacy Measurements .............45
12.4.2.3.
Treatment States for Exacerbation Data.....................45
12.4.2.4.
Treatment States for AE Data.....................................45
12.5.
Appendix 5: Data Display Standards & Handling Conventions....................46
12.5.1.
Study Treatment & Sub-group Display Descriptors......................46
12.5.2.
Baseline Definition & Derivations .................................................46
12.5.2.1.
Baseline Definitions....................................................46
12.5.2.2.
Derivations and Handling of Missing Baseline 
Data ...........................................................................46
12.5.3.
Reporting Process & Standards...................................................46
12.6.
Appendix 6: Derived and Transformed Data ...............................................48
12.6.1.
General........................................................................................48
12.6.2.
Study Population..........................................................................48
12.6.3.
Efficacy........................................................................................49
12.6.4.
Safety ..........................................................................................56
12.7.
Appendix 7: Premature Withdrawals & Handling of Missing Data ...............57
12.7.1.
Premature Withdrawals................................................................57
12.7.2.
Handling of Missing Data.............................................................57
12.7.2.1.
Handling of Missing or Partial Dates...........................57
12.7.2.2.
Handling of Missing Data for Statistical 
Analysis......................................................................58
12.8.
Appendix 8: Values of Potential Clinical Importance ...................................59
12.8.1.
Vital Signs....................................................................................59
12.9.
Appendix 9: Multicenter Studies..................................................................60
12.9.1.
Methods for Handling Centres .....................................................60
12.10. Appendix 10: Examination of Covariates, Subgroups & Other Strata..........61
12.10.1. Examination of Strata and Covariates..........................................61
12.10.2. Examination of subgroups ...........................................................61
12.10.3. Examination of seasonal effect ....................................................62
12.11. Appendix 11: Multiple Comparisons & Multiplicity .......................................63
12.11.1. Handling of Multiple Comparisons & Multiplicity...........................63
12.12. Appendix 12: Model Checking and Diagnostics for Statistical 
Analyses.....................................................................................................64
12.12.1. Statistical Analysis Assumptions..................................................64
12.13. Appendix 13: Blinding Strategy...................................................................66
12.14. Appendix 14: Abbreviations & Trade Marks ................................................67
12.14.1. Abbreviations...............................................................................67
12.14.2. Trademarks .................................................................................68
12.15. Appendix 15: List of Data Displays..............................................................69
12.15.1. Data Display Numbering..............................................................69
12.15.2. Mock Example Shell Referencing ................................................69
12.15.3. Deliverable [Priority].....................................................................69
12.15.4. Study Population Tables..............................................................70
12.15.5. Study Population Figures.............................................................74
12.15.6. Efficacy Tables ............................................................................75
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12.15.7. Efficacy Figures ...........................................................................93
12.15.8. Safety Tables...............................................................................97
12.15.9. Safety Figures ...........................................................................100
12.15.10.ICH Listings ...............................................................................101
12.15.11.Non-ICH Listings........................................................................102
12.16. Appendix 16: Example Mock Shells for Data Displays ..............................104
12.16.1. Study Population Table Shells ...................................................104
12.16.2. Study Population Figure Shells..................................................118
12.16.3. Efficacy Table Shells .................................................................119
12.16.4. Efficacy Figure Shells ................................................................166
12.16.5. Safety Table Shells....................................................................177
12.16.6. Safety Figure Shells...................................................................181
12.16.7. Non-ICH Listing Shells...............................................................183
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HZA116492
5
1.
REPORTING & ANALYSIS PLAN SYNPOSIS
Overview
Key Elements of the RAP
Purpose
This RAP details all planned analyses and output required for the final Clinical Study Report 
of study HZA116492.
Protocol
This RAP is based on the protocol amendment 02 (Dated: 28-APR-2016) of study 
HZA116492 (GSK Document No.: 2014N190259_02).
Primary 
Objective 
To compare the efficacy of fluticasone furoate (FF)/vilanterol(VI) 92 mcg/22 mcg or FF 184
mcg/22 mcg with usual fixed combinations inhaled corticosteroid / long-acting beta agonist 
(ICS/LABA) for asthma maintenance therapy at Week 12 (Visit 4).
Primary 
Endpoint
Change from baseline in the Asthma Control Test (ACT) total score at Week 12 (Visit 4).
Study 
Design
This is a Phase IIIb multi-center randomised open label, parallel group study performed in 
subjects in primary and in respiratory specialist care / research sites who have a diagnosis 
of asthma and a regular treatment for asthma. Subjects with unsatisfactorily controlled 
asthma (defined as an ACT < 20) and intended to be treated by usual ICS/LABA 
maintenance therapy to seek a better control of their asthma will be randomised to receive 
either FF/VI (FF/VI 92 mcg/22 mcg or FF/VI 184 mcg/22 mcg) once daily or another usual 
ICS/LABA combination therapy in inhalation powder twice daily (fluticasone 
propionate[FP]/salmeterol [S] or budesonide[BUD]/formoterol [F]) decided by the physician. 
Physicians will be allowed during the treatment period to adapt prescription to different 
doses if necessary as well as to adapt doses of any comparative treatment according to 
products label.
Planned 
Analyses
No interim analysis is planned for this study.
All decisions regarding final analysis for the reporting effort, as defined in this RAP 
document, will be made prior to Database Freeze (DBF) (unblinding) of the study data.
All planned analyses will be carried out once DBF has taken place. Once this has been 
achieved, unblinding will occur and the analyses will be performed.
The open-label study design and the method of recording study medication data in the 
datasets means that extra steps must be taken to ensure that Statistics and Programming 
(S&P) remain blinded to study investigator prescribing of study medication until the formal 
unblinding takes place at DBF. See Section 12.13 for more details. 
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HZA116492
6
Overview
Key Elements of the RAP
Analysis 
Populations
All Subjects Enrolled (ASE) population: All subjects screened (provided consent) and for 
whom a record exists on the study database. Note, this population is not identified in the 
protocol, but is needed for displays that include subjects screened but not in the intent-to-
treat (ITT) population (e.g. tabulation of reasons for withdrawal before randomisation).
Intent-to-treat (ITT) population: All randomized subjects having received at least one dose 
of the prescription of study medication (either FF/VI or usual ICS/LABA asthma maintenance 
therapy). The ITT population will be used to analyze the primary efficacy endpoint analysis, 
the secondary efficacy endpoint and other efficacy endpoints. Subjects will be assigned to 
the treatment group as randomized for the ITT population. 
Per protocol (PP) population: all ITT subjects without any protocol deviations specifically 
defined in this RAP. Protocol deviations will be reviewed and will be classified as important 
or not important during data review meetings that will be held before DBF. Deviations 
classified as important will be further defined according to whether they require the patient to 
be excluded from the PP population. Deviations that exclude a patient from the PP 
population are defined in this RAP (see Section 12.1.2). Subjects will be assigned to the 
treatment group as treated for the PP population.
Safety population: All enrolled subjects having received at least one dose of the 
prescription of study medication (either FF/VI or usual ICS/LABA asthma maintenance 
therapy) and considered as-treated. The Safety population will be the basis for safety 
analyses. Subjects will be assigned to the treatment group as treated for the Safety 
population.
Hypothesis
The primary analysis is designed to determine whether the fixed combination FF/VI is non-
inferior to any other ICS/LABA combinations in inhalation powder assuming a non-inferiority 
margin of 1.5. Non-inferiority will be claimed if the 95% two-sided confidence interval (CI) on 
the difference in mean primary efficacy endpoints (FF/VI versus ICS/LABA comparator) 
precludes the non-inferiority margin of -1.5. 
If (and only if) non-inferiority is significantly achieved at Week 12 (Visit 4) with regard to the 
primary endpoint, then non-inferiority of the fixed combination FF/VI to any other ICS/LABA 
combinations will be tested at Week 24 (Visit 6) considering the same non-inferiority margin 
of 1.5. Non-inferiority will be claimed if the 95% two-sided CI on the difference in mean 
primary efficacy endpoints (FF/VI versus ICS/LABA comparator) at Week 24 (Visit 6) 
precludes the non-inferiority margin of -1.5. This step-down testing procedure strongly 
controls the overall type I error of the non-inferiority endpoints at the 0.05 two-sided level. 
Primary 
Analyses
The primary endpoint will be analysed using a mixed model repeated measures (MMRM) 
approach. The model will include factors and covariates as follows: randomised treatment, 
scheduled visit time point (Week 6 and Week 12), baseline ACT total score, randomised 
treatment-by-visit interaction, baseline ACT total score-by-visit interaction, gender, age, 
country and patient will be fitted as a random factor. The Restricted Maximum Likelihood 
(REML) estimation approach will be used, and the default covariance structure will be 
unstructured.  Consistent with MMRM model fitting, no explicit imputation of missing 
assessments for a given time point will be performed. The adjusted means for each 
treatment and the estimated treatment differences for the treatment comparisons will be 
presented together with the 95% CIs for the differences (FF/VI versus ICS/LABA 
comparator) and p-values at Week 12 (Visit 4).
If non-inferiority is statistically achieved at Week 12 (Visit 4), then superiority of FF/VI to any 
other comparator will be tested at the usual 0.05 two-sided nominal level of significance.
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HZA116492
7
Overview
Key Elements of the RAP
The same models and analyses mentioned above will be used to assess the superiority 
hypothesis. 
Secondary 
Analyses
Key secondary analysis
The key secondary endpoint assessed at Week 24 (Visit 6) will also be analyzed using a 
MMRM approach where data up to and including Week 24 (Visit 6) will be used in the model.  
The model will include factors and covariates as follows: randomised treatment, scheduled 
visit time point (Week 6, Week 12, Week 18 and Week 24), baseline ACT total score, 
randomised treatment-by-visit interaction, baseline ACT total score-by-visit interaction, 
gender, age, country and patient will be fitted as a random factor. The REML estimation 
approach will be used, and the default covariance structure will be unstructured.  Consistent 
with MMRM model fitting, no explicit imputation of missing assessments for a given time 
point will be performed. The adjusted means for each treatment and the estimated treatment 
difference for the treatment comparison will be presented together with the 95% CI for the 
difference (FF/VI versus ICS/LABA comparator) and p-value at Week 24 (Visit 6). If non-
inferiority is statistically achieved at Week 24 (Visit 6), then superiority of FF/VI versus any 
other comparator will be tested at the usual 0.05 two-sided nominal level of significance.
The same models and analyses mentioned above will be used to assess the superiority 
hypothesis. 
Other secondary analyses
The other key secondary endpoint will be the correct use of the inhaler device assessed at 
randomisation (Visit 2), at Week 12 (Visit 4) and at Week 24 (Visit 6). The device will be 
considered as correctly used if the patient didn’t make any critical or non-critical errors at the 
corresponding visits (randomisation [Visit 2], Week 12 [Visit 4] and Week 24 [Visit 6]). 
Percentages of subjects correctly using the device will be calculated within each group. A 
corresponding 95% CI of the difference in percentages will also be provided.
An exploratory analysis of the categorised data will be performed using logistic regression 
models with covariates as follows: randomised treatment, correct use of inhaler device at 
baseline, randomised treatment-by-visit interaction, gender, age and country. The estimated 
treatment differences will be displayed as odds ratios together with 95% CIs and p-values.
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HZA116492
8
2.
RAP AMENDMENTS
A summary of the amendments made to the RAP are listed here.
Amendment Details
RAP-HZA116492 [05-DEC-2016]
GSK2285997-116492 Statistical Analysis Plan Reporting and Analysis Plan
(Amendment 1) Version 001 [21-AUG-2017]
Subjects with a missed or out of window Visit 4 will no longer lead to exclusion from the 
PP population.
Treatment compliance calculation now covers changes in dose.
Clarified age range to be used, multiple sections
Updated standard shell references in Section 12.15
Added time since last dose derivation.
Resolved discrepancies between main body and example shells for terms included in 
subgroup analyses 
Clarified labelling: “Day 0” to be labelled as “Randomisation (Day 0)”
Clarified labelling for MARS-A subgroups
Other label ordering clarifications
Removed references to PCI values for Vital Signs and updated tables accordingly
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HZA116492
9
3.
SUMMARY OF KEY PROTOCOL INFORMATION
3.1.
Changes to the Protocol Defined Statistical Analysis Plan
Any changes from the originally planned statistical analysis specified in the protocol are outlined 
in Table 1.
Table 1
Changes to Protocol Defined Analysis Plan
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes
!
N/A
!
The open-label study 
design and the method of
recording study medication 
data in the datasets means 
that extra steps must be 
taken to ensure that S&P 
remain blinded to study 
investigator prescribing of 
study medication until the 
formal unblinding takes 
place at DBF. See Section 
12.13 for more details.
!
To preserve the integrity of 
the analyses, S&P will 
remain blinded prior to 
formal unblinding at DBF. 
All planned analyses will be 
carried out after this point.
!
N/A
!
All Subjects Enrolled 
(ASE) Population: All
subjects screened (provided 
consent) and for whom a 
record exists on the study 
database. Note, this 
population is not identified 
in the protocol, but is 
needed for displays that 
include subjects screened 
but not in the ITT 
Population (e.g. tabulation 
of reasons for withdrawal 
before randomisation).
!
Population needed for 
displays that include 
subjects screened but not in 
the ITT population.
!
Continuous variables will be 
summarized using descriptive 
statistics (number of observed 
and missing data, mean, 
standard deviation (SD), median, 
Q1, Q3, minimum, and
maximum).
!
Categorical variables will be 
summarized as numbers of 
observed and missing data,
counts and percentage for each 
category (reported to the number 
of non-missing values). For 
binary variables, 95% confidence 
!
See Appendix 16: 
Example Mock Shells for 
Data Displays for example 
mock shells for data 
displays
!
Continuous and categorical 
variables will be 
summarized in line with 
GSK Integrated Data 
Standards Library (IDSL)
data standards
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HZA116492
10
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes
intervals for proportions will be 
estimated based on the Clopper-
Pearson method.
!
If treatment is withdrawn, then 
the missing ACT score at the 
nearest visit after treatment 
withdrawal will be replaced by 
the ACT score assessed at 
withdrawal time. If no ACT score 
is assessed at withdrawal time, 
then the ACT missing score at 
the nearest visit after treatment 
withdrawal will not be replaced.
!
Consistent with MMRM 
model fitting, no explicit 
imputation of missing 
assessments for a given 
time point will be performed.
!
The protocol inconsistently 
describes whether or not 
missing scores will be 
imputed. Consistent with 
MMRM models and the 
MAR assumption they are 
based upon, no missing 
data will be imputed for the 
primary efficacy analysis. 
Sensitivity analyses for the
primary endpoint are 
proposed in Section 8.1.2
and will consider imputation 
of missing data.
!
The primary endpoint will be 
analysed using a mixed model 
repeated measures (MMRM) 
approach. The model will include 
factors and covariates as 
follows: treatment, scheduled 
visit time point (Week 6 and 
Week 12), baseline ACT, 
treatment by visit interaction, 
baseline ACT by visit interaction, 
gender, age and patient will be 
fitted as a random factor.
!
The primary endpoint will be 
analysed using a MMRM 
approach. The model will 
include factors and 
covariates as follows: 
randomised treatment, 
scheduled visit time point 
(Week 6 and Week 12), 
baseline ACT total score, 
randomised treatment-by-
visit interaction, baseline 
ACT total score-by-visit 
interaction, gender, age, 
country and patient will be 
fitted as a random factor.
!
Clarified that randomised
treatment and baseline ACT 
total score will be included. 
Additionally country will be 
included in the model due to 
the addition of Germany, 
and separate randomisation 
schedules for France and 
Germany achieving 
stratification by country
!
Same changes for 
secondary and other 
analyses
!
Sensitivity analyses (for the 
primary endpoint)
!
Text changed and clarified
!
The text from the protocol 
regarding sensitivity 
analyses has been updated 
and clarified where 
necessary. Description of 
the multiple imputation (MI) 
process has been brought 
in line with GSK standard 
text.
!
Usual ICS/LABA maintenance 
therapy
!
Usual ICS/LABA
!
The comparator arm is 
described as “Usual 
ICS/LABA” for consistency 
with reporting of the 
HZA115150 study (GSK 
Document No.:
2011N129785_02).
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HZA116492
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Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes
!
EQ-5D
!
EQ-5D-5L
!
Clarity as to which version 
of the EuroQol 
questionnaire is being used
!
Binary response defined as an 
ACT score ≥ 20 at a given visit 
OR a 3 point increase from 
baseline in ACT change.
!
The responder analyses will be 
conducted using a logistic 
regression model at a given Visit 
or Phone Call adjusting for 
treatment and stratification 
factors (baseline ACT score 
categorized into two classes, 
baseline asthma therapy, and 
potentially season at
randomization). Treatment by 
stratification factors interaction 
effects will be further
investigated in additional logistic 
models adjusting for these 
specific effects.
!
This endpoint will be 
analysed using a logistic 
regression model adjusting 
for randomised treatment, 
gender, country, baseline 
ACT total score, baseline 
ACT total score squared 
and age
!
Clarified that randomised
treatment will be included. 
!
Country will be included in 
the model due to the 
addition of Germany, and 
separate randomisation 
schedules for France and 
Germany achieving 
stratification by country
!
Due to this being a 
composite endpoint, a 
quadratic relationship is 
expected between baseline 
score and probability of 
response. Baseline ACT 
total score and baseline 
ACT total score squared will 
be included (instead of 
“baseline ACT score 
categorised into two 
classes”) to account for this
!
All patients are on the same 
baseline asthma therapy 
class (ICS), therefore this 
will not be included as a 
covariate
!
Season at randomisation 
will not be included; this is 
only considered as 
sensitivity analysis for the 
primary efficacy endpoint
!
N/A
!
≥ 3 point increase from 
baseline in ACT total score 
at Week 12 (Visit 4) and 
Week 24 (Visit 6)
!
Time to first severe asthma 
exacerbation
!
These endpoints have been 
added for consistency with 
the HZA115150 study (GSK 
Document No.: 
2011N129785_02).
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HZA116492
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3.2.
Study Objectives and Endpoints
Objectives
Endpoints
Primary Objective
Primary Endpoint
!
To compare the efficacy of FF/VI 92 mcg/ 22
mcg or FF 184 mcg/22 mcg with usual fixed 
combinations ICS/LABA for asthma 
maintenance therapy at Week 12 (Visit 4).
!
Change from baseline in the ACT total score at 
Week 12 (Visit 4).
Secondary Objectives
Secondary Endpoints
!
To assess effect of FF/VI on asthma control 
compared with usual ICS/LABA fixed 
combination at Week 24 (Visit 6).
!
Change from baseline in ACT score at Week 24 
(Visit 6).
!
To assess Ellipta™ inhaler correct use 
compared with other dry powder inhaler (DPI)
(Diskus and Turbuhaler) at Week 12 (Visit 4) 
and at Week 24 (Visit 6) independently of the 
use at Week 12 (Visit 4).
!
Percentage of subjects with correct use of device 
(defined as not making any critical error or non-
critical error) at Week 12 (Visit 4) and at Week 24 
(Visit 6) independently of the use at Week 12 (Visit 
4).
Other Objectives
Other Endpoints
!
To assess effect of FF/VI on trough (pre-
dose) forced expiratory volume in 1 second 
(FEV1) compared with usual ICS/LABA fixed 
combination at Week 12 (Visit 4)
!
Change from baseline in trough (pre-dose) FEV1 
at Week 12 (Visit 4).
!
To assess the effect of FF/VI on response to 
treatment at Week 12 (Visit 4) and Week 24 
(Visit 6)
!
ACT score ≥ 20 or ≥ 3 point increase from 
baseline in ACT at Week 12 (Visit 4) and Week 24 
(Visit 6). Note: A 3 point increase in ACT total 
score was suggested as the Minimal Clinically 
Important Difference (MCID) in the literature 
(Schatz, 2009).
!
ACT score ≥ 20 at Week 12 (Visit 4) and Week 24 
(Visit 6). 
!
≥ 3 Point Increase from Baseline in ACT Total 
Score at Week 12 (Visit 4) and Week 24 (Visit 6)
!
Change from baseline in individual question 
scores for ACT at Weeks 12, 24
!
To assess the compliance with study 
medication and self-reported adherence to 
study medication at Week 12 (Visit 4) and 
Week 24 (Visit 6)
!
Compliance 
with 
study 
medication 
from 
Randomisation (Day 0) to Week 12 (Visit 4), from 
Week 12 (Visit 4) to Week 24 (Visit 6) and from 
randomisation (Day 0) to Week 24 (Visit 6).
!
Score of the Medication Adherence Report Scale 
for 
Asthma 
(MARS-A) 
questionnaire 
at 
Randomisation (Day 0), Week 12 (Visit 4) and 
Week 24 (Visit 6).
!
To assess the effect of FF/VI on severe 
asthma exacerbation over the study period
!
Number of subject with at least 1 severe asthma 
exacerbation*, number of severe asthma 
exacerbation and annual severe exacerbation rate 
over the study period.
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HZA116492
13
Objectives
Endpoints
!
Time to first severe asthma exacerbation
!
To assess the effect of FF/VI on Health 
Related Quality of Life at Week 24 (Visit 6)
!
Change from baseline in total score and domain 
scores of standardised Asthma Quality of Life 
Questionnaire (AQLQ[S]) at Week 24 (Visit 6).
!
An increase from baseline of ≥ 0.5 in AQLQ(s) 
total score at Week 24 (Visit 6).
!
An increase from baseline of ≥ 0.5 in AQLQ(s) 
environmental stimuli domain score at Week 24 
(Visit 6).
!
Percentage of subjects who have an increase from 
baseline of ≥ 0.5 in AQLQ(S) individual domain 
scores at Week 24 (Visit 6).
!
Change from baseline in total score and domain 
scores of AQLQ(S) at Week 24 (Visit 6). 
!
Health status using the EuroQol Questionnaire 
(EQ-5D-5L) at Week 24 (Visit 6).
!
To assess Patient Satisfaction and 
Preference assessment with different 
inhalers at Week 12 (Visit 4)
!
Score of Patient Satisfaction and Preference
Questionnaire (PASAP-Q) at Week 12 (Visit 4).
!
To evaluate the Safety of FF/VI compared 
with usual ICS/LABA (FP/S and BUD/F).
!
Serious Adverse Events (SAE) and non-serious 
Adverse Drug Reactions (ADR):
o
Frequency and type of SAEs,
o
Frequency and type of non-serious ADRs 
related to treatment.
* A severe asthma exacerbation will be defined as deterioration of asthma requiring the use of systemic 
corticosteroids2 (tablets, suspension, or injection) for at least 3 days or an inpatient hospitalisation, or 
emergency department visit due to asthma that required systemic corticosteroids 1,2,3.
Notes defining endpoints:
1. Contacts with a doctor or hospitalisation are defined as exacerbation-related contacts if these contacts 
were a direct result of an acute worsening of asthma symptoms.
2. A prescription of systemic corticosteroid is defined as exacerbation-related if the reason the drug was 
given, in whole or in part, was to treat an acute worsening of asthma symptoms.
3. Exacerbation-related hospitalisation includes hospitalisation that is prolonged as a result of an asthma 
exacerbation.
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HZA116492
14
Overview of Study Design and Key Features
HZA 116492: study design 
V2
Day 0
Randomisation
V1
Day-7-1
Screening
ACT , MARS-A, 
AQLQ, EQ-5D, 
Spirometry
Asthma treated with
ICS (MDI, DPI), n=422
Relvar 92/22 or 184/22 μg
ICS/LABA DPI on the market
Seretide®, Symbicort®
1-7 days
R
6 months
ACT < 20
V2, errors ass-t:
• Read,
•Demonstration by HCP,
•1 dose,
•Errors asst & correction
V4
Week 12
V6
Week 24
Possibility to combine 
V1+V2= Day 0
V3
Phone call 1
Week 6
V5
Phone call 2 
Week 18
V4, errors ass-t:
•1 dose,
•Errors asst
•Demonstration by 
HCP if critical errors
V6, errors ass-t:
•1 dose,
•Errors asst
•Demonstration by 
HCP if critical errors
ACT, safety
ACT, safety
ACT , MARS-A, 
PASAP, 
Spirometry
ACT , MARS-A, 
AQLQ, EQ-5D
!
A phone call is provided at Week 6 and Week 18 in order to check whether the subject has 
experienced any AEs and then the Investigator calling the patient must determine whether the 
event is related to study medication (either arm) and whether the event is serious. At these 
telephone calls subjects will also be asked to complete the ACT questionnaire and to send it back 
to the Investigator.
!
Week 12 (Visit 4) should be scheduled at the same time of day as the randomisation visit (Visit 2).
Design 
Features
!
This is a Phase IIIb multi-center randomised open label, parallel group study 
performed in subjects in primary and respiratory specialist care / research sites who 
have a diagnosis of asthma and a regular treatment for asthma.
!
Subjects with unsatisfactorily controlled asthma (defined as ACT total score < 20) and 
intended to be treated by usual ICS/LABA maintenance therapy to seek a better 
control of their asthma will be randomised to receive either FF/VI once daily or another 
usual ICS/LABA combination therapy in inhalation powder twice daily (FP/S or BUD/F) 
decided by the physician.
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HZA116492
15
Overview of Study Design and Key Features
Treatment 
Assignment
Subjects will be assigned to study treatment in accordance with the randomisation 
schedule.
Subjects will be randomised in a 1:1 ratio to one of the 2 following treatment groups: 
FF/VI (as per dose guidance below) 
Initiate on usual inhaled dry powder ICS/LABA fixed combination for asthma 
maintenance therapy (i.e. Seretide Diskus or SymbicortTurbuhaler) according to usual 
physician’s prescription. 
Dose Guidance:
For subjects randomised to FF/VI, Investigator can make dosing decision based on the 
guidance below:
!
FF/VI 92 mcg/22mcg dose once a day is approximately equivalent to FP/S medium 
dose (250 mcg/50mcg) and BUD/F medium dose (200 mcg/6 mcg) twice a day. See 
Table 2 for further guidance for doses conversion for other corticosteroids.
!
FF/VI 184 mcg/22 mcg dose once a day is approximately equivalent to FP/S high 
dose (500 mcg/50 mcg) and to BUD/F high dose (400 mcg/12 mcg) twice a day. See 
Table 2 for guidance for dose conversion for other corticosteroids.
!
Starting doses are: 92 mcg/22 mcg once daily for FF/VI; 250 mcg/50 mcg twice daily 
for FP/S and 200 mcg/6 mcg twice daily for BUD/F.
Table 2
ICS/LABA Daily Dose (SmPC Seretide Diskus; Symbicort 
Turbuhaler)
Formulation
Inhaler Devices
Doses Available (mcg)  
ICS/LABA and 
Inhalations/day 
Fluticasone propionate/salmeterol
DPI (Diskus)
1 inhalation x 2
Medium-dose 250/50
High-dose 500/50
Budesonide/formoterol
DPI (Turbuhaler)
1-2 inhalations  x 2
Medium-dose 200/6 
High-dose 400/12 
Information extracted from Global Initiative for Asthma (GINA, 2012).
For patients with moderate to severe hepatic impairment, the 92/22 micrograms dose of 
FF/VI should be used and patients should be monitored for systemic corticosteroid-related 
adverse reactions.
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HZA116492
16
Overview of Study Design and Key Features
Planned Dose Adjustments
Subjects for whom it is considered appropriate/necessary to adjust treatment can 
have their dose increased from the starting dose as would be normal clinical 
practice at the Investigator’s discretion. This will not require the subject to be 
withdrawn from the study.
It is not permitted for patients to be switched to a different treatment i.e. patients 
randomised to the usual ICS/LABA arm cannot change to a different ICS/LABA or 
receive FF/VI. Patients randomised to the FF/VI arm cannot receive usual 
ICS/LABA. If a switch between products is required, the patient should be 
withdrawn from the study.
Interim 
Analysis
No interim analysis is planned for this study.
From this point onwards in the RAP, usual ICS/LABA maintenance therapy will be referred to as 
usual ICS/LABA.
3.3.
Statistical Hypotheses
The primary endpoint is defined as the change from baseline in the ACT total score assessed at 
Week 12 (Visit 4). The primary analysis will assess the non-inferiority of fixed combination 
FF/VI to usual ICS/LABA in inhalation powder assuming a non-inferiority margin of 1.5. Non-
inferiority will be claimed if the 95% two-sided confidence interval on the difference in mean 
primary efficacy endpoints (FF/VI versus usual ICS/LABA) precludes the non-inferiority margin 
of -1.5. 
If (and only if) non-inferiority is significantly achieved at Week 12 (Visit 4) with regard to the 
primary endpoint, then non-inferiority of the fixed combination FF/VI to usual ICS/LABA will be 
tested at Week 24 (Visit 6) considering the same non-inferiority margin of 1.5. Non-inferiority 
will be claimed if the 95% two-sided confidence interval on the difference in mean primary 
efficacy endpoints (FF/VI versus usual ICS/LABA) at Week 24 (Visit 6) precludes the non-
inferiority margin of -1.5. 
Of note, as the two tests for non-inferiority are sequentially performed, the closure principle holds 
and there is no need to adjust the two-sided nominal level of significance (i.e. 0.05) for each test. 
3.4.
Sample Size Assumptions
Results based on the HZA106829 study have shown that the estimated SD of the change in ACT 
score was 3.7.  Unpublished data have shown that the standard deviation of change of ACT 
ranged from 3.8 to 4.8. Therefore, a somewhat conservative choice of SD of 4.5 point is retained.  
Based on the literature (Schatz, 2009), the Minimally Important Difference (MID) of the ACT 
could be considered as 3 points. Half this MID (i.e. 1.5) could therefore be used to define the non-
inferiority margin.
Assuming a 4.5 point standard deviation for the change in ACT total score at Week 12 (Visit 4), a 
1.5 point non-inferiority margin, and a two-sided nominal significance level of 0.05, the sample 
size needed per group to achieve at least a 90% power is 191 (i.e. a total of 382 subjects). 
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Assuming a 10% dropout rate, around 422 subjects must be randomized either to FF/VI or to 
usual ICS/LABA in 1:1 ratio to achieve at least a 90% power.
4.
PLANNED ANALYSES
4.1.
Interim Analyses
Not applicable.
4.2.
Data Look
At a date agreed by the study team and the contract research organisation (CRO) (selected to 
execute the statistical analyses specified in this RAP), a data look will be performed using blinded 
treatment codes on a subset of the data. The aim of the data look is solely to ensure that all of the 
required tables, figures and listings are being produced and formatted correctly, such that the 
output produced on unblinded data at the end of the study is correct and complete.  This data look 
will be performed when sufficient data are available, but early enough to leave time for changes 
to be made to the planned outputs and methods prior to database release (DBR). Any changes will 
be documented before DBR.
4.3.
Final Analyses
All planned analyses will be performed after the completion of the following sequential steps:
1.
All subjects have completed the study as defined in the protocol 
2.
All required database cleaning activities have been completed and final DBR has been 
declared by Data Management.
3.
All protocol deviations (PDs) have been confirmed
4.
All criteria for unblinding the randomisation codes have been met. 
5.
Randomisation codes have been distributed according to RandAll NG procedures.
6.
DBF has been declared by Data Management.
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5.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
All Subjects 
Enrolled (ASE)
!
Comprise of all subjects screened (provided 
consent) and for whom a record exists on the study 
database. 
!
Note, this population is not identified in the 
protocol, but is needed for displays that include 
subjects screened but not in the ITT Population 
(e.g. tabulation of reasons for withdrawal before 
randomisation)
!
Subject disposition 
tables
Intent-to-Treat (ITT)
!
Comprise of all randomized subjects having 
received at least one dose of the prescription of 
study medication (either FF/VI or usual ICS/LABA)
!
Subjects will be assigned to the treatment group as 
randomized for the ITT population
!
Study Population
!
Efficacy
Per Protocol (PP)
!
Comprise of all randomized subjects who receive 
at least one dose of study treatment and who 
comply with the protocol. 
!
Protocol deviations that would exclude subjects 
from the PP population are defined in Section 5.1
(Protocol Deviations) and Appendix 1 (Protocol 
Deviation Management and Definition for Per-
Protocol Population).
!
This population will be 
used for summaries 
and re-analyses of the 
primary efficacy 
secondary efficacy 
endpoints. 
Safety
!
Comprise of all enrolled subjects having received 
at least one dose of study medication (either FF/VI 
or usual ICS/LABA) and considered as-treated.
!
Subjects will be assigned to the treatment group as 
treated for the Safety population
!
Safety
NOTES: 
!
Please refer to Appendix 15: List of Data Displays which details the population to be used for each displays being 
generated.
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5.1.
Protocol Deviations
All PDs (any deviation from the protocol) are tracked and monitored during the study. Important 
PDs are those deviations that may compromise subject rights, safety, or well-being, and/or data
integrity, and/or study end-points, and are defined in the protocol deviation management plan 
(PDMP). Apart from any incorrect treatment deviations, all protocol deviations will be agreed 
upon prior the unblinding and the freezing of the database. All deviations from the 
inclusion/exclusion criteria, and important PDs will be summarised. A listing of treatment 
misallocations will be produced.
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6.
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS
Table 3 provides an overview of appendices within the RAP for outlining general considerations 
for data analyses and data handling conventions. 
Table 3
Overview of Appendices
Section
Component
12.1
Appendix 1: Protocol Deviation Management and Definitions for PP Population
12.2
Appendix 2: Time & Events
12.3
Appendix 3: Assessment Windows
12.4
Appendix 4: Treatment States and Phases
12.5
Appendix 5: Data Display Standards & Handling Conventions
12.6
Appendix 6: Derived and Transformed Data
12.7
Appendix 7: Premature Withdrawals & Handling of Missing Data
12.8
Appendix 8: Values of Potential Clinical Importance
12.9
Appendix 9: Multicenter Studies
12.10
Appendix 10: Examination of Covariates, Subgroups & Other Strata
12.11
Appendix 11: Multiple Comparisons & Multiplicity
12.12
Appendix 12: Model Checking and Diagnostics for Statistical Analyses
12.13
Appendix 13: Blinding Strategy
12.14
Appendix 14: Abbreviations & Trade Marks
12.15
Appendix 15: List of Data Displays
12.16
Appendix 16: Example Mock Shells for Data Displays
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7.
STUDY POPULATION ANALYSES
7.1.
Overview of Planned Analyses
The study population analyses will be based on the ITT population, unless otherwise specified.
Table 4 provides an overview of the planned study population analyses, with full details of data 
displays being presented in Appendix 15: List of Data Displays.
Table 4
Overview of Planned Study Population Analyses
Display Type
Data Displays Generated
Table
Figure
Listing
Subject Disposition
Subject Populations
Y[1]
Y
Inclusion/exclusion Criteria Failures for Subjects Not 
Starting Treatment
Y[1]
End of Study Record 
Y[2]
Y
Attendance at Each Clinic Visit and Phone Call Visit
Y
Number of Subjects by Country and Centre
Y[2,3]
Randomised and Actual Treatments
Y
Protocol Deviations
Deviations from the Inclusion/Exclusion Criteria 
Y
Y
Important Protocol Deviations 
Y
Y
Important Protocol Deviations Resulting in Exclusion from 
the PP Population
Y
Y
Treatment Misallocations
Y
Demographic and Baseline Characteristics
Demographic Characteristics
Y[2,4]
Y
Race and Racial Combinations
Y
Y
Race and Racial Combinations Details
Y
Current and Past Medical Conditions
Y
Asthma Duration at Baseline 
Y[2]
Y
Asthma Exacerbation History at Baseline
Y[2]
Y
Lung Function at Baseline
Y
Smoking History at Baseline
Y[2]
Y
Concomitant Medications
Pre-Treatment Concomitant Medications 
Y
Y
On-Treatment Concomitant Medications
Y
Y
On-Treatment Asthma Concomitant Medications
Y
Relationship between Ingredient and Verbatim Text
Y
Exposure and Medication Modifications
Study Medication Dosage Modification
Y
Extent of Exposure to Study Medication (Regardless of 
Modification to Study Medication Dosage)
Y
Y
Y
Extent of Exposure to Study Medication (up to First 
Modification of Study Medication Dosage)
Y
Extent of Exposure to Study Medication by Medication and 
Dosage
Y
Number of Subjects by Subgroup
Y
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NOTES:
!
Y = Yes display generated.
!
[1] Display will be based on ASE population
!
[2] Display will be repeated for the PP population
!
[3] Display will be repeated for the ASE population
!
[4] Display will be repeated for the Safety population
8.
PRIMARY STATISTICAL ANALYSES
8.1.
Efficacy Analyses
8.1.1.
Overview of Planned Efficacy Analyses
The primary efficacy analyses will be based on the ITT population and repeated for the PP 
population, unless otherwise specified. 
Table 5 provides an overview of the planned efficacy analyses, with full details of data displays 
being presented in: List of Data Displays.
Table 5
Overview of Planned Efficacy Analyses
Endpoint
Data displays generated
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
ACT Total Score
Change from Baseline 
in the ACT Total Score 
at Week 12 (Visit 4)
Y[1,2,3,4,5,6,
7]
Y[1,2,3,4,5,7]
Y[1]
Y[8]
NOTES:
!
T = Table, F = Figure, L = Listing, Y = Yes display generated.
!
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.
!
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.
!
Individual = Represents FL related to any displays of individual subject observed raw data.
!
Display will be repeated for the following subgroups (ITT only) (see Section 12.10 for more details):
[1]:
Country
[2]:
Number of severe asthma exacerbations in the previous year prior to randomisation
[3]:
Smoking status at baseline
[4]:
Age group
[5]:
Gender
!
[6] Sensitivity analyses will be produced for the following approaches:
!
Last observation carried forward (LOCF) (ITT only)
!
MI analyses utilizing covariates (ITT only)
!
Semi-parametric Hodges-Lehmann (HL) approach (ITT only)
!
Worst observation carried forward (WOCF) for treatment withdrawals (ITT only)
!
Adjusting for seasonal effect
!
[7] Display will be repeated for:
!
FF/VI versus the subset of Usual ICS/LABA subjects prescribed FP/S at randomisation (only if ≥25% of 
Usual ICS/LABA patients are prescribed FP/S at randomisation)
!
FF/VI versus the subset of Usual ICS/LABA subjects prescribed BUD/F at randomisation (only if ≥25% of 
Usual ICS/LABA patients are prescribed BUD/F at randomisation)
!
[8] Display will be produced for the ITT population only.
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8.1.2.
Planned Efficacy Statistical Analyses
Primary Statistical Analyses
Endpoint(s)
!
Change from Baseline in the ACT Total Score at Week 12 (Visit 4) 
Model Specification
!
The primary endpoint will be performed on both the ITT and the PP populations, and analysed using an 
MMRM model utilizing the REML estimation approach and a default covariance structure of 
unstructured 
!
Terms fitted in the model will include:
Response
: Change from Baseline in ACT Total Score
Fixed Categorical
: Randomised treatment, visit (Week 6 and Week 12), gender, country
Fixed Continuous
: Baseline ACT total score, age 
Interaction terms
: Randomised treatment-by-visit, baseline ACT total score-by-visit
Random effect
: Subject
SAS Code to Perform Analysis
proc mixed data=input_data;
class trtcd gender country visit subjid ;
model ACT = trtcd gender country age baseline  
visit visit*baseline visit*trtcd / ddfm=kr ;
repeated visit / subject=subjid type=un ;
random intercept / subject=subjid ;
lsmeans visit*trtcd / cl diff e om=OMdset at (baseline age)=(&blm. &agem.) ;
run ; 
where OMdset is a dataset with a row for every visit-subject combination that contains all of the covariates 
and blm and agem are macro variables containing the means for baseline and age for the subjects used in 
the analysis. These are used to derive the adjusted means using coefficients which are based on the 
subjects used in the analysis.
Model Checking & Diagnostics
!
Refer to Appendix 12: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation
!
For Week 12 (Visit 4), the adjusted (least squares [LS]) mean change from baseline for each treatment 
and the estimated treatment difference for FF/VI versus Usual ICS/LABA (i.e. the difference in LS mean 
change from baseline) will be presented together with the associated 95% CI and p-value.
!
Summary statistics will be produced for absolute value of and change from baseline in ACT total score 
at each post-baseline visit (Week 6 [Visit 3], Week 12 [Visit 4], Week 18 [Visit 5] and Week 24 [Visit 6]).
!
A listing of ACT total and change from baseline scores will be provided. 
!
Mean ACT total score ∀SD will be plotted by visit.
Subgroup Analyses
!
For the analyses by country (France, Germany) and gender (male, female), the model will additionally 
include the randomised treatment-by-subgroup and randomised treatment-by-subgroup-by-visit
interactions as a covariate.
!
For the analyses by number of severe asthma exacerbations in the previous year prior to 
randomisation (0, >1) and smoking status at baseline (Current smoker, Former smoker and Never 
smoked), the model will additionally include the subgroup, randomised treatment-by-subgroup 
interaction and randomised treatment-by-subgroup-by-visit interaction as covariates.
!
For the analysis by age group (≤50 years, >50 years), the continuous covariate age will be replaced by 
age group, randomised treatment-by-age group interaction and randomised treatment-by-age group-by-
visit interaction.
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Sensitivity and Supportive Statistical Analyses
Justification for Sensitivity Analyses Handling Missing Data
!
While subjects missing Week 12 (Visit 4) data but having earlier data will be included in the MMRM 
primary analysis, the interpretability of the results from the primary model will depend on the missing 
data satisfying the Missing at Random (MAR) assumption.  To support the validity of the conclusions 
drawn from this analysis, several sensitivity analyses will be performed to explore the dropout pattern 
and its possible impact on treatment comparisons. These sensitivity analyses will be performed on the 
ITT population only.
Last Observation Carried Forward
!
Missing values at Week 12 (Visit 4) will be replaced by the last available post-randomization value 
(either the Week 6 (Visit 2) ACT score or the ACT score at treatment withdrawal time, if applicable), i.e. 
based on the LOCF method.  The change from baseline in ACT at Week 12 (Visit 4) will be analyzed 
using an analysis of covariance (ANCOVA) model adjusting for randomised treatment, baseline ACT 
score, gender, country and age. For Week 12 (Visit 4), the LS mean change from baseline for each 
treatment and estimated LS mean change from baseline difference for FF/VI versus Usual ICS/LABA
will be presented together with the associated 95% CI and p-value.
Multiple Imputation
!
Sensitivity analyses will be performed using MI methods based on pattern mixture models. First, a 
repeated measures Normal model will be fitted to the data using a Bayesian approach, with non-
informative priors for the mean and variance-covariance matrix to provide a joint posterior for the 
parameters in this model. The repeated measures Normal model will include separate mean profiles for 
each treatment group and the same covariates as those in the primary efficacy analysis.
!
Independent samples will then be drawn from the posterior distributions for the mean and variance-
covariance matrix to provide inputs into an imputation model. For each subject with missing data, these 
sampled values of the parameters for mean vectors and the variance-covariance matrices specify a 
joint distribution for their observed and unobserved outcome data.
!
The post-withdrawal part of each pattern-specific distribution will be modelled using the approach
discussed below. This imputation model will have the same covariates as those in the primary efficacy
analysis.
!
Based on this imputation model, a single set of data will be sampled for the missing data based on the 
distribution for the subject’s missing data conditional upon their observed data. Each imputed data set 
will then be analysed using simple ANCOVA at Week 12 (Visit 4) and the resulting treatment 
differences and their standard errors combined using Rubin’s rules.
!
The post-withdrawal part of each pattern-specific distribution will be modelled using these two 
approaches:
o
MAR Approach. The means and variance-covariances following withdrawal are chosen to 
reflect the subject’s own treatment group. This approach will provide similar results to using a 
mixed effects model where the unstructured covariance matrix is estimated separately for 
each arm, and all covariates are crossed with treatment. As such it is not truly a sensitivity 
analysis as we expect to get very similar results. Like the MMRM this answers an on-treatment 
question.
o
Copy Differences from Reference Approach. This approach addresses a potential pattern of 
informative missingness, in which subjects withdrawn from the test groups would have 
followed the same trend over time (difference in mean value between time-points) as those in 
the reference group, had they continued in the study. Therefore, this approach may be 
considered conservative because it will assume that following withdrawal from a test treatment 
arm, imputation for their missingness will be derived from observed reference data. The 
intention is to represent an ITT-like approach.
!
For each method, the LS mean change from baseline at Week 12 (Visit 4) for each treatment and 
estimated LS mean change from baseline difference for FF/VI versus Usual ICS/LABA will be 
presented together with the associated 95% CI and p-value.
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Sensitivity and Supportive Statistical Analyses
Hodges-Lehmann Approach
!
A sensitivity analysis based on the semi parametric HL approach will be proposed to assess the 
robustness of the MMRM Model-based non-inferiority results. The HL difference between groups at 
Week 12 (Visit 4) and corresponding 95% CI will be provided.
Worst Observation Carried Forward
!
When treatment withdrawal occurs, an alternative method for imputing the missing value at the nearest 
visit after withdrawal time will be proposed: the primary endpoint missing value will be estimated by the 
worst ACT score observed between baseline visit and withdrawal time, inclusive – i.e. using the WOCF 
method. An ANCOVA model adjusting for randomised treatment, baseline ACT score, gender, country 
and age will be used to analyse this imputed data, with the LS mean change from baseline for each 
treatment presented at Week 12 (Visit 4) together with the estimated LS mean change from baseline 
difference and associated 95% CI 
Summary of Sensitivity Statistical Analyses
!
A plot will be produced displaying the treatment differences and 95% CIs for the primary analysis and 
each of the sensitivity analyses described above.
Seasonal effect
!
A sensitivity analysis adjusting for seasonal effect will be performed by repeating the primary efficacy 
analysis with the addition of season at randomisation, season-by-visit, randomised treatment-by-season 
at randomisation interaction and randomised treatment-by-season at randomisation-by-visit interaction. 
See Section 12.10.3 for the definition of season at randomisation. The LS mean change from baseline 
at Week 12 (Visit 4) for each treatment and estimated LS mean change from baseline difference will be 
displayed for each season at randomisation together with the associated 95% CI and p-value, and the 
interaction p-value.
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9.
SECONDARY STATISTICAL ANALYSES
9.1.
Efficacy Analyses
9.1.1.
Overview of Planned Efficacy Analyses
The secondary efficacy analyses will be based on the ITT population, unless specified otherwise. 
Table 6 provides an overview of the planned efficacy analyses, with further details of data 
displays being presented in Appendix 15: List of Data Displays.
Table 6
Overview of Planned Efficacy Analyses
Endpoint
Data displays generated
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
ACT Total Score
Change from Baseline 
in the ACT Total Score 
at Week 24 (Visit 4)
Y[1,2,3,4]
Y
Y[1,2,4,5,6,7,
8]
Y[1,2]
Correct Use of Device 
Percentage of Subjects 
with Correct Use of 
Inhaler Device at Week 
12 (Visit 4) and at 
Week 24 (Visit 6) 
Independently of the 
Use at Week 12 (Visit 
4)
Y[1]
Y[1]
Y
NOTES:
!
T = Table, F = Figure, L = Listing, Y = Yes display generated.
!
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.
!
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.
!
Individual = Represents FL related to any displays of individual subject observed raw data.
!
[1] Display will be repeated for the PP population
!
[2] Display will be repeated by Country (ITT only)
!
[3] Sensitivity analyses will be produced for the following approaches:
!
LOCF (ITT only)
!
MI analyses utilizing covariates (ITT only)
!
Semi-parametric HL approach (ITT only)
!
WOCF for treatment withdrawals (ITT only)
!
Adjusting for seasonal effect
!
[4] Display will be repeated for:
!
FF/VI versus the subset of Usual ICS/LABA subjects prescribed FP/S at randomisation (only if ≥25% of 
Usual ICS/LABA patients are prescribed FP/S at randomisation)
!
FF/VI versus the subset of Usual ICS/LABA subjects prescribed BUD/F at randomisation (only if ≥25% of 
Usual ICS/LABA patients are prescribed BUD/F at randomisation)
!
Display will be repeated for the following subgroups (ITT only) (see Section 12.10 for more details):
[5]:
Number of severe asthma exacerbations in the previous year prior to randomisation
[6]:
Smoking status at baseline
[7]:
Age group
[8]:
Gender
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9.1.2.
Planned Efficacy Statistical Analyses
Secondary Statistical Analyses
Endpoint(s)
!
Change from Baseline in the ACT Total Score at Week 24 (Visit 6) 
Model Specification
!
This endpoint will be performed on both the ITT and the PP populations, and analysed using an MMRM 
model utilizing the REML estimation approach and a default variance-covariance structure of 
unstructured 
!
Terms fitted in the model will include:
Response
: Change from Baseline in ACT Total Score
Fixed Categorical
: Randomised treatment, visit (Week 6, Week 12, Week 18 and Week 24), 
gender, country
Fixed Continuous
: Baseline ACT total score, age 
Interaction terms
: Randomised treatment-by-visit, baseline ACT total score-by-visit
Random effect
: Subject
Model Checking & Diagnostics
!
Refer to Appendix 12: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation
!
For Week 24 (Visit 6), the LS mean change from baseline for each treatment and the estimated 
difference in LS mean change from baseline for FF/VI versus Usual ICS/LABA will be presented 
together with the associated 95% CI and p-value.
!
Summary statistics, a listing and plots of mean ACT total score ∀SD will be produced as part of the 
primary efficacy endpoint analysis (see Section 8.1.2).
Subgroup Analysis
!
For the analysis by country (France, Germany), the model will additionally include the randomised 
treatment-by-country, country-by-visit and randomised treatment-by-country-by-visit interactions as a 
covariate.
Sensitivity and Supportive Statistical Analyses
!
The same sensitivity analyses as those described for the primary endpoint will be performed for the key 
secondary endpoint of change from baseline in the ACT total score at Week 24 (Visit 6) .
Secondary Statistical Analyses
Endpoint(s)
!
Percentage of subjects with correct use of inhaler device at Week 12 (Visit 4) and at Week 24 (Visit 6) 
independently of the use at Week 12 (Visit 4)
Model Specification
!
These endpoints will be analysed for both the ITT and the PP populations using logistic regression 
models
!
Terms fitted in the model will include:
Response
: Endpoint
Fixed Categorical
: Randomised treatment, correct use of inhaler device at baseline, gender, 
country
Fixed Continuous
: Age 
SAS Code to Perform Analysis
proc logistic data=input_data plots=(all);
class trtcd country baseline gender / ref=first param=ref; 
  model corr_use (event=”Y”) = trtcd baseline age gender country;
  contrast “Trt_effect” trtcd 1 / estimate=exp;
run;
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Secondary Statistical Analyses
Model Checking & Diagnostics
!
Refer to Appendix 12: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation
!
The number and percentage of subjects with correct use within each randomised treatment group will 
be presented by visit, together with the adjusted odds ratio comparing FF/VI with Usual ICS/LABA, 
associated p-value and 95% CI.
!
A summary and listing of correct use / errors of inhaler use will be produced.
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9.2.
Safety Analyses
9.2.1.
Overview of Planned Analyses
The safety analyses will be based on the Safety population.
Table 7 provides an overview of the planned analyses, with further details of data displays being 
presented in Appendix 15: List of Data Displays.
Table 7
Overview of Planned Safety Analyses
Endpoint
Data displays generated
Stats Analysis
Summary
Individual
T
F
T
F
F
L
Adverse Events
SAEs and ADRs Overview
Y
Non-Serious ADRs
Y
Y
Serious ADRs
Y
All ADRs
Y
SAEs
Y
Y
SAEs and ADRs Leading to Permanent 
Discontinuation of Study Medication or 
Withdrawal from Study
Y
Y
SAEs Leading to Permanent 
Discontinuation of Study Medication or 
Withdrawal from Study
Y
ADRs Leading to Permanent 
Discontinuation of Study Medication or 
Withdrawal from Study
Y
Non-Serious ADRs Leading to 
Permanent Discontinuation of Study 
Medication or Withdrawal from Study
Y
Most Frequent Non-Serious ADRs, 
Reported by ≥1% or More of Subjects in 
Any Treatment Group
Y
Non-Serious ADRs of Special Interest
Y
Serious ADRs of Special Interest
Y
All ADRs of Special Interest
Y
SAEs of Special Interest
Y
Fatal SAEs 
Y
Y
Fatal Serious ADRs
Y
Fatal SAEs of Special Interest
Y
Non-Fatal SAEs
Y
Y
Non-Fatal SAEs of Special Interest
Y
AE terms of Special Interest
Y
Top Ten Most Commonly Reported On-
treatment ADRs per Treatment Group
Y
Vital Signs
Vital Signs
Y
Y
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Endpoint
Data displays generated
Stats Analysis
Summary
Individual
T
F
T
F
F
L
Inhaler Device Malfunctions
Inhaler Device Malfunctions
Y
Liver chemistry
Liver event
Y
Liver biopsy
Y
Liver imaging
Y
Other
Pregnancy
Y
NOTES:
!
T = Table, F = Figure, L = Listing, Y = Yes display generated.
!
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.
!
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.
!
Individual = Represents FL related to any displays of individual subject observed raw data.
9.2.2.
Benefit:Risk analyses
Benefit:Risk analyses will be based on the ITT population for Benefit, and Safety population for 
Risk.
Table 8 provides an overview of the planned analyses, with further details of data displays being 
presented in Appendix 15: List of Data Displays.
Table 8
Overview of Planned Benefit:Risk Analyses
Endpoint
Data displays generated
Stats Analysis
Summary
Individual
T
F
T
F
L
Summary of Benefit:Risk 
Y
NOTES: 
!
T = Table, F = Figure, L = Listing, Y = Yes display generated.
!
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.
!
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.
!
Individual = Represents FL related to any displays of individual subject observed raw data.  
Benefit Risk Statistical Safety Analyses
Endpoint(s)
!
Summary of Benefit:Risk: various endpoints analyses in the context of safety and effectiveness 
analyses 
Model Specification
!
Estimates and their 95% CIs obtained from selected safety and effectiveness analyses will be 
presented for the ITT population on a multiple panel forest plot which will display effectiveness and 
safety data.
!
For certain endpoints, the x-axis may be reversed to ensure benefit/risk to either FF/VI or Usual 
ICS/LABA is shown accurately.
!
Due to endpoints being presented using different scales, the forest plot will be split into additional 
panels to allow better visibility of the results.
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Benefit Risk Statistical Safety Analyses
Model Checking & Diagnostics
!
Model checking and diagnostics are described in each endpoint analysis section.
Model Results Presentation
!
The top panel (“Benefits”) of the forest plot will display:
o
difference in LS mean change from baseline from the MMRM analysis of the primary efficacy 
endpoint, defined as the change from baseline in ACT total score at Week 12 (Visit 4), as 
described in Section 8.1.2
o
difference in LS mean change from baseline from the MMRM analysis of the change from 
baseline in ACT total score at Week 24 (Visit 6), as described in Section 9.1.2
o
adjusted odds ratio from the logistic regression analysis of percentage of subjects with correct 
use of inhaler device at Week 12 (Visit 4), as described in Section 9.1.2
o
adjusted odds ratio from the logistic regression analysis of percentage of subjects with correct 
use of inhaler device at Week 24 (Visit 6) independently of the use at Week 12 (Visit 4), as 
described in Section 9.1.2
!
The bottom panel (“Risks”) of the forest plot will display the risk difference for FF/VI vs. usual ICS/LABA
of the incidence of the following SAEs of special interest:
o
Asthma/bronchospasm, cardiovascular effects, decreased bone mineral density and 
associated fractures, hypersensitivity, local steroid effects, lower respiratory tract infection 
(LRTI) excluding pneumonia, pneumonia, adrenal suppression, ocular effects, effects on 
glucose, effects on potassium, tremor
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10.
OTHER STATISTICAL ANALYSES
10.1.
Other Analyses
10.1.1.
Overview of Planned Other Analyses
The other statistical analyses will be based on the ITT population, unless otherwise specified.
Table 9 provides an overview of the planned other analyses, with full details of data displays 
being presented in Appendix 15: List of Data Displays.
Table 9
Overview of Planned Other Analyses
Endpoint
Absolute
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
Trough (Pre-dose) FEV1
Change from Baseline 
in Trough (Pre-dose) 
FEV1 at Week 12 
(Visit 4)
Y
Y
Y
ACT
ACT Total Score ≥ 20 
or ≥ 3 Point Increase 
from Baseline in ACT
Total Score at Week 
12 (Visit 4) and Week 
24 (Visit 6)
Y
Y
Y
ACT Total Score ≥ 20 
at Week 12 (Visit 4) 
and Week 24 (Visit 6)
Y
Y
≥ 3 Point Increase 
from Baseline in ACT 
Total Score at Week
12 (Visit 4) and Week 
24 (Visit 6)
Y
Y
Change from Baseline 
in Individual ACT 
Questions at Week 12 
(Visit 4) and Week 24 
(Visit 6)
Y
Compliance with Study Medication
Compliance with Study 
Medication from 
Randomisation (Day 0) 
to Week 12 (Visit 4), 
from Week 12 (Visit 4) 
to Week 24 (Visit 6) 
and from 
Randomisation (Day 0) 
to Week 24 (Visit 6)
Y[1]
Y
Y
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Endpoint
Absolute
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
MARS-A Score at
Randomisation (Day
0), Week 12 (Visit 4) 
and Week 24 (Visit 6).
Y[2]
Y[2]
Y
Severe asthma exacerbations
Number of Subjects 
With at Least 1 Severe 
Asthma Exacerbation 
and Number of Severe 
Asthma Exacerbations
Y[3]
Y
Annual Severe Asthma 
Exacerbation Rate 
over the Study Period
Y
Y
Time to First Severe 
Asthma Exacerbation
Y
Y
Asthma Quality of Life Questionnaire (AQLQ[S])
Change from Baseline 
in Total Score and 
Domain Scores of 
AQLQ(S) at Week 24 
(Visit 6)
Y
Y
An Increase from 
Baseline of ≥ 0.5 in 
AQLQ(s) Total Score 
at Week 24 (Visit 6)
Y
Y
An Increase from 
Baseline of ≥ 0.5 in 
AQLQ(s) 
Environmental Stimuli 
Domain Score at Week 
24 (Visit 6)
Y
Y
An Increase from 
Baseline of ≥ 0.5 in 
AQLQ(S) Individual 
Domain Scores 
(Symptoms, Activity 
limitations and 
Emotional Function) at 
Week 24 (Visit 6)
Y
EQ-5D-5L
EQ-5D-5L Descriptive 
System Dimensions at 
Week 24 (Visit 6)
Y
Y
Y
EQ-5D-5L Utility Score
at Week 24 (Visit 6)
Y
Y
Y
EQ-5D-5L Visual 
Analogue Scale (VAS) 
Score at Week 24 
(Visit 6)
Y
Y
Y
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Endpoint
Absolute
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
PASAP-Q
PASAP-Q Scores at 
Week 12 (Visit 4)
Y
Y
NOTES:
!
T = Table, F = Figure, L = Listing, Y = Yes display generated.
!
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.
!
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.
!
Individual = Represents FL related to any displays of individual subject observed raw data.
!
[1] Display will be repeated for the PP population
!
[2] A reminder was sent to centres in France instructing that the MARS-A questionnaire refers to the patient’s 
preventer inhaler (i.e. their maintenance therapy prior to entering the study, and study medication while on-study). 
See Section 12.6.3 for further details. Display will be repeated split by:
!
Patients in France, all MARS-A assessments completed pre-reminder
!
Patients in France, some MARS-A assessments completed pre-reminder, some post-reminder
!
Patients in France, all MARS-A assessments completed post-reminder
!
Patients in Germany
!
[3] Display will be repeated by season.
10.1.2.
Planned Other Statistical Analyses
Other Statistical Analyses
Endpoint(s)
!
Change from baseline in trough (pre-dose) FEV1 at Week 12 (Visit 4)
!
Change from baseline in EQ-5D-5L Utility Score at Week 24 (Visit 6)
!
Change from baseline in EQ-5D-5L VAS Score at Week 24 (Visit 6)
Model Specification
!
These endpoints will be analysed for the ITT population using ANCOVA models
!
Terms fitted in the model will include:
Response
: Endpoint
Fixed Categorical
: Randomised treatment, gender, country
Fixed Continuous
FEV1 endpoint: Baseline trough (pre-dose) FEV1 and age
EQ-5D-5L Utility Score endpoint: Baseline EQ-5D-5L Utility Score 
and age
EQ-5D-5L VAS Score endpoint: Baseline EQ-5D-5L VAS Score 
and age
Model Checking & Diagnostics
!
Refer to Appendix 12: Model Checking and Diagnostics for Statistical Analyses.
SAS Code to Perform Analysis
proc mixed data=input_data;
class trtcd gender country;
model FEV1 = trtcd gender country age baseline  / ddfm=kr ;
lsmeans trtcd / cl diff e;
run ; 
Model Results Presentation
!
The LS mean change from baseline for each treatment and the difference in estimated LS mean 
change from baseline for FF/VI versus Usual ICS/LABA will be presented together with the associated 
95% CI and p-value.
!
Summary statistics. 
!
Listings will be provided.  
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Other Statistical Analyses
Endpoint(s)
!
Percentage of subjects who had either an ACT total score ≥ 20 or ≥ 3 point increase from baseline in 
ACT total score at Week 12 (Visit 4) and Week 24 (Visit 6)
!
Percentage of subjects who have an increase from baseline of ≥ 0.5 in AQLQ(S) total score at Week 24 
(Visit 6)
!
Percentage of subjects who have an increase from baseline of ≥ 0.5 in AQLQ(S) environmental stimuli 
domain score at Week 24 (Visit 6)
!
Percentage of subjects with ‘no problems’ in each dimension of the EQ-5D-5L questionnaire at Week 
24 (Visit 6)
Model Specification
!
These endpoints will be analysed for the ITT population using logistic regression models
!
Terms fitted in the model will include:
Response
: Endpoint
Fixed Categorical
: Randomised treatment, gender, country
Fixed Continuous
ACT endpoints: Baseline ACT total score, baseline ACT total 
score squared and age
AQLQ(S) endpoints: Baseline AQLQ(S) score and age
EQ-5D-5L endpoints: Baseline EQ-5D-5L dimension score and 
age
Model Checking & Diagnostics
!
Refer to Appendix 12: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation
!
The number and percentage of subjects with a response within each randomised treatment group will 
be presented by visit, together with the adjusted odds ratio comparing FF/VI with Usual ICS/LABA, 
associated 95% CIs and p-values.
!
The number and percentage of subjects with ACT total score ≥20 or ≥3 point increase from baseline in 
ACT total score will be summarized by visit to include the tabulations of frequencies together and 
separately. 
!
The number and percentage of subjects with an increase from baseline of ≥ 0.5 in AQLQ(S) total and 
individual domain scores at Week 24 (Visit 6) will be summarized.
!
The responses to each EQ-5D-5L dimension will be descriptively summarised
Other Statistical Analyses
Endpoint(s)
!
Annual severe asthma exacerbation rate over the study period
Model Specification
!
This endpoint will be analysed for the ITT population using a generalised linear model (GLM), assuming 
the Negative Binomial distribution
!
Terms fitted in the model will include:
Response
: Annual severe asthma exacerbation rate over the study period
Fixed Categorical
: Randomised treatment, gender, country, number of severe 
asthma exacerbations in the previous year prior to randomisation 
(0, ≥1)
Fixed Continuous
: Age
Offset variable
: Logarithm of time on treatment
Model Checking & Diagnostics
!
Refer to Appendix 12: Model Checking and Diagnostics for Statistical Analyses.
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Other Statistical Analyses
SAS Code to Perform Analysis
proc genmod data=input_data;
class trtcd gender country;
model no_exac = trtcd exacbl gender country age / dist=negbin link=log offset=log_tm type3;
lsmeans trtcd /cl diff=control("0") om exp;
run;
Model Results Presentation
!
The LS mean number / annual rate, adjusted treatment ratio and associated 95% CI and p-value will be 
presented.
!
Percentage reduction in mean number / annual rate and associated 95% CI will also be presented.
!
The severe asthma exacerbation data will be summarized to include the tabulations of exacerbation 
frequencies, exacerbation duration (days) and the outcome, the prescription of oral corticosteroids 
and/or antibiotics to treat exacerbations, hospitalisations and emergency department visits due to an 
exacerbation, intubations due to an exacerbation and withdrawal of IP or withdrawal from the study as a 
result of an exacerbation.
!
A listing of severe exacerbations will be provided. 
!
Box plots will be provided for the severe annual exacerbation rates.
Other Statistical Analyses
Endpoint(s)
!
Time to first severe asthma exacerbation
Model Specification
!
The cumulative distribution of this endpoint will be illustrated for the ITT population using Kaplan-Meier 
estimates and evaluated using the Wald Chi-Square test based on a Cox proportional hazards model.
!
The analyses and summaries will include on-treatment exacerbations, from start date of exposure to 
min(stop date of exposure + 1 day, date of study discontinuation). 
!
The exact method for handling ties in times will be used.
!
Terms fitted in the model will include:
Response
: Time to first severe asthma exacerbation
Fixed Categorical
: Randomised treatment, gender, country
Fixed Continuous
: Age
Model Checking & Diagnostics
!
Refer to Appendix 12: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation
!
The hazard ratio for FF/VI versus Usual ICS/LABA with associated 95% CI and p-value will be 
presented.
!
Cumulative incidence curves of time to first severe asthma exacerbation will be presented.
!
Summary statistics will also be presented.
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11.
REFERENCES
Devlin N., Shah K., Feng Y., Mulhern B., Van Hou, B. Valuing Health-Related Quality of Life: 
An EQ-5D-5L Value Set for England. Office of Health Economics. January 2016.
Efron, B. The Efficiency of Cox’s Likelihood Function for Censored Data. J Am Stat Assoc. 
1977;72:557–565.
EuroQol. EQ-5D-3L User Guide. EuroQol, Europe: 2013. Version 5. 
Firth D. Bias Reduction of Maximum Likelihood Estimates. Biometrika. 1993;80:27–38.
GINA 2012, http://www.ginasthma.org/local/uploads/files/GINA_Report_March13.pdf
GlaxoSmithKline Document Number 2011N129785_02 Study ID HZA115150. A 12-month, 
open 
label, 
randomised, 
effectiveness 
study 
to 
evaluate 
fluticasone 
furoate 
(FF, 
GW685698)/vilanterol (VI, GW642444) Inhalation Powder delivered once daily via a Novel Dry 
Powder Inhaler compared with usual maintenance therapy in subjects with Asthma. Report Date 
11-Mar-2014.
GlaxoSmithKline Document number 2014N190259_02
Study HZA116492: A 6-month, open 
label, randomised, efficacy study to evaluate fluticasone furoate (FF, GW685698)/vilanterol (VI, 
GW642444) Inhalation Powder delivered once daily via the Dry Powder Inhaler Ellipta™ 
compared with usual ICS/LABA maintenance therapy delivered by Dry Powder Inhaler in 
subjects with Persistent Asthma. Report Date 28-APR-2016
Juniper E.F., Guyatt G.H, Ferrie P.J., Griffith L.E. Measuring quality of life in asthma. Am Rev 
Respir Dis. 1993;147:832–838.
Kozma C.M., Slaton T.L., Monz B.U., Hodder R., Reese P.R. Development and Validation of a 
Patient Satisfaction and Preference Questionnaire for Inhalation Devices (PASAPQ). Treat Respir 
Med. 2005; 4 (1): 41-52.
Schatz M., Kosinski M., Yarlas A.S., Hanlon J., Watson M.E., Jhingran P. The minimally 
important difference of the Asthma Control Test. J Allergy Clin Immunol. 2009;124(4):719–23.
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12.
APPENDICES
Section
Appendix
RAP Section 5 : Analysis Populations
Section 12.1
Appendix 1: Protocol Deviation Management and Definitions for PP Population
RAP Section 6 : General Considerations for Data Analyses & Data Handling Conventions
Section 12.2
Appendix 2: Time & Events
Section 12.3
Appendix 3: Assessment Windows
Section 12.4
Appendix 4: Treatment States and Phases
Section 12.5
Appendix 5: Data Display Standards & Handling Conventions
Section 12.6
Appendix 6: Derived and Transformed Data
Section 12.7
Appendix 7: Premature Withdrawals & Handling of Missing Data
Section 12.8
Appendix 8: Values of Potential Clinical Importance
Section 12.9
Appendix 9: Multicenter Studies
Section 12.10
Appendix 10: Examination of Covariates, Subgroups & Other Strata
Section 12.11
Appendix 11: Multiple Comparisons & Multiplicity
Section 12.12
Appendix 12: Model Checking and Diagnostics for Statistical Analyses
Other RAP Appendices
Section 12.13
Appendix 13: Blinding Strategy
Section 12.14
Appendix 14: Abbreviations & Trade Marks
Section 12.15
Appendix 15: List of Data Displays
Section 12.16
Appendix 16: Example Mock Shells for Data Displays
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12.1.
Appendix 1: Protocol Deviation Management and Definitions 
for PP Population
12.1.1.
Protocol Deviations
All PDs (any deviation from the protocol) are tracked and monitored during the study. Important 
PDs are those deviations that may compromise subject rights, safety, or well-being, and/or data 
integrity, and/or study end-points, and are defined in the PDMP. Apart from any incorrect 
treatment deviations, all protocol deviations will be agreed upon prior the unblinding and the 
freezing of the database. All deviations from the inclusion/exclusion criteria, and important PDs 
will be summarised. A listing of treatment misallocations will be produced.
12.1.2.
Exclusions from PP Population
Important PDs that will result in exclusion from the PP population are specified in Table 10, 
and will be summarised in a data display.
Table 10
PDs resulting in exclusion from the PP population
Deviation Category
Deviation Subcategory
Informed consent
!
Signed informed consent/assent not available on site[1]
!
Wrong informed consent/assent version signed[1]
!
Informed consent/assent not signed and/or dated by 
subject (parent/Legally Acceptable representative, if 
applicable)
!
Informed consent/assent not signed and/or dated by 
appropriate site staff. [1]
!
Informed consent/assent not signed prior to any study 
procedure[1]
!
Other informed consent/assent deviations[1]
Eligibility criteria not met –
inclusion criteria
!
Informed consent
!
Gender and Age[2]
!
Type of subject
!
Current Asthma Therapy
!
Inability of subject to complete questionnaires
Eligibility criteria not met –
exclusion criteria
!
History of Life-threatening asthma
!
Subjects having a severe and unstable asthma
!
COPD Respiratory Disease
!
Other diseases/abnormalities[1]
!
Subjects with a history of adverse reaction to any 
intranasal, inhaled, or systemic corticosteroid and LABA 
therapy and to components of the inhalation powder[1]
!
Investigational Medications used within 30 days or five 
half-lives of prior study[1]
!
Chronic user of systemic corticosteroids
!
Subjects treated by the monoclonal antibody omalizumab 
(Xolair) or mepolizumab (Nucala™)
!
Subjects involved in other clinical trials[1]
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Deviation Category
Deviation Subcategory
Not withdrawn after developing 
withdrawal criteria
!
Not withdrawn from study[1]
!
Not discontinued from study treatment[1]
!
Other deviation of not being withdrawn after developing 
withdrawal criteria[1]
Excluded medication, vaccine 
or device
!
Medication, excluded by the protocol, was administered[3]
!
Other excluded medication, vaccine or device deviation[3]
Wrong study treatment / 
administration / dose
!
Study treatment not administered per protocol[1]
!
Wrong study treatment or assignment administered
!
Expired study treatment administered[1]
!
Use of study treatment impacted by a temperature 
excursion which was not reported or approved or which 
was disapproved for further use.[1]
!
Study treatment not available at site for administration[1]
!
Other deviations related to wrong study 
treatment/administration/dose[1]
Study procedures
!
Non study treatment supply procedures[1]
!
Equipment procedures[1]
!
Other deviations from study procedures[1]
[1] To be reviewed on a case-by-case basis
[2] Patients < 18 years will be excluded from PP population, others will be reviewed on a case-
by-case basis
[3] To be judged by the medical monitor
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12.2.
Appendix 2: Time & Events
12.2.1.
Protocol Defined Time & Events
Study Visits
Visit 1*
Screening
Visit 2*
Randomisation
Visit 3
Phone 
call 1
Visit 
4**
Visit 5
Phone 
call 2
Visit 6
Early 
Withdrawal
Study Week (± 
specified no. of 
days)
Day -7 to -
1
Day 0
Week 
6 (±3 
days)
Week 
12 
(±7 
days)
Week 
18 (±3 
days)
Week 
24 
(±14 
days)
Early 
Withdrawal
Visit 
x
x
x
x
x 
Phone interview 
x
x
Assessments
Informed Consent
x
Eligibility criteria
x
x
Demography
x
Smoking status
x
Medical/Family history 
of consented subjects 
including CV Risk 
factors and 
exacerbation history
x
PGx (saliva sample)***
x
Physical examination
x
x
x
x
x 
Safety Assessments
Urine Pregnancy 
Test¥
x
x
x
x
Exacerbation 
Assessment
x
x
x
x
x
x
Vital signs
x
x
x
x
x
Serious Adverse Event 
and Adverse Drug 
Reaction Assessment1
x
x
x
x
x
x
Efficacy 
Assessments
Spirometry Testing 
(Pre-dose trough 
FEV1)
x
x
x ****
Subject 
Questionnaires 
Asthma Control Test
x
x
x
x
x
x
x
EQ-5D
x
x
x
Asthma Quality of
Life Questionnaire
x
x
x
MARS-A questionnaire
x
x
x
x
Patient Satisfaction 
and Preference 
x
x
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Study Visits
Visit 1*
Screening
Visit 2*
Randomisation
Visit 3
Phone 
call 1
Visit 
4**
Visit 5
Phone 
call 2
Visit 6
Early 
Withdrawal
Study Week (± 
specified no. of 
days)
Day -7 to -
1
Day 0
Week 
6 (±3 
days)
Week 
12 
(±7 
days)
Week 
18 (±3 
days)
Week 
24 
(±14 
days)
Early 
Withdrawal
Visit 
x
x
x
x
x 
Phone interview 
x
x
(PASAP-Q)
Inhaler correct use 
assessment
Type A/overall errors 
record
x
x
x
Medication 
Assessments
Concomitant 
Medication 
Assessment
x
x
x
x
x
Dispense Study 
Medication²
x
x
Collect Study 
Medication²
x
x
x
RAMOS/eCRF
RAMOS NG
x
x
eCRF
x
x
x
x
x
x
x
1.
SAE and ADR monitoring will occur from Day 1. SAE related to study participation should begin from 
signing of informed consent form (ICF). An additional safety and ACT check is provided by phone at 
Week 6 and 18.
2.
Throughout the study the study medication will be dispensed and collected by the investigator site.
* Visit 1 and Visit 2 can be combined if the subject did not take his usual asthma medication before coming 
on site. Then this visit will be Randomisation (Day 0) and all baseline characteristics will be collected at this 
visit. Written Informed Consent must be obtained prior to initiation of study procedures or initiating changes 
in medications.
** Visit 4 (Week 12) should be scheduled at the same time of day as Visit 2 (Randomisation visit).
***PGx saliva sample collected at Visit 2 (Randomisation) or any scheduled clinic visit thereafter.
**** Only if early withdrawal occurs before Week 12.
¥ Only for childbearing women.
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12.3.
Appendix 3: Assessment Windows
Clinic visits/phone calls are scheduled to take place as specified in the protocol. For the ACT and 
MARS-A questionnaires, measurements that are not within ±7 days of the visit target day for 
Week 6 (Visit 3) and Week 18 (Visit 5), or ±14 days for Week 12 (Visit 4) and Week 24 (Visit 6) 
will be excluded from the analyses. For EQ-5D-5L and AQLQ(S), measurements that are not 
within ±14 days of the visit target day of Week 24 (Visit 6) will be excluded from the summaries. 
For PASAP-Q, measurements that are not within ±14 days of the visit target day of Week 12 
(Visit 4) will be excluded from the summaries.
Table 11
Visit slotting rules for ACT and MARS-A
Days relative to randomisation *
Target Study Day
Visit Slot
35 – 49
42
Week 6 (Visit 3)
70 – 98
84
Week 12 (Visit 4)
119 – 133
126
Week 18 (Visit 5)
154 – 182
168
Week 24 (Visit 6)
* Date of assessment – Randomisation date + 1
Table 12
Visit slotting rules for EQ-5D-5L and AQLQ(S)
Days relative to randomisation *
Target Study Day
Visit Slot
154 – 182
168
Week 24 (Visit 6)
* Date of assessment – Randomisation date + 1
Table 13
Visit slotting rules for PASAP-Q
Days relative to randomisation *
Target Study Day
Visit Slot
70 – 98
84
Week 12 (Visit 4)
* Date of assessment – Randomisation date + 1
For all other endpoints, individual measurements collected outside of the assessment window for 
scheduled visits will be included in the ITT and PP analyses without adjustment.  
All available data will be assigned to an assessment window where possible, including Early 
Withdrawal visits.  If multiple measurements are collected within the same assessment window, 
the last valid value prior to randomisation will be used as the baseline value and the value closest 
to the target day for that window will be used for all post-randomisation visits. If values are the 
same distance from the target, then the earlier value will be taken.
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12.4.
Appendix 4: Treatment States and Phases
12.4.1.
Treatment Phases
In general, assessments and events will be classified according to the time of occurrence relative 
to study treatment, unless otherwise specified. Endpoint/measurement specific definitions are 
defined in Section 12.4.2.
Treatment Phase
Definition
Pre-Treatment 
Date < Study Treatment Start Date
On-Treatment
Study Treatment Start Date ≤ Date ≤ Study Treatment Stop Date + 1
Post-Treatment
Date > Study Treatment Stop Date + 1
NOTES: 
!
If it is not possible to determine the treatment phase of an assessment or event, it will be 
considered as On-Treatment.
12.4.2.
Treatment States
Assessments and events will be classified according to time of occurrence relative to the start 
and/or stop date of the study treatment. The earliest and latest exposure treatment start and stop 
dates will be used to determine whether an assessment or event was pre-treatment, on-treatment 
or post-treatment. If it is not possible to tell whether an assessment or event was on-treatment or 
not, it will be considered as on-treatment.
12.4.2.1.
Treatment States for Concomitant Medications
Treatment State
Definition
Pre-Treatment
(Start Date of Medication < Study Treatment Start Date) and (End Date of Medication < 
Study Treatment Start Date)
On-Treatment
[(Start Date of Medication < Study Treatment Start Date) and (End Date of Medication 
≥Study Treatment Start Date)] or (Study Treatment Start Date ≤Start Date of 
Medication ≤ Study Treatment Stop Date + 1)
Post-Treatment
Start Date of Medication > Study Treatment Stop Date +1
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12.4.2.2.
Treatment States for Efficacy Measurements
Treatment State
Definition
Pre-Treatment
Date of Measurement ≤ Study Treatment Start Date
On-Treatment
Study Treatment Start Date < Date of Measurement ≤ Study Treatment Stop Date + 1
Post-Treatment
Date of Measurement > Study Treatment Stop Date +1
12.4.2.3.
Treatment States for Exacerbation Data
Treatment State
Definition
Pre-Treatment
Exacerbation Onset Date < Study Treatment Start Date
On-Treatment
Study Treatment Start Date ≤ Exacerbation Onset Date ≤ Study Treatment Stop Date 
+ 1
Post-Treatment
Exacerbation Onset Date > Study Treatment Stop Date + 1
NOTES: 
!
If the study treatment stop date is missing, then the exacerbation will be considered to be On-Treatment
!
See Section 12.6.3 for details on missing onset and/or resolution dates.
12.4.2.4.
Treatment States for AE Data
Treatment states for adverse events are described below. Severe asthma exacerbations will be 
treated in the same way, with the exacerbation start date used in place of the AE start date.
Treatment State
Definition
Pre-Treatment
AE Onset Date < Study Treatment Start Date
On-Treatment
Study Treatment Start Date # AE Onset Date # Study Treatment Stop Date + 1
Post-Treatment
AE Onset Date > Study Treatment Stop Date + 1
Onset Time
Since 1st Dose 
(Days)
If Study Treatment Start Date ˃ AE Onset Date = AE Onset Date - Study Treatment 
Start Date
If Study Treatment Start Date ≤ AE Onset Date = AE Onset Date - Study Treatment 
Start Date +1
Missing otherwise.
Duration (Days) 
AE Resolution Date – AE Onset Date + 1
Drug-related
If relationship is marked ‘YES’ or is missing on the AE case report form (CRF) page.
NOTES: 
!
If the study treatment stop date is missing, then the AE will be considered to be On-Treatment.
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12.5.
Appendix 5: Data Display Standards & Handling 
Conventions
12.5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting 
Code
Description
Description
Order [1]
A
Fluticasone furoate /vilanterol inhalation 
Powder delivered once daily
FF/VI
2
B
Usual ICS/LABA maintenance therapy 
delivered by Dry Powder Inhaler
Usual ICS/LABA
1
NOTES:
1.
Order represents treatments being presented in data displays, as appropriate.
12.5.2.
Baseline Definition & Derivations
12.5.2.1.
Baseline Definitions
For all endpoints the baseline value will be the last assessment prior to randomisation.
12.5.2.2.
Derivations and Handling of Missing Baseline Data
Definition
Reporting Details
Change from Baseline
= Post-Dose Visit Value – Baseline
% Change from Baseline
= 100 x [(Post-Dose Visit Value – Baseline) / Baseline]
Maximum Change from Baseline
= Calculate the change from baseline at each given timepoint 
   and determine the maximum change
NOTES:
!
Unless otherwise specified, the baseline definitions specified in Section 12.5.2.1 will be used for derivations for 
endpoints / parameters and indicated on summaries and listings.
!
Unless otherwise stated, if baseline data is missing no derivation will be performed and will be set to missing.
!
The baseline definition will be footnoted on all change from baseline displays.
12.5.3.
Reporting Process & Standards
Reporting Process
Software
!
The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
: uk1salx00175
HARP Area
: /arenv/arprod/gw685698_gw642444/hza116492/final
QC Spreadsheet
: /arenv/arwork/gw685698_gw642444/hza116492/final/qc
Analysis Datasets 
!
Analysis datasets will be created according to CDISC standards.
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Reporting Process
!
For creation of ADaM datasets (e.g. ADCM, ADAE) the same version of dictionary datasets will be 
implemented for conversion from SI to SDTM.
Generation of RTF Files
!
RTF files will be generated for all tables in the final reporting effort. 
Reporting Standards
General
!
The current GSK IDSL will be applied for reporting, unless otherwise stated:
o
4.03 to 4.23: General Principles
o
5.01 to 5.08: Principles Related to Data Listings
o
6.01 to 6.11: Principles Related to Summary Tables
o
7.01 to 7.13: Principles Related to Graphics 
Formats
!
All data will be reported according to the treatment the subject was randomised to unless otherwise 
stated.
!
GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DPs) will be adopted for reporting of 
data based on the raw data collected.
!
Numeric data will be reported at the precision collected on the electronic case report form (eCRF) or 
recorded in the raw dataset if from non eCRF sources.
!
The reported precision from non eCRF sources will follow the IDSL statistical principles but may be 
adjusted to a clinically interpretable number of DP’s. 
Planned and Actual Times
!
Reporting for tables, figures and formal statistical analyses:
!
Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.
!
The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate.
!
Reporting for Data Listings: 
!
Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).
!
Unscheduled or unplanned readings will be presented within the subject’s listings. 
!
For visits outside the time-windows, please see Section 12.3.
Unscheduled Visits
!
Unscheduled visits will not be included in summary tables or figures.
!
All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Graphical Displays
!
Refer to IDSL Statistical Principals 7.01 to 7.13. 
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12.6.
Appendix 6: Derived and Transformed Data
12.6.1.
General
Multiple Measurements at One Time Point
!
If there are multiples values within a time window the last valid value prior to randomisation will be used 
as the baseline value and the value closest to the target day for that window will be used for all post-
randomisation visits. If values are the same distance from the target, then for efficacy outputs where 
visit slotting is used the earlier record will be used.  For all other cases of multiple valid measurements 
the mean will be taken.
!
Subjects having both High and Low values for Normal Ranges at any post-baseline visits for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance summary 
tables.
Study Day
!
Calculated as the number of days from randomisation date:
!
Ref Date = Missing                       →Study Day = Missing 
!
Ref Date < Randomisation Date   →Study Day = Ref Date – Randomisation Date    
!
Ref Data ≥ Randomisation Date   →Study Day = Ref Date – (Randomisation Date) + 1    
Time Since First Dose
!
Calculated as the number of days from the date of first dose:
!
Ref Date = Missing                  →Time Since First Dose = Missing 
!
Ref Date < First Dose Date     →Time Since First Dose = Ref Date – First Dose Date
!
Ref Date ≥ First Dose Date    →Time Since First Dose = Ref Date – (First Dose Date) + 1    
Time Since Last Dose
!
Calculated as the number of days from the date of last dose:
!
Ref Date = Missing                  → Time Since Last Dose = Missing 
!
Ref Date < Last Dose Date     → Time Since Last Dose = Ref Date – Last Dose Date
!
Ref Date ≥ Last Dose Date    → Time Since Last Dose = Ref Date – Last Dose Date) + 1    
Study Treatment Discontinuation
!
In this study, subjects who are intentionally and permanently withdrawn from study medication may not 
continue in the study attending the remaining visits (excluding the Follow-up contact) and completing 
the scheduled assessments. 
12.6.2.
Study Population
Demographics
Age
!
GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed as 
follows:
o
Any subject with a missing day will have this imputed as day ‘15’. 
o
Any subject with a missing date and month will have this imputed as ‘30th June’.
!
Birth date will be presented in listings as ‘YYYY’.
!
Completely missing dates of birth will remain as missing, with no imputation applied. Consequently, the 
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Demographics
age of the subject will not be calculated and will remain missing.
!
Age, in whole years, will be calculated with respect to the date of screening (Visit 1).
Body Mass Index
!
Calculated as Weight (kg) / [Height (m)]2
Race 
!
In the demographic summary table race will be summarised as follows; White is defined as those 
subjects who chose only the White (Arabic/North African Heritage) and/or White 
(White/Caucasian/European Heritage) categories on the CRF, Black is defined as those subjects who 
chose only the African American/African Heritage category on the CRF, and Other is defined as those 
subjects who chose any of the other races on the CRF.
Extent of Exposure
Subjects for whom it is considered appropriate/necessary to adjust treatment can have their dose 
increased from the starting dose, and will be recorded in the eCRF. Treatment sequence identifier will be 
incremented by 1 each time the study medication is modified, and recorded on eCRF.
Extent of exposure will be presented in three different ways:
!
The extent of exposure to study medication, regardless of study medication dosage modifications during 
the study, will be defined as the number of days on study medication and will be calculated for each 
subject as follows:
Exposure = (study medication stop date – study medication start date) + 1
If medication start date is missing, then the randomisation date (i.e. date of Visit 2) of the subject will be used 
for medication start date. If the medication stop date is missing, the Visit 6 date or early withdrawal visit date 
will be used instead. If all these dates are missing, then the extent of exposure will be set to missing.
!
The extent of exposure to study medication, up to first study medication dosage modification
!
The extent of exposure to each dose of study medication, presented separately for FF/VI 92 mcg/22 
mcg, FF/VI 184 mcg/22mcg, FP/S 250 mcg/50 mcg, FP/S 500 mcg/50 mcg, BUD/F 200 mcg/6 mcg, 
BUD/F 400 mcg/12 mcg
Note: do not split by dose frequency
12.6.3.
Efficacy
Primary Endpoint
ACT
The ACT is a validated self-administered questionnaire utilising 5 questions to assess asthma control during 
the past 4 Weeks on a 5-point categorical scale (1 to 5). 
By answering all 5 questions, a subject with asthma can obtain a score that may range between 5 and 25, 
with higher scores indicating better control. An ACT score of 5 to 19 suggests that the subject’s asthma is 
unlikely to be well controlled. A score of 20 to 25 suggests that the subject’s asthma is likely to be well 
controlled. The MID for ACT is 3 (Schatz, 2009).
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Primary Endpoint
The total score is calculated as the sum of the scores from all 5 questions, provided all scores are non-
missing; if any individual scores are missing then the overall score will be set to missing.
Secondary Endpoint
Correct Use of Device
Inhaler use will be assessed at Randomisation (Visit 2), Week 12 (Visit 4) and Week 24 (Visit 6). Correct use 
of device is defined as making no critical or non-critical errors.
Critical and Non-Critical Errors for Ellipta
Critical errors:
!
Failed to open cover 
!
Shook the device upside down after dose preparation
!
Exhaled directly into mouthpiece 
!
No seal by the lips around the mouthpiece during the inhalation
Non-critical errors:
!
No exhalation before an inhalation
!
Inhalation manoeuvre was not:
-
long 
-
steady
-
deep
!
Blocked air inlet during inhalation manoeuvre
!
Did not hold breath 
!
Did not close the device (Note:  this is an error but one which does not affect the medication that is 
inhaled)
Critical and Non-Critical Errors for Diskus
Critical errors:
!
Failed to open cover
!
Lever is not pushed back 
!
Shook the device after dose preparation
!
Exhaled directly into mouthpiece 
!
No seal by the lips round the mouthpiece during the inhalation
Non-critical errors:
!
No exhalation before an inhalation
!
Inhalation manoeuvre was not:
-
steady
-
deep
!
Did not hold breath
!
Did not close the device (Note:  this is an error but one which does not affect the medication that is 
inhaled)
Critical and Non-Critical Errors for Turbuhaler
Critical errors:
!
Failed to remove cap
!
Did not hold device upright (±45° OK) during dose preparation
!
Base not twisted fully backwards and forwards, no click heard
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Primary Endpoint
!
Shook the device after dose preparation
!
Exhaled directly into mouthpiece
!
No seal by the lips round the mouthpiece during the inhalation
Non-critical errors:
!
Device tipped downwards after dose preparation
!
No exhalation before an inhalation
!
Inhalation manoeuvre was not:
-
forceful
-
deep
!
Blocked air inlet during inhalation manoeuvre
!
Did not hold breath
!
Did not close the device (Note:  this is an error but one which does not affect the medication that is 
inhaled)
Other Endpoints
FEV1
FEV1 will be measured to assess lung function at Randomisation (Visit 2) and Week 12 (Visit 4). Visit 4 
should be scheduled at the same time of day as Visit 2, FEV1 measurements should be taken pre-dose and 
subjects should be instructed not to take their asthma medication/study drug prior to coming into the clinic at 
these visits. Subjects should also withhold from using their rescue medication for at least 4 hours prior to 
Visit 2 and Visit 4.
All sites will use standardised spirometry equipment provided by GSK. For each observation, at least 3 (with 
no more than 8) efforts will be obtained. At least two of the spirometry efforts should be acceptable and 
repeatable. The best FEV1 value will be recorded in the eCRF.
MARS-A
The MARS-A questionnaire is a 10-item questionnaire. The response to all ten questions will be presented
and included in the calculation of the MARS-A 10-score. 
The responses to the MARS-A questions will be scored as follows: Always=1, Often=2, Sometimes=3, 
Rarely=4, Never=5. The MARS-A 10-Score will be calculated for each subject as the sum of scores for each 
of the ten questions divided by the number of non-missing responses to the ten questions.
If some responses are missing the MARS-A 10-score is calculated as follows for each subject:
!
If eight or more of the questions have been answered, the missing responses for that subject will be 
imputed to the average score
!
If less than eight of the questions have been answered, the overall MARS-A 10-score for that 
subject will be set to missing
The French translation of the MARS-A questionnaire did not go through cognitive debriefing; therefore, while 
the study was ongoing it was determined that there is no word for “preventer” in French. “Preventer inhaler” 
was translated as “dispositif d’inhalation” (i.e., “inhalation device”). A reminder was sent to centres in France 
instructing that the MARS-A questionnaire refers to the patient’s preventer inhaler (i.e. their maintenance 
therapy prior to entering the study, and study medication while on-study) as opposed to their reliever inhaler. 
The German translation went through cognitive debriefing and was correctly translated. The MARS-A data 
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Other Endpoints
displays will therefore be repeated split by:
!
Patients in France, all MARS-A assessments completed pre-reminder
!
Patients in France, some MARS-A assessments completed pre-reminder, some post-reminder
!
Patients in France, all MARS-A assessments completed post-reminder
!
Patients in Germany
The reminder was sent on 17OCT2016, and it was assumed that the centres started implementing the 
instructions two days after this, i.e. on 19OCT2016.  If a visit occurs on the 19OCT2016 then it will be 
categorised as having happened before the reminder.
Severe Asthma Exacerbations
Missing onset or resolution dates will be handled as follows:
!
Single event with missing onset and/or resolution dates:
(a)
Missing onset date: set onset date = study treatment start date
(b)
Missing resolution date: set resolution date = study treatment stop date
(c)
Both missing: imputed per both (a) and (b)
!
Multiple events, one event with some missing onset/resolution dates; on the assumption any partial date 
information does not occur during the other events:
(a)
Missing onset date: set onset date = max[(resolution date of the nearest previous event) + 1 
day, study treatment start date]
(b)
Missing resolution date: set resolution date = min[(onset date of the nearest subsequent event) -
1 day, study treatment stop date] 
(c)
Both missing: determine the largest gap between study treatment start date and first event onset 
date, between first event resolution date and next event(s) onset dates (if any), between last 
event resolution date and study treatment stop date. If there is more than one gap which is the 
largest, then take the first occurrence. Then impute as follows:
onset date = (onset date of largest gap) + 1 day
resolution date = (resolution date of largest gap) + 1 day
Time to First Severe Asthma Exacerbation  
The date of a severe asthma exacerbation is defined as the exacerbation onset date. Subjects who complete 
the study without a severe asthma exacerbation will be censored.  Time to first severe asthma exacerbation 
is measured from the date of randomisation (i.e., study treatment start date) to the onset date of first severe 
asthma exacerbation, as recorded on eCRF, or study treatment stop date (Visit 6 or early withdrawal visit) for 
subject who complete the study without any severe asthma exacerbations (censored). Analyses of time to 
first severe asthma exacerbation will be censored at Day 168.
AQLQ(S) Domain and Total Scores
The AQLQ(S) contains 32 items in four domains: activity limitation (11 items), symptoms (12 items), 
emotional function (5 items) and environmental stimuli (4 items). The following items are included in each of 
the 4 domains:
!
Symptoms: 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 29, 30
!
Activity Limitation: 1, 2, 3, 4, 5, 11, 19, 25, 28, 31, 32
!
Emotional Function: 7, 13, 15, 21, 27
!
Environmental Stimuli: 9, 17, 23, 26
The response format consists of a seven-point scale where a value of 1 indicates “total impairment” and a 
value of 7 indicates “no impairment”. The total AQLQ(S) score is the mean of all 32 items in the 
questionnaire and each individual domain score is calculated as the mean of the items within that domain. 
Hence, the total and domain scores are also each defined on a range from 1 to 7 with higher scores 
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Other Endpoints
indicating a higher quality of life. The MID for AQLQ(S) is 0.5 (Juniper, 1993).
For the total AQLQ(S) score, the score for a subject at any time point will only be calculated if at least 90% of 
the questions were answered (calculated as the mean of those non-missing questions). If fewer than 90% of 
the questions were answered, then the mean score for that subject at that time point will be considered 
missing.
For each individual domain of the AQLQ(S) score, the score for a subject at any time point will only be 
calculated if at least 90% of the questions for that domain were answered (calculated as the mean of those 
non-missing questions). If fewer than 90% of the questions were answered for that domain, then the mean 
score for that subject and domain at that time point will be considered missing.
EQ-5D-5L Utility and VAS Scores
The EQ-5D-5L is administered at randomisation (Visit 2), Week 24 (Visit 6) and Early Withdrawal. The EQ-
5D-5L consists of 2 parts: the EQ-5D-5L descriptive system and the EQ VAS.
The EQ-5D-5L descriptive system comprises the following 5 dimensions: Mobility, Self-Care, Usual Activities, 
Pain/Discomfort and Anxiety/Depression. Each dimension has 5 levels, where Level 1 (coded as ‘1’) = ‘No 
problems’, Level 2 (coded as ‘2’) = ‘Slight problems’, Level 3 (coded as ‘3’) = ‘Moderate problems’, Level 4 
(coded as ‘4’) = ‘Severe problems’ and Level 5 (coded as ‘5’) = ‘Extreme problems’. Subjects indicate their 
health state for each dimension by ticking (or placing a cross) in the box of the most appropriate level for that 
dimension. Ambiguous values (e.g. 2 boxes are ticked for a single dimension) will be considered missing. 
Missing values will be coded as ‘9’. The responses (1, 2, 3, 4 or 5) to the five questions will be converted into 
a single utility score using the developer’s instructions (EuroQol, 2013): the responses (1, 2, 3, 4 or 5) to the 
five questions in the descriptive system can be represented as one of 55=3125 possible health states (11111, 
11112, ... , 55555). These will be converted into a single summary index (y) that attaches value to each of 
the levels in each dimension by applying the formula below, which is based on the EQ-5D-5L value set for 
England (Devlin, 2016).
where variables with subscript 
are indicator variables equal to 1 when the corresponding level for the 
dimension is ‘ ’ and equal to 0 otherwise,
variables represent responses for the mobility domain, 
variables represent responses for the self-care domain,
variables represent responses for the usual 
activities domain,
variables represent responses for the pain / discomfort domain, and
variables 
represent responses for the anxiety / depression domain.
For example, health state where domains MSUPA = 11223 would be equal to:
The EQ VAS records the subject’s self-rated health state on a vertical, VAS where 0=’worst imaginable 
health state’ and 100=’best imaginable health state’. Subjects indicate their own health state by drawing a 
line from the box on the left of the scale to whichever point on the scale indicates how good or bad their own 
health state is that day. Ambiguous values (e.g. the line crosses the VAS twice) will be considered missing. 
Missing values will be coded as ‘999’.
Only validated EuroQoLs completed in the same language as that completed at Baseline (Visit 2) will be 
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Other Endpoints
summarised.
PASAP-Q Domain and Total Scores
The PASAP-Q is a self-administered 16-item questionnaire measuring satisfaction and preference with 
inhaler devices (Kozma, 2005). Two domains (performance and convenience) are calculated from 13 
satisfaction items, measured on a Likert-type scale where a value of 1 indicates “very dissatisfied” and 7 
indicates “very satisfied”. The performance and convenience domains together form the total score. The 
other items include an overall satisfaction question (again measured from 1 to 7), a preference question (not 
applicable and so not asked for this study) and a question on willingness to continue using the device in the 
future, measured on a scale of 0 (not willing) to 100 (definitely willing).
The performance and convenience domains include the following items:
!
Performance: 1, 2, 3, 4, 5, 10, 11
!
Convenience: 6, 7, 8, 9, 12, 13
If the patient completes at least half of the items in a domain, values for missing items are imputed using the 
mean of the completed items in that domain. The domain score is then transformed to a scale from 0 (least) 
to 100 (most) as follows:
If the patient completes less than half of the items in a domain, then the missing items are not imputed and 
the domain score is set to missing. The total score can be calculated only when both domain scores are 
computable and substitution for missing items at the domain level has taken place, and is calculated on the 
same scale as:
The overall satisfaction and willingness questions are summarised on their original scales of 1 to 7 and 0 to 
100 respectively.
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Other Endpoints
Treatment Compliance
Overall percentage treatment compliance for every subject will be calculated for each type of inhaler (Diskus, 
Turbuhaler and Ellipta) separately. 
Compliance for Diskus, Turbuhaler and Ellipta will be based on the total number of inhalations taken from 
each type of inhaler and the expected number of inhalations to be taken. The expected number of inhalations 
will be derived as the sum over the number of days on study drug (based on the subject’s treatment start and 
stop date for that type of inhaler) of the expected number of inhalations per day (from each inhaler) .
The total number of inhalations taken will be based on the dose counter for each type of inhaler, all of which 
are re-supplied during the study. If there is no dose counter information at all then the compliance will be 
missing; however, as long as the information from one dose counter is present, the compliance will be 
calculated assuming that all doses were taken for the missing inhalers. If a dose counter start count is 
missing, then it will be assumed to be 30 for Ellipta and 60 for both Diskus and Turbuhaler.
In each calculation, all inhalers dispensed will be used, provided the dose counter stop counts are non-
missing. The following formula will be used:
Where:
!
. Start_date and Stop_date are the earliest treatment start 
date and latest treatment stop date respectively recorded for all inhalers used during the time 
period.
!
Total_number_of_inhalations_taken is the sum of (dose counter start count – dose counter stop 
count) for all inhalers used during the time period
!
Expected_inhalations_for_dayi is equal to 1 for Ellipta and 2 for Diskus and 2 or 4 for Turbuhaler for 
any given day, depending on the dose
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12.6.4.
Safety
SAEs of Special Interest
SAE groups of special interest have been defined as SAEs which are included in specified areas of interest 
for one or more of the treatment groups (FF/VI, FF and/or VI).  They are identified by groupings of preferred 
terms based on the Medical Dictionary for Regulatory Activities (MedDRA) dictionary version used in each 
reporting effort.  Groupings or subgroups may be defined, based on relevant combination of preferred terms, 
or on Standardised MedDRA queries (SMQs).
SAEs of special interest will be confirmed prior to final data, based on the MedDRA version in use at the 
time.
Special Interest SAE Group
Asthma/bronchospasm
Cardiovascular effects
Decreased bone mineral density and associated fractures
Hypersensitivity
Local steroid effects
LRTI excluding pneumonia
Pneumonia
Adrenal suppression
Ocular effects
Effects on glucose
Effects on potassium
Tremor
Laboratory Parameters
!
If a laboratory value which is expected to have a numeric value for summary purposes, has a non-
detectable level reported in the database, where the numeric value is missing, but typically a character 
value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the comment field) is 
present, the number of significant digits in the observed values will be used to determine how much to 
add or subtract in order to impute the corresponding numeric value. 
o
Example 1: 2 Significant Digits =  ‘< x ‘ becomes x – 0.01
o
Example 2: 1 Significant Digit   =  ‘> x’ becomes x + 0.1
o
Example 3: 0 Significant Digits = ‘< x’ becomes x – 1    
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12.7.
Appendix 7: Premature Withdrawals & Handling of Missing 
Data
12.7.1.
Premature Withdrawals
Element
Reporting Detail
General
!
Subject study completion was defined in the protocol as a subject who has completed all 
study visits. The end of the study is defined as the last subject’s last visit.
!
The definition of subject early withdrawal from the study will be any subject who is 
randomised and, for any reason, does not complete all study visits.
!
Withdrawn subjects will not be replaced in the study.
!
All available data from subjects who were withdrawn from the study will be listed and all 
available planned data will be included in summary tables and figures, unless otherwise 
specified.
12.7.2.
Handling of Missing Data
Element
Reporting Detail
General
!
Missing data occurs when any requested data is not provided, leading to blank fields on 
the collection instrument:
o
These data will be indicated by the use of a “blank” in subject 
listing displays (if applicable). Unless all data for a specific visit are missing in 
which case the data is excluded from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not 
considered to be missing data and should be displayed as such.
Outliers
!
Any subjects excluded from the summaries and/or statistical 
analyses will be documented along with the reason for exclusion in the clinical study 
report.
Exposure 
start and 
stop date
!
If a subject’s treatment start date is missing, then their Visit 2 date will be assumed to 
be the exposure start date. If a subject’s treatment stop date is missing, this will be 
taken to be the date of Week 24 (Visit 6) (if the subject completes Visit 6) or the early 
withdrawal visit date.
12.7.2.1.
Handling of Missing or Partial Dates
Element
Reporting Detail
General
Partial dates will be displayed as captured in subject listing displays.
SAEs and 
ADRs
!
The eCRF does not allow the possibility of partial dates (i.e., only month and year) to be 
recorded for SAE and ADR start and end dates; 
!
Completely missing start or end dates will remain missing, with no imputation applied. 
Consequently, time to onset and duration of such events will be missing.
Concomitant 
Medications
!
Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will be 
used for the month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month.
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Element
Reporting Detail
!
The recorded partial date will be displayed in listings.
12.7.2.2.
Handling of Missing Data for Statistical Analysis
In general, missing data will not be imputed except for the sensitivity analyses defined in Section
8.1.2.
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12.8.
Appendix 8: Values of Potential Clinical Importance
12.8.1.
Vital Signs
Not applicable
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12.9.
Appendix 9: Multicenter Studies
12.9.1.
Methods for Handling Centres
In this multicentre study conducted in France and Germany, enrolment will be presented by 
investigative site.
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12.10.
Appendix 10: Examination of Covariates, Subgroups & 
Other Strata
12.10.1.
Examination of Strata and Covariates
The following is a list of covariates that may be used in descriptive summaries and statistical 
analyses, some of which may also be used for subgroup analyses.
Additional covariates of clinical interest may also be considered. 
Category
Covariates and / or Subgroups
Strata
Separate randomisation schedules were utilised for France and 
Germany respectively thereby stratifying the randomisation by 
country. Country will be included in all analyses as a covariate. A 
sensitivity analysis will examine the randomized treatment-by-country 
interaction for the primary and key secondary endpoints.
Covariates
For the primary efficacy analysis, the following baseline variables will 
be adjusted for: 
!
Randomised treatment (FF/VI, Usual ICS/LABA)
!
Baseline ACT total score
!
Age
!
Gender
!
Country
Similar covariates will be considered for all other analyses; in each
case the relevant baseline score (e.g. baseline AQLQ[S] score for the 
AQLQ[S] endpoints) will be included instead of baseline ACT total 
score.
12.10.2.
Examination of subgroups
!
If the percentage of subjects is small within a particular subgroup, then the subgroup 
categories may be refined prior to unblinding the trial.
!
If the category cannot be refined further, then descriptive rather than statistical comparisons 
may be performed for the particular subgroup.
!
For statistical analyses by subgroup, models will include subgroup and treatment by subgroup 
interaction as covariates.
Category
Subgroups
Country
!
France
!
Germany
Number of severe asthma 
exacerbations in the previous year 
prior to randomisation
!
0
!
≥ 1
Smoking Status at Baseline
!
Current smoker
!
Former smoker
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Category
Subgroups
!
Never smoked
Age Group
!
≤50 years old
!
> 50 years old
Gender
!
Male
!
Female
12.10.3.
Examination of seasonal effect
A sensitivity analysis for the primary efficacy endpoint examining seasonal effect is defined in 
Section 8.1.2, specifying a season at randomisation covariate defined as follows:
Season at Randomisation
Calendar Month of Randomisation
Spring
!
March
!
April
!
May
Summer
!
June
!
July
!
August
Autumn
!
September
!
October
!
November
Winter
!
December
!
January
!
February
Furthermore, the summary of severe asthma exacerbations will be repeated by season using the 
same definition (according to calendar month) as specified above.
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12.11.
Appendix 11: Multiple Comparisons & Multiplicity
12.11.1.
Handling of Multiple Comparisons & Multiplicity
Non inferiority of FF/VI to ICS/LABA will be first tested at the 0.05 two-sided nominal level of 
significance. If non-inferiority is statistically achieved, then superiority of FF/VI to ICS/LABA 
will be tested at the 0.05 two-sided nominal level of significance. 
If and only if non-inferiority is achieved for the primary endpoint at Week 12 (Visit 4), then the 
key secondary endpoint, i.e. the change from baseline in the total ACT score assessed at Week 24 
(Visit 6) will be tested. At Week 24 (Visit 6), non-inferiority of FF/VI to ICS/LABA will be first 
tested at the 0.05 two-sided nominal level of significance. If non-inferiority is achieved, then 
superiority of FF/VI to ICS/LABA will be tested at the 0.05 two-sided nominal level of 
significance. 
Of note, this step-down testing procedure still strongly controls the overall type I error at the 0.05 
two-sided level for the non-inferiority endpoints. The overall type I error is not controlled for the 
superiority tests at Week 12 (Visit 4) and Week 24 (Visit 6).
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12.12.
Appendix 12: Model Checking and Diagnostics for 
Statistical Analyses
12.12.1.
Statistical Analysis Assumptions
Endpoint(s)
!
Change from Baseline in the ACT Total Score at Week 12 (Visit 4)
!
Change from Baseline in the ACT Total Score at Week 24 (Visit 6)
Analysis
!
MMRM (ANCOVA for LOCF and WOCF sensitivity analyses)
!
Should computational issues be encountered when running the model with an unstructured variance-
covariance matrix, other structures including autoregressive 1 and compound symmetry will be 
considered.
!
Distributional assumptions underlying the model will be checked with graphical methods (including 
quantile-quantile (Q-Q) plots of studentized residuals, plots of studentized residuals versus fitted
values, etc.). To investigate the relationship between baseline ACT total score and the change from 
baseline in ACT total score, baseline ACT total will be categorized according to the distribution quartiles 
and the model will be fitted using this categorized variable in place of continuous baseline ACT total 
score.
!
If the distributional assumption of normality fails then the LS means, estimated LS mean treatment 
difference and associated 95% CI from the model will be presented, with the p-value for the difference 
between treatment groups from a model on the rank-transformed values. Should the distributional 
assumption of normality also fail for the ranked model, other methods of analysis will be investigated. 
Endpoint(s)
!
Percentage of subjects with correct use of inhaler device at Week 12 (Visit 4) and at 
Week 24 (Visit 6) independently of the use at Week 12 (Visit 4)
!
ACT total score of ≥ 20 or ≥ 3 point increase from baseline in ACT total score at Week 
12 (Visit 4) and Week 24 (Visit 6)
!
Increase from baseline of ≥ 0.5 in AQLQ(S) total score at Week 24 (Visit 6)
!
Increase from baseline of ≥ 0.5 in AQLQ(S) environmental stimuli domain score at 
Week 24 (Visit 6)
!
Proportion of subjects with ‘no problems’ at Endpoint in the EQ-5D-5L questionnaire
Analysis
!
Logistic regression model
!
If the likelihood maximisation algorithm fails to converge due to complete or quasi-complete separation 
of the data then Firth’s penalized likelihood (Firth, 1993) will be implemented by use of the FIRTH 
option on the MODEL statement in PROC LOGISTIC.
!
The fit of the logistic regression model will be assessed by examining the ROC curve and other 
diagnostic plots. 
Endpoint(s)
!
Change from baseline in trough (pre-dose) FEV1 at Week 12 (Visit 4)
!
Change from baseline in EQ-5D Utility Score
!
Change from baseline in EQ-5D VAS Score
Analysis
!
ANCOVA model
!
Distributional assumptions underlying the model will be checked with graphical methods (including 
quantile-quantile (Q-Q) plots of studentized residuals, plots of studentized residuals versus fitted 
values, etc.). 
!
If the distributional assumption of normality fails then the LS means, estimated LS mean treatment 
difference and associated 95% CI from the ANCOVA model will be presented, with the p-value for the 
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difference between treatment groups from an ANCOVA model on the rank-transformed values. Should 
the distributional assumption of normality also fail for the ranked ANCOVA, an exact p-value from a 
two-sample Wilcoxon Rank Sum test will be presented for the difference between treatment groups.  
Endpoint(s)
!
Annual severe asthma exacerbation rate over the study period
Analysis
!
GLM assuming the Negative Binomial distribution
!
If a GLM assuming the Negative Binomial distribution cannot be fitted due to the lack of repeat events 
within a subject, a GLM assuming the Poisson distribution will be used. The underlying assumption for 
the Poisson distribution that the mean and variance of the response variable are equal will be 
examined. If the variance of the fitted model exceeds the mean (over-dispersion), the dispersion 
parameter will be estimated as a ratio of the Pearson Chi-Square to its associated degrees of freedom 
(using the PSCALE option in PROC GENMOD).
Endpoint(s)
!
Time to first severe asthma exacerbation
Analysis
!
Cox proportional hazards model
!
Proportional hazards assumptions will be checked by plotting the log of the negative log of the 
estimated survivor functions against log time, for each treatment group. If hazards are proportional, the 
lines should be approximately parallel.
!
If the assumption of proportionality is not met, the use of other models such as models including time-
dependent covariates will be considered. 
!
If there are computational issues in implementing the exact method for handling ties, then the Efron 
method (Efron, 1977) will be used instead.
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12.13.
Appendix 13: Blinding Strategy
The Blinding Strategy is maintained separately in a document entitled HZA116492 - Blinding 
Strategy.
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12.14.
Appendix 14: Abbreviations & Trade Marks
12.14.1.
Abbreviations
Abbreviation
Description
ACT
Asthma Control Test
ADR
Adverse Drug Reaction
AE
Adverse Event
AESI
Adverse Event of Special Interest
ANCOVA
Analysis of Covariance
AQLQ(S)
Standardised Asthma Quality of Life Questionnaire
ASE
All Subjects Enrolled
BMI
Body Mass Index
BUD
Budesonide
CI
Confidence Interval
CIL
Clinical Investigational Lead
CRF
Case Report Form
CRO
Contract Research Organisation
DBF
Database Freeze
DBP
Diastolic Blood Pressure
DBR
Database Release
DM
Data Management
DP
Decimal Place
DPI
Dry Powder Inhaler
DQL
Data Quality Lead
eCRF
Electronic Case Report Form
EQ-5D-5L
EuroQol Questionnaire
F
Formoterol
FEV1
Forced Expiratory Volume in 1 Second
FF
Fluticasone Furoate
FP
Fluticasone Propionate
GINA
Global Initiative for Asthma
GLM
Generalised Linear Model
GSK
GlaxoSmithKline
HL
Hodges-Lehmann
HR
Heart Rate
ICF
Informed Consent Form
ICS
Inhaled Corticosteroid
IDSL
Integrated Data Standards Library
IP
Investigational Product
ITT
Intent-to-Treat
LABA
Long-acting Beta Agonist
LOCF
Last Observation Carried Forward
LRTI
Lower Respiratory Tract Infection
LS
Least Squares
MAR
Missing at Random
MARS-A
Medication Adherence Report Scale for Asthma
MCID
Minimal Clinically Important Difference
MedDRA
Medical Dictionary for Regulatory Activities 
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Abbreviation
Description
MI
Multiple Imputation
MID
Minimally Important Difference
MMRM
Mixed Model Repeated Measures
PASAP-Q
Patient Satisfaction and Preference  Questionnaire
PD
Protocol Deviation
PDMP
Protocol Deviation Management Plan
PP
Per Protocol
Q-Q
Quantile-Quantile
RAP
Reporting and Analysis Plan
REML
Restricted Maximum Likelihood
S
Salmeterol
S&P
Statistics and Programming
SAC
Statistical Analysis Complete
SAE
Serious Adverse Event
SBP
Systolic Blood Pressure
SD
Standard Deviation
SMQ
Standardised MedDRA Query
VAS
Visual Analogue Scale
VI
Vilanterol
WOCF
Worst Observation Carried Forward
12.14.2.
Trademarks
Trademarks of the GlaxoSmithKline Group 
of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
DISKUS
ACT
ELLIPTA
Asthma Quality of Life Questionnaire -
AQLQ(S)
GSK
EQ-5D
NUCALA
MARS-A Questionnaire
SERETIDE
PASAP Questionnaire
Symbicort Turbuhaler
TURBUHALER
XOLAIR
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12.15.
Appendix 15: List of Data Displays
12.15.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.n
1.1 to 1.n
Efficacy
2.1 to 2.n
2.1 to 2.n
Safety
3.1 to 3.n
3.1 to 3.n
Section
Listings
ICH Listings
1 to x
Other Listings
y to z
12.15.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required an example mock-up 
displays provided in Appendix 11: Example Mock Shells for Data Displays
.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Efficacy
EFF_Fn
EFF_Tn
EFF_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
NOTES: 
!
Non-Standard displays are indicated in the ‘IDSL / TST ID / Example Shell’ or ‘Programming Notes’ column as 
‘[Non-Standard] + Reference.’
12.15.3.
Deliverable [Priority]
Delivery [Priority] [1]
Description
Data Look [1]
Data Look Outputs (blinded review)
SAC [2]
Final Statistical Analysis Complete
NOTES: 
1.
Indicates priority (i.e. order) in which displays will be generated for the reporting effort.
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12.15.4.
Study Population Tables
Study Population: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
All Enrolled 
Subjects
Non-Standard 
POP_T1
Summary of Subject Populations
Randomised population line will provide 
the denominators for the ITT, PP and 
Safety percentages.
Data Look [1] 
SAC [2]
1.2.
All Enrolled 
Subjects
IE2
Summary of Inclusion/Exclusion Criteria Failures for Subjects 
Not Starting Treatment
Data Look [1] 
SAC [2]
1.3.
ITT
ES1
Summary of End of Study Record
Data Look [1] 
SAC [2]
1.4.
PP
ES1
Summary of End of Study Record
Per Protocol Population
Data Look [1] 
SAC [2]
1.5.
ITT
Non-Standard 
POP_T2
Summary of Attendance at Each Clinic Visit and Phone Call Visit
Data Look [1] 
SAC [2]
1.6.
All Enrolled 
Subjects
NS1
Summary of Number of Subjects by Country and Centre
SAC [2]
1.7.
ITT
NS1
Summary of Number of Subjects by Country and Centre
Data Look [1] 
SAC [2]
1.8.
PP
NS1
Summary of Number of Subjects by Country and Centre
Per Protocol Population
SAC [2]
Protocol Deviations
1.9.
ITT
IE2
Summary of Deviations from the Inclusion/Exclusion Criteria
Data Look [1] 
SAC [2]
1.10.
ITT
Non-Standard 
POP_T3
Summary of Important Protocol Deviations
Data Look [1] 
SAC [2]
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Study Population: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.11.
ITT
Non-Standard 
POP_T3
Summary of Important Protocol Deviations Resulting in 
Exclusion from the PP Population
Data Look [1] 
SAC [2]
Demographic and Baseline Characteristics
1.12.
ITT
DM1
Summary of Demographic Characteristics
Data Look [1] 
SAC [2]
1.13.
PP
DM1
Summary of Demographic Characteristics
Per Protocol Population
SAC [2]
1.14.
Safety
DM1
Summary of Demographic Characteristics
Safety Population
SAC [2]
1.15.
All Enrolled 
Subjects
DM11
Summary of Age Ranges
Data Look [1] 
SAC [2]
1.16.
ITT
DM5
Summary of Race and Racial Combinations
Data Look [1] 
SAC [2]
1.17.
ITT
DM6
Summary of Race and Racial Combinations Details
Data Look [1] 
SAC [2]
1.18.
ITT
MH4
Summary of Current Medical Conditions
Data Look [1] 
SAC [2]
1.19.
ITT
MH4
Summary of Past Medical Conditions
SAC [2]
1.20.
ITT
Non-Standard 
POP_T4
Summary of Asthma Duration at Baseline
Data Look [1] 
SAC [2]
1.21.
PP
Non-Standard 
POP_T4
Summary of Asthma Duration at Baseline
Per Protocol Population
Data Look [1] 
SAC [2]
1.22.
ITT
Non-Standard 
POP_T5
Summary of Asthma Exacerbation History at Baseline
Data Look [1] 
SAC [2]
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Study Population: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.23.
PP
Non-Standard 
POP_T5
Summary of Asthma Exacerbation History at Baseline
Per Protocol Population
Data Look [1] 
SAC [2]
1.24.
ITT
Non-Standard 
POP_T6
Summary of Smoking History at Baseline
Data Look [1] 
SAC [2]
1.25.
PP
Non-Standard 
POP_T6
Summary of Smoking History at Baseline
Per Protocol Population
SAC [2]
Concomitant Medications
1.26.
ITT
CM8
Summary of Pre-Treatment Concomitant Medications
SAC [2]
1.27.
ITT
CM8
Summary of On-Treatment Concomitant Medications
SAC [2]
1.28.
ITT
CM8
Summary of On-Treatment Asthma Concomitant Medications
Data Look [1] 
SAC [2]
Exposure
1.29.
ITT
Non-Standard 
POP_T7
Summary of Study Medication Dosage Modification
Data Look [1] 
SAC [2]
1.30.
ITT
Non-Standard 
POP_T8
Summary of Extent of Exposure to Study Medication 
(Regardless of Modification to Study Medication Dosage)
Data Look [1] 
SAC [2]
1.31.
ITT
Non-Standard 
POP_T8
Summary of Extent of Exposure to Study Medication (up to First 
Modification to Study Medication Dosage)
SAC [2]
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Study Population: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.32.
ITT
Non-Standard 
POP_T9
Summary of Extent of Exposure to Study Medication by 
Medication and Dosage
Repeat on subsequent pages for 
Medication/Dosage = FF/VI 184 mcg/22 
mcg OD, FP/S 250 mcg/50 mcg BID, 
FP/S 500 mcg/50 mcg BID, BUD/F 200 
mcg/6 mcg BID (1 inhalation per dose), 
BUD/F 200 mcg/6 mcg BID (2 
inhalations per dose), BUD/F 400 
mcg/12 mcg BID (1 inhalation per 
dose), BUD/F 400 mcg/12 mcg BID (2 
inhalations per dose).
Data Look [1] 
SAC [2]
Number of Subjects by Subgroup
1.33.
ITT
Non-Standard 
POP_T10
Summary of Number of Subjects by Subgroup
SAC [2]
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12.15.5.
Study Population Figures
Study Population: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Exposure
1.1.
ITT
Non-Standard 
POP_F1
Plot of Exposure to Study Medication (Regardless of 
Modification to Study Medication Dosage)
Display increments of 6 weeks on the x-
axis, up to the maximum exposure (e.g. 
0, 6, 12, 18, 24, 30).
Data Look [1] 
SAC [2]
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12.15.6.
Efficacy Tables
Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Change from Baseline in ACT Total Score at Week 12 (Visit 4)
2.1.
ITT
Non-Standard 
EFF_T1
Summary of Change from Baseline in ACT Total Score
Data Look [1] 
SAC [2]
2.2.
PP
Non-Standard 
EFF_T1
Summary of Change from Baseline in ACT Total Score
Per Protocol Population
SAC [2]
2.3.
ITT
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 12 (Visit 4)
Data Look [1] 
SAC [2]
2.4.
PP
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 12 (Visit 4)
Per Protocol Population
SAC [2]
2.5.
ITT
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 12 (Visit 4) (ANCOVA with LOCF)
Footnotes as follows: “Note: The 
analysis method was an ANCOVA 
model adjusted for randomised 
treatment, baseline ACT total score, 
gender, age and country. Note: Missing 
values at Week 12 (Visit 4) were 
replaced by last available post-
randomization value based on the last 
observation carried forward (LOCF) 
method.”
Data Look [1] 
SAC [2]
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.6.
ITT
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 12 (Visit 4) (Multiple Imputation –
Missing at Random Approach)
Footnotes as follows:
“Note: Missing values post-
randomisation were imputed using 
multiple imputation methods based on 
pattern mixture models.
Note: Each imputed data set was 
analysed using an ANCOVA model at 
Week 12 (Visit 4) adjusted for 
randomised treatment, baseline ACT
total score, gender, age and country 
and the resulting treatment differences 
and their standard errors combined 
using Rubin’s rules.”
Data Look [1] 
SAC [2]
2.7.
ITT
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 12 (Visit 4) (Multiple Imputation –
Copy Differences from Reference Approach)
Footnotes as follows:
“Note: Missing values post-
randomisation were imputed using 
multiple imputation methods based on 
pattern mixture models.
Note: Each imputed data set was 
analysed using an ANCOVA model at 
Week 12 (Visit 4) adjusted for 
randomised treatment, baseline ACT 
total score, gender, age and country 
and the resulting treatment differences 
and their standard errors combined 
using Rubin’s rules.”
Data Look [1] 
SAC [2]
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.8.
ITT
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 12 (Visit 4) (Hodges-Lehmann 
Approach)
Present the “Difference” and “95% CI” 
lines of “FF/VI vs. Usual ICS/LABA” 
section only. Footnotes as follows:
“Note: The difference between 
treatment groups at Week 12 (Visit 4) 
was calculated using the Hodges-
Lehmann approach.”
Data Look [1] 
SAC [2]
2.9.
ITT
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 12 (Visit 4) (ANCOVA with WOCF)
Footnotes as follows:
“Note: The analysis method was an 
ANCOVA model adjusted for 
randomised treatment, baseline ACT 
total score, gender, age and country.
Note: Missing values at Week 12 (Visit 
4) due to treatment withdrawal prior to 
this time point were replaced by worst 
post-randomisation value based on the 
worst observation carried forward 
(WOCF) method.”
Data Look [1] 
SAC [2]
2.10.
ITT
Non-Standard 
EFF_T3
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 12 (Visit 4), Adjusting for Seasonal 
Effect
Repeat on subsequent pages for 
Season at randomisation = Summer, 
Autumn, Winter.
Data Look [1] 
SAC [2]
2.11.
PP
Non-Standard 
EFF_T3
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 12 (Visit 4), Adjusting for Seasonal 
Effect
Per Protocol Population
Repeat on subsequent pages for 
Season at randomisation = Summer, 
Autumn, Winter.
SAC [2]
2.12.
ITT
Non-Standard 
EFF_T1
Summary of Change from Baseline in ACT Total Score, FF/VI 
Versus the Subset of Usual ICS/LABA Subjects Prescribed FP/S 
at Randomisation
Data Look [1]
SAC [2]
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.13.
ITT
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 12 (Visit 4), FF/VI Versus the Subset 
of Usual ICS/LABA Subjects Prescribed FP/S at Randomisation
Output only to be produced if ≥25% of 
Usual ICS/LABA patients are 
prescribed FP/S at randomisation.
Data Look [1]
SAC [2]
2.14.
ITT
Non-Standard 
EFF_T1
Summary of Change from Baseline in ACT Total Score, FF/VI 
Versus the Subset of Usual ICS/LABA Subjects Prescribed 
BUD/F at Randomisation
SAC [2]
2.15.
ITT
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 12 (Visit 4), FF/VI Versus the Subset 
of Usual ICS/LABA Subjects Prescribed BUD/F at 
Randomisation
Output only to be produced if ≥25% of 
Usual ICS/LABA patients are 
prescribed BUD/F at randomisation.
SAC [2]
2.16.
ITT
Non-Standard 
EFF_T1S
Summary of Change from Baseline in ACT Total Score by 
Country
Data Look [1] 
SAC [2]
2.17.
ITT
Non-Standard 
EFF_T2S
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 12 (Visit 4) by Country
Data Look [1] 
SAC [2]
2.18.
ITT
Non-Standard 
EFF_T1S
Summary of Change from Baseline in ACT Total Score by 
Number of Severe Asthma Exacerbations in the Previous Year 
Prior to Randomisation
SAC [2]
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.19.
ITT
Non-Standard 
EFF_T2S
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 12 (Visit 4) by Number of Severe 
Asthma Exacerbations in the Previous Year Prior to 
Randomisation
First footnote as follows:
“Note: The analysis method was an 
MMRM adjusted for randomised 
treatment, visit (Week 6 and Week 12), 
baseline ACT total score, baseline ACT 
total score-by-visit interaction, gender, 
age, country, number of severe asthma 
exacerbations in the previous year prior 
to randomisation, two- and three- way 
interactions between randomised 
treatment, visit and number of severe 
asthma exacerbations in the previous 
year prior to randomisation, and patient 
fitted as a random factor.”
SAC [2]
2.20.
ITT
Non-Standard 
EFF_T1S
Summary of Change from Baseline in ACT Total Score by 
Smoking Status at Baseline
SAC [2]
2.21.
ITT
Non-Standard 
EFF_T2S
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 12 (Visit 4) by Smoking Status at 
Baseline
First footnote as follows: “Note: The 
analysis method was an MMRM 
adjusted for randomised treatment, visit 
(Week 6 and Week 12), baseline ACT 
total score, baseline ACT total score-
by-visit interaction, gender, age, 
country, smoking status at baseline, 
two- and three- way interactions 
between randomised treatment, visit 
and smoking status at baseline, and 
patient fitted as a random factor.”
SAC [2]
2.22.
ITT
Non-Standard 
EFF_T1S
Summary of Change from Baseline in ACT Total Score by Age 
Group
SAC [2]
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80
Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.23.
ITT
Non-Standard 
EFF_T2S
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 12 (Visit 4) by Age Group
First footnote as follows: “Note: The 
analysis method was an MMRM 
adjusted for randomised treatment, visit 
(Week 6 and Week 12), baseline ACT 
total score, baseline ACT total score-
by-visit interaction, gender, country, 
age group, two- and three- way 
interactions between randomised 
treatment, visit and age group, and 
patient fitted as a random factor.”
SAC [2]
2.24.
ITT
Non-Standard 
EFF_T1S
Summary of Change from Baseline in ACT Total Score by 
Gender
SAC [2]
2.25.
ITT
Non-Standard 
EFF_T2S
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 12 (Visit 4) by Gender
First footnote as follows: “Note: The 
analysis method was an MMRM 
adjusted for randomised treatment, visit 
(Week 6 and Week 12), baseline ACT 
total score, baseline ACT total score-
by-visit interaction, gender, age, 
country, two- and three- way 
interactions between randomised 
treatment, visit and gender, and patient 
fitted as a random factor.”
SAC [2]
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81
Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Change from Baseline in ACT Total Score at Week 24 (Visit 6)
2.26.
ITT
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 24 (Visit 6)
First footnote as follows:
“Note: The analysis method was an 
MMRM adjusted for randomised 
treatment, visit (Week 6, Week 12, 
Week 18 and Week 24), baseline ACT 
total score, randomised treatment-by-
visit interaction, baseline ACT total 
score-by-visit interaction, gender, age, 
country and patient fitted as a random 
factor.”
Data Look [1] 
SAC [2]
2.27.
PP
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 24 (Visit 6)
Per Protocol Population
First footnote as follows:
“Note: The analysis method was an 
MMRM adjusted for randomised 
treatment, visit (Week 6, Week 12, 
Week 18 and Week 24), baseline ACT 
total score, randomised treatment-by-
visit interaction, baseline ACT total 
score-by-visit interaction, gender, age, 
country and patient fitted as a random 
factor.”
SAC [2]
2.28.
ITT
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 24 (Visit 6) (ANCOVA with LOCF)
Footnotes as follows: “Note: The 
analysis method was an ANCOVA 
model adjusted for randomised 
treatment, baseline ACT total score, 
gender, age and country. Note: Missing 
values at Week 24 (Visit 6) were 
replaced by last available post-
randomization value based on the last 
observation carried forward (LOCF) 
method.”
SAC [2]
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CONFIDENTIAL
HZA116492
82
Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.29.
ITT
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 24 (Visit 6) (Multiple Imputation –
Missing at Random Approach)
Footnotes as follows:
“Note: Missing values post-
randomisation were imputed using 
multiple imputation methods based on 
pattern mixture models.
Note: Each imputed data set was 
analysed using an ANCOVA model at 
Week 24 (Visit 6) adjusted for 
randomised treatment, baseline ACT 
total score, gender, age and country 
and the resulting treatment differences 
and their standard errors combined 
using Rubin’s rules.”
SAC [2]
2.30.
ITT
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 24 (Visit 6) (Multiple Imputation –
Copy Differences from Reference Approach)
Footnotes as follows:
“Note: Missing values post-
randomisation were imputed using 
multiple imputation methods based on 
pattern mixture models.
Note: Each imputed data set was 
analysed using an ANCOVA model at 
Week 24 (Visit 6) adjusted for 
randomised treatment, baseline ACT 
total score, gender, age and country 
and the resulting treatment differences 
and their standard errors combined 
using Rubin’s rules.”
SAC [2]
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CONFIDENTIAL
HZA116492
83
Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.31.
ITT
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 24 (Visit 6) (Hodges-Lehmann 
Approach)
Present the “Difference” and “95% CI” 
lines of “FF/VI vs. Usual ICS/LABA” 
section only. Footnotes as follows:
“Note: The difference between 
treatment groups at Week 24 (Visit 6) 
was calculated using the Hodges-
Lehmann approach.”
SAC [2]
2.32.
ITT
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 24 (Visit 6) (ANCOVA with WOCF)
Footnotes as follows:
“Note: The analysis method was an 
ANCOVA model adjusted for 
randomised treatment, baseline ACT 
total score, gender, age and country.
Note: Missing values at Week 24 (Visit 
6) due to treatment withdrawal prior to 
this time point were replaced by worst 
post-randomisation value based on the 
worst observation carried forward 
(WOCF) method.”
SAC [2]
2.33.
ITT
Non-Standard 
EFF_T3
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 24 (Visit 6), Adjusting for Seasonal 
Effect
First footnote as follows:
“Note: The analysis method was an 
MMRM adjusted for randomised 
treatment, visit (Week 6, Week 12, 
Week 18 and Week 24), baseline ACT 
total score, baseline ACT total score-
by-visit interaction, gender, age, 
country, season at randomisation, two-
and three- way interactions between 
randomised treatment, visit and season 
at randomisation, and patient fitted as a 
random factor.”
SAC [2]
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CONFIDENTIAL
HZA116492
84
Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.34.
PP
Non-Standard 
EFF_T3
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 24 (Visit 6), Adjusting for Seasonal 
Effect
Per Protocol Population
First footnote as follows:
“Note: The analysis method was an 
MMRM adjusted for randomised 
treatment, visit (Week 6, Week 12, 
Week 18 and Week 24), baseline ACT 
total score, baseline ACT total score-
by-visit interaction, gender, age, 
country, season at randomisation, two-
and three- way interactions between 
randomised treatment, visit and season 
at randomisation, and patient fitted as a 
random factor.”
SAC [2]
2.35.
ITT
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 24 (Visit 6), FF/VI Versus the Subset 
of Usual ICS/LABA Subjects Prescribed FP/S at Randomisation
Output only to be produced if ≥25% of 
Usual ICS/LABA patients are 
prescribed FP/S at randomisation. First 
footnote as follows:
“Note: The analysis method was an 
MMRM adjusted for randomised 
treatment, visit (Week 6, Week 12, 
Week 18 and Week 24), baseline ACT 
total score, randomised treatment-by-
visit interaction, baseline ACT total 
score-by-visit interaction, gender, age, 
country and patient fitted as a random 
factor.”
SAC [2]
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85
Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.36.
ITT
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 12 (Visit 4), FF/VI Versus the Subset 
of Usual ICS/LABA Subjects Prescribed BUD/F at 
Randomisation
Output only to be produced if ≥25% of 
Usual ICS/LABA patients are 
prescribed BUD/F at randomisation. 
First footnote as follows:
“Note: The analysis method was an 
MMRM adjusted for randomised 
treatment, visit (Week 6, Week 12, 
Week 18 and Week 24), baseline ACT 
total score, randomised treatment-by-
visit interaction, baseline ACT total 
score-by-visit interaction, gender, age, 
country and patient fitted as a random 
factor.”
SAC [2]
2.37.
ITT
Non-Standard 
EFF_T2S
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 24 (Visit 6) by Country
First footnote as follows:
“Note: The analysis method was an 
MMRM adjusted for randomised 
treatment, visit (Week 6, Week 12, 
Week 18 and Week 24), baseline ACT 
total score, baseline ACT total score-
by-visit interaction, gender, age, 
country, two- and three- way 
interactions between randomised 
treatment, visit and country, and patient 
fitted as a random factor.”
SAC [2]
Correct Use of Inhaler Device 
2.38.
ITT
Non-Standard 
EFF_T4
Summary of Inhaler Device Use Errors
Repeat on subsequent pages for Visit = 
Week 12 and Week 24. “Number of 
patients using...” line will provide the 
denominators for each section’s 
percentages.
Data Look [1] 
SAC [2]
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CONFIDENTIAL
HZA116492
86
Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.39.
PP
Non-Standard 
EFF_T4
Summary of Inhaler Device Use Errors
Per Protocol Population
Repeat on subsequent pages for Visit = 
Week 12 and Week 24. “Number of 
patients using...” line will provide the 
denominators for each section’s 
percentages.
SAC [2]
2.40.
ITT
Non-Standard 
EFF_T5
Summary of Correct Use of Inhaler Device
Data Look [1] 
SAC [2]
2.41.
PP
Non-Standard 
EFF_T5
Summary of Correct Use of Inhaler Device
Per Protocol Population
SAC [2]
2.42.
ITT
Non-Standard 
EFF_T6
Summary of the Statistical Analysis of Correct Use of Inhaler 
Device at Week 12 (Visit 4) and at Week 24 (Visit 6) 
Independently of the Use at Week 12 (Visit 4)
Data Look [1] 
SAC [2]
2.43.
PP
Non-Standard 
EFF_T6
Summary of the Statistical Analysis of Correct Use of Inhaler 
Device at Week 12 (Visit 4) and at Week 24 (Visit 6) 
Independently of the Use at Week 12 (Visit 4)
Per Protocol Population
SAC [2]
Lung Function Tests
2.44.
ITT
Non-Standard 
EFF_T1
Summary of Change from Baseline in Lung Function Tests
Present an additional column to the left 
of “Visit”, labelled “Test” with values 
“Trough (Pre-dose) FEV1 (L)” and 
“Trough (Pre-dose) Percent Predicted 
FEV1 (%)” to allow presentation of 
results by Test. Present the following 
visits: Randomisation (Day 0), Week 
12, Change from Baseline at Week 12, 
Early Withdrawal and Change from
Baseline at Early Withdrawal.
Data Look [1] 
SAC [2]
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87
Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.45.
ITT
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
Trough (Pre-dose) FEV1 at Week 12 (Visit 4)
Footnote as follows:
“Note: The analysis method was an 
ANCOVA model adjusted for 
randomised treatment, baseline trough 
(pre-dose) FEV1, gender, age and 
country.”
Data Look [1] 
SAC [2]
Subjects Who Have Either an ACT Total Score >= 20 or >= 3 Point Increase from Baseline in ACT Total Score
2.46.
ITT
Non-Standard 
EFF_T7
Summary of Percentage of Subjects Who Have Either an ACT 
Total Score >= 20 or >= 3 Point Increase from Baseline in ACT 
Total Score
Repeat for Visit = Week 18, Week 24, 
Early Withdrawal.
Data Look [1] 
SAC [2]
2.47.
ITT
Non-Standard 
EFF_T6
Summary of the Statistical Analysis of Percentage of Subjects 
Who Have Either an ACT Total Score >= 20 or >= 3 Point 
Increase from Baseline in ACT Total Score at Week 12 (Visit 4) 
and Week 24 (Visit 6)
Replace “With correct use [1]” with 
“Responder [1]” and “Without correct 
use” with “Non-Responder”. 
Footnotes as follows:
“[1] Responder is defined as an ACT 
total score >= 20 or >= 3 point increase 
from baseline in ACT total score at that 
visit.
Note: The analysis method was logistic 
regression adjusted for randomised 
treatment, baseline ACT total score, 
baseline ACT total score squared, 
gender, age and country.”
SAC [2]
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CONFIDENTIAL
HZA116492
88
Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Individual ACT Question Scores
2.48.
ITT
Non-Standard 
EFF_T8
Summary of Individual ACT Question Scores
Repeat on subsequent pages for 
Question = 2. Shortness of breath, 3. 
Asthma symptoms woken up at night or 
earlier than usual, 4. Used rescue 
inhaler or nebuliser medication, 5. 
Asthma control.
Data Look [1] 
SAC [2]
Compliance with Study Medication
2.49.
ITT
Non-Standard 
EFF_T9
Summary of Compliance with Study Medication
Data Look [1] 
SAC [2]
2.50.
PP
Non-Standard 
EFF_T9
Summary of Compliance with Study Medication
Per Protocol Population
SAC [2]
MARS-A
2.51.
ITT
Non-Standard 
EFF_T10
Summary of Use of Medication Adherence Report Scale for 
Asthma (MARS-A) During the Study
Repeat on subsequent pages for Visit = 
Week 12, Week 24 and Early 
Withdrawal.
Data Look [1] 
SAC [2]
2.52.
ITT
Non-Standard 
EFF_T10S
Summary of Use of Medication Adherence Report Scale for 
Asthma (MARS-A) During the Study by Status of Patient in 
Relation to the Reminder Sent to French Centres
Repeat on subsequent pages for Visit = 
Week 12, Week 24 and Early 
Withdrawal, and for Status = Patients in 
France, all MARS-A assessments 
completed pre-reminder, 
Patients in France, some MARS-A 
assessments completed pre-reminder, 
some post-reminder, Patients in 
France, all MARS-A assessments 
completed post-reminder,
Patients in Germany
Data Look [1]
SAC [2]
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HZA116492
89
Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Severe On-Treatment Asthma Exacerbations
2.53.
ITT
Non-Standard 
EFF_T11
Summary of Severe On-Treatment Asthma Exacerbations
Data Look [1] 
SAC [2]
2.54.
ITT
Non-Standard 
EFF_T11S
Summary of Severe On-Treatment Asthma Exacerbations by 
Season
Repeat on subsequent pages for 
Season = Summer, Autumn, Winter.
Data Look [1] 
SAC [2]
2.55.
ITT
Non-Standard 
EFF_T12
Summary of the Statistical Analysis of Severe On-Treatment 
Asthma Exacerbations
Data Look [1] 
SAC [2]
2.56.
ITT
Non-Standard 
EFF_T13
Summary of the Statistical Analysis of Time to First Severe On-
Treatment Asthma Exacerbation
Data Look [1] 
SAC [2]
AQLQ(S)
2.57.
ITT
Non-Standard 
EFF_T1
Summary of Change from Baseline in AQLQ(S) Total Score and 
Domain Scores
Present an additional column to the left 
of “Visit”, labelled “Domain” with values 
“Total Score”, “Environmental Stimuli”, 
“Symptoms”, “Activity Limitations” and 
“Emotional Function” to allow 
presentation of results by Domain. 
Present the following visits: 
Randomisation (Day 0), Week 24, 
Change from Baseline at Week 24, 
Early Withdrawal and Change from 
Baseline at Early Withdrawal.
SAC [2]
2.58.
ITT
Non-Standard 
EFF_T14
Summary of Percentage of Subjects Who Have an Increase 
from Baseline of >=0.5 in AQLQ(S) Total Score and Domain 
Scores
Repeat on subsequent pages for 
Domain = Environmental Stimuli, 
Symptoms, Activity Limitations and 
Emotional Function.
Data Look [1] 
SAC [2]
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CONFIDENTIAL
HZA116492
90
Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.59.
ITT
Non-Standard 
EFF_T6
Summary of the Statistical Analysis of Percentage of Subjects 
Who Have an Increase from Baseline of >=0.5 in AQLQ(S) Total 
Score and Environmental Stimuli Domain Score at Week 24 
(Visit 6)
Replace “With correct use [1]” with 
“Responder [1]” and “Without correct
use” with “Non-Responder”. Do not 
display the “Visit” column.
Footnotes as follows:
“[1] Responder is defined as an 
increase from baseline of >= 0.5.
Note: The analysis method was logistic 
regression adjusted for randomised 
treatment, baseline score, gender, age 
and country.”
SAC [2]
EQ-5D-5L
2.60.
ITT
Non-Standard 
EFF_T15
Summary of EQ-5D-5L Descriptive System Dimensions
Repeat on subsequent pages for Visit = 
Early Withdrawal and for Dimension = 
Self-Care, Usual Activities, 
Pain/Discomfort, and 
Anxiety/Depression.
Data Look [1] 
SAC [2]
2.61.
ITT
Non-Standard 
EFF_T6
Summary of the Statistical Analysis of Proportion of Responders 
According to EQ-5D-5L Descriptive System Dimensions at Week 
24 (Visit 6)
Replace “With correct use [1]” with 
“Responder [1]” and “Without correct 
use” with “Non-Responder”. Do not 
display the “Visit” column.
Footnotes as follows: 
“[1] Responder is defined as a score of 
1 (‘no problems’).
Note: The analysis method was logistic 
regression adjusted for randomised 
treatment, baseline EQ-5D-5L domain 
score, gender, age and country.”
SAC [2]
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CONFIDENTIAL
HZA116492
91
Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.62.
ITT
Non-Standard 
EFF_T1
Summary of EQ-5D-5L Utility Score
Present the following visits: 
Randomisation (Day 0), Week 24, 
Change from Baseline at Week 24, 
Early Withdrawal and Change from 
Baseline at Early Withdrawal.
Data Look [1] 
SAC [2]
2.63.
ITT
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
EQ-5D-5L Utility Score at Week 24 (Visit 6)
Footnote as follows:
“Note: The analysis method was an 
ANCOVA model adjusted for 
randomised treatment, baseline EQ-5D-
5L utility score, gender, age and 
country.”
SAC [2]
2.64.
ITT
Non-Standard 
EFF_T1
Summary of EQ-5D-5L Visual Analogue Scale (VAS) Score
Present the following visits: 
Randomisation (Day 0), Week 24, 
Change from Baseline at Week 24, 
Early Withdrawal and Change from 
Baseline at Early Withdrawal.
SAC [2]
2.65.
ITT
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
EQ-5D-5L Visual Analogue Scale (VAS) Score at Week 24 (Visit 
6)
Footnote as follows:
“Note: The analysis method was an 
ANCOVA model adjusted for 
randomised treatment, baseline EQ-5D-
5L VAS score, gender, age and 
country.”
SAC [2]
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CONFIDENTIAL
HZA116492
92
Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PASAP-Q
2.66.
ITT
Non-Standard 
EFF_T1
Summary of PASAP-Q Scores
Present an additional column to the left 
of “Visit”, labelled “Score” with values 
“Performance”, “Convenience”, “Overall 
Satisfaction”, “Total Score” and 
“Willingness to Continue Using Inhaler” 
to allow presentation of results by 
Domain. Present the following visits: 
Week 12 and Early Withdrawal.
Add the following footnotes:
“Note: Performance, Convenience, 
Total Score, and Willingness to 
Continue Using Inhaler are expressed 
on a scale of 0 to 100.
Note: Overall Satisfaction is expressed 
on a scale of 1 to 7.”
SAC [2]
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HZA116492
93
12.15.7.
Efficacy Figures
Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Change from Baseline in ACT Total Score at Week 12 (Visit 4)
2.1.
ITT
Non-Standard 
EFF_F1
Summary of Change from Baseline in ACT Total Score
Present “ACT Total Score” on y-axis 
and “Visit” on x-axis (Randomisation 
(Day 0), Week 6, Week 12, Week 18, 
Week 24). Present mean ACT Total 
Score ∀SD separately for treatment 
group (FF/VI, Usual ICS/LABA) at each 
visit, connecting the means with a solid 
line. Distinguish the treatment groups 
by different line types.
Data Look [1] 
SAC [2]
2.2.
PP
Non-Standard 
EFF_F1
Summary of Change from Baseline in ACT Total Score
Per Protocol Population
Present “ACT Total Score” on y-axis 
and “Visit” on x-axis (Randomisation 
(Day 0), Week 6, Week 12, Week 18, 
Week 24). Present mean ACT Total 
Score ∀SD separately for treatment 
group (FF/VI, Usual ICS/LABA) at each 
visit, connecting the means with a solid 
line. Distinguish the treatment groups 
by different line types.
SAC [2]
2.3.
ITT
Non-Standard 
EFF_F1
Summary of Change from Baseline in ACT Total Score by 
Country
Present “ACT Total Score” on y-axis 
and “Visit” on x-axis (Randomisation 
(Day 0), Week 6, Week 12, Week 18, 
Week 24). Present mean ACT Total 
Score ∀SD separately for treatment 
group (FF/VI, Usual ICS/LABA) at each 
visit, connecting the means with a solid 
line. Distinguish the treatment groups 
by different line types.
SAC [2]
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CONFIDENTIAL
HZA116492
94
Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.4.
ITT/PP
Non-Standard 
EFF_F2
Summary of Primary and Sensitivity Analyses for Change from 
Baseline in ACT Total Score at Week 12 (Visit 4)
Present “Treatment difference” on the 
x-axis, and reverse axis so treatment 
difference increases from left to right. 
Replace “Ratio (95% CI)” with 
“Treatment Difference (95% CI)”. 
Present lines for the following: Primary 
analysis (ITT), Primary analysis (PP), 
ANCOVA with LOCF (ITT), Multiple 
Imputation (Missing at Random) (ITT), 
Multiple Imputation (Copy Differences 
from Reference) (ITT), Hodges-
Lehmann (ITT), ANCOVA with WOCF 
(ITT).
Data Look [1] 
SAC [2]
2.5.
ITT
Non-Standard 
EFF_F3
Summary of Interaction Tests for Change from Baseline in ACT 
Total Score at Week 12 (Visit 4)
Present “LS Mean Change” on the x-
axis, and reverse axis so it increases 
from left to right. Replace “Ratio (95% 
CI)” with “LS Mean Change (95% CI)”. 
Present the following subgroups: 
Country (France, Germany); Number of 
Severe Asthma Exacerbations in the 
Previous Year Prior to Randomisation 
(0, >= 1); Smoking Status at Baseline 
(Current smoker, Former smoker, 
Never smoked); Age Group (≤50 
Years Old, > 50 Years Old); Gender 
(Male, Female).
Data Look [1] 
SAC [2]
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CONFIDENTIAL
HZA116492
95
Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Change from Baseline in ACT Total Score at Week 24 (Visit 6)
2.6.
ITT/PP
Non-Standard 
EFF_F2
Summary of Key Secondary and Sensitivity Analyses for 
Change from Baseline in ACT Total Score at Week 24 (Visit 6)
Present “Treatment difference” on the 
x-axis, and reverse axis so treatment 
difference increases from left to right. 
Replace “Ratio (95% CI)” with 
“Treatment Difference (95% CI)”. 
Present lines for the following: Primary 
analysis (ITT), Primary analysis (PP), 
ANCOVA with LOCF (ITT), Multiple 
Imputation (Missing at Random) (ITT), 
Multiple Imputation (Copy Differences 
from Reference) (ITT), Hodges-
Lehmann (ITT), ANCOVA with WOCF 
(ITT).
SAC [2]
Subjects Who Have Either an ACT Total Score >= 20 or >= 3 Point Increase from Baseline in ACT Total Score
2.7.
ITT
Non-Standard 
EFF_F4
Summary of Percentage of Subjects Who Have Either an ACT 
Total Score >= 20 or >= 3 Point Increase from Baseline in ACT 
Total Score
Present “Percent of Subjects (%)” on y-
axis and “Visit” on x-axis (Week 6, 
Week 12, Week 18, Week 24, Early 
Withdrawal). For each visit, present 3 
vertical bars distinguished by fill pattern 
(similar to non-standard EFF_F6). Each 
bar represents: “ACT Total Score >= 20 
or >= 3 Point Increase from Baseline in 
ACT Total Score”, “ACT Total Score >= 
20” and “>= 3 Point Increase from 
Baseline in ACT Total Score” 
respectively and should be labelled as 
such on the legend.
Data Look [1] 
SAC [2]
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96
Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Compliance with Study Medication
2.8.
ITT
Non-Standard 
EFF_F5
Box Plot of Compliance with Study Medication
Label y-axis title as “Compliance (%)”, 
maximum of y-axis may be > 100%.
Data Look [1] 
SAC [2]
MARS-A
2.9.
ITT
Non-Standard 
EFF_F6
Histogram of the Questions and Answers of the MARS-A 
Questionnaire
Repeat on subsequent pages for Visit = 
Week 24, Week 52 and Early 
Withdrawal; and for Randomised 
Treatment = FF/VI.
Data Look [1] 
SAC [2]
2.10.
ITT
Non-Standard 
EFF_F6
Histogram of the Questions and Answers of the MARS-A 
Questionnaire by Status of Patient in Relation to the Reminder 
Sent to French Centres
Present bylines and footnotes per 
“Repeat for” programming note on 
shell.
SAC [2]
2.11.
ITT
Non-Standard 
EFF_F7
Histogram of the Distribution of MARS-A Scores During the 
Study
Repeat on subsequent pages for Visit = 
Week 52 and Early Withdrawal.
Data Look [1] 
SAC [2]
2.12.
ITT
Non-Standard 
EFF_F7
Histogram of the Distribution of MARS-A Scores During the 
Study by Status of Patient in Relation to the Reminder Sent to 
French Centres
Present bylines and footnotes per 
“Repeat for” programming note on 
shell.
SAC [2]
Severe On-Treatment Asthma Exacerbations
2.13.
ITT
Non-Standard 
EFF_F8
Box Plot of Severe On-Treatment Asthma Exacerbation Rates 
Adjusted for Exposure to Treatment
Data Look [1] 
SAC [2]
2.14.
ITT
Non-Standard 
EFF_F9
Kaplan-Meier Plot of Time to First Severe On-Treatment Asthma 
Exacerbation
Display increments of 6 weeks on the x-
axis, up to the maximum exposure (e.g. 
0, 6, 12, 18, 24, 30).
Data Look [1] 
SAC [2]
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97
12.15.8.
Safety Tables
Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
SAEs and ADRs
3.1.
Safety
Non-Standard 
SAFE_T1
On-Treatment Serious Adverse Events and Adverse Drug 
Reactions Overview
Based on IDSL standard template 
AE13.
Data Look [1] 
SAC [2]
3.2.
Safety
AE1
Summary of On-Treatment Non-Serious Adverse Drug 
Reactions
SAC [2]
3.3.
Safety
AE1
Summary of On-Treatment Serious Adverse Drug Reactions
SAC [2]
3.4.
Safety
AE1
Summary of On-Treatment Adverse Drug Reactions
Data Look [1] 
SAC [2]
3.5.
Safety
AE1
Summary of On-Treatment Serious Adverse Events
Data Look [1] 
SAC [2]
3.6.
Safety
AE1
Summary of On-Treatment or Post-Treatment Serious Adverse 
Events and Adverse Drug Reactions Leading to Permanent 
Discontinuation of Study Drug or Withdrawal from the Study
SAC [2]
3.7.
Safety
AE1
Summary of On-Treatment or Post-Treatment Serious Adverse 
Events Leading to Permanent Discontinuation of Study Drug or 
Withdrawal from the Study
SAC [2]
3.8.
Safety
AE1
Summary of On-Treatment or Post-Treatment Adverse Drug 
Reactions Leading to Permanent Discontinuation of Study Drug 
or Withdrawal from the Study
SAC [2]
3.9.
Safety
AE1
Summary of Most Frequent On-Treatment Non-Serious Adverse 
Drug Reactions, Reported by 1% or More of Subjects in Any 
Treatment Group
SAC [2]
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Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
SAEs and ADRs of Special Interest
3.10.
Safety
Non-Standard 
SAFE_T2
Summary of On-Treatment Non-Serious Adverse Drug 
Reactions of Special Interest
Based on IDSL standard template AE1.
Data Look [1]
SAC [2]
3.11.
Safety
Non-Standard 
SAFE_T2
Summary of On-Treatment Serious Adverse Drug Reactions of 
Special Interest
Based on IDSL standard template AE1.
SAC [2]
3.12.
Safety
Non-Standard 
SAFE_T2
Summary of On-Treatment Adverse Drug Reactions of Special 
Interest
Based on IDSL standard template AE1.
SAC [2]
3.13.
Safety
Non-Standard 
SAFE_T2
Summary of On-Treatment Serious Adverse Events of Special 
Interest
Based on IDSL standard template AE1.
SAC [2]
Fatal SAEs and ADRs
3.14.
Safety
AE1
Summary of On-Treatment Fatal Serious Adverse Events
SAC [2]
3.15.
Safety
AE1
Summary of On-Treatment Fatal Serious Adverse Drug 
Reactions
SAC [2]
3.16.
Safety
Non-Standard 
SAFE_T2
Summary of On-Treatment Fatal Serious Adverse Events of 
Special Interest
Based on IDSL standard template AE1.
SAC [2]
Non-Fatal SAEs and ADRs
3.17.
Safety
AE1
Summary of On-Treatment Non-Fatal Serious Adverse Events
SAC [2]
3.18.
Safety
Non-Standard 
SAFE_T2
Summary of On-Treatment Non-Fatal Serious Adverse Events of 
Special Interest
Based on IDSL standard template AE1.
SAC [2]
Top Ten Most Commonly Reported ADRs
3.19.
Safety
Non-Standard 
SAFE_T3
Top Ten Most Commonly Reported On-Treatment Adverse Drug 
Reactions Per Treatment Group
Present the ten most frequent preferred 
terms in Usual ICS/LABA, and the ten 
most frequent in FF/VI (do not use 
percentages to determine “most 
frequent”)
Data Look [1]
SAC [2]
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Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Vital Signs
3.20.
Safety
VS1
Summary of Vital Signs
SAC [2]
3.21.
Safety
VS1
Summary of Change from Baseline in Vital Signs
SAC [2]
3.22.
Safety
AE15
Summary of Common (>=3%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Subjects 
and Occurrences)  
SAC [2]
3.23.
Safety
AE16
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Subjects and Occurrences)
SAC [2]
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100
12.15.9.
Safety Figures
Safety : Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Benefit:Risk
3.1.
ITT/Safety
Non-Standard 
SAFE_F1
Summary of Benefit:Risk for FF/VI vs. Usual ICS/LABA
Data Look [1] 
SAC [2]
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101
12.15.10.
ICH Listings
ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Study Population
1.
ITT
ES2
Reasons for Study Withdrawal
SAC [2]
2.
ITT
TA1
Randomised and Actual Treatments
SAC [2]
3.
ITT
IE3
Subjects with Inclusion, Exclusion or Randomisation Criteria 
Deviations
SAC [2]
4.
ITT
DM2
Demographic Characteristics
SAC [2]
5.
ITT
DM9
Race
SAC [2]
Adverse Events
6.
Safety
AE7
Subject Numbers for Individual Serious Adverse Events and 
Non-Serious Adverse Drug Reactions
SAC [2]
7.
Safety
AE8
All Serious Adverse Events and Non-Serious Adverse Drug 
Reactions
SAC [2]
8.
Safety
AE8
Fatal Serious Adverse Events 
SAC [2]
9.
Safety
AE8
Serious Adverse Events Leading to Permanent Discontinuation 
of Study Drug or Withdrawal from the Study
SAC [2]
10.
Safety
AE8
Non-Serious Adverse Drug Reactions Leading to Permanent 
Discontinuation of Study Drug or Withdrawal from the Study
SAC [2]
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12.15.11.
Non-ICH Listings
Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Study Population
11.
ASE
Non-Standard 
POP_L1
Subjects Screened but Not in the Intent-to-Treat Population
SAC [2]
12.
ITT
Non-Standard 
POP_L2
Reasons for Important Protocol Deviations
SAC [2]
13.
ITT
MH2
Medical Conditions
SAC [2]
14.
ITT
Non-Standard 
POP_L3
Asthma History
SAC [2]
15.
ITT
Non-Standard 
POP_L4
Smoking History
SAC [2]
16.
ITT
CM3
Concomitant Medications
Only include medications included in 
pre-treatment and on-treatment 
summary tables.
SAC [2]
17.
ITT
CM6
Relationship between Ingredient and Verbatim Text
SAC [2]
18.
ITT
Non-Standard 
POP_L5
Exposure to Study Medication
Repeat on subsequent pages for 
Treatment = FF/VI, and use GSK drug 
synonym as drug name.
SAC [2]
Efficacy
19.
ITT
Non-Standard 
EFF_L1
ACT Scores
Repeat on subsequent pages for 
Treatment = FF/VI.
SAC [2]
20.
ITT
Non-Standard 
EFF_L2
Inhaler Device Use
Repeat on subsequent pages for 
Treatment = FF/VI.
SAC [2]
21.
ITT
Non-Standard 
EFF_L3
Lung Function Tests
Repeat on subsequent pages for 
Treatment = FF/VI.
SAC [2]
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Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
22.
ITT
Non-Standard 
EFF_L4
Medication Adherence Report Scale for Asthma (MARS-A) 
Scores
Repeat on subsequent pages for 
Treatment = FF/VI.
SAC [2]
23.
ITT
Non-Standard 
EFF_L5
Severe Asthma Exacerbations
Repeat on subsequent pages for 
Treatment = FF/VI.
SAC [2]
24.
ITT
Non-Standard 
EFF_L6
AQLQ(S) Scores
Repeat on subsequent pages for 
Treatment = FF/VI.
SAC [2]
25.
ITT
Non-Standard 
EFF_L7
EQ-5D-5L Descriptive System Dimension Scores
Repeat on subsequent pages for 
Treatment = FF/VI.
SAC [2]
26.
ITT
Non-Standard 
EFF_L8
PASAP-Q Scores
Repeat on subsequent pages for 
Treatment = FF/VI.
SAC [2]
Safety
27.
Safety
Non-Standard 
SAFE_L1
AE Terms of Special Interest
The AE special interest dataset and the 
AE SMQ dataset will be set together in 
order to report this table and all the 
subgroups that come from the AE SMQ 
dataset will be flagged with a [1].
SAC [2]
28.
Safety
VS4
Vital Signs
SAC [2]
29.
Safety
Non-Standard 
SAFE_L2
Inhaler Device Malfunctions
SAC [2]
Liver Chemistry
30.
Safety
LIVER5
Liver Event Results and Time of Event Relative to Treatment
SAC [2]
31.
Safety
LIVER6
Liver Event Information for RUCAM Score
SAC [2]
32.
Safety
LIVER7
Liver Biopsy Details
SAC [2]
33.
Safety
LIVER8
Liver Imaging Details
SAC [2]
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104
12.16.
Appendix 16: Example Mock Shells for Data Displays
12.16.1.
Study Population Table Shells
Example 
: POP_T1
Protocol
: HZA116492
Page 1 of 1
Population
: All Subjects Enrolled
Table 1.xx
Summary of Subject Populations
Population
Usual ICS/LABA
FF/VI 
Total
All Subjects Enrolled (ASE)
xxx
Randomised
xxx 
xxx
xxx
Intent-to-Treat (ITT)
xxx (xx%)
xxx (xx%)
xxx (xx%)
Per Protocol (PP)
xxx (xx%)
xxx (xx%)
xxx (xx%)
Safety
xxx (xx%)
xxx (xx%)
xxx (xx%)
ASE: All subjects screened and for whom a record exists on the study database.
ITT: All randomised subjects having received at least one dose of the prescription of study medication (FF/VI or Usual ICS/LABA).
PP: All ITT subjects who without any protocol deviations excluding them from this population.
Safety: All randomised subjects having received at least one dose of the prescription of study medication (FF/VI or Usual ICS/LABA).
Note: The randomised summary is not a defined population and consists of all subjects who were randomised and given a randomisation number.
Programming Note: randomised population line will provide the denominators for the ITT, PP and Safety percentages.
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Example 
: POP_T2
Protocol
: HZA116492
Page 1 of 1
Population
: Intent-to-Treat
Table 1.xx 
Summary of Attendance at Each Clinic Visit
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Total
(N=xxx)
Screening
xxx (xx%)
xxx (xx%)
xxx (xx%)
Randomisation (Day 0)
xxx (xx%)
xxx (xx%)
xxx (xx%)
Week 6
xxx (xx%)
xxx (xx%)
xxx (xx%)
Week 12
xxx (xx%)
xxx (xx%)
xxx (xx%)
Week 18
xxx (xx%)
xxx (xx%)
xxx (xx%)
Week 24
xxx (xx%)
xxx (xx%)
xxx (xx%)
Early Withdrawal
xxx (xx%)
xxx (xx%)
xxx (xx%)
Note: Weeks 6 and 18 are telephone contacts.
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Example 
: POP_T3 
Protocol
: HZA116492
Page 1 of n
Population
: Intent-to-Treat
Table 1.xx 
Summary of Important Protocol Deviations
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Total
(N=xxx)
Any Important Protocol Deviation
xxx (xx%)
xxx (xx%)
xxx (xx%)
  Reason 1                                     
xxx (xx%)
xxx (xx%)
xxx (xx%)
  Reason 2                                    
xxx (xx%)
xxx (xx%)
xxx (xx%)
  Reason 3                                     
xxx (xx%)
xxx (xx%)
xxx (xx%)
     ...
xxx (xx%)
xxx (xx%)
xxx (xx%)
Note: A subject may have more than one protocol deviation.
Note: Includes any important deviation from the protocol.
Repeat for: 
Summary of Important Protocol Deviations Resulting in Exclusion from the PP Population (ITT Population)
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107
Example 
: POP_T4
Protocol
: HZA116492
Page 1 of 1
Population
: Intent-to-Treat
Table 1.xx 
Summary of Asthma Duration at Baseline
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Total
(N=xxx)
Duration of Asthma
  < 6 months
xxx (xx%)
xxx (xx%)
xxx (xx%)
  >= 6 months to < 1 year
xxx (xx%)
xxx (xx%)
xxx (xx%)
  >= 1 year to < 5 years
xxx (xx%)
xxx (xx%)
xxx (xx%)
  >= 5 years to < 10 years
xxx (xx%)
xxx (xx%)
xxx (xx%)
  >= 10 years
xxx (xx%)
xxx (xx%)
xxx (xx%)
Duration of Asthma (years):
  n
xx
xx
xx
  Mean
xx.x
xx.x
xx.x
  SD
  x.xx
  x.xx
  x.xx
  Median
xx.x
xx.x
xx.x
  Min.
xx
xx
xx
  Max.
xx
xx
Xx
Repeat for: 
Summary of Asthma Duration at Baseline (PP Population)
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108
Example 
: POP_T5
Protocol
: HZA116492
Page 1 of 2
Population
: Intent-to-Treat
Table 1.xx 
Summary of Asthma Exacerbation History at Baseline
Usual ICS/LABA
(N=xxx)
FF/VI 
(N=xxx)
Total
(N=xxx)
Did not require oral/systemic corticosteroids (not involving 
hospitalisation)
  n                      
xx 
xx 
xx 
  0
xx (xx%)
xx (xx%)
xx (xx%)
  1
xx (xx%)
xx (xx%)
xx (xx%)
  > 1
xx (xx%)
xx (xx%)
xx (xx%)
Required oral/systemic corticosteroids (not involving hospitalisation)
  n                      
xx 
xx 
xx 
  0
xx (xx%)
xx (xx%)
xx (xx%)
  1
xx (xx%)
xx (xx%)
xx (xx%)
  > 1
xx (xx%)
xx (xx%)
xx (xx%)
Required hospitalisation                  
  n                      
xx 
xx 
xx 
  0
xx (xx%)
xx (xx%)
xx (xx%)
  1
xx (xx%)
xx (xx%)
xx (xx%)
  > 1
xx (xx%)
xx (xx%)
xx (xx%)
Note: Number of severe asthma exacerbations reported in the 12 months prior to Randomisation (Day 0).
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109
Example 
: POP_T5
Protocol
: HZA116492
Page 2 of 2
Population
: Intent-to-Treat
Table 1.xx 
Summary of Asthma Exacerbation History at Baseline
Usual ICS/LABA
(N=xxx)
FF/VI 
(N=xxx)
Total
(N=xxx)
Total number of exacerbations during the 12 months prior to 
randomisation
  n                      
xx 
xx 
xx 
  0
xx (xx%)
xx (xx%)
xx (xx%)
  1
xx (xx%)
xx (xx%)
xx (xx%)
  > 1
xx (xx%)
xx (xx%)
xx (xx%)
Number of exacerbations during the 12 months prior to randomisation
  n
xx
xx
xx
  Mean
xx.x
xx.x
xx.x
  SD
  x.xx
  x.xx
  x.xx
  Median
xx.x
xx.x
xx.x
  Min.
xx
xx
xx
  Max.
xx
xx
xx
Note: Number of severe asthma exacerbations reported in the 12 months prior to Randomisation (Day 0).
Repeat for: 
Summary of Asthma Exacerbation History at Baseline (PP Population)
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Example 
: POP_T6
Protocol
: HZA116492
Page 1 of 2
Population
: Intent-to-Treat
Table 1.xx 
Summary of Smoking History at Baseline
Usual ICS/LABA
(N=xxx)
FF/VI  
(N=xxx)
Total
(N=xxx)
History of Smoking Use
Current smoker
xxx (xx%)
xxx (xx%)
xxx (xx%)
Former smoker
xxx (xx%)
xxx (xx%)
xxx (xx%)
Never smoked
xxx (xx%)
xxx (xx%)
xxx (xx%)
For Current and Former Smokers:
   Years Smoked
n
xx
xx
xx
Mean
xx.x
xx.x
xx.x
SD
  x.xx
  x.xx
  x.xx
Median
xx.x
xx.x
xx.x
Min.
xx
xx
xx
Max.
xx
xx
xx
   Cigarettes/Day
n
xx
xx
xx
Mean
xx.x
xx.x
xx.x
SD
  x.xx
  x.xx
  x.xx
Median
xx.x
xx.x
xx.x
Min.
xx
xx
xx
Max.
xx
xx
xx
[1] Smoking Pack Years = (Number of cigarettes smoked per day/20) x number of years smoked.
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Example 
: POP_T6
Protocol
: HZA116492
Page 2 of 2
Population
: Intent-to-Treat
Table 1.xx 
Summary of Smoking History at Baseline
Usual ICS/LABA
(N=xxx)
FF/VI  
(N=xxx)
Total
(N=xxx)
  Smoking Pack Years[1]
      Overall
n
xx
xx
xx
Mean
xx.x
xx.x
xx.x
SD
  x.xx
  x.xx
  x.xx
Median
xx.x
xx.x
xx.x
Min.
xx
xx
xx
Max.
xx
xx
xx
    Current Smokers
n
xx
xx
xx
Mean
xx.x
xx.x
xx.x
SD
  x.xx
  x.xx
  x.xx
Median
xx.x
xx.x
xx.x
Min.
xx
xx
xx
Max.
xx
xx
xx
    Former Smokers
n
xx
xx
xx
Mean
xx.x
xx.x
xx.x
SD
  x.xx
  x.xx
  x.xx
Median
xx.x
xx.x
xx.x
Min.
xx
xx
xx
Max.
xx
xx
xx
[1] Smoking Pack Years = (Number of cigarettes smoked per day/20) x number of years smoked.
Repeat for: Summary of Smoking History at Baseline (PP Population)
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112
Example 
: POP_T7
Protocol
: HZA116492
Page 1 of n
Population
: Intent-to-Treat
Table 1.xx
Summary of Study Medication Dosage Modification
Dosage Modification / Prescription
   Treatment Path
Usual ICS/LABA
(N=xxx)
FF/VI 
(N=xxx)
Total
(N=xxx)
Did Not Modify Dose During the Study
xxx (xx%)
xxx (xx%)
xxx (xx%)
Modified Dose at Least Once During the Study
xxx (xx%)
xxx (xx%)
xxx (xx%)
Randomised to FF/VI
xxx
xxx 
  FF/VI 92 mcg/22 mcg OD
xxx (xx%)
xxx (xx%)
  FF/VI 92 mcg/22 mcg OD -> FF/VI 184 mcg/22 mcg OD
xxx (xx%)
xxx (xx%)
Randomised to Usual ICS/LABA and Prescribed FP/S
xxx
xxx
  FP/S 250 mcg/50 mcg BID
xxx (xx%)
xxx (xx%)
  FP/S 250 mcg/50 mcg BID -> FP/S 500 mcg/50 mcg BID
xxx (xx%)
xxx (xx%)
Randomised to Usual ICS/LABA and Prescribed BUD/F
xxx
xxx
  BUD/F 200 mcg/6 mcg BID (1 inh)
xxx (xx%)
xxx (xx%)
xxx (xx%)
  BUD/F 200 mcg/6 mcg BID (1 inh) -> BUD/F 200 mcg/6 mcg BID (2 inh)
xxx (xx%)
xxx (xx%)
xxx (xx%)
  BUD/F 200 mcg/6 mcg BID (1 inh) -> BUD/F 400 mcg/12 mcg BID (1 inh)
xxx (xx%)
xxx (xx%)
xxx (xx%)
  BUD/F 200 mcg/6 mcg BID (2 inh)
xxx (xx%)
xxx (xx%)
xxx (xx%)
  BUD/F 200 mcg/6 mcg BID (2 inh) -> BUD/F 400 mcg/12 mcg BID (1 inh)
xxx (xx%)
xxx (xx%)
xxx (xx%)
  BUD/F 200 mcg/6 mcg BID (2 inh) -> BUD/F 400 mcg/12 mcg BID (2 inh)
xxx (xx%)
xxx (xx%)
xxx (xx%)
Note: 1 inh = 1 inhalation per dose, 2 inh = 2 inhalations per dose.
Note: Subjects randomised to FF/VI initiated treatment on 92 mcg/22 mcg OD and could increase to 184 mcg/22 mcg OD. 
Note: Subjects randomised to Usual ICS/LABA and prescribed FP/S initiated treatment on 250 mcg/50 mcg BID and could increase to 500 mcg/50 mcg BID.
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113
Note: Subjects randomised to Usual ICS/LABA and prescribed BUD/F could: initiate treatment on 200 mcg/6 mcg BID (1 inh) and increase to 200 mcg/6 mcg BID (2 
inh) or 400 mcg/12 mcg BID (1 inh); or initiate on 200 mcg/6 mcg BID (2 inh) and modify to 400 mcg/12 mcg BID (1 inh) or increase to 400 mcg/12 mcg BID (2 inh).
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114
Example 
: POP_T8
Protocol
: HZA116492
Page 1 of 1
Population
: Intent-to-Treat
Table 1.xx 
Summary of Extent of Exposure to Study Medication (Regardless of Modification to Study Medication Dosage)
Overall
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Exposure  (days) [1]
n
xx
xx
Mean
xx.x
xx.x
SD
  x.xx
  x.xx
Median
xx.x
xx.x
Min.
xx
xx
Max.
xx
xx
Total Years Exposed (yrs)
xx
xx
Range of Exposure (days)
<= 6 weeks
xxx (xx%)
xxx (xx%)
<= 12 weeks
xxx (xx%)
xxx (xx%)
<= 18 weeks
xxx (xx%)
xxx (xx%)
<= 24 weeks
xxx (xx%)
xxx (xx%)
> 24 weeks
xxx (xx%)
xxx (xx%)
Subjects Exposed for six 
months (24 weeks ± 2 
weeks)
xxx (xx%)
xxx (xx%)
[1] Exposure to study medication = treatment stop date – treatment start date + 1, regardless of dosage modification.
Repeat for: 
Summary of Summary of Extent of Exposure to Study Medication (up to First Modification to Study Medication Dosage) (ITT Population)
Footnote: “[1] Exposure to study medication = treatment stop date - treatment start date + 1.”
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Example 
: POP_T9
Protocol
: HZA116492
Page 1 of 6
Population
: Intent-to-Treat
Table 1.xx 
Summary of Extent of Exposure to Study Medication by Medication and Dosage
Medication/Dosage
Overall
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
FF/VI 92 mcg/22 mcg OD
Exposure (days) [1]
n
xx
xx
Mean
xx.x
xx.x
SD
  x.xx
  x.xx
Median
xx.x
xx.x
Min.
xx
xx
Max.
xx
xx
Total Years Exposed (yrs)
xx
xx
Range of Exposure (days)
<= 6 weeks
xxx (xx%)
xxx (xx%)
<= 12 weeks
xxx (xx%)
xxx (xx%)
<= 18 weeks
xxx (xx%)
xxx (xx%)
<= 24 weeks
xxx (xx%)
xxx (xx%)
> 24 weeks
xxx (xx%)
xxx (xx%)
Subjects Exposed for six 
months (24 weeks ± 2 
weeks)
xxx (xx%)
xxx (xx%)
[1] Exposure to study medication = treatment stop date – treatment start date + 1.
Programming note: repeat on subsequent pages for Medication/Dosage = FF/VI 184 mcg/22 mcg OD, FP/S 250 mcg/50 mcg BID, FP/S 500 mcg/50 mcg BID, BUD/F 
200 mcg/6 mcg BID (1 inhalation per dose), BUD/F 200 mcg/6 mcg BID (2 inhalations per dose), BUD/F 400 mcg/12 mcg BID (1 inhalation per dose), BUD/F 400 
mcg/12 mcg BID (2 inhalations per dose).
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Example 
: POP_T10
Protocol
: HZA116492
Page 1 of 2
Population
: Intent-to-Treat
Table 1.xx 
Summary of Number of Subjects by Subgroup
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Total
(N=xxx)
Country
  n
xxx
xxx
xxx
  France
xxx (xx%)
xxx (xx%)
xxx (xx%)
  Germany
xxx (xx%)
xxx (xx%)
xxx (xx%)
Number of Severe Asthma Exacerbations in 
the Previous Year Prior to Randomisation
  n
xxx
xxx
xxx
  0
xxx (xx%)
xxx (xx%)
xxx (xx%)
   >= 1
xxx (xx%)
xxx (xx%)
xxx (xx%)
Smoking Status at Baseline
  n
xxx
xxx
xxx
  Current smoker
xxx (xx%)
xxx (xx%)
xxx (xx%)
  Former smoker
xxx (xx%)
xxx (xx%)
xxx (xx%)
  Never smoked
xxx (xx%)
xxx (xx%)
xxx (xx%)
Age Group
  n
xxx
xxx
xxx
  ≤50 years old
xxx (xx%)
xxx (xx%)
xxx (xx%)
  > 50 years old
xxx (xx%)
xxx (xx%)
xxx (xx%)
Note: Spring = March, April and May; Summer = June, July and August; Autumn = September, October and November; Winter = December, January and February.
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Example 
: POP_T10
Protocol
: HZA116492
Page 2 of 2
Population
: Intent-to-Treat
Table 1.xx 
Summary of Number of Subjects by Subgroup
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Total
(N=xxx)
Gender
  n
xxx
xxx
xxx
  Male
xxx (xx%)
xxx (xx%)
xxx (xx%)
  Female
xxx (xx%)
xxx (xx%)
xxx (xx%)
Season at randomisation
  n
xxx
xxx
xxx
  Spring
xxx (xx%)
xxx (xx%)
xxx (xx%)
  Summer
xxx (xx%)
xxx (xx%)
xxx (xx%)
  Autumn
xxx (xx%)
xxx (xx%)
xxx (xx%)
  Winter
xxx (xx%)
xxx (xx%)
xxx (xx%)
Note: Spring = March, April and May; Summer = June, July and August; Autumn = September, October and November; Winter = December, January and February.
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12.16.2.
Study Population Figure Shells
Example 
: POP_F1
Protocol
: HZA116492
Page 1 of 1
Population
: Intent-to-Treat
Figure 1.xx
Plot of Exposure to Study Medication (Regardless of Modification to Study Medication Dosage)
Programming note: display increments of 6 weeks on the x-axis, up to the maximum exposure (e.g. 0, 6, 12, 18, 24, 30).
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12.16.3.
Efficacy Table Shells
Example
: EFF_T1
Protocol
: HZA116492                                                                            
Page 1 of n
Population
: Intent-to-Treat
Table 2.xx
Summary of Change from Baseline in ACT Total Score
Visit
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Randomisation (Day 0)
n
xx
xx
Mean
xx.x
xx.x
SD
  x.xx
  x.xx
Median
xx.x
xx.x
Min.
xx
xx
Max.
xx
xx
Week 6
n
xx
xx
Mean
xx.x
xx.x
SD
  x.xx
  x.xx
Median
xx.x
xx.x
Min.
xx
xx
Max.
xx
xx
Change from Baseline at Week 6
n
xx
xx
Mean
xx.x
xx.x
SD
  x.xx
  x.xx
Median
xx.x
xx.x
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Min.
xx
xx
Max.
xx
xx
Programming note: repeat for Week 12, Change from Baseline at Week 12, Week 18, Change from Baseline at Week 18, Week 24, Change from Baseline at Week 
24, Early Withdrawal, Change from Baseline at Early Withdrawal
Repeat for:
Summary of Change from Baseline in ACT Total Score Per Protocol Population (PP Population)
Summary of Change from Baseline in Lung Function Tests (ITT Population)
Programming note: Present an additional column to the left of “Visit”, labelled “Test” with values “Trough (Pre-dose) FEV1 (L)” and “Trough (Pre-dose) Percent 
Predicted FEV1 (%)” to allow presentation of results by Test. Present the following visits: Randomisation (Day 0), Week 12, Change from Baseline at Week 12, Early 
Withdrawal and Change from Baseline at Early Withdrawal.
Summary of Change from Baseline in AQLQ(S) Total Score and Domain Scores (ITT Population)
Programming note: Present an additional column to the left of “Visit”, labelled “Domain” with values “Total Score”, “Environmental Stimuli”, “Symptoms”, “Activity 
Limitations”, “Emotional Function” to allow presentation of results by Domain. Present the following visits: Randomisation (Day 0), Week 24, Change from Baseline at 
Week 24, Early Withdrawal and Change from Baseline at Early Withdrawal.
Summary of PASAP-Q Scores (ITT Population)
Programming note: Present an additional column to the left of “Visit”, labelled “Score” with values “Performance”, “Convenience”, “Total Score”, “Overall Satisfaction”, 
and “Willingness to Continue Using Inhaler” to allow presentation of results by Domain. Present the following visits: Week 12 and Early Withdrawal.
Add the following footnotes:
“Note: Performance, Convenience, Total Score, and Willingness to Continue Using Inhaler are expressed on a scale of 0 to 100.
Note: Overall Satisfaction is expressed on a scale of 1 to 7.”
Summary of EQ-5D-5L Utility Score (ITT Population)
Summary of EQ-5D-5L Visual Analogue Scale (VAS) Score (ITT Population)
Programming note: Present the following visits: Randomisation (Day 0), Week 24, Change from Baseline at Week 24, Early Withdrawal, Change from Baseline at Early 
Withdrawal.
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Example
: EFF_T1S
Protocol
: HZA116492                                                                            
Page 1 of 2
Population
: Intent-to-Treat
Table 2.xx
Summary of Change from Baseline in ACT Total Score by Country
Country: France
Visit
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Randomisation (Day 0)
n
xx
xx
Mean
xx.x
xx.x
SD
  x.xx
  x.xx
Median
xx.x
xx.x
Min.
xx
xx
Max.
xx
xx
Week 6
n
xx
xx
Mean
xx.x
xx.x
SD
  x.xx
  x.xx
Median
xx.x
xx.x
Min.
xx
xx
Max.
xx
xx
Change from Baseline at Week 6
n
xx
xx
Mean
xx.x
xx.x
SD
  x.xx
  x.xx
Median
xx.x
xx.x
Min.
xx
xx
Max.
xx
xx
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Example
: EFF_T1S
Protocol
: HZA116492                                                                            
Page 2 of 2
Population
: Intent-to-Treat
Table 2.xx
Summary of Change from Baseline in ACT Total Score by Country
Country: Germany
Visit
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Randomisation (Day 0)
n
xx
xx
Mean
xx.x
xx.x
SD
  x.xx
  x.xx
Median
xx.x
xx.x
Min.
xx
xx
Max.
xx
xx
Week 6
n
xx
xx
Mean
xx.x
xx.x
SD
  x.xx
  x.xx
Median
xx.x
xx.x
Min.
xx
xx
Max.
xx
xx
Change from Baseline at Week 6
n
xx
xx
Mean
xx.x
xx.x
SD
  x.xx
  x.xx
Median
xx.x
xx.x
Min.
xx
xx
Max.
xx
xx
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Repeat for:
Summary of Change from Baseline in ACT Total Score by Number of Severe Asthma Exacerbations in the Previous Year Prior to Randomisation (ITT Population)
Number of Severe Asthma Exacerbations in the Previous Year Prior to Randomisation: 0
Number of Severe Asthma Exacerbations in the Previous Year Prior to Randomisation: >= 1
Summary of Change from Baseline in ACT Total Score by Smoking Status at Baseline (ITT Population)
Smoking Status at Baseline: Current smoker
Smoking Status at Baseline: Former smoker
Smoking Status at Baseline: Never smoked
Summary of Change from Baseline in ACT Total Score by Age Group (ITT Population)
Age Group: ≤50 Years Old
Age Group: > 50 Years Old
Summary of Change from Baseline in ACT Total Score by Gender (ITT Population)
Gender: Male
Gender: Female
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Example 
: EFF_T2
Protocol
: HZA116492
Page 1 of 1
Population
: Intent-to-Treat
Table 2.xx
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 12 (Visit 4)
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
n
xx 
xx 
LS Mean Change (SE)
xx.xx (x.xxx)
xx.xx (x.xxx)
FF/VI vs. Usual ICS/LABA
  Difference 
xx.x 
  95% CI
(xx.x, xx.x)
  p-value
x.xxx
Note: The analysis method was an MMRM adjusted for randomised treatment, visit (Week 6 and Week 12), baseline ACT total score, randomised treatment-by-visit 
interaction, baseline ACT total score-by-visit interaction, gender, age, country and patient fitted as a random factor.
Note: The Restricted Maximum Likelihood (REML) estimation approach was used with a default covariance structure of unstructured.
Programming note: Should computational issues be encountered when using an unstructured covariance structure, other structures including AR1 and CS should be 
considered and the second footnote updated as appropriate. Should the distributional assumption of normality fail then the p-value from a model on the rank-
transformed values should be presented and the following footnote added: “Note: the p-value presented was obtained from an MMRM on the rank-transformed values 
of change from baseline in ACT total score at Week 12 (Visit 4) with the same specification as the untransformed model.”
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Repeat for:
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 12 (Visit 4) Per Protocol Population (PP Population)
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 12 (Visit 4) (ANCOVA with LOCF) (ITT Population)
Programming note: Should the distributional assumption of normality fail then the p-value from a model on the rank-transformed values should be presented and the 
following footnote added: “Note: the p-value presented was obtained from an ANCOVA on the rank-transformed values of change from baseline in ACT total score at 
Week 12 (Visit 4) with the same specification as the untransformed model.”
Footnotes as follows:
“Note: The analysis method was an ANCOVA model adjusted for randomised treatment, baseline ACT total score, gender, age and country.
Note: Missing values at Week 12 (Visit 4) were replaced by last available post-randomisation value based on the last observation carried forward (LOCF) method.”
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 12 (Visit 4) (Multiple Imputation – Missing at Random Approach) (ITT 
Population)
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 12 (Visit 4) (Multiple Imputation – Copy Differences from Reference 
Approach) (ITT Population)
Programming note: Present the “FF/VI vs. Usual ICS/LABA” section only. Footnotes as follows:
“Note: Missing values post-randomisation were imputed using multiple imputation methods based on pattern mixture models.
Note: Each imputed data set was analysed using an ANCOVA model at Week 12 (Visit 4) adjusted for randomised treatment, baseline ACT total score, gender, age 
and country and the resulting treatment differences and their standard errors combined using Rubin’s rules.”
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 12 (Visit 4) (Hodges-Lehmann Approach) (ITT Population)
Programming note: Present the “Difference” and “95% CI” lines of “FF/VI vs. Usual ICS/LABA” section only. Footnotes as follows:
“Note: The difference between treatment groups at Week 12 (Visit 4) was calculated using the Hodges-Lehmann approach.”
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 12 (Visit 4) (ANCOVA with WOCF) (ITT Population)
Programming note: Should the distributional assumption of normality fail then the p-value from a model on the rank-transformed values should be presented and the 
following footnote added: “Note: the p-value presented was obtained from an ANCOVA on the rank-transformed values of change from baseline in ACT total score at 
Week 12 (Visit 4) with the same specification as the untransformed model.”
Footnotes as follows:
“Note: The analysis method was an ANCOVA model adjusted for randomised treatment, baseline ACT total score, gender, age and country.
Note: Missing values at Week 12 (Visit 4) due to treatment withdrawal prior to this time point were replaced by worst post-randomisation value based on the worst 
observation carried forward (WOCF) method.”
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Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 12 (Visit 4), FF/VI Versus the Subset of Usual ICS/LABA Subjects 
Prescribed FP/S at Randomisation (ITT Population)
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 12 (Visit 4), FF/VI Versus the Subset of Usual ICS/LABA Subjects 
Prescribed BUD/F at Randomisation (ITT Population)
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 24 (Visit 6) (ITT Population)
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 24 (Visit 6) Per Protocol Population (PP Population)
Programming note: first footnote as follows:
“Note: The analysis method was an MMRM adjusted for randomised treatment, visit (Week 6, Week 12, Week 18 and Week 24), baseline ACT total score, randomised 
treatment-by-visit interaction, baseline ACT total score-by-visit interaction, gender, age, country and patient fitted as a random factor.”
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 24 (Visit 6) (ANCOVA with LOCF) (ITT Population)
Programming note: Should the distributional assumption of normality fail then the p-value from a model on the rank-transformed values should be presented and the 
following footnote added: “Note: the p-value presented was obtained from an ANCOVA on the rank-transformed values of change from baseline in ACT total score at 
Week 24 (Visit 6) with the same specification as the untransformed model.”
Footnotes as follows:
“Note: The analysis method was an ANCOVA model adjusted for randomised treatment, baseline ACT total score, gender, age and country.
Note: Missing values at Week 24 (Visit 6) were replaced by last available post-randomisation value based on the last observation carried forward (LOCF) method.”
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 24 (Visit 6) (Multiple Imputation – Missing at Random Approach) (ITT 
Population)
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 24 (Visit 6) (Multiple Imputation – Copy Differences from Reference 
Approach) (ITT Population)
Programming note: Present the “FF/VI vs. Usual ICS/LABA” section only. Footnotes as follows:
“Note: Missing values post-randomisation were imputed using multiple imputation methods based on pattern mixture models.
Note: Each imputed data set was analysed using an ANCOVA model at Week 24 (Visit 6) adjusted for randomised treatment, baseline ACT total score, gender, age 
and country and the resulting treatment differences and their standard errors combined using Rubin’s rules.”
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 24 (Visit 6) (Hodges-Lehmann Approach) (ITT Population)
Present the “Difference” and “95% CI” lines of “FF/VI vs. Usual ICS/LABA” section only. Footnotes as follows:
“Note: The difference between treatment groups at Week 24 (Visit 6) was calculated using the Hodges-Lehmann approach.”
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 24 (Visit 6) (ANCOVA with WOCF) (ITT Population)
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Programming note: Should the distributional assumption of normality fail then the p-value from a model on the rank-transformed values should be presented and the 
following footnote added: “Note: the p-value presented was obtained from an ANCOVA on the rank-transformed values of change from baseline in ACT total score at 
Week 24 (Visit 6) with the same specification as the untransformed model.”
Footnotes as follows:
“Note: The analysis method was an ANCOVA model adjusted for randomised treatment, baseline ACT total score, gender, age and country.
Note: Missing values at Week 24 (Visit 6) due to treatment withdrawal prior to this time point were replaced by worst post-randomisation value based on the worst 
observation carried forward (WOCF) method.”
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 24 (Visit 6), FF/VI Versus the Subset of Usual ICS/LABA Subjects 
Prescribed FP/S at Randomisation (ITT Population)
Programming note: Output only to be produced if ≥25% of Usual ICS/LABA patients are prescribed FP/S at randomisation. First footnote as follows:
“Note: The analysis method was an MMRM adjusted for randomised treatment, visit (Week 6, Week 12, Week 18 and Week 24), baseline ACT total score, randomised 
treatment-by-visit interaction, baseline ACT total score-by-visit interaction, gender, age, country and patient fitted as a random factor.”
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 24 (Visit 6), FF/VI Versus the Subset of Usual ICS/LABA Subjects 
Prescribed BUD/F at Randomisation (ITT Population) 
Programming note: Output only to be produced if ≥25% of Usual ICS/LABA patients are prescribed BUD/F at randomisation. First footnote as follows:
“Note: The analysis method was an MMRM adjusted for randomised treatment, visit (Week 6, Week 12, Week 18 and Week 24), baseline ACT total score, randomised 
treatment-by-visit interaction, baseline ACT total score-by-visit interaction, gender, age, country and patient fitted as a random factor.”
Summary of the Statistical Analysis of Change from Baseline in Trough (Pre-dose) FEV1 at Week 12 (Visit 4) (ITT Population)
Programming note: Should the distributional assumption of normality fail then the p-value from a model on the rank-transformed values should be presented and the 
following footnote added: “Note: the p-value presented was obtained from an ANCOVA on the rank-transformed values of change from baseline in trough (pre-dose) 
FEV1 at Week 12 (Visit 4) with the same specification as the untransformed model.”
Footnote as follows:
“Note: The analysis method was an ANCOVA model adjusted for randomised treatment, baseline trough (pre-dose) FEV1, gender, age and country.”
Summary of the Statistical Analysis of Change from Baseline in EQ-5D-5L Utility Score at Week 24 (Visit 6) (ITT Population)
Programming note: Should the distributional assumption of normality fail then the p-value from a model on the rank-transformed values should be presented and the 
following footnote added: “Note: the p-value presented was obtained from an ANCOVA on the rank-transformed values of change from baseline in EQ-5D-5L utility 
score at Week 24 (Visit 6) with the same specification as the untransformed model.”
Footnote as follows:
“Note: The analysis method was an ANCOVA model adjusted for randomised treatment, baseline EQ-5D-5L utility score, gender, age and country.”
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Summary of the Statistical Analysis of Change from Baseline in EQ-5D-5L Visual Analogue Scale (VAS) Score at Week 24 (Visit 6) (ITT Population) 
Programming note: Should the distributional assumption of normality fail then the p-value from a model on the rank-transformed values should be presented and the 
following footnote added: “Note: the p-value presented was obtained from an ANCOVA on the rank-transformed values of change from baseline in EQ-5D-5L VAS 
score at Week 24 (Visit 6) with the same specification as the untransformed model.” 
Footnote as follows:
“Note: The analysis method was an ANCOVA model adjusted for randomised treatment, baseline EQ-5D-5L VAS score, gender, age and country.”
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Example 
: EFF_T2S
Protocol
: HZA116492
Page 1 of 2
Population
: Intent-to-Treat
Table 2.xx
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 12 (Visit 4) by Country
Country: France
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
n
xx 
xx 
LS Mean Change (SE)
xx.xx (x.xxx)
xx.xx (x.xxx)
FF/VI vs. Usual ICS/LABA
  Difference 
xx.x 
  95% CI
(xx.x, xx.x)
Note: The analysis method was an MMRM adjusted for randomised treatment, visit (Week 6 and Week 12), baseline ACT total score, baseline ACT total score-by-visit 
interaction, gender, age, country, two- and three- way interactions between randomised treatment, visit and country, and patient fitted as a random factor.
Note: The Restricted Maximum Likelihood (REML) estimation approach was used with a default covariance structure of unstructured.
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Example 
: EFF_T2S
Protocol
: HZA116492
Page 2 of 2
Population
: Intent-to-Treat
Table 2.xx
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 12 (Visit 4) by Country
Country: Germany
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
n
xx 
xx 
LS Mean Change (SE)
xx.xx (x.xxx)
xx.xx (x.xxx)
FF/VI vs. Usual ICS/LABA
  Difference 
xx.x 
  95% CI
(xx.x, xx.x)
Note: The analysis method was an MMRM adjusted for randomised treatment, visit (Week 6 and Week 12), baseline ACT total score, randomised treatment-by-visit 
interaction, baseline ACT total score-by-visit interaction, gender, age, country, randomised treatment-by-country interaction and patient fitted as a random factor.
Note: The Restricted Maximum Likelihood (REML) estimation approach was used with a default covariance structure of unstructured.
Programming note: Should computational issues be encountered when using an unstructured covariance structure, other structures including AR1 and CS should be 
considered and the second footnote updated as appropriate. 
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Repeat for:
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 12 (Visit 4) by Number of Severe Asthma Exacerbations in the Previous 
Year Prior to Randomisation (ITT Population)
Number of Severe Asthma Exacerbations in the Previous Year Prior to Randomisation: 0
Number of Severe Asthma Exacerbations in the Previous Year Prior to Randomisation: >= 1
Programming note: first footnote as follows:
“Note: The analysis method was an MMRM adjusted for randomised treatment, visit (Week 6 and Week 12), baseline ACT total score, baseline ACT total score-by-visit 
interaction, gender, age, country, number of severe asthma exacerbations in the previous year prior to randomisation, two- and three- way interactions between 
randomised treatment, visit and number of severe asthma exacerbations in the previous year prior to randomisation, and patient fitted as a random factor.”
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 12 (Visit 4) by Smoking Status at Baseline (ITT Population)
Programming note: first footnote as follows: 
“Note: The analysis method was an MMRM adjusted for randomised treatment, visit (Week 6 and Week 12), baseline ACT total score, baseline ACT total score-by-visit 
interaction, gender, age, country, smoking status at baseline, two- and three- way interactions between randomised treatment, visit and smoking status at baseline, 
and patient fitted as a random factor.”
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 12 (Visit 4) by Age Group (ITT Population)
Programming note: first footnote as follows: 
“Note: The analysis method was an MMRM adjusted for randomised treatment, visit (Week 6 and Week 12), baseline ACT total score, baseline ACT total score-by-visit 
interaction, gender, country, age group, two- and three- way interactions between randomised treatment, visit and age group, and patient fitted as a random factor.”
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 12 (Visit 4) by Gender (ITT Population)
Programming note: first footnote as follows: 
“Note: The analysis method was an MMRM adjusted for randomised treatment, visit (Week 6 and Week 12), baseline ACT total score, baseline ACT total score-by-visit 
interaction, gender, age, country, two- and three- way interactions between randomised treatment, visit and gender, and patient fitted as a random factor.”
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 24 (Visit 6) by Country (ITT Population)
Programming note: first footnote as follows:
“Note: The analysis method was an MMRM adjusted for randomised treatment, visit (Week 6, Week 12, Week 18 and Week 24), baseline ACT total score, baseline 
ACT total score-by-visit interaction, gender, age, country, two- and three- way interactions between randomised treatment, visit and country, and patient fitted as a 
random factor.”
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Example 
: EFF_T3
Protocol
: HZA116492
Page 1 of n
Population
: Intent-to-Treat
Table 2.xx
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 12 (Visit 4), Adjusting for Seasonal Effect
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Randomised treatment-by-season at 
randomisation interaction
  p-value
x.xxx
Season at randomisation: Spring
  n
xx
xx
  LS Mean Change (SE)
xx.xx (x.xxx)
xx.xx (x.xxx)
  FF/VI vs. Usual ICS/LABA
    Difference 
xx.x 
    95% CI
(xx.x, xx.x)
....
Note: The analysis method was an MMRM adjusted for randomised treatment, visit (Week 6 and Week 12), baseline ACT total score, baseline ACT total score-by-visit 
interaction, gender, age, country, season at randomisation, two- and three- way interactions between randomised treatment, visit and season at randomisation, and 
patient fitted as a random factor.
Note: The Restricted Maximum Likelihood (REML) estimation approach was used with a default covariance structure of unstructured.
Note: Spring = March, April and May; Summer = June, July and August; Autumn = September, October and November; Winter = December, January and February.
Programming note: repeat on subsequent pages for Season at randomisation = Summer, Autumn, Winter. Should computational issues be encountered when using 
an unstructured covariance structure, other structures including AR1 and CS should be considered and the second footnote updated as appropriate. 
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Repeat for:
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 12 (Visit 4), Adjusting for Seasonal Effect Per Protocol Population (PP 
Population)
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 24 (Visit 6), Adjusting for Seasonal Effect (ITT Population)
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 24 (Visit 6), Adjusting for Seasonal Effect Per Protocol Population (PP 
Population) 
First footnote as follows:
“Note: The analysis method was an MMRM adjusted for randomised treatment, visit (Week 6, Week 12, Week 18 and Week 24), baseline ACT total score, baseline 
ACT total score-by-visit interaction, gender, age, country, season at randomisation, two- and three- way interactions between randomised treatment, visit and season 
at randomisation, and patient fitted as a random factor.”
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Example
: EFF_T4
Protocol
: HZA116492                                                                            
  Page 1 of 9
Population
: Intent-to-Treat
Table 2.xx
Summary of Inhaler Device Use Errors
[1] Correct use is defined as not making any critical or non-critical errors at that visit.
Visit
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Randomisation (Day 0)
Number of patients using Ellipta
xxx
Number of patients with correct use [1]
xxx (xx%)
Number of patients without correct use
xxx (xx%)
Number of patients with at least one critical error
xxx (xx%)
Type of critical error:
  Failed to open cover
xxx (xx%)
  Shook the device upside down after dose preparation
xxx (xx%)
  Exhaled directly into mouthpiece
xxx (xx%)
  No seal by the lips around the mouthpiece during the inhalation
xxx (xx%)
Number of patients with at least one non-critical error
xxx (xx%)
Type of non-critical error:
  No exhalation before an inhalation   
xxx (xx%)
Inhalation manoeuvre was not: long, steady and deep
xxx (xx%)
  Blocked air inlet during inhalation manoeuvre
xxx (xx%)
Did not hold breath
xxx (xx%)
Did not close the device
xxx (xx%)
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Example
: EFF_T4
Protocol
: HZA116492                                                                            
Page 2 of 9
Population
: Intent-to-Treat
Table 2.xx
Summary of Inhaler Device Use Errors
[1] Correct use is defined as not making any critical or non-critical errors at that visit.
Visit
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Randomisation (Day 0)
Number of patients using Diskus
xxx
Number of patients with correct use [1]
xxx (xx%)
Number of patients without correct use
xxx (xx%)
Number of patients with at least one critical error
xxx (xx%)
Type of critical error:
  Failed to open cover
xxx (xx%)
  Lever is not pushed back
xxx (xx%)
  Shook the device after dose preparation
xxx (xx%)
  Exhaled directly into mouthpiece
xxx (xx%)
  No seal by the lips around the mouthpiece during the inhalation
xxx (xx%)
Number of patients with at least one non-critical error
xxx (xx%)
Type of non-critical error:
  No exhalation before an inhalation   
xxx (xx%)
Inhalation manoeuvre was not: steady and deep
xxx (xx%)
Did not hold breath
xxx (xx%)
Did not close the device
xxx (xx%)
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Example
: EFF_T4
Protocol
: HZA116492                                                                            
  Page 2 of 9
Population
: Intent-to-Treat
Table 2.xx
Summary of Inhaler Device Use Errors
Visit
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Randomisation (Day 0)
Number of patients using Turbuhaler
xxx
Number of patients with correct use [1]
xxx (xx%)
Number of patients without correct use
xxx (xx%)
Number of patients with at least one critical error
xxx (xx%)
Type of critical error:
  Failed to remove cap
xxx (xx%)
  Did not hold device upright during dose preparation
xxx (xx%)
  Base not twisted fully backwards and forwards, no click heard
xxx (xx%)
  Shook the device after dose preparation
xxx (xx%)
  Exhaled directly into mouthpiece
xxx (xx%)
  No seal by the lips around the mouthpiece during the inhalation
xxx (xx%)
Number of patients with at least one non-critical error
xxx (xx%)
Type of non-critical error:
  Device tipped downwards after dose preparation
xxx (xx%)
  No exhalation before an inhalation   
xxx (xx%)
Inhalation manoeuvre was not: forceful and deep
xxx (xx%)
  Blocked air inlet during inhalation manoeuvre
xxx (xx%)
Did not hold breath
xxx (xx%)
Did not close the device
xxx (xx%)
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[1] Correct use is defined as not making any critical or non-critical errors at that visit.
Programming note: repeat on subsequent pages for Visit = Week 12 and Week 24. “Number of patients using...” line will provide the denominators for each section’s 
percentages.
Repeat for:
Summary of Inhaler Device Use Errors Per Protocol Population (PP Population)
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Example 
: EFF_T5
Protocol
: HZA116492
Page 1 of 1
Population
: Intent-to-Treat
Table 2.xx 
Summary of Correct Use of Inhaler Device
Visit
Usual ICS/LABA
(N=xxx)
FF/VI  
(N=xxx)
Randomisation 
(Day 0)
n
xxx
xxx
Number of patients with correct use [1]
xxx (xx%)
xxx (xx%)
Number of patients without correct use
xxx (xx%)
xxx (xx%)
  Number of patients with at least one critical error
xxx (xx%)
xxx (xx%)
  Number of patients with at least one non-critical error
xxx (xx%)
xxx (xx%)
Week 12
n
xxx
xxx
Number of patients with correct use [1]
xxx (xx%)
xxx (xx%)
Number of patients without correct use
xxx (xx%)
xxx (xx%)
  Number of patients with at least one critical error
xxx (xx%)
xxx (xx%)
  Number of patients with at least one non-critical error
xxx (xx%)
xxx (xx%)
Week 24
n
xxx
xxx
Number of patients with correct use [1]
xxx (xx%)
xxx (xx%)
Number of patients without correct use
xxx (xx%)
xxx (xx%)
  Number of patients with at least one critical error
xxx (xx%)
xxx (xx%)
  Number of patients with at least one non-critical error
xxx (xx%)
xxx (xx%)
[1] Correct use is defined as not making any critical or non-critical errors at that visit.
Repeat for:
Summary of Correct Use of Inhaler Device Per Protocol Population (PP Population)
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Example
: EFF_T6
Protocol
: HZA116492                                                                            
Page 1 of 1
Population
: Intent-to-Treat
Table 2.xx
Summary of the Statistical Analysis of Correct Use of Inhaler Device at Week 12 (Visit 4) and at Week 24 (Visit 6) Independently of the Use at Week 12 (Visit 4)
Visit
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Week 12
n
xxx
xxx
With correct use [1]
xxx (xx%)
xxx (xx%)
Without correct use
xxx (xx%)
xxx (xx%)
FF/VI vs. Usual ICS/LABA
  Adjusted Odds Ratio 
x.xx
  95% CI
(x.xx, x.xx)
  p-value
x.xxx
Week 24
n
xxx
xxx
With correct use [1]
xxx (xx%)
xxx (xx%)
Without correct use
xxx (xx%)
xxx (xx%)
FF/VI vs. Usual ICS/LABA
  Adjusted Odds Ratio 
x.xx
  95% CI
(x.xx, x.xx)
  p-value
x.xxx
[1] Correct use is defined as not making any critical or non-critical errors at that visit.
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Note: The analysis method was logistic regression adjusted for randomised treatment, correct use of inhaler device at baseline, gender, age and country.
Programming note: If the likelihood maximisation algorithm fails to converge due to complete or quasi-complete separation of the data then implement Firth’s penalized 
likelihood and add the following footnote: “Note: Firth’s penalized likelihood was implemented due to [complete / quasi-complete] separation of data.”, deleting 
“complete” or “quasi-complete” as appropriate. 
Repeat for:
Summary of the Statistical Analysis of Correct Use of Inhaler Device at Week 12 (Visit 4) and at Week 24 (Visit 6) Independently of the Use at Week 12 (Visit 4) Per 
Protocol Population (PP Population)
Summary of the Statistical Analysis of Percentage of Subjects Who Have Either an ACT Total Score >= 20 or >= 3 Point Increase from Baseline in ACT Total Score at 
Week 12 (Visit 4) and Week 24 (Visit 6) (ITT Population)
Programming note: Replace “With correct use [1]” with “Responder [1]” and “Without correct use” with “Non-Responder”. 
Footnotes as follows:
“[1] Responder is defined as an ACT total score >= 20 or >= 3 point increase from baseline in ACT total score at that visit.
Note: The analysis method was logistic regression adjusted for randomised treatment, baseline ACT total score, baseline ACT total score squared, gender, age and 
country.”
Summary of the Statistical Analysis of Percentage of Subjects Who Have an Increase from Baseline of >=0.5 in AQLQ(S) Total Score and Environmental Stimuli 
Domain Score at Week 24 (Visit 6) (ITT Population) 
Domain: Total Score
Domain: Environmental Stimuli
Programming note: Replace “With correct use [1]” with “Responder [1]” and “Without correct use” with “Non-Responder”. Do not display the “Visit” column.
Footnotes as follows:
“[1] Responder is defined as an increase from baseline of >= 0.5.
Note: The analysis method was logistic regression adjusted for randomised treatment, baseline score, gender, age and country.”
Summary of the Statistical Analysis of Proportion of Responders According to EQ-5D-5L Descriptive System Dimensions at Week 24 (Visit 6) (ITT Population)
Dimension: Mobility
Dimension: Self-care
Dimension: Usual activities
Dimension: Pain/Discomfort
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Dimension: Anxiety/Depression
Programming note: Replace “With correct use [1]” with “Responder [1]” and “Without correct use” with “Non-Responder”. Do not display the “Visit” column.
Footnotes as follows: 
“[1] Responder is defined as a score of 1 (‘no problems’).
Note: The analysis method was logistic regression adjusted for randomised treatment, baseline EQ-5D-5L domain score, gender, age and country.”
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Example
: EFF_T7
Protocol
: HZA116492                                                                            
  Page 1 of 1
Population
: Intent-to-Treat
Table 2.xx
Summary of Percentage of Subjects Who Have Either an ACT Total Score of >= 20 or >= 3 Point Increase from Baseline in ACT Total Score
Programming note: repeat for Visit = Week 18, Week 24, Early Withdrawal.
Visit
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Week 6
n
xxx
xxx
ACT Total Score >= 20 or >= 3 Point Increase from Baseline
xxx (xx%)
xxx (xx%)
ACT Total Score >= 20
xxx (xx%)
xxx (xx%)
>= 3 Point Increase from Baseline
xxx (xx%)
xxx (xx%)
  
Week 12
n
xxx
xxx
ACT Total Score >= 20 or >= 3 Point Increase from Baseline
xxx (xx%)
xxx (xx%)
ACT Total Score >= 20
xxx (xx%)
xxx (xx%)
>= 3 Point Increase from Baseline
xxx (xx%)
xxx (xx%)
...
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Example
: EFF_T8
Protocol
: HZA116492
Page 1 of 10
Population
: Intent-to-Treat
Table 2.xx
Summary of Individual ACT Question Scores
Question: 1. Getting as much done at work, school or home
Visit
Response
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Randomisation (Day 0)
n
xxx
xxx
1. All of the time
xxx (xx%)
xxx (xx%)
2. Most of the time
xxx (xx%)
xxx (xx%)
3. Some of the time
xxx (xx%)
xxx (xx%)
4. A little of the time
xxx (xx%)
xxx (xx%)
5. None of the time.
xxx (xx%)
xxx (xx%)
Week 6
n
xxx
xxx
1. All of the time
xxx (xx%)
xxx (xx%)
2. Most of the time
xxx (xx%)
xxx (xx%)
3. Some of the time
xxx (xx%)
xxx (xx%)
4. A little of the time
xxx (xx%)
xxx (xx%)
5. None of the time.
xxx (xx%)
xxx (xx%)
Week 12
n
xxx
xxx
1. All of the time
xxx (xx%)
xxx (xx%)
2. Most of the time
xxx (xx%)
xxx (xx%)
3. Some of the time
xxx (xx%)
xxx (xx%)
4. A little of the time
xxx (xx%)
xxx (xx%)
5. None of the time.
xxx (xx%)
xxx (xx%)
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Example
: EFF_T8
Protocol
: HZA116492
Page 2 of 10
Population
: Intent-to-Treat
Table 2.xx
Summary of Individual ACT Question Scores
Question: 1. Getting as much done at work, school or home
Visit
Response
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Week 18
n
xxx
xxx
1. All of the time
xxx (xx%)
xxx (xx%)
2. Most of the time
xxx (xx%)
xxx (xx%)
3. Some of the time
xxx (xx%)
xxx (xx%)
4. A little of the time
xxx (xx%)
xxx (xx%)
5. None of the time.
xxx (xx%)
xxx (xx%)
Week 24
n
xxx
xxx
1. All of the time
xxx (xx%)
xxx (xx%)
2. Most of the time
xxx (xx%)
xxx (xx%)
3. Some of the time
xxx (xx%)
xxx (xx%)
4. A little of the time
xxx (xx%)
xxx (xx%)
5. None of the time.
xxx (xx%)
xxx (xx%)
Early Withdrawal
n
xxx
xxx
1. All of the time
xxx (xx%)
xxx (xx%)
2. Most of the time
xxx (xx%)
xxx (xx%)
3. Some of the time
xxx (xx%)
xxx (xx%)
4. A little of the time
xxx (xx%)
xxx (xx%)
5. None of the time.
xxx (xx%)
xxx (xx%)
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Programming note: repeat on subsequent pages for Question = 2. Shortness of breath, 3. Asthma symptoms woken up at night or earlier than usual, 4. Used rescue 
inhaler or nubuliser medication, 5. Asthma control.
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Example
: EFF_T9
Protocol
: HZA116492
Page 1 of 3
Population
: Intent-to-Treat
Table 2.xx
Summary of Compliance with Study Medication
Note: 
Compliance = {[Total no. of inhalations taken]/[Dose frequency x (Stop date – Start date)]} x 100.
Note: Total number of inhalations taken is the sum of (dose counter start count – dose counter stop count) for all inhalers used during the time period, Dose frequency 
is equal to 1 for Ellipta, 2 for Diskus and 2 or 4 for Turbuhaler, and Start date and Stop date are the earliest treatment start date and latest treatment stop date 
respectively recorded for all inhalers used during the time period. 
Programming note: repeat on subsequent pages for Time period = Randomisation (Day 0) to Week 12, Week 12 to Week 24.
Repeat for:
Summary of Compliance with Study Medication Per Protocol Population (PP Population) 
Time period
Compliance (%)
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Randomisation (Day 0) to 
Week 24
n
xxx
xxx
< 80%
xxx (xx%)
xxx (xx%)
80% to 120% inclusive
xxx (xx%)
xxx (xx%)
> 120%
xxx (xx%)
xxx (xx%)
n
xx
xx
Mean
xx.x
xx.x
SD
  x.xx
  x.xx
Median
xx.x
xx.x
Min.
xx
xx
Max.
xx
xx
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Example 
: EFF_T10
Protocol
: HZA116492
Page 1 of 12
Population
: Intent-to-Treat
Table 2.xx
Summary of Use of Medication Adherence Report Scale for Asthma (MARS-A) During the Study
Visit: Randomisation (Day 0)
MARS-A Questions
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
I only use it when I need it
n
xxx
xxx
Always
xxx (xx%)
xxx (xx%)
Often
xxx (xx%)
xxx (xx%)
Sometimes
xxx (xx%)
xxx (xx%)
Rarely
xxx (xx%)
xxx (xx%)
Never
xxx (xx%)
xxx (xx%)
Only use it when I feel breathless
n
xxx
xxx
Always
xxx (xx%)
xxx (xx%)
Often
xxx (xx%)
xxx (xx%)
Sometimes
xxx (xx%)
xxx (xx%)
Rarely
xxx (xx%)
xxx (xx%)
Never
xxx (xx%)
xxx (xx%)
I decide to miss out a dose
n
xxx
xxx
Always
xxx (xx%)
xxx (xx%)
Often
xxx (xx%)
xxx (xx%)
Sometimes
xxx (xx%)
xxx (xx%)
Rarely
xxx (xx%)
xxx (xx%)
Never
xxx (xx%)
xxx (xx%)
Note: MARS-A: Medication Adherence Report Scale for Asthma.
[1] MARS-A 10-Score is based on the mean score across all ten questions.
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Example 
: EFF_T10
Protocol
: HZA116492
Page 2 of 12
Population
: Intent-to-Treat
Table 2.xx
Summary of Use of Medication Adherence Report Scale for Asthma (MARS-A) During the Study
Visit: Randomisation (Day 0)
MARS-A Questions
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
I try to avoid using it
n
xxx
xxx
Always
xxx (xx%)
xxx (xx%)
Often
xxx (xx%)
xxx (xx%)
Sometimes
xxx (xx%)
xxx (xx%)
Rarely
xxx (xx%)
xxx (xx%)
Never
xxx (xx%)
xxx (xx%)
I forget to take it
n
xxx
xxx
Always
xxx (xx%)
xxx (xx%)
Often
xxx (xx%)
xxx (xx%)
Sometimes
xxx (xx%)
xxx (xx%)
Rarely
xxx (xx%)
xxx (xx%)
Never
xxx (xx%)
xxx (xx%)
I alter the dose
n
xxx
xxx
Always
xxx (xx%)
xxx (xx%)
Often
xxx (xx%)
xxx (xx%)
Sometimes
xxx (xx%)
xxx (xx%)
Rarely
xxx (xx%)
xxx (xx%)
Never
xxx (xx%)
xxx (xx%)
Note: MARS-A: Medication Adherence Report Scale for Asthma.
[1] MARS-A 10-Score is based on the mean score across all ten questions.
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Example 
: EFF_T10
Protocol
: HZA116492
Page 3 of 12
Population
: Intent-to-Treat
Table 2.xx
Summary of Use of Medication Adherence Report Scale for Asthma (MARS-A) During the Study
Visit: Randomisation (Day 0)
MARS-A Questions
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
I stop taking it for a while
n
xxx
xxx
Always
xxx (xx%)
xxx (xx%)
Often
xxx (xx%)
xxx (xx%)
Sometimes
xxx (xx%)
xxx (xx%)
Rarely
xxx (xx%)
xxx (xx%)
Never
xxx (xx%)
xxx (xx%)
Reserve if treatment doesn't work
n
xxx
xxx
Always
xxx (xx%)
xxx (xx%)
Often
xxx (xx%)
xxx (xx%)
Sometimes
xxx (xx%)
xxx (xx%)
Rarely
xxx (xx%)
xxx (xx%)
Never
xxx (xx%)
xxx (xx%)
Before doing something
n
xxx
xxx
Always
xxx (xx%)
xxx (xx%)
Often
xxx (xx%)
xxx (xx%)
Sometimes
xxx (xx%)
xxx (xx%)
Rarely
xxx (xx%)
xxx (xx%)
Never
xxx (xx%)
xxx (xx%)
Note: MARS-A: Medication Adherence Report Scale for Asthma.
[1] MARS-A 10-Score is based on the mean score across all ten questions.
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Example 
: EFF_T10
Protocol
: HZA116492
Page 4 of 12
Population
: Intent-to-Treat
Table 2.xx
Summary of Use of Medication Adherence Report Scale for Asthma (MARS-A) During the Study
Visit: Randomisation (Day 0)
MARS-A Questions
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
I take less than instructed
n
xxx
xxx
Always
xxx (xx%)
xxx (xx%)
Often
xxx (xx%)
xxx (xx%)
Sometimes
xxx (xx%)
xxx (xx%)
Rarely
xxx (xx%)
xxx (xx%)
Never
xxx (xx%)
xxx (xx%)
MARS-A 10-Score [1]
n
xx
xx
Mean
xx.x
xx.x
SD
  x.xx
  x.xx
Median
xx.x
xx.x
Min.
xx
xx
Max.
xx
xx
Note: MARS-A: Medication Adherence Report Scale for Asthma.
[1] MARS-A 10-Score is based on the mean score across all ten questions.
Programming note: Repeat on subsequent pages for Visit = Week 12, Week 24 and Early Withdrawal.
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Example 
: EFF_T10S
Protocol
: HZA116492
Page 1 of 48
Population
: Intent-to-Treat
Table 2.xx
Summary of Use of Medication Adherence Report Scale for Asthma (MARS-A) During the Study by Status of Patient in Relation to the Reminder Sent to French 
Centres
Status: Patients in France who had completed all MARS-A assessments prior to the reminder being implemented
Visit: Randomisation (Day 0)
MARS-A Questions
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
I only use it when I need it
n
xxx
xxx
Always
xxx (xx%)
xxx (xx%)
Often
xxx (xx%)
xxx (xx%)
Sometimes
xxx (xx%)
xxx (xx%)
Rarely
xxx (xx%)
xxx (xx%)
Never
xxx (xx%)
xxx (xx%)
Only use it when I feel breathless
n
xxx
xxx
Always
xxx (xx%)
xxx (xx%)
Often
xxx (xx%)
xxx (xx%)
Sometimes
xxx (xx%)
xxx (xx%)
Rarely
xxx (xx%)
xxx (xx%)
Never
xxx (xx%)
xxx (xx%)
I decide to miss out a dose
n
xxx
xxx
Always
xxx (xx%)
xxx (xx%)
Often
xxx (xx%)
xxx (xx%)
Sometimes
xxx (xx%)
xxx (xx%)
Rarely
xxx (xx%)
xxx (xx%)
Never
xxx (xx%)
xxx (xx%)
Note: MARS-A: Medication Adherence Report Scale for Asthma.
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Note: Due to an issue identified with the French translation of the MARS-A, a reminder was sent to centres in France instructing that the questionnaire refers to the 
patient’s preventer inhaler (i.e. their maintenance therapy prior to entering the study, and study medication while on-study).
[1] MARS-A 10-Score is based on the mean score across all ten questions.
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Example 
: EFF_T10S
Protocol
: HZA116492
Page 2 of 48
Population
: Intent-to-Treat
Table 2.xx
Summary of Use of Medication Adherence Report Scale for Asthma (MARS-A) During the Study by Status of Patient in Relation to the Reminder Sent to French 
Centres
Status: Patients in France who had completed all MARS-A assessments prior to the reminder being implemented
Visit: Randomisation (Day 0)
MARS-A Questions
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
I try to avoid using it
n
xxx
xxx
Always
xxx (xx%)
xxx (xx%)
Often
xxx (xx%)
xxx (xx%)
Sometimes
xxx (xx%)
xxx (xx%)
Rarely
xxx (xx%)
xxx (xx%)
Never
xxx (xx%)
xxx (xx%)
I forget to take it
n
xxx
xxx
Always
xxx (xx%)
xxx (xx%)
Often
xxx (xx%)
xxx (xx%)
Sometimes
xxx (xx%)
xxx (xx%)
Rarely
xxx (xx%)
xxx (xx%)
Never
xxx (xx%)
xxx (xx%)
I alter the dose
n
xxx
xxx
Always
xxx (xx%)
xxx (xx%)
Often
xxx (xx%)
xxx (xx%)
Sometimes
xxx (xx%)
xxx (xx%)
Rarely
xxx (xx%)
xxx (xx%)
Never
xxx (xx%)
xxx (xx%)
Note: MARS-A: Medication Adherence Report Scale for Asthma.
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Note: Due to an issue identified with the French translation of the MARS-A, a reminder was sent to centres in France instructing that the questionnaire refers to the 
patient’s preventer inhaler (i.e. their maintenance therapy prior to entering the study, and study medication while on-study).
[1] MARS-A 10-Score is based on the mean score across all ten questions.
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Example 
: EFF_T10S
Protocol
: HZA116492
Page 3 of 48
Population
: Intent-to-Treat
Table 2.xx
Summary of Use of Medication Adherence Report Scale for Asthma (MARS-A) During the Study by Status of Patient in Relation to the Reminder Sent to French 
Centres
Status: Patients in France who had completed all MARS-A assessments prior to the reminder being implemented
Visit: Randomisation (Day 0)
MARS-A Questions
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
I stop taking it for a while
n
xxx
xxx
Always
xxx (xx%)
xxx (xx%)
Often
xxx (xx%)
xxx (xx%)
Sometimes
xxx (xx%)
xxx (xx%)
Rarely
xxx (xx%)
xxx (xx%)
Never
xxx (xx%)
xxx (xx%)
Reserve if treatment doesn't work
n
xxx
xxx
Always
xxx (xx%)
xxx (xx%)
Often
xxx (xx%)
xxx (xx%)
Sometimes
xxx (xx%)
xxx (xx%)
Rarely
xxx (xx%)
xxx (xx%)
Never
xxx (xx%)
xxx (xx%)
Before doing something
n
xxx
xxx
Always
xxx (xx%)
xxx (xx%)
Often
xxx (xx%)
xxx (xx%)
Sometimes
xxx (xx%)
xxx (xx%)
Rarely
xxx (xx%)
xxx (xx%)
Never
xxx (xx%)
xxx (xx%)
Note: MARS-A: Medication Adherence Report Scale for Asthma.
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Note: Due to an issue identified with the French translation of the MARS-A, a reminder was sent to centres in France instructing that the questionnaire refers to the 
patient’s preventer inhaler (i.e. their maintenance therapy prior to entering the study, and study medication while on-study).
[1] MARS-A 10-Score is based on the mean score across all ten questions.
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Example 
: EFF_T10S
Protocol
: HZA116492
Page 4 of 48
Population
: Intent-to-Treat
Table 2.xx
Summary of Use of Medication Adherence Report Scale for Asthma (MARS-A) During the Study by Status of Patient in Relation to the Reminder Sent to French 
Centres
Status: Patients in France, all MARS-A assessments completed pre-reminder
Visit: Randomisation (Day 0)
MARS-A Questions
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
I take less than instructed
n
xxx
xxx
Always
xxx (xx%)
xxx (xx%)
Often
xxx (xx%)
xxx (xx%)
Sometimes
xxx (xx%)
xxx (xx%)
Rarely
xxx (xx%)
xxx (xx%)
Never
xxx (xx%)
xxx (xx%)
MARS-A 10-Score [1]
n
xx
xx
Mean
xx.x
xx.x
SD
  x.xx
  x.xx
Median
xx.x
xx.x
Min.
xx
xx
Max.
xx
xx
Note: MARS-A: Medication Adherence Report Scale for Asthma.
Note: Due to an issue identified with the French translation of the MARS-A, a reminder was sent to centres in France instructing that the questionnaire refers to the 
patient’s preventer inhaler (i.e. their maintenance therapy prior to entering the study, and study medication while on-study).
[1] MARS-A 10-Score is based on the mean score across all ten questions.
Programming note: Repeat on subsequent pages for Visit = Week 12, Week 24 and Early Withdrawal, and for Status = “Patients in France, some MARS-A 
assessments completed pre-reminder, some post-reminder”, “Patients in France, all MARS-A assessments completed post-reminder”, “Patients in Germany”
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Example 
: EFF_T11
Protocol
: HZA116492
Page 1 of 2
Population
: Intent-to-Treat
Table 2.xx 
Summary of Severe On-Treatment Asthma Exacerbations
Usual ICS/LABA
(N=xxx)
FF/VI 
(N=xxx)
No. of subjects with one or more severe asthma exacerbation
xx (xx%)
xx (xx%)
                      
Total no. of severe asthma exacerbations
xx 
xx 
Number of severe asthma exacerbations per subject
  0
xx (xx%)
xx (xx%)
  1
xx (xx%)
xx (xx%)
  > 1
xx (xx%)
xx (xx%)
Duration of severe asthma exacerbation (days) [1]
  n 
xx
xx
  Mean
xx.x
xx.x
  SD
  x.xx
  x.xx
  Median
xx.x
xx.x
  Min.
xx
xx
  Max.
xx
xx
[1] Summary only includes exacerbations for which a date of resolution or death is provided.
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Example 
: EFF_T11
Protocol
: HZA116492
Page 2 of 2
Population
: Intent-to-Treat
Table 2.xx 
Summary of Severe On-Treatment Asthma Exacerbations
Usual ICS/LABA
(N=xxx)
FF/VI 
(N=xxx)
Outcome
  Resolved
xx (xx%)
xx (xx%)
  Fatal
xx (xx%)
xx (xx%)
  Not resolved
xx (xx%)
xx (xx%)
No. of exacerbations: 
  Requiring use of systemic/oral corticosteroids
xx (xx%)
xx (xx%)
  Leading to hospitalisation
xx (xx%)
xx (xx%)
  Requiring emergency room visit
xx (xx%)
xx (xx%)
No. of exacerbations requiring intubation
xx (xx%)
xx (xx%)
No. of exacerbations leading to withdrawal from study
xx (xx%)
xx (xx%)
[1] Summary only includes exacerbations for which a date of resolution or death is provided. 
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Example 
: EFF_T11S
Protocol
: HZA116492
Page 1 of 8
Population
: Intent-to-Treat
Table 2.xx 
Summary of Severe On-Treatment Asthma Exacerbations by Season
Season: Spring
Usual ICS/LABA
(N=xxx)
FF/VI 
(N=xxx)
No. of subjects with one or more severe asthma exacerbation
xx (xx%)
xx (xx%)
                      
Total no. of severe asthma exacerbations
xx 
xx 
Number of severe asthma exacerbations per subject
  0
xx (xx%)
xx (xx%)
  1
xx (xx%)
xx (xx%)
  > 1
xx (xx%)
xx (xx%)
Duration of severe asthma exacerbation (days) [1]
  n 
xx
xx
  Mean
xx.x
xx.x
  SD
  x.xx
  x.xx
  Median
xx.x
xx.x
  Min.
xx
xx
  Max.
xx
xx
Note: Spring = March, April and May; Summer = June, July and August; Autumn = September, October and November; Winter = December, January and February. 
[1] Summary only includes exacerbations for which a date of resolution or death is provided.
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Example 
: EFF_T11
Protocol
: HZA116492
Page 2 of 8
Population
: Intent-to-Treat
Table 2.xx 
Summary of Severe On-Treatment Asthma Exacerbations by Season
Season: Spring
Usual ICS/LABA
(N=xxx)
FF/VI 
(N=xxx)
Outcome
  Resolved
xx (xx%)
xx (xx%)
  Fatal
xx (xx%)
xx (xx%)
  Not resolved
xx (xx%)
xx (xx%)
No. of exacerbations: 
  Requiring use of systemic/oral corticosteroids
xx (xx%)
xx (xx%)
  Leading to hospitalisation
xx (xx%)
xx (xx%)
  Requiring emergency room visit
xx (xx%)
xx (xx%)
No. of exacerbations requiring intubation
xx (xx%)
xx (xx%)
No. of exacerbations leading to withdrawal from study
xx (xx%)
xx (xx%)
Note: Spring = March, April and May; Summer = June, July and August; Autumn = September, October and November; Winter = December, January and February. 
[1] Summary only includes exacerbations for which a date of resolution or death is provided. 
Programming note: repeat on subsequent pages for Season = Summer, Autumn, Winter.
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Example
: EFF_T12
Protocol 
: HZA116492                       
Page 1 of 1
Population 
: Intent-to-Treat
Table 2.xx
Summary of the Statistical Analysis of Severe On-Treatment Asthma Exacerbations
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
n
xxx
xxx
LS Mean Annual Rate
x.xx
x.xx
FF/VI vs. Usual ICS/LABA
  Ratio
x.xx
  95% CI
(x.xx, x.xx)
  p-value
x.xxx
  Percent Reduction
x.xx
  95% CI
(x.xx, x.xx)
Note: The analysis method was Generalised Linear Model assuming an underlying negative binomial distribution with a log-link function and logarithm of time on 
treatment as an offset variable and adjusted for randomised treatment, number of severe asthma exacerbations in the previous year prior to randomisation, gender, 
age and country.
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Example 
: EFF_T13
Protocol
: HZA116492
Page 1 of 1
Population
: Intent-to-Treat
Table 2.xx
Summary of the Statistical Analysis of Time to First Severe On-Treatment Asthma Exacerbation
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Number of subjects with event
xx (xx%)
xx (xx%)
Number of subjects censored
xx (xx%)
xx (xx%)
Probability of having event (%) [1]                      
xx.x 
xx.x 
  95% CI
(xx.x, xx.x)
(xx.x, xx.x)
FF/VI vs. Usual ICS/LABA
  Hazard Ratio [2] 
x.xx
  95% CI 
(xx.x, xx.x)
  p-value 
  x.xxx
[1] Kaplan-Meier estimates.
[2] Overall hazard ratios, CIs and p-values are from a Cox proportional hazards model with randomised treatment, gender, age and country as covariates.  A hazard 
ratio <1 indicates a lower risk with FF/VI compared with Usual ICS/LABA.
Note: At Day 168 all subjects who have not experienced a severe asthma exacerbation are considered censored, regardless of whether their on-treatment phase 
continues beyond Day 168.
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Example
: EFF_T14
Protocol
: HZA116492
Page 1 of 5
Population
: Intent-to-Treat
Table 2.xx
Summary of Percentage of Subjects Who Have an Increase from Baseline of >=0.5 in AQLQ(S) Total Score and Domain Scores
Domain: Total Score
[1] Responder is defined as an increase from baseline of >= 0.5.
Programming note: repeat on subsequent pages for Domain = Environmental Stimuli, Symptoms, Activity Limitations, Emotional Function.
Visit
Response
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Week 24
n
xxx
xxx
Responder [1]
xxx (xx%)
xxx (xx%)
Non-Responder
xxx (xx%)
xxx (xx%)
Early Withdrawal
n
xxx
xxx
Responder [1]
xxx (xx%)
xxx (xx%)
Non-Responder
xxx (xx%)
xxx (xx%)
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Example
: EFF_T15
Protocol
: HZA116492
Page 1 of 10
Population
: Intent-to-Treat
Table 2.xx
Summary of EQ-5D-5L Descriptive System Dimensions
Dimension: Mobility
Visit
  
                       
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Randomisation (Day 0)
n
xxx
xxx
I am not anxious or depressed
xxx (xx%)
xxx (xx%)
I am slightly anxious or depressed
xxx (xx%)
xxx (xx%)
I am moderately anxious or depressed
xxx (xx%)
xxx (xx%)
I am severely anxious or depressed
xxx (xx%)
xxx (xx%)
I am extremely anxious or depressed
xxx (xx%)
xxx (xx%)
Missing
xxx (xx%)
xxx (xx%)
Week 24
n
xxx
xxx
I am not anxious or depressed
xxx (xx%)
xxx (xx%)
I am slightly anxious or depressed
xxx (xx%)
xxx (xx%)
I am moderately anxious or depressed
xxx (xx%)
xxx (xx%)
I am severely anxious or depressed
xxx (xx%)
xxx (xx%)
I am extremely anxious or depressed
xxx (xx%)
xxx (xx%)
Missing
xxx (xx%)
xxx (xx%)
Programming note: repeat on subsequent pages for Visit = Early Withdrawal and for Dimension = Self-Care, Usual Activities, Pain/Discomfort, Anxiety/Depression.
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12.16.4.
Efficacy Figure Shells
Example 
: EFF_F1
Protocol
: HZA116492
Page 1 of 1
Population
: Intent-to-Treat
Figure 2.xx
Summary of ACT Total Score
Programming note: present “ACT Total Score” on y-axis and “Visit” on x-axis (Randomisation (Day 0), Week 6, Week 12, Week 18, Week 24). Present mean ACT 
Total Score ∀SD separately for treatment group (FF/VI, Usual ICS/LABA) at each visit, connecting the means with a solid line. Distinguish the treatment groups by 
different line types and colours.
Repeat for:
Summary of Change from Baseline in ACT Total Score Per Protocol Population (PP Population)
Summary of Change from Baseline in ACT Total Score by Country (ITT Population)
Country: France
Country: Germany
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Example 
: EFF_F2
Protocol
: HZA116492
Page 1 of 1
Population
: Intent-to-Treat
Figure 2.xx
Summary of Primary and Sensitivity Analyses for Change from Baseline in ACT Total Score at Week 12 (Visit 4)
Programming note: present “Treatment difference” on the x-axis, and reverse axis so treatment difference increases from left to right. Replace “Ratio (95% CI)” with 
“Treatment Difference (95% CI)”. Present lines for the following: Primary analysis (ITT), Primary analysis (PP), ANCOVA with LOCF (ITT), Multiple Imputation (Missing 
at Random) (ITT), Multiple Imputation (Copy Differences from Reference) (ITT), Hodges-Lehmann (ITT), ANCOVA with WOCF (ITT).
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Repeat for:
Summary of Key Secondary and Sensitivity Analyses for Change from Baseline in ACT Total Score at Week 24 (Visit 6)
Example 
: EFF_F3
Protocol
: HZA116492
Page 1 of 1
Population
: Intent-to-Treat
Figure 2.xx
Summary of Interaction Tests for Change from Baseline in ACT Total Score at Week 12 (Visit 4)
Programming note: present “LS Mean Change” on the x-axis, and reverse axis so it increases from left to right. Replace “Ratio (95% CI)” with “LS Mean Change (95% 
CI)”. Present the following subgroups: Country (France, Germany); Number of Severe Asthma Exacerbations in the Previous Year Prior to Randomisation (0, >= 1); 
Smoking Status at Baseline (Current smoker, Former smoker, Never smoked); Age Group (≤50 Years Old, > 50 Years Old); Gender (Male, Female).
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Example 
: EFF_F4
Protocol
: HZA116492
Page 1 of 1
Population
: Intent-to-Treat
Figure 2.xx
Histogram of Percentage of Subjects Who Have Either an ACT Total Score of >= 20 or >= 3 Point Increase from Baseline in ACT Total Score
Programming note: present “Percent of Subjects (%)” on y-axis and “Visit” on x-axis (Week 6, Week 12, Week 18, Week 24, Early Withdrawal). For each visit, present 
3 vertical bars distinguished by fill pattern (similar to non-standard EFF_F6). Each bar represents: “ACT Total Score >= 20 or >= 3 Point Increase from Baseline in ACT 
Total Score”, “ACT Total Score >= 20” and “>= 3 Point Increase from Baseline in ACT Total Score” respectively and should be labelled as such on the legend.
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Example 
: EFF_F5
Protocol
: HZA116492
Page 1 of 1
Population
: Intent-to-Treat
Figure 2.xx
Box Plot of Compliance with Study Medication
Programming Note: label y-axis title as “Compliance (%)”, maximum of y-axis may be > 100%.
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Example 
: EFF_F6
Protocol
: HZA116492
Page 1 of 8
Population
: Intent-to-Treat
Figure 2.xx
Histogram of the Questions and Answers of the MARS-A Questionnaire
Randomised Treatment: Usual ICS/LABA
Visit: Randomisation (Day 0)
Note: MARS-A = Medication Adherence Report Scale for Asthma.
Programming note: repeat on subsequent pages for Visit = Day 0 and repeated for Week 12, Week 24, and Early Withdrawal; and for Randomised Treatment = FF/VI.
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Repeat for:
Histogram of the Questions and Answers of the MARS-A Questionnaire by Status of Patient in Relation to the Reminder Sent to French Centres (ITT Population)
Status: Patients in France, all MARS-A assessments completed pre-reminder
Status: Patients in France, some MARS-A assessments completed pre-reminder, some post-reminder
Status: Patients in France, all MARS-A assessments completed post-reminder
Status: Patients in Germany
Add the following footnote: “Note: Due to an issue identified with the French translation of the MARS-A, a reminder was sent to centres in France instructing that the 
questionnaire refers to the patient’s preventer inhaler (i.e. their maintenance therapy prior to entering the study, and study medication while on-study).”
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Example 
: EFF_F7
Protocol
: HZA116492
Page 1 of 4
Population
: Intent-to-Treat
Figure 2.xx
Histogram of the Distribution of MARS-A Scores During the Study
Visit: Randomisation (Day 0)
Note: MARS-A = Medication Adherence Report Scale for Asthma.
Note: MARS-A 10-Score is based on the mean score across all ten questions.
Programming note: repeat on subsequent pages for Visit = Week 52 and Early Withdrawal.
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Repeat for:
Histogram of the Distribution of MARS-A Scores During the Study by Status of Patient in Relation to the Reminder Sent to French Centres (ITT Population)
Status: Patients in France, all MARS-A assessments completed pre-reminder
Status: Patients in France, some MARS-A assessments completed pre-reminder, some post-reminder
Status: Patients in France, all MARS-A assessments completed post-reminder
Status: Patients in Germany
Add the following footnote: “Note: Due to an issue identified with the French translation of the MARS-A, a reminder was sent to centres in France instructing that the 
questionnaire refers to the patient’s preventer inhaler (i.e. their maintenance therapy prior to entering the study, and study medication while on-study).”
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Example 
: EFF_F8
Protocol
: HZA116492
Page 1 of 1
Population
: Intent-to-Treat
Figure 2.xx
Box Plot of Severe On-Treatment Asthma Exacerbation Rates Adjusted for Exposure to Treatment
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Example 
: EFF_F9
Protocol
: HZA116492
Page 1 of 1
Population
: Intent-to-Treat
Figure 2.xx
Kaplan-Meier Plot of Time to First Severe On-Treatment Asthma Exacerbation
Programming note: display increments of 6 weeks on the x-axis, up to the maximum exposure (e.g. 0, 6, 12, 18, 24).
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12.16.5.
Safety Table Shells
Example 
: SAFE_T1
Protocol
: HZA116492
Page 1 of 1
Population
: Safety
Table 3.xx
On-Treatment Serious Adverse Events and Adverse Drug Reactions Overview
  
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Any on-treatment ADRs
xxx (xx%)
xxx (xx%)
Any on-treatment non serious ADRs
xxx (xx%)
xxx (xx%)
Any on-treatment serious ADRs
xxx (xx%)
xxx (xx%)
Any post-treatment serious ADRs
xxx (xx%)
xxx (xx%)
Any on-treatment SAEs
xxx (xx%)
xxx (xx%)
Any post-treatment SAEs
xxx (xx%)
xxx (xx%)
Any SAEs or ADRs leading to permanent discontinuation of 
study drug or withdrawal from study [1]
xxx (xx%)
xxx (xx%)
Any on-treatment fatal serious ADRs
xxx (xx%)
xxx (xx%)
Any on-treatment fatal SAEs
xxx (xx%)
xxx (xx%)
Any post-treatment fatal SAEs
xxx (xx%)
xxx (xx%)
[1] Includes both on-treatment and post-treatment SAEs and ADRs.
Programming note: Based on IDSL standard template AE13.
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Example 
: SAFE_T2
Protocol
: HZA116492
Page 1 of 1
Population
: Safety
Table 3.xx
Summary of On-Treatment Non-Serious Adverse Drug Reactions of Special Interest
Special Interest Group/
  Subgroup
     Preferred Term
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Adrenal suppression
  Any event
xxx (xx%)
xxx (xx%)
  Blood cortisol decreased
xxx (xx%)
xxx (xx%)
Cardiovascular effects
  Any event
xxx (xx%)
xxx (xx%)
  Cardiac Arrhytmia [1]
xxx (xx%)
xxx (xx%)
     Any event
xxx (xx%)
xxx (xx%)
     Palpitations 
xxx (xx%)
xxx (xx%)
     Extrasystoles
xxx (xx%)
xxx (xx%)
  Cardiac Ischaemia [1]
xxx (xx%)
xxx (xx%)
     Any event
xxx (xx%)
xxx (xx%)
     Angina pectoris
xxx (xx%)
xxx (xx%)
     Chest pain
xxx (xx%)
xxx (xx%)
Effects on potassium
  Any event
xxx (xx%)
xxx (xx%)
  XXXXXXX
xxx (xx%)
xxx (xx%)
  XXXXXXX
xxx (xx%)
xxx (xx%)
[1] This special interest group/subgroup was defined using Special MedDRA Queries.
Programming note: Based on IDSL standard template AE1.
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Repeat for:
Summary of On-Treatment Serious Adverse Drug Reactions of Special Interest (ITT Population)
Summary of On-Treatment Adverse Drug Reactions of Special Interest (ITT Population)
Summary of On-Treatment Serious Adverse Events of Special Interest (ITT Population)
Summary of On-Treatment Fatal Serious Adverse Events of Special Interest (ITT Population)
Summary of On-Treatment Non-Fatal Serious Adverse Events of Special Interest (ITT Population)
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Example
: SAFE_T3
Protocol
: HZA116492
Page 1 of n
Population
: Safety
Table 3.xx
Top Ten Most Commonly Reported On-Treatment Adverse Drug Reactions Per Treatment Group
Preferred Term
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
xxxxxxx
xxx (xx%)
xxx (xx%)
xxxxxxx
xxx (xx%)
xxx (xx%)
xxxxxxx
xxx (xx%)
xxx (xx%)
xxxxxxx
xxx (xx%)
xxx (xx%)
xxxxxxx
xxx (xx%)
xxx (xx%)
xxxxxxx
xxx (xx%)
xxx (xx%)
xxxxxxx
xxx (xx%)
xxx (xx%)
xxxxxxx
xxx (xx%)
xxx (xx%)
xxxxxxx
xxx (xx%)
xxx (xx%)
xxxxxxx
xxx (xx%)
xxx (xx%)
......
Programming note: Present the ten most frequent preferred terms in Usual ICS/LABA, and the ten most frequent in FF/VI (do not use percentages to determine “most 
frequent”).
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12.16.6.
Safety Figure Shells
Example 
: SAFE_F1
Protocol
: HZA116492
Page 1 
of 1
Population
: Intent-to-Treat/Safety
Figure 2.xx
Summary of Benefit:Risk for FF/VI vs. Usual ICS/LABA
* = Number of subjects with event
(a) Difference in LS mean change from baseline from an MMRM
(b) Difference in LS mean change from baseline from an ANCOVA model
(c) Adjusted odds ratio obtained from a logistic regression model
(d) Risk difference
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Programming note: present the following endpoints:
!
Benefits:
!
First panel, x-axis decreasing from left to right:
o
Difference in LS mean change from baseline and 95% CI for: change from baseline in 
ACT total score at Week 12 (Visit 4) and at Week 24 (Visit 6) (labeled (a)) 
o
Difference in LS mean change from baseline and 95% CI for change from baseline in 
trough (pre-dose) FEV1 at Week 12 (Visit 4) (labeled (b))
!
Second panel, x-axis increasing from left to right:
o
Adjusted odds ratio and 95% CI for: percentage of subjects with correct use of inhaler 
device at Week 12 (Visit 4) and at Week 24 (Visit 6) (labeled (c))
!
Risks:
!
Third panel, x-axis increasing from left to right:
o
Risk difference and 95% CI of the following SAEs of special interest: 
asthma/bronchospasm, cardiovascular effects, decreased bone mineral density and 
associated fractures, hypersensitivity, local steroid effects, lower respiratory tract infection 
(LRTI) excluding pneumonia, pneumonia, adrenal suppression, ocular effects, effects on 
glucose, effects on potassium, tremor (labeled (d))
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183
12.16.7.
Non-ICH Listing Shells
Example 
: POP_L1 
Protocol
: HZA116492
Page 1 of n
Population
: All Subjects Enrolled
Listing x
Subjects Screened but Not in the Intent-to-Treat Population
Randomised 
Treatment
Site Id./
Unique Subject Id.
Disposition Status
Reason for Screen Failure/Withdrawal
Screen Failure
xxxxxx
Screen Failure
Xxxxxxxxxxxxx
FF/VI 
xxxxxx
Early Withdrawal
Xxxxxxxxxxxxx
...
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184
Example
: POP_L2
Protocol
: HZA116492
Page 1 of n
Population
: Intent-to-Treat
Listing x
Reasons for Important Protocol Deviations
Randomised
Treatment
Site Id./
Unique 
Subject Id.
Important Protocol Deviation
Excluded
from PP?
Date of Deviation
Study Day of Deviation
FF/VI        
xxxxx
xxxxxxxxxxxx
No
DDMMMYYYY          
xx
xxxxx
xxxxxxxxxxxx
No
DDMMMYYYY          
xx
Usual ICS/LABA
xxxxx
xxxxxxxxxxxx
No
DDMMMYYYY
xx
xxxxx
xxxxxxxxxxxx
Yes
DDMMMYYYY          
xx
xxxxx
xxxxxxxxxxxx
No
DDMMMYYYY          
xx
xxxxx
xxxxxxxxxxxx
No
DDMMMYYYY          
xx
....
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185
Example 
: POP_L3   
      
Protocol
: HZA116492
Page 1 of n
Population
: Intent-to-Treat
Listing x
Asthma History
Number of asthma exacerbations in the last 12 months that:
Treatment
Site Id./
Unique 
Subject Id.
Asthma Duration
Did not require oral/systemic 
corticosteroids (not involving 
hospitalisation)
Required oral/systemic 
corticosteroids (not involving 
hospitalisation)
Required hospitalisation
xxxxxx
xxxxxx
xxxxxxxxxxxxx
xx
xx
xx
xxxxxx
xxxxxxxxxxxxx
xx
xx
xx
xxxxxx
xxxxxxxxxxxxx
xx
xx
xx
xxxxxx
xxxxxxxxxxxxx
xx
xx
xx
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186
Example 
: POP_L4
Protocol
: HZA116492
Page 1 of n
Population
: Intent-to-Treat
Listing x
Smoking History
Treatment
Site Id./
Unique 
Subject Id.
Smoking
Status
Years Smoked/
Cigarettes per day
Smoking 
Pack Years
xxxxxx
Xxxxxx/
xxxxxx
Current
xx/
xx
xx
Xxxxxx/
xxxxxx
Former
xx/
xx
xx
Xxxxxx/
xxxxxx
Never
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187
Example 
: POP_L5
Protocol
: HZA116492
Page 1 of n
Population
: Intent-to-Treat
Listing x
Exposure to Study Medication
Treatment: Usual ICS/LABA
Site Id./
Unique 
Subject Id.
Treatment Start Date/ 
Treatment End date
Start date of dose/
End date of dose/
Duration of dose (days)
Drug
Dose/ Dose 
Units/ Dose 
Frequency
Inhalers 
Dispensed/
Inhalers Returns
Dose counter start/
Dose counter stop
Compliance (%) 
During the study 
XXXX
DDMMMYYY/
DDMMMYYY
XX.XX
DDMMMYYYY/
DDMMMYYYY/
xx
XXXXXXX
XX/ XX/XXXX
X/X
XXX/XX
DDMMMYYYY/
DDMMMYYYY
xx
XXXXXXX
XX/ XX/XXXX
X/X
XXX/XX
XXXX
DDMMMYYY
XX.XX
DDMMMYYYY/
DDMMMYYYY/
xx
XXXXXXX 
XX/ XX/XXXX
X/X
XXX/XX
Programming note: Repeat on subsequent pages for Treatment = FF/VI, and use GSK drug synonym as drug name. 
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188
Example 
: EFF_L1
Protocol
: HZA116492                                                                              
Page 1 of n
Population
: Intent-to-Treat 
Listing x
ACT Scores
Treatment: Usual ICS/LABA
Site Id./
Unique 
Subject Id.
Visit/
Study Date/
Study Day
Impact at 
home or work 
[1]
Frequency of 
shortness of 
breath [1]
Frequency of 
sleep trouble 
[1]
Frequency of 
rescue 
medication [1]
Asthma control 
rating [1]
ACT Total 
Score [2] /
Change from 
Baseline
xxxxxx/
xxxxx
Randomisation 
(Day 0)/
DDMMMYYYY/
xx
x
x
x
x
x
xx 
Week 6/
DDMMMYYYY/
xx
x
x
x
x
x
xx / 
-x
Week 12/
DDMMMYYYY/
xx
x
x
x
x
x
xx / 
x
...
[1] Responses range between 1 (worst response) and 5 (best response).
[2] ACT Total Score ranges between 5 (worst asthma control state) and 25 (best asthma control state).
Programming note: Repeat on subsequent pages for Treatment = FF/VI.
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189
Example 
: EFF_L2
Protocol
: HZA116492
Page 1 of n
Population
: Intent-to-Treat 
Listing x
Inhaler Device Use
Treatment: Usual ICS/LABA
Critical errors
Non-critical errors
Site Id./
Unique 
Subject Id.
Visit/
Study Date/
Study Day
Inhaler
Any?
If yes, errors:
Any?
If yes, errors:
xxxxxx/
xxxxx
Randomisation (Day 0)/
DDMMMYYYY/
xx
Turbuhaler
No
No
Week 12/
DDMMMYYYY/
xx
Turbuhaler
No
Yes
Did not hold breath
Week 24/
DDMMMYYYY/
xx
Turbuhaler
Yes
Exhaled directly into mouthpiece
No
xxxxxx/
xxxxx
Randomisation (Day 0)/
DDMMMYYYY/
xx
Diskus
Yes
Did not hold device upright during dose 
preparation
Shook the device after dose 
preparation
Yes
No exhalation before an inhalation
Week 12/
DDMMMYYYY/
xx
Diskus
Yes
Shook the device after dose 
preparation
No
Programming note: Repeat on subsequent pages for Treatment = FF/VI.
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190
Example
: EFF_L3
Protocol
: HZA116492
Page 1 of n
Population
: Intent-to-Treat 
Listing x
Lung Function Tests
Treatment: Usual ICS/LABA
Trough (Pre-dose) FEV1 (L)
Trough (Pre-dose) Percent 
Predicted FEV1 (%)
Site Id./
Unique 
Subject Id.
Visit
Study Date/
Time
Study
Day
Absolute
Change from
Baseline
Predicted
normal FEV1 (L)
Absolute
Change from
Baseline
Bronchodilator 
taken in last 4 
hours?
xxxxxx/
xxxxx
Randomisation 
(Day 0)
DDMMMYYYY/
HH:MM
xx
x.xxx
x.xxx
xx.x
No
Week 6
DDMMMYYYY/ 
HH:MM
xx
x.xxx
x.xxx
x.xxx
xx.x
xx.x
No
xxxxxx/
xxxxx
Randomisation 
(Day 0)
DDMMMYYYY/
HH:MM
xx
x.xxx
x.xxx
x.xxx
xx.x
xx.x
No
Programming note: Repeat on subsequent pages for Treatment = FF/VI.
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191
Example 
: EFF_L4
Protocol
: HZA116492                                                                              
       Page 1 of n
Population
: Intent-to-Treat 
Listing x
Medication Adherence Report Scale for Asthma (MARS-A) Scores
Treatment: Usual ICS/LABA
Site Id./
Unique 
Subject Id.
Status [1]
Visit/
Study Date/
Study Day
Assessor Code
MARS-A Questions
Score [2]
xxxxxx/
xxxxx
During
Randomisation 
(Day 0)/
DDMMMYYYY/
xx
Subject/Other
I only use it when I need it
x
Only use it when I feel breathless
x
I decide to miss out a dose
x
I try to avoid using it
x
I forget to take it
x
I alter the dose
x
I stop taking it for a while
x
Reserve if treatment doesn't work
x
Before doing something
x
I take less than instructed
x
MARS-A 10-Score [3]
x.xx
Week 12/
DDMMMYYYY/
xx
Subject/Other
I only use it when I need it 
x
Only use it when I feel breathless  .....etc
x
[1] Due to an issue identified with the French translation of the MARS-A, a reminder was sent to centres in France instructing that the questionnaire refers to the 
patient’s preventer inhaler (i.e. their maintenance therapy prior to entering the study, and study medication while on-study. Status = Prior (patient in France who had 
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192
completed all MARS-A assessments prior to the reminder), During (patient in France who had completed at least one MARS-A assessment prior to the reminder but 
also completed at least one MARS-A assessment after the reminder), After (patient in France who had not completed any MARS-A assessments prior to the 
reminder), Germany (patient in Germany).
[2] Question scores range between 1 (always) and 5 (never).
[3] MARS-A 10-Score is based on the mean score across all ten questions.
Programming note: Repeat on subsequent pages for Treatment = FF/VI.
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193
Example 
: EFF_L5
Protocol
: HZA116492                                                                              
Page 1 of n
Population
: Intent-to-Treat 
Listing x
Severe Asthma Exacerbations
Treatment: Usual ICS/LABA
Site Id./
Unique 
Subject Id.
Date of Onset/
Study day/
Date of Resolution/
Study day
Resolution/
Withdrawn from Study?
Required use of 
systemic/oral 
corticosteroids?
Led to 
hospitalisation?
Required 
emergency 
room visit?
Required 
intubation?
Xxxxxx/
xxxxx
DDMMMYYYY/
xx/
DDMMMYYYY/
xx
Resolved/
N
Y
N
N
N
DDMMMYYYY/
xx/
DDMMMYYYY/
xx
Resolved/
N
N
N
Y
N
DDMMMYYYY/
xx/
DDMMMYYYY/
xx
Fatal/
Y
Y
Y
N
Y
Programming note: Repeat on subsequent pages for Treatment = FF/VI.
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194
Example 
: EFF_L6
Protocol
: HZA116492                                                                              
Page 1 of n
Population
: Intent-to-Treat 
Listing x
AQLQ(S) Scores
Treatment: Usual ICS/LABA
Site Id./
Unique 
Subject Id.
Visit/
Study Date/
Study Day
Symptoms [1]
Activity Limitations 
[1]
Emotional 
Function [1]
Environmental 
Stimuli [1]
AQLQ(S) Total 
Score [1] / 
Change from 
Baseline
xxxxxx/
xxxxx
Randomisation 
(Day 0)/
DDMMMYYYY/
xx
x.x
x.x
x.x
x.x
x.x
Week 24/
DDMMMYYYY/
xx
x.x
x.x
x.x
x.x
x.x /
x.x
...
[1] Scores range between 1 (lower quality of life) and 7 (higher quality of life) for AQLQ(S) total and domains.
Programming note: Repeat on subsequent pages for Treatment = FF/VI.
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195
Example 
: EFF_L7
Protocol
: HZA116492                                                                              
Page 1 of n
Population
: Intent-to-Treat 
Listing x
EQ-5D-5L Descriptive System Dimension Scores
Treatment: Usual ICS/LABA
Site Id./
Unique 
Subject Id.
Visit/
Study Date/
Study Day
Assessor Code
Subscale/
    Item
Level of Problem 
Score [1]
xxxxxx/
xxxxx
Randomisation 
(Day 0)
DDMMMYYYY/
xx
Subject/Other
EQ-5D-5L Utility 
Score
xx.xx
  Mobility
1
  Self-Care
1
  Usual Activities
1
  Pain/Discomfort 
1
  Anxiety/Depression
1
EQ-5D-5L VAS
xx.xx
Week 12
DDMMMYYYY/
xx
Subject/Other
EQ-5D-5L Utility 
Score
xx.xx
Mobility  .........etc
1
[1] Scores range between 0 (worst imaginable health state) and 1 (best imaginable health state) for EQ-5D-5L Utility Score and range between 0 (worst imaginable 
health state) and 100 (best imaginable health state) for EQ-5D-5L Visual Analogue Scale (VAS).
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Example 
: EFF_L8
Protocol
: HZA116492                                                                              
Page 1 of n
Population
: Intent-to-Treat 
Listing x
PASAP-Q Scores
Treatment: Usual ICS/LABA
Site Id./
Unique 
Subject Id.
Visit/
Study Date/
Study Day
Domain /
   Question
Response
Score [1]
xxxxxx/
xxxxx
Randomisation 
(Day 0)
DDMMMYYYY/
xx
Performance
xx.x
   Overall feeling of inhaling
x
   Inhaled dose goes to lungs
x
   Medication left
x
   Works reliably
x
   Ease of inhaling a dose
x
   Using the inhaler
x
   Speed medicine comes out
x
Convenience
xx.x
   Instructions for use
x
   Size of inhaler
x
   Durability of inhaler
x
   Ease of cleaning inhaler
x
   Ease of holding during use
x
   Convenience of carrying
x
Total Score
xx.x
Overall Satisfaction
x
Willingness to Continue Using Inhaler
xx.x
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[1] Performance, Convenience, Total Score, and Willingness to Continue Using Inhaler are expressed on a scale of 0 to 100. Overall Satisfaction is expressed on a 
scale of 1 to 7.
Programming note: Repeat on subsequent pages for Treatment = FF/VI.
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198
Example 
: SAFE_L1
Protocol
: HZA116492
Page 1 of n
Population
: Intent-to-Treat
Listing x
AE Terms of Special Interest
Special Interest Group
Subgroup
Preferred Term
xxxxx xxxxx xxxxxx
Xxxxxxx
xxxxxxx
xxxxxxx xxxxxxx
xxxx
xxxxxxx xxx
xxxxxxx xxxxxxxxxx
xxxxxxxxxxxxxxx [1]
xxxxxxx xxxxxx
xxxxxxx xxxx xxxxx xxxxx
xxxx
xxxxxxxxxxx
xxxxxxx [1]
xxxxxxx
xxxx xxxxxx xxxxxxx
xxxxxx xxxxxxx
xxxxxxxxx
xxxxx xxxxxx xxxxxxx xxxxxx
[1] This special interest group/subgroup was defined using Special MedDRA Queries.Note: All of the pre-specified preferred terms that were assigned to special 
interest terms are shown, regardless of whether they actually occurred in the study.
Programming Note: The AE special interest dataset and the AE SMQ dataset will be set together in order to report this table and all the subgroups that come from the 
AE SMQ dataset will be flagged with a [1].
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Example 
: SAFE_L2
Protocol
: HZA116492
Page 1 of n
Population
: Intent-to-Treat
Listing x
Inhaler Device Malfunctions
Treatment
Site Id./
Unique Subject Id.
Inhaler Device
Comment / Reason for Malfunction
Usual ICS/LABA
xxxxxx/
xxxxx
Turbuhaler
XXXXXXXXXXX
Usual ICS/LABA
xxxxxx/
xxxxx
Diskus
XXXXXXXXXXX
FF/VI
xxxxxx/
xxxxx
Ellipta
Powder fell out prior to use
Other: XXXXXXXX
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CONFIDENTIAL
The GlaxoSmithKline group of companies
HZA116492
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for A 6-month, open label, 
randomised, efficacy study to evaluate fluticasone furoate 
(FF, GW685698)/vilanterol (VI, GW642444) Inhalation 
Powder delivered once daily via the Dry Powder Inhaler 
Ellipta™ compared with usual ICS/LABA maintenance 
therapy delivered by Dry Powder Inhaler in subjects with 
Persistent Asthma
Compound Number 
:
GW685698+GW642444
Effective Date 
:
05-DEC-2016
Description :
The purpose of this document is to describe the final planned analyses and output to be 
included in the Clinical Study Report for Protocol HZA116492.
This RAP is intended to describe the planned efficacy and safety analyses required for the 
study.
This RAP will be provided to the study team members to convey the content of the final 
Statistical Analysis Complete (SAC) deliverable.
Author’s Name and Functional Area: 
05-DEC-2016
Principal Statistician (Clinical Statistics)
Approved by: 
05-DEC-2016
Director, Statistics & Programming (Clinical Statistics)
Copyright 2016 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
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HZA116492
2
TABLE OF CONTENTS
PAGE
1.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................8
1.1.
Changes to the Protocol Defined Statistical Analysis Plan............................8
1.2.
Study Objectives and Endpoints .................................................................11
1.3.
Statistical Hypotheses.................................................................................15
1.4.
Sample Size Assumptions ..........................................................................15
2.
PLANNED ANALYSES ..........................................................................................17
2.1.
Interim Analyses .........................................................................................17
2.2.
Data Look ...................................................................................................17
2.3.
Final Analyses ............................................................................................17
3.
ANALYSIS POPULATIONS ...................................................................................18
3.1.
Protocol Deviations.....................................................................................19
4.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................20
5.
STUDY POPULATION ANALYSES .......................................................................21
5.1.
Overview of Planned Analyses ...................................................................21
6.
PRIMARY STATISTICAL ANALYSES....................................................................22
6.1.
Efficacy Analyses........................................................................................22
6.1.1.
Overview of Planned Efficacy Analyses .......................................22
6.1.2.
Planned Efficacy Statistical Analyses...........................................23
7.
SECONDARY STATISTICAL ANALYSES .............................................................26
7.1.
Efficacy Analyses........................................................................................26
7.1.1.
Overview of Planned Efficacy Analyses .......................................26
7.1.2.
Planned Efficacy Statistical Analyses...........................................27
7.2.
Safety Analyses..........................................................................................29
7.2.1.
Overview of Planned Analyses ....................................................29
7.2.2.
Benefit:Risk analyses...................................................................30
8.
OTHER STATISTICAL ANALYSES .......................................................................32
8.1.
Other Analyses ...........................................................................................32
8.1.1.
Overview of Planned Other Analyses...........................................32
8.1.2.
Planned Other Statistical Analyses ..............................................34
9.
REFERENCES.......................................................................................................37
10. APPENDICES........................................................................................................38
10.1.
Appendix 1: Protocol Deviation Management and Definitions for PP 
Population...................................................................................................39
10.1.1.
Protocol Deviations......................................................................39
10.1.2.
Exclusions from PP Population....................................................39
10.2.
Appendix 2: Time & Events.........................................................................41
10.2.1.
Protocol Defined Time & Events ..................................................41
10.3.
Appendix 3: Assessment Windows .............................................................43
10.4.
Appendix 4: Treatment States and Phases.................................................44
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10.4.1.
Treatment Phases .......................................................................44
10.4.2.
Treatment States .........................................................................44
10.4.2.1.
Treatment States for Concomitant Medications ..........44
10.4.2.2.
Treatment States for Efficacy Measurements .............45
10.4.2.3.
Treatment States for Exacerbation Data.....................45
10.4.2.4.
Treatment States for AE Data.....................................45
10.5.
Appendix 5: Data Display Standards & Handling Conventions....................46
10.5.1.
Study Treatment & Sub-group Display Descriptors......................46
10.5.2.
Baseline Definition & Derivations .................................................46
10.5.2.1.
Baseline Definitions....................................................46
10.5.2.2.
Derivations and Handling of Missing Baseline 
Data ...........................................................................46
10.5.3.
Reporting Process & Standards...................................................46
10.6.
Appendix 6: Derived and Transformed Data ...............................................48
10.6.1.
General........................................................................................48
10.6.2.
Study Population..........................................................................48
10.6.3.
Efficacy........................................................................................49
10.6.4.
Safety ..........................................................................................55
10.7.
Appendix 7: Premature Withdrawals & Handling of Missing Data ...............57
10.7.1.
Premature Withdrawals................................................................57
10.7.2.
Handling of Missing Data.............................................................57
10.7.2.1.
Handling of Missing or Partial Dates...........................57
10.7.2.2.
Handling of Missing Data for Statistical 
Analysis......................................................................58
10.8.
Appendix 8: Values of Potential Clinical Importance ...................................59
10.8.1.
Vital Signs....................................................................................59
10.9.
Appendix 9: Multicenter Studies..................................................................60
10.9.1.
Methods for Handling Centres .....................................................60
10.10. Appendix 10: Examination of Covariates, Subgroups & Other Strata..........61
10.10.1. Examination of Strata and Covariates..........................................61
10.10.2. Examination of subgroups ...........................................................61
10.10.3. Examination of seasonal effect ....................................................62
10.11. Appendix 11: Multiple Comparisons & Multiplicity .......................................63
10.11.1. Handling of Multiple Comparisons & Multiplicity...........................63
10.12. Appendix 12: Model Checking and Diagnostics for Statistical 
Analyses.....................................................................................................64
10.12.1. Statistical Analysis Assumptions..................................................64
10.13. Appendix 13: Blinding Strategy...................................................................66
10.14. Appendix 14: Abbreviations & Trade Marks ................................................68
10.14.1. Abbreviations...............................................................................68
10.14.2. Trademarks .................................................................................69
10.15. Appendix 15: List of Data Displays..............................................................70
10.15.1. Data Display Numbering..............................................................70
10.15.2. Mock Example Shell Referencing ................................................70
10.15.3. Deliverable [Priority].....................................................................70
10.15.4. Study Population Tables..............................................................71
10.15.5. Study Population Figures.............................................................75
10.15.6. Efficacy Tables ............................................................................76
10.15.7. Efficacy Figures ...........................................................................94
10.15.8. Safety Tables...............................................................................98
10.15.9. Safety Figures ...........................................................................101
10.15.10.ICH Listings ...............................................................................102
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10.15.11.Non-ICH Listings........................................................................103
10.16. Appendix 16: Example Mock Shells for Data Displays ..............................105
10.16.1. Study Population Table Shells ...................................................105
10.16.2. Study Population Figure Shells..................................................121
10.16.3. Efficacy Table Shells .................................................................122
10.16.4. Efficacy Figure Shells ................................................................170
10.16.5. Safety Table Shells....................................................................181
10.16.6. Safety Figure Shells...................................................................185
10.16.7. Non-ICH Listing Shells...............................................................187
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HZA116492
5
REPORTING & ANALYSIS PLAN SYNPOSIS
Overview
Key Elements of the RAP
Purpose
This RAP details all planned analyses and output required for the final Clinical Study Report 
of study HZA116492.
Protocol
This RAP is based on the protocol amendment 02 (Dated: 28-APR-2016) of study 
HZA116492 (GSK Document No.: 2014N190259_02).
Primary 
Objective 
To compare the efficacy of fluticasone furoate (FF)/vilanterol(VI) 92 mcg/22 mcg or FF 184
mcg/22 mcg with usual fixed combinations inhaled corticosteroid / long-acting beta agonist 
(ICS/LABA) for asthma maintenance therapy at Week 12 (Visit 4).
Primary 
Endpoint
Change from baseline in the Asthma Control Test (ACT) total score at Week 12 (Visit 4).
Study 
Design
This is a Phase IIIb multi-center randomised open label, parallel group study performed in 
subjects in primary and in respiratory specialist care / research sites who have a diagnosis 
of asthma and a regular treatment for asthma. Subjects with unsatisfactorily controlled 
asthma (defined as an ACT < 20) and intended to be treated by usual ICS/LABA 
maintenance therapy to seek a better control of their asthma will be randomised to receive 
either FF/VI (FF/VI 92 mcg/22 mcg or FF/VI 184 mcg/22 mcg) once daily or another usual 
ICS/LABA combination therapy in inhalation powder twice daily (fluticasone 
propionate[FP]/salmeterol [S] or budesonide[BUD]/formoterol [F]) decided by the physician. 
Physicians will be allowed during the treatment period to adapt prescription to different 
doses if necessary as well as to adapt doses of any comparative treatment according to 
products label.
Planned 
Analyses
No interim analysis is planned for this study.
All decisions regarding final analysis for the reporting effort, as defined in this RAP 
document, will be made prior to Database Freeze (DBF) (unblinding) of the study data.
All planned analyses will be carried out once DBF has taken place. Once this has been 
achieved, unblinding will occur and the analyses will be performed.
The open-label study design and the method of recording study medication data in the 
datasets means that extra steps must be taken to ensure that Statistics and Programming 
(S&P) remain blinded to study investigator prescribing of study medication until the formal 
unblinding takes place at DBF. See Section 10.13 for more details. 
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Overview
Key Elements of the RAP
Analysis 
Populations
All Subjects Enrolled (ASE) population: All subjects screened (provided consent) and for 
whom a record exists on the study database. Note, this population is not identified in the 
protocol, but is needed for displays that include subjects screened but not in the intent-to-
treat (ITT) population (e.g. tabulation of reasons for withdrawal before randomisation).
Intent-to-treat (ITT) population: All randomized subjects having received at least one dose 
of the prescription of study medication (either FF/VI or usual ICS/LABA asthma maintenance 
therapy). The ITT population will be used to analyze the primary efficacy endpoint analysis, 
the secondary efficacy endpoint and other efficacy endpoints. Subjects will be assigned to 
the treatment group as randomized for the ITT population. 
Per protocol (PP) population: all ITT subjects without any protocol deviations specifically 
defined in this RAP. Protocol deviations will be reviewed and will be classified as important 
or not important during data review meetings that will be held before DBF. Deviations 
classified as important will be further defined according to whether they require the patient to 
be excluded from the PP population. Deviations that exclude a patient from the PP 
population are defined in this RAP (see Section 10.1.2). Subjects will be assigned to the 
treatment group as treated for the PP population.
Safety population: All enrolled subjects having received at least one dose of the 
prescription of study medication (either FF/VI or usual ICS/LABA asthma maintenance 
therapy) and considered as-treated. The Safety population will be the basis for safety 
analyses. Subjects will be assigned to the treatment group as treated for the Safety 
population.
Hypothesis
The primary analysis is designed to determine whether the fixed combination FF/VI is non-
inferior to any other ICS/LABA combinations in inhalation powder assuming a non-inferiority 
margin of 1.5. Non-inferiority will be claimed if the 95% two-sided confidence interval (CI) on 
the difference in mean primary efficacy endpoints (FF/VI versus ICS/LABA comparator) 
precludes the non-inferiority margin of -1.5. 
If (and only if) non-inferiority is significantly achieved at Week 12 (Visit 4) with regard to the 
primary endpoint, then non-inferiority of the fixed combination FF/VI to any other ICS/LABA 
combinations will be tested at Week 24 (Visit 6) considering the same non-inferiority margin 
of 1.5. Non-inferiority will be claimed if the 95% two-sided CI on the difference in mean 
primary efficacy endpoints (FF/VI versus ICS/LABA comparator) at Week 24 (Visit 6) 
precludes the non-inferiority margin of -1.5. This step-down testing procedure strongly 
controls the overall type I error of the non-inferiority endpoints at the 0.05 two-sided level. 
Primary 
Analyses
The primary endpoint will be analysed using a mixed model repeated measures (MMRM) 
approach. The model will include factors and covariates as follows: randomised treatment, 
scheduled visit time point (Week 6 and Week 12), baseline ACT total score, randomised 
treatment-by-visit interaction, baseline ACT total score-by-visit interaction, gender, age, 
country and patient will be fitted as a random factor. The Restricted Maximum Likelihood 
(REML) estimation approach will be used, and the default covariance structure will be 
unstructured.  Consistent with MMRM model fitting, no explicit imputation of missing 
assessments for a given time point will be performed. The adjusted means for each 
treatment and the estimated treatment differences for the treatment comparisons will be 
presented together with the 95% CIs for the differences (FF/VI versus ICS/LABA 
comparator) and p-values at Week 12 (Visit 4).
If non-inferiority is statistically achieved at Week 12 (Visit 4), then superiority of FF/VI to any 
other comparator will be tested at the usual 0.05 two-sided nominal level of significance.
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Overview
Key Elements of the RAP
The same models and analyses mentioned above will be used to assess the superiority 
hypothesis. 
Secondary 
Analyses
Key secondary analysis
The key secondary endpoint assessed at Week 24 (Visit 6) will also be analyzed using a 
MMRM approach where data up to and including Week 24 (Visit 6) will be used in the model.  
The model will include factors and covariates as follows: randomised treatment, scheduled 
visit time point (Week 6, Week 12, Week 18 and Week 24), baseline ACT total score, 
randomised treatment-by-visit interaction, baseline ACT total score-by-visit interaction, 
gender, age, country and patient will be fitted as a random factor. The REML estimation 
approach will be used, and the default covariance structure will be unstructured.  Consistent 
with MMRM model fitting, no explicit imputation of missing assessments for a given time 
point will be performed. The adjusted means for each treatment and the estimated treatment 
difference for the treatment comparison will be presented together with the 95% CI for the 
difference (FF/VI versus ICS/LABA comparator) and p-value at Week 24 (Visit 6). If non-
inferiority is statistically achieved at Week 24 (Visit 6), then superiority of FF/VI versus any 
other comparator will be tested at the usual 0.05 two-sided nominal level of significance.
The same models and analyses mentioned above will be used to assess the superiority 
hypothesis. 
Other secondary analyses
The other key secondary endpoint will be the correct use of the inhaler device assessed at 
randomisation (Visit 2), at Week 12 (Visit 4) and at Week 24 (Visit 6). The device will be 
considered as correctly used if the patient didn’t make any critical or non-critical errors at the 
corresponding visits (randomisation [Visit 2], Week 12 [Visit 4] and Week 24 [Visit 6]). 
Percentages of subjects correctly using the device will be calculated within each group. A 
corresponding 95% CI of the difference in percentages will also be provided.
An exploratory analysis of the categorised data will be performed using logistic regression 
models with covariates as follows: randomised treatment, correct use of inhaler device at 
baseline, randomised treatment-by-visit interaction, gender, age and country. The estimated
treatment differences will be displayed as odds ratios together with 95% CIs and p-values.
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1.
SUMMARY OF KEY PROTOCOL INFORMATION
1.1.
Changes to the Protocol Defined Statistical Analysis Plan
Any changes from the originally planned statistical analysis specified in the protocol are outlined 
in Table 1.
Table 1
Changes to Protocol Defined Analysis Plan
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes
!
N/A
!
The open-label study 
design and the method of 
recording study medication 
data in the datasets means 
that extra steps must be 
taken to ensure that S&P 
remain blinded to study 
investigator prescribing of 
study medication until the 
formal unblinding takes 
place at DBF. See Section 
10.13 for more details.
!
To preserve the integrity of 
the analyses, S&P will 
remain blinded prior to 
formal unblinding at DBF. 
All planned analyses will be 
carried out after this point.
!
N/A
!
All Subjects Enrolled 
(ASE) Population: All 
subjects screened (provided 
consent) and for whom a 
record exists on the study 
database. Note, this 
population is not identified 
in the protocol, but is 
needed for displays that 
include subjects screened 
but not in the ITT 
Population (e.g. tabulation 
of reasons for withdrawal 
before randomisation).
!
Population needed for 
displays that include 
subjects screened but not in 
the ITT population.
!
Continuous variables will be 
summarized using descriptive 
statistics (number of observed 
and missing data, mean, 
standard deviation (SD), median, 
Q1, Q3, minimum, and
maximum).
!
Categorical variables will be 
summarized as numbers of 
observed and missing data,
counts and percentage for each 
category (reported to the number 
of non-missing values). For 
binary variables, 95% confidence 
!
See Appendix 16: 
Example Mock Shells for 
Data Displays for example 
mock shells for data 
displays
!
Continuous and categorical 
variables will be 
summarized in line with 
GSK Integrated Data 
Standards Library (IDSL)
data standards
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Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes
intervals for proportions will be 
estimated based on the Clopper-
Pearson method.
!
If treatment is withdrawn, then 
the missing ACT score at the 
nearest visit after treatment 
withdrawal will be replaced by 
the ACT score assessed at 
withdrawal time. If no ACT score 
is assess at withdrawal time, 
then the ACT missing score at 
the nearest visit after treatment 
withdrawal will not be replaced.
!
Consistent with MMRM 
model fitting, no explicit 
imputation of missing 
assessments for a given 
time point will be performed.
!
The protocol inconsistently 
describes whether or not 
missing scores will be 
imputed. Consistent with 
MMRM models and the 
MAR assumption they are 
based upon, no missing 
data will be imputed for the 
primary efficacy analysis. 
Sensitivity analyses for the
primary endpoint are 
proposed in Section 6.1.2
and will consider imputation 
of missing data.
!
The primary endpoint will be 
analysed using a mixed model 
repeated measures (MMRM) 
approach. The model will include 
factors and covariates as 
follows: treatment, scheduled 
visit time point (Week 6 and 
Week 12), baseline ACT, 
treatment by visit interaction, 
baseline ACT by visit interaction, 
gender, age and patient will be 
fitted as a random factor.
!
The primary endpoint will be 
analysed using a MMRM 
approach. The model will 
include factors and 
covariates as follows: 
randomised treatment, 
scheduled visit time point 
(Week 6 and Week 12), 
baseline ACT total score, 
randomised treatment-by-
visit interaction, baseline 
ACT total score-by-visit 
interaction, gender, age, 
country and patient will be 
fitted as a random factor.
!
Clarified that randomised
treatment and baseline ACT 
total score will be included. 
Additionally country will be 
included in the model due to 
the addition of Germany, 
and separate randomisation 
schedules for France and 
Germany achieving 
stratification by country
!
Same changes for 
secondary and other 
analyses
!
Sensitivity analyses (for the 
primary endpoint)
!
Text changed and clarified
!
The text from the protocol 
regarding sensitivity 
analyses has been updated 
and clarified where 
necessary. Description of 
the multiple imputation (MI) 
process has been brought 
in line with GSK standard 
text.
!
Usual ICS/LABA maintenance 
therapy
!
Usual ICS/LABA
!
The comparator arm is 
described as “Usual 
ICS/LABA” for consistency 
with reporting of the 
HZA115150 study (GSK 
Document No.:
2011N129785_02).
!
EQ-5D
!
EQ-5D-5L
!
Clarity as to which version 
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Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes
of the EuroQol 
questionnaire is being used
!
Binary response defined as an 
ACT score ≥ 20 at a given visit 
OR a 3 point increase from 
baseline in ACT change.
!
The responder analyses will be 
conducted using a logistic 
regression model at a given Visit 
or Phone Call adjusting for 
treatment and stratification 
factors (baseline ACT score 
categorized into two classes, 
baseline asthma therapy, and 
potentially season at
randomization). Treatment by 
stratification factors interaction 
effects will be further
investigated in additional logistic 
models adjusting for these 
specific effects.
!
This endpoint will be 
analysed using a logistic 
regression model adjusting 
for randomised treatment, 
gender, country, baseline 
ACT total score, baseline 
ACT total score squared 
and age
!
Clarified that randomised
treatment will be included. 
!
Country will be included in 
the model due to the 
addition of Germany, and 
separate randomisation 
schedules for France and 
Germany achieving 
stratification by country
!
Due to this being a 
composite endpoint, a 
quadratic relationship is 
expected between baseline 
score and probability of 
response. Baseline ACT 
total score and baseline 
ACT total score squared will 
be included (instead of 
“baseline ACT score 
categorised into two 
classes”) to account for this
!
All patients are on the same 
baseline asthma therapy 
class (ICS), therefore this 
will not be included as a 
covariate
!
Season at randomisation 
will not be included; this is 
only considered as 
sensitivity analysis for the 
primary efficacy endpoint
!
N/A
!
≥ 3 point increase from 
baseline in ACT total score 
at Week 12 (Visit 4) and 
Week 24 (Visit 6)
!
Time to first severe asthma 
exacerbation
!
These endpoints have been 
added for consistency with 
the HZA115150 study (GSK 
Document No.: 
2011N129785_02).
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1.2.
Study Objectives and Endpoints
Objectives
Endpoints
Primary Objective
Primary Endpoint
!
To compare the efficacy of FF/VI 92 mcg/ 22
mcg or FF 184 mcg/22 mcg with usual fixed 
combinations ICS/LABA for asthma 
maintenance therapy at Week 12 (Visit 4).
!
Change from baseline in the ACT total score at 
Week 12 (Visit 4).
Secondary Objectives
Secondary Endpoints
!
To assess effect of FF/VI on asthma control 
compared with usual ICS/LABA fixed 
combination at Week 24 (Visit 6).
!
Change from baseline in ACT score at Week 24 
(Visit 6).
!
To assess Ellipta™ inhaler correct use 
compared with other dry powder inhaler (DPI)
(Diskus™ and Turbuhaler) at Week 12 (Visit 
4) and at Week 24 (Visit 6) independently of 
the use at Week 12 (Visit 4).
!
Percentage of subjects with correct use of device 
(defined as not making any critical error or non-
critical error) at Week 12 (Visit 4) and at Week 24 
(Visit 6) independently of the use at Week 12 (Visit 
4).
Other Objectives
Other Endpoints
!
To assess effect of FF/VI on trough (pre-
dose) forced expiratory volume in 1 second 
(FEV1) compared with usual ICS/LABA fixed 
combination at Week 12 (Visit 4)
!
Change from baseline in trough (pre-dose) FEV1 
at Week 12 (Visit 4).
!
To assess the effect of FF/VI on response to 
treatment at Week 12 (Visit 4) and Week 24 
(Visit 6)
!
ACT score ≥ 20 or ≥ 3 point increase from 
baseline in ACT at Week 12 (Visit 4) and Week 24 
(Visit 6). Note: A 3 point increase in ACT total 
score was suggested as the Minimal Clinically 
Important Difference (MCID) in the literature 
(Schatz, 2009).
!
ACT score ≥ 20 at Week 12 (Visit 4) and Week 24 
(Visit 6). 
!
≥ 3 Point Increase from Baseline in ACT Total 
Score at Week 12 (Visit 4) and Week 24 (Visit 6)
!
Change from baseline in individual question 
scores for ACT at Weeks 12, 24
!
To assess the compliance with study 
medication and self-reported adherence to 
study medication at Week 12 (Visit 4) and 
Week 24 (Visit 6)
!
Compliance 
with 
study 
medication 
from 
randomisation (Day 0) to Week 12 (Visit 4), from 
Week 12 (Visit 4) to Week 24 (Visit 6) and from 
randomisation (Day 0) to Week 24 (Visit 6).
!
Score of the Medication Adherence Report Scale 
for 
Asthma 
(MARS-A) 
questionnaire 
at 
randomisation (Day 0), Week 12 (Visit 4) and 
Week 24 (Visit 6).
!
To assess the effect of FF/VI on severe 
asthma exacerbation over the study period
!
Number of subject with at least 1 severe asthma 
exacerbation*, number of severe asthma 
exacerbation and annual severe exacerbation rate 
over the study period.
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Objectives
Endpoints
!
Time to first severe asthma exacerbation
!
To assess the effect of FF/VI on Health 
Related Quality of Life at Week 24 (Visit 6)
!
Change from baseline in total score and domain 
scores of standardised Asthma Quality of Life 
Questionnaire (AQLQ[S]) at Week 24 (Visit 6).
!
An increase from baseline of ≥ 0.5 in AQLQ(s) 
total score at Week 24 (Visit 6).
!
An increase from baseline of ≥ 0.5 in AQLQ(s) 
environmental stimuli domain score at Week 24 
(Visit 6).
!
Percentage of subjects who have an increase from 
baseline of ≥ 0.5 in AQLQ(S) individual domain 
scores at Week 24 (Visit 6).
!
Change from baseline in total score and domain 
scores of AQLQ(S) at Week 24 (Visit 6). 
!
Health status using the EuroQol Questionnaire 
(EQ-5D-5L) at Week 24 (Visit 6).
!
To assess Patient Satisfaction and 
Preference assessment with different 
inhalers at Week 12 (Visit 4)
!
Score of Patient Satisfaction and Preference  
Questionnaire (PASAP-Q) at Week 12 (Visit 4).
!
To evaluate the Safety of FF/VI compared 
with usual ICS/LABA (FP/S and BUD/F).
!
Serious Adverse Events (SAE) and non-serious 
Adverse Drug Reactions (ADR):
o
Frequency and type of SAEs,
o
Frequency and type of non-serious ADRs 
related to treatment.
* A severe asthma exacerbation will be defined as deterioration of asthma requiring the use of systemic 
corticosteroids2 (tablets, suspension, or injection) for at least 3 days or an inpatient hospitalisation, or 
emergency department visit due to asthma that required systemic corticosteroids 1,2,3.
Notes defining endpoints:
1. Contacts with a doctor or hospitalisation are defined as exacerbation-related contacts if these contacts 
were a direct result of an acute worsening of asthma symptoms.
2. A prescription of systemic corticosteroid is defined as exacerbation-related if the reason the drug was 
given, in whole or in part, was to treat an acute worsening of asthma symptoms.
3. Exacerbation-related hospitalisation includes hospitalisation that is prolonged as a result of an asthma 
exacerbation.
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Overview of Study Design and Key Features
HZA 116492: study design 
V2
Day 0
Randomisation
V1
Day-7-1
Screening
ACT , MARS-A, 
AQLQ, EQ-5D, 
Spirometry
Asthma treated with
ICS (MDI, DPI), n=422
Relvar 92/22 or 184/22 μg
ICS/LABA DPI on the market
Seretide®, Symbicort®
1-7 days
R
6 months
ACT < 20
V2, errors ass-t:
• Read,
•Demonstration by HCP,
•1 dose,
•Errors asst & correction
V4
Week 12
V6
Week 24
Possibility to combine 
V1+V2= Day 0
V3
Phone call 1
Week 6
V5
Phone call 2 
Week 18
V4, errors ass-t:
•1 dose,
•Errors asst
•Demonstration by 
HCP if critical errors
V6, errors ass-t:
•1 dose,
•Errors asst
•Demonstration by 
HCP if critical errors
ACT, safety
ACT, safety
ACT , MARS-A, 
PASAP, 
Spirometry
ACT , MARS-A, 
AQLQ, EQ-5D
!
A phone call is provided at Week 6 and Week 18 in order to check whether the subject has 
experienced any AEs and then the Investigator calling the patient must determine whether the 
event is related to study medication (either arm) and whether the event is serious. At these 
telephone calls subjects will also be asked to complete the ACT questionnaire and to send it back 
to the Investigator.
!
Week 12 (Visit 4) should be scheduled at the same time of day as the randomisation visit (Visit 2).
Design 
Features
!
This is a Phase IIIb multi-center randomised open label, parallel group study 
performed in subjects in primary and respiratory specialist care / research sites who 
have a diagnosis of asthma and a regular treatment for asthma.
!
Subjects with unsatisfactorily controlled asthma (defined as ACT total score < 20) and 
intended to be treated by usual ICS/LABA maintenance therapy to seek a better 
control of their asthma will be randomised to receive either FF/VI once daily or another 
usual ICS/LABA combination therapy in inhalation powder twice daily (FP/S or BUD/F) 
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Overview of Study Design and Key Features
decided by the physician.
Treatment 
Assignment
Subjects will be assigned to study treatment in accordance with the randomisation 
schedule.
Subjects will be randomised in a 1:1 ratio to one of the 2 following treatment groups: 
FF/VI (as per dose guidance below) 
Initiate on usual inhaled dry powder ICS/LABA fixed combination for asthma 
maintenance therapy (i.e. Seretide Diskus™or SymbicortTurbuhaler) according to 
usual physician’s prescription. 
Dose Guidance:
For subjects randomised to FF/VI, Investigator can make dosing decision based on the 
guidance below:
!
FF/VI 92 mcg/22mcg dose once a day is approximately equivalent to FP/S medium 
dose (250 mcg/50mcg) and BUD/F medium dose (200 mcg/6 mcg) twice a day. See 
Table 2 for further guidance for doses conversion for other corticosteroids.
!
FF/VI 184 mcg/22 mcg dose once a day is approximately equivalent to FP/S high 
dose (500 mcg/50 mcg) and to BUD/F high dose (400 mcg/12 mcg) twice a day. See 
Table 2 for guidance for dose conversion for other corticosteroids.
!
Starting doses are: 92 mcg/22 mcg once daily for FF/VI; 250 mcg/50 mcg twice daily 
for FP/S and 200 mcg/6 mcg twice daily for BUD/F.
Table 2
ICS/LABA Daily Dose (SmPC Seretide Diskus™; Symbicort 
Turbuhaler)
Formulation
Inhaler Devices
Doses Available (mcg)  
ICS/LABA and 
Inhalations/day 
Fluticasone propionate/salmeterol
DPI (Diskus)
1 inhalation x 2
Medium-dose 250/50
High-dose 500/50
Budesonide/formoterol
DPI (Turbuhaler)
1-2  inhalations  x 2
Medium-dose 200/6 
High-dose 400/12 
Information extracted from Global Initiative for Asthma (GINA, 2012).
For patients with moderate to severe hepatic impairment, the 92/22 micrograms dose of 
FF/VI should be used and patients should be monitored for systemic corticosteroid-related 
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Overview of Study Design and Key Features
adverse reactions.
Planned Dose Adjustments
Subjects randomised to the usual ICS/LABA asthma maintenance therapy arm can have 
their treatment adjusted as would be normal clinical practice at the Investigator’s 
discretion. This will not require the subject to be withdrawn from the study. These subjects 
should not receive FF/VI, if the medication is marketed during the study period.
Subjects randomized to the FF/VI arm and for whom it is considered appropriate/ 
necessary to adjust treatment, can have their regimen changed as required as per normal 
clinical practice at any point in the study and the subject could remain in the study. 
Subjects on FF/VI arm can also change between the two FF/VI doses as appropriate and 
at the Investigator’s discretion.
Interim 
Analysis
No interim analysis is planned for this study.
From this point onwards in the RAP, usual ICS/LABA maintenance therapy will be referred to as 
usual ICS/LABA.
1.3.
Statistical Hypotheses
The primary endpoint is defined as the change from baseline in the ACT total score assessed at 
Week 12 (Visit 4). The primary analysis will assess the non-inferiority of fixed combination 
FF/VI to usual ICS/LABA in inhalation powder assuming a non-inferiority margin of 1.5. Non-
inferiority will be claimed if the 95% two-sided confidence interval on the difference in mean 
primary efficacy endpoints (FF/VI versus usual ICS/LABA) precludes the non-inferiority margin 
of -1.5. 
If (and only if) non-inferiority is significantly achieved at Week 12 (Visit 4) with regard to the 
primary endpoint, then non-inferiority of the fixed combination FF/VI to usual ICS/LABA will be 
tested at Week 24 (Visit 6) considering the same non-inferiority margin of 1.5. Non-inferiority 
will be claimed if the 95% two-sided confidence interval on the difference in mean primary 
efficacy endpoints (FF/VI versus usual ICS/LABA) at Week 24 (Visit 6) precludes the non-
inferiority margin of -1.5. 
Of note, as the two tests for non-inferiority are sequentially performed, the closure principle holds 
and there is no need to adjust the two-sided nominal level of significance (i.e. 0.05) for each test. 
1.4.
Sample Size Assumptions
Results based on the HZA106829 study have shown that the estimated SD of the change in ACT 
score was 3.7.  Unpublished data have shown that the standard deviation of change of ACT 
ranged from 3.8 to 4.8. Therefore, a somewhat conservative choice of SD of 4.5 point is retained.  
Based on the literature (Schatz, 2009), the Minimally Important Difference (MID) of the ACT 
could be considered as 3 points. Half this MID (i.e. 1.5) could therefore be used to define the non-
inferiority margin.
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Assuming a 4.5 point standard deviation for the change in ACT total score at Week 12 (Visit 4), a 
1.5 point non-inferiority margin, and a two-sided nominal significance level of 0.05, the sample 
size needed per group to achieve at least a 90% power is 191  (i.e. a total of 382 subjects). 
Assuming a 10% dropout rate, around 422 subjects must be randomized either to FF/VI or to 
usual ICS/LABA in 1:1 ratio to achieve at least a 90% power.
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2.
PLANNED ANALYSES
2.1.
Interim Analyses
Not applicable.
2.2.
Data Look
At a date agreed by the study team and the contract research organisation (CRO) (selected to 
execute the statistical analyses specified in this RAP), a data look will be performed using blinded 
treatment codes on a subset of the data. The aim of the data look is solely to ensure that all of the 
required tables, figures and listings are being produced and formatted correctly, such that the 
output produced on unblinded data at the end of the study is correct and complete.  This data look 
will be performed when sufficient data are available, but early enough to leave time for changes 
to be made to the planned outputs and methods prior to database release (DBR). Any changes will 
be documented before DBR.
2.3.
Final Analyses
All planned analyses will be  performed after the completion of the following sequential steps:
1.
All subjects have completed the study as defined in the protocol 
2.
All required database cleaning activities have been completed and final DBR has been 
declared by Data Management.
3.
All protocol deviations (PDs) have been confirmed
4.
All criteria for unblinding the randomisation codes have been met. 
5.
Randomisation codes have been distributed according to RandAll NG procedures.
6.
DBF has been declared by Data Management.
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3.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
All Subjects 
Enrolled (ASE)
!
Comprise of all subjects screened (provided 
consent) and for whom a record exists on the study 
database. 
!
Note, this population is not identified in the 
protocol, but is needed for displays that include 
subjects screened but not in the ITT Population 
(e.g. tabulation of reasons for withdrawal before 
randomisation)
!
Subject disposition 
tables
Intent-To-Treat 
(ITT)
!
Comprise of all randomized subjects having 
received at least one dose of the prescription of 
study medication (either FF/VI or usual ICS/LABA)
!
Subjects will be assigned to the treatment group as 
randomized for the ITT population
!
Study Population
!
Efficacy
Per Protocol (PP)
!
Comprise of all ITT subjects without any major 
violations of study procedures.
!
Major protocol violations will be identified prior to 
database lock. 
!
Protocol deviations will be reviewed and classified 
as minor or major during a data review meeting 
that will be held before database lock.
!
Exclusion of subjects from the PP population are 
defined in Section 3.1 (Protocol Deviations) and 
Appendix 1: Protocol Deviation Management and 
Definitions for PP Population
!
Subjects will be assigned to the treatment group as 
treated for the PP population
!
This population will be 
used for summaries 
and analyses of the 
primary efficacy 
secondary efficacy 
endpoints. 
Safety
!
Comprise of all enrolled subjects having received 
at least one dose of study medication (either FF/VI 
or usual ICS/LABA) and considered as-treated.
!
Subjects will be assigned to the treatment group as 
treated for the Safety population
!
Safety
NOTES : 
!
Please refer to Appendix 15: List of Data Displays which details the population to be used for each displays being 
generated.
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3.1.
Protocol Deviations
All PDs (any deviation from the protocol) are tracked and monitored during the study. Important 
PDs are those deviations that may compromise subject rights, safety, or well-being, and/or data 
integrity, and/or study end-points, and are defined in the protocol deviation management plan 
(PDMP). Apart from any incorrect treatment deviations, all full and partial protocol deviations 
will be agreed upon prior the unblinding and the freezing of the database. All deviations from the 
inclusion/exclusion criteria, and important PDs will be summarised. A listing of treatment 
misallocations will be produced.
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4.
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS
Table 3 provides an overview of appendices within the RAP for outlining general considerations 
for data analyses and data handling conventions. 
Table 3
Overview of Appendices
Section
Component
10.1
Appendix 1: Protocol Deviation Management and Definitions for PP Population
10.2
Appendix 2: Time & Events
10.3
Appendix 3: Assessment Windows
10.4
Appendix 4: Treatment States and Phases
10.5
Appendix 5: Data Display Standards & Handling Conventions
10.6
Appendix 6: Derived and Transformed Data
10.7
Appendix 7: Premature Withdrawals & Handling of Missing Data
10.8
Appendix 8: Values of Potential Clinical Importance
10.9
Appendix 9: Multicenter Studies
10.10
Appendix 10: Examination of Covariates, Subgroups & Other Strata
10.11
Appendix 11: Multiple Comparisons & Multiplicity
10.12
Appendix 12: Model Checking and Diagnostics for Statistical Analyses
10.13
Appendix 13: Blinding Strategy
10.14
Appendix 14: Abbreviations & Trade Marks
10.15
Appendix 15: List of Data Displays
10.16
Appendix 16: Example Mock Shells for Data Displays
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5.
STUDY POPULATION ANALYSES
5.1.
Overview of Planned Analyses
The study population analyses will be based on the ITT population, unless otherwise specified.
Table 4 provides an overview of the planned study population analyses, with full details of data 
displays being presented in Appendix 15: List of Data Displays.
Table 4
Overview of Planned Study Population Analyses
Display Type
Data Displays Generated
Table
Figure
Listing
Subject Disposition
Subject Populations
Y[1]
Y
Inclusion/exclusion Criteria Failures for Subjects Not 
Starting Treatment
Y[1]
End of Study Record 
Y[2]
Y
Attendance at Each Clinic Visit and Phone Call Visit
Y
Number of Subjects by Country and Centre
Y[2,3]
Randomised and Actual Treatments
Y
Protocol Deviations
Deviations from the Inclusion/Exclusion Criteria 
Y
Y
Important Protocol Deviations 
Y
Y
Important Protocol Deviations Resulting in Exclusion from 
the PP Population
Y
Y
Treatment Misallocations
Y
Demographic and Baseline Characteristics
Demographic Characteristics
Y[2,4]
Y
Race and Racial Combinations
Y
Y
Race and Racial Combinations Details
Y
Current and Past Medical Conditions
Y
Asthma Duration at Baseline 
Y[2]
Y
Asthma Exacerbation History at Baseline
Y[2]
Y
Lung Function at Baseline
Y
Smoking History at Baseline
Y[2]
Y
Concomitant Medications
Pre-Treatment Concomitant Medications 
Y
Y
On-Treatment Concomitant Medications
Y
Y
On-Treatment Asthma Concomitant Medications
Y
Relationship between Ingredient and Verbatim Text
Y
Exposure and Medication Modifications
Study Medication Dosage Modification
Y
Extent of Exposure to Study Medication (Regardless of 
Modification to Study Medication Dosage)
Y
Y
Y
Extent of Exposure to Study Medication (up to First 
Modification of Study Medication Dosage)
Y
Extent of Exposure to Study Medication by Medication and 
Dosage
Y
Number of Subjects by Subgroup
Y
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NOTES :
!
Y = Yes display generated.
!
[1]: Display will be based on ASE population
!
[2]: Display will be repeated for the PP population
!
[3]: Display will be repeated for the ASE population
!
[4]: Display will be repeated for the Safety population
6.
PRIMARY STATISTICAL ANALYSES
6.1.
Efficacy Analyses
6.1.1.
Overview of Planned Efficacy Analyses
The primary efficacy analyses will be based on the ITT population and repeated for the PP 
population, unless otherwise specified. 
Table 5 provides an overview of the planned efficacy analyses, with full details of data displays 
being presented in: List of Data Displays.
Table 5
Overview of Planned Efficacy Analyses
Endpoint
Data displays generated
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
ACT Total Score
Change from Baseline 
in the ACT Total Score 
at Week 12 (Visit 4)
Y[1,2,3,4,5,6,
7]
Y[1,2,3,4,5,7]
Y[1]
Y[8]
NOTES :
!
T = Table, F = Figure, L = Listing, Y = Yes display generated.
!
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.
!
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.
!
Individual = Represents FL related to any displays of individual subject observed raw data.
!
Display will be repeated for the following subgroups (ITT only) (see Section 10.10 for more details):
[1]:
Country
[2]:
Number of severe asthma exacerbations in the previous year prior to randomisation
[3]:
Smoking status at baseline
[4]:
Age group
[5]:
Gender
!
[6]: Sensitivity analyses will be produced for the following approaches:
!
Last observation carried forward (LOCF) (ITT only)
!
MI analyses utilizing covariates (ITT only)
!
Semi-parametric Hodges-Lehmann (HL) approach (ITT only)
!
Worst observation carried forward (WOCF) for treatment withdrawals (ITT only)
!
Adjusting for seasonal effect
!
[7]: Display will be repeated for:
!
FF/VI versus the subset of Usual ICS/LABA subjects prescribed FP/S at randomisation (only if ≥25% of 
Usual ICS/LABA patients are prescribed FP/S at randomisation)
!
FF/VI versus the subset of Usual ICS/LABA subjects prescribed BUD/F at randomisation (only if ≥25% of 
Usual ICS/LABA patients are prescribed BUD/F at randomisation)
!
[8]: Display will be produced for the ITT population only.
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6.1.2.
Planned Efficacy Statistical Analyses
Primary Statistical Analyses
Endpoint(s)
!
Change from Baseline in the ACT Total Score at Week 12 (Visit 4) 
Model Specification
!
The primary endpoint will be performed on both the ITT and the PP populations, and analysed using an 
MMRM model utilizing the REML estimation approach and a default covariance structure of 
unstructured 
!
Terms fitted in the model will include:
Response
: Change from Baseline in ACT Total Score
Fixed Categorical
: Randomised treatment, visit (Week 6 and Week 12), gender, country
Fixed Continuous
: Baseline ACT total score, age 
Interaction terms
: Randomised treatment-by-visit, baseline ACT total score-by-visit
Random effect
: Subject
SAS Code to Perform Analysis
proc mixed data=input_data;
class trtcd gender country visit subjid ;
model ACT = trtcd gender country age baseline  
visit visit*baseline visit*trtcd / ddfm=kr ;
repeated visit / subject=subjid type=un ;
random intercept / subject=subjid ;
lsmeans visit*trtcd / cl diff e om=OMdset at (baseline age)=(&blm. &agem.) ;
run ; 
where OMdset is a dataset with a row for every visit-subject combination that contains all of the covariates 
and blm and agem are macro variables containing the means for baseline and age for the subjects used in 
the analysis. These are used to derive the adjusted means using coefficients which are based on the 
subjects used in the analysis.
Model Checking & Diagnostics
!
Refer to Appendix 12: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation
!
For Week 12 (Visit 4), the adjusted (least squares [LS]) mean change from baseline for each treatment 
and the estimated treatment difference for FF/VI versus Usual ICS/LABA (i.e. the difference in LS mean 
change from baseline) will be presented together with the associated 95% CI and p-value.
!
Summary statistics will be produced for absolute value of and change from baseline in ACT total score 
at each post-baseline visit (Week 6 [Visit 3], Week 12 [Visit 4], Week 18 [Visit 5] and Week 24 [Visit 6]).
!
A listing of ACT total and change from baseline scores will be provided. 
!
Mean ACT total score ∀SD will be plotted by visit.
Subgroup Analyses
!
For the analyses by country (France, Germany) and gender (male, female), the model will additionally 
include the randomised treatment-by-subgroup and randomised treatment-by-subgroup-by-visit
interactions as a covariate.
!
For the analyses by number of severe asthma exacerbations in the previous year prior to randomisation 
(0, >1) and smoking status at baseline (non-smoker, former smoker, current smoker), the model will 
additionally include the subgroup, randomised treatment-by-subgroup interaction and randomised 
treatment-by-subgroup-by-visit interaction as covariates.
!
For the analysis by age group (<50 years, ≥50 years), the continuous covariate age will be replaced by 
age group, randomised treatment-by-age group interaction and randomised treatment-by-age group-by-
visit interaction.
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Sensitivity and Supportive Statistical Analyses
Justification for Sensitivity Analyses Handling Missing Data
!
While subjects missing Week 12 (Visit 4) data but having earlier data will be included in the MMRM 
primary analysis, the interpretability of the results from the primary model will depend on the missing 
data satisfying the Missing at Random (MAR) assumption.  To support the validity of the conclusions 
drawn from this analysis, several sensitivity analyses will be performed to explore the dropout pattern 
and its possible impact on treatment comparisons. These sensitivity analyses will be performed on the 
ITT population only as subjects with missing ACT total score at Week 12 (Visit 4) are excluded from the 
PP population.
Last Observation Carried Forward
!
Missing values at Week 12 (Visit 4) will be replaced by the last available post-randomization value 
(either the Week 6 (Visit 2) ACT score or the ACT score at treatment withdrawal time, if applicable), i.e. 
based on the LOCF method.  The change from baseline in ACT at Week 12 (Visit 4) will be analyzed 
using an analysis of covariance (ANCOVA) model adjusting for randomised treatment, baseline ACT 
score, gender, country and age. For Week 12 (Visit 4), the LS mean change from baseline for each 
treatment and estimated LS mean change from baseline difference for FF/VI versus Usual ICS/LABA
will be presented together with the associated 95% CI and p-value.
Multiple Imputation
!
Sensitivity analyses will be performed using MI methods based on pattern mixture models. First, a 
repeated measures Normal model will be fitted to the data using a Bayesian approach, with non-
informative priors for the mean and variance-covariance matrix to provide a joint posterior for the 
parameters in this model. The repeated measures Normal model will include separate mean profiles for 
each treatment group and the same covariates as those in the primary efficacy analysis.
!
Independent samples will then be drawn from the posterior distributions for the mean and variance-
covariance matrix to provide inputs into an imputation model. For each subject with missing data, these 
sampled values of the parameters for mean vectors and the variance-covariance matrices specify a 
joint distribution for their observed and unobserved outcome data.
!
The post-withdrawal part of each pattern-specific distribution will be modelled using the approach
discussed below. This imputation model will have the same covariates as those in the primary efficacy
analysis.
!
Based on this imputation model, a single set of data will be sampled for the missing data based on the 
distribution for the subject’s missing data conditional upon their observed data. Each imputed data set 
will then be analysed using simple ANCOVA at Week 12 (Visit 4) and the resulting treatment 
differences and their standard errors combined using Rubin’s rules.
!
The post-withdrawal part of each pattern-specific distribution will be modelled using these two 
approaches:
o
MAR Approach. The means and variance-covariances following withdrawal are chosen to 
reflect the subject’s own treatment group. This approach will provide similar results to using a 
mixed effects model where the unstructured covariance matrix is estimated separately for 
each arm, and all covariates are crossed with treatment. As such it is not truly a sensitivity 
analysis as we expect to get very similar results. Like the MMRM this answers an on-treatment 
question.
o
Copy Differences from Reference Approach. This approach addresses a potential pattern of 
informative missingness, in which subjects withdrawn from the test groups would have 
followed the same trend over time (difference in mean value between time-points) as those in 
the reference group, had they continued in the study. Therefore, this approach may be 
considered conservative because it will assume that following withdrawal from a test treatment 
arm, imputation for their missingness will be derived from observed reference data. The 
intention is to represent an ITT-like approach.
!
For each method, the LS mean change from baseline at Week 12 (Visit 4) for each treatment and 
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Sensitivity and Supportive Statistical Analyses
estimated LS mean change from baseline difference for FF/VI versus Usual ICS/LABA will be 
presented together with the associated 95% CI and p-value.
Hodges-Lehmann Approach
!
A sensitivity analysis based on the semi parametric HL approach will be proposed to assess the 
robustness of the MMRM Model-based non-inferiority results. The HL difference between groups at 
Week 12 (Visit 4) and corresponding 95% CI will be provided.
Worst Observation Carried Forward
!
When treatment withdrawal occurs, an alternative method for imputing the missing value at the nearest 
visit after withdrawal time will be proposed: the primary endpoint missing value will be estimated by the 
worst ACT score observed between baseline visit and withdrawal time, inclusive – i.e. using the WOCF 
method. An ANCOVA model adjusting for randomised treatment, baseline ACT score, gender, country 
and age will be used to analyse this imputed data, with the LS mean change from baseline for each 
treatment presented at Week 12 (Visit 4) together with the estimated LS mean change from baseline 
difference and associated 95% CI and p-value
Summary of Sensitivity Statistical Analyses
!
A plot will be produced displaying the treatment differences and 95% CIs for the primary analysis and 
each of the sensitivity analyses described above.
Seasonal effect
!
A sensitivity analysis adjusting for seasonal effect will be performed by repeating the primary efficacy 
analysis with the addition of season at randomisation, randomised treatment-by-season at 
randomisation interaction and randomised treatment-by-season at randomisation-by-visit interaction. 
See Section 10.10.3 for the definition of season at randomisation. The LS mean change from baseline 
at Week 12 (Visit 4) for each treatment and estimated LS mean change from baseline difference will be 
displayed for each season at randomisation together with the associated 95% CI and p-value, and the 
interaction p-value.
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7.
SECONDARY STATISTICAL ANALYSES
7.1.
Efficacy Analyses
7.1.1.
Overview of Planned Efficacy Analyses
The secondary efficacy analyses will be based on the ITT population, unless specified otherwise. 
Table 6 provides an overview of the planned efficacy analyses, with further details of data 
displays being presented in Appendix 15: List of Data Displays.
Table 6
Overview of Planned Efficacy Analyses
Endpoint
Data displays generated
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
ACT Total Score
Change from Baseline 
in the ACT Total Score 
at Week 24 (Visit 4)
Y[1,2,3,4]
Y
Y[1,2,4,5,6,7,
8]
Y[1,2]
Correct Use of Device 
Percentage of Subjects 
with Correct Use of 
Inhaler Device at Week 
12 (Visit 4) and at 
Week 24 (Visit 6) 
Independently of the 
Use at Week 12 (Visit 
4)
Y[1]
Y[1]
Y
NOTES :
!
T = Table, F = Figure, L = Listing, Y = Yes display generated.
!
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.
!
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.
!
Individual = Represents FL related to any displays of individual subject observed raw data.
!
[1]: Display will be repeated for the PP population
!
[2]: Display will be repeated by Country (ITT only)
!
[3]: Sensitivity analyses will be produced for the following approaches:
!
LOCF (ITT only)
!
MI analyses utilizing covariates (ITT only)
!
Semi-parametric HL approach (ITT only)
!
WOCF for treatment withdrawals (ITT only)
!
Adjusting for seasonal effect
!
[4]: Display will be repeated for:
!
FF/VI versus the subset of Usual ICS/LABA subjects prescribed FP/S at randomisation (only if ≥25% of 
Usual ICS/LABA patients are prescribed FP/S at randomisation)
!
FF/VI versus the subset of Usual ICS/LABA subjects prescribed BUD/F at randomisation (only if ≥25% of 
Usual ICS/LABA patients are prescribed BUD/F at randomisation)
!
Display will be repeated for the following subgroups (ITT only) (see Section 10.10 for more details):
[5]:
Number of severe asthma exacerbations in the previous year prior to randomisation
[6]:
Smoking status at baseline
[7]:
Age group
[8]:
Gender
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7.1.2.
Planned Efficacy Statistical Analyses
Secondary Statistical Analyses
Endpoint(s)
!
Change from Baseline in the ACT Total Score at Week 24 (Visit 6) 
Model Specification
!
This endpoint will be performed on both the ITT and the PP populations, and analysed using an MMRM 
model utilizing the REML estimation approach and a default variance-covariance structure of 
unstructured 
!
Terms fitted in the model will include:
Response
: Change from Baseline in ACT Total Score
Fixed Categorical
: Randomised treatment, visit (Week 6, Week 12, Week 18 and Week 24), 
gender, country
Fixed Continuous
: Baseline ACT total score, age 
Interaction terms
: Randomised treatment-by-visit, baseline ACT total score-by-visit
Random effect
: Subject
Model Checking & Diagnostics
!
Refer to Appendix 12: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation
!
For Week 24 (Visit 6), the LS mean change from baseline for each treatment and the estimated 
difference in LS mean change from baseline for FF/VI versus Usual ICS/LABA will be presented 
together with the associated 95% CI and p-value.
!
Summary statistics, a listing and plots of mean ACT total score ∀SD will be produced as part of the 
primary efficacy endpoint analysis (see Section 6.1.2).
Subgroup Analysis
!
For the analysis by country (France, Germany), the model will additionally include the randomised 
treatment-by-country and randomised treatment-by-country-by-visit interactions as a covariate.
Sensitivity and Supportive Statistical Analyses
!
The same sensitivity analyses as those described for the primary endpoint will be performed for the key 
secondary endpoint of change from baseline in the ACT total score at Week 24 (Visit 6) .
Secondary Statistical Analyses
Endpoint(s)
!
Percentage of subjects with correct use of inhaler device at Week 12 (Visit 4) and at Week 24 (Visit 6) 
independently of the use at Week 12 (Visit 4)
Model Specification
!
These endpoints will be analysed for both the ITT and the PP populations using logistic regression 
models
!
Terms fitted in the model will include:
Response
: Endpoint
Fixed Categorical
: Randomised treatment, correct use of inhaler device at baseline, gender, 
country
Fixed Continuous
: Age 
SAS Code to Perform Analysis
proc logistic data=input_data plots=(all);
class trtcd country baseline gender / ref=first param=ref; 
  model corr_use (event=”Y”) = trtcd baseline age gender country;
  contrast “Trt_effect” trtcd 1 / estimate=exp;
run;
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Secondary Statistical Analyses
Model Checking & Diagnostics
!
Refer to Appendix 12: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation
!
The number and percentage of subjects with correct use within each randomised treatment group will 
be presented by visit, together with the adjusted odds ratio comparing FF/VI with Usual ICS/LABA, 
associated p-value and 95% CI.
!
A summary and listing of correct use / errors of inhaler use will be produced.
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7.2.
Safety Analyses
7.2.1.
Overview of Planned Analyses
The safety analyses will be based on the Safety population.
Table 7 provides an overview of the planned analyses, with further details of data displays being 
presented in Appendix 15: List of Data Displays.
Table 7
Overview of Planned Safety Analyses
Endpoint
Data displays generated
Stats Analysis
Summary
Individual
T
F
T
F
F
L
Adverse Events
SAEs and ADRs Overview
Y
Non-Serious ADRs
Y
Y
Serious ADRs
Y
All ADRs
Y
SAEs
Y
Y
SAEs and ADRs Leading to Permanent 
Discontinuation of  Study Medication or 
Withdrawal from Study
Y
Y
SAEs Leading to Permanent 
Discontinuation of Study Medication or 
Withdrawal from Study
Y
ADRs Leading to Permanent 
Discontinuation of Study Medication or 
Withdrawal from Study
Y
Non-Serious ADRs Leading to 
Permanent Discontinuation of Study 
Medication or Withdrawal from Study
Y
Most Frequent Non-Serious ADRs, 
Reported by ≥1% or More of Subjects in 
Any Treatment Group
Y
Non-Serious ADRs of Special Interest
Y
Serious ADRs of Special Interest
Y
All ADRs of Special Interest
Y
SAEs of Special Interest
Y
Fatal SAEs 
Y
Y
Fatal Serious ADRs
Y
Fatal SAEs of Special Interest
Y
Non-Fatal SAEs
Y
Y
Non-Fatal SAEs of Special Interest
Y
AE terms of Special Interest
Y
Top Ten Most Commonly Reported On-
treatment ADRs per Treatment Group
Y
Vital Signs
Vital Signs
Y
Y
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Endpoint
Data displays generated
Stats Analysis
Summary
Individual
T
F
T
F
F
L
Inhaler Device Malfunctions
Inhaler Device Malfunctions
Y
Liver chemistry
Liver event
Y
Liver biopsy
Y
Liver imaging
Y
Other
Pregnancy
Y
NOTES :
!
T = Table, F = Figure, L = Listing, Y = Yes display generated.
!
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.
!
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.
!
Individual = Represents FL related to any displays of individual subject observed raw data.
7.2.2.
Benefit:Risk analyses
Benefit:Risk analyses will be based on the ITT population for Benefit, and Safety population for 
Risk.
Table 8 provides an overview of the planned analyses, with further details of data displays being 
presented in Appendix 15: List of Data Displays.
Table 8
Overview of Planned Benefit:Risk Analyses
Endpoint
Data displays generated
Stats Analysis
Summary
Individual
T
F
T
F
L
Summary of Benefit:Risk 
Y
NOTES : 
!
T = Table, F = Figure, L = Listing, Y = Yes display generated.
!
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.
!
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.
!
Individual = Represents FL related to any displays of individual subject observed raw data. 
Benefit Risk Statistical Safety Analyses
Endpoint(s)
!
Summary of Benefit:Risk: various endpoints analyses in the context of safety and effectiveness 
analyses 
Model Specification
!
Estimates and their 95% CIs obtained from selected safety and effectiveness analyses will be 
presented for the ITT population on a multiple panel forest plot which will display effectiveness and 
safety data.
!
For certain endpoints, the x-axis may be reversed to ensure benefit/risk to either FF/VI or Usual 
ICS/LABA is shown accurately.
!
Due to endpoints being presented using different scales, the forest plot will be split into additional 
panels to allow better visibility of the results.
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Benefit Risk Statistical Safety Analyses
Model Checking & Diagnostics
!
Model checking and diagnostics are described in each endpoint analysis section.
Model Results Presentation
!
The top panel (“Benefits”) of the forest plot will display:
o
difference in LS mean change from baseline from the MMRM analysis of the primary efficacy 
endpoint, defined as the change from baseline in ACT total score at Week 12 (Visit 4), as 
described in Section 6.1.2
o
difference in LS mean change from baseline from the MMRM analysis of the change from 
baseline in ACT total score at Week 24 (Visit 6), as described in Section 7.1.2
o
adjusted odds ratio from the logistic regression analysis of percentage of subjects with correct 
use of inhaler device at Week 12 (Visit 4), as described in Section 7.1.2
o
adjusted odds ratio from the logistic regression analysis of percentage of subjects with correct 
use of inhaler device at Week 24 (Visit 6) independently of the use at Week 12 (Visit 4), as 
described in Section 7.1.2
!
The bottom panel (“Risks”) of the forest plot will display the risk difference for FF/VI vs. usual ICS/LABA
of the incidence of the following SAEs of special interest:
o
Asthma/bronchospasm, cardiovascular effects, decreased bone mineral density and 
associated fractures, hypersensitivity, local steroid effects, lower respiratory tract infection 
(LRTI) excluding pneumonia, pneumonia, adrenal suppression, ocular effects, effects on 
glucose, effects on potassium, tremor
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8.
OTHER STATISTICAL ANALYSES
8.1.
Other Analyses
8.1.1.
Overview of Planned Other Analyses
The other statistical analyses will be based on the ITT population, unless otherwise specified.
Table 9 provides an overview of the planned other analyses, with full details of data displays 
being presented in Appendix 15: List of Data Displays.
Table 9
Overview of Planned Other Analyses
Endpoint
Absolute
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
Trough (Pre-dose) FEV1
Change from Baseline 
in Trough (Pre-dose) 
FEV1 at Week 12 
(Visit 4)
Y
Y
Y
ACT
ACT Total Score ≥ 20 
or ≥ 3 Point Increase 
from Baseline in ACT
Total Score at Week 
12 (Visit 4) and Week 
24 (Visit 6)
Y
Y
Y
ACT Total Score ≥ 20 
at Week 12 (Visit 4) 
and Week 24 (Visit 6)
Y
Y
≥ 3 Point Increase 
from Baseline in ACT 
Total Score at Week
12 (Visit 4) and Week 
24 (Visit 6)
Y
Y
Change from Baseline 
in Individual ACT 
Questions at Week 12 
(Visit 4) and Week 24 
(Visit 6)
Y
Compliance with Study Medication
Compliance with Study 
Medication from 
Randomisation (Day 0) 
to Week 12 (Visit 4), 
from Week 12 (Visit 4) 
to Week 24 (Visit 6) 
and from 
Randomisation (Day 0) 
to Week 24 (Visit 6)
Y[1]
Y
Y
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Endpoint
Absolute
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
MARS-A Score at
Randomisation (Day
0), Week 12 (Visit 4) 
and Week 24 (Visit 6).
Y[2]
Y[2]
Y
Severe asthma exacerbations
Number of Subjects 
With at Least 1 Severe 
Asthma Exacerbation 
and Number of Severe 
Asthma Exacerbations
Y[3]
Y
Annual Severe Asthma 
Exacerbation Rate 
over the Study Period
Y
Y
Time to First Severe 
Asthma Exacerbation
Y
Y
Asthma Quality of Life Questionnaire (AQLQ[S])
Change from Baseline 
in Total Score and 
Domain Scores of 
AQLQ(S) at Week 24 
(Visit 6)
Y
Y
An Increase from 
Baseline of ≥ 0.5 in 
AQLQ(s) Total Score 
at Week 24 (Visit 6)
Y
Y
An Increase from 
Baseline of ≥ 0.5 in 
AQLQ(s) 
Environmental Stimuli 
Domain Score at Week 
24 (Visit 6)
Y
Y
An Increase from 
Baseline of ≥ 0.5 in 
AQLQ(S) Individual 
Domain Scores 
(Symptoms, Activity 
limitations and 
Emotional Function) at 
Week 24 (Visit 6)
Y
EQ-5D-5L
EQ-5D-5L Descriptive 
System Dimensions at 
Week 24 (Visit 6)
Y
Y
Y
EQ-5D-5L Utility Score  
at Week 24 (Visit 6)
Y
Y
Y
EQ-5D-5L Visual 
Analogue Scale (VAS)
Score at Week 24 
(Visit 6)
Y
Y
Y
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Endpoint
Absolute
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
PASAP-Q
PASAP-Q Scores at 
Week 12 (Visit 4)
Y
Y
NOTES :
!
T = Table, F = Figure, L = Listing, Y = Yes display generated.
!
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.
!
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.
!
Individual = Represents FL related to any displays of individual subject observed raw data.
!
[1]: Display will be repeated for the PP population
!
[2]: A reminder was sent to centres in France instructing that the MARS-A questionnaire refers to the patient’s 
preventer inhaler (i.e. their maintenance therapy prior to entering the study, and study medication while on-study). 
See Section 10.6.3 for further details. Display will be repeated split by:
!
Patients in France who had completed all MARS-A assessments prior to the reminder being implemented
!
Patients in France who had completed at least one MARS-A assessment prior to the reminder being 
implemented but also completed at least one MARS-A assessment after the reminder being implemented
!
Patients in France who had not completed any MARS-A assessments prior to the reminder being 
implemented
!
Patients in Germany
!
[3]: Display will be repeated by season.
8.1.2.
Planned Other Statistical Analyses
Other Statistical Analyses
Endpoint(s)
!
Change from baseline in trough (pre-dose) FEV1 at Week 12 (Visit 4)
!
Change from baseline in EQ-5D-5L Utility Score at Week 24 (Visit 6)
!
Change from baseline in EQ-5D-5L VAS Score at Week 24 (Visit 6)
Model Specification
!
These endpoints will be analysed for the ITT population using ANCOVA models
!
Terms fitted in the model will include:
Response
: Endpoint
Fixed Categorical
: Randomised treatment, gender, country
Fixed Continuous
FEV1 endpoint: Baseline trough (pre-dose) FEV1 and age
EQ-5D-5L Utility Score endpoint: Baseline EQ-5D-5L Utility Score 
and age
EQ-5D-5L VAS Score endpoint: Baseline EQ-5D-5L VAS Score 
and age
Model Checking & Diagnostics
!
Refer to Appendix 12: Model Checking and Diagnostics for Statistical Analyses.
SAS Code to Perform Analysis
proc mixed data=input_data;
class trtcd gender country;
model FEV1 = trtcd gender country age baseline  / ddfm=kr ;
lsmeans trtcd / cl diff e;
run ; 
Model Results Presentation
!
The LS mean change from baseline for each treatment and the difference in estimated LS mean 
change from baseline for FF/VI versus Usual ICS/LABA will be presented together with the associated 
95% CI and p-value.
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Other Statistical Analyses
!
Summary statistics. 
!
Listings will be provided.  
Other Statistical Analyses
Endpoint(s)
!
Percentage of subjects who had either an ACT total score ≥ 20 or ≥ 3 point increase from baseline in 
ACT total score at Week 12 (Visit 4) and Week 24 (Visit 6)
!
Percentage of subjects who have an increase from baseline of ≥ 0.5 in AQLQ(S) total score at Week 24 
(Visit 6)
!
Percentage of subjects who have an increase from baseline of ≥ 0.5 in AQLQ(S) environmental stimuli 
domain score at Week 24 (Visit 6)
!
Percentage of subjects with ‘no problems’ in each dimension of the EQ-5D-5L questionnaire at Week 
24 (Visit 6)
Model Specification
!
These endpoints will be analysed for the ITT population using logistic regression models
!
Terms fitted in the model will include:
Response
: Endpoint
Fixed Categorical
: Randomised treatment, gender, country
Fixed Continuous
ACT endpoints: Baseline ACT total score, baseline ACT total 
score squared and age
AQLQ(S) endpoints: Baseline AQLQ(S) score and age
EQ-5D-5L endpoints: Baseline EQ-5D-5L dimension score and 
age
Model Checking & Diagnostics
!
Refer to Appendix 12: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation
!
The number and percentage of subjects with a response within each randomised treatment group will 
be presented by visit, together with the adjusted odds ratio comparing FF/VI with Usual ICS/LABA, 
associated 95% CIs and p-values.
!
The number and percentage of subjects with ACT total score ≥20 or ≥3 point increase from baseline in 
ACT total score will be summarized by visit to include the tabulations of frequencies together and 
separately. 
!
The number and percentage of subjects with an increase from baseline of ≥ 0.5 in AQLQ(S) total and 
individual domain scores at Week 24 (Visit 6) will be summarized.
!
The responses to each EQ-5D-5L dimension will be descriptively summarised
Other Statistical Analyses
Endpoint(s)
!
Annual severe asthma exacerbation rate over the study period
Model Specification
!
This endpoint will be analysed for the ITT population using a generalised linear model (GLM), assuming 
the Negative Binomial distribution
!
Terms fitted in the model will include:
Response
: Annual severe asthma exacerbation rate over the study period
Fixed Categorical
: Randomised treatment, gender, country, number of severe 
asthma exacerbations in the previous year prior to randomisation 
(0, ≥1)
Fixed Continuous
: Age
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Other Statistical Analyses
Offset variable
: Logarithm of time on treatment
Model Checking & Diagnostics
!
Refer to Appendix 12: Model Checking and Diagnostics for Statistical Analyses.
SAS Code to Perform Analysis
proc genmod data=input_data;
class trtcd gender country;
model no_exac = trtcd exacbl gender country age / dist=negbin link=log offset=log_tm type3;
lsmeans trtcd /cl diff=control("0") om exp;
run;
Model Results Presentation
!
The LS mean number / annual rate, adjusted treatment ratio and associated 95% CI and p-value will be 
presented.
!
Percentage reduction in mean number / annual rate and associated 95% CI will also be presented.
!
The severe asthma exacerbation data will be summarized to include the tabulations of exacerbation 
frequencies, exacerbation duration (days) and the outcome, the prescription of oral corticosteroids 
and/or antibiotics to treat exacerbations, hospitalisations and emergency department visits due to an 
exacerbation, intubations due to an exacerbation and withdrawal of IP or withdrawal from the study as a 
result of an exacerbation.
!
A listing of severe exacerbations will be provided. 
!
Box plots will be provided for the severe annual exacerbation rates.
Other Statistical Analyses
Endpoint(s)
!
Time to first severe asthma exacerbation
Model Specification
!
The cumulative distribution of this endpoint will be illustrated for the ITT population using Kaplan-Meier 
estimates and evaluated using the Wald Chi-Square test based on a Cox proportional hazards model.
!
The analyses and summaries will include on-treatment exacerbations, from start date of exposure to 
min(stop date of exposure + 1 day, date of study discontinuation). 
!
The exact method for handling ties in times will be used.
!
Terms fitted in the model will include:
Response
: Time to first severe asthma exacerbation
Fixed Categorical
: Randomised treatment, gender, country
Fixed Continuous
: Age
Model Checking & Diagnostics
!
Refer to Appendix 12: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation
!
The hazard ratio for FF/VI versus Usual ICS/LABA with associated 95% CI and p-value will be 
presented.
!
Cumulative incidence curves of time to first severe asthma exacerbation will be presented.
!
Summary statistics will also be presented.
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9.
REFERENCES
Devlin N., Shah K., Feng Y., Mulhern B., Van Hou, B. Valuing Health-Related Quality of Life: 
An EQ-5D-5L Value Set for England. Office of Health Economics. January 2016.
Efron, B. The Efficiency of Cox’s Likelihood Function for Censored Data. J Am Stat Assoc. 
1977;72:557–565.
EuroQol. EQ-5D-3L User Guide. EuroQol, Europe: 2013. Version 5. 
Firth D. Bias Reduction of Maximum Likelihood Estimates. Biometrika. 1993;80:27–38.
GINA 2012, http://www.ginasthma.org/local/uploads/files/GINA_Report_March13.pdf
GlaxoSmithKline Document Number 2011N129785_02 Study ID HZA115150. A 12-month, 
open 
label, 
randomised, 
effectiveness 
study 
to 
evaluate 
fluticasone 
furoate 
(FF, 
GW685698)/vilanterol (VI, GW642444) Inhalation Powder delivered once daily via a Novel Dry 
Powder Inhaler compared with usual maintenance therapy in subjects with Asthma. Report Date 
11-Mar-2014.
GlaxoSmithKline Document number 2014N190259_02. Study HZA116492: A 6-month, open 
label, randomised, efficacy study to evaluate fluticasone furoate (FF, GW685698)/vilanterol (VI, 
GW642444) Inhalation Powder delivered once daily via the Dry Powder Inhaler Ellipta™ 
compared with usual ICS/LABA maintenance therapy delivered by Dry Powder Inhaler in 
subjects with Persistent Asthma.
Juniper E.F., Guyatt G.H, Ferrie P.J., Griffith L.E. Measuring quality of life in asthma. Am Rev 
Respir Dis. 1993;147:832–838.
Kozma C.M., Slaton T.L., Monz B.U., Hodder R., Reese P.R. Development and Validation of a 
Patient Satisfaction and Preference Questionnaire for Inhalation Devices (PASAPQ). Treat Respir 
Med. 2005; 4 (1): 41-52.
Schatz M., Kosinski M., Yarlas A.S., Hanlon J., Watson M.E., Jhingran P. The minimally 
important difference of the Asthma Control Test. J Allergy Clin Immunol. 2009;124(4):719–23.
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10.
APPENDICES
Section
Appendix
RAP Section 3 : Analysis Populations
Section 10.1
Appendix 1: Protocol Deviation Management and Definitions for PP Population
RAP Section 4 : General Considerations for Data Analyses & Data Handling Conventions
Section 10.2
Appendix 2: Time & Events
Section 10.3
Appendix 3: Assessment Windows
Section 10.4
Appendix 4: Treatment States and Phases
Section 10.5
Appendix 5: Data Display Standards & Handling Conventions
Section 10.6
Appendix 6: Derived and Transformed Data
Section 10.7
Appendix 7: Premature Withdrawals & Handling of Missing Data
Section 10.8
Appendix 8: Values of Potential Clinical Importance
Section 10.9
Appendix 9: Multicenter Studies
Section 10.10
Appendix 10: Examination of Covariates, Subgroups & Other Strata
Section 10.11
Appendix 11: Multiple Comparisons & Multiplicity
Section 10.12
Appendix 12: Model Checking and Diagnostics for Statistical Analyses
Other RAP Appendices
Section 10.13
Appendix 13: Blinding Strategy
Section 10.14
Appendix 14: Abbreviations & Trade Marks
Section 10.15
Appendix 15: List of Data Displays
Section 10.16
Appendix 16: Example Mock Shells for Data Displays
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10.1.
Appendix 1: Protocol Deviation Management and Definitions 
for PP Population
10.1.1.
Protocol Deviations
All PDs (any deviation from the protocol) are tracked and monitored during the study. Important 
PDs are those deviations that may compromise subject rights, safety, or well-being, and/or data 
integrity, and/or study end-points, and are defined in the PDMP. Apart from any incorrect 
treatment deviations, all full and partial protocol deviations will be agreed upon prior the 
unblinding and the freezing of the database. All deviations from the inclusion/exclusion criteria, 
and important PDs will be summarised. A listing of treatment misallocations will be produced.
10.1.2.
Exclusions from PP Population
Important PDs that will result in exclusion from the PP population are specified in Table 10, 
and will be summarised in a data display.
Table 10
PDs resulting in exclusion from the PP population
Deviation Category
Deviation Subcategory
Informed consent
!
Signed informed consent/assent not available on site
!
Wrong informed consent/assent  version signed[1]
!
Informed consent/assent not signed and/or dated by 
subject (parent/Legally Acceptable representative, if 
applicable)
!
Informed consent/assent not signed and/or dated by 
appropriate site staff. [1]
!
Informed consent/assent  not signed prior to any study 
procedure[1]
!
Other informed consent/assent deviations[1]
Eligibility criteria not met –
inclusion criteria
!
Informed consent
!
Gender and Age[2]
!
Type of subject
!
Current Asthma Therapy
!
Inability of subject to complete questionnaires
Eligibility criteria not met –
exclusion criteria
!
History of Life-threatening asthma
!
Subjects having a severe and unstable asthma
!
COPD Respiratory Disease
!
Other diseases/abnormalities[1]
!
Subjects with a history of adverse reaction to any 
intranasal, inhaled, or systemic corticosteroid and LABA 
therapy and to components of the inhalation powder[1]
!
Investigational Medications used within 30 days or five 
half-lives of prior study[1]
!
Chronic user of systemic corticosteroids
!
Subjects treated by the monoclonal antibody omalizumab 
(Xolair) or mepolizumab (Nucala™)
!
Subjects involved in other clinical trials[1]
Not withdrawn after developing 
!
Not withdrawn from study[1]
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Deviation Category
Deviation Subcategory
withdrawal criteria
!
Not discontinued from study treatment[1]
!
Other deviation of not being withdrawn after developing 
withdrawal criteria[1]
Excluded medication, vaccine 
or device
!
Medication, excluded by the protocol, was administered[3]
!
Other excluded medication, vaccine or device deviation[3]
Visit completion
!
Missed visit/phone contact[4]
!
Out of window visit/phone contact[4]
!
Other visit window deviation[4]
Wrong study treatment / 
administration / dose
!
Study treatment not administered per protocol[1]
!
Wrong study treatment or assignment administered
!
Expired study treatment administered[1]
!
Use of study treatment impacted by a temperature 
excursion which was not reported or approved or which 
was disapproved for further use.[1]
!
Study treatment not available at site for administration[1]
!
Other deviations related to wrong study 
treatment/administration/dose[1]
Study procedures
!
Non study treatment supply procedures[1]
!
Equipment procedures[1]
!
Other deviations from study procedures[1]
[1]: To be reviewed on a case-by-case basis
[2]: Patients < 18 years will be excluded from PP population, others will be reviewed on a case-
by-case basis
[3]: To be judged by the medical monitor
[4]: Missed or out of window Visit 4 will lead to exclusion from the PP population, missed or out 
of window other visits will not
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10.2.
Appendix 2: Time & Events
10.2.1.
Protocol Defined Time & Events
Study Visits
Visit 1*
Screening
Visit 2*
Randomisation
Visit 3
Phone 
call 1
Visit 
4**
Visit 5
Phone 
call 2
Visit 6
Early 
Withdrawal
Study Week (± 
specified no. of days)
Day -7 to -
1
Day 0
Week 
6 (±3 
days)
Week 
12 
(±7 
days)
Week 
18 (±3 
days)
Week 
24 
(±14 
days)
Early 
Withdrawal
Visit 
x
x
x
x
x 
Phone interview 
x
x
Assessments
Informed Consent
x
Eligibility criteria
x
x
Demography
x
Smoking status
x
Medical/Family history of 
consented subjects 
including CV Risk factors 
and exacerbation history
x
PGx (saliva sample)***
x
Physical examination
x
x
x
x
x 
Safety Assessments
Urine Pregnancy Test¥
x
x
x
x
Exacerbation 
Assessment
x
x
x
x
x
x
Vital signs
x
x
x
x
x
Serious Adverse Event 
and Adverse Drug 
Reaction Assessment1
x
x
x
x
x
x
Efficacy Assessments
Spirometry Testing (Pre-
dose trough FEV1)
x
x
x ****
Subject Questionnaires 
Asthma Control Test
x
x
x
x
x
x
x
EQ-5D
x
x
x
Asthma Quality of
Life Questionnaire
x
x
x
MARS-A questionnaire
x
x
x
x
Patient Satisfaction and 
Preference (PASAP-Q)
x
x
Inhaler correct use 
assessment
Type A/overall errors 
record
x
x
x
Medication 
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Study Visits
Visit 1*
Screening
Visit 2*
Randomisation
Visit 3
Phone 
call 1
Visit 
4**
Visit 5
Phone 
call 2
Visit 6
Early 
Withdrawal
Study Week (± 
specified no. of days)
Day -7 to -
1
Day 0
Week 
6 (±3 
days)
Week 
12 
(±7 
days)
Week 
18 (±3 
days)
Week 
24 
(±14 
days)
Early 
Withdrawal
Visit 
x
x
x
x
x 
Phone interview 
x
x
Assessments
Concomitant Medication 
Assessment
x
x
x
x
x
Dispense Study 
Medication²
x
x
Collect Study 
Medication²
x
x
x
RAMOS/eCRF
RAMOS NG
x
x
eCRF
x
x
x
x
x
x
x
1.
SAE and ADR monitoring will occur from Day 1. SAE related to study participation should begin from 
signing of informed consent form (ICF). An additional safety and ACT check is provided by phone at 
Week 6 and 18.
2.
Throughout the study the study medication will be dispensed and collected by the investigator site.
* Visit 1 and Visit 2 can be combined if the subject did not take his usual asthma medication before coming 
on site. Then this visit will be Day 0 and all baseline characteristics will be collected at this visit. Written 
Informed Consent must be obtained prior to initiation of study procedures or initiating changes in 
medications.
** Visit 4 (Week 12) should be scheduled at the same time of day as Visit 2 (Randomisation visit).
***PGx saliva sample collected at Visit 2 (Randomisation) or any scheduled clinic visit thereafter.
**** Only if early withdrawal occurs before Week 12.
¥ Only for childbearing women.
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10.3.
Appendix 3: Assessment Windows
Clinic visits/phone calls are scheduled to take place as specified in the protocol. For the ACT and 
MARS-A questionnaires, measurements that are not within ±7 days of the visit target day for 
Week 6 (Visit 3) and Week 18 (Visit 5), or ±14 days for Week 12 (Visit 4) and Week 24 (Visit 6) 
will be excluded from the analyses. For EQ-5D-5L and AQLQ(S), measurements that are not 
within ±14 days of the visit target day of Week 24 (Visit 6) will be excluded from the summaries. 
For PASAP-Q, measurements that are not within ±14 days of the visit target day of Week 12 
(Visit 4) will be excluded from the summaries.
Table 11
Visit slotting rules for ACT and MARS-A
Days relative to randomisation *
Target Study Day
Visit Slot
35 – 49
42
Week 6 (Visit 3)
70 – 98
84
Week 12 (Visit 4)
119 – 133
126
Week 18 (Visit 5)
154 – 182
168
Week 24 (Visit 6)
* Date of assessment – Randomisation date + 1
Table 12
Visit slotting rules for EQ-5D-5L and AQLQ(S)
Days relative to randomisation *
Target Study Day
Visit Slot
154 – 182
168
Week 24 (Visit 6)
* Date of assessment – Randomisation date + 1
Table 13
Visit slotting rules for PASAP-Q
Days relative to randomisation *
Target Study Day
Visit Slot
70 – 98
84
Week 12 (Visit 4)
* Date of assessment – Randomisation date + 1
For all other endpoints, individual measurements collected outside of the assessment window for 
scheduled visits will be included in the ITT and PP analyses without adjustment.  
If multiple measurements are collected within the same assessment window, the last valid value 
prior to randomisation will be used as the baseline value and the value closest to the target day for 
that window will be used for all post-randomisation visits.
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10.4.
Appendix 4: Treatment States and Phases
10.4.1.
Treatment Phases
In general, assessments and events will be classified according to the time of occurrence relative 
to study treatment, unless otherwise specified. Endpoint/measurement specific definitions are 
defined in Section 10.4.2.
Treatment Phase
Definition
Pre-Treatment 
Date < Study Treatment Start Date
On-Treatment
Study Treatment Start Date ≤ Date ≤ Study Treatment Stop Date + 1
Post-Treatment
Date > Study Treatment Stop Date + 1
NOTES: 
!
If it is not possible to determine the treatment phase of an assessment or event it will be 
considered as On-Treatment.
10.4.2.
Treatment States
Assessments and events will be classified according to time of occurrence relative to the start 
and/or stop date of the study treatment. The earliest and latest exposure treatment start and stop 
dates will be used to determine whether an assessment or event was pre-treatment, on-treatment 
or post-treatment. If it is not possible to tell whether an assessment or event was on-treatment or 
not it will be considered as on-treatment.
10.4.2.1.
Treatment States for Concomitant Medications
Treatment State
Definition
Pre-Treatment
(Start Date of Medication < Study Treatment Start Date) and (End Date of Medication <
Study Treatment Start Date)
On-Treatment
[(Start Date of Medication < Study Treatment Start Date) and (End Date of Medication 
≥Study Treatment Start Date)] or (Study Treatment Start Date ≤Start Date of 
Medication ≤ Study Treatment Stop Date + 1)
Post-Treatment
Start Date of Medication > Study Treatment Stop Date +1
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10.4.2.2.
Treatment States for Efficacy Measurements
Treatment State
Definition
Pre-Treatment
Date of Measurement ≤ Study Treatment Start Date
On-Treatment
Study Treatment Start Date < Date of Measurement ≤ Study Treatment Stop Date + 1
Post-Treatment
Date of Measurement > Study Treatment Stop Date +1
10.4.2.3.
Treatment States for Exacerbation Data
Treatment State
Definition
Pre-Treatment
Exacerbation Onset Date < Study Treatment Start Date
On-Treatment
Study Treatment Start Date ≤ Exacerbation Onset Date ≤ Study Treatment Stop Date 
+ 1
Post-Treatment
Exacerbation Onset Date > Study Treatment Stop Date + 1
NOTES: 
!
If the study treatment stop date is missing then the exacerbation will be considered to be On-Treatment
!
See Section 10.6.3 for details on missing onset and/or resolution dates.
10.4.2.4.
Treatment States for AE Data
Treatment states for adverse events are described below. Severe asthma exacerbations will be 
treated in the same way, with the exacerbation start date used in place of the AE start date.
Treatment State
Definition
Pre-Treatment
AE Onset Date < Study Treatment Start Date
On-Treatment
Study Treatment Start Date # AE Onset Date # Study Treatment Stop Date + 1
Post-Treatment
AE Onset Date > Study Treatment Stop Date + 1
Onset Time
Since 1st Dose 
(Days)
If Study Treatment Start Date ˃ AE Onset Date = AE Onset Date - Study Treatment 
Start Date
If Study Treatment Start Date ≤ AE Onset Date = AE Onset Date - Study Treatment 
Start Date +1
Missing otherwise.
Duration (Days) 
AE Resolution Date – AE Onset Date + 1
Drug-related
If relationship is marked ‘YES’ or is missing on the AE case report form (CRF) page.
NOTES: 
!
If the study treatment stop date is missing then the AE will be considered to be On-Treatment.
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10.5.
Appendix 5: Data Display Standards & Handling 
Conventions
10.5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting 
Code
Description
Description
Order [1]
A
Fluticasone furoate /vilanterol inhalation 
Powder delivered once daily
FF/VI
2
B
Usual ICS/LABA maintenance therapy 
delivered by Dry Powder Inhaler
Usual ICS/LABA
1
NOTES:
1.
Order represents treatments being presented in data displays, as appropriate.
10.5.2.
Baseline Definition & Derivations
10.5.2.1.
Baseline Definitions
For all endpoints the baseline value will be the last assessment prior to randomisation.
10.5.2.2.
Derivations and Handling of Missing Baseline Data
Definition
Reporting Details
Change from Baseline
= Post-Dose Visit Value – Baseline
% Change from Baseline
= 100 x [(Post-Dose Visit Value – Baseline) / Baseline]
Maximum Change from Baseline
= Calculate the change from baseline at each given timepoint 
   and determine the maximum change
NOTES :
!
Unless otherwise specified, the baseline definitions specified in Section 10.5.2.1 will be used for derivations for 
endpoints / parameters and indicated on summaries and listings.
!
Unless otherwise stated, if baseline data is missing no derivation will be performed and will be set to missing.
!
The baseline definition will be footnoted on all change from baseline displays.
10.5.3.
Reporting Process & Standards
Reporting Process
Software
!
The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
: uk1salx00175
HARP Area
: /arenv/arprod/gw685698_gw642444/hza116492/final
QC Spreadsheet
: /arenv/arwork/gw685698_gw642444/hza116492/final/qc
Analysis Datasets 
!
Analysis datasets will be created according to CDISC standards.
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Reporting Process
!
For creation of ADaM datasets (e.g. ADCM, ADAE) the same version of dictionary datasets will be 
implemented for conversion from SI to SDTM.
Generation of RTF Files
!
RTF files will be generated for all tables in the final reporting effort. 
Reporting Standards
General
!
The current GSK IDSL will be applied for reporting, unless otherwise stated:
o
4.03 to 4.23: General Principles
o
5.01 to 5.08: Principles Related to Data Listings
o
6.01 to 6.11: Principles Related to Summary Tables
o
7.01 to 7.13: Principles Related to Graphics 
Formats
!
All data will be reported according to the treatment the subject was randomised to unless otherwise 
stated.
!
GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DPs) will be adopted for reporting of 
data based on the raw data collected.
!
Numeric data will be reported at the precision collected on the electronic case report form (eCRF) or 
recorded in the raw dataset if from non eCRF sources.
!
The reported precision from non eCRF sources will follow the IDSL statistical principles but may be 
adjusted to a clinically interpretable number of DP’s. 
Planned and Actual Times
!
Reporting for tables, figures and formal statistical analyses :
!
Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.
!
The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate.
!
Reporting for Data Listings: 
!
Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).
!
Unscheduled or unplanned readings will be presented within the subject’s listings. 
!
For visits outside the time-windows, please see Section 10.3.
Unscheduled Visits
!
Unscheduled visits will not be included in summary tables or figures.
!
All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Graphical Displays
!
Refer to IDSL Statistical Principals 7.01 to 7.13. 
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10.6.
Appendix 6: Derived and Transformed Data
10.6.1.
General
Multiple Measurements at One Time Point
!
If there are multiples values within a time window the last valid value prior to randomisation will be used 
as the baseline value and the value closest to the target day for that window will be used for all post-
randomisation visits. If values are the same distance from the target then the mean will be taken.
!
Subjects having both High and Low values for Normal Ranges at any post-baseline visits for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance summary 
tables.
Study Day
!
Calculated as the number of days from randomisation date :
!
Ref Date = Missing                       →Study Day = Missing 
!
Ref Date < Randomisation Date   →Study Day = Ref Date – Randomisation Date    
!
Ref Data ≥ Randomisation Date   →Study Day = Ref Date – (Randomisation Date) + 1    
Time Since First Dose
!
Calculated as the number of days from the date of first dose :
!
Ref Date = Missing                  →Time Since First Dose = Missing 
!
Ref Date < First Dose Date     →Time Since First Dose = Ref Date – First Dose Date
!
Ref Date ≥ First Dose Date    →Time Since First Dose = Ref Date – (First Dose Date) + 1    
Study Treatment Discontinuation
!
In this study, subjects who are intentionally and permanently withdrawn from study medication may not 
continue in the study attending the remaining visits (excluding the Follow-up contact) and completing 
the scheduled assessments. 
10.6.2.
Study Population
Demographics
Age
!
GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed as 
follows:
o
Any subject with a missing day will have this imputed as day ‘15’. 
o
Any subject with a missing date and month will have this imputed as ‘30th June’.
!
Birth date will be presented in listings as ‘YYYY’.
!
Completely missing dates of birth will remain as missing, with no imputation applied. Consequently, the 
age of the subject will not be calculated and will remain missing.
!
Age, in whole years, will be calculated with respect to the date of screening (Visit 1).
Body Mass Index
!
Calculated as Weight (kg) / [Height (m)]2
Race 
!
In the demographic summary table race will be summarised as follows; White is defined as those 
subjects who chose only the White (Arabic/North African Heritage) and/or White 
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Demographics
(White/Caucasian/European Heritage) categories on the CRF, Black is defined as those subjects who 
chose only the African American/African Heritage category on the CRF, and Other is defined as those 
subjects who chose any of the other races on the CRF.
Extent of Exposure
Subjects randomised to FF/VI or to Usual ICS/LABA can have their treatment dosage adjusted at the 
investigators discretion, and will be recorded in the eCRF. Treatment sequence identifier will be incremented 
by 1 each time the study medication is modified, and recorded on eCRF.
Extent of exposure will be presented in three different ways:
!
The extent of exposure to study medication, regardless of study medication dosage modifications during 
the study, will be defined as the number of days on study medication and will be calculated for each 
subject as follows:
Exposure = (study medication stop date – study medication start date) + 1
If medication start date is missing then the randomisation date (i.e. date of Visit 2) of the subject will be used 
for medication start date. If the medication stop date is missing, the Visit 6 date or early withdrawal visit date 
will be used instead. If all these dates are missing, then the extent of exposure will be set to missing.
!
The extent of exposure to study medication, up to first study medication dosage modification
!
The extent of exposure to each dose of study medication, presented separately for FF/VI 92 mcg/22
mcg, FF/VI 184 mcg/22mcg, FP/S 250 mcg/50 mcg, FP/S 500 mcg/50 mcg, BUD/F 200 mcg/6 mcg, 
BUD/F 400 mcg/12 mcg
10.6.3.
Efficacy
Primary Endpoint
ACT
The ACT is a validated self-administered questionnaire utilising 5 questions to assess asthma control during 
the past 4 Weeks on a 5-point categorical scale (1 to 5). 
By answering all 5 questions, a subject with asthma can obtain a score that may range between 5 and 25, 
with higher scores indicating better control. An ACT score of 5 to 19 suggests that the subject’s asthma is 
unlikely to be well controlled. A score of 20 to 25 suggests that the subject’s asthma is likely to be well 
controlled. The MID for ACT is 3 (Schatz, 2009).
The total score is calculated as the sum of the scores from all 5 questions, provided all scores are non-
missing; if any individual scores are missing then the overall score will be set to missing.
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Secondary Endpoint
Correct Use of Device
Inhaler use will be assessed at Randomisation (Visit 2), Week 12 (Visit 4) and Week 24 (Visit 6). Correct use 
of device is defined as making no critical or non-critical errors.
Critical and Non-Critical Errors for Ellipta
Critical errors:
!
Failed to open cover 
!
Shook the device upside down after dose preparation
!
Exhaled directly into mouthpiece 
!
No seal by the lips around the mouthpiece during the inhalation
Non-critical errors:
!
No exhalation before an inhalation
!
Inhalation manoeuvre was not:
-
long 
-
steady
-
deep
!
Blocked air inlet during inhalation manoeuvre
!
Did not hold breath 
!
Did not close the device (Note:  this is an error but one which does not affect the medication that is 
inhaled)
Critical and Non-Critical Errors for Diskus
Critical errors:
!
Failed to open cover
!
Lever is not pushed back 
!
Shook the device after dose preparation
!
Exhaled directly into mouthpiece 
!
No seal by the lips round the mouthpiece during the inhalation
Non-critical errors:
!
No exhalation before an inhalation
!
Inhalation manoeuvre was not:
-
steady
-
deep
!
Did not hold breath
!
Did not close the device (Note:  this is an error but one which does not affect the medication that is 
inhaled)
Critical and Non-Critical Errors for Turbuhaler
Critical errors:
!
Failed to remove cap
!
Did not hold device upright (±45° OK) during dose preparation
!
Base not twisted fully backwards and forwards, no click heard
!
Shook the device after dose preparation
!
Exhaled directly into mouthpiece
!
No seal by the lips round the mouthpiece during the inhalation
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Primary Endpoint
Non-critical errors:
!
Device tipped downwards after dose preparation
!
No exhalation before an inhalation
!
Inhalation manoeuvre was not:
-
forceful
-
deep
!
Blocked air inlet during inhalation manoeuvre
!
Did not hold breath
!
Did not close the device (Note:  this is an error but one which does not affect the medication that is 
inhaled)
Other Endpoints
FEV1
FEV1 will be measured to assess lung function at Randomisation (Visit 2) and Week 12 (Visit 4). Visit 4 
should be scheduled at the same time of day as Visit 2, FEV1 measurements should be taken pre-dose and 
subjects should be instructed not to take their asthma medication/study drug prior to coming into the clinic at 
these visits. Subjects should also withhold from using their rescue medication for at least 4 hours prior to 
Visit 2 and Visit 4.
All sites will use standardised spirometry equipment provided by GSK. For each observation, at least 3 (with 
no more than 8) efforts will be obtained. At least two of the spirometry efforts should be acceptable and 
repeatable. The best FEV1 value will be recorded in the eCRF.
MARS-A
The MARS-A questionnaire is a 10-item questionnaire. The response to all ten questions will be presented
and included in the calculation of the MARS-A 10-score. 
The responses to the MARS-A questions will be scored as follows: Always=1, Often=2, Sometimes=3, 
Rarely=4, Never=5. The MARS-A 10-Score will be calculated for each subject as the sum of scores for each 
of the ten questions divided by the number of non-missing responses to the ten questions.
If some responses are missing the MARS-A 10-score is calculated as follows for each subject:
!
If eight or more of the questions have been answered, the missing responses for that subject will be 
imputed to the average score
!
If less than eight of the questions have been answered, the overall MARS-A 10-score for that 
subject will be set to missing
The French translation of the MARS-A questionnaire did not go through cognitive debriefing; therefore while 
the study was ongoing it was determined that there is no word for “preventer” in French. “Preventer inhaler”
was translated as “dispositif d’inhalation” (i.e., “inhalation device”). A reminder was sent to centres in France 
instructing that the MARS-A questionnaire refers to the patient’s preventer inhaler (i.e. their maintenance 
therapy prior to entering the study, and study medication while on-study) as opposed to their reliever inhaler.
The German translation went through cognitive debriefing and was correctly translated. The MARS-A data 
displays will therefore be repeated split by:
!
Patients in France who had completed all MARS-A assessments prior to the reminder being 
implemented
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Other Endpoints
!
Patients in France who had completed at least one MARS-A assessment prior to the reminder being 
implemented but also completed at least one MARS-A assessment after the reminder being 
implemented
!
Patients in France who had not completed any MARS-A assessments prior to the reminder being 
implemented
!
Patients in Germany
The reminder was sent on 17OCT2016, and it was assumed that the centres started implementing the 
instructions two days after this, i.e. on 19OCT2016.
Severe Asthma Exacerbations
Missing onset or resolution dates will be handled as follows:
!
Single event with missing onset and/or resolution dates:
(a)
Missing onset date: set onset date = study treatment start date
(b)
Missing resolution date: set resolution date = study treatment stop date
(c)
Both missing: imputed per both (a) and (b)
!
Multiple events, one event with some missing onset/resolution dates; on the assumption any partial date 
information does not occur during the other events:
(a)
Missing onset date: set onset date = max[(resolution date of the nearest previous event) + 1 
day, study treatment start date]
(b)
Missing resolution date: set resolution date = min[(onset date of the nearest subsequent event) -
1 day, study treatment stop date] 
(c)
Both missing: determine the largest gap between study treatment start date and first event onset 
date, between first event resolution date and next event(s) onset dates (if any), between last 
event resolution date and study treatment stop date. If there is more than one gap which is the 
largest, then take the first occurrence. Then impute as follows:
onset date = (onset date of largest gap) + 1 day
resolution date = (resolution date of largest gap) + 1 day
Time to First Severe Asthma Exacerbation  
The date of a severe asthma exacerbation is defined as the exacerbation onset date. Subjects who complete 
the study without a severe asthma exacerbation will be censored.  Time to first severe asthma exacerbation 
is measured from the date of randomisation (i.e., study treatment start date) to the onset date of first severe 
asthma exacerbation, as recorded on eCRF, or study treatment stop date (Visit 6 or early withdrawal visit) for 
subject who complete the study without any severe asthma exacerbations (censored). Analyses of time to 
first severe asthma exacerbation will be censored at Day 168.
AQLQ(S) Domain and Total Scores
The AQLQ(S) contains 32 items in four domains: activity limitation (11 items), symptoms (12 items), 
emotional function (5 items) and environmental stimuli (4 items). The following items are included in each of 
the 4 domains:
!
Symptoms: 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 29, 30
!
Activity Limitation: 1, 2, 3, 4, 5, 11, 19, 25, 28, 31, 32
!
Emotional Function: 7, 13, 15, 21, 27
!
Environmental Stimuli: 9, 17, 23, 26
The response format consists of a seven-point scale where a value of 1 indicates “total impairment” and a 
value of 7 indicates “no impairment”. The total AQLQ(S) score is the mean of all 32 items in the 
questionnaire and each individual domain score is calculated as the mean of the items within that domain. 
Hence, the total and domain scores are also each defined on a range from 1 to 7 with higher scores 
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Other Endpoints
indicating a higher quality of life. The MID for AQLQ(S) is 0.5 (Juniper, 1993).
For the total AQLQ(S) score, the score for a subject at any time point will only be calculated if at least 90% of 
the questions were answered (calculated as the mean of those non-missing questions). If fewer than 90% of 
the questions were answered then the mean score for that subject at that time point will be considered 
missing.
For each individual domain of the AQLQ(S) score, the score for a subject at any time point will only be 
calculated if at least 90% of the questions for that domain were answered (calculated as the mean of those 
non-missing questions). If fewer than 90% of the questions were answered for that domain then the mean 
score for that subject and domain at that time point will be considered missing.
EQ-5D-5L Utility and VAS Scores
The EQ-5D-5L is administered at randomisation (Visit 2), Week 24 (Visit 6) and Early Withdrawal. The EQ-
5D-5L consists of 2 parts: the EQ-5D-5L descriptive system and the EQ VAS.
The EQ-5D-5L descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression. Each dimension has 5 levels, where Level 1 (coded as ‘1’) = ‘No 
problems’, Level 2 (coded as ‘2’) = ‘Slight problems’, Level 3 (coded as ‘3’) = ‘Moderate problems’, Level 4
(coded as ‘4’) = ‘Severe problems’ and Level 5 (coded as ‘5’) = ‘Extreme problems’. Subjects indicate their 
health state for each dimension by ticking (or placing a cross) in the box of the most appropriate level for that 
dimension. Ambiguous values (e.g. 2 boxes are ticked for a single dimension) will be considered missing. 
Missing values will be coded as ‘9’. The responses (1, 2, 3, 4 or 5) to the five questions will be converted into 
a single utility score using the developer’s instructions (EuroQol, 2013): the responses (1, 2, 3, 4 or 5) to the 
five questions in the descriptive system can be represented as one of 55=3125 possible health states (11111, 
11112, ... , 55555). These will be converted into a single summary index (y) that attaches value to each of 
the levels in each dimension by applying the formula below, which is based on the EQ-5D-5L value set for 
England (Devlin, 2016).
where variables with subscript 
are indicator variables equal to 1 when the corresponding level for the 
dimension is ‘ ’ and equal to 0 otherwise,
variables represent responses for the mobility domain, 
variables represent responses for the self-care domain,
variables represent responses for the usual 
activities domain,
variables represent responses for the pain / discomfort domain, and
variables 
represent responses for the anxiety / depression domain.
For example, health state where domains MSUPA = 11223 would be equal to:
The EQ VAS records the subject’s self-rated health state on a vertical, VAS where 0=’worst imaginable 
health state’ and 100=’best imaginable health state’. Subjects indicate their own health state by drawing a 
line from the box on the left of the scale to whichever point on the scale indicates how good or bad their own 
health state is that day. Ambiguous values (e.g. the line crosses the VAS twice) will be considered missing. 
Missing values will be coded as ‘999’.
Only validated EuroQoLs completed in the same language as that completed at Baseline (Visit 2) will be 
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Other Endpoints
summarised.
PASAP-Q Domain and Total Scores
The PASAP-Q is a self-administered 16-item questionnaire measuring satisfaction and preference with 
inhaler devices (Kozma, 2005). Two domains (performance and convenience) are calculated from 13 
satisfaction items, measured on a Likert-type scale where a value of 1 indicates “very dissatisfied” and 7 
indicates “very satisfied”. The performance and convenience domains together form the total score. The 
other items include an overall satisfaction question (again measured from 1 to 7), a preference question (not 
applicable and so not asked for this study) and a question on willingness to continue using the device in the 
future, measured on a scale of 0 (not willing) to 100 (definitely willing).
The performance and convenience domains include t he following items:
!
Performance: 1, 2, 3, 4, 5, 10, 11
!
Convenience: 6, 7, 8, 9, 12, 13
If the patient completes at least half of the items in a domain, values for missing items are imputed using the 
mean of the completed items in that domain. The domain score is then transformed to a scale from 0 (least) 
to 100 (most) as follows:
If the patient completes less than half of the items in a domain, then the missing items are not imputed and 
the domain score is set to missing. The total score can be calculated only when both domain scores are 
computable and substitution for missing items at the domain level has taken place, and is calculated on the 
same scale as:
The overall satisfaction and willingness questions are summarised on their original scales of 1 to 7 and 0 to 
100 respectively.
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Other Endpoints
Treatment Compliance
Overall percentage treatment compliance for every subject will be calculated for each type of inhaler (Diskus, 
Turbuhaler and Ellipta) separately. 
Compliance for Diskus, Turbuhaler and Ellipta will be based on the total number of inhalations taken from 
each type of inhaler and the expected number of inhalations to be taken. The expected number of inhalations 
will be derived as the expected number of inhalations per day (from each inhaler) multiplied by the number of 
days on study drug based on the subjects treatment start and stop date for that type of inhaler.
The total number of inhalations taken will be based on the dose counter for each type of inhaler, all of which 
are re-supplied during the study. If there is no dose counter information at all then the compliance will be 
missing; however, as long as the information from one dose counter is present, the compliance will be 
calculated. If a dose counter start count is missing then it will be assumed to be 30 for Ellipta and 60 for both 
Diskus and Turbuhaler.
In each calculation, all inhalers dispensed will be used, provided the dose counter stop counts are non-
missing. The following formula will be used:
where Total number of inhalations taken is the sum of (dose counter start count – dose counter stop count) 
for all inhalers used during the time period, Dose frequency is equal to 1 for Ellipta and 2 for Diskus and 
Turbuhaler, and Start date and Stop date are the earliest treatment start date and latest treatment stop date 
respectively recorded for all inhalers used during the time period. 
10.6.4.
Safety
SAEs of Special Interest
SAE groups of special interest have been defined as SAEs which are included in specified areas of interest 
for one or more of the treatment groups (FF/VI, FF and/or VI).  They are identified by groupings of preferred 
terms based on the Medical Dictionary for Regulatory Activities (MedDRA) dictionary version used in each 
reporting effort.  Groupings or subgroups may be defined, based on relevant combination of preferred terms, 
or on Standardised MedDRA queries (SMQs).
SAEs of special interest will be confirmed prior to final data, based on the MedDRA version in use at the 
time.
Special Interest SAE Group
Asthma/bronchospasm
Cardiovascular effects
Decreased bone mineral density and associated fractures
Hypersensitivity
Local steroid effects
LRTI excluding pneumonia
Pneumonia
Adrenal suppression
Ocular effects
Effects on glucose
Effects on potassium
Tremor
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Laboratory Parameters
!
If a laboratory value which is expected to have a numeric value for summary purposes, has a non-
detectable level reported in the database, where the numeric value is missing, but typically a character 
value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the comment field) is 
present, the number of significant digits in the observed values will be used to determine how much to 
add or subtract in order to impute the corresponding numeric value. 
o
Example 1: 2 Significant Digits =  ‘< x ‘ becomes x – 0.01
o
Example 2: 1 Significant Digit   =  ‘> x’ becomes x + 0.1
o
Example 3: 0 Significant Digits = ‘< x’ becomes x – 1    
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10.7.
Appendix 7: Premature Withdrawals & Handling of Missing 
Data
10.7.1.
Premature Withdrawals
Element
Reporting Detail
General
!
Subject study completion was defined in the protocol as a subject who has completed all 
study visits. The end of the study is defined as the last subject’s last visit.
!
The definition of subject early withdrawal from the study will be any subject who is 
randomised and, for any reason, does not complete all study visits.
!
Withdrawn subjects will not be replaced in the study.
!
All available data from subjects who were withdrawn from the study will be listed and all 
available planned data will be included in summary tables and figures, unless otherwise 
specified.
10.7.2.
Handling of Missing Data
Element
Reporting Detail
General
!
Missing data occurs when any requested data is not provided, leading to blank fields on
the collection instrument :
o
These data will be indicated by the use of a “blank” in subject 
listing displays (if applicable). Unless all data for a specific visit are missing in 
which case the data is excluded from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not 
considered to be missing data and should be displayed as such.
Outliers
!
Any subjects excluded from the summaries and/or statistical 
analyses will be documented along with the reason for exclusion in the clinical study 
report.
Exposure 
start and 
stop date
!
If a subject’s treatment start date is missing then their Visit 2 date will be assumed to be 
the exposure start date. If a subject’s treatment stop date is missing, this will be taken to 
be the date of Week 24 (Visit 6) (if the subject completes Visit 6) or the early withdrawal 
visit date.
10.7.2.1.
Handling of Missing or Partial Dates
Element
Reporting Detail
General
Partial dates will be displayed as captured in subject listing displays.
SAEs and 
ADRs
!
The eCRF does not allow the possibility of partial dates (i.e., only month and year) to be 
recorded for SAE and ADR start and end dates; 
!
Completely missing start or end dates will remain missing, with no imputation applied. 
Consequently, time to onset and duration of such events will be missing.
Concomitant 
Medications
!
Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will be 
used for the month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month.
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Element
Reporting Detail
!
The recorded partial date will be displayed in listings.
10.7.2.2.
Handling of Missing Data for Statistical Analysis
In general, missing data will not be imputed except for the sensitivity analyses defined in Section
6.1.2.
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10.8.
Appendix 8: Values of Potential Clinical Importance
10.8.1.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Clinical Concern Range
Lower
Upper
Systolic Blood Pressure (SBP)
mmHg
< 85
> 160
Diastolic Blood Pressure
(DBP)
mmHg
< 45
> 100
Heart Rate (HR)
bpm
< 40
> 110
Vital Sign Parameter
(Change from Baseline)
Units
Clinical Concern Range
Decrease
Increase
Lower
Upper
Lower
Upper
SBP
mmHg
≥ 20
≥ 40
≥ 20
≥ 40
DBP
mmHg
≥ 10
≥ 20
≥ 10
≥ 20
HR
bpm
≥ 15
≥ 30
≥ 15
≥ 30
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10.9.
Appendix 9: Multicenter Studies
10.9.1.
Methods for Handling Centres
In this multicentre study conducted in France and Germany, enrolment will be presented by 
investigative site.
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10.10.
Appendix 10: Examination of Covariates, Subgroups & 
Other Strata
10.10.1.
Examination of Strata and Covariates
The following is a list of covariates that may be used in descriptive summaries and statistical 
analyses, some of which may also be used for subgroup analyses.
Additional covariates of clinical interest may also be considered. 
Category
Covariates and / or Subgroups
Strata
Separate randomisation schedules were utilised for France and 
Germany respectively thereby stratifying the randomisation by 
country. Country will be included in all analyses as a covariate. A 
sensitivity analysis will examine the randomized treatment-by-country 
interaction for the primary and key secondary endpoints.
Covariates
For the primary efficacy analysis, the following baseline variables will 
be adjusted for: 
!
Randomised treatment (FF/VI, Usual ICS/LABA)
!
Baseline ACT total score
!
Age
!
Gender
!
Country
Similar covariates will be considered for all other analyses; in each 
case the relevant baseline score (e.g. baseline AQLQ[S] score for the 
AQLQ[S] endpoints) will be included instead of baseline ACT total 
score.
10.10.2.
Examination of subgroups
!
If the percentage of subjects is small within a particular subgroup, then the subgroup 
categories may be refined prior to unblinding the trial.
!
If the category cannot be refined further, then descriptive rather than statistical comparisons 
may be performed for the particular subgroup.
!
For statistical analyses by subgroup, models will include subgroup and treatment by subgroup 
interaction as covariates.
Category
Subgroups
Country
!
France
!
Germany
Number of severe asthma 
exacerbations in the previous year 
prior to randomisation
!
0
!
≥ 1
Smoking Status at Baseline
!
Current smokers
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Category
Subgroups
!
Former smokers
!
Non-smokers
Age Group
!
18 – 50 years old
!
> 50 years old
Gender
!
Male
!
Female
10.10.3.
Examination of seasonal effect
A sensitivity analysis for the primary efficacy endpoint examining seasonal effect is defined in 
Section 6.1.2, specifying a season at randomisation covariate defined as follows:
Season at Randomisation
Calendar Month of Randomisation
Spring
!
March
!
April
!
May
Summer
!
June
!
July
!
August
Autumn
!
September
!
October
!
November
Winter
!
December
!
January
!
February
Furthermore, the summary of severe asthma exacerbations will be repeated by season using the 
same definition (according to calendar month) as specified above.
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10.11.
Appendix 11: Multiple Comparisons & Multiplicity
10.11.1.
Handling of Multiple Comparisons & Multiplicity
Non inferiority of FF/VI to ICS/LABA will be first tested at the 0.05 two-sided nominal level of 
significance. If non-inferiority is statistically achieved, then superiority of FF/VI to ICS/LABA 
will be tested at the 0.05 two-sided nominal level of significance. 
If and only if non-inferiority is achieved for the primary endpoint at Week 12 (Visit 4), then the 
key secondary endpoint, i.e. the change from baseline in the total ACT score assessed at Week 24 
(Visit 6) will be tested. At Week 24 (Visit 6), non inferiority of FF/VI to ICS/LABA will be first 
tested at the 0.05 two-sided nominal level of significance. If non-inferiority is achieved, then 
superiority of FF/VI to ICS/LABA will be tested at the 0.05 two-sided nominal level of 
significance. 
Of note, this step-down testing procedure still strongly controls the overall type I error at the 0.05 
two-sided level for the non-inferiority endpoints. The overall type I error is not controlled for the 
superiority tests at Week 12 (Visit 4) and Week 24 (Visit 6).
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10.12.
Appendix 12: Model Checking and Diagnostics for 
Statistical Analyses
10.12.1.
Statistical Analysis Assumptions
Endpoint(s)
!
Change from Baseline in the ACT Total Score at Week 12 (Visit 4)
!
Change from Baseline in the ACT Total Score at Week 24 (Visit 6)
Analysis
!
MMRM (ANCOVA for LOCF and WOCF sensitivity analyses)
!
Should computational issues be encountered when running the model with an unstructured variance-
covariance matrix, other structures including autoregressive 1 and compound symmetry will be 
considered.
!
Distributional assumptions underlying the model will be checked with graphical methods (including 
quantile-quantile (Q-Q) plots of studentized residuals, plots of studentized residuals versus fitted 
values, etc.). To investigate the relationship between baseline ACT total score and the change from 
baseline in ACT total score, baseline ACT total will be categorized according to the distribution quartiles 
and the model will be fitted using this categorized variable in place of continuous baseline ACT total 
score.
!
If the distributional assumption of normality fails then the LS means, estimated LS mean treatment 
difference and associated 95% CI from the model will be presented, with the p-value for the difference 
between treatment groups from a model on the rank-transformed values. Should the distributional 
assumption of normality also fail for the ranked model, other methods of analysis will be investigated.
Endpoint(s)
!
Percentage of subjects with correct use of inhaler device at Week 12 (Visit 4) and at 
Week 24 (Visit 6) independently of the use at Week 12 (Visit 4)
!
ACT total score of ≥ 20 or ≥ 3 point increase from baseline in ACT total score at Week 
12 (Visit 4) and Week 24 (Visit 6)
!
Increase from baseline of ≥ 0.5 in AQLQ(S) total score at Week 24 (Visit 6)
!
Increase from baseline of ≥ 0.5 in AQLQ(S) environmental stimuli domain score at 
Week 24 (Visit 6)
!
Proportion of subjects with ‘no problems’ at Endpoint in the EQ-5D-5L questionnaire
Analysis
!
Logistic regression model
!
If the likelihood maximisation algorithm fails to converge due to complete or quasi-complete separation 
of the data then Firth’s penalized likelihood (Firth, 1993) will be implemented by use of the FIRTH 
option on the MODEL statement in PROC LOGISTIC.
!
The fit of the logistic regression model will be assessed by examining the ROC curve and other 
diagnostic plots. 
Endpoint(s)
!
Change from baseline in trough (pre-dose) FEV1 at Week 12 (Visit 4)
!
Change from baseline in EQ-5D Utility Score
!
Change from baseline in EQ-5D VAS Score
Analysis
!
ANCOVA model
!
Distributional assumptions underlying the model will be checked with graphical methods (including 
quantile-quantile (Q-Q) plots of studentized residuals, plots of studentized residuals versus fitted 
values, etc.). 
!
If the distributional assumption of normality fails then the LS means, estimated LS mean treatment 
difference and associated 95% CI from the ANCOVA model will be presented, with the p-value for the 
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difference between treatment groups from an ANCOVA model on the rank-transformed values. Should 
the distributional assumption of normality also fail for the ranked ANCOVA, an exact p-value from a 
two-sample Wilcoxon Rank Sum test will be presented for the difference between treatment groups.  
Endpoint(s)
!
Annual severe asthma exacerbation rate over the study period
Analysis
!
GLM assuming the Negative Binomial distribution
!
If a GLM assuming the Negative Binomial distribution cannot be fitted due to the lack of repeat events 
within a subject, a GLM assuming the Poisson distribution will be used. The underlying assumption for 
the Poisson distribution that the mean and variance of the response variable are equal will be 
examined. If the variance of the fitted model exceeds the mean (over-dispersion), the dispersion 
parameter will be estimated as a ratio of the Pearson Chi-Square to its associated degrees of freedom 
(using the PSCALE option in PROC GENMOD).
Endpoint(s)
!
Time to first severe asthma exacerbation
Analysis
!
Cox proportional hazards model
!
Proportional hazards assumptions will be checked by plotting the log of the negative log of the 
estimated survivor functions against log time, for each treatment group. If hazards are proportional, the 
lines should be approximately parallel.
!
If the assumption of proportionality is not met, the use of other models such as models including time-
dependent covariates will be considered. 
!
If there are computational issues in implementing the exact method for handling ties, then the Efron 
method (Efron, 1977) will be used instead.
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10.13.
Appendix 13: Blinding Strategy
Purpose
!
The trial design (open label) and the ways the study medication data are recorded in the 
datasets means that extra steps must be taken to ensure that S&P remain blinded to 
investigational product (IP) data until the formal unblinding takes place at DBF. 
Maintaining the blind prior to DBF is a requirement for the French Ethics Committee.
!
S&P also need to be able to have sufficient data to pre-program up to the point of DBF. 
This needs to done on sufficient ‘real’ data to ensure the programs can handle all 
possibilities of data, particularly regarding treatment modifications during the study.
!
Datasets containing IP data that need to be considered: EXPOSURE and INVPCOMP
!
Other datasets that contain data that could unblind S&P and therefore also need to be 
considered: DS, DV1, FADTH, INDEVERR, and IPDEVMAL
!
Note: assigning subjects to dummy (blinded) randomised treatment group (FF/VI or 
Other ICS/LABA) prior to DBF will be done in the usual way using standard GSK 
procedures.
!
To ensure unblinding does not occur through other sources, access to INFORM, E-Track, 
Study Explorer, DMENV 
(\\uk1salx00175.corpnet2.com\dmenv\dmwork\gw685698_gw642444\hza116492) and 
SPECTRE is prohibited for S&P.
Proposal for the EXPOSURE dataset
Prior to DBF:
Data Management (DM) to provide two datasets to S&P based on the source EXPOSURE 
dataset.
(1) Dataset EXPOSURE – same as the source EXPOSURE dataset but with EXINVPCD 
(study treatment code) and EXINVP (study treatment) blanked out as ‘999’ and 
‘CENSORED’ respectively. This will allow S&P to use the subjects’ real exposure start 
dates and times and stop dates in order to assign other data items to pre, during and post 
treatment, derive study day, overall exposure duration etc
(2) Dataset named DUM_EXP_SP, which will be a scrambled sample of the EXPOSURE 
dataset. Each time S&P are provided a new update of data from DM a different 
scrambled sample of data will be used. 
The method to be used by DM to sample and scramble the data is as follows:
!
Select a sample of subjects, in the EXPOSURE dataset using a random sampling method 
which uses a seed (so that the same ones could be chosen again if it needs to be re-run). 
The exact size of this sample will change according to the number of subjects in the 
EXPOSURE dataset at that time, ensuring that no more than ≈50% of the total sample 
size (N=422) is used at any point and defined per the following table:
No. of subjects in 
EXPOSURE dataset
Percentage of subjects 
used for sampling
≤ 199
94%
200 to 299 inclusive
70%
≥ 300
40%
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!
Store which subjects have been chosen so it can be checked over time that all subjects get 
seen by programmers before DBR
!
Make a random adjustment to the dates and times in the sample, such that e.g. the first 
subject has 10 days added to all their dates and 34 minutes added to their start times, the 
second subject has 17 days subtracted from all their dates and 95 minutes added to their 
start times – this means they do not match with any real dates or times in the 
EXPOSURE dataset above, but it means the within-subject integrity of dates remains. 
The range of the date adjustment is set at the range ± 60 days, and the range of the time 
adjustment is set at the range ± 120 minutes.
!
Rename subjid to orig_subj – this enables DM to be able to trace the subject in the event 
of data queries from S&P
!
Randomly map this sampled data onto the SUBJIDs in the EXPOSURE dataset, so that 
every true SUBJID in the EXPOSURE dataset has scrambled subject data assigned to it
!
Data management keep a copy of this with the orig_subj number in it
!
Data management remove orig_subj and pass this data to S&P
At DBF: 
DM will provide to S&P the one unmodified version of EXPOSURE dataset, with all variables 
uncensored.
Proposal for the INVPCOMP, INDEVERR and IPDEVMAL datasets
Prior to DBF:
DM to provide a single version of each dataset to S&P based on the source datasets.
(1) Dataset named DUM_INVP_SP, DUM_IERR_SP and DUM_IMAL_SP which will be a 
scrambled (subjid) sample of the INVPCOMP, INDEVERR and IPDEVMAL datasets 
respectively. Each time S&P are provided a new update of data from DM a different 
scrambled sample of data will be used. 
These datasets must be produced in conjunction with DUM_EXP so that the same subjects get 
selected, the same date adjustment per subject is made and the same merging onto real subject 
data gets done.
At DBF:
DM will provide the single unmodified versions of INVPCOMP, INDEVERR and IPDEVMAL 
datasets, with all variables uncensored
Other datasets and variables to be censored before being sent to S&P up until DBF
Dataset
Variables to be censored before being sent to 
S&P up until DBF
DS
DSRSSP, DSSBRSSP
DV1
DVTERM
FADTH
DDORRSTX, DDORRSSP
Documentation
Once this blinding strategy has been agreed between S&P and DM, and approved by the study 
Clinical Investigation Lead (CIL), the Data Quality Lead (DQL) will send an email to S&P 
stating that the blinding strategy is in place and is being followed.
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10.14.
Appendix 14: Abbreviations & Trade Marks
10.14.1.
Abbreviations
Abbreviation
Description
ACT
Asthma Control Test
ADR
Adverse Drug Reaction
AE
Adverse Event
AESI
Adverse Event of Special Interest
ANCOVA
Analysis of Covariance
AQLQ(S)
Standardised Asthma Quality of Life Questionnaire
ASE
All Subjects Enrolled
BMI
Body Mass Index
BUD
Budesonide
CI
Confidence Interval
CIL
Clinical Investigational Lead
CRF
Case Report Form
CRO
Contract Research Organisation
DBF
Database Freeze
DBP
Diastolic Blood Pressure
DBR
Database Release
DM
Data Management
DP
Decimal Place
DPI
Dry Powder Inhaler
DQL
Data Quality Lead
eCRF
Electronic Case Report Form
EQ-5D-5L
EuroQol Questionnaire
F
Formoterol
FEV1
Forced Expiratory Volume in 1 Second
FF
Fluticasone Furoate
FP
Fluticasone Propionate
GINA
Global Initiative for Asthma
GLM
Generalised Linear Model
GSK
GlaxoSmithKline
HL
Hodges-Lehmann
HR
Heart Rate
ICF
Informed Consent Form
ICS
Inhaled Corticosteroid
IDSL
Integrated Data Standards Library
IP
Investigational Product
ITT
Intent-to-Treat
LABA
Long-acting Beta Agonist
LOCF
Last Observation Carried Forward
LRTI
Lower Respiratory Tract Infection
LS
Least Squares
MAR
Missing at Random
MARS-A
Medication Adherence Report Scale for Asthma
MCID
Minimal Clinically Important Difference
MedDRA
Medical Dictionary for Regulatory Activities 
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Abbreviation
Description
MI
Multiple Imputation
MID
Minimally Important Difference
MMRM
Mixed Model Repeated Measures
PASAP-Q
Patient Satisfaction and Preference  Questionnaire
PD
Protocol Deviation
PDMP
Protocol Deviation Management Plan
PP
Per Protocol
Q-Q
Quantile-Quantile
RAP
Reporting and Analysis Plan
REML
Restricted Maximum Likelihood
S
Salmeterol
S&P
Statistics and Programming
SAC
Statistical Analysis Complete
SAE
Serious Adverse Event
SBP
Systolic Blood Pressure
SD
Standard Deviation
SMQ
Standardised MedDRA Query
VAS
Visual Analogue Scale
VI
Vilanterol
WOCF
Worst Observation Carried Forward
10.14.2.
Trademarks
Trademarks of the GlaxoSmithKline Group 
of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
DISKUS
ACT
ELLIPTA
Asthma Quality of Life Questionnaire -
AQLQ(S)
GSK
EQ-5D
NUCALA
MARS-A Questionnaire
SERETIDE
PASAP Questionnaire
Symbicort Turbuhaler
TURBUHALER
XOLAIR
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10.15.
Appendix 15: List of Data Displays
10.15.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.n
1.1 to 1.n
Efficacy
2.1 to 2.n
2.1 to 2.n
Safety
3.1 to 3.n
3.1 to 3.n
Section
Listings
ICH Listings
1 to x
Other Listings
y to z
10.15.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required an example mock-up 
displays provided in Appendix 11: Example Mock Shells for Data Displays
.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Efficacy
EFF_Fn
EFF_Tn
EFF_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
NOTES: 
!
Non-Standard displays are indicated in the ‘IDSL / TST ID / Example Shell’ or ‘Programming Notes’ column as 
‘[Non-Standard] + Reference.’
10.15.3.
Deliverable [Priority]
Delivery [Priority] [1]
Description
Data Look [1]
Data Look Outputs (blinded review)
SAC [2]
Final Statistical Analysis Complete
NOTES: 
1.
Indicates priority (i.e. order) in which displays will be generated for the reporting effort.
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10.15.4.
Study Population Tables
Study Population: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
All Enrolled 
Subjects
Non-Standard 
POP_T1
Summary of Subject Populations
Randomised population line will provide 
the denominators for the ITT, PP and 
Safety percentages.
Data Look [1] 
SAC [2]
1.2.
All Enrolled 
Subjects
IE2
Summary of Inclusion/Exclusion Criteria Failures for Subjects 
Not Starting Treatment
Data Look [1] 
SAC [2]
1.3.
ITT
ES1
Summary of End of Study Record
Data Look [1] 
SAC [2]
1.4.
PP
ES1
Summary of End of Study Record
Per Protocol Population
Data Look [1] 
SAC [2]
1.5.
ITT
Non-Standard 
POP_T2
Summary of Attendance at Each Clinic Visit and Phone Call Visit
Data Look [1] 
SAC [2]
1.6.
All Enrolled 
Subjects
NS3
Summary of Number of Subjects by Country and Centre
SAC [2]
1.7.
ITT
NS3
Summary of Number of Subjects by Country and Centre
Data Look [1] 
SAC [2]
1.8.
PP
NS3
Summary of Number of Subjects by Country and Centre
Per Protocol Population
SAC [2]
Protocol Deviations
1.9.
ITT
IE2
Summary of Deviations from the Inclusion/Exclusion Criteria
Data Look [1] 
SAC [2]
1.10.
ITT
Non-Standard 
POP_T3
Summary of Important Protocol Deviations
Data Look [1] 
SAC [2]
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Study Population: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.11.
ITT
Non-Standard 
POP_T3
Summary of Important Protocol Deviations Resulting in 
Exclusion from the PP Population
Data Look [1] 
SAC [2]
Demographic and Baseline Characteristics
1.12.
ITT
DM1
Summary of Demographic Characteristics
Data Look [1] 
SAC [2]
1.13.
PP
DM1
Summary of Demographic Characteristics
Per Protocol Population
SAC [2]
1.14.
Safety
DM1
Summary of Demographic Characteristics
Safety Population
SAC [2]
1.15.
All Enrolled 
Subjects
DM11
Summary of Age Ranges
Data Look [1] 
SAC [2]
1.16.
ITT
DM5
Summary of Race and Racial Combinations
Data Look [1] 
SAC [2]
1.17.
ITT
DM6
Summary of Race and Racial Combinations Details
Data Look [1] 
SAC [2]
1.18.
ITT
MH4
Summary of Current Medical Conditions
Data Look [1] 
SAC [2]
1.19.
ITT
MH4
Summary of Past Medical Conditions
SAC [2]
1.20.
ITT
Non-Standard 
POP_T4
Summary of Asthma Duration at Baseline
Data Look [1] 
SAC [2]
1.21.
PP
Non-Standard 
POP_T4
Summary of Asthma Duration at Baseline
Per Protocol Population
Data Look [1] 
SAC [2]
1.22.
ITT
Non-Standard 
POP_T5
Summary of Asthma Exacerbation History at Baseline
Data Look [1] 
SAC [2]
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Study Population: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.23.
PP
Non-Standard 
POP_T5
Summary of Asthma Exacerbation History at Baseline
Per Protocol Population
Data Look [1] 
SAC [2]
1.24.
ITT
Non-Standard 
POP_T6
Summary of Smoking History at Baseline
Data Look [1] 
SAC [2]
1.25.
PP
Non-Standard 
POP_T6
Summary of Smoking History at Baseline
Per Protocol Population
SAC [2]
Concomitant Medications
1.26.
ITT
CM8
Summary of Pre-Treatment Concomitant Medications
SAC [2]
1.27.
ITT
CM8
Summary of On-Treatment Concomitant Medications
SAC [2]
1.28.
ITT
CM8
Summary of On-Treatment Asthma Concomitant Medications
Data Look [1] 
SAC [2]
Exposure
1.29.
ITT
Non-Standard 
POP_T7
Summary of Study Medication Dosage Modification
Data Look [1] 
SAC [2]
1.30.
ITT
Non-Standard 
POP_T8
Summary of Extent of Exposure to Study Medication 
(Regardless of Modification to Study Medication Dosage)
Data Look [1] 
SAC [2]
1.31.
ITT
Non-Standard 
POP_T8
Summary of Extent of Exposure to Study Medication (up to First 
Modification to Study Medication Dosage)
SAC [2]
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Study Population: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.32.
ITT
Non-Standard 
POP_T9
Summary of Extent of Exposure to Study Medication by 
Medication and Dosage
Repeat on subsequent pages for 
Medication/Dosage = FF/VI 184 mcg/22 
mcg OD, FP/S 250 mcg/50 mcg BID, 
FP/S 500 mcg/50 mcg BID, BUD/F 200 
mcg/6 mcg BID (1 inhalation per dose), 
BUD/F 200 mcg/6 mcg BID (2 
inhalations per dose), BUD/F 400 
mcg/12 mcg BID (1 inhalation per 
dose), BUD/F 400 mcg/12 mcg BID (2 
inhalations per dose).
Data Look [1] 
SAC [2]
Number of Subjects by Subgroup
1.33.
ITT
Non-Standard 
POP_T10
Summary of Number of Subjects by Subgroup
SAC [2]
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10.15.5.
Study Population Figures
Study Population: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Exposure
1.1.
ITT
Non-Standard 
POP_F1
Plot of Exposure to Study Medication (Regardless of 
Modification to Study Medication Dosage)
Display increments of 6 weeks on the x-
axis, up to the maximum exposure (e.g. 
0, 6, 12, 18, 24, 30).
Data Look [1] 
SAC [2]
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10.15.6.
Efficacy Tables
Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Change from Baseline in ACT Total Score at Week 12 (Visit 4)
2.1.
ITT
Non-Standard 
EFF_T1
Summary of Change from Baseline in ACT Total Score
Data Look [1] 
SAC [2]
2.2.
PP
Non-Standard 
EFF_T1
Summary of Change from Baseline in ACT Total Score
Per Protocol Population
SAC [2]
2.3.
ITT
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 12 (Visit 4)
Data Look [1] 
SAC [2]
2.4.
PP
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 12 (Visit 4)
Per Protocol Population
SAC [2]
2.5.
ITT
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 12 (Visit 4) (ANCOVA with LOCF)
Footnotes as follows: “Note: The 
analysis method was an ANCOVA 
model adjusted for randomised 
treatment, baseline ACT total score, 
gender, age and country. Note: Missing 
values at Week 12 (Visit 4) were 
replaced by last available post-
randomization value based on the last 
observation carried forward (LOCF) 
method.”
Data Look [1] 
SAC [2]
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.6.
ITT
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 12 (Visit 4) (Multiple Imputation –
Missing at Random Approach)
Footnotes as follows:
“Note: Missing values post-
randomisation were imputed using 
multiple imputation methods based on 
pattern mixture models.
Note: Each imputed data set was 
analysed using an ANCOVA model at 
Week 12 (Visit 4) adjusted for 
randomised treatment, baseline ACT 
total score, gender, age and country 
and the resulting treatment differences 
and their standard errors combined 
using Rubin’s rules.”
Data Look [1] 
SAC [2]
2.7.
ITT
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 12 (Visit 4) (Multiple Imputation –
Copy Differences from Reference Approach)
Footnotes as follows:
“Note: Missing values post-
randomisation were imputed using 
multiple imputation methods based on 
pattern mixture models.
Note: Each imputed data set was 
analysed using an ANCOVA model at 
Week 12 (Visit 4) adjusted for 
randomised treatment, baseline ACT 
total score, gender, age and country 
and the resulting treatment differences 
and their standard errors combined 
using Rubin’s rules.”
Data Look [1] 
SAC [2]
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.8.
ITT
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 12 (Visit 4) (Hodges-Lehmann 
Approach)
Present the “Difference” and “95% CI” 
lines of “FF/VI vs. Usual ICS/LABA” 
section only. Footnotes as follows:
“Note: The difference between 
treatment groups at Week 12 (Visit 4) 
was calculated using the Hodges-
Lehmann approach.”
Data Look [1] 
SAC [2]
2.9.
ITT
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 12 (Visit 4) (ANCOVA with WOCF)
Footnotes as follows:
“Note: The analysis method was an 
ANCOVA model adjusted for 
randomised treatment, baseline ACT 
total score, gender, age and country.
Note: Missing values at Week 12 (Visit 
4) due to treatment withdrawal prior to 
this time point were replaced by worst 
post-randomisation value based on the 
worst observation carried forward 
(WOCF) method.”
Data Look [1] 
SAC [2]
2.10.
ITT
Non-Standard 
EFF_T3
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 12 (Visit 4), Adjusting for Seasonal 
Effect
Repeat on subsequent pages for 
Season at randomisation = Summer, 
Autumn, Winter.
Data Look [1] 
SAC [2]
2.11.
PP
Non-Standard 
EFF_T3
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 12 (Visit 4), Adjusting for Seasonal 
Effect
Per Protocol Population
Repeat on subsequent pages for 
Season at randomisation = Summer, 
Autumn, Winter.
SAC [2]
2.12.
ITT
Non-Standard 
EFF_T1
Summary of Change from Baseline in ACT Total Score, FF/VI 
Versus the Subset of Usual ICS/LABA Subjects Prescribed FP/S 
at Randomisation
Data Look [1]
SAC [2]
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.13.
ITT
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 12 (Visit 4), FF/VI Versus the Subset 
of Usual ICS/LABA Subjects Prescribed FP/S at Randomisation
Output only to be produced if ≥25% of 
Usual ICS/LABA patients are 
prescribed FP/S at randomisation.
Data Look [1]
SAC [2]
2.14.
ITT
Non-Standard 
EFF_T1
Summary of Change from Baseline in ACT Total Score, FF/VI 
Versus the Subset of Usual ICS/LABA Subjects Prescribed 
BUD/F at Randomisation
SAC [2]
2.15.
ITT
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 12 (Visit 4), FF/VI Versus the Subset 
of Usual ICS/LABA Subjects Prescribed BUD/F at 
Randomisation
Output only to be produced if ≥75% of 
Usual ICS/LABA patients are 
prescribed BUD/F at randomisation.
SAC [2]
2.16.
ITT
Non-Standard 
EFF_T1S
Summary of Change from Baseline in ACT Total Score by 
Country
Data Look [1] 
SAC [2]
2.17.
ITT
Non-Standard 
EFF_T2S
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 12 (Visit 4) by Country
Data Look [1] 
SAC [2]
2.18.
ITT
Non-Standard 
EFF_T1S
Summary of Change from Baseline in ACT Total Score by 
Number of Severe Asthma Exacerbations in the Previous Year 
Prior to Randomisation
SAC [2]
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.19.
ITT
Non-Standard 
EFF_T2S
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 12 (Visit 4) by Number of Severe 
Asthma Exacerbations in the Previous Year Prior to 
Randomisation
First footnote as follows:
“Note: The analysis method was an 
MMRM adjusted for randomised 
treatment, visit (Week 6 and Week 12), 
baseline ACT total score, baseline ACT 
total score-by-visit interaction, gender, 
age, country, number of severe asthma 
exacerbations in the previous year prior 
to randomisation, two- and three- way 
interactions between randomised 
treatment, visit and number of severe 
asthma exacerbations in the previous 
year prior to randomisation, and patient 
fitted as a random factor.”
SAC [2]
2.20.
ITT
Non-Standard 
EFF_T1S
Summary of Change from Baseline in ACT Total Score by 
Smoking Status at Baseline
SAC [2]
2.21.
ITT
Non-Standard 
EFF_T2S
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 12 (Visit 4) by Smoking Status at 
Baseline
First footnote as follows: “Note: The 
analysis method was an MMRM 
adjusted for randomised treatment, visit 
(Week 6 and Week 12), baseline ACT 
total score, baseline ACT total score-
by-visit interaction, gender, age, 
country, smoking status at baseline, 
two- and three- way interactions 
between randomised treatment, visit 
and smoking status at baseline, and 
patient fitted as a random factor.”
SAC [2]
2.22.
ITT
Non-Standard 
EFF_T1S
Summary of Change from Baseline in ACT Total Score by Age 
Group
SAC [2]
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.23.
ITT
Non-Standard 
EFF_T2S
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 12 (Visit 4) by Age Group
First footnote as follows: “Note: The 
analysis method was an MMRM 
adjusted for randomised treatment, visit 
(Week 6 and Week 12), baseline ACT 
total score, baseline ACT total score-
by-visit interaction, gender, country, 
age group, two- and three- way 
interactions between randomised 
treatment, visit and age group, and 
patient fitted as a random factor.”
SAC [2]
2.24.
ITT
Non-Standard 
EFF_T1S
Summary of Change from Baseline in ACT Total Score by 
Gender
SAC [2]
2.25.
ITT
Non-Standard 
EFF_T2S
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 12 (Visit 4) by Gender
First footnote as follows: “Note: The 
analysis method was an MMRM 
adjusted for randomised treatment, visit 
(Week 6 and Week 12), baseline ACT 
total score, baseline ACT total score-
by-visit interaction, gender, age, 
country, two- and three- way 
interactions between randomised 
treatment, visit and gender, and patient 
fitted as a random factor.”
SAC [2]
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82
Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Change from Baseline in ACT Total Score at Week 24 (Visit 6)
2.26.
ITT
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 24 (Visit 6)
First footnote as follows:
“Note: The analysis method was an 
MMRM adjusted for randomised 
treatment, visit (Week 6, Week 12, 
Week 18 and Week 24), baseline ACT 
total score, randomised treatment-by-
visit interaction, baseline ACT total 
score-by-visit interaction, gender, age,
country and patient fitted as a random 
factor.”
Data Look [1] 
SAC [2]
2.27.
PP
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 24 (Visit 6)
Per Protocol Population
First footnote as follows:
“Note: The analysis method was an 
MMRM adjusted for randomised 
treatment, visit (Week 6, Week 12, 
Week 18 and Week 24), baseline ACT 
total score, randomised treatment-by-
visit interaction, baseline ACT total 
score-by-visit interaction, gender, age, 
country and patient fitted as a random 
factor.”
SAC [2]
2.28.
ITT
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 24 (Visit 6) (ANCOVA with LOCF)
Footnotes as follows: “Note: The 
analysis method was an ANCOVA 
model adjusted for randomised 
treatment, baseline ACT total score, 
gender, age and country. Note: Missing 
values at Week 24 (Visit 6) were 
replaced by last available post-
randomization value based on the last 
observation carried forward (LOCF) 
method.”
SAC [2]
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.29.
ITT
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 24 (Visit 6) (Multiple Imputation –
Missing at Random Approach)
Footnotes as follows:
“Note: Missing values post-
randomisation were imputed using 
multiple imputation methods based on 
pattern mixture models.
Note: Each imputed data set was 
analysed using an ANCOVA model at 
Week 24 (Visit 6) adjusted for 
randomised treatment, baseline ACT 
total score, gender, age and country 
and the resulting treatment differences 
and their standard errors combined 
using Rubin’s rules.”
SAC [2]
2.30.
ITT
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 24 (Visit 6) (Multiple Imputation –
Copy Differences from Reference Approach)
Footnotes as follows:
“Note: Missing values post-
randomisation were imputed using 
multiple imputation methods based on 
pattern mixture models.
Note: Each imputed data set was 
analysed using an ANCOVA model at 
Week 24 (Visit 6) adjusted for 
randomised treatment, baseline ACT 
total score, gender, age and country 
and the resulting treatment differences 
and their standard errors combined 
using Rubin’s rules.”
SAC [2]
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.31.
ITT
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 24 (Visit 6) (Hodges-Lehmann 
Approach)
Present the “Difference” and “95% CI” 
lines of “FF/VI vs. Usual ICS/LABA” 
section only. Footnotes as follows:
“Note: The difference between 
treatment groups at Week 24 (Visit 6) 
was calculated using the Hodges-
Lehmann approach.”
SAC [2]
2.32.
ITT
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 24 (Visit 6) (ANCOVA with WOCF)
Footnotes as follows:
“Note: The analysis method was an 
ANCOVA model adjusted for 
randomised treatment, baseline ACT 
total score, gender, age and country.
Note: Missing values at Week 24 (Visit 
6) due to treatment withdrawal prior to 
this time point were replaced by worst 
post-randomisation value based on the 
worst observation carried forward 
(WOCF) method.”
SAC [2]
2.33.
ITT
Non-Standard 
EFF_T3
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 24 (Visit 6), Adjusting for Seasonal 
Effect
First footnote as follows:
“Note: The analysis method was an 
MMRM adjusted for randomised 
treatment, visit (Week 6, Week 12, 
Week 18 and Week 24), baseline ACT 
total score, baseline ACT total score-
by-visit interaction, gender, age, 
country, season at randomisation, two-
and three- way interactions between 
randomised treatment, visit and season 
at randomisation, and patient fitted as a 
random factor.”
SAC [2]
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.34.
PP
Non-Standard 
EFF_T3
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 24 (Visit 6), Adjusting for Seasonal 
Effect
Per Protocol Population
First footnote as follows:
“Note: The analysis method was an 
MMRM adjusted for randomised 
treatment, visit (Week 6, Week 12, 
Week 18 and Week 24), baseline ACT 
total score, baseline ACT total score-
by-visit interaction, gender, age, 
country, season at randomisation, two-
and three- way interactions between 
randomised treatment, visit and season 
at randomisation, and patient fitted as a 
random factor.”
SAC [2]
2.35.
ITT
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 24 (Visit 6), FF/VI Versus the Subset 
of Usual ICS/LABA Subjects Prescribed FP/S at Randomisation
Output only to be produced if ≥25% of 
Usual ICS/LABA patients are 
prescribed FP/S at randomisation. First 
footnote as follows:
“Note: The analysis method was an 
MMRM adjusted for randomised 
treatment, visit (Week 6, Week 12, 
Week 18 and Week 24), baseline ACT 
total score, randomised treatment-by-
visit interaction, baseline ACT total 
score-by-visit interaction, gender, age, 
country and patient fitted as a random 
factor.”
SAC [2]
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.36.
ITT
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 12 (Visit 4), FF/VI Versus the Subset 
of Usual ICS/LABA Subjects Prescribed BUD/F at 
Randomisation
Output only to be produced if ≥25% of 
Usual ICS/LABA patients are 
prescribed BUD/F at randomisation. 
First footnote as follows:
“Note: The analysis method was an 
MMRM adjusted for randomised 
treatment, visit (Week 6, Week 12, 
Week 18 and Week 24), baseline ACT 
total score, randomised treatment-by-
visit interaction, baseline ACT total 
score-by-visit interaction, gender, age, 
country and patient fitted as a random 
factor.”
SAC [2]
2.37.
ITT
Non-Standard 
EFF_T2S
Summary of the Statistical Analysis of Change from Baseline in 
ACT Total Score at Week 24 (Visit 6) by Country
First footnote as follows:
“Note: The analysis method was an 
MMRM adjusted for randomised 
treatment, visit (Week 6, Week 12, 
Week 18 and Week 24), baseline ACT 
total score, baseline ACT total score-
by-visit interaction, gender, age, 
country, two- and three- way 
interactions between randomised 
treatment, visit and country, and patient 
fitted as a random factor.”
SAC [2]
Correct Use of Inhaler Device 
2.38.
ITT
Non-Standard 
EFF_T4
Summary of Inhaler Device Use Errors
Repeat on subsequent pages for Visit = 
Week 12 and Week 24. “Number of 
patients using...” line will provide the 
denominators for each section’s 
percentages.
Data Look [1] 
SAC [2]
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.39.
PP
Non-Standard 
EFF_T4
Summary of Inhaler Device Use Errors
Per Protocol Population
Repeat on subsequent pages for Visit = 
Week 12 and Week 24. “Number of 
patients using...” line will provide the 
denominators for each section’s 
percentages.
SAC [2]
2.40.
ITT
Non-Standard 
EFF_T5
Summary of Correct Use of Inhaler Device
Data Look [1] 
SAC [2]
2.41.
PP
Non-Standard 
EFF_T5
Summary of Correct Use of Inhaler Device
Per Protocol Population
SAC [2]
2.42.
ITT
Non-Standard 
EFF_T6
Summary of the Statistical Analysis of Correct Use of Inhaler 
Device at Week 12 (Visit 4) and at Week 24 (Visit 6) 
Independently of the Use at Week 12 (Visit 4)
Data Look [1] 
SAC [2]
2.43.
PP
Non-Standard 
EFF_T6
Summary of the Statistical Analysis of Correct Use of Inhaler 
Device at Week 12 (Visit 4) and at Week 24 (Visit 6) 
Independently of the Use at Week 12 (Visit 4)
Per Protocol Population
SAC [2]
Lung Function Tests
2.44.
ITT
Non-Standard 
EFF_T1
Summary of Change from Baseline in Lung Function Tests
Present an additional column to the left 
of “Visit”, labelled “Test” with values 
“Trough (Pre-dose) FEV1” and “Trough 
(Pre-dose) Percent Predicted FEV1” to 
allow presentation of results by Test. 
Present the following visits: Day 0, 
Week 12, Change from Baseline at 
Week 12, Early Withdrawal and 
Change from Baseline at Early 
Withdrawal.
Data Look [1] 
SAC [2]
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.45.
ITT
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
Trough (Pre-dose) FEV1 at Week 12 (Visit 4)
Footnote as follows:
“Note: The analysis method was an 
ANCOVA model adjusted for 
randomised treatment, baseline trough 
(pre-dose) FEV1, gender, age and 
country.”
Data Look [1] 
SAC [2]
Subjects Who Have Either an ACT Total Score >= 20 or >= 3 Point Increase from Baseline in ACT Total Score
2.46.
ITT
Non-Standard 
EFF_T7
Summary of Percentage of Subjects Who Have Either an ACT 
Total Score >= 20 or >= 3 Point Increase from Baseline in ACT 
Total Score
Repeat for Visit = Week 18, Week 24, 
Early Withdrawal.
Data Look [1] 
SAC [2]
2.47.
ITT
Non-Standard 
EFF_T6
Summary of the Statistical Analysis of Percentage of Subjects 
Who Have Either an ACT Total Score >= 20 or >= 3 Point 
Increase from Baseline in ACT Total Score at Week 12 (Visit 4) 
and Week 24 (Visit 6)
Replace “With correct use [1]” with 
“Responder [1]” and “Without correct 
use” with “Non-Responder”. 
Footnotes as follows:
“[1] Responder is defined as an ACT 
total score >= 20 or >= 3 point increase 
from baseline in ACT total score at that 
visit.
Note: The analysis method was logistic 
regression adjusted for randomised 
treatment, baseline ACT total score, 
baseline ACT total score squared, 
gender, age and country.”
SAC [2]
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Individual ACT Question Scores
2.48.
ITT
Non-Standard 
EFF_T8
Summary of Individual ACT Question Scores
Repeat on subsequent pages for 
Question = 2. Shortness of breath, 3. 
Asthma symptoms woken up at night or 
earlier than usual, 4. Used rescue 
inhaler or nubuliser medication, 5. 
Asthma control.
Data Look [1] 
SAC [2]
Compliance with Study Medication
2.49.
ITT
Non-Standard 
EFF_T9
Summary of Compliance with Study Medication
Data Look [1] 
SAC [2]
2.50.
PP
Non-Standard 
EFF_T9
Summary of Compliance with Study Medication
Per Protocol Population
SAC [2]
MARS-A
2.51.
ITT
Non-Standard 
EFF_T10
Summary of Use of Medication Adherence Report Scale for 
Asthma (MARS-A) During the Study
Repeat on subsequent pages for Visit = 
Week 12, Week 24 and Early 
Withdrawal.
Data Look [1] 
SAC [2]
2.52.
ITT
Non-Standard 
EFF_T10S
Summary of Use of Medication Adherence Report Scale for 
Asthma (MARS-A) During the Study by Status of Patient in 
Relation to the Reminder Sent to French Centres
Repeat on subsequent pages for Visit = 
Week 12, Week 24 and Early 
Withdrawal, and for Status = Patients in 
France who had completed at least one 
MARS-A assessment prior to the 
reminder being implemented but also 
completed at least one MARS-A 
assessment after the reminder being 
implemented, Patients in France who 
had not completed any MARS-A 
assessments prior to the reminder
being implemented, Patients in 
Germany.
Data Look [1]
SAC [2]
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Severe On-Treatment Asthma Exacerbations
2.53.
ITT
Non-Standard 
EFF_T11
Summary of Severe On-Treatment Asthma Exacerbations
Data Look [1] 
SAC [2]
2.54.
ITT
Non-Standard 
EFF_T11S
Summary of Severe On-Treatment Asthma Exacerbations by 
Season
Repeat on subsequent pages for 
Season = Summer, Autumn, Winter.
Data Look [1] 
SAC [2]
2.55.
ITT
Non-Standard 
EFF_T12
Summary of the Statistical Analysis of Severe On-Treatment 
Asthma Exacerbations
Data Look [1] 
SAC [2]
2.56.
ITT
Non-Standard 
EFF_T13
Summary of the Statistical Analysis of Time to First Severe On-
Treatment Asthma Exacerbation
Data Look [1] 
SAC [2]
AQLQ(S)
2.57.
ITT
Non-Standard 
EFF_T1
Summary of Change from Baseline in AQLQ(S) Total Score and 
Domain Scores
Present an additional column to the left 
of “Visit”, labelled “Domain” with values 
“Total Score”, “Environmental Stimuli”, 
“Symptoms”, “Activity Limitations” and 
“Emotional Function” to allow 
presentation of results by Domain. 
Present the following visits: Day 0, 
Week 24, Change from Baseline at 
Week 24, Early Withdrawal and 
Change from Baseline at Early 
Withdrawal.
SAC [2]
2.58.
ITT
Non-Standard 
EFF_T14
Summary of Percentage of Subjects Who Have an Increase 
from Baseline of >=0.5 in AQLQ(S) Total Score and Domain 
Scores
Repeat on subsequent pages for 
Domain = Environmental Stimuli, 
Symptoms, Activity Limitations and 
Emotional Function.
Data Look [1] 
SAC [2]
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.59.
ITT
Non-Standard 
EFF_T6
Summary of the Statistical Analysis of Percentage of Subjects 
Who Have an Increase from Baseline of >=0.5 in AQLQ(S) Total 
Score  and Environmental Stimuli Domain Score at Week 24 
(Visit 6)
Replace “With correct use [1]” with 
“Responder [1]” and “Without correct 
use” with “Non-Responder”. Do not 
display the “Visit” column.
Footnotes as follows:
“[1] Responder is defined as an 
increase from baseline of >= 0.5.
Note: The analysis method was logistic 
regression adjusted for randomised 
treatment, baseline score, gender, age 
and country.”
SAC [2]
EQ-5D-5L
2.60.
ITT
Non-Standard 
EFF_T15
Summary of EQ-5D-5L Descriptive System Dimensions
Repeat on subsequent pages for Visit = 
Early Withdrawal and for Dimension = 
Mobility, Pain/Discomfort, Self-care, 
Usual activities.
Data Look [1] 
SAC [2]
2.61.
ITT
Non-Standard 
EFF_T6
Summary of the Statistical Analysis of Proportion of Responders 
According to EQ-5D-5L Descriptive System Dimensions at Week 
24 (Visit 6)
Replace “With correct use [1]” with 
“Responder [1]” and “Without correct 
use” with “Non-Responder”. Do not 
display the “Visit” column.
Footnotes as follows: 
“[1] Responder is defined as a score of 
1 (‘no problems’).
Note: The analysis method was logistic 
regression adjusted for randomised 
treatment, baseline EQ-5D-5L domain 
score, gender, age and country.”
SAC [2]
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.62.
ITT
Non-Standard 
EFF_T1
Summary of EQ-5D-5L Utility Score
Present the following visits: Day 0, 
Week 24, Change from Baseline at 
Week 24, Early Withdrawal and 
Change from Baseline at Early 
Withdrawal.
Data Look [1] 
SAC [2]
2.63.
ITT
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
EQ-5D-5L Utility Score at Week 24 (Visit 6)
Footnote as follows:
“Note: The analysis method was an 
ANCOVA model adjusted for 
randomised treatment, baseline EQ-5D-
5L utility score, gender, age and 
country.”
SAC [2]
2.64.
ITT
Non-Standard 
EFF_T1
Summary of EQ-5D-5L Visual Analogue Scale (VAS) Score
Present the following visits: Day 0, 
Week 24, Change from Baseline at 
Week 24, Early Withdrawal and
Change from Baseline at Early 
Withdrawal.
SAC [2]
2.65.
ITT
Non-Standard 
EFF_T2
Summary of the Statistical Analysis of Change from Baseline in 
EQ-5D-5L Visual Analogue Scale (VAS) Score at Week 24 (Visit 
6)
Footnote as follows:
“Note: The analysis method was an 
ANCOVA model adjusted for 
randomised treatment, baseline EQ-5D-
5L VAS score, gender, age and 
country.”
SAC [2]
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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PASAP-Q
2.66.
ITT
Non-Standard 
EFF_T1
Summary of PASAP-Q Scores
Present an additional column to the left 
of “Visit”, labelled “Score” with values 
“Performance”, “Convenience”, “Overall 
Satisfaction”, “Total Score” and 
“Willingness to Continue Using Inhaler” 
to allow presentation of results by 
Domain. Present the following visits: 
Week 12 and Early Withdrawal.
Add the following footnotes:
“Note: Performance, Convenience, 
Total Score, and Willingness to 
Continue Using Inhaler are expressed 
on a scale of 0 to 100.
Note: Overall Satisfaction is expressed 
on a scale of 1 to 7.”
SAC [2]
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10.15.7.
Efficacy Figures
Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Change from Baseline in ACT Total Score at Week 12 (Visit 4)
2.1.
ITT
Non-Standard 
EFF_F1
Summary of Change from Baseline in ACT Total Score
Present “ACT Total Score” on y-axis 
and “Visit” on x-axis (Day 0, Week 6, 
Week 12, Week 18, Week 24). Present 
mean ACT Total Score ∀SD 
separately for treatment group (FF/VI, 
Usual ICS/LABA) at each visit, 
connecting the means with a solid line. 
Distinguish the treatment groups by 
different line types.
Data Look [1] 
SAC [2]
2.2.
PP
Non-Standard 
EFF_F1
Summary of Change from Baseline in ACT Total Score
Per Protocol Population
Present “ACT Total Score” on y-axis 
and “Visit” on x-axis (Day 0, Week 6, 
Week 12, Week 18, Week 24). Present 
mean ACT Total Score ∀SD 
separately for treatment group (FF/VI, 
Usual ICS/LABA) at each visit, 
connecting the means with a solid line. 
Distinguish the treatment groups by 
different line types.
SAC [2]
2.3.
ITT
Non-Standard 
EFF_F1
Summary of Change from Baseline in ACT Total Score by 
Country
Present “ACT Total Score” on y-axis 
and “Visit” on x-axis (Day 0, Week 6, 
Week 12, Week 18, Week 24). Present 
mean ACT Total Score ∀SD 
separately for treatment group (FF/VI, 
Usual ICS/LABA) at each visit, 
connecting the means with a solid line. 
Distinguish the treatment groups by 
different line types.
SAC [2]
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Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.4.
ITT/PP
Non-Standard 
EFF_F2
Summary of Primary and Sensitivity Analyses for Change from 
Baseline in ACT Total Score at Week 12 (Visit 4)
Present “Treatment difference” on the 
x-axis, and reverse axis so treatment 
difference increases from left to right. 
Replace “Ratio (95% CI)” with 
“Treatment Difference (95% CI)”. 
Present lines for the following: Primary 
analysis (ITT), Primary analysis (PP), 
ANCOVA with LOCF (ITT), Multiple 
Imputation (Missing at Random) (ITT), 
Multiple Imputation (Copy Differences 
from Reference) (ITT), Hodges-
Lehmann (ITT), ANCOVA with WOCF 
(ITT).
Data Look [1] 
SAC [2]
2.5.
ITT
Non-Standard 
EFF_F3
Summary of Interaction Tests for Change from Baseline in ACT 
Total Score at Week 12 (Visit 4)
Present “LS Mean Change” on the x-
axis, and reverse axis so it increases 
from left to right. Replace “Ratio (95% 
CI)” with “LS Mean Change (95% CI)”. 
Present the following subgroups: 
Country (France, Germany); Number of 
Severe Asthma Exacerbations in the 
Previous Year Prior to Randomisation 
(0, >= 1); Smoking Status at Baseline 
(Current Smokers, Former Smokers, 
Never Smoked); Age Group (18 – 50 
Years Old, > 50 Years Old); Gender 
(Male, Female).
Data Look [1] 
SAC [2]
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96
Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Change from Baseline in ACT Total Score at Week 24 (Visit 6)
2.6.
ITT/PP
Non-Standard 
EFF_F2
Summary of Key Secondary and Sensitivity Analyses for 
Change from Baseline in ACT Total Score at Week 24 (Visit 6)
Present “Treatment difference” on the 
x-axis, and reverse axis so treatment 
difference increases from left to right. 
Replace “Ratio (95% CI)” with 
“Treatment Difference (95% CI)”. 
Present lines for the following: Primary 
analysis (ITT), Primary analysis (PP), 
ANCOVA with LOCF (ITT), Multiple 
Imputation (Missing at Random) (ITT), 
Multiple Imputation (Copy Differences 
from Reference) (ITT), Hodges-
Lehmann (ITT), ANCOVA with WOCF 
(ITT).
SAC [2]
Subjects Who Have Either an ACT Total Score >= 20 or >= 3 Point Increase from Baseline in ACT Total Score
2.7.
ITT
Non-Standard 
EFF_F4
Summary of Percentage of Subjects Who Have Either an ACT 
Total Score >= 20 or >= 3 Point Increase from Baseline in ACT 
Total Score
Present “Percent of Subjects (%)” on y-
axis and “Visit” on x-axis (Week 6, 
Week 12, Week 18, Week 24, Early 
Withdrawal). For each visit, present 3 
vertical bars distinguished by fill pattern 
(similar to non-standard EFF_F6). Each 
bar represents: “ACT Total Score >= 20 
or >= 3 Point Increase from Baseline in 
ACT Total Score”, “ACT Total Score >= 
20” and “>= 3 Point Increase from 
Baseline in ACT Total Score” 
respectively and should be labelled as 
such on the legend.
Data Look [1] 
SAC [2]
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97
Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Compliance with Study Medication
2.8.
ITT
Non-Standard 
EFF_F5
Box Plot of Compliance with Study Medication
Label y-axis title as “Compliance (%)”, 
maximum of y-axis may be > 100%.
Data Look [1] 
SAC [2]
MARS-A
2.9.
ITT
Non-Standard 
EFF_F6
Histogram of the Questions and Answers of the MARS-A 
Questionnaire
Repeat on subsequent pages for Visit = 
Week 24, Week 52 and Early 
Withdrawal; and for Randomised 
Treatment = FF/VI.
Data Look [1] 
SAC [2]
2.10.
ITT
Non-Standard 
EFF_F6
Histogram of the Questions and Answers of the MARS-A 
Questionnaire by Status of Patient in Relation to the Reminder 
Sent to French Centres
Present bylines and footnotes per 
“Repeat for” programming note on 
shell.
SAC [2]
2.11.
ITT
Non-Standard 
EFF_F7
Histogram of the Distribution of MARS-A Scores During the 
Study
Repeat on subsequent pages for Visit = 
Week 52 and Early Withdrawal.
Data Look [1] 
SAC [2]
2.12.
ITT
Non-Standard 
EFF_F7
Histogram of the Distribution of MARS-A Scores During the 
Study by Status of Patient in Relation to the Reminder Sent to 
French Centres
Present bylines and footnotes per 
“Repeat for” programming note on 
shell.
SAC [2]
Severe On-Treatment Asthma Exacerbations
2.13.
ITT
Non-Standard 
EFF_F8
Box Plot of Severe On-Treatment Asthma Exacerbation Rates 
Adjusted for Exposure to Treatment
Data Look [1] 
SAC [2]
2.14.
ITT
Non-Standard 
EFF_F9
Kaplan-Meier Plot of Time to First Severe On-Treatment Asthma 
Exacerbation
Display increments of 6 weeks on the x-
axis, up to the maximum exposure (e.g. 
0, 6, 12, 18, 24, 30).
Data Look [1] 
SAC [2]
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98
10.15.8.
Safety Tables
Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
SAEs and ADRs
3.1.
Safety
Non-Standard 
SAFE_T1
On-Treatment Serious Adverse Events and Adverse Drug 
Reactions Overview
Based on IDSL standard template 
AE13.
Data Look [1] 
SAC [2]
3.2.
Safety
AE1
Summary of On-Treatment Non-Serious Adverse Drug 
Reactions
SAC [2]
3.3.
Safety
AE1
Summary of On-Treatment Serious Adverse Drug Reactions
SAC [2]
3.4.
Safety
AE1
Summary of On-Treatment Adverse Drug Reactions
Data Look [1] 
SAC [2]
3.5.
Safety
AE1
Summary of On-Treatment Serious Adverse Events
Data Look [1] 
SAC [2]
3.6.
Safety
AE1
Summary of On-Treatment or Post-Treatment Serious Adverse 
Events and Adverse Drug Reactions Leading to Permanent 
Discontinuation of Study Drug or Withdrawal from the Study
SAC [2]
3.7.
Safety
AE1
Summary of On-Treatment or Post-Treatment Serious Adverse 
Events Leading to Permanent Discontinuation of Study Drug or 
Withdrawal from the Study
SAC [2]
3.8.
Safety
AE1
Summary of On-Treatment or Post-Treatment Adverse Drug 
Reactions Leading to Permanent Discontinuation of Study Drug 
or Withdrawal from the Study
SAC [2]
3.9.
Safety
AE1
Summary of Most Frequent On-Treatment Non-Serious Adverse 
Drug Reactions, Reported by 1% or More of Subjects in Any 
Treatment Group
SAC [2]
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99
Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
SAEs and ADRs of Special Interest
3.10.
Safety
Non-Standard 
SAFE_T2
Summary of On-Treatment Non-Serious Adverse Drug 
Reactions of Special Interest
Based on IDSL standard template AE1.
Data Look [1]
SAC [2]
3.11.
Safety
Non-Standard 
SAFE_T2
Summary of On-Treatment Serious Adverse Drug Reactions of 
Special Interest
Based on IDSL standard template AE1.
SAC [2]
3.12.
Safety
Non-Standard 
SAFE_T2
Summary of On-Treatment Adverse Drug Reactions of Special 
Interest
Based on IDSL standard template AE1.
SAC [2]
3.13.
Safety
Non-Standard 
SAFE_T2
Summary of On-Treatment Serious Adverse Events of Special 
Interest
Based on IDSL standard template AE1.
SAC [2]
Fatal SAEs and ADRs
3.14.
Safety
AE1
Summary of On-Treatment Fatal Serious Adverse Events
SAC [2]
3.15.
Safety
AE1
Summary of On-Treatment Fatal Serious Adverse Drug 
Reactions
SAC [2]
3.16.
Safety
Non-Standard 
SAFE_T2
Summary of On-Treatment Fatal Serious Adverse Events of 
Special Interest
Based on IDSL standard template AE1.
SAC [2]
Non-Fatal SAEs and ADRs
3.17.
Safety
AE1
Summary of On-Treatment Non-Fatal Serious Adverse Events
SAC [2]
3.18.
Safety
Non-Standard 
SAFE_T2
Summary of On-Treatment Non-Fatal Serious Adverse Events of 
Special Interest
Based on IDSL standard template AE1.
SAC [2]
Top Ten Most Commonly Reported ADRs
3.19.
Safety
Non-Standard 
SAFE_T3
Top Ten Most Commonly Reported On-Treatment Adverse Drug 
Reactions Per Treatment Group
Present the ten most frequent preferred 
terms in Usual ICS/LABA, and the ten 
most frequent in FF/VI (do not use 
percentages to determine “most 
frequent”)
Data Look [1]
SAC [2]
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100
Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Vital Signs
3.20.
Safety
VS1
Summary of Vital Signs
SAC [2]
3.21.
Safety
VS2
Summary of Vital Sign Data Outside Clinical Concern Range
SAC [2]
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101
10.15.9.
Safety Figures
Safety : Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Benefit:Risk
3.1.
ITT/Safety
Non-Standard 
SAFE_F1
Summary of Benefit:Risk for FF/VI vs. Usual ICS/LABA
Data Look [1] 
SAC [2]
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102
10.15.10.
ICH Listings
ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Study Population
1.
ITT
ES2
Reasons for Study Withdrawal
SAC [2]
2.
ITT
TA1
Randomised and Actual Treatments
For subjects with multiple ‘actual’ 
treatments, present in the order the 
treatments were received.
SAC [2]
3.
ITT
IE3
Subjects with Inclusion, Exclusion or Randomisation Criteria 
Deviations
SAC [2]
4.
ITT
DM2
Demographic Characteristics
SAC [2]
5.
ITT
DM9
Race
SAC [2]
Adverse Events
6.
Safety
AE7
Subject Numbers for Individual Serious Adverse Events and 
Non-Serious Adverse Drug Reactions
SAC [2]
7.
Safety
AE8
All Serious Adverse Events and Non-Serious Adverse Drug 
Reactions
SAC [2]
8.
Safety
AE8
Fatal Serious Adverse Events 
SAC [2]
9.
Safety
AE8
Serious Adverse Events Leading to Permanent Discontinuation 
of Study Drug or Withdrawal from the Study
SAC [2]
10.
Safety
AE8
Non-Serious Adverse Drug Reactions Leading to Permanent 
Discontinuation of Study Drug or Withdrawal from the Study
SAC [2]
11.
Safety
AE7
Subject Numbers for Individual Serious Adverse Events and 
Non-Serious Adverse Drug Reactions
SAC [2]
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103
10.15.11.
Non-ICH Listings
Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Study Population
12.
ASE
Non-Standard
POP_L1
Subjects Screened but Not in the Intent-to-Treat Population
SAC [2]
13.
ITT
Non-Standard
POP_L2
Reasons for Important Protocol Deviations
SAC [2]
14.
ITT
MH3
Medical Conditions
SAC [2]
15.
ITT
Non-Standard
POP_L3
Asthma History
SAC [2]
16.
ITT
Non-Standard
POP_L4
Smoking History
SAC [2]
17.
ITT
CM3
Concomitant Medications
Only include medications included in 
pre-treatment and on-treatment 
summary tables.
SAC [2]
18.
ITT
CM6
Relationship between Ingredient and Verbatim Text
SAC [2]
19.
ITT
Non-Standard 
POP_L5
Exposure to Study Medication
Repeat on subsequent pages for 
Treatment = FF/VI, and use GSK drug 
synonym as drug name.
SAC [2]
Efficacy
20.
ITT
Non-Standard
EFF_L1
ACT Scores
Repeat on subsequent pages for 
Treatment = FF/VI.
SAC [2]
21.
ITT
Non-Standard
EFF_L2
Inhaler Device Use
Repeat on subsequent pages for 
Treatment = FF/VI.
SAC [2]
22.
ITT
Non-Standard
EFF_L3
Lung Function Tests
Repeat on subsequent pages for 
Treatment = FF/VI.
SAC [2]
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104
Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
23.
ITT
Non-Standard
EFF_L4
Medication Adherence Report Scale for Asthma (MARS-A) 
Scores
Repeat on subsequent pages for 
Treatment = FF/VI.
SAC [2]
24.
ITT
Non-Standard
EFF_L5
Severe Asthma Exacerbations
Repeat on subsequent pages for 
Treatment = FF/VI.
SAC [2]
25.
ITT
Non-Standard
EFF_L6
AQLQ(S) Scores
Repeat on subsequent pages for 
Treatment = FF/VI.
SAC [2]
26.
ITT
Non-Standard
EFF_L7
EQ-5D-5L Descriptive System Dimension Scores
Repeat on subsequent pages for 
Treatment = FF/VI.
SAC [2]
27.
ITT
Non-Standard
EFF_L8
PASAP-Q Scores
Repeat on subsequent pages for 
Treatment = FF/VI.
SAC [2]
Safety
28.
Safety
Non-Standard
SAFE_L1
AE Terms of Special Interest
The AE special interest dataset and the 
AE SMQ dataset will be set together in 
order to report this table and all the 
subgroups that come from the AE SMQ 
dataset will be flagged with a [1].
SAC [2]
29.
Safety
VS4
Vital Signs
SAC [2]
30.
Safety
Non-Standard 
SAFE_L2
Inhaler Device Malfunctions
SAC [2]
Liver Chemistry
31.
Safety
LIVER5
Liver Event Results and Time of Event Relative to Treatment
SAC [2]
32.
Safety
LIVER6
Liver Event Information for RUCAM Score
SAC [2]
33.
Safety
LIVER7
Liver Biopsy Details
SAC [2]
34.
Safety
LIVER8
Liver Imaging Details
SAC [2]
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105
10.16.
Appendix 16: Example Mock Shells for Data Displays
10.16.1.
Study Population Table Shells
Example 
: POP_T1
Protocol
: HZA116492
Page 1 of 1
Population
: All Subjects Enrolled
Table 1.xx
Summary of Subject Populations
Population
Usual ICS/LABA
FF/VI 
Total
All Subjects Enrolled (ASE)
xxx
Randomised
xxx 
xxx
xxx
Intent-to-Treat (ITT)
xxx (xx%)
xxx (xx%)
xxx (xx%)
Per Protocol (PP)
xxx (xx%)
xxx (xx%)
xxx (xx%)
Safety
xxx (xx%)
xxx (xx%)
xxx (xx%)
ASE: All subjects screened and for whom a record exists on the study database.
ITT: All randomised subjects having received at least one dose of the prescription of study medication (FF/VI or Usual ICS/LABA).
PP: All ITT subjects who without any protocol deviations excluding them from this population.
Safety: All randomised subjects having received at least one dose of the prescription of study medication (FF/VI or Usual ICS/LABA).
Note: The randomised summary is not a defined population and consists of all subjects who were randomised and given a randomisation number.
Programming Note: randomised population line will provide the denominators for the ITT, PP and Safety percentages.
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106
Example 
: POP_T2
Protocol
: HZA116492
Page 1 of 1
Population
: Intent-to-Treat
Table 1.xx 
Summary of Attendance at Each Clinic Visit
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Total
(N=xxx)
Visit 1: Screening
xxx (xx%)
xxx (xx%)
xxx (xx%)
Visit 2: Randomisation (Day 0)
xxx (xx%)
xxx (xx%)
xxx (xx%)
Visit 3: Week 6
xxx (xx%)
xxx (xx%)
xxx (xx%)
Visit 4: Week 12
xxx (xx%)
xxx (xx%)
xxx (xx%)
Visit 5: Week 18
xxx (xx%)
xxx (xx%)
xxx (xx%)
Visit 6: Week 24
xxx (xx%)
xxx (xx%)
xxx (xx%)
Early Withdrawal
xxx (xx%)
xxx (xx%)
xxx (xx%)
Note: Weeks 6 and 18 are telephone contacts.
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107
Example 
: POP_T3 
Protocol
: HZA116492
Page 1 of n
Population
: Intent-to-Treat
Table 1.xx 
Summary of Important Protocol Deviations
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Total
(N=xxx)
Any Important Protocol Deviation
xxx (xx%)
xxx (xx%)
xxx (xx%)
  Reason 1                                     
xxx (xx%)
xxx (xx%)
xxx (xx%)
  Reason 2                                    
xxx (xx%)
xxx (xx%)
xxx (xx%)
  Reason 3                                     
xxx (xx%)
xxx (xx%)
xxx (xx%)
     ...
xxx (xx%)
xxx (xx%)
xxx (xx%)
Note: A subject may have more than one protocol deviation.
Note: Includes any important deviation from the protocol.
Repeat for: 
Summary of Important Protocol Deviations Resulting in Exclusion from the PP Population (ITT Population)
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108
Example 
: POP_T4
Protocol
: HZA116492
Page 1 of 1
Population
: Intent-to-Treat
Table 1.xx 
Summary of Asthma Duration at Baseline
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Total
(N=xxx)
Duration of Asthma
  < 6 months
xxx (xx%)
xxx (xx%)
xxx (xx%)
  >= 6 months to < 1 year
xxx (xx%)
xxx (xx%)
xxx (xx%)
  >= 1 year to < 5 years
xxx (xx%)
xxx (xx%)
xxx (xx%)
  >= 5 years to < 10 years
xxx (xx%)
xxx (xx%)
xxx (xx%)
  >= 10 years
xxx (xx%)
xxx (xx%)
xxx (xx%)
Duration of Asthma (years):
  n
xx
xx
xx
  Mean
xx.x
xx.x
xx.x
  SD
  x.xx
  x.xx
  x.xx
  Median
xx.x
xx.x
xx.x
  Min.
xx
xx
xx
  Max.
xx
xx
Xx
Repeat for: 
Summary of Asthma Duration at Baseline (PP Population)
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109
Example 
: POP_T5
Protocol
: HZA116492
Page 1 of 2
Population
: Intent-to-Treat
Table 1.xx 
Summary of Asthma Exacerbation History at Baseline
Usual ICS/LABA
(N=xxx)
FF/VI 
(N=xxx)
Total
(N=xxx)
Did not require oral/systemic corticosteroids (not involving 
hospitalisation)
  n                      
xx 
xx 
xx 
  0
xx (xx%)
xx (xx%)
xx (xx%)
  1
xx (xx%)
xx (xx%)
xx (xx%)
  > 1
xx (xx%)
xx (xx%)
xx (xx%)
Required oral/systemic corticosteroids (not involving hospitalisation)
  n                      
xx 
xx 
xx 
  0
xx (xx%)
xx (xx%)
xx (xx%)
  1
xx (xx%)
xx (xx%)
xx (xx%)
  > 1
xx (xx%)
xx (xx%)
xx (xx%)
Required hospitalisation                  
  n                      
xx 
xx 
xx 
  0
xx (xx%)
xx (xx%)
xx (xx%)
  1
xx (xx%)
xx (xx%)
xx (xx%)
  > 1
xx (xx%)
xx (xx%)
xx (xx%)
Note: Number of severe asthma exacerbations reported in the 12 months prior to Day 0.
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110
Example 
: POP_T5
Protocol
: HZA116492
Page 2 of 2
Population
: Intent-to-Treat
Table 1.xx 
Summary of Asthma Exacerbation History at Baseline
Usual ICS/LABA
(N=xxx)
FF/VI 
(N=xxx)
Total
(N=xxx)
Total number of exacerbations during the 12 months prior to 
randomisation
  n                      
xx 
xx 
xx 
  0
xx (xx%)
xx (xx%)
xx (xx%)
  1
xx (xx%)
xx (xx%)
xx (xx%)
  > 1
xx (xx%)
xx (xx%)
xx (xx%)
Number of exacerbations during the 12 months prior to randomisation
  n
xx
xx
xx
  Mean
xx.x
xx.x
xx.x
  SD
  x.xx
  x.xx
  x.xx
  Median
xx.x
xx.x
xx.x
  Min.
xx
xx
xx
  Max.
xx
xx
xx
Note: Number of severe asthma exacerbations reported in the 12 months prior to Visit 2 (Day 0).
Repeat for: 
Summary of Asthma Exacerbation History at Baseline (PP Population)
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Example 
: POP_T6
Protocol
: HZA116492
Page 1 of 2
Population
: Intent-to-Treat
Table 1.xx 
Summary of Smoking History at Baseline
Usual ICS/LABA
(N=xxx)
FF/VI  
(N=xxx)
Total
(N=xxx)
History of Smoking Use
Current Smokers
xxx (xx%)
xxx (xx%)
xxx (xx%)
Former Smokers
xxx (xx%)
xxx (xx%)
xxx (xx%)
Never Smoked
xxx (xx%)
xxx (xx%)
xxx (xx%)
For Current and Former Smokers:
   Years Smoked
n
xx
xx
xx
Mean
xx.x
xx.x
xx.x
SD
  x.xx
  x.xx
  x.xx
Median
xx.x
xx.x
xx.x
Min.
xx
xx
xx
Max.
xx
xx
xx
   Cigarettes/Day
n
xx
xx
xx
Mean
xx.x
xx.x
xx.x
SD
  x.xx
  x.xx
  x.xx
Median
xx.x
xx.x
xx.x
Min.
xx
xx
xx
Max.
xx
xx
xx
[1] Smoking Pack Years = (Number of cigarettes smoked per day/20) x number of years smoked.
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112
Example 
: POP_T6
Protocol
: HZA116492
Page 2 of 2
Population
: Intent-to-Treat
Table 1.xx 
Summary of Smoking History at Baseline
Usual ICS/LABA
(N=xxx)
FF/VI  
(N=xxx)
Total
(N=xxx)
  Smoking Pack Years[1]
      Overall
n
xx
xx
xx
Mean
xx.x
xx.x
xx.x
SD
  x.xx
  x.xx
  x.xx
Median
xx.x
xx.x
xx.x
Min.
xx
xx
xx
Max.
xx
xx
xx
    Current Smokers
n
xx
xx
xx
Mean
xx.x
xx.x
xx.x
SD
  x.xx
  x.xx
  x.xx
Median
xx.x
xx.x
xx.x
Min.
xx
xx
xx
Max.
xx
xx
xx
    Former Smokers
n
xx
xx
xx
Mean
xx.x
xx.x
xx.x
SD
  x.xx
  x.xx
  x.xx
Median
xx.x
xx.x
xx.x
Min.
xx
xx
xx
Max.
xx
xx
xx
[1] Smoking Pack Years = (Number of cigarettes smoked per day/20) x number of years smoked.
Repeat for: 
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Summary of Smoking History at Baseline (PP Population)
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Example 
: POP_T7
Protocol
: HZA116492
Page 1 of n
Population
: Intent-to-Treat
Table 1.xx
Summary of Study Medication Dosage Modification
Dosage Modification / Prescription
   Treatment Path
Usual ICS/LABA
(N=xxx)
FF/VI 
(N=xxx)
Total
(N=xxx)
Did Not Modify Dose During the Study
xxx (xx%)
xxx (xx%)
xxx (xx%)
Modified Dose at Least Once During the Study
xxx (xx%)
xxx (xx%)
xxx (xx%)
Randomised to FF/VI
xxx
xxx 
  FF/VI 92 mcg/22 mcg OD
xxx (xx%)
xxx (xx%)
  FF/VI 92 mcg/22 mcg OD -> FF/VI 184 mcg/22 mcg OD
xxx (xx%)
xxx (xx%)
Randomised to Usual ICS/LABA and Prescribed FP/S
xxx
xxx
  FP/S 250 mcg/50 mcg BID
xxx (xx%)
xxx (xx%)
  FP/S 250 mcg/50 mcg BID -> FP/S 500 mcg/50 mcg BID
xxx (xx%)
xxx (xx%)
Randomised to Usual ICS/LABA and Prescribed BUD/F
xxx
xxx
  BUD/F 200 mcg/6 mcg BID (1 inh)
xxx (xx%)
xxx (xx%)
xxx (xx%)
  BUD/F 200 mcg/6 mcg BID (1 inh) -> BUD/F 200 mcg/6 mcg BID (2 inh)
xxx (xx%)
xxx (xx%)
xxx (xx%)
  BUD/F 200 mcg/6 mcg BID (1 inh) -> BUD/F 400 mcg/12 mcg BID (1 inh)
xxx (xx%)
xxx (xx%)
xxx (xx%)
  BUD/F 200 mcg/6 mcg BID (2 inh)
xxx (xx%)
xxx (xx%)
xxx (xx%)
  BUD/F 200 mcg/6 mcg BID (2 inh) -> BUD/F 400 mcg/12 mcg BID (1 inh)
xxx (xx%)
xxx (xx%)
xxx (xx%)
  BUD/F 200 mcg/6 mcg BID (2 inh) -> BUD/F 400 mcg/12 mcg BID (2 inh)
xxx (xx%)
xxx (xx%)
xxx (xx%)
Note: 1 inh = 1 inhalation per dose, 2 inh = 2 inhalations per dose.
Note: Subjects randomised to FF/VI initiated treatment on 92 mcg/22 mcg OD and could increase to 184 mcg/22 mcg OD. 
Note: Subjects randomised to Usual ICS/LABA and prescribed FP/S initiated treatment on 250 mcg/50 mcg BID and could increase to 500 mcg/50 mcg BID.
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Note: Subjects randomised to Usual ICS/LABA and prescribed BUD/F could: initiate treatment on 200 mcg/6 mcg BID (1 inh) and increase to 200 mcg/6 mcg BID (2 
inh) or 400 mcg/12 mcg BID (1 inh); or initiate on 200 mcg/6 mcg BID (2 inh) and modify to 400 mcg/12 mcg BID (1 inh) or increase to 400 mcg/12 mcg BID (2 inh).
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Example 
: POP_T8
Protocol
: HZA116492
Page 1 of 1
Population
: Intent-to-Treat
Table 1.xx 
Summary of Extent of Exposure to Study Medication (Regardless of Modification to Study Medication Dosage)
Overall
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Exposure  (days) [1]
n
xx
xx
Mean
xx.x
xx.x
SD
  x.xx
  x.xx
Median
xx.x
xx.x
Min.
xx
xx
Max.
xx
xx
Total Years Exposed (yrs)
xx
xx
Range of Exposure (days)
<= 6 weeks
xxx (xx%)
xxx (xx%)
<= 12 weeks
xxx (xx%)
xxx (xx%)
<= 18 weeks
xxx (xx%)
xxx (xx%)
<= 24 weeks
xxx (xx%)
xxx (xx%)
> 24 weeks
xxx (xx%)
xxx (xx%)
Subjects Exposed for six 
months (24 weeks ± 2 
weeks)
xxx (xx%)
xxx (xx%)
[1] Exposure to study medication = treatment stop date – treatment start date + 1, regardless of dosage modification.
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Repeat for: 
Summary of Summary of Extent of Exposure to Study Medication (up to First Modification to Study Medication Dosage) (ITT Population)
Footnote: “[1] Exposure to study medication = treatment stop date - treatment start date + 1.”
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Example 
: POP_T9
Protocol
: HZA116492
Page 1 of 6
Population
: Intent-to-Treat
Table 1.xx 
Summary of Extent of Exposure to Study Medication by Medication and Dosage
Medication/Dosage
Overall
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
FF/VI 92 mcg/22 mcg OD
Exposure  (days) [1]
n
xx
xx
Mean
xx.x
xx.x
SD
  x.xx
  x.xx
Median
xx.x
xx.x
Min.
xx
xx
Max.
xx
xx
Total Years Exposed (yrs)
xx
xx
Range of Exposure (days)
<= 6 weeks
xxx (xx%)
xxx (xx%)
<= 12 weeks
xxx (xx%)
xxx (xx%)
<= 18 weeks
xxx (xx%)
xxx (xx%)
<= 24 weeks
xxx (xx%)
xxx (xx%)
> 24 weeks
xxx (xx%)
xxx (xx%)
Subjects Exposed for six 
months (24 weeks ± 2 
weeks)
xxx (xx%)
xxx (xx%)
[1] Exposure to study medication = treatment stop date – treatment start date + 1.
Programming note: repeat on subsequent pages for Medication/Dosage = FF/VI 184 mcg/22 mcg OD, FP/S 250 mcg/50 mcg BID, FP/S 500 mcg/50 mcg BID, BUD/F 
200 mcg/6 mcg BID (1 inhalation per dose), BUD/F 200 mcg/6 mcg BID (2 inhalations per dose), BUD/F 400 mcg/12 mcg BID (1 inhalation per dose), BUD/F 400 
mcg/12 mcg BID (2 inhalations per dose).
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Example 
: POP_T10
Protocol
: HZA116492
Page 1 of 2
Population
: Intent-to-Treat
Table 1.xx 
Summary of Number of Subjects by Subgroup
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Total
(N=xxx)
Country
  n
xxx
xxx
xxx
  France
xxx (xx%)
xxx (xx%)
xxx (xx%)
  Germany
xxx (xx%)
xxx (xx%)
xxx (xx%)
Number of Severe Asthma Exacerbations in 
the Previous Year Prior to Randomisation
  n
xxx
xxx
xxx
  0
xxx (xx%)
xxx (xx%)
xxx (xx%)
   >= 1
xxx (xx%)
xxx (xx%)
xxx (xx%)
Smoking Status at Baseline
  n
xxx
xxx
xxx
  Current smokers
xxx (xx%)
xxx (xx%)
xxx (xx%)
  Former smokers
xxx (xx%)
xxx (xx%)
xxx (xx%)
  Never smoked
xxx (xx%)
xxx (xx%)
xxx (xx%)
Age Group
  n
xxx
xxx
xxx
  18 – 50 years old
xxx (xx%)
xxx (xx%)
xxx (xx%)
  > 50 years old
xxx (xx%)
xxx (xx%)
xxx (xx%)
Note: Spring = March, April and May; Summer = June, July and August; Autumn = September, October and November; Winter = December, January and February.
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Example 
: POP_T10
Protocol
: HZA116492
Page 2 of 2
Population
: Intent-to-Treat
Table 1.xx 
Summary of Number of Subjects by Subgroup
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Total
(N=xxx)
Gender
  n
xxx
xxx
xxx
  Male
xxx (xx%)
xxx (xx%)
xxx (xx%)
  Female
xxx (xx%)
xxx (xx%)
xxx (xx%)
Season at randomisation
  n
xxx
xxx
xxx
  Spring
xxx (xx%)
xxx (xx%)
xxx (xx%)
  Summer
xxx (xx%)
xxx (xx%)
xxx (xx%)
  Autumn
xxx (xx%)
xxx (xx%)
xxx (xx%)
  Winter
xxx (xx%)
xxx (xx%)
xxx (xx%)
Note: Spring = March, April and May; Summer = June, July and August; Autumn = September, October and November; Winter = December, January and February.
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10.16.2.
Study Population Figure Shells
Example 
: POP_F1
Protocol
: HZA116492
Page 1 of 1
Population
: Intent-to-Treat
Figure 1.xx
Plot of Exposure to Study Medication (Regardless of Modification to Study Medication Dosage)
Programming note: display increments of 6 weeks on the x-axis, up to the maximum exposure (e.g. 0, 6, 12, 18, 24, 30).
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10.16.3.
Efficacy Table Shells
Example
: EFF_T1
Protocol
: HZA116492                                                                            
Page 1 of n
Population
: Intent-to-Treat
Table 2.xx
Summary of Change from Baseline in ACT Total Score
Visit
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Day 0
n
xx
xx
Mean
xx.x
xx.x
SD
  x.xx
  x.xx
Median
xx.x
xx.x
Min.
xx
xx
Max.
xx
xx
Week 6
n
xx
xx
Mean
xx.x
xx.x
SD
  x.xx
  x.xx
Median
xx.x
xx.x
Min.
xx
xx
Max.
xx
xx
Change from Baseline at Week 6
n
xx
xx
Mean
xx.x
xx.x
SD
  x.xx
  x.xx
Median
xx.x
xx.x
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Min.
xx
xx
Max.
xx
xx
Programming note: repeat for Week 12, Change from Baseline at Week 12, Week 18, Change from Baseline at Week 18, Week 24, Change from Baseline at Week 
24, Early Withdrawal, Change from Baseline at Early Withdrawal
Repeat for:
Summary of Change from Baseline in ACT Total Score Per Protocol Population (PP Population)
Summary of Change from Baseline in Lung Function Tests (ITT Population)
Programming note: Present an additional column to the left of “Visit”, labelled “Test” with values “Trough (Pre-dose) FEV1” and “Trough (Pre-dose) Percent Predicted 
FEV1” to allow presentation of results by Test. Present the following visits: Day 0, Week 12, Change from Baseline at Week 12, Early Withdrawal and Change from 
Baseline at Early Withdrawal.
Summary of Change from Baseline in AQLQ(S) Total Score and Domain Scores (ITT Population)
Programming note: Present an additional column to the left of “Visit”, labelled “Domain” with values “Total Score”, “Environmental Stimuli”, “Symptoms”, “Activity 
Limitations” and “Emotional Function” to allow presentation of results by Domain. Present the following visits: Day 0, Week 24, Change from Baseline at Week 24, 
Early Withdrawal and Change from Baseline at Early Withdrawal.
Summary of PASAP-Q Scores (ITT Population)
Programming note: Present an additional column to the left of “Visit”, labelled “Score” with values “Performance”, “Convenience”, “Overall Satisfaction”, “Total Score” 
and “Willingness to Continue Using Inhaler” to allow presentation of results by Domain. Present the following visits: Week 12 and Early Withdrawal.
Add the following footnotes:
“Note: Performance, Convenience, Total Score, and Willingness to Continue Using Inhaler are expressed on a scale of 0 to 100.
Note: Overall Satisfaction is expressed on a scale of 1 to 7.”
Summary of EQ-5D-5L Utility Score (ITT Population)
Summary of EQ-5D-5L Visual Analogue Scale (VAS) Score (ITT Population)
Programming note: Present the following visits: Day 0, Week 24, Change from Baseline at Week 24, Early Withdrawal, Change from Baseline at Early Withdrawal.
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Example
: EFF_T1S
Protocol
: HZA116492                                                                            
Page 1 of 2
Population
: Intent-to-Treat
Table 2.xx
Summary of Change from Baseline in ACT Total Score by Country
Country: France
Visit
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Day 0
n
xx
xx
Mean
xx.x
xx.x
SD
  x.xx
  x.xx
Median
xx.x
xx.x
Min.
xx
xx
Max.
xx
xx
Week 6
n
xx
xx
Mean
xx.x
xx.x
SD
  x.xx
  x.xx
Median
xx.x
xx.x
Min.
xx
xx
Max.
xx
xx
Change from Baseline at Week 6
n
xx
xx
Mean
xx.x
xx.x
SD
  x.xx
  x.xx
Median
xx.x
xx.x
Min.
xx
xx
Max.
xx
xx
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Example
: EFF_T1S
Protocol
: HZA116492                                                                            
Page 2 of 2
Population
: Intent-to-Treat
Table 2.xx
Summary of Change from Baseline in ACT Total Score by Country
Country: Germany
Visit
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Day 0
n
xx
xx
Mean
xx.x
xx.x
SD
  x.xx
  x.xx
Median
xx.x
xx.x
Min.
xx
xx
Max.
xx
xx
Week 6
n
xx
xx
Mean
xx.x
xx.x
SD
  x.xx
  x.xx
Median
xx.x
xx.x
Min.
xx
xx
Max.
xx
xx
Change from Baseline at Week 6
n
xx
xx
Mean
xx.x
xx.x
SD
  x.xx
  x.xx
Median
xx.x
xx.x
Min.
xx
xx
Max.
xx
xx
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Repeat for:
Summary of Change from Baseline in ACT Total Score by Number of Severe Asthma Exacerbations in the Previous Year Prior to Randomisation (ITT Population)
Number of Severe Asthma Exacerbations in the Previous Year Prior to Randomisation: 0
Number of Severe Asthma Exacerbations in the Previous Year Prior to Randomisation: >= 1
Summary of Change from Baseline in ACT Total Score by Smoking Status at Baseline (ITT Population)
Smoking Status at Baseline: Current Smokers
Smoking Status at Baseline: Former Smokers
Smoking Status at Baseline: Never Smoked
Summary of Change from Baseline in ACT Total Score by Age Group (ITT Population)
Age Group: 18 – 50 Years Old
Age Group: > 50 Years Old
Summary of Change from Baseline in ACT Total Score by Gender (ITT Population)
Gender: Male
Gender: Female
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Example 
: EFF_T2
Protocol
: HZA116492
Page 1 of 1
Population
: Intent-to-Treat
Table 2.xx
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 12 (Visit 4)
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
n
xx 
xx 
LS Mean Change (SE)
xx.xx (x.xxx)
xx.xx (x.xxx)
FF/VI vs. Usual ICS/LABA
  Difference 
xx.x 
  95% CI
(xx.x, xx.x)
  p-value
x.xxx
Note: The analysis method was an MMRM adjusted for randomised treatment, visit (Week 6 and Week 12), baseline ACT total score, randomised treatment-by-visit 
interaction, baseline ACT total score-by-visit interaction, gender, age, country and patient fitted as a random factor.
Note: The Restricted Maximum Likelihood (REML) estimation approach was used with a default covariance structure of unstructured.
Programming note: Should computational issues be encountered when using an unstructured covariance structure, other structures including AR1 and CS should be 
considered and the second footnote updated as appropriate. Should the distributional assumption of normality fail then the p-value from a model on the rank-
transformed values should be presented and the following footnote added: “Note: the p-value presented was obtained from an MMRM on the rank-transformed values 
of change from baseline in ACT total score at Week 12 (Visit 4) with the same specification as the untransformed model.”
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Repeat for:
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 12 (Visit 4) Per Protocol Population (PP Population)
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 12 (Visit 4) (ANCOVA with LOCF) (ITT Population)
Programming note: Should the distributional assumption of normality fail then the p-value from a model on the rank-transformed values should be presented and the 
following footnote added: “Note: the p-value presented was obtained from an ANCOVA on the rank-transformed values of change from baseline in ACT total score at 
Week 12 (Visit 4) with the same specification as the untransformed model.”
Footnotes as follows:
“Note: The analysis method was an ANCOVA model adjusted for randomised treatment, baseline ACT total score, gender, age and country.
Note: Missing values at Week 12 (Visit 4) were replaced by last available post-randomisation value based on the last observation carried forward (LOCF) method.”
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 12 (Visit 4) (Multiple Imputation – Missing at Random Approach) (ITT 
Population)
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 12 (Visit 4) (Multiple Imputation – Copy Differences from Reference 
Approach) (ITT Population)
Programming note: Present the “FF/VI vs. Usual ICS/LABA” section only. Footnotes as follows:
“Note: Missing values post-randomisation were imputed using multiple imputation methods based on pattern mixture models.
Note: Each imputed data set was analysed using an ANCOVA model at Week 12 (Visit 4) adjusted for randomised treatment, baseline ACT total score, gender, age 
and country and the resulting treatment differences and their standard errors combined using Rubin’s rules.”
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 12 (Visit 4) (Hodges-Lehmann Approach) (ITT Population)
Programming note: Present the “Difference” and “95% CI” lines of “FF/VI vs. Usual ICS/LABA” section only. Footnotes as follows:
“Note: The difference between treatment groups at Week 12 (Visit 4) was calculated using the Hodges-Lehmann approach.”
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 12 (Visit 4) (ANCOVA with WOCF) (ITT Population)
Programming note: Should the distributional assumption of normality fail then the p-value from a model on the rank-transformed values should be presented and the 
following footnote added: “Note: the p-value presented was obtained from an ANCOVA on the rank-transformed values of change from baseline in ACT total score at 
Week 12 (Visit 4) with the same specification as the untransformed model.”
Footnotes as follows:
“Note: The analysis method was an ANCOVA model adjusted for randomised treatment, baseline ACT total score, gender, age and country.
Note: Missing values at Week 12 (Visit 4) due to treatment withdrawal prior to this time point were replaced by worst post-randomisation value based on the worst 
observation carried forward (WOCF) method.”
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Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 12 (Visit 4), FF/VI Versus the Subset of Usual ICS/LABA Subjects 
Prescribed FP/S at Randomisation (ITT Population)
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 12 (Visit 4), FF/VI Versus the Subset of Usual ICS/LABA Subjects 
Prescribed BUD/F at Randomisation (ITT Population)
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 24 (Visit 6) (ITT Population)
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 24 (Visit 6) Per Protocol Population (PP Population)
Programming note: first footnote as follows:
“Note: The analysis method was an MMRM adjusted for randomised treatment, visit (Week 6, Week 12, Week 18 and Week 24), baseline ACT total score, randomised 
treatment-by-visit interaction, baseline ACT total score-by-visit interaction, gender, age, country and patient fitted as a random factor.”
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 24 (Visit 6) (ANCOVA with LOCF) (ITT Population)
Programming note: Should the distributional assumption of normality fail then the p-value from a model on the rank-transformed values should be presented and the 
following footnote added: “Note: the p-value presented was obtained from an ANCOVA on the rank-transformed values of change from baseline in ACT total score at 
Week 24 (Visit 6) with the same specification as the untransformed model.”
Footnotes as follows:
“Note: The analysis method was an ANCOVA model adjusted for randomised treatment, baseline ACT total score, gender, age and country.
Note: Missing values at Week 24 (Visit 6) were replaced by last available post-randomisation value based on the last observation carried forward (LOCF) method.”
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 24 (Visit 6) (Multiple Imputation – Missing at Random Approach) (ITT 
Population)
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 24 (Visit 6) (Multiple Imputation – Copy Differences from Reference
Approach) (ITT Population)
Programming note: Present the “FF/VI vs. Usual ICS/LABA” section only. Footnotes as follows:
“Note: Missing values post-randomisation were imputed using multiple imputation methods based on pattern mixture models.
Note: Each imputed data set was analysed using an ANCOVA model at Week 24 (Visit 6) adjusted for randomised treatment, baseline ACT total score, gender, age 
and country and the resulting treatment differences and their standard errors combined using Rubin’s rules.”
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 24 (Visit 6) (Hodges-Lehmann Approach) (ITT Population)
Present the “Difference” and “95% CI” lines of “FF/VI vs. Usual ICS/LABA” section only. Footnotes as follows:
“Note: The difference between treatment groups at Week 24 (Visit 6) was calculated using the Hodges-Lehmann approach.”
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 24 (Visit 6) (ANCOVA with WOCF) (ITT Population)
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Programming note: Should the distributional assumption of normality fail then the p-value from a model on the rank-transformed values should be presented and the 
following footnote added: “Note: the p-value presented was obtained from an ANCOVA on the rank-transformed values of change from baseline in ACT total score at 
Week 24 (Visit 6) with the same specification as the untransformed model.”
Footnotes as follows:
“Note: The analysis method was an ANCOVA model adjusted for randomised treatment, baseline ACT total score, gender, age and country.
Note: Missing values at Week 24 (Visit 6) due to treatment withdrawal prior to this time point were replaced by worst post-randomisation value based on the worst 
observation carried forward (WOCF) method.”
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 24 (Visit 6), FF/VI Versus the Subset of Usual ICS/LABA Subjects 
Prescribed FP/S at Randomisation (ITT Population)
Programming note: Output only to be produced if ≥25% of Usual ICS/LABA patients are prescribed FP/S at randomisation. First footnote as follows:
“Note: The analysis method was an MMRM adjusted for randomised treatment, visit (Week 6, Week 12, Week 18 and Week 24), baseline ACT total score, randomised 
treatment-by-visit interaction, baseline ACT total score-by-visit interaction, gender, age, country and patient fitted as a random factor.”
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 24 (Visit 6), FF/VI Versus the Subset of Usual ICS/LABA Subjects 
Prescribed BUD/F at Randomisation (ITT Population) 
Programming note: Output only to be produced if ≥25% of Usual ICS/LABA patients are prescribed BUD/F at randomisation. First footnote as follows:
“Note: The analysis method was an MMRM adjusted for randomised treatment, visit (Week 6, Week 12, Week 18 and Week 24), baseline ACT total score, randomised 
treatment-by-visit interaction, baseline ACT total score-by-visit interaction, gender, age, country and patient fitted as a random factor.”
Summary of the Statistical Analysis of Change from Baseline in Trough (Pre-dose) FEV1 at Week 12 (Visit 4) (ITT Population)
Programming note: Should the distributional assumption of normality fail then the p-value from a model on the rank-transformed values should be presented and the 
following footnote added: “Note: the p-value presented was obtained from an ANCOVA on the rank-transformed values of change from baseline in trough (pre-dose) 
FEV1 at Week 12 (Visit 4) with the same specification as the untransformed model.”
Footnote as follows:
“Note: The analysis method was an ANCOVA model adjusted for randomised treatment, baseline trough (pre-dose) FEV1, gender, age and country.”
Summary of the Statistical Analysis of Change from Baseline in EQ-5D-5L Utility Score at Week 24 (Visit 6) (ITT Population)
Programming note: Should the distributional assumption of normality fail then the p-value from a model on the rank-transformed values should be presented and the 
following footnote added: “Note: the p-value presented was obtained from an ANCOVA on the rank-transformed values of change from baseline in EQ-5D-5L utility 
score at Week 24 (Visit 6) with the same specification as the untransformed model.”
Footnote as follows:
“Note: The analysis method was an ANCOVA model adjusted for randomised treatment, baseline EQ-5D-5L utility score, gender, age and country.”
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Summary of the Statistical Analysis of Change from Baseline in EQ-5D-5L Visual Analogue Scale (VAS) Score at Week 24 (Visit 6) (ITT Population) 
Programming note: Should the distributional assumption of normality fail then the p-value from a model on the rank-transformed values should be presented and the 
following footnote added: “Note: the p-value presented was obtained from an ANCOVA on the rank-transformed values of change from baseline in EQ-5D-5L VAS 
score at Week 24 (Visit 6) with the same specification as the untransformed model.” 
Footnote as follows:
“Note: The analysis method was an ANCOVA model adjusted for randomised treatment, baseline EQ-5D-5L VAS score, gender, age and country.”
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Example 
: EFF_T2S
Protocol
: HZA116492
Page 1 of 2
Population
: Intent-to-Treat
Table 2.xx
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 12 (Visit 4) by Country
Country: France
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
n
xx 
xx 
LS Mean Change (SE)
xx.xx (x.xxx)
xx.xx (x.xxx)
FF/VI vs. Usual ICS/LABA
  Difference 
xx.x 
  95% CI
(xx.x, xx.x)
Note: The analysis method was an MMRM adjusted for randomised treatment, visit (Week 6 and Week 12), baseline ACT total score, baseline ACT total score-by-visit 
interaction, gender, age, country, two- and three- way interactions between randomised treatment, visit and country, and patient fitted as a random factor.
Note: The Restricted Maximum Likelihood (REML) estimation approach was used with a default covariance structure of unstructured.
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Example 
: EFF_T2S
Protocol
: HZA116492
Page 2 of 2
Population
: Intent-to-Treat
Table 2.xx
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 12 (Visit 4) by Country
Country: Germany
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
n
xx 
xx 
LS Mean Change (SE)
xx.xx (x.xxx)
xx.xx (x.xxx)
FF/VI vs. Usual ICS/LABA
  Difference 
xx.x 
  95% CI
(xx.x, xx.x)
Note: The analysis method was an MMRM adjusted for randomised treatment, visit (Week 6 and Week 12), baseline ACT total score, randomised treatment-by-visit 
interaction, baseline ACT total score-by-visit interaction, gender, age, country, randomised treatment-by-country interaction and patient fitted as a random factor.
Note: The Restricted Maximum Likelihood (REML) estimation approach was used with a default covariance structure of unstructured.
Programming note: Should computational issues be encountered when using an unstructured covariance structure, other structures including AR1 and CS should be 
considered and the second footnote updated as appropriate. 
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Repeat for:
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 12 (Visit 4) by Number of Severe Asthma Exacerbations in the Previous 
Year Prior to Randomisation (ITT Population)
Number of Severe Asthma Exacerbations in the Previous Year Prior to Randomisation: 0
Number of Severe Asthma Exacerbations in the Previous Year Prior to Randomisation: >= 1
Programming note: first footnote as follows:
“Note: The analysis method was an MMRM adjusted for randomised treatment, visit (Week 6 and Week 12), baseline ACT total score, baseline ACT total score-by-visit 
interaction, gender, age, country, number of severe asthma exacerbations in the previous year prior to randomisation, two- and three- way interactions between 
randomised treatment, visit and number of severe asthma exacerbations in the previous year prior to randomisation, and patient fitted as a random factor.”
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 12 (Visit 4) by Smoking Status at Baseline (ITT Population)
Programming note: first footnote as follows: 
“Note: The analysis method was an MMRM adjusted for randomised treatment, visit (Week 6 and Week 12), baseline ACT total score, baseline ACT total score-by-visit 
interaction, gender, age, country, smoking status at baseline, two- and three- way interactions between randomised treatment, visit and smoking status at baseline, 
and patient fitted as a random factor.”
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 12 (Visit 4) by Age Group (ITT Population)
Programming note: first footnote as follows: 
“Note: The analysis method was an MMRM adjusted for randomised treatment, visit (Week 6 and Week 12), baseline ACT total score, baseline ACT total score-by-visit 
interaction, gender, country, age group, two- and three- way interactions between randomised treatment, visit and age group, and patient fitted as a random factor.”
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 12 (Visit 4) by Gender (ITT Population)
Programming note: first footnote as follows: 
“Note: The analysis method was an MMRM adjusted for randomised treatment, visit (Week 6 and Week 12), baseline ACT total score, baseline ACT total score-by-visit 
interaction, gender, age, country, two- and three- way interactions between randomised treatment, visit and gender, and patient fitted as a random factor.”
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 24 (Visit 6) by Country (ITT Population)
Programming note: first footnote as follows:
“Note: The analysis method was an MMRM adjusted for randomised treatment, visit (Week 6, Week 12, Week 18 and Week 24), baseline ACT total score, baseline 
ACT total score-by-visit interaction, gender, age, country, two- and three- way interactions between randomised treatment, visit and country, and patient fitted as a 
random factor.”
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Example 
: EFF_T3
Protocol
: HZA116492
Page 1 of n
Population
: Intent-to-Treat
Table 2.xx
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 12 (Visit 4), Adjusting for Seasonal Effect
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Randomised treatment-by-season at 
randomisation interaction
  p-value
x.xxx
Season at randomisation: Spring
  n
xx
xx
  LS Mean Change (SE)
xx.xx (x.xxx)
xx.xx (x.xxx)
  FF/VI vs. Usual ICS/LABA
    Difference 
xx.x 
    95% CI
(xx.x, xx.x)
....
Note: The analysis method was an MMRM adjusted for randomised treatment, visit (Week 6 and Week 12), baseline ACT total score, baseline ACT total score-by-visit 
interaction, gender, age, country, season at randomisation, two- and three- way interactions between randomised treatment, visit and season at randomisation, and 
patient fitted as a random factor.
Note: The Restricted Maximum Likelihood (REML) estimation approach was used with a default covariance structure of unstructured.
Note: Spring = March, April and May; Summer = June, July and August; Autumn = September, October and November; Winter = December, January and February.
Programming note: repeat on subsequent pages for Season at randomisation = Summer, Autumn, Winter. Should computational issues be encountered when using 
an unstructured covariance structure, other structures including AR1 and CS should be considered and the second footnote updated as appropriate. 
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Repeat for:
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 12 (Visit 4), Adjusting for Seasonal Effect Per Protocol Population (PP 
Population)
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 24 (Visit 6), Adjusting for Seasonal Effect (ITT Population)
Summary of the Statistical Analysis of Change from Baseline in ACT Total Score at Week 24 (Visit 6), Adjusting for Seasonal Effect Per Protocol Population (PP 
Population) 
First footnote as follows:
“Note: The analysis method was an MMRM adjusted for randomised treatment, visit (Week 6, Week 12, Week 18 and Week 24), baseline ACT total score, baseline 
ACT total score-by-visit interaction, gender, age, country, season at randomisation, two- and three- way interactions between randomised treatment, visit and season 
at randomisation, and patient fitted as a random factor.”
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Example
: EFF_T4
Protocol
: HZA116492                                                                            
  Page 1 of 9
Population
: Intent-to-Treat
Table 2.xx
Summary of Inhaler Device Use Errors
[1] Correct use is defined as not making any critical or non-critical errors at that visit.
Visit
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Day 0
Number of patients using Ellipta
xxx
Number of patients with correct use [1]
xxx (xx%)
Number of patients without correct use
xxx (xx%)
Number of patients with at least one critical error
xxx (xx%)
Type of critical error:
  Failed to open cover
xxx (xx%)
  Shook the device upside down after dose preparation
xxx (xx%)
  Exhaled directly into mouthpiece
xxx (xx%)
  No seal by the lips around the mouthpiece during the inhalation
xxx (xx%)
Number of patients with at least one non-critical error
xxx (xx%)
Type of non-critical error:
  No exhalation before an inhalation   
xxx (xx%)
Inhalation manoeuvre was not: long, steady and deep
xxx (xx%)
  Blocked air inlet during inhalation manoeuvre
xxx (xx%)
Did not hold breath
xxx (xx%)
Did not close the device
xxx (xx%)
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Example
: EFF_T4
Protocol
: HZA116492                                                                            
  Page 2 of 9
Population
: Intent-to-Treat
Table 2.xx
Summary of Inhaler Device Use Errors
[1] Correct use is defined as not making any critical or non-critical errors at that visit.
Visit
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Day 0
Number of patients using Diskus
xxx
Number of patients with correct use [1]
xxx (xx%)
Number of patients without correct use
xxx (xx%)
Number of patients with at least one critical error
xxx (xx%)
Type of critical error:
  Failed to open cover
xxx (xx%)
  Lever is not pushed back
xxx (xx%)
  Shook the device after dose preparation
xxx (xx%)
  Exhaled directly into mouthpiece
xxx (xx%)
  No seal by the lips around the mouthpiece during the inhalation
xxx (xx%)
Number of patients with at least one non-critical error
xxx (xx%)
Type of non-critical error:
  No exhalation before an inhalation   
xxx (xx%)
Inhalation manoeuvre was not: steady and deep
xxx (xx%)
Did not hold breath
xxx (xx%)
Did not close the device
xxx (xx%)
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Example
: EFF_T4
Protocol
: HZA116492                                                                            
  Page 2 of 9
Population
: Intent-to-Treat
Table 2.xx
Summary of Inhaler Device Use Errors
Visit
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Day 0
Number of patients using Turbuhaler
xxx
Number of patients with correct use [1]
xxx (xx%)
Number of patients without correct use
xxx (xx%)
Number of patients with at least one critical error
xxx (xx%)
Type of critical error:
  Failed to remove cap
xxx (xx%)
  Did not hold device upright during dose preparation
xxx (xx%)
  Base not twisted fully backwards and forwards, no click heard
xxx (xx%)
  Shook the device after dose preparation
xxx (xx%)
  Exhaled directly into mouthpiece
xxx (xx%)
  No seal by the lips around the mouthpiece during the inhalation
xxx (xx%)
Number of patients with at least one non-critical error
xxx (xx%)
Type of non-critical error:
  Device tipped downwards after dose preparation
xxx (xx%)
  No exhalation before an inhalation   
xxx (xx%)
Inhalation manoeuvre was not: forceful and deep
xxx (xx%)
  Blocked air inlet during inhalation manoeuvre
xxx (xx%)
Did not hold breath
xxx (xx%)
Did not close the device
xxx (xx%)
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[1] Correct use is defined as not making any critical or non-critical errors at that visit.
Programming note: repeat on subsequent pages for Visit = Week 12 and Week 24. “Number of patients using...” line will provide the denominators for each section’s 
percentages.
Repeat for:
Summary of Inhaler Device Use Errors Per Protocol Population (PP Population)
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Example 
: EFF_T5
Protocol
: HZA116492
Page 1 of 1
Population
: Intent-to-Treat
Table 2.xx 
Summary of Correct Use of Inhaler Device
Visit
Usual ICS/LABA
(N=xxx)
FF/VI  
(N=xxx)
Day 0
n
xxx
xxx
Number of patients with correct use [1]
xxx (xx%)
xxx (xx%)
Number of patients without correct use
xxx (xx%)
xxx (xx%)
  Number of patients with at least one critical error
xxx (xx%)
xxx (xx%)
  Number of patients with at least one non-critical error
xxx (xx%)
xxx (xx%)
Week 12
n
xxx
xxx
Number of patients with correct use [1]
xxx (xx%)
xxx (xx%)
Number of patients without correct use
xxx (xx%)
xxx (xx%)
  Number of patients with at least one critical error
xxx (xx%)
xxx (xx%)
  Number of patients with at least one non-critical error
xxx (xx%)
xxx (xx%)
Week 24
n
xxx
xxx
Number of patients with correct use [1]
xxx (xx%)
xxx (xx%)
Number of patients without correct use
xxx (xx%)
xxx (xx%)
  Number of patients with at least one critical error
xxx (xx%)
xxx (xx%)
  Number of patients with at least one non-critical error
xxx (xx%)
xxx (xx%)
[1] Correct use is defined as not making any critical or non-critical errors at that visit.
Repeat for:
Summary of Correct Use of Inhaler Device Per Protocol Population (PP Population)
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Example
: EFF_T6
Protocol
: HZA116492                                                                            
Page 1 of 1
Population
: Intent-to-Treat
Table 2.xx
Summary of the Statistical Analysis of Correct Use of Inhaler Device at Week 12 (Visit 4) and at Week 24 (Visit 6) Independently of the Use at Week 12 (Visit 4)
Visit
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Week 12
n
xxx
xxx
With correct use [1]
xxx (xx%)
xxx (xx%)
Without correct use
xxx (xx%)
xxx (xx%)
FF/VI vs. Usual ICS/LABA
  Adjusted Odds Ratio 
x.xx
  95% CI
(x.xx, x.xx)
  p-value
x.xxx
Week 24
n
xxx
xxx
With correct use [1]
xxx (xx%)
xxx (xx%)
Without correct use
xxx (xx%)
xxx (xx%)
FF/VI vs. Usual ICS/LABA
  Adjusted Odds Ratio 
x.xx
  95% CI
(x.xx, x.xx)
  p-value
x.xxx
[1] Correct use is defined as not making any critical or non-critical errors at that visit.
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Note: The analysis method was logistic regression adjusted for randomised treatment, correct use of inhaler device at baseline, gender, age and country.
Programming note: If the likelihood maximisation algorithm fails to converge due to complete or quasi-complete separation of the data then implement Firth’s penalized 
likelihood and add the following footnote: “Note: Firth’s penalized likelihood was implemented due to [complete / quasi-complete] separation of data.”, deleting 
“complete” or “quasi-complete” as appropriate. 
Repeat for:
Summary of the Statistical Analysis of Correct Use of Inhaler Device at Week 12 (Visit 4) and at Week 24 (Visit 6) Independently of the Use at Week 12 (Visit 4) Per 
Protocol Population (PP Population)
Summary of the Statistical Analysis of Percentage of Subjects Who Have Either an ACT Total Score >= 20 or >= 3 Point Increase from Baseline in ACT Total Score at 
Week 12 (Visit 4) and Week 24 (Visit 6) (ITT Population)
Programming note: Replace “With correct use [1]” with “Responder [1]” and “Without correct use” with “Non-Responder”. 
Footnotes as follows:
“[1] Responder is defined as an ACT total score >= 20 or >= 3 point increase from baseline in ACT total score at that visit.
Note: The analysis method was logistic regression adjusted for randomised treatment, baseline ACT total score, baseline ACT total score squared, gender, age and 
country.”
Summary of the Statistical Analysis of Percentage of Subjects Who Have an Increase from Baseline of >=0.5 in AQLQ(S) Total Score and Environmental Stimuli 
Domain Score at Week 24 (Visit 6) (ITT Population) 
Domain: Total Score
Domain: Environmental Stimuli
Programming note: Replace “With correct use [1]” with “Responder [1]” and “Without correct use” with “Non-Responder”. Do not display the “Visit” column.
Footnotes as follows:
“[1] Responder is defined as an increase from baseline of >= 0.5.
Note: The analysis method was logistic regression adjusted for randomised treatment, baseline score, gender, age and country.”
Summary of the Statistical Analysis of Proportion of Responders According to EQ-5D-5L Descriptive System Dimensions at Week 24 (Visit 6) (ITT Population)
Dimension: Anxiety/Depression
Dimension: Mobility
Dimension: Pain/Discomfort
Dimension: Self-care
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Dimension: Usual activities
Programming note: Replace “With correct use [1]” with “Responder [1]” and “Without correct use” with “Non-Responder”. Do not display the “Visit” column.
Footnotes as follows: 
“[1] Responder is defined as a score of 1 (‘no problems’).
Note: The analysis method was logistic regression adjusted for randomised treatment, baseline EQ-5D-5L domain score, gender, age and country.”
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Example
: EFF_T7
Protocol
: HZA116492                                                                            
  Page 1 of 1
Population
: Intent-to-Treat
Table 2.xx
Summary of Percentage of Subjects Who Have Either an ACT Total Score of >= 20 or >= 3 Point Increase from Baseline in ACT Total Score
Programming note: repeat for Visit = Week 18, Week 24, Early Withdrawal.
Visit
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Week 6
n
xxx
xxx
ACT Total Score >= 20 or >= 3 Point Increase from Baseline
xxx (xx%)
xxx (xx%)
ACT Total Score >= 20
xxx (xx%)
xxx (xx%)
>= 3 Point Increase from Baseline
xxx (xx%)
xxx (xx%)
  
Week 12
n
xxx
xxx
ACT Total Score >= 20 or >= 3 Point Increase from Baseline
xxx (xx%)
xxx (xx%)
ACT Total Score >= 20
xxx (xx%)
xxx (xx%)
>= 3 Point Increase from Baseline
xxx (xx%)
xxx (xx%)
...
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Example
: EFF_T8
Protocol
: HZA116492
Page 1 of 10
Population
: Intent-to-Treat
Table 2.xx
Summary of Individual ACT Question Scores
Question: 1. Getting as much done at work, school or home
Visit
Response
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Day 0
n
xxx
xxx
1. All of the time
xxx (xx%)
xxx (xx%)
2. Most of the time
xxx (xx%)
xxx (xx%)
3. Some of the time
xxx (xx%)
xxx (xx%)
4. A little of the time
xxx (xx%)
xxx (xx%)
5. None of the time.
xxx (xx%)
xxx (xx%)
Week 6
n
xxx
xxx
1. All of the time
xxx (xx%)
xxx (xx%)
2. Most of the time
xxx (xx%)
xxx (xx%)
3. Some of the time
xxx (xx%)
xxx (xx%)
4. A little of the time
xxx (xx%)
xxx (xx%)
5. None of the time.
xxx (xx%)
xxx (xx%)
Week 12
n
xxx
xxx
1. All of the time
xxx (xx%)
xxx (xx%)
2. Most of the time
xxx (xx%)
xxx (xx%)
3. Some of the time
xxx (xx%)
xxx (xx%)
4. A little of the time
xxx (xx%)
xxx (xx%)
5. None of the time.
xxx (xx%)
xxx (xx%)
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Example
: EFF_T8
Protocol
: HZA116492
Page 2 of 10
Population
: Intent-to-Treat
Table 2.xx
Summary of Individual ACT Question Scores
Question: 1. Getting as much done at work, school or home
Visit
Response
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Week 18
n
xxx
xxx
1. All of the time
xxx (xx%)
xxx (xx%)
2. Most of the time
xxx (xx%)
xxx (xx%)
3. Some of the time
xxx (xx%)
xxx (xx%)
4. A little of the time
xxx (xx%)
xxx (xx%)
5. None of the time.
xxx (xx%)
xxx (xx%)
Week 24
n
xxx
xxx
1. All of the time
xxx (xx%)
xxx (xx%)
2. Most of the time
xxx (xx%)
xxx (xx%)
3. Some of the time
xxx (xx%)
xxx (xx%)
4. A little of the time
xxx (xx%)
xxx (xx%)
5. None of the time.
xxx (xx%)
xxx (xx%)
Early Withdrawal
n
xxx
xxx
1. All of the time
xxx (xx%)
xxx (xx%)
2. Most of the time
xxx (xx%)
xxx (xx%)
3. Some of the time
xxx (xx%)
xxx (xx%)
4. A little of the time
xxx (xx%)
xxx (xx%)
5. None of the time.
xxx (xx%)
xxx (xx%)
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Programming note: repeat on subsequent pages for Question = 2. Shortness of breath, 3. Asthma symptoms woken up at night or earlier than usual, 4. Used rescue 
inhaler or nubuliser medication, 5. Asthma control.
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Example
: EFF_T9
Protocol
: HZA116492
Page 1 of 3
Population
: Intent-to-Treat
Table 2.xx
Summary of Compliance with Study Medication
Note: Compliance = {[Total no. of inhalations taken]/[Dose frequency x (Stop date – Start date)]} x 100.
Note: Total number of inhalations taken is the sum of (dose counter start count – dose counter stop count) for all inhalers used during the time period, Dose frequency 
is equal to 1 for Ellipta, 2 for Diskus and 2 or 4 for Turbuhaler, and Start date and Stop date are the earliest treatment start date and latest treatment stop date
respectively recorded for all inhalers used during the time period. 
Programming note: repeat on subsequent pages for Time period = Day 0 to Week 12, Week 12 to Week 24.
Repeat for:
Summary of Compliance with Study Medication Per Protocol Population (PP Population) 
Time period
Compliance (%)
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Day 0 to Week 24
n
xxx
xxx
< 80%
xxx (xx%)
xxx (xx%)
80% to 120% inclusive
xxx (xx%)
xxx (xx%)
> 120%
xxx (xx%)
xxx (xx%)
n
xx
xx
Mean
xx.x
xx.x
SD
  x.xx
  x.xx
Median
xx.x
xx.x
Min.
xx
xx
Max.
xx
xx
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Example 
: EFF_T10
Protocol
: HZA116492
Page 1 of 12
Population
: Intent-to-Treat
Table 2.xx
Summary of Use of Medication Adherence Report Scale for Asthma (MARS-A) During the Study
Visit: Day 0
MARS-A Questions
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
I only use it when I need it
n
xxx
xxx
Always
xxx (xx%)
xxx (xx%)
Often
xxx (xx%)
xxx (xx%)
Sometimes
xxx (xx%)
xxx (xx%)
Rarely
xxx (xx%)
xxx (xx%)
Never
xxx (xx%)
xxx (xx%)
Only use it when I feel breathless
n
xxx
xxx
Always
xxx (xx%)
xxx (xx%)
Often
xxx (xx%)
xxx (xx%)
Sometimes
xxx (xx%)
xxx (xx%)
Rarely
xxx (xx%)
xxx (xx%)
Never
xxx (xx%)
xxx (xx%)
I decide to miss out a dose
n
xxx
xxx
Always
xxx (xx%)
xxx (xx%)
Often
xxx (xx%)
xxx (xx%)
Sometimes
xxx (xx%)
xxx (xx%)
Rarely
xxx (xx%)
xxx (xx%)
Never
xxx (xx%)
xxx (xx%)
Note: MARS-A: Medication Adherence Report Scale for Asthma.
[1]: MARS-A 10-Score is based on the mean score across all ten questions.
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Example 
: EFF_T10
Protocol
: HZA116492
Page 2 of 12
Population
: Intent-to-Treat
Table 2.xx
Summary of Use of Medication Adherence Report Scale for Asthma (MARS-A) During the Study
Visit: Day 0
MARS-A Questions
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
I try to avoid using it
n
xxx
xxx
Always
xxx (xx%)
xxx (xx%)
Often
xxx (xx%)
xxx (xx%)
Sometimes
xxx (xx%)
xxx (xx%)
Rarely
xxx (xx%)
xxx (xx%)
Never
xxx (xx%)
xxx (xx%)
I forget to take it
n
xxx
xxx
Always
xxx (xx%)
xxx (xx%)
Often
xxx (xx%)
xxx (xx%)
Sometimes
xxx (xx%)
xxx (xx%)
Rarely
xxx (xx%)
xxx (xx%)
Never
xxx (xx%)
xxx (xx%)
I alter the dose
n
xxx
xxx
Always
xxx (xx%)
xxx (xx%)
Often
xxx (xx%)
xxx (xx%)
Sometimes
xxx (xx%)
xxx (xx%)
Rarely
xxx (xx%)
xxx (xx%)
Never
xxx (xx%)
xxx (xx%)
Note: MARS-A: Medication Adherence Report Scale for Asthma.
[1]: MARS-A 10-Score is based on the mean score across all ten questions.
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Example 
: EFF_T10
Protocol
: HZA116492
Page 3 of 12
Population
: Intent-to-Treat
Table 2.xx
Summary of Use of Medication Adherence Report Scale for Asthma (MARS-A) During the Study
Visit: Day 0
MARS-A Questions
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
I stop taking it for a while
n
xxx
xxx
Always
xxx (xx%)
xxx (xx%)
Often
xxx (xx%)
xxx (xx%)
Sometimes
xxx (xx%)
xxx (xx%)
Rarely
xxx (xx%)
xxx (xx%)
Never
xxx (xx%)
xxx (xx%)
Reserve if treatment doesn't work
n
xxx
xxx
Always
xxx (xx%)
xxx (xx%)
Often
xxx (xx%)
xxx (xx%)
Sometimes
xxx (xx%)
xxx (xx%)
Rarely
xxx (xx%)
xxx (xx%)
Never
xxx (xx%)
xxx (xx%)
Before doing something
n
xxx
xxx
Always
xxx (xx%)
xxx (xx%)
Often
xxx (xx%)
xxx (xx%)
Sometimes
xxx (xx%)
xxx (xx%)
Rarely
xxx (xx%)
xxx (xx%)
Never
xxx (xx%)
xxx (xx%)
Note: MARS-A: Medication Adherence Report Scale for Asthma.
[1]: MARS-A 10-Score is based on the mean score across all ten questions.
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Example 
: EFF_T10
Protocol
: HZA116492
Page 4 of 12
Population
: Intent-to-Treat
Table 2.xx
Summary of Use of Medication Adherence Report Scale for Asthma (MARS-A) During the Study
Visit: Day 0
MARS-A Questions
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
I take less than instructed
n
xxx
xxx
Always
xxx (xx%)
xxx (xx%)
Often
xxx (xx%)
xxx (xx%)
Sometimes
xxx (xx%)
xxx (xx%)
Rarely
xxx (xx%)
xxx (xx%)
Never
xxx (xx%)
xxx (xx%)
MARS-A 10-Score [1]
n
xx
xx
Mean
xx.x
xx.x
SD
  x.xx
  x.xx
Median
xx.x
xx.x
Min.
xx
xx
Max.
xx
xx
Note: MARS-A: Medication Adherence Report Scale for Asthma.
[1]: MARS-A 10-Score is based on the mean score across all ten questions.
Programming note: Repeat on subsequent pages for Visit = Week 12, Week 24 and Early Withdrawal.
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Example 
: EFF_T10S
Protocol
: HZA116492
Page 1 of 48
Population
: Intent-to-Treat
Table 2.xx
Summary of Use of Medication Adherence Report Scale for Asthma (MARS-A) During the Study by Status of Patient in Relation to the Reminder Sent to French 
Centres
Status: Patients in France who had completed all MARS-A assessments prior to the reminder being implemented
Visit: Day 0
MARS-A Questions
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
I only use it when I need it
n
xxx
xxx
Always
xxx (xx%)
xxx (xx%)
Often
xxx (xx%)
xxx (xx%)
Sometimes
xxx (xx%)
xxx (xx%)
Rarely
xxx (xx%)
xxx (xx%)
Never
xxx (xx%)
xxx (xx%)
Only use it when I feel breathless
n
xxx
xxx
Always
xxx (xx%)
xxx (xx%)
Often
xxx (xx%)
xxx (xx%)
Sometimes
xxx (xx%)
xxx (xx%)
Rarely
xxx (xx%)
xxx (xx%)
Never
xxx (xx%)
xxx (xx%)
I decide to miss out a dose
n
xxx
xxx
Always
xxx (xx%)
xxx (xx%)
Often
xxx (xx%)
xxx (xx%)
Sometimes
xxx (xx%)
xxx (xx%)
Rarely
xxx (xx%)
xxx (xx%)
Never
xxx (xx%)
xxx (xx%)
Note: MARS-A: Medication Adherence Report Scale for Asthma.
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Note: Due to an issue identified with the French translation of the MARS-A, a reminder was sent to centres in France instructing that the questionnaire refers to the 
patient’s preventer inhaler (i.e. their maintenance therapy prior to entering the study, and study medication while on-study).
[1]: MARS-A 10-Score is based on the mean score across all ten questions.
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Example 
: EFF_T10S
Protocol
: HZA116492
Page 2 of 48
Population
: Intent-to-Treat
Table 2.xx
Summary of Use of Medication Adherence Report Scale for Asthma (MARS-A) During the Study by Status of Patient in Relation to the Reminder Sent to French 
Centres
Status: Patients in France who had completed all MARS-A assessments prior to the reminder being implemented
Visit: Day 0
MARS-A Questions
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
I try to avoid using it
n
xxx
xxx
Always
xxx (xx%)
xxx (xx%)
Often
xxx (xx%)
xxx (xx%)
Sometimes
xxx (xx%)
xxx (xx%)
Rarely
xxx (xx%)
xxx (xx%)
Never
xxx (xx%)
xxx (xx%)
I forget to take it
n
xxx
xxx
Always
xxx (xx%)
xxx (xx%)
Often
xxx (xx%)
xxx (xx%)
Sometimes
xxx (xx%)
xxx (xx%)
Rarely
xxx (xx%)
xxx (xx%)
Never
xxx (xx%)
xxx (xx%)
I alter the dose
n
xxx
xxx
Always
xxx (xx%)
xxx (xx%)
Often
xxx (xx%)
xxx (xx%)
Sometimes
xxx (xx%)
xxx (xx%)
Rarely
xxx (xx%)
xxx (xx%)
Never
xxx (xx%)
xxx (xx%)
Note: MARS-A: Medication Adherence Report Scale for Asthma.
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Note: Due to an issue identified with the French translation of the MARS-A, a reminder was sent to centres in France instructing that the questionnaire refers to the 
patient’s preventer inhaler (i.e. their maintenance therapy prior to entering the study, and study medication while on-study).
[1]: MARS-A 10-Score is based on the mean score across all ten questions.
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Example 
: EFF_T10S
Protocol
: HZA116492
Page 3 of 48
Population
: Intent-to-Treat
Table 2.xx
Summary of Use of Medication Adherence Report Scale for Asthma (MARS-A) During the Study by Status of Patient in Relation to the Reminder Sent to French 
Centres
Status: Patients in France who had completed all MARS-A assessments prior to the reminder being implemented
Visit: Day 0
MARS-A Questions
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
I stop taking it for a while
n
xxx
xxx
Always
xxx (xx%)
xxx (xx%)
Often
xxx (xx%)
xxx (xx%)
Sometimes
xxx (xx%)
xxx (xx%)
Rarely
xxx (xx%)
xxx (xx%)
Never
xxx (xx%)
xxx (xx%)
Reserve if treatment doesn't work
n
xxx
xxx
Always
xxx (xx%)
xxx (xx%)
Often
xxx (xx%)
xxx (xx%)
Sometimes
xxx (xx%)
xxx (xx%)
Rarely
xxx (xx%)
xxx (xx%)
Never
xxx (xx%)
xxx (xx%)
Before doing something
n
xxx
xxx
Always
xxx (xx%)
xxx (xx%)
Often
xxx (xx%)
xxx (xx%)
Sometimes
xxx (xx%)
xxx (xx%)
Rarely
xxx (xx%)
xxx (xx%)
Never
xxx (xx%)
xxx (xx%)
Note: MARS-A: Medication Adherence Report Scale for Asthma.
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Note: Due to an issue identified with the French translation of the MARS-A, a reminder was sent to centres in France instructing that the questionnaire refers to the 
patient’s preventer inhaler (i.e. their maintenance therapy prior to entering the study, and study medication while on-study).
[1]: MARS-A 10-Score is based on the mean score across all ten questions.
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Example 
: EFF_T10S
Protocol
: HZA116492
Page 4 of 48
Population
: Intent-to-Treat
Table 2.xx
Summary of Use of Medication Adherence Report Scale for Asthma (MARS-A) During the Study by Status of Patient in Relation to the Reminder Sent to French 
Centres
Status: Patients in France who had completed all MARS-A assessments prior to the reminder being implemented
Visit: Day 0
MARS-A Questions
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
I take less than instructed
n
xxx
xxx
Always
xxx (xx%)
xxx (xx%)
Often
xxx (xx%)
xxx (xx%)
Sometimes
xxx (xx%)
xxx (xx%)
Rarely
xxx (xx%)
xxx (xx%)
Never
xxx (xx%)
xxx (xx%)
MARS-A 10-Score [1]
n
xx
xx
Mean
xx.x
xx.x
SD
  x.xx
  x.xx
Median
xx.x
xx.x
Min.
xx
xx
Max.
xx
xx
Note: MARS-A: Medication Adherence Report Scale for Asthma.
Note: Due to an issue identified with the French translation of the MARS-A, a reminder was sent to centres in France instructing that the questionnaire refers to the 
patient’s preventer inhaler (i.e. their maintenance therapy prior to entering the study, and study medication while on-study).
[1]: MARS-A 10-Score is based on the mean score across all ten questions.
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Programming note: Repeat on subsequent pages for Visit = Week 12, Week 24 and Early Withdrawal, and for Status = Patients in France who had completed at least 
one MARS-A assessment prior to the reminder being implemented but also completed at least one MARS-A assessment after the reminder being implemented, 
Patients in France who had not completed any MARS-A assessments prior to the reminder being implemented, Patients in Germany.
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Example 
: EFF_T11
Protocol
: HZA116492
Page 1 of 2
Population
: Intent-to-Treat
Table 2.xx 
Summary of Severe On-Treatment Asthma Exacerbations
Usual ICS/LABA
(N=xxx)
FF/VI 
(N=xxx)
No. of subjects with one or more severe asthma exacerbation
xx (xx%)
xx (xx%)
                      
Total no. of severe asthma exacerbations
xx 
xx 
Number of severe asthma exacerbations per subject
  0
xx (xx%)
xx (xx%)
  1
xx (xx%)
xx (xx%)
  > 1
xx (xx%)
xx (xx%)
Duration of severe asthma exacerbation (days) [1]
  n 
xx
xx
  Mean
xx.x
xx.x
  SD
  x.xx
  x.xx
  Median
xx.x
xx.x
  Min.
xx
xx
  Max.
xx
xx
[1] Summary only includes exacerbations for which a date of resolution or death is provided.
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Example 
: EFF_T11
Protocol
: HZA116492
Page 2 of 2
Population
: Intent-to-Treat
Table 2.xx 
Summary of Severe On-Treatment Asthma Exacerbations
Usual ICS/LABA
(N=xxx)
FF/VI 
(N=xxx)
Outcome
  Resolved
xx (xx%)
xx (xx%)
  Fatal
xx (xx%)
xx (xx%)
  Not resolved
xx (xx%)
xx (xx%)
Total no. of severe asthma exacerbations
xx
xx
No. of exacerbations: 
  Requiring use of systemic/oral corticosteroids
xx (xx%)
xx (xx%)
  Leading to hospitalisation
xx (xx%)
xx (xx%)
  Requiring emergency room visit
xx (xx%)
xx (xx%)
No. of exacerbations requiring intubation
xx (xx%)
xx (xx%)
No. of exacerbations leading to withdrawal from study
xx (xx%)
xx (xx%)
[1] Summary only includes exacerbations for which a date of resolution or death is provided. 
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Example 
: EFF_T11S
Protocol
: HZA116492
Page 1 of 8
Population
: Intent-to-Treat
Table 2.xx 
Summary of Severe On-Treatment Asthma Exacerbations by Season
Season: Spring
Usual ICS/LABA
(N=xxx)
FF/VI 
(N=xxx)
No. of subjects with one or more severe asthma exacerbation
xx (xx%)
xx (xx%)
                      
Total no. of severe asthma exacerbations
xx 
xx 
Number of severe asthma exacerbations per subject
  0
xx (xx%)
xx (xx%)
  1
xx (xx%)
xx (xx%)
  > 1
xx (xx%)
xx (xx%)
Duration of severe asthma exacerbation (days) [1]
  n 
xx
xx
  Mean
xx.x
xx.x
  SD
  x.xx
  x.xx
  Median
xx.x
xx.x
  Min.
xx
xx
  Max.
xx
xx
Note: Spring = March, April and May; Summer = June, July and August; Autumn = September, October and November; Winter = December, January and February. 
[1] Summary only includes exacerbations for which a date of resolution or death is provided.
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Example 
: EFF_T11
Protocol
: HZA116492
Page 2 of 8
Population
: Intent-to-Treat
Table 2.xx 
Summary of Severe On-Treatment Asthma Exacerbations by Season
Season: Spring
Usual ICS/LABA
(N=xxx)
FF/VI 
(N=xxx)
Outcome
  Resolved
xx (xx%)
xx (xx%)
  Fatal
xx (xx%)
xx (xx%)
  Not resolved
xx (xx%)
xx (xx%)
Total no. of severe asthma exacerbations
xx
xx
No. of exacerbations: 
  Requiring use of systemic/oral corticosteroids
xx (xx%)
xx (xx%)
  Leading to hospitalisation
xx (xx%)
xx (xx%)
  Requiring emergency room visit
xx (xx%)
xx (xx%)
No. of exacerbations requiring intubation
xx (xx%)
xx (xx%)
No. of exacerbations leading to withdrawal from study
xx (xx%)
xx (xx%)
Note: Spring = March, April and May; Summer = June, July and August; Autumn = September, October and November; Winter = December, January and February. 
[1] Summary only includes exacerbations for which a date of resolution or death is provided. 
Programming note: repeat on subsequent pages for Season = Summer, Autumn, Winter.
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Example
: EFF_T12
Protocol 
: HZA116492                       
Page 1 of 1
Population 
: Intent-to-Treat
Table 2.xx
Summary of the Statistical Analysis of Severe On-Treatment Asthma Exacerbations
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
n
xxx
xxx
LS Mean Annual Rate
x.xx
x.xx
FF/VI vs. Usual ICS/LABA
  Ratio
x.xx
  95% CI
(x.xx, x.xx)
  p-value
x.xxx
  Percent Reduction
x.xx
  95% CI
(x.xx, x.xx)
Note: The analysis method was Generalised Linear Model assuming an underlying negative binomial distribution with a log-link function and logarithm of time on 
treatment as an offset variable and adjusted for randomised treatment, number of severe asthma exacerbations in the previous year prior to randomisation, gender, 
age and country.
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Example 
: EFF_T13
Protocol
: HZA116492
Page 1 of 1
Population
: Intent-to-Treat
Table 2.xx
Summary of the Statistical Analysis of Time to First Severe On-Treatment Asthma Exacerbation
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Number of subjects with event
xx (xx%)
xx (xx%)
Number of subjects censored
xx (xx%)
xx (xx%)
Probability of having event (%) [1]                      
xx.x 
xx.x 
  95% CI
(xx.x, xx.x)
(xx.x, xx.x)
FF/VI vs. Usual ICS/LABA
  Hazard Ratio [2] 
x.xx
  95% CI 
(xx.x, xx.x)
  p-value 
  x.xxx
[1] Kaplan-Meier estimates.
[2] Overall hazard ratios, CIs and p-values are from a Cox proportional hazards model with randomised treatment, gender, age and country as covariates.  A hazard 
ratio <1 indicates a lower risk with FF/VI compared with Usual ICS/LABA.
Note: At Day 168 all subjects who have not experienced a severe asthma exacerbation are considered censored, regardless of whether their on-treatment phase 
continues beyond Day 168.
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Example
: EFF_T14
Protocol
: HZA116492
Page 1 of 5
Population
: Intent-to-Treat
Table 2.xx
Summary of Percentage of Subjects Who Have an Increase from Baseline of >=0.5 in AQLQ(S) Total Score and Domain Scores
Domain: Total Score
[1] Responder is defined as an increase from baseline of >= 0.5.
Programming note: repeat on subsequent pages for Domain = Environmental Stimuli, Symptoms, Activity Limitations and Emotional Function.
Visit
Response
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Week 24
n
xxx
xxx
Responder [1]
xxx (xx%)
xxx (xx%)
Non-Responder
xxx (xx%)
xxx (xx%)
Early Withdrawal
n
xxx
xxx
Responder [1]
xxx (xx%)
xxx (xx%)
Non-Responder
xxx (xx%)
xxx (xx%)
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Example
: EFF_T15
Protocol
: HZA116492
Page 1 of 10
Population
: Intent-to-Treat
Table 2.xx
Summary of EQ-5D-5L Descriptive System Dimensions
Dimension: Anxiety/Depression
Visit
  
                       
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Day 0
n
xxx
xxx
I am not anxious or depressed
xxx (xx%)
xxx (xx%)
I am slightly anxious or depressed
xxx (xx%)
xxx (xx%)
I am moderately anxious or depressed
xxx (xx%)
xxx (xx%)
I am severely anxious or depressed
xxx (xx%)
xxx (xx%)
I am extremely anxious or depressed
xxx (xx%)
xxx (xx%)
Missing
xxx (xx%)
xxx (xx%)
Week 24
n
xxx
xxx
I am not anxious or depressed
xxx (xx%)
xxx (xx%)
I am slightly anxious or depressed
xxx (xx%)
xxx (xx%)
I am moderately anxious or depressed
xxx (xx%)
xxx (xx%)
I am severely anxious or depressed
xxx (xx%)
xxx (xx%)
I am extremely anxious or depressed
xxx (xx%)
xxx (xx%)
Missing
xxx (xx%)
xxx (xx%)
Programming note: repeat on subsequent pages for Visit = Early Withdrawal and for Dimension = Mobility, Pain/Discomfort, Self-care, Usual activities.
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10.16.4.
Efficacy Figure Shells
Example 
: EFF_F1
Protocol
: HZA116492
Page 1 of 1
Population
: Intent-to-Treat
Figure 2.xx
Summary of ACT Total Score
Programming note: present “ACT Total Score” on y-axis and “Visit” on x-axis (Day 0, Week 6, Week 12, Week 18, Week 24). Present mean ACT Total Score ∀SD 
separately for treatment group (FF/VI, Usual ICS/LABA) at each visit, connecting the means with a solid line. Distinguish the treatment groups by different line types
and colours.
Repeat for:
Summary of Change from Baseline in ACT Total Score Per Protocol Population (PP Population)
Summary of Change from Baseline in ACT Total Score by Country (ITT Population)
Country: France
Country: Germany
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Example 
: EFF_F2
Protocol
: HZA116492
Page 1 of 1
Population
: Intent-to-Treat
Figure 2.xx
Summary of Primary and Sensitivity Analyses for Change from Baseline in ACT Total Score at Week 12 (Visit 4)
Programming note: present “Treatment difference” on the x-axis, and reverse axis so treatment difference increases from left to right. Replace “Ratio (95% CI)” with 
“Treatment Difference (95% CI)”. Present lines for the following: Primary analysis (ITT), Primary analysis (PP), ANCOVA with LOCF (ITT), Multiple Imputation (Missing 
at Random) (ITT), Multiple Imputation (Copy Differences from Reference) (ITT), Hodges-Lehmann (ITT), ANCOVA with WOCF (ITT).
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Repeat for:
Summary of Key Secondary and Sensitivity Analyses for Change from Baseline in ACT Total Score at Week 24 (Visit 6)
Example 
: EFF_F3
Protocol
: HZA116492
Page 1 of 1
Population
: Intent-to-Treat
Figure 2.xx
Summary of Interaction Tests for Change from Baseline in ACT Total Score at Week 12 (Visit 4)
Programming note: present “LS Mean Change” on the x-axis, and reverse axis so it increases from left to right. Replace “Ratio (95% CI)” with “LS Mean Change (95% 
CI)”. Present the following subgroups: Country (France, Germany); Number of Severe Asthma Exacerbations in the Previous Year Prior to Randomisation (0, >= 1); 
Smoking Status at Baseline (Current Smokers, Former Smokers, Never Smoked); Age Group (18 – 50 Years Old, > 50 Years Old); Gender (Male, Female).
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Example 
: EFF_F4
Protocol
: HZA116492
Page 1 of 1
Population
: Intent-to-Treat
Figure 2.xx
Histogram of Percentage of Subjects Who Have Either an ACT Total Score of >= 20 or >= 3 Point Increase from Baseline in ACT Total Score
Programming note: present “Percent of Subjects (%)” on y-axis and “Visit” on x-axis (Week 6, Week 12, Week 18, Week 24, Early Withdrawal). For each visit, present 
3 vertical bars distinguished by fill pattern (similar to non-standard EFF_F6). Each bar represents: “ACT Total Score >= 20 or >= 3 Point Increase from Baseline in ACT 
Total Score”, “ACT Total Score >= 20” and “>= 3 Point Increase from Baseline in ACT Total Score” respectively and should be labelled as such on the legend.
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Example 
: EFF_F5
Protocol
: HZA116492
Page 1 of 1
Population
: Intent-to-Treat
Figure 2.xx
Box Plot of Compliance with Study Medication
Programming Note: label y-axis title as “Compliance (%)”, maximum of y-axis may be > 100%.
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Example 
: EFF_F6
Protocol
: HZA116492
Page 1 of 8
Population
: Intent-to-Treat
Figure 2.xx
Histogram of the Questions and Answers of the MARS-A Questionnaire
Randomised Treatment: Usual ICS/LABA
Visit: Day 0
Note: MARS-A = Medication Adherence Report Scale for Asthma.
Programming note: repeat on subsequent pages for Visit = Week 24, Week 52 and Early Withdrawal; and for Randomised Treatment = FF/VI.
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Repeat for:
Histogram of the Questions and Answers of the MARS-A Questionnaire by Status of Patient in Relation to the Reminder Sent to French Centres (ITT Population)
Status: Patients in France who had completed all MARS-A assessments prior to the reminder being implemented
Status: Patients in France who had completed at least one MARS-A assessment prior to the reminder being implemented but also completed at least one MARS-A 
assessment after the reminder being implemented
Status: Patients in France who had not completed any MARS-A assessments prior to the reminder being implemented
Status: Patients in Germany
Add the following footnote: “Note: Due to an issue identified with the French translation of the MARS-A, a reminder was sent to centres in France instructing that the 
questionnaire refers to the patient’s preventer inhaler (i.e. their maintenance therapy prior to entering the study, and study medication while on-study).”
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Example 
: EFF_F7
Protocol
: HZA116492
Page 1 of 4
Population
: Intent-to-Treat
Figure 2.xx
Histogram of the Distribution of MARS-A Scores During the Study
Visit: Day 0
Note: MARS-A = Medication Adherence Report Scale for Asthma.
Note: MARS-A 10-Score is based on the mean score across all ten questions.
Programming note: repeat on subsequent pages for Visit = Week 52 and Early Withdrawal.
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Repeat for:
Histogram of the Distribution of MARS-A Scores During the Study by Status of Patient in Relation to the Reminder Sent to French Centres (ITT Population)
Status: Patients in France who had completed all MARS-A assessments prior to the reminder being implemented
Status: Patients in France who had completed at least one MARS-A assessment prior to the reminder being implemented but also completed at least one MARS-A 
assessment after the reminder being implemented
Status: Patients in France who had not completed any MARS-A assessments prior to the reminder being implemented
Status: Patients in Germany
Add the following footnote: “Note: Due to an issue identified with the French translation of the MARS-A, a reminder was sent to centres in France instructing that the 
questionnaire refers to the patient’s preventer inhaler (i.e. their maintenance therapy prior to entering the study, and study medication while on-study).”
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Example 
: EFF_F8
Protocol
: HZA116492
Page 1 of 1
Population
: Intent-to-Treat
Figure 2.xx
Box Plot of Severe On-Treatment Asthma Exacerbation Rates Adjusted for Exposure to Treatment
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Example 
: EFF_F9
Protocol
: HZA116492
Page 1 of 1
Population
: Intent-to-Treat
Figure 2.xx
Kaplan-Meier Plot of Time to First Severe On-Treatment Asthma Exacerbation
Programming note: display increments of 6 weeks on the x-axis, up to the maximum exposure (e.g. 0, 6, 12, 18, 24, 30).
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10.16.5.
Safety Table Shells
Example 
: SAFE_T1
Protocol
: HZA116492
Page 1 of 1
Population
: Safety
Table 3.xx
On-Treatment Serious Adverse Events and Adverse Drug Reactions Overview
  
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Any on-treatment ADRs
xxx (xx%)
xxx (xx%)
Any on-treatment non serious ADRs
xxx (xx%)
xxx (xx%)
Any on-treatment serious ADRs
xxx (xx%)
xxx (xx%)
Any post-treatment serious ADRs
xxx (xx%)
xxx (xx%)
Any on-treatment SAEs
xxx (xx%)
xxx (xx%)
Any post-treatment SAEs
xxx (xx%)
xxx (xx%)
Any SAEs or ADRs leading to permanent discontinuation of 
study drug or withdrawal from study [1]
xxx (xx%)
xxx (xx%)
Any on-treatment fatal serious ADRs
xxx (xx%)
xxx (xx%)
Any on-treatment fatal SAEs
xxx (xx%)
xxx (xx%)
Any post-treatment fatal SAEs
xxx (xx%)
xxx (xx%)
[1] Includes both on-treatment and post-treatment SAEs and ADRs.
Programming note: Based on IDSL standard template AE13.
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Example 
: SAFE_T2
Protocol
: HZA116492
Page 1 of 1
Population
: Safety
Table 3.xx
Summary of On-Treatment Non-Serious Adverse Drug Reactions of Special Interest
Special Interest Group/
  Subgroup
     Preferred Term
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
Adrenal suppression
  Any event
xxx (xx%)
xxx (xx%)
  Blood cortisol decreased
xxx (xx%)
xxx (xx%)
Cardiovascular effects
  Any event
xxx (xx%)
xxx (xx%)
  Cardiac Arrhytmia [1]
xxx (xx%)
xxx (xx%)
     Any event
xxx (xx%)
xxx (xx%)
     Palpitations 
xxx (xx%)
xxx (xx%)
     Extrasystoles
xxx (xx%)
xxx (xx%)
  Cardiac Ischaemia [1]
xxx (xx%)
xxx (xx%)
     Any event
xxx (xx%)
xxx (xx%)
     Angina pectoris
xxx (xx%)
xxx (xx%)
     Chest pain
xxx (xx%)
xxx (xx%)
Effects on potassium
  Any event
xxx (xx%)
xxx (xx%)
  XXXXXXX
xxx (xx%)
xxx (xx%)
  XXXXXXX
xxx (xx%)
xxx (xx%)
[1]: This subgroup was defined using Special MedDRA queries.
Programming note: Based on IDSL standard template AE1.
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Repeat for:
Summary of On-Treatment Serious Adverse Drug Reactions of Special Interest (ITT Population)
Summary of On-Treatment Adverse Drug Reactions of Special Interest (ITT Population)
Summary of On-Treatment Serious Adverse Events of Special Interest (ITT Population)
Summary of On-Treatment Fatal Serious Adverse Events of Special Interest (ITT Population)
Summary of On-Treatment Non-Fatal Serious Adverse Events of Special Interest (ITT Population)
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Example
: SAFE_T3
Protocol
: HZA116492
Page 1 of n
Population
: Safety
Table 3.xx
Top Ten Most Commonly Reported On-Treatment Adverse Drug Reactions Per Treatment Group
Preferred Term
Usual ICS/LABA
(N=xxx)
FF/VI
(N=xxx)
xxxxxxx
xxx (xx%)
xxx (xx%)
xxxxxxx
xxx (xx%)
xxx (xx%)
xxxxxxx
xxx (xx%)
xxx (xx%)
xxxxxxx
xxx (xx%)
xxx (xx%)
xxxxxxx
xxx (xx%)
xxx (xx%)
xxxxxxx
xxx (xx%)
xxx (xx%)
xxxxxxx
xxx (xx%)
xxx (xx%)
xxxxxxx
xxx (xx%)
xxx (xx%)
xxxxxxx
xxx (xx%)
xxx (xx%)
xxxxxxx
xxx (xx%)
xxx (xx%)
......
Programming note: Present the ten most frequent preferred terms in Usual ICS/LABA, and the ten most frequent in FF/VI (do not use percentages to determine “most 
frequent”).
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10.16.6.
Safety Figure Shells
Example 
: SAFE_F1
Protocol
: HZA116492
Page 1 
of 1
Population
: Intent-to-Treat/Safety
Figure 2.xx
Summary of Benefit:Risk for FF/VI vs. Usual ICS/LABA
* = Number of subjects with event
(a) Difference in LS mean change from baseline from an MMRM
(b) Difference in LS mean change from baseline from an ANCOVA model
(c) Adjusted odds ratio obtained from a logistic regression model
(d) Risk difference
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Programming note: present the following endpoints:
!
Benefits:
!
First panel, x-axis decreasing from left to right:
o
Difference in LS mean change from baseline and 95% CI for: change from baseline in 
ACT total score at Week 12 (Visit 4) and at Week 24 (Visit 6) (labeled (a)) 
o
Difference in LS mean change from baseline and 95% CI for change from baseline in 
trough (pre-dose) FEV1 at Week 12 (Visit 4) (labeled (b))
!
Second panel, x-axis increasing from left to right:
o
Adjusted odds ratio and 95% CI for: percentage of subjects with correct use of inhaler 
device at Week 12 (Visit 4) and at Week 24 (Visit 6) (labeled (c))
!
Risks:
!
Third panel, x-axis increasing from left to right:
o
Risk difference and 95% CI of the following SAEs of special interest: 
asthma/bronchospasm, cardiovascular effects, decreased bone mineral density and 
associated fractures, hypersensitivity, local steroid effects, lower respiratory tract infection 
(LRTI) excluding pneumonia, pneumonia, adrenal suppression, ocular effects, effects on 
glucose, effects on potassium, tremor (labeled (d))
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10.16.7.
Non-ICH Listing Shells
Example 
: POP_L1 
Protocol
: HZA116492
Page 1 of n
Population
: All Subjects Enrolled
Listing x
Subjects Screened but Not in the Intent-to-Treat Population
Randomised 
Treatment
Inv.
Subj.
Disposition Status
Reason for Screen Failure/Withdrawal
Screen Failure
xxxxxx
xxxxxx
Screen Failure
Xxxxxxxxxxxxx
FF/VI 
xxxxxx
xxxxxx
Early Withdrawal
Xxxxxxxxxxxxx
...
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Example
: POP_L2
Protocol
: HZA116492
Page 1 of n
Population
: Intent-to-Treat
Listing x
Reasons for Important Protocol Deviations
Randomised
Treatment
Inv.
Subj.
Important Protocol Deviation
Excluded
from PP?
Date of Deviation
Study Day of Deviation
FF/VI        
xxxxx
xxxxx
xxxxxxxxxxxx
No
DDMMMYYYY          
xx
xxxxx
xxxxx
xxxxxxxxxxxx
No
DDMMMYYYY          
xx
Usual ICS/LABA
xxxxx
xxxxx
xxxxxxxxxxxx
No
DDMMMYYYY
xx
xxxxx
xxxxx
xxxxxxxxxxxx
Yes
DDMMMYYYY          
xx
xxxxx
xxxxx
xxxxxxxxxxxx
No
DDMMMYYYY          
xx
xxxxx
xxxxx
xxxxxxxxxxxx
No
DDMMMYYYY          
xx
....
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Example 
: POP_L3   
      
Protocol
: HZA116492
Page 1 of n
Population
: Intent-to-Treat
Listing x
Asthma History
Number of asthma exacerbations in the last 12 months that:
Treatment
Inv.
Subj.
Asthma Duration
Did not require oral/systemic 
corticosteroids (not involving 
hospitalisation)
Required oral/systemic 
corticosteroids (not involving 
hospitalisation)
Required hospitalisation
xxxxxx
xxxxxx
xxxxxx
xxxxxxxxxxxxx
xx
xx
xx
xxxxxx
xxxxxx
xxxxxxxxxxxxx
xx
xx
xx
xxxxxx
xxxxxx
xxxxxxxxxxxxx
xx
xx
xx
xxxxxx
xxxxxx
xxxxxxxxxxxxx
xx
xx
xx
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Example 
: POP_L4
Protocol
: HZA116492
Page 1 of n
Population
: Intent-to-Treat
Listing x
Smoking History
Treatment
Inv./
Subj.
Smoking
Status
Years Smoked/
Cigarettes per day
Smoking 
Pack Years
xxxxxx
Xxxxxx/
xxxxxx
Current
xx/
xx
xx
Xxxxxx/
xxxxxx
Former
xx/
xx
xx
Xxxxxx/
xxxxxx
Never
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191
Example 
: POP_L5
Protocol
: HZA116492
Page 1 of n
Population
: Intent-to-Treat
Listing x
Exposure to Study Medication
Treatment: Usual ICS/LABA
Inv./
Subj.
Treatment Start Date/ 
Treatment End date
Start date of  dose/
End date of dose/
Duration of dose (days)
Drug
Dose/ Dose 
Units/ Dose 
Frequency
Inhalers 
Dispensed/
Inhalers Returns
Dose counter start/
Dose counter stop
Compliance (%) 
During the study 
XXXX
DDMMMYYY/
DDMMMYYY
XX.XX
DDMMMYYYY/
DDMMMYYYY/
xx
XXXXXXX
XX/ XX/XXXX
X/X
XXX/XX
DDMMMYYYY/
DDMMMYYYY
xx
XXXXXXX
XX/ XX/XXXX
X/X
XXX/XX
XXXX
DDMMMYYY
XX.XX
DDMMMYYYY/
DDMMMYYYY/
xx
XXXXXXX 
XX/ XX/XXXX
X/X
XXX/XX
Programming note: Repeat on subsequent pages for Treatment = FF/VI, and use GSK drug synonym as drug name. 
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Example 
: EFF_L1
Protocol
: HZA116492                                                                              
Page 1 of n
Population
: Intent-to-Treat 
Listing x
ACT Scores
Treatment: Usual ICS/LABA
Inv./
Subj.
Visit/
Study Date/
Study Day
Impact at 
home or work 
[1]
Frequency of 
shortness of 
breath [1]
Frequency of 
sleep trouble 
[1]
Frequency of 
rescue 
medication [1]
Asthma control 
rating [1]
ACT Total 
Score [2] /
Change from 
Baseline
xxxxxx/
xxxxx
Day 0/
DDMMMYYYY/
xx
x
x
x
x
x
xx 
Week 6/
DDMMMYYYY/
xx
x
x
x
x
x
xx / 
-x
Week 12/
DDMMMYYYY/
xx
x
x
x
x
x
xx / 
x
...
[1] Responses range between 1 (worst response) and 5 (best response).
[2] ACT Total Score ranges between 5 (worst asthma control state) and 25 (best asthma control state).
Programming note: Repeat on subsequent pages for Treatment = FF/VI.
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Example 
: EFF_L2
Protocol
: HZA116492
Page 1 of n
Population
: Intent-to-Treat 
Listing x
Inhaler Device Use
Treatment: Usual ICS/LABA
Critical errors
Non-critical errors
Inv./
Subj.
Visit/
Study Date/
Study Day
Inhaler
Any?
If yes, errors:
Any?
If yes, errors:
xxxxxx/
xxxxx
Day 0/
DDMMMYYYY/
xx
Turbuhaler
No
No
Week 12/
DDMMMYYYY/
xx
Turbuhaler
No
Yes
Did not hold breath
Week 24/
DDMMMYYYY/
xx
Turbuhaler
Yes
Exhaled directly into mouthpiece
No
xxxxxx/
xxxxx
Day 0/
DDMMMYYYY/
xx
Diskus
Yes
Did not hold device upright during dose 
preparation
Shook the device after dose preparation
Yes
No exhalation before an inhalation
Week 12/
DDMMMYYYY/
xx
Diskus
Yes
Shook the device after dose preparation
No
Programming note: Repeat on subsequent pages for Treatment = FF/VI.
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Example
: EFF_L3
Protocol
: HZA116492
Page 1 of n
Population
: Intent-to-Treat 
Listing x
Lung Function Tests
Treatment: Usual ICS/LABA
Trough (pre-dose) FEV1 (L)
Trough (pre-dose) percent 
predicted normal FEV1 (%)
Inv./
Subj.
Visit
Study Date/
Time
Study
Day
Absolute
Change from
Baseline
Predicted
normal FEV1 (L)
Absolute
Change from
Baseline
Bronchodilator 
taken in last 4 
hours?
xxxxxx/
xxxxx
Day 0
DDMMMYYYY/
HH:MM
xx
x.xxx
x.xxx
xx.x
No
Week 6
DDMMMYYYY/ 
HH:MM
xx
x.xxx
x.xxx
x.xxx
xx.x
xx.x
No
xxxxxx/
xxxxx
Day 0
DDMMMYYYY/
HH:MM
xx
x.xxx
x.xxx
x.xxx
xx.x
xx.x
No
Programming note: Repeat on subsequent pages for Treatment = FF/VI.
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Example 
: EFF_L4
Protocol
: HZA116492                                                                              
       Page 1 of n
Population
: Intent-to-Treat 
Listing x
Medication Adherence Report Scale for Asthma (MARS-A) Scores
Treatment: Usual ICS/LABA
Inv./
Subj.
Status [1]
Visit/
Study Date/
Study Day
Assessor Code
MARS-A Questions
Score [2]
xxxxxx/
xxxxx
During
Day 0/
DDMMMYYYY/
xx
Subject/Other
I only use it when I need it
x
Only use it when I feel breathless
x
I decide to miss out a dose
x
I try to avoid using it
x
I forget to take it
x
I alter the dose
x
I stop taking it for a while
x
Reserve if treatment doesn't work
x
Before doing something
x
I take less than instructed
x
MARS-A 10-Score [3]
x.xx
Week 12/
DDMMMYYYY/
xx
Subject/Other
I only use it when I need it 
x
Only use it when I feel breathless  .....etc
x
[1] Due to an issue identified with the French translation of the MARS-A, a reminder was sent to centres in France instructing that the questionnaire refers to the 
patient’s preventer inhaler (i.e. their maintenance therapy prior to entering the study, and study medication while on-study. Status = Prior (patient in France who had 
completed all MARS-A assessments prior to the reminder), During (patient in France who had completed at least one MARS-A assessment prior to the reminder but 
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196
also completed at least one MARS-A assessment after the reminder), After (patient in France who had not completed any MARS-A assessments prior to the 
reminder), Germany (patient in Germany).
[2] Question scores range between 1 (always) and 5 (never).
[3] MARS-A 10-Score is based on the mean score across all ten questions.
Programming note: Repeat on subsequent pages for Treatment = FF/VI.
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Example 
: EFF_L5
Protocol
: HZA116492                                                                              
Page 1 of n
Population
: Intent-to-Treat 
Listing x
Severe Asthma Exacerbations
Treatment: Usual ICS/LABA
Inv./
Subj.
Date of Onset/
Study day/
Date of Resolution/
Study day
Resolution/
Withdrawn from Study?
Required use of 
systemic/oral 
corticosteroids?
Led to 
hospitalisation?
Required 
emergency 
room visit?
Required 
intubation?
Xxxxxx/
xxxxx
DDMMMYYYY/
xx/
DDMMMYYYY/
xx
Resolved/
N
Y
N
N
N
DDMMMYYYY/
xx/
DDMMMYYYY/
xx
Resolved/
N
N
N
Y
N
DDMMMYYYY/
xx/
DDMMMYYYY/
xx
Fatal/
Y
Y
Y
N
Y
Programming note: Repeat on subsequent pages for Treatment = FF/VI.
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Example 
: EFF_L6
Protocol
: HZA116492                                                                              
Page 1 of n
Population
: Intent-to-Treat 
Listing x
AQLQ(S) Scores
Treatment: Usual ICS/LABA
Inv./
Subj.
Visit/
Study Date/
Study Day
Symptoms [1]
Activity Limitations 
[1]
Emotional 
Function [1]
Environmental 
Stimuli [1]
AQLQ(S) Total 
Score [1] / 
Change from 
Baseline
xxxxxx/
xxxxx
Day 0/
DDMMMYYYY/
xx
x.x
x.x
x.x
x.x
x.x
Week 24/
DDMMMYYYY/
xx
x.x
x.x
x.x
x.x
x.x /
x.x
...
[1] Scores range between 1 (lower quality of life) and 7 (higher quality of life) for AQLQ(S) total and domains.
Programming note: Repeat on subsequent pages for Treatment = FF/VI.
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Example 
: EFF_L7
Protocol
: HZA116492                                                                              
Page 1 of n
Population
: Intent-to-Treat 
Listing x
EQ-5D-5L Descriptive System Dimension Scores
Treatment: Usual ICS/LABA
Inv./
Subj.
Visit/
Study Date/
Study Day
Assessor Code
Subscale/
    Item
Level of Problem 
Score [1]
xxxxxx/
xxxxx
Day 0
DDMMMYYYY/
xx
Subject/Other
EQ-5D-5L Utility 
Score
xx.xx
  Mobility
1
  Self-Care
1
  Usual Activities
1
  Pain/Discomfort 
1
  Anxiety/Depression
1
EQ-5D-5L VAS
xx.xx
Week 12
DDMMMYYYY/
xx
Subject/Other
EQ-5D-5L Utility 
Score
xx.xx
Mobility  .........etc
1
[1] Scores range between 0 (worst imaginable health state) and 1 (best imaginable health state) for EQ-5D-5L Utility Score and range between 0 (worst imaginable 
health state) and 100 (best imaginable health state) for EQ-5D-5L Visual Analogue Scale (VAS).
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Example 
: EFF_L8
Protocol
: HZA116492                                                                              
Page 1 of n
Population
: Intent-to-Treat 
Listing x
PASAP-Q Scores
Treatment: Usual ICS/LABA
Inv./
Subj.
Visit/
Study Date/
Study Day
Domain /
   Question
Response
Score [1]
xxxxxx/
xxxxx
Day 0
DDMMMYYYY/
xx
Performance
xx.x
   Overall feeling of inhaling
x
   Inhaled dose goes to lungs
x
   Medication left
x
   Works reliably
x
   Ease of inhaling a dose
x
   Using the inhaler
x
   Speed medicine comes out
x
Convenience
xx.x
   Instructions for use
x
   Size of inhaler
x
   Durability of inhaler
x
   Ease of cleaning inhaler
x
   Ease of holding during use
x
   Convenience of carrying
x
Total Score
xx.x
Overall Satisfaction
x
Willingness to Continue Using Inhaler
xx.x
[1] Performance, Convenience, Total Score, and Willingness to Continue Using Inhaler are expressed on a scale of 0 to 100. Overall Satisfaction is expressed on a 
scale of 1 to 7.
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Programming note: Repeat on subsequent pages for Treatment = FF/VI.
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Example 
: SAFE_L1
Protocol
: HZA116492
Page 1 of n
Population
: Intent-to-Treat
Listing x
AE Terms of Special Interest
Special Interest Term
Subgroup
Preferred Term
xxxxx xxxxx xxxxxx
Xxxxxxx
xxxxxxx
xxxxxxx xxxxxxx
xxxx
xxxxxxx xxx
xxxxxxx xxxxxxxxxx
xxxxxxxxxxxxxxx [1]
xxxxxxx xxxxxx
xxxxxxx xxxx xxxxx xxxxx
xxxx
xxxxxxxxxxx
xxxxxxx [1]
xxxxxxx
xxxx xxxxxx xxxxxxx
xxxxxx xxxxxxx
xxxxxxxxx
xxxxx xxxxxx xxxxxxx xxxxxx
[1]: This special interest term was defined using Special MedDRA Queries.
Note: All of the pre-specified preferred terms that were assigned to special interest terms are shown, regardless of whether they actually occurred in the study.
Programming Note: The AE special interest dataset and the AE SMQ dataset will be set together in order to report this table and all the subgroups that come from the 
AE SMQ dataset will be flagged with a [1].
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Example 
: SAFE_L2
Protocol
: HZA116492
Page 1 of n
Population
: Intent-to-Treat
Listing x
Inhaler Device Malfunctions
Treatment
Inv./
Subj.
Inhaler Device
Comment / Reason for Malfunction
Usual ICS/LABA
xxxxxx/
xxxxx
Turbuhaler
XXXXXXXXXXX
Usual ICS/LABA
xxxxxx/
xxxxx
Diskus
XXXXXXXXXXX
FF/VI
xxxxxx/
xxxxx
Ellipta
Powder fell out prior to use
Other: XXXXXXXX
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