Clinical trial NCT03184987
Conditions: Asthma
Keywords: fluticasone furoate fixed dose combination Japanese subjects vilanterol asthma umeclidinium bromide closed triple therapy
Sponsor: GlaxoSmithKline
Start date: 2017-06-22; Completion date: 2019-06-25
Enrollment: 111 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Despite availability of treatments and published guidelines, subjects may have asthma that is inadequately controlled. GlaxoSmithKline is currently developing a once-daily 'closed' triple therapy of an Inhaled Corticosteroids/Long-Acting Beta-2-Agonists/Long-Acting Muscarinic Antagonist (ICS/LAMA/LABA) combination (Fluticasone Furoate/Umeclidinium Bromide/Vilanterol Trifenatate \[FF/UMEC/VI\]) in a single device, with the aim of providing a new treatment option for the management of asthma by improving lung function, health-related quality of life (HRQoL) and symptom control over established combination therapies. This study has 3 study periods: Run-in, Treatment period and a Follow-up period. Eligible subjects who meet the pre-defined criteria at screening (Visit 1) will enter into a 2-week run-in period. Subjects will continue their pre-screening inhaled medications for asthma (ICS+LABA or ICS+LABA+LAMA) without any change in regimen/dosage until day before Visit 2. At Visit 2 subjects will be allocated to either FF/UMEC/VI 100/62.5/25 or FF/UMEC/VI 200/62.5/25 micrograms (mcg) treatment depending on the asthma control status for 52 weeks. Switching medication from FF/UMEC/VI 100/62.5/25 to FF/UMEC/VI 200/62.5/25 will be permitted in accordance with the control status of the subject assessed by Asthma Control Questionnaire (ACQ)-7 at Week 24 of the treatment period. A follow-up visit will be conducted for approximately 1 week. Subjects will be provided with salbutamol as a rescue medication throughout the study.

Detailed description:

Arms: arm 1: Subjects will receive FF/UMEC/VI 100/62.5/25 mcg inhalation powder via ELLIPTA, once daily, 1 puff/time, in the morning. Subjects may receive salbutamol as a rescue medication when needed throughout the run-in and treatment period. arm 2: Subjects will receive FF/UMEC/VI 200/62.5/25 mcg inhalation powder via ELLIPTA, once daily, 1 puff/time, in the morning. Subjects may receive salbutamol as a rescue medication when needed throughout the run-in and treatment period.
Interventions: intervention 1: FF/UMEC/VI 100/62.5/25 mcg intervention 2: FF/UMEC/VI 200/62.5/25 mcg intervention 3: Salbutamol intervention 4: ACQ-7
Intervention descriptions: intervention 1: Subjects will self-administer the study treatment via the ELLIPTA device. The ELLIPTA holds 2 individual blister strips with 30 blisters on each strip: the first strip contains FF 100 mcg in each blister and the second strip contains UMEC 62.5 mcg and VI 25 mcg in each blister. ELLIPTA is a registered trademark of GSK groups of companies. intervention 2: Subjects will self-administer the study treatment via the ELLIPTA device. The ELLIPTA holds 2 individual blister strips with 30 blisters on each strip: the first strip contains FF 200 mcg in each blister and the second strip contains UMEC 62.5 mcg and VI 25 mcg in each blister. ELLIPTA is a registered trademark of GSK groups of companies. intervention 3: Salbutamol is a rescue medication administered via metered-dose inhaler (MDI) which will be used when needed during the study. intervention 4: ACQ-7 will be used for the assessment of control status of asthma.

Protocol documents:
Prot_001.pdf: 
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TITLE PAGE
Protocol Title:
A Phase III, 52-week, Open-label Study to Evaluate Long-term Safety of Fixed Dose 
Combination Therapy Fluticasone Furoate/Umeclidinium Bromide/Vilanterol Trifenatate 
in Japanese Patients with Asthma
Protocol Number: 207236 Amendment 02
Short Title:
A Long-term Safety Study of Fixed Dose Combination Therapy Fluticasone 
Furoate/Umeclidinium Bromide/Vilanterol Trifenatate in Japanese Patients with Asthma
Compound Number：GW685698/GW642444/GSK573719
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline K.K. (GSK)
8-1, Akasaka 1-chome Minato-ku, Tokyo 107-0052 Japan
Study Director: 
, Medicines Development (Respiratory Therapy Area 
Office, Head)
Medical Monitor Name and Contact: See the Study Reference Manual (SRM)
Regulatory Agency Identifying Number(s): Not applicable
Approval Date: 25 Oct 2017
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 02
25-Oct-2017
Amendment 01
24-May-2017
Original Protocol
13-Mar-2017
Amendment 02: 25-Oct-2017
Overall Rationale for the Amendment: Relocation of Sponsor, etc. (See below table) 
Section # and 
Name
Description of Change
Brief Rationale
TITLE PAGE
Changed from:
Sponsor Name and Legal Registered 
Address: 
GlaxoSmithKline K.K. (GSK)
6-15, Sendagaya 4-chome Shibuya-ku, Tokyo 
151-8566 Japan
Changed to:
Sponsor Name and Legal Registered 
Address: 
GlaxoSmithKline K.K. (GSK)
8-1, Akasaka 1-chome Minato-ku, Tokyo 107-
0052 Japan
Relocation of 
Sponsor
2. 
SCHEDULE 
OF 
ACTIVITIES 
(SOA)
Changed from:
Table 1.  SCHEDULE OF ACTIVITIES
Procedure; Serum pregnancy test
Visit 1, 4, 5, 7, Early Withdrawal; X6
Footnote 6.
Assessments at only Visit1 to be conducted in 
all females.   Assessments at Visit except for 
the Visit 1 only to be conducted in females of 
To align with on-
going 205715 study
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Section # and 
Name
Description of Change
Brief Rationale
reproductive potential.
Changed to: 
Table 1.  SCHEDULE OF ACTIVITIES
Procedure; Serum pregnancy test6
Visit 1, 4, 5, 7, Early Withdrawal; X
Footnote 6.
Assessments are only to be conducted in 
females of reproductive potential.
12.2. 
Appendix 2: 
Study 
Governance 
Considerations
Study Period
Changed from: June 2017 ~ Mar 2019
Changed to: June 2017 ~ Sep 2019
Extension of 
recruitment periods
12.2. 
Appendix 2: 
Study 
Governance 
Considerations
Sponsor Information Page
Changed from:
Sponsor Legal Registered Address:
GlaxoSmithKline K.K. (GSK)
6-15, Sendagaya 4-chome Shibuya-ku, Tokyo 
151-8566 Japan
Study Director: 
, Head of 
Respiratory TA Office, Medicines 
Development
Sponsor Contact Address:
Leading Author：
, Respiratory 
TA Office, Medicines Development 
TEL：
FAX：
Sponsor's Contact Information (10:00-18:00, 
Monday to Friday, except national holidays, 
Relocation of 
Sponsor
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Section # and 
Name
Description of Change
Brief Rationale
year-end and new-year holidays); 
207236 team, JDMA, GlaxoSmithKline K.K. 
TEL: 
 (dial-in)
FAX: 
 
Sponsor’s Medical Monitor: 
, 
Head of Nurology Science TA Office, 
Medicines Development 
TEL：
FAX：
Changed to:
Sponsor Legal Registered Address:
GlaxoSmithKline K.K. (GSK)
8-1, Akasaka 1-chome Minato-ku, Tokyo 107-
0052 Japan
Study Director: 
, Head of 
Respiratory TA Office, Medicines 
Development
Sponsor Contact Address:
Leading Author：
, Respiratory 
TA Office, Medicines Development 
TEL：
FAX：
Sponsor's Contact Information (10:00-18:00, 
Monday to Friday, except national holidays, 
year-end and new-year holidays); 
207236 team, JDMA, GlaxoSmithKline K.K. 
TEL: 
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Section # and 
Name
Description of Change
Brief Rationale
FAX: 
Sponsor’s Medical Monitor: 
, 
Head of Nurology Science TA Office, 
Medicines Development 
TEL：
FAX：
12.2. 
Appendix 2: 
Study 
Governance 
Considerations
Changed from:
Laboratory
Clinical Laboratory
SRL Medisearch Inc. 
Shinjuku I-Land-Tower 10F, 6-5-1, 
Nishishinjuku, Shinjuku-ku, Tokyo, 163-1310, 
Japan 
Q2 Solutions LLC
(Only items that can not be measured in SRL 
Medisearch in the laboratory test after liver 
event)
Changed to:
Laboratory
Clinical Laboratory
SRL Medisearch Inc. 
Shinjuku I-Land-Tower 10F, 6-5-1, 
Nishishinjuku, Shinjuku-ku, Tokyo, 163-1310, 
Japan
To be able to perform 
only in SRL 
Medisearch Inc.
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TABLE OF CONTENTS
PAGE
1.
SYNOPSIS.............................................................................................................10
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................15
3.
INTRODUCTION....................................................................................................18
3.1.
Study Rationale ..........................................................................................18
3.2.
Background ................................................................................................18
3.3.
Benefit/Risk Assessment ............................................................................19
3.3.1.
Risk Assessment .........................................................................20
3.3.2.
Benefit Assessment.....................................................................26
3.3.3.
Overall Benefit: Risk Conclusion..................................................26
4.
OBJECTIVES AND ENDPOINTS...........................................................................27
5.
STUDY DESIGN ....................................................................................................28
5.1.
Overall Design ............................................................................................28
5.2.
Number of Participants ...............................................................................30
5.3.
Participant and Study Completion...............................................................30
5.4.
Scientific Rationale for Study Design ..........................................................30
5.5.
Dose Justification........................................................................................31
6.
STUDY POPULATION...........................................................................................32
6.1.
Inclusion Criteria.........................................................................................32
6.2.
Exclusion Criteria........................................................................................33
6.3.
Lifestyle Restrictions...................................................................................37
6.3.1.
Meals and Dietary Restrictions ....................................................37
6.3.2.
Caffeine, Alcohol, and Tobacco ...................................................37
6.3.3.
Activity .........................................................................................37
6.4.
Screen Failures...........................................................................................38
7.
TREATMENTS.......................................................................................................38
7.1.
Treatments Administered............................................................................38
7.2.
Dose Modification .......................................................................................39
7.3.
Method of Treatment Assignment ...............................................................40
7.4.
Blinding.......................................................................................................41
7.5.
Preparation/Handling/Storage/Accountability..............................................41
7.6.
Treatment Compliance................................................................................41
7.7.
Concomitant Therapy..................................................................................42
7.7.1.
Prohibited Concomitant Medications............................................42
7.7.2.
Permitted Concomitant Medications.............................................44
7.7.2.1.
Permitted Asthma Medications ...................................44
7.7.2.2.
Permitted Non-Asthma Medications ...........................45
7.7.2.3.
Permitted Non-Drug Therapies...................................46
7.8.
Treatment after the End of the Study ..........................................................46
8.
DISCONTINUATION CRITERIA.............................................................................46
8.1.
Discontinuation of Study Treatment ............................................................46
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8.1.1.
Liver Chemistry Stopping Criteria ................................................47
8.1.2.
QTc Stopping Criteria ..................................................................48
8.1.3.
Temporary Discontinuation ..........................................................49
8.1.4.
Rechallenge.................................................................................49
8.1.4.1.
Study Treatment Restart or Rechallenge....................49
8.2.
Withdrawal from the Study..........................................................................49
8.3.
Lost to Follow Up........................................................................................49
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................50
9.1.
Efficacy Assessments.................................................................................51
9.2.
Adverse Events...........................................................................................52
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................52
9.2.2.
Method of Detecting AEs and SAEs.............................................52
9.2.3.
Follow-up of AEs and SAEs.........................................................53
9.2.4.
Regulatory Reporting Requirements for SAEs .............................53
9.2.5.
Cardiovascular and Death Events................................................53
9.2.6.
Pneumonia ..................................................................................54
9.2.7.
Pregnancy ...................................................................................54
9.2.8.
Adverse Events of Special Interest (AESIs) .................................54
9.3.
Treatment of Overdose...............................................................................55
9.4.
Safety Assessments ...................................................................................56
9.4.1.
Physical Examinations.................................................................56
9.4.2.
Vital Signs....................................................................................56
9.4.3.
Electrocardiograms......................................................................56
9.4.4.
Clinical Safety Laboratory Assessments ......................................57
9.4.5.
Paper Medical Problems/Medications Taken Worksheet .............58
9.5.
Other Assessments ....................................................................................58
9.5.1.
Other endpoints ...........................................................................58
9.5.2.
Questionnaires ............................................................................59
9.5.2.1.
Asthma Control Questionnaire (ACQ).........................59
9.5.2.2.
St. George’s Respiratory Questionnaire 
(SGRQ) ......................................................................60
9.5.2.3.
Asthma Quality of Life Questionnaire (AQLQ) ............60
9.5.2.4.
Healthcare Resource Utilization..................................60
9.5.3.
Pulmonary Function Tests ...........................................................60
9.5.4.
Asthma Exacerbations.................................................................61
9.5.4.1.
Moderate Asthma Exacerbation..................................61
9.5.4.2.
Severe Asthma Exacerbation .....................................62
9.6.
Pharmacokinetics .......................................................................................62
9.7.
Pharmacodynamics ....................................................................................62
9.8.
Genetics/Pharmacogenetics .......................................................................63
9.9.
Biomarkers .................................................................................................63
9.10.
Health Economics.......................................................................................63
10. STATISTICAL CONSIDERATIONS........................................................................64
10.1.
Sample Size Determination ........................................................................64
10.2.
Populations for Analyses ............................................................................64
10.3.
Statistical Analyses.....................................................................................64
10.3.1.
Efficacy Analyses.........................................................................64
10.3.2.
Safety Analyses...........................................................................64
10.3.3.
Other Analyses ............................................................................65
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10.3.4.
Interim Analyses ..........................................................................65
11. REFERENCES.......................................................................................................66
12. APPENDICES........................................................................................................69
12.1.
Appendix 1: Abbreviations and Trademarks................................................69
12.2.
Appendix 2: Study Governance Considerations..........................................72
12.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................78
12.4.
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................84
12.5.
Appendix 5: Genetics/Pharmacogenomics..................................................87
12.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................87
12.7.
Appendix 7: Country-specific requirements.................................................91
12.8.
Appendix 8: Protocol Amendment History.................................................912
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1.
SYNOPSIS
Protocol Title:
A Phase III, 52-week, Open-label Study to Evaluate Long-term Safety of Fixed Dose 
Combination Therapy Fluticasone Furoate/Umeclidinium Bromide/Vilanterol Trifenatate 
in Japanese Patients with Asthma
Short Title:
A Long-term Safety Study of Fixed Dose Combination Therapy Fluticasone 
Furoate/Umeclidinium Bromide/Vilanterol Trifenatate in Japanese Patients with Asthma
Rationale:
Despite availability of treatments and published guidelines, patients may have asthma 
that is inadequately controlled. The prevalence of inadequately controlled asthma varies 
based on the definition used for control. In a sample of asthmatics visiting their 
healthcare provider for any reason, 58% of adult asthmatics were estimated to have 
uncontrolled asthma based on the Asthma Control Test (ACT, defined as an ACT score 
!19).
The Global Initiative for Asthma (GINA) guidelines recommend include a long-acting 
muscarinic antagonist (LAMA) as add-on treatment option for adults with asthma that are 
currently taking medium to high dose inhaled corticosteroid/long-acting β2 agonist 
(ICS/LABA) treatment and have a history of exacerbations. Exacerbations are an 
important endpoint in asthma therapy; however, symptom control is also important in 
determining what patients could benefit from step-up therapy. Data from the 
GlaxoSmithKline (GSK) Phase IIb study 200699 demonstrated that the 
LAMA/umeclidinium (UMEC), when added to the ICS fluticasone furoate (FF), reduced  
salbutamol use and improved symptoms in a sub-group of subjects with the primary 
diagnosis of asthma.
GSK is currently developing a once-daily ‘closed’ triple therapy of an 
ICS/LAMA/LABA combination [FF/UMEC/vilanterol (VI)] in a single device, with the 
aim of providing a new treatment option for the management of asthma by improving 
lung function, health-related quality of life (HRQoL) and symptom control over 
established combination therapies. The objective of this study is to evaluate long-term 
safety of fixed dose combination therapy FF/UMEC/VI in Japanese patients with asthma. 
A global study comparing FF/UMEC/VI with a standard of care ICS/LABA combination 
therapy (Study 205715) is ongoing in parallel with this study, which will provide 
important information to prescribers regarding the benefit of step-up to closed triple 
therapy to patients uncontrolled on ICS/LABA.
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Objectives and Endpoints:
Objective
Endpoint
Primary
∀
To evaluate the safety of long-term 
treatment with FF/UMEC/VI 
combination therapy
∀
Incidence and type of adverse events 
(AE)/serious adverse events (SAE)
Secondary
∀
To evaluate the safety of FF/UMEC/VI 
combination therapy
Secondary Endpoints
∀
Blood pressure/pulse measurements
∀
12-lead Electrocardiogram (ECG)
∀
Clinical laboratory tests (hematology , 
biochemistry and urinalysis)
Other
∀
To evaluate the efficacy of 
FF/UMEC/VI combination therapy
Other Endpoints
∀
Mean change from baseline in trough 
Forced Expiratory Volume in 1 second 
(FEV1) at Week 24 and Week 52
∀
Mean change from baseline in Asthma 
Control Questionnaire – 7 (ACQ-7)
total score at Week 24 and Week 52
∀
Mean change from baseline in St. 
George's Respiratory Questionnaire 
(SGRQ) total score at Week 24 and 
Week 52
∀
Mean change from baseline in the 
Asthma Quality of Life Questionnaire 
(AQLQ) total score at Week 24 and 
Week 52
∀
Unscheduled asthma-related healthcare 
resource utilization over the 52 weeks 
of the treatment period
∀
Annualized rate of severe asthma 
exacerbations
∀
Annualized rate of moderate/severe 
asthma exacerbations
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Overall Design:
The present study is a phase III, multicenter, non-comparator, non-randomized, open-
label study in Japanese patients with asthma to evaluate long-term safety of 
FF/UMEC/VI 100/62.5/25 micrograms (mcg) and FF/UMEC/VI 200/62.5/25 mcg.
* Switching medication from FF/UMEC/VI 100/62.5/25 mcg to FF/UMEC/VI 200/62.5/25 mcg will be permitted in 
accordance with the control status of the subject assessed by ACQ-7 at Week 24 of the treatment period.
Eligible patients who meet the pre-defined criteria at screening (Visit 1) will enter into a 
2-week run-in period. During the run-in period, the subjects will continue their pre-
screening inhaled medications for asthma (ICS+LABA or ICS+ LABA+LAMA) until the 
day before Visit 2 without any change in regimen/dosage. After completion of the run-in 
period, subjects who meet pre-defined criteria at Visit 2 will be allocated to either 
FF/UMEC/VI 100/62.5/25 or FF/UMEC/VI 200/62.5/25 treatment depending on the 
asthma control status with inhaled asthma therapy during the run-in period as shown in 
the table below, and initiate a 52-week treatment period. Only at Week 24 of the 
treatment period (Visit 5), switching medication from FF/UMEC/VI 100/62.5/25 to 
FF/UMEC/VI 200/62.5/25 will be permitted if the control status of the subject assessed 
by ACQ-7 is not well controlled (i.e., ACQ score >0.75).
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Correspondence between Asthma Control Status with inhaled Asthma 
Therapy during the run-in period and Allocated Study Treatment
Group
Asthma control status with inhaled asthma 
therapy1
Allocated study treatment
Group 1
Not well controlled with ICS (mid-
dose)+LABA   
or
Controlled with ICS (mid-dose)+LABA + 
LAMA
FF/UMEC/VI 100/62.5/25 mcg via 
ELLIPTA, once-daily, 1 puff/time, 
morning
Group 2
Not well controlled with ICS (high-
dose)+LABA    
or
Not well controlled with ICS (mid-
dose)+LABA + LAMA    
or
Controlled with ICS (high-dose)+LABA + 
LAMA
FF/UMEC/VI 200/62.5/25 mcg via 
ELLIPTA, once-daily, 1 puff/time, 
morning
1.
Asthma Control Questionnaire (ACQ-6 at screening and ACQ-7 at Week 0, week 24, week52/Withdrawal) will be 
used for the assessment of control status of asthma, i.e.,!0.75 points shows controlled and >0.75 shows not well 
controlled.
Number of Participants:
The number of asthmatic adult subjects (with the control status on inhaled asthma therapy
with medium to high dose ICS + LABA or medium to high dose ICS + LAMA + LABA 
[as shown in the table above]) required to be enrolled in this study is 110 (a total number 
of subjects to be allocated in Group 1 [FF/UMEC/VI 100/62.5/25] and Group 2
[FF/UMEC/VI 200/62.5/25]). According to the ICH guidelines, the sample size of 110 
subjects would allow 100 subjects to complete the 52-week treatment period, assuming a 
drop-out rate of approximately 10%.
Treatment Groups and Duration:
This is a 55-week study consisting of the following three study periods:
∀
Run-in period (2 weeks): Eligible patients who meet the pre-defined criteria at 
screening (Visit 1) will enter into a 2-week run-in period. During the run-in period, 
the subjects will continue their pre-screening inhaled medications for asthma 
(ICS+LABA or ICS+LABA+LAMA) until the day before Visit 2 without any 
change in regimen/dosage.
∀
Treatment period (52 weeks): subjects who meet pre-defined criteria at Visit 2 will 
be allocated to either FF/UMEC/VI 100/62.5/25 or FF/UMEC/VI 200/62.5/25 
treatment depending on the asthma control status with inhaled asthma therapy during 
the run-in period, and initiate a 52-week treatment period.
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Switching medication from FF/UMEC/VI 100/62.5/25 to FF/UMEC/VI 200/62.5/25 
will be permitted in accordance with the control status of the subject assessed by 
ACQ-7 at Week 24 of the treatment period (Visit 5).
∀
Follow-up period (1 week): A safety follow-up telephone contact or clinic visit will 
be conducted at the end of the follow-up period.
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2.
SCHEDULE OF ACTIVITIES (SOA)
Table 1
SCHEDULE OF ACTIVITIES
Procedure
Pre-screen
Run-in
Treatment period
Follow-up
Visit
0
1
Screening
2
Baseline
3
4
5
6
7
End of 
Treatment 
(EOT)
Early 
Withdrawa
l (EW)
Safety 
follow-up 
contact
Day
-28 to -14
-14
1
29
85
169
253
365
Week
-4 to -2
-2
0
4
12
24
36
52
Window
-3
-5/+2d
-5/+2d
-5/+2d
-5/+2d
-5/+2d
Informed consent1
X
Genetics/Pharmacogenetic informed 
consent2
X
Inclusion and exclusion criteria
X
X
Demography
X
Past and current medical conditions 
including asthma history3 and exacerbation 
history
X
Smoking history and status
X
Concomitant medication review
X
X
X
X
X
X
X
X
X
Allocation/registration4
X
Register visit in IRT (RAMOS NG)5
X
X
X
X
X
X
X
X
X
X
Safety Assessment
Physical examination
X
X
X
X
Weight/height
X
Adverse events
X
X
X
X
X
X
X
X
Serious adverse events
X
X
X
X
X
X
X
X
X
X
Vital signs (blood pressure and pulse rate)
X
X
X
X
X
X
X
X
ECG
X
X
X
X
X
Hematology and clinical chemistry
X
X
X
X
X
Urinalysis
X
X
X
X
X
Serum pregnancy test6
X
X
X
X
X
Urine pregnancy test 6
X
X
X
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Procedure
Pre-screen
Run-in
Treatment period
Follow-up
Visit
0
1
Screening
2
Baseline
3
4
5
6
7
End of 
Treatment 
(EOT)
Early 
Withdrawa
l (EW)
Safety 
follow-up 
contact
Day
-28 to -14
-14
1
29
85
169
253
365
Week
-4 to -2
-2
0
4
12
24
36
52
Window
-3
-5/+2d
-5/+2d
-5/+2d
-5/+2d
-5/+2d
Other Assessment
ACQ7
X8
X9
X9
X9
X9
SGRQ7
X
X
X
X
AQLQ7
X
X
X
X
Pre-dose spirometry 10
X
X
X
X
Moderate/severe asthma exacerbation
X
X
X
X
X
X
X
X
Genetics/Pharmacogenetic sampling 11
X
Dispense paper Medical 
Problems/Medications Taken worksheet
X
X
X
X
X
X
X
X
X
Review paper Medical 
Problems/Medications Taken worksheet
X
X
X
X
X
X
X
X
X
Healthcare resource utilization
X
X
X
X
X
X
X
Dispense investigational product
X
X
X
X
X
Collect investigational product    
X
X
X
X
X
X
Dispense  salbutamol (as required)
X
X
X
X
X
X
Collect  salbutamol (as required)
X
X
X
X
X
X
X
1.
The Informed Consent Form (ICF) must be signed before any study procedures, including medication cessation.
2.
Genetics/Pharmacogenetic research consent may be obtained at the same time as the study Informed Consent and must be obtained prior to obtaining a 
Genetics/pharmacogenetic blood sample.
3.
The assessment of asthma history will include: the age of the subject when they were first provided with an inhaler for asthma; completion of an asthma medical history 
questionnaire (a copy of this questionnaire and instructions for its use can be found in the SRM).
4.
Subjects must not be allocated prior to confirming their eligibility to participate in the study.
5.
The IRT will be used for allocation, and study treatment supply management (Please refer to the RAMOS NG IRT manual and SRM for more information).
6.
Assessments are only to be conducted in females of reproductive potential.
7.
Assessment(s) to be completed before any study procedures .Study treatment should be administered at the same time of day each applicable clinic visit,
8.
Assessment to be conducted by using ACQ-6
9.
Assessment to be conducted by using ACQ-7
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10. Spirometry to be performed after withholding rescue medication for at least 6 hours and prior to taking the morning dose of study treatment. Pre-dose spirometry assessments 
should be performed at the same time of day at each applicable visit.
11. Pharmacogenetic sample may be drawn any time from Visit 2 onwards.
ACQ: Asthma Control Questionnaire, AQLQ: Asthma Quality of Life Questionnaire, IRT: Interactive Response Technology, SGRQ: St. George’s Respiratory Questionnaire
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3.
INTRODUCTION
3.1.
Study Rationale
The Global Initiative for Asthma guidelines [GINA, 2016] recommend include a long-
acting muscarinic antagonist (LAMA) as add-on treatment option for adults (#18 years) 
with asthma that are currently taking medium-to-high dose inhaled corticosteroid and 
long-acting beta2 agonist (ICS/LABA) maintenance therapy and have a history of 
exacerbations. Exacerbations are an important endpoint in asthma therapy; however, 
symptom control is also important in determining what patients could benefit from step-
up therapy.
GSK is currently developing a once-daily ‘closed’ triple therapy of an 
ICS/LAMA/LABA combination [FF/UMEC/vilanterol (VI)] in a single device, with the 
aim of providing a new treatment option for the management of asthma by improving 
lung function, health-related quality of life (HRQoL) and symptom control over 
established combination therapies. The objective of this study is to evaluate long-term 
safety of fixed dose combination therapy FF/UMEC/VI in Japanese patients with asthma. 
A global study comparing FF/UMEC/VI with a standard of care ICS/LABA combination 
therapy (Study 205715) is ongoing in parallel with this study, which will provide 
important information to prescribers regarding the benefit of step-up to closed triple 
therapy to patients uncontrolled on ICS/LABA.
3.2.
Background
Despite the availability of treatments and published guidelines, patients may have asthma 
that is inadequately controlled. The prevalence of inadequately controlled asthma varies 
based on the definition used for control. In a sample of asthmatics visiting their 
healthcare provider for any reason, 58% of adult asthmatics were estimated to have 
uncontrolled asthma based on the Asthma Control Test (ACT, defined as an ACT score 
!19) [Stanford, 2010].
Consistent with these observations, an analysis of asthma patients in the United States 
(US) found that 29%-31% of asthma patients treated with high dose ICS/LABA therapy 
experienced exacerbations [Schatz, 2014]. In a Dutch survey of 929 patients treated with 
high dose ICS/LABA or medium/high dose ICS/LABA and maintenance oral 
corticosteroid (OCS), who self-reported asthma or chronic obstructive pulmonary disease 
(COPD) with <10 smoking pack years, 74% of patients were classified as difficult to 
control (Asthma Control Questionnaire [ACQ] score >1.5, or experienced #3 
exacerbations in a year, or #1 hospitalization in a year). Half (50.6%) of these patients 
had an ACQ score >1.5, 21.7% had #3 exacerbations in a year, and 21.7% had #1 
hospitalization in a year. Based on this sample, an estimated 17.4% of the Dutch asthma 
population was estimated to be on high dose ICS/LABA or medium/high dose 
ICS/LABA and maintenance OCS and have difficult to control asthma [Hekking, 2015].
In summary, although patients with asthma can be effectively treated with available 
controller medications, a subset of patients do not adequately respond to current standard 
therapy, as measured by symptom questionnaires (ACT, ACQ) and exacerbations.
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The goal of asthma treatment is to achieve and maintain asthma control and to reduce the 
future risk of exacerbations. ICSs are considered the most effective anti-inflammatory 
treatments for all severities of persistent asthma [National Institutes of Health (NIH),
2007; GINA, 2016]. Treatment with ICS controls asthma symptoms, improves quality of 
life and lung function, decreases airway hyper-responsiveness, controls airway 
inflammation, and reduces the frequency and severity of asthma exacerbations, thereby 
reducing asthma morbidity. The dose of ICS is selected based on the severity of the 
patient’s asthma. In patients who are symptomatic on ICS alone, add-on therapy with 
another controller, in particular a LABA is preferred to increasing the dose of ICS to 
achieve asthma control. The addition of a LABA to an ICS improves symptom scores, 
decreases nocturnal asthma symptoms, improves lung function and reduces the number of 
asthma exacerbations [Ducharme, 2010]. Combination ICS/LABA inhalation products 
have been developed as a result of this need. In difficult to treat persistent asthma, some 
patients continue to be symptomatic despite treatment with ICS and LABA combination 
medications and the current guidelines [GINA, 2016; NIH, 2007; British Thoracic 
Society / Scottish Intercollegiate Guidelines Network (BTS/SIGN), 2014] recommend 
treatment with high-dose inhaled or oral glucocorticosteroids in combination with 
LABAs and/or additional controller medications.
In the European Union (EU), tiotropium bromide (LAMA) is licensed as an add-on 
maintenance bronchodilator treatment in adult patients with asthma who are currently 
treated with the maintenance combination of ICS (#800 micrograms (mcg) 
budesonide/day or equivalent) and LABA and who experienced one or more severe 
exacerbations in the previous year [Spiriva Respimat Summary of Product Characteristics 
(SPC), 2016]. In the US, tiotropium bromide was recently approved for the maintenance 
treatment of asthma, in patients 12 years of age and older [Spiriva Respimat United 
States Product Insert (USPI), 2016]. In Japan, tiotropium bromide is approved for use in 
patients with asthma aged 15 years or older if ICS or other medications fails in improving 
symptoms or if combination of tiotropium bromide with ICS is considered appropriate 
based on the disease severity of the patient [Spiriva Respimat Japan Product Insert
(Tiotropium bromide), 2016]. The benefit of adding a LAMA to both ICS monotherapy 
and ICS/LABA fixed combination therapy was demonstrated in four Phase III 
confirmatory studies (416, 417 [Kerstjens, 2012]; 418 and 419 [Kerstjens, 2015]), in 
symptomatic asthma patients (ACQ score #1.5). The Phase III studies supporting the 
tiotropium application showed that addition of tiotropium bromide to ICS/LABA 
maintenance therapy significantly improved lung function and reduced the risk of severe 
asthma exacerbation.
3.3.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of GW685698/GSK573719/GW642444 
(FF/UMEC/VI) may be found in the Investigator’s Brochure (IB), Participant 
Information Leaflet.
Summaries of findings from both clinical and non-clinical studies of FF/UMEC/VI 
conducted by GSK can be found in the IB. The following section outlines the risk 
assessment and mitigation strategy for this protocol.
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3.3.1.
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [FF/UMEC/VI]
Cardiovascular effects of 
UMEC and VI
UMEC
Cardiovascular effects are a potential class effect associated with anti-
muscarinic therapies.
In the UMEC/VI clinical development program in Chronic Obstructive 
Pulmonary Disease (COPD) patients, UMEC/VI was generally well tolerated. 
Overall, a low number of atrial arrhythmias were reported based on 12-lead 
ECGs, Holter ECGs, or AEs, of which some occurred with a higher incidence 
in active treatment groups compared to placebo.  There was no additive 
effect with the combination over individual components.  Few of these 
findings were reported as Serious Adverse Events (SAEs) and none were 
fatal. In a narrow* Major Adverse Cardiac Event (MACE) analysis , the 
incidence of non-fatal myocardial infarction (Medical Dictionary for 
Regulatory Activities (MedDRA) Preferred Terms (PTs) of myocardial 
infarction and acute myocardial infarction) was low (<1%) across all 
treatment groups, although small imbalances in exposure adjusted frequency 
were observed between UMEC- and VI containing treatment groups when 
compared with placebo and tiotropium.  There was no obvious dose 
relationship or additive effect from the combination.  Whether this represents 
a true effect is difficult to determine due to the small numbers. During clinical 
studies in COPD (62.5 and 125mcg daily dose of UMEC) and in Healthy 
Volunteers (in the Thorough QT study, UMEC 500mcg daily dose), no effect 
was observed on heart rate, blood pressure or QT.
VI
In the FF/VI clinical development program in patients with COPD, the 
Mitigation strategy for UMEC and VI:
- Exclusion criteria as specified in 
Section 6.2. of the protocol
- Collection of cardiovascular risk factors 
and medical history at baseline
- ECGs as per schedule in the SoA 
(Table 1)
- Vital sign assessments (blood pressure 
and pulse rate) as per schedule in the 
SoA (Table 1)
- Cardiovascular AEs and Serious AEs 
(SAEs) will be captured on the electronic 
Case Report Form (CRF) (see Section 
9.2.5.)
- Protocol defined stopping criteria as 
per Section 8
- MACE analysis
- Instream review .
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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
cardiovascular safety profile of VI and FF/VI was broadly consistent with the 
known pharmacology of LABAs in patients with COPD. VI at doses up to 
100mcg in healthy subjects and subjects with asthma or COPD was not 
consistently associated with clinically relevant or statistically significant 
effects on blood pressure after either single or repeat dose administration.
Data from Thorough QT (TQT) studies with FF, FF/VI and UMEC/VI suggest 
that, at the doses to be used in phase III studies, the closed triple 
(FF/UMEC/VI) is unlikely to cause clinically relevant effects on QTc1. No 
difference in QTcF2 was observed between UMEC/VI 125/25mcg or UMEC 
500mcg and placebo. UMEC/VI 500/100mcg increased QTcF on average by 
8.2msec (milliseconds) (90% Confidence Intervals (CI): 6.2, 10.2) at 30 
minutes (min) only. A lack of effect was demonstrated for QTcF with FF/VI 
200/25mcg (for 7 days). At a supratherapeutic dose of FF/VI (800/100mcg 
for 7 days), the largest mean time-matched difference from placebo was 9.6 
msec (90% CI: 7.2, 12.0) at 30 min only.
1 QT interval corrected for heart rate
2 QT interval corrected for heart rate by Fridericia’s formula
Anticholinergic effects 
(including constipation 
nausea, dry mouth, 
glaucoma, raised intraocular 
pressure and blurred vision, 
urinary retention)
In clinical studies in COPD, few anticholinergic effects were associated with 
UMEC; those observed included dry mouth, constipation and cough.  Based 
on post-marketing experience dysgeusia has been added as an Adverse 
Drug Reaction (ADR) for inhaled UMEC and UMEC/VI.   
ICS has a similar class risk of glaucoma and elevated intraocular pressure 
(IOP); however these effects occur by a different mechanism that is not 
expected to be synergistic or additive when FF is used in combination with 
UMEC.
- Patients with known narrow-angle 
glaucoma, prostatic hyperplasia or 
bladder outflow obstruction that, in the 
opinion of the Investigator, 
contraindicates study participation or use 
of an inhaled anticholinergic, will be 
excluded from participating in the study.
- Review AEs/SAEs
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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Systemic ICS effects
- Adrenal suppression
- Cataracts & glaucoma
- Reduced bone mineral 
density and associated 
fractures
No studies have shown a clinically relevant effect of FF/VI or FF on the 
hypothalamic pituitary axis (HPA). This includes a formal HPA study 
(HZA106851), which assessed the effects of FF/VI 100/25 and 200/25 on 
serum cortisol and 24 hour serum cortisol excretion, and multiple studies with 
COPD and asthma subjects which monitored urinary cortisol.   
During clinical development of FF & FF/VI no events of Adrenal Suppression 
were reported.  There has been no evidence for adrenal suppression based 
on post-marketing experience to date.  
In study HZA106839 (FF/VI, FF and fluticasone propionate (FP) in subjects 
with asthma), formal Ophthalmic assessments were conducted (including 
Lens Opacities Classification System III (LOCS III) evaluations for ocular 
opacities) throughout the study. This study showed no apparent effects on 
lens opacification, compared to baseline assessment.  
During studies in both subjects with asthma and COPD, no associated affect 
on ocular disorders was observed.  Spontaneous data received to date does 
not alter the understanding of this risk.  
A decrease in bone mineral density and the risk of fractures is a class 
concern for any ICS-containing product for the treatment of COPD.
In two replicate 12 month studies in the FF/VI clinical program, in a total of 
3,255 patients with COPD, the incidence of bone fractures overall was low in 
all treatment groups, with a higher incidence in all FF/VI groups (2%) 
compared with the VI 25 mcg group (<1%).  Although there were more 
fractures in the FF/VI groups compared with the VI 25 mcg group, fractures 
typically associated with corticosteroid use (e.g., spinal 
compression/thoracolumbar vertebral fractures, hip and acetabular fractures) 
- Review AEs/SAEs
- The occurrence of bone fractures will 
be recorded in the eCRF.
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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
occurred in <1% of the FF/VI and VI treatment arms.  In an integrated 
analysis of 11 studies in asthma with FF/VI (7,034 patients) and 10 studies in
asthma with FF (6,219), the incidence of fractures with FF/VI and FF was 
≤1%, and usually associated with trauma.  
Pneumonia
While ICS use is a recognised risk for pneumonia in patients with COPD.  A 
clear causal relationship between inhaled corticosteroid use and pneumonia 
in subjects with asthma has not been established.   
In an 18 study integration in the FF/VI asthma program, the incidence of 
pneumonia (adjusted for exposure) observed with FF/VI 100/25 and FF 100 
(8.5/1000 patient years and 9.6/1000 patient years, respectively) was similar 
to that seen with placebo (9.3/1000 patient years). A higher incidence in the 
FF/VI 200/25 and FF 200 arms were observed (18.3/1000 patient years and 
23.6/1000 patient years, respectively). However, the 95% CIs were wide and 
overlapped across all treatment groups, including placebo. Few of the 
pneumonia events led to hospitalisation with either strength, and there were 
no observed differences in the incidence of serious events between the two 
treatment strengths.  The risk of pneumonia in asthma patients is very low 
and is consistent with the risk of other ICS.  
Pneumonia experience with UMEC
In the All Clinical Studies grouping, the incidence of on-treatment AEs in the 
Pneumonia and lower respiratory tract infection (LRTI) adverse events of 
special interest (AESI) category with UMEC 62.5 mcg (1%; 34.6/1000SY) 
was similar to placebo (1%; 34.8/1000SY) and lower than the incidence 
reported in the UMEC 125 mcg (3%; 72.6/1000SY). A higher incidence of 
AEs in the Pneumonia AESI category was reported for UMEC 125 mcg (2%; 
37.4/1000SY) compared with UMEC 62.5 mcg (<1%; 19.8/1000SY) and 
Exclusion criteria:
- Immune suppression (e.g., Human 
Immunodeficiency Virus [HIV], Lupus) or 
other risk factors for pneumonia 
(e.g.,neurological disorders affecting 
control of the upper airway, such as 
Parkinson’s Disease, Myasthenia 
Gravis).
- Subjects at potentially high risk (e.g., 
very low body mass index [BMI] or 
severely malnourished) will only be 
included at the discretion of the 
Investigator.
Medical history will also be taken for 
pneumonia in previous 12 months, 
including recording of any episodes 
resulting in hospitalisation.   
The occurrence of pneumonia will be 
recorded in the eCRF.
Where possible a chest X-ray should be 
performed to confirm a diagnosis, 
whenever a subject has a suspected 
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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
placebo (<1%; 10.7/1000SY). The proportion of subjects with SAEs in the 
Pneumonia AESI category was similar between both UMEC treatment
groups, UMEC 62.5 mcg (<1%; 4.9/1000SY) and UMEC 125 mcg (<1%; 
17.6/1000SY) and placebo (<1%; 10.7/1000SY).
pneumonia.
All reports of pneumonia 
(radiographically confirmed and 
unconfirmed) must be reported as an AE 
or SAE, if applicable.
Instream review.
Review of AESI relevant for pneumonia 
using pre-specified MedDRA preferred 
terms. AE terms relating to other Lower 
Respiratory Tract Infections (excluding 
pneumonia) will also be reviewed.  
Hypersensitivity
There have been post-marketing reports of hypersensitivity reactions with 
FF/VI and UMEC/VI, including anaphylaxis, angioedema, rash, and urticaria.  
The formulation also contains lactose.
Subjects with a history of allergy or 
hypersensitivity to any corticosteroid, 
anticholinergic/muscarinic receptor 
antagonist, beta2-agonist, lactose/milk 
protein or magnesium stearate are 
excluded from participation in this study 
(Section 6.2.) 
- Review AEs/SAEs
Paradoxical bronchospasm
Rare reports of paradoxical bronchospasm (which may be life threatening) 
with other inhalational products have been reported.  There have been rare 
post-marketing reports of paradoxical bronchospasm with FF/VI and 
UMEC/VI.
Patients will undergo regular medical 
assessments during clinical studies.   
- Review AEs/SAEs
Pregnancy and lactation
There are no data from the use of FF/UMEC/VI in pregnant women.   
There has been limited pregnancy exposure to FF and FF/VI in humans. 
Animal studies have shown reproductive toxicity after administration of 
corticosteroids and beta2-agonists.
Females who are pregnant or breast-
feeding are not eligible for participating 
in the study.
Females of child-bearing potential will 
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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
There is a limited amount of data from the use of umeclidinium in pregnant 
women. Animal studies do not indicate direct or indirect harmful effects with 
respect to reproductive toxicity.
There is limited information on the excretion of FF or VI or their metabolites 
in human milk. However, other corticosteroids and beta2-agonists are 
detected in human milk.
It is unknown whether umeclidinium is excreted in human milk. The excretion 
of FF/UMEC/VI in breast milk has not been evaluated. A risk to breastfed 
newborns/infants cannot be excluded.
need to follow the contraceptive 
requirements that are specified in 
Appendix 5.
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3.3.2.
Benefit Assessment
The addition of UMEC to FF/VI in asthma has the potential to improve lung function, 
reduce moderate/severe exacerbations and improve quality of life in patients whose 
asthma is inadequately controlled on ICS/LABA alone.  Current asthma treatment 
guidelines recommend the addition of a LAMA (tiotropium) for patients that are 
uncontrolled on ICS/LABA (GINA 2016 Steps 4 and 5); the availability of the 
FF/UMEC/VI combination would therefore be consistent with this approach.  The 
combination in a closed triple combination would provide the convenience of once daily 
dosing and reduce the need for multiple inhalers.  
3.3.3.
Overall Benefit: Risk Conclusion
Taking into account the measures taken to minimize risk to subjects participating in the 
study, the potential risks identified in association with FF/UMEC/VI are justified by the 
anticipated benefits that may be afforded to subjects with asthma.
The current experience with FF, UMEC and VI and the lack of significant safety 
concerns relevant to the asthma population provides reassurance that the potential risks 
associated with the known pharmacology of these compounds is offset by the potential 
significant benefits that are afforded to patients inadequately controlled on inhaled 
asthma therapy (ICS+LABA or ICS+LAMA+LABA).
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4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
∀
To evaluate the safety of long-term 
treatment with FF/UMEC/VI 
combination therapy
∀
Incidence and type of adverse events 
(AE)/serious adverse events (SAE)
Secondary
∀
To evaluate the safety of FF/UMEC/VI 
combination therapy
Secondary Endpoints
∀
Blood pressure/pulse measurements
∀
12-lead electrocardiogram (ECG)
∀
Clinical laboratory tests (hematology, 
biochemistry and urinalysis)
Other
∀
To evaluate the efficacy of 
FF/UMEC/VI combination therapy
Other Endpoints
∀
Mean change from baseline in trough 
Forced Expiratory Volume in 1 second 
(FEV1) at Week 24 and Week 52
∀
Mean change from baseline in Asthma 
Control Questionnaire–7 (ACQ-7) 
total score at Week 24 and Week 52
∀
Mean change from baseline in St. 
George's Respiratory Questionnaire 
(SGRQ) total score at Week 24 and 
Week 52
∀
Mean change from baseline in the 
Asthma Quality of Life Questionnaire 
(AQLQ) total score at Week 24 and 
Week 52
∀
Unscheduled asthma-related healthcare 
resource utilization over the 52 weeks 
of the treatment period
∀
Annualized rate of severe asthma 
exacerbations
∀
Annualized rate of moderate/severe 
asthma exacerbations
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5.
STUDY DESIGN
5.1.
Overall Design
The present study is a phase III, multicenter, non-comparator, non-randomized, open-
label study in Japanese patients with asthma. This is a approximately 55-week study 
consisting of the run-in, treatment and follow-up periods.
* Switching medication from FF/UMEC/VI 100/62.5/25 mcg to FF/UMEC/VI 200/62.5/25 mcg will be permitted in 
accordance with the asthma control status of the subject assessed by ACQ-7 at Week 24 of the treatment period.
Figure 1
Study Schematic
Eligible patients who meet the pre-defined criteria at screening (Visit 1) will enter into a 
2-week run-in period. During the run-in period, the subjects will continue their pre-
screening inhaled medications for asthma (ICS+ LABA or ICS+LABA+ LAMA) until 
the day before Visit 2 without any change in regimen/dosage. After completion of the 
run-in period, subjects who meet pre-defined criteria at Visit 2 will be allocated to either 
FF/UMEC/VI 100/62.5/25 mcg (Group 1) or FF/UMEC/VI 200/62.5/25 mcg (Group 2) 
depending on the asthma control status with inhaled asthma therapy during the run-in 
period (see Table 2), and initiate a 52-week treatment period. Only at Week 24 of the 
treatment period (Visit 5), switching medication from FF/UMEC/VI 100/62.5/25 mcg to 
FF/UMEC/VI 200/62.5/25 mcg will be permitted if the control status of the subject 
assessed by ACQ-7 is inadequate (i.e., ACQ score >0.75). As a rescue medication,  
salbutamol is permitted throughout the run-in and treatment periods.
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Table 2
Correspondence between Asthma Control Status with Inhaled 
Asthma Therapy during the run-in period and Allocated Study
Treatment
Group
Asthma control status with inhaled asthma 
therapy1
Allocated study treatment
Group 1
Not well controlled with ICS (mid-
dose)+LABA   
or
Controlled with ICS (mid-dose)+LABA + 
LAMA
FF/UMEC/VI 100/62.5/25 mcg  via 
ELLIPTA, once-daily, 1 puff/time, morning
Group 2
Not well controlled with ICS (high-
dose)+LABA    
or
Not well controlled with ICS (mid-
dose)+LABA + LAMA    
or
Controlled with ICS (high-dose)+LABA + 
LAMA
FF/UMEC/VI 200/62.5/25 mcg via 
ELLIPTA, once-daily, 1 puff/time, morning
1.
Asthma Control Questionnaire (ACQ-6 at screening and ACQ-7 at week 0, week 24, week52/Withdrawal) will be 
used for the assessment of control status of asthma, i.e., !0.75 points shows controlled and >0.75 shows not well 
controlled.
Subjects will visit the clinic/hospital at screening (Visit 1), Week 0 (Visit 2), Week 4
(Visit 3), Week 12 (Visit 4), Week 24 (Visit 5), Week 36 (Visit 6), Week 52 (Visit 7/End 
of Treatment [EOT]) or Early Withdrawal (EW) , and about one week after Week 52 
(Visit 7/EOT) or EW Visit as a safety follow-up visit.. Telephone contact can be selected 
for follow-up period.
This study consists of three periods as described below: run-in, treatment and follow-up 
periods. Details of study procedures and assessments in these periods are provided in the 
Study Reference Manual (SRM).
∀
Run-in period (2 weeks): Eligible patients who meet the pre-defined criteria at 
screening (Visit 1) will enter into a 2-week run-in period. During the run-in period, 
the subjects will continue their pre-screening inhaled medications for asthma 
(ICS+LABA or ICS+LABA+LAMA) until the day before Visit 2 without any 
change in regimen/dosage.
∀
Treatment period (52 weeks): subjects who meet pre-defined criteria at Visit 2 will 
be allocated to either FF/UMEC/VI 100/62.5/25 mcg or FF/UMEC/VI 
200/62.5/25 mcg treatment depending on the asthma control status with inhaled 
asthma therapy during the run-in period, and initiate a 52-week treatment period.
Switching medication from FF/UMEC/VI 100/62.5/25 mcg to FF/UMEC/VI 
200/62.5/25 mcg will be permitted in accordance with the control status of the 
subject assessed by ACQ-7 at Week 24 of the treatment period (Visit 5).
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∀
Follow-up period (1 week): A safety follow-up telephone contact or clinic visit will 
be conducted at the end of the follow-up period.
5.2.
Number of Participants
The number of asthmatic adult subjects (with the control status on inhaled asthma therapy 
with medium to high dose ICS + LABA or medium to high dose ICS +LAMA + LABA 
[as shown in the table above]) required to be enrolled in this study is 110 (a total number 
of subjects to be allocated in Group 1 [FF/UMEC/VI 100/62.5/25 mcg] and Group 2
[FF/UMEC/VI 200/62.5/25 mcg]). According to the ICH guidelines, the sample size of 
110 subjects would allow 100 subjects to complete the 52-week treatment period, 
assuming a drop-out rate of approximately 10% (Section 10.1.).
5.3.
Participant and Study Completion
A subject is considered to have completed the study if he/she has completed all phases of 
the study including the safety follow-up telephone contact or clinic visit. The end of the 
study is defined as the date of the last safety follow-up telephone contact or clinic visit of 
the last subject in the study.
A subject who continues the study treatment until Visit 7/EOT is considered to have 
completed the study treatment.
5.4.
Scientific Rationale for Study Design
The present study employs multicenter, non-comparator, non-randomized, open-label 
design. Eligible patients who meet pre-defined criteria will be allocated to either 
FF/UMEC/VI 100/62.5/25 mcg or 200/62.5/25 mcg which will be administrated in an 
open-label manner.  As a step-up of the treatment during the treatment period, medication 
switching from FF/UMEC/VI 100/62.5/25 mcg to FF/UMEC/VI 200/62.5/25 mcg is 
permitted in accordance with the control status of the patient at Week 24.  However, step-
down is not permitted in order to ensure the long-term safety data of FF/UMEC/VI 
200/62.5/25 mcg which contains higher dose of ICS (FF).  Comparison between 
treatment groups is not planned and no stastistical tests will be performed because the 
purpose of this study is to evaluate mainly safety of overall FF/UMEC/VI containing 
UMEC 62.5 mcg. The duration of the treatment period is 52 weeks for the evaluation of 
long-term safety by reference to ICH E-1 guideline, “The Extent of Population Exposure 
to Assess Clinical Safety for Drugs Intended for Long-Term Treatment of Non-Life-
Threatening Conditions”.
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5.5.
Dose Justification
At the moment, the candidate dosages of UMEC as a component of FF/UMEC/VI are 
31.25 mcg and 62.5 mcg based on the result of Phase IIb study, 2006991 and suggestions 
from the authorities (Food and Drug Administration [FDA] and the European Medicines 
Agency [EMA)]). The proposed marketed dosage of UMEC as a component of 
FF/UMEC/VI in Japan will be determined based on the results of the global phase III 
study (Study 205715).  This safety study with FF/UMEC/VI 100/62.5/25 mcg and 
200/62.5/25 mcg in Japanese subjects will add to the safety database in the Japanese sub-
population of study 205715.The long-term safety of FF/UMEC/VI can be established 
with the data of FF/UMEC 62.5 mcg/ VI because the safety profile for 
FF/UMEC62.5 mcg/VI would cover all UMEC doses lower than 62.5 mcg as 
FF/UMEC/VI, thus, the only single higher dosage of UMEC as a component of 
FF/UMEC/VI will be employed in the present study. In addition, the doses of FF and VI 
as components of FF/UMEC/VI were selected based on the worldwide approved doses 
for the treatment of asthma (i.e., FF/VI 100/25 mcg and FF/VI 200/25 mcg). Therefore, 
FF/UMEC/VI 100/62.5/25 mcg and 200/62.5/25 mcg will be employed as the dose of 
FF/UMEC/VI in this study.
                                                
1
Study 200699 is a dose-ranging study that evaluated the efficacy and safety of four doses of UMEC 
(15.6, 62.5, 125 and 250 mcg) in combination with FF (100 mcg) over a 4-week treatment period in 
irreversible subjects with fixed airway obstruction. The primary endpoint of Study 200699 was the 
change from baseline in trough FEV1. After 4 weeks of treatment in patients with a primary diagnosis 
of asthma, an increase in trough FEV1 of 136 mL was observed in those subjects treated with 
FF/UMEC (100/62.5 mcg) compared to those subjects treated with FF (100 mcg) alone. No safety 
signal was identified with any of the UMEC doses (15.6, 62.5, 125 and 250 mcg) evaluated in Study 
200699. Based on these results, 62.5 mcg was selected as the dosage of UMEC as a component of 
FF/UMEC/VI.
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6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
Prior to screening, the Investigator will review each prospected subject’s medical records 
and medical history to determine the subject’s eligibility based on the inclusion/exclusion 
criteria at the time of informed consent (Visit 0) and at screening (Visit 1). The subject’s 
eligibility should be confirmed again at the end of the run-in period based on the 
inclusion/exclusion criteria at Visit 2.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1.
Participant must be 18 years of age or older at the time of signing the informed 
consent.
Type of Participant and Disease Characteristics
2.
Ethnicity: Japanese 
3.
Diagnosis: Subjects with a diagnosis of asthma as defined by the National Institutes 
of Health [NIH, 2007] at least one year prior to providing informed consent.
4.
Current Asthma Maintenance Therapy: Outpatients are eligible if they have received 
ICS+LABA with or without LAMA as inhaled medications for asthma in stable 
regimen and dosage for at least 4 weeks prior to screening visit (Visit 1) (with 
medium to high dose of ICS defined by the Japanese Guidelines [JGL Asthma, 
2015]) and have control status as shown in Table 3. Asthma Control Questionnaire 
(ACQ-6) will be used for the assessment of control status of asthma at Visit 1 
(screening Visit) (i.e., !0.75 points shows controlled and > 0.75 shows not well 
controlled).
Table 3
Asthma therapy and Control Status
Pre-screening inhaled asthma
therapy
Control status of asthma1
ICS+LABA
Not well controlled with ICS (mid-dose) +LABA
Not well controlled with ICS (high-dose) +LABA
ICS+LABA＋LAMA
Controlled with ICS (mid-dose) +LABA + LAMA
Not well controlled with ICS (mid-dose) +LABA + LAMA
Controlled with ICS (high-dose) +LABA + LAMA
1.
Asthma Control Questionnaire (ACQ-6 at screening and ACQ-7 at week 0, week 24, week52/Withdrawal) will be
used for the assessment of control status of asthma, i.e., !0.75 points shows controlled and >0.75 shows not well 
controlled.
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5.
Short-Acting β2 Agonists (SABAs): All subjects must be able to replace their current 
SABA inhaler with salbutamol aerosol inhaler at Visit 1 as needed for the duration of 
the study. Subjects should be able to withhold salbutamol for at least 6 hours prior to 
clinic visit.
Sex
6.
Male and/or female
A female participant is eligible to participate if she is not pregnant (see Appendix 4), not 
breastfeeding, and at least one of the following conditions applies:
(i)Not a woman of childbearing potential (WOCBP) as defined in Appendix 4.
or
(ii)A WOCBP who agrees to follow the contraceptive guidance in Appendix 4 from the 
screening visit until after the last dose of study medication and completion of the follow-
up visit.
Informed Consent
7.
Capable of giving signed informed consent as described in Appendix 2 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
Pneumonia: Chest X-ray documented pneumonia in the 6 weeks prior to Visit 1.
2.
Asthma Exacerbation: Any asthma exacerbation requiring a change in maintenance 
asthma therapy in the 6 weeks prior to Visit 1.
Note: Subjects requiring a temporary change in asthma therapy (e.g., oral 
corticosteroids or increased dose of ICS) to treat an exacerbation in the 6 weeks 
prior to Visit 1 are not explicitly excluded at Visit 1 provided that, at the 
Investigator’s discretion, the subject’s condition is stable after they have resumed 
their pre-exacerbation maintenance asthma therapy (without modification) and they 
are considered appropriate for enrolment into this study of up to 12 months’ 
duration.
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3.
COPD: Subjects with the diagnosis of chronic obstructive pulmonary disease, as per 
Global Initiative for Chronic Obstructive Lung Disease (GOLD 2016) guidelines, 
including all of the following:
∀
History of exposure to risk factors (i.e., especially tobacco smoke, occupational 
dusts and chemicals, smoke from home cooking and heating fuels) (for tobacco 
smoke, see Exclusion Criterion 16);
and
∀
A post- salbutamol FEV1/forced vital capacity (FVC) ratio of <0.70 and a post-
salbutamol FEV1 of !70% of predicted normal values (diagnosis prior to Visit 1 
acceptable);
and
∀
Onset of disease #40 years of age
4.
Concurrent respiratory disorders: Subjects with current evidence of pneumonia, 
active tuberculosis, lung cancer, significant bronchiectasis, sarcoidosis, lung fibrosis, 
pulmonary hypertension, interstitial lung diseases or other active pulmonary diseases 
or abnormalities other than asthma.
5.
Risk Factors for Pneumonia: Immune suppression (e.g., HIV, lupus) or other risk 
factors for pneumonia (e.g., neurological disorders affecting control of the upper 
airway, such as Parkinson’s disease, myasthenia gravis). Patients at potentially high 
risk (e.g., very low BMI, severely malnourished, or very low FEV1) will only be 
included at the discretion of the Investigator.
6.
Other diseases/abnormalities: Subjects with historical or current evidence of 
clinically significant cardiovascular, neurological, psychiatric, renal, hepatic, 
immunological, gastrointestinal, urogenital, nervous system, musculoskeletal, skin, 
sensory, endocrine (including uncontrolled diabetes or thyroid disease) or 
hematological abnormalities that are uncontrolled. Significant is defined as any 
disease that, in the opinion of the Investigator, would put the safety of the subject at 
risk through participation, or which would affect the efficacy or safety analysis if the 
disease/condition exacerbated during the study.
7.
Unstable liver disease as defined by the presence of ascites, encephalopathy, 
coagulopathy, hypoalbuminemia, esophageal or gastric varices or persistent jaundice, 
cirrhosis, known biliary abnormalities (with the exception of Gilbert’s syndrome or 
asymptomatic gallstones).
Note: Chronic stable hepatitis B and C are acceptable if the subject otherwise meets entry 
criteria.
8.
Clinically significant ECG abnormality: Evidence of a clinically significant 
abnormality in the 12-lead ECG performed during screening. The Investigator will 
determine the clinical significance of each abnormal ECG finding in relation to the 
subject’s medical history and exclude subjects who would be at undue risk by 
participating in the trial. An abnormal and clinically significant finding is defined as 
a 12-lead tracing that is interpreted as, but not limited to, any of the following:
∀
Atrial fibrillation (AF) with rapid ventricular rate >120 beats per minute (BPM)
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∀
Sustained or nonsustained ventricular tachycardia (VT)
∀
Second degree heart block Mobitz type II and third degree heart block (unless 
pacemaker or defibrillator had been inserted)
∀
QTcF #500 msec in patients with QRS <120 msec and QTcF #530 msec in 
patients with QRS ≥120 msec
9.
Unstable or life threatening cardiac disease: subjects with any of the following at 
screening (Visit 1) would be excluded:
∀
Myocardial infarction or unstable angina in the last 6 months
∀
Unstable or life threatening cardiac arrhythmia requiring intervention in the last 
3 months
∀
New York Heart Association (NYHA) Class IV heart failure [American Heart 
Association, 2016]
10. Antimuscarinic effects: Subjects with a medical condition such as narrow-angle 
glaucoma, urinary retention, prostatic hypertrophy or bladder neck obstruction 
should only be included if in the opinion of the Investigator the benefit outweighs the 
risk and that the condition would not contraindicate study participation.
11. Cancer: Subjects with carcinoma that has not been in complete remission for at least 
5 years. Subjects who have had carcinoma in situ of the cervix, squamous cell 
carcinoma and basal cell carcinoma of the skin would not be excluded based on the 5 
year waiting period if the subject has been considered cured by treatment.
12. Questionable validity of consent: Subjects with a history of psychiatric disease, 
intellectual deficiency, poor motivation or other conditions that will limit the validity 
of informed consent to participate in the study.
Prior/Concomitant Therapy
13. Medication prior to spirometry: Subjects who are medically unable to withhold their 
salbutamol for the 6-hour period required prior to spirometry testing at each study 
visit.
Diagnostic assessments
14. Drug/alcohol abuse: Subjects with a known or suspected history of alcohol or drug 
abuse within the last 2 years.
15. Allergy or hypersensitivity: A history of allergy or hypersensitivity to any 
corticosteroid, anticholinergic/muscarinic receptor antagonist, β2-agonist, 
lactose/severe milk protein or magnesium stearate.
16. Tobacco use: Subjects who are:
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∀
Current smokers (defined as subjects who have used inhaled tobacco products 
within the 12 months prior to Visit 1 [i.e., cigarettes, e-cigarettes/vaping, cigars 
or pipe tobacco]).
∀
Former smokers with a smoking history of #10 pack years (e.g., #20 
cigarettes/day for 10 years).
Note: Refer to the SRM for the formula for calculating pack years.
Other Exclusions
17. Non-compliance: Subjects at risk of non-compliance, or unable to comply with the 
study procedures. Any infirmity, disability, or geographic location that would limit 
compliance for scheduled visits.
18. Affiliation with Investigator site: Study Investigators, sub-Investigators, study 
coordinators, employees of a participating Investigator or study site, or immediate 
family members of the aforementioned that is involved with this study.
19. Inability to read: In the opinion of the Investigator, any subject who is unable to read 
and/or would not be able to complete study related materials.
Eligibility criteria at the end of the run-in period (Visit 2)
At the end of the run-in period, subjects must meet all of the additional criteria listed 
below in order to continue participation in the study. Subjects who meet these criteria can 
initiate a 52-week treatment period.
Inclusion criteria at the end of the run-in period (Visit 2)
Asthma maintenance therapy
1.
Asthma maintenance therapy: No changes in asthma maintenance therapy (excluding 
salbutamol inhalation aerosol provided at Visit 1) and control status during the run-in 
period.  Asthma Control Questionnaire (ACQ-6 at screening and ACQ-7 at the end
of the run-in period) will be used for the assessment of control status of asthma, i.e., 
0.75 points shows controlled and >0.75 shows not well controlled.
Concurrent conditions/medical history
2.
Liver function test at Visit1
∀
Alanine aminotransferase (ALT) <2 x upper limit of normal (ULN)
∀
Alkaline phosphatase !1.5 x ULN
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∀
Bilirubin !1.5 x ULN (isolated bilirubin >1.5 x ULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%)
Exclusion criteria at the end of the run-in period (Visit 2)
Concurrent conditions/medical history
1.
Respiratory Infection: Occurrence of a culture-documented or suspected bacterial or 
viral infection of the upper or lower respiratory tract, sinus or middle ear during the 
run-in period that led to a change in asthma management or, in the opinion of the 
Investigator, is expected to affect the subject’s asthma status or the subject’s ability 
to participate in the study.
2.
Severe asthma exacerbation: Evidence of a severe exacerbation during screening or 
the run-in period, defined as deterioration of asthma requiring the use of systemic 
corticosteroids (tablets, suspension, or injection) for at least 3 days2 or an in-patient 
hospitalization or emergency department visit due to asthma that required systemic 
corticosteroids.
Diagnostic assessments and other criteria
3.
Laboratory test abnormalities: Evidence of clinically significant abnormal laboratory 
tests during screening or the run-in period which are still abnormal upon repeat 
analysis and are not believed to be due to disease(s) present.  Each Investigator will 
use his/her own discretion in determining the clinical significance of the abnormality.
6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions
There is no restriction on diet in this study.
6.3.2.
Caffeine, Alcohol, and Tobacco
Use of tobacco products will not be allowed from screening until after the final follow-up 
visit. Caffeine and alcohol is allowed ad libitum.
6.3.3.
Activity
There is no restriction on activity in this study.
                                                
2
For subjects on maintenance systemic corticosteroids, at least double the existing maintenance dose for 
at least 3 days is required.
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6.4.
Screen Failures
For the purpose of this study, pre-screen failures, screen failures and run-in failures will 
be defined as follows:
Pre-screen failures: Those subjects that sign the informed consent document but do not 
have a Visit 1 (screening) procedure.
Screen failures: Those subjects that complete at least one Visit 1 (screening) procedure 
but do not enter the run-in period. A subject who complete Visit 1 assessments is 
considered to have entered the run-in period.
Run-in failures: Those subjects that enter the run-in period but do not subsequently enter 
the treatment period, including those subjects that complete the run-in period and then 
meet the eligibility criteria but are not assigned to treatment at Visit 2.
The study interactive response technology (IRT) system (RAMOS NG) will be contacted 
to report pre-screen, screen and ruin-in failures.
A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure subjects to meet the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, and any serious adverse events (SAEs).
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened once. Rescreened subjects should be assigned a subject number 
different from that for the initial screening. Advance written approval to proceed with 
rescreening a subject must be obtained from the Medical Monitor (see the SRM for 
contact details).
7.
TREATMENTS
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.
7.1.
Treatments Administered
Study treatment will be administered via the ELLIPTA device. The ELLIPTA device is a 
molded plastic two-sided device that can hold two individual blister strips. Description of 
the study treatment administered via the ELLIPTA is provided in Table 4.
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Table 4
Description of Study Treatment
Investigational product:
FF/UMEC/VI
Dosage formulation:
ELLIPTA with 30 doses of inhalation powder 
(2 strips with 30 blisters per strip)
Unit dose strengths/ 
dosage levels:
Strip 1: 
FF blended with lactose
100 or 200 mcg per blister
Strip 2: 
UMEC and VI blended with 
lactose and magnesium stearate
UMEC 62.5 mcg and VI 25 mcg 
per blister
Route of administration
Inhaled
Dosing instructions:
1 puff at approximately the same time in each morning
Packaging and labelling
Each will be labeled as required per country requirement.
Manufacturer
GSK
Subjects will self-administer their first dose in the clinic and will continue to administer 
FF/UME/VI at approximately the same time each morning for the duration of the 
treatment period. Each subject will be instructed on the proper use of the ELLIPTA and 
will inhale once from the ELLIPTA each morning.
At Visit 1, an salbutamol metered-dose inhaler (MDI) as rescue medication will be 
provided for as-needed use throughout the study period starting at Visit 1. At the 
Investigator’s discretion, more than one MDI may be provided at any one time.  
Salbutamol will be sourced from local commercial stock. The contents of the label will 
be in accordance with all applicable regulatory requirements in Japan.
All used and unused study treatment and salbutamol will be returned to GSK at the end of 
the study to be available for disposal. Detailed instructions for the return of the study 
drug can be found in the SRM.
If any ELLIPTA fails to function properly, the subject should return to the clinic as soon 
as possible to obtain a new inhaler.
In addition, any ELLIPTA that fails to function properly must be identified and returned 
to GSK for testing.
7.2.
Dose Modification
During the run-in period, the subjects will continue their current (pre-screening) inhaled 
medications for asthma (ICS+LABA or ICS+LABA+LAMA) until the day before Visit 2 
without any change in regimen/dosage.
At Visit 2, subjects will be assigned to study treatment as shown in Table 5 and will be 
provided with the assigned investigational product.
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Table 5
Study Treatment Assignment
Group
Current inhaled therapy and control status of 
asthma during the run-in period1
Study treatment
Group 1
Not well controlled with ICS (mid-dose)+LABA   
or
Controlled with ICS (mid-dose)+LABA + LAMA
FF/UMEC/VI 100/62.5/25 mcg via 
ELLIPTA, once-daily, 1 puff/time, 
morning
Group 2
Not well controlled with ICS (high-dose)+LABA    
or
Not well controlled with ICS (mid-dose)+LABA + 
LAMA    
or
Controlled with ICS (high-dose)+LABA + LAMA
FF/UMEC/VI 200/62.5/25 mcg via 
ELLIPTA, once-daily, 1 puff/time, 
morning
1.
ACQ-7 score (Week 0) will be used for the assessment of control status of asthma, i.e., !0.75 points shows 
controlled and >0.75 shows not well controlled.
On the morning of scheduled clinic study visit at Visit 2, Visit 5 and Visit 7, subjects will 
refrain from taking their morning dose of study treatment until instructed to do so by 
clinic personnel.
Study treatment will be taken at the clinic at approximately the same time of day as taken 
at Visit 2. Each Investigator will be provided with sufficient supplies to conduct the trial. 
Additional treatment packs will be supplied as needed to the sites.
The last dose of the investigational product will be taken at the clinical at Visit 7/EOT (or 
at the early withdrawal visit as appropriate) and safety follow-up assessments will be 
performed approximately 1 weeks later.
At Week 24 of the treatment period (Visit 5), switching medication from FF/UMEC/VI 
100/62.5/25 mcg to FF/UMEC/VI 200/62.5/25 mcg will be permitted if the control status 
of the subject assessed by ACQ-7 is inadequate (i.e., ACQ score >0.75).
7.3.
Method of Treatment Assignment
Treatment will not be assigned by randomisation, but by current inhaled therapy and 
control status of asthma during the run-in period as described in Section 7.2.. Details of 
procedures of treatment assignment of subjects and study treatment supply management 
using RAMOS NG (including study drug supply) are provided in the RAMOS NG 
Manual and the SRM.
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7.4.
Blinding
This will be an open-label (non-blind) study.
7.5.
Preparation/Handling/Storage/Accountability
1.
The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment.
2.
Only participants enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment. All study treatments 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access 
limited to the investigator and authorized site staff. 
3.
The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records). 
4.
Further guidance and information for the final disposition of unused study treatment 
are provided in the SRM.
∀
Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to 
avoid direct eye or skin contact. In the case of unintentional occupational exposure 
notify the monitor, Medical Monitor and/or GSK study contact. 
∀
A equivalent document describing occupational hazards and recommended handling 
precautions either will be provided to the investigator, where this is required by local 
laws, or is available upon request from GSK. 
7.6.
Treatment Compliance
When subjects are dosed at the study site, they will receive study treatment under medical 
supervision by the Investigator or designee. The dose of study treatment and study 
subject identification will be confirmed at the time of dosing by a member of the study 
site staff other than the person responsible for study treatment accountability.
When subjects self-administer study treatment at home, the Investigator or designee will 
assess compliance with study treatment by counting the remained doses of FF/UMEC/VI 
in ELLIPTA as appropriate at the clinic visits and by querying the subject during the 
clinic visits as necessary, and document it in the source documents and CRF. A record of 
the number of the investigational product dispensed to and taken by each subject must be 
maintained and reconciled with study treatment and compliance records by the person 
responsible for study treatment accountability. Treatment start and stop dates will also be 
recorded in the CRF. Subjects should be #80% to !120% compliant on taking study 
treatment between each pair of scheduled and consecutive on-treatment clinic visits. 
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Subjects who fall outside this range should be re-educated on treatment compliance by 
their site. The Investigator should document this re-education in the source documents.
If the study treatment is withdrawn early or a subject is unable comply with the study 
treatment method and repeatedly falls outside the acceptable compliance range, the 
sponsor/monitor should be notified of it for discussion about appropriateness of 
continuation of the study in the subject.
7.7.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrollment or receives during the treatment period must be recorded along with:
∀
reason for use
∀
dates of administration including start and end dates
∀
dosage information including dose and frequency
All asthma medications used within approximately 4 weeks prior to screening should also 
be recorded in the CRF. Medications initiated after completion of the assessments at Visit 
7/EOT or the Early Withdrawal Visit will not be recorded in the CRF unless taken to treat 
an AE or asthma exacerbation. Concomitant medications relating to a SAE need to be 
entered on the CRF, if SAE is occurred from informed consent until the initiation of 
treatment period.
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
Detailed information of permitted and prohibited medications is included in the SRM. 
Participants who have completed the Visit 7/EOT or Early Withdrawal Visit are allowed 
to use any medications prescribed by the Investigator or primary care physician.
7.7.1.
Prohibited Concomitant Medications
Use of the medications listed in Table 6 is not permitted during the study.
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Table 6
Concomitant Medications (○: permitted, X: prohibited)
Medication
Prior to Visit 1
Run-in period
Treatment 
period
Follow-up 
period
Inhaled short-acting 
anticholinergics
Prohibited within 
6 hours
X
X
○
Inhaled short-acting 
anticholinergics + short-
acting β2 agonist 
combination
Prohibited within 
6 hours
X
X
○
Inhaled long-acting 
anticholinergics
○
○1
X
○
Immunosuppressive 
medications including 
immunomodulators
Prohibited within 
12 weeks
X
X
○
Inhaled LABA (e.g., 
salmeterol, formoterol, 
indacaterol, olodaterol) or 
combination products 
containing inhaled LABA
(e.g., Adoaire, Symbicort)
○
○1
X
○
Non-Inhaled LABA (e.g., 
Hokunalin Tape)
Prohibited within 
24 hours
X
X
○
Inhaled short-acting 
beta2-agonist (rescue  
salbutamol will be 
provided and is permitted 
during the study)
Prohibited within 
6 hours
X
X
○
ICS
○
○1
X
○
Theophyllines, slow-
release bronchodilators, 
ketotifen, nedocromil 
sodium, sodium 
cromoglycate, roflumilast
Prohibited within 
48 hours
X
X
○
Medicinal marijuana2
Prohibited within 
6 months
X
X
X
Other investigational 
products
Within 30 days or 
within 5 drug half-
lives of the 
investigational 
drug (whichever 
is longer)
X
X
X
1.
Start of use is prohibited.
2.
Use of inhaled medicinal cannabis is prohibited. Use of medicinal cannabis by any other route of administration is 
also prohibited unless written approval is obtained from the Medical Monitor prior to Visit 1.
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7.7.2.
Permitted Concomitant Medications
7.7.2.1.
Permitted Asthma Medications
In addition to study treatment, the following medications are permitted during this study:
∀
Systemic corticosteroids (!5 mg/day of prednisolone or equivalent) will be permitted 
provided that treatment was initiated at least 12 weeks prior to Visit 1, remains stable 
for the 8 weeks prior to Visit 1 and the subject remains in the maintenance phase 
throughout the study (the only exception being the treatment of moderate/severe 
asthma exacerbations [see below]).
∀
Anti-immunoglobulin E (IgE) (e.g. omalizumab) treatment will be permitted 
provided that treatment was initiated at least 16 weeks prior to Visit 1 and the subject 
remains in the maintenance phase throughout the study.
∀
Anti-interleukin (IL)-5 (e.g. mepolizumab) treatment will be permitted provided that 
treatment was initiated at least 16 weeks prior to Visit 1 and the subject remains in 
the maintenance phase throughout the study.
∀
Anti-leukotriene treatment will be permitted provided that treatment was initiated at 
least 12 weeks prior to Visit 1 and the subject remains in the maintenance phase 
throughout the study.
∀
Study-provided  salbutamol will be dispensed at Visit 1 for use as rescue medication 
throughout the duration of the study. GSK will not provide any recue drug to the 
sites in principle.
Temporary additions of medications are permitted for the treatment of moderate asthma 
exacerbations at the Investigator’s/treating physician’s discretion. Asthma exacerbations 
should be treated in line with national and international recommendations and local 
medical standards. Asthma medications permitted on a temporary basis to treat a 
moderate asthma exacerbation include but are not limited to the following (the Medical 
Monitor may be contacted for additional guidance, see the Medical Monitor/Sponsor 
Information Page):
∀
An increase in ICS dose
∀
Systemic corticosteroids (tablets, suspension or injection) (or an increase in systemic 
corticosteroid dose for those subjects receiving maintenance systemic 
corticosteroids)
∀
Change in SABA use (i.e., routinely scheduled versus as needed use)
∀
Leukotriene receptor antagonists (LTRAs)
∀
Oral theophylline
∀
By definition, a severe asthma exacerbation will be treated with systemic 
corticosteroid (tablets, suspension or injection) for at least 3 consecutive days (or at 
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least double the existing maintenance dose of systemic corticosteroid, if applicable, 
for at least 3 consecutive days). See Section 9.5.4.2..
7.7.2.2.
Permitted Non-Asthma Medications
The following medications are permitted during this study:
∀
Medications for rhinitis (e.g., intranasal corticosteroids, antihistamines [including 
ocular and intranasal], cromolyn, nedocromil, nasal decongestants)
∀
Antibiotics for short term treatment of acute infections. Long term treatment with 
topical or ophthalmic antibiotics are permitted.
∀
Decongestants: Subjects may take decongestants during the study, but these are 
disallowed for 24 hours prior to ECG measurements.
∀
Immunotherapy: Immunotherapy for the treatment of allergies is allowed during the 
study provided it was initiated 4 weeks prior to Visit 1 and subjects remain in the 
maintenance phase for the duration of the study.
∀
Topical and ophthalmic corticosteroids
∀
Systemic and ophthalmic β-blockers: Administer with caution as systemic β-blockers 
block the pulmonary effect of β-agonists and may produce severe bronchospasm in 
patients with reversible obstructive airways disease. Cardioselective β-blockers also 
should be administered with caution.
∀
Localized corticosteroid injections (e.g. intra-articular and epidural)
∀
Tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs). Administer 
with extreme caution as they may potentiate the effects of β-agonists on the 
cardiovascular system, including QTc prolongation.
∀
Diuretics. Caution is advised in the co-administration of β-agonists with non-
potassium sparing diuretics as this may result in ECG changes and/or hypokalemia.
∀
Cytochrome P450 3A4 (CYP3A4) inhibitors: Caution should be exercised when 
considering the coadministration of long-term ketoconazole and other known strong 
CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, 
itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, 
troleandomycin, voriconazole) because increased systemic corticosteroid and 
increased cardiovascular adverse effects may occur.
∀
Vaccinations (e.g., influenza vaccine, pneumonia vaccine, herpes zoster vaccine). 
Administration of influenza and pneumonia vaccines should be considered based on 
clinical discretion of the Investigator and local/national guidelines. Current influenza 
vaccines and pneumonia vaccines will be captured on the concomitant medication 
pages of the CRF.)
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All medications for other disorders may be continued throughout the study provided their 
use would not be expected to affect the subjects’ lung function or safety assessments (e.g., 
cardiac measurements). However, no systemic corticosteroids for other conditions will be 
permitted.
7.7.2.3.
Permitted Non-Drug Therapies
Use of continuous positive airway pressure (CPAP) for treatment of obstructive sleep 
apnea syndrome will be permitted provided that the treatment was initiated at least 6 
weeks prior to the screening visit (Visit 1) and the subject remains on CPAP throughout 
the study.
7.8.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because other treatment options are available.
The Investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific 
post-study treatment.
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
A subject may be withdrawn from study treatment at any time. A reason for premature 
discontinuation of study treatment (e.g., AE, lack of efficacy [including acute moderate 
or severe asthma exacerbation], protocol deviation, Investigator discretion, consent 
withdrawn) must be captured in the CRF.
A subject must be withdrawn from study treatment if any of the following stopping 
criteria are met:
∀
Liver Chemistry: Meets any of the protocol-defined liver chemistry stopping criteria 
(see Section 8.1.1. and Appendix 6).
∀
QTc: Meets any of the protocol-defined stopping criteria (see Section 8.1.2.).
∀
Pregnancy: Positive pregnancy test (see Section 9.2.7. and Appendix 4) 
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8.1.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). These protocol guidelines are in alignment 
with FDA premarketing clinical liver safety guidance:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Discontinuation of study treatment for abnormal liver tests should be considered by the 
investigator when a participant meets one of the conditions outlined in the algorithm or if 
the investigator believes that it is in the best interest of the participant.
Algorithm A: Phase III-IV Liver Chemistry Stopping and Increased 
Monitoring Algorithm
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Algorithm B: Phase III-IV Liver Chemistry Increased Monitoring Algorithm 
with Continued Therapy for ALT #3xULN but <8xULN
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 6.
8.1.2.
QTc Stopping Criteria
Details on performing ECG assessments can be found in Section 9.4.3..
∀
The QTcF (QT interval corrected by Fridericia’s formula) must be used for each 
individual participant to determine eligibility for and discontinuation from the study.  
This formula may not be changed or substituted once the participant has been 
enrolled.
∀
The QTcF must be continued to be used for all QTc data being collected from all 
subjects for data analysis. Safety ECGs and other non-protocol specified ECGs are 
an exception.
∀
The QTc should be based on single or averaged QTc values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minutes) recording period.
∀
For this study, the following QTc stopping criteria will apply:
∀
QTcF >500 msec or uncorrected QT >600 msec
∀
For patients with bundle branch block: QTcF # 530 msec
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∀
Change from baseline in QTcF > 60 msec
See the SoA for data to be collected at the time of treatment discontinuation and follow-
up and for any further evaluations that need to be completed.
8.1.3.
Temporary Discontinuation
A subject who discontinue the study treatment must be withdrawn from the study.
8.1.4.
Rechallenge
8.1.4.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed.
8.2.
Withdrawal from the Study
∀
A participant may withdraw from the study at any time at his/her own request, or 
may be withdrawn at any time at the discretion of the investigator for safety, 
behavioral, compliance or administrative reasons.
∀
If the participant withdraws consent for disclosure of future information, the sponsor 
may retain and continue to use any data collected before such a withdrawal of 
consent.
∀
If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records.
∀
Refer to the SoA for data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed.
8.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:
∀
The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study.
∀
Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record.
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∀
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.
9.
STUDY ASSESSMENTS AND PROCEDURES
∀
Study procedures and their timing are summarized in the SoA (see Table 1). 
∀
Protocol waivers or exemptions are not allowed.
∀
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment.
∀
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
∀
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.
∀
Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the time frame defined in the SoA.
∀
Repeat or unscheduled blood samples may be taken for safety reasons or for 
technical issues with the samples
Screening and critical baseline assessments
No study related procedures may be performed until the informed consent form has been 
signed by the subject.  A pre-screening visit (Visit 0) is required in order to administer 
the informed consent before any changes are made to the subject’s current medical 
regimen.  Selection and modification of the subject’s medications prior to study 
participation is based on the physician’s judgment according to sound medical practice, 
principles, and each subject’s needs.  A subject’s treatment must not be changed merely 
for the purpose of enabling the subject’s participation in the study.
At the pre-screening visit (Visit 0) the following information will be assessed for each 
subject:
∀
Date of ICF signature
∀
Demographic information including race, age and gender
∀
Subject number
∀
Serious Adverse Event information (only in the case assessed as related to study 
participation)
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The following additional critical baseline assessments will be conducted at screening 
(Visit 1):
∀
Weight and height
∀
Asthma diagnosis history including:
∀
The age of the subject when they were first provided with an inhaler for asthma
∀
Completion of an asthma medical history questionnaire (A copy of this 
questionnaire and instructions for its use can be found in the SRM.)
∀
Smoking history and status
∀
Exacerbation history
∀
Asthma and other concurrent medications and non-drug therapies
∀
Medical history including previous and/or concurrent medical conditions, detailed 
cardiovascular risk factor history, pneumonia, and pneumonia vaccine status
∀
Reason for screen failure (if applicable)
∀
Vital signs
∀
ACQ-6
∀
Inclusion/Exclusion criteria assessment
∀
Physical examination
∀
12-lead ECG
∀
Child bearing status assessment for all potential female subjects
∀
Clinical laboratory tests (including hematology, clinical chemistry, urinalysis and 
serum pregnancy test)
∀
SAE assessment
In addition, the following procedures must be completed at screening (Visit 1):
∀
Review/dispense Medical Problems/Medication Taken worksheet
∀
Dispense  salbutamol
9.1.
Efficacy Assessments
This is an open-label study and the efficacy will be assessed in an exploratory manner. 
Therefore, the efficacy endpoints are considered other endpoints and hence described in 
section 9.5. .
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9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 3.
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study, 
or that caused the participant to discontinue the study treatment/study (see Section 8.). 
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information
∀
All SAEs will be collected from the start of study treatment until the follow-up visit 
at the time points specified in the SoA (Table 1). Any SAEs assessed as related to 
study participation (e.g., protocol-mandated procedures, invasive tests, or change in 
existing therapy) or related to a GSK product will be recorded from the time a 
subject consents to participate in the study up to and including any follow-up contact. 
∀
All AEs will be collected from the start of treatment until the follow-up visit at the 
time points specified in the SoA (Table 1).
∀
Medical occurrences that begin before the start of study treatment but after obtaining 
informed consent will be recorded on the Medical History/Current Medical 
Conditions section of the case report form (CRF) not the AE section.
∀
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, 
as indicated in Appendix 3. The investigator will submit any updated SAE data to the 
sponsor within 24 hours of it being available.
∀
Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the investigator learns of any SAE, including a death, at 
any time after a participant has been discharged from the study, and he/she considers 
the event to be reasonably related to the study treatment or study participation, the 
investigator must promptly notify the sponsor.
∀
The method of recording, evaluating, and assessing causality of AEs and SAEs and 
the procedures for completing and transmitting SAE reports are provided in 
Appendix 3.
9.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
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9.2.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AE/SAEs will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as 
defined in Section 8.3.). Further information on follow-up procedures is given in 
Appendix 3.
9.2.4.
Regulatory Reporting Requirements for SAEs
∀
Prompt notification by the investigator to the sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and 
the safety of a study treatment under clinical investigation are met. 
∀
The sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study treatment under clinical 
investigation. The sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, Institutional 
Review Boards (IRB)/Independent Ethics Committees (IEC), and investigators.
∀
Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and sponsor 
policy and forwarded to investigators as necessary.
∀
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAE) from the sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements.
9.2.5.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 3 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will 
be required to be completed.  These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms.  The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV event data query prompting its completion.  
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
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9.2.6.
Pneumonia
Medical history will also be taken for pneumonia in previous 12 months, including 
recording of any episodes resulting in hospitalization.  Where possible a chest X-ray 
should be performed to confirm a diagnosis, whenever a subject has a suspected 
pneumonia.  Suspected pneumonias will require confirmation as defined by the presence 
of new infiltrate(s) on chest X-ray AND at least 2 of the following signs and symptoms: 
∀
Increased cough
∀
Increased sputum purulence (color) or production 
∀
Auscultatory findings of adventitious sounds (e.g., egophony, bronchial breath 
sounds, rales)
∀
Dyspnea or tachypnea
∀
Fever (oral temperature >37.5°C)
∀
Elevated white blood cells (WBC) (>10,000/mm3 or >15% immature forms)
∀
Hypoxemia (oxyhemoglobin [HbO2] saturation <88% or at least 2% lower than 
baseline value)
All pneumonias must be captured on the AE/SAE page of the CRF and on the pneumonia 
page of the CRF.
For all suspected cases of pneumonia, investigators are strongly encouraged to confirm 
the diagnosis (this includes obtaining a chest X-ray) and to initiate appropriate therapy as 
promptly as possible. All diagnoses of pneumonia (radiographically confirmed or 
unconfirmed) must be reported as an AE or SAE (if applicable).
9.2.7.
Pregnancy
∀
Details of all pregnancies in female will be collected after the start of dosing and 
until the safety follow-up contact/visit.
∀
If a pregnancy is reported, the investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4.
∀
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth,
congenital anomalies, ectopic pregnancy) are considered SAE.
9.2.8.
Adverse Events of Special Interest (AESIs)
AE groups of special interest have been defined as AEs which are associated with the 
already acknowledged pharmacological effects (class effects) of any of ICS, LAMA, and 
LABA. Some AE groups may have subgroups defined.
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The following Table 7 presents the current special interest AE groups and subgroups. 
These may be updated prior to conclusion of the study reporting. The final list, including 
the preferred terms which contribute to each of the groups will be documented a priori in 
the study Reporting and Analysis Plan (RAP).
Table 7
The Special interest groups and subgroups
Special interest AE group
Special interest AE subgroup
Cardiovascular effects
Cardiac arrhythmia
Cardiac failure
Cardiac ischemia
Stroke
Anticholinergic syndrome
-
Urinary retention
-
Dry mouth / drying of airway secretions
-
Gastrointestinal obstruction
-
Antimuscarinic ocular effects / 
Corticosteroids associated eye disorders
Glaucoma (antimuscarinic/corticosteroid)
Cataracts (corticosteroid)
Pneumonia and LRTI
Pneumonia
LRTI excluding pneumonia
Adrenal suppression
-
Decreased bone mineral density and 
associated fractures
-
Effects on glucose
-
Effects on potassium
-
Tremor
-
Asthma intubations, and deaths
-
Hypersensitivity
-
Local steroid effects
-
9.3.
Treatment of Overdose
An overdose is defined as a dose greater than the total doses described above which 
results in clinical signs and symptoms. These should be recorded by the investigator on 
the AE/SAE pages. In the event of an overdose of study treatment, the investigator should 
use clinical judgment in treating the overdose and contact the GSK medical monitor.
GSK is not recommending specific treatment guidelines for overdose and toxicity 
management. The Investigator is advised to refer to the relevant document(s) for detailed 
information regarding warnings, precautions, contraindications, adverse events, and other 
significant data pertaining to the study drug being used in this study. Such documents 
may include, but not be limited to, the IB or equivalent document provided by GSK.
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9.4.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
9.4.1.
Physical Examinations
∀
A complete physical examination will include, at a minimum, assessments of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. Height and 
weight will also be measured and recorded. Height will be measured at Visit 1.
∀
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
9.4.2.
Vital Signs
∀
Pulse rate and blood pressure will be assessed.
∀
Blood pressure (systolic and diastolic) and pulse measurements will be assessed in 
the sitting position with a completely automated device. Manual techniques will be 
used only if an automated device is not available.
∀
Blood pressure and pulse measurements should be preceded by at least 5 minutes of 
rest for the participant in a quiet setting without distractions (eg, television, cell 
phones).
∀
A single set of values will be collected and recorded in the source documentation and 
CRF.
9.4.3.
Electrocardiograms
∀
Single 12-lead ECG will be obtained as outlined in the SoA (see Table 1) using an 
ECG machine of the site that automatically calculates the heart rate and measures PR, 
QRS, QT, and QTc intervals. A single 12-lead ECG and rhythm strip will be 
recorded after measurement of vital signs and spirometry.
∀
For subjects who meet the protocol defined QTc stopping criteria, triplicate ECGs 
(over a brief period of time) should be performed (Section 8.1.2.).
∀
At each time point at which triplicate ECG are required, 3 individual ECG tracings 
should be obtained as closely as possible in succession, but no more than 2 minutes 
apart. The full set of triplicates should be completed in less than 4 minutes.
∀
The Investigator, a designated sub-Investigator or other appropriately trained site 
personnel will be responsible for performing each 12-lead ECG. The Investigator 
must provide his/her dated signature on the original paper tracing, attesting to the 
authenticity of the ECG machine interpretation.
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9.4.4.
Clinical Safety Laboratory Assessments
∀
Refer to Table 8 for the list of clinical laboratory tests to be performed and to the 
SoA (Table 1) for the timing and frequency.
∀
The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
CRF. The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than 
expected for the participant's condition.
∀
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study should be repeated until the values return to normal 
or baseline. 
∀
If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified. 
∀
All protocol-required laboratory assessments, as defined in Table 8, must be 
conducted in accordance with the laboratory manual and the SoA (Table 1). 
∀
If laboratory values from non-protocol specified laboratory assessments performed at 
the institution’s local laboratory require a change in participant management or are 
considered clinically significant by the investigator (eg, SAE or AE), then the results 
must be recorded in the CRF.  
∀
Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Laboratory requisition forms must be completed and samples must be clearly labelled 
with the subject number, protocol number, site/centre number, and visit date.  Details for 
the preparation and shipment of samples will be provided by the laboratory and are 
detailed in the Laboratory Manual. Reference ranges for all safety parameters will be 
provided to the site by the laboratory responsible for the assessments.
All blood samples which will be taken pre-dose, will be sent to a central laboratory for 
analysis (details provided in the Laboratory Manual). Standard reference ranges will be 
used.
Refer to the Laboratory Manual for appropriate processing and handling of samples to 
avoid duplicate and/or additional blood draws.
Hematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 8.
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Table 8
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet count
RBC Indices:
WBC count with 
differential:
Red blood cell (RBC) 
count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry 1
Blood urea nitrogen 
(BUN)
Potassium
AST (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
ALT (SGPT)
Total protein
Glucose
Calcium
Alkaline phosphatise
Albumin
Routine 
Urinalysis
∀
pH, glucose, protein, blood and ketones by dipstick
∀
Specific gravity, Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests
∀
Follicle-stimulating hormone and estradiol (as needed in females of non-
reproductive potential only)
∀
Serum/urine hCG pregnancy test (see the SoA in Table 1)
NOTES :
1.
Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up Assessments after liver stopping 
or monitoring event are given in Section 8.1.1. and Section 12.6. (Appendix 6).
BUN: Blood Urea Nitrogen, FSH: Follicle Stimulating Hormone, hCG: Human Chorionic Gonadotropin, MCH: Mean Corpuscular Hemoglobin, MCV: 
Mean Corpuscular Volume, SGOT: Serum glutamic-oxaloacetic tranaminase, SGPT: Serum glutamic-pyruvic tranaminase 
9.4.5.
Paper Medical Problems/Medications Taken Worksheet
Subjects will be issued with a Paper Medical Problems/Medications Taken Worksheet to 
record any medical problems and non-study specific medications used during the study. 
Subjects must also use this paper worksheet to record all emergency department visits 
and/or hospitalizations that occur during their participation in the study. Subjects will be 
asked to bring their paper worksheet to every study site visit as it will be used to assist 
subject recall in discussions with the Investigator (or designee), for site staff to then enter 
as appropriate in the CRF.
9.5.
Other Assessments
9.5.1.
Other endpoints
The exact timing of each of the following assessments is shown in the SoA (see Table 1).
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∀
Change from baseline in trough FEV1 at Week 24 and Week 52
∀
Change from baseline in ACQ-7 total score at Week 24 and Week 52
∀
Change from baseline in SGRQ total score at Week 24 and Week 52
∀
Change from baseline in AQLQ total score at Week 24 and Week 52
∀
Unscheduled asthma-related healthcare resource utilization over the 52 weeks of the 
treatment period
∀
Annualized rate of severe asthma exacerbations
∀
Annualized rate of moderate/severe asthma exacerbations
9.5.2.
Questionnaires 
The questionnaires should be completed before any procedures are performed on the 
subject to avoid influencing the subject’s response. To avoid biasing responses, the 
subjects should not be told the results of diagnostic tests prior to completing the 
questionnaires and it is recommended that the questionnaires be administered at the same 
time of day during each visit. Adequate time must be allowed to complete all items on the 
questionnaires; the questionnaires must be reviewed for completeness and, if necessary, 
the subject must be encouraged to complete any missing assessments or items.
Instructions for completing the questionnaires can be found in the SRM.
9.5.2.1.
Asthma Control Questionnaire (ACQ)
The ACQ measures seven attributes of asthma control [Juniper, 1999].  Six attributes are 
measured with a patient-completed questionnaire, and the questions are designed to be
self-completed by the subject.  Subjects will complete the ACQ at specified study visits.  
The six questions (concerning nocturnal awakening, waking in the morning, activity 
limitation, shortness of breath, wheeze and rescue medication use) enquire about the 
frequency and/or severity of symptoms over the previous week.  The response options for 
all these questions consist of a zero (no impairment/limitation) to six (total impairment/ 
limitation) scale.  The recall period is the past week.  The seventh attribute of the ACQ-7 
is lung function (FEV1%-predicted) which will be included via study visit spirometry. 
Two shortened versions of the ACQ exist.  The two shortened versions include the ACQ-
5 (a five-item measure using only the symptoms items) and the ACQ-6 (six-item 
measures and rescue bronchodilator use). The measurement properties were very similar 
for all versions of the ACQ (original 7-item ACQ and shortened versions) [Juniper, 2005; 
Virchow, 2015].  For all versions, a score of !0.75 indicates well-controlled asthma and a 
score #1.5 indicates poorly controlled asthma [Juniper, 2006].  A change of 0.5 in score 
suggests a clinically important change in score [Juniper, 2005].
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9.5.2.2.
St. George’s Respiratory Questionnaire (SGRQ)
The St. George’s Respiratory Questionnaire is a well-established instrument, comprising 
50 questions designed to measure Quality of Life in patients with diseases of airway 
obstruction, measuring symptoms, impact, and activity. The questions are designed to be 
self-completed by the subject [Jones, 1992] with a recall over the past 3 months. Higher 
scores indicate worse health status, and a change of 4 points is considered a clinically 
relevant change [Jones, 2005].
9.5.2.3.
Asthma Quality of Life Questionnaire (AQLQ)
The Asthma Quality of Life Questionnaire (AQLQ) was developed to measure the 
functional impairments related to asthma experienced by adults 17+ years old.  The 
AQLQ (+12), is a modified version of the original AQLQ and validated for use in asthma 
patients between the ages of 12 and 70 [Juniper, 2005]. The response scale ranges from 1 
(totally impaired) to 7 (not at all impaired).  The questions are designed to be self-
completed by the subject with a recall over the past 2 weeks.  Higher scores indicate 
better asthma-related HRQoL, and a change of 0.5 is considered clinically important 
[Juniper, 1994].
9.5.2.4.
Healthcare Resource Utilization
All unscheduled asthma-related healthcare utilization will be recorded in the CRF at the 
time points specified in the SoA (Table 1). Unscheduled asthma-related healthcare 
utilization includes telephone contacts, specialist nurse visits, visits to a physician’s 
office, home visits (day and night time), outpatient visits, visits to urgent care, visits to 
the emergency department, and hospitalizations associated with the subject’s worsening 
of symptoms.  The Medical Problems/Medication Taken worksheet (see Section 9.4.5.) 
used by the subject to record all healthcare contacts experienced since the last visit will 
be presented to the Investigator (or designee) at the clinic visits.  Subjects will be asked 
to bring their worksheet to every study site visit as it will be used to assist subject recall 
in discussions with the investigator, for site staff to then enter as appropriate in the CRF.  
The Investigator (or designee) should ask the subject if any of the healthcare contacts that 
are recorded on the worksheet were due to a worsening of asthma symptoms.  The 
investigator can refer to his/her records to verify or supplement information given by the 
subject, if necessary.
9.5.3.
Pulmonary Function Tests
Spirometry will be performed at the study site to assess FEV1 and FVC. At least 3 
acceptable spirometry maneuvers (from a maximum of 8 attempts) should be achieved on 
each occasion that spirometry assessments are performed, in accordance with the 
American Thoracic Society (ATS) / European Respiratory Society (ERS) standards 
[Miller, 2005]. The highest of 3 technically acceptable measurements will be recorded at 
each visit:
∀
Pre-dose Spirometry: At Visit 2, Visit 5 and Visit 7/EOT (and the Early Withdrawal 
Visit, if applicable), subjects should withhold salbutamol for at least 6 hours prior to 
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study visits, if possible. Spirometry assessments must be performed at the following 
time points:
∀
At the same time of day (±1 hour) as the assessment performed at Visit 2 (the 
baseline assessment)
∀
At least 24 hours after the subject’s last morning dose of study treatment on the 
day prior to the visit
∀
Before the subject’s morning dose of study treatment on the day of the visit
9.5.4.
Asthma Exacerbations
For the purposes of this study, moderate/severe asthma exacerbations will be collected 
and recorded on the asthma exacerbation eCRF page from the start of treatment period
until Visit 7/EOT Visit or the Early Withdrawal Visit for those subjects that withdraw 
from participation in the study (see Section 8.1.). Moderate/severe asthma exacerbations 
should not be recorded as an adverse event unless:
∀
They meet the definition of an Adverse Event (see Appendix3) and occur: 
∀
After completion of the Visit 7/EOT Visit (or Early Withdrawal Visit) 
assessments until the follow-up contact.
OR
∀
They meet the definition of a Serious Adverse Event (see Appendix 3).
Note: The SAE page of the eCRF should be completed in addition to the asthma 
exacerbation eCRF page if the exacerbation occurs after the start of treatment period 
but before completion of the Visit 7/EOT Visit or Early Withdrawal Visit assessments.
For consistency, exacerbations separated by less than 7 days will be treated as a 
continuation of the same exacerbation.
Subjects are also instructed to contact the investigator for signs of worsening asthma.
Subjects will also complete a paper Medical Problems/Medications Taken worksheet to 
record medical problems experienced and medications used during the study, as well as 
all emergency department visits and/or hospitalizations that occur during their 
participation in the study. This paper worksheet must be reviewed by the Investigator (or 
designee) at each visit to the study site to assist the investigator in the identification of 
new asthma exacerbations.
All moderate/severe asthma exacerbations will be recorded in the eCRF by the 
Investigator (or designee).
9.5.4.1.
Moderate Asthma Exacerbation
The investigator will utilize clinical discretion and available objective evidence 
(including a paper Medical Problems/Medications Taken worksheet) to determine if the 
patient is experiencing a moderate asthma exacerbation.  Examples of key considerations 
include subject’s past medical history, severity and duration of current symptoms, and 
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known asthma triggers. Guidance for identifying moderate exacerbations includes the 
following [Reddel, 2009, Virchow, 2015]:
∀
A moderate asthma exacerbation is considered to be a deterioration in asthma 
symptoms, deterioration in lung function, or increased rescue bronchodilator use 
lasting for at least 2 days or more, but will not be severe enough to warrant systemic 
corticosteroid use (or a doubling or more of the maintenance systemic corticosteroid 
dose, if applicable) for 3 days or more and/or hospitalisation.
∀
A moderate asthma exacerbation is an event that, when recognized, should result in a 
temporary change in treatment, in an effort to prevent the exacerbation from 
becoming severe.
Subjects are also instructed to contact the investigator for signs of worsening asthma. The 
paper Medical Problems/Medications Taken worksheet must also be reviewed by the 
Investigator (or appropriately trained designee) at each visit to the study site to assist the 
Investigator in the identification of new asthma exacerbations.  At the Investigator’s 
discretion, a temporary change in background asthma medication will be permitted in 
order to treat the symptoms of a moderate asthma exacerbation (see Section 7.7.2.1. for 
details). If a subject experiences a second moderate asthma exacerbation requiring a 
change in therapy, the Investigator may choose to continue the additional therapy for as 
long as medically appropriate.
9.5.4.2.
Severe Asthma Exacerbation
A severe asthma exacerbation is defined as:
The deterioration of asthma requiring the use of systemic corticosteroids (tablets, 
suspension or injection), or an increase from a stable maintenance dose1, for at least 3 
days.
1 For subjects receiving maintenance systemic corticosteroids, at least double the 
maintenance systemic corticosteroid dose for at least 3 days is required.
OR
An inpatient hospitalization or emergency department visit because of asthma, requiring 
systemic corticosteroids.
9.6.
Pharmacokinetics
PK parameters are not evaluated in this study.
9.7.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
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9.8.
Genetics/Pharmacogenetics 
In this study, genetics may be evaluated after review by the ethical review committee 
established by GSK in accordance with Japanese ethical guidelines for human 
genome/gene analysis research. 
In conducting pharmacogenetics(PGx) research in this study, the objectives are as 
follows;
The objective of the PGx research is to understand the relationship between genetic 
factors and response to FF/UMEC/VI. To achieve this objective, the relationship between 
genetic variants and the followings are investigated.
∀
Response to medicine, including FF/UMEC/VI or any concomitant medicines; 
∀
Asthma susceptibility, severity, and progression and related conditions
A 6 mL blood sample for DNA isolation will be collected from participants who have 
consented to participate in the genetics analysis component of the study. Participation is 
optional. Participants who do not wish to participate in the genetics research may still 
participate in the study.
In the event of DNA extraction failure, a replacement genetic blood sample may be 
requested from the participant. Signed informed consent will be required to obtain a 
replacement sample unless it was included in the original consent.
See Appendix 5 for information regarding genetic research. Details on processes for 
collection and shipment and destruction of these samples can be found in SRM.
9.9.
Biomarkers
Biomarkers are not evaluated in this study.
9.10.
Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study.
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10.
STATISTICAL CONSIDERATIONS
10.1.
Sample Size Determination
Sample size in this study is not based on statistical consideration.  The number of 
asthmatic adult subjects (with the control status on inhaled asthma therapy with medium 
to high dose ICS + LABA or medium to high dose ICS +LABA +LAMA as shown in the 
Table 2) required to be enrolled in this study is 110 (a total number of subjects to be 
allocated in Group 1 [FF/UMEC/VI 100/62.5/25 mcg] and Group 2 [FF/UMEC/VI 
200/62.5/25 mcg]). According to the ICH guidelines, the sample size of 110 subjects 
would allow 100 subjects to complete the 52-week treatment period, assuming a drop-out 
rate of approximately 10%.
10.2.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Screened
All screened subjects.
This population will be used for the summary of reasons for screening failures.
Enrolled
All subjects who are found to be eligible for the study based on the screening 
examination result.
This population will be used for the summary tables required by EudraCT.
ITT
All subjects who take at least one dose of study treatment in the treatment period. 
Subjects will be analyzed according to the treatment they actually received.
This population will be used for all safety and efficacy analyses.
EudraCT: European Drug Regulatory Authorities Clinical Trial, ITT: Intent to Treat
10.3.
Statistical Analyses
10.3.1.
Efficacy Analyses
This is an open-label study and its efficacy assessment has limitations. Therefore, the 
efficacy will be assessed in an exploratory manner as other endpoints.
10.3.2.
Safety Analyses
All safety analyses will be performed on the ITT Population. 
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Endpoint
Statistical Analysis Methods
Primary
The primary endpoint is incidence and type of AEs/SAEs.
This endpoint will be summarized using the following two approaches:
1. Summary statistics will be provided for the integration of the groups and for each 
group separately (only FF/UMEC/VI 100/62.5/25 mcg, only FF/UMEC/VI 
200/62.5/25 mcg and switching medication from FF/UMEC/VI 100/62.5/25 mcg to 
FF/UMEC/VI 200/62.5/25 mcg).
2. Summary statistics will be provided by the dose received at the time of 
experiencing the AE. (FF/UMEC/VI 100/62.5/25 mcg and FF/UMEC/VI 
200/62.5/25 mcg)
The number and proportion of subjects experiencing at least one AE will be 
calculated and presented by system organ class (SOC) and by preferred term (PT). 
Summary statistics will also be presented for all AEs, treatment-related AEs, SAEs, 
AEs leading to treatment or study discontinuation,.and AESI.
Secondary
Secondary endpoints will be summarized using the approach described in 
approach 1 above (i.e., provided for only FF/UMEC/VI 100/62.5/25 mcg, only 
FF/UMEC/VI 200/62.5/25 mcg and switching medication from FF/UMEC/VI 
100/62.5/25 mcg to FF/UMEC/VI 200/62.5/25 mcg).
Specific details will be provided in the Reporting and Analysis Plan (RAP).
10.3.3.
Other Analyses
No statistical analysis will be performed for any of the other endpoints but only summary 
of them will be presented. The approach 1 described in the table above will be used for 
the other endpoints (i.e., summary statistics will be provided for only FF/UMEC/VI 
100/62.5/25 mcg, only FF/UMEC/VI 200/62.5/25 mcg and switching medication from 
FF/UMEC/VI 100/62.5/25 mcg to FF/UMEC/VI 200/62.5/25 mcg). Specific details will 
be provided in the RAP.
10.3.4.
Interim Analyses
No statistical interim analysis requiring hypothesis test is planned. However, the data will 
be summarized when all subjects (who have not withdrawn) have completed 24-week 
administration during treatment period and the CRF data up to Week 24 for all subjects is 
locked. It is used for JNDA submission.
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11.
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Asthma Prevention and Management Guideline, Japan for adults 2015 (JGL Asthma 
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British Thoracic Society / Scottish Intercollegiate Guidelines Network (BTS/SIGN). 
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Ducharme FM, Ni Chroinin M, Greenstone I, et al. Addition of long-acting beta2-
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with persistent asthma. Cochrane Database Syst Rev. 2010; 14(4):CD005533.
National Asthma Education and Prevention Programme, National Heart, Lung and Blood 
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Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and 
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Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the 
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Hekking PP, Wener RR, Amelink M, et al. The prevalence of severe refractory asthma. J 
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James LP, Letzig L, Simpson PM, et al. Pharmacokinetics of acetaminophen-protein 
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Jones PW, Quirk FH, Baveystock CM, et al. A self-complete measure of health status for 
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Jones PW. St. George’s Respiratory Questionnaire: MCID. Journal of Chronic 
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Juniper EF, Bousquet J, Abetz L, et al. GOAL Committee. Identifying 'well-controlled' 
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Juniper EF, Guyatt GH, Willan A, et al. Determining a minimal important change in a 
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Juniper EF, O'Byrne PM, Guyatt GH, et al. Development and validation of a 
questionnaire to measure asthma control. Eur Respir J. 1999; 14:902-907.
Juniper EF, Svensson K, Mörk AC, et al. Measurement properties and interpretation of 
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Kerstjens H, Casale T, Bleecker E, et al. Tiotropium or salmeterol as add-on therapy to 
inhaled corticosteroids for patients with moderate symptomatic asthma: two replicate, 
double-blind, placebo-controlled, parallel-group, active-comparator, randomised trials. 
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Kerstjens H, Engle M, Dahl R, et al. Tiotropium in asthma poorly controlled with 
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Virchow JC, Backer V, de Blay F, et al. Defining moderate asthma exacerbations in 
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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
ACQ
Asthma Control Questionnaire
ACT
Asthma Control Test
ADR
Adverse Drug Reaction
ALT
Alanine aminotransferase
AQLQ
Asthma Quality of Life Questionnaire
AST
Aspartate Transaminase
BMI
Body Mass Index
BTS/SIGN
British Thoracic Society / Scottish Intercollegiate Guidelines Network
BUN
Blood Urea Nitrogen
CI
Confidence Interval
CIOMS
Council for International Organizations of Medical Sciences
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic Obstructive Pulmonary Disease
CPAP
Continuous positive airway pressure
CPK
Creatine PhosphoKinase
(e)CRF
(Electronic) Case Report Form
CSR
Clinical Study Report
CV
Cardiovascular
CYP3A4
Cytochrome P450 3A4
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
EMA
European Medicines Agency
EudraCT
European Drug Regulatory Authorities Clinical Trial
EOT
End of Treatment
EU
European Union
EW
Early Withdrawal
FDA
Food and Drug Administration
FEV1
Forced expiratory volume in 1 second
FF
Fluticasone Furoate
FP
Fluticasone Propionate
FSH
Follicle Stimulating Hormone
FVC
Forced Vital Capacity
GCP
Good clinical practice
GINA
Global Initiative for Asthma
GOLD
Global Initiative for Chronic Obstructive Lung Disease
GSK
GlaxoSmithKline
HbO2
Oxyhemoglobin
hCG
Human Chorionic Gonadotropin
HIV
Human Immunodeficiency Virus
HPA
Hypothalamic Pituitary Axis
HRQoL
Health-Related Quality of Life
HRT
Hormone Replacement Therapy
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IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
ICS
Inhaled Corticosteroids
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IL
Interleukin
INR
International normalized ratio
IOP
Intraocular Pressure
IP
Investigational Product
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
Intent to Treat
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
LABA
Long-Acting Beta-2-Agonists
LAMA
Long-Acting Muscarinic Antagonist
LDH
Lactate Dehydrogenase
LOCS III
Lens Opacities Classification System III
LRTI
Lower Respiratory Tract Infection
LTRA
Leukotriene Receptor Antagonist
MACE
Major Adverse Cardiac Event
MAOI
Monoamine Oxidase Inhibitors
MCH
Mean Corpuscular Hemoglobin
MCV
Mean Corpuscular Volume
MDI
Metered Dose Inhaler
MedDRA
Medicinal Dictionary for Regulatory Activities
mcg (μg)
Microgram
NIH
National Institutes of Health
OCS
Oral Corticosteroids
PGx
Pharmacogenetics
PK
Pharmacokinetic
PT
Preferrd Term
QOL
Quality of Life
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate by Fridericia’s formula
RAP
Reporting and Analysis Plan
SABA
Short-Acting Beta-2-Agonists
SGOT
Serum glutamic-oxaloacetic tranaminase
SGPT
Serum glutamic-pyruvic tranaminase
SGRQ
St. George’s Respiratory Questionnaire
SoA
Schedule of Activities
SOC
System Organ Class
SPC
Summary of Product Characteristics
SRM
Study Reference Manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
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ULN
Upper Limit of Normal
UMEC
Umeclidinium Bromide
US
United States
WBC
White Blood Cell
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
ELIPTA
－
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12.2.
Appendix 2: Study Governance Considerations
Regulatory and Ethical Considerations
∀
This study will be conducted in accordance with the protocol and with:
∀
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines
∀
The Ministerial Ordinance on the Standards for the Conduct of Clinical Trials of 
Medicinal Products (MHW Notification No.28 dated 27th March, 1997)” and 
the Pharmaceuticals and Medical Devices Act. 
∀
GSK will submit the CTN to the regulatory authorities in accordance with 
Pharmaceuticals and Medical Devices Act before conclusion of any contract for the 
conduct of the study with study sites.
∀
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator 
and reviewed and approved by the IRB/IEC before the study is initiated. 
∀
Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants. 
∀
The investigator will be responsible for the following:
∀
Providing written summaries of the status of the study to the IRB/IEC annually 
or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/IEC
∀
Notifying the IRB/IEC of SAE or other significant safety findings as required by 
IRB/IEC procedures
∀
Providing oversight of the conduct of the study at the site and adherence to 
requirements of ICH guidelines, the IRB/IEC,  and all other applicable local 
regulations
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
Informed Consent Process
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Prior to participation in the study, the investigator (or subinvestigator) should fully 
inform the potential subject and/or the subject's legally acceptable representative of the 
study including the written information. The investigator (or subinvestigator) should 
provide the subject and/or the subject's legally acceptable representative ample time and 
opportunity to inquire about details of the study. The subject and/or the subject’s legally 
acceptable representative should sign and personally date the consent form. The subject 
may consider the content of the written information at home. The person, who conducted 
the informed consent discussion and the study collaborator giving supplementary 
explanation, where applicable, should sign and personally date the consent form. If an 
impartial witness is required, the witness should sign and personally date the consent 
form. The investigator (or subinvestigator) should retain this signed and dated form (and 
other written information) together with the source medical records, such as clinical 
charts (in accordance with the rules for records retention, if any, at each medical 
institution) and give a copy to the subject and/or the subject’s legally acceptable 
representative. Participants who are rescreened are required to sign a new ICF.
Data Protection
∀
Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier only; 
participant names or any information which would make the participant identifiable 
will not be transferred. 
∀
The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 
∀
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.
Publication Policy
∀
The results of this study may be published or presented at scientific meetings. If this 
is foreseen, the investigator agrees to submit all manuscripts or abstracts to the 
sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments. 
∀
The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
site data. In this case, a coordinating investigator will be designated by mutual 
agreement.
∀
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.
Dissemination of Clinical Study Data
∀
Disclosure of Clinical Study Reports (CSRs) after review by regulatory authorities. 
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∀
The posting of company-sponsored study information and tabular study results on 
the US National Institutes of Health’s website www.ClinTrials.gov and other 
publically-accessible sites. 
∀
Publication planning to peer-reviewed publications. 
Data Quality Assurance
∀
All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (eg, laboratory data). 
The investigator is responsible for verifying that data entries are accurate and correct 
by physically or electronically signing the CRF. 
∀
The investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF. 
∀
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
∀
The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 
∀
Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
∀
Records and documents, including signed ICF, pertaining to the conduct of this study 
must be retained by the investigator for 25 years from the issue of the final Clinical 
Study Report (CSR)/ equivalent summary unless local regulations or institutional 
policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. 
Source Documents
∀
Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.
∀
Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must 
be explained. The investigator may need to request previous medical records or 
transfer records, depending on the study. Also, current medical records must be 
available.
∀
Definition of what constitutes source data can be found in SRM.
Study and Site Closure
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GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:
∀
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines
∀
Inadequate recruitment of participants by the investigator
∀
Discontinuation of further study treatment development
Study Period
June 2017 ~ Sep 2019
Sponsor Information Page
Sponsor Legal Registered Address:
GlaxoSmithKline K.K. (GSK)
8-1, Akasaka 1-chome Minato-ku, Tokyo 107-0052 Japan
Study Director: 
, Head of Respiratory TA Office, Medicines 
Development
Sponsor Contact Address:
Leading Author：
, Respiratory TA Office, Medicines Development 
TEL：
FAX：
Sponsor's Contact Information (10:00-18:00, Monday to Friday, except national holidays, 
year-end and new-year holidays); 
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207236 team, JDMA, GlaxoSmithKline K.K. 
TEL: 
FAX: 
Contact Inforamtion at Night and on Holidays (Monday to Friday: 18:00-10:00, Saturday, 
Sunday, national holidays, year-end and new-year holidays) 
BI Medical, Inc. 
TEL: 
 (local toll-free)
FAX: 
(local toll-free)
Sponsor’s Medical Monitor: 
, Head of Nurology Science TA Office, 
Medicines Development 
TEL：
FAX：
Laboratory
Clinical Laboratory
SRL Medisearch Inc. 
Shinjuku I-Land-Tower 10F, 6-5-1, Nishishinjuku, Shinjuku-ku, Tokyo, 163-1310, Japan 
Pharmacokinetic Measurement Facilities
York Bioanalytical Solutions Limited
Cedar House, Northminster Business Park, Upper Poppleton, York 
YO26 6QR, UK
Contract Reserch Organization
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Parexel International Inc.
Kayabacho-First-Building 6F, 1-17-21, Shinkawa, Chuo-ku, Tokyo, 104-0033, Japan
Gx/PGx Research Administration
Gx/PGx Sample Management
Team Leader DNA Sample Management
GlaxoSmithKline
Medicines Research Centre, Gunnels Wood Road, Stevenage Hertfordshire
SG1 2NY, UK
Tel: 
Gx/PGx Sample Storage
RUCDR
Nelson Biological Laboratories,
Room B101, 604 Allison Road, Piscataway, NJ 08854, USA
DNA Extraction
Specimen Processing,
Q2 Solutions LLC
27027 Tourney Road, Ste 2E, Valencia, CA 91355, USA
Contact Person
Q2 Solutions LLC
Global Laboratory Director
27027 Tourney Road
Ste 2E, Valencia, CA 91355, USA
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Person in charge of Gx/PGx Research
Director, Therapy Aligned Applied Genetics
GlaxoSmithKline
709 Swedeland Road, King of Prussia, PA, 19406, USA
Tel: 
12.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
Definition of AE
AE Definition
∀
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study treatment, whether or not considered related to the 
study treatment.
∀
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
Events Meeting the AE Definition
∀
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, vital signs measurements), including those that 
worsen from baseline, considered clinically significant in the medical and scientific 
judgment of the investigator (ie, not related to progression of underlying disease).
∀
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
∀
New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.
∀
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
∀
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.
∀
"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
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lack of efficacy will be reported as AE or SAE if they fulfill the definition of an AE 
or SAE.
Events NOT Meeting the AE Definition
∀
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.
∀
The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.
∀
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.
∀
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
∀
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
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d.
Results in persistent disability/incapacity
∀
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
∀
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:
∀
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:
∀
Myocardial infarction/unstable angina
∀
Congestive heart failure
∀
Arrhythmias
∀
Valvulopathy
∀
Pulmonary hypertension
∀
Cerebrovascular events/stroke and transient ischemic attack
∀
Peripheral arterial thromboembolism
∀
Deep venous thrombosis/pulmonary embolism
∀
Revascularization
Recording AE and SAE
AE and SAE Recording
∀
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.
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∀
The investigator will then record all relevant AE/SAE information in the CRF.
∀
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK AE/SAE CRF page.
∀
There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.
∀
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 
∀
Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.
∀
Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities.
∀
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality
∀
The investigator is obligated to assess the relationship between study treatment and 
each occurrence of each AE/SAE.
∀
A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.
∀
The investigator will use clinical judgment to determine the relationship.
∀
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated.
∀
The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.
∀
For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.
∀
There may be situations in which an SAE has occurred and the investigator has 
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minimal information to include in the initial report to GSK. However, it is very 
important that the investigators always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK.
∀
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.
∀
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE
∀
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.
∀
If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology.
∀
New or updated information will be recorded in the originally completed CRF.
∀
The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.
Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool
∀
The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.
∀
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper SAE data collection tool (see next section).
∀
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
∀
The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hours of SAE 
entry into the eCRF. After the study is completed at a given site, the electronic data 
collection tool will be taken off-line to prevent the entry of new data or changes to 
existing data.
∀
If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
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next section) or via telephone to the sponcer.
∀
Contacts for SAE reporting can be found in Appendix 2.
SAE Reporting to GSK via Paper CRF
∀
Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the sponcer.
∀
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
∀
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
∀
Contacts for SAE reporting can be found in Appendix 2.
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12.4.
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below).
Women in the following categories are not considered WOCBP
1.
Premenarchal
2.
Premenopausal female with ONE of the following:
∀
Documented hysterectomy
∀
Documented bilateral salpingectomy
∀
Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
3.
Postmenopausal female
∀
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormone replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 
∀
Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment.
Contraception Guidance
Female participants
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in 
Table 9. 
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Table 9
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly.
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb
∀
Oral
Highly Effective Methods That Are User Independent
∀
Intrauterine device (IUD)
∀
Intrauterine hormone-releasing system (IUS)
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is the 
sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used.)
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.)
NOTES: 
a.
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants in clinical studies. 
b.
Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of 
the contraceptive method. In this case two highly effective methods of contraception should be utilized from the 
screening visit until after the last dose of study medication and completion of the follow-up visit.
Pregnancy Testing
∀
WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive serum pregnancy test.
∀
Additional pregnancy testing should be performed from the screening visit until after 
the last dose of study medication and completion of the follow-up visit as required 
locally.
∀
Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected.
∀
Pregnancy testing, with a sensitivity of 25 mIU/mL will be performed and assayed in 
the central laboratory using the test kit provided by the central laboratory in 
accordance with instructions provided in its package insert.  
Collection of Pregnancy Information
Female Participants who become pregnant
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∀
Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 
∀
Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy. 
∀
Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK. Generally, follow-up will not be required for longer than 6 to 
8 weeks beyond the estimated delivery date.  
∀
Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 
∀
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. 
∀
A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  
∀
Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in Appendix 3. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 
Any female participant who becomes pregnant while participating will discontinue study 
treatment or be withdrawn from the study.
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12.5.
Appendix 5: Genetics/Pharmacogenomics
USE/ANALYSIS OF DNA
∀
Genetic variation may impact a participant’s response to therapy, susceptibility, 
severity and progression of disease. Variable response to therapy may be due to 
genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular 
subtype of the disease being treated. Therefore, where local regulations and IRB/IEC 
allow, a blood sample will be collected for DNA analysis.
∀
DNA samples will be used for research related to FF/UMEC/VI or asthma and 
related diseases. They may also be used to develop tests/assays (including diagnostic 
tests) related to FF/UMEC/VI, and asthma. Genetic research may consist of the 
analysis of one or more candidate genes or the analysis of genetic markers 
throughout the genome or analysis of the entire genome (as appropriate).
∀
DNA samples will be analyzed if it is hypothesized that this may help further
understand the clinical data. 
∀
The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to FF/UMEC/VI or study treatments of this class. The 
results of genetic analyses may be reported in the clinical study report or in a 
separate study summary.
∀
The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
∀
The samples will be retained while research on FF/UMEC/VI (or study treatments of 
this class) or asthma continues but no longer than 15 years after the last subject last 
visit or other period as per local requirements.
12.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments 
Phase III-IV liver chemistry stopping and increased monitoring criteria have been 
designed to assure participant safety and evaluate liver event.
Liver Chemistry Stopping Criteria - Liver Stopping Event
ALT-absolute
ALT # 8xULN
ALT Increase
ALT # 5xULN but <8xULN  persists for #2 weeks
ALT # 3xULN but <5xULN  persists for #4 weeks
Bilirubin1, 2
ALT # 3xULN and bilirubin # 2xULN (>35% direct bilirubin)
INR2
ALT # 3xULN and INR>1.5, if INR(International normalized ratio) measured
Cannot Monitor
ALT # 5xULN but <8xULN and cannot be monitored weekly for #2 weeks
ALT # 3xULN but <5xULN and cannot be monitored weekly for #4 
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weeks
Symptomatic3
ALT # 3xULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments
∀
Immediately discontinue study 
treatment 
∀
Report the event to GSK within 24 
hours
∀
Complete the liver event CRF and 
complete an SAE data collection tool 
if the event also meets the criteria for 
an SAE2
∀
Perform liver event follow up 
assessments (see Follow Up 
Assessments )
∀
Monitor the participant until liver 
chemistries resolve, stabilize, or return 
to within baseline (see 
MONITORING below)
∀
Do not restart/rechallenge participant 
with study treatment unless allowed 
per protocol and GSK Medical 
Governance approval is granted
∀
If restart/rechallenge not  allowed or 
not granted, permanently discontinue 
study treatment and may continue 
participant in the study for any 
protocol specified follow up 
assessments
MONITORING:
For bilirubin or INR criteria: 
∀
Repeat liver chemistries (include ALT, 
AST, alkaline phosphatase, bilirubin) 
and perform liver event follow up 
assessments within 24 hrs
∀
Monitor participants twice weekly 
until liver chemistries resolve, stabilize 
or return to within baseline
∀
A specialist or hepatology consultation 
is recommended
For All other criteria: 
∀
Viral hepatitis serology4
∀
Obtain INR and recheck with each 
liver chemistry assessment until the 
transaminases values show downward 
trend
∀
Only in those with underlying chronic 
hepatitis B at study entry (identified by 
positive hepatitis B surface antigen) 
and quantitative hepatitis B DNA 
∀
Blood sample for pharmacokinetic 
(PK) analysis, obtained within 72 
hours after last dose5
∀
Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH).
∀
Fractionate bilirubin, if total 
bilirubin#2xULN
∀
Obtain complete blood count with 
differential count of leukocytes to 
assess eosinophilia
∀
Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report 
form
∀
Record use of concomitant 
medications on the concomitant 
medications report form including 
acetaminophen, herbal remedies, other 
over the counter medications.
∀
Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:
∀
Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG or gamma globulins).
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∀
Repeat liver chemistries (include ALT, 
AST, alkaline phosphatase, bilirubin) 
and perform liver event follow up 
assessments within 24-72 hrs 
∀
Monitor participants weekly until liver 
chemistries resolve, stabilize or return 
to within baseline
∀
Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF 
forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that participant if ALT #3xULN and bilirubin # 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT # 3xULN and bilirubin # 2xULN (>35% direct bilirubin) or ALT # 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to participants receiving anticoagulants.
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)   
4.
Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C RNA; 
Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody or Hepatitis E RNA
5.
PK sample may not be required for participants known to be receiving placebo or non-GSK comparator treatments.  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the participant’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.  
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Phase III-IV liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT #5xULN and <8xULN and bilirubin <2xULN 
without symptoms believed to be related to 
liver injury or hypersensitivity, and who can be 
monitored weekly for 2 weeks.
OR
ALT #3xULN and <5xULN and bilirubin <2xULN 
without symptoms believed to be related to 
liver injury or hypersensitivity, and who can be 
monitored weekly for 4 weeks.
∀
Notify the GSK medical monitor 
within 24 hours of learning of the 
abnormality to discuss participant 
safety.
∀
Participant can continue study 
treatment.
∀
Participant must return weekly for 
repeat liver chemistries (ALT, AST, 
alkaline phosphatase, bilirubin) until 
they resolve, stabilise or return to 
within baseline.
∀
If at any time participant meets the 
liver chemistry stopping criteria, 
proceed as described above.
∀
If ALT decreases from ALT #5xULN 
and <8xULN to #3xULN but 
<5xULN, continue to monitor liver 
chemistries weekly. 
∀
If, after 4 weeks of monitoring, ALT 
<3xULN and bilirubin <2xULN, 
monitor participants twice monthly 
until liver chemistries normalize or 
return to within baseline.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E. Quantification of 
Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates Different 
Patterns of Virological Response to Interferon Therapy in Chronically Infected Patients. J 
Clin Microbiol. 2005;43(5):2363–2369.
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12.7.
Appendix 7: Country-specific requirements
No country-specific requirements
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12.8
Appendix 8: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located directly 
before the Table of Contents (TOC).
Amendment 01: 24-May-2017
Overall Rationale for the Amendment: Correction of typographical errors and 
description adjustment
Section # and 
Name
Description of Change
Brief Rationale
4. 
OBJECTIVES 
AND 
ENDPOINTS
Secondary Objective
Changed from:
To evaluate the efficacy and safety of
FF/UMEC/VI combination therapy 
Changed to:
To evaluate the safety of FF/UMEC/VI 
combination therapy
Correction of a 
mistake
7.7.1. 
Prohibited 
Concomitant 
Medications 
Table 6 Concomitant Medications 
Non-Inhaled LABA (e.g., Hokunalin Tape)
Follow-up period
Changed from: X
Changed to: ○
Correction of a 
typographical error
12.1. 
Appendix 1: 
Abbreviations 
and 
Trademarks
UMEC
Changed from: Umeclidinium
Changed to: Umeclidinium Bromide
Description 
adjustment to add 
base of UMEC
12.4. 
Appendix 4: 
Contraceptive 
Guidance and 
Collection of
Pregnancy 
Information 
Foot note “b” in the Table 9 Highly Effective 
Contraceptive Methods 
Changed from:
b. Hormonal contraception may be susceptible 
to interaction with the study drug, which may 
reduce the efficacy of the contraceptive method. 
In this case two highly effective methods of 
contraception should be utilized from the
treatment period until after the last dose of 
Description 
adjustment to align 
with the contraceptive 
period defined in this 
study
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Section # and 
Name
Description of Change
Brief Rationale
study medication and completion of the follow-
up visit.
Changed to:
b. Hormonal contraception may be susceptible 
to interaction with the study drug, which may 
reduce the efficacy of the contraceptive method. 
In this case two highly effective methods of 
contraception should be utilized from the 
screening visit until after the last dose of study 
medication and completion of the follow-up 
visit.
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The GlaxoSmithKline group of companies
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Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for A Phase III, 52-week, Open-
label Study to Evaluate Long-term Safety of Fixed Dose 
Combination Therapy Fluticasone Furoate/Umeclidinium 
Bromide/Vilanterol Trifenatate in Japanese Patients with 
Asthma
Compound Number 
:
GSK573719+GW642444+GW685698
Effective Date 
:
17-DEC-2018
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol [GSK Document Number
2016N305271_02].

This RAP also describes the outputs to be produced for the interim analysis at 24 
weeks.

This RAP is intended to describe the safety and other analyses required for the 
study. 

This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable.
RAP Author(s):
Author
Date
NA
Statistician, Biostatistics Group 2, Biomedical Data Sciences, 
Japan
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
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RAP Team Review Confirmations:
Reviewer
Date
10-DEC-2018
Lead Programmer, Statistical Programming & Reporting 
Group, Biomedical Data Sciences, Japan
04-DEC-2018
Japan Project Leader, Respiratory TA Office, Medicines 
Development, Japan
10-DEC-2018
Clinical Investigation Lead, Respiratory TA Office, 
Medicines Development, Japan
07-DEC-2018
Operations and Science Leader, Clinical Operation, Japan
07-DEC-2018
Data Quality Lead, Data Practice Group, Biomedical Data 
Sciences, Japan
06-DEC-2018
Medical Writer, Medical Writing Office, Medicines 
Development, Japan
Clinical Statistics and Clinical Programming Line Approvals:
Approver
Date
13-DEC-2018
Manager (statistics), Biostatistics Group 2, Biomedical Data 
Sciences, Japan
17-DEC-2018
Manager (programming), Statistical Programming & 
Reporting Group, Biomedical Data Sciences, Japan
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TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................6
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................6
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................6
2.2.
Study Objective(s) and Endpoint(s)...............................................................6
2.3.
Study Design ................................................................................................7
2.4.
Statistical Hypotheses / Statistical Analyses .................................................8
3.
PLANNED ANALYSES ............................................................................................8
3.1.
Interim Analyses ...........................................................................................8
3.2.
Final Analyses ..............................................................................................9
4.
ANALYSIS POPULATIONS .....................................................................................9
4.1.
Protocol Deviations.....................................................................................10
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................10
5.1.
Study Treatment & Sub-group Display Descriptors.....................................10
5.1.1.
Interim Analyses ..........................................................................10
5.1.2.
Final Analyses .............................................................................11
5.1.2.1.
Analyses by dose group .............................................11
5.1.2.2.
Analyses by dose the time of onset of the AE 
(by dose at AE)...........................................................11
5.2.
Baseline Definitions ....................................................................................12
5.3.
Multicentre Studies .....................................................................................12
5.4.
Examination of Covariates, Other Strata and Subgroups............................13
5.4.1.
Covariates and Other Strata ........................................................13
5.5.
Multiple Comparisons and Multiplicity .........................................................13
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................13
6.
STUDY POPULATION ANALYSES .......................................................................13
6.1.
Overview of Planned Study Population Analyses........................................13
6.1.1.
Subject Disposition ......................................................................13
6.1.2.
Protocol Deviation........................................................................14
6.1.3.
Demographic and Baseline Characteristics..................................14
6.1.4.
Prior and Concomitant Medications .............................................15
6.1.5.
Treatment Compliance.................................................................15
7.
EFFICACY ANALYSES..........................................................................................15
8.
SAFETY ANALYSES .............................................................................................15
8.1.
Extent of Exposure .....................................................................................16
8.2.
Adverse Events Analyses ...........................................................................16
8.3.
Adverse Events of Special Interest Analyses..............................................18
8.4.
MACE.........................................................................................................19
8.5.
Clinical Laboratory Analyses.......................................................................20
8.6.
Other Safety Analyses ................................................................................20
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8.6.1.
Vital signs ....................................................................................21
8.6.2.
ECG.............................................................................................21
8.6.3.
Pregnancy ...................................................................................21
9.
OTHER ANALYSES...............................................................................................22
9.1.
Other Analyses ...........................................................................................22
9.1.1.
Overview of Planned Other Analyses...........................................22
10. REFERENCES.......................................................................................................24
11. APPENDICES........................................................................................................25
11.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................25
11.2.
Appendix 2: Schedule of Activities ..............................................................26
11.2.1.
Protocol Defined Schedule of Events...........................................26
11.3.
Appendix 3: Assessment Windows .............................................................29
11.3.1.
Clinical visits ................................................................................29
11.3.2.
Definitions of Assessment Windows for Adverse Events in 
Treatment Period.........................................................................29
11.3.2.1.
In Interim Analyses.....................................................29
11.3.2.2.
In Final Analyses ........................................................29
11.3.2.3.
By dose at the time of onset of the AEs (by 
dose at AE) ................................................................31
11.4.
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................32
11.4.1.
Study Phases ..............................................................................32
11.4.1.1.
Study Phases for Concomitant Medication .................32
11.4.2.
Treatment Emergent Flag for Adverse Events .............................32
11.5.
Appendix 5: Data Display Standards & Handling Conventions....................33
11.5.1.
Reporting Process .......................................................................33
11.5.2.
Reporting Standards....................................................................33
11.6.
Appendix 6: Derived and Transformed Data ...............................................35
11.6.1.
General........................................................................................35
11.6.2.
Study Population..........................................................................37
11.6.3.
Safety ..........................................................................................40
11.6.4.
Other ...........................................................................................40
11.7.
Appendix 7: Reporting Standards for Missing Data.....................................55
11.7.1.
Premature Withdrawals................................................................55
11.7.2.
Handling of Missing Data.............................................................55
11.7.2.1.
Handling of Missing and Partial Dates ........................55
11.8.
Appendix 8: Values of Potential Clinical Importance ...................................56
11.9.
Appendix 9: Implementation and mitigation strategy of Statistical 
Output Review (SOR) .................................................................................57
11.10. Appendix 10: Abbreviations & Trade Marks ................................................58
11.10.1. Abbreviations...............................................................................58
11.10.2. Trademarks .................................................................................59
11.11. Appendix 11: List of Data Displays..............................................................60
11.11.1. Data Display Numbering..............................................................60
11.11.2. Deliverables.................................................................................60
11.11.3. Study Population Tables (interim) ................................................61
11.11.4. Study Population Tables (final) ....................................................63
11.11.5. Safety Tables (interim).................................................................65
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11.11.6. Safety Tables (final).....................................................................69
11.11.7. Other Tables (interim)..................................................................75
11.11.8. Other Tables (final)......................................................................76
11.11.9. ICH Listings (interim) ...................................................................77
11.11.10.Non-ICH Listings (interim)............................................................81
11.11.11.ICH Listings (final) .......................................................................82
11.11.12.Non-ICH Listings (final)................................................................86
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1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol as well as the analyses to be included 
in the interim report for the protocol:
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
There were no changes or deviations to the originally planned statistical analysis 
specified in the protocol (Dated: 13/MAR/2017), amendment 1 (Dated:24/MAY/2017) or 
amendment 2 (Dated: 25/OCT/2017).
In order to comply with regulatory guidance where the protocol referred to “Subjects” the 
analysis plan refers to “Participants”, with the exception of displays and study 
populations.
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To evaluate the safety of long-term 
treatment with FF/UMEC/VI 
combination therapy

Incidence and type of adverse events (AE)/serious 
adverse events (SAE)
Secondary Objectives
Secondary Endpoints

To evaluate the safety of 
FF/UMEC/VI combination therapy

Blood pressure/pulse measurements

12-lead ECG

Clinical laboratory tests (hematology, biochemistry
and urinalysis)
Other Objectives
Other Endpoints

To evaluate the efficacy of 
FF/UMEC/VI combination therapy

Mean change from baseline in trough Forced 
Expiratory Volume in 1 second (FEV1) at Week 24 
and Week 52*1

Mean change from baseline in ACQ-7 total score at 
Week 24 and Week 52*1

Mean change from baseline in St. George's 
Respiratory Questionnaire (SGRQ) total score at 
Week 24 and Week 52*1

Mean change from baseline in the Asthma Quality 
of Life Questionnaire (AQLQ) total score at Week 
24 and Week 52*1

Unscheduled asthma-related healthcare resource 
utilization over the 52 weeks of the treatment 
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Objectives
Endpoints
period*2

Annualized rate of severe asthma exacerbations*2

Annualized rate of moderate/severe asthma 
exacerbations*2
NOTES:

*1: Week 24 will be presented for the interim and the final analysis. Week 52 will be presented 
for the final analysis only.

*2: This will be presented for the final analysis only.
2.3.
Study Design
Overview of Study Design and Key Features
Design
Features

The present study is a phase III, multicenter, non-comparator, non-
randomized, open-label study in Japanese patients with asthma. This is an 
approximately 55-week study consisting of the run-in, treatment and follow-up 
periods.

The number of asthmatic adult subjects (with the control status on ICS 
[medium to high dose]/ LABA and/or LAMA) required to be enrolled in this 
study is 110 (a total number of participants to be allocated in Group 1
[FF/UMEC/VI 100/62.5/25] and Group 2 [FF/UMEC/VI 200/62.5/25]). There is 
NOT any target allocation ratio in Group 1 and Group 2.

Switching medication from FF/UMEC/VI 100/62.5/25 mcg to FF/UMEC/VI 
200/62.5/25 mcg will be permitted in accordance with the control status of the 
subject assessed by ACQ-7 at Week 24 of the treatment period (Visit 5).
Dosing

Participants will self-administer their first dose in the clinic and will continue to 
administer FF/UME/VI at approximately the same time each morning for the 
duration of the treatment period. Each subject will be instructed on the proper 
use of the ELLIPTA and will inhale once from the ELLIPTA each morning
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Overview of Study Design and Key Features
Time & 
Events

Refer to Appendix 2: Schedule of Activities: Schedule of Activities
Treatment 
Assignment

Eligible patients who meet the pre-defined criteria at screening (Visit 1) will 
enter into a 2-week run-in period. During the run-in period, the participants will 
continue their pre-screening inhaled medications for asthma (ICS+ LABA or 
ICS+LABA+ LAMA) until the day before Visit 2 without any change in 
regimen/dosage. 

After completion of the run-in period, participants who meet pre-defined criteria 
at Visit 2 will be allocated to either FF/UMEC/VI 100/62.5/25 mcg (Group 1) or 
FF/UMEC/VI 200/62.5/25 mcg (Group 2) depending on the asthma control 
status with inhaled asthma therapy during the run-in period and initiate a 52-
week treatment period.
Interim 
Analysis

No statistical interim analysis requiring hypothesis test is planned. However, 
the data will be summarized when all participants (who have not withdrawn) 
have completed 24-week administration during treatment period and the CRF 
data up to Week 24 for all participants is locked. It will be used for a JNDA 
submission.
2.4.
Statistical Hypotheses / Statistical Analyses
This study has no statistical hypotheses since this is an open-label non-randomised study.
3.
PLANNED ANALYSES
3.1.
Interim Analyses
No statistical interim analysis requiring any hypothesis tests is planned. However, the 
data will be summarized when all participants (who have not withdrawn) have completed 
24-week administration of IP during the treatment period and the CRF data up to Week 
24 for all participants is locked. It will be used for a JNDA submission.
Data up to week 24 (specifically, data up to the date of visit 5 (week 24) or the date of 
withdrawal before week 24 visit for a given subject) will be used for outputs (i.e., 
tables/figures). The definition of the cut-off date for the interim analysis will be the date 
of Visit 5 (Week 24) for the last enrolled participant in this study. As for the AE data to 
be included in interim analyses, please also refer to the definition of AE assessment 
window (11.3.2.1).
The interim planned primary analyses will be performed after the completion of the 
following sequential steps for this Clinical Data Interchange Standards Consortium 
[CDISC] study:
1.
All participants have completed the 24-week administration during treatment period
(except for the premature withdrawals) as defined in the protocol.
2.
All required database cleaning activities have been completed and interim DBR for 
the 24-week during treatment period has been declared by Data Management (DM).
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3.
System Independent (SI) data to Study Data Tabulation Model (SDTM) data 
conversion has been completed by Conversion Service Provider at interim Source 
Data Lock (SDL).
4.
Randomisation codes have been distributed according to RandAll NG procedures
5.
Interim Database freeze (DBF) on interim SDTM datasets has been declared by DM.
3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps for a CDISC study:
1.
All participants 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 (DM).
3.
System Independent (SI) data to Study Data Tabulation Model (SDTM) data 
conversion has completed by Conversion Service at final Source Data Lock (SDL).
4.
Final DBF on final SDTM datasets has been declared by DM.
Note: Randomisation codes had already been distributed in interim analyses.
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
All Subjects

All participants for whom a record exist on the 
study database, including pre-screened subjects 
that sign the informed consent document but do not 
complete a screening procedure (i.e., pre-
screening failures)

This population will be used for the summary of 
“study populations” as study disposition

Study Population
Screened

All screened participants.

This population will be used for the summary of 
reasons for screening failures.

Study Population
Enrolled

All participants who are found to be eligible for the 
study based on the screening examination result.

This population will be used for the summary tables 
required by EudraCT.

Study Population
Intent-To-Treat 
(ITT)

All participants who take at least one dose of study 
treatment in the treatment period. Participants will 
be analyzed according to the treatment they 
actually received.

This population will be used for all safety and other
analyses.

Safety

Study Population

Other
Refer to Appendix 11: List of Data Displays which details the population used for each display.
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4.1.
Protocol Deviations
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed.
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan [1Aug2018 Version 3.0].
o Data will be reviewed prior to freezing the database to ensure all important 
deviations are captured and categorised on the protocol deviations dataset. 
o
Participants who received an incorrect treatment will be captured as an important 
protocol deviation. The incorrect treatment will be identified in eCRF (if “No” to 
the question “Did the subject receive the correct treatment?” then this participants
will be regarded as having received an incorrect container).
o
This dataset will be the basis for the summaries and listings of protocol 
deviations.
A separate listing of all inclusion/exclusion criteria deviations will also be provided. This 
will be based on data as recorded on the inclusion/exclusion page of the eCRF.
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
5.1.1.
Interim Analyses
In interim analyses, only data until 24 weeks after first treatment will be used. This 
means the data after switching medication will NOT be included. Therefore, description 
in data displays will be the same as description in RandAll NG.
Treatment Group Descriptions for Interim Analyses
RandAll NG 
Data Displays for Reporting 
Code
Description
Description
Order [1]
A
FF/UMEC/VI 100/62.5/25
FF/UMEC/VI 100/62.5/25
1
B
FF/UMEC/VI 200/62.5/25
FF/UMEC/VI 200/62.5/25
2
NOTES:
1.
Order represents treatments being presented in TFL, as appropriate.
Treatment comparisons will not be displayed.
If a given subject has incorrect study treatment during all period, then this subject will be 
analysed according to the treatment which he/she received. However, since it is uncertain 
whether a given subject has incorrect study treatment during all period (for 52 weeks) as 
of the timing of interim analyses, all analysis will be according to the allocated dose for 
interim analyses.
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5.1.2.
Final Analyses
In final analyses, two approaches for summaries will be used depending on summary 
tables.
5.1.2.1.
Analyses by dose group
In principle, description in data displays will follow the patterns taking the treatment 
switching into account. All final analyses will use these descriptions below, except for 
summaries for “AE analyses by dose at the time of onset of the AE”.This approach is 
based on both the allocated doses and status of treatment switch at Week 24. Note that 
the participants will be allocated to either FF/UMEC/VI 100/62.5/25 mcg or 
FF/UMEC/VI 200/62.5/25 mcg, and only the participants who are allocated to 
FF/UMEC/VI 100/62.5/25 mcg will be allowed to switch treatment to FF/UMEC/VI 
200/62.5/25 mcg only at Week24. Therefore, treatment descriptions will be three as 
below table.
In this approach, summaries for total (overall) will be also presented.
Treatment Group Descriptions for Final Analyses by dose group
RandAll NG
Switched treatment at Week 24
Data Displays for 
Reporting 
Code
Description
Description
Description
Order 
[1]
A
FF/UMEC/VI 
100/62.5/25
No (FF/UMEC/VI 100/62.5/25
after week 24 or discontinued 
this study by week 24)
Only 
FF/UMEC/VI 
100/62.5/25
1
A
FF/UMEC/VI 
100/62.5/25
Yes (Switched to FF/UMEC/VI 
200/62.5/25 at week 24)
FF/UMEC/VI 
100/62.5/25 to 
FF/UMEC/VI 
200/62.5/25
2
B
FF/UMEC/VI 
200/62.5/25
N/A (Switched treatment will not 
be acceptable)
Only 
FF/UMEC/VI 
200/62.5/25
3
NOTES:
1.
Order represents treatments being presented in TFL, as appropriate.
5.1.2.2.
Analyses by dose the time of onset of the AE (by dose at AE)
“AE analyses by dose at the time of onset of the AE” will be planned in this study due to 
Japan regulatory authority requirement. In these analyses, the following descriptions will 
be used.
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Treatment Group Descriptions for Final Analyses by dose at AE
Dose at AE
Data Displays for Reporting 
Description
Description
Order [1]
A
FF/UMEC/VI 100/62.5/25
FF/UMEC/VI 100/62.5/25
1
B
FF/UMEC/VI 200/62.5/25
FF/UMEC/VI 200/62.5/25
2
NOTES:
1.
Order represents treatments being presented in TFL, as appropriate.
In “by dose at AE” approach, the following rule will be applied.

If a given subject is allocated to FF/UMEC/VI 100/62.5/25 at visit 2 and not 
switched at visit 5 then this subject will be handled as FF/UMEC/VI 100/62.5/25.

If a given subject is allocated to FF/UMEC/VI 200/62.5/25 at visit 2 then this 
subject will be handled as FF/UMEC/VI 200/62.5/25.

If a given subject is allocated to FF/UMEC/VI 100/62.5/25 at visit 2 and switched 
at visit 5 then this subject will be handled as FF/UMEC/VI 100/62.5/25 until the 
day before visit 5 (week 24 visit) and as FF/UMEC/VI 200/62.5/25 after the day 
of visit 5 (week 24 visit). This means AEs which occurred until the day before 
visit 5 (week 24 visit) will be summarized in FF/UMEC/VI 100/62.5/25 and AEs 
which occurred after the day of visit 5 (week 24 visit) will be summarized in 
FF/UMEC/VI 200/62.5/25.
Treatment comparisons will not be displayed.
If a given subject has incorrect study treatment during all period, then this subject will be 
analysed according to the treatment which he/she received. This will be identified as all 
answers will be “No” to the question “Did the subject receive the correct treatment?” for 
all visits on eCRF.
5.2.
Baseline Definitions
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
latest pre-dose assessment with a non-missing value, including those from unscheduled 
visits. If time is not collected, Day 1 assessments (except any assessments from 
unscheduled visit at the same date as Day1) are assumed to be taken prior to first dose 
and used as baseline.
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing.
5.3.
Multicentre Studies
In this multicentre local study, enrolment will be presented by investigative site.
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5.4.
Examination of Covariates, Other Strata and Subgroups
5.4.1.
Covariates and Other Strata
Any covariates and other strata will not be used in descriptive summaries and statistical 
analyses.
Subgroup analyses will not be planned in this study.
5.5.
Multiple Comparisons and Multiplicity
Since this study does not plan efficacy analyses, multiple comparisons and multiplicity 
will not be applied.
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
11.3
Appendix 3: Assessment Windows
11.4
Appendix 4: Study Phases and Treatment Emergent Adverse Events
11.5
Appendix 5: Data Display Standards & Handling Conventions
11.6
Appendix 6: Derived and Transformed Data
11.7
Appendix 7: Reporting Standards for Missing Data
6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the ITT population, unless otherwise 
specified.
Study population analyses including analyses of subject’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure and treatment compliance will be based on GSK Core Data Standards.  
Details of the planned displays are presented in Appendix 11: List of Data Displays. All 
outputs unless specified otherwise will be produced for the interim analysis and final 
analysis.
6.1.1.
Subject Disposition
The overall subject disposition as well as the reason for withdrawal will be summarized 
for the ITT population, including the number and percentage of participants in each dose 
group and total. In interim analysis, “completed” means completion of Visit 5 (Week 24 
visit).
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The number and percentage of participants who completed the study treatment as well as 
the number who stopped the study treatment prior to the end of the study will be 
summarized, along with the reasons for discontinuation of the study treatment.
The reasons for Screen Failure or Run-in Failure will be summarized for the Screened 
Population for interim analysis only. Listings of failures prior to treatment will be 
generated.
The number and percentage of participants in each dose group and total will be 
summarized by status (entered, completed or withdrawn) at each epoch (run-in period, 
treatment period and follow-up period). In interim analysis, “completed” means 
completion of Visit 5 (Week 24 visit).
Using All Subjects, the number of participants in each population (Screened, Enrolled, 
ITT) will be summarized by dose group and total.
The number and percentage of participants at each center and within each country will be 
summarized.  Note that this study includes only Japan as country.
6.1.2.
Protocol Deviation
The number and percentage of participants with important protocol deviations determined 
by the study team will also be summarized. Listing for important protocol deviations will 
be prepared as well.
Listing will be provided for inclusion / exclusion criteria deviation record.
6.1.3.
Demographic and Baseline Characteristics
Each of the following types of data will be summarized by dose group and total:

Demographic data (age, sex, ethnicity, weight, height, body mass index (BMI), 
race)

Duration of asthma 

Asthma medical history questionnaire

Smoking history (smoking status of non-smoker or former smoker, and pack years 
for former smokers)

Exacerbation history

Cardiovascular history / risk factors and family history of cardiovascular risk 
factors

ACQ-6 scores at Visit 1

Pulmonary function (FEV1, FVC, %predicted FEV1)
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Note: % predicted FEV1 will be derived. See Section 11.6.2.
6.1.4.
Prior and Concomitant Medications
Summaries will be provided for the asthma medications before study treatment, as well as 
summaries for both asthma and non-asthma medication during the treatment period and 
during follow-up period. A total column will be included for the all summaries. Listings 
will be provided for the asthma and non-asthma concomitant medications.
Non-Asthma medication tables will report by Anatomical Therapeutic Chemical (ATC) 
level 1 and ingredient.  Asthma medication tables will report by respiratory medication 
class (RMC) and ingredient. 
Multi-ingredient medications will be presented according to their combination ATC 
classification rather than the classification of the ingredients.
6.1.5.
Treatment Compliance
Treatment compliance will be assessed during the treatment period by dose group and 
total.
For the treatment period, the actual total number of doses received by each subject will be 
calculated as the sum of (dose counter start value – dose counter stop value) over all 
inhalers dispensed to the subject during the treatment period and returned prior to or at 
the EOT/EW visit, and percentage compliance will be calculated as follows:
.
100
1



date
start
treatment
date
stop
treatment
received
doses
of
number
total
Compliance
Treatment
In interim analysis, treatment compliance will be calculated based on data until the day 
before visit 5 (i.e., treatment stop date will be replaced with the day before visit 5). 
Details on the derivations are provided in Section 11.6.2.
7.
EFFICACY ANALYSES
This is an open-label study and the efficacy will be assessed in an exploratory manner. 
Therefore, no efficacy endpoint is defined and the efficacy will be assessed as other 
endpoints.
8.
SAFETY ANALYSES
The safety analyses will be based on the ITT population, unless otherwise specified. All
outputs unless specified otherwise will be produced for the interim analysis and final 
analysis.
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8.1.
Extent of Exposure
Overall extent of exposure to study treatment will be summarized in increments of 4 
weeks for ≥1 day, ≥4 weeks, ≥8 weeks, ≥12 weeks, ≥16 weeks, ≥20 weeks, ≥24 weeks, 
≥28 weeks, ≥32 weeks, ≥36 weeks, ≥40 weeks, ≥44 weeks, ≥48 weeks, ≥52 weeks, in 
addition to providing summary statistics and total treatment exposure (person-year).
8.2.
Adverse Events Analyses
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs)
and other significant AEs will be based on GSK Core Data Standards. The details of the 
planned displays are provided in Appendix 11: List of Data Displays.
All AEs will be classified using the standard GSK Medical Dictionary for Regulatory 
Activities (MedDRA) dictionary, and grouped by SOC and PT, unless otherwise stated. 
The investigator will evaluate all AEs with respect to seriousness, severity, and causality.
The tabular summary for each type of AE listed below will include the number of 
participants who reported at least one event, and percentage of participants who reported 
at least one AE (incidence) for each SOC (where applicable), each PT, and overall. By 
default, adverse events will be sorted by MedDRA SOCs, in descending order from the 
SOC with the highest total incidence (i.e., summed across all dose groups) for any 
adverse event within the class, to the SOC with the lowest total incidence. If the total 
incidence for any two or more adverse events is equal, the events will be presented in 
alphabetical order. Only SOCs with observed AE PTs will be presented. Repeat sort 
order for MedDRA PTs within each SOC.
In principle, all safety analyses will be provided by dose group and total. However, due to 
Japan regulatory authority requirement, AE analyses by dose at the time of onset of the
AE will be prepared in final analyses of this study. Note that dose at the time of onset of 
the AE will be decided by allocated dose even if a given subject has incorrect study 
treatment in certain period (but not during all period). If a given subject has incorrect 
study treatment during all period, then this subject will be analysed according to the 
treatment which he/she received. In interim analyses, selected tables will be provided. 
Please refer to Section 11.11.5.
Each type of the following will be summarized for both approaches (i.e., by dose group 
and total, by dose at the time of onset of the AE)

AE overview during treatment period

All AEs during treatment period (by SOC and PT; by SOC and PT and maximum 
severity)

Drug related AEs during treatment period (by SOC and PT; by SOC and PT and 
maximum severity)

Serious AEs during treatment period (by SOC and PT)

AEs resulting in withdrawal from study (by SOC and PT)
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
AEs of Special Interest during treatment period (by SOC and PT)

Most Common Adverse Events during treatment period (3% or More of subjects in 
Any Treatment Group) (by PT)
The following AE summaries will be provided only by dose group and total.

All AEs adjusted for exposure (per thousand person years) during treatment period 
(by SOC and PT)

All AEs during follow-up period (by SOC and PT)

Drug related AEs adjusted for exposure (per thousand person years) during treatment 
period (by SOC and PT)

Drug related AEs during treatment period and follow-up period (by SOC and PT)

All AEs for week 0-12, week 13-24, week 25-36 and week 37-52 during treatment 
period (by SOC and PT)

All AEs for week 0-24, week 25-52 during treatment period (by SOC and PT)

Serious AEs adjusted for exposure (per thousand person years) during treatment 
period (by SOC and PT)

AEs of Special Interest adjusted for exposure (per thousand person years) during 
treatment period (by SOC and PT)

Common Non-Serious AEs by SOC and PT during treatment period (Number of 
Subjects and Occurrences) (5% or More of subjects in Any Treatment Group)

Summary of Serious Adverse Events by System Organ Class and Preferred Term 
during treatment period (Number of Participants and Occurrences)

Major Adverse Cardiac Events 

Serious Drug Related Adverse Events during treatment period (for PLS, final 
analysis only)

Non-Serious Drug Related Adverse Events during treatment period (for PLS, final 
analysis only)
The following AE listings will be provided. These listing include information of dose 
group, not dose at AE.

All AEs, Fatal serious AEs, Non-Fatal AEs, AEs leading to permanent 
discontinuation of study treatment or withdrawal from study

Relationship of AE SOCs, PTs and Verbatim text

Reasons for considering as a serious AE
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8.3.
Adverse Events of Special Interest Analyses
A comprehensive list of MedDRA terms based on clinical review will be used to identify 
each type of event. The details of the planned displays are provided in Appendix 11: List 
of Data Displays.
Adverse Events of Special Interest (AESI) are those AEs associated with the known 
pharmacological action of ICSs and/or LAMAs and/or LABAs, regardless of whether the 
AE has been specifically described for FF and/or UMEC and/or VI. AESI groupings are 
compiled in one of two ways: where SMQs (pre-defined lists of MedDRA PTs) are 
available from MedDRA for specific AESIs, these are used; and where SMQs are not 
available, a GSK-defined list of all relevant MedDRA PTs is used.
For FF/UMEC/VI, the special interest groups are: adrenal suppression, corticosteroid-
associated and antimuscarinic-associated ocular effects, decreased bone mineral density 
and associated fractures, hypersensitivity, pneumonia, LRTI excluding pneumonia, local 
steroid effects, effects on potassium, tremor, CV effects, effects on glucose, 
asthma/bronchospasm, anticholinergic syndrome. Gastrointestinal obstruction, urinary 
retention.
Table 1 presents the special interest AE groups for FF, UMEC and VI.
Table 1
AESI definitions
Special Interest AE Group
Special Interest AE 
Subgroup
PTs for Inclusion
Cardiovascular effects*
Cardiac arrhythmia
Cardiac arrhythmia (SMQ)
, excluding congential and 
neonatal arrhythmias
(SMQ)
Cardiac failure 
Cardiac Failure (SMQ)
Cardiac ischaemia 
Ischaemic Heart Disease 
(SMQ)
Stroke
Central nervous system 
haemorrhages and 
cerebrovascular conditions 
(SMQ)
Hypertension
Hypertension (SMQ)
Pneumonia*
Pneumonia
Infective Pneumonia 
(Narrow SMQ)
LRTI excluding infective pneumonia SMQ*
LRTI excluding infective 
pneumonia SMQ
Selected PTs
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Special Interest AE Group
Special Interest AE 
Subgroup
PTs for Inclusion
Decreased bone mineral density and associated 
fractures
Decreased bone mineral 
density and associated 
fractures
Osteoporosis/Osteopenia 
(SMQ)
Selected PTs
Hypersensitivity*
Hypersensitivity
Hypersensitivity (SMQ)
Angioedema (SMQ)
Anaphylactic reaction 
(SMQ)
Anticholinergic Syndrome*
Anticholinergic syndrome
Anticholinergic Syndrome 
(SMQ)
Gastrointestinal obstruction*
Gastrointestinal 
obstruction 
Gastrointestinal 
obstruction (SMQ)
Adrenal Suppression
Adrenal Suppression
Selected PTs
Antimuscarinic ocular effects* / Corticosteroid 
Associated Eye Disorders
Glaucoma (antimuscarinic 
/ corticosteroid)
Glaucoma (SMQ)
Cataracts (corticosteroids)
Lens disorders (SMQ)
Effects on Glucose 
Effects on Glucose 
Hyperglycaemia/new 
onset diabetes mellitus 
(SMQ)
Local steroid effects 
Local steroid effects 
Selected PTs
Urinary retention*
Urinary retention 
Selected PTs
Effects on potassium
Effects on potassium
Selected PTs
Tremor
Tremor
Selected PTs
Asthma/Bronchospasm for Asthma-related 
intubations and deaths
Asthma/Bronchospasm 
for Asthma-related 
intubations and deaths
Asthma/bronchospasm 
(SMQ)
Dry mouth / Drying airway secretions*
Dry mouth / Drying airway 
secretions
Selected PTs (narrow & 
broad focus)
*: of interest for UMEC .
Adverse events of special interest will be summarized in the same manner outlined in 
Section 8.2 for overall AEs.
8.4.
MACE
The MACE (Major Adverse Cardiac Events) endpoint will be analyzed using broad and 
narrow definitions. 
The Broad MACE will be defined as follows:
-
Cardiac Ischaemia Special Interest AE Subgroup (Ischaemic Heart Disease SMQ)
including fatalities, 
-
Stroke Special Interest AE Subgroup (Central Nervous System Haemorrhages and 
Cerebrovascular Conditions SMQ) including fatalities
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The narrow MACE definition will include only the PTs of “myocardial infarction” and 
“acute myocardial infarction” in place of the Cardiac Ischaemia Special Interest AE 
subgroup.
8.5.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, Hematology 
laboratory tests, Urinalysis, and liver function tests will be based on GSK Core Data 
Standards. The details of the planned displays are in Appendix 11: List of Data Displays.
Clinical laboratory will be measured at visit 1 (screening visit), 4 (Week 12), 5 (Week 
24), 7 (Week 52) or EW. and will be summarized by dose group.
Raw value and change from baseline for laboratory data will be summarized by dose
group and total for each visit.
Shifts from baseline relative to the normal range will be also summarized by dose group
and total for each visit.
The number of participants with worst case chemistry or hematology will be summarized 
by test and category.  The categories for normal range are: To Low, To Normal or No 
Change, To High. The categorization is determined by comparing the baseline category 
to the worst case post-baseline category.  The determination of the worst case post-
baseline takes into account both planned and unscheduled assessments.  The percentages 
are based on the number of participants in the dose group with data for the test post-
baseline.  Participants with missing baseline value are to be assumed to have 
normal/within range baseline value. Note that if a subject has both a decrease ‘To Low’ 
and an increase ‘To High’, then the subject is counted in both the ‘To Low’ and ‘To 
High’ categories, so the percentages may not add to 100%. 
The number of participants with worst case protein (category: NEG, TRA, 1+, 2+, 3+) or 
occult blood (category: NEG, TRA, 1+, 2+, 3+) urinalysis results will be summarized by 
test and category.  The categories for worst case are: No Change/Decresed, Any 
Increase, Increase to TRA, Increase to 1+, Increase to 2+, Increase to 3+. The 
categorization is determined by comparing the baseline category to the worst case post-
baseline category.  The determination of the worst case post-baseline takes into account 
both planned and unscheduled assessments.  The percentages are based on the number 
of participants in the dose group with data for the test post-baseline.  Participants with 
missing baseline value are to be assumed to have normal/within range baseline value.
8.6.
Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. The details of the 
planned displays are presented in Appendix 11: List of Data Displays.
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8.6.1.
Vital signs
Vital signs will be measured at every clinical visit and will be summarized by dose group
and total.
Raw value and change from baseline for Vital signs will be summarized by dose group
and total for each visit.
8.6.2.
ECG
12-lead ECGs are measured at Visit 1, 3, 5 and 7, and at Early Withdrawal visit. The 
ECG measurements of interest are QTc (F), heart rate, and PR interval. All ECG data 
present in the database will be considered valid and will be reported (even if the ECG had 
a technical error).
Raw value and change from baseline for ECG values will be summarized by dose group
and total for each visit.
A ‘maximum post-baseline’ QTc (F), PR interval, and heart rate value will be derived as 
the maximum on-treatment value recorded at any scheduled, unscheduled, or EW visit 
after the start of study treatment.
QTc (F) values (including ‘maximum post-baseline’) will be categorized as follows: 
≤450msec, >450 to ≤ 480msec, >480 to ≤500msec, >500 to ≤530msec and >530msec.  
Change from baseline QTc (F) values (including change to ‘maximum post baseline’) 
will be categorized as follows: ≤-60msec, >-60 to ≤-30msec, >-30 to ≤0msec, >0 to 
≤30msec, >30 to ≤60msec, and >60msec.
An ‘any time post-baseline’ ECG interpretation will be derived as the worst on-treatment 
interpretation recorded at a scheduled, unscheduled, or EW visit after the start of study 
treatment. The worst case post-baseline is defined as:

‘Abnormal’ if any assessment during treatment period is evaluated as ‘Abnormal’

‘Unable to evaluate’ if all assessments during treatment period are ‘Unable to 
evaluate’ 

‘Normal’ if any assessment during treatment period is evaluated as ‘Normal’ and 
there are no assessments evaluated as ‘Abnormal’ during treatment period
8.6.3.
Pregnancy
Any pregnancies reported during the study will be summarized in case narratives. Any 
pregnancy complication or elective termination of a pregnancy for medical reasons will 
be recorded as an AE or SAE and included in summaries and listings of AEs/SAEs.
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9.
OTHER ANALYSES
9.1.
Other Analyses
This is an open-label study and the efficacy will be assessed in an exploratory manner. 
Therefore, no efficacy endpoint is defined and the efficacy will be assessed as other 
endpoints. No statistical analyses (using statistical models or tests) will be planned in this 
RAP. Only summary tables or listings will be provided.
9.1.1.
Overview of Planned Other Analyses
The other analyses will be based on “ITT” population, unless otherwise specified. All 
outputs unless specified otherwise will be produced for the interim analysis and final 
analysis.
Summary statistics for absolute value and change from baseline will be provided for 
following endpoints at visit 2 (Week 0), 5 (Week 24) and 6 (Week 52) by dose group and 
total.

Trough Forced Expiratory Volume in 1 second (FEV1)

ACQ-7 total score

St. George's Respiratory Questionnaire (SGRQ) total score

Asthma Quality of Life Questionnaire (AQLQ) total score
ACQ-6 will be measured at visit 1 for eligibility criteria. ACQ-6 will not be summarized 
in other analyses, but in demographic and baseline characteristics, see Section 6.1.3.
Summaries of all-cause unscheduled asthma related healthcare resource utilization over 
52 weeks of the treatment period will be provided in only final analysis. Total below 
means total number of contacts across all participants.

Unscheduled healthcare utilization (Yes or No)

Number of telephone call (n, 0, 1, 2, 3, >3, Total) 

Number of home visit (day) (n, 0, 1, 2, 3, >3, Total)

Number of home visit (night) (n, 0, 1, 2, 3, >3, Total)

Number of physician office/practice visits (n, 0, 1, 2, 3, >3, Total)

Number of urgent care / outpatient clinic visits (n, 0, 1, 2, 3, >3, Total)

Number of emergency room visits (n, 0, 1, 2, 3, >3, Total)

Number of inpatient hospitalisation days (ICU) (n, 0, 1, 2, 3, >3, Total)

Number of inpatient hospitalisation days (General ward) (n, 0, 1, 2, 3, >3, Total)

Was this contact due to an exacerbation (Yes or No)
Summary of annualized rate of severe asthma exacerbations and annualized rate of 
moderate/severe asthma exacerbations will be provided (only the number of participants
and calculated annualized rate will be provided for this summary). Annualized rate for a 
given dose group will be calculated as follows, but only at final analysis:
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
Summation of (total number of exacerbations) for all participants in a given dose 
group (or all participants for total) is divided by summation of ((date of Visit 7 / 
EOT visit or EW visit – treatment start date +1) / 365) for all participants in a 
given dose group (or all participants for total).
As for asthma exacerbations, following information will be provided.

Number of events
o
Hospitalization
o
Emergency room visit
o
Systemic/oral corticosteroid use
o
Outcome (Resolved, Fatal or Not Resolved)
o
Duration (days), which will be calculated as Date of Outcome – Date of 
Onset + 1. If Outcome is Not resolved, then duration will be missing

Number of participants with events (0, 1, 2, >2)
o
Severe

Hospitalization

Emergency room visit

Systemic/oral corticosteroid use
o
Moderate
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10.
REFERENCES
Asthma Control Questionnaire, Background, Administration and Analysis, April, 2008. 
Asthma Quality of Life Questionnaires (AQLQ, AQLQ(S), MiniAQLQ and Acute 
AQLQ), Background, Administration and Analysis, June, 2005.
GlaxoSmithKline Document Number 2016N305271_02 Study 207236, A Phase III, 52-
week, Open-label Study to Evaluate Long-term Safety of Fixed Dose Combination 
Therapy Fluticasone Furoate/Umeclidinium Bromide/Vilanterol Trifenatate in Japanese 
Patients with Asthma. Effective Date: 25-OCT-2017.
Implementing GLI-2012 regression equations, July 16, 2015
Philip H. Quanjer et al, Multi-ethnic reference values for spirometry for the 3–95-yr age 
range: the global lung function 2012 equations, Eur Respir J 2012; 40: 1324–1343
St George’s Respiratory Questionnaire (SGRQ) Manual, Version 2.3 June, 2009
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11.
APPENDICES
11.1.
Appendix 1: Protocol Deviation Management and Definitions
for Per Protocol Population
Per Protocol Population is not defined in this study.
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11.2.
Appendix 2: Schedule of Activities
11.2.1.
Protocol Defined Schedule of Events
Procedure
Pre-screen
Run-in
Treatment period
Follow-up
Visit
0
1
Screening
2
Baseline
3
4
5
6
7
End of 
Treatment 
(EOT)
Early 
Withdrawa
l (EW)
Safety 
follow-up 
contact
Day
-28 to -14
-14
1
29
85
169
253
365
Week
-4 to -2
-2
0
4
12
24
36
52
Window
-3
-5/+2d
-5/+2d
-5/+2d
-5/+2d
-5/+2d
Informed consent1
X
Genetics/Pharmacogenetic informed 
consent2
X
Inclusion and exclusion criteria
X
X
Demography
X
Past and current medical conditions 
including asthma history3 and exacerbation 
history
X
Smoking history and status
X
Concomitant medication review
X
X
X
X
X
X
X
X
X
Allocation/registration4
X
Register visit in IRT (RAMOS NG)5
X
X
X
X
X
X
X
X
X
X
Safety Assessment
Physical examination
X
X
X
X
Weight/height
X
Adverse events
X
X
X
X
X
X
X
X
Serious adverse events
X
X
X
X
X
X
X
X
X
X
Vital signs (blood pressure and pulse rate)
X
X
X
X
X
X
X
X
ECG
X
X
X
X
X
Hematology and clinical chemistry
X
X
X
X
X
Urinalysis
X
X
X
X
X
Serum pregnancy test
X6
X6
X6
X6
X6
Urine pregnancy test 6
X
X
X
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Procedure
Pre-screen
Run-in
Treatment period
Follow-up
Visit
0
1
Screening
2
Baseline
3
4
5
6
7
End of 
Treatment 
(EOT)
Early 
Withdrawa
l (EW)
Safety 
follow-up 
contact
Day
-28 to -14
-14
1
29
85
169
253
365
Week
-4 to -2
-2
0
4
12
24
36
52
Window
-3
-5/+2d
-5/+2d
-5/+2d
-5/+2d
-5/+2d
Other Assessment
ACQ7
X8
X9
X9
X9
X9
SGRQ7
X
X
X
X
AQLQ7
X
X
X
X
Pre-dose spirometry 10
X
X
X
X
Moderate/severe asthma exacerbation
X
X
X
X
X
X
X
X
Genetics/Pharmacogenetic sampling 11
X
Dispense paper Medical 
Problems/Medications Taken worksheet
X
X
X
X
X
X
X
X
X
Review paper Medical 
Problems/Medications Taken worksheet
X
X
X
X
X
X
X
X
X
Healthcare resource utilization
X
X
X
X
X
X
X
Dispense investigational product
X
X
X
X
X
Collect investigational product    
X
X
X
X
X
X
Dispense  salbutamol (as required)
X
X
X
X
X
X
Collect  salbutamol (as required)
X
X
X
X
X
X
X
1.
The Informed Consent Form (ICF) must be signed before any study procedures, including medication cessation.
2.
Genetics/Pharmacogenetic research consent may be obtained at the same time as the study Informed Consent and must be obtained prior to obtaining a 
Genetics/pharmacogenetic blood sample.
3.
The assessment of asthma history will include: the age of the subject when they were first provided with an inhaler for asthma; completion of an asthma medical history 
questionnaire (a copy of this questionnaire and instructions for its use can be found in the SRM).
4.
Subjects must not be allocated prior to confirming their eligibility to participate in the study.
5.
The IRT will be used for allocation, and study treatment supply management (Please refer to the RAMOS NG IRT manual and SRM for more information).
6.
Assessments are only to be conducted in females of reproductive potential.
7.
Assessment(s) to be completed before any study procedures .Study treatment should be administered at the same time of day each applicable clinic visit,
8.
Assessment to be conducted by using ACQ-6
9.
Assessment to be conducted by using ACQ-7
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10. Spirometry to be performed after withholding rescue medication for at least 6 hours and prior to taking the morning dose of study treatment. Pre-dose spirometry assessments 
should be performed at the same time of day at each applicable visit.
11. Pharmacogenetic sample may be drawn any time from Visit 2 onwards.
ACQ: Asthma Control Questionnaire, AQLQ: Asthma Quality of Life Questionnaire, IRT: Interactive Response Technology, SGRQ: St. George’s Respiratory Questionnaire
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11.3.
Appendix 3: Assessment Windows
11.3.1.
Clinical visits
Clinic visits are scheduled to take place as specified in the protocol. Measurements 
outside visit windows will not be excluded from analyses on any population.
For all clinic visits, nominal visits will be used for reporting.  
All unscheduled visits will be included in listings.
11.3.2.
Definitions of Assessment Windows for Adverse Events in 
Treatment Period
Definition of assessment windows is different among dose groups. Day 1 is defined as 
the study treatment start day. Section 11.3.2.1 and Section 11.3.2.2 are applicable only 
AE summaries by period (i.e., All AEs for week 0-12 and week 13-24 during treatment 
period in interim analysis, and All AEs for week 0-12, week 13-24, week 25-36 and week 
37-52 during treatment period in final analysis). Section 11.3.2.3 is applicable for the 
approach “by dose at AE”.
11.3.2.1.
In Interim Analyses
In interim analyses, the table below will be applied (i.e., data up to the day before visit 5 
(week 24 visit) will be used for AE/SAE related analyses).
Analysis Window
Analysis Timepoint
Beginning Timepoint
Ending Timepoint
Day 1
Day 84
Week 0-12
Day 85
The day before visit 5 
(week 24 visit)
Or
Day 168 (only for 
participants who 
withdraw early)
Week 13-24
Note that the data except for AE/SAEs up to the day OF visit 5 (week 24 visit) will be 
used in interim analyses. This means data except for AE/SAEs (e.g., clinical laboratory) 
will include visit 5 (week 24 visit), but data for AE/SAEs will not include the day of 
visit5 (week 24 visit) in interim analyses.
11.3.2.2.
In Final Analyses
For treatment group of “only FF/UMEC/VI 100/62.5/25” and “only FF/UMEC/VI 
200/62.5/25”, the table below will be applied (see Section 11.5.1 for treatment group 
description).
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Analysis Window
Analysis Timepoint
Beginning Timepoint
Ending Timepoint
Day 1
Day 84
Week 0-12
Day 85
Day 168
Week 13-24
Day 169
Day 252
Week 25-36
Day 253
Day 365
Or 
The day of visit 7 (week 
52 visit) if this is later 
than Day 365
Week 37-52
Day 1
Day 168
Week 0-24
Day 169
Day 365
Or 
The day of visit 7 (week 
52 visit) if this is later 
than Day 365
Week 25-52
For treatment group of “FF/UMEC/VI 100/62.5/25 to FF/UMEC/VI 200/62.5/25”, the 
table below will be applied (see Section 5.1 for treatment group description). The reason 
to use separate analysis window for “FF/UMEC/VI 100/62.5/25 to FF/UMEC/VI 
200/62.5/25” is to consider the day of switched treatment (i.e. the day of week 24).
Analysis Window
Analysis Timepoint
Beginning Timepoint
Ending Timepoint
Day 1
Day 84
Week 0-12
Day 85
The day before visit 5 
(week 24 visit)
Week 13-24
The day of visit 5 (week 24 
visit)
Day 252
Week 25-36
Day 253
Day 365
Or 
The day of visit 7 (week 
52 visit) if this is later 
than Day 365
Week 37-52
Day 1
The day before visit 5 
(week 24 visit)
Week 0-24
The day of visit 5 (week 24 
visit)
Day 365
Or 
The day of visit 7 (week 
52 visit) if this is later 
than Day 365
Week 25-52
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11.3.2.3.
By dose at the time of onset of the AEs (by dose at AE)
For treatment group of “only FF/UMEC/VI 100/62.5/25” and “only FF/UMEC/VI 
200/62.5/25”, the approach “by dose at AE” will summarized AEs during treatment 
period as each dose.
For treatment group of “FF/UMEC/VI 100/62.5/25 to FF/UMEC/VI 200/62.5/25”, the 
table below will be applied for an approach “by dose at AE” analyses.
Analysis Window
By dose at AE
Beginning Timepoint
Ending Timepoint
Day 1
The day before visit 5 
(week 24 visit)
As FF/UMEC/VI 100/62.5/25
The day of visit 5 (week 24 
visit)
Day 365
Or 
The day of visit 7 (week 
52 visit) if this is later 
than Day 365
As FF/UMEC/VI 200/62.5/25
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11.4.
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events
11.4.1.
Study Phases
Assessments and events will be classified according to the time of occurrence relative 
time of asessment.
Study Phase
Definition
Screening/Run-In 
period
Visit 1 date ≤ Assessment Date/Time < Date of study treatment start date
Treatment period
Study Treatment Start Date ≤Date ≤ Date of Visit7/EOT or EW
Follow-up period
Date > Date of Visit7/EOT or EW
11.4.1.1.
Study Phases for Concomitant Medication
Study Phase
Definition
Prior
If medication end date is not missing and is before study treatment start date
Concomitant
Any medication that is not a prior
NOTES: 

Please refer to Appendix 7: Reporting Standards for Missing Data for handling of missing and partial dates for 
concomitant medication. Use the rules in this table if concomitant medication date is completely missing.
11.4.2.
Treatment Emergent Flag for Adverse Events
Flag
Definition
Treatment 
Emergent

If AE onset date is on or after treatment start date & on or before treatment stop 
date.

Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment Stop.
NOTES: 

If the study treatment stop date is missing, then the AE will be considered to be On-Treatment.
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11.5.
Appendix 5: Data Display Standards & Handling 
Conventions
11.5.1.
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
¥¥uk1salx00175.corpnet2.com¥
HARP Compound
Primary (interim) analysis: 
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Final analysis: ¥arenv¥arprod¥gsk2834425¥mid207236¥final_01
Analysis Datasets 

Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.2& ADaM IG 
Version 1.0).
Generation of RTF Files

RTF files will not be generated
11.5.2.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: 
https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 
Formats

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected, unless otherwise stated.

Numeric data will be reported at the precision collected on the eCRF.

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 Time

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. 
Unscheduled Visits

Unscheduled visits will not be included in summary tables and/or figures except as part of a ‘worst case 
post-baseline’ assessment.
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
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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11.6.
Appendix 6: Derived and Transformed Data
11.6.1.
General
Multiple Measurements at One Analysis Time Point

If there are two values within a time window, the value closest to the target day for that window will be 
used. If values are the same distance from the target, then the mean will be taken.

Participants having both High and Low values for Normal Ranges at any post-baseline visit 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 First Dose Date:

Ref Date = Missing              → Study Day = Missing 

Ref Date < Treatment Start Date → Study Day = Ref Date – Treatment Start Date

Ref Data ≥ Treatment Start Date → Study Day = Ref Date – (Treatment Start Date) + 1    
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Example of Handling the Incorrect Treatment and Dose at the Timing of Onset of the AE
Here are the examples 1- 3 which a given subject had the incorrect treatment in certain period or 
all periods in treatment period (week 0 to week 52). It is assumed that all participants here 
complete study (i.e., do not withdraw).
Example
1
2
3
Dose group
FF/UMEC/VI 
100/62.5/25
FF/UMEC/VI 
100/62.5/25 to 
FF/UMEC/VI 
200/62.5/25
FF/UMEC/VI 
100/62.5/25
allocated 
dose at 
week0
FF/UMEC/VI 
100/62.5/25
FF/UMEC/VI 
100/62.5/25
FF/UMEC/VI 
200/62.5/25
Switch 
treatment at 
week24
No
Yes
No
Plan dose/
Actual dose/ 
dose at AE
Plan
Actual
dose 
at AE
Plan
Actual
dose 
at AE
Plan
Actual
dose 
at AE
week0 -4
FF100
FF100
FF100
FF100
FF100
FF100
FF200
FF100
FF100
week4 - 12
FF100
FF100
FF100
FF100
FF200
FF100
FF200
FF100
FF100
week12 - 24
FF100
FF100
FF100
FF100
FF100
FF100
FF200
FF100
FF100
week24 - 36
FF100
FF100
FF100
FF200
FF200
FF200
FF200
FF100
FF100
week36 - 52
FF100
FF200
FF100
FF200
FF100
FF200
FF200
FF100
FF100
Example 1 is the case that a given participant was allocated FF/UMEC/VI 100/62.5/25 at week0 and not 
switch the study treatment at week24, but had incorrect treatment (i.e., FF/UMEC/VI 200/62.5/25) at week 
36 to 52. Therefore, as described in Section 5.1 and Section 8.2, dose group for this participant will be 
FF/UMEC/VI 100/62.5/25, and AE at week 36 – 52 will be handled as AE at FF/UMEC/VI 100/62.5/25 for 
dose at AE analyses.
Example 2 is the case that a given participant was allocated FF/UMEC/VI 100/62.5/25 at week0 and 
switched the study treatment at week24, but had incorrect treatment (i.e., FF/UMEC/VI 200/62.5/25 at week 
4-12 and FF/UMEC/VI 100/62.5/25 at week 36-52) at two periods. Therefore, as described in Section 5.1
and Section 8.2, dose group for this participant will be FF/UMEC/VI 100/62.5/25 to FF/UMEC/VI 
200/62.5/25, and AE at week 4 – 12 will be handled as AE at FF/UMEC/VI 100/62.5/25 and AE at week 36 –
52 will be handled as AE at FF/UMEC/VI 200/62.5/25 for dose at AE analyses.
Example 3 is the case that a given participant was allocated FF/UMEC/VI 200/62.5/25 at week0 and not 
switch the study treatment at week24, but had incorrect treatment (i.e., FF/UMEC/VI 100/62.5/25) during all 
periods. This participant HAD incorrect treatment during all periods. Therefore, as described in Section 5.1
and Section 8.2, dose group for this participant will be FF/UMEC/VI 100/62.5/25, and AE at any time will be 
handled as AE at FF/UMEC/VI 100/62.5/25 for dose at AE analyses.
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11.6.2.
Study Population
Demographics
Age

Age will be calculated based on the Pre-Screening Visit date (or Screening, if pre-screening 
not performed).

Birth date will be imputed as follows:
o
Any participant with a missing day and month will have this imputed as ‘30th June’.
o
All participants with imputed age of 17 or 18 years will be source data verified, and 
presence / absence of protocol deviation on the inclusion criteria #1 will be taken into 
consideration in the derivation for the analysis variable age. 

Birth date will be presented in listings as ‘YYYY’.
Age Category

Age categories (unless otherwise specified) are based on age at Pre-screening and are 
defined as:
o
18 to < 65
o
65 to <75 years
o
75 to <85 years
o
≥ 85 years

Age categories in age range summary for EudraCT are based on age at Pre-screening and are 
defined as:
o
Adolescents (12-17 years)
o
Adult (18-64 years)
o
>=65-84 years
o
>=85 years
Body Mass Index (BMI)
o
Calculated as Weight (kg) / Height (m)2
Cardiovascular History and Risk Factor
Cardiovascular history and risk factors will be assessed at Visit 1. Participants with one or more of 
the following terms recorded as either current or past medical conditions at Visit 1 is considered to 
have cardiovascular history/risk factors: 
•
Cardiovascular history 

arrhythmia, 

congestive heart failure, 

coronary artery disease, 

myocardial infarction, 

cerebrovascular accidents, 
•
Cardiovascular risk factors 

hypertension, 

diabetes mellitus

hypercholesterolemia.  
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Treatment Compliance

The actual total number of doses received by each participant will be calculated as the sum of 
(dose counter start value – dose counter stop value) over all inhalers dispensed to the 
participant during the treatment period, and percentage treatment compliance will be 
calculated as described in Section 6.1.5.
If a dose counter start count is missing then it will be assumed to be 30 for the Ellipta DPI.  If 
a dose counter stop value is missing then number of doses received will be set to missing for 
that container.
Treatment compliance will be based only on the returned devices prior to or at end of 
study/early withdrawal visit that were dispensed during the treatment period.

Overall compliance will be categorized as follows:
< 50 %
≥50 % to < 80 %
≥80 % to < 95 %
≥95 % to ≤105 %
>105 % to ≤120 %
>120 %.

If a participant receives a treatment other than the allocated treatment during the study, the 
compliance will still be calculated using data from all containers received and overall exposure 
start and stop dates

In interim analysis, treatment compliance will be calculated based on data until the day before 
visit 5 (i.e., treatment stop date will be replaced with the day before visit 5).

One dose per one day will be received in this study.
Derivation of Complete for Study Disposition in Interim Analysis

In interim analysis, “completed” means completion of Visit 5 (Week 24 visit).

If the response to the question “Did the subject fail to complete this phase of the study?” is 
“No” in eCRF, then this participant will be regarded as “completed” in interim analysis.
Derivation of % predicted FEV1

% predicted FEV1 will be derived according to [Implementing GLI-2012 regression equations, 
July 16, 2015].
% predicted FEV1 = (measured FEV1 value / M) x 100
M = exp(a0 + a1 x ln(Height) + a2 x ln(Age) + a6 + Mspline)
Note: The integer value of calculated Age will be used in this study.
Note: ln() = natural log transformation.
Note: M is the predicted value of FEV1.
Note: Since this study includes only Japanese participants, a3 to a5 are not used in this study. See 
Philip H. Quanjer et al (Philip, 2012) more detail.

Coefficients of M
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Derivation of % predicted FEV1
Different coefficients of M need to be used for males and females.
Coefficients of M in males
Coefficients of M in females
a0
-10.3420
-9.6987
a1
2.2196
2.1211
a2
0.0574
-0.0270
a6
-0.0708
-0.0708

Mspline
Different Msplines need to be used depending on a participant’s age and sex.
For 18-24 years, Msplines below will be used. These values come from “lookup tables” described 
in [Implementing GLI-2012 regression equations, July 16, 2015].
For 25-95 years, Mspline will be calculated by using the formula below and coefficients.
Mspline = b0 + b1*(Age/100) + b2*(Age/100)2 + b3*(Age/100)3 + b4*(Age/100)4 + b5*(Age/100)5
Coefficients of Mspline in males
Coefficients of Mspline in females
b0
0.3901
0.0552
b1
-1.0579
1.6029
b2
1.4743
-6.4845
b3
-2.1077
10.2723
b4
-0.1215
-9.8630
b5
0.8873
3.8802
Age
Mspline in males
Mspline in females
18
0.1924
0.1785
19
0.2029
0.1823
20
0.2081
0.1839
21
0.2091
0.1841
22
0.2071
0.1832
23
0.2030
0.1812
24
0.1970
0.1785
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11.6.3.
Safety
Adverse Events
Adverse Event Rate
Event rate per thousand person-years will be displayed for AE data in separate tables as listed in 
Section 11.11.5 and Section 11.11.6. Event rate per thousand person-years will be calculated as 
the number of events x 1000 divided by the total participant exposure during the time-period of 
interest (i.e., during treatment period).
AE’S OF Special Interest
Adverse events of special interest have been defined as AEs which have specified areas of 
interest. These consist in groupings of preferred terms based on the MedDRA dictionary version 
used in each reporting effort.  Subgroups may be defined, based on relevant combination of 
preferred terms, or on Standardized MedDRA queries (SMQ). 
11.6.4.
Other
Asthma Control Questionnaire (ACQ), ACQ-6 and ACQ-7
General

All 6 or 7 items (5 most important symptoms, one question about
 and 
one about 
of ACQ have response on 0-6 ordinal scale (
). The total score is calculated as the 
average of all non-missing item responses [Asthma Control Questionnaire, Background, 
Administration and Analysis, April, 2008]. 

ACQ-6 will be used at screening (visit 1). ACQ-7 will be used at all visit 2, 5, 7 or EW visit.
Questions, Responses and Calculation Method for ACQ

Table below shows questions of ACQ.

Each question has the response on 0-6 ordinal scale (
). The wordings of responses are not the same for all responses, but they 
are not described in this RAP.

The total score for ACQ-7 is the mean of the response to the 7 questions. The total score for 
ACQ-6 is the mean of the response to the 6 questions excluding a question about 
Question
Item 
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Asthma Control Questionnaire (ACQ), ACQ-6 and ACQ-7
Handling of Missing Items

Only one of the first five item responses are allowed to be missing in calculating the total 
scores for all versions of ACQ. One question about 
(item 6) and one 
about
(item 7, for ACQ-7 only) are not allowed to be missing.

If one of the first five item responses is missing, then total score will be calculated based on 
just the available data. This means missing value will be excluded from the denominator.
If there are unacceptable missing items, then ACQ will be regarded as missing.
Example
Visit 2
Visit 5
Visit 7
Item 1
4
6
3
Item 2
3
5
4
Item 3
4
4
3
Item 4
5
5
4
Item 5
2
Missing
3
Item 6
4
4
2
Item 7
1
3
Missing

ACQ-7 score at visit 2: (4 + 3 + 4 + 5 + 2 + 4 + 1) / 7 = 3.3
Since there is no missing value, ACQ-7 is calculated by using all 7 responses. Data will be rounded 
to one decimal place. 

ACQ-7 score at visit 5: (6 + 5 + 4 + 5 + 4 + 3) /6 = 4.5
Since there is one missing value for the first five item, ACQ-7 is calculated by using 6 responses. 

ACQ-7 score at visit 7: missing
Since question about 
 is missing, ACQ-7 should not be calculated and be missing at this 
visit.
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St. George’s Respiratory Questionnaire (SGRQ)
General

Details for how to score the SGRQ, including handling of missing data, are outlined in the 
SGRQ manual (June, 2009).

Changes from baseline in total score will be calculated.
Questions, Response and Weight for SGRQ

Table below shows questions and responses of SGRQ, their weight for SGRQ score calculation 
and its number in aCRF.

Each questionnaire response has a unique ‘weight’ to be used for score calculation.

This questionnaire requests a single response to questions 
, 
 and 
. If multiple 
responses are given to one of these questions, then averaging the weights for the positive 
responses for that question are acceptable.

SGRQ has three components: Symptoms; Activity; Impacts
SYMPTOMS COMPONENT

This is calculated from the summed weights for the positive responses to questions 
.
ACTIVITY COMPONENT

This is calculated from the summed weights for the positive responses to questions 
 and 
. 
IMPACTS COMPONENT

This is calculated from the summed weights for the positive responses to questions 
, 
 
and 
. 
TOTAL SCORE

The Total score is calculated by summing all positive responses in the questionnaire and 
expressing the result as a percentage of the total weight for the questionnaire
Calculation method is described in next box.
Question
Item 
Number 
in aCRF
Response
Weight
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St. George’s Respiratory Questionnaire (SGRQ)
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St. George’s Respiratory Questionnaire (SGRQ)
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St. George’s Respiratory Questionnaire (SGRQ)
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St. George’s Respiratory Questionnaire (SGRQ)
Calculation Method
Each component of the questionnaire is scored separately in three steps:
I. The weights for all items with positive responses are summed.
II. The weights for missed items are deducted from the maximum possible weight for each 
component. The weights for all missed items are deducted from the maximum possible 
weight for the Total score.
III. The score is calculated by dividing the summed weights by the adjusted maximum possible 
weight for that component and expressing the result as a percentage:
Score = 
The Total score is calculated in similar way:
Score = 
Sum of maximum possible weights for each component and Total:

Symptoms: 

Activity: 

Impacts: 

Total: 
Handling of Missing Items
Symptoms
The Symptoms component will tolerate a maximum of 2 missed items. The weight for the missed 
item is subtracted from the total possible weight for the Symptoms component (
) and from the 
Total weight (
).
Activity
The Activity component will tolerate a maximum of 4 missed items. The weight for the missed 
item is subtracted from the total possible weight for the Activity component (
) and from the 
Total weight (
). 
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and therefore have been excluded.
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St. George’s Respiratory Questionnaire (SGRQ)
Impacts
The Impacts component will tolerate a maximum of 6 missed items. The weight for the missed 
item is subtracted from the total possible weight for the Impacts component (
) and from the 
Total weight (
).
If there were unacceptable number of missed items for any component, then SGRQ total score will 
be handled as missing.
Example
Table below is example data for calculation of SGRQ total score. Since this questionnaire requests 
a single response to questions 
,
and 
, this table shows only one selected response for 
questions 
, 
 and
 (Data columns are 
). For other questions, this table shows the 
results of
or
. In this example, it is assumed that there is no missed item.
In this study, each component score will not be calculated. However, we would like to show how to 
calculate each component score and total score in this example.
Symptoms
This is calculated from the summed weights for the positive responses to questions 
 In this 
example, weights for 
data for questions 
need to be summed. Summed weight is 
(
) = 
 Since maximum possible weight for symptoms is 
, symptoms component score can be calculated as 
Activity
This is calculated from the summed weights for the positive responses to questions 
 and 
. In 
this example, weights for
 data for questions 
 and 
 need to be summed. Summed weight 
is (
) =
. Since maximum possible weight for activity is 
, symptoms component score can be calculated as
Impacts
This is calculated from the summed weights for the positive responses to questions
, 
and 
. In this example, weights for
 data for questions 
, 
and weights for 
data for questions 
, 
 need to be summed. Summed weight is (
) =
. Since maximum possible weight for 
impacts is
symptoms component score can be calculated as 
Total
The Total score is calculated by summing all positive responses in the questionnaire and 
expressing the result as a percentage of the total weight for the questionnaire. Summed weights for 
total is summed weights for three components above, (
) = 
 Since 
maximum possible weight for total score is 
, SGRQ total score can be calculated as 
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St. George’s Respiratory Questionnaire (SGRQ)
Question
Item 
Response
Weight
Data
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St. George’s Respiratory Questionnaire (SGRQ)
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St. George’s Respiratory Questionnaire (SGRQ)
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CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are 
protected by third party copyright laws and therefore have been excluded
CCI - This section contained Clinical Outcome Assessment data collection 
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and therefore have been excluded


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Asthma Quality of Life Questionnaire (AQLQ)
General

Details for how to score the AQLQ, including handling of missing data, are outlined in the 
AQLQ manual (June, 2005). 

Changes from baseline in total score will be calculated for the converted scores.
Questions, Responses and Calculation Method for AQLQ

Table below shows questions of AQLQ.

Each question has the response on a 7 – point scale (
, 
 
). The wordings of responses are not the same for all responses, but they are not 
described in this RAP.

Individual items are equally weighted. The overall AQLQ score is the mean of the responses to 
each of the 32 questions. Therefore, AQLQ score can be calculated to add all 32 responses 
together and divided the total by 32.

AQLQ has four domains: Activity limitations, Symptoms, Emotional function, Environmental 
stimuli
Activity limitations: item: 
Symptoms: item: 
Emotional function: item: 
Environmental stimuli: item: 

Note that only AQLQ total score will be calculated in this study, not each domain score. But 
acceptable missing items depends on each domain. Handling of missing items is described in 
next section
Question
Item 
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Handling of Missing Items

Acceptable number of missed items
Activity limitations and Symptoms: only one missing value per domain
Emotional function, Environmental stimuli: Not accept any missing responses

If there are missing items, then total score will be calculated based on just the available data. 
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This means missing value will be excluded from the denominator.

If there were unacceptable number of missed items for any component, then AQLQ total score 
will be handled as missing.
Example
Visit 2
Visit 5
Visit 7
Item 1
3
missing
5
Item 2
4
1
6
Item 3
3
2
5
Item 4
4
2
3
Item 5
2
2
4
Item 6
1
missing
5
Item 7
4
1
missing
Item 8
6
4
7
Item 9
4
2
6
Item 10
3
3
5
Item 11
4
5
4
Item 12
5
2
3
Item 13
4
4
2
Item 14
2
2
1
Item 15
3
3
2
Item 16
4
4
3
Item 17
5
5
4
Item 18
6
2
5
Item 19
2
3
6
Item 20
4
4
7
Item 21
5
5
4
Item 22
6
7
4
Item 23
3
4
4
Item 24
2
2
5
Item 25
4
4
6
Item 26
5
5
7
Item 27
6
6
3
Item 28
2
6
4
Item 29
4
2
5
Item 30
5
5
6
Item 31
6
5
2
Item 32
4
5
3

AQLQ total score at visit 2: (3 + 4 + 3 + , , , + 5 + 6 + 4) / 32 = 3.9
Since there is no missing value, AQLQ total score is calculated by using all 32 responses. Data will 
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be rounded to one decimal place. 

AQLQ total score at visit 5: (1 + 2 + 2 + , , , + 5 + 5 + 5) /30 = 3.6
Although there is one missing value for Activity limitations domain (item 1) and one for Symptoms 
domain (item 6), the number of missed items is acceptable. AQLQ total score is calculated by using 
30 responses available. 

AQLQ total score at visit 7: missing
Since one response for Emotional function domain (item 7) is missing and this is not acceptable, 
AQLQ total score should not be calculated and be missing at this visit.
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11.7.
Appendix 7: Reporting Standards for Missing Data
11.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Participant study completion (i.e. as specified in the protocol) was defined as he/she 
has completed all phases of the study including the safety follow-up telephone contact 
or clinic visit.

Withdrawn participants were not replaced in the study.

All available data from participants 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.

Withdrawal visits will not be slotted and not be summarized as Withdrawal visit.
11.7.2.
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 participant listing displays. 
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 participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
11.7.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in participant listing displays.
Adverse 
Events

The eCRF does not allow for the possibility of partial dates (i.e., only month and year) 
to be recorded for AE start and end dates; that is, the day of the month may be missing.

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/
Medical 
History

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.

The recorded partial date will be displayed in listings.
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11.8.
Appendix 8: Values of Potential Clinical Importance
This is not applicable to this study.
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11.9.
Appendix 9: Implementation and mitigation strategy of 
Statistical Output Review (SOR)
This appendix describes what Japan S&P team will do as SOR and its mitigation strategy 
to maintain integrity of study.
Background:
In this study, SOR will be planned before release of randomization code from RandAll. 
The purpose of SOR is to make sure programming was in place and to check formatting 
of outputs, NOT to review the data itself. According to GSK SOP_57860, a dry run on a 
single arm open label study is the same as an interim analysis, so unless it’s detailed in 
the protocol, that should not be done. Therefore, the mitigation strategy should be 
described in this RAP.
What Japan S&P team will do:

Lead statistician and lead programmer will make sure programming was in place and 
to check formatting of outputs.

Additional reviewers in Japan S&P will help to make sure programming works well 
and check formatting of outputs.
Mitigation strategy: 

Japan S&P team will NOT share any results with outside of Japan S&P team at the 
timing of SOR or prior to interim SAC.

HARP environment will also be restricted to Japan S&P team and programmers.
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11.10.
Appendix 10: Abbreviations & Trade Marks
11.10.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
AIC
Akaike's Information Criteria
A&R
Analysis and Reporting 
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CS
Clinical Statistics
CSR
Clinical Study Report
CTR
Clinical Trial Register
DBF
Database Freeze
DBR
Database Release
DOB
Date of Birth
DP
Decimal Places
eCRF
Electronic Case Record Form
EMA
European Medicines Agency
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Clinical Results Disclosure 
Requirements
GSK
GlaxoSmithKline
IA
Interim Analysis
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
IMMS
International Modules Management System
IP
Investigational Product
ITT
Intent-To-Treat
MACE
Major Adverse Cardiac Event
MMRM
Mixed Model Repeated Measures
PCI
Potential Clinical Importance 
PDMP
Protocol Deviation Management Plan
PLS
Plain Language Summary
PP
Per Protocol
QC
Quality Control
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RAMOS
Randomization & Medication Ordering System 
SAC
Statistical Analysis Complete
SDSP
Study Data Standardization Plan
SDTM
Study Data Tabulation Model
SOP
Standard Operation Procedure
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Abbreviation
Description
TA
Therapeutic Area
TFL
Tables, Figures & Listings 
11.10.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
ELLIPTA
SAS
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11.11.
Appendix 11: List of Data Displays
11.11.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
At interim analysis:
Section
Tables
Figures
Study Population
1.1 to 1.n
NA
Safety
2.1 to 2.n
NA
Other
3.1 to 3.n
NA
Section
Listings
ICH Listings
1 to x
Other Listings
y to z
At final analysis:
Section
Tables
Figures
Study Population
11.1 to 1.n
NA
Safety
12.1 to 2.n
NA
Other
13.1 to 3.n
NA
Section
Listings
ICH Listings
44 to x
Other Listings
y to z
11.11.2.
Deliverables
Delivery [Priority] [1]
Description
IA [X]
Interim Analysis Statistical Analysis Complete
SAC [X]
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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11.11.3.
Study Population Tables (interim)
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
ITT
ES1
Summary of Subject Disposition (Interim)
ICH E3, FDAAA, EudraCT
IA [1]
1.2.
ITT
SD1
Summary of Treatment Status (Interim)
ICH E3
IA [1]
1.3.
Enrolled
ES4
Summary of Participant Disposition at Each Study Epoch 
(Interim)
ICH E3
IA [1]
1.4.
Screened
ES6
Summary of Screening Status and Reasons for Screen Failure 
and Run-in Failure (Interim)
Journal Requirements
IA [1]
1.5.
Enrolled
NS1
Summary of Number of Participant by Country and Site ID 
(Interim)
EudraCT/Clinical Operations
IA [1]
Protocol Deviation
1.6.
ITT
DV1
Summary of Important Protocol Deviations (Interim)
ICH E3
IA [1]
Population Analysed
1.7.
All Subjects
SP1
Summary of Study Populations (Interim)
IDSL
IA [1]
Demographic and Baseline Characteristics
1.8.
ITT
DM1
Summary of Demographic Characteristics (Interim)
ICH E3, FDAAA, EudraCT
IA [1]
1.9.
Enrolled
DM11
Summary of Age Ranges (Interim)
EudraCT
IA [1]
1.10.
ITT
DM5
Summary of Race and Racial Combinations (Interim)
ICH E3, FDA, FDAAA, EudraCT
IA [1]
1.11.
ITT
Study Specific
Summary of Disease Duration (Interim)
IA [1]
1.12.
ITT
Study Specific
Summary of Asthma Medical History Questionnaire (Interim)
IA [1]
1.13.
ITT
Study Specific
Summary of Exacerbation History (Interim)
IA [1]
1.14.
ITT
SU1 (subset)
Summary of Smoking Status (Interim)
IA [1]
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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.15.
ITT
Study Specific
Summary of Cardiovascular History / Risk Factors (Interim)
IA [1]
1.16.
ITT
FH1
Summary of Family History of Cardiovascular Risk Factors 
(Interim)
IA [1]
1.17.
ITT
Study Specific
Summary of ACQ-6 score at Screening (Interim)
IA [1]
1.18.
ITT
Study Specific
Summary of Clinic Spirometry at Baseline (Interim)
IA [1]
Prior and Concomitant Medications
1.19.
ITT
MH4
Summary of Current Medical Conditions (Interim)
ICH E3 
IA [1]
1.20.
ITT
MH4
Summary of Past Medical Conditions (Interim)
ICH E3 
IA [1]
1.21.
ITT
CM1
Summary of Asthma Concomitant Medications Before Study 
Treatment (Interim)
IA [1]
1.22.
ITT
CM1
Summary of Asthma Concomitant Medications During the 
Treatment Period (Interim)
IA [1]
1.23.
ITT
CM1
Summary of Non-Asthma Concomitant Medications During the 
Treatment Period (Interim)
IA [1]
Exposure and Treatment Compliance
1.24.
ITT
Study Specific
Summary of Treatment Compliance (Interim)
IA [1]
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11.11.4.
Study Population Tables (final)
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
11.1.
ITT
ES1
Summary of Subject Disposition
ICH E3, FDAAA, EudraCT
SAC [1]
11.2.
ITT
SD1
Summary of Treatment Status
ICH E3
SAC [1]
11.3.
Enrolled
ES4
Summary of Participant Disposition at Each Study Epoch
ICH E3
SAC [1]
Protocol Deviation
11.4.
ITT
DV1
Summary of Important Protocol Deviations
ICH E3
SAC [1]
Population Analysed
11.5.
All Subjects
SP1
Summary of Study Populations 
IDSL
SAC [1]
Demographic and Baseline Characteristics
11.6.
ITT
DM1
Summary of Demographic Characteristics
ICH E3, FDAAA, EudraCT
SAC [1]
11.7.
Enrolled
DM11
Summary of Age Ranges
EudraCT
SAC [1]
11.8.
ITT
DM5
Summary of Race and Racial Combinations
ICH E3, FDA, FDAAA, EudraCT
SAC [1]
11.9.
ITT
Study Specific
Summary of Disease Duration
SAC [1]
11.10.
ITT
Study Specific
Summary of Asthma Medical History Questionnaire
SAC [1]
11.11.
ITT
Study Specific
Summary of Exacerbation History
SAC [1]
11.12.
ITT
SU1 (subset)
Summary of Smoking Status
SAC [1]
11.13.
ITT
Study Specific
Summary of Cardiovascular History / Risk Factors
SAC [1]
11.14.
ITT
FH1
Summary of Family History of Cardiovascular Risk Factors
SAC [1]
11.15.
ITT
Study Specific
Summary of ACQ-6 score at Screening
SAC [1]
11.16.
ITT
Study Specific
Summary of Clinic Spirometry at Baseline
IA [1]
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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Prior and Concomitant Medications
11.17.
ITT
MH4
Summary of Current Medical Conditions
ICH E3
SAC [1]
11.18.
ITT
CM1
Summary of Asthma Concomitant Medications During the
Treatment Period
SAC [1]
11.19.
ITT
CM1
Summary of Asthma Concomitant Medications During the 
Follow-Up Period
SAC [1]
11.20.
ITT
CM1
Summary of Non-Asthma Concomitant Medications During the 
Treatment Period
SAC [1]
11.21.
ITT
CM1
Summary of Non-Asthma Concomitant Medications During the 
Follow-Up Period
SAC [1]
Exposure and Treatment Compliance
11.22.
ITT
Study Specific
Summary of Treatment Compliance
SAC [1]
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11.11.5.
Safety Tables (interim)
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Treatment Exposure
2.1.
ITT
EX1
Summary of Exposure to Study Treatment (Interim)
ICH E3
IA [1]
Adverse Events (AEs)
2.2.
ITT
AE13
Summary of All Adverse Events Overview During Treatment 
Period (Interim)
ICH E3
IA [1]
2.3.
ITT
AE1
Summary of All Adverse Events During Treatment Period 
(Interim)
ICH E3
IA [1]
2.4.
ITT
Study Specific
Summary of All Adverse Events During Treatment Period per 
Thousand Person-Year (Interim)
2.5.
ITT
AE5A
Summary of All Adverse Events During Treatment Period by 
maximum severity (Interim)
ICH E3
IA [1]
2.6.
ITT
AE1
Summary of All Drug-Related Adverse Events During 
Treatment Period (Interim)
ICH E3
IA [1]
2.7.
ITT
Study Specific
Summary of All Drug-Related Adverse Events During 
Treatment Period per Thousand Person-Year (Interim)
IA [1]
2.8.
ITT
AE3
Summary of Most Common Adverse Events (3% or more of 
Subjects in Any Treatment Group) During Treatment Period by 
dose group (interim)
ICH E3
3% or more of Subjects in Any 
Treatment Group
IA [1]
2.9.
ITT
Study Specific
Summary of Adverse Events for week 0-12 and week 13-24 
During Treatment Period (interim)
IA [1]
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.10.
ITT
AE15
Summary of Common (>=5%) Non-serious Adverse Events by 
System Organ Class and Preferred Term During Treatment 
Period (Number of Participant and Occurrences) (Interim)
FDAAA, EudraCT
‘Common’ to be defined by 
study/project team. For studies with 
very few events/participants, listing 
is sufficient: discuss this option with 
your disclosure representative.
IA [1]
Serious and Other Significant Adverse Events
2.11.
ITT
AE1
Summary of Serious Adverse Events During Treatment Period 
(Interim)
IA [1]
2.12.
ITT
Study Specific
Summary of Serious Adverse Events During Treatment Period 
per Thousand Person-Year (Interim)
IA [1]
2.13.
ITT
AE1
Summary of Adverse Events Leading to Withdrawal from Study
During Treatment Period (Interim)
IA [1]
2.14.
ITT
AE1
Summary of Adverse Events of Special Interest During 
Treatment Period (Interim)
IA [1]
2.15.
ITT
Study Specific
Summary of Adverse Events of Special Interest During 
Treatment Period per Thousand Person-Year (Interim)
IA [1]
2.16.
ITT
AE16
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term during treatment period (Number of 
Participants and Occurrences) (Interim)
FDAAA, EudraCT
For studies with few 
events/participants listing is 
sufficient: discuss this option with 
your disclosure representative.
IA [1]
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
MACE 
2.17.
ITT
Study Specific
Summary of Major Cardiac Events (MACE) – Narrow Definition
(Interim)
IA [1]
2.18.
ITT
Study Specific
Summary of Major Cardiac Events (MACE) – Broad Definition
(Interim)
IA [1]
Laboratory: Chemistry 
2.19.
ITT
LB1
Summary of Chemistry Data (Interim)
IA [1]
2.20.
ITT
LB1
Summary of Chemistry Changes from Baseline (Interim)
ICH E3
Includes Baseline values.
Includes pre-specified 
parameters repeated in 
conventional units.
IA [1]
2.21.
ITT
LB3
Summary of Chemistry Shifts from Baseline Relative to Normal 
Range (Interim)
IA [1]
Laboratory: Hematology
2.22.
ITT
LB1
Summary of Hematology Data (Interim)
IA [1]
2.23.
ITT
LB1
Summary of Hematology Changes from Baseline (Interim)
ICH E3
Includes baseline values.
IA [1]
2.24.
ITT
LB3
Summary of Hematology Shifts from Baseline Relative to 
Normal Range (Interim)
IA [1]
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Laboratory: Urinalysis
2.25.
ITT
UR1
Summary of Worst Case Urinalysis Results (Discrete or 
Character Values) Post-Baseline Relative to Baseline (Interim)
ICH E3
As above for Chemistry, using 
dipstick categories.
Define change categories according 
to actual values expected from lab 
dataset
IA [1]
Vital Signs
2.26.
ITT
VS1
Summary of Vital Signs (Interim)
ICH E3
Includes Baseline values.
IA [1]
2.27.
ITT
VS1
Summary of Change from Baseline in Vital Signs (Interim)
ICH E3
Includes Baseline values.
IA [1]
ECG
2.28.
ITT
EG2
Summary of ECG Values (Interim)
IDSL
IA [1]
2.29.
ITT
EG2
Summary of Change from Baseline in ECG Values (Interim)
IDSL
IA [1]
2.30.
ITT
Study Specific
Summary of Categories for QTc (F) Values (Interim)
IDSL
IA [1]
2.31.
ITT
Study Specific
Summary of Categories for Change from Baseline in QTc (F) 
Values (Interim)
IDSL
IA [1]
2.32.
ITT
EG1
Summary of ECG Findings (Interim)
IDSL
As above for Chemistry, using ECG
findings categories (and change 
from baseline categories, if 
applicable).
IA [1]
2.33.
ITT
Study Specific
Summary of ECG Findings Shifts from Baseline (Interim)
IA [1]
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Pneumonia and Radiography (Chest X-Rays)
2.34.
ITT
Study Specific
Summary of On-Treatment Pneumonia, Including Chest X-
ray Finding (Interim)
IDSL
IA [1]
11.11.6.
Safety Tables (final)
Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Treatment Exposure
12.1.
ITT
EX1
Summary of Exposure to Study Treatment
ICH E3
SAC [1]
Adverse Events (AEs)
12.2.
ITT
AE13
Summary of All Adverse Events Overview During Treatment 
Period
ICH E3
SAC [1]
12.3.
ITT
AE1
Summary of All Adverse Events During Treatment Period by 
dose group
ICH E3
SAC [1]
12.4.
ITT
AE1
Summary of All Adverse Events During Treatment Period by 
dose at AE (dose: FF/UMEC/VI 100/62.5/25)
ICH E3
SAC [1]
12.5.
ITT
AE1
Summary of All Adverse Events During Treatment Period by 
dose at AE (dose: FF/UMEC/VI 200/62.5/25)
ICH E3
SAC [1]
12.6.
ITT
AE1
Summary of All Adverse Events During Follow-Up Period by 
dose group
ICH E3
SAC [1]
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Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
12.7.
ITT
Study Specific
Summary of All Adverse Events During Treatment Period per 
Thousand Person-Year by dose group
12.8.
ITT
AE5A
Summary of All Adverse Events During Treatment Period by 
maximum severity and dose group
ICH E3
SAC [1]
12.9.
ITT
AE5A
Summary of All Adverse Events During Treatment Period by 
maximum severity and dose at AE (dose: FF/UMEC/VI 
100/62.5/25)
ICH E3
SAC [1]
12.10.
ITT
AE5A
Summary of All Adverse Events During Treatment Period by 
maximum severity and dose at AE (dose: FF/UMEC/VI 
200/62.5/25)
ICH E3
SAC [1]
12.11.
ITT
AE1
Summary of All Drug-Related Adverse Events During 
Treatment Period by dose group
ICH E3
SAC [1]
12.12.
ITT
AE1
Summary of All Drug-Related Adverse Events During 
Treatment Period by dose at AE (dose: FF/UMEC/VI 
100/62.5/25)
ICH E3
SAC [1]
12.13.
ITT
AE1
Summary of All Drug-Related Adverse Events During 
Treatment Period by dose at AE (dose: FF/UMEC/VI 
200/62.5/25)
ICH E3
SAC [1]
12.14.
ITT
Study Specific
Summary of All Drug-Related Adverse Events During 
Treatment Period per Thousand Person-Year by dose 
group
SAC [1]
12.15.
ITT
AE3
Summary of Most Common Adverse Events (3% or more of 
Subjects in Any Treatment Group) During Treatment Period by 
dose group
ICH E3
SAC [1]
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Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
12.16.
ITT
AE3
Summary of Most Common Adverse Events (3% or more of 
Subjects in Any Treatment Group) During Treatment Period by 
dose at AE (dose: FF/UMEC/VI 100/62.5/25)
ICH E3
SAC [1]
12.17.
ITT
AE3
Summary of Most Common Adverse Events (3% or more of 
Subjects in Any Treatment Group) During Treatment Period by 
dose at AE (dose: FF/UMEC/VI 200/62.5/25)
ICH E3
SAC [1]
12.18.
ITT
Study Specific
Summary of Adverse Events for week 0-12, week 13-24, week 
25-36 and week 37-52 During Treatment Period by dose 
group
SAC [1]
12.19.
ITT
Study Specific
Summary of Adverse Events for week 0-24, week 25-52 During 
Treatment Period by dose group
SAC [1]
12.20.
ITT
AE15
Summary of Common (>=5%) Non-serious Adverse Events by 
System Organ Class and Preferred Term During Treatment 
Period (Number of Participant and Occurrences)
FDAAA, EudraCT
‘Common’ to be defined by 
study/project team. For studies 
with very few events/participants, 
listing is sufficient: discuss this 
option with your disclosure 
representative.
SAC [1]
12.21.
ITT
AE3
Summary of Non-Serious Drug-Related Adverse Events During 
Treatment Period by dose group
PLS
SAC [1]
12.22.
ITT
AE1
Summary of All Drug-Related Adverse Events During 
Treatment Period and Follow-Up Period by dose group
SAC [1]
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Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Serious and Other Significant Adverse Events
12.23.
ITT
AE1
Summary of Serious Adverse Events During Treatment Period 
by dose group
SAC [1]
12.24.
ITT
AE1
Summary of Serious Adverse Events During Treatment Period 
by dose at AE (dose: FF/UMEC/VI 100/62.5/25)
SAC [1]
12.25.
ITT
AE1
Summary of Serious Adverse Events During Treatment Period 
by dose at AE (dose: FF/UMEC/VI 200/62.5/25)
SAC [1]
12.26.
ITT
Study Specific
Summary of Serious Adverse Events During Treatment Period 
per Thousand Person-Year by dose group
IA [1]
12.27.
ITT
AE1
Summary of Adverse Events Leading to Withdrawal from Study
During Treatment Period by dose group
SAC [1]
12.28.
ITT
AE1
Summary of Adverse Events Leading to Withdrawal from Study
During Treatment Period by dose at AE (dose: 
FF/UMEC/VI 100/62.5/25)
SAC [1]
12.29.
ITT
AE1
Summary of Adverse Events Leading to Withdrawal from Study
During Treatment Period by dose at AE (dose: 
FF/UMEC/VI 200/62.5/25)
SAC [1]
12.30.
ITT
AE1
Summary of Adverse Events of Special Interest During 
Treatment Period by dose group
SAC [1]
12.31.
ITT
AE1
Summary of Adverse Events of Special Interest During 
Treatment Period by dose at AE (dose: FF/UMEC/VI 
100/62.5/25)
SAC [1]
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Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
12.32.
ITT
AE1
Summary of Adverse Events of Special Interest During 
Treatment Period by dose at AE (dose: FF/UMEC/VI 
200/62.5/25)
SAC [1]
12.33.
ITT
Study Specific
Summary of Adverse Events of Special Interest During 
Treatment Period per Thousand Person-Year by dose 
group
IA [1]
12.34.
ITT
AE16
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term during treatment period (Number of 
Participants and Occurrences)
FDAAA, EudraCT
For studies with few 
events/participants listing is 
sufficient: discuss this option with 
your disclosure representative.
SAC [1]
12.35.
ITT
AE3
Summary of Serious Drug-Related Adverse Events by dose 
group
PLS
SAC [1]
MACE 
12.36.
ITT
Study Specific
Summary of Major Cardiac Events (MACE) – Narrow Definition
SAC [1]
12.37.
ITT
Study Specific
Summary of Major Cardiac Events (MACE) – Broad Definition
SAC [1]
Laboratory: Chemistry 
12.38.
ITT
LB1
Summary of Chemistry Data
SAC [1]
12.39.
ITT
LB1
Summary of Chemistry Changes from Baseline 
ICH E3
Includes Baseline values.
Includes pre-specified parameters 
repeated in conventional units.
SAC [1]
12.40.
ITT
LB3
Summary of Chemistry Shifts from Baseline Relative to Normal 
Range
SAC [1]
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Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Laboratory: Hematology
12.41.
ITT
LB1
Summary of Hematology Data
SAC [1]
12.42.
ITT
LB1
Summary of Hematology Changes from Baseline
ICH E3
Includes baseline values.
SAC [1]
12.43.
ITT
LB3
Summary of Hematology Shifts from Baseline Relative to 
Normal Range
SAC [1]
Laboratory: Urinalysis
12.44.
ITT
UR1
Summary of Worst Case Urinalysis Results (Discrete or 
Character Values) Post-Baseline Relative to Baseline
ICH E3
As above for Chemistry, using 
dipstick categories.
Define change categories according 
to actual values expected from lab 
dataset
SAC [1]
Vital Signs
12.45.
ITT
VS1
Summary of Vital Signs
ICH E3
Includes Baseline values.
SAC [1]
12.46.
ITT
VS1
Summary of Change from Baseline in Vital Signs
ICH E3
Includes Baseline values.
SAC [1]
ECG
12.47.
ITT
EG2
Summary of ECG Values 
IDSL
SAC [1]
12.48.
ITT
EG2
Summary of Change from Baseline in ECG Values
IDSL
SAC [1]
12.49.
ITT
Study Specific
Summary of Categories for QTc (F) Values (Interim)
IDSL
SAC [1]
12.50.
ITT
Study Specific
Summary of Categories for Change from Baseline in QTc (F) 
Values (Interim)
IDSL
SAC [1]
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Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
12.51.
ITT
EG1
Summary of ECG Findings 
IDSL
As above for Chemistry, using ECG 
findings categories (and change 
from baseline categories, if 
applicable).
SAC [1]
12.52.
ITT
Study Specific
Summary of ECG Findings Shifts from Baseline
SAC [1]
Pneumonia and Radiography (Chest X-Rays)
12.53.
ITT
Study Specific
Summary of On-Treatment Pneumonia, Including Chest X-ray 
Finding
IDSL
SAC [1]
11.11.7.
Other Tables (interim)
Other Endpoint: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Other Endpoints
3.1.
ITT
Study Specific
Summary of Trough FEV1 (L) (Interim)
IA [1]
3.2.
ITT
Study Specific
Summary of ACQ-7 Total Score (Interim)
IA [1]
3.3.
ITT
Study Specific
Summary of SGRQ Total Score (Interim)
IA [1]
3.4.
ITT
Study Specific
Summary of AQLQ Total Score (Interim)
IA [1]
3.5.
ITT
Study Specific
Summary of Severe Asthma Exacerbations (Interim)
IA [1]
3.6.
ITT
Study Specific
Summary of Moderate/Severe Asthma Exacerbations (Interim)
IA [1]
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11.11.8.
Other Tables (final)
Other Endpoint: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Other Endpoints
13.1.
ITT
Study Specific
Summary of Trough FEV1 (L)
SAC [1]
13.2.
ITT
Study Specific
Summary of ACQ-7 Total Score
SAC [1]
13.3.
ITT
Study Specific
Summary of SGRQ Total Score
SAC [1]
13.4.
ITT
Study Specific
Summary of AQLQ Total Score
SAC [1]
13.5.
ITT
Study Specific
Summary of Unscheduled Asthma-Related Healthcare Resource 
Utilization Over the 52 Weeks of the Treatment Period
SAC [1]
13.6.
ITT
Study Specific
Summary of Severe Asthma Exacerbations 
SAC [1]
13.7.
ITT
Study Specific
Summary of Moderate/Severe Asthma Exacerbations 
SAC [1]
13.8.
ITT
Study Specific
Summary of Annualized rate of Severe Asthma Exacerbations 
and Moderate/Severe Asthma Exacerbations 
SAC [1]
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11.11.9.
ICH Listings (interim)
ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.
Screened
ES7
Listing of Reasons for Screen Failure or Run-in Failure
Journal Guidelines
IA [1]
2.
ITT
ES2
Listing of Reasons for Study Withdrawal
ICH E3
Required for all studies except 
single dose studies.
IA [1]
3.
ITT
SD3
Listing of Reasons for Study Treatment Discontinuation
ICH E3
IA [1]
4.
ITT
TA1
Listing of Planned and Actual Treatments
IDSL
Note: IDSL shell in development.
IA [1]
Protocol Deviations
5.
ITT
DV2
Listing of Important Protocol Deviations 
ICH E3
Listing also includes analysis 
population exclusions.
IA [1]
6.
ITT
IE3
Listing of Participants with Inclusion/Exclusion Criteria 
Deviations
ICH E3
IA [1]
Populations Analysed
7.
Enrolled
SP3
Listing of Participants Excluded from Any Population
ICH E3
e.g., participants screened but not 
randomized, participants 
randomized but not treated, 
participants with deviations leading 
to exclusion from per protocol 
population (can be separate listing 
per population).
IA [1]
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ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Demographic and Baseline Characteristics
8.
ITT
DM2
Listing of Demographic Characteristics
ICH E3
IA [1]
9.
ITT
DM9
Listing of Race
ICH E3
IA [1]
Prior and Concomitant Medications
10.
ITT
CM3
Listing of Asthma Concomitant Medications
IA [1]
11.
ITT
CM3
Listing of Non-Asthma Concomitant Medications
IA [1]
12.
ITT
CM6
Relationship between ATC Level 1, Ingredient and Verbatim 
Text for Non-Asthma Medications
IA [1]
Exposure and Treatment Compliance
13.
ITT
EX3
Listing of Exposure Data
ICH E3
IA [1]
14.
ITT
Study Specific
Listing of Treatment Compliance Data
ICH E3
IA [1]
Adverse Events
15.
ITT
AE8
Listing of All Adverse Events
ICH E3
IA [1]
16.
ITT
AE7
Listing of Subject Numbers for Individual Adverse Events
ICH E3
IA [1]
17.
ITT
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text
IDSL
IA [1]
Serious and Other Significant Adverse Events
18.
ITT
AE8
Listing of Fatal Serious Adverse Events
ICH E3
Fatal and Non-Fatal SAEs are 
combined into a single listing for 
ClinPharm studies (i.e., “Listing of 
Serious Adverse Events”).
IA [1]
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ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
19.
ITT
AE8
Listing of Non-Fatal Serious Adverse Events
ICH E3
Fatal and Non-Fatal SAEs are 
combined into a single listing for 
ClinPharm studies (i.e., “Listing of 
Serious Adverse Events”).
IA [1]
20.
ITT
AE14
Listing of Reasons for Considering as a Serious Adverse Event
ICH E3
IA [1]
21.
ITT
AE8
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment
ICH E3
IA [1]
22.
ITT
AE8
Listing of Adverse Events of Special Interest
ICH E3
Required for studies where 
interventions other than withdrawal 
from treatment or study are 
possible.
IA [1]
Hepatobiliary (Liver)
23.
ITT
MH2
Listing of Medical Conditions for Participants with Liver 
Stopping Events
IDSL
IA [1]
24.
ITT
SU2
Listing of Substance Use for Participants with Liver Stopping 
Events
IDSL
IA [1]
25.
ITT
LIVER5
Listing of Liver Monitoring/Stopping Event Reporting
IDSL
IA [1]
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ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
All Laboratory
26.
ITT
LB5
Listing of Chemistry Values for Subjects with Any Value 
Outside Normal Range
ICH E3
May be split into separate listings 
by chemistry, hematology, etc. 
Display ALL labs for a subject who 
experienced a value of potential 
clinical importance.
IA [1]
27.
ITT
LB5
Listing of Haematology Values for Subjects with Any Value 
Outside Normal Range
ICH E3
May be split into separate listings 
by chemistry, hematology, etc. 
Display ALL labs for a subject who 
experienced a value of potential 
clinical importance.
IA [1]
ECG
28.
ITT
EG3 
(modified)
Listing of ECG Values for Subjects with any Abnormal ECG 
Finding
IDSL
Required for ClinPharm studies 
only.
IA [1]
29.
ITT
EG5
Listing of Abnormal ECG Findings
IDSL
Required for ClinPharm studies 
only.
IA [1]
Vital Signs
30.
ITT
VS4
Listing of Vital Signs
IDSL
Required for ClinPharm studies 
only.
IA [1]
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11.11.10. Non-ICH Listings (interim)
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Study Population
31.
ITT
MH2
Listing of Medical Conditions
IA [1]
32.
ITT
Study Specific
Listing of Family History of Cardiovascular Risk Factors
IA [1]
33.
ITT
Study Specific
Listing of Asthma Duration and Exacerbation History
IA [1]
34.
ITT
SU2
Listing of Smoking History and Status
IA [1]
35.
ITT
Study Specific
Listing of Inhaler Malfunctions
IA [1]
36.
ITT
Study Specific
Listing of Clinic Spirometry at Baseline
IA [1]
Other
37.
ITT
Study Specific
Listing of Trough FEV1 (L) Data
IA [1]
38.
ITT
Study Specific
Listing of ACQ Scores
IA [1]
39.
ITT
Study Specific
Listing of SGRQ Scores
IA [1]
40.
ITT
Study Specific
Listing of AQLQ Scores
IA [1]
41.
ITT
Study Specific
Listing of Moderate/Severe Asthma Exacerbations
IA [1]
Safety
42.
ITT
Study Specific
Listing of Pneumonia Data, including Chest X-ray Finding
IA [1]
43.
ITT
Study Specific
Listing of Bone Fracture Data
IA [1]
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11.11.11. ICH Listings (final)
ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
44.
Screened
ES7
Listing of Reasons for Screen Failure or Run-in Failure
Journal Guidelines
SAC [1]
45.
ITT
ES2
Listing of Reasons for Study Withdrawal
ICH E3
Required for all studies except 
single dose studies.
SAC [1]
46.
ITT
SD3
Listing of Reasons for Study Treatment Discontinuation
ICH E3
SAC [1]
47.
ITT
TA1
Listing of Planned and Actual Treatments
IDSL
Note: IDSL shell in development.
SAC [1]
Protocol Deviations
48.
ITT
DV2
Listing of Important Protocol Deviations 
ICH E3
Listing also includes analysis 
population exclusions.
SAC [1]
49.
ITT
IE3
Listing of Participants with Inclusion/Exclusion Criteria 
Deviations
ICH E3
SAC [1]
Populations Analysed
50.
Enrolled
SP3
Listing of Participants Excluded from Any Population
ICH E3
e.g., participants screened but not 
randomized, participants 
randomized but not treated, 
participants with deviations leading 
to exclusion from per protocol 
population (can be separate listing 
per population).
SAC [1]
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ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Demographic and Baseline Characteristics
51.
ITT
DM2
Listing of Demographic Characteristics
ICH E3
SAC [1]
52.
ITT
DM9
Listing of Race
ICH E3
SAC [1]
Prior and Concomitant Medications
53.
ITT
CM3
Listing of Asthma Concomitant Medications
SAC [1]
54.
ITT
CM3
Listing of Non-Asthma Concomitant Medications
SAC [1]
55.
ITT
CM6
Relationship between ATC Level 1, Ingredient and Verbatim 
Text for Non-Asthma Medications
SAC [1]
Exposure and Treatment Compliance
56.
ITT
EX3
Listing of Exposure Data
ICH E3
SAC [1]
57.
ITT
Study Specific
Listing of Treatment Compliance Data
ICH E3
SAC [1]
Adverse Events
58.
ITT
AE8
Listing of All Adverse Events
ICH E3
SAC [1]
59.
ITT
AE7
Listing of Subject Numbers for Individual Adverse Events
ICH E3
SAC [1]
60.
ITT
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text
IDSL
SAC [1]
Serious and Other Significant Adverse Events
61.
ITT
AE8
Listing of Fatal Serious Adverse Events
ICH E3
Fatal and Non-Fatal SAEs are 
combined into a single listing for 
ClinPharm studies (i.e., “Listing of 
Serious Adverse Events”).
SAC [1]
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ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
62.
ITT
AE8
Listing of Non-Fatal Serious Adverse Events
ICH E3
Fatal and Non-Fatal SAEs are 
combined into a single listing for 
ClinPharm studies (i.e., “Listing of 
Serious Adverse Events”).
SAC [1]
63.
ITT
AE14
Listing of Reasons for Considering as a Serious Adverse Event
ICH E3
SAC [1]
64.
ITT
AE8
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment
ICH E3
SAC [1]
65.
ITT
AE8
Listing of Adverse Events of Special Interest
ICH E3
Required for studies where 
interventions other than withdrawal 
from treatment or study are 
possible.
SAC [1]
Hepatobiliary (Liver)
66.
ITT
MH2
Listing of Medical Conditions for Participants with Liver 
Stopping Events
IDSL
SAC [1]
67.
ITT
SU2
Listing of Substance Use for Participants with Liver Stopping 
Events
IDSL
SAC [1]
68.
ITT
LIVER5
Listing of Liver Monitoring/Stopping Event Reporting
IDSL
SAC [1]
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ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
All Laboratory
69.
ITT
LB5
Listing of Chemistry Values for Subjects with Any Value 
Outside Normal Range
ICH E3
May be split into separate listings 
by chemistry, hematology, etc. 
Display ALL labs for a subject who 
experienced a value of potential 
clinical importance.
SAC [1]
70.
ITT
LB5
Listing of Haematology Values for Subjects with Any Value 
Outside Normal Range
ICH E3
May be split into separate listings 
by chemistry, hematology, etc. 
Display ALL labs for a subject who 
experienced a value of potential 
clinical importance.
SAC [1]
71.
ITT
UR2A
Listing of Urinalysis Data (Protein and Occult Blood)
Protein and occult blood only.
All subjects data need to be 
displayed.
SAC [1]
ECG
72.
ITT
EG3 
(modified)
Listing of ECG Values for Subjects with any Abnormal ECG 
Finding
IDSL
Required for ClinPharm studies 
only.
SAC [1]
73.
ITT
EG5
Listing of Abnormal ECG Findings
IDSL
Required for ClinPharm studies 
only.
SAC [1]
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ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Vital Signs
74.
ITT
VS4
Listing of Vital Signs
IDSL
Required for ClinPharm studies 
only.
SAC [1]
11.11.12. Non-ICH Listings (final)
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Study Population
75.
ITT
MH2
Listing of Medical Conditions
SAC [1]
76.
ITT
Study Specific
Listing of Family History of Cardiovascular Risk Factors
SAC [1]
77.
ITT
Study Specific
Listing of Asthma Duration and Exacerbation History
SAC [1]
78.
ITT
SU2
Listing of Smoking History and Status
SAC [1]
79.
ITT
Study Specific
Listing of Inhaler Malfunctions
SAC [1]
80.
ITT
Study Specific
Listing of Clinic Spirometry at Baseline
SAC [1]
Other
81.
ITT
Study Specific
Listing of Trough FEV1 (L) Data
SAC [1]
82.
ITT
Study Specific
Listing of ACQ Scores
SAC [1]
83.
ITT
Study Specific
Listing of SGRQ Scores
SAC [1]
84.
ITT
Study Specific
Listing of AQLQ Scores
SAC [1]
2019N423945_00


CONFIDENTIAL
207236
87
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
85.
ITT
Study Specific
Listing of Unscheduled Asthma-Related Healthcare 
Resource Utilization Over the 52
SAC [1]
86.
ITT
Study Specific
Listing of Moderate/Severe Asthma Exacerbations
SAC [1]
Safety
87.
ITT
Study Specific
Listing of Pneumonia Data, including Chest X-ray Finding
SAC [1]
88.
ITT
Study Specific
Listing of Bone Fracture Data
SAC [1]
89.
ITT
LIVER5
Listing of Liver Event Results and Time of Event Relative to
Treatment
SAC [1]
90.
ITT
LIVER6
Listing of Liver Event Information for RUCAM Score
SAC [1]
91.
ITT
LIVER7
Listing of Liver Biopsy Details
SAC [1]
92.
ITT
LIVER8
Listing of Liver Imaging Details
SAC [1]
93.
Screened
IDSL
Patient Profile for Arrhythmias
SAC [1]
94.
Screened
IDSL
Patient Profile for Congestive Heart Failure
SAC [1]
95.
Screened
IDSL
Patient Profile for Cerebrovascular Events/Stroke
SAC [1]
96.
Screened
IDSL
Patient Profile for Deep Vein Thrombosis / Pulmonary Embolism
SAC [1]
97.
Screened
IDSL
Patient Profile for Myocardial Infarction / Unstable Angina
SAC [1]
98.
Screened
IDSL
Patient Profile for Hypertension
SAC [1]
99.
Screened
IDSL
Patient Profile for Revascularization
SAC [1]
100.
Screened
IDSL
Patient Profile for Valvulopathy
SAC [1]
101.
Screened
IDSL
Patient Profile for All Cause Deaths
SAC [1]
2019N423945_00