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
Phase: PHASE3
Conditions: Asthma
Sponsor: GlaxoSmithKline

2016N305271_02_English
CONFIDENTIAL
207236
1
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.
2019N423945_00
PPD

2019N423945_00
PPD
PPD

2016N305271_02_English
CONFIDENTIAL
207236
3
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
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
4
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
2019N423945_00
PPD
PPD
PPD
PPD

2016N305271_02_English
CONFIDENTIAL
207236
5
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: 
2019N423945_00
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

2016N305271_02_English
CONFIDENTIAL
207236
6
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.
2019N423945_00
PPD
PPD
PPD
PPD

2016N305271_02_English
CONFIDENTIAL
207236
7
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
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
8
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
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
9
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
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
10
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.
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
11
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
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
12
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).
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
13
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.
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
14
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.
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 15 -
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
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 16 -
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
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 17 -
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
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 18 -
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.
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 19 -
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.
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 20 -
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 .
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 21 -
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
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 22 -
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.
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 23 -
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 
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 24 -
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 
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 25 -
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.
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 26 -
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).
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 27 -
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
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 28 -
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.
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 29 -
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).
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 30 -
∀
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”.
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 31 -
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.
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 32 -
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.
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 33 -
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.
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 34 -
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)
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 35 -
∀
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:
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 36 -
∀
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
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 37 -
∀
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.
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 38 -
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.
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 39 -
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.
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 40 -
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.
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 41 -
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. 
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 42 -
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.
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 43 -
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.
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 44 -
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 
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 45 -
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.)
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 46 -
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) 
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 47 -
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
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 48 -
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
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 49 -
∀
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.
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 50 -
∀
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)
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 51 -
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. .
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 52 -
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. 
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 53 -
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.
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 54 -
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.
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 55 -
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.
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 56 -
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.
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 57 -
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.
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 58 -
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).
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 59 -
∀
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].
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 60 -
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 
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 61 -
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 
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 62 -
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.
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 63 -
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.
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 64 -
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. 
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 65 -
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.
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 66 -
11.
REFERENCES
American Heart Association. Classes of Heart Failure. Available at URL (2017.1.30): 
http://www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classes-
of-Heart-Failure_UCM_306328_Article.jsp. 2016 May 4:.
Asthma Prevention and Management Guideline, Japan for adults 2015 (JGL Asthma 
2015), guideline 2015 committee, Japan Kyowa Kikaku, 2015 May 25.
British Thoracic Society / Scottish Intercollegiate Guidelines Network (BTS/SIGN). 
British Guideline on the Management of Asthma. Available at URL (2017.1.30): 
https://www.brit-thoracic.org.uk/guidelines-and-quality-standards/asthma-guideline/. 
2014:.
Ducharme FM, Ni Chroinin M, Greenstone I, et al. Addition of long-acting beta2-
agonists to inhaled steroids versus higher dose inhaled steroids in adults and children 
with persistent asthma. Cochrane Database Syst Rev. 2010; 14(4):CD005533.
National Asthma Education and Prevention Programme, National Heart, Lung and Blood 
Institute, National Institutes of Health (NIH). Expert Panel Report 3: Guidelines for the 
Diagnosis and Management of Asthma. Available at URL (2017.1.30): 
http://www.nhlbi.nih.gov/health-pro/guidelines/current/asthma-guidelines. 2007:.
Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and 
Prevention. Available at URL (2017.1.30): http://www.ginasthma.org. 2016:.
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the 
Diagnosis, Management and Prevention of chronic obstructive pulmonary disease. 
Available at URL (2017.1.30): http://goldcopd.org/. 2016:. 
Hekking PP, Wener RR, Amelink M, et al. The prevalence of severe refractory asthma. J 
Allergy Clin Immunol. 2015; 135(4):896-902.
James LP, Letzig L, Simpson PM, et al. Pharmacokinetics of acetaminophen-protein 
adducts in adults with acetaminophen overdose and acute liver failure. Drug Metab 
Dispos. 2009; 37: 1779-1784.
Jones PW, Quirk FH, Baveystock CM, et al. A self-complete measure of health status for 
chronic airflow limitation. The St. George's Respiratory Questionnaire. Am Rev Respir 
Dis. 1992; 145: 1321-1327. 
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 67 -
Jones PW. St. George’s Respiratory Questionnaire: MCID. Journal of Chronic 
Obstructive Pulmonary Disease. 2005; 2: 75-79.
Juniper EF, Bousquet J, Abetz L, et al. GOAL Committee. Identifying 'well-controlled' 
and 'not well-controlled' asthma using the Asthma Control Questionnaire. Respir Med. 
2006;100:616-621.
Juniper EF, Guyatt GH, Willan A, et al. Determining a minimal important change in a 
disease-specific quality of life instrument. J Clin Epidemiol. 1994; 47:81-87.
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 
three shortened versions of the asthma control questionnaire. Respir Med. 2005; 99:553-
558.
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. 
Lancet Respir Med. 2015; 3: 367-376.
Kerstjens H, Engle M, Dahl R, et al. Tiotropium in asthma poorly controlled with 
standard combination therapy. N Engl J Med. 2012; 367:1198-1207.
Le Gal F, Gordien E, Affolabi D, et al. 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.
Miller MR. Standardization of Lung Function Testing. Eur Resp J. 2005; 26:153-161.
Reddel HK, Taylor DR, Bateman ED, et al. on behalf of the American Thoracic 
Society/European Respiratory Society task force on asthma control and exacerbations. An 
official American Thoracic Society/European Respiratory Society statement: asthma 
control and exacerbations; standardizing endpoints for clinical asthma trials and clinical 
practice. Am J Respir Crit Care Med. 2009; 180: 59-99.
Schatz M, Meckley LM, Kim M, et al. Asthma exacerbation rates in adults are unchanged 
over a 5-year period despite high-intensity therapy. J Allergy Clin Immunol Pract. 2014;
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 68 -
2:570-574. 
Spiriva Respimat Summary of Product Characteristics (SPC), Boerhringer Ingelheim. 
Available at URL (2017.1.30): http://www.medicines.org.uk/emc/medicine/20134/SPC. 
2016:. 
Spiriva Respimat US Prescribing Information (USPI), Boehringer Ingelheim. Available at 
URL (2017.1.30): http://docs.boehringer-
ingelheim.com/Prescribing%20Information/PIs/Spiriva%20Respimat/spirivarespimat.pdf. 
2016:. 
Spiriva® 1.25 mcg/2.5 mcg Respimat® 60 puffs. Tiotropium bromide hydrate package 
insert. August 2016 Revision (Version 7). 2016.
Stanford RH, Gilsenan AW, Ziemiecki R, et al. Predictors of uncontrolled asthma in adult 
and pediatric patients: analysis of the Asthma Control Characteristics and Prevalence 
Survey Studies (ACCESS). J Asthma. 2010; 47:257-262.
U.S. Department of Health and Human Services Food and Drug Administration (FDA). 
Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation. 
Available at URL (2017.1): 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guida
nces/UCM174090.pdf. 
Virchow JC, Backer V, de Blay F, et al. Defining moderate asthma exacerbations in 
clinical trials based on ATS/ERS joint statement. Respiratory Medicine. 2015; 109:547-
556.
Wyrwich KW, Khan SA, Navaratnam P, et al. Validation and agreement across four 
versions of the asthma control questionnaire in patients with persistent asthma. Resp Med.
2011; 105: 698-712.
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 69 -
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
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 70 -
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
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 71 -
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
－
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 72 -
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
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 73 -
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. 
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 74 -
∀
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
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 75 -
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); 
2019N423945_00
PPD
PPD
PPD
PPD

2016N305271_02_English
CONFIDENTIAL
207236
- 76 -
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
2019N423945_00
PPD
PPD
PPD
PPD
PPD
PPD
PPD

2016N305271_02_English
CONFIDENTIAL
207236
- 77 -
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
2019N423945_00
PPD

2016N305271_02_English
CONFIDENTIAL
207236
- 78 -
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 
2019N423945_00
PPD

2016N305271_02_English
CONFIDENTIAL
207236
- 79 -
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.
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 80 -
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.
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 81 -
∀
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 
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 82 -
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 
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 83 -
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.
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 84 -
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. 
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 85 -
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
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 86 -
∀
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.
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 87 -
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 
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 88 -
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).
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 89 -
∀
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.  
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 90 -
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.
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 91 -
12.7.
Appendix 7: Country-specific requirements
No country-specific requirements
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 92 -
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
2019N423945_00

2016N305271_02_English
CONFIDENTIAL
207236
- 93 -
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.
2019N423945_00