A Phase IIIB, 24-week Randomised, Double-blind Study to Compare 'Closed' Triple Therapy (FF/UMEC/VI) With 'Open' Triple Therapy (FF/VI + UMEC), in Subjects With Chronic Obstructive Pulmonary Disease (COPD)
Phase: PHASE3
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: GlaxoSmithKline

2015N261999_03
CONFIDENTIAL
The GlaxoSmithKline group of companies
200812
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A phase IIIB, 24-week randomised, double-blind study to 
compare ‘closed’ triple therapy (FF/UMEC/VI) with 'open' triple 
therapy (FF/VI + UMEC), in subjects with chronic obstructive 
pulmonary disease (COPD)
Compound Number:
GW642444+GSK573719+GW685698
Development Phase:
IIIB
Effective Date:
29-JUN-2016
Protocol Amendment Number:  03
Author (s):
 
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD

2015N261999_03
CONFIDENTIAL
The GlaxoSmithKline group of companies
200812
2
Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2015N261999_00
2015-DEC-09
Original
2015N261999_01
2016-JAN-25
Amendment No. 1- Global
1. Synopsis, Section 1 and Overall Design, Section 4.1: Text updated to include the 
requirement for an early withdrawal study for subjects who stop study treatment 
early. 
2. Time and Events Table, Section 7.1: Scheduling of pulse oximetry corrected and 
scheduling of genetics sample collection revised.
3. Appendix 3 - Genetics Research: Text corrected to include combinations of study 
medications used in the protocol and the scheduled visit for sample collection revised. 
Appendix 8 – Hair Sample, Scalp & Finger Secretion PK Sub-Study: Discrepancy 
regarding the timing of sample collection corrected.
2015N261999_02
2016-FEB-11
Amendment No. 2- South 
Korea ONLY
Appendix 6 updated, for South Korea, with study medication labeling and information 
regarding study equipment.
2015N261999_03
2016-JUN-29
Amendment No. 3- Global 
(excluding South Korea)
1. Minor discrepancies corrected and clarifications made to some of the footnotes in 
the Time and Events Table. 
2. The requirement of two views (posteroanterior and lateral) for Screening chest x-
rays and chest x-rays for suspected pneumonias and moderate/severe 
exacerbations specified. 
3. Reference section updated.
4. A minor update to the wording for when the genetics sample can be collected 
made in the Time and Events Table and  Appendix 3. 

PPD
PPD
PPD

2015N261999_03
CONFIDENTIAL
200812
4
MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information: 
Role
Name
Day Time Phone Number and 
email address
After-hours 
Phone/Cell/
Pager 
Number
Site Address
Primary 
Medical 
Monitor 
 
 
GlaxoSmithKline
Stockley Park 
West, 
Uxbridge, 
Middlesex, UB11 
1BT, UK
Secondary 
Medical 
Monitor
 
 
709 Swedeland 
Road, UW2531
King of Prussia, PA 
19406
SAE contact  
information 
Medical 
monitor as 
above 
Sponsor Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.   
Regulatory Agency Identifying Number:
EudraCT Number: 2015-005212-14
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

2015N261999_03
CONFIDENTIAL
200812
5
INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 200812
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:  _____________________________
Investigator Signature
Date

2015N261999_03
CONFIDENTIAL
200812
6
TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 200812......................................................10
2.
INTRODUCTION....................................................................................................14
2.1.
Study Rationale ..........................................................................................14
2.2.
Brief Background ........................................................................................15
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................15
4.
STUDY DESIGN ....................................................................................................17
4.1.
Overall Design ............................................................................................17
4.2.
Treatment Arms and Duration.....................................................................18
4.3.
Type and Number of Subjects.....................................................................19
4.4.
Design Justification.....................................................................................19
4.5.
Dose Justification........................................................................................19
4.6.
Benefit: Risk Assessment ...........................................................................19
4.6.1.
Risk Assessment .........................................................................20
4.6.2.
Benefit Assessment.....................................................................28
4.6.3.
Overall Benefit: Risk Conclusion..................................................29
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............30
5.1.
Inclusion Criteria.........................................................................................30
5.2.
Exclusion Criteria........................................................................................32
5.3.
Randomisation Criteria ...............................................................................35
5.4.
Screening/Baseline/Run-in Failures............................................................35
5.5.
Withdrawal/Stopping Criteria.......................................................................36
5.5.1.
Protocol defined withdrawal criteria..............................................36
5.5.2.
Liver Chemistry Stopping Criteria ................................................36
5.6.
Subject and Study Completion....................................................................38
6.
STUDY TREATMENT ............................................................................................38
6.1.
Investigational Product and Other Study Treatment....................................38
6.1.1.
Storage........................................................................................40
6.1.2.
Investigational Product and albuterol/salbutamol Return..............40
6.2.
Medical Devices..........................................................................................40
6.3.
Treatment Assignment................................................................................41
6.4.
Blinding.......................................................................................................41
6.5.
Packaging and Labeling..............................................................................42
6.6.
Preparation/Handling/Storage/Accountability..............................................42
6.7.
Compliance with Study Treatment Administration.......................................43
6.8.
Treatment of Study Treatment Overdose....................................................43
6.9.
Treatment after the End of the Study ..........................................................43
6.10.
Concomitant Medications and Non-Drug Therapies....................................43
6.10.1.
Permitted Medications and Non-Drug Therapies..........................44
6.10.2.
Prohibited Medications and Non-Drug Therapies.........................45
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................46
7.1.
Time and Events Table...............................................................................47
7.2.
Screening and Critical Baseline Assessments ............................................50

2015N261999_03
CONFIDENTIAL
200812
7
7.2.1.
COPD Assessment Test (CAT)....................................................51
7.3.
Efficacy.......................................................................................................51
7.3.1.
Primary Efficacy Endpoint............................................................51
7.3.2.
Secondary Efficacy Endpoints .....................................................51
7.3.3.
Spirometry and Reversibility Testing............................................51
7.3.3.1.
Spirometry..................................................................51
7.3.3.2.
Reversibility................................................................52
7.3.4.
SGRQ-C ......................................................................................52
7.3.5.
Baseline Dyspnoea Index/Transitional Dyspnoea Index...............53
7.3.6.
COPD Exacerbations...................................................................53
7.4.
Safety .........................................................................................................53
7.4.1.
Safety endpoints..........................................................................53
7.4.2.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........53
7.4.2.1.
Time period and Frequency for collecting AE 
and SAE information...................................................54
7.4.2.2.
Method of Detecting AEs and SAEs ...........................54
7.4.2.3.
Follow-up of AEs and SAEs........................................54
7.4.2.4.
Cardiovascular and Death Events ..............................55
7.4.2.5.
Regulatory Reporting Requirements for SAEs............55
7.4.3.
Adverse Events of Special Interest (AESIs) .................................55
7.4.4.
Electrocardiogram (ECG).............................................................56
7.4.5.
Vital Signs....................................................................................57
7.4.6.
Clinical Safety Laboratory Assessments ......................................57
7.4.7.
Other Safety Assessments ..........................................................58
7.4.8.
Physical Exams ...........................................................................58
7.4.9.
Pneumonia ..................................................................................59
7.4.10.
Pulse oximetry .............................................................................59
7.4.11.
Radiography (Chest X-Rays) .......................................................59
7.4.12.
Pregnancy ...................................................................................60
7.4.13.
Medical Problems and Concomitant Medications.........................60
7.5.
Pharmacokinetics .......................................................................................60
7.5.1.
Blood Sample Collection..............................................................60
7.5.2.
Sample Analysis ..........................................................................61
7.6.
Genetics .....................................................................................................61
8.
DATA MANAGEMENT ...........................................................................................61
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................61
9.1.
Hypotheses.................................................................................................61
9.2.
Sample Size Considerations.......................................................................62
9.2.1.
Sample Size Assumptions ...........................................................62
9.2.1.1.
Sample Size Sensitivity ..............................................62
9.2.2.
Sample Size Re-estimation or Adjustment...................................63
9.3.
Data Analysis Considerations .....................................................................64
9.3.1.
Analysis Populations....................................................................64
9.4.
Key Elements of Analysis Plan ...................................................................64
9.4.1.
Treatment Comparisons ..............................................................64
9.4.2.
Primary Analyses.........................................................................65
9.4.3.
Other Efficacy Analyses...............................................................65
9.4.4.
Safety Analyses...........................................................................65
10. STUDY GOVERNANCE CONSIDERATIONS........................................................66

2015N261999_03
CONFIDENTIAL
200812
8
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............66
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................66
10.3.
Quality Control (Study Monitoring) ..............................................................67
10.4.
Quality Assurance.......................................................................................67
10.5.
Study and Site Closure ...............................................................................67
10.6.
Records Retention......................................................................................68
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................69
11. REFERENCES.......................................................................................................70
12. APPENDICES........................................................................................................74
12.1.
Appendix 1 – Abbreviations and Trademarks..............................................74
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................76
12.3.
Appendix 3 - Genetic Research ..................................................................80
12.4.
Appendix 4: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................83
12.4.1.
Definition of Adverse Events........................................................83
12.4.2.
Definition of Serious Adverse Events...........................................84
12.4.3.
Definition of Cardiovascular Events .............................................85
12.4.4.
Recording of AEs and SAEs ........................................................86
12.4.5.
Evaluating AEs and SAEs............................................................86
12.4.6.
Reporting of SAEs to GSK...........................................................88
12.5.
Appendix 5: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in FRP and Collection of Pregnancy Information.......................90
12.5.1.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) ..............90
12.5.2.
Collection of Pregnancy Information ............................................91
12.6.
Appendix 6 - Country Specific Requirements..............................................92
12.7.
Appendix 7 – COPD Exacerbation Identification, Categorization and 
Treatment Guidelines..................................................................................93
12.7.1.
Guidelines for Identifying COPD Exacerbations...........................93
12.7.1.1.
COPD Exacerbation Severity .....................................94
12.7.1.2.
Treatment of COPD Exacerbations ............................94
12.7.1.3.
Guidelines for Treatment with Corticosteroids ............95
12.7.1.4.
Guidelines for Treatment with Antibiotics....................95
12.7.1.5.
Onset and Resolution of COPD Exacerbations...........95
12.7.1.6.
Guideline for assessing multiple mild 
exacerbations.............................................................95
12.7.1.7.
Guideline for assessing exacerbations that 
increase in severity.....................................................96
12.8.
Appendix 8 – Hair Sample, Scalp & Finger Secretion PK Sub-Study ..........97
12.8.1.
Introduction..................................................................................97
12.8.2.
Objective......................................................................................97
12.8.3.
Investigational Plan......................................................................98
12.8.4.
Subject Selection and Withdrawal Criteria .................................101
12.8.4.1.
Inclusion Criteria.......................................................101
12.8.4.2.
Exclusion Criteria .....................................................101
12.8.5.
Sub-study Withdrawal Criteria....................................................101
12.8.6.
Potential Risks Associated with Sub-Study Participation............102

2015N261999_03
CONFIDENTIAL
200812
9
12.9.
Appendix 9 – Protocol Changes................................................................103
12.9.1.
Protocol Amendment 1 ..............................................................103
12.9.2.
Country-Specific Protocol Amendment 2 for South Korea..........105
12.9.3.
Protocol Amendment 3 (excluding South Korea)........................105

2015N261999_03
CONFIDENTIAL
200812
10
1.
PROTOCOL SYNOPSIS FOR STUDY 200812
Rationale
GlaxoSmithKline (GSK) is currently developing a once-daily ‘closed’ triple therapy of a 
ICS/LAMA/LABA combination [fluticasone furoate (FF)/umeclidinium (UMEC)/ 
vilanterol (VI) (100mcg/62.5mcg/25mcg)] in a single inhaler, with the aim of providing a 
new treatment option for the management of advanced (GOLD Group D) COPD which 
will reduce the exacerbation frequency, allow for a reduced burden of polypharmacy, 
convenience, and improve lung function, health related quality of life (HRQoL) and 
symptom control over established dual/monotherapies.
The primary purpose of this study is to demonstrate the non-inferiority of closed triple 
therapy (FF/UMEC/VI) to open triple therapy (FF/VI + UMEC) on lung function.
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary

To compare the effect of FF/UMEC/VI 
with FF/VI + UMEC on lung function 
after 24 weeks of treatment

Change from baseline in trough FEV1
at 24 weeks
Secondary

To compare the effects of 
FF/UMEC/VI with FF/VI + UMEC on 
health related quality of life and 
dyspnoea after 24 weeks of treatment

Proportion of Responders based on the 
St George Respiratory Questionnaire 
(SGRQ) Total Score at Week 24

Change from baseline in SGRQ Total 
Score at Week 24

Proportion of Responders based on 
Transitional Dyspnoea Index (TDI) 
focal score at Week 24

TDI focal score at Week 24

To compare the effect of FF/UMEC/VI 
with FF/VI + UMEC on time to first 
moderate or severe exacerbation during 
24 weeks of treatment

Time to first moderate or severe 
exacerbation

2015N261999_03
CONFIDENTIAL
200812
11
Objectives
Endpoints
Pharmacokinetics (PK)

To compare the PK of FF, UMEC and 
VI when given as FF/UMEC/VI or 
FF/VI+UMEC in a subset of subjects 

Population PK (in a subset of 
approximately 180 subjects)
Safety

To compare the safety profile of
FF/UMEC/VI with FF/VI + UMEC
over 24 weeks of treatment

Incidence of adverse events

Incidence of adverse events of special 
interest1

ECG measurements

Vital signs

Haematological and clinical chemistry 
parameters
Overall Design
This is a phase IIIB, 24-week, randomised, double-blind, parallel group multicenter study 
evaluating FF/UMEC/VI (100mcg/62.5mcg/25mcg) via a single ELLIPTA™(‘closed 
triple’) plus matching placebo versus FF/VI + UMEC delivered via two ELLIPTA’s 
(‘open triple’), all taken once daily. The target enrollment is 1020 randomised subjects at 
approximately 150 study centres globally. Subjects will run-in on their existing COPD 
medications for 2 weeks and in addition will be provided with short acting 
albuterol/salbutamol to be used on an as-needed basis (rescue medication) throughout the 
study. Subjects will discontinue all existing COPD medications at the start of the 
randomised treatment period but may continue their study-supplied rescue 
albuterol/salbutamol.
Clinic Visits will occur at Pre-Screening (V0), Screening (V1), Randomisation (Week 0, 
V2), Week 4 (V3), Week 12 (V4) and Week 24 (V5). A safety follow-up telephone 
contact or clinic visit will be conducted 1 week after completing either randomised 
treatment or an Early Withdrawal Visit. Subjects will sign an informed consent form 
(ICF) at a Pre-Screen or Screening Visit (V1) and will be assigned a subject identifier.  
At Screening (V1), responses to the COPD Assessment Tool (CAT) questionnaire will be 
collected using an electronic device, prior to completing other Screening assessments. 
Subjects will self-administer their first doses of study treatment in the clinic during 
Randomisation (V2). On the morning of each study clinic visit, subjects will refrain from 
                                                
1 See Section 7.4.3. for further information on AESI’s 

2015N261999_03
CONFIDENTIAL
200812
12
taking their morning doses of study treatmentuntil instructed to do so by clinic personnel. 
At clinic visits, responses to questionnaires, SGRQ-C and Baseline Dyspnoea Index 
(BDI) and TDI, will be collected using an electronic device, in that order and prior to 
dosing or completing other assessments. Subjects will take their last dose of study 
treatment in the clinic during V5 and a safety follow-up will be conducted either by 
phone call or clinic visit approximately one week later. 
Approximately 180 subjects, in selected sites, will be asked to participate in PK research. 
There will be two PK groups (subset A and subset B). Approximately 120 subjects will 
be assigned to subset A and approximately 60 subjects will be assigned to subset B. 
Subjects in subset A will provide a blood sample at two time-points at Week 12 (V4) and 
at Week 24 (V5). Subjects in subset B will provide blood samples at seven time points at 
Week 12 (V4). 
Subjects providing PK samples for subset A may also be asked to take part in a hair 
sample, scalp & finger secretion PK Sub-Study. See Appendix 8 (Section 12.8).
A subject will be considered to have completed the study when they have completed all 
phases of the study including screening, run-in, the randomised treatment phase, and 
safety follow-up. Subjects who stop study treatment early will complete an Early
Withdrawal Visit, followed by a Safety Follow-Up a week later and finally be withdrawn 
from the study.
Treatment Arms and Duration
Subjects who meet all the inclusion/exclusion criteria and who have successfully 
completed all protocol procedures at Screening (V1) will enter the two-week run-in 
period. Following the run-in period, eligible subjects will be randomised (1:1) to one of 
the following double-blind treatment groups for 24 weeks.  

FF/UMEC/VI 100mcg/62.5mcg/25mcg and placebo, both via the ELLIPTA once 
daily in the morning.
or,

FF/VI 100mcg/25mcg and UMEC 62.5mcg, both via the ELLIPTA once daily in 
the morning.
The ELLIPTA contains 30 doses (FF/UMEC/VI, FF/VI, UMEC or placebo) and subjects 
will be instructed to administer one dose from each ELLIPTA once daily in the morning. 
The randomisation will be stratified based on long-acting bronchodilator usage during 
the run-in (none, one or two long-acting bronchodilators per day).
The total duration of subject participation will be approximately 27 weeks, consisting of a 
2-week run-in period, 24-week treatment period and a 1-week follow-up period.

2015N261999_03
CONFIDENTIAL
200812
13
Type and Number of Subjects
Approximately 1275 subjects with advanced COPD (GOLD Group D) will be screened in 
order to randomise approximately 1020 subjects in order to achieve an estimated 816 
subjects who are included in the Adherent Population and complete V5.
Approximately 150 centres globally will be required to recruit the study.
Analysis
The null hypothesis is that the difference in trough FEV1 between treatment groups is less 
than or equal to a pre-specified non-inferiority margin -Δ:
H0: T1 – T2 ≤ -Δ
The alternative hypothesis is that the difference between treatment groups is greater than 
the margin.
H1: T1 – T2 > -Δ
where T1 and T2 are the treatment means for FF/UMEC/VI and FF/VI+UMEC, 
respectively.
The non-inferiority margin has been set at 50mL, which is half the generally accepted 
minimal clinically important difference (MCID) for trough FEV1.
If the lower bound of the two-sided 95% confidence interval around the (FF/UMEC/VI 
vs. FF/VI+UMEC) treatment difference is above -50mL then FF/UMEC/VI will be 
considered non-inferior to FF/VI+UMEC.
The primary analysis population will be the Adherent Population, comprising all subjects 
randomized to treatment except those randomized in error, who do not have a full 
protocol deviation or other event considered to impact efficacy.
The primary treatment comparison is the comparison of FF/UMEC/VI with 
FF/VI+UMEC for the primary endpoint of trough FEV1 at Week 24. This comparison 
will be performed for the Adherent population, using data collected prior to 
withdrawal/completion of study treatment.
The primary treatment comparison will evaluate the “de jure” estimand for the primary 
endpoint of trough FEV1 at Week 24, in the Adherent population, using a mixed model 
repeated measures (MMRM) analysis, including trough FEV1 recorded at each of Weeks 
4, 12 and 24. The model will include covariates of stratum (number of long-acting 
bronchodilators taken per day during the run-in), baseline FEV1, Week, centre group, 
treatment and Week by baseline interaction. A Week by treatment interaction term will 
also be included to allow treatment effects to be estimated at each visit separately. The 
variance-covariance matrix will be assumed unstructured.

2015N261999_03
CONFIDENTIAL
200812
14
A “tipping point” sensitivity analysis of trough FEV1 will be conducted for the Adherent 
Population. This will explore the impact of missing data by using differing assumptions 
regarding the mean treatment effect in subjects who discontinue study treatment or have 
data excluded from Adherent Population analyses.  Assumptions will include scenarios 
where subjects who discontinue FF/UMEC/VI have a lower treatment effect than those 
who discontinue FF/VI+UMEC. The analysis results will be used to explore the 
conditions under which the conclusion of non-inferiority no longer holds. 
2.
INTRODUCTION
COPD guidelines advocate the use of one or more long-acting bronchodilators (long-
acting muscarinic receptor antagonists [LAMA]) or long-acting β2-adrenergic receptor 
agonists [LABA]) in addition to inhaled corticosteroids (ICS) as second line therapy for 
the most advanced patients with significant symptoms and a high risk of exacerbations. 
Regular treatment with ICS has been reported to improve respiratory symptoms, lung 
function, health related quality of life (HRQoL) and reduce the frequency COPD 
exacerbation in patients with a FEV1<60% predicted. Additionally, withdrawal of ICS 
treatment has also lead to exacerbations in some patients [GOLD, 2013].
Population based studies of COPD treatment patterns demonstrate that ‘open’ triple 
therapy (use of ICS/LAMA/LABA delivered via multiple inhalers) is already widely used 
in the real-life management of COPD. In 2011, 26% of patients in the USA who were 
taking controller medicines for the treatment of COPD were taking an ‘open’ triple 
therapy, typically by adding fluticasone propionate/salmeterol (ICS/LABA) to tiotropium 
(LAMA) or vice versa [Wolters, 2012]. A study in the UK Clinical Practice Research 
Database (CPRD) revealed that over a two year period of time, 35% of COPD patients 
initially prescribed a LAMA and 39% initially prescribed an ICS/LABA stepped up to an 
‘open’ triple therapy regimen [Wurst, 2013]. In the four year long term safety study 
conducted with tiotropium (LAMA), 46% of patients were receiving a concurrent fixed 
combination of ICS/LABA in addition to tiotropium [Tashkin, 2008]. 
2.1.
Study Rationale
GlaxoSmithKline (GSK) is currently developing a once-daily ‘closed’ triple therapy of an 
ICS/LAMA/LABA [Fluticasone furoate (FF)/Umeclidinium (UMEC)/Vilanterol (VI) 
(100mcg/62.5mcg/25mcg)] in a single inhaler, with the aim of providing a new treatment 
option for the management of advanced (GOLD Group D) COPD.  It is expected that this 
therapy will reduce the exacerbation frequency, allow for a reduced burden of 
polypharmacy, convenience, and improve lung function, HRQoL and symptom control 
compared to established dual/monotherapies.
The primary purpose of this study is to demonstrate the non-inferiority of closed triple 
therapy (FF/UMEC/VI) to open triple therapy (FF/VI + UMEC) on lung function.

2015N261999_03
CONFIDENTIAL
200812
15
2.2.
Brief Background
Adult patients with a clinical diagnosis of COPD have previously been exposed to the 
open triple combination FF/VI + UMEC, in two 12-week, placebo controlled studies 
(200109 and 200110).  In these studies, the addition of UMEC (62.5) to FF/VI (100/25) 
once daily, resulted in statistically significant and clinically meaningful improvements in 
the primary endpoint of trough FEV1 at Day 85 compared to placebo plus FF/VI (124 mL 
(95% CI 93, 154, p<0.001) and 122 mL (95% CI 91, 152, p<0.001)).  The safety profile 
for UMEC in combination with FF/VI was similar across treatment arms, and no additive 
effects or new safety concerns were identified.
Two healthy volunteer clinical pharmacology studies have also been conducted 
(CTT116415 and 200587) which supports the conclusion that there are no clinically 
relevant systemic pharmacokinetic or systemic pharmacodynamic interactions between 
the components of the closed triple combination product (FF, UMEC and VI) when 
administered through a single inhaler.
A number of studies have assessed the use of an ‘open’ triple therapy of fluticasone 
propionate/salmeterol or budesonide/formoterol (ICS/LABA) with tiotropium (LAMA) 
in moderate-severe COPD patients. These studies have reported greater improvements in 
lung function, HRQoL, hospitalization rates and rescue medication use, compared to dual 
(ICS/LABA) or LAMA alone, thus supporting the use of triple therapy in COPD [Aaron, 
2007; Cazzola, 2007; Hanania, 2012; Jung, 2012; Welte, 2009]. These studies have also 
shown that the number and type of reported adverse events (AE) were generally similar 
with administration of dual or monotherapy doses for periods of up to one year, and were 
mostly related to their pharmacological mode of action.
3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary

To  compare the effect of FF/UMEC/VI  
with FF/VI + UMEC on lung function 
after 24 weeks of treatment

Change from baseline in trough FEV1
at 24 weeks
Secondary

To  compare the effects of 
FF/UMEC/VI  with FF/VI + UMEC 
on health related quality of life and 
dyspnoea after 24 weeks of treatment

Proportion of  Responders  based on 
the St George Respiratory 
Questionnaire (SGRQ) Total Score at 
Week 24

Change from baseline in SGRQ Total 
Score at Week 24

Proportion of Responders based on 
Transitional Dyspnoea Index (TDI) 
focal score at Week 24 

TDI focal score at Week 24

2015N261999_03
CONFIDENTIAL
200812
16
Objectives
Endpoints

To  compare the effect of FF/UMEC/VI  
with FF/VI + UMEC on time to first 
moderate or severe exacerbation during 
24 weeks of treatment

Time to first moderate or severe 
exacerbation
Pharmacokinetics (PK)

To compare the PK of FF, UMEC and 
VI when given as FF/UMEC/VI or 
FF/VI+UMEC in a subset of subjects 

Population PK (in a subset of 
approximately 180 subjects)
Safety

To  compare the safety profile of
FF/UMEC/VI  with FF/VI + UMEC
over 24 weeks of treatment

Incidence of adverse events

Incidence of adverse events of special 
interest 2

ECG measurements

Vital signs

Haematological and clinical chemistry 
parameters
                                                
2 See section 7.4.3. for further information on AESI’s

2015N261999_03
CONFIDENTIAL
200812
17
4.
STUDY DESIGN
4.1.
Overall Design
Figure 1
Study Schema
This is a phase IIIB, 24-week, randomised, double-blind, parallel group multicenter study 
evaluating FF/UMEC/VI (100mcg/62.5mcg/25mcg) via a single ELLIPTA (‘closed 
triple’) plus matching placebo versus FF/VI + UMEC delivered via two ELLIPTA’s 
(‘open triple’), all taken once daily. The target enrollment is 1020 randomised subjects at 
approximately 150 study centres globally. Subjects will run-in on their existing COPD 
medications for 2 weeks and in addition will be provided with short acting 
albuterol/salbutamol to be used on an as-needed basis (rescue medication) throughout the 
study. Subjects will discontinue all existing COPD medications at the start of the 
randomised treatment period but may continue their study-supplied rescue 
albuterol/salbutamol.
Clinic Visits will occur at Pre-Screening (V0), Screening (V1), Randomisation (Week 0, 
V2), Week 4 (V3), Week 12 (V4) and Week 24 (V5). A safety follow-up telephone 
contact or clinic visit will be conducted 1 week after completing either randomised 
treatment or an Early Withdrawal Visit. Subjects will sign an informed consent form 
(ICF) at a Pre-Screen or Screening Visit (V1) and will be assigned a subject identifier.  
At Screening (V1), responses to the COPD Assessment Tool (CAT) questionnaire will be 
collected using an electronic device, prior to completing other Screening (V1) 
assessments. Subjects will self-administer their first doses of study treatment in the clinic 

2015N261999_03
CONFIDENTIAL
200812
18
during Randomisation (V2). On the morning of each study clinic visit, subjects will 
refrain from taking their morning doses of study treatment until instructed to do so by 
clinic personnel. At clinic visits, responses to questionnaires, SGRQ-C and Baseline 
Dyspnoea Index (BDI) and TDI, will be collected using an electronic device, in that order 
and prior to dosing or collecting other assessments. Subjects will take their last dose of 
study treatment in the clinic during V5 and a safety follow-up will be conducted either by 
phone call or clinic visit approximately one week later. 
Approximately 180 subjects, in selected sites, will be asked to participate in 
pharmacokinetic (PK) research. There will be two PK groups (subset A and subset B). 
Approximately 120 subjects will be assigned to subset A and approximately 60 subjects 
will be assigned to subset B. 
Subjects in subset A will provide a blood sample at two time-points at Week 12 (V4) and 
at Week 24 (V5). Subjects in subset B will provide blood samples at seven time points at 
Week 12 (V4). 
Subjects providing PK samples for subset A may also be asked to take part in a hair 
sample, scalp & finger secretion PK Sub-Study. See Appendix 8 (Section 12.8).
A subject will be considered to have completed the study when they have completed all 
phases of the study including screening, run-in, the randomised treatment phase, and 
safety follow-up. Subjects who stop study treatment early will complete an Early 
Withdrawal Visit, followed by a Safety Follow-Up a week later and finally be withdrawn 
from the study.
4.2.
Treatment Arms and Duration
Subjects who meet all the inclusion/exclusion criteria and who have successfully 
completed all protocol procedures at Screening (V1) will enter the two-week run-in 
period. Following the run-in period, eligible subjects will be randomised (1:1) to one of 
the following double-blind treatment groups for 24-weeks.  

FF/UMEC/VI 100mcg/62.5mcg/25mcg and placebo, both via the ELLIPTA once 
daily in the morning.
or,

FF/VI 100mcg/25mcg and UMEC 62.5mcg, both via the ELLIPTA once daily in 
the morning.
The ELLIPTA contains 30 doses (FF/UMEC/VI, FF/VI, UMEC or placebo) and subjects 
will be instructed to administer one dose from each ELLIPTA once daily in the morning. 
The randomisation will be stratified based on long-acting bronchodilator usage during 
the run-in (none, one or two long-acting bronchodilators per day).
The total duration of subject participation will be approximately 27 weeks, consisting of a 
2-week run-in period, 24-week treatment period and a 1-week follow-up period.

2015N261999_03
CONFIDENTIAL
200812
19
4.3.
Type and Number of Subjects
Approximately 1275 subjects with advanced COPD (GOLD Group D) will be screened in 
order to randomise approximately 1020 subjects in order to achieve an estimated 816 
subjects who are included in the Adherent Population and complete V5.
Approximately 150 centres globally will be required to recruit the study.
4.4.
Design Justification
This study will use a multicenter, randomised, double-blind, matching placebo, parallel-
group design. Eligible subjects will be included in a 24-week treatment period; a duration 
which is compatible with the guidelines and previous recommendations of national health 
technology assessment agencies in countries including France (Haute Autorité de Santé, 
2009), Germany (Institute for Quality and Efficiency in Health Care, 2015) and Australia 
(Pharmaceutical Benefits Advisory Committee, 2013). A placebo arm is not included 
because the primary comparison of interest is FF/UMEC/VI (closed triple) vs. FF/VI + 
UMEC (open triple) and it is not considered appropriate to include a placebo arm in a 
study in patients with advanced COPD. A placebo ELLIPTA is included in the closed 
triple arm to maintain the double-blind by requiring each dose to be administered using 
two ELLIPTA’s.
Eligible subjects must have been on continuous daily maintenance COPD medication for 
at least 3 months prior to Screening (V1). During the 2-week run-in period they must not 
change their COPD medication (dosage or regimen). The 2-week run-in period is 
necessary in order to allow sufficient time for the results of screening assessments to be 
returned to the site in order to establish eligibility. 
4.5.
Dose Justification
The FF/UMEC/VI (100/62.5/25mcg) dose was selected based on the doses that have been 
licensed for COPD for the FF/VI (100/25mcg) and UMEC/VI (62.5/25mcg) dual 
combinations through extensive studies in the mono and dual therapy programmes. They 
are the doses which are currently being studied in the ongoing Phase IIIA closed triple 
registration programme.
4.6.
Benefit: Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK2834425 can be found in the Investigator’s Brochure (IB).  The following section 
outlines the risk assessment and mitigation strategy for this protocol:  

2015N261999_03
CONFIDENTIAL
200812
20
4.6.1.
Risk Assessment
Potential Risk of 
Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Treatment [GSK2834425]
Pneumonia in
patients with COPD
Pneumonia is a class concern for any ICS containing product for the treatment 
of COPD. In two replicate 12 month studies with FF/VI (HZC102871 & 
HZC102970) in a total of 3,255 patients with COPD who had experienced a 
COPD exacerbation in the previous year, there was a higher incidence of 
pneumonia (6%- 7%) reported in patients receiving the FF (at strengths of 50, 
100, and 200 mcg)/VI 25 mcg combination than in those receiving VI 25 mcg 
alone (3%). Pneumonia which required hospitalisation occurred in 3% of 
patients receiving FF/VI (all strengths) and in <1% of patients receiving VI. In 
these studies, nine fatal cases of pneumonia were reported. Of these, seven 
were reported during treatment with FF/VI 200/25 mcg, one during treatment 
with FF/VI 100/25 mcg and one post-treatment with VI monotherapy. Risk 
factors for pneumonia on FF/VI compared with VI in these studies included 
current smokers, patients with a history of prior pneumonia, patients with a 
body mass index <25 kg/m2 and patients with an FEV1<50% predicted. These 
factors should be taken into consideration when using an ICS in patients with 
COPD. 
Initial results from the recently completed Study to Understand Mortality and 
MorbidITy (SUMMIT) with Relvar/Breo ELLIPTA provide further data for the 
risk of pneumonia in patients with COPD. This study included 16,485 patients 
(from 43 countries) with COPD who had moderate airflow limitation (FEV1 50-
70% predicted) and either a history or increased risk of cardiovascular 
disease.  The preliminary results from this study indicate that the incidence of 
-
Exclusion criteria as specified in Section 
5.2 of the protocol
-
Collection of information on previous 
history of pneumonia in past 12 months, 
including hospitalisation at baseline
-
Use of pneumonia electronic Case 
Report Form (eCRF)
-
All diagnoses of pneumonia 
(radiographically confirmed or 
unconfirmed) must be reported as an AE 
or SAE (if applicable), as specified in 
Section 7.4.9
-
Chest x-ray (CXR) required at baseline 
and whenever a patient has suspected 
pneumonia or mod/severe exacerbations 
during the study. The chest x-rays will be 
reviewed by the investigator and 
appropriate action taken (if required) 
based on the investigator’s clinical 

2015N261999_03
CONFIDENTIAL
200812
21
Potential Risk of 
Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
pneumonia was 5.7% on FF/VI 100/25mcg and 5.2% on placebo and the 
incidence of serious pneumonia was 3.4% on FF/VI 100/25mcg and 3.1% on 
placebo (data on file).
Pneumonia risk will be important in the benefit-risk assessment for both open 
triple and closed triple in COPD patients, hence a robust risk mitigation 
strategy is being proposed.
discretion
-
Instream review of blinded data
Systemic effects
of
corticosteroids:
bone disorders,
bone mineral
density decrease
and associated
fractures
A decrease in bone mineral density and risk of fractures is a class concern for 
any ICS-containing product for treatment of COPD.
The incidence of bone fractures in patients with COPD (n=3,255) administered 
FF/VI in two replicate 12 month studies (HZC102871 and HZC102970) was 
higher in all FF/VI groups (2%) compared with the VI 25 mcg group (<1%). 
Overall, the incidence of fractures was low. Although there were more 
fractures in the FF/VI groups compared to the VI 25 mcg group, fractures 
typically associated with corticosteroid use (e.g. spinal compression/ 
thoracolumbar vertebral fractures) occurred in <1% of the FF/VI and VI 
treatment arms. 
As part of the FF/VI development program, a bone mineral density study with 
FF/VI is being conducted, and this will provide data relevant to both closed 
and open triple.  
-
Evaluation of the potential for bone 
systemic corticosteroid effects will be 
conducted through instream assessment 
of reported bone adverse events
-
Use of bone fracture eCRF
Systemic effects
of
corticosteroids:
cortisol
Although all steroids are likely to have some impact on the hypothalamic 
pituitary axis (HPA axis), the proposed dose of inhaled FF in this study is 
unlikely to lead to any clinically significant changes. No studies have shown a 
clinically relevant effect of FF/VI on HPA axis. This includes a formal HPA 
-
Instream review of AE/SAE reports

2015N261999_03
CONFIDENTIAL
200812
22
Potential Risk of 
Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
suppression
study in asthma subjects, which assessed the effects of FF/VI 100/25 and 
200/25 doses on serum cortisol and 24 hour urinary cortisol excretion, and 
multiple studies with COPD subjects which monitored 24 hour urinary cortisol. 
During clinical development of FF & FF/VI, no events of Adrenal Suppression 
were reported.
Systemic ocular
effects of
corticosteroids:
glaucoma,
cataract, raised
intra-ocular
pressure
Systemic ocular effects (e.g. cataract and glaucoma) may occur with any 
inhaled corticosteroid, particularly at high doses prescribed for long periods. 
However, these effects are much less likely to occur with inhaled 
corticosteroids compared with oral corticosteroids. 
In study HZA106839 (FF/VI, FF and FP in subjects with asthma), formal 
ophthalmic assessments were conducted (including LOCS III evaluations for 
ocular opacities) throughout the study. The study showed no apparent effects 
on lens opacification compared to baseline.
During studies with FF/VI in subjects with asthma and COPD, no associated 
effect on ocular disorders was observed.
-
As per Section 5.2 of the protocol, 
patients with known narrow-angle 
glaucoma that, in the opinion of the 
investigator contraindicates study 
participation or use of an inhaled 
anticholinergic, will be excluded from 
participating in this study.
-
Instream review of AE/SAE reports
Cardiovascular 
effects of UMEC 
and VI
Cardiovascular effects are a potential class effect associated with LAMA and 
LABA class of drugs. 
Clinical data from VI and FF/VI
In clinical studies, changes in heart rate >6bpm compared with placebo were 
uncommon except at supra-therapeutic doses of 400mcg VI (formulated in 
lactose alone) or at a VI dose of 100mcg or greater. No clinically relevant 
effect on heart rate was observed from Phase IIb studies (up to 50mcg VI). 
-
Exclusion criteria as specified in Section 
5.2 of the protocol
-
Collection of cardiovascular risk factors 
and medical history at baseline
-
ECGs as per protocol
-
Vital sign assessments (heart rate and 

2015N261999_03
CONFIDENTIAL
200812
23
Potential Risk of 
Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Pooled QT analysis for VI Phase I and II studies did not suggest any effect on 
QT at recommended therapeutic doses. There were no statistically or clinically 
significant differences compared to placebo observed in weighted mean or 
maximum change from baseline (0 to 4 hour) in QTc(F) in Phase IIb studies
In subjects with asthma and COPD, there were no significant effects on 
systolic blood pressure at VI doses up to 200mcg. Small (less than or equal to 
4mmHg) but statistically significant mean decreases in diastolic blood 
pressure seen with VI (25 - 100mcg) versus placebo were not considered 
clinically significant. No clinically relevant effect on blood pressure was 
observed from Phase IIb studies (up to 50mcg VI).
Analysis from NHANES III data from COPD and asthma participants suggests 
an independent association between asthma and QTcB prolongation. In 
COPD, the risk of QTc prolongation did not appear related to severity. Due to 
having multiple co-morbidities, COPD patients are likely to be more at risk 
than asthma patients for adverse cardiovascular adverse events.
A significant proportion of subjects (>60%) in the Phase III FF/VI COPD 
program had cardiovascular comorbidities described. In the placebo controlled 
studies (HZC112206/ HZC112207), the incidence of serious adverse events 
from the cardiac disorder system organ class was similar across treatment 
arms
The overall incidence of cardiac disorder events was higher in the one year 
exacerbation studies than in the 6 month studies, but this is likely to be due to 
the longer duration of treatment, and may also be as a consequence of more 
blood pressure) as per protocol
-
Cardiovascular eCRF for collection of 
AEs and SAEs (see Section 7.4.2.4)
-
Instream review of blinded data
Based on non-clinical, clinical pharmacology, 
clinical trial data and labelling background with 
FF/VI and UMEC/VI, there are no pre-specified 
protocol defined QTc based exclusion or study 
treatment stopping criteria. However, as 
mentioned in Section 5.2 and Section 5.5, 
investigators should use their clinical judgment to 
assess the suitability of  patients to enrol and 
continue study treatment in the study

2015N261999_03
CONFIDENTIAL
200812
24
Potential Risk of 
Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
severe COPD disease, in relation to their exacerbation risk.
An analysis performed on the FF/VI pivotal studies (HZC112206, HZC112207, 
HZC102871, HZC102970, HZC110946, HZC111348, and B2C111045) to 
summarise events that could be considered cardiac in nature found that the 
percentages of subjects with fatal events that were cardiovascular in nature 
were similar across all treatment groups (0 to <1%).
Clinical data from UMEC/VI
Overall, the UMEC/VI clinical studies revealed a similar incidence of AEs in 
the Cardiac Disorders SOC and CNS haemorrhages and cerebrovascular 
conditions (SMQ) for UMEC/VI, the individual components and placebo. A low 
number of AEs relating to atrial arrhythmias (e.g. supraventricular 
extrasystoles, atrial fibrillation) were reported, of which some occurred with a 
higher incidence in active treatment groups compared to placebo, in the 
Primary Efficacy Studies and the Long-term Safety Study. There were no 
additive effects on AE incidence with the combination over individual 
components. A slightly higher proportion of subjects with ECG abnormalities 
(e.g. ectopic supraventricular beats/rhythm) relating to atrial arrhythmias 
reported at any time post-baseline in the Primary Efficacy Studies and Long-
term Safety Study were reported compared with placebo. These arrhythmias 
appeared to be clinically silent and were not associated with relevant 
symptoms or sequelae. 
Pooled QT analysis for VI Phase I and II studies did not suggest any effect on 
QT at recommended therapeutic doses. There were no statistically or clinically 
significant differences compared to placebo observed in weighted mean or 
maximum change from baseline (0 to 4 hour) in QTc(F) in Phase IIb studies

2015N261999_03
CONFIDENTIAL
200812
25
Potential Risk of 
Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Anticholinergic
effects
(including
Narrow angle 
glaucoma, bladder 
outflow obstruction 
and urinary 
retention)
There was one report of angle closure glaucoma (UMEC/VI 62.5/25 mcg) in 
the UMEC/VI development program in COPD. 
The incidence of urinary retention AESIs was low (<1%) in all treatment 
groups including placebo. Three PTs were reported for this AESI group: 
urinary hesitation, urinary retention, and urine flow decreased. No subjects 
had urinary retention AESIs in the placebo, UMEC 62.5 mcg group or UMEC 
125/25 mcg group. The PT of ‘urinary retention’ was reported by one subject 
each (<1%) in the UMEC/VI 62.5/25 mcg, VI 25 mcg and tiotropium treatment 
groups, with 2 subjects (<1%) reporting the event in the UMEC 125 mcg 
treatment group. One event of ‘urinary hesitation’ was reported in the UMEC 
125 mcg treatment group. No subjects in the Long-term Safety Study had an 
event in the urinary retention AESI group. None of the urinary retention AESIs 
reported were considered serious.
ICS has a similar class risk of glaucoma and elevated 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.
-
Instream review of AE/SAE reports
Hypersensitivity
Clinical data from FF/VI
In the COPD placebo controlled studies (HZC102206/HZC102207), events 
related to hypersensitivity, such as pruritis and rash occurred at similar 
incidences in the active treatment groups (<1% to 2%) and placebo (<1%) and 
there appeared to be no increased risk of drug- associated hypersensitivity.  
-
As specified in Section 5.2 of the 
protocol, subjects with a history of 
allergy or hypersensitivity to lactose/milk 
protein or magnesium stearate, any 
corticosteroid, anticholinergic/muscarinic 
receptor antagonist, and/or beta2-

2015N261999_03
CONFIDENTIAL
200812
26
Potential Risk of 
Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Adverse events in the Anaphylactic reactions SMQ occurred at similar 
incidences in all active treatment groups (3% to 4%) and placebo (4%) except 
for a lower incidence in the FF/VI 200/25 mcg treatment group (<1%). 
Angioedema occurred at a slightly higher incidence in the FF/VI 200/25 mcg 
group (2%) and at lower incidences within each of the remaining treatment 
groups (<1% to 1%). 
In the COPD one year exacerbation studies (HZC102871/HZC102970), events 
related to hypersensitivity such as pruritis and rash occurred at similar 
incidences in the FF/VI groups (4% to 5%) and the VI 25 mcg group (3%) and 
analysis indicated no increased risk of drug-associated hypersensitivity in any 
treatment group. Adverse events in the anaphylactic reaction SMQ occurred at 
similar incidences in all FF/VI treatment groups (10% to 13%) and at similar 
incidence to that in the VI 25 mcg treatment group (11%). Angioedema 
occurred at similar incidences in the FF/VI groups (3% to 5%) to the VI 25 mcg 
group (5%). In these studies as all patients were on VI, either as monotherapy 
or in combination with FF assessment of hypersensitivity to an individual 
component is not possible. 
Spontaneous data from FF/VI
Spontaneous reports consistent with hypersensitivity reactions to inhaled 
FF/VI were identified on the GSK safety database. Seventeen post-marketing 
spontaneous reports were considered typical of hypersensitivity reactions and 
a further seven cases documenting atypical reactions that may possibly have 
indicated a hypersensitivity reaction were identified. There were four serious 
cases, of which two were considered life-threatening. A fatal case of 
agonist, that in the opinion of the 
investigator contraindicates study 
participation, would not be included in 
the study
-
Instream review of AE/SAE reports

2015N261999_03
CONFIDENTIAL
200812
27
Potential Risk of 
Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
angioedema and swollen tongue was reported by a health care professional; 
however the case was poorly documented and insufficient for evaluation.
FF/VI formulation contains lactose. There have been reports of serious allergic 
reactions in patients with severe milk protein allergy after inhalation of other 
powder products containing lactose.
Clinical data from UMEC/VI
Following a safety evaluation which included serious spontaneous case 
reports of hypersensitivity reactions it was concluded that there is sufficient 
evidence for an association between UMEC/VI and these events.
Paradoxical 
bronchospasm
There have been no reports of paradoxical bronchospasm with UMEC/VI in 
the clinical development program in COPD. Rare reports of paradoxical 
bronchospasm (which may be life threatening) with other bronchodilators have 
been reported.
-
Instream review of AE/SAEs

2015N261999_03
CONFIDENTIAL
200812
28
4.6.2.
Benefit Assessment
COPD guidelines advocate the use of one or more long-acting bronchodilators (long-
acting muscarinic receptor antagonists [LAMA]) or long-acting β2-adrenergic receptor 
agonists [LABA]) in addition to inhaled corticosteroids (ICS) as second line therapy for 
the most advanced patients with significant symptoms and a high risk of exacerbations. 
Patients enrolled in this study will receive triple combination as FF/UMEC/VI or FF/VI + 
UMEC. Based on available data with the components FF, UMEC and VI, it is expected 
that patients will potentially derive clinical benefit from studytreatment:
-
Benefits of dual combination FF/VI have already been demonstrated. In clinical 
studies in COPD patients, FF/VI demonstrated clinically meaningful and 
sustained improvement in lung function and there were clinically meaningful 
reductions in rate of moderate or severe COPD exacerbations. FF/VI is licensed 
for COPD indication in a number of countries around the world. 
-
The UMEC/VI development program demonstrated that UMEC/VI provided 
clinically relevant efficacy, as defined by measures of lung function over 24 
weeks of treatment, as compared with placebo, the individual monotherapies and 
tiotropium in a broad range of subjects with COPD. UMEC/VI is licensed for 
COPD indication in number of countries. 
-
Benefits of open triple therapy with an ICS, LAMA and LABA have been shown 
in published studies which assessed the use of an ‘open’ triple therapy in 
moderate-severe COPD patients, These studies reported improvements in lung 
function, HRQoL, hospitalisation rates and rescue medication use, compared to 
dual therapy (ICS/LABA) or LAMA alone [Aaron, 2007; Cazzola, 2007; 
Hanania, 2012; Jung, 2012; Welte, 2009]. These studies also showed that the 
number and type of reported AEs were generally similar with administration of 
dual or monotherapy doses for periods of up to one year, and were mostly related 
to their pharmacological mode of action. 
-
Patients with COPD have been exposed to the open triple combination FF/VI + 
UMEC in GSK sponsored studies. In two 12-week, placebo controlled studies 
(200109 and 200110), the addition of UMEC to FF/VI (100/25) once daily in 
adult patients with a clinical diagnosis of COPD, resulted in statistically 
significant and clinically meaningful improvements in the primary endpoint of 
trough FEV1 at Day 85 compared to placebo plus FF/VI (124 mL (95% CI 93, 
154, p<0.001) and 122 mL (95%CI 91, 152, p<0.001)).  The safety profile for 
UMEC in combination with FF/VI was similar across treatment arms, and no 
additive effects or new safety concerns were identified.
-
No efficacy data is available for the closed triple combination FF/UMEC/VI as 
the two Phase III efficacy and safety studies are currently ongoing (CTT116855, 
CTT116853). However, as the delivery of the components of the triple 
combination product (FF, UMEC and VI) are comparable when delivered as the 

2015N261999_03
CONFIDENTIAL
200812
29
closed triple or the open triple, the efficacy of closed triple is expected to be as 
good as open triple. 
The current study will provide data to demonstrate non-inferiority of closed triple and 
open triple on lung function. In a disease where polypharmacy is common, the ‘closed’ 
triple, once-daily combination has the potential to optimise bronchodilator therapy, 
improve patient adherence to therapy and, as a result, improve overall disease 
management in COPD patients. 
4.6.3.
Overall Benefit: Risk Conclusion
Current risks that have been identified for closed triple and open triple are based on the 
known pharmacology of the individual components FF, UMEC and VI. These include 
key risks of pneumonia and bone disorders/fractures from ICS-containing combinations, 
and the risk of adverse cardiovascular effects from LAMA/LABA-containing 
combinations.
The clinical development programs for dual combinations FF/VI and UMEC/VI 
demonstrated a favourable benefit/risk for these therapies in patients with COPD. This 
led to their approval and both dual combinations are now marketed for COPD indication 
in a number of countries around the world.  
The safety profile for UMEC in combination with FF/VI was similar across treatment 
arms, and no additive effects or new safety concerns were identified in replicate studies 
in COPD patients exposed  to the open triple combination FF/VI + UMEC for 12 weeks. 
Patients with COPD have been exposed to the closed triple combination FF/UMEC/VI as 
part of ongoing clinical studies (CTT116853 and CTT116855). There are currently no 
new safety signals based on review of blinded data from these studies. Additionally an 
Independent Data Monitoring Committee (IDMC) is in place for CTT116855 study, 
which meets periodically to review unblinded safety data. 
For the current study, a safety monitoring strategy is being proposed for all the risks, 
including key risks (Section 4.6).
Given the clinical experience with FF, UMEC and VI, and that the associated risks with 
these compounds are anticipated from their known pharmacology, the potential benefit of 
a new therapy option in patients with moderate to severe COPD supports the conduct of 
this study as part of the clinical development program for closed triple combination.

2015N261999_03
CONFIDENTIAL
200812
30
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the IB.
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
5.1.
Inclusion Criteria
Subjects eligible for enrolment in the study must meet all of the following criteria:
1.
Informed Consent: A signed and dated written informed consent prior to study 
participation.
2.
Type of subject: Outpatient.
3.
Age:  Subjects 40 years of age or older at Screening (V1).
4.
Gender: Male or female subjects.
Females: 
A female subject is eligible to participate if she is not pregnant (as confirmed by a 
negative urine human chorionic gonadotrophin (hCG) test), not lactating, and at least one 
of the following conditions applies:
a.
Non-reproductive potential defined as:
Pre-menopausal females with one of the following:
Documented tubal ligation
Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion 
Hysterectomy
Documented Bilateral Oophorectomy
Postmenopausal defined as 12 months of spontaneous amenorrhea [in 
questionable cases a blood sample with simultaneous follicle stimulating 
hormone (FSH) and estradiol levels consistent with menopause (refer to 
laboratory reference ranges for confirmatory levels)].  Females on hormone 
replacement therapy (HRT) and whose menopausal status is in doubt will be 
required to use one of the highly effective contraception methods if they wish to 
continue their HRT during the study.  Otherwise, they must discontinue HRT to 
allow confirmation of post-menopausal status prior to study enrolment.

2015N261999_03
CONFIDENTIAL
200812
31
b.
Reproductive potential and agrees to follow one of the options listed in the Modified 
List of Highly Effective Methods for Avoiding Pregnancy in Females of 
Reproductive Potential (FRP) (see Appendix 5) from 30 days prior to the first dose 
of study treatmentand until after the last dose of study treatmentand completion of 
the follow-up visit.
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.
5.
COPD Diagnosis:  An established clinical history of COPD in accordance with the 
definition by the American Thoracic Society/European Respiratory Society [Celli, 
2004].
6.
Smoking History:  Current or former cigarette smokers with a history of cigarette 
smoking of 10 pack-years at Screening (V1) [number of pack years = (number of 
cigarettes per day / 20) x number of years smoked (e.g., 20 cigarettes per day for 10 
years, or 10 cigarettes per day for 20 years)].  Previous smokers are defined as those 
who have stopped smoking for at least 6 months prior to Screening (V1).  
NOTES:

Pipe and/or cigar use cannot be used to calculate pack-year history.
7.
Severity of COPD symptoms: A score of ≥10 on the COPD Assessment Test 
(CAT) at Screening (V1).
8.
Severity of COPD Disease: A post-albuterol/salbutamol FEV1/FVC ratio of <0.70 
at Screening (V1).  
9.
Existing COPD maintenance treatment:  Subject must be receiving daily 
maintenance treatment for their COPD for at least 3 months prior to Screening (V1).  
NOTES: 

Subjects receiving only PRN COPD medications are not eligible.
10. History of Exacerbations: Subjects must demonstrate:
a post-bronchodilator FEV1 < 50% predicted normal at Screening (V1) and a 
documented history of ≥ 1 moderate or severe COPD exacerbation in the 12 
months prior to Screening
OR
a post-bronchodilator 50% ≤FEV1 < 80% predicted normal at Screening (V1) 
and a documented history of ≥ 2 moderate exacerbations or a documented history 
of ≥1 severe COPD exacerbation (hospitalised) in the 12 months prior to 
Screening (V1).
NOTES: 

Percent predicted will be calculated using the European Respiratory Society 
Global Lung Function Initiative reference equations [Quanjer, 2012].

2015N261999_03
CONFIDENTIAL
200812
32

A documented history of a COPD exacerbation (e.g., medical record 
verification) is a medical record of worsening COPD symptoms that required 
systemic/oral corticosteroids and/or antibiotics (for a moderate exacerbation) or 
hospitalisation (for a severe exacerbation). Prior use of antibiotics alone does not 
qualify as an exacerbation history unless the use was associated with treatment 
of worsening symptoms of COPD, such as increased dyspnoea, sputum volume, 
or sputum purulence (colour). Subject verbal reports are not acceptable. 
11. French subjects: In France, a subject will be eligible for inclusion in this study only 
if either affiliated to or a beneficiary of a social security category.
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
1.
Pregnancy: Women who are pregnant or lactating or are planning on becoming 
pregnant during the study.
2.
Asthma: Subjects with a current diagnosis of asthma. (Subjects with a prior history 
of asthma are eligible if they have a current diagnosis of COPD, which is the primary 
cause of their respiratory symptoms).
3.
α1-antitrypsin deficiency: Subjects with α1-antitrypsin deficiency as the underlying 
cause of COPD.
4.
Other respiratory disorders: Subjects with active tuberculosis are excluded. 
Subjects with other respiratory disorders (e.g. clinically significant: bronchiectasis, 
sarcoidosis, lung fibrosis, pulmonary hypertension, interstitial lung diseases) are 
excluded if these conditions are the primary cause of their respiratory symptoms.
5.
Lung resection: Subjects with lung volume reduction surgery (including procedures
such as endobronchial valves) within the 12 months prior to Screening (V1).
6.
Risk Factors for Pneumonia: immune suppression (e.g. advanced HIV with high 
viral load and low CD4 count, Lupus on immunosuppressants that would increase 
risk of pneumonia) or other risk factors for pneumonia (e.g. neurological disorders 
affecting control of the upper airway, such as Parkinson’s Disease, Myasthenia 
Gravis). 
NOTES:

Patients at a high risk for pneumonia (e.g. very low BMI, severely 
malnourished or very low FEV1) will only be included at the discretion of the 
investigator.
7.
Pneumonia and/or moderate or severe COPD exacerbation that has not resolved 
at least 14 days prior to Screening (V1) and at least 30 days following the last dose 
of oral/systemic corticosteroids (if applicable). 
8.
Other Respiratory tract infections that have not resolved at least 7 days prior to 
Screening (V1).

2015N261999_03
CONFIDENTIAL
200812
33
9.
Abnormal Chest x-ray: Chest x-ray (posteroanterior and later) reveals evidence of 
pneumonia or a clinically significant abnormality not believed to be due to the 
presence of COPD, or another condition that would hinder the ability to detect an 
infiltrate on chest x-ray (e.g. significant cardiomegaly, pleural effusion or scarring). 
All subjects will have a chest x-ray at Screening (V1) [or historical radiograph or CT 
scan obtained within 3 months prior to Screening (V1). 
NOTES:

Subjects who have experienced pneumonia and/or moderate or severe COPD 
exacerbation within 3 months of Screening (V1) must provide a post 
pneumonia/exacerbation chest x-ray or have a chest x-ray conducted at 
Screening (V1). 

For sites in Germany: If a chest x-ray (or CT scan) within 3 months prior to 
Screening (V1) is not available, approval to conduct a diagnostic chest x-ray 
will need to be obtained  from the Federal Office for Radiation Protection (BfS).
10. 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 
haematological 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.  
11. Unstable liver disease: ALT >2xULN; and bilirubin >1.5xULN (isolated bilirubin 
>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)
Current active liver or biliary disease (with the exception of Gilbert’s syndrome or 
asymptomatic gallstones or otherwise stable chronic liver disease per investigator 
assessment). 
NOTES: 

Stable chronic liver disease should generally be defined by the absence of 
ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or 
gastric varices, or persistent jaundice, or cirrhosis.

Chronic stable hepatitis B and C (e.g., presence of hepatitis B surface antigen 
(HBsAg) or positive hepatitis C antibody test result at screening or within 3 
months prior to first dose of study treatment) are acceptable if subject otherwise 
meets entry criteria.
12. Unstable or life threatening cardiac disease: subjects with any of the following at 
Screening (V1) 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  

NYHA Class IV Heart failure 

2015N261999_03
CONFIDENTIAL
200812
34
13. Abnormal and clinically significant 12-Lead ECG finding: Investigators will be 
provided with ECG reviews conducted by a centralized independent cardiologist to 
assist in evaluation of subject eligibility. 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 that would preclude a subject from 
entering the trial is defined as a 12-lead tracing that is interpreted as, but not limited 
to, any of the following:

AF with rapid ventricular rate >120 BPM; 

sustained or nonsustained VT; 

Second degree heart block Mobitz type II and third degree heart block (unless 
pacemaker or defibrillator had been inserted)
14. Contraindications: A history of allergy or hypersensitivity to any corticosteroid, 
anticholinergic/muscarinic receptor antagonist, beta2-agonist, lactose/milk protein or 
magnesium stearate or a medical condition such as narrow-angle glaucoma, prostatic 
hypertrophy or bladder neck obstruction that, in the opinion of the investigator 
contraindicates study participation.
15. Cancer: Subjects with carcinoma that has not been in complete remission for at least 
3 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 3 
year waiting period if the subject has been considered cured by treatment.
16. Oxygen therapy: Use of long-term oxygen therapy (LTOT) described as resting 
oxygen therapy >3L/min (Oxygen use 3L/min flow is not exclusionary.)
17. Medication prior to spirometry: Subjects who are medically unable to withhold 
their albuterol/salbutamol for the 4-hour period required prior to spirometry testing at 
each study visit.
18. Drug/alcohol abuse: Subjects with a known or suspected history of alcohol or drug 
abuse within the last 2 years.
19. 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.
20. 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.
21. 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.
22. 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.

2015N261999_03
CONFIDENTIAL
200812
35
23. Medication prior to Screening: Use of the following medications within the 
following time intervals prior to Screening (V1) or requirement for their use during 
the study:
Table 1
Prohibited medications prior to Screening (V1)
Medication
No use within the following time intervals prior to Screening
Long term continuous antibiotic 
therapy for 30 days 
30 days
Systemic, Oral, parenteral 
corticosteroids
30 days
(Intra-spinal and intra-articular injections are allowed)
Any other investigational drug
30 days or 5 half lives whichever is longer.
5.3.
Randomisation Criteria
Those subjects who meet the randomisation criteria will be randomised into the study 
until the target of approximately 1020 randomised subjects is reached. At the end of the 
run-in period, study subjects must not meet any of the following criteria in order to be 
randomised to study treatment:
1. Pneumonia or moderate/severe COPD exacerbation during run-in
2. Any change to COPD maintenance medications (including dosage and regimen) 
during the run-in
3. Antibiotics for respiratory tract infections during the run-in
5.4.
Screening/Baseline/Run-in Failures
A subject will be assigned a subject number at the time the informed consent is signed. A 
subject who is assigned a subject number but does not have Screening (V1) will be 
considered a pre-screen failure.
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized. In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and Serious Adverse Events (see Section 7.4.2.5).
Subjects who are Pre-Screen (V0) or Screen (V1) failures cannot be re-screened.

2015N261999_03
CONFIDENTIAL
200812
36
5.5.
Withdrawal/Stopping Criteria
5.5.1.
Protocol defined withdrawal criteria
A subject must be permanently withdrawn if any of the following stopping criteria are 
met: 

Liver Chemistry: Meets any of the protocol-defined liver chemistry stopping 
criteria3 as defined in Section 5.5.2. 

Pregnancy: Positive urine pregnancy test.
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as 
soon as possible. 

The site must counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or should 
continue in the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and if necessary a certified letter to the subject’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be considered 
to have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons. If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records. Subjects who are withdrawn from the study will not be replaced.
5.5.2.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
                                                
3 Based on findings from any routine labs done at site

2015N261999_03
CONFIDENTIAL
200812
37
Phase III-IV Liver Chemistry Stopping and Increased Monitoring Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus 
Bilirubin≥2x
ULN (>35% 
direct) or plus
INR>1.5, if 
measured*
Possible  
Hy’s Law
ALT≥3xULN
ALT
≥8xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
No
Yes
Yes
Yes
No
No
No
See algorithm 
for continued 
therapy with 
increased liver 
chemistry 
monitoring
Yes
*INR value not applicable to subjects on anticoagulants 
ALT 
≥3xULN 
but 
<8xULN
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 2, Section 12.2
Phase III-IV Liver Chemistry Increased Monitoring Algorithm with Continued 
Therapy for ALT 3xULN but <8xULN
Continue Study Treatment   and   Monitor Liver Chemistry
Discontinue Study Treatment 
ALT≥5xULN 
but <8xULN
+ bili <2xULN +
no symptoms
No
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Yes
ALT ≥3xULN 
but <5xULN
+ bili <2xULN  +
no symptoms
Able to 
monitor  
weekly 
for  ≥2 
weeks
Persists for 
≥2 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
No
No
Able to 
monitor  
weekly 
for  ≥4 
weeks
Persists for 
≥4 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
Yes
ALT ≥5xULN 
ALT <5xULN 
Yes
Yes
*INR value not applicable to subjects on anticoagulants 
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*

2015N261999_03
CONFIDENTIAL
200812
38
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 2, Section 12.2.
5.6.
Subject and Study Completion
A completed subject is one who has completed all phases of the study including the 
follow-up phone-call or visit.
The end of the study is defined as the last subject’s last visit.
6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
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.
All treatments will be delivered by ELLIPTA containing 30 doses.
Following the run-in period, eligible subjects will be randomized (1:1) to one of the 
following double-blind treatment groups: 

FF/UMEC/VI 100mcg/62.5mcg/25mcg and placebo, both via the ELLIPTA 
once daily in the morning
or,

FF/VI 100mcg/25mcg and UMEC 62.5mcg, both via the ELLIPTA once daily 
in the morning.
The randomisation will be stratified based on long-acting bronchodilator usage during the 
run-in (none, one or two long-acting bronchodilators per day).
The ELLIPTA contains 30 doses (FF/UMEC/VI, FF/VI, UMEC or placebo). Each 
subject will be instructed on the proper use of the ELLIPTA and will inhale once from 
each of their ELLIPTAs each morning for the duration of the 24-week treatment period. 
Subjects will self-administer their first dose of blinded study treatment in the clinic 
during Randomisation (V2). On the morning of the other study clinic visits, subjects will 
refrain from taking their morning dose of study treatment until instructed to do so by 
clinic personnel. Subjects will take their last dose of study treatment at the clinic at Visit 
5 and a safety follow-up will be conducted either by phone call or clinic visit 
approximately one week later. Subjects will discontinue their existing COPD medication 
on the day before Randomisation (V2) but may continue their study-supplied rescue 
albuterol/salbutamol.
There are no plans to provide the study drug for compassionate use following study 
completion.
Descriptions of the study treatment s administered via the ELLIPTA are provided in 
Table 2.

2015N261999_03
CONFIDENTIAL
200812
39
Table 2
Description of study treatment inhalation powder via ELLIPTA
FF/UMEC/VI 
First strip 
Second strip 
FF blended with lactose
UMEC and VI blended with lactose 
and magnesium stearate
Dosage Form 
ELLIPTA with 30 doses (2 strips with 30 blisters per strip)
Unit Dose 
Strengths 
100mcg per blister
62.5 mcg per blister UMEC, 25 mcg 
per blister VI 
Physical 
description 
Dry white powder
Dry white powder
Route of 
Administration 
Inhaled
FF/VI
First strip
Second strip
FF blended with lactose
VI blended with lactose and 
magnesium stearate
Dosage Form 
ELLIPTA with 30 doses (2 strips with 30 blisters per strip)
Unit Dose 
Strengths 
100mcg per blister
25 mcg per blister
Physical 
description 
Dry white powder
Dry white powder
Route of 
Administration 
Inhaled
UMEC
First strip
Second strip
UMEC blended with lactose 
and magnesium stearate
NA – one strip only
Dosage Form 
ELLIPTA with 30 doses (1 strip with 30 blisters)
Unit Dose 
Strengths 
62.5 mcg per blister
NA
Physical 
description 
Dry white powder
NA
Route of 
Administration 
Inhaled
Placebo to match 
First strip
Second strip
Lactose
NA – one strip only
Dosage Form
ELLIPTA with 30 doses (1 strip with 30 blisters)
Unit Dose 
Strengths
NA
NA
Physical 
description
Dry white powder
NA
Route of 
Administration
Inhaled

2015N261999_03
CONFIDENTIAL
200812
40
Albuterol/salbutamol via metered-dose inhaler (MDI) with a spacer will be issued for 
reversibility testing at Screening (V1).  Albuterol/salbutamol MDI or NEBULES™ for as 
needed (prn) use throughout the study will be provided starting at Screening (V1). 
Albuterol/salbutamol and spacers will be sourced from local commercial stock.  If not 
available locally, GSK will source centrally.
6.1.1.
Storage
All study treatment should be stored up to 25C (77F). Each ELLIPTA contains 30 
doses and is packaged in a foil pouch with a desiccant sachet and stored in a carton. The 
inhaler should not be used for more than 30 days after opening the foil.  The sites must 
maintain a daily temperature log for the storage of investigational product. 
Investigational product must be stored in a secure area under the appropriate physical 
conditions for the product.  Access to and administration of the investigational product 
will be limited to the investigator and authorized site staff.  Details of study treatment 
administration oversight are provided in the Study Procedures Manual (SPM).  
Investigational product must be dispensed or administered only to subjects enrolled in the 
study and in accordance with the protocol.
6.1.2.
Investigational Product and albuterol/salbutamol Return
All used and unused study treatment and albuterol/salbutamol will be returned to GSK at 
the end of the study to be available for disposal.  In some instances for sites outside the 
US, study supplies will be disposed of locally either by the site, the country medical 
department or third-party vendor.  Detailed instructions for the return of the study drug 
can be found in the SPM.
If any ELLIPTA fails to function properly, the subject should return to the clinic as soon 
as possible to obtain a new inhaler.  The site will use the interactive response technology 
(IRT) system to obtain a new treatment pack number for the subject and dispense a new 
study treatment kit from the site’s investigational product supply as instructed by the IRT 
system.
In addition, any ELLIPTA or metered-dose-inhaler (MDI) that fails to function properly 
must be identified and returned to GSK for testing.  Details of the failure will be 
documented in the eCRF.  
6.2.
Medical Devices
Medical devices (not manufactured by or for GSK) provided for use in this study are 
spacers/holding chambers.
Instructions for medical device use are provided in the SPM. 

2015N261999_03
CONFIDENTIAL
200812
41
6.3.
Treatment Assignment
Subjects will be assigned to study treatment in accordance with the randomisation 
schedule.  The randomisation code will be generated by GSK using a validated 
computerized system. Subjects will be randomized using an IRT System, RAMOS NG.  
The study will use country based randomisation to allocate treatments. Once a 
randomisation number is assigned to a subject it cannot be reassigned to any other subject 
in the study.
Subjects who meet the eligibility criteria and successfully complete the 2-week run-in 
period will be randomized (1:1) to one of the following study treatment regimens:

FF/UMEC/VI 100mcg/62.5mcg/25mcg and placebo, both via the ELLIPTA 
once daily in the morning
or,

FF/VI 100mcg/25mcg and UMEC 62.5mcg, both via the ELLIPTA once daily 
in the morning.
The randomization will be stratified based on long-acting bronchodilator usage during 
the run-in (none, one or two long-acting bronchodilators per day).
Subjects will be instructed to take one dose each morning from each ELLIPTA. 
The duration of treatment for each subject is 24 weeks.  On the morning of each clinic 
study visit, subjects will refrain from taking their morning dose of study treatment until 
instructed to do so by clinic personnel.  Study treatment will be given at the clinic at 
approximately the same time of day as Randomisation (V2).  On the other days during 
the treatment period (i.e. “non-clinic days”), subjects will be instructed to take their study 
treatment each morning at approximately the same time of day. The IRT system will 
provide a means for site-based allocation of drug.  Each investigator will be supplied with 
sufficient supplies to conduct the trial.  Additional treatment packs will be supplied as 
needed to the sites.  Details of how to use the IRT system to randomize subjects is 
provided in the SPM. 
6.4.
Blinding
This will be double-blind study (with a placebo ELLIPTA used to maintain the blind) and 
the following will apply. 

The investigator or treating physician may unblind a subject’s treatment 
assignment only in the case of an emergency OR in the event of a serious 
medical condition when knowledge of the study treatment is essential for the 
appropriate clinical management or welfare of the subject as judged by the 
investigator. 

Investigators have direct access to the subject’s individual study treatment. 

2015N261999_03
CONFIDENTIAL
200812
42

It is preferred (but not required) that the investigator first contacts the Medical 
Monitor or appropriate GSK study personnel to discuss options before unblinding 
the subject’s treatment assignment. 

If GSK personnel are not contacted before the unblinding, the investigator must 
notify GSK as soon as possible after unblinding, but without revealing the 
treatment assignment of the unblinded subject, unless that information is 
important for the safety of subjects currently in the study. 

The date and reason for the unblinding must be fully documented in the eCRF 
A subject will be withdrawn if the subject’s treatment code is unblinded by the 
investigator or treating physician. The primary reason for discontinuation (the event or 
condition which led to the unblinding) will be recorded in the eCRF.

GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind 
the treatment assignment for any subject with an SAE. If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of 
the report, identifying the subject’s treatment assignment, may be sent to 
investigators in accordance with local regulations and/or GSK policy. Subjects 
will not be withdrawn from the study.
6.5.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.6.
Preparation/Handling/Storage/Accountability
No special preparation of study treatment is required.

Only subjects enrolled in the study may receive study treatment and only 
authorized site staff may supply study treatment.  All study treatments must be 
stored in a secure environmentally controlled and monitored (manual or 
automated) area in accordance with the labelled storage conditions with access 
limited to the investigator and authorized site staff. 

The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e. receipt, reconciliation and final disposition records).  

Further guidance and information for final disposition of unused study treatment 
are provided in the SPM. 

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 and the generation of aerosols or mists. In the case 
of unintentional occupational exposure notify the monitor, Medical Monitor 
and/or GSK study contact.

2015N261999_03
CONFIDENTIAL
200812
43

A Material Safety Data Sheet (MSDS)/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.
6.7.
Compliance with Study Treatment Administration
When subjects are dosed at the site, they will receive study treatment under medical 
supervision.  The date and time of each dose administered in the clinic will be recorded in 
the source documents.  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. When subjects 
self-administer study treatmentat home, compliance with study treatment will be assessed 
through querying the subject during the site visits and recording the number of doses 
remaining in the ELLIPTA in the eCRF.  A record of the number of ELLIPTAs 
dispensed to each subject must be maintained and reconciled with study treatment and 
compliance records.  Treatment start and stop dates will also be recorded in the eCRF. 
Study treatment non-compliance is defined as <80% or >120% over the 24-week 
treatment period. 
6.8.
Treatment of Study Treatment 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.
6.9.
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.
6.10.
Concomitant Medications and Non-Drug Therapies
All COPD medications used within approximately 3 months prior to Screening (V1) and 
during the study (including the post-treatment period) should be recorded in the eCRF. 

2015N261999_03
CONFIDENTIAL
200812
44
All non-COPD medications taken during the study (after randomisation including post-
treatment) and any changes to concomitant medications will be recorded in the eCRF.  
[Note: Study provided albuterol/salbutamol should not be recorded in the eCRF however 
non-study supplied albuterol/salbutamol will be recorded in the eCRF].  The minimum 
requirement is that drug name, dose, route and the dates of administration are to be 
recorded.
Medications initiated after completion of the randomized treatment phase of the study 
(V5) or started after withdrawal from the study must be recorded in the eCRF, along with 
any changes up to the Safety Follow-Up Visit/Phone-call.
6.10.1.
Permitted Medications and Non-Drug Therapies

The following COPD medications are permitted during the study treatment 
period: 

Study supplied albuterol/salbutamol MDI or Nebules (must be withheld for at 
least 4 hours prior to spirometry testing).

Oral or injectable corticosteroids (short course ≤14 days) only for the short term 
treatment of COPD exacerbations and/or pneumonia.

Antibiotics (short course ≤14 days) for the short term treatment of COPD 
exacerbations and/or pneumonia.

Mucolytics such as acetylcysteine.

Long term oxygen therapy.  (To be eligible to enter the study subjects who are on 
LTOT must be using at a flow rate of ≤3 litres/minute at rest.  However, oxygen 
therapy may be adjusted as deemed medically necessary at any time during the 
study.) Oxygen therapy must be captured on the concomitant medication page of 
the eCRF.  Supplemental oxygen is recommended for patients who exhibit 
oxyhemoglobin desaturation with rest or exertion (e.g. SaO2 ≤88%).

Maintenance phase of pulmonary rehabilitation treatment (subjects are not 
allowed to initiate treatment during the study).

Any COPD medication deemed medically necessary for the short term treatment 
(≤14days) of a moderate/severe COPD exacerbation or pneumonia.
The following relevant Non-COPD medications are permitted during the study:

Medications for rhinitis (e.g. intranasal corticosteroids, antihistamines, cromolyn, 
nedocromil, nasal decongestants).

Topical and ophthalmic corticosteroids.

Localized corticosteroid injections (e.g. intra-spinal and intra-articular).

Vaccinations (Influenza vaccine, Pneumonia vaccine, Shingles vaccine, etc.) 
(Administration of influenza and pneumonia vaccines should be considered based 
on clinical discretion of the Investigator and local/national guidelines. Current 

2015N261999_03
CONFIDENTIAL
200812
45
influenza vaccines and pneumonia vaccines will be captured on the concomitant 
medication pages of the eCRF).

Allergy immunotherapy.

Antibiotics for short-term treatment (≤14 days) of acute infections. (Long term 
treatment with antibiotics is not allowed).

Systemic and ophthalmic beta-blockers. (Administer with caution as systemic 
beta-blockers block the pulmonary effect of beta-agonists, and may produce 
severe bronchospasm in patients with reversible obstructive airways disease. 
Cardioselective beta-blockers should be considered, although they also should be 
administered with caution).

Smoking cessation treatments. 

Cough suppressants. 

Tricyclic 
antidepressants 
and 
monoamine oxidase 
inhibitors 
(MAOIs). 
(Administer with extreme caution as they may potentiate the effects of beta-
agonists on the cardiovascular system, including QTc prolongation).

Diuretics.  (Caution is advised in the co-administration of beta-agonists with non-
potassium sparing diuretics as this may result in ECG changes and/or 
hypokalaemia).

Use of positive airway pressure for sleep apnoea.

Oral muscarinic antagonists for the treatment of overactive bladder are permitted 
but should be used with caution as they may exacerbate medical conditions that 
are contraindicated for anticholinergics (e.g., narrow angle glaucoma and bladder 
outflow obstruction).

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).
6.10.2.
Prohibited Medications and Non-Drug Therapies
Medications prohibited at specific time intervals prior to Visit 1 (and at any time during 
the study) are identified in the Exclusion Criteria (Section 5.2).  
NOTE: All COPD medications (except for rescue albuterol/salbutamol, mucolytics and 
oxygen) are prohibited during the randomised period of the study except during the 
treatment of a moderate/severe COPD exacerbation or pneumonia. In the event of an 
exacerbation or pneumonia, sites should attempt to follow protocol treatment guidelines 
(Section 12.7); however, treatment with any medication that the health care provider 
deems necessary is allowed.  Caution is advised in using a LABA or LAMA to treat a 
subject currently taking study treatment as these additional medications may increase the 
risk of overdose. If necessary the investigator or other health care personnel may stop the 

2015N261999_03
CONFIDENTIAL
200812
46
subjects study treatmenttemporarily in order to treat the COPD exacerbation.  Subjects 
who require more than two consecutive 14 day courses of treatment (i.e. antibiotics or 
corticosteroids) should be evaluated for their continuation on study treatment by the 
investigator in consultation with the GSK medical monitor.
Eligible subjects will be allowed to continue their usual COPD medications during 
screening and the 2-week run-in period.  On the morning of the Screening Visit subjects 
will refrain from taking their morning dose of their usual COPD medications until 
instructed to do so by clinic personnel. During the run-in period subjects will continue to 
use their usual COPD medications with no change in medication or dose.  
The number of long-acting bronchodilators taken each day during the run-in period (0, 1 
or 2) will be recorded.
On the day before the Randomisation Visit (V2), subjects will take their last dose of their 
usual COPD medications and will not use any other COPD medications (except for those 
allowed per protocol: rescue albuterol, oxygen, mucolytics and medications for the 
treatment of a COPD exacerbation or pneumonia) until the end of the study.  Rescue 
albuterol/salbutamol can be used throughout the study as needed but must be withheld for 
at least 4 hours prior to conducting spirometry.
COPD Medications and non-drug therapies that are prohibited during the 
randomized portion of the study:

Inhaled and systemic corticosteroids (Except for the short term treatment [≤14 
days] of a COPD exacerbation or pneumonia.)  Note: Topical and ophthalmic 
corticosteroids, and localized corticosteroid injections (intra-spinal and intra-
articular) are allowed. 

Long and short acting muscarinic antagonists

Long and short acting 2 -agonists

PDE4 inhibitors (roflumilast)

Theophylline preparations

Cromoglycate and nedocromil inhalers

Zafirlukast, montelukast, zileuton

Acute phase of pulmonary rehabilitation (at any time during the study including 
run-in)

Long term systemic antibiotic therapy (antibiotics used for ≤14 days are allowed)
7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.

2015N261999_03
CONFIDENTIAL
200812
47
7.1.
Time and Events Table
Protocol Activity
Pre-Screen
Screen
Treatment
Follow Up
Visit 0
Pre-screen
Visit 1 Screening
Visit 2
Randomisation 
Visit 3
Visit 4
Visit 5
Early Withdrawal 
Visit
Safety
Follow-up 
Contact
Study Week
Week -2
Week 0
Week 4
Week 12
Week 24
1 week Fw-up
Window
-3/+8d
-4/+2d
-8/+6d
-8/+6d
-1/+4d
Written Informed Consent a
X
X
Genetic Informed Consent b
X
X
Demography c
X
X
Medical History, including 
cardiovascular history
X
COPD and Exacerbation History
X
Concomitant Medication 
Assessment
X
X
X
X
X
X
X
X
Inclusion/Exclusion Criteria
X
Randomisation Criteria
X
Smoking History
X
Smoking status
X
X
X
Smoking Cessation Counselling
X
X
X
Register Visit in IRT/ RAMOS NG d
X
X
X
X
X
X
Reversibility Testing e
X
Spirometry
Xf
Xf
Xf
Xf
Device training and registration
X
X
Exacerbation Assessment
X
X
X
X
X
X
X
SGRQ-C g
X
X
X
BDI g
X
TDI g
X
X
CAT g
X
eDevice close out h
X
X
X
Physical examination i
X
X
X

2015N261999_03
CONFIDENTIAL
200812
48
Protocol Activity
Pre-Screen
Screen
Treatment
Follow Up
Visit 0
Pre-screen
Visit 1 Screening
Visit 2
Randomisation 
Visit 3
Visit 4
Visit 5
Early Withdrawal 
Visit
Safety
Follow-up 
Contact
Study Week
Week -2
Week 0
Week 4
Week 12
Week 24
1 week Fw-up
Window
-3/+8d
-4/+2d
-8/+6d
-8/+6d
-1/+4d
Adverse Events Assessment
X
X
X
X
X
X
X
Vital signs j
X
X
X
X
ECG
X
Xk
Xk
Chest X-ray l
X
Pulse oximetry m
X
Blood draw for PK 
Xn
Xo
Blood Draw for Genetics research 
Xp
Haematology/biochemistry q
X
X
X
Urine Pregnancy Test r
X
X
X
X
X
Hepatitis B and C tests 
X
Dispense study treatment
X
X
X
Administer study treatment in clinic s
X
X
X
X
X
Assess study treatment compliance
X
X
X
X
Collect study treatment
X
X
X
X
Dispense albuterol/salbutamol
X
X
X
X
Collect albuterol/salbutamol
X
X
X
X
X
Issue/review paper diary t
X
X
X
X
X
X
a.
Informed consent must be conducted at the Pre-screen Visit prior to performing any study procedures including the changing or withholding of medications. The (IC) may be given at 
Screening Visit 1 if the subject does not take or has not taken any protocol excluded medications.
b.
Genetics research consent may be obtained at the same time as the study IC and must be obtained prior to obtaining a genetic blood sample.
c.
Demography may be captured at either the Pre-screen Visit or Screening Visit (for subjects who do not have a Pre-screen Visit).
d.
The IRT will be used for randomisation, emergency unblinding and study treatment supply management (Please refer RAMOS NG IRT manual for more information)
e.
At Screening Visit 1 both pre and post-bronchodilator spirometry will be conducted. Pre-bronchodilator spirometry will be performed prior to the subject taking their morning dose of 
their usual COPD treatment, between 6am and 11am and after withholding rescue albuterol/salbutamol for ≥4 hours.
f.
At Visits 2-5 (and the Early Withdrawal Visit), pre-bronchodilator spirometry will be performed prior to taking the morning dose of study treatment, between 6am and 11am and after 
withholding rescue albuterol/salbutamol for ≥4 hours.   

2015N261999_03
CONFIDENTIAL
200812
49
g.
Patient reported assessments should be conducted in the following order and before other study assessments: SGRQ-C, BDI/TDI.
h.
Close out eDevice for any subject who fails to randomize, withdraws early, or completes Visit 5.
i.
Physical examination may include height, weight, blood pressure, temperature, heart rate.
j.
Vital signs must be performed prior to spirometry and prior to taking morning dose of study mediation.
k.
ECG to be obtained 15 - 45 minutes post-dose at treatment Visit 5 and Early Withdrawal Visit (if possible).If a subject is not dosed at Early Withdrawal, then an ECG can be taken at 
any time during the visit
l.
Chest X-ray (PA and lateral) is required at Screening (or historical x-ray obtained within 3 months prior to Screening) and at anytime there is a suspected pneumonia or a mod/severe 
exacerbation.
m.
Pulse oximetry must be performed at V2 and anytime there is a suspected pneumonia or a moderate or severe exacerbation.
n.
PK subset A: PK samples of 120 subjects at selected sites, to be obtained at two time points at Visit 4: pre-dose and in the window 5 to15 minutes post-dose.
PK subset B: PK samples of 60 subjects at selected sites, to be obtained and Visit 4: pre-dose, 5-15min, 45-90min, 2.5-4h, 6-8h, 10-12h, 23-24h post-dose. 
o.
PK subset A: PK samples of 120 subjects at selected sites, to be obtained at two time points at Visit 5: 5 to 15 minutes post–dose and 45 to 90 minutes post-dose.
p.
The genetics blood sample should be taken at V5 or at any visit after Randomisation (V2). 
q.
Haematology and chemistry panels will include liver chemistry, and potassium and glucose levels.
r.
All female subjects of child bearing potential will have a urine pregnancy test at each visit except Visits 2 and follow-up.
s.
Subjects must withhold their morning dose of study treatment at each clinic visit and not take their study treatment dose until instructed to do so by study staff.
t.
Subjects will be issued a paper diary, at screening and other clinic visits (if required) in order to note any changes to concomitant medications and/or incidence of adverse events that 
may have occurred between clinic visits. 

2015N261999_03
CONFIDENTIAL
200812
50
7.2.
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 may be 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.  The informed consent 
may be given at the Screening Visit (V1) if the subject does not take or has not taken any 
protocol excluded medications.  
During the pre-screening visit (V0) each subject will have the following procedures 
performed. The following demographic parameters will be captured: 

Year of birth, sex, race and ethnicity.

Concomitant medication review. 
The additional following critical baseline assessments will be conducted at Screening 
(V1):

Medical history including COPD history (comprised of COPD type [emphysema 
and/or chronic bronchitis]), smoking history, COPD exacerbations history, 
smoking status and previous and/or current medical conditions.

Concomitant Medications review (COPD concomitant medications in the 3 
months prior to Screening)

COPD exacerbation assessment (documented history of exacerbation(s) in the 12 
months prior to Screening)

Cardiovascular medical history/risk factors 

Inclusion/Exclusion criteria assessment

COPD Assessment Test (CAT)

Physical examination 

Pulse rate, blood pressure measurements 

12-lead ECG

Pre- and post-albuterol/salbutamol spirometry (reversibility) 

SAE assessment (if related to study participation)

Chest X-Ray [or historical radiograph obtained within 3 months prior to 
Screening (V1)]

Laboratory assessments (chemistry and hematology, hepatitis and pregnancy 
testing)

2015N261999_03
CONFIDENTIAL
200812
51
In addition the following procedures must be completed at Screening (V1):

Smoking cessation counseling

Electronic device training

Dispense albuterol/salbutamol
7.2.1.
COPD Assessment Test (CAT)
The CAT will be completed by subjects at Screening (V1) using an electronic device, 
before any other Screening (V1) assessments, in order to assess eligibility.
The COPD Assessment Test (Jones, 2009; Jones, 2012) is a validated, short and simple 
patient completed questionnaire which has been developed for use in routine clinical 
practice to measure the health status of patients with COPD. The CAT is an 8-item 
questionnaire suitable for completion by all patients diagnosed with COPD.  When 
completing the questionnaire, subjects rate their experience on a 6-point scale, ranging 
from 0 (no impairment) to 5 (maximum impairment) with a scoring range of 0-40. Higher 
scores indicate greater disease impact.
7.3.
Efficacy
7.3.1.
Primary Efficacy Endpoint

Change from baseline in trough FEV1 at 24 weeks
Measured using centralised spirometry by fully qualified and trained study site personnel. 
7.3.2.
Secondary Efficacy Endpoints

Proportion of Responders based on the SGRQ Total Score at Week 24

Change from baseline in SGRQ Total Score at Week 24

Proportion of Responders based on TDI focal score at Week 24 

TDI focal score at Week 24

Time to first moderate or severe exacerbation
7.3.3.
Spirometry and Reversibility Testing
7.3.3.1.
Spirometry
Spirometry measurements will be obtained using spirometry equipment that meets or
exceeds the minimal performance recommendations of the ATS [Miller, 2005]. All sites
will use standardised spirometry equipment provided by an external vendor. All subjects

2015N261999_03
CONFIDENTIAL
200812
52
will have spirometry performed at screening (pre- and post-salbutamol) and pre-dose at 
each scheduled clinic visit during the treatment period. For FEV1
and FVC 
determinations, at least 3 acceptable spirometry efforts (with no more than 8) should be 
obtained. Acceptable spirometry efforts should have a satisfactory start of test and end of 
test (e.g. a plateau in the volume-time curve) and be free from artefacts due to cough, 
early termination, poor effort, obstructed mouthpiece, equipment malfunction, or other 
reasons [Miller, 2005].
The largest FEV1 and FVC from the 3 acceptable efforts should be recorded, even if they
do not come from the same effort. Spirometry must be performed as follows:

Started approximately between 6:00AM and 11:00AM.

After withholding albuterol/salbutamol for 4 hours.

At Screening (V1), before the morning dose of their usual COPD medications.

At Randomisation (V2) and all treatment visits, before the morning dose of study 
treatment.

At Screening (V1), the CAT must be administered prior to spirometry 

At Randomisation (V2), V4 and V5, questionnaires must be completed prior to 
spirometry (SGRQ-C should be administered first followed by BDI/TDI)

Subjects should refrain from smoking for 1 hour prior to each pulmonary function 
test.

Subjects should abstain from drinking beverages with high levels of caffeine such 
as tea and coffee for 2 hours prior to each pulmonary function test.
A full description of the timing and conduct of spirometry procedures is provided in the
SPM.
7.3.3.2.
Reversibility
At Screening (V1), both pre- and post-albuterol/salbutamol spirometry will be obtained. 
Post albuterol/salbutamol FEV1 and FEV1/FVC findings will be used to determine 
subject eligibility. Reversibility testing will be completed as follows: Following pre-
albuterol/salbutamol spirometry (three acceptable spirometry efforts), the subject will 
self-administer 4 puffs of albuterol/salbutamol MDI using a spacer/valved holding-
chamber. Three acceptable spirometry efforts will be obtained approximately 10 to 30 
minutes after albuterol/salbutamol administration.
7.3.4.
SGRQ-C
The St George’s Respiratory Questionnaire -COPD specific (SGRQ-C) will be completed 
by subjects at Randomisation (V2), Week 12 (V4) and Week 24 (V5).
The SGRQ-C [Meguro, 2007] is a disease-specific questionnaire designed to measure the 
impact of respiratory disease and its treatment on a COPD patient’s HRQoL.  As well as 
producing an overall summary score, scores for the individual domains of symptoms, 

2015N261999_03
CONFIDENTIAL
200812
53
activity and impacts are also produced.  It has been used in studies of COPD subjects and 
has been translated and validated for use in most major languages.  The SGRQ-C is 
derived from the original SGRQ, and produces SGRQ scores equivalent to the SGRQ 
instrument [Meguro, 2007].
7.3.5.
Baseline Dyspnoea Index/Transitional Dyspnoea Index
The BDI is used to measure the severity of dyspnoea in patients at baseline. The TDI 
measures changes in the patient’s dyspnoea from baseline. The scores in both indexes 
depend on ratings for three different categories: functional impairment; magnitude of 
task; and magnitude of effort. The BDI will be measured at Randomisation (V2). TDI 
will be measured at Week 12 (V4) and at Week 24 (V5).
7.3.6.
COPD Exacerbations
COPD exacerbations will be identified based on the investigator’s clinical judgment.
If the subject experiences a moderate or severe exacerbation, every effort should be made 
to complete the following assessments within 48 hours of the exacerbation:

Chest X-ray 

Pulse oximetry
See Appendix 7 (Section 12.7).
7.4.
Safety
7.4.1.
Safety endpoints

Incidence of adverse events

Incidence of adverse events of special interest

ECG measurements

Vital signs

Haematological and clinical chemistry parameters
7.4.2.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 4, Section 12.4. 
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 

2015N261999_03
CONFIDENTIAL
200812
54
7.4.2.1.
Time period and Frequency for collecting AE and SAE information

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. 

AEs will be collected from the start of Study Treatment until the follow-up 
contact (see Section 7.4.2.3), at the time points specified in the Time and Events 
Table (Section 7.1).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the eCRF.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 4 (Section 12.4.6).

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the 
investigator must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 4 (Section 12.4.6).
7.4.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?”

“Have you had any (other) medical problems since your last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?”
7.4.2.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs, and non-serious AEs of special interest 
(as defined in Section 4.6.1) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.5). Further information on follow-up procedures is given in 
Appendix 4 (Section 12.4).

2015N261999_03
CONFIDENTIAL
200812
55
7.4.2.4.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 4, Section 12.4 and all deaths, 
whether or not they are considered SAEs, specific Cardiovascular (CV) and Death 
sections of the eCRF will be required to be completed. These sections include questions 
regarding cardiovascular (including sudden cardiac death) and non-cardiovascular death. 
The CV eCRFs 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 eCRF within one week of receipt of a CV Event data query prompting its completion. 
The Death eCRF 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.
7.4.2.5.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs related to study treatment (even 
for non- interventional post-marketing studies) is essential so that legal obligations and 
ethical responsibilities towards the safety of subjects and the safety of a product under 
clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.4.3.
Adverse Events of Special Interest (AESIs)
AE groups of special interest have been defined as AEs which have specified areas of 
interest for one or more of class of drugs (ICS, LAMA, LABA). Some AE groups may 
have subgroups defined.
The following table 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 RAP.

2015N261999_03
CONFIDENTIAL
200812
56
Special interest AE group
Special interest AE subgroup
Cardiovascular effects
Cardiac arrhythmia
Cardiac failure
Cardiac ischemia
Hypertension
Stroke
Pneumonia and LRTI
Pneumonia 
LRTI excluding pneumonia
Adrenal suppression
Anticholinergic syndrome
Corticosteroids associated 
eye disorders
Decreased bone mineral 
density and associated 
fractures
Effects on glucose
Effects on potassium
Gastrointestinal obstruction
Hypersensitivity
Local steroid effects
Ocular effects 
Tremor
Urinary retention
7.4.4.
Electrocardiogram (ECG)
Sites will use standardised ECG equipment provided by a centralised external vendor. All 
ECG measurements will be made with the subject in a supine position having rested in 
this position for approximately 5 minutes before each reading at Screening (V1) and at 
Week 24 (V5) or at the Early Withdrawal Visit.

2015N261999_03
CONFIDENTIAL
200812
57

Single12-lead ECGs will be obtained at each time point during the study using an 
ECG machine that automatically calculates the heart rate and measures PR, QRS, 
QT, and QTc intervals.  
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. 
All ECGs will be electronically transmitted to an independent cardiologist and evaluated. 
The independent cardiologist, blinded to treatment assignment, will be responsible for 
providing measurements of heart rate, QT intervals and an interpretation of all ECGs 
collected in this study. A hard copy of these results will be sent to the Investigator. The 
Investigator must provide his/her dated signature on the confirmed report, attesting to 
his/her review of the independent cardiologist’s assessment.
Details of the cardiac monitoring procedures will be provided by the centralised 
cardiology service provider.
7.4.5.
Vital Signs
Vital signs will be performed prior to conducting spirometry and prior to taking the 
morning dose of study treatment. Vital signs will be collected at Screening (V1), Week 4 
(V3), and Week 24 (V5) or at the Early Withdrawal Visit. Blood pressure (systolic and 
diastolic) and pulse rate will be measured in the sitting position after approximately 5 
minutes rest.  A single set of values will be collected and recorded in the source 
documentation and eCRF.
7.4.6.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 3, must be conducted in 
accordance with the Laboratory Manual, and Protocol Time and Events Schedule.
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.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the eCRF.
Refer to the SPM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
Haematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 3. 

2015N261999_03
CONFIDENTIAL
200812
58
Table 3
Protocol Required Safety Laboratory Assessments
CHEMISTRY
HEMATOLOGY 
OTHER
Albumin 
Haemoglobin
Hepatitis B surface antigen1
Alkaline phosphatase 
Hematocrit
Hepatitis C virus antibody1
Alanine amino-transferase (ALAT or SGPT)
Platelet count
Urine pregnancy test2
Aspartate amino-transferase (ASAT or SGOT)
WBC count
Bilirubin, direct
Neutrophils, absolute
Bilirubin, indirect
Neutrophils, segs (%)
Bilirubin, total
Neutrophils, bands (%)
Calcium
Basophils (%)
Chloride
Eosinophils (%)
CO2 content/Bicarbonate
Eosinophils , absolute
Creatinine
Lymphocytes (%)
Creatine phosphokinase (CPK), total
Monocytes (%)
Gamma glutamyl transferase (GGT)
RBC count
Glucose
Phosphorus 
Potassium
Protein, total serum
Sodium
Urea nitrogen (BUN)
Uric Acid 
1.
Assessed at Visit 1 (Screening) only, result is not exclusionary
2.
Only females of child-bearing potential; refer to Time and Events Table for specific visit information
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study or within 7 days after the last dose of study treatment 
should be repeated until the values return to normal or baseline.  If such values do not 
return to normal within a period judged reasonable by the investigator, the etiology
should be identified and the sponsor notified.
7.4.7.
Other Safety Assessments

Physical examinations 

Pneumonia reporting

Pulse oximetry

Radiography (CXR)

Urine pregnancy test (for women of child-bearing potential)

Medical Problems and Concomitant Medications
7.4.8.
Physical Exams

A complete physical examination will include, at a minimum, assessment of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. Height 
and weight will also be measured and recorded. 

2015N261999_03
CONFIDENTIAL
200812
59
7.4.9.
Pneumonia
All 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 (colour) or production 

Auscultatory findings of adventitious sounds (e.g. egophony, bronchial breath 
sounds, rales, etc.)

Dyspnoea or tachypnoea

Fever (oral temperature > 37.5 °C)

Elevated WBC (>10,000/mm3 or >15% immature forms)

Hypoxemia (HbO2 saturation ≤88% or at least 2% lower than baseline value)
All pneumonias must be captured on the AE/SAE page of the eCRF and on the 
pneumonia page of the eCRF. 
The investigators and site staff should remain vigilant for the possible development of 
pneumonia in patients with COPD as the clinical features of such infections overlap with 
the symptoms of COPD exacerbations. 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).
Note: Pulse oximetry should be measured at any time a moderate or severe exacerbation 
is reported or pneumonia is suspected and recorded in the source documents and on the 
pneumonia page of the eCRF if applicable. 
7.4.10.
Pulse oximetry
Pulse oximetry will be conducted at randomisation and recorded in the eCRF.  Pulse 
oximetry should be measured at any time a moderate or severe exacerbation is reported or 
pneumonia is suspected and recorded in the source documents and on the pneumonia 
page of the eCRF if applicable.
7.4.11.
Radiography (Chest X-Rays)
Confirmation by chest x-ray (posteroanterior and lateral) should be performed as 
soon as possible and preferably within 48 hours of suspected pneumonia and/or 
moderate or severe exacerbation. All chest x-rays will be reviewed by the investigator 
to confirm the presence of new radiographic findings compatible with pneumonia.  In all 
cases, the signs and symptoms that were used to identify the pneumonia must be 
documented in the source documents and eCRF. Diagnoses of pneumonia must be 
recorded as adverse events in the eCRF.

2015N261999_03
CONFIDENTIAL
200812
60
7.4.12.
Pregnancy

Details of all pregnancies in female subjects will be collected after the start of 
dosing and until the Follow-up Visit.

If a pregnancy is reported then the investigator should inform GSK within 2 
weeks of learning of the pregnancy and should follow the procedures outlined in 
Appendix 5.
7.4.13.
Medical Problems and Concomitant Medications
Subjects will be instructed to record any medical problems and the medications used to 
treat them in a paper diary each day. These entries will be reviewed by the study 
coordinator at each study visit and recorded in the eCRF as adverse events as appropriate. 
7.5.
Pharmacokinetics
7.5.1.
Blood Sample Collection
Blood samples for PK analysis of FF, UMEC and VI will be collected at the time points 
indicated in Section 7.1, Time and Events Table.  The actual date and time of each blood 
sample collection will be recorded. A population pharmacokinetics approach will be 
employed in this study with samples collected in approximately 180 subjects (to achieve 
approximately 150 subjects treated with FF/UMEC/VI or FF/VI + UMEC). Subjects at 
selected sites will either be included in subset A or subset B. 
PK Subset A (Sparse PK Samples): Approximately 120 subjects will be included, to 
achieve approximately 100 subjects treated with FF/UMEC/V1 or FF/VI + UMEC and 
providing the required samples. Two 6mL blood samples at each of the two visits will be 
collected as follows:

Week 12 (V4): Pre-dose and in the window 5 to 15 minutes post-dose

Week 24 (V5): In the windows 5 to 15 minutes and 45 to 90 minutes post-dose
PK Subset B (Serial PK Samples): Approximately 60 subjects will be included, to 
achieve approximately 50 subjects treated with FF/UMEC/V1 or FF/VI + UMEC and 
providing the required samples. Seven 6mL blood samples at one visit will be collected 
as follows:

Week 12 (V4): Pre-dose and in the windows 5 to 15 mins and 45 to 90 mins, 2.5 
to 4 hours, 6 to 8 hours, 10 to 12 hours and 23 to 24 hours post-dose
Processing, storage and shipping procedures are provided in the SPM.

2015N261999_03
CONFIDENTIAL
200812
61
7.5.2.
Sample Analysis
Plasma analysis will be performed under the control of PTS-DMPK/Scinovo, 
GlaxoSmithKline, the details of which will be included in the SPM. Concentrations of 
parent compound and metabolites OR compound numbers or names will be determined in 
plasma OR matrix to be used samples using the currently approved bioanalytical 
methodology. Raw data will be archived at the bioanalytical site (detailed in the SPM).
Once the plasma OR matrix to be used has been analyzed for parent compound and 
metabolites OR compound numbers or names any remaining plasma OR matrix to be 
used may be analyzed for other compound-related metabolites and the results reported 
under a separate PTS-DMPK/Scinovo, GlaxoSmithKline protocol.
7.6.
Genetics
Information regarding genetic research is included in Appendix 3.
8.
DATA MANAGEMENT

For this study subject data will be entered into GSK defined eCRFs, transmitted 
electronically to GSK or designee and combined with data provided from other 
sources in a validated data system. 

Management of clinical data will be performed in accordance with applicable 
GSK standards and data cleaning procedures to ensure the integrity of the data, 
e.g., removing errors and inconsistencies in the data.

Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated 
medication dictionary, GSKDrug.  

eCRFs (including queries and audit trails) will be retained by GSK, and copies 
will be sent to the investigator to maintain as the investigator copy.  Subject 
initials will not be collected or transmitted to GSK according to GSK policy.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
The primary objective of this study is to compare FF/UMEC/VI with FF/VI+UMEC in 
COPD subjects. The primary endpoint is trough FEV1 at Week 24. The primary analysis 
is the comparison of this endpoint for FF/UMEC/VI vs. FF/VI+UMEC.  
The null hypothesis is that the difference in trough FEV1 between treatment groups is less 
than or equal to a pre-specified non-inferiority margin -Δ:
H0: T1 – T2 ≤ -Δ

2015N261999_03
CONFIDENTIAL
200812
62
The alternative hypothesis is that the difference between treatment groups is greater than 
the margin.
H1: T1 – T2 > -Δ
where T1 and T2 are the treatment means for FF/UMEC/VI and FF/VI+UMEC, 
respectively.
The non-inferiority margin has been set at 50mL, which is half the generally accepted 
minimal clinically important difference (MCID) for trough FEV1.
If the lower bound of the two-sided 95% confidence interval around the (FF/UMEC/VI 
vs. FF/VI+UMEC) treatment difference is above -50mL then FF/UMEC/VI will be 
considered non-inferior to FF/VI+UMEC.
9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
The sample size calculations use a one-sided 2.5% significance level and an estimate of 
residual standard deviation (SD) for trough FEV1 at Week 24 of 220mL. The estimate of 
SD is based on mixed model repeated measures (MMRM) analyses of previous phase 
IIIA studies in COPD subjects.  A study with 816 evaluable subjects for the primary 
analysis will have 90% power to determine non-inferiority of FF/UMEC/VI to 
FF/VI+UMEC based on trough FEV1 at Week 24, when the margin of non-inferiority is 
50mL and the true mean treatment difference is assumed to be 0mL.
It is estimated that approximately 20% of subjects who are randomised will either 
discontinue study treatmentor be excluded from the Adherent population at Week 24, 
therefore approximately 1020 subjects will be randomised. 
However, subjects who provide trough FEV1 data prior to Week 24 and are in the 
Adherent population will be included in and contribute to the analysis and so the power 
of the study may be higher than stated here.
9.2.1.1.
Sample Size Sensitivity
If the standard deviation observed in the study is different from the 220 mL used in the 
sample size calculation, the power to determine non-inferiority based on trough FEV1 at 
Week 24 will be affected. Table 4 illustrates the power which would be obtained with 
various standard deviations, assuming the number of evaluable subjects remains constant 
at 408 per arm and the non-inferiority margin is 50 mL. Table 4 and Figure 2 illustrate 
the impact on power of different estimates of standard deviation.

2015N261999_03
CONFIDENTIAL
200812
63
Table 4
Impact on Power of Different Estimates of Standard Deviation
Parameter
SD (mL)
Power for Margin of 50mL
Trough FEV1
180
98%
200
95%
220
90%
240
84%
260
78%
If the SD increased to 260 mL, the study would have 78% power to conclude 
noninferiority based on a margin of 50 mL.
Figure 2
Impact on Power of Different Estimates of Standard Deviation
S1=standard deviation (mL)
Based on a SD of 220 mL and a sample size of 408 evaluable subjects per arm, the lower 
confidence bound for the treatment difference would be greater than 0 at an observed 
treatment difference of 31 mL [detectable effect].
9.2.2.
Sample Size Re-estimation or Adjustment
No sample size re-estimation or adjustment is planned for this study.

2015N261999_03
CONFIDENTIAL
200812
64
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
Population
Definition / Criteria
Analyses Evaluated
All 
Subjects 
Enrolled 
(ASE)

All subjects for whom a record exists in the 
study database, including screen failures and 
any subject who was not screened but 
experienced an SAE between the date of 
informed consent and the planned date of the 
Screening visit. 

Subject 
Disposition

Reasons for 
withdrawal prior
to randomisation

Inclusion, 
exclusion and 
randomisation 
criteria deviations

SAEs for non-
randomised 
subjects
Intent-to-
treat (ITT)

All randomized subjects, excluding those who 
were randomized in error. A subject who is 
recorded as a screen or run-in failure and also 
randomized will be considered to be 
randomized in error.  Any other subject who 
receives a randomisation number will be 
considered to have been randomized.

Displays will be based on the treatment to 
which the subject was randomized.

Study Population

Efficacy

Health-related 
Quality of Life

Inhaler 
Assessments

Safety
Adherent

All subjects in the ITT Population who do not 
have a full protocol deviation considered to 
impact efficacy.

Data following a COPD exacerbation or 
pneumonia will be excluded from analysis due 
to the potential impact of the exacerbation or 
the medications used to treat it 

Subjects with partial protocol deviations 
considered to impact efficacy will be included 
in the Adherent Population but will have their 
data excluded from analyses from the time of 
deviation onwards. 

Primary treatment 
comparison of the 
primary endpoint 
only
9.4.
Key Elements of Analysis Plan
9.4.1.
Treatment Comparisons
The primary treatment comparison of FF/UMEC/VI with FF/VI+UMEC will be 
performed on trough FEV1 at Week 24, for the Adherent Population.

2015N261999_03
CONFIDENTIAL
200812
65
The treatment comparison of FF/UMEC/VI with FF/VI+UMEC will be performed for the 
primary endpoint and all other efficacy and health related quality of life endpoints for the 
ITT Population.
Treatment comparisons will not be adjusted for multiplicity.
9.4.2.
Primary Analyses
The “de jure” estimand will be used to demonstrate non-inferiority of FF/UMEC/VI to 
FF/VI + UMEC.
The primary endpoint of trough FEV1 at Week 24 will be analysed for the Adherent 
Population using a mixed model repeated measures (MMRM) analysis, including trough 
FEV1 recorded at each of Weeks 4, 12 and 24. The model will include covariates of 
stratum (number of long-acting bronchodilators per day during the run-in), baseline 
FEV1, Week, centre group, treatment and Week by baseline interaction. A Week by 
treatment interaction term will also be included to allow treatment effects to be estimated 
at each visit separately. The variance-covariance matrix will be assumed unstructured.
Estimated differences between FF/UMEC/VI and FF/VI+UMEC will be presented 
together with 95% confidence intervals (CIs) for the difference and p-values.
A “tipping point” sensitivity analysis of trough FEV1 at Week 24 will be conducted for 
the Adherent Population. This will explore the impact of missing data by using differing 
assumptions regarding the mean treatment effect in subjects who discontinue study 
treatment or have data excluded from Adherent Population analyses.  Assumptions will 
include scenarios where subjects who discontinue FF/UMEC/VI have a lower treatment 
effect than those who discontinue FF/VI+UMEC. The analysis results will be used to 
explore the conditions under which the conclusion of non-inferiority no longer holds. 
9.4.3.
Other Efficacy Analyses
The MMRM analysis will be repeated for the ITT Population.
Full details of the analyses to be performed on the primary and other efficacy endpoints 
will be given in the RAP.
9.4.4.
Safety Analyses
Adverse events (AEs) will be coded using the standard GSK dictionary, Medical 
Dictionary for Regulatory Activities (MedDRA), and grouped by body system. The 
number and percentage of subjects experiencing at least one AE of any type, AEs within 
each body system and AEs within each preferred term will be presented for each 
treatment group. Separate summaries will be provided for all AEs, drug related AEs, fatal 
AEs, non-fatal SAEs, AESIs and AEs leading to withdrawal.
Deaths and SAEs will be documented in case narrative format.

2015N261999_03
CONFIDENTIAL
200812
66
Full details of the analyses to be performed on all safety endpoints will be given in the 
RAP.
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable

Obtaining signed informed consent

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol 
deviations to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, 
or both.

Signed informed consent must be obtained for each subject prior to participation 
in the study

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, 
written approval of the clinical protocol should state that approval of optional 

2015N261999_03
CONFIDENTIAL
200812
67
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the Insert the 
appropriate text, either “CRF” or “PIMS record” for studies conducted at a GSK 
Phase I unit will serve as the source document.
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents
10.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and 
the regulatory agencies may conduct a regulatory inspection at any time during or 
after completion of the study. 

In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss 
the conduct of the study, any findings/relevant issues and to implement any 
corrective and/or preventative actions to address any findings/issues identified.
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard 
Operating Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this 
study at any time for reasons including, but not limited to, safety or ethical issues 
or severe non-compliance. For multicenter studies, this can occur at one or more 
or at all sites.  

2015N261999_03
CONFIDENTIAL
200812
68

If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable).  When feasible, GSK will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the 
impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.  

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical 
institution (where applicable) must maintain all site study records (except for 
those required by local regulations to be maintained elsewhere), in a safe and 
secure location.  

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review 
in conjunction with assessment of the facility, supporting systems, and relevant 
site staff.  

Where permitted by local laws/regulations or institutional policy, some or all of 
these records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.  

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, 
including re-generating a hard copy, if required.  Furthermore, the investigator 
must ensure there is an acceptable back-up of these reproductions and that an 
acceptable quality control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by 
any 
institutional 
requirements 
or 
local 
laws 
or 
regulations, 
GSK 
standards/procedures, and/or institutional requirements.  

The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of 
ownership of the records in the event the investigator is no longer associated with 
the site.

2015N261999_03
CONFIDENTIAL
200812
69
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
GSK will provide the investigator with the randomisation codes for their site only after 
completion of the full statistical analysis.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.
A manuscript will be progressed for publication in the scientific literature if the results 
provide important scientific or medical knowledge.

2015N261999_03
CONFIDENTIAL
200812
70
11.
REFERENCES
Aaron SD, Vandemheen KL, Fergusson D, Maltais F, Bourbeau J, Goldstein R, Balter M 
et al. (2007) Tiotropium in Combination with Placebo, Salmeterol, or Fluticasone–
Salmeterol for Treatment of Chronic Obstructive Pulmonary Disease A Randomized 
Trial. Ann Intern Med. 146:545-555.
Aguis R and Kintz P (2010) Drug and alcohol testing in hair, collection and analysis.  
European workplace drug testing society, version 1.0, 1-18
Barbosa, J, Faria, J, Carvalho, F, Pedro, M, Queiros, O, Moreira, R and Dinis-Oliveira RJ 
(2013) Hair as an alternative matrix in bioanalysis. Bioanalysis 5 (8): 895-914
Breekveldt-Postma, NS,Koerselman, J, Erkhens, JA, Lammers, J-WJ and Herings RMC 
(2007) Enhanced persistence with Tiotropium compared with other respiratory drugs in 
COPD. Resp. Med. 101: 1398-1405
Bryant, J, McDonald, VM, Boyes, A, Sandon-Fisher, R, Paul, C and Melville, J (2013) 
Improving medication adherence in chronic obstructive pulmonary disease: a systematic 
review. Resp. Research 14: 109-116
Cazzola M et al. (2007) A pilot study to assess the effects of combining fluticasone 
propionate/salmeterol and tiotropium on the airflow obstruction of patients with severe-
to-very severe COPD. Pul. Pharm. & Therapeu. 20:556–561.
Celli BR, MacNee W. Standards for the diagnosis and treatment of patients with COPD: 
A summary of the ATS/ERS position paper.  Eur Respir J 2004; 23: 932-946
Dominguez-Romero JC, Garcia-Rayes, JF and Molina-Diaz A (2011) Screening and 
quantitation of multiclass drugs of abuse and pharmaceuticals by fast liquid 
chromatography electrospray time-of-flight mass spectrometry. J. of Chromatography B 
879:2034-2042
Global Strategy for the Diagnosis, Management and Prevention of COPD, Global 
Initiative for Chronic Obstructive Lung Disease (GOLD) 2013. Available from: 
http://www.goldcopd.org/.
Hanania, HA et al. (2012) Benefits of adding fluticasone propionate/salmeterol to 
tiotropium in moderate to severe COPD. Resp. Med. 106: 91-101.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, editors. 
Contraceptive Technology. 19th edition. New York: Ardent Media, 2007(a): 24. Table 3-
2.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, editors.
Contraceptive Technology. 19th edition. New York: Ardent Media, 2007(b): 28.

2015N261999_03
CONFIDENTIAL
200812
71
Haute Autorité de Santé, Government of France. Guide pour le dossier de demande 
d’inscription, de modification des conditions d’inscription et de renouvellement 
d’inscription d’un produit inscrit sous le nom de marque sur la liste prévue à l’article L. 
165-1 par la commission d’évaluation des produits et prestations. Saint-Denis La Plaine, 
2009.
Institute for Quality and Efficiency in Health Care. Allgemeine Methoden (Version 4.2). 
Cologne, 22 April 2015.
International Conference of Harmonisation [ICH] of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (2009). Guidance on nonclinical safety 
studies for the conduct of human clinical trials and marketing authorization for 
pharmaceuticals M3(R2).
Jones, P., Harding, G., Berry, P., Wiklund, I., Chen, W-H., Leidy, N. Development and 
first validation of the COPD Assessment Test (CAT) Eur Respir J (2009) 34: 648–654 
Jones, PW., Harding, G., Wiklund, I., Berry, P., Tabberer, M., Yu, R., Leidy, N. ‘Tests of 
the Responsiveness of the Chronic Obstructive Pulmonary Disease (COPD) Assessment 
Test (CAT) Following Acute Exacerbation and Pulmonary Rehabilitation.’ Chest (2012) 
142 134-140 
Jung KS, et al. Comparison of tiotropium plus fluticasone propionate/salmeterol with 
tiotropium in COPD: A randomized controlled study. Resp. Med. .(2012) 106: 382-389 
doi:10.1016/j.rmed.2011.09.004.
Kardas, P (2002) Patient compliance with antibiotic treatment for respiratory tract 
infections. J. Antimicrobial chemotherapy 49: 897-903
Kuwayama K, Yamamuro T,Tsujikawa K, Miyaguchi H, Kanamori T,Iwata U and Inoue 
H (2014) Time-course measurements of drugs and metabolites transferred from finger 
tipsafter drug administration: Usefulness of fingertips for drug testing. Forensic 
Toxicology 32: 235-242
Laforest, L, Denis, F, Van Ganse, E, Ritleng, C, Saussier, C, Passante, N, Devouassoux, 
G, Chatte, G, Freymond, N and Pacheco, Y (2010) Correlates of adherence to respiratory 
drugs in COPD patients.  Primary care Res. Med. 19 (2): 148-154
Meguro M, Barley EA, Spencer S et al. Development and validation of an improved 
COPD-Specific Version of the St. George Respiratory Questionnaire.  Chest. 
2007;132:456-463
Miller MR, Hankinson J, Odencrantz J, Standardisation of spirometry. Eur Respir J. 
2005;26:319-388.
Nielsen, MKK, Johansen, SS, Dalsgaard, PW and Linnet K (2010) Simultaneous 
screening and quantification of 52 common pharmaceuticals and drugs of abuse in hair 
using UPLC-TOF-MS. Forensic sci. Int. 196: 85-92

2015N261999_03
CONFIDENTIAL
200812
72
Pharmaceutical Benefits Advisory Committee, Department of Health, Government of 
Australia. Guidelines for preparing submissions to the Pharmaceutical Benefits Advisory 
Committee (Version 4.4). Canberra, June 2013.
Porta, T, Varesio, E, Kraemer, T and Hopfgartner G (2011) Molecular imaging by mass 
spectrometry: application to forensics. Spectroscopy Europe 23 (5): 6-12
Quanjer, P., Stanojevic, S., Cole, T., Baur, X., Hall, G., Culver, B., Enright, P., 
Hankinson, J., Ip, M., Zheng, J., Stocks, J., & ERS Global Lung Function Initiative, 
(2012). Multi-ethnic reference values for spirometry for the 3-95-yr age range: The 
global lung function 2012 equations. European Respiratory Journal, 40(6), 1324-1343.
Restrepo, R, Alvarez, MT, Wittenbel, L, Sorenson, H, Wettstein, R, Vines DL, Sikkema-
Ortiz, J, Gardner DD and Wilkins RL (2008) Medication adherence issues in patients 
treated for COPD.  Int. J. COPD 3 (3): 371-384
Tamura G and Ohta K (2007) Adherence to treatment by patients with asthma or COPD: 
Comparison between inhaled drugs and transdermal patch. Resp. Medicine 101: 1895-
1902
Tashkin, DP. et al (2008) A 4-year Trial of Tiotropium in Chronic Obstructive 
Pulmonary Disease. N Engl J Med 2008 359:1543-1554.
Vulic A, Pleadin, J, Stojkovic, R and Ivankovic S (2011) Accumulation of b-agonists 
clenbuterol and salbutamol in black and white mouse hair. J. Analytical Toxicol. 35: 566-
570
Waki, ML, Onoue, K, Takahashi, T, Goto, K, Saito, Y, Inami, K, Makita, I, Angata, Y, 
Suzuki, T, Yamashita, M, Sato, N, Nakamura, S, Yuli, D, Sugiura, Y, Zaima, N, Goto-
Inoue, N, Hayasaka, T, Shimomura Y and Setou M (2011) Investigation by imaging mass 
spectrometry of biomarker candidates for aging in the hair cortex. PLos ONE 6 (10): 1-9
Welte, T et al. (2009) Efficacy and Tolerability of Budesonide/Formoterol Added to 
Tiotropium in Patients with Chronic Obstructive Pulmonary Disease. Am. J. Respir. Crit. 
Care Med. 180:741–750.
Wilson P and Chambers D (2010) Evidence briefing on adherence to treatment for 
respiratory diseases. National Institute for Health research, centre for reviews and 
dissemination , University of York. 1-6.
Wolters Kluwer's Source Lx Database (2012) Hierarchical Regimen Analysis (HRA) 
Application SLED Report With Filtering On Patients Aged 18+ With COPD Only. Data 
from February 2011 through January 2012.
World Health Organisation (2003) Adherence to long term therapies – evidence for 
action. 47-59
Wurst KE, Bushnell G, Shukla A, Muellerova H, Davis KJ. Factors Associated with 
Time to Triple Therapy in Newly Diagnosed COPD Patients in the UK General Practice 

2015N261999_03
CONFIDENTIAL
200812
73
Research Database. (2013) 29th International Conference on Pharmacoepidemiology and 
Therapeutic Risk Management, Montreal, Canada. Abstract 62. 
Yilmaz, I, Erkekol FO, Celen, S, Karaca, MZ, Aydin, O, Celik, G, Misirligil, Z and 
Mungan, D (2013) Does drug compliance change in asthmatic patients during pregnancy? 
Multidisciplinary Resp. Med. 8:38-42

2015N261999_03
CONFIDENTIAL
200812
74
12.
APPENDICES
12.1.
Appendix 1 – Abbreviations and Trademarks
Abbreviations
AE
Adverse Event
ALT
Alanine Transaminase
AST
Aspartate Aminotransferase
ATS
American Thoracic Society
AV
Atrioventricular
BDI
Baseline Dyspnoea Index
Bpm
Beats Per Minute
CAT
COPD Assessment Test
CI
Confidence Intervals
COPD
Chronic Obstructive Pulmonary Disease
CPK
Creatinine Phosphokinase
CPRD
Clinical Practice Research Database
CRF
Case Report Form
CT
Computed Tomography
CXR
Chest X-Ray
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
FEV1
Forced Expiratory Volume in One Second
FF
Fluticasone Furoate 
FSH
Follicle Stimulating Hormone
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GGT
Gamma Glutamyl Transferase
GSK
GlaxoSmithKline
GSK573719
Umeclidinium (UMEC)
GW642444
Vilanterol Trifenatate (VI)
GW685698
Fluticasone Furoate (FF)
HRQoL
Health Related Quality of Life
IB
Investigator Brochure
ICS
Inhaled Corticosteroid
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IgM
Immunoglobulin M
IND
Investigational New Drug
IRB
Independent Review Board
IRT
Interactive Response Technology
ITT
Intent-to-Treat
IUD
Intrauterine Device
IUS
Intrauterine System

2015N261999_03
CONFIDENTIAL
200812
75
LABA
Long Acting Beta-Agonist
LAMA
Long-acting Muscarinic Receptor Antagonists
LDH
Lactate Dehydrogenase
LTOT
Long Term Oxygen Therapy 
MACE
Major Adverse Cardiac Event
mcg
Microgram
MDI
Metered Dose Inhaler
mL
Milliliter
mm
Millimeter
MMRM
Mixed Models Repeated Measures
MSDS
Material Safety Data Sheet
NHANES
National Health and Nutrition Examination Survey
NHS
National Health Service
PDE4
Phosphodiesterase 4
PA
Posteroanterior
PK
Pharmacokinetic
prn
As required
QD
Once daily
QTc
QT interval corrected for heart rate
QTcB
QT interval corrected for heart rate by Bazett’s formula
QTcF
QT interval corrected for heart rate by Fridericia’s formula
RAP
Reporting and Analysis Plan
SABAs
Short-acting 2-adrenergic receptor agonists
SAE
Serious Adverse Event
SD
Standard Deviation
SGRQ
St Georges Respiratory Questionnaire
SPM
Study Procedures Manual
TDI
Transitional Dyspnoea Index 
ULN
Upper Limit of Normal
UMEC
Umeclidinium
VI
Vilanterol Trifenatate
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
ADVAIR
Chiron RIBA
ELLIPTA
SAS
NEBULES
WinNonlin

2015N261999_03
CONFIDENTIAL
200812
76
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments
Phase III-IV liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and evaluate liver event aetiology (in alignment with the 
FDA premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Phase III-IV liver chemistry stopping criteria and required follow up assessments
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 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 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 

Monitor the subject until liver chemistries 
resolve , stabilize, or return to within baseline 
(see MONITORING below)

Viral hepatitis serology4

Only in those with underlying chronic 
hepatitis B at study entry (identified by 
positive hepatitis B surface antigen) 
quantitative hepatitis B DNA and hepatitis 
delta antibody5.

Blood sample for pharmacokinetic (PK) 
analysis, obtained within 72 hours after 
last dose6

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

2015N261999_03
CONFIDENTIAL
200812
77

Do not restart/rechallenge subject with 
study treatment unless allowed per protocol 

If restart/rechallenge not allowed per 
protocol , permanently discontinue study 
treatment and may continue subject 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 subjects twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 
recommended
For All other criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24-
72 hrs 

Monitor subjects weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential 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).

Serum acetaminophen adduct HPLC 
assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with 
definite or likely acetaminophen use in the 
preceding week [James, 2009]). NOTE: 
not required in China

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 subject 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 subjects receiving anticoagulants

2015N261999_03
CONFIDENTIAL
200812
78
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.
Includes: 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 
5.
If hepatitis delta antibody assay cannot be performed,, it can be replaced with a PCR of hepatitis D RNA virus 
(where needed) [Le Gal, 2005].
6.
PK sample may not be required for subjects 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 subject’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 SPM.  
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 subject 
safety. 

Subject can continue study treatment  

Subject 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 subject 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 subjects 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.

2015N261999_03
CONFIDENTIAL
200812
79
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. 

2015N261999_03
CONFIDENTIAL
200812
80
12.3.
Appendix 3 - Genetic Research
Genetics – Background
Naturally occurring genetic variation may contribute to inter-individual variability in 
response to medicines, as well as an individual's risk of developing specific diseases. 
Genetic factors associated with disease characteristics may also be associated with 
response to therapy, and could help to explain some clinical study outcomes. For 
example, genetic variants associated with age-related macular degeneration (AMD) are 
reported to account for much of the risk for the condition [Gorin, 2012] with certain 
variants reported to influence treatment response [Chen, 2012]. Thus, knowledge of the 
genetic aetiology of disease may better inform understanding of disease and the 
development of medicines. Additionally, genetic variability may impact the 
pharmacokinetics 
(absorption, 
distribution, 
metabolism, 
and 
elimination), 
or 
pharmacodynamics (relationship between concentration and pharmacologic effects or the 
time course of pharmacologic effects) of a specific medicine and/or clinical outcomes 
(efficacy and/or safety) observed in a clinical study.
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and: 

Response to medicine, including Fluticasone Furoate (FF)/Umeclidinium 
(UMEC)/Vilanterol (VI); Umeclidinium (UMEC); and Fluticasone Furoate 
(FF)/Vilanterol (VI) or any concomitant medicines;

COPD susceptibility, severity, and progression and related conditions
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic 
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the study can participate in genetic research.  Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research.

2015N261999_03
CONFIDENTIAL
200812
81
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.  

A 6 ml blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. 
A blood sample is collected at V5 or at any visit after Randomisation (V2), after 
the subject has provided informed consent for genetic research. Instructions for 
collection and shipping of the genetic sample are described in the laboratory 
manual. The DNA from the blood sample may undergo quality control analyses to 
confirm the integrity of the sample. If there are concerns regarding the quality of 
the sample, then the sample may be destroyed. The blood sample is taken on a 
single occasion unless a duplicate sample is required due to an inability to utilize 
the original sample.  
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study.   This number can be traced or linked back to 
the subject by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number). 
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study, or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 
for the purpose stated in this protocol and in the informed consent form.  Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study.  Genetic informed consent must be obtained prior to any blood/saliva being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA 
sample is retained

Discontinue participation in the genetic research and destroy the genetic DNA 
sample 

2015N261999_03
CONFIDENTIAL
200812
82
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. 
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis. 

If a subject withdraws consent for genetic research and genotype data has not been 
analyzed, it will not be analyzed or used for future research.  

Genetic data that has been analyzed at the time of withdrawn consent will 
continue to be stored and used, as appropriate. 
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to 
complete this process as it will be completed as part of the consent and sample 
reconciliation process.  In this instance a sample destruction form will not be available to 
include in the site files.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic 
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined.  Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care.
References
Chen H, Yu KD, Xu GZ. Association between Variant Y402H in Age-Related Macular 
Degeneration (AMD) Susceptibility Gene CFH and Treatment Response of AMD: A 
Meta-Analysis. PloS ONE 2012; 7: e42464.
Gorin MB. Genetic insights into age-related macular degeneration: Controversies 
addressing risk, causality, and therapeutics. Mol. Asp. Med. 2012; 33: 467-486.

2015N261999_03
CONFIDENTIAL
200812
83
12.4.
Appendix 4: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.4.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

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 medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

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 prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected 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 this is an intentional overdose taken with possible suicidal/self-
harming intent.  This 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.  However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition 
of an AE or SAE.
Events NOT meeting definition of an AE include:

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 subject’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 subject’s 

2015N261999_03
CONFIDENTIAL
200812
84
condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where 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.
12.4.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalisation for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject 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 hospitalisation or prolongation of existing hospitalisation
NOTE:

In general, hospitalisation signifies that the subject 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 out-patient setting.  Complications that occur during hospitalisation are 
AEs.  If a complication prolongs hospitalisation or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalisation” occurred or was 
necessary, the AE should be considered serious.

Hospitalisation for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

2015N261999_03
CONFIDENTIAL
200812
85

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere 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 reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.

Examples of such events are 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 hospitalisation, or development of drug dependency 
or drug abuse
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.
12.4.3.
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

2015N261999_03
CONFIDENTIAL
200812
86

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
12.4.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’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 instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.

Subject-completed Value Evidence and Outcomes questionnaires and the collection 
of AE data are independent components of the study.

Responses to each question in the Value Evidence and Outcomes questionnaire will 
be treated in accordance with standard scoring and statistical procedures detailed by 
the scale’s developer.

The use of a single question from a multidimensional health survey to designate a 
cause-effect relationship to an AE is inappropriate.
12.4.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 

2015N261999_03
CONFIDENTIAL
200812
87
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence 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 natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of 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 when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important 
that the investigator always make an assessment of causality for every event 
prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests 

2015N261999_03
CONFIDENTIAL
200812
88
or investigations, histopathological examinations or consultation with other health 
care professionals.

If a subject 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 the designated 
reporting time frames.
12.4.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the Medical Monitor or the SAE 
coordinator

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) 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 subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the Medical 
Monitor or the SAE coordinator by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
SAE reporting to GSK via paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the Medical Monitor or the SAE coordinator

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

2015N261999_03
CONFIDENTIAL
200812
89

Initial notification via the 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 receipt can be found at this beginning of the protocol on the 
Sponsor/Medical Monitor Contact Information page.

2015N261999_03
CONFIDENTIAL
200812
90
12.5.
Appendix 5: Modified List of Highly Effective Methods for 
Avoiding Pregnancy in FRP and Collection of Pregnancy 
Information
12.5.1.
Modified List of Highly Effective Methods for Avoiding Pregnancy 
in Females of Reproductive Potential (FRP)
This list does not apply to FRP with same sex partners, when this is their preferred and 
usual lifestyle or for subjects who are and will continue to be abstinent from penile-
vaginal intercourse on a long term and persistent basis.

Contraceptive subdermal implant 

Intrauterine device or intrauterine system 

Oral Contraceptive, either combined or progestogen alone [Hatcher, 2007a] 

Injectable progestogen [Hatcher, 2007a]

Contraceptive vaginal ring [Hatcher, 2007a]

Percutaneous contraceptive patches [Hatcher, 2007a]

Male partner sterilisation with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2007a].  

Male condom plus partner use of one of the contraceptive options below:
o
Contraceptive subdermal implant 
o
Intrauterine device or intrauterine system 
o
Oral Contraceptive, either combined or progestogen alone [Hatcher, 
2007a] Injectable progestogen [Hatcher, 2007a]
o
Contraceptive vaginal ring [Hatcher, 2007a]
o
Percutaneous contraceptive patches [Hatcher, 2007a]
This is an all inclusive list of those methods that meet the GSK definition of highly 
effective: having a failure rate of less than 1% per year when used consistently and, 
correctly and, when applicable, in accordance with the product label.  For non-product 
methods (e.g.  male sterility), the investigator determines what is consistent and correct 
use. The GSK definition is based on the definition provided by the ICH [ICH, M3 (R2) 
2009]. 
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.

2015N261999_03
CONFIDENTIAL
200812
91
12.5.2.
Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 2 
weeks of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, 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 foetal 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 4 (Section 12.4.6). 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 subject who becomes pregnant while participating 

will discontinue study treatment and be withdrawn from the study

2015N261999_03
CONFIDENTIAL
200812
92
12.6.
Appendix 6 - Country Specific Requirements

2015N261999_03
CONFIDENTIAL
200812
93
12.7.
Appendix 7 – COPD Exacerbation Identification, 
Categorization and Treatment Guidelines
12.7.1.
Guidelines for Identifying COPD Exacerbations
The following are symptoms used to ascertain an exacerbation of COPD:
Worsening of two or more of the following major symptoms for at least two consecutive 
days:

Dyspnea

Sputum volume

Sputum purulence (color)
OR
Worsening of any one major symptom together with any one of the following minor 
symptoms for at least two consecutive days:

Sore throat

Colds (nasal discharge and/or nasal congestion)

Fever (oral temperature > 37.5 °C) without other cause

Increased cough

Increased wheeze
Subjects who experience worsening COPD symptoms for greater than 24 hours should: 

Contact their study Investigator and/or research coordinator immediately, and 
report to the study clinic as required

If the subject is unable to contact their study Investigator and/or research 
coordinator, they should contact their primary care physician (or other health 
care practitioner as required) and contact their study site as soon as possible

Continue to record their symptoms and rescue albuterol/salbutamol 

If the subject seeks emergency/acute care for worsening respiratory symptoms, 
he/she should request the caring Health Care Provider (HCP) to contact the 
Investigator as soon as possible.
Subjects with worsening respiratory symptoms will be classified as having:

A mild/moderate/severe exacerbation and/or pneumonia
OR

A Lower Respiratory Tract Infection (LRTI)

Background variability of COPD

A non-respiratory related disease

2015N261999_03
CONFIDENTIAL
200812
94

Other respiratory related disease
Definitions for COPD exacerbations and pneumonia are given in Section 12.7.1.1 and in 
Section 7.4.9, respectively. If, based on these criteria, a subject’s symptoms do not fulfill 
the diagnosis of an exacerbation and/or pneumonia, then the investigator should use their 
clinical judgment to assess the subject’s symptoms (including increased volume of 
sputum production and/or change in the sputum color) for a diagnosis of LRTI (e.g. acute 
bronchitis), background variability of COPD, a non-respiratory related disease or other 
respiratory related disease. Investigator judgment should be used in deciding whether to 
report the signs and symptoms (and/or determined diagnosis) as recorded in the diary as 
an AE/SAE in the eCRF.  Refer to Section 12.4.1 and Section 12.4.2 for definitions of 
AE and SAE, respectively.
12.7.1.1.
COPD Exacerbation Severity
Each COPD exacerbation will be categorized based on severity as follows:
Mild:  Worsening symptoms of COPD that are self-managed by the subject.  Mild 
exacerbations are not associated with the use of corticosteroids or antibiotics.
Moderate:  Worsening symptoms of COPD that require treatment with oral/systemic 
corticosteroids and/or antibiotics.
Severe: Worsening symptoms of COPD that require treatment with in-patient 
hospitalisation.
Every effort should be made to conduct a chest x-ray within 48 hours of 
identification of a moderate or severe exacerbation. 
Details of an exacerbation should be recorded in the exacerbation page of the eCRF. 
However, exacerbations should not be recorded in the AE section of the eCRF unless 
they meet the definition of an SAE. (Pneumonia must be recorded in the AE or SAE 
section of the eCRF and on the Pneumonia page of the eCRF.)
Use of antibiotics for the treatment of upper or lower respiratory tract infections will not 
be considered a COPD exacerbation unless the subject experiences worsening symptoms 
of COPD which match the definition of an exacerbation as given above.
12.7.1.2.
Treatment of COPD Exacerbations
All medications used for the treatment of exacerbations must be recorded in the source 
documents and the exacerbation page of the eCRF.  All sites should follow the protocol 
treatment guidelines (as outline below), but any medications deemed medically necessary 
may be used to treat a COPD exacerbation. However, caution is advised in using a LABA 
or LAMA to treat a subject currently taking study treatmentas these additional 
medications may increase the risk of overdose. If necessary the Investigator or other 
health care personnel may stop the subjects study treatmenttemporarily in order to treat 
the COPD exacerbation.

2015N261999_03
CONFIDENTIAL
200812
95
12.7.1.3.
Guidelines for Treatment with Corticosteroids
If in the opinion of the investigator/treating physician the exacerbation is severe enough 
to warrant the need for oral or systemic corticosteroids (with or without antibiotics) the 
following guidelines should be used.

The duration of treatment with oral/systemic corticosteroids should be 14 days 
(dose and type according to local practice) 

The duration of treatment with oral/systemic corticosteroids should not exceed 14 
days unless approval is given by the sponsor or representative

Any course of oral/systemic corticosteroids started within 7 days of finishing a 
previous course will be considered as treatment for a single exacerbation
12.7.1.4.
Guidelines for Treatment with Antibiotics
If there is evidence of respiratory infection that in the opinion of the investigator or 
treating physician warrants the need for antibiotics the following guidelines should be 
followed:

The duration of treatment with antibiotics should be 7 to 14 days (dose and type 
according to local practice). If first line antibiotic treatment fails and additional 
antibiotics are used, the total duration of antibiotic treatment should not exceed 
30 days unless approval is given by the sponsor or representative

Any course of antibiotics started within 7 days of finishing a previous course 
will be considered as treatment for a single exacerbation
Use of antibiotics for the treatment of upper or lower respiratory tract infections is not 
considered a COPD exacerbation unless the subject experiences worsening of symptoms 
of COPD as described in Section 12.7.1.
12.7.1.5.
Onset and Resolution of COPD Exacerbations
For each mild, moderate and severe exacerbation, the date of onset and the date of 
resolution will be recorded in the study source documents and eCRF.
The date of onset is the first day (of at least 2 consecutive days) of worsening symptoms 
of COPD as described in Section 12.7.1.
The date of resolution should be based on when the Investigator and/or subject 
determines that the COPD symptoms have returned to pre-exacerbation levels or to a new 
baseline.  In determining this resolution date, consideration should be given to diary 
recorded symptoms and/or study subject evaluation.
12.7.1.6.
Guideline for assessing multiple mild exacerbations
Two mild exacerbations can be combined into one, per the Investigator’s judgement, if a 
subject’s diary reveals that the two mild COPD exacerbations are separated by no more 
than three exacerbation free days.

2015N261999_03
CONFIDENTIAL
200812
96
12.7.1.7.
Guideline for assessing exacerbations that increase in severity
If an exacerbation starts off as mild, but becomes moderate or severe or starts off as 
moderate and becomes severe, the exacerbation should be captured as one exacerbation 
and classified by its highest level of severity.

2015N261999_03
CONFIDENTIAL
200812
97
12.8.
Appendix 8 – Hair Sample, Scalp & Finger Secretion PK 
Sub-Study
12.8.1.
Introduction
Adherence and compliance to inhaled drug treatment is poor, relative to oral therapies 
with strong evidence to suggest that over time, compliance remains a challenge for both 
COPD and asthma (Restrepo, 2008; Tamura, 2007; Laforest, 2010; Yilmaz, 2013; 
Bryant, 2013; Aguis, 2010; Barbosa, 2013; Breekveldt, 2007; Kardas, 2002; Wilson, 
2010). There is currently no robust quantitative or semi-quantitative way of assessing 
patient compliance to inhaled products. This is primarily due to the small doses (often in 
micrograms) used during treatment, leading to low systemic exposure and the relatively 
short timeframe when systemic exposure can be measured using available bioanalytical 
methods. Normal methods of monitoring drug compliance are poor for inhaled therapies 
so an alternative approach is being developed. 
Testing of orally administered drugs from human head hair is well established in the 
monitoring of a wide range of drugs including benzodiazepines, opiates, amphetamines 
and other potential drugs of abuse.  A broad spectrum of other pharmaceuticals including 
orally administered salbutamol and steroids such as stanozolol and nandrolone have also 
been shown to offer a retrospective analysis of drug use over time (World Health 
Organisation, 2003; Barbosa, 2013; Porta, 2011; Dominguez-Romero, 2011). The same is 
not true for drugs taken by the inhaled route, so this study is seeking to find out whether 
head hair along with finger smears can be used to detect inhaled drugs to assess patient 
compliance. Sensitive analytical techniques have been developed such as matrix-assisted 
laser desorption/ionisation (MALDI) (Vulic, 2011) or secondary ion mass spectrometry 
(SIMS) (Aguis, 2010) with the potential to look at drug use over time. This study will 
examine the utility of these alternative approaches to detect inhaled drugs.
Human head hair grows at the rate of ~1cm/month, offering the potential to detect and 
monitor drug deposition in the hair as it grows.  Secretions from hair follicles and from 
the fingers (termed sweat for the purpose of this document) also secrete drugs onto the 
skin surface (Kuwayama, 2014).The aim of this exploratory sub-study is to establish 
whether human head hair or human skin sweat samples (scalp or finger smear) can be 
used to detect and if possible to quantify drug concentrations that have accumulated 
directly into hair/finger sweat from inhaled respiratory therapies in patients being treated 
for COPD. Successful detection of inhaled therapies in hair or from sweat over time 
should allow verification against patient reported adherence to therapy or direct physician 
assessment of compliance. This sub-study will help inform whether it is possible to 
collect adherence data in clinical programmes in the future. 
12.8.2.
Objective
To collect hair samples, and scalp and finger sweat, in a non-invasive way, for PK 
analysis among COPD subjects taking part in PK subset A, in Study 200812. This sub-
study will, therefore be conducted at a selection of sites, in subjects who have also 
consented to participate in the PK group A.  Subjects who consent to participate in this 

2015N261999_03
CONFIDENTIAL
200812
98
sub-study, will continue on study treatment and study visits as per the core study (study 
200812).
12.8.3.
Investigational Plan
This is a hair sample, scalp and finger sweat PK sub-study to collect samples of head 
hair, and sweat from the scalp and fingers in subjects who have consented and been 
randomized to study 200812 (Core Study), “A phase IIIb 24-week randomised, double-
blind study to compare ‘closed’ triple therapy (FF/UMEC/VI) with 'open' triple therapy 
(FF/VI + UMEC), in subjects with chronic obstructive pulmonary disease (COPD)and 
they have consented to take part in PK sub-group A (see Section 7.5 for more details). 
A subset of subjects randomised to the Core Study will provide blood samples for PK 
analysis. For the purpose of this sub-study, subjects who are consented and randomized 
to the Core Study, in PK subgroup A, will provide hair samples along with scalp and 
finger sweat samples.  Subjects will also provide details of any medicines taken in 
addition to those being administered within the trial in the 6 weeks preceding the sample 
collection.  In addition, the subjects will provide information on any hair treatments they 
use, or have used (other than simple washing) just prior to the hair sample collection. 
Subjects of this sub-study will provide a hair, finger and scalp sweat sample at Visits 2, 4 
and 5.  Details of the samples being taken at each of these visits are described below:
Hair Sample
A hair sample (the width of a thin pencil) will be taken from the back of the scalp, at a 
site which is acceptable to the subject, and unlikely to be visible. The hair sample will be 
taken before study treatment is taken at Visits 2, 4 and 5.  
Figure 3
Hair Sample Collection

2015N261999_03
CONFIDENTIAL
200812
99
(A pencil width of hair is removed as close to the scalp as possible). 
Scalp sweat sample 
At the same time, each subject will have a scalp sweat sample taken near the site of the 
hair sample collection. See Figure 4.  The scalp sweat sample will be taken before study 
treatment is taken at Visits 2, 4 and 5. 
Figure 4
Scalp Swab
(A scalp swab for a scalp sweat sample will be taken near the same site as the hair 
sample).
Finger sweat smear
A finger sweat smear will be taken from three separate fingers of one hand (in general: 
index, 2nd finger and thumb of same hand for each collection). The subject will be 
required to smear their fingers across an aluminium slide (provided for such purposes), to 
collect the smear. See Figure 5. 
These finger sweat samples will be collected in such a way to ensure that identifiable 
finger prints are not taken from the subject, therefore ensuring that only a smear is 
obtained. The finger sweat smear will be taken approximately 15 minutes after hair 
sampling has been taken in clinic at Visits 2, 4 and 5.  Immediately after taking study 
treatment and 15 minutes before the finger smear is taken, the subject will be required to 
wash their hands. 

2015N261999_03
CONFIDENTIAL
200812
100
Figure 5
Finger Smear Sample
Finger sweat samples will be taken 15minutes after subjects take their inhaled medication 
(having washed their hands immediately after dosing with 50:50 water/ethanol).
Both head hair, scalp sweat and finger sweat samples will be used to assess levels of the 
inhaled drugs the subjects are receiving at scheduled visits starting from Week 0. 
Samples will be collected at Randomisation (V2), at Week 12 (V4) and Week 24 (V5). 
Further details on hair, scalp and finger sweat sampling are described in the SPM.
All subjects who participate in this sub-study will be required to provide a separate 
consent in order to give hair, scalp and finger sweat samples, along with the supporting 
information on other medication use and hair treatments. 

2015N261999_03
CONFIDENTIAL
200812
101
Figure 6
Hair Sample, Scalp & Finger Sweat PK Sub-Study Schematic
12.8.4.
Subject Selection and Withdrawal Criteria
12.8.4.1.
Inclusion Criteria
Subjects eligible for enrolment in this sub-study must meet both of the following criteria:
1.
Informed Consent: A signed and dated written informed consent for the study 
200812 (Core Study).
2.
Separate Informed Consent for hair, scalp and finger sweat sample sub-study:  A 
signed and dated written informed consent for the sub-study, for hair sample, scalp 
secretions and finger secretion collection. 
12.8.4.2.
Exclusion Criteria
There are no exclusion criteria to this sub-study.
12.8.5.
Sub-study Withdrawal Criteria
Every effort should be made by the investigator to keep the subject in this sub-study.  
However a subject may voluntarily withdraw from participation in this sub-study at any 
time.  
In the event that a subject withdraws consent from this Hair Sample, Scalp & Finger 
Sweat PK Sub-Study, they will still be eligible to continue in the PK sub-study subset A 
and they can still continue participation in the Core Study. 

2015N261999_03
CONFIDENTIAL
200812
102
12.8.6.
Potential Risks Associated with Sub-Study Participation
The overall risk to the subject participating in this sub-study is considered minimal. 
However, there is a small chance of the subject being injured with the scissors used for 
the hair sample collection. The chance of this happening is very low and any injury that 
may be sustained is expected to be minor i.e. not requiring treatment. 
Wherever possible, the site staff will aim to collect the hair sample from a part of the 
scalp where it would not be noticeable. 
All finger sweat samples will be taken as a smear to ensure that a finger print is not 
obtained. Therefore, there is no risk of obtaining identifiable finger prints from these 
samples.  

2015N261999_03
CONFIDENTIAL
200812
103
12.9.
Appendix 9 – Protocol Changes
Revision History
2015N261999_00
2015-DEC-09
Original
2015N261999_01
2016-JAN-25
Amendment No.: 01 Global
2015N261999_02
2016-FEB-11
Amendment No.: 02 South Korea only
2015N261999_03
2016-JUN-29
Amendment No.: 03 Global 
(excluding South Korea)
12.9.1.
Protocol Amendment 1
Amendment 01 applies to all countries and study centres participating in the 200812 
study. Amendment 01 purpose is to correct discrepancies in the Time and Events Table, 
Appendix 3 - Genetic Research and Appendix 8 – Hair Sample, Scalp & Finger Secretion 
PK Sub-Study. 
The specific areas were changes were made to the protocol are listed below. Wording that 
has been deleted will be indicated with a strikethrough (ex. Word) and new wording will 
be indicated in Bold type (ex. Word).
1. PROTOCOL Synopsis for study 200812 and 4.1. Overall Design:
The following text updated to include the requirement for an early withdrawal study for 
subjects who stop study treatment early:
Subjects who stop study treatment early will complete an Early Withdrawal Visit, 
followed by a Safety Follow-Up a week later the safety follow-up and finally be 
withdrawn from the study.
7.1. Time and Events Table:
The letters corresponding to the T&E footnotes have been corrected and updated, as 
detailed below. The scheduled visit for pulse oximetry, and footnote ‘p’ inserted for the 
genetics blood draw:

2015N261999_03
CONFIDENTIAL
200812
104
12.3. Appendix 3 - Genetic Research: 
The bullet describing the objectives of the genetics research incorrectly references 
Umeclidinium (UMEC)/Vilanterol (VI). The text has been corrected match the study 
medication in 200812:

Response to medicine, including Fluticasone Furoate (FF)/Umeclidinium 
(UMEC)/Vilanterol 
(VI); 
Umeclidinium 
(UMEC)/Vilanterol 
(VI); 
and 
Fluticasone Furoate (FF)/Vilanterol (VI) or any concomitant medicines;
The scheduled collection of the genetics blood sample has been corrected to match the 
Time and Events Table:

A 6 ml blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. 
A blood sample is collected at V5 or at any visit after Randomisation (V2) 
where there is a scheduled blood draw the baseline visit, after the subject has 
been randomized and provided informed consent for genetic research. 
12.8. Appendix 8 – Hair Sample, Scalp & Finger Secretion PK Sub-Study:
Text that contradicts timings of sample collections referenced in other parts of the 
protocol has been removed. 
Both head hair, scalp sweat and finger sweat samples will be used to assess levels of the 
inhaled drugs the subjects are receiving at scheduled visits starting from Week 0. 
Samples will be collected at Randomisation (V2) prior to first dose of study treatment, at
Week 12 (V4) and Week 24 (V5) after the collection of blood PK samples. Further 
details on hair, scalp and finger sweat sampling are described in the SPM.

2015N261999_03
CONFIDENTIAL
200812
105
12.9.2.
Country-Specific Protocol Amendment 2 for South Korea
Amendment 02 applies to South Korea. The purpose of Amendment 2 is to include study 
medication labelling for South Korea and details of study equipment that will be 
supplied. 
12.9.3.
Protocol Amendment 3 (excluding South Korea)
Amendment 03 applies to all countries except South Korea. A country-specific 
amendment for South Korea i.e. Amendment 4 will include required local revisions and 
information from the Global Amendment 01 and Global Amendment 03. 
Amendment 03 purpose is to clarify and correct minor discrepancies in the protocol 
sections detailed below.
The specific areas were changes were made to the protocol are listed below. Wording that 
has been deleted will be indicated with a strikethrough (ex. Word) and new wording will 
be indicated in Bold type (ex. Word). 
5.2. Exclusion Criteria
Exclusion criteria 9 has been updated to reference the views required from the Screening 
chest x-ray.
9. Abnormal Chest x-ray: Chest x-ray (posteroanterior and later) reveals evidence of 
pneumonia or a clinically significant abnormality not believed to be due to the presence 
of COPD, or another condition that would hinder the ability to detect an infiltrate on 
chest x-ray (e.g. significant cardiomegaly, pleural effusion or scarring). All subjects will 
have a chest x-ray at Screening (V1) [or historical radiograph or CT scan obtained within 
3 months prior to Screening (V1). 
7.1. Time and Events Table
The check boxes to register visits in RAMOS have been checked for V1, V3-V5 and the 
Early Withdrawal Visit and the checkbox to administer study treatment at V5 has been 
checked. Clarifications have been made to footnote e, k, l and p. 

2015N261999_03
CONFIDENTIAL
200812
106

2015N261999_03
CONFIDENTIAL
200812
107

2015N261999_03
CONFIDENTIAL
200812
108

2015N261999_03
CONFIDENTIAL
200812
109
7.4.11. Radiography (Chest X-Rays)
The views required for chest x-rays performed for suspected pneumonias and/or 
moderate/severe exacerbations have been specified in brackets. 
Confirmation by chest x-ray (posteroanterior and lateral) should be performed as 
soon as possible and preferably within 48 hours of suspected pneumonia and/or 
moderate or severe exacerbation. All chest x-rays will be reviewed by the investigator 
to confirm the presence of new radiographic findings compatible with pneumonia.  In all 
cases, the signs and symptoms that were used to identify the pneumonia must be 
documented in the source documents and eCRF. Diagnoses of pneumonia must be 
recorded as adverse events in the eCRF.
11. References
The reference below for a citation used in Appendix 5 has been added to the reference 
list.
International Conference of Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (2009). Guidance on nonclinical 
safety studies for the conduct of human clinical trials and marketing authorization 
for pharmaceuticals M3(R2).
12.3. Appendix 3 – Genetic Research
Text has been updated to reflect the changes to the footnote p in the Time and Events 
Table. 

A 6 ml blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. 
A blood sample is collected at V5 or at any visit after Randomisation (V2) where 
there is a scheduled blood draw, after the subject has provided informed consent 
for genetic research. Instructions for collection and shipping of the genetic sample 
are described in the laboratory manual. The DNA from the blood sample may 
undergo quality control analyses to confirm the integrity of the sample. If there 
are concerns regarding the quality of the sample, then the sample may be 
destroyed. The blood sample is taken on a single occasion unless a duplicate 
sample is required due to an inability to utilize the original sample.