A Phase III, 52 Week, Randomized, Double-blind, 3-arm Parallel Group Study, Comparing the Efficacy, Safety and Tolerability of the Fixed Dose Triple Combination FF/UMEC/VI With the Fixed Dose Dual Combinations of FF/VI and UMEC/VI, All Administered Once-daily in the Morning Via a Dry Powder Inhaler in Subjects With Chronic Obstructive Pulmonary Disease
Phase: PHASE3
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: GlaxoSmithKline

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The GlaxoSmithKline group of companies
CTT116855
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TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A phase III, 52 week, randomized, double-blind, 3-arm parallel 
group study, comparing the efficacy, safety and tolerability of 
the fixed dose triple combination FF/UMEC/VI with the fixed 
dose dual combinations of FF/VI and UMEC/VI, all 
administered once-daily in the morning via a dry powder inhaler 
in subjects with chronic obstructive pulmonary disease
Compound Number:
GSK2834425
Development Phase:
IIIB
Effective Date:
30-JUN-2016
Protocol Amendment Number:  05
Author(s): 
 
 
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD

2013N176913_05
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The GlaxoSmithKline group of companies
CTT116855
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Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2013N176913_00
2014-MAR-17
Original
2013N176913_01
2014-MAR-31
Amendment No. 1
To clarify approval status of products in the protocol, add additional wording concerning 
hematology collection and to correct minor errors in the time and Events Table.
2013N176913_02
2014-APR-10
Amendment No. 2
Amendment 02 purpose was to add post-bronchodilator FEV1 to each visit and include 
this as an Other Efficacy Endpoint. A mortality endpoint was also added as an “Other 
Efficacy Endpoint”. Other changes included changing the predicted FEV1 reference 
values from NHANES III to the European Respiratory Society Global Lung Function 
Initiative and to correct minor errors in CAT, contraceptive methods, and ECG wording. 
In addition changes were made to correct minor errors and to clarify ambiguous wording.
2013N176913_03
2014-DEC-05
Amendment No. 3 China 
ONLY
Amendment 03 purpose was to clarify that Serious AEs in China will be recorded from 
the time the consent form is signed until the 7-day safety follow-up visit/telephone 
contact has been completed, or until Visit 7(telephone contact) for subjects who have 
discontinued IP but continue in the study.
2013N176913_04
2015-MAY-12
Amendment No. 4 China 
ONLY
Amendment 04 purpose was to clarify that no study centers in China will participate in 
genetic research in this study and the addition of a China-specific sub-study to collect the 
unit-cost data for healthcare utilization among subjects recruited in China
2013N176913_05
2016-JUN-30
Amendment No. 5
Amendment 05 applies to all countries and study centers participating in the CTT116855 
study.  Amendment 05 purpose was to simplify the statistical hierarchy for the analysis of 
secondary endpoints.  In addition there are minor changes to the definitions of the 
Analysis populations, changes in model terms that will be included in the primary 
efficacy endpoint analysis and clarification on the primary endpoint sensitivity analyses. 
For the safety analysis there were minor changes to clarify the analyses of Pneumonia 
Adverse events and MACE events.

PPD
PPD

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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol CTT116855
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 Address:
Investigator Phone Number:
Investigator Signature
Date

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TABLE OF CONTENTS
PAGE
LIST OF ABBREVIATIONS.............................................................................................9
PROTOCOL SUMMARY...............................................................................................11
1.
INTRODUCTION....................................................................................................16
1.1.
Background ................................................................................................16
1.2.
Rationale ....................................................................................................17
1.3.
Benefit:Risk Assessment ............................................................................18
1.3.1.
Risk Assessment .........................................................................19
1.3.2.
Benefit Assessment.....................................................................23
1.3.3.
Overall Benefit: Risk Conclusion..................................................24
2.
OBJECTIVES.........................................................................................................25
3.
INVESTIGATIONAL PLAN.....................................................................................25
3.1.
Study Design ..............................................................................................25
3.2.
Discussion of Design ..................................................................................27
4.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA.......................................28
4.1.
Number of Subjects ....................................................................................28
4.2.
Inclusion Criteria.........................................................................................28
4.3.
Exclusion Criteria........................................................................................30
4.4.
Investigational Product (IP) Discontinuation Criteria ...................................34
4.4.1.
Protocol defined stopping IP criteria.............................................34
4.4.2.
Permanent Discontinuation of Investigational Product (IP)...........34
4.4.3.
IP Discontinuation Study Assessments........................................35
4.4.4.
Reasons for Permanent Discontinuation of IP..............................36
4.5.
Study Withdrawal Criteria ...........................................................................36
4.5.1.
Withdrawal from study .................................................................37
4.5.2.
Study Withdrawal assessments ...................................................37
4.5.3.
Lost to follow-up...........................................................................37
4.5.4.
Reasons for Study Withdrawal.....................................................38
4.6.
Follow-up Contact.......................................................................................38
4.7.
Pre-Screen Failures and Screening Failures...............................................39
5.
STUDY TREATMENTS..........................................................................................40
5.1.
Investigational Product and Other Study Treatment....................................40
5.1.1.
Storage........................................................................................42
5.1.2.
Investigational Product and albuterol/salbutamol Return..............42
5.2.
Treatment Assignment................................................................................42
5.3.
Blinding.......................................................................................................43
5.4.
Product Accountability ................................................................................44
5.5.
Treatment Compliance................................................................................44
5.6.
Concomitant Medications and Non-Drug Therapies....................................44
5.6.1.
Permitted Medications and Non-Drug Therapies..........................44
5.6.2.
Prohibited Medications and Non-Drug Therapies.........................46
5.7.
Treatment after the End of the Study ..........................................................47
5.8.
Treatment of Study Treatment Overdose....................................................47

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6.
STUDY ASSESSMENTS AND PROCEDURES .....................................................48
6.1.
Critical Baseline Assessments....................................................................52
6.2.
Efficacy.......................................................................................................53
6.2.1.
Co-Primary Efficacy Endpoints ....................................................53
6.2.2.
Secondary Efficacy Endpoints .....................................................53
6.2.3.
Other Efficacy endpoints..............................................................53
6.2.4.
COPD Exacerbations...................................................................54
6.2.4.1.
Guidelines for Identifying COPD Exacerbations..........54
6.2.4.2.
COPD Exacerbation Severity .....................................56
6.2.4.3.
Treatment of COPD Exacerbations ............................56
6.2.4.4.
Guidelines for Treatment with Corticosteroids ............56
6.2.4.5.
Guidelines for Treatment with Antibiotics....................57
6.2.4.6.
Onset and Resolution of COPD Exacerbations...........57
6.2.4.7.
Guideline for assessing multiple mild 
exacerbations.............................................................57
6.2.4.8.
Guideline for assessing exacerbations that 
increase in severity.....................................................57
6.2.5.
Spirometry Testing.......................................................................57
6.2.5.1.
Reversibility Testing ...................................................58
6.2.6.
SGRQ-C ......................................................................................58
6.2.7.
Diary Assessments......................................................................59
6.2.8.
Rescue Albuterol/Salbutamol Use ...............................................59
6.2.9.
Baseline Dyspnoea Index/Transitional Dyspnoea Index...............59
6.2.10.
COPD Assessment Test (CAT)....................................................60
6.2.11.
Subject Global Rating of Activity Limitation and Subject 
Global Impression of Change in Activity Limitation.......................60
6.2.12.
Subject Global Rating Severity of COPD and Subject 
Global Impression of Change in COPD........................................60
6.3.
Safety .........................................................................................................60
6.3.1.
Liver chemistry stopping and follow up criteria.............................61
6.3.2.
Adverse Events............................................................................64
6.3.2.1.
Definition of an AE......................................................64
6.3.2.2.
Definition of an SAE ...................................................65
6.3.2.3.
Sentinel Events ..........................................................66
6.3.3.
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs.........................................................67
6.3.4.
Cardiovascular Events.................................................................67
6.3.5.
Death Events...............................................................................67
6.3.6.
Disease-Related Outcomes Not Subject to Expedited 
Reporting to Regulatory Authorities .............................................67
6.3.7.
Pregnancy ...................................................................................68
6.3.8.
Medical Devices...........................................................................68
6.3.9.
Time Period and Frequency of Detecting AEs and SAEs.............70
6.3.10.
Method of Detecting AEs and SAEs.............................................70
6.3.11.
Prompt Reporting of Serious Adverse Events and Other 
Events to GSK.............................................................................70
6.3.11.1.
Regulatory Reporting Requirements for SAEs............72
6.3.12.
Laboratory Assessments .............................................................73
6.3.13.
Vital Signs....................................................................................74
6.3.14.
Medical Problems and Concomitant Medications.........................74
6.3.15.
ECG.............................................................................................74
6.3.16.
Pneumonia ..................................................................................74

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6.3.17.
Radiography (Chest X-Rays) .......................................................75
6.3.18.
Oropharyngeal Examinations.......................................................76
6.3.19.
Pulse oximetry .............................................................................76
6.4.
Health Outcomes........................................................................................76
6.4.1.
EuroQol Questionnaire (EQ-5D-5L) .............................................76
6.4.2.
Healthcare resource utilisation.....................................................77
6.5.
Pharmacokinetics .......................................................................................77
6.6.
Genetic Research.......................................................................................77
6.7.
Novel Biomarkers .......................................................................................77
7.
DATA MANAGEMENT ...........................................................................................78
8.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................................78
8.1.
Hypotheses.................................................................................................78
8.2.
Study Design Considerations......................................................................79
8.2.1.
Sample Size Assumptions ...........................................................79
8.2.2.
Sample Size Sensitivity................................................................80
8.2.3.
Sample Size Re-estimation..........................................................80
8.3.
Data Analysis Considerations .....................................................................81
8.3.1.
Analysis Populations....................................................................81
8.3.2.
Analysis Data Sets.......................................................................81
8.3.3.
Treatment Comparisons ..............................................................81
8.3.3.1.
Primary Comparisons of Interest ................................81
8.3.3.2.
Other Comparisons of Interest....................................82
8.3.4.
Interim Analysis ...........................................................................82
8.3.5.
Key Elements of Analysis Plan ....................................................83
8.3.5.1.
Efficacy Analyses .......................................................83
8.3.5.2.
Safety Analyses..........................................................84
8.3.5.3.
Health Outcomes Analyses ........................................84
8.3.5.4.
Pharmacokinetic Analyses..........................................85
8.3.5.5.
Genetic Analyses .......................................................85
8.3.5.6.
Novel Biomarker(s) Analyses .....................................85
9.
STUDY CONDUCT CONSIDERATIONS ...............................................................85
9.1.
Posting of Information on Publicly Available Clinical Trial Registers............85
9.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................85
9.3.
Quality Control (Study Monitoring) ..............................................................86
9.4.
Quality Assurance.......................................................................................86
9.5.
Study and Site Closure ...............................................................................86
9.6.
Records Retention......................................................................................87
9.7.
Provision of Study Results to Investigators, Posting of Information 
on Publicly Available Clinical Trials Registers and Publication....................87
9.8.
Independent Data Monitoring Committee (IDMC) .......................................88
9.9.
Adjudication Committee..............................................................................88
10. REFERENCES.......................................................................................................89
11. APPENDICES........................................................................................................92
11.1.
Appendix 1: Genetic research.....................................................................92
11.2.
Appendix 2: Country Specific Requirements...............................................95

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11.2.1.
China-specific sub-study:  Collection of unit-cost data for 
healthcare utilization among COPD subjects recruited to 
Study CTT116855 in China..........................................................95
11.2.1.1.
Introduction ................................................................95
11.2.1.2.
Objective ....................................................................95
11.2.1.3.
Investigational Plan ....................................................95
11.2.1.4.
Subject Selection and Withdrawal Criteria..................96
11.2.1.4.1.
Inclusion Criteria.....................................96
11.2.1.4.2.
Exclusion Criteria....................................96
11.2.1.4.3.
Sub-study Withdrawal Criteria ................97
11.3.
Appendix 3: Liver Chemistry Stopping and Follow-up Criteria...................102
11.4.
Appendix 4: Laboratory Assessments.......................................................103
11.5.
Appendix 5: Protocol Changes..................................................................104
11.5.1.
Amendment 1 ............................................................................104
11.5.2.
Amendment 2 ............................................................................106
11.5.3.
Amendment 3 ............................................................................110
11.5.4.
Amendment 4 ............................................................................113
11.5.5.
Amendment 5 ............................................................................122

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LIST OF ABBREVIATIONS
AE
Adverse Event
ALT
Alanine Transaminase
AST
Aspartate Aminotransferase
ATS
American Thoracic Society
AV
Atrioventricular
BODE
Body mass index (B), the degree of airflow obstruction(O), 
and dyspnoea (D), and exercise capacity (E)
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
DPI
Dry Powder Inhaler
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EQ-5D-5L
EuroQol Questionnaire
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
IEC
Independent Ethics Committee
IgM
Immunoglobulin M
IND
Investigational New Drug
IRB
Independent Review Board
ITT
Intent-to-Treat
IUD
Intrauterine Device
IUS
Intrauterine System
IVRS
Interactive Voice Recognition System
LABA
Long Acting Beta-Agonist
LAMA
Long-acting Muscarinic Receptor Antagonists
LDH
Lactate Dehydrogenase
LTOT
Long Term Oxygen Therapy 

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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
PA
Posteroanterior
PDE4
Phosphodiesterase 4
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. George Respiratory Questionnaire
SPM
Study Procedures Manual
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
SAS
ELLIPTA
NEBULES
SERETIDE

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PROTOCOL SUMMARY
Rationale
COPD guidelines advocate the use of one or more long-acting bronchodilators (long-
acting muscarinic receptor antagonists [LAMA]) or long-acting 2-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 of 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]. 
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 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.
The benefit of adding a LAMA to ICS/LABA was demonstrated in the SPARK study 
which examined a LABA/LAMA (QVA149) vs. glycopyrronium vs. tiotropium. The 
dual therapy demonstrated a 12% reduction in COPD exacerbations over glycopyrronium 
and 10% reduction over tiotropium alone.  In ICS users (~ 3/4 of subjects) there was a 
16% and 12% decrease in exacerbations, respectively [Wedzicha, 2013]. A recently 
conducted retrospective cohort study conducted in a UK-based COPD cohort (National 
Health Service NHS Tayside Respiratory Disease Information System) assessed the 
impact of the addition of tiotropium (LAMA) to ICS/LABA [Short, 2012]. This study 
revealed that triple therapy may confer benefits in reducing all-cause mortality, hospital 
admissions and oral corticosteroid bursts compared to ICS/LABA alone. A further 
retrospective cohort study reported that tiotropium (LAMA) added to fluticasone
propionate/salmeterol (ICS/LABA)  was associated with significant reductions in the 
adjusted risks of a moderate exacerbation and any exacerbation over a follow-up period 
of up to 1 year, compared to tiotropium alone [Chatterjee, 2012]. 

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GlaxoSmithKline (GSK) is currently developing a once-daily ‘closed’ triple therapy of a 
ICS/LAMA/LABA combination [Fluticasone furoate (FF)/Umeclidinium (UMEC)/
Vilanterol (VI)] in a single device, 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 
the potential for improvement in lung function, HRQoL and symptom control over 
established dual-/monotherapies.
Objective(s)
Primary Objective

To evaluate the efficacy of FF/UMEC/VI to reduce the annual rate of moderate 
and severe exacerbations compared with dual therapy of FF/VI or UMEC/VI in 
subjects with COPD. 
Secondary Objectives

To evaluate the long term safety and other efficacy assessments of 
FF/UMEC/VI compared with dual therapy of FF/VI or UMEC/VI. 

To evaluate the efficacy of FF/UMEC/VI to reduce exacerbations compared 
with UMEC/VI in the subset of subjects with a blood eosinophil count ≥150 
cells/µl
Other Objectives

To evaluate the patient perspective of the efficacy of FF/UMEC/VI in subjects 
with COPD. 

To evaluate the population pharmacokinetic profiles of FF, UMEC and VI in 
subjects with COPD

To collect blood samples for a genetics research study.
Study Design
This is a phase IIIa, randomized, double-blind, 3-arm parallel group, global multicenter 
study evaluating FF/UMEC/VI inhalation powder versus FF/VI inhalation powder and 
UMEC/VI inhalation powder, all given once daily in the morning. The target enrollment 
is 10,000 randomized subjects at approximately 1,200 study centers globally. The total 
duration of subject participation will be approximately 55 weeks, consisting of a 2-week 
run-in period, 52-week treatment period and a 1-week safety follow-up period. There will 
be a total of 7 to 8 clinic visits conducted on an outpatient basis. Clinic visits will occur at 
pre-screening/screening, Randomization (Day1), and after 4, 16, 28, 40, and 52 weeks of 
treatment. In addition, a safety follow-up telephone contact or clinic visit will be 
conducted 7 days after completing visit 7 or the discontinuation from IP visit.  
Subjects will sign the informed consent form (ICF) at a pre-screen or screening visit and 
will be assigned a subject identifier.  Subjects meeting all inclusion/exclusion criteria and 
who have successfully completed all protocol procedures at screening will enter the 2-
week run-in. Subjects will continue the use of their existing COPD medications during 

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the run-in and in addition will be provided with short acting albuterol/salbutamol to be 
used on an as-needed basis (rescue medication) throughout the study. Following the 2-
week run-in period, eligible subjects will be randomized (2:2:1) to one of the following 
double-blind treatment groups:

FF/UMEC/VI 100mcg/62.5mcg/25mcg QD

FF/VI 100mcg/25mcg QD

UMEC/VI 62.5mcg/25mcg QD
All treatments will be delivered by ELLIPTA™ dry powder inhaler (DPI).  Each DPI will 
contain 30 doses of IP. Subjects will be instructed to administer medication once daily in 
the morning for the duration of the 52-week treatment period. Subjects will self-
administer their first dose of IP in the clinic during Randomization (Day1) Visit 2.  On 
the morning of each clinic study visit, subjects will refrain from taking their morning 
dose of IP until instructed to do so by clinic personnel. Subjects will take their last dose 
of IP in the clinic during Visit 7 (or IP Discontinuation Visit). A safety follow-up will be 
conducted either by phone call or clinic visit after successfully completing Visit 7 (or the 
IP Discontinuation visit).  
Subjects will discontinue all COPD medications during the randomized treatment period 
but may continue their mucolytics and study-supplied rescue albuterol/salbutamol.  
Subjects will complete a daily electronic diary (eDiary) that captures symptoms of 
COPD, activity limitation and albuterol/salbutamol use.  Subjects with increasing 
respiratory symptoms will automatically be notified through the eDiary to contact their 
investigator for further evaluation of their increasing symptoms. The real-time 
notification of increasing respiratory symptoms from the diary will assist the investigator 
in the identification of new COPD exacerbations.
A subject will be considered to have completed the study when they have completed all 
phases of the study including screening, run-in, randomization, the randomized treatment 
phase and safety follow-up.  
Subjects that permanently stop IP are not required to withdraw from the study. 
Subjects who wish to permanently discontinue from their IP should be encouraged to stay 
on their IP until they are able to return to complete the IP Discontinuation Visit.  After 
completing the IP Discontinuation Visit and the safety follow-up visit, subjects will be 
encouraged to continue in the study by participating in telephone contacts in order to 
assess exacerbations, serious adverse events (SAEs) and concomitant medications post-
treatment.  Subjects will continue to be evaluated until they have completed all the 
remaining protocol specified study visits by telephone contact; up to and including Visit 
7. 
Subjects who have previously discontinued IP (and have completed their IP 
Discontinuation Visit and safety follow-up) and who no longer wish to participate in the 
study by telephone contacts may withdraw from the study by contacting the site by 
telephone to notify the site of their intention to withdraw; no additional safety follow-up 
visit is required.

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Subjects who are currently on IP and wish to withdraw from further participation in the 
study should be encouraged to return to the clinic as soon as possible to complete the IP 
Discontinuation Visit and also to complete the safety follow-up visit. No further study 
visits or study-related telephone contacts can be conducted; however, if the subject’s 
consent allows for contact after withdrawing from the study then every effort should be 
made by the Investigator and site to determine the subject’s survival status at the end of 
the Subject’s planned 52 week participation.
Study Endpoints/Assessments
Co-Primary Efficacy Endpoints

Annual rate of on-treatment moderate and severe exacerbations comparing 
FF/UMEC/VI with UMEC/VI 

Annual rate of on-treatment moderate and severe exacerbations comparing 
FF/UMEC/VI with FF/VI
Secondary Efficacy Endpoints

Change from baseline trough FEV1 at Week 52 comparing FF/UMEC/VI with 
FF/VI

Change from baseline SGRQ Total Score at Week 52 comparing FF/UMEC/VI 
with FF/VI

Time to first on-treatment moderate or severe exacerbation comparing 
FF/UMEC/VI with FF/VI and with UMEC/VI

Annual rate of on-treatment moderate and severe exacerbations comparing 
FF/UMEC/VI with UMEC/VI in the subset of subjects with a blood eosinophil 
count ≥150 cells/µl

Time to first on-treatment moderate or severe exacerbation comparing 
FF/UMEC/VI with UMEC/VI in the subset of subjects with a blood eosinophil 
count ≥ 150 cells/µl

Annual rate of on-treatment severe exacerbations comparing FF/UMEC/VI with 
FF/VI and with UMEC/VI
Other Efficacy endpoints

Change from baseline in post-bronchodilator FEV1

Time to death from any cause

Responder rate based on the SGRQ Total Score 

Annual rate of all on-treatment exacerbations (mild, moderate, severe)

Annual rate of on-treatment moderate exacerbations

Time to first on-treatment COPD hospitalization and COPD re-hospitalization

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
Annual rate of exacerbations requiring systemic/oral corticosteroids

Annual rate of exacerbations requiring antibiotics

Transitional Dyspnoea Index (TDI) focal score comparing FF/UMEC/VI with 
FF/VI

Use of rescue albuterol/salbutamol

Change from baseline trough FEV1 at Week 52 comparing FF/UMEC/VI with 
UMEC/VI

Change from baseline in SGRQ Total Score comparing FF/UMEC/VI with 
UMEC/VI

COPD Assessment Test (CAT) score

Subject Global Rating of Activity Limitation and Subject Global Impression of 
Change in Activity Limitation

Subject Global Rating of severity of COPD and Change in COPD

Annual rate of on-treatment severe exacerbations comparing FF/UMEC/VI with 
UMEC/VI in the subset of subjects with a blood eosinophil count ≥ 150 cells/µl
Safety endpoints

Incidence of adverse events

Incidence of pneumonia

Incidence of cardiovascular events (including supraventricular arrhythmia and 
non-fatal myocardial infarction)

ECG measurements

Vital signs

Hematological and clinical chemistry parameters

Oropharyngeal examinations

Incidence of bone fractures
Health outcome endpoints

EQ-5D-5L score (standardized instrument for measuring health status)

Health care utilization (all-cause and COPD related), including hospitalization, 
emergency department and physician office/clinic visits
Pharmacokinetic endpoint

Population PK data from subset of subjects 

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1.
INTRODUCTION
1.1.
Background
Chronic obstructive pulmonary disease (COPD) is a progressive disease characterised by 
increasing obstruction to airflow and the progressive development of respiratory 
symptoms including chronic cough, increased sputum production, dyspnea and wheezing.  
In 2011, the Global Initiative for Chronic Obstructive Lung Disease (GOLD, 2011) 
issued a guideline that outlined a new classification system for COPD aimed to more 
comprehensively assess disease severity and guide therapy choice, ultimately improving 
COPD management.
The GOLD, 2011 classification system incorporates symptoms (measured by either the 
modified Medical Research Council (mMRC) dyspnea score or a health status measure 
such as the COPD Assessment Test [CAT] score), in addition to COPD exacerbation 
history and airflow limitation measured by forced expiratory volume in one second 
(FEV1). This combined assessment results in the grouping of COPD patients into four 
categories (Table 1). A 2013 update to the 2011 strategy included an additional criterion 
to characterise patients that have had a hospitalised exacerbation as high risk, regardless 
of GOLD status [GOLD, 2013]. 
Table 1
GOLD 2013 Classification
GOLD 
Classification
Risk Class Determinant*
Symptom Category 
Determinant**
A:  Low risk, 
less symptoms
GOLD Grade 1-2 AND            
≤1 exacerbation, prior year
mMRC < 2;  CAT < 10
B:  Low risk, 
more symptoms
GOLD Grade 1-2 AND            
≤1 exacerbation, prior year
mMRC 2;  CAT ≥ 10
C:  High risk, 
less symptoms
GOLD Grade 3-4 OR                   ≥ 
2 exacerbations, prior year OR
COPD hospitalization, prior year
mMRC < 2;  CAT < 10
D:  High risk, 
more symptoms
GOLD Grade 3-4 OR                   ≥ 
2 exacerbations, prior year OR
COPD hospitalization, prior year
mMRC 2;  CAT ≥ 10
* - GOLD Grade 1-2: FEV1 ≥ 50% of predicted normal; GOLD Grade 3-4: FEV1 < 50% of predicted normal.
** - Symptomatic category determined by either instrument.
Population-based studies have reported that between 38% and 60% of COPD patients 
meet the criteria for GOLD D (high symptoms and high risk), dependent on the use of 
mMRC or CAT to define symptom burden [Han, 2013; Augsti, 2013; Mullerova, 2012]. 
Patients characterised as GOLD D consistently demonstrate higher BODE (body mass 
index (B), the degree of airflow obstruction(O), and dyspnoea (D), and exercise capacity 
(E)) scores on the BODE Index and higher rates of poor COPD outcomes, including 

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acute and hospitalised exacerbation episodes, FEV1 decline, and mortality [Han, 2013;
Augsti, 2013]. These data suggest that the GOLD D patient population is at the highest 
risk of future COPD exacerbations and represents a large proportion of all COPD 
patients. 
The GOLD, 2011 guideline also outlined suggested management strategies for COPD 
based upon disease severity. For milder patients (GOLD Group A), the guidelines 
encourage active risk reduction (e.g., smoking cessation and influenza vaccination) with 
the addition of short-acting 2-adrenergic receptor agonists (SABAs) on an ‘as needed’ 
basis.  However, as disease severity increases, the guidelines recommend an incremental 
approach to pharmacological treatment, involving the use of combinations of drug classes 
with different or complementary mechanisms of action [Celli, 2004; GOLD, 2011].  
Long-acting bronchodilators (long-acting muscarinic receptor antagonists [LAMA] or 
long-acting 2-adrenergic receptor agonists [LABA]) have been shown to relieve 
symptoms, increase exercise capacity, improve health-related quality of life and reduce 
COPD exacerbations to a greater extent than SABAs.  For advanced cases, or those with 
repeated exacerbations, the incorporation of inhaled corticosteroids (ICS) or triple 
therapy, is recommended.
1.2.
Rationale
COPD guidelines advocate the use of one or more long-acting bronchodilators (LAMA or 
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 of 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]. 
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 AEs were generally similar with 

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administration of dual or monotherapy doses for periods of up to one year, and were 
mostly related to their pharmacological mode of action.
The benefit of adding a LAMA to ICS/LABA was demonstrated in the SPARK study 
which examined a LABA/LAMA (QVA149) vs. glycopyrronium vs. tiotropium. The 
dual therapy demonstrated a 12% reduction in COPD exacerbations over glycopyrronium 
and 10% reduction over tiotropium alone.  In ICS users (~ 3/4 of subjects) there was a 
16% and 12% decrease in exacerbations, respectively [Wedzicha, 2013]. A recently 
conducted retrospective cohort study conducted in a UK-based COPD cohort (National 
Health Service NHS Tayside Respiratory Disease Information System) assessed the 
impact of the addition of tiotropium (LAMA) to ICS/LABA [Short, 2012]. This study 
revealed that triple therapy may confer benefits in reducing all-cause mortality, hospital 
admissions and oral corticosteroid bursts compared to ICS/LABA alone. A further 
retrospective cohort study reported that tiotropium (LAMA) added to fluticasone
propionate/salmeterol (ICS/LABA)  was associated with significant reductions in the 
adjusted risks of a moderate exacerbation and any exacerbation over a follow-up period 
of up to 1 year, compared to tiotropium alone [Chatterjee, 2012]. 
GlaxoSmithKline (GSK) is currently developing a once-daily ‘closed’ triple therapy of a 
ICS/LAMA/LABA combination [Fluticasone furoate (FF)/Umeclidinium (UMEC)/
Vilanterol (VI)] in a single device, 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 
the potential for improvement in lung function, HRQoL and symptom control over 
established dual-/monotherapies.
1.3.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK2834425 can be found in the Investigator’s Brochure.  The following section 
outlines the risk assessment and mitigation strategy for this protocol:  

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1.3.1.
Risk Assessment
Potential Risk of 
Clinical 
Significance
Mitigation Strategy
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, in the FF/VI clinical 
program, 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 μg)/VI 25 μg 
combination than in those receiving VI 
25 μg alone (3%). In some instances 
these pneumonia events were fatal 
(including one fatality on FF/VI 100/25 
µg dose).  Risk factors for pneumonia 
observed 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. Pneumonia risk 
will be important in the benefit-risk 
assessment for FF/UMEC/VI in COPD 
patients, hence a robust risk mitigation 
strategy is being proposed.
- Exclusion criteria as 
specified in Section 4.3 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 6.3.16
- Central CXR read
required at baseline and 
whenever a patient has 
suspected pneumonia or 
mod/severe exacerbations 
during the study
- Instream review of
blinded data
- IDMC review of 
unblinded data 
Systemic effects 
of 
corticosteroids: 
bone disorders, 
bone mineral 
density decrease 
and associated 
fractures
A decrease in bone mineral density and 
the risk of fractures is a class concern 
for any ICS-containing product for the 
treatment of COPD.
In two replicate 12 month studies, in the 
FF/VI clinical program, in a total of 
3,255 patients with COPD, the 
incidence of bone fractures overall was 
low in all treatment groups, with a 
higher incidence in all FF/VI groups 
(2%) compared with the VI 25 μg group 
(<1%).  Although there were more 
fractures in the FF/VI groups compared 
- Evaluation of the 
potential for bone 
systemic corticosteroid 
effects will be conducted 
through assessment of 
reported bone adverse 
events
- Use of bone fracture
eCRF

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Potential Risk of 
Clinical 
Significance
Mitigation Strategy
with the VI 25 μg group, fractures 
typically associated with corticosteroid 
use (e.g., spinal 
compression/thoracolumbar vertebral 
fractures, hip and acetabular 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 
FF/UMEC/VI.
Systemic effects 
of 
corticosteroids: 
cortisol 
suppression
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 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.
- Review AE/SAE reports

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Potential Risk of 
Clinical 
Significance
Mitigation Strategy
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.
During studies with FF and FF/VI in 
asthma subjects, and with FF/VI and 
UMEC/VI in COPD subjects, no 
associated effect on ocular disorders 
was observed. In addition, no effects on 
lens opacification were observed on 
formal ophthalmic assessments in a 
study with FF/VI, FF and FP in subjects 
with asthma.
- As per Section 4.3 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. 
- Review AE/SAE reports
Cardiovascular 
effects of UMEC 
and VI
UMEC
Cardiovascular effects are a potential 
class effect associated with anti-
muscarinic therapies.
In the UMEC/VI clinical development 
program in COPD patients, UMEC/VI 
was generally well tolerated. Overall, a 
low number of atrial arrhythmias were 
reported based on 12-lead ECGs, Holter 
ECGs, or AEs, of which some occurred 
with a higher incidence in active 
treatment groups compared to placebo.  
There was no additive effect with the 
combination over individual 
components.  Few of these findings 
were reported as SAEs and none were 
fatal. In a narrow* Major Adverse 
Cardiac Event (MACE) analysis , the 
incidence of non-fatal myocardial 
infarction (MedDRA PTs of myocardial 
infarction and acute myocardial 
infarction) was low (<1%) across all 
treatment groups, although small 
imbalances in exposure adjusted 
frequency were observed between 
UMEC- and VI containing treatment 
Mitigation strategy for 
UMEC and VI:
- Exclusion criteria as 
specified in Section 4.3 of 
the protocol
- Collection of 
cardiovascular risk factors 
and medical history at 
baseline
- ECGs as per protocol
- Vital sign assessments 
(heart rate and blood 
pressure) as per protocol
- Cardiovascular eCRF for 
collection of AEs and 
SAEs (see Section 6.3.4)
- Prospective independent 
SAE adjudication 
- Protocol defined 
stopping criteria as per 
Section 4.4.1
-Pre-specified Major 
Adverse Cardiac Event 
(MACE) analysis
- Instream review of
blinded data
-IDMC review of 

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Potential Risk of 
Clinical 
Significance
Mitigation Strategy
groups when compared with placebo 
and tiotropium.  There was no obvious 
dose relationship or additive effect from 
the combination.  Whether this 
represents a true effect is difficult to 
determine due to the small numbers. 
During clinical studies in COPD (62.5 
and 125 μg daily dose of UMEC) and in 
Healthy Volunteers (in the Thorough 
QT study, UMEC 500 μg daily dose), 
no effect was observed on heart rate, 
blood pressure or QT.
VI
In the FF/VI clinical development 
program in patients with COPD, the 
cardiovascular safety profile of VI and 
FF/VI was broadly consistent with the 
known pharmacology of LABAs in 
patients with COPD. VI at doses up to 
100 μg in healthy subjects and subjects 
with asthma or COPD was not 
consistently associated with clinically 
relevant or statistically significant 
effects on blood pressure after either 
single or repeat dose administration.
Data from Thorough QT (TQT) studies 
with FF, FF/VI and UMEC/VI suggest 
that, at the doses to be used in phase III 
studies, the closed triple 
(FF/UMEC/VI) is unlikely to cause 
clinically relevant effects on QTc. No 
difference in QTcF was observed 
between UMEC/VI 125/25mcg or 
UMEC 500mcg and placebo. UMEC/VI 
500/100mcg increased QTcF on 
average by 8.2msec (90% CI: 6.2, 10.2) 
at 30 min only. A lack of effect was 
demonstrated for QTcF with FF/VI 
200/25 mcg (for 7 days). At a 
supratherapeutic dose of FF/VI 
(800/100 mcg for 7 days), the largest 
mean time-matched difference from 
unblinded data

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Potential Risk of 
Clinical 
Significance
Mitigation Strategy
placebo was 9.6 msec (90% CI: 7.2, 
12.0) at 30 min only.
Anticholinergic 
effects 
(including 
constipation, 
nausea, dry 
mouth, 
glaucoma, raised 
intraocular 
pressure and 
blurred vision, 
urinary 
retention) 
In clinical studies in COPD, few 
anticholinergic effects were associated 
with UMEC; those observed included 
dry mouth, constipation and cough.
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.
- Review AE/SAE reports
Hypersensitivity
Although not associated with FF/VI 
during the clinical studies, isolated 
cases of hypersensitivity reactions have 
been observed, post marketing, with the 
licensed intranasal spray, AVAMYS.
In addition, the FF inhaled formulation 
has had some reports of 
hypersensitivity-type reactions.
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.
-As specified in Section 
4.3 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-agonist, that in the 
opinion of the investigator 
contraindicates study 
participation, would not be 
included in the study
-Review AE/SAE reports
*The narrow MACE definition refers to the preferred terms of “myocardial ischemia” 
and “acute myocardial infarction”. 
1.3.2.
Benefit Assessment
In a disease where polypharmacy is common, the ‘closed’ triple, once-daily combination 
of FF/UMEC/VI (100mcg/62.5mcg/25mcg), has the potential to optimise bronchodilator 
therapy, improve patient adherence to therapy and, as a result, improve overall disease 
management in COPD patients.
Published studies which assessed the use of an ‘open’ triple therapy (use of 
ICS/LAMA/LABA delivered via multiple inhalers) in moderate-severe COPD patients, 

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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 have also shown
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.
A retrospective cohort study conducted in a UK-based COPD cohort (National Health 
Service NHS Tayside Respiratory Disease Information System) revealed that triple 
therapy (tiotropium added to ICS+LABA) may confer benefits in reducing all-cause 
mortality, hospital admissions and oral corticosteroid bursts compared to ICS+LABA 
alone [Short, 2012]. A further retrospective cohort study reported that tiotropium 
(LAMA) added to fluticasone/salmeterol (ICS/LABA) was associated with significant 
reductions in the adjusted risks of a moderate exacerbation and any exacerbation over a 
follow-up period of up to 1 year, compared to tiotropium alone [Chatterjee, 2012]. 
Additionally, the benefits of once-daily dosing and single-inhalers were observed in 
recently published studies.  A retrospective database analysis of 8 million insured lives in 
the US found that COPD patients who initiated treatment with once-daily dosing had 
significantly higher adherence than other daily dosing frequencies, which yielded 
reductions in healthcare resource utilization and cost over 12 months follow-up period 
[Toy, 2011].  Similarly, a study of 11,747 matched pairs of COPD patients in the US 
Market Scan database demonstrated that multiple-inhaler users were less likely to be 
adherent than single-inhaler users. After adjusting for confounding factors, multiple-
inhaler users experienced significantly more exacerbations, incurred significantly more 
inpatient hospitalizations, inpatient days, urgent care visits, outpatient visits and other 
medical service visits than single-inhaler users, resulting in significantly higher all-cause 
health care costs [Yu, 2011]. Improved patient outcomes might therefore be expected 
from the use of a single inhaler to deliver triple therapy due to improved adherence to 
therapy.
1.3.3.
Overall Benefit: Risk Conclusion
Current risks that have been identified for the FF/UMEC/VI (100mcg/62.5 mcg/25mcg) 
combination 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. 
In the United States, the FF/VI combination is approved for the maintenance treatment of 
airflow obstruction and for reduction of exacerbations in COPD. The UMEC/VI 
combination is approved for maintenance treatment of airflow obstruction in COPD.
In the EU, the FF/VI combination is approved for the symptomatic treatment of adults 
with COPD with a FEV1<70% predicted normal (post-bronchodilator) with an 
exacerbation history despite regular bronchodilator therapy. The UMEC/VI combination 
has a CHMP Positive Opinion for the indication: maintenance treatment to relieve 
symptoms in adults with COPD.

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A comprehensive safety monitoring strategy is being proposed for all the risks, including 
key risks (Section 1.3.1).
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 further 
development of the closed triple combination.
2.
OBJECTIVES
Primary Objective

To evaluate the efficacy of FF/UMEC/VI to reduce the annual rate of moderate 
and severe exacerbations compared with dual therapy of FF/VI or UMEC/VI in 
subjects with COPD. 
Secondary Objectives

To evaluate the long term safety and other efficacy assessments of 
FF/UMEC/VI compared with dual therapy of FF/VI or UMEC/VI. 

To evaluate the efficacy of FF/UMEC/VI to reduce exacerbations compared 
with UMEC/VI in the subset of subjects with a blood eosinophil count ≥150 
cells/µl
Other Objectives

To evaluate the patient perspective of the efficacy of FF/UMEC/VI in subjects 
with COPD. 

To evaluate the population pharmacokinetic profiles of FF, UMEC and VI in 
subjects with COPD

To collect blood samples for a genetics research study.
3.
INVESTIGATIONAL PLAN
3.1.
Study Design
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. 
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM). The SPM will provide 
the site personnel with administrative and detailed technical information that does not 
impact subject safety.
This is a phase IIIa, randomized, double-blind, 3-arm parallel group, global multicenter 
study evaluating FF/UMEC/VI inhalation powder versus FF/VI inhalation powder and 
UMEC/VI inhalation powder, all given once daily in the morning. The target enrollment 

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is 10,000 randomized subjects at approximately 1,200 study centers globally. The total 
duration of subject participation will be approximately 55 weeks, consisting of a 2-week 
run-in period, 52-week treatment period and a 1-week safety follow-up period. There will 
be a total of 7 or 8 clinic visits conducted on an outpatient basis. Clinic visits will occur 
at pre-screening/screening, Randomization (Day1), and after 4, 16, 28, 40, and 52 weeks 
of treatment. In addition, a safety follow-up telephone contact or clinic visit will be 
conducted 7 days after completing visit 7 or the IP Discontinuation visit.
Subjects will sign an informed consent form (ICF) at a pre-screen or screening visit and 
will be assigned a subject identifier.  Subjects meeting all inclusion/exclusion criteria and 
who have successfully completed all protocol procedures at screening will enter the 2-
week run-in. Subjects will continue the use of their existing COPD medications during 
the run-in and in addition will be provided with short acting albuterol/salbutamol to be 
used on an as-needed basis (rescue medication) throughout the study. Following the 2-
week run-in period, eligible subjects will be randomized (2:2:1) to one of the following 
double-blind treatment groups:

FF/UMEC/VI 100mcg/62.5mcg/25mcg QD

FF/VI 100mcg/25mcg QD

UMEC/VI 62.5mcg/25mcg QD
All treatments will be delivered by ELLIPTA™ dry powder inhaler (DPI).  Each DPI will 
contain 30 doses of IP. Subjects will be instructed to administer medication once daily in 
the morning for the duration of the 52-week treatment period. Subjects will self-
administer their first dose of IP in the clinic during Randomization (Day1) Visit 2.  On 
the morning of each clinic study visit, subjects will refrain from taking their morning 
dose of IP until instructed to do so by clinic personnel. Subjects will take their last dose 
of IP in the clinic during Visit 7 (or the IP Discontinuation visit). A safety follow-up will 
be conducted either by phone call or clinic visit after successfully completing Visit 7 (or 
the IP Discontinuation Visit).  
Subjects will discontinue all COPD medications during the randomized treatment period 
but may continue their mucolytics and study-supplied rescue albuterol/salbutamol.  
Subjects will complete a daily electronic diary (eDiary) that captures symptoms of 
COPD, activity limitation and albuterol/salbutamol use.  Subjects with increasing 
respiratory symptoms will automatically be notified through the eDiary to contact their 
investigator for further evaluation of their increasing symptoms. The real-time 
notification of increasing respiratory symptoms from the diary will assist the investigator 
in the identification of new COPD exacerbations.
A subject will be considered to have completed the study when they have completed all 
phases of the study including screening, run-in, randomization, the randomized treatment 
phase and safety follow-up.  
Subjects that permanently stop IP are not required to withdraw from the study. 
Subjects who wish to permanently discontinue their IP should be encouraged to continue 
to take their IP until they are able to return to complete the IP Discontinuation Visit.  
After completing the IP Discontinuation Visit and the safety follow-up visit, subjects will

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be encouraged to continue in the study by participating in study-related telephone 
contacts in order to assess exacerbations, serious adverse events (SAEs) and concomitant 
medications post-treatment.  Subjects will continue to be evaluated until they have 
completed all the remaining protocol specified study visits by telephone contact, up to 
and including Visit 7. 
Subjects who are currently on IP and wish to withdraw from further participation in the 
study should be encouraged to return to the clinic as soon as possible to complete the IP 
Discontinuation Visit and also to complete the safety follow-up visit. No further study 
visits or study-related telephone contacts will be conducted unless the subject’s consent 
allows for contact after withdrawing from the study then every effort should be made by 
the Investigator and site to determine the subject’s survival status at the end of the 
Subject’s planned 52 week participation.
Subjects who have discontinued IP and are continuing in the study by completing study-
related telephone contacts (after having completed their IP Discontinuation Visit and 
safety follow-up phone call/visit), but then decide that they no longer wish to participate 
in the study, may withdraw from the study by contacting the site by telephone to notify 
the site of their intention to withdraw; no additional safety follow-up visit is required.
Figure 1
Study Schematic
3.2.
Discussion of Design
This study will use a multicenter, randomized, double-blind, parallel-group design. This 
is a well-established design to evaluate the efficacy and safety of an investigational drug. 
A placebo arm is not included because the comparisons of primary interest are 
FF/UMEC/VI versus FF/VI and versus UMEC/VI. In addition, it is not considered 
appropriate to include a placebo control arm for a duration of 1 year in patients with 
advanced COPD and a history of COPD exacerbations.

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Eligible subjects must have been on daily maintenance COPD medications for at least 3 
months and will continue these medications unchanged during the 2-week run-in period.  
The 2-week run-in period is necessary in order to assess subject compliance with the 
daily diary and to establish baseline diary symptoms and albuterol/salbutamol use.
Subjects who permanently discontinue IP before the end of the 52-week treatment period 
and agree to continue in the study will be followed by the Investigator until the end of the 
subjects’ planned 52-week participation in order to capture important efficacy and safety 
assessments.
The FF/UMEC/VI dose was selected based on the doses that have been determined for 
the FF/VI and UMEC/VI dual combinations through extensive studies in the mono and 
dual therapy programs. The doses licensed and/or anticipated to be licensed by the FDA 
and the EMA for FF/VI and UMEC/VI are 100mcg/25mcg and 62.5mcg/25mcg 
(equivalent to 92mcg/22mcg and 55mcg/22mcg delivered dose); respectively. 
While both the FF/VI and UMEC/VI programs allowed for a broader COPD population, 
there were still a large number of patients studied in those programs who would be 
considered as part of the target FF/UMEC/VI patient population. For the FF/VI phase III 
program, approximately 70% of patients from the COPD exacerbation studies and 
approximately half of the patients from the six-month studies would be considered ‘high 
risk’ (GOLD C or D according to respiratory guidelines). For the UMEC/VI phase III 
program, approximately half of the patients would be classified as GOLD D.  The safety 
experience with FF/VI, UMEC/VI and their individual components, in previous clinical 
development, provides sufficient data to support the dose selection of 100/62.5/25 mcg 
for FF/UMEC/VI.
4.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA
4.1.
Number of Subjects
Approximately 16,000 subjects will be screened in order to randomize approximately 
10,000 subjects.  All randomized subjects are considered evaluable. Approximately 1,200 
centers globally will be required to recruit the study.
4.2.
Inclusion 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/IB supplements.     
Deviations from inclusion criteria are not allowed because they can potentially jeopardise 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.   
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 
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2.
Type of subject: Outpatient.
3.
Age:  Subjects 40 years of age or older at Visit 1.
4.
Gender: Male or female subjects.
A female is eligible to enter and participate in the study if she is of:
Non-child bearing potential (i.e. physiologically incapable of becoming pregnant, 
including any female who is post-menopausal or surgically sterile). Surgically sterile 
females are defined as those with a documented hysterectomy and/or bilateral 
oophorectomy or tubal ligation. Post-menopausal females are defined as being 
amenorrhoeic for greater than 1 year with an appropriate clinical profile, e.g. age 
appropriate, > 45 years, in the absence of hormone replacement therapy.
OR
Child bearing potential, has a negative pregnancy test at screening, and agrees to 
one of the following acceptable contraceptive methods used consistently and 
correctly (i.e. in accordance with the approved product label and the instructions of 
the physician for the duration of the study – screening to safety follow-up contact):

Abstinence 

Oral Contraceptive, either combined or progestogen alone

Injectable progestogen

Implants of levonorgestrel

Estrogenic vaginal ring

Percutaneous contraceptive patches

Intrauterine device (IUD) or intrauterine system (IUS)

Male partner sterilization (vasectomy with documentation of azoospermia) 
prior to the female subject's entry into the study, and this male is the sole 
partner for that subject. For this definition, “documented” refers to the 
outcome of the investigator's/designee’s medical examination of the subject 
or review of the subject's medical history for study eligibility, as obtained via 
a verbal interview with the subject or from the subject’s medical records.

Double barrier method: condom and an occlusive cap (diaphragm or 
cervical/vault caps) with a vaginal spermicidal agent 
(foam/gel/film/cream/suppository)
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 (visit 1) [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 

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who have stopped smoking for at least 6 months prior to Visit 1.  Note: 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.
8.
Severity of COPD Disease: A post-albuterol/salbutamol FEV1/FVC ratio of <0.70 
at Screening.  
9.
Existing COPD maintenance treatment:  Subject must be receiving daily 
maintenance treatment for their COPD for at least 3 months prior to Screening. 
Note: Subjects receiving only PRN COPD medications are not eligible.
10. History of Exacerbations: Subjects must demonstrate:
a post-bronchodilator FEV1 < 50% predicted normal and a documented history of ≥ 1 
moderate or severe COPD exacerbation in the previous 12 months
OR
a post-bronchodilator 50% ≤FEV1 < 80% predicted normal and a  documented history 
of ≥ 2 moderate exacerbations or a documented history of ≥1 severe COPD exacerbation 
(hospitalized) in the previous 12 months.
Note: Percent predicted will be calculated using the European Respiratory Society 
Global Lung Function Initiative reference equations [Quanjer, 2012].
Note: 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 hospitalization (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 dyspnea, sputum volume, or sputum purulence (color). Subject verbal 
reports are not acceptable. 
11. Liver function tests: 

alanine aminotransferase (ALT) <2x upper limit of normal (ULN); 

alkaline phosphatase  ≤1.5xULN 

bilirubin ≤1.5xULN (isolated bilirubin >1.5 x ULN is acceptable if bilirubin 
is fractionated and direct bilirubin <35%). 
12. 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.
4.3.
Exclusion Criteria
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardise the scientific integrity of the study, regulatory acceptability or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential. 
Subjects meeting any of the following criteria must not be enrolled in the study:

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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).
3.
α1-antitrypsin deficiency: Subjects with α1-antitrypsin deficiency as the underlying 
cause of COPD.
4.
Other respiratory disorders: Subjects with active tuberculosis, lung cancer, 
significant bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, 
interstitial lung diseases or other active pulmonary diseases.
5.
Lung resection: Subjects with lung volume reduction surgery within the 12 months 
prior to Screening.
6.
Risk Factors for Pneumonia: immune suppression (e.g. HIV, Lupus) or other risk
factors for pneumonia (e.g. neurological disorders affecting control of the upper 
airway, such as Parkinson’s Disease, Myasthenia Gravis)
Patients at potentially high risk (e.g. very low BMI, severely malnourished, or very 
low FEV1) will only be included at the discretion of the Investigator.
7.
Pneumonia and/or moderate or severe COPD exacerbation that has not resolved 
at least 14 days prior to Screening and at least 30 days following the last dose of 
oral/systemic corticosteroids (if applicable). In addition, any subject that experiences 
pneumonia and/or moderate or severe COPD exacerbation during the run-in period 
will be excluded.
8.
Other Respiratory tract infections that have not resolved at least 7 days prior to 
screening.
9.
Abnormal Chest x-ray: Chest x-ray (posteroanterior and lateral) 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 CXR (e.g. significant cardiomegaly, pleural effusion or scarring). All 
subjects will have a chest x-ray at Screening Visit 1 (or historical radiograph or CT 
scan obtained within 3 months prior to screening) that will be over-read by a central 
vendor.  Note: Subjects who have experienced pneumonia and/or moderate or severe 
COPD exacerbation within 3 months of screening must provide a post 
pneumonia/exacerbation chest x-ray to be over-read by the central vendor or have a 
chest x-ray conducted at screening. 
For sites in Germany: If a chest x-ray (or CT scan) within 3 months prior to 
Screening (Visit 1) 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 
hematological abnormalities that are uncontrolled. Significant is defined as any 
disease that, in the opinion of the Investigator, would put the safety of the subject at 

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risk through participation, or which would affect the efficacy or safety analysis if the 
disease/condition exacerbated during the study. 
11. Unstable liver disease as defined by the presence of ascites, encephalopathy, 
coagulopathy, hypoalbuminaemia, esophageal or gastric varices or persistent 
jaundice, cirrhosis, known biliary abnormalities (with the exception of Gilbert’s 
syndrome or asymptomatic gallstones). Note: Chronic stable hepatitis B and C are 
acceptable if the subject otherwise meets entry criteria 
12. Unstable or life threatening cardiac disease: subjects with any of the following at 
Screening (Visit 1) would be excluded:

Myocardial infarction or unstable angina in the last 6 months 

Unstable or life threatening cardiac arrhythmia requiring intervention in the last 
3 months  

NYHA Class IV Heart failure 
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 PI 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)

QTcF ≥500 msec in patients with QRS <120 msec and QTcF ≥530 msec in 
patients with QRS ≥ 120 msec 
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 
5 years. Subjects who have had carcinoma in situ of the cervix, squamous cell 
carcinoma and basal cell carcinoma of the skin would not be excluded based on the 5 
year waiting period if the subject has been considered cured by treatment.
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.)

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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. Pulmonary rehabilitation: Subjects who have participated in the acute phase of a 
Pulmonary Rehabilitation Program within 4 weeks prior to Screening or subjects 
who plan to enter the acute phase of a Pulmonary Rehabilitation Program during the 
study. Subjects who are in the maintenance phase of a Pulmonary Rehabilitation 
Program are not excluded.
19. Drug/alcohol abuse: Subjects with a known or suspected history of alcohol or drug 
abuse within the last 2 years.
20. 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.
21. 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.
22. 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.
23. 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.
24. Medication prior to screening: Use of the following medications within the 
following time intervals prior to Screening (Visit 1) or during the study:
Table 2
Prohibited medications prior to Screening or during the study
Medication
No use within the following time intervals prior to Screening 
or during the study
Long term antibiotic therapy
Subjects receiving antibiotics for long term therapy are not eligible 
for the study.
(Antibiotics are allowed for the short term treatment of an 
exacerbation or for short term treatment of other acute infections 
during the study)
Systemic, Oral, parenteral 
corticosteroids
30 days
(Except during the study oral/systemic corticosteroids may be used 
to treat COPD exacerbations/pneumonia) 
Intra-articular injections are allowed
Any other investigational drug
30 days or 5 half lives whichever is longer. 

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4.4.
Investigational Product (IP) Discontinuation Criteria
Subjects that permanently stop IP are not required to withdraw from the study. If 
for any reason a subject must permanently stop IP every effort should be made by the 
Investigator/staff to keep the subject in the study to collect important efficacy and safety 
data.  
4.4.1.
Protocol defined stopping IP criteria
A subject must be permanently discontinued from IP if any of the following stopping 
criteria are met: 

Liver Chemistry: Meets any of the protocol-defined liver chemistry stopping 
criteria as defined in Section 6.3.1. 

Pregnancy: Positive urine pregnancy test.

ECG: An increase in QTcF by > 60msec from baseline or to a QTcF >530 msec 
(based on an average of triplicate ECGs)
NOTE: These criteria should be based on the average QTcF value of triplicate ECGs. 
For example, if an ECG demonstrates a prolonged QT interval, two more ECGs will be 
obtained over a brief period and then the averaged QTcF values of the three ECGs will be 
used to determine whether the patient should be discontinued from the study.  

Non-Compliance with Study treatment: Subjects’ compliance with study treatment 
will be assessed at each study visit. Subjects who are non-compliant should be re-
educated on the requirement for treatment compliance. Every effort will be made to 
keep subjects in the study and to re-educate those subjects who continue to be non-
compliant.  Subjects who continue to be non-compliant after multiple visit 
assessments may be permanently discontinued from IP after consultation with the 
GSK clinical team.

Non-Compliance with daily diary:  Subjects must be compliant in completing their 
daily diary between each pair of on-treatment visits.  Subjects who are non-
compliant should be re-educated on the requirement for daily diary entry 
compliance. Subjects who continue to be non-compliant after multiple visit 
assessments may be permanently discontinued from IP after consultation with the 
GSK clinical team.
4.4.2.
Permanent Discontinuation of Investigational Product (IP)
Subjects have the right to stop taking IP before the end of the study. A subject may also 
be asked to stop IP at the investigator’s discretion.
Subjects who have permanently discontinued IP are not required to withdraw from the 
study. Subjects who have permanently discontinued IP and have not withdrawn 
consent may continue in the study and will complete all remaining protocol specified
visits by phone contact.
In the event that a subject permanently discontinues IP before the end of the randomized 
treatment period, every effort will be made by the investigator to encourage the subject to 

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remain in the study and to complete all remaining study visits by telephone contact. The 
Investigator must document the reason for discontinuation of IP in the eCRF. The 
Investigator/site staff should contact the subject by phone at the protocol designated visit 
time intervals to capture the following:

Exacerbations,

SAEs,

concomitant medications.
4.4.3.
IP Discontinuation Study Assessments
The Investigator must make every effort to have the subject return to the clinic as soon as 
possible after the subject permanently discontinues IP (or informs him they wish to 
withdraw from study) in order to complete the IP Discontinuation Visit.  The following 
evaluations and procedures as outlined in the Time and Events Table should be 
completed and recorded in the eCRF as required:

Concurrent medication assessment

Adverse event assessment

COPD exacerbation assessment

Smoking status

Physical examination (source document only) including oropharyngeal 
examination

Vital signs

ECG

Spirometry

TDI

EQ-5D-5L

CAT

SGRQ-C

Subject Global Rating of Activity Limitation and Subject Global Impression of 
Change in Activity Limitation

Subject Global Rating of Change in COPD

Healthcare resource utilization

Collect used IP and rescue albuterol/salbutamol

Assess compliance with investigational product

Urine pregnancy test for females of childbearing potential 

Hematology & Biochemistry

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
Smoking cessation counseling

Review and Collect eDiary

Call IVRS (RAMOS) to record visit
A safety follow-up contact as described in Section 4.6 should be conducted 7 days 
following completion of Visit 7 or the  IP Discontinuation Visit.
4.4.4.
Reasons for Permanent Discontinuation of IP
The primary reason for permanent discontinuation of IP will be recorded in the electronic 
Case Report Form (eCRF). Specific regard should be given to distinguishing permanent 
discontinuation of IP due to an adverse event from other reasons for permanent 
discontinuation of IP.  
The primary reason for permanent discontinuation of IP will be categorized as:
1. Adverse event
2. Lack of efficacy
3. Protocol deviation
4. Subject reached protocol-defined stopping criteria

ECG abnormality 

Lab abnormality (Liver event or Pregnancy)

Non-compliance
5. Study closed/terminated
6. Lost to follow-up
7. Investigator discretion
8.
Withdrew consent

subject relocated

frequency of visits

burden of procedures

other (specify)
4.5.
Study Withdrawal Criteria
For this study there are no pre-determined protocol specific study withdrawal criteria (see 
Section 4.4.1 for protocol defined stopping IP criteria). 
Every effort should be made by the investigator to keep the subject in the study.  
However a subject may voluntarily withdraw from participation in this study at any time. 
The investigator may also, at his or her discretion, withdraw a subject from further study 
participation. Subjects who are withdrawn from the study will not be replaced.

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4.5.1.
Withdrawal from study
Subjects have the right to withdraw from the study and to withdraw their consent for 
further participation in the study (i.e. this precludes continued data collection). 
The Investigator must document the reason (if specified by the subject) for withdrawal of 
consent in the eCRF. Subjects who wish to withdraw from further participation in the 
study should be encouraged to return to the clinic as soon as possible to complete the IP 
Discontinuation Visit and also to complete the safety follow-up visit in order to collect 
important safety information. 
No further study visits or study-related telephone contacts can be conducted unless the 
subject’s consent allows for contact after withdrawing from the study then every effort 
should be made by the Investigator and site to determine the subject’s survival status at 
the end of the Subject’s planned 52 week participation.
Note: If contact is lost with the subject, only the specific additional actions as clearly 
outlined in each subjects Informed Consent form (e.g. attempt contact with subject’s 
listed contact and/or a primary care physician; request access to the subject’s medical 
record) should be attempted to collect survival status.
4.5.2.
Study Withdrawal assessments
Subjects who are on IP and wish to withdraw from further participation in the study 
should be encouraged to return to the clinic as soon as possible to complete the IP 
Discontinuation Visit assessments (Section 4.4.3) and to complete the safety follow-up 
contact 7 days later. 
Subjects who have previously discontinued IP (and have already completed their IP 
Discontinuation Visit and safety follow-up contact) but then decide that they no longer 
wish to participate in the study, may withdraw from the study by contacting the site by 
telephone to notify the site of their intention to withdraw; no additional safety follow-up 
visit is required.
4.5.3.
Lost to follow-up
If a subject fails to attend the clinic for a required study visit, the site should attempt to 
contact the subject and re-schedule the missed visit as soon as possible. The site should 
also 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 based 
on previous non-compliance. In cases where the subject does not return for the 
rescheduled visit or cannot be reached to reschedule the missed visit, the site should 
make every effort to regain contact with the subject (3 telephone calls and if necessary a 
certified letter to the subject’s last known mailing address) so that they can appropriately 
be withdrawn from the study. These contact attempts should be documented in the 
subject’s medical record. If the subject continues 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”. For all other subjects withdrawing from the study, an alternative reason for 

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discontinuation should be recorded in the eCRF. Every effort should be made to collect 
survival status (whether the subject is still alive). 
Note: If contact is lost with the subject, only the specific additional actions as clearly 
outlined in each subjects Informed Consent form (e.g. attempt contact with subject’s 
listed contact and/or a primary care physician; request access to the subject’s medical 
record) should be attempted to collect survival status.
4.5.4.
Reasons for Study Withdrawal
The primary reason for study withdrawal will be recorded in the eCRF. When a subject 
withdraws consent, the Investigator must document the reason (if specified by the 
subject) in the eCRF. 
The primary reason for study withdrawal will be categorized as:
1. Adverse event
2. Study closed/terminated
3. Lost to follow-up
4. Withdrew consent

subject relocated

frequency of visits

burden of procedures

other (specify)
4.6.
Follow-up Contact
A safety follow-up contact will be conducted 7 days (-1/+4) following the completion of 
the randomized treatment period (Visit 7) or following the IP Discontinuation Visit.
The follow-up contact can be made by phone call or by site visit.  The following 
procedures will be performed:

Adverse event assessment

Concurrent medication assessment

COPD exacerbation assessment

Call IVRS to report safety follow-up contact
Subjects who have successfully completed all on-treatment randomized visits (including 
Visit 7) will be discharged from the study upon completion of the safety follow-up 
contact. 
Subjects who have discontinued IP will complete the  IP Discontinuation Visit followed 7 
days (-1/+4) later by the safety follow-up contact but then will continue in the study to 

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complete all remaining visits by telephone contact and will be discharged from the study 
once they complete the Visit 7 telephone contact.
Subjects who are on IP and wish to withdraw from further participation in the study will 
complete the IP Discontinuation Visit followed 7 days (-1/+4) later by the safety follow-
up contact. 
Subjects who have discontinued IP and are continuing in the study by completing study-
related telephone contacts (after completing their IP Discontinuation Visit and safety 
follow-up phone call), but who now wish to withdraw from the study, should contact the 
site by phone to notify the site of their intention to withdraw; no additional safety follow-
up visit is required.
4.7.
Pre-Screen Failures and Screening 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 Visit 1 will be considered a 
pre-screen failure.
Any subject who performs a Visit 1 procedure but does not continue in the study beyond 
Visit 1 or any subject who completes Visit 1 and enters the run-in period, but is 
subsequently found to be ineligible for the study (e.g. ECG, spirometry, CXR, laboratory 
tests conducted) prior to randomization to the study treatment medication, is classified as 
a Screen Failure.
The study interactive voice response system (IVRS - RAMOS) will be contacted to report 
pre-screen failures.  The following information will be collected in the eCRF for subjects 
who are pre-screen failures:

Date of Pre-Screening Visit

Subject number

Date of ICF signature

Demographic information including race, age and gender

Details of COPD medications within 90 days of Visit 0 (For subjects that 
experience an SAE)

Serious Adverse Events (SAE) information, if applicable, only for any SAE 
considered as related to study participation (e.g. study treatment, protocol 
mandated procedures, invasive tests, or change in existing therapy) or related to 
GSK concomitant medication

Investigator signature page

IVRS-RAMOS will be contacted to report screen failures.  In addition to the 
information above, the following information will be collected for screen 
failures:

Date of Screening Visit

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
Reason for screen failure (screening failure and inclusion/exclusion criteria)
Subjects who are pre-screen or screen failures cannot be re-screened.
5.
STUDY TREATMENTS
5.1.
Investigational Product and Other Study Treatment
The contents of the label will be in accordance with all applicable regulatory 
requirements.
Under normal conditions of handling and administration, investigational product 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. Notify the monitor of 
any unintentional occupational exposure.  A Material Safety Data Sheet (MSDS) 
describing the occupational hazards and recommended handling precautions will be 
provided to site staff if required by local laws or will otherwise be available from GSK 
upon request.
Investigational product (IP) 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 authorised site staff.  Investigational product must 
be dispensed or administered only to subjects enrolled in the study and in accordance 
with the protocol.
All treatments will be delivered by ELLIPTA dry powder inhaler (DPI). There are two 
double-foil laminate blister strips within each DPI, each containing 30 blisters. The DPI 
will provide a total of 30 doses (60 blisters) and will deliver, when actuated, the contents 
of both blisters simultaneously from each of the two blister strips. 
Following the run-in period, eligible subjects will be randomized (2:2:1) to one of the 
following double-blind treatment groups:

Fluticasone Furoate (FF)/Umeclidinium (UMEC)/Vilanterol (VI) 
100mcg/62.5mcg/25mcg QD via DPI

FF/VI 100mcg/25mcg QD via DPI

UMEC/VI 62.5mcg/25mcg QD via DPI
Subjects will be instructed to administer IP once daily in the morning for the duration of 
the 52-week treatment period. Each subject should be advised to adhere to this dosing 
regimen throughout the study. In addition, each subject will be instructed on the proper 
use of the DPI. Subjects will self-administer their first dose of blinded IP in the clinic 
during Visit 2. On the morning of each clinic study visit, subjects will refrain from taking 
their morning dose of IP until instructed to do so by clinic personnel. Subjects will take 
their last dose of IP at the clinic at Visit 7 (or Discontinuation of IP visit).
There are no plans to provide the study drug for compassionate use following study 
completion.
Descriptions of the IPs administered via the DPI are provided in Table 3.

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Table 3
Description of IP Inhalation powder via ELLIPTA™DPI
FF/UMEC/VI 
First strip 
Second strip 
GW685698 blended with 
lactose 
GW642444 and GSK573719 
blended with lactose and 
magnesium stearate 
Dosage Form 
ELLIPTA DPI with 30 doses (2 strips with 30 blisters per strip) 
Unit Dose 
Strengths 
100mcg per blister 
25 mcg per blister GW642444, 62.5 
mcg per blister GSK573719 
Physical 
description 
Dry white powder 
Dry white powder 
Route of 
Administration 
Inhaled 
FF/VI
First strip 
Second strip 
GW685698 blended with 
lactose
GW642444 blended with lactose 
and magnesium stearate
Dosage Form 
ELLIPTA DPI 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/VI
First strip 
Second strip 
GSK573719 blended with 
lactose and magnesium 
stearate 
GW642444 blended with lactose 
and magnesium stearate 
Dosage Form 
ELLIPTA DPI with 30 doses (2 strips with 30 blisters per strip) 
Unit Dose 
Strengths 
62.5 mcg per blister 
25 mcg per blister 
Physical 
description 
Dry white powder 
Dry white powder 
Route of 
Administration 
Inhaled 
Albuterol/salbutamol via metered-dose inhaler (MDI) with a spacer will be issued for 
reversibility testing at Visit 1.  Albuterol/salbutamol MDI or NEBULES™for as needed 
(prn) use throughout the study will be provided starting at Visit 1. Albuterol/salbutamol 
and spacers will be sourced from local commercial stock.  If not available locally, GSK 
will source centrally.

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5.1.1.
Storage
All IP should be stored up to 25C (77F). Excursions permitted up to 30C (86F). Each 
DPI 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 IP administration 
oversight are provided in the SPM.  Investigational product must be dispensed or 
administered only to subjects enrolled in the study and in accordance with the protocol.
5.1.2.
Investigational Product and albuterol/salbutamol Return
All used and unused IP 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 DPI fails to function properly, the subject should return to the clinic as soon as 
possible to obtain a new inhaler.  The site will call IVRS to obtain a new treatment pack 
number for the subject and dispense a new IP kit from the site’s investigational product 
supply as instructed by IVRS.
In addition, any DPI 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.  
5.2.
Treatment Assignment
Subjects will be assigned to study treatment in accordance with the randomisation 
schedule.  The randomization code will be generated by GSK using a validated 
computerized system. Subjects will be randomized using an Interactive Voice Response 
System (IVRS-RAMOS).  The study will use site-based randomization to allocate 
treatments. Once a randomization number is assigned to a subject it cannot be reassigned 
to any other subject in the study.
Subjects who meet the eligibility criteria and complete the 2-week run-in period will be 
randomized (2:2:1) to one of the following study treatment regimens:

FF/UMEC/VI 100mcg/62.5mcg/25mcg QD via ELLIPTA DPI

FF/VI 100mcg/25mcg QD via ELLIPTA DPI

UMEC/VI 62.5mcg/25mcg QD via ELLIPTA DPI
Subjects will be instructed to take one dose each morning from the DPI. 

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The duration of treatment for each subject is 52 weeks.  On the morning of each clinic 
study visit, subjects will refrain from taking their morning dose of IP until instructed to 
do so by clinic personnel.  IP will be given at the clinic at approximately the same time of 
day as Day 1 (Visit 2).  On the other days during the treatment period (i.e. “non-clinic 
days”), subjects will be instructed to take their IP each morning at approximately the 
same time of day. The IVRS 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 IVRS to 
register and randomize subjects is provided in the SPM.
5.3.
Blinding
Investigational product taken during the 52 week treatment period will be double-blinded
and will be delivered by DPIs that are identical in appearance.  Neither the subject nor the 
Investigator will know which IP the subject is receiving.  Details of administration of 
study drug are provided in the SPM.
Subjects who have been unblinded by the investigator or treating physician must have 
their IP permanently discontinued, but may continue in the study to complete protocol 
assessments and visits.  The primary reason for permanent discontinuation of IP (the 
event or condition that led to the unblinding) will be recorded in the eCRF.
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.  It is preferred (but not required) that the 
Investigator first contacts the GSK Medical Monitor or appropriate GSK study personnel 
to discuss options before unblinding the subject’s treatment assignment.  If GSK study 
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 
appropriate data collection tool.
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 clinical investigators in 
accordance with local regulations and/or GSK policy.
An IDMC will be utilised in this study to ensure external objective medical and/or 
statistical review of safety and/or efficacy data in order to protect the ethical and safety 
interests of subjects and to protect the scientific validity of the study.  In order to 
maintain blinding in communication with the IDMC, non-blinded persons separate from 
the study team (e.g. an unblinded statistician or data manager) will be appointed to 
provide required information to the IDMC.  

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5.4.
Product Accountability
In accordance with local regulatory requirements, the Investigator, designated site staff, 
or head of the medical institution (where applicable) must document the amount of 
investigational product dispensed and/or administered to study subjects, the amount 
returned by study subjects, and the amount received from and returned to GSK, when 
applicable.  Product accountability records must be maintained throughout the course of 
the study.
5.5.
Treatment Compliance
Subjects’ compliance with study treatment will be assessed at each study visit. Subjects 
who are non-compliant should be re-educated on the importance of treatment compliance. 
Every effort will be made to keep subjects in the study and to re-educate those subjects 
who continue to be non-compliant.  Subjects who continue to be non-compliant after 
multiple visit assessments may be permanently discontinued from IP after consultation 
with the GSK clinical team.
5.6.
Concomitant Medications and Non-Drug Therapies
All COPD medications used within approximately 3 months prior to screening and during 
the study (including the post-treatment period) should be recorded in the eCRF. 
All non-COPD medications taken during the study (after randomization 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 
(Visit 7) or started after withdrawal from the study must be recorded in the eCRF up to 
the safety follow-up Visit. 
Subjects who have permanently discontinued IP and are continuing in the study will 
continue to collect and record concomitant medications up to Visit 7. Subjects that have 
completed the IP Discontinuation Visit are allowed to use any medications prescribed by 
the Investigator or primary care physician.
5.6.1.
Permitted Medications and Non-Drug Therapies
The following COPD medications are permitted during the study while the subject is on 
IP: 

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

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
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 liters/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 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-articular and epidural)

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 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 
hypokalemia.)

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
Use of positive airway pressure for sleep apnea

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)
5.6.2.
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 4.3).  
NOTE: All COPD medications (except for rescue albuterol/salbutamol, mucolytics and 
oxygen) are prohibited during the randomized 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 6.2.4); 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 IP as these additional medications may increase the risk of 
overdose. If necessary the PI or other health care personnel may stop the subjects IP 
temporarily 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 IP by the PI 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.  
On the day before the Randomization visit, 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 

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corticosteroids, and localized corticosteroid injections (intra-articular and 
epidural) 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 for the 
acute infections or for exacerbations or pneumonia is allowed)
5.7.
Treatment after the End of the Study
The Investigator is responsible for ensuring that consideration has been given to the post-
study care of the patient’s medical condition.
GSK will not provide post-study treatment.  There are no plans to provide IP for 
compassionate use following study completion.  
At the end of the treatment period Visit 7, or after the IP Discontinuation Visit, or 
withdrawal from study, subjects can resume conventional COPD therapy as prescribed by 
the Investigator.  Post-treatment concomitant medication should be entered into the eCRF 
until the safety follow-up visit for subjects that successfully complete Visit 7 on IP and 
for subjects that withdraw from the study.  For subjects that discontinue IP, post-
treatment concomitant medication should be entered into the eCRF until they complete 
telephone contact at the planned Visit 7 date.
5.8.
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 IP, the Investigator should use clinical 
judgment in treating the overdose and contact the GSK medical monitor.
GSK is not recommending specific treatment guidelines for overdose and toxicity 
management. The Investigator is advised to refer to the relevant document(s) for detailed 
information regarding warnings, precautions, contraindications, adverse events, and other 
significant data pertaining to the study drug being used in this study. Such documents 
may include, but not be limited to, the IB or equivalent document provided by GSK. 

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6.
STUDY ASSESSMENTS AND PROCEDURES
Table 4
Time and Events Table
Protocol Activity
Pre-
Screen
Screen
Treatment
Follow Up
Visit 0
Visit 1 
Screen/
run-in
Visit 2
Random-
ization 
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
IP 
Discontinu-
ation Visit
Safety
Follow-up Contact
Study Day
Week -2
Week 0
Week 4
Week 16
Week 28
Week 40
Week 52
1 week Fw-up
Window
-3/+8d
-4/+2d
-8/+6d
-8/+6d
-8/+6d
-8/+6d
-1/+4d
Procedures
Written Informed Consenta
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
X
X
Inclusion/Exclusion Criteria
X
X
     Smoking History
X
Smoking status
X
X
X
X
Smoking Cessation Counseling
X
X
X
Register Visit in RAMOS 
X
X
X
X
X
X
X
X
X
X
Efficacy assessments
Spirometry
X
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Reversibility Testing e
X
Diary/device training and 
registration
X
X
Diary Review
X
X
X
X
X
X
X
Exacerbation Assessment
X
X
X
X
X
X
X
X
X

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Protocol Activity
Pre-
Screen
Screen
Treatment
Follow Up
Visit 0
Visit 1 
Screen/
run-in
Visit 2
Random-
ization 
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
IP 
Discontinu-
ation Visit
Safety
Follow-up Contact
Study Day
Week -2
Week 0
Week 4
Week 16
Week 28
Week 40
Week 52
1 week Fw-up
Window
-3/+8d
-4/+2d
-8/+6d
-8/+6d
-8/+6d
-8/+6d
-1/+4d
Procedures
SGRQ-C f
X
X
X
X
X
BDIf
X
TDIf
X
X
X
X
CATf
X
X
X
X
X
X
EQ-5D-5Lf
X
X
X
X
Subject Global Rating of Activity 
Limitationf
X
X
X
X
X
X
X
Subject Global Impression of 
Change in Activity Limitationf
X
X
X
X
X
X
Subject Global rating of severity of 
COPDf
X
Subject Global rating of Change in 
COPDf
X
X
X
X
X
X
Healthcare Resource Utilisation
X
X
X
X
X
X
eDiary close outg
X
X
X
Safety Assessments
Physical examinationh
X
X
X
X
Adverse Events Assessment *
X
X
X
X
X
X
X
X
X
Vital signsi
X
X
X
X
X
ECG
X
Xj
X
X
X
Chest X-rayk
X
Oropharyngeal examination
X
X
X
X
X
X
X
X
Pulse oximetryl
X
Laboratory Assessments
Blood draw for PK
Xm
Xn
Blood Draw for Genetics researcho
X
Hematology
X

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Protocol Activity
Pre-
Screen
Screen
Treatment
Follow Up
Visit 0
Visit 1 
Screen/
run-in
Visit 2
Random-
ization 
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
IP 
Discontinu-
ation Visit
Safety
Follow-up Contact
Study Day
Week -2
Week 0
Week 4
Week 16
Week 28
Week 40
Week 52
1 week Fw-up
Window
-3/+8d
-4/+2d
-8/+6d
-8/+6d
-8/+6d
-8/+6d
-1/+4d
Procedures
Hematology/biochemistryp
X
X
X
X
X
Urine Pregnancy Testq
X
X
X
X
X
X
X
Hepatitis B and C tests 
X
Exploratory Lab Assessment
      Blood draw for fibrinogen
X
Study Treatment
Dispense IP
X
X
X
X
X
Administer IP in clinicr
X
X
X
X
X
X
X
Assess IP compliance
X
X
X
X
X
X
Collect IP
X
X
X
X
X
X
Dispense albuterol/salbutamol
X
X
X
X
X
X
Collect albuterol/salbutamol
X
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. No study centers in China will 
participate in genetic research in this study.
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.
At Visits 2-7 (and the IP discontinuation visit) both pre and post-bronchodilator spirometry will be conducted. Pre-bronchodilator spirometry will be performed prior to taking morning 
dose of IP, between 6am and 11am and after withholding rescue albuterol/salbutamol for ≥4 hours. Post-bronchodilator spirometry will be conducted (prior to taking morning dose of 
IP) approximately 10-30 minutes after administering 4 puffs of albuterol/salbutamol. 
e.
Subjects are required to withhold their usual morning doses of their COPD meds including rescue albuterol/salbutamol for the protocol designated period prior to reversibility testing.
f.
Patient reported assessments should be conducted in the following order and before other study assessments: SGRQ-C, BDI/TDI,  EQ-5D-5L, CAT, Subject Global Rating of Activity 
Limitation, Subject Global Impression of Change in Activity Limitation, Subject Global Rating of severity of COPD and Change in COPD. BDI/TDI will be conducted in a subset of 
subjects at selected sites.
g.
Close out eDiary for any subject who fails to randomize, discontinues IP, or completes visit 7.
h.
Physical examination may include height, weight, blood pressure, temperature, heart rate.
i.
Vital signs must be performed prior to spirometry and prior to taking morning dose of IP.

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j.
ECG to be obtained 15 minutes to 45 minutes post-dose at treatment Visits 3, 5 and 7 and IP Discontinuation Visit (if applicable).  In addition, at V3 (in a subset of subjects at 
selected sites) one additional ECG will be collected pre-dose.
k.
Chest X-ray 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
l.
Pulse oximetry must be performed at V2 and anytime there is a suspected pneumonia or a moderate or severe exacerbation.
m.
In a subset of 300 subjects at selected sites, PK samples to be obtained at two timepoints at Visit 4: pre-dose and in the window 5 to15 minutes post-dose.
n.
In a subset of 300 subjects at selected sites, PK samples to be obtained at two timepoints at Visit 5: 5 to 15 minutes post–dose and 45 to 90 minutes post-dose.
o.
Genetic consent must be obtained prior to obtaining a blood sample. No study centers in China will participate in genetic research in this study.
p.
Hematology and chemistry panels will include liver chemistry, and potassium and glucose levels.
q.
All female subjects of child bearing potential will have a urine pregnancy test at each visit except Visits 2 and follow-up.
r.
Subjects must withhold their morning dose of IP at each clinic visit and not take their IP dose until instructed to do so by study staff.
NOTE: 
1. Subjects who have permanently discontinued IP (and have not withdrawn consent) will complete the discontinuation IP visit and the 
safety follow-up contact and then will continue in the study to complete all remaining per protocol scheduled visits by phone contact 
to collect Exacerbations, SAEs and Concomitant Medications. 
2.
* In China only, Serious AEs will be recorded from the time the consent form is signed until the 7-day safety follow-up 
visit/telephone contact has been completed, or until Visit 7(telephone contact) for subjects who have discontinued IP but continue in 
the study.

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6.1.
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 (Visit 1) if the subject does not take or has not taken 
any protocol excluded medications.  During the pre-screening visit (Visit 0) each subject 
will have the following information collected:

Demographic history (including gender, ethnic origin, year of birth).

Concomitant medication review.

Register visit in RAMOS IVRS
The additional following critical baseline assessments will be conducted at Visit 1:

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.

Demography

Concomitant Medications

COPD exacerbation assessment (documented history of exacerbation(s))

Cardiovascular medical history/risk factors

Inclusion/Exclusion criteria 

Physical examination (including oropharyngeal 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)

Laboratory assessments (chemistry and hematology, hepatitis and pregnancy 
testing)

COPD Assessment Test (CAT)

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In addition the following procedures must be completed at Visit 1:

Smoking cessation counseling

eDiary training

Register visit in RAMOS

Dispense albuterol/salbutamol
See Section 4.7 for specific data to be collected for screen failures.
6.2.
Efficacy
6.2.1.
Co-Primary Efficacy Endpoints

Annual rate of on-treatment moderate and severe exacerbations comparing 
FF/UMEC/VI with UMEC/VI 

Annual rate of on-treatment moderate and severe exacerbations comparing 
FF/UMEC/VI with FF/VI
6.2.2.
Secondary Efficacy Endpoints

Change from baseline trough FEV1 at Week 52 comparing FF/UMEC/VI with 
FF/VI

Change from baseline SGRQ Total Score at Week 52 comparing FF/UMEC/VI 
with FF/VI 

Time to first on-treatment moderate or severe exacerbation comparing 
FF/UMEC/VI with FF/VI and with UMEC/VI

Annual rate of on-treatment moderate and severe exacerbations comparing 
FF/UMEC/VI with UMEC/VI in the subset of subjects with a blood eosinophil 
count ≥150 cells/µl

Time to first on-treatment moderate or severe exacerbation comparing 
FF/UMEC/VI with UMEC/VI in the subset of subjects with a blood eosinophil 
count ≥150 cells/µl

Annual rate of on-treatment severe exacerbations comparing FF/UMEC/VI with 
FF/VI and with UMEC/VI
6.2.3.
Other Efficacy endpoints

Change from baseline in post-bronchodilator FEV1

Time to death from any cause

Responder rate based on the SGRQ Total Score

Annual rate of all on-treatment exacerbations (mild, moderate, severe)

Annual rate of on-treatment moderate exacerbations

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
Time to first on-treatment COPD hospitalization and COPD re-hospitalization

Annual rate of exacerbations requiring systemic/oral corticosteroids

Annual rate of exacerbations requiring antibiotics

Transitional Dyspnoea Index (TDI) focal score  comparing FF/UMEC/VI with 
FF/VI

Use of rescue albuterol/salbutamol (percentage of rescue-free days and 
occasions/day)

Change from baseline trough FEV1 at Week 52 comparing FF/UMEC/VI with 
UMEC/VI

Change from baseline in SGRQ Total Score comparing FF/UMEC/VI with 
UMEC/VI

CAT score (change from baseline and responder rate)

Subject Global Rating of Activity Limitation and Subject Global Impression of 
Change in Activity Limitation

Subject Global Rating of Severity of COPD and Change in COPD

Annual rate of on-treatment severe exacerbations comparing FF/UMEC/VI with 
UMEC/VI in the subset of subjects with a blood eosinophil count ≥ 150 cells/µl
6.2.4.
COPD Exacerbations
Potential COPD exacerbations will be identified based on symptoms reported via the 
eDiary (triggering contact with the investigator for review via phone contact or at a clinic 
visit) and the Investigator’s 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
Refer to Section 6.3.17 for chest x-rays.
6.2.4.1.
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)

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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 usage in 
their daily eDiary 

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

Other respiratory related disease
Definitions for COPD exacerbations and pneumonia are given in Section 6.2.4.2 and in 
Section 6.3.16, 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 6.3.2.1 and Section 6.3.2.2 for 
definitions of AE and SAE, respectively.

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6.2.4.2.
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 
hospitalization.
Every effort should be made to conduct a chest x-ray within 48 hours of 
identification of a moderate or severe exacerbation. All chest x-rays will be over-read 
centrally to determine if there are new radiographic findings compatible with pneumonia.
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.
6.2.4.3.
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 IP as these additional medications may 
increase the risk of overdose. If necessary the Investigator or other health care personnel 
may stop the subjects IP temporarily in order to treat the COPD exacerbation.
6.2.4.4.
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 
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6.2.4.5.
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 6.2.4.1.
6.2.4.6.
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 6.2.4.1.
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.
6.2.4.7.
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.
6.2.4.8.
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.
6.2.5.
Spirometry Testing
Spirometry measurements will be obtained using spirometry equipment that meets or 
exceeds the minimal performance recommendations of the ATS [Miller, 2005].  All 
subjects will have spirometry performed at Screening and each scheduled clinic visit 
during the treatment period.  At the screening visit both pre- and post-
albuterol/salbutamol spirometry measurements will be measured in order to assess 
eligibility and reversibility (see Section 6.2.5.1). At Visits 2-7 (and discontinuation of IP 

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visit) both pre- and post-albuterol/salbutamol spirometry will be measured prior to the 
subject taking their morning dose of IP.  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 artifacts 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.

If applicable, after completing the health outcomes assessments (SGRQ-C,
BDI/TDI, EQ5D, CAT, Activity limitation, HRU, COPD assessment).

After withholding albuterol/salbutamol for 4 hours. 

At screening, before the morning dose of their usual COPD medications.  

At randomization and all treatment visits, before the morning dose of IP.

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.
6.2.5.1.
Reversibility Testing
At Visit 1, 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.
6.2.6.
SGRQ-C
The St George’s Respiratory Questionnaire -COPD specific (SGRQ-C) will be completed 
by subjects at Randomization, at Week 4, Week 28 and Week 52 (or at the IP 
Discontinuation Visit).
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 
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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].
6.2.7.
Diary Assessments
Subjects will complete a daily eDiary to provide the following information:

Number of nighttime awakenings due to COPD symptoms

Use of supplemental albuterol/salbutamol

Major symptoms concerning the subject’s dyspnea, sputum volume, sputum 
purulence (color)

Minor symptoms of cough, wheezing, sore throat, colds (nasal discharge and/or 
nasal congestion), fever without other cause

Subjects will also be asked ‘Did your respiratory symptoms stop you performing 
your usual activities in the last 24 hours?’ with a Yes/No answer. 
Subjects will be instructed to complete the daily eDiary in the morning, prior to taking 
any IP medication. Subjects will be instructed on how to use the eDiary to score each of 
these major and minor symptoms daily. COPD exacerbations will be identified based on 
eDiary review, and Investigator judgment. In addition, subjects will also capture their use 
of albuterol/salbutamol, the number of nighttime awakenings and if their activity level 
was affected by their respiratory symptoms.
Investigator judgment should be used in deciding whether to report the signs and 
symptoms (and/or determine diagnosis) as recorded in the diary as an AE/SAE in the 
eCRF. Refer to Section 6.3.2.1 and Section 6.3.2.2 for definitions of AE and SAE, 
respectively.
6.2.8.
Rescue Albuterol/Salbutamol Use
Study supplied albuterol/salbutamol MDI and/or Nebules for use as rescue medication 
throughout the study will be sourced by GSK for centers in the United States of America; 
for all other centers it will be sourced locally where possible. Subjects will be instructed 
to record via daily eDiary the number of occasions rescue albuterol/salbutamol was used 
in the past 24 hours for the relief of COPD symptoms.
6.2.9.
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. TDI will be 
measured at Week 4, Week 28 and Week 52 (or IP Discontinuation Visit). Data will be 
collected in a subset of subjects at selected sites where translations are available.

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6.2.10.
COPD Assessment Test (CAT)
The CAT will be completed by subjects at screening, randomization, Week 4, Week 28
and Week 52 (or IP Discontinuation Visit).
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.
6.2.11.
Subject Global Rating of Activity Limitation and Subject Global 
Impression of Change in Activity Limitation
Subjects will complete the Global Rating of Activity Limitation at randomisation and all 
subsequent visits including the final visit (or IP Discontinuation Visit). This single global 
question will ask subjects to rate their activity limitation on a four-point scale (not 
limited, slightly limited, limited, very limited).
Subjects will complete a Global Impression of Change in Activity Limitation question at 
all visits subsequent to randomisation including the final visit (or IP Discontinuation 
Visit). Response options will be on a 7 point Likert scale ranging from much better to 
much worse.
(Note:  The above assessments are in addition to the subject’s daily diary recording of 
activity level that was affected by their respiratory symptoms.)
6.2.12.
Subject Global Rating Severity of COPD and Subject Global 
Impression of Change in COPD
Subjects will complete the Global rating severity of COPD at randomization. This single 
global question will ask subjects to rate their severity of COPD on a four point scale 
(mild, moderate, severe, very severe).
Subjects will complete a Global Rating of Change in COPD (overall disease) question at 
all visits subsequent to randomisation including the final visit (or IP Discontinuation 
Visit). Response options will be on a 7 point Likert scale ranging from much better to 
much worse. Asking at each visit allows for early detection of response as well as 
continued response.
6.3.
Safety
See Section 9.8 and Section 9.9 for information on IDMC and adjudication of SAEs.
Safety endpoints and other assessments

Incidence of adverse events

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
Incidence of pneumonia

Incidence of cardiovascular events (including supraventricular arrhythmia and 
non fatal myocardial infarction)

ECG measurements

Vital signs

Hematological and clinical chemistry parameters

Oropharyngeal examinations

Incidence of bone fractures

Radiography (CXR)

Physical examinations 

Pulse oximetry

Urine pregnancy test (for women of child-bearing potential)
6.3.1.
Liver chemistry stopping and follow up criteria
Phase III-IV liver chemistry stopping and follow up criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance).  
Phase III-IV liver chemistry stopping criteria 1-5 are defined below and are presented in a 
figure in Appendix 3:
1.
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) (or ALT 3xULN 
and INR>1.5, if INR measured)
NOTE: if serum bilirubin fractionation is not immediately available, discontinue study 
drug for that subject if ALT 3xULN and bilirubin 2xULN. Serum bilirubin 
fractionation should be performed if testing is available. If testing is unavailable, record 
presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin 
elevations and suggesting liver injury.
2.
ALT 8xULN.
3.
ALT 5xULN but <8 xULN persists for 2 weeks
4.
ALT  3xULN if associated with symptoms (new or worsening) believed to be 
related to  hepatitis (such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, or jaundice) or hypersensitivity (such as fever, rash or eosinophilia).
5.
ALT 5xULN but <8 xULN and cannot be monitored weekly for 2 weeks
When any of the liver chemistry stopping criteria 1-5 is met, do the following:

Immediately discontinue investigational product for that subject

Report the event to GSK within 24 hours of learning its occurrence

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
Complete the liver event CRF and SAE data collection tool if the event also meets 
the criteria for an SAE. All events of ALT 3xULN and bilirubin 2xULN (>35% 
direct) (or ALT 3xULN and INR>1.5, if INR measured); INR measurement is not 
required and the threshold value stated will not apply to patients receiving 
anticoagulants), termed ‘Hy’s Law’, must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis). 
NOTE: if serum bilirubin fractionation is not immediately available, discontinue IP for 
that subject if ALT 3xULN and bilirubin 2xULN. Serum bilirubin fractionation 
should be performed if testing is available. If testing is unavailable, record presence of 
detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and 
suggesting liver injury.

Complete the liver imaging and/or liver biopsy CRFs if these tests are performed

Perform liver event follow up assessments, and monitor the subject until liver 
chemistries resolve, stabilise, or return to baseline values as described below. 

Discontinue investigational product after completion of the liver chemistry 
monitoring as described below.

Do not restart investigational product.
In addition, for criterion 1:

Make every reasonable attempt to have subjects return to clinic within 24 hours for 
repeat liver chemistries, liver event follow up assessments (see below), and close 
monitoring

A specialist or hepatology consultation is recommended

Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilise or return to within baseline values
For criteria 2, 3, 4 and 5:

Make every reasonable attempt to have subjects return to clinic within 24-72 hrs for 
repeat liver chemistries and liver event follow up assessments (see below)

Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilise or return to within baseline values; criterion 5 subjects 
should be monitored as frequently as possible.
Subjects with ALT 5xULN and <8xULN which exhibit a decrease to ALT x3xULN, 
but <5xULN and bilirubin <2xULN without hepatitis symptoms or rash, 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

Can continue investigational product 

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
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 these subjects meet the liver chemistry stopping criteria, proceed as 
described above

If, after 4 weeks of monitoring, ALT <3xULN and bilirubin < 2xULN, monitor 
subjects twice monthly until liver chemistries normalise or return to within baseline 
values. 
For criteria 1-5, make every attempt to carry out the liver event follow up assessments
described below:

Viral hepatitis serology including:

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 

Blood sample for PK analysis, obtained within 72 hours of last dose.  Record the 
date/time of the PK blood sample draw and the date/time of the last dose of 
investigational product 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. 

Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total bilirubin 2xULN.

Obtain complete blood count with differential to assess eosinophilia.

Record the appearance or worsening of clinical symptoms of hepatitis or 
hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever rash or eosinophilia as relevant on the AE report form.

Record use of concomitant medications, acetaminophen, herbal remedies, other over 
the counter medications, or putative hepatotoxins, on the concomitant medications 
report form.

Record alcohol use on the liver event alcohol intake case report form.
The following are required for subjects with ALT 3xULN and bilirubin 2xULN (>35% 
direct) but are optional for other abnormal liver chemistries:

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
Anti-nuclear antibody, anti-smooth muscle antibody, and 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.

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 antibody.  NOTE:  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].

Liver imaging (ultrasound, magnetic resonance, or computerised tomography) to 
evaluate liver disease.
6.3.2.
Adverse Events
The investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE. Subjects will be provided with a paper 
diary worksheet in which to record any medications they use or AEs they may have 
experienced.  In addition, the worksheet will be used by the subject to record healthcare 
contacts between visits.
For the purposes of this study, all COPD exacerbations will be collected and recorded on 
the COPD exacerbation eCRF page. COPD exacerbations should not be recorded as an 
adverse event, unless they meet the definition of a Serious Adverse Event (see Section
6.3.2.2).  For COPD exacerbations that are considered serious, the SAE page of eCRF 
should be completed, in addition to the COPD eCRF page.
6.3.2.1.
Definition of an AE
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.  For marketed medicinal products, this 
also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse.
Events meeting the definition of an AE include:

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

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
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 that do not meet the definition of an AE include:

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

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
condition
6.3.2.2.
Definition of an SAE
A serious adverse event is 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, or

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NOTE:  The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include experiences of 
relatively minor medical significance such as uncomplicated headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (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.
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 
jeopardise 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. All events of possible drug-induced liver injury with hyperbilirubinaemia defined 
as ALT 3xULN and bilirubin 2xULN (>35% direct) (or ALT 3xULN and 
INR>1.5, if INR measured) termed ‘Hy’s Law’ events (INR measurement is not 
required and the threshold value stated will not apply to patients receiving 
anticoagulants).
NOTE: bilirubin fractionation is performed if testing is available. If testing is unavailable, 
record presence of detectable urinary bilirubin on dipstick indicating direct bilirubin 
elevations and suggesting liver injury. If testing is unavailable and a subject meets the 
criterion of total bilirubin 2xULN, then the event is still reported as an SAE. If INR is 
obtained, include values on the SAE form. INR elevations >1.5 suggest severe liver 
injury.
6.3.2.3.
Sentinel Events
A Sentinel Event is a GSK-defined SAE that is not necessarily drug-related but has been 
associated historically with adverse reactions for other drugs and is therefore worthy of 
heightened pharmacovigilance. Medical monitor review of all SAEs for possible Sentinel 
Events is mandated at GSK.  The GSK medical monitor may request additional clinical 
information on an urgent basis if a possible Sentinel Event is identified on SAE review. 
The current GSK-defined Sentinel Events are listed below:

Acquired Long QT Syndrome

Agranulocytosis/Severe Neutropenia 

Anaphylaxis & Anaphylactoid Reactions 

Hepatotoxicity

Acute Renal Failure

Seizure

Stevens Johnson syndrome/Toxic epidermal necrosis

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6.3.3.
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs
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 are to be recorded as AEs or SAEs.
However, any clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the subject’s condition, are not to be reported as AEs or SAEs.
6.3.4.
Cardiovascular Events
Investigators will be required to fill out event specific data collection tools for the 
following AEs and SAEs:  

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularisation
This information should be recorded in the specific cardiovascular eCRF within one week 
of when the AE/SAE(s) are first reported.
6.3.5.
Death Events
In addition, all deaths will require a specific death data collection tool to be completed.  
The death data collection tool includes questions regarding cardiovascular (including 
sudden cardiac death) and non-cardiovascular death.
This information should be recorded in the specific death eCRF within one week of when 
the death is first reported.
6.3.6.
Disease-Related Outcomes Not Subject to Expedited Reporting 
to Regulatory Authorities
The primary endpoint of this study is the annual rate of on-treatment moderate and severe 
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COPD exacerbations should not be recorded as an adverse event, unless they meet the 
definition of a SAE (Section 6.3.2.2).
COPD exacerbation SAEs will not be subject to expedited reporting regardless of the
“expectedness” or “relatedness” of the event.
6.3.7.
Pregnancy
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy form.  To ensure subject safety, each pregnancy must be reported to GSK 
within 2 weeks of learning of its occurrence.  The pregnancy must be followed up to 
determine outcome (including premature termination) and status of mother and child.  
Pregnancy complications and elective terminations for medical reasons must be reported 
as an AE or SAE.  Spontaneous abortions must be reported as an SAE.
Any SAE occurring in association with a pregnancy, brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
possibly related to the study treatment, must be promptly reported to GSK.
6.3.8.
Medical Devices
Medical devices (spacers/holding chambers) are being provided by GSK for use in this 
study.  GSK medical device incidents, including those resulting from malfunctions of the 
device, must be detected, documented, and reported by the investigator throughout the 
study.
Medical Device – this is any instrument, apparatus, appliance, material or other article, 
whether used alone or in combination, including the software necessary for its proper 
application intended by the manufacturer to be used for human beings for the purpose of:

diagnosis, prevention, monitoring, treatment or alleviation of disease;

diagnosis, monitoring, treatment, alleviation of or compensation for an injury or 
handicap;

investigation, replacement or modification of the anatomy or of a physiological 
process;

control of conception
and which does not achieve its principle action in or on the human body by 
pharmacological, immunological or metabolic means, but may be assisted in its function 
by such means.
Note: if these means fulfill the main purpose of the product, it is a Medicinal Product. 
The term medical device includes in vitro diagnostic (IVD) devices. 
The detection and documentation procedures described in this protocol apply to all GSK 
medical devices provided for use in the study.

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Incident – Any malfunction or deterioration in the characteristics and/or performance of 
a device, as well as any inadequacy in the labeling or the instructions for use which, 
directly or indirectly might lead to or might have led to the death of a patient, or user or 
of other persons or to a serious deterioration in their state of health.  
Not all incidents lead to death or serious deterioration in health. The non-occurrence of 
such a result might have been due to other fortunate circumstances or to the intervention 
of health care personnel.
It is sufficient that 

An incident associated with a device happened and

The incident was such that, if it occurred again, it might lead to death or serious 
deterioration in health
A serious deterioration in state of health can include:

A life-threatening illness (a)

Permanent impairment of body function or permanent damage to a body structure (b)

A condition necessitating medical or surgical intervention to prevent (a) or (b)

Any indirect harm as a consequence of an incorrect diagnostic or IVD test results 
when used within the manufacturer’s instructions for use

Fetal distress, fetal death or any congenital abnormality or birth defects
Incidents include, for example:

inhalation of an object that has accidentally entered a spacer device and resulted in 
tracheal obstruction.
Incidents do not include for example:

medical occurrences associated with metered-dose inhalers that do not fulfill the 
definition of a medical device (such events will be reported as medicinal product 
AEs)

non-serious medical occurrences which have no further safety implications for the 
subject or the device
Malfunction – A failure of a device to perform in accordance with its intended purpose 
when used in accordance with the manufacturer’s instructions.
Remedial Action – Any action other than routine maintenance or servicing of a device 
where such action is necessary to prevent recurrence of a reportable incident [this 
includes any amendment to the design to prevent recurrence].

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6.3.9.
Time Period and Frequency of Detecting AEs and SAEs
The investigator or site staff is responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.
AEs and SAEs will be collected from the time of Visit 2 (Randomization) until the 7-day 
safety follow-up visit/telephone contact has been completed or until Visit 7 for subjects 
who have discontinued IP but continue in the study. Additionally, SAEs assessed as 
related to study participation (e.g., study treatment, protocol-mandated procedures, 
invasive tests, or change in existing therapy) or related to a GSK concomitant medication, 
will be recorded from the time a subject consents to participate in the study up to and 
including any follow up contact. All SAEs will be reported to GSK within 24 hours, as 
indicated in Section 6.3.11.
All SAEs will be followed up until resolution, until the condition stabilizes, until the 
event is otherwise explained, or until the subject is lost to follow-up.  Once resolved, the 
SAE eCRF page will be updated.  The investigator will ensure that follow-up includes 
any supplemental investigations as may be indicated to elucidate the nature and/or 
causality of the SAE.  This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals.
COPD exacerbations will be collected from the time of Visit 2 (Randomization) until the 
7-day safety follow-up visit/telephone contact has been completed or until Visit 7 for 
subjects who have discontinued IP but continue in the study. COPD Exacerbations will 
not be collected as AEs unless they meet the definition of an SAE.
NOTE: In China only, Serious AEs will be recorded from the time the consent form is 
signed until the 7-day safety follow-up visit/telephone contact has been completed, or 
until Visit 7(telephone contact) for subjects who have discontinued IP but continue in the 
study.
6.3.10.
Method of Detecting AEs and SAEs
Care must 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?” 
6.3.11.
Prompt Reporting of Serious Adverse Events and Other Events 
to GSK
SAEs, pregnancies, medical device incidents, and liver function abnormalities meeting 
pre-defined criteria will be reported promptly by the investigator to GSK as described in 

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the following table once the investigator determines that the event meets the protocol 
definition for that event.
Initial Reports
Follow-up Information on a Previous 
Report
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours
“SAE” data 
collection tool
24 hours
Updated “SAE” 
data collection tool
Cardiovascular or 
death event
Initial and 
follow up 
reports to be 
completed 
within one 
week of when 
the 
cardiovascular 
event or death 
is reported 
“CV events” 
and/or “death” 
data collection 
tool(s) if 
applicable
Initial and follow 
up reports to be 
completed within 
one week of when 
the cardiovascular 
event or death is 
reported
Updated “CV 
events” and/or 
“death” data 
collection tool(s) if 
applicable
Device Incident
24 hours
“Medical Device 
Incident Report 
Form”
24 hours
Updated “Medical 
Device Incident 
Report Form”
Pregnancy
2 weeks
“Pregnancy 
Notification Form”
2 weeks
“Pregnancy Follow-
up Form”
Liver chemistry abnormalities for Phase I to IV:
ALT3xULN and
Bilirubin2xULN 
(>35% direct) (or 
ALT3xULN and
INR>1.5, if INR 
measured)1
24 hours2
“SAE” data 
collection tool.  
“Liver Event CRF” 
and “Liver 
Imaging” and/or 
“Liver Biopsy” 
CRFs, if 
applicable3
24 hours
Updated “SAE” 
data collection 
tool/“Liver Event” 
Documents3
Remaining liver chemistry abnormalities Phase III to IV:
ALT8xULN; 
ALT3xULN with 
hepatitis or rash or 
3xULN and < 5xULN 
that persists4 
weeks
24 hours2
“Liver Event” 
Documents 
(defined above) 3
24 hours
Updated “Liver 
Event” Documents3

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Initial Reports
Follow-up Information on a Previous 
Report
Type of Event
Time Frame
Documents
Time Frame
Documents
ALT5xULN plus 
bilirubin <2xULN
24 hours2
“Liver Event” 
Documents 
(defined above) 
do not need 
completing unless 
elevations persist
for 2 weeks or 
subject cannot be 
monitored weekly 
for 2 weeks3
24 hours
Updated “Liver 
Event” Documents, 
if applicable3
ALT5xULN and 
bilirubin <2xULN that 
persists 2 weeks
24 hours2
“Liver Event” 
Documents 
(defined above) 3
24 hours
Updated “Liver 
Event” Documents3
ALT3xULN and <5x 
ULN and bilirubin 
<2xULN
24 hours2
“Liver Event” 
Documents 
(defined above) 
do not need 
completing unless 
elevations persist 
for 4 weeks or 
subject cannot be 
monitored weekly 
for 4 weeks3
24 hours
Updated “Liver 
Event” Documents, 
if applicable3
1.
INR measurement is not required; if measured, the threshold value stated will not apply to patients receiving 
anticoagulants.
2.
GSK must be contacted at onset of liver chemistry elevations to discuss subject safety
3.
Liver Event Documents (i.e., “Liver Event CRF” and “Liver Imaging CRF” and/or “Liver Biopsy CRF”, as 
applicable) should be completed as soon as possible.
The method of recording, evaluating and follow-up of AEs and SAEs plus procedures for 
completing and transmitting SAE reports to GSK are provided in the SPM.  Procedures 
for post-study AEs/SAEs are provided in the SPM.
Procedures for documenting, transmitting and follow-up of medical device incidents 
along with the regulatory reporting requirements for medical devices are provided in the 
SPM.
6.3.11.1.
Regulatory Reporting Requirements for SAEs
Prompt notification of SAEs by the investigator to GSK is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects 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 

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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.
6.3.12.
Laboratory Assessments
Routine non-fasting clinical laboratory tests (hematology, chemistry), including serum 
glucose and serum potassium levels, will be performed at Screening (Visit 1) and at 
Week 16, Week 28, and Week 52 (or IP Discontinuation Visit). Hepatitis B and C will be 
collected as part of the Screening Visit blood draw. Hematology (alone) will be collected 
at Visit 2.  The Week 16 hematology blood draw will also be used to assess fibrinogen as 
an exploratory biomarker of COPD.
All female subjects of child bearing potential will have urine pregnancy tests performed 
at the Screening (Visit 1) and at Weeks 4, Week 16, Week 28, Week 40, and Week 52 
(or IP Discontinuation Visit). 
At the discretion of the Investigator, additional samples may be taken for safety reasons. 
All blood will be analyzed by a central laboratory. Full details regarding sample 
collection, processing and shipping are provided in the central laboratory manual.
Please see Appendix 4 for a specific list of laboratory analytes to be tested.
All protocol required laboratory assessments, as defined in Appendix 4, must be 
performed by the central laboratory, Quest Diagnostics. Laboratory assessments must be 
conducted in accordance with the Central 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 Quest
Diagnostics. Reference ranges for all safety parameters will be provided to the site by 
Quest Diagnostics.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in patient management or are 
considered clinically significant by the Investigator (e.g., SAE or AE) the results must be 
recorded in the subject’s CRF. Refer to the SPM for appropriate processing and handling 
of samples to avoid duplicate and/or additional blood draws.

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6.3.13.
Vital Signs
Vital signs will be performed prior to taking the morning dose of IP and prior to 
conducting spirometry. Vital signs will be collected at Screening, Weeks 4, 28, and 52 (or 
IP Discontinuation 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.
6.3.14.
Medical Problems and Concomitant Medications
Subjects will be instructed to record any medical problems and the medications used to 
treat them over 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.
6.3.15.
ECG
All sites will use standardized ECG equipment provided by a centralized external vendor. 
A single 12-lead ECG and rhythm strip will be recorded after measurement of vital signs
and spirometry. Recordings will be made at Screening (Visit 1) and approximately 15-45 
minutes after dosing on treatment Week 4, Week 28, Week 52 (or IP Discontinuation 
Visit). In addition, in a subset of subjects, at selected sites one pre-dose measurement will
also be assessed at Week 4. 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. 
For subjects who meet the QTc, protocol defined stopping criteria, triplicate ECGs (over 
a brief period of time) should be performed (see Section 4.4.1).
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 centralized 
cardiology service provider.
6.3.16.
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:

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
Increased cough 

Increased sputum purulence (color) or production 

Auscultatory findings of adventitious sounds (e.g. egophony, bronchial breath 
sounds, rales, etc.)

Dyspnea or tachypnea

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. Risk factors for pneumonia in patients with 
COPD receiving fluticasone furoate/vilanterol include 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.  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. 
6.3.17.
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 over-read by a central vendor
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.

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6.3.18.
Oropharyngeal Examinations
Oropharyngeal examinations for clinical evidence of infection (e.g. Candida albicans) 
will be performed at each study visit as shown in the Time and Events Table. If there is 
evidence of infection, appropriate therapy should be instituted at the discretion of the 
Investigator. Subjects may continue in the study on appropriate anti-infective treatment at 
the discretion of the Investigator.  The results of these assessments, and any resulting
pharmacotherapy, will be recorded in the subject’s clinic notes and in the eCRF. All 
suspected cases of candidiasis must be reported as adverse events.
6.3.19.
Pulse oximetry
Pulse oximetry will be conducted at randomization 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.
6.4.
Health Outcomes
All patient reported outcomes should be administered at the beginning of a study visit 
before any physical activity or spirometry. SGRQ-C should be administered first 
followed by BDI/TDI, EQ-5D-5L, CAT, Subject Global Rating of Activity Limitation 
and Subject Global Impression of Change in Activity Limitation and Subject Global 
Rating of COPD Severity and Subject Global Rating of Change in COPD. (See Section 
6.2.6 for information on SGRQ-C, Section 6.2.9 for BDI/TDI, Section 6.2.10 for CAT, 
Section 6.2.11 for Activity limitation and change in activity limitation and Section 6.2.12
for COPD severity and change in COPD).
6.4.1.
EuroQol Questionnaire (EQ-5D-5L)
The EQ-5D-5L questionnaire will be completed by subjects at randomization, at Week 28
and Week 52 (or IP Discontinuation Visit).
The EQ-5D-5L is a standardised instrument for use as a measure of health utility. It is 
designed for self-completion and is cognitively simple, taking only a few minutes to 
complete. The EQ-5D-5L is a two-part self-assessment questionnaire. The first part 
consists of five items covering five dimensions (mobility, self care, usual activities,
pain/discomfort, and anxiety/depression). Each dimension is measured by a five-point 
Likert scale (no problems, slight problems, moderate problems, severe problems, and
extreme problems). Respondents are asked to choose one level that reflects their "own 
health state today" for each of the five dimensions. Respondents can be then classified 
into one of 243 distinct health states. The second part is a 20-cm visual analogue scale 
(EQ-VAS) that has endpoints labelled "best imaginable health state" and "worst 
imaginable health state "anchored at 100 and 0, respectively. Respondents are asked to 
indicate how they rate their own health by drawing a line from an anchor box to that 
point on the EQ-VAS which best represents their own health on that day. EQ-5D-5L 
health states are converted to a single summary index by applying a formula that 
essentially attaches weights to each of the levels in each dimension. The formula is based 
on the valuation of EQ-5D health states from general population samples.

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6.4.2.
Healthcare resource utilisation
All unscheduled visits to a physician office, visits to urgent care, visits to emergency 
department, and hospitalizations will be recorded in the eCRF.  In addition visits and 
contacts that are due to a COPD exacerbation will be assessed and recorded. Patients will 
be provided with a paper worksheet diary to record any health care contacts between 
clinic visits. In addition, the paper worksheet diary will be used by subjects to record any 
medications they have taken or adverse events they have experienced. 
6.5.
Pharmacokinetics
Concentrations of FF, UMEC and VI in plasma will be determined using currently 
approved assay methodology under the control of GSK PTS-DMPK. A population 
pharmacokinetics approach will be employed in this study with samples collected in 
approximately 300 subjects (to achieve approximately 120 subjects treated with 
FF/UMEC/VI). At Visits 4 and 5, two 6mL blood samples will be collected from each of 
the 300 subject as follows:
Visit 4: Predose and in the window 5 to 15 minutes post-dose
Visit 5: In the windows 5 to 15 minutes and 45 to 90 minutes post-dose
Refer to the SPM for details of the sample collection, information to document and 
treatment, shipment and processing procedures. Raw data will be archived at the 
bioanalytical site (detailed in the SPM).
6.6.
Genetic Research
Information regarding genetic research is included in Appendix 1.
Note: No study centers in China will participate in genetic research in this study.
6.7.
Novel Biomarkers
Plasma samples will be collected at Week 16 to analyze fibrinogen, a known 
inflammatory marker. 
After completion of the clinical trial, an exploratory analysis will be conducted on the 
relationship of plasma fibrinogen with measures of response to each study treatment. The 
results gained may also be of application for future COPD trials.

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7.
DATA MANAGEMENT
For this study subject data will be entered into GSK defined electronic case report forms
(eCRFs), transmitted electronically to GSK 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 Medical Dictionary for Regulatory Activities (MedDRA) and an 
internal validated medication dictionary. 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". In all cases, subject initials will not be collected or transmitted to 
GSK according to GSK policy.
8.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
8.1.
Hypotheses
The primary objective of this study is to evaluate the efficacy of FF/UMEC/VI to reduce 
the annual rate of moderate and severe exacerbations compared with dual therapy of 
FF/VI or UMEC/VI in subjects with COPD over a 52 week period.
The aim of this study is to demonstrate the contribution of the ICS when used in 
combination with a fixed dose of a LABA/LAMA, and the contribution of the LAMA 
above the efficacy of an ICS/LABA combination, in reducing the rate of on-treatment 
moderate and severe exacerbations in patients with COPD. This is a superiority study.
The primary endpoint is the annual rate of on-treatment moderate and severe 
exacerbations (calculated as the number of moderate and severe exacerbations during the 
treatment period). 
The primary analyses will be the pair-wise comparisons of FF/UMEC/VI against FF/VI 
and against UMEC/VI, with inferences adjusted for multiplicity as described in Section 
8.3.3. The primary analyses will be based on a two-sided hypothesis testing approach.
The hypotheses associated with the statistical test of the primary efficacy endpoint are 
H0:  λT/λD=1 versus HA:  λT/λD≠1 where λT is the annual rate for triple therapy 
(FF/UMEC/VI) and λD is the annual rate for the respective dual therapies (FF/VI and 
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8.2.
Study Design Considerations
8.2.1.
Sample Size Assumptions
Sample size calculations are based on the co-primary endpoints, the annual rate of on-
treatment moderate and severe exacerbations for the comparison of FF/UMEC/VI with 
FF/VI and with UMEC/VI.
The treatment benefit for moderate and severe exacerbation rates when adding the ICS 
component to a LABA in studies with Advair™/Seretide™[Ferguson, 2008] and with 
FF/VI [Dransfield, 2013] were approximately 20-30%, where all subjects were restricted 
from concomitant LAMA therapy.  It will be assumed that the ICS effect will be largely 
maintained even on a background of dual bronchodilation (LABA/LAMA), therefore the 
study will target a treatment benefit of 15% for FF/UMEC/VI versus UMEC/VI.
As an estimate of dual bronchodilator effect, the SPARK study [Wedzicha, 2013] showed 
a benefit of a dual bronchodilator over LAMA monotherapy to be approximately 10-
12%.
The annual rate of on-treatment moderate and severe exacerbations in the FF/VI 
treatment arm was 0.92 based on those subjects in the FF/VI arms from the FF/VI Phase 
IIIa program who can be classified as 'high risk' (unpublished data: studies HZC102871 
and HZC102970) according to the most recent COPD guidelines [GOLD, 2013]. Based 
on these data, the exacerbation rate for FF/UMEC/VI in the current study is estimated to 
be 0.80 for purposes of sample size calculations, with the estimate for FF/VI being 12% 
higher (approximately 0.91) and the estimate for UMEC/VI being 15% higher 
(approximately 0.94). The co-primary endpoints will be controlled for multiplicity using 
the truncated Hochberg method [Dmitrienko, 2008]. In order to have 90% power to 
detect a 15% reduction in the annual rate of moderate and severe exacerbations in the 
FF/UMEC/VI arm compared with the UMEC/VI arm and a 12% reduction compared 
with the FF/VI arm, 4000 subjects will be randomized to each of the FF/UMEC/VI and 
FF/VI arms, along with 2000 subjects to the UMEC/VI arm. Calculations are based on a 
negative binomial regression and use a two-sided 1% significance level in order to satisfy 
regulatory requirements of substantial evidence of efficacy for a single study.  For the 
multiplicity hierarchy, a 2-sided 5% risk associated with incorrectly rejecting the null 
hypothesis (significance level) is considered acceptable for this study. The estimate of the 
dispersion parameter for the negative binomial model is 0.75, which is similar to that 
seen with fluticasone propionate/salmeterol in the TORCH study [Calverley, 2007] and 
the dispersion in the FF/VI exacerbation program [Dransfield, 2013].  
Subjects will be randomized in a 2:2:1 proportion to the FF/UMEC/VI, FF/VI and 
UMEC/VI arms, respectively.  All randomized subjects (approximately 10,000 in total) 
are considered to be evaluable for the measurement of exacerbations, irrespective of 
whether they permanently discontinue from IP. Assuming a 38% screen failure rate, 
based on the FF/VI Phase III exacerbation program, it is estimated that approximately 
16,000 subjects will be screened.

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8.2.2.
Sample Size Sensitivity
If the annual rate of moderate and severe exacerbations in the FF/UMEC/VI treatment 
arm is different from the 0.8 used in the sample size calculation, the power to detect the 
change in exacerbations rates will be affected. 
Table 5 illustrates the power which would be obtained from various moderate and severe 
exacerbation rates and rate reductions for the FF/UMEC/VI treatment arm compared with 
the FF/VI treatment arm.  The sample size, dispersion factor and two-sided significance 
threshold of 1% remain fixed.
Table 5
Power for varying FF/UMEC/VI exacerbation rates and treatment 
improvements versus FF/VI
True Rate of Exacerbation Improvement, 
FF/UMEC/VI versus FF/VI 
FF/UMEC/VI 
rate
8% 
Reduction
10% 
reduction
12% 
reduction
0.90
51%
76%
92%
0.80
47%
72%
90%
0.70
43%
67%
87%
0.60
38%
62%
82%
Table 6 illustrates the power which would be obtained from various moderate and severe 
exacerbation rates and rate reductions for the FF/UMEC/VI treatment arm compared with 
the UMEC/VI treatment arm.  The sample size, randomization ratio (2:1), dispersion 
factor and two-sided significance threshold of 1% remain fixed.
Table 6
Power for varying FF/UMEC/VI exacerbation rates and treatment 
improvements versus UMEC/VI
True Rate of Exacerbation Improvement, 
FF/UMEC/VI versus UMEC/VI 
FF/UMEC/VI 
rate
10% 
reduction
12% 
reduction
15% 
reduction
0.90
53%
75%
94%
0.80
49%
71%
92%
0.70
45%
66%
89%
0.60
40%
60%
85%
8.2.3.
Sample Size Re-estimation
Blinded evaluation of exacerbation rates is planned for this study.  A blinded evaluation 
of exacerbation rates for the purpose of sample size re-estimation will be done after one 
year of enrolment, or when 5,000 subjects have been randomized, whichever is earlier.  A 
subsequent evaluation will be done after approximately 18 months of enrolment, or when 
7,500 subjects have been randomized, whichever is earlier. 

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If the exacerbation rates for the study are lower than planned, a sample size re-estimation 
may be conducted. Any subsequent change to the planned number of subjects 
randomized would be documented in a protocol amendment.
8.3.
Data Analysis Considerations
8.3.1.
Analysis Populations

All Subjects Enrolled Population: This population includes all subjects for whom a 
record exists on the study database, including screened subjects and subjects who 
were not screened but signed an ICF. This population will be used for the summary 
of subject disposition and the listing of SAEs for non-randomised subjects.

Intent-to-Treat (ITT) Population: The ITT Population will comprise all subjects 
randomised to treatment apart from those randomised in error. A subject who is 
recorded as a screen or run-in failure and also randomised, but did not receive a dose 
of study treatment, will be considered to be randomised in error. Any other subject 
who receives a randomisation number will be considered to have been randomised. 
The ITT Population is the primary analysis population of interest.

Pharmacokinetic (PK) Population: The PK Population will comprise the subset of 
subjects in the ITT Population for whom a PK sample was obtained and analyzed. 
This population will be used for all concentration-time and PK parameter tables, 
listings and figures.
8.3.2.
Analysis Data Sets
Details of the analysis datasets to be created will be given in the RAP.
8.3.3.
Treatment Comparisons
8.3.3.1.
Primary Comparisons of Interest
The primary comparisons of interest will be the pair-wise comparisons of FF/UMEC/VI 
against FF/VI and FF/UMEC/VI against UMEC/VI.  The primary comparisons will be 
tested for the primary endpoint, the annual rate of on-treatment moderate and severe 
exacerbations.  
The primary analysis will be based on a two-sided hypothesis testing approach. The 
hypotheses associated with the statistical test of the primary efficacy endpoint are H0:  
λT/λD=1 versus HA:  λT/λD≠1 where λT is the annual rate for triple therapy (FF/UMEC/VI) 
and λD is the annual rate for the respective dual therapies (FF/VI and UMEC/VI).  
Both primary comparisons will be tested using the ITT population.  In order to account 
for multiplicity, the truncated Hochberg procedure [Dmitrienko, 2008] with a truncation 
parameter of γ=0.6 will be used to control overall Type I error at α=0.05.
For the primary comparisons, both comparisons will be declared statistically significant if 
the p-value for both comparisons is significant at the 0.04 level.  Should the largest p-
value for the two comparisons be above 0.04, the other comparison will be declared 

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statistically significant if the smaller p-value is below 0.025.  If at least one of the 
comparisons is significant, this will allow inference of secondary endpoints.
8.3.3.2.
Other Comparisons of Interest
If one or both of the primary endpoints is considered statistically significant, inferences 
will be made from unadjusted p-values for treatment comparisons on secondary and 
other endpoints. If both co-primary treatment comparisons are statistically significant, 
these secondary and other treatment comparisons will be declared significant if the 
unadjusted p-value is <0.05.  If only one co-primary treatment comparison is 
statistically significant, these secondary and other treatment comparisons will be 
declared significant if the unadjusted p-value is <0.01.
Where strong control of type I error is required for secondary endpoints, multiplicity will 
be controlled using a hierarchical, closed testing procedure. The secondary hypothesis 
tests will be grouped sequentially in two blocks of two comparisons each, grouped 
according to specific clinical concepts (lung function and symptoms, and time-to-first 
exacerbation event). Each block of comparisons will also be adjusted for multiplicity 
using the truncated Hochberg method as described for the primary endpoint analysis, 
with a truncation parameter of γ=0.6 for the first block and a truncation parameter of γ=1 
for the second block.  
Within each block, at least one endpoint must be considered statistically significant in 
order to make inferences in the subsequent block.  For example, as shown in Figure 2 at 
least one of endpoints S1a and S1b would need to be significant in order to make 
inferences for the S2a/S2b comparisons contained in the next block.
Figure 2
Secondary endpoint hierarchy
Methods for handling missing data for summaries of the secondary efficacy endpoints 
will be detailed in the RAP.
8.3.4.
Interim Analysis
An Independent Data and Monitoring Committee (IDMC) will monitor progress of the 
study and ensure that it meets the highest standards of ethics and patient safety. Only the 
IDMC will be authorized to review unblinded interim safety analyses during the trial.

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This committee will be formed specifically to oversee trial progression with regards to 
occurrence of adverse events. The committee, which will comprise a minimum of 3 
people, will include an independent statistician and an independent respiratory clinician 
with experience in COPD and a cardiologist.
The unblinded periodic safety updates will be performed and delivered to the IDMC by 
an independent Statistical Data Analysis Centre (SDAC).
The IDMC will give a recommendation to the central study team as to whether the trial 
should be stopped prematurely following review of the interim results for safety. The 
central study team will decide whether to act on this recommendation.
In the event of early stopping, subjects will be brought to the investigational sites for a 
final visit, where possible. The final analysis will include all data collected up to and 
including the final visit.
Membership, functions and operating procedures of IDMC and other organisational 
groups for this study will be defined in a separate document. Operating procedures for the 
IDMC will be established before the first review of unblinded data.
8.3.5.
Key Elements of Analysis Plan
8.3.5.1.
Efficacy Analyses
The primary efficacy endpoint of the annual rate of on-treatment moderate and severe 
exacerbations will be analyzed using a generalized linear model assuming the negative 
binomial distribution, with the logarithm of time on treatment as an offset variable.  The 
model will include terms for treatment group, gender, exacerbation history (one, two or 
more), smoking status at screening, baseline disease severity (as % predicted FEV1) and 
geographical region.  The adjusted mean annual rates, pair-wise treatment ratios and 
associated p-values and confidence limits will be presented. The fit of the negative 
binomial model will be examined using “Q-Q” plots of standardized residuals with 
simulated envelopes.
For the co-primary endpoints, sensitivity analyses will be performed where all 
available data collected until the time of study withdrawal will be used. For these 
sensitivity analyses, the total number of events and the total time in the study (both 
on- treatment and post-treatment) prior to study withdrawal will be used in the 
analysis model. Imputations made for the period following study withdrawal will be 
described in the RAP. Additional sensitivity analyses using multiple imputation 
methods will be described in the RAP.
The secondary endpoints of trough (pre-dose AM) FEV1 and SGRQ total score will be 
analysed using mixed models repeated measures with covariates of treatment group, 
smoking status at screening, baseline, region, and visit, plus interaction terms for visit by
baseline and visit by treatment group.

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The secondary endpoints involving time to first moderate and/or severe exacerbation will 
compare the treatment groups using Cox’s proportional hazards model, adjusting for 
treatment group, gender, exacerbation history (one, two or more), smoking status at 
screening, baseline disease severity (as % predicted FEV1),  and geographical region. 
Secondary and other endpoints involving the annual rate of exacerbations will be 
analysed as described for the primary endpoint. 
The additional endpoint of time to onset of multiple moderate and severe exacerbations 
will be analysed using an Anderson-Gill model for time to recurrent events. 
Full details of the analyses to be performed on all primary, secondary and other efficacy 
endpoints will be given in the RAP.
8.3.5.2.
Safety Analyses
The extent of exposure to study drug will be summarized by treatment group, using the 
statistics n, mean, SD, median, minimum and maximum.
AEs and SAEs occurring pre-treatment, during active treatment and post-treatment will 
be summarized separately.  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, SAEs, and for AEs leading to permanent discontinuation of study 
drug or withdrawal from the study. 
Time to first event in the Pneumonia Adverse Event of Special Interest subgroup and 
time to first serious event in the Pneumonia Adverse Event of Special Interest subgroup 
will be analysed using Cox’s proportional hazards model. Deaths due to pneumonia will 
be summarised and tabulated.
Incidence of bone fractures will be summarised. Full details will be given in the RAP.
Incidence of cardiovascular events (including supraventricular arrhythmia and non-fatal 
myocardial infarction) will be summarised. 
All laboratory parameters will be summarised and tabulated. 
A pre-specified MACE analysis (broad analysis and narrow analysis) will be performed 
using adjudicated cardiovascular deaths and other non-fatal SAEs.  MACE events to be 
included in both the broad and narrow analysis would be defined a priori.
Full details of the analyses to be performed on all safety endpoints will be given in the 
RAP.
8.3.5.3.
Health Outcomes Analyses
Details of the analysis of all health care utilization endpoints will be specified in the 
RAP. 

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8.3.5.4.
Pharmacokinetic Analyses
The purpose of PK sampling in this study is for characterisation of patient population PK 
of FF, UMEC and VI.  Plasma concentration-time data for FF, UMEC and VI will be 
subjected separately to nonlinear mixed effects modelling using the program NONMEM 
to develop a population PK models. Full details of the analyses for PK endpoints will be 
provided in the RAP.
8.3.5.5.
Genetic Analyses
See Appendix 1 for details about the Genetics Analysis Plan.
8.3.5.6.
Novel Biomarker(s) Analyses
The results of these biomarker investigations will be reported separately from the main
clinical study report.  All endpoints of interest from all comparisons will be descriptively 
and/or graphically summarised as appropriate to the data.
9.
STUDY CONDUCT CONSIDERATIONS
9.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of subjects begins.
9.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a study 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.
The study will be conducted in accordance with ICH GCP, all applicable subject privacy 
requirements, and the ethical principles that are outlined in the Declaration of Helsinki 
2008, including, but not limited to:
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
favourable opinion/approval of study protocol and any subsequent amendments.
Subject informed consent.
Investigator reporting requirements.
GSK will provide full details of the above procedures, either verbally, in writing, or both.
Written informed consent must be obtained from each subject prior to participation in the 
study.

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In approving the clinical protocol the IEC/IRB and, where required, the applicable 
regulatory agency are also approving the optional assessments e.g., Genetics research 
assessments described in Appendix 1 unless otherwise indicated.  Where permitted by 
regulatory authorities, approval of the optional assessments can occur after approval is 
obtained for the rest of the study.  If so, then the written approval will clearly indicate 
approval of the optional assessments is being deferred and the study, except for the 
optional assessments, can be initiated.  When the optional assessments are not approved, 
then the approval for the rest of the study will clearly indicate this and therefore, the 
optional assessments will not be conducted.
9.3.
Quality Control (Study Monitoring)
In accordance with applicable regulations, 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 include 
identification, agreement and documentation of data items for which the CRF will serve 
as the source document.
GSK will monitor the study to ensure 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.
9.4.
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.
9.5.
Study and Site Closure
The end of study is when the last subject completes the last visit.
Upon completion or termination of the study, the GSK monitor will conduct site closure 
activities with the investigator or site staff (as appropriate), in accordance with applicable 
regulations, GCP, and GSK Standard Operating Procedures.

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GSK reserves the right to temporarily suspend or terminate the study at any time for 
reasons including (but not limited to) safety issues, ethical issues, or severe non-
compliance. If GSK determines that such action is required, GSK will discuss the reasons 
for taking such action with the investigator or head of the medical institution (where 
applicable).  When feasible, GSK will provide advance notice to the investigator or head 
of the medical institution of the impending action.
If a study is suspended or terminated for safety reasons, GSK will promptly inform all 
investigators, heads of the medical institutions (where applicable),and/or institutions 
conducting the study.  GSK will also promptly inform the relevant regulatory authorities 
of the suspension/termination along with the reasons for such action.  Where required by 
applicable regulations, the investigator or head of the medical institution must inform the 
IRB/IEC promptly and provide the reason(s) for the suspension/termination.
9.6.
Records Retention
Following closure of the study, the investigator or 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 easily accessible 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 the 
records may be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution must 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.  In addition, they must meet accessibility and retrieval standards, 
including regeneration of a hard copy, if required.  The investigator must also ensure that 
an acceptable back-up of the reproductions exists and that there is an acceptable quality 
control procedure in place for creating the reproductions.
GSK will inform the investigator of the time period for retaining the site records in order 
to comply with all applicable regulatory requirements.  The minimum retention time will 
meet the strictest standard applicable to a particular site, as dictated by local 
laws/regulations, GSK standard operating procedures, and/or institutional requirements.
The investigator must notify GSK of any changes in the archival arrangements, including, 
but not limited to archival of records at an off-site facility or transfer of ownership of the 
records in the event that the investigator is no longer associated with the site.
9.7.
Provision of Study Results to Investigators, Posting of 
Information on Publicly 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 

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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 results summary will be posted to the Clinical Study Register no later than eight 
months after the final primary completion date, the date that the final subject was 
examined or received an intervention for the purposes of final collection of data for the 
primary outcome.  In addition, a manuscript will be submitted to a peer reviewed journal 
for publication no later than 18 months after the last subject’s last visit (LSLV).  When 
manuscript publication in a peer reviewed journal is not feasible, a statement will be 
added to the register to explain the reason for not publishing.
9.8.
Independent Data Monitoring Committee (IDMC)
An IDMC will be utilised in this study to ensure external objective medical and/or 
statistical review of safety and/or efficacy data in order to protect the ethical and safety 
interests of subjects and to protect the scientific validity of the study.  In order to 
maintain blinding in communication with the IDMC, non-blinded persons separate from 
the study team (e.g. an unblinded statistician or data manager) will be appointed to 
provide required information to the IDMC.  The analysis plan for IDMC review is 
described in the charter, which is available upon request.
9.9.
Adjudication Committee
An adjudication committee will be established to independently review and categorize 
the cause of each Serious Adverse Event.  The committee members will remain blinded 
to treatment. The adjudication plan is described in the charter, which is available upon 
request.

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10.
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global lung function 2012 equations. European Respiratory Journal, 40(6), 1324-1343.
Short, PM, Williamson, PA, Elder, DHJ & IW Samuel. (2012) The Impact of Tiotropium 
on Mortality and Exacerbations When Added to Inhaled Corticosteroids and Long-Acting 
b -Agonist Therapy in COPD. Chest 141:81–86.

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Tashkin, DP. et al (2008) A 4-year Trial of Tiotropium in Chronic Obstructive 
Pulmonary Disease. N Engl J Med 2008 359:1543-1554.
Toy, Edmond L.; Beaulieu, U., Nicolas, McHale, Joshua M.; Welland, Timothy R.;
Plauschinat, Craig A.; Swensen, Andrine; Sheng Duh, Mei. Treatment of COPD: 
Relationships between daily dosing frequency, adherence, resource use, and costs
Respiratory Medicine (2011) 105:435-441
Wedzicha, Jadwiga; Decramer, Marc; et al. Analysis of Chronic Obstructive Pulmonary 
disease exacerbations with the dual bronchodilator QVA 149 compared with 
glycopyrronium and tiotropium (SPARK): A randomized, double-blind, parallel-group 
study. The Lancet Respiratory Medicine, Volume 1, Issue 3, pages 199-209, May 2013
doi:10. 1016/S2213-2600(13)70052-3
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.
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.
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 
Research Database. (2013) 29th International Conference on Pharmacoepidemiology and 
Therapeutic Risk Management, Montreal, Canada. Abstract 62. 
Yu, Andrew P.; Guerin, Annie; Ponce de Leon, Diego; Ramakrishnan, Karthik; Wu, Eric 
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outcomes of multiple versus single long-acting inhalers in COPD Respiratory Medicine 
(2011) 105; 1861-1871 

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11.
APPENDICES
11.1.
Appendix 1: Genetic research
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)/Vilanterol (VI); 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 clinical 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 
clinical 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 clinical study, can participate in genetic research.  Any 
subject who has received an allogeneic bone marrow transplant must be excluded from 
the genetic research.
Note: No study centers in China will participate in genetic research in this study.
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. 
Blood sample is collected at the baseline visit, after the subject has been 
randomized and provided informed consent for genetic research. If a subject 
initially declines to participate in genetic research and then changes their mind, a 
sample should be obtained at the earliest opportunity. Instructions for collection 

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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 inability to utilize the original sample.  
The genetic sample is labelled (or “coded”) with the same study specific number as 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 
clinical study.  Genetic informed consent must be obtained prior to any blood 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 
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 clinical study or after completion of the 
clinical study and may be analyzed during the clinical 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.  

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
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 clinical study, then the investigator 
should instruct the participant 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 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.

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11.2.
Appendix 2: Country Specific Requirements
In China only, Serious AEs will be recorded from the time the consent form is signed 
until the 7-day safety follow-up visit/telephone contact has been completed, or until Visit 
7(telephone contact) for subjects who have discontinued IP but continue in the study.
No study centers in China will participate in genetic research in this study.
11.2.1.
China-specific sub-study:  Collection of unit-cost data for 
healthcare utilization among COPD subjects recruited to Study 
CTT116855 in China
11.2.1.1.
Introduction
Globally, health economic (HE) evidence is becoming more and more critical to ensure 
that the value of new medicines is demonstrated and that patients with unmet need have
access to these new medicines.  In China, recent high-profile meetings, including 
Healthcare State Council meetings have highlighted the importance of generating HE 
evidence.  In line with this, the first health technology assessment (HTA) center, to 
evaluate the cost-effectiveness of drugs, was established in Zhejiang Province in 2014. It 
is expected that more and more HTA centers will be established in many other areas of
China in coming years. 
This China-specific sub-study will collect the unit cost data for healthcare utilization 
among COPD subjects recruited to Study CTT116855 (called the Core Study throughout 
this document) in China; through the use of a “modified healthcare resource utilization” 
(“Modified HRU”) paper diary.
11.2.1.2.
Objective
To collect unit cost data (direct and indirect) for healthcare utilization among COPD 
subjects recruited to Study CTT116855 in China
11.2.1.3.
Investigational Plan
This is a China-specific sub-study to collect direct and indirect unit cost  data for 
healthcare utilization in subjects who have consented and been randomized to study 
CTT116855 (Core Study), “A phase III, 52 week, randomized, double-blind, 3-arm 
parallel group study, comparing the efficacy, safety and tolerability of the fixed dose 
triple combination FF/UMEC/VI with the fixed dose dual combinations of FF/VI and 
UMEC/VI, all administered once-daily in the morning via a dry powder inhaler in 
subjects with chronic obstructive pulmonary disease”, in China.
Currently, subjects randomized to the Core Study complete a healthcare resource 
utilization (HRU) paper diary, when they have any contact with a health care provider.  
The current HRU paper diary, in the Core Study, does not require collection of the unit 

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cost (direct or indirect) for healthcare utilization.  For the purpose of this China-specific 
sub-study, subjects who are consented and randomized to the Core Study in China will 
complete a “modified healthcare resource utilization” (“Modified HRU”) paper diary.  
This “Modified HRU” paper diary will collect data in response to five additional 
questions (see Supplement 1), two of which relate to the direct costs of healthcare 
services used by a subject and three of which relate to the indirect costs of the subject’s 
COPD.  These questions are:
1.
Cost paid by the subject for each healthcare contact due to any health problem1
2.
Cost covered by health insurance for each healthcare contact due to any health 
problem2
3.
Days of work missed by the subject due to their COPD
4.
Hours of paid caregiver services due to the subject’s COPD
5.
Hours of work missed by family members/relatives due to the subject’s COPD 
Subjects of this sub-study will be issued the “Modified HRU” paper diary at scheduled 
visits starting from Visit 2, and will be required to record their answers to these questions 
on the paper diary between scheduled visits. 
All subjects who participate in this sub-study will be required to provide a separate 
consent to the use of the “Modified HRU” paper diary.  Subjects who do not consent or 
withdraw consent from this sub-study will continue to use the HRU (unmodified and 
without the additional questions relating to direct and indirect costs) paper diary, as per 
the Core Study.
11.2.1.4.
Subject Selection and Withdrawal Criteria
11.2.1.4.1.
Inclusion Criteria
Subjects eligible for enrolment in the study must meet all of the following criteria:
1.
Subjects in China, who have provided written informed consent and have been 
randomized to study CTT116855 (Core Study).
2.
Separate Informed Consent for China-specific sub-study:  A signed and dated 
separate written informed consent to the sub-study, to assess direct and indirect unit 
cost data, prior to participation in the sub-study is required.
11.2.1.4.2.
Exclusion Criteria
There are no exclusion criteria to this sub-study.
                                                
1, 2 Both of these are mutually exclusive and comprehensive.  Therefore the sums of 1 and 2 should equate 
to the total unit cost of healthcare resource used

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11.2.1.4.3.
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 sub-study, they will be 
encouraged to continue to use the HRU paper diary (unmodified and without the 
additional questions relating to direct and indirect costs) paper diary, as per the Core 
Study.
Discontinuation criteria from IP and withdrawal criteria from the Core Study will be dealt 
with as outlined in the Core Study protocol (CTT116855); Section 4.4.  Investigational 
Product (IP) Discontinuation Criteria.

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Supplement 1:
Modified Healthcare Resource Utilization Paper Diary (“Modified HRU”), page 1
Date of Healthcare 
Contact
Day Month Year
Type of Healthcare Contact
Reason for
Healthcare Contact
Cost paid
by
subject 
(Chinese 
Currency)
Cost paid
by 
insurance
(Chinese 
Currency)
Site 
validation
of reason
for contact*
(Site Use 
Only) 
Home 
Visits
Physician
Office/
Clinic 
Visits
Urgent 
Care/
Outpatient 
Clinic Visits
Accident 
and 
Emergency
Room
Visits
Inpatient 
Hospitalization
Day
Night
ICU
General
Ward
e.g., 15 MAR 14
√
Shortness of Breath
338.45
0
e.g., 15 MAR 14
√
Shortness of Breath
1000.00
7755.87
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
TOTAL (Site use only)
UK:ENG (United Kingdom/English)
* 1=COPD exacerbation; 2=COPD not exacerbation; 3=Other healthcare contact; 4=Not a healthcare contact

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Modified Healthcare Resource Utilization Paper Diary (“Modified HRU”) page 2 
Since your last scheduled visit, if you are currently having paid employment and you 
have to skip work, due to your COPD (e.g., feel breathless or chest tightness, cough, or 
wake up at night because of these and related complaints), please fill in this paper diary 
with the date(s) when you miss work and the number of days of work you miss each time.
Date
Day Month Year
Days of work you miss due to your COPD
(Days)
e.g. 15 July 2015 – 18 July 2015
3.5
Total (Site use only)

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Modified Healthcare Resource Utilization Paper Diary (“Modified HRU”) page 3
Since your last scheduled visit, if you pay someone to take care of you, due to your 
COPD (e.g., feel breathless or chest tightness, cough, or wake up at night because of 
these and related complaints), please fill in this paper diary with the date(s) when this 
happens and the number of hours of using such service each time. If you hire two or more 
persons to take care of you at the same time, please list the date(s) and hours of using 
each hired service separately. 
Date
Day Month Year
Hours using paid caregiver service due to 
your COPD
(Hours)
e.g. 17 July 2015 – 18 July 2015
6
Total (Site use only)

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Modified Healthcare Resource Utilization Paper Diary (“Modified HRU”) page 4 
Since your last scheduled visit, if your family members/relatives have to skip their work 
to take care of you, due to your COPD (e.g., feel breathless or chest tightness, cough, or 
wake up at night because of these and related complaints), please fill in this paper diary 
with the date(s) when this happens and the number of hours of work they miss each time. 
If two or more family members/relatives have to skip work to take care of you at the 
same time, please list the date(s) and hours of missed work by each individual separately.
Date
Day Month Year
Hours of work your family 
members/relatives miss when they take care 
of you due to your COPD
(Hours)
e.g. 19 July 2015
4
Total (Site use only)

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11.3.
Appendix 3: Liver Chemistry Stopping and Follow-up 
Criteria
Phase III-IV Liver Safety Algorithms
ALT>3xULN
plus 
bilirubin >2x 
ULN (>35%
direct) (or plus
INR >1.5, if   
measured)*
No
Yes
Yes
•Instruct subject to stop investigational product (IP)
•Notify GSK within 24h and arrange clinical followup 
within 24-72h
•Perform liver chemistries and liver event follow up 
assessments (serology, PK sample etc as in protocol) 
•Complete liver event CRF, SAE data collection tool if 
appropriate, and liver imaging and/or biopsy CRFs if  
tests performed.
•Obtain weekly liver chemistries [**as far as possible in 
these subjects] until resolved, stabilised or returned to 
baseline 
•Withdraw subject from study after monitoring 
complete unless protocol has option to restart drug
•Instruct subject to stop investigational product (IP)
•Notify GSK and arrange clinical followup within 24h
•Perform liver chemistries and liver event follow up 
assessments (serology, PK sample etc as in protocol) 
•Report as SAE (excl. hepatic impairment or cirrhosis 
studies) and complete liver event CRF, SAE data 
collection tool, and liver imaging and/or biopsy CRFs if 
tests performed.
•Obtain twice weekly liver chemistries until resolved, 
stabilised or returned to baseline values
•Consultation with hepatologist/specialist recommended
•Withdraw subject from study after monitoring 
complete unless protocol has option to restart drug
Hepatitis 
symptoms
or rash?
No
Able to 
monitor 
weekly for 
4 weeks?
Yes
No**
Yes
Continue IP
Obtain twice 
monthly liver 
chemistries until 
normalised or 
back to baseline 
values
Yes
Yes
ALT<3xULN 
+ bilirubin 
<2xULN 
after ≤ 4 
wks?
Yes
ALT 
>5xULN 
but 
<8xULN
No
ALT  
>8xULN
Yes
ALT >5 
and 
<8xULN 
for > 2 
wks
Yes
No
ALT>3xULN 
but <5xULN + 
bilirubin 
<2xULN+no 
symptoms
No
Able to 
monitor 
weekly for 
> 2 wks?
No
No
Notify GSK within 24h 
to discuss subject 
safety; continue IP;
check liver chemistry 
weekly for 4 weeks
Yes
No
*INR value not applicable to subjects on anticoagulants

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11.4.
Appendix 4: Laboratory Assessments
Refer to the Time and Events Table for information regarding the timing of laboratory 
tests.
CHEMISTRY
HEMATOLOGY 
OTHER
Albumin 
Hemoglobin
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
Biomarker of COPD 
(Fibrinogen)
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

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11.5.
Appendix 5: Protocol Changes
Revision History
2013N176913_00
2014-MAR-17
Original
2013N176913_01
2014-MAR-31
Amendment No.: 01
2013N176913_02
2014-APR-10
Amendment No.:02
2013N176913_03
2014-DEC-05
Amendment NO.:03 (China Only)
2013N176913_04
2015-MAY-12
Amendment NO.:04 (China Only)
2013N176913_05
2016-JUN-30
Amendment No.:05
11.5.1.
Amendment 1
Amendment 01 applies to all countries and study centers participating in the CTT116855 
study. Amendment 01 purpose is to clarify verbiage pertaining to approval status of 
products in the protocol and to also clarify information concerning hematology collection
and to correct minor errors in the Time and events table.   
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). 
In Section 3.2 Discussion of design (4th paragraph) wording was changed to clarify 
approval status of UMEC/VI and to be consistent with Section 1.3.3. Overall 
Benefit:Risk.
The FF/UMEC/VI dose was selected based on the doses that have been determined for 
the FF/VI and UMEC/VI dual combinations through extensive studies in the mono and 
dual therapy programs. The doses licensed and/or anticipated to be licensed by the FDA 
and Europe the EMA for FF/VI and UMEC/VI are 100mcg/25mcg and 62.5mcg/25mcg 
(equivalent to 92mcg/22mcg and 55mcg/22mcg delivered dose); respectively.
In Section 6 Study Assessment and Procedures (Table 4 Time and Events Table) In the 
Safety Assessments section of the T&E table there is an error in the ECG row in the Visit 
3 column. The visit 3 column mistakenly references the “i” table reference which 
provides additional information for vital signs. The “i” table reference has been changed 
to the “j’ table reference which provides the correct information on ECG collection 
timings.
Safety Assessments
Visit 0 Visit 1 Visit 2 Visit 3
Visit 4 Visit 5 Visit 6 Visit 7 IP discont
Safety follow-up
ECG
X
Xi j
X
X
X

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In Section 6 Study Assessment and Procedures (Table 4 Time and Events Table) In the 
Study Treatment section of the T&E table there is an error in the Dispense 
albuterol/salbutamol row in the Visit 7 column. Albuterol/salbutamol is not dispensed at 
Visit 7 therefore the “X” has been deleted from Visit 7 column.
Study Treatments
Visit 0 Visit 1 Visit 2
Visit 3
Visit 4 Visit 5
Visit 6
Visit 7 IP discont
Safety 
follow-up
Dispense 
albuterol/salbutamol
X
X
X
X
X
X
X
In Section 6.3.12 Laboratory Assessments (first paragraph) hematology collection at visit 
2 was inadvertently omitted.  Additional wording was added to be consistent with the 
Time and Events Table. 
Routine non-fasting clinical laboratory tests (hematology, chemistry), including serum 
glucose and serum potassium levels, will be performed at Screening (Visit 1) and at Week 
16, Week 28, and Week 52 (or IP Discontinuation Visit). Hepatitis B and C will be 
collected as part of the Screening Visit blood draw. Hematology (alone) will be collected 
at Visit 2. The Week 16 hematology blood draw will also be used to assess fibrinogen as 
an exploratory biomarker of COPD.
In Section 11.4 Appendix 4: Laboratory Assessment (in the table) “RBC count” was 
inadvertently omitted.  “RBC count” was added to the hematology column to correct the 
omission.
CHEMISTRY
HEMATOLOGY 
OTHER
Albumin 
Hemoglobin
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
Biomarker of COPD 
(Fibrinogen)
Phosphorus 
Potassium
Protein, total serum
Sodium
Urea nitrogen (BUN)
Uric Acid 

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11.5.2.
Amendment 2
Amendment 02 applies to all countries and study centers participating in the CTT116855 
study. Amendment 02 purpose was to add post-bronchodilator FEV1 to each visit and 
include this as an Other Efficacy Endpoint. A mortality endpoint was also added as an 
“Other Efficacy Endpoint”. Other changes included changing the predicted FEV1
reference values from NHANES III to the European Respiratory Society Global Lung 
Function Initiative and to correct minor errors in CAT, contraceptive methods, and ECG 
wording. In addition changes were made to correct minor errors and to clarify ambiguous 
wording.
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). 
In the List of Abbreviations there was an error in the abbreviation for EuroQol 
Questionnaire.
eCRF
Electronic Case Report Form
EQ-5D-5L
EuroQol Questionnaire
FEV1
Forced Expiratory Volume in One Second
In the Protocol Summary in the Study Design Section (second paragraph) wording was 
added to clarify that subjects usual COPD medications could only be used during the 2 
week run-in period. This change was also made to Section 3.1 Study design (fourth 
paragraph).
Subjects will sign the informed consent form (ICF) at a pre-screen or screening visit and 
will be assigned a subject identifier.  Subjects meeting all inclusion/exclusion criteria and 
who have successfully completed all protocol procedures at screening will enter the 2-
week run-in. Subjects will continue the use of their existing COPD medications during 
the run-in and in addition will be provided with short acting albuterol/salbutamol to be 
used on an as-needed basis (rescue medication) throughout the study.
In the Protocol Summary in the Study Design Section (sixth paragraph) wording was 
changed to clarify that subjects IP will be stopped at the IP Discontinuation visit. This 
change was also made to Section 3.1 Study design (eighth paragraph).
Subjects who wish to permanently discontinue from their IP should be encouraged to stay 
on their IP until they are able to return to complete the IP Discontinuation Visit. and their 
safety follow-up visit 7 days later.  After completing the IP Discontinuation Visit and the 
safety follow-up visit, subjects will be encouraged to continue in the study by 
participating in telephone contacts in order to assess exacerbations, serious adverse 
events (SAEs) and concomitant medications post-treatment.  
In the Protocol Summary, under Study Endpoints/Assessments, in the Other Efficacy 
Endpoints Section “Change from baseline in post-bronchodilator FEV1” and “Time to 

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death from any cause” were added as other endpoints.  These endpoints were also added 
to Section 6.2.3 “Other Efficacy endpoints”. 
Other Efficacy endpoints

Change from baseline in post-bronchodilator FEV1

Time to death from any cause

Responder rate based on the SGRQ Total Score 

Annual rate of all on-treatment exacerbations (mild, moderate, severe)
In Section 1.3.3 Overall Benefit:Risk Conclusion (second paragraph) a missing word was 
added. 
In the United States, the FF/VI combination is approved for the maintenance treatment
of airflow obstruction and for reduction of exacerbations in COPD. The UMEC/VI 
combination is approved for maintenance treatment of airflow obstruction in COPD.
In Section 4.2 Inclusion Criteria (Inclusion criteria 4; Gender) under “Child Bearing 
potential” in the seventh bullet (intrauterine device) erroneous wording was deleted.
Child bearing potential, has a negative pregnancy test at screening, and agrees to one 
of the following acceptable contraceptive methods used consistently and correctly 
(i.e. in accordance with the approved product label and the instructions of the 
physician for the duration of the study – screening to safety follow-up contact):

Abstinence 

Oral Contraceptive, either combined or progestogen alone

Injectable progestogen

Implants of levonorgestrel

Estrogenic vaginal ring

Percutaneous contraceptive patches

Intrauterine device (IUD) or intrauterine system (IUS) that meets the SOP 
effectiveness Criteria as stated in the product label.
In Section 4.2 Inclusion Criteria (Inclusion criteria 10; History of Exacerbations) the 
reference equations used for calculation of percent predicted were changed from 
NHANES III to the European Respiratory Society Global Lung Function Initiative.
History of Exacerbations: Subjects must demonstrate:
a post-bronchodilator FEV1 < 50% predicted normal and a documented history of ≥ 1 
moderate or severe COPD exacerbation in the previous 12 months
OR

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a post-bronchodilator 50% ≤FEV1 < 80% predicted normal and a  documented history of 
≥ 2 moderate exacerbations or a documented history of ≥1 severe COPD exacerbation 
(hospitalized) in the previous 12 months.
Note: Percent predicted will be calculated using the European Respiratory Society 
Global Lung Function Initiative NHANES III reference equations [Quanjer, 2012
Hankinson, 1999; Hankinson, 2010]
In Section 6 Study Assessment and Procedures (Table 4 Time and Events Table) In the 
Efficacy Assessments section of the T&E table (in the spirometry row) in both the T&E 
table and in the table reference, new wording was added to clarify that both pre and post 
spirometry will be captured at Visits 2-7. 
Efficacy Assessments
Visit 0 Visit 1 Visit 2
Visit 3
Visit 4 Visit 5
Visit 6
Visit 7 IP discont
Safety 
follow-up
Spirometry d
X
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Reversibility Testing e
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.
At Visits 2-7 (and the IP discontinuation visit) both pre and post-bronchodilator spirometry will be 
conducted. Pre-bronchodilator Sspirometry to be will be performed prior to taking morning dose of IP, 
between 6am and 11am and after withholding rescue albuterol/salbutamol for ≥4 hours. Post-
bronchodilator spirometry will be conducted (prior to taking morning dose of IP) approximately 10-30 
minutes after administering 4 puffs of albuterol/salbutamol. 
In Section 6.2.5 Spirometry Testing, wording was added to clarify that both pre and post 
spirometry would be captured at Visit 2-7. 
Spirometry measurements will be obtained using spirometry equipment that meets or 
exceeds the minimal performance recommendations of the ATS [Miller, 2005].  All 
subjects will have spirometry performed at Screening and each scheduled clinic visit 
during the treatment period.  At the screening visit both pre- and post-
albuterol/salbutamol spirometry measurements will be measured in order to assess 
eligibility and reversibility (see Section 6.2.5.1). At Visits 2-7 (and discontinuation of 
IP visit) both pre- and post-albuterol/salbutamol spirometry will be measured prior 
to the subject taking their morning dose of IP. For FEV1 and FVC determinations, at 
least 3 acceptable spirometry efforts (with no more than 8) should be obtained.
In Section 6.2.10 COPD Assessment Test (CAT) wording was changed to correct a 
mistake in how the range was defined.
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 

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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 impairmentmaximum impairment) to 5 (maximum impairmentno 
impairment) with a scoring range of 0-40. Higher scores indicate greater disease impact.
In Section 6.3.15 ECG wording was changed to correct the order of when an ECG was 
conducted in relation to vitals and spirometry.
All sites will use standardized ECG equipment provided by a centralized external vendor. 
A single 12-lead ECG and rhythm strip will be recorded after measurement of vital signs
and prior to spirometry.
In Section 10 References, the Hankinson references were deleted and Quanjer 2012 was 
added as the reference equations for calculation of percent predicted was changed from 
NHANES III to the European Respiratory Society Global Lung Function Initiative.
Hanania, HA et al. (2012) Benefits of adding fluticasone propionate/salmeterol to 
tiotropium in moderate to severe COPD. Resp. Med. 106: 91-101.
Hankinson JL, Kawut SM, Shahar E, Smith LJ, MD, Hinckley Stukovsky K, and Barr 
RG. Performance of American Thoracic Society-Recommended Spirometry Reference 
Values in a Multiethnic Sample of Adults: The Multi-ethnic Study of Antherosclerosis 
(MESA) Lung Study. Chest, 2010;137:138-45.
Hankinson JL. Odencrantz JR, Fedan KB. Spirometric reference values from a sample of 
the general US population. Am J Resp Crit Care Med. 1999;159:179-187.
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Protein Adducts in Adults with 
Acetaminophen Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37(8): 
1779-1784. 
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.
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E.  Quantification 
of Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates 
Different Patterns of Virological Response to Interferon Therapy in Chronically Infected 
Patients.  J Clin Microbiol. 2005;43(5):2363–2369. 

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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.
Mullerova H, Locantore N, Jones P. GOLD assessment of COPD patients: impact of 
symptoms assessment choice.[abstract]. Eur Respir J. 2012;40(Suppl 56): 279s.
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.
Short, PM, Williamson, PA, Elder, DHJ & IW Samuel. (2012) The Impact of Tiotropium 
on Mortality and Exacerbations When Added to Inhaled Corticosteroids and Long-Acting 
b -Agonist Therapy in COPD. Chest 141:81–86.
11.5.3.
Amendment 3
This country specific protocol amendment 03 applies to all study centers in China.
Reason for protocol amendment 03:
This amendment is written to meet the requirements of the China Good Clinical Practice 
(GCP) of Pharmaceutical Products. This amendment is specific to China that Serious AEs 
will be recorded from the time the consent form is signed until the 7-day safety follow-up 
visit/telephone contact has been completed, or until Visit 7(telephone contact) for 
subjects who have discontinued IP but continue in the study.
Section 6. STUDY ASSESSMENTS AND PROCEDURES, Table 4 Time and Events
An asterisk (*) was added to the row that contains “Adverse Events Assessment” and an 
additional note was added at the bottom of the T&E table to define the asterisk.
Original text:
NOTE: Subjects who have permanently discontinued IP (and have not withdrawn 
consent) will complete the discontinuation IP visit and the safety follow-up contact and 
then will continue in the study to complete all remaining per protocol scheduled visits by 
phone contact to collect Exacerbations, SAEs and Concomitant Medications. 
Amended text:
NOTE: 
1. Subjects who have permanently discontinued IP (and have not withdrawn 
consent) will complete the discontinuation IP visit and the safety follow-up 
contact and then will continue in the study to complete all remaining per protocol 

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scheduled visits by phone contact to collect Exacerbations, SAEs and 
Concomitant Medications. 
2. * In China only, Serious AEs will be recorded from the time the consent form is 
signed until the 7-day safety follow-up visit/telephone contact has been 
completed, or until Visit 7(telephone contact) for subjects who have discontinued 
IP but continue in the study.
Reason for change:
This requirement is in accordance to new China GCP regulations, where the definition of 
SAE in the Chinese GCP regulations note: “A Serious Adverse Event includes inpatient 
hospitalization, prolongation of hospitalization, disability/incapacity, effect on work 
capability, life threatening, death, congenital anomaly etc., which occur during a clinical 
trial.”

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Section 6.3.9. Time Period and Frequency of Detecting AEs and SAEs
Additional text:
NOTE: In China only, Serious AEs will be recorded from the time the consent form is 
signed until the 7-day safety follow-up visit/telephone contact has been completed, or 
until Visit 7(telephone contact) for subjects who have discontinued IP but continue in the 
study.
Reason for change:
This requirement is in accordance to new China GCP regulations, where the definition of 
SAE in the Chinese GCP regulations note: “A Serious Adverse Event includes inpatient 
hospitalization, prolongation of hospitalization, disability/incapacity, effect on work 
capability, life threatening, death, congenital anomaly etc., which occur during a clinical 
trial.”
Section 11.2 Appendix 2: Country Specific Requirements
Additional text:
In China only, Serious AEs will be recorded from the time the consent form is signed 
until the 7-day safety follow-up visit/telephone contact has been completed, or until Visit 
7 (telephone contact) for subjects who have discontinued IP but continue in the study.
Reason for change:
This requirement is in accordance to new China GCP regulations, where the definition of 
SAE in the Chinese GCP regulations note: “A Serious Adverse Event includes inpatient 
hospitalization, prolongation of hospitalization, disability/incapacity, effect on work 
capability, life threatening, death, congenital anomaly etc., which occur during a clinical 
trial.”

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11.5.4.
Amendment 4
This country specific protocol amendment applies to all study centers in China.
Amendment 04 purpose was to:
Clarify that no study centers in China will participate in genetic research in this study.
The reason for change is that due to a new interpretation of Chinese regulations, the main 
study cannot be initiated until the pharmacogenetic research portion obtained a permit 
from the Human Genetic Resource Administration of China (HGRAC). This would incur 
a substantial delay to the start of the study in China and prevent China from being able to 
recruit a sufficient number of subjects into the study. Therefore, China will not 
participate in the pharmacogenetic research portion of the study.
The addition of a China-specific sub-study to collect the unit-cost data for healthcare 
utilization among subjects recruited in China.
The specific areas where changes were made to the protocol are listed below.
Section 6. STUDY ASSESSMENTS AND PROCEDURES, Table 4 Time and Events
Original text:
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.
o. Genetic consent must be obtained prior to obtaining a blood sample.
Amended text:
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. No study centers in China will 
participate in genetic research in this study.
o. Genetic consent must be obtained prior to obtaining a blood sample. No study centers 
in China will participate in genetic research in this study.
Section 6. 6. Genetic Research
Original text:
Information regarding genetic research is included in Appendix 1.
Amended text:
Information regarding genetic research is included in Appendix 1.
Note: No study centers in China will participate in genetic research in this study.

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Section 11.1. Appendix 1: Genetic Research
Original text:
Study Population
Any subject who is enrolled in the clinical study, can participate in genetic research.  Any 
subject who has received an allogeneic bone marrow transplant must be excluded from 
the genetic research.
Amended text:
Study Population
Any subject who is enrolled in the clinical study, can participate in genetic research.  Any 
subject who has received an allogeneic bone marrow transplant must be excluded from 
the genetic research.
Note: No study centers in China will participate in genetic research in this study.
Section 11.2 Appendix 2: Country Specific Requirements
Original text:
In China only, Serious AEs will be recorded from the time the consent form is signed 
until the 7-day safety follow-up visit/telephone contact has been completed, or until Visit 
7(telephone contact) for subjects who have discontinued IP but continue in the study.
Amended text:
In China only, Serious AEs will be recorded from the time the consent form is signed 
until the 7-day safety follow-up visit/telephone contact has been completed, or until Visit 
7(telephone contact) for subjects who have discontinued IP but continue in the study.
No study centers in China will participate in genetic research in this study.

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11.2.1
China-specific sub-study:  Collection of unit-cost data for 
healthcare utilization among COPD subjects recruited to 
Study CTT116855 in China
11.2.1.1
Introduction
Globally, health economic (HE) evidence is becoming more and more critical to ensure 
that the value of new medicines is demonstrated and that patients with unmet need have 
access to these new medicines.  In China, recent high-profile meetings, including 
Healthcare State Council meetings have highlighted the importance of generating HE 
evidence.  In line with this, the first health technology assessment (HTA) center, to 
evaluate the cost-effectiveness of drugs, was established in Zhejiang Province in 2014. It 
is expected that more and more HTA centers will be established in many other areas of
China in coming years. 
This China-specific sub-study will collect the unit cost data for healthcare utilization 
among COPD subjects recruited to Study CTT116855 (called the Core Study throughout 
this document) in China; through the use of a “modified healthcare resource utilization” 
(“Modified HRU”) paper diary.
11.2.1.2
Objective
To collect unit cost data (direct and indirect) for healthcare utilization among COPD 
subjects recruited to Study CTT116855 in China
11.2.1.3
Investigational Plan
This is a China-specific sub-study to collect direct and indirect unit cost  data for 
healthcare utilization in subjects who have consented and been randomized to study 
CTT116855 (Core Study), “A phase III, 52 week, randomized, double-blind, 3-arm 
parallel group study, comparing the efficacy, safety and tolerability of the fixed dose 
triple combination FF/UMEC/VI with the fixed dose dual combinations of FF/VI and 
UMEC/VI, all administered once-daily in the morning via a dry powder inhaler in 
subjects with chronic obstructive pulmonary disease”, in China.
Currently, subjects randomized to the Core Study complete a healthcare resource 
utilization (HRU) paper diary, when they have any contact with a health care provider.  
The current HRU paper diary, in the Core Study, does not require collection of the unit 
cost (direct or indirect) for healthcare utilization.  For the purpose of this China-specific 
sub-study, subjects who are consented and randomized to the Core Study in China will 
complete a “modified healthcare resource utilization” (“Modified HRU”) paper diary.  
This “Modified HRU” paper diary will collect data in response to five additional 
questions (see Supplement 1), two of which relate to the direct costs of healthcare 
services used by a subject and three of which relate to the indirect costs of the subject’s 
COPD.  These questions are:

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1.
Cost paid by the subject for each healthcare contact due to any health problem 1
2.
Cost covered by health insurance for each healthcare contact due to any health 
problem 2
3.
Days of work missed by the subject due to their COPD
4.
Hours of paid caregiver services due to the subject’s COPD
5.
Hours of work missed by family members/relatives due to the subject’s COPD
Subjects of this sub-study will be issued the “Modified HRU” paper diary at scheduled 
visits starting from Visit 2, and will be required to record their answers to these questions 
on the paper diary between scheduled visits. 
All subjects who participate in this sub-study will be required to provide a separate 
consent to the use of the “Modified HRU” paper diary.  Subjects who do not consent or 
withdraw consent from this sub-study will continue to use the HRU (unmodified and 
without the additional questions relating to direct and indirect costs) paper diary, as per 
the Core Study.
11.2.1.4
Subject Selection and Withdrawal Criteria
11.2.1.4.1
Inclusion Criteria
Subjects eligible for enrolment in the study must meet all of the following criteria:
1.
Subjects in China, who have provided written informed consent and have been 
randomized to study CTT116855 (Core Study).
2.
Separate Informed Consent for China-specific sub-study:  A signed and dated 
separate written informed consent to the sub-study, to assess direct and indirect unit 
cost data, prior to participation in the sub-study is required.
11.2.1.4.2
Exclusion Criteria
There are no exclusion criteria to this sub-study.
11.2.1.4.3
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.
1, 2 Both of these are mutually exclusive and comprehensive.  Therefore the sums of 1 and 2 should equate
to the total unit cost of healthcare resource used

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In the event that a subject withdraws consent from this sub-study, they will be 
encouraged to continue to use the HRU paper diary (unmodified and without the 
additional questions relating to direct and indirect costs) paper diary, as per the Core 
Study.
Discontinuation criteria from IP and withdrawal criteria from the Core Study will be dealt 
with as outlined in the Core Study protocol (CTT116855); Section 4.4.  Investigational 
Product (IP) Discontinuation Criteria.

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Supplement 1:
Modified Healthcare Resource Utilization Paper Diary (“Modified HRU”), page 1
Date of Healthcare 
Contact
Day Month Year
Type of Healthcare Contact
Reason for
Healthcare Contact
Cost paid
by
subject 
(Chinese 
Currency)
Cost paid
by 
insurance
(Chinese 
Currency)
Site 
validation
of reason
for contact*
(Site Use 
Only) 
Home 
Visits
Physician
Office/
Clinic 
Visits
Urgent 
Care/
Outpatient 
Clinic Visits
Accident 
and 
Emergency
Room
Visits
Inpatient 
Hospitalization
Day
Night
ICU
General
Ward
e.g., 15 MAR 14
√
Shortness of Breath
338.45
0
e.g., 15 MAR 14
√
Shortness of Breath
1000.00
7755.87
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
TOTAL (Site use only)
UK:ENG (United Kingdom/English)
* 1=COPD exacerbation; 2=COPD not exacerbation; 3=Other healthcare contact; 4=Not a healthcare contact

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Modified Healthcare Resource Utilization Paper Diary (“Modified HRU”) page 2 
Since your last scheduled visit, if you are currently having paid employment and you 
have to skip work, due to your COPD (e.g., feel breathless or chest tightness, cough, or 
wake up at night because of these and related complaints), please fill in this paper diary 
with the date(s) when you miss work and the number of days of work you miss each time.
Date
Day Month Year
Days of work you miss due to your COPD
(Days)
e.g. 15 July 2015 – 18 July 2015
3.5
Total (Site use only)

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Modified Healthcare Resource Utilization Paper Diary (“Modified HRU”) page 3
Since your last scheduled visit, if you pay someone to take care of you, due to your 
COPD (e.g., feel breathless or chest tightness, cough, or wake up at night because of 
these and related complaints), please fill in this paper diary with the date(s) when this 
happens and the number of hours of using such service each time. If you hire two or more 
persons to take care of you at the same time, please list the date(s) and hours of using 
each hired service separately. 
Date
Day Month Year
Hours using paid caregiver service due to 
your COPD
(Hours)
e.g. 17 July 2015 – 18 July 2015
6
Total (Site use only)

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Modified Healthcare Resource Utilization Paper Diary (“Modified HRU”) page 4 
Since your last scheduled visit, if your family members/relatives have to skip their work 
to take care of you, due to your COPD (e.g., feel breathless or chest tightness, cough, or 
wake up at night because of these and related complaints), please fill in this paper diary 
with the date(s) when this happens and the number of hours of work they miss each time. 
If two or more family members/relatives have to skip work to take care of you at the 
same time, please list the date(s) and hours of missed work by each individual separately.
Date
Day Month Year
Hours of work your family 
members/relatives miss when they take care 
of you due to your COPD
(Hours)
e.g. 19 July 2015
4
Total (Site use only)

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11.5.5.
Amendment 5
Amendment 05 applies to all countries and study centers participating in the CTT116855 
study.  Amendment 05 purpose was to simplify the statistical hierarchy for the analysis of 
secondary endpoints.  In addition, there are minor changes to the definitions of the 
Analysis populations, changes in model terms that will be included in the primary 
efficacy endpoint analysis and clarification on the primary endpoint sensitivity analyses.
For the safety analysis there were minor changes to clarify the analyses of Pneumonia 
Adverse events and MACE events.   
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). 
In Section 8.3.1 Analysis Populations the All Subjects Screened Population was deleted 
and the ITT Population definition was clarified.

All Subjects Enrolled Population: This population includes all subjects for whom a 
record exists on the study database, including screened subjects and subjects who 
were not screened but signed an ICF. This population will be used for the summary 
of subject disposition and the listing of SAEs for non-randomised subjects.

All Subjects Screened Population: This population contains all subjects screened and 
attending Visit 1. This population will be used for the summary of reasons for non-
randomisation.

Intent-to-Treat (ITT) Population: The ITT Population will comprise all subjects 
randomised to treatment apart from those randomised in error. A subject who is 
recorded as a screen or run-in failure and also randomised, but did not receive 
a dose of study treatment, will be considered to be randomised in error. Any 
other subject who receives a randomisation number will be considered to have 
been randomised. and who have received at least one dose of double-blind 
medication.  Randomised subjects will be assumed to have received double-blind 
medication unless definitive evidence to the contrary exists. The ITT Population is 
the primary analysis population of interest. 

Pharmacokinetic (PK) Population: The PK Population will comprise the subset of 
subjects in the ITT Population for whom a PK sample was obtained and analyzed. 
This population will be used for all concentration-time and PK parameter tables, 
listings and figures.
In Section 8.3.3.1 Primary Comparisons of Interest the fifth paragraph on sensitivity 
analysis was deleted and was moved to Section 8.3.5.1 Efficacy Analysis.
The primary comparisons of interest will be the pair-wise comparisons of 
FF/UMEC/VI against FF/VI and FF/UMEC/VI against UMEC/VI. The primary
comparisons will be tested for the primary endpoint, the annual rate of on-treatment 
moderate and severe exacerbations.

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The primary analysis will be based on a two-sided hypothesis testing approach. The 
hypotheses associated with the statistical test of the primary efficacy endpoint are H0: 
λT/λD=1 versus HA:  λT/λD≠1 where λT is the annual rate for triple therapy
(FF/UMEC/VI) and λD is the annual rate for the respective dual therapies (FF/VI and 
UMEC/VI).
Both primary comparisons will be tested using the ITT population.  In order to account 
for multiplicity, the truncated Hochberg procedure [Dmitrienko, 2008] with a 
truncation parameter of γ=0.6 will be used to control overall Type I error at α=0.05.
For the primary comparisons, both comparisons will be declared statistically significant 
if the p-value for both comparisons is significant at the 0.04 level.  Should the largest p-
value for the two comparisons be above 0.04, the other comparison will be declared
statistically significant if the smaller p-value is below 0.025.  If at least one of 
the comparisons is significant, this will allow inference of secondary endpoints.
For the co-primary efficacy endpoints, sensitivity analyses will be performed where all 
available data collected until the time of study withdrawal will be used. For these 
sensitivity analyses, the total number of events and the total time in the study (both on-
treatment and post-treatment) prior to study withdrawal will be used in the primary 
analysis model.
In Section 8.3.3.2 Other Comparisons of Interest the text was modified to amend how 
multiplicity will be controlled using a hierarchical closed testing procedure.  The 
secondary hypothesis tests were amended from being grouped in four blocks to only two 
blocks of two comparisons, each grouped according to specific clinical concepts.
If one or both of the primary endpoints is considered statistically significant, inferences 
will be made for secondary hypotheses from unadjusted p-values for treatment 
comparisons on secondary and other endpoints. If both co-primary treatment 
comparisons are statistically significant, these secondary and other treatment 
comparisons will be declared significant if the unadjusted p-value is <0.05.  If 
only one co-primary treatment comparison is statistically significant, these 
secondary and other treatment comparisons will be declared significant if the 
unadjusted p-value is <0.01. The secondary hypothesis tests will be grouped 
sequentially in four blocks, with each block of comparisons also adjusted using the 
truncated Hochberg method as described for the primary endpoint analysis.  Note that 
the significance level required for each block within the secondary hierarchy will 
depend on whether one or both comparisons were significant at the prior step.
The comparisons within each block have been grouped according to specific clinical 
concepts (lung function and symptoms, time-to-first exacerbation event, endpoints 
specific to the subgroup with raised eosinophils, COPD hospitalizations in all subjects).
Where strong control of type I error is required for secondary endpoints, 
multiplicity will be controlled using a hierarchical, closed testing procedure. The 
secondary hypothesis tests will be grouped sequentially in two blocks of two 
comparisons each, grouped according to specific clinical concepts (lung function and 

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symptoms, and time-to-first exacerbation event). Each block of comparisons will 
also be adjusted for multiplicity using the truncated Hochberg method as described 
for the primary endpoint analysis, with a truncation parameter of γ=0.6 for the first 
block and a truncation parameter of γ=1 for the second block.
Within each block, at least one endpoint must be considered statistically significant in 
order to make inferences in the subsequent block.  For example, as shown in Figure 2 at 
least one of endpoints S1a and S1b would need to be significant in order to make 
inferences for the S2a/S2b comparisons contained in the next block.
In Section 8.3.3.2 Other Comparisons of Interest Figure 2 Secondary endpoint hierarchy
was modified by deleting block 3 and block 4 from the figure and deleting the paragraph 
directly below the figure.

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Original Figure 2 and text:
Figure 2
Secondary endpoint hierarchy
Should the gate-keeping fail at any step in the testing hierarchy, p-values for the 
remaining secondary endpoints will be provided for evaluation outside the context of 
multiplicity adjustment. Other efficacy endpoints not listed as part of the primary and 
secondary endpoint hierarchy will be evaluated without multiplicity adjustment.
Methods for handling missing data for summaries of the secondary efficacy endpoints 
will be detailed in the RAP.
Amended Figure 2 and text:
Figure 2
Secondary endpoint hierarchy
Should the gate-keeping fail at any step in the testing hierarchy, p-values for the 
remaining secondary endpoints will be provided for evaluation outside the context of 
multiplicity adjustment. Other efficacy endpoints not listed as part of the primary and 
secondary endpoint hierarchy will be evaluated without multiplicity adjustment.

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Methods for handling missing data for summaries of the secondary efficacy 
endpoints will be detailed in the RAP.
In Section 8.3.5.1 Efficacy Analyses the text was modified to remove from the model the 
term “screening blood eosinophil levels” that was erroneously included in the proposed 
primary efficacy endpoint analysis and the secondary time to first moderate and /or 
severe exacerbation analysis.  In addition, for the co-primary endpoints sensitivity 
analyses the text was modified to exclude a supporting analysis of the rate of 
exacerbations based on quarterly intervals.
The primary efficacy endpoint of the annual rate of on-treatment moderate and severe 
exacerbations will be analyzed using a generalized linear model assuming the negative 
binomial distribution, with the logarithm of time on treatment as an offset variable. The 
model will include terms for treatment group, gender, exacerbation history (one, two or 
more), smoking status at screening, baseline disease severity (as % predicted FEV1), 
screening blood eosinophil level and geographical region.  The adjusted mean annual 
rates, pair-wise treatment ratios and associated p-values and confidence limits will be 
presented. The fit of the negative binomial model will be examined using “Q-Q” plots of 
standardized residuals with simulated envelopes.
For the co-primary endpoints, sensitivity analyses will be performed where all 
available data collected until the time of study withdrawal will be used. For these 
sensitivity analyses, the total number of events and the total time in the study
(both on- treatment and post-treatment) prior to study withdrawal will be used 
in the analysis model. Imputations made for the period following study 
withdrawal will be described in the RAP. Additional sensitivity analyses using 
multiple imputation methods will be described in the RAP.
For the purpose of analysis of the exacerbations, data will not be imputed.  The method of 
analysis incorporates the length of time that each individual subject received treatment.  
However, for summaries of raw exacerbation rate data the number of exacerbations for 
subjects who withdraw prior to the end of treatment will be imputed to prevent 
unreasonably high values.  Details of the imputation method will be described in the 
RAP.
In addition to the sensitivity analysis using any post-treatment data collected from 
subjects during the study, the pattern of missing data due to study withdrawals will be 
examined to determine if the missing data at random assumption for the analysis of 
exacerbation rate is met. To further examine any effect of study withdrawals, a 
supporting analysis of the rate of exacerbations will be performed on <1-year intervals 
(e.g, quarterly intervals), and study withdrawals will also be presented in graphical 
display (e.g., Kaplan-Meier plot of study withdrawals).
The secondary endpoints of trough (pre-dose AM) FEV1 and SGRQ total score will be 
analysed using mixed models repeated measures with covariates of treatment group, 
smoking status at screening, baseline, region, and visit, plus interaction terms for visit 
by baseline and visit by treatment group.

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The secondary endpoints involving time to first moderate and/or severe exacerbation 
will compare the treatment groups using Cox’s proportional hazards model, adjusting 
for treatment group, gender, exacerbation history (one, two or more), smoking status at 
screening, baseline disease severity (as % predicted FEV1), screening blood eosinophil 
level and geographical region.
Secondary and other endpoints involving the annual rate of exacerbations will 
be analysed as described for the primary endpoint.
The additional endpoint of time to onset of multiple moderate and severe 
exacerbations will be analysed using an Anderson-Gill model for time to recurrent 
events.
Full details of the analyses to be performed on all primary, secondary and other 
efficacy endpoints will be given in the RAP.
In Section 8.3.5.2 Safety Analyses the text was modified to clarify analysis of pneumonia 
events and MACE analysis. 
The extent of exposure to study drug will be summarized by treatment group, using the 
statistics n, mean, SD, median, minimum and maximum.
AEs and SAEs occurring pre-treatment, during active treatment and post-treatment will 
be summarized separately.  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, SAEs, and for AEs leading to permanent discontinuation of study 
drug or withdrawal from the study. 
Time to first event in the pPneumonia Adverse Event of Special Interest subgroup and 
time to first hospitalisation for serious event in the pPneumonia Adverse Event of 
Special Interest subgroup will be analysed using Cox’s proportional hazards model. 
Deaths due to pneumonia will be summarised and tabulated.
Incidence of bone fractures will be summarised. Full details will be given in the RAP.
Incidence of cardiovascular events (including supraventricular arrhythmia and non-fatal 
myocardial infarction) will be summarised. 
All laboratory parameters will be summarised and tabulated. 
A pre-specified MACE analysis (broad analysis and narrow analysis) will be performed 
using data from the adjudicated cardiovascular deaths and other non-fatal SAEs.  
MACE events to be included in both the broad and narrow analysis would be defined a 
priori.
Full details of the analyses to be performed on all safety endpoints will be given in the 
RAP.