Clinical trial NCT02164513
Conditions: Pulmonary Disease, Chronic Obstructive
Keywords: COPD umeclidinium fluticasone furoate vilanterol triple therapy exacerbation
Sponsor: GlaxoSmithKline
Start date: 2014-06-30; Completion date: 2017-07-17
Enrollment: 10355 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study evaluates the efficacy of fluticasone furoate/umeclidinium bromide/vilanterol (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. Published studies which assessed the use of an 'open' triple therapy (use of Inhaled Corticosteroid \[ICS\]/ Long-acting Muscarinic Receptor Antagonists \[LAMA\])/ Long Acting Beta-Agonist \[LABA\] delivered via multiple inhalers) in moderate-severe COPD patients, reported improvements in lung function, Health Related Quality of Life (HRQoL), hospitalization rates and rescue medication use, compared to dual therapy (ICS/LABA) or LAMA alone. These studies have also shown similar safety profile with dual or monotherapy doses for periods of up to one year. 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 (delivered via one inhaler). In the current study subjects meeting all inclusion/exclusion criteria will complete 2-week run-in period; 52 week treatment period and a 1-week safety follow-up period. Eligible subjects will be randomized to one of the following double-blind treatment groups FF/UMEC/VI 100 micrograms (mcg)/62.5 mcg/25 mcg once daily (QD), FF/VI 100 mcg/25 mcg QD, or UMEC/VI 62.5 mcg/25 mcg QD

Detailed description:

Arms: arm 1: Eligible Subjects completing 2-weeks run-in period will receive FF/UMEC/VI 100 mcg/62.5 mcg/25 mcg QD (morning) for a period of 52 weeks via DPI arm 2: Eligible Subjects completing 2-weeks run-in period will receive FF/VI 100 mcg/25 mcg QD (morning) for a treatment period of 52 weeks via DPI) arm 3: Eligible Subjects completing 2-weeks run-in period will receive UMEC/VI 62.5 mcg/25 mcg QD (morning) for a treatment period of 52 weeks via DPI
Interventions: intervention 1: fluticasone furoate (FF) intervention 2: vilanterol (VI) intervention 3: umeclidinium bromide (UMEC)
Intervention descriptions: intervention 1: FF will be available in combination as dry powder for inhalation as FF/UMEC/VI 100 mcg/62.5 mcg/25 mcg and FF/VI 100 mcg/25 mcg intervention 2: VI will be available in combination as dry powder for inhalation as FF/UMEC/VI 100 mcg/62.5 mcg/25 mcg, FF/VI 100 mcg/25 mcg and UMEC/VI 62.5 mcg/25 mcg intervention 3: UMEC will be available in combination as dry powder for inhalation as FF/UMEC/VI 100 mcg/62.5 mcg/25 mcg, and UMEC/VI 62.5 mcg/25 mcg

Protocol documents:
Prot_000.pdf: 
2013N176913_05
CONFIDENTIAL
The GlaxoSmithKline group of companies
CTT116855
1
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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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.


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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 
participation.


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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 
producing an overall summary score, scores for the individual domains of symptoms, 


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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 
UMEC/VI).


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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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Han MK, Muellerova H, Currran-Everet D, et al. GOLD 2011 disease severity 
classification in COPDGene: a prospective cohort study. The Lancet Res Med 2013; Mar 
1(1):43-50 doi: 10.1016/S2213-2600 (12)70044-9. Epub 2012 Sep 3.
Hanania, HA et al. (2012) Benefits of adding fluticasone propionate/salmeterol to 
tiotropium in moderate to severe COPD. Resp. Med. 106: 91-101.
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. 
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.


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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 
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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.

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
CTT116855
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for 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 (GSK573719+GW642444+GW685698)
Effective Date 
:
14-JUL-2017
Description :

The purpose of this Reporting and Analysis Plan (RAP) is to describe the planned 
analyses and output to be included in the Clinical Study Report (CSR) for Protocol 
CTT116855.

This RAP is intended to describe the planned efficacy, safety and health outcomes 
analyses required for the study.

This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable.
Author’s Name and Functional Area: 
Statistics Leader, RD PCPS Qsci Clinical Statistics
Approved by: 
14-JUL-2017
Senior Statistics Director, RD PCPS Qsci Clinical Statistics
14-JUL-2017
Programming Manager, RD PCPS Qsci Clinical Statistics
Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorized copying or use of this information is prohibited.
 
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TABLE OF CONTENTS
PAGE
1.
REPORTING & ANALYSIS PLAN SYNPOSIS.........................................................7
2.
SUMMARY OF KEY PROTOCOL INFORMATION ................................................12
2.1.
Changes to the Protocol Defined Statistical Analysis Plan..........................12
2.2.
Study Objectives and Endpoints .................................................................14
2.3.
Study Design ..............................................................................................18
2.4.
Statistical Hypotheses.................................................................................19
3.
PLANNED ANALYSES ..........................................................................................20
3.1.
Interim Analyses .........................................................................................20
3.2.
Final Analyses ............................................................................................20
4.
ANALYSIS POPULATIONS ...................................................................................20
4.1.
Protocol Deviations.....................................................................................21
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................22
5.1.
Handling of Data from Subset Populations..................................................22
5.2.
Handling of Data Collected After Study Treatment Discontinuation.............22
5.3.
Overview of Appendices .............................................................................23
6.
STUDY POPULATION ANALYSES .......................................................................24
6.1.
Overview of Planned Analyses ...................................................................24
6.1.1.
Disposition...................................................................................25
6.1.2.
Disease Characteristics ...............................................................25
6.1.3.
Concomitant Medications.............................................................26
6.1.4.
Treatment Compliance.................................................................26
6.1.5.
Percent Oxygen in Blood .............................................................26
7.
PRIMARY EFFICACY STATISTICAL ANALYSES .................................................27
7.1.
Overview of Planned Efficacy Analyses for the Primary Endpoint...............27
7.1.1.
COPD Exacerbations...................................................................28
7.2.
Planned Primary Statistical Analyses for Primary Endpoint.........................28
7.3.
Planned Supportive and Sensitivity Statistical Analyses .............................29
7.3.1.
Supportive Analyses ....................................................................29
7.3.1.1.
Poisson Model............................................................29
7.3.1.2.
Investigation of Interactions........................................30
7.3.2.
Sensitivity Analyses – Investigating Missing Data........................30
7.3.2.1.
Including both On and Off-treatment Data ..................30
7.3.2.2.
Jump to Reference (J2R) - Using On-treatment 
Data ...........................................................................31
7.3.2.3.
Jump to Reference (J2R) - Using On and Off-
treatment Data............................................................32
8.
SECONDARY EFFICACY STATISTICAL ANALYSES ...........................................32
8.1.
Overview of Planned Efficacy Analyses for Secondary Endpoints ..............32
8.2.
Trough FEV1 and SGRQ Total Score.........................................................34
8.2.1.
Planned Primary Statistical Analyses for Trough FEV1 and 
SGRQ Total Score.......................................................................34
 
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8.2.2.
Planned Sensitivity Statistical Analyses for Trough FEV1 
and SGRQ Total Score................................................................36
8.2.2.1.
Jump to Reference - Using On-treatment Data...........36
8.3.
Time to First COPD Moderate/Severe Exacerbation...................................37
8.3.1.
Planned Primary Statistical Analyses for Time to First On-
treatment Moderate/Severe Exacerbation....................................37
8.3.2.
Planned Sensitivity Statistical Analyses for Time to First 
On-treatment Moderate/Severe Exacerbation..............................38
8.3.2.1.
Time to First Moderate/Severe Exacerbation 
Including Off-treatment Data.......................................38
8.3.2.2.
Time to First On-treatment Moderate/Severe 
Exacerbation or Premature Treatment 
Discontinuation...........................................................38
8.4.
Time to First On-treatment Moderate/severe Exacerbation by 
Eosinophil Subgroup...................................................................................39
8.5.
Annual Rate of On-treatment Severe Exacerbations...................................40
8.6.
Annual Rate of On-treatment Moderate/severe Exacerbations by 
Eosinophil Subgroup...................................................................................40
9.
OTHER STATISTICAL ANALYSES .......................................................................41
9.1.
Other Efficacy and Health Outcomes Analyses...........................................41
9.1.1.
Overview of Planned Efficacy and Health Outcomes 
Analyses for Other Endpoints ......................................................41
9.1.1.1.
All Cause Mortality......................................................45
9.1.1.2.
St. George’s Respiratory Questionnaire 
Responder Analysis....................................................45
9.1.1.3.
Baseline Dyspnea Index (BDI)/Transitional 
Dyspnea Index (TDI) Focal Score...............................45
9.1.1.4.
COPD Assessment Test (CAT) ..................................45
9.1.1.5.
Subject Global Ratings...............................................46
9.1.1.6.
Daily Diary Assessments............................................46
9.1.1.7.
EuroQol Questionnaire (EQ-5D-5L)............................46
9.1.1.8.
Unscheduled Healthcare Resource Utilization............47
9.1.2.
Planned Efficacy Statistical Analyses of Other Endpoints ............47
9.1.2.1.
Time to First On-treatment Exacerbation....................47
9.1.2.2.
Time to First On-treatment Severe 
Exacerbation by Eosinophil Subgroup ........................47
9.1.2.3.
Annual Rate of On-treatment Exacerbations...............48
9.1.2.4.
Time to Onset of Each Exacerbation ..........................48
9.1.2.5.
Trough FEV1, SGRQ Total Score, CAT score 
and TDI by Eosinophil Subgroup ................................49
9.1.2.6.
Post-bronchodilator FEV1 and FVC, Trough 
FVC, CAT, TDI ...........................................................49
9.1.2.7.
Proportion of Responders According to FEV1, 
SGRQ, CAT and TDI..................................................50
9.1.2.8.
Proportion of Responders According to FEV1, 
SGRQ, CAT and TDI by Eosinophil Subgroup............51
9.1.2.9.
Time to Death from Any Cause...................................51
9.1.2.10.
Rescue Use, Symptoms and Nighttime 
Awakenings................................................................52
9.1.2.11.
Subject Global Ratings of Change..............................52
9.2.
Safety Analyses..........................................................................................53
 
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9.2.1.
Overview of Planned Analyses ....................................................53
9.2.2.
Overview of Planned Exposure Analyses.....................................53
9.2.3.
Overview of Planned Adverse Event Analyses ............................53
9.2.3.1.
Adverse Events of Special Interest.............................54
9.2.3.2.
Pneumonia Risk Factors ............................................55
9.2.3.3.
Pregnancy..................................................................55
9.2.3.4.
Oropharyngeal Examination .......................................55
9.2.4.
Overview of Major Adverse Cardiac Events (MACE) ...................55
9.2.4.1.
Major Adverse Cardiac Events ...................................56
9.2.5.
Overview of Pneumonia Details (from the eCRF 
Pneumonia Form)........................................................................56
9.2.6.
Overview of the Composite Endpoints .........................................56
9.2.7.
Overview of Bone Fractures.........................................................57
9.2.8.
Overview of Chest Imaging..........................................................57
9.2.9.
Overview of Liver Events .............................................................57
9.2.10.
Overview of Laboratory Parameters.............................................58
9.2.11.
Overview of Vital Signs................................................................58
9.2.11.1.
Vital Signs ..................................................................59
9.2.12.
Overview of ECGs .......................................................................59
9.2.12.1.
ECGs..........................................................................60
9.2.13.
Planned Statistical Analyses of Safety Endpoints ........................60
9.2.13.1.
Vital Signs and ECGs.................................................60
9.2.13.2.
Time to First Event in the Pneumonia AESI 
Group, Cardiovascular AESI Group............................61
9.2.13.3.
Time to First Event in the Pneumonia AESI 
Group by Eosinophil Subgroup...................................63
9.2.13.4.
Time to First Event in the Pneumonia AESI 
Group or COPD Exacerbation ....................................63
9.2.13.5.
Time to First Exacerbation, Event in the CV 
AESI Group and Event in the Pneumonia AESI 
Group Composite Endpoints.......................................64
9.3.
Pharmacokinetic Analyses..........................................................................64
9.4.
Pharmacogenetics Analyses.......................................................................64
9.5.
Biomarker Analyses....................................................................................64
10. REFERENCES.......................................................................................................65
11. APPENDICES........................................................................................................67
11.1.
Appendix 1: Time & Events.........................................................................67
11.2.
Appendix 2: Assessment Windows .............................................................71
11.2.1.
General........................................................................................71
11.3.
Appendix 3: Treatment States and Phases.................................................72
11.3.1.
Concomitant Medication Data......................................................72
11.3.2.
All Cause Mortality.......................................................................73
11.3.3.
Other Data...................................................................................74
11.3.3.1.
Post-treatment and Post-study Phases.......................74
11.3.3.2.
Pre-treatment and On-treatment where Time is 
Recorded....................................................................75
11.3.3.3.
Pre-treatment and On-treatment where Time is 
Not Recorded .............................................................75
11.4.
Appendix 4: Data Display Standards and Handling Conventions ................76
11.4.1.
Study Treatment and Subgroup Display Descriptors....................76
 
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11.4.1.1.
Study Treatment.........................................................76
11.4.1.2.
Treatment Comparisons .............................................76
11.4.1.3.
Eosinophils Subgroup and Display Descriptors ..........76
11.4.2.
Baseline Definitions & Derivations ...............................................77
11.4.3.
Reporting Process & Standards...................................................78
11.5.
Appendix 5: Derived and Transformed Data ...............................................81
11.5.1.
General........................................................................................81
11.5.1.1.
Study Day...................................................................81
11.5.1.2.
Treatment Stop Date ..................................................81
11.5.1.3.
Study and Treatment Completion ...............................81
11.5.1.4.
Projected Week 52 Date.............................................81
11.5.1.5.
At Risk Period for Calculation of Raw Event 
Rate ...........................................................................81
11.5.1.5.1.
All Cause Mortality..................................81
11.5.1.5.2.
Other Data..............................................82
11.5.2.
Study Population..........................................................................83
11.5.2.1.
Demographics ............................................................83
11.5.2.2.
Subject Disposition.....................................................83
11.5.2.3.
Treatment Compliance ...............................................84
11.5.2.4.
Cardiovascular Risk Factors.......................................84
11.5.2.5.
Pneumonia Risk Factors ............................................84
11.5.2.6.
Concomitant Medications ...........................................85
11.5.2.7.
Smoking Status ..........................................................86
11.5.2.8.
COPD Exacerbation History .......................................86
11.5.2.9.
Screening Lung Function and GOLD Grade ...............86
11.5.3.
Efficacy and Health Outcomes.....................................................87
11.5.3.1.
Exacerbations.............................................................87
11.5.3.2.
Lung Function.............................................................89
11.5.3.3.
SGRQ.........................................................................90
11.5.3.4.
CAT............................................................................91
11.5.3.5.
All Cause Mortality......................................................91
11.5.3.6.
BDI/TDI ......................................................................92
11.5.3.7.
eDiary.........................................................................93
11.5.3.8.
EQ-5D-5L...................................................................94
11.5.3.9.
Healthcare Resource Utilization..................................95
11.5.4.
Safety ..........................................................................................95
11.5.4.1.
Exposure....................................................................95
11.5.4.2.
Adverse Events ..........................................................95
11.5.4.3.
Bone Fracture.............................................................97
11.5.4.4.
Maximum/Minimum Post-Baseline and Worst-
Case Post-Baseline....................................................98
11.5.4.5.
Laboratory Parameters...............................................98
11.5.4.6.
ECG ...........................................................................99
11.5.4.7.
Pneumonia ...............................................................100
11.5.4.8.
Time to First Event ...................................................100
11.5.4.9.
MACE.......................................................................100
11.6.
Appendix 6: Handling of Missing Data ......................................................101
11.6.1.
Missing or Partial Dates.............................................................101
11.6.1.1.
Missing Data for Statistical Analysis .........................102
11.7.
Appendix 7: Multicenter Studies................................................................103
11.7.1.
Geographical Region .................................................................103
11.8.
Appendix 8: Examination of Covariates, Subgroups & Other Strata..........104
 
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11.8.1.
Handling of Covariates, Subgroups & Other Strata....................104
11.9.
Appendix 9: Handling Multiple Comparisons and Multiplicity.....................105
11.10. Appendix 10: Model Checking and Diagnostics for Statistical 
Analysis ....................................................................................................107
11.10.1. Statistical Analysis Assumptions................................................107
11.10.1.1. Negative Binomial Regression and Poisson 
Regression ...............................................................107
11.10.1.2. Cox Proportional Hazards.........................................107
11.10.1.3. Andersen-Gill............................................................108
11.10.1.4. Mixed Model Repeated Measures ............................108
11.10.1.5. Generalized Linear Model.........................................108
11.10.1.6. Analysis of Covariance.............................................109
11.10.1.7. Logistic Regression ..................................................109
11.11. Appendix 11: Abbreviations & Trademarks ...............................................110
11.11.1. Abbreviations.............................................................................110
11.11.2. Trademarks ...............................................................................112
11.12. Appendix 12: List of Data Displays............................................................113
11.12.1. Data Display Numbering............................................................113
11.12.2. Deliverable.................................................................................113
11.12.3. Study Population Tables............................................................114
11.12.4. Study Population Figures...........................................................116
11.12.5. Efficacy Tables ..........................................................................116
11.12.6. Efficacy Figures .........................................................................121
11.12.7. Safety Tables.............................................................................125
11.12.8. Safety Figures ...........................................................................129
11.12.9. ICH Listings ...............................................................................132
11.12.10.Non-ICH Listings........................................................................134
 
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1.
REPORTING & ANALYSIS PLAN SYNPOSIS
Overview
Key Elements of the RAP
Purpose

This Reporting and Analysis Plan (RAP) details planned analyses and 
outputs required for the final Clinical Study Report (CSR) of study 
CTT116855.
Protocol

This RAP is based on the following protocol and protocol amendments:

Original protocol [Dated: 17MAR2014, GlaxoSmithKline Document 
Number 2013N176913_00]

Protocol amendment 01 [Dated: 31MAR2014, GlaxoSmithKline Document 
Number 2013N176913_01]

Protocol amendment 02 [Dated: 10APR2014, GlaxoSmithKline Document 
Number 2013N176913_02]

Protocol amendment 03 [Dated: 05DEC2014, GlaxoSmithKline Document 
Number 2013N176913_03]

Protocol amendment 04 [Dated: 12MAY2015, GlaxoSmithKline Document 
Number 2013N176913_04]

Protocol amendment 05 [Dated: 30JUN2016, GlaxoSmithKline Document 
Number 2013N176913_05]

Protocol amendments 3 and 4 are for China only.
Primary 
Objective

To evaluate the efficacy of fluticasone furoate (FF)/umeclidinium 
(UMEC)/vilanterol (VI) to reduce the annual rate of moderate/severe 
exacerbations compared with dual therapy of FF/VI or UMEC/VI in subjects 
with chronic obstructive pulmonary disease (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 ≥0.15 
10^9/L
Primary 
Endpoint
and Co-
primary 
Treatment 
Comparisons

Annual rate of on-treatment moderate/severe exacerbations comparing 
FF/UMEC/VI with UMEC/VI

Annual rate of on-treatment moderate/severe exacerbations comparing 
FF/UMEC/VI with FF/VI
Secondary 
Endpoints
and 
Treatment 
Comparisons

Change from baseline in trough forced expiratory volume in 1 second 
(FEV1) at Week 52 comparing FF/UMEC/VI with FF/VI

Change from baseline in St. George’s Respiratory Questionnaire (SGRQ)
Total Score at Week 52 comparing FF/UMEC/VI with FF/VI

Time to first on-treatment moderate/severe exacerbation comparing 
FF/UMEC/VI with FF/VI and with UMEC/VI 

Annual rate of on-treatment moderate/severe exacerbations comparing 
FF/UMEC/VI with UMEC/VI in the subset of subjects with a blood 
 
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Overview
Key Elements of the RAP
eosinophil count ≥ 0.15 10^9/L

Time to first on-treatment moderate/severe exacerbation comparing 
FF/UMEC/VI with UMEC/VI in the subset of subjects with a blood 
eosinophil count ≥ 0.15 10^9/L

Annual rate of on-treatment severe exacerbations comparing FF/UMEC/VI 
with FF/VI and with UMEC/VI
Study 
Design

This is a phase IIIa, randomized, double-blind, 3-arm parallel group, global 
multicenter study evaluating FF/UMEC/VI (100/62.5/25 mcg) inhalation 
powder versus FF/VI (100/25 mcg) inhalation powder and UMEC/VI
(62.5/25 mcg) inhalation powder all given once daily in the morning. The 
target enrollment is 10,000 randomized subjects at approximately 1,000 
study centers globally.

Eligible subjects will be randomized (2:2:1) to one of the following double-
blind treatment groups: 

FF/UMEC/VI 100/62.5/25 mcg (n=4,000)

FF/VI 100/25 mcg (n=4,000)

UMEC/VI 62.5/25 mcg (n=2,000)

The total duration of subject participation will be approximately 55 weeks, 
consisting of a 2-week run-in period, up to 52-week treatment period and a 
1-week safety follow-up period.

Subjects who have permanently discontinued study treatment are not 
required to withdraw from the study. Subjects who have permanently 
discontinued study treatment and have not withdrawn consent may continue 
in the study and complete all remaining protocol specified visits by telephone 
contact to collect exacerbations, SAEs and concomitant medications. This 
off-treatment data will be used in sensitivity analyses for assessing the effect 
of missing data on study conclusions.
Planned 
Analyses

An Independent Data and Monitoring Committee (IDMC) will review 
unblinded safety data (including exacerbation data) during the conduct of this 
study. Blinded review of exacerbation data for potential sample size 
adjustment will be performed by GSK during the recruitment period of the 
study.

No interim analysis of unblinded data is planned. One final statistical 
analysis will be conducted.

All decisions regarding final analysis, as defined in this RAP document, will 
be made by Source Data Lock (SDL) prior to Study Data Tabulation Model 
(SDTM) Database Freeze (DBF) of the study data. Identification of taking 
incorrect treatment will be identified following DBF.
Analysis 
Populations

Intent-to-Treat (ITT) population, which comprises all randomized subjects, 
excluding those who were randomized in error and did not receive a dose of 
study medication. A subject who is recorded as a screen or run-in failure and 
also randomized, but did not receive a dose of study treatment, will be 
considered to be randomized in error. Any other subject who receives a
 
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Overview
Key Elements of the RAP
randomization number will be considered to have been randomized.  

All Subjects Enrolled (ASE) population includes all subjects for whom a 
record exists on the study database, both screened subjects and subjects who 
were not screened but signed an informed consent form (ICF).

Pre-dose Electrocardiogram (ECG) population will comprise all subjects in
the ITT population from sites included in the ECG substudy who performed 
an on-treatment pre-dose ECG assessment at Week 4.

Transitional Dyspnea Index (TDI) population will comprise all subjects in 
the ITT population who completed a pre-dose Baseline Dyspnea Index (BDI)
at Day 1.
Hypothesis

The primary purpose of this study is to evaluate the efficacy of FF/UMEC/VI 
to reduce the annual rate of on-treatment moderate/severe exacerbations
compared with dual therapy of FF/VI or UMEC/VI in subjects with COPD 
over a 52-week period. 

The co-primary treatment comparison will be the pairwise comparisons of 
FF/UMEC/VI with FF/VI and FF/UMEC/VI with UMEC/VI for the primary 
endpoint, the annual rate of on-treatment moderate/severe exacerbations.

The hypotheses (two-sided) associated with the statistical test of the primary 
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).  
Primary 
Analyses

The primary analyses will be performed using a generalized linear model 
(GLM) assuming the negative binomial distribution. The primary analyses 
will be based on a two-sided hypothesis testing approach and will use data 
for the ITT population collected while subjects were on study treatment.

To account for multiplicity of the co-primary treatment comparisons, the 
truncated Hochberg method [Dmitrienko, 2008] with a truncation parameter 
of γ=0.6 will be used to control overall type I error at α=0.05. Using this 
approach, both comparisons will be declared statistically significant if the 
unadjusted 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 unadjusted 
p-value is below 0.025.
Secondary 
Analyses

Pairwise comparisons of FF/UMEC/VI versus FF/VI and FF/UMEC/VI
versus UMEC/VI will be performed for the secondary efficacy and other 
endpoints. If at least one of the co-primary treatment comparisons is 
considered statistically significant, inferences will be drawn from p-values 
for the treatment comparisons on secondary and other endpoints. If neither of 
the co-primary treatment comparisons is considered statistically significant, 
testing on the secondary and other endpoints will be performed and presented 
for descriptive purposes only.

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 
 
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Key Elements of the RAP
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 selected 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 health-related quality of life, 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.

Pairwise comparisons of FF/UMEC/VI versus FF/VI and FF/UMEC/VI 
versus UMEC/VI on other endpoints will not be adjusted for multiplicity.

Pairwise comparisons of UMEC/VI versus FF/VI will not be adjusted for 
multiplicity for any endpoint.
Secondary 
and Other 
Analyses

Pairwise comparisons of FF/UMEC/VI versus FF/VI and FF/UMEC/VI 
versus UMEC/VI will be performed for the secondary efficacy and other
endpoints. 

If at least one of the co-primary treatment comparisons is considered 
statistically significant, inferences will be drawn from p-values for the 
secondary and other treatment comparisons.

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.

If neither of the co-primary treatment comparisons is considered statistically 
significant, testing on the secondary and other endpoints will be performed 
and presented for descriptive purposes only.

No adjustment for multiplicity will be made across these secondary and other 
treatment comparisons.
Secondary 
and Other 
Analyses 
where strong 
control of 
type I error 
is required

Where strong control of type I error is required, multiplicity will be 
controlled across selected secondary endpoints and treatment comparisons 
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 health-related 
quality of life, 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. 
 
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Key Elements of the RAP

Within each block, at least one endpoint must be considered statistically 
significant in order to make inferences in the subsequent block.

If at least one endpoint is statistically significant in the final block, inferences 
will be drawn from p-values for the remaining secondary and other treatment 
comparisons.  The reference level for declaring statistical significance will 
depend on the results obtained from tests within the hierarchy.

If neither of the treatment comparisons in the final block is considered 
statistically significant, testing on the remaining secondary and other 
endpoints will be performed and presented for descriptive purposes only.

No adjustment for multiplicity will be made across the remaining secondary 
and other treatment comparisons.

In addition, pairwise comparisons of UMEC/VI and FF/VI will be performed 
for all endpoints. These are not adjusted for multiplicity.
 
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2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
There were changes to the originally planned statistical analysis specified in the protocol 
amendment 05 (Dated: 30JUN2016) of study CTT116855 [GlaxoSmithKline Document 
Number 2013N176913_05].  
The protocol only states that comparisons of FF/UMEC/VI with FF/VI and with 
UMEC/VI will be performed.  In addition, comparisons of UMEC/VI with FF/VI will 
also be performed for all endpoints.
Additional endpoints to those mentioned in the protocol will be analyzed as listed below. 
These are related to protocol-defined endpoints and will be used to further characterize 
the effects of FF/UMEC/VI, FF/VI and UMEC/VI.
COPD Exacerbations:

Time to first on-treatment moderate/severe exacerbation by Eosinophil subgroup
(comparing FF/UMEC/VI with FF/VI)

Time to each on-treatment moderate/severe exacerbationTime to first on-treatment 
severe exacerbation by Eosinophil subgroup

Time to first on-treatment mild/moderate/severe exacerbation

Time to first on-treatment moderate exacerbation

Time to first on-treatment exacerbation requiring systemic/oral corticosteroids

Time to first on-treatment exacerbation requiring antibiotics
Spirometry:

Change from baseline in trough FEV1 by Eosinophil subgroup

FEV1 reversibility 

Percentage of subjects with an increase from baseline in trough FEV1 ≥100mL

Percentage of subjects with an increase from baseline in trough FEV1 ≥100mLby 
Eosinophil subgroup

Change from baseline in trough Forced Vital Capacity (FVC) 

Change from baseline in post-bronchodilator FVC
 
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All Cause Mortality:

Time to death from any cause (on and off treatment)
SGRQ:

Change from baseline in SGRQ Total score by Eosinophil subgroup

Proportions of responders according to the SGRQ Total score by Eosinophil 
subgroup
TDI:

TDI focal score comparing FF/UMEC/VI with UMEC/VI (note, the comparison of 
FF/UMEC/VI with FF/VI is in the protocol)

TDI Focal Score by Eosinophil subgroup

Proportion of responders according to TDI

Proportion of responders according to TDI by Eosinophil subgroup
CAT:

Change from baseline in COPD Assessment Test (CAT) score by Eosinophil 
subgroup

Proportion of responders according to CAT score by Eosinophil subgroup
Daily Diary:

Change from baseline in mean nighttime awakenings per night due to COPD 
symptoms

Change from baseline in the percentage of days symptoms stopped usual activities
Composite Endpoints:

Time to first event in the pneumonia AESI group and moderate/severe COPD 
exacerbation composite

Time to first event in the pneumonia AESI group resulting in hospitalization,
prolonged hospitalization or death and severe COPD exacerbation composite

Time to first event in the pneumonia AESI group resulting in hospitalization,
prolonged hospitalization or death, event in the CV AESI group resulting in 
hospitalization, prolonged hospitalization or death and severe COPD exacerbation 
composite
 
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Even though some endpoints only state one treatment comparison, all treatment 
comparisons (FF/UMEC/VI compared with FF/VI, FF/UMEC/VI compared with
UMEC/VI and UMEC/VI compared with FF/VI) will be performed and displayed for 
completeness for all endpoints except for J2R sensitivity analyses.
The Safety Analyses section of the protocol includes reference to analyses of time to first 
pneumonia and time to first hospitalization for pneumonia. The analyses are clarified in 
this RAP as time to first event in the ‘Pneumonia’ Adverse Event of Special Interest 
(AESI) group and time to first event in the ‘Pneumonia’ AESI group resulting in 
hospitalization, prolonged hospitalization or death.  
2.2.
Study Objectives and Endpoints
Objectives
Primary Objective

To evaluate the efficacy of FF/UMEC/VI to reduce the annual rate of moderate/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 population of subjects with a screening eosinophil count ≥0.15 10^9/L
Other Objectives

To evaluate the patient perspective of the efficacy of FF/UMEC/VI in subjects with COPD

To evaluate the population pharmacokinetic (PK) profiles of FF, UMEC and VI in subjects 
with COPD

To collect blood samples for a genetics research study
Note: PK and genetics analyses as well as any analysis performed on the single 
biomarker (fibrinogen) data collected for this study will be detailed in separate RAPs.
Endpoints
Co-Primary Treatment Comparisons on the Primary Efficacy Endpoint

Annual rate of on-treatment moderate/severe exacerbations comparing FF/UMEC/VI with 
UMEC/VI

Annual rate of on-treatment moderate/severe exacerbations comparing FF/UMEC/VI with 
FF/VI
Secondary Efficacy Endpoints and Treatment Comparisons

Change from baseline in trough FEV1 at Week 52 comparing FF/UMEC/VI with FF/VI

Change from baseline in SGRQ Total Score at Week 52 comparing FF/UMEC/VI with FF/VI

Time to first on-treatment moderate/severe exacerbation comparing FF/UMEC/VI with FF/VI 
and with UMEC/VI

Annual rate of on-treatment moderate/severe exacerbations comparing FF/UMEC/VI with 
UMEC/VI in the subset of subjects with a blood eosinophil count ≥0.15 10^9/L

Time to first on-treatment moderate/severe exacerbation comparing FF/UMEC/VI with 
 
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Endpoints
UMEC/VI in the subset of subjects with a blood eosinophil count ≥0.15 10^9/L

Annual rate of on-treatment severe exacerbations comparing FF/UMEC/VI with FF/VI and 
with UMEC/VI
Other Efficacy Endpoints

Annual rate of all on-treatment exacerbations (mild, moderate, severe)

Annual rate of on-treatment moderate exacerbations

Annual rate of on-treatment exacerbations requiring systemic/oral corticosteroids

Annual rate of on-treatment exacerbations requiring antibiotics

Annual rate of on-treatment severe exacerbations by Eosinophil subgroup (note, annual rate 
of on-treatment moderate/severe exacerbations comparing FF/UMEC/VI with UMEC/VI in 
the subset of subjects with a blood eosinophil count ≥0.15 10^9/L is a secondary endpoint)

Time to first on-treatment mild/moderate/severe exacerbation

Time to first on-treatment moderate exacerbation

Time to first on-treatment COPD exacerbation requiring systemic/oral corticosteroids

Time to first on-treatment exacerbations requiring antibiotics

Time to first on-treatment severe exacerbation

Time to first on-treatment moderate/severe exacerbation by Eosinophil subgroup (note: time 
to first on-treatment moderate/severe exacerbation comparing FF/UMEC/VI with UMEC/VI 
in the subset of subjects with a blood eosinophil count ≥0.15 10^9/L is a secondary endpoint)

Time to first on-treatment severe exacerbation by Eosinophil subgroup

Time to each on-treatment moderate/severe exacerbation

Time to each on-treatment severe exacerbation

Time to death from any cause (on-treatment only)

Time to death from any cause (on and off treatment)

Change from baseline in trough FEV1 (note, comparing FF/UMEC/VI with FF/VI at Week 
52 is a secondary endpoint)

Change from baseline in trough FEV1 by Eosinophil Subgroup

Percentage of subjects with an increase from baseline in trough FEV1 ≥100mL

Percentage of subjects with an increase from baseline in trough FEV1 ≥100mL by Eosinophil 
Subgroup

Change from baseline in post-bronchodilator FEV1 

FEV1 reversibility

Change from baseline in trough FVC 

Change from baseline in post-bronchodilator FVC 

Change from baseline in SGRQ Total score (note, comparing FF/UMEC/VI with FF/VI at 
Week 52 is a secondary endpoint)
 
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Endpoints

Change from baseline in SGRQ Total score by Eosinophil Subgroup

Proportion of responders according to the SGRQ Total score 

Proportion of responders according to the SGRQ Total score by Eosinphil Subgroup

Change from baseline in CAT score 

Change from baseline in CAT score by Eosinophil Subgroup

Proportion of responders according to the CAT score 

Proportion of responders according to the CAT score by Eosinophil Subgroup

TDI focal score (in a subset of subjects)

TDI focal score by Eosinophil Subgroup

Proportion of responders according to TDI

Proportion of responders according to TDI by Eosinophil Subgroup

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 severity

Change from baseline in use of rescue albuterol/salbutamol (occasions/day)

Change from baseline in percentage of rescue-free days

Change from baseline in mean number of nighttime awakenings per night due to COPD 
symptoms

Change from baseline in the percentage of days symptoms stopped usual activities
Safety Endpoints

Incidence of adverse events (AEs).  To include:
o
AEs collected on the eCRF page
o
SAEs collected on the eCRF page
o
AEs of Special Interest
o
SAE’s of Special Interest
o
Fatal On-treatment AE’s of Special Interest

Adjudicated Serious Adverse Reports 

Incidence of pneumonia. To include:
o
Pneumonia details collected on the eCRF page
o
Events in the Pneumonia AEs of Special Interest Group  
o
Serious events in the Pneumonia AE’s of Special Interest Group  

Incidence of cardiovascular events.  To include:
o
MACE
o
Events in the Cardiovascular AEs of Special Interest Group
 
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Endpoints

Events in the pneumonia AESI group and moderate/severe exacerbations composite

Events in the pneumonia AESI group leading to hospitalization, prolonged hospitalization or 
death and severe exacerbations 

Events in the pneumonia AESI group resulting in hospitalization, prolonged hospitalization
or death, severe exacerbation and event in the cardiovascular AESI group resulting in 
hospitalization, prolonged hospitalization or death

ECG measurements

Vital signs 

Hematological and clinical chemistry parameters

Oropharyngeal examinations (reported as part of the AEs)

Incidence of bone fractures

Health Outcome Endpoints

EuroQol Questionnaire (EQ-5D-5L)

Healthcare resource utilization (all-cause and COPD related)
 
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2.3.
Study Design
Overview of Study Design and Key Features
Design Features

This is a phase IIIa, randomized, double-blind, 3-arm parallel 
group, global multicenter study evaluating FF/UMEC/VI
(100/62.5/25 mcg) inhalation powder versus FF/VI (100/25 mcg)
inhalation powder and UMEC/VI (62.5/25 mcg) inhalation 
powder all given once daily in the morning. The target 
enrollment is 10,000 randomized subjects at approximately 
1,000 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.

Subjects who have permanently discontinued study treatment are 
not required to withdraw from the study. Subjects who have 
permanently discontinued study treatment and have not 
withdrawn consent may continue in the study and complete all 
remaining protocol specified visits by telephone contact. This 
off-treatment data will be used in an assessment of the sensitivity 
of primary analyses to missing data as described in Section 7.3, 
Section 8.2.2 and Section 8.3.2. Data collected after 
discontinuation of study treatment may include exacerbations, 
serious adverse events (SAEs) and concomitant medications.
Dosing

Study treatment will be delivered by the ELLIPTA Dry Powder 
Inhaler (DPI). The ELLIPTA DPI will contain 30 doses 
(FF/UMEC/VI or FF/VI or UMEC/VI). Subjects will be 
instructed to administer the ELLIPTA DPI once daily in the 
morning for the duration of the 52 week treatment period.  
Treatment Assignment

Following the run-in period, eligible subjects are to be 
randomized (2:2:1) to one of the following double-blind 
treatment groups for 52 weeks: 

FF/UMEC/VI 100/62.5/25 mcg (n=4,000)

FF/VI 100/25 mcg QD (n=4,000)

UMEC/VI 62.5/25 mcg QD (n=2,000)

The randomization schedule was generated using 
GlaxoSmithKline (GSK) software (RANDALL NG). The study 
Treatment Period, 1 year
 
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Overview of Study Design and Key Features
will use site-based randomization to allocate treatments.

Subjects will be assigned to study treatment in accordance with 
the randomization schedule using an Interactive Voice Response 
System (IVRS) (RAMOS).
Interim Analysis

No interim analysis of unblinded data will be performed. 

An IDMC will review unblinded safety data (including 
exacerbation data) during the conduct of the study.

Blinded review of exacerbation data for potential sample size 
adjustment will be performed during the recruitment period of the 
study.
2.4.
Statistical Hypotheses
The primary purpose of this study is to evaluate the efficacy of FF/UMEC/VI to reduce
the annual rate of moderate/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 inhaled corticosteroid (ICS
(FF)) when used in combination with a fixed dose of a long-acting beta-agonist / long-
acting muscarinic receptor antagonist (LABA/LAMA (UMEC/VI)), and the contribution 
of the LAMA (UMEC) above the efficacy of an ICS/LABA (FF/VI) combination, in 
reducing the rate of on-treatment moderate/severe exacerbations in subjects with COPD. 
The primary endpoint is the annual rate of on-treatment moderate/severe exacerbations 
(calculated from the number of moderate and severe exacerbations during the treatment 
period).
The primary analyses will be the pairwise comparisons of FF/UMEC/VI with FF/VI and 
FF/UMEC/VI with UMEC/VI, with inferences adjusted for multiplicity as described in 
Section 11.9. 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 UMEC/VI).  
In addition the comparison of UMEC/VI with FF/VI will be presented on all analysis 
tables with the exception of the Jump to Reference sensitivity analyses.
 
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3.
PLANNED ANALYSES
3.1.
Interim Analyses
No interim analyses will be performed.
3.2.
Final Analyses
No interim analysis of unblinded data is planned for this study. 
The final planned analyses for this Clinical Data Interchange Standards Consortium 
(CDISC) study will be performed after the completion of the following sequential steps:
1.
All subjects have completed the study as defined in the protocol.
2.
All required database cleaning activities have been completed and final System 
Independent (SI) Source Data Lock has been declared by Data Management (DM).
3.
Unblinded randomization schedules, container data and PK data (SI PC) are released 
to conversion service by Randomization coordinator
4.
SI data to SDTM data conversion has been completed by the Conversion Service 
including unblinding activities as per Temporary Treatment Process and quality 
control (QC) of unblinded SDTM has been completed by DM.
5.
Database freeze on unblinded SDTM datasets has been declared by DM.
6.
Study is unblinded
Randomization schedules and container data are released in RANDALL NG.
SMS2000 data is released in HARP
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
All Subjects 
Enrolled (ASE)

Comprised of all subjects for whom a record 
exists on the study database, including 
screened subjects and subjects who were not 
screened but signed an ICF. 

Subject disposition

SAEs for non-
randomized subjects
Intent-to-Treat
(ITT)

Comprised of all randomized subjects, 
excluding those who were randomized in 
error who did not receive a dose of study 
medication. A subject who is recorded as a 
screen or run-in failure and also randomized, 
but did not receive a dose of study treatment, 
will be considered to be randomized in error.
Any other subject who receives a 
randomization number will be considered to 
have been randomized.

Study population

Efficacy

Safety

Health outcomes
Pre-dose ECG

Comprised of all subjects in the ITT 

Study Population
 
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Population
Definition / Criteria
Analyses Evaluated
(ECG) 
population from sites included in the ECG 
substudy who performed an on-treatment pre-
dose ECG assessment at Week 4.

ECG
TDI (TDI)

Comprised of all subjects in the ITT 
population who completed a pre-dose BDI 
assessment at Day 1.

Study Population

BDI/TDI
NOTES : 

Refer to Section 11.12 which details the population to be used for each data display being generated.
In the event one or more investigators are withdrawn from the study due to concerns over 
protocol deviation then a further population will be defined which will consist of all 
subjects in the ITT population excluding subjects from those investigative sites. This 
population will be used to perform additional sensitivity analysis for the primary efficacy 
endpoint only, and will only be defined if the combined enrolment at these sites exceeds 
≥2% of the overall ITT study enrolment.
4.1.
Protocol Deviations

PDs will be tracked by the study team throughout the conduct of the study in 
accordance with the Protocol Deviation Management Plan (PDMP) and updated 
throughout the course of the study. 

Data will be reviewed prior to SDL to ensure all important deviations are captured 
and categorized in the protocol deviations dataset. 

Subjects who received an incorrect treatment container will be captured as an 
important protocol deviation. Whether or not the incorrect container contained 
incorrect treatment will be identified following DBF in the Analysis Data Model 
(ADaM) dataset and the PD will be flagged accordingly. 

Important protocol deviations (as identified in the PDMP) will be summarized and 
listed.  

A separate summary and listing of all inclusion/exclusion criteria deviations will also 
be provided. This summary will be based on data as recorded on the 
inclusion/exclusion page of the electronic case report form (eCRF).
 
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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Handling of Data from Subset Populations
Certain subsets of subjects will undergo the following additional procedures during the 
study: BDI/TDI, PK blood draws, and/or an additional pre-dose ECG at Week 4.  These 
subsets are not mutually exclusive.
In addition, a blood eosinophil subgroup will be derived based on the baseline blood 
eosinophil count (detailed in Section 11.4.1.3). 
Separate populations will be defined for the TDI and pre-dose ECG analysis as described 
in this RAP in Section 4. The PK analysis population will be described in a separate 
RAP. Any analysis performed on the pharmacogenetic or single biomarker data collected 
for this study will be detailed in a separate analysis plan.  
5.2.
Handling of Data Collected After Study Treatment
Discontinuation
Subjects who have permanently discontinued study treatment are not required to 
withdraw from the study. Subjects who have permanently discontinued study treatment
and have not withdrawn consent may continue in the study and complete all remaining 
protocol specified visits by telephone contact. Data collected after discontinuation of 
study treatment may include exacerbations (off-treatment efficacy data), SAEs (post-
treatment safety data) and concomitant medications (post-treatment study population 
data). Subjects who have permanently discontinued study treatment and are continuing in 
the study are allowed to use any medications prescribed by the Investigator or their 
treating physician.
This off-treatment exacerbation data will be used in the exacerbation sensitivity analyses 
for assessing the effect of missing data on study conclusions and in summaries of off-
treatment exacerbation data. A detailed description of the sensitivity analyses for 
exacerbations is provided in Section 7.3 and Section 8.3.2.
Post-treatment study population and safety data will be summarized as described in 
Section 6 and Section 9.2.
 
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5.3.
Overview of Appendices
Table 1 provides an overview of appendices within the RAP for outlining general 
considerations for data analyses and data handling conventions. 
Table 1
Overview of Appendices
Section
Component
11.1
Appendix 1: Time & Events
11.2
Appendix 2: Assessment Windows
11.3
Appendix 3: Treatment States and Phases
11.4
Appendix 4: Data Display Standards and Handling Conventions
11.5
Appendix 5: Derived and Transformed Data
11.6
Appendix 6: Handling of Missing Data
11.7
Appendix 7: Multicenter Studies
11.8
Appendix 8: Examination of Covariates, Subgroups & Other Strata
11.9
Appendix 9: Handling Multiple Comparisons and Multiplicity
11.10
Appendix 10: Model Checking and Diagnostics for Statistical Analysis
11.11
Appendix 11: Abbreviations & Trademarks
11.12
Appendix 12: List of Data Displays
 
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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Analyses
The study population outputs will be based on the ITT population unless otherwise stated.
Table 2 provides an overview of the planned study population outputs, with the detailed
list of data displays being presented in Section 11.12.
Table 2
Overview of Planned Study Population Analyses
Display Type
Data Displays Generated
Table
Figure
Listing
Subject Disposition
Study Populations and Reasons for Screen Failures 
Y1
Y1
Clinic Visits (Clinic Attendance/Phone Contact)
Y
Study Treatment Status
Y
Y5
Y
End of Study Record
Y
Y5
Y
Number of Subjects Enrolled
Y6
Inclusion and Exclusion Criteria Deviations
Y7
Y7
Important Protocol Deviations
Y
Y
Demography
Demographic Characteristics
Y2,3,4,8
Y
Race and Racial Combinations
Y2,3,4
Y
Medical Conditions 
Medical Conditions (Current/Past )
Y2,3
Cardiovascular Risk Factors
Y2,3
Family History of Cardiovascular Risk Factors
Y2,3
Smoking History at Screening
Y2,3
Smoking Status
Y2,3
Pneumonia Risk Factors at Screening
Y2
Disease Characteristics
COPD Duration
Y2
Y
COPD Exacerbation History
Y2,8
Y
Screening Lung Function
Y2,8
Reversibility and GOLD Grade(1-4) at Screening
Y2,8
CAT Score at Screening
Y2
Shift in CAT Score Category from Screening to Baseline
Y2
Pulse Oximetry
Percent Oxygen in Blood 
Y
Concomitant Medications
COPD Medications
Y9
Y
COPD Medication Combination at Screening
Y2,8
COPD Medication Combination at IP Discontinuation
Y
COPD Medication Combination at IP Discontinuation for 
those Subjects Providing Off-treatment Information
Y
Pneumonia and Influenza Vaccines Taken at Any Time up 
to the End of Study Treatment
Y
Non-COPD Medications
Y10
 
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Display Type
Data Displays Generated
Table
Figure
Listing
Treatment Compliance
Treatment Compliance
Y
Study Population Listings
Randomized and Actual Treatments by Country and 
Center
Y
Treatment Blind Broken During Study 
Y
Study Treatment Misallocations
Y
NOTES :
Y = Yes display generated.
1.
ASE population
2.
Repeat for Eosinophil subgroup
3.
Repeat for ECG population
4.
Repeat for TDI population
5.
Kaplan-Meier plot displaying FF/UMEC/VI, FF/VI and UMEC/VI and repeated displaying 
FF/VI and UMEC/VI only. 
6.
By country (ASE population); by age category (ASE population); by geographical region, 
country and center (ITT, ECG and TDI) 
7.
Screen failures (ASE population) and ITT population separately
8.
Repeat by country (ITT population)
9.
Prior to screening and then also Run-in/On-treatment/Post-treatment given for reasons other than 
an exacerbation and On-treatment/Post-treatment given for an exacerbation separately. 
10. On-treatment/Post-treatment
6.1.1.
Disposition
The study population summary will show the number of subjects who were enrolled, pre-
screen failures, screen failures and the number with each reason for screen failure. In 
addition it will also show the number of subjects in each treatment group and overall who 
were randomized, in the ITT population, pre-dose ECG population, TDI population and 
each level of the Eosinophil subgroup. 
The end of study record summary will show the number of subjects who completed the 
study as well as the number who withdrew early from the study along with reasons for 
early withdrawal. 
The summary of study treatment status will show the number of subjects who completed 
study treatment as well as the number who stopped study treatment prior to the end of the 
study, along with the reasons for treatment discontinuation. 
6.1.2.
Disease Characteristics
The screening lung function summary will include pre-bronchodilator and post-
bronchodilator FEV1, FVC, FEV1/FVC ratio, FEV1 as a percentage of predicted normal, 
and FEV1 reversibility to salbutamol (expressed in milliliters [mL] and as a percentage). 
These assessments, with the exception of pre-bronchodilator FEV1/FVC ratio and pre-
bronchodilator FEV1 as a percentage of predicted normal, will be collected in the eCRF 
and no recalculation of these values will be performed. Pre-bronchodilator FEV1/FVC 
ratio and pre-bronchodilator FEV1 as a percentage of predicted normal will be derived as 
 
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defined in Section 11.4.2 and Section 11.5.2.9. The reversibility to salbutamol status 
(Reversible or Non-reversible) will also be summarized as defined in Section 11.5.2.9. 
COPD exacerbation history at screening (see Section 11.5.2.8) will be summarized with 
frequency distributions (0, 1, 2, ≥3 and ≥2) of the number of moderate exacerbations, the 
number of severe exacerbations, the number of moderate/severe exacerbations, the 
number of exacerbations treated with systemic/oral corticosteroids (with or without 
antibiotics), and the number of exacerbations treated with antibiotics (with or without
systemic/oral corticosteroids). For each moderate/severe exacerbation the severity, 
duration, whether the exacerbation led to hospitalization, systemic/oral corticosteroids 
being taken and antibiotics being taken will be summarized.  See Section 11.5.2.8 for the 
definition of exacerbation severity.
6.1.3.
Concomitant Medications
COPD concomitant medications that have been stopped greater than three months prior to 
Visit 1 and non-COPD concomitant medications that have been stopped prior to 
randomization will not be included in any summary tables with the exception of the 
concomitant medications included in the summary of influenza and/or pneumonia 
vaccines. 
A summary of the number and percentage of subjects having received an influenza and/or 
pneumonia vaccine anytime on or before the study treatment stop date will also be 
presented.
Non-COPD medication tables will report by Anatomical Therapeutic Chemical (ATC) 
level 1 classification and ingredient. COPD medication tables will report by respiratory 
medication class (RMC) and ingredient (See Section 11.5.2.6). 
Multi-ingredient non-COPD medications will be presented according to their 
combination ATC classification rather than the classifications of the ingredients.
The number and percentage of subjects taking each medication in the RMC categories 
ICS, LABA, LAMA, PDE4 inhibitors, xanthines and combinations of these RMCs on the 
day of the Screening visit and IP discontinuation (for all subjects and separately for 
subjects that provide post-study treatment information and defined in Section 11.3.1 and 
Section 11.5.2.6) will be presented.
6.1.4.
Treatment Compliance
Calculation of treatment compliance will be based on the ELLIPTA DPI dose counter
(which displays the number of doses remaining) as described in Section 11.5.2.3. 
Percentage of compliance will be summarized categorically and with descriptive 
statistics. 
6.1.5.
Percent Oxygen in Blood
Percent oxygen in blood will be measured pre-dose at Visit 2 and will be summarized 
with descriptive statistics.
 
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7.
PRIMARY EFFICACY STATISTICAL ANALYSES
7.1.
Overview of Planned Efficacy Analyses for the Primary 
Endpoint
The co-primary treatment comparisons are the pairwise treatment comparisons of 
FF/UMEC/VI against FF/VI and FF/UMEC/VI against UMEC/VI for the annual rate of 
on-treatment moderate/severe exacerbations. The primary analyses detailed below will be 
based on the ITT population using data collected on-treatment.    
Table 3 provides an overview of the planned primary efficacy analyses, with the detailed 
list of data displays presented in Section 11.12.
Table 3
Overview of Planned Efficacy Analyses
Absolute
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
COPD Exacerbations
Primary Analyses:
Annual Rate of on-treatment Moderate/Severe 
Exacerbations
Y3
Y4
Y1
Y5
On-treatment Moderate/Severe Exacerbations Details
Y
Y2
Supportive Analysis:
On-treatment Moderate/Severe Exacerbations –
Negative Binomial Analysis with Interaction Terms
Y
Sensitivity Analyses:
Moderate/Severe Exacerbations, Including Off-
treatment Data – Negative Binomial Analysis
Y
Y4
Sensitivity Analyses:
On-treatment Moderate/Severe Exacerbations, 
imputing data following FF/UMEC/VI 
discontinuation using jump to reference assumption–
Negative Binomial Analysis
Y6
Y4
Sensitivity Analyses:
On and Off-treatment Moderate/Severe 
Exacerbations, imputing data following 
FF/UMEC/VI discontinuation using jump to 
reference assumption– Negative Binomial Analysis
Y6
Y4
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw 
data.

Individual = Represents FL related to any displays of individual subject observed raw data.
1.
Repeat by country for the summary of exacerbation data only.
2.
Listing will include all reported exacerbations
3.
Negative binomial regression model; repeat with Poisson regression model
4.
Plot of moderate/severe adjusted exacerbation rate ratios as a separate plot for the primary analyses. 
Rate ratios from both the primary and all sensitivity analyses to be included as a forest plot.
5.
Box plot of annual exacerbation raw rates (see Section 11.5.3.1 for derivations of individual subject 
raw COPD exacerbation rate)
 
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6.
This analyses will be performed twice; once using FF/VI as the reference group and a second time 
using UMEC/VI as the reference group
7.1.1.
COPD Exacerbations
The definition of exacerbation severity (mild, moderate, severe) is provided in Section 
11.5.3.1. The classification of on-treatment and off-treatment exacerbation is also 
provided in Section 11.3.3. 
For the primary analysis of moderate/severe exacerbations, missing data will not be 
imputed. For statistical analysis, the response variable will be the number of recorded, 
on-treatment, moderate and severe exacerbations. The number and severity of 
exacerbations will be based on assessments as recorded in the eCRF. Symptom data 
recorded on the daily eDiary and concomitant medication use will not be used to 
determine exacerbations. The method of statistical analysis will also incorporate the 
length of time that each subject was at risk of an exacerbation.
Summaries of recorded, on-treatment exacerbations will be provided. Details of the 
exacerbations to be summarized overall and by country includes the number and percent 
of subjects reporting an exacerbation (by severity; moderate, severe and 
moderate/severe), number and percent of subjects with each number of moderate/severe 
exacerbations (0, 1, 2, ≥3), the number of subjects with ≥2 moderate/severe 
exacerbations, the total number of exacerbations per treatment and annual raw 
exacerbation rate. For each exacerbation, the outcome, severity, duration, whether the 
exacerbation led to hospitalization, systemic/oral corticosteroids being taken, antibiotics 
being taken, and emergency room visit will be summarized. For calculation of the raw 
exacerbation rate, see Section 11.5.3.1.
7.2.
Planned Primary Statistical Analyses for Primary Endpoint
Primary Statistical Analyses
Endpoint(s)

Annual rate of on-treatment moderate/severe exacerbations comparing FF/UMEC/VI with 
FF/VI

Annual rate of on-treatment moderate/severe exacerbations comparing FF/UMEC/VI with 
UMEC/VI
Model Specification

Generalized linear model assuming a negative binomial distribution

Terms in the model:

Response: number of recorded, on-treatment, moderate/severe exacerbations experienced 
per subject.

Categorical: treatment group, gender, exacerbation history (≤1, ≥2 moderate/severe),
smoking status (screening), geographical region

Continuous: post-bronchodilator % predicted FEV1 (Screening)

Offset: As defined in Section 11.5.3.1
Model Checking & Diagnostics

Refer to Appendix 10: Model Checking and Diagnostics for Statistical Analysis
 
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Primary Statistical Analyses
Model Results Presentation

Treatment group model estimated exacerbation rates and associated 95% confidence intervals 
(CI), pairwise treatment rate ratios and associated 95% CIs will be presented. The pairwise
treatment percent reductions in annual exacerbation rate and associated 95% CIs will also be 
presented in the same table.

Both adjusted (accounting for the Hochberg multiplicity adjustment, see Section 11.9) and 
unadjusted p-values will be presented for the pairwise treatment comparisons of 
FF/UMEC/VI versus FF/VI, FF/UMEC/VI versus UMEC/VI. Unadjusted p-values will be 
presented for UMEC/VI versus FF/VI.

The pairwise treatment rate ratios and associated 95% CIs for FF/UMEC/VI versus FF/VI 
and FF/UMEC/VI versus UMEC/VI will also be presented graphically
Example of SAS Code
proc genmod data=dsetin;
class trtcd gender exachis  smk region;
model no_exac = trtcd gender exachis smk pctpredFEV region 
                           / dist=negbin link=log offset=log_tm wald type3;
[note: both contrast and estimate statements will be used for the pairwise comparisons]
lsmeans trtcd / cl diff om;
run;
7.3.
Planned Supportive and Sensitivity Statistical Analyses
7.3.1.
Supportive Analyses
7.3.1.1.
Poisson Model
A supportive analysis will be performed whereby the number of on-treatment 
moderate/severe exacerbations will be analyzed using a Poisson regression model with 
deviance over-dispersion correction. The model specification and presentation of results 
will be the same as that with the negative binomial regression analysis.
Supportive Statistical Analyses – Poisson Model
Endpoint(s)

Annual rate of on-treatment moderate/severe exacerbations comparing FF/UMEC/VI with 
FF/VI

Annual rate of on-treatment moderate/severe exacerbations comparing FF/UMEC/VI with 
UMEC/VI
Model Specification

Generalized linear model assuming a Poisson distribution

As defined in Section 7.2
Model Checking & Diagnostics

Refer to Appendix 10: Model Checking and Diagnostics for Statistical Analysis
Model Results Presentation

As defined in Section 7.2.

Note, only unadjusted p-values will be displayed.
Example SAS code

Poisson regression:
 
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Supportive Statistical Analyses – Poisson Model
proc genmod data=dsetin; 
        class trtcd gender exachis smk region subjid;
       model no_exac = trtcd gender exachis smk pctpredFEV region
                 / dist=poisson link=log offset=log_tm type3 lrci; 
       [note: both contrast and estimate statements will be used for the pairwise comparisons]
       lsmeans trtcd /cl diff om;
run;
7.3.1.2.
Investigation of Interactions
The interactions between treatment and other factors (gender, exacerbation history, 
smoking status, region, percent predicted FEV1) will be investigated.
Supportive Statistical Analyses – Interactions
Endpoint(s)

Annual rate of on-treatment moderate/severe exacerbations 
Model Specification

The interactions between treatment and other factors will be investigated as follows by 
adding interaction terms to the negative binomial regression model as defined in Section 7.2

Separate negative binomial models will be fitted to investigate the effect of treatment by 
covariate interactions: (i) with the addition of an interaction term for treatment by gender; (ii) 
with the addition of an interaction term for treatment by exacerbation history; (iii) with the 
addition of an interaction term for treatment by smoking status; (iv) with the addition of an 
interaction term for treatment by geographical region and (v) with the addition of an 
interaction term for treatment by post-bronchodilator percent predicted FEV1 (Screening). 
Model Checking & Diagnostics

Refer to Appendix 10: Model Checking and Diagnostics for Statistical Analysis
Model Results Presentation

The p-value for each interaction test will be presented.

If any interaction p-value is less than 0.10 further investigations will be carried out, for example running 
the analysis by each category of the subgroup. Interaction p-values and any output from interaction 
investigation will be presented.
7.3.2.
Sensitivity Analyses – Investigating Missing Data
7.3.2.1.
Including both On and Off-treatment Data
The negative binomial regression model will be rerun to include both on- and off-
treatment moderate/severe exacerbations as the response variable. The analysis will 
include all post-randomization (on-treatment and off-treatment, see Section 11.3.3) 
moderate/severe exacerbations.
Supportive Statistical Analyses – Including Both On and Off-treatment Data
Endpoints

Annual rate of  moderate/severe exacerbations comparing FF/UMEC/VI with FF/VI

Annual rate of  moderate/severe exacerbations comparing FF/UMEC/VI with UMEC/VI
 
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Supportive Statistical Analyses – Including Both On and Off-treatment Data
Model Specification

As defined in Section 7.2
Model Checking & Diagnostics

Refer to Appendix 10: Model Checking and Diagnostics for Statistical Analysis
Model Results Presentation

As defined in Section 7.2

Note, only unadjusted p-values will be displayed.
7.3.2.2.
Jump to Reference (J2R) - Using On-treatment Data 
On-treatment exacerbations will be analysed in a sensitivity analysis to examine the 
robustness of the exacerbation analysis to departures from the implicit assumption that 
missing data is missing-at-random (MAR).
Subjects that have prematurely withdrawn from study treatment will have their “missing” 
data from the date of the end of study treatment up to their projected Week 52 date (see 
Section 11.5.1.4) imputed and analysed.
The (unconditional) jump-to-reference (J2R) multiple imputation method is based on 
pattern mixture models [Keene et al, 2014], and uses two assumptions about the imputed 
exacerbations during the “unobserved” period: 1) exacerbations in all treatment groups
during the “unobserved” period are imputed using model estimates from the ‘reference’ 
treatment group, 2) the imputed exacerbations are computed using the subject’s baseline 
characteristics (their model covariates), but this estimate is not conditioned on the 
observed data.
First the on-treatment negative binomial analysis is run so that samples of all the model 
parameters i.e. the estimated “betas” associated with treatment, gender, exacerbation 
history etc., and the estimated dispersion parameter can be taken (from their joint 
posterior distribution). From each sample, it is possible to construct a mean for any 
subjects with “missing” data. This mean together with the estimated dispersion parameter 
makes it possible to sample from the negative binomial distribution for the number of 
exacerbations “experienced” by the subject during their unobserved period.
The counts from the unobserved period are added to the counts from the observed period 
and the full data set will be analysed up to Week 52 for each sample. The results from the 
analyses of each sample are combined using Rubin’s formulae [Rubin, 87] as 
implemented in PROC MIANALYZE in SAS.
Jump-to-reference might be considered a worst case scenario which is likely to give a 
conservative estimate of treatment effect because the missing data is assumed to follow 
the same ‘reference pattern’ in all subjects regardless of their study treatment.
This J2R sensitivity analysis will be repeated twice, once using the FF/VI treatment 
group as the reference, and once using the UMEC/VI treatment group as the reference. 
However note that in both models, data from all treatment groups will be used in the 
model, but only one comparison will be presented.
 
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Supportive Statistical Analyses – Jump to Reference
Endpoint(s)

Annual rate of on-treatment + imputed moderate/severe exacerbations (FF/VI as reference).

Annual rate of  on-treatment +imputed moderate/severe exacerbations (UMEC/VI as 
reference)
Model Specification

Covariates defined in Section 7.2.  Analysis described above.
Model Checking & Diagnostics

Refer to Appendix 10: Model Checking and Diagnostics for Statistical Analysis
Model Results Presentation

As defined in Section 7.2.  

Note, only unadjusted p-values will be displayed.

Although all subjects will contribute to the models, only a comparison of FF/UMEC/VI and 
FF/VI will be presented for the FF/VI as reference analysis, and only a comparison of 
FF/UMEC/VI and UMEC/VI will be presented for the UMEC/VI as reference analysis
7.3.2.3.
Jump to Reference (J2R) - Using On and Off-treatment Data 
All exacerbations (on and off-treatment) will be analysed with a J2R missing data 
sensitivity analysis as for on-treatment exacerbations. Here however, the unobserved 
period will be defined for subjects that prematurely withdraw from the study from the 
date of study conclusion up to the projected Week 52 date (see Section 11.5.1.4). Thus, 
all exacerbations observed in the study will be included in this analysis, not just on-
treatment exacerbations.
8.
SECONDARY EFFICACY STATISTICAL ANALYSES
8.1.
Overview of Planned Efficacy Analyses for Secondary 
Endpoints
The secondary efficacy analyses will be based on the ITT population.  Since off-
treatment data was not collected for Trough FEV1 and SGRQ, all analyses for these 
endpoints will use on-treatment data only.  
Table 4 provides an overview of the planned secondary efficacy analyses, with the 
detailed list of data displays being presented in Section 11.12.
Table 4
Overview of Planned Efficacy Analyses
Absolute
Change from Baseline
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Trough FEV1
Baseline FEV1
Y
Y
Trough FEV1 
Y1
Y
Y
Y1
Y2,13
Y
Y
Sensitivity Analysis:
Trough FEV1, 
imputing data 
following 
FF/UMEC/VI 
Y10
Y10
Y11
 
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Absolute
Change from Baseline
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
discontinuation
using jump to 
reference 
assumption
SGRQ Total Score
Baseline SGRQ 
Scores
Y
Y
SGRQ Total Score 
Y1
Y9
Y9
Y1
Y2,13
Y9
Y3
Y9
SGRQ Individual 
Item Responses
Y
Sensitivity Analysis:
SGRQ Total Score, 
imputing data 
following 
FF/UMEC/VI 
discontinuation 
using jump to 
reference 
assumption
Y10
Y10
Y11
COPD Exacerbations
Time to First On-
treatment 
Moderate/Severe 
Exacerbation 
Y4
Y6
Y
Y5
Sensitivity Analysis:
Time to First 
Moderate/Severe 
Exacerbation 
Including Off-
treatment Data 
Y4
Y12
Y5
Sensitivity Analysis:
Time to First On-
treatment 
Moderate/Severe 
Exacerbation or 
treatment 
discontinuation 
Y4
Y12
Y5
Time to First On-
treatment 
Moderate/Severe 
Exacerbation by 
Eosinophil Subgroup
Y4
Y6
Y
Y5
Annual Rate of On-
treatment 
Moderate/Severe 
Exacerbations by 
Eosinophil Subgroup  
Y7
Y8
 
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Absolute
Change from Baseline
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Annual Rate of On-
treatment Severe 
Exacerbations 
Y7
Y8
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw 
data.

Individual = Represents FL related to any displays of individual subject observed raw data.
1.
Mixed Models Repeated Measures (MMRM) analysis
2.
Least squares (LS) means (95% CI) change from baseline and LS mean (95% CI) treatment differences
3.
Box plot and empirical distribution function plot at Week 52
4.
Cox proportional hazards analysis
5.
Kaplan-Meier plot displaying FF/UMEC/VI, FF/VI and UMEC/VI and repeated displaying FF/VI and 
UMEC/VI only 
6.
Plot of hazard ratios (95% CI)
7.
Negative binomial regression model
8.
Plot of on-treatment adjusted exacerbation rate ratios
9.
Summary and listing will include all individual SGRQ domain scores as well as the SGRQ total score
10. Analysis of Covariance (ANCOVA). This analyses will be performed twice; once using FF/VI as the 
reference group and a second time using UMEC/VI as the reference group
11. LS mean (95% CI) treatment differences at Week 52 for both the primary and all sensitivity analyses 
for each endpoint separately to be included as a forest plot
12. Hazard ratios (95% CI) for both the primary analyses and all sensitivity analyses to be included as a 
forest plot
13. Additional plot of LS means (95% CI) change from baseline for UMEC/VI and FF/VI treatment groups 
only
8.2.
Trough FEV1 and SGRQ Total Score
8.2.1.
Planned Primary Statistical Analyses for Trough FEV1 and SGRQ 
Total Score
Secondary Statistical Analyses
Endpoint(s)

Change from baseline in trough FEV1

Change from baseline SGRQ total score 
Model Specification

Mixed Models Repeated Measures (MMRM) model.

While missing data are not explicitly imputed in the primary MMRM analyses, there is an 
underlying assumption that the data are missing at random. All available scheduled post-
baseline assessments will be utilized and via modeling of the within-subject correlation 
structure, the derived treatment differences will be adjusted to take into account missing data.

The MMRM analysis for trough FEV1 will include on-treatment FEV1 measurements at 
Weeks 4, 16, 28, 40 and 52. The MMRM analysis for SGRQ total score will include on-
treatment SGRQ total scores at Weeks 4, 28 and 52.

Although the secondary endpoints are Change from baseline in trough FEV1 at Week 52 for 
 
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Secondary Statistical Analyses
FF/UMEC/VI vs. FF/VI and Change from baseline in SGRQ total Score at Week 52 for 
FF/UMEC/VI vs. FF/VI, results for all treatment comparisons at all time points where data 
are scheduled to be collected will be included in the analysis and presented in the displays.

Terms in the model:

Response: trough FEV1 or SGRQ Total score at each visit.

Categorical: treatment group, smoking status (screening), geographical region, visit 

Continuous: baseline FEV1 or baseline SGRQ Total score 

Interaction: baseline*visit, treatment group*visit

Repeated:  visit 

The model will be fit with an unstructured variance-covariance matrix.

The Kenward and Roger method (KR) for approximating the denominator degrees of 
freedom and correcting for bias in the estimated variance-covariance of the fixed effects will 
be used.  In the event the model fails to run using the KR method, then the residual method 
will be used instead.   

Baseline is defined in Section 11.4.2

Two models will be fitted; one with a response variable of change from baseline and one with 
the response variable as the raw value.
Model Checking & Diagnostics

Refer to Appendix 10: Model Checking and Diagnostics for Statistical Analysis.
Model Results Presentation

Least-square (LS) means and LS mean change from baseline values for each treatment group 
will be presented with their associated standard errors as well as 95% CIs. The estimated 
treatment difference along with corresponding standard error, 95% CI for each Week will be 
presented.

Both adjusted (accounting for the Hochberg multiplicity adjustment, see Section 11.9) and 
unadjusted p-values will be presented for the pairwise treatment comparison at Week 52 of 
FF/UMEC/VI versus FF/VI. Unadjusted p-values only will be presented at other visits for the 
comparison of FF/UMEC/VI versus FF/VI and at all visits for the treatment comparisons of
FF/UMEC/VI versus UMEC/VI and UMEC/VI versus FF/VI.

The LS mean treatment differences (and associated 95% CIs) for all weeks will also be 
presented graphically for FF/UMEC/VI versus FF/VI and FF/UMEC/VI versus UMEC/VI.

The LS mean change from baseline values (and 95% CIs) for the three treatment groups 
across weeks will be presented and repeated displaying the FF/VI and UMEC/VI treatment 
groups only. 
Example SAS Code
proc mixed data=dsetin;
class trtcd visit subjid smk region;
model endpoint=trtcd baseline smk region visit visit*baseline visit*trtcd / ddfm =kr;
repeated visit / subject=subjid type=un;
lsmeans trtcd*visit / cl diff e om=OMdset at (baseline)=(&blm.);
ods output lsmeans=lsmeans;
ods output diffs=diffs;
 
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Secondary Statistical Analyses
run;
[where OMdset is a dataset with a row for every subject-visit combination that contains all of the 
covariates and blm is a macro variable containing the mean baseline for the subjects used in the 
analysis. This is used to derive the LS means using coefficients which are based on the subjects 
used in the analysis.]
8.2.2.
Planned Sensitivity Statistical Analyses for Trough FEV1 and 
SGRQ Total Score
8.2.2.1.
Jump to Reference - Using On-treatment Data
On-treatment trough FEV1 will be analysed in a sensitivity analysis to examine the 
robustness of the FEV1 analysis to departures from the implicit assumption that missing 
data is missing-at-random (MAR).
Subjects with missing on-treatment FEV1 data will have their “missing” data  imputed 
and the Week 52 data (actual or imputed) will be analysed.
The jump-to-reference (J2R) multiple imputation method is based a pattern mixture 
model fully described by [Carpenter et al, 2013].
First the on-treatment MMRM analysis is run so that samples of all the model parameters 
i.e. the estimated “betas” associated with treatment, gender, exacerbation history, etc., 
and the estimated variance and covariance parameters can be taken (from their joint 
posterior distribution). From each sample it is possible to construct a mean for any 
subjects with “missing” data. In the J2R method, the mean estimate is constructed using 
the estimated beta associated with the reference treatment, as well as all the subject’s 
other covariates. This estimated mean together with the sampled estimated variance 
parameters makes it possible to sample from a normal distribution for the trough FEV1 at 
a particular missing visit. First however, the unconditional distribution is updated using 
the appropriate conditional distribution algebra and the subject’s own observed data.
Then the sample is taken using the conditional normal distribution parameters.
The Week 52 data from each sample (imputed for some subjects, and non-missing for 
most subjects) is analysed using an ANCOVA model using the same covariates as the 
original model of FEV1 (with the exception of the visit covariate and its interactions). 
The results from the analyses of each sample are combined using Rubin’s formulae 
[Rubin, 1987] as implemented in PROC MIANALYZE in SAS.
Jump-to-reference might be considered a worst case scenario which is likely to give a 
conservative estimate of treatment effect because the missing data is assumed to follow 
the same ‘reference pattern’ in all subjects regardless of their study treatment.
This J2R sensitivity analysis will be repeated twice, once using the FF/VI treatment 
group as the reference, and once using the UMEC/VI treatment group as the reference. 
However note that in both models, data from all treatment groups will be used in the 
model, but only one comparison will be presented.
 
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SGRQ will be analysed in exactly the same way.
Sensitivity Statistical Analyses – Jump to Reference
Endpoint(s)

Change from baseline in trough FEV1

Change from baseline SGRQ total score 
Model Specification, Checking & Diagnostics, Results Presentation and SAS Code

Analysis of Covariance (ANCOVA) model using data generated from multiple imputation 
methods and the same covariates as the original model (except visit and its interactions).

Analysis model and results presentation will be the same as described in Section 8.2.1, but 
imputing for missing data as described above using the Jump to Reference method and only 
presenting unadjusted p-values.
8.3.
Time to First COPD Moderate/Severe Exacerbation
8.3.1.
Planned Primary Statistical Analyses for Time to First On-
treatment Moderate/Severe Exacerbation
Secondary Statistical Analyses
Endpoint

Time to first on-treatment moderate/severe exacerbation 
Model Specification

Cox’s proportional hazards model

Terms in the model:

Response: time to first on-treatment, moderate/severe exacerbation 

Categorical: treatment group, gender, exacerbation history (≤1, ≥2 moderate/severe), 
smoking status (screening), geographical region 

Continuous: post-bronchodilator % predicted FEV1 (Screening)
                         

The ‘exact’ method will be used for handling ties. If the analysis will not run using the 
‘exact’ method, then the ‘Efron’ method for handling ties will be used instead.

Kaplan-Meier survivor functions will be obtained for each treatment group using PROC 
LIFETEST with a TIME statement.
Model Checking & Diagnostics

Refer to Appendix 10: Model Checking and Diagnostics for Statistical Analysis
Model Results Presentation

Hazard ratios and the percent reduction in risk for the pairwise treatment comparisons with 
associated 95% CIs and p-values will be presented.

Both adjusted (accounting for the Hochberg multiplicity adjustment, see Section 11.9) and 
unadjusted p-values will be presented for the pairwise treatment comparisons of 
FF/UMEC/VI versus FF/VI and FF/UMEC/VI versus UMEC/VI. Only unadjusted p-values 
will be presented for the treatment comparison of UMEC/VI versus FF/VI. The probability of 
having a moderate/severe exacerbation, 95% CI and first quartile and median time to 
exacerbation for each treatment group will be presented. 

The Kaplan-Meier curves will be presented showing the probability of having an event over 
 
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time for each treatment group separately plotted on the same figure. This will be repeated 
displaying UMEC/VI and FF/VI only.
Example SAS Code
proc phreg data=dsetin;
class trtcd smk region exachis gender;
model timeto1*eventflag(0) = trtcd smk region gender pctpredFEV exachis/ risklimits 
ties=exact;
hazardratio trtcd / diff=all;
run;
proc lifetest data=destin outsurv=survest;  
       time timeto1*eventflag(0);
      strata trtcd;
run;
8.3.2.
Planned Sensitivity Statistical Analyses for Time to First On-
treatment Moderate/Severe Exacerbation
8.3.2.1.
Time to First Moderate/Severe Exacerbation Including Off-treatment 
Data
Secondary Statistical Analyses
Endpoint

Time to first moderate/severe exacerbation including off-treatment data
Model Specification

As specified in Section 8.3.1
Model Checking & Diagnostics

Refer to Appendix 10: Model Checking and Diagnostics for Statistical Analysis.
Model Results Presentation

As specified in Section 8.3.1

Note, only unadjusted p-values will be displayed.
8.3.2.2.
Time to First On-treatment Moderate/Severe Exacerbation or Premature 
Treatment Discontinuation
Secondary Statistical Analyses
Endpoint

Time to first on-treatment moderate/severe exacerbation or premature treatment 
discontinuation (See Section 11.5.3.1)
Model Specification

As specified in Section 8.3.1
Model Checking & Diagnostics

Refer to Appendix 10: Model Checking and Diagnostics for Statistical Analysis.
Model Results Presentation

As specified in Section 8.3.1

Note, only unadjusted p-values will be displayed.
 
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8.4.
Time to First On-treatment Moderate/severe Exacerbation by 
Eosinophil Subgroup
Secondary Statistical Analyses
Endpoint

Time to first on-treatment moderate/severe exacerbation by Eosinophil Subgroup 
Model Specification

Cox’s proportional hazards model

Terms in the model:

Response: time to first on-treatment, moderate/severe exacerbations 

Categorical: treatment group, gender, exacerbation history (≤1, ≥2 moderate/severe), 
smoking status (screening), geographical region, EOS subgroup

Continuous: post-bronchodilator % predicted FEV1 (Screening) 

Interaction: treatment group*EOS subgroup

The ‘exact’ method will be used for handling ties. If the analysis will not run using the 
‘exact’ method, then the ‘Efron’ method for handling ties will be used instead.

Kaplan-Meier survivor functions will be obtained for each treatment group using PROC 
LIFETEST with a TIME statement.
Model Checking & Diagnostics

Refer to Appendix 10: Model Checking and Diagnostics for Statistical Analysis.
Model Results Presentation

Hazard ratios (percent reduction in risk) for pairwise treatment comparisons, within each 
level of eosinophil subgroup, with associated 95% CIs and unadjusted p-values will be 
presented.

The probability of having a moderate/severe exacerbation, 95% CI and first quartile and 
median time to exacerbation for each treatment group within each level of eosinophil 
subgroup will be presented. 

The Kaplan-Meier curves will be presented showing the probability of having an event over 
time for each treatment group separately plotted on the same figure. This will be repeated for 
each level of the eosinophil subgroup. This will be repeated displaying the FF/VI and 
UMEC/VI treatment groups only.
Example SAS Code
proc phreg data=dsetin;
class trtcd smk eosinsubgroup region exachis gender;
model timeto1*eventflag(0) = trtcd gender exachis smk region eosinsubgroup pctpredFEV 
trtcd*eosinsubgroup / risklimits ties=exact;
[note: contrast statements will be used for the pairwise comparisons];
run;
proc lifetest data=destin outsurv=survest;  
       time timeto1*eventflag(0);
      strata trtcd eosinsubgroup;
run;
 
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8.5.
Annual Rate of On-treatment Severe Exacerbations
Secondary Statistical Analyses
Endpoint(s)

Annual rate of on-treatment severe exacerbations
Model Specification, Checking & Diagnostics, Results, Presentation and SAS Code

This endpoints will be analyzed using the same methodology as the primary analysis of 
annual rate of moderate/severe exacerbations in Section 7.2

Note, only unadjusted p-values will be displayed.
8.6.
Annual Rate of On-treatment Moderate/severe 
Exacerbations by Eosinophil Subgroup
Secondary Statistical Analyses
Endpoint(s)

Annual rate of on-treatment moderate/severe exacerbations by Eosinophil Subgroup
Model Specification

Generalized linear model assuming a negative binomial distribution

Terms in the model:

Response: number of recorded, on-treatment, moderate/severe exacerbations experienced 
per subject.

Categorical: treatment group, gender, exacerbation history (≤1, ≥2 moderate/severe), 
smoking status (screening), geographical region, EOS subgroup 

Continuous: post-bronchodilator % predicted FEV1 (Screening) 

Interaction: treatment*EOS subgroup

Offset:  As defined in Section 11.5.3.1
Model Checking & Diagnostics

Refer to Appendix 10: Model Checking and Diagnostics for Statistical Analysis
Model Results Presentation

Treatment group model estimated exacerbation rates and associated 95% CIs, pairwise 
treatment rate ratios and associated 95% CIs and unadjusted p-values will be presented for 
each level of subgroup. The pairwise treatment percent reductions in annual exacerbation rate 
and associated 95% CIs will also be presented in the same table.

The pairwise treatment rate ratios for FF/UMEC/VI versus FF/VI and FF/UMEC/VI versus 
UMEC/VI and associated 95% CIs will also be presented graphically for each level of 
subgroup.
Example of SAS Code
proc genmod data=dsetin;
        class trtcd gender exachis  smk region eosinsubgroup;
        model no_exac = trtcd gender exachis smk pctpredFEV region eosinsubgroup  
         trtcd*eosinsubgroup / dist=negbin link=log offset=log_tm wald type3;
[note: both contrast and estimate statements will be used for the pairwise comparisons]
lsmeans trtcd*eosinsubgroup / cl diff om;
run;
 
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9.
OTHER STATISTICAL ANALYSES
9.1.
Other Efficacy and Health Outcomes Analyses
9.1.1.
Overview of Planned Efficacy and Health Outcomes Analyses for 
Other Endpoints
The other efficacy and health outcome analyses will be based on the ITT population 
including on-treatment data only, unless otherwise specified. Summaries and analyses of 
the BDI/TDI will use the TDI population.
Table 5 provides an overview of the planned analyses for the other efficacy endpoints, 
with the detailed list of data displays being presented in Section 11.12.
Table 5
Overview of Planned Efficacy and Health Outcome Analyses for 
Other Endpoints
Absolute
Change from Baseline
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
COPD Exacerbations
Post-treatment 
Moderate/Severe 
Exacerbations
Y
Y
Annual Rate of All 
(Mild, Moderate and 
Severe) On-treatment 
Exacerbations (repeat 
for moderate; requiring 
systemic/oral 
corticosteroids; 
requiring antibiotics)
Y1
Y
Annual Rate of On-
treatment Severe 
Exacerbations by 
Eosinophil Subgroup 
Y1
Y
Time to Each On-
treatment 
Moderate/Severe 
Exacerbation (repeat 
for severe 
exacerbations)
Y2
Time to first on-
treatment severe 
exacerbation by 
eosinophil subgroup
Y3
Time to first on-
treatment severe 
exacerbation (repeat 
for 
Y3
 
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Absolute
Change from Baseline
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
mild/moderate/severe; 
moderate; requiring 
systemic/oral 
corticosteroids; 
requiring antibiotics)  
All Cause Mortality
Adjudicated Cause of 
On-treatment Death 
(repeat for both on-
and off-treatment 
combined)
Y12
Time to Death from 
Any Cause (On-
treatment, repeat for 
on and off treatment 
combined)
Y3
Y3
Y3
Spirometry
Baseline Pre-
bronchodilator FEV1 
by Eosinophil 
Subgroup
Y
Trough FEV1 by 
Eosinophil Subgroup
Y5
Y
Y5
Y
Post-bronchodilator 
FEV1
Y5
Y
Y
Y5
Y6, 
13
Y
FEV1 Reversibility
Y5
Y
Y5
Y
Percentage of subjects
with an increase from 
baseline in trough 
FEV1 ≥100mL
Y10
Y10
Y
Percentage of subjects 
with an increase from 
baseline in trough 
FEV1 ≥100mL by 
Eosinophil Subgroup
Y10
Y10
Baseline FVC
Y
Y
Trough FVC
Y5
Y
Y5
Y6, 
13
Y
Post-Bronchodilator 
FVC
Y5
Y
Y
Y5
Y6, 
13
Y
SGRQ 
Baseline SGRQ Total 
Score by Eosinophil 
Subgroup
Y
SGRQ Total Score by 
Eosinophil Subgroup
Y5
Y
Y5
Y
SGRQ Total Score by 
Y8
Y9
 
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Absolute
Change from Baseline
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Subject Global Rating 
of Change in COPD 
Severity
Proportion of 
Responders according 
to SGRQ Total Score 
Y10
Y10
Y
Proportion of 
Moderate/Major 
Responders according 
to SGRQ Total Score
Y10
Y10
Proportion of Major 
Responders according 
to SGRQ Total Score
Y10
Y10
Proportion of 
Responders according 
to SGRQ Total Score 
by Eosinophil 
Subgroup
Y10
Y10
COPD Assessment Test (CAT)
Baseline CAT Score
Y12
CAT Score
Y5
Y
Y5
Y6,
13
Y
CAT Score  by 
Eosinophil Subgroup
Y5
Y
Y5
Y
Proportion of 
Responders according 
to CAT Score
Y10
Y10
Proportion of 
Responders according 
to CAT Score by 
Eosinophil Subgroup
Y10
Y10
BDI/TDI (TDI Population)
BDI 
Y12
TDI Focal Score 
Y5
Y6, 
13
Y
TDI Focal Score by 
Eosinophil Subgroup
Y5
Y
TDI Category of 
Improvement and 
Deterioration
Y
Proportion of 
Responders according 
to TDI Focal Score
Y10
Y10
Proportion of 
Moderate/Major 
Responders according 
to TDI Focal Score
Y10
Y10
 
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Absolute
Change from Baseline
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Proportion of Major 
Responders according 
to TDI Focal Score
Y10
Y10
Proportion of 
Responders according 
to TDI Focal Score by 
Eosinophil Subgroup
Y10
Y10
Daily Diary Assessments
Mean Number of 
Occasions of Rescue 
Use per Day, Four 
Week Intervals
Y5
Y
Y5
Y6, 
13
Y
Percentage of Rescue-
Free Days, Four Week 
Intervals
Y5
Y
Y5
Y6,
13
Y
Mean Number of 
Nighttime Awakenings 
per night, Four Week 
Intervals
Y5
Y
Y5
Y6, 
13
Y
Percentage of Days 
Symptoms Stopped 
Usual Activities, Four 
Week Intervals
Y5
Y
Y5
Y6, 
13
Y
Subject Global Ratings
Subject Global Rating 
of Activity Limitation
Y
Subject Global 
Impression of Change 
in Activity Limitation
Y11
Y
Subject Global Rating 
of COPD Severity
Y
Subject Global Rating 
of Change in COPD 
Severity
Y11
Y
EQ-5D-5L
Utility Index
Y
VAS Scores
Y
Healthcare Resource Use
Healthcare Resource 
Utilization (all-cause 
and repeated by 
contact type)
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modeling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw 
 
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data.

Individual = Represents FL related to any displays of individual subject observed raw data.
1.
Negative binomial regression model 
2.
Andersen-Gill model for recurrent events
3.
Cox proportional hazards analysis of time to event and Kaplan-Meier plot
4.
Domain and total scores
5.
MMRM analysis
6.
Least squares (LS) means (95% CI) change from baseline and LS mean (95% CI) treatment differences. 
Note: TDI will present LS means for the analysis of the absolute value and not the change from 
baseline.
7.
Box plot and empirical distribution function plot
8.
For combined treatment groups and by treatment group at Week 52
9.
Box plot for combined treatment groups and by treatment group at Week 52
10. Generalized linear mixed model with responder status
11. Logistic regression analysis
12. Repeat for by eosinophil subgroup
13. Additional plot of LS means (95% CI) change from baseline for UMEC/VI and FF/VI treatment groups
only
9.1.1.1.
All Cause Mortality
Summaries of on-treatment and on/off-treatment adjudicated cause of death will be 
provided. The definitions of on-treatment and off-treatment for all cause mortality are 
defined in Section 11.3.2. The censoring rules for time to all cause mortality for on-
treatment and on/off-treatment death are defined in Section 11.5.3.5.
9.1.1.2.
St. George’s Respiratory Questionnaire Responder Analysis
Subjects will be classified as responders or non-responders according to the SGRQ total 
score as described in Section 11.5.3.3.
Week 52 SGRQ total score and change from baseline total score will be summarized by 
Week 52 subject global rating of change in COPD severity for the combined treatment 
groups. Results of this summary will be used to define cut-offs for moderate and major 
responders as described in Section 11.5.3.3. A similar table will also be produced by 
treatment group.  
9.1.1.3.
Baseline Dyspnea Index (BDI)/Transitional Dyspnea Index (TDI) Focal 
Score
The BDI and TDI focal scores [Mahler, 2004] will be calculated as described in Section
11.5.3.5.  
Subjects will be classified as responders or non-responders according to the TDI focal 
score as defined in Section 11.5.3.5. Response will be further classified as moderate or 
major as defined in Section 11.5.3.5.
9.1.1.4.
COPD Assessment Test (CAT)
The CAT score is computed as detailed in Section 11.5.3.4. Subjects will be classified as
responders or non-responders according to the CAT score as described in Section 
11.5.3.4.  
 
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9.1.1.5.
Subject Global Ratings
The Week 52 subject global rating of change in COPD severity will be used to define cut-
offs for moderate and major responders according to the SGRQ total score as defined in 
Section 11.5.3.3.  
9.1.1.6.
Daily Diary Assessments
Rescue salbutamol use recorded on the daily eDiary will be summarized as the mean 
number of occasions of rescue use per day and the percentage of rescue-free days in four-
week interval periods as described in Section 11.5.3.7. 
Symptoms stopping usual activities (yes/no) recorded on the daily eDiary will be 
summarized as the percentage of days symptoms did stop usual activities by four-week 
interval periods as described in Section 11.5.3.7.
Night-time awakenings recorded on the daily eDiary will be summarized as the mean 
number of night-time awakenings per night by four-week interval periods as described in 
Section 11.5.3.7.
All diary analyses performed will be performed by four-weekly periods; the table will 
display estimates for each 4-weekly period.
Symptoms concerning sputum purulence (color), sputum volume, wheezing, sore throat,
cough, colds (nasal discharge and/or nasal congestion), shortness of breath, fever without 
other cause were used solely for the purpose of triggering contact with site personnel for 
exacerbation assessment and will not be reported in any statistical displays.
9.1.1.7.
EuroQol Questionnaire (EQ-5D-5L)
The EQ-5D-5L will be completed on Day 1, Week 28 and Week 52. Two scores will be 
summarized; the EQ-5D-5L utility score and the EQ-5D-5L visual analogue scale (VAS) 
score.
For the EQ-5D-5L utility score, EQ-5D-5L health states will be converted to a single 
summary utility 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-5L health 
states from general population samples in the country. The weights to be applied in the 
formula are not yet available for all countries participating in the study. Therefore, utility 
scores will be calculated using England weighting as published at the EuroQol website 
[EuroQol website]. 
Missing individual response for any dimension will not be imputed. Consequently, the 
summary index will be missing since it is based only on a complete set of responses for 
all 5 dimensions.
Individual country data may be analyzed post hoc using appropriate country based tariffs.
 
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9.1.1.8.
Unscheduled Healthcare Resource Utilization
Summaries of all-cause unscheduled healthcare resource utilization will be provided for 
the on-treatment period for the ITT population.  This will be repeated by contact type.
9.1.2.
Planned Efficacy Statistical Analyses of Other Endpoints
9.1.2.1.
Time to First On-treatment Exacerbation
Secondary Statistical Analyses
Endpoint

Time to first on-treatment severe exacerbation

Time to first on-treatment mild/moderate/severe exacerbation

Time to first on-treatment moderate exacerbation

Time to first on-treatment exacerbation requiring systemic/oral corticosteroids

Time to first on-treatment exacerbations requiring antibiotics
Model Specification

Cox’s proportional hazards model

Terms in the model:

Response: time to first on-treatment exacerbation (type of exacerbation dependent on 
endpoint)

Categorical: treatment group, gender, exacerbation history (≤1, ≥2 moderate/severe), 
smoking status (screening), geographical region 

Continuous: post-bronchodilator % predicted FEV1 (Screening) 
                  

The ‘exact’ method will be used for handling ties. If the analysis will not run using the 
‘exact’ method, then the ‘Efron’ method for handling ties will be used instead.

Kaplan-Meier survivor functions will be obtained for each treatment group using PROC 
LIFETEST with a TIME statement.
Model Checking & Diagnostics

Refer to Appendix 10: Model Checking and Diagnostics for Statistical Analysis.
Model Results Presentation

Results will be presented as described in Section 8.3.1

Note, only unadjusted p-values will be displayed.
9.1.2.2.
Time to First On-treatment Severe Exacerbation by Eosinophil 
Subgroup
Secondary Statistical Analyses
Endpoint

Time to first on-treatment severe exacerbation by eosinophil subgroup
Model Specification, Model Checking & Diagnostics, Model Results Presentation

Defined in Section 8.4
 
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9.1.2.3.
Annual Rate of On-treatment Exacerbations
Other Efficacy Statistical Analyses
Endpoint(s)

Annual rate of all on-treatment exacerbations (mild, moderate, severe)

Annual rate of on-treatment moderate exacerbations

Annual rate of on-treatment exacerbations requiring systemic/oral corticosteroids

Annual rate of on-treatment exacerbations requiring antibiotics

Annual rate of on-treatment severe exacerbations by eosinophil subgroup
Model Specification, Checking & Diagnostics, Results Presentation and SAS Code

These endpoints will be analyzed and presented as described in Section 7.2 and Section 8.6.

Note, only unadjusted p-values will be displayed.
9.1.2.4.
Time to Onset of Each Exacerbation
Other Efficacy Statistical Analyses
Endpoint(s)

Time to onset of each on-treatment moderate/severe exacerbation

Time to onset of each on-treatment severe exacerbation
Model Specification

Andersen-Gill regression model for recurrent events

Terms in the model:

Response: time to each on-treatment exacerbation (type of exacerbation dependent on 
endpoint)

Categorical: treatment group, gender, exacerbation history (≤1, ≥2 moderate/severe), 
smoking status (screening), geographical region 

Continuous: post-bronchodilator % predicted FEV1 (Screening)

A robust sandwich covariance matrix structure for the within subject correlation [Therneau, 
2000] will be used to allow for the lack of independence among multiple events per subject 
over time (to achieve this, the COVS(AGGREGATE) option will be used in the PHREG 
statement).

The ‘exact’ method will be used for handling ties. If the analysis will not run using the 
‘exact’ method, then the ‘Efron’ method for handling ties will be used instead.
Model Checking & Diagnostics

Refer to Appendix 10: Model Checking and Diagnostics for Statistical Analysis.
Model Results Presentation

Hazard ratios and the percent reduction in risk for the pairwise treatment comparisons with 
associated 95% CIs and unadjusted p-values will be presented.
Example SAS Code
proc phreg data=dsetin covsandwich(aggregate);
id subjid;
class trtcd smk region exachis gender;
model (start stop)*eventflag(0) = trtcd smk gender exachis region pctpredFEV / risklimits 
ties=exact;
hazardratio trtcd / diff=all;
run;
 
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9.1.2.5.
Trough FEV1, SGRQ Total Score, CAT score and TDI by Eosinophil 
Subgroup
Other Efficacy Statistical Analyses
Endpoint(s)

Change from baseline in trough FEV1 by Eosinophil Subgroup

Change from baseline in SGRQ total score by Eosinophil Subgroup

Change from baseline in CAT score by Eosinophil Subgroup

TDI focal score by Eosinophil Subgroup
Model Specification, Checking & Diagnostics, Results Presentation and SAS Code

These endpoints will be analyzed using the same methodology as trough FEV1 in Section 
8.2.1. Eosinophil subgroup will be added to the model as a categorical variable as well as the 
following interactions: treatment group*Eosinophil subgroup, visit*Eosinophil subgroup, 
treatment group*visit*Eosinophil subgroup

Since TDI is a transitional index there will be no change from baseline analysis for TDI.

Baseline is defined in Section 11.4.2.

LS means and LS mean change from baseline values for each treatment group within each 
level of Eosinophil subgroup will be presented with their associated standard errors as well as 
95% CIs. 

The estimated treatment difference for FF/UMEC/VI versus FF/VI and FF/UMEC/VI versus 
UMEC/VI along with corresponding standard error, 95% CI and p-value for each Week 
within each level of Eosinophil subgroup will be presented. 

Note, only unadjusted p-values will be displayed.

For this subgroup analyses, OMdset is a dataset with a row for every subject-visit 
combination that contains all of the covariates and blm is a macro variable containing the 
mean baseline for the subjects used in the analysis, with a separate OMdset created for each 
level of the subgroup.
9.1.2.6.
Post-bronchodilator FEV1 and FVC, Trough FVC, CAT, TDI
Other Efficacy Statistical Analyses
Endpoint(s)

Change from baseline  in post-bronchodilator FEV1

Change from baseline in post-bronchodilator FVC

Change from baseline in trough FVC

Change from baseline in FEV1 reversibility

Change from baseline in CAT Score

TDI
Model Specification, Checking & Diagnostics, Results Presentation and SAS Code

These endpoints will be analyzed using the same methodology as trough FEV1 in Section 
8.2.1

Since TDI is a transitional index there will be no change from baseline analysis for TDI.

Baseline is defined in Section 11.4.2.
 
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Other Efficacy Statistical Analyses

Note, only unadjusted p-values will be displayed.
9.1.2.7.
Proportion of Responders According to FEV1, SGRQ, CAT and TDI
Other Efficacy Statistical Analyses
Endpoint(s)

Percentage of subjects with an increase from baseline in trough FEV1 ≥ 100mL

Proportion of responders according to SGRQ total score

Proportion of moderate/major responders according to SGRQ total score

Proportion of major responders according to SGRQ total score

Proportion of responders according to CAT score

Proportion of responders according to TDI focal score

Proportion of moderate/major responders according to TDI

Proportion of major responders according to TDI
Model Specification

Generalized linear mixed model

Terms in the model:
  Dependent :       response (yes/no) 
  Categorical :      treatment group, smoking status (screening), geographical  
region, visit, subject  
  Continuous :      baseline (FEV1, SGRQ total , CAT score or BDI)
  Interaction :       baseline*visit, treatment group*visit

The model will be fit with an unstructured variance-covariance matrix with one single model 
to include all visits where the assessment in question is scheduled to be performed.

Computation of confidence intervals for the odds ratios is based on the individual Wald tests.
Model Checking & Diagnostics

Refer to Appendix 10: Model Checking and Diagnostics for Statistical Analysis.
Model Results Presentation

Number and percentage of responders and non-responders for each treatment at each week

Odds ratio for pairwise comparisons with associated 95 % CIs and unadjusted p-values
Example SAS Code
proc glimmix data=dsetin;
class trtcd smk region visit subjid;
model respond(event=”1”)=trtcd baseline smk region 
visit visit*baseline visit*treatment 
/ dist=binary link=logit ddfm=kr solution;
lsmeans trtcd*visit / cl diff or om;
random visit / subject=subjid residual type=un;
ods outputs diffs=differs;
run;
 
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9.1.2.8.
Proportion of Responders According to FEV1, SGRQ, CAT and TDI by 
Eosinophil Subgroup
Other Efficacy Statistical Analyses
Endpoint(s)

Percentage of subjects with an increase from baseline in trough FEV1 ≥ 100mL by 
Eosinophil Subgroup

Proportion of responders according to SGRQ total score by Eosinophil Subgroup

Proportion of responders according to CAT score by Eosinophil Subgroup

Proportion of responders according to TDI focal score by Eosinophil Subgroup
Model Specification, Checking & Diagnostics, Results Presentation and SAS Code

These endpoints will be analyzed using the same methodology as in Section 9.1.2.7. 
Eosinophil subgroup will be added to the model as a categorical variable as well as the 
following interactions: treatment group*Eosinophil subgroup, visit*Eosinophil subgroup, 
treatment group*visit*Eosinophil subgroup

Baseline is defined in Section 11.4.2.

Number and percentage of responders and non-responders for each treatment at each week
within each level of Eosinophil subgroup will be presented

Odds ratio for pairwise comparisons at each visit within each level of eosinophil subgroup
with associated 95 % CIs will be presented

Note, only unadjusted p-values will be displayed.
9.1.2.9.
Time to Death from Any Cause
Other Efficacy Statistical Analyses
Endpoint(s)

Time to death from any cause (on-treatment)

Time to death from any cause (on- and off-treatment)
Model Specification, Checking & Diagnostics, Results Presentation and SAS Code

Cox’s proportional hazards model

Terms in the model:

Response: time to death

Categorical: treatment group, gender

Continuous: age
                         

The ‘exact’ method will be used for handling ties. If the analysis will not run using the 
‘exact’ method, then the ‘Efron’ method for handling ties will be used instead.

Kaplan-Meier survivor functions will be obtained for each treatment group using PROC 
LIFETEST with a TIME statement.
Model Checking & Diagnostics and Results Presentation

The model checking and results presentation is detailed in Section 8.3.1

Note, only unadjusted p-values will be displayed.
 
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9.1.2.10.
Rescue Use, Symptoms and Nighttime Awakenings
Other Efficacy Statistical Analyses
Endpoint(s)

Mean number of occasions of rescue use per day by four weekly intervals

Percentage of rescue-free days by four weekly intervals

Percentage of days symptoms stopped usual activities by four weekly intervals

Mean number of nighttime awakenings per night by four weekly intervals
Model Specification, Checking & Diagnostics, Results Presentation and SAS Code

These endpoints will be analyzed using the same methodology and presentation as trough 
FEV1 in Section 8.2.1.

Visit will be replaced with all available four-weekly periods (Weeks 1-4, 5-8 and up to 
Weeks 49-52) and LS Means for each four weekly interval will be presented.

Baseline is defined in Section 11.4.2.

Note, only unadjusted p-values will be displayed.
9.1.2.11.
Subject Global Ratings of Change
Other Efficacy Statistical Analyses
Endpoint(s)

Subject global rating of change in activity limitation

Subject global rating of change in COPD severity
Model Specification

Logistic regression model

Terms in the model:
  Dependent :       change response (7-point scale) 
  Categorical :      treatment group, smoking status (screening), geographical   
region  

The model will be fit at each visit (Weeks 4, 16, 28, 40 and 52).

Computation of confidence intervals for the odds ratios is based on the individual Wald tests
Model Checking & Diagnostics

Refer to Appendix 10: Model Checking and Diagnostics for Statistical Analysis.
Model Results Presentation

Number and percentage of subjects reporting each category of change at each visit

Odds ratio, 95% CI and unadjusted p-values for the pairwise treatment comparisons
Example SAS Code
proc logistic data=dsetin;
class trtcd smk region / param=glm;
model changevar = trtcd smk region / l=logit;
[note: both contrast and estimate statements will be used for the pairwise comparisons]
run;
 
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9.2.
Safety Analyses
9.2.1.
Overview of Planned Analyses
The safety analyses will be based on the ITT population unless stated otherwise.
Section 9.2.2 to Section 9.2.12 provide the overviews of the planned safety analyses, with 
the detailed list of data displays being presented in Section 11.12. 
9.2.2.
Overview of Planned Exposure Analyses
Table 6
Overview of Planned Exposure Analyses
Data Displays Generated
Table
Figure
Listing
Exposure 
Exposure Data
Y1
Y
Y
Post-treatment Duration on Study
Y1
Y
On and Post-treatment Duration on Study
Y1
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modeling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.     
1.
Repeat by eosinophil subgroup
9.2.3.
Overview of Planned Adverse Event Analyses
Table 7
Overview of Planned Adverse Event Analyses
Data Displays Generated
Table
Figure
Listing
Adverse Events (AEs)
Overview of On-treatment AEs
Y
All AEs (ASE)
Y
On-treatment AEs
Y1
On-treatment Drug-Related AEs
Y
On-treatment AEs Leading to Permanent Discontinuation of Study 
Treatment or Withdrawal from the Study
Y
Y5
Ten Most Frequent On-treatment AEs in Each Treatment Group
Y
On-treatment Common Non-Serious AEs (3% or More of Subjects in 
Any Treatment Group) 
Y
On-treatment AE Categories of Interest in the Elderly by Age
Y
Relationship of AE System Organ Class, Preferred Term and Verbatim 
Text (ASE)
Y
Subject Numbers for Individual AEs (ASE)
Y
Serious Adverse Events (SAEs)
Pre-treatment SAEs
Y2
Y5
Pre-treatment Fatal SAEs (ASE)
Y
Pre-treatment SAEs Leading to Withdrawal from Study (ASE)
Y
 
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Data Displays Generated
Table
Figure
Listing
Subjects and Number of Occurrences of on-treatment serious, drug-
related serious, fatal and drug-related SAEs
Y
On-treatment SAE
Y3
Y5
On-treatment Drug-Related SAEs
Y
On-treatment Drug-Related Fatal SAEs
Y
Post-treatment SAEs
Y
Y5
Post-treatment Fatal SAEs
Y
Reasons for Considering as a Serious AE
Y
Adjudicated Serious Adverse Reports
Adjudicated On-treatment Serious Adverse Reports
Y3
Adjudicated Post-treatment Serious Adverse Reports
Y3
AEs of Special Interest (AESI)
On-treatment AESI 
Y6
Analysis of Time to First On-treatment Event in the Pneumonia AESI 
Group
Y4,6
Y4,7
Pneumonia Risk Factors at Screening for those Subjects with an on-
treatment event in the pneumonia AESI group
Y6
Analysis of Time to First On-treatment Event in the CV AESI Group
Y4
Y4,7
Summary of Incidence of On-treatment Pneumonia AESI and 
Adjudicated Pneumonia
Y
SAEs of Special Interest (SAESI)
On-treatment Serious AESI 
Y3
Analysis of Time to First On-treatment event in the Pneumonia AESI 
group  resulting in hospitalization, prolonged hospitalization or death
Y4
Y4,7
Analysis of Time to First On-treatment event in the CV AESI group 
resulting in hospitalization, prolonged hospitalization or death
Y4
Y4,7
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modeling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.     
1.
Repeat by country
2.
Repeat for ASE population
3.
Repeat for fatal and non-fatal separately
4.
Cox proportional hazards analysis and Kaplan-Meier plot for time to first event
5.
Combined listing for all reported AEs (any treatment phase). SAE listing will be split by fatal and non-fatal SAEs 
and based on the ASE population
6.
Repeat by eosinophil subgroup
7.
Additional Kaplan-Meier plot for UMEC/VI and FF/VI treatment groups only
9.2.3.1.
Adverse Events of Special Interest
Adverse events of special interest (AESI) have been defined as AEs which have specified 
areas of interest for FF, VI, or UMEC or for the COPD population. A list of 
Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries (SMQs) 
and other groupings for AESI is provided in Section 11.5.4.2. 
 
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A summary of AE categories of interest in the elderly by age and overall for each 
treatment group will be provided for AESI.  The list of AE categories of interest in the 
elderly is provided in Section 11.5.4.2.
A summary of the number of events in the pneumonia AESI group and the number of 
these that had investigator-reported pneumonia (on the pneumonia eCRF form, and split 
by those supported/not supported by x-ray/CT scan) and/or that had an associated 
adjudicated report of pneumonia will be provided. This will be repeated for serious 
events in the pneumonia AESI group within the same table. The number of investigator-
reported pneumonia events not reported as pneumonia AESI will also be provided and 
the number of adjudicated serious adverse reports of pneumonia not associated with a 
pneumonia AESI. Association between events in the pneumonia AESI group and 
adjudicated reports of pneumonia is defined in Section 11.5.4.2.
9.2.3.2.
Pneumonia Risk Factors
Baseline characteristics to identify potential pneumonia risk factors at screening, as 
defined in Section 11.5.2.5, will be summarised for those subjects who have an on-
treatment event in the pneumonia AESI group.
9.2.3.3.
Pregnancy
Any pregnancies reported during the study will be summarized in case narratives. Any 
pregnancy complication or elective termination of a pregnancy for medical reasons will 
be recorded as an AE or SAE and included in summaries and listings of AEs/SAEs.
9.2.3.4.
Oropharyngeal Examination
Oropharyngeal examination was conducted as part of the physical examination and 
included in source documentation.  Any adverse finding will be recorded as an AE or 
SAE and included in summaries and listings of AEs/SAEs.
9.2.4.
Overview of Major Adverse Cardiac Events (MACE)
Table 8
Overview of Planned MACE Analyses
Data Displays Generated
Table
Figure
Listing
Major Adverse Cardiac Events (MACE)
On-treatment MACE (Narrow Definition)
Y
On-treatment MACE (Broad Definition)
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modeling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.     
 
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9.2.4.1.
Major Adverse Cardiac Events
Major adverse cardiac event (MACE) endpoints will be based on both eCRF and 
adjudicated data. The definition is shown in Section 11.5.4.9.
9.2.5.
Overview of Pneumonia Details (from the eCRF Pneumonia Form)
Table 9
Overview of Planned Pneumonia Details (from the eCRF pneumonia 
form) Analyses
Data Displays Generated
Table
Figure
Listing
Pneumonia (eCRF Pneumonia Form)
On-treatment Pneumonia Incidence
Y1
On-treatment Details of Pneumonia
Y1
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modeling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.     
1.
Repeat tables for events resulting in hospitalization, prolonged hospitalization or death
9.2.6.
Overview of the Composite Endpoints
Table 10
Overview of Planned Composite Endpoint Analyses
Data Displays Generated
Table
Figure
Listing
Composite endpoints
Analysis of Time to First event in the Pneumonia AESI group or 
moderate/severe exacerbation Composite
Y
Y1
Analysis of time to first severe exacerbation or event in the 
pneumonia AESI group resulting in hospitalization, prolonged 
hospitalization or death
Y
Y1
Analysis of time to first severe exacerbation or event in the CV AESI
group resulting in hospitalization, prolonged hospitalization or death 
or event in the pneumonia AESI group resulting in hospitalization, 
prolonged hospitalization or death
Y
Y1
Percentage of subjects with an event in the pneumonia AESI group 
and percentage of subjects with a moderate/severe exacerbation.
Y1
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modeling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data. 
1.
Kaplan-Meier plot displaying FF/UMEC/VI, FF/VI and UMEC/VI and repeated displaying FF/VI and UMEC/VI only
 
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9.2.7.
Overview of Bone Fractures
Table 11
Overview of Bone Fracture Analyses
Data Displays Generated
Table
Figure
Listing
Bone Fractures
On-treatment Bone Fractures
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modeling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data
9.2.8.
Overview of Chest Imaging
Table 12
Overview of Planned Chest Imaging Analyses
Data Displays Generated
Table
Figure
Listing
Radiography (Chest Imaging)
On-treatment Chest Imaging
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modeling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data
9.2.9.
Overview of Liver Events
Table 13
Overview of Planned Liver Events Analyses
Data Displays Generated
Table
Figure
Listing
Liver Events
Liver Monitoring/Stopping Event Reporting
Y
Hepatobiliary Laboratory Abnormalities  
Y
Medical Conditions for Subjects with Liver Stopping Events
Y
Liver Event Substance Use
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modeling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

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9.2.10.
Overview of Laboratory Parameters
Table 14
Overview of Planned Laboratory Parameters Analyses
Absolute
Change from 
Baseline
Summary
Individual
Summary
T
F
F
L
T
F
Laboratory Parameters
Liver Function Tests
Y1
Chemistry Values for Subjects with at Least 
One Value Outside the Normal Range
Y
Chemistry Data
Y
Y2
Y
Y3
Chemistry Data Outside the Normal Range
Y
Chemistry Changes from Baseline Relative 
to the Normal Range
Y
Hematology Values for Subjects with at 
Least One Value Outside the Normal Range
Y
Hematology Data
Y
Y2
Y
Y3
Hematology Data Outside the Normal 
Range
Y
Hematology Changes from Baseline 
Relative to the Normal Range
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modeling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.     
1.
Trellis display of maximum post-baseline liver function test values (to include alanine aminotransferase, 
aspartate aminotransferase, alkaline phosphotase and bilirubin ) versus baseline liver function test values 
divided by Upper Limit of Normal (ULN)
2.
Separate scatter plots for maximum and minimum post-baseline versus baseline divided by ULN for maximum 
and Lower Limit of Normal (LLN) for minimum 
3.
Separate box plots of change from baseline in maximum and minimum post-baseline values
9.2.11.
Overview of Vital Signs
Table 15
Overview of Planned Vital Signs Analyses
Absolute
Change from 
Baseline
Summary
Individual
Summary
T
F
F
L
T
F
Vital Signs
Vital Sign Data (Pulse Rate, Systolic Blood 
Pressure (BP), Diastolic BP)
Y
Y
Statistical Analysis of Pulse Rate (bpm)
Y1
Y1
Statistical Analysis of Systolic BP (mmHg)
Y1
Y1
Statistical Analysis of Diastolic BP (mmHg)
Y1
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NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modeling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.     
1.
MMRM analysis
9.2.11.1.
Vital Signs
Vital signs collected at study treatment discontinuation will be included in ‘worst case 
post-baseline’ summaries but will not be summarized separately. See Section 11.5.4.4 for 
the definition of ‘worst case post-baseline’. See Section 9.2.13.1 for details on the 
statistical analysis of vital signs data.
9.2.12.
Overview of ECGs
Absolute
Change from 
Baseline
Summary
Individual
Summary
T
F
F
L
T
F
12-Lead ECGs
ECG Values (PR interval, QTcB, QTcF, 
and mean heart rate)
Y1
Y1
ECG Values (PR interval, QTcB, QTcF, 
and mean heart rate) for Subjects with Any 
Abnormal Finding
Y
ECG Findings
Y1
ECG Findings Shifts from Baseline, 
repeated for shift between pre and post 
treatment at Week 4
Y1
ECG Abnormalities
Y1,6
Y
ECG Abnormalities (>3% in Any Treatment 
Group)
Y
QTcF Categories
Y1
Y1
Maximum Post-Baseline QTcF
Y1,3
Y1,3
Statistical Analysis of Pre-dose QTcF at 
Week 4
Y5
Y5
Statistical Analysis of Post-dose QTcF
Y2
Y2,4
Change from pre-dose to post-dose ECG 
Heart Rate at Week 4 (Pre-dose ECG 
population)
Y
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modeling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.     
1.
Repeat for pre-dose ECG population
2.
MMRM analysis
3.
Empirical distribution function plot; maximum defined as the maximum value of individual measurements (including 
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4.
One combined table for endpoint and change from baseline endpoint
5.
ANCOVA analysis
6.
Summary will include event rates
9.2.12.1.
ECGs
12-Lead ECGs are collected at Screening (Visit 1) and approximately 15-45 minutes after 
dosing on treatment at Week 4, Week 28 and Week 52, or at the Study Treatment 
Discontinuation Visit. In addition, at Week 4 (from sites included in the ECG substudy) 
one additional ECG will be collected pre-dose. This pre-dose ECG will not be included 
on the ITT displays of scheduled post-dose ECG assessments but will be included in the 
determination of the maximum/worst case post baseline summaries for all ECG 
summaries, see Section 11.5.4.4.  ECG displays will be repeated for the ECG population 
summarizing all ECG data as detailed in Section 9.2.12.
All ECG data present in the database will be considered valid and will be reported.
ECGs collected at study treatment discontinuation will be included in ‘worst case post-
baseline’ summaries but will not be summarized separately. See Section 11.5.4.4 for the 
definition of ‘worst case post-baseline’. See Section 9.2.13.1 for details on the statistical 
analysis of ECG data.
9.2.13.
Planned Statistical Analyses of Safety Endpoints
9.2.13.1.
Vital Signs and ECGs
Statistical Analysis of Safety Endpoints – MMRM Analysis
Endpoints

Pulse rate

Systolic BP

Diastolic BP

QTcF (Post-dose)
Model Specification, Checking, Results Presentation and SAS code

These endpoints will be analyzed using similar methodology and presentation as trough 
FEV1 in Section 8.2.1.

Terms in the model:

Response: Value (dependent on endpoint) at each visit.

Categorical: treatment group, smoking status (screening), geographical region, visit

Continuous: baseline 

Interaction: baseline*visit, treatment group*visit

Repeated:  visit 

Baseline is defined in Section 11.4.2

Two models will be fitted; one with a response variable of change from baseline and one with 
the response variable as the raw value.
 
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Statistical Analysis of Safety Endpoints – ANCOVA Analysis
Endpoints

QTcF (Pre-dose) at Week 4 (Pre-dose ECG population only)
Model Specification

ANCOVA model.

Terms in the model:

Response: Pre-dose QTc(F) at Week 4.

Categorical: treatment group, smoking status (screening), geographical region 

Continuous: baseline QTc(F)

Baseline is defined in Section 11.4.2

Two models will be fitted; one with a response variable of change from baseline and one with 
the response variable as the raw value.
Model Checking & Diagnostics

Refer to Appendix 10: Model Checking and Diagnostics for Statistical Analysis
Model Results Presentation

Least-square (LS) means and LS mean change from baseline values for each treatment group 
will be presented with their associated standard errors as well as 95% CIs. The estimated 
treatment difference along with corresponding standard error, 95% CI and unadjusted p-
values will be presented.
Example SAS Code
proc mixed data=dsetin;
class trtcd visit subjid smk region;
model endpoint=trtcd baseline smk region / ddfm =kr;
lsmeans trtcd / cl diff e om;
ods output lsmeans=lsmeans;
ods output diffs=diffs;
run;
9.2.13.2.
Time to First Event in the Pneumonia AESI Group, Cardiovascular AESI 
Group
Safety  Statistical Analyses Time to First Pneumonia
Endpoint

Time to first on-treatment event in the Pneumonia AESI group

Time to first on-treatment event in the Pneumonia AESI group resulting in hospitalization, 
prolonged hospitalization or death.

Time to first on-treatment event in the Cardiovascular AESI group

Time to first on-treatment event in the Cardiovascular AESI group resulting in 
hospitalization, prolonged hospitalization or death.
 
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Model Specification

Cox’s proportional hazards model

Terms in the model:

Response: time to first event in the Pneumonia/Cardiovascular AESI group (definition 
dependent on endpoint)

Categorical: treatment group, geographical region 
                         

The ‘exact’ method will be used for handling ties. If the analysis will not run using the 
‘exact’ method, then the ‘Efron’ method for handling ties will be used instead.

Kaplan-Meier survivor functions will be obtained for each treatment group using PROC 
LIFETEST with a TIME statement.
Model Checking & Diagnostics

Refer to Appendix 10: Model Checking and Diagnostics for Statistical Analysis.
Model Results Presentation

Hazard ratios (and percent reduction in risk for pairwise treatment comparisons with 
associated 95% CIs and unadjusted p-values will be presented.

The probability of having an event, 95% CI and first quartile and median time to event for 
each treatment group will be presented.

The Kaplan-Meier curves will be presented showing the probability of having an event over 
time for each treatment group separately plotted on the same figure. This will be repeated 
displaying FF/VI and UMEC/VI treatment groups only.
Example SAS Code
proc phreg data=dsetin;
class trtcd region;
model timeto1*eventflag(0) = trtcd region / risklimits ties=exact;
hazardratio trtcd / diff=all;
run;
proc lifetest data=destin outsurv=survest;  
       time timeto1*eventflag(0);
     strata trtcd;
run;
 
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9.2.13.3.
Time to First Event in the Pneumonia AESI Group by Eosinophil 
Subgroup 
Safety  Statistical Analyses Time to First Pneumonia by Eosinophil Subgroup
Endpoint

Time to first on-treatment event in the Pneumonia AESI group by eosinophil subgroup
Model Specification, Checking & Diagnostics, Results Presentation and SAS Code

This endpoint will be analyzed using the same methodology as in Section 9.2.13.2 with
Eosinophil subgroup added to the model as a categorical variable as well as the interaction: 
treatment group*Eosinophil subgroup

Hazard ratios (and percent reduction in risk for pairwise treatment comparisons within each 
level of eosinophil subgroup with associated 95% CIs and unadjusted p-values will be 
presented.

The probability of having an event, 95% CI and first quartile and median time to pneumonia 
for each treatment group within each level of eosinophil subgroup will be presented. 

The Kaplan-Meier curves will be presented showing the probability of having an event over 
time for each treatment group separately plotted on the same figure. This will be repeated for 
each level of the eosinophil subgroup.  These will be repeated displaying FF/VI and 
UMEC/VI treatment groups only.
9.2.13.4.
Time to First Event in the Pneumonia AESI Group or COPD 
Exacerbation 
Safety  Statistical Analyses Time to First Pneumonia
Endpoint

Time to first on-treatment event in the Pneumonia AESI group or moderate/severe 
exacerbation composite

Time to first on-treatment event in the Pneumonia AESI group resulting in hospitalization,
prolonged hospitalization or death or severe exacerbation composite
Model Specification

Cox’s proportional hazards model

Terms in the model:

Response: time to first event in the Pneumonia AESI group or exacerbation (definition 
dependent on endpoint)

Categorical: treatment group, gender, exacerbation history (≤1, ≥2 moderate/severe), 
smoking status (screening), geographical region 

Continuous: post-bronchodilator % predicted FEV1 (Screening) 
                         

The ‘exact’ method will be used for handling ties. If the analysis will not run using the 
‘exact’ method, then the ‘Efron’ method for handling ties will be used instead.

Kaplan-Meier survivor functions will be obtained for each treatment group using PROC 
LIFETEST with a TIME statement.
Model Checking & Diagnostics

Refer to Appendix 10: Model Checking and Diagnostics for Statistical Analyses.
 
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Model Results Presentation

Hazard ratios (and percent reductions in risk for pairwise treatment comparisons with 
associated 95% CIs and unadjusted p-values will be presented.

The probability of having an event, 95% CI and first quartile and median time to pneumonia 
for each treatment group will be presented. Risk reductions will also be presented.

The Kaplan-Meier curves will be presented showing the probability of having an event over 
time for each treatment group separately plotted on the same figure. This will be repeated 
displaying FF/VI and UMEC/VI treatment groups only.
Example SAS Code
proc phreg data=dsetin;
class trtcd smk region gender exachis;
model timeto1*eventflag(0) = trtcd smk region gender exachis pctpred/ risklimits 
ties=exact;
hazardratio trtcd / diff=all;
run;
proc lifetest data=destin outsurv=survest;  
       time timeto1*eventflag(0);
      strata trtcd;
run;
9.2.13.5.
Time to First Exacerbation, Event in the CV AESI Group and Event in 
the Pneumonia AESI Group Composite Endpoints
Other Efficacy Statistical Analyses
Endpoint(s)

Time to first severe COPD exacerbation, event in the CV AESI group that resulted in 
hospitalization, prolonged hospitalization or death and event in the pneumonia AESI group
that resulted in hospitalization, prolonged hospitalization or death composite
Model Specification and Presentation

These endpoints will be analysed and presented as described in Section 9.2.13.4

Note, only unadjusted p-values will be displayed.
9.3.
Pharmacokinetic Analyses
Population PK analysis will be the subject of a separate RAP.
9.4.
Pharmacogenetics Analyses
Pharmacogenetics analyses will be the subjects of a separate RAP
9.5.
Biomarker Analyses
The analyses of fibrinogen will be the subject of a separate RAP
 
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10.
REFERENCES
Andersen PK, Gill RD. (1982) Cox’s regression model for counting processes: a large 
sample study. Annals of Statistics 10:1100-1120.
Atkinson, AC. (1985) Plots, Transformations and Regression. Clarendon Press.
Carpenter J, Roger J, Kenward M. Analysis of longitudinal trials with missing data: a 
framework for relevant, accessible assumptions, and inference via multiple imputation. J 
Biopharm Stat. 2013;23(6):1352-7
Dmitrienko A, Tamhane A, Wiens B. (2008) General Multistage Gatekeeping 
Procedures. Biometrical Journal 50(5):667-677.
EuroQol website: Valuing Health-Related Quality of Life: An EQ-5D-5L Value Set for 
England.  https://www.ohe.org/publications/valuing-health-related-quality-of-life-eq-5d-
5l-value-set-england.
GlaxoSmithKline Document Number 2013N176913_00, CTT116855 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 
17-MAR-2014.
GlaxoSmithKline Document Number 2013N176913_01, CTT116855 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 
31-MAR-2014.
GlaxoSmithKline Document Number 2013N176913_02, CTT116855 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 
10-APR-2014.
GlaxoSmithKline Document Number 2013N176913_03, CTT116855 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 
05-DEC-2014.
 
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GlaxoSmithKline Document Number 2013N176913_04, CTT116855 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 
12-MAY-2015.
GlaxoSmithKline Document Number 2013N176913_05, CTT116855 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 
30-JUN-2016.
GOLD. Global Initiative for Chronic Obstructive Lung Disease (Updated 
2015).http://www.goldcopd.org.
Jones PW and Forde Y (2016). St. Georges Respiratory Questionnaire for COPD Patients 
Manual, version 1.3. 
Keene ON, Roger JH, Hartley BF, Kenward MG. Missing data sensitivity analysis for 
recurrent event data using controlled imputation. Pharmaceutical Statistics. 2014;13:258-
264 
Mahler DA, Ward J, Fierro-Carrion G, Waterman LA, Lentine TF, Mejia-Alfaro R, Baird 
JC (2004). Development of Self-Administered Versions of Modified Baseline and 
Transition Dyspnea Indexes in COPD.  COPD Journal of Chronic Obstructive Pulmonary 
Disease 1(2), pp. 165-172.
Rubin DB. Multiple Imputation for Nonresponse in Surveys. Wiley: New York, 1987.
Therneau TM, Grambsch PM. (2000) Modelling Survival Data: extending the Cox 
model. New York:Springer.
 
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11.
APPENDICES
11.1.
Appendix 1: Time & Events
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 Counselling
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
 
 
 
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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
Exacerbation Assessment
X
X
X
X
X
X
X
X
X
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
 
 
 
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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
X
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
 
 
 
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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 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.
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/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.
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
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11.2.
Appendix 2: Assessment Windows
11.2.1.
General
In general, data will be reported according to the nominal time of clinic visits and 
assessments as specified in the protocol. For example, if a subject recorded values for the 
Week 4 visit that were actually made on the 21st day of treatment, they will be presented 
as Week 4 values in the summary tables. 
Subjects that permanently stop study medication early between scheduled clinic visits 
should undergo all assessments listed for the Study Treatment Discontinuation Visit.  
Data collected at this visit will be listed and used in summary or analysis tables as part of
the ‘worst case post baseline’ summary/analysis if appropriate.  
Subjects that permanently stop study medication early at the time of a scheduled study 
visit will have data collected in the eCRF as part of the scheduled study visit. In order to 
collect all questionnaires that are scheduled to be performed at the Study Treatment 
Discontinuation Visit, diary data is reported on the Logpad as a Study Treatment 
Discontinuation Visit. If the date of the Study Treatment Discontinuation diary 
assessment is the same as the date of a scheduled visit date from the eCRF and there is no 
diary data present at the scheduled visit in question, the Study Treatment Discontinuation 
diary data will be listed, summarized and analyzed as part of the scheduled visit (if the 
diary data was scheduled to be performed at the visit in question). 
 
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11.3.
Appendix 3: Treatment States and Phases
Assessments and events will be classified according to time of occurrence relative to the 
start and/or stop date of the study treatment. The ‘worst case-post baseline’ derivation for 
summaries will consider all scheduled and unscheduled measurements that have been 
assigned a treatment phase of ‘On-treatment’.
11.3.1.
Concomitant Medication Data
COPD medication combinations taken at screening will include all COPD medications 
that were taken on the day of the screening visit, excluding medications that stopped on 
the day of the screening visit. COPD medication combinations taken at study treatment
discontinuation will include all COPD medications that were taken between study 
treatment discontinuation date and study treatment discontinuation date + 14 days 
inclusive.
Treatment phases for summaries of COPD and non-COPD concomitant medications will 
be assigned as follows:
Treatment Phase
Definition
Prior to Screening
Medications taken between date of Screening – 90 days and date of 
Screening (inclusive) defined as:
(conmed start date <= date of Screening or ‘Taken prior to study?’ is 
‘Yes’) and (conmed stop date >= date of Screening – 90 or (conmed 
stop date is completely missing and date of Screening is non-missing)) 
Note: this screening data will only be summarized for COPD 
medications. All screening data will be listed.
Run-in
Medications taken any time between the date of Screening and 
Treatment Start Date (exclusive) defined as:
(conmed start date < study treatment start date or study treatment not 
started or conmed start date is missing) and (conmed stop date > date 
of Screening or (conmed stop date is completely missing and date of 
Screening is non-missing))  
On-treatment
If study treatment stop date > study treatment start date then this 
includes medications taken between the study treatment start date and 
study treatment stop date - 1 (inclusive) defined as follows:
(conmed start date < study treatment stop date or conmed start date is 
missing) and (conmed stop date >= study treatment start date or 
(conmed stop date is completely missing and study treatment start date 
is non-missing))
If study treatment stop date = study treatment start date then this 
includes medications taken on the study treatment start date (which is 
 
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Treatment Phase
Definition
equal to the study treatment stop date) defined as follows.
(conmed start date <= study treatment stop date or conmed start date is 
missing) and (conmed stop date >= study treatment start date or 
(conmed stop date is completely missing and study treatment start date 
is non-missing))
Post-treatment
If study treatment stop date > study treatment start date then this 
includes medications taken between the date of study treatment stop 
date and the date of study conclusion (inclusive) defined as follows:
(conmed start date <= study conclusion date or conmed start date is 
missing) and (conmed stop date >= study treatment stop date or 
(conmed stop date is completely missing and study treatment stop date 
is non-missing))
If study treatment stop date = study treatment start date then this 
includes medications taken between the date of study treatment stop 
date + 1 and the date of study conclusion (inclusive) defined as follows.
(conmed start date <= study conclusion date or conmed start date is 
missing) and (conmed stop date > study treatment stop date or 
(conmed stop date is completely missing and study treatment stop date 
is non-missing))
Post-study
Medications that start after the date of study conclusion. Defined as:
conmed start date > study conclusion date
Note: this post-study data will not be included in any summaries or 
analyses (but will be listed)
NOTES: 

A concomitant medication will be classed in every period of the study in which it was taken (e.g., prior to 
screening, run-in, on- treatment, post-treatment, post-study). 

See Section 11.6.1 for handling of partial dates.

If the study treatment stop date is missing, it will be imputed as described in Section 11.5.1.2.
11.3.2.
All Cause Mortality
For the summaries and analyses of the efficacy endpoint of all cause mortality, treatment 
phases will be defined as described in the table below after any imputation of partial 
death dates as described in Section 11.6.1:
 
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Pre-treatment
Death Date < Treatment Start Date (i.e. subject did not start study treatment)
On-treatment
Treatment Start Date ≤ Death Date ≤ Treatment Stop Date + 7
Off-treatment
Subjects that prematurely discontinued study treatment that attended the Week 
52 visit:
Treatment Stop Date + 7 < Death Date ≤ date of Week 52 + 7
Subjects that prematurely discontinued study treatment that withdrew from the 
study prior to Week 52:
Treatment Stop Date + 7 < Death Date ≤ projected Week 52 date + 7
Post-study
Subjects that completed study treatment:
Death Date > Treatment Stop Date + 7
Subjects that prematurely discontinued study treatment that attended the Week 
52 visit:
Death Date > date of Week 52 + 7
Subjects that prematurely discontinued study treatment that withdrew from the 
study prior to Week 52:
Death Date > projected Week 52 date + 7
Note: Study treatment completion is defined in Section 11.5.1.3. The projected Week 52 date is 
defined in Section 11.5.1.4.
11.3.3.
Other Data
11.3.3.1.
Post-treatment and Post-study Phases
For all events and assessments the post-treatment and post-study phases will be defined 
as follows:
Post/Off-
treatment
Event Onset Date or Assessment Date Treatment Stop Date + 2 AND
Event Onset Date or Assessment Date ≤ study conclusion date
Note: the study conclusion date reflects the safety F/U contact for study 
treatment completers or the maximum of (the subjects last phone contact or 
their last clinic visit or the date the subject was lost to follow-up) for those 
subjects who discontinued study treatment prematurely.
Post-study
Event Onset Date or Assessment Date > study conclusion date. 
Note: this post-study data will not be included in any summaries or analyses 
(but will be listed)
 
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11.3.3.2.
Pre-treatment and On-treatment where Time is Recorded
Any events/assessments for subjects not in the ITT population will be assigned a Pre-
treatment phase.
For all events and assessments where time is recorded, the pre-treatment and on-
treatment phases will be defined as follows:
Pre-treatment
Event Onset Date/Time or Assessment Date/Time ≤Treatment Start Date/Time
On-treatment
Treatment Start Date/Time < (Event Onset or Assessment Date/Time) ≤ 
Treatment Stop Date + 1 or any assessment with a missing or partial date 
unless there is evidence it was not on-treatment
11.3.3.3.
Pre-treatment and On-treatment where Time is Not Recorded
The pre-treatment and on-treatment phases will be defined as described in the table below
for the following events and assessments:

Event-based data with an onset date reported

Unscheduled assessments that have a date reported

Assessments for which no planned relative time is recorded in the database, the 
scheduled Day 1 assessment is to be performed post-dose and have a date reported
Pre-treatment
Event Onset Date or Assessment Date < Treatment Start Date
On-treatment
Treatment Start Date ≤ Event Onset Date or Assessment Date ≤ Treatment 
Stop Date + 1 or any assessment with a missing or partial date unless there is 
evidence it was not on-treatment
The pre-treatment and on-treatment phases will be defined as described in the table below 
for the following events and assessments:

Assessments for which no planned relative time is recorded in the database, the 
scheduled Day 1 assessment is to be performed pre-dose and have a date reported
Pre-treatment
Event Onset Date or Assessment Date ≤ Treatment Start Date
On-treatment
Treatment Start Date < Event Onset Date or Assessment Date ≤ Treatment 
Stop Date + 1 or any assessment with a missing or partial date unless there is 
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11.4.
Appendix 4: Data Display Standards and Handling 
Conventions
11.4.1.
Study Treatment and Subgroup Display Descriptors
11.4.1.1.
Study Treatment
Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting 
Code
Description
Description
Order
1
FF/UMEC/VI 100/62.5/25
FF/UMEC/VI 100/62.5/25
1
2
FF/VI 100/25
FF/VI 100/25
2
3
UMEC/VI 62.5/25
UMEC/VI 62.5/25
3
11.4.1.2.
Treatment Comparisons
For all analyses outputs the treatment comparisons that will be displayed are as follows:

FF/UMEC/VI 100/62.5/25 vs. FF/VI 100/25

FF/UMEC/VI 100/62.5/25 vs. UMEC/VI 62.5/25

UMEC/VI 62.5/25 vs FF/ VI 100/25. Note this comparison will not be displayed 
on any sensitivity analyses that involve imputation.
11.4.1.3.
Eosinophils Subgroup and Display Descriptors
Baseline eosinophil subgroup will be derived using the most recent individual eosinophil 
value prior to the first dose of study treatment and categorized into the following groups:

< 0.15 10^9/L

>= 0.15 10^9/L
Eosinophils Subgroup
Code
Table Decode 
Order 
1
< 0.15 10^9/L
1
2
>= 0.15 10^9/L
2
 
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11.4.2.
Baseline Definitions & Derivations
Parameter
Study Assessments Collected 
Prior to Dosing
Baseline Definition
Screening
Day 1 Pre-Dose
Efficacy and Health Outcomes
Trough FEV1, 
Trough FVC
X
X
Day 1 pre-dose and pre-
bronchodilator nominal time-point
Post-bronchodilator 
FEV1,
Post-bronchodilator 
FVC
X
X
Day 1 pre-dose and post-
bronchodilator nominal time-point
FEV1 reversibility 
(mL)
X
X
Day 1 FEV1 reversibility (mL)
SGRQ total and 
domain scores
X
Day 1 
CAT score
X
X
Day 1 
EQ-5D-5L
X
Day 1 
BDI (TDI Baseline)
X
Day 1
Subject global 
ratings
X
Day 1 
Mean number of 
occasions of rescue 
use, mean number of 
nighttime 
awakenings per night
X
X
Average of measurements from Day 
-13 to Day 1 inclusive (at least 7 
days must be non-missing)
Percentage of 
rescue-free days, 
percentage of days 
symptoms stopped 
usual activities
X
X
Percentage is calculated as total 
number of rescue-free days (or total 
number of days symptoms stopped 
usual activities) divided by total 
number of days with non-missing 
value (from Day -13 to Day 1 
inclusive (at least 7 days must be 
non-missing)) x100
Safety
Blood pressure
X
Values from most recent assessment 
prior to first dose of study treatment 
which records both systolic and 
diastolic BP (generally Screening but 
could be a test repeat).
Pulse rate
X
Most recent individual value prior to 
first dose of study treatment 
 
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Parameter
Study Assessments Collected 
Prior to Dosing
Baseline Definition
Screening
Day 1 Pre-Dose
Laboratory tests: 
Excluding 
hematology
X
Most recent individual value prior to 
first dose of study treatment 
Laboratory tests: 
Hematology 
(including blood 
eosinophils)
X
X
Most recent individual value prior to 
first dose of study treatment
ECG endpoints
X
Values from most recent ECG 
conducted prior to first dose of study 
treatment 
NOTES :

Only records that have been assigned a treatment phase of ‘pre-treatment’ as defined in Section 11.3.3 will be 
considered as baseline assessments.

Baseline Definitions will be used for derivations for endpoints / parameters and indicated on summaries and 
listings.

Unless otherwise stated, if baseline data is missing no derivation will be performed and will be set to missing.
11.4.3.
Reporting Process & Standards
Reporting Process
Software

The currently supported versions of SAS and TCSG software will be used.
Reporting Area
HARP Server
: UK1SALX00175
HARP Area
: /arenv/arprod/gsk2834425/ctt116855/final_01
QC Spreadsheet
: /arenv/arwork/gsk2834425/ctt116855/final_01/documents
Analysis Datasets 

Analysis datasets will be created according to CDISC standards (SDTM Implementation Guide 
Version 3.1.3 & ADaM Implementation Guide Version 1.0).

For creation of ADaM datasets (ADCM/ADAE), the same version of dictionary datasets will be 
implemented for conversion from SI to SDTM.
Generation of RTF Files

Rich Text Format (RTF) files will be generated for the final reporting effort for use in writing the 
CSR.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated:
 
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Reporting Standards
o
4.03 to 4.23: General Principles
o
5.01 to 5.08: Principles Related to Data Listings
o
6.01 to 6.11: Principles Related to Summary Tables
o
7.01 to 7.13: Principles Related to Graphics 
Formats

All data (including data collected post-study treatment discontinuation) will be reported 
according to the treatment to which the subject was randomized unless otherwise stated. 
However, there may be additional adhoc displays for individual subjects using the actual 
treatment received.

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places will be adopted for reporting 
of eCRF data based on the raw data collected.

The reported precision from non eCRF sources will follow the IDSL statistical principles but 
may be adjusted to a clinically interpretable number of decimal places.

Summaries of continuous data will include number of subjects, mean, standard deviation, 
median, first quartile, third quartile, minimum and maximum, 

Percentages between 1% and 99%, inclusive, will be rounded to integers. Percentages greater 
than 0%, but less than 1%, will be reported as <1%, and percentages greater than 99%, but 
less than 100%, will be reported as >99%. 

Numeric data will be reported at the precision collected in the eCRF.
Planned and Actual Time

Reporting for tables, figures and statistical analyses:
o
Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.  Actual time will be used 
for calculation of times to events and Kaplan-Meier plots.

Reporting for listings:
o
Planned and actual time relative to study treatment dosing will be shown in listings (refer to 
IDSL Statistical Principle 5.05.1).
Unscheduled Visits

Unscheduled visits will not be included in summary tables except as part of a 
maximum/minimum/worst case post-baseline assessment or if they are assigned as the 
baseline assessment as detailed in Section 11.4.2.

All unscheduled visits/unplanned readings will be included in listings.
Cardiovascular Event Reports

Laboratory results, ECG results/findings and vital signs measurements collected as part of 
cardiovascular event reports will not be included in any tables, listings or any 
minimum/maximum post-baseline assessments.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
p-value

Both adjusted and unadjusted p-values will be displayed on the primary analyses outputs for 
 
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Reporting Standards
the endpoints within the hierarchy (detailed in Section 11.9) and will be labeled ‘Adjusted p-
value’ and ‘Unadjusted p-value’

All other p-values will be unadjusted and labeled purely as ‘p-value’.
Time to event results

For all time to event analyses, the first quartile and median time to event will be presented. If 
less than 25% of subjects experienced the event within a treatment group then the first quartile
will be displayed as NA (not applicable) for that treatment. If less than 50% of subjects 
experienced the event within a treatment group then the median will be displayed as NA (not 
applicable) for that treatment.
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.
 
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11.5.
Appendix 5: Derived and Transformed Data
11.5.1.
General
11.5.1.1.
Study Day
Study Day

Calculated as the number of days from treatment start date:
o
Reference date = missing                     → Study Day = missing 
o
Reference date <  treatment start date → Study Day = reference date –  treatment start 
date
o
Reference date ≥  treatment start date → Study Day = reference date –  treatment start 
date + 1
11.5.1.2.
Treatment Stop Date
Study Treatment Stop Date

If the treatment stop date is missing, it will be imputed as follows:
o If any of Study Treatment Discontinuation Visit date, Visit 7 (Week 52) date, date of death 
are non-missing then the study treatment stop date will be imputed as the minimum of 
(Study Treatment Discontinuation Visit date, Visit 7 (Week 52) date, date of death, date 
that all study treatment containers were returned).
o For all other subjects, the last recorded exposure start or stop date will be used.
11.5.1.3.
Study and Treatment Completion
Study and Treatment Completion Definitions

A subject is considered to have completed the treatment period if they have not prematurely 
discontinued IP and attended Visit 7. 

A subject is considered to have completed the study if they either attended Visit 7 or had a 
phone contact at Visit 7.
11.5.1.4.
Projected Week 52 Date
For those subjects who have withdrawn from the study prior to Week 52, a projected 
Week 52 date will be derived as follows:
Projected Week 52 Date=Date of randomisation + 52 weeks
11.5.1.5.
At Risk Period for Calculation of Raw Event Rate
11.5.1.5.1. All Cause Mortality
For calculations of raw event rate the ‘at risk period’ in years (used for the denominator) 
will be defined as follows:
 
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
On-treatment at risk period:
o
For subjects that completed the study up to Week 52 the on-treatment at 
risk period will derived as:
(minimum (date of end of study treatment + 7, date of death, date of study 
conclusion) – date of start of treatment + 1)/365.25
o
For subjects that prematurely withdrew from the study prior to Week 52 
and that have a survival status reported the on-treatment at risk period will 
derived as:
(minimum (date of end of study treatment + 7, date of death, date last known 
alive) – date of start of treatment + 1)/365.25 
o
For subjects that prematurely withdrew from the study prior to Week 52 
and that do not have a survival status reported the on-treatment at risk 
period will derived as:
(minimum (date of end of study treatment + 7, date of death, date of study 
conclusion) – date of start of treatment + 1)/365.25

On and off-treatment at risk period:
o
For subjects that did not prematurely discontinue study treatment the on 
and off-treatment at risk period will derived as:
(minimum (date of end of study treatment + 7, date of death, date of study 
conclusion) – date of start of treatment + 1)/365.25
o
For subjects that prematurely discontinued the study treatment period and 
completed the study up to Week 52 the on and off-treatment at risk period 
will derived as:
(Date of study conclusion – date of start of treatment + 1)/365.25
o
For subjects that prematurely discontinued the study treatment period and 
prematurely withdrew from the study prior to Week 52 the on and off-
treatment at risk period will derived as
(minimum(Date last known alive, Date of Death, Projected date of Week 
52 (as defined in Section 11.5.1.4) + 7) – date of start of treatment + 
1)/365.25
o
For subjects that prematurely withdrew from the study prior to Week 52 
and that do not have a survival status reported the on and off-treatment at 
risk period will derived as:
(Date of study conclusion – date of start of treatment + 1)/365.25
11.5.1.5.2. Other Data
For calculations of raw event rate the ‘at risk period’ in years (used for the denominator) 
will be defined as follows:
 
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
On-treatment at risk period:
o
(minimum (date of end of study treatment+1, date of death, date of study 
conclusion) – date of start of treatment + 1)/365.25

Post-treatment at risk period:
o
if date of study conclusion > date of end of treatment as follows:
(date of study conclusion – date of end of treatment  - 1)/365.25
o
Else post-treatment at risk period will be set to 0
11.5.2.
Study Population 
11.5.2.1.
Demographics
Demographics
Age

Age will be calculated based on the Pre-Screening Visit date (or Screening, if pre-screening not 
performed).

Only year of birth is collected on the eCRF, therefore day and month of birth are imputed as 
‘30JUN’ in order to derive age.

Birth date will be presented in listings as ‘YYYY’.
Age Category

Age categories are based on age as derived above and are defined as:
o
≤ 64 years
o
65 - 74 years
o
75 – 84 years
o
≥ 85 years
11.5.2.2.
Subject Disposition 
Subject Disposition 

For Kaplan-Meier plots of study withdrawal over time and discontinuation from study treatment 
over time, censoring will be performed as follows:
O
For study withdrawal, subjects are represented from their Day 1 date to the date of early 
withdrawal from the study (or date of death). Subjects that completed the study are 
censored at the earliest of the date of completion and Day 365.
O
For discontinuation from study treatment, subjects are represented from their Day 1 date to 
the date of discontinuation from study treatment (or date of death). Subjects that complete 
study treatment per protocol are censored at the earliest of their study treatment stop date 
and Day 365.
 
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11.5.2.3.
Treatment Compliance
Treatment Compliance

If a dose counter start count is missing then it will be assumed to be 30. If any dose counter 
stop is missing then the treatment compliance will be set to missing for that subject.

Number of doses of study treatment taken by each subject from each inhaler = dose counter 
start- dose counter stop.
O
Compliance=sum of (dose counter start–dose counter stop) from each inhaler x 100 / 
(treatment stop date – treatment start date +1)

Compliance will be categorized as follows:
       < 80 %
80 % to < 95 %
95 % to 105 %
>105 % to 120 %
>120 %

If a subject received a treatment other than the randomized treatment during the study, the 
compliance will still be calculated using data from all containers received and overall treatment 
start and stop dates.
11.5.2.4.
Cardiovascular Risk Factors
Cardiovascular Risk Factors

Subjects with at least one of the following current or past medical conditions at Screening will
be classed as having a cardiovascular (CV) risk factor. The number of CV risk factors at 
Screening (0, 1, or >=2) will be derived.       

Angina pectoris

Coronary artery disease

Myocardial infarction

Arrhythmia

Congestive heart failure

Hypertension

Cerebrovascular accident

Carotid or aorto-femoral vascular disease

Diabetes mellitus

Hypercholesterolemia
11.5.2.5.
Pneumonia Risk Factors
Pneumonia Risk Factors at Screening

The following categories will be summarized to identify pneumonia risk factors: 

Age (<65, ≥65)  

Gender

BMI (will be defined twice; <21 kg/m2, ≥21 kg/m2; <25 kg/m2, ≥25 kg/m2)
 
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Pneumonia Risk Factors at Screening

Smoking status at screening

Pneumonia history

GOLD Grade
11.5.2.6.
Concomitant Medications
Concomitant Medications
COPD Concomitant Medications

COPD concomitant medications will be grouped into the following RMCs based on pre-defined 
code lists derived from ATC classifications:

Antiinfectives (antibiotics, antifungals, antivirals, antiseptics)

Short-acting anticholinergic

Short-acting beta-2 agonist

Long-acting anticholinergic

Long-acting beta-2 agonist

Xanthine

PDE4 inhibitor

Corticosteroid – inhaled

Corticosteroid – depot

Corticosteroid - systemic oral parenteral and intra-articular

Corticosteroid – other

Leukotriene receptor antagonist

Nedocromil or cromolyn sodium

Mucolytic

Oxygen

Other medication given for exacerbation

Other COPD medication 
COPD Medication Combination

COPD medications taken on the day of the Screening visit and at IP discontinuation will be 
grouped into the following categories based on the RMC classification:

ICS

LABA

LAMA

Xanthine

PDE4 Inhibitors

Any combination of the above

No selected RMC medication combination

COPD medication combinations taken at study treatment discontinuation for subjects that 
provided post-treatment information will include all subjects that prematurely discontinued study 
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11.5.2.7.
Smoking Status
Smoking Status

Smoking Status at Screening is determined directly from the eCRF.

A subject’s smoking status from Visit 2 (Day 1) onwards will be derived from the smoking 
status at the visit in question and any changes in smoking status from the time of the previous 
assessment (e.g., date of any changes in status were made).  

Only smoking status responses recorded at scheduled visits will be included in the summary 
tables.
11.5.2.8.
COPD Exacerbation History
COPD Exacerbation History

Individual exacerbations during the 12 months prior to Screening and during the study were to 
be collected on the eCRF by the Investigator.

COPD exacerbations with onset date on or after the date of Screening will not be included in 
the counts of number of exacerbations in the past year; all other exacerbations recorded on the 
eCRF will be included in the counts, even if onset/resolution dates are missing or earlier than 
the start of the exact 12 month period prior to Screening.

COPD exacerbations reported in the past 12 months will be categorized as 0, 1, 2, ≥3 and a 
separate category of ≥2. 

Number of COPD exacerbations reported in the past 12 months prior to Screening will be 
summarized according to three categories: moderate COPD exacerbations, severe COPD 
exacerbations and moderate/severe COPD exacerbations. Exacerbation severity is defined in 
Section 11.5.3.1.

Total number of moderate/severe COPD exacerbations are defined as total numbers of 
moderate and severe COPD exacerbations for each subject.

Summaries of moderate/severe exacerbations by treatment course are defined as 
exacerbations treated with systemic/oral corticosteroids (with or without antibiotics), and 
exacerbations treated with antibiotics (with or without systemic/oral corticosteroids).
11.5.2.9.
Screening Lung Function and GOLD Grade
Screening Lung Function
Pre-bronchodilator FEV1/FVC, FEV1 Percent Predicted and Reversibility

Pre-bronchodilator FEV1/FVC ratio and pre-bronchodilator FEV1 as a percentage of predicted 
normal at Screening are not collected in the eCRF and will be calculated as:
o Pre-bronchodilator FEV1/FVC = Pre-bronchodilator FEV1/Pre-bronchodilator FVC
o Pre-bronchodilator Percent Predicted = (Pre-bronchodilator FEV1/Predicted FEV1) * 100

The reversibility to salbutamol status of a subject is calculated at Screening and is based on the 
 
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Screening Lung Function
Pre-bronchodilator FEV1/FVC, FEV1 Percent Predicted and Reversibility
difference (absolute change and % change) between a subject’s pre-salbutamol assessment of 
FEV1 and their post-salbutamol assessment of FEV1 and is defined as follows:
o Reversible, if they had a difference in FEV1 of ≥12% and ≥ 200 mL, or
o Non-reversible, if they had a difference in FEV1 of <200 mL or a ≥200 mL difference that 
was <12% of the pre-salbutamol FEV1.
GOLD Grade 1-4 at Screening

Subjects will be classified into Global Initiative on Obstructive Lung Disease (GOLD) Grades 1-
4 using the post-salbutamol percent predicted FEV1 assessment at Screening: 
o
GOLD Grade 1 (Mild):  percent predicted FEV1 80%
o
GOLD Grade 2 (Moderate): 50%percent predicted FEV1 <80%
o
GOLD Grade 3 (Severe):  30%percent predicted FEV1 <50%
o
GOLD Grade 4 (Very Severe): percent predicted FEV1 <30%  
11.5.3.
Efficacy and Health Outcomes
11.5.3.1.
Exacerbations
COPD Exacerbations
General

Each COPD exacerbation will be categorized based on severity as follows:
o Mild:  no treatment with systemic/oral corticosteroids and/or antibiotics and no 
hospitalization and that did not result in death
o Moderate: required treatment with systemic/oral corticosteroids and/or antibiotics (not 
involving hospitalization or resulting in death)
o Severe: required hospitalization or resulted in death

The duration of an exacerbation will be calculated as exacerbation resolution date or date of 
death - exacerbation onset date + 1.

Summaries of moderate/severe exacerbations by treatment course are defined as 
exacerbations treated with systemic/oral corticosteroids (with or without antibiotics), and 
exacerbations treated with antibiotics (with or without systemic/oral corticosteroids).

The raw event rate per thousand subject-years for exacerbations will be calculated as the 
number of events x 1000 divided by the at risk period during the time-period of interest as 
defined in Section 11.5.1.5.2

For the boxplot of on-treatment moderate/severe annual raw COPD exacerbation rates the 
individual subject rate will be derived as number of events experienced by the subject x 1000 
divided by the individual subject’s on-treatment at risk period as defined in Section 11.5.1.5.2.
 
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COPD Exacerbations
Offset variable for rate of exacerbations
For analyses of rate of moderate/severe COPD exacerbations, the offset variable will be 
defined as follows:

Including on-treatment data only
o
logarithm of (on-treatment at risk period, as defined in Section 11.5.1.5.2)

Including both on and off-treatment data
o
logarithm of ([total time in study per subject (defined in Section 
11.5.4.1)]/365.25).

Jump to reference (using on-treatment data)
o
For subjects that complete study treatment: 
logarithm of (on-treatment at risk period, as defined in Section 11.5.1.5.2)
o
For subjects that prematurely discontinue study treatment but complete the 
study up to Week 52:
logarithm of ([Actual date of Week 52 – date of start of treatment + 
1]/365.25)
o
For subjects that prematurely discontinue from study treatment and 
withdraw from the study prior to Week 52:
logarithm of ([Projected Week 52 date (as defined in Section 11.5.1.4) –
date of start of treatment + 1]/365.25)

Jump to reference (using on and off-treatment data)
o
For subjects that complete study treatment: 
logarithm of ([total time in study per subject (defined in Section 
11.5.4.1)]/365.25)
o
For subjects that prematurely discontinue study treatment but complete the 
study up to Week 52:
logarithm of ([Actual date of Week 52 – date of start of treatment + 
1]/365.25)
o
For subjects that prematurely discontinue from study treatment and 
withdraw from the study prior to Week 52:
logarithm of ([Projected Week 52 date (as defined in Section 11.5.1.4) –
date of start of treatment + 1]/365.25)
Time to First On-treatment Exacerbation

The time to first on-treatment exacerbation will be calculated as exacerbation onset date of first 
on-treatment exacerbation – date of start of treatment + 1.

Subjects will be represented from their Day 1 date to the start date of their first exacerbation or 
date of censoring. Subjects that have not experienced an on-treatment exacerbation are 
censored at the earliest of the date of their treatment stop date +1 day or the date of death. 
 
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COPD Exacerbations
Time to First Exacerbation Including Off-treatment data

The time to first exacerbation including off-treatment data will be calculated as exacerbation 
onset date of first exacerbation – date of start of treatment + 1.

Only exacerbations reported during the on-treatment and post-treatment study phases will be 
considered (see Section 11.3.3 for details of assigning study phase)

Subjects will be represented from their Day 1 date to the start date of their first exacerbation or 
date of censoring. Subjects that have not experienced an on or off-treatment exacerbation are 
censored at the earliest of (date of study conclusion or the date of death). 
Time to First On-treatment Moderate/severe Exacerbation or Premature Study Treatment 
Discontinuation

The time to first on-treatment moderate/severe exacerbation will be calculated as exacerbation 
onset date of first on-treatment moderate/severe exacerbation – date of start of treatment + 1.

The time to study treatment discontinuation will be calculated as the date of premature study 
treatment discontinuation – date of start of treatment + 1.

The time to first on-treatment moderate/severe exacerbation or study treatment discontinuation 
is defined as the earliest of the time to first on-treatment moderate/severe exacerbation or time 
to premature study treatment discontinuation.

Subjects will be represented from their Day 1 date to the earliest of the event or censoring.  
Subjects who do not experience the event will be censored at the earliest of the date of their 
treatment stop date +1 day or the date of death. 
Time to Each On-treatment Exacerbation

Subjects will be defined as at risk while on treatment from the start of treatment until their first 
exacerbation, and then from the day after each exacerbation had resolved.

Subjects will be represented from their study treatment start date to the earliest of the date of 
their treatment stop date +1 day or the date of death.  
Association to Chest X-Ray

A chest X-ray is considered associated with an exacerbation if it is performed within the 
duration of the exacerbation or performed between -7 days to +10 days (inclusive) of the onset 
date of the exacerbation.
11.5.3.2.
Lung Function
Spirometry
Trough FEV1 and FVC

The trough value for FEV1 and FVC at Weeks 4, 16, 28, 40 and 52 visit is the pre-dose (prior 
to taking the morning dose of study treatment) and pre-bronchodilator assessment at that visit.
 
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Spirometry
Post-Bronchodilator FEV1 and FVC

The post-bronchodilator value for FEV1 and FVC at Weeks 4, 16, 28, 40 and 52 is the pre-
dose (prior to taking the morning dose of study treatment), post-bronchodilator assessment 
(approximately 10 to 30 minutes after administering four puffs of salbutamol). 
FEV1 Reversibility (mL)

The reversibility to salbutamol is calculated at each visit where FEV1 is collected as follows:
FEV1 reversibility (mL) = post-salbutamol FEV1 (mL) - pre-salbutamol FEV1 (mL)
11.5.3.3.
SGRQ
St. George’s Respiratory Questionnaire for COPD Patients (SGRQ-C)
General

The SGRQ-C contains 14 questions with a total of 40 items grouped into three domains 
(Symptoms, Activity and Impacts).  

Details for how to score the SGRQ-C, including handling of missing data or multiple responses 
to questions, are outlined in the SGRQ-C manual (Jones, 2016). 

SGRQ-C domain and total scores will be converted to SGRQ scores as described in the 
manual.

Changes from baseline in domain and total score will be calculated for the converted scores.

If the language of the SGRQ-C conducted at a post-treatment visit is different to the language 
used at Day 1 baseline, all SGRQ scores at that visit and all subsequent visits will be set to 
missing.
Responder Status according to SGRQ Total Score

A subject will be considered a responder according to SGRQ total score if their on-treatment 
SGRQ total score has decreased at least 4 units from the baseline SGRQ total score.

A subject will be considered a non-responder if their on-treatment SGRQ total score has 
decreased by less than 4 units, has not changed, or has increased compared to baseline.

Moderate and major response will be defined using cut-offs determined as follows:
o Cut-off for defining moderate responder will use the integer value of the mean change from 
baseline in SGRQ total score at Week 52 for all subjects (combined treatment groups) who 
rated ‘better’ in the subject global rating of change in COPD severity at Week 52. 
o Cut-off for defining major responder will use the integer value of the mean change from 
baseline in SGRQ total score at Week 52 for all subjects (combined treatment groups) who 
rated ‘much better’ in the subject global rating of change in COPD severity at Week 52.

A subject will be considered a major responder if their on-treatment change from baseline in 
SGRQ total score is ≤ the cut-off value for major responder.

A subject will be considered a moderate or major responder if their on-treatment change from 
 
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St. George’s Respiratory Questionnaire for COPD Patients (SGRQ-C)
baseline in SGRQ total score is ≤ the cut-off value for moderate responder.

Missing data will be handled as detailed in Section 11.6.
11.5.3.4.
CAT
COPD Assessment Test (CAT)
CAT Score

The CAT consists of eight items each formatted as a six-point differential scale: 0 (no impact) to 
5 (high impact). A CAT score will be calculated by summing the non-missing scores on the 
eight items with a range from 0 to 40. 

If one item is missing, then the score for that item is set as the average of the non-missing 
items. If more than one item is missing, then the CAT score will be set to missing.

If the language of the CAT conducted at a post-baseline visit is different to the language used 
at Day 1 baseline, the CAT score for that visit and all subsequent visits will be set to missing.

If there is more than one response to a question at a visit or duplicate questionnaires, the CAT 
score for that visit will be set to missing.
Responder Status according to CAT Score

A subject will be considered a responder according to CAT score if their on-treatment CAT 
score has decreased at least 2 units from the baseline CAT total score.

A subject will be considered a non-responder if their on-treatment CAT score has decreased by 
less than 2 units, has not changed, or has increased compared to baseline.

Missing data will be handled as detailed in Section 11.6.
CAT Score Categories
The CAT score categories will be defined as:

A score < 10

A score ≥ 10
11.5.3.5.
All Cause Mortality
Rate of all cause mortality
The raw event rate per thousand subject-years for adjudicated deaths will be calculated as the 
number of events x 1000 divided by the at risk period during the time-period of interest as defined in 
Section 11.5.1.5.1.
Time to On-treatment All Cause Mortality

The time to on-treatment all cause mortality will be calculated as death date – date of start of 
treatment + 1.

Subjects will be represented from their Day 1 date to the date of death (on-treatment) or date of 
censoring. Subjects that have not experienced an on-treatment death are censored as follows:
 
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
Subjects that have completed the study are censored at the earliest of (date of 
study conclusion and date of study treatment stop + 7 days). 

Subjects that have an off-treatment or post-study death reported are censored at 
the date of their study treatment stop + 7 days

Subjects that prematurely withdraw from the study and have a survival status 
present are censored at the earliest of (date last known alive and date of study 
treatment stop + 7 days)

Subjects that prematurely withdraw from the study and do not have a survival 
status reported at 52 weeks post-randomisation are censored at the earliest of 
(date of study conclusion and date of study treatment stop + 7 days)
Time to On and Off-treatment All Cause Mortality

The time to on and off-treatment all cause mortality will be calculated as death date – date of 
start of treatment + 1.

Subjects will be represented from their Day 1 date to the date of death (on and off-treatment, as 
defined in Section 11.3.2) or date of censoring. Subjects that have not experienced an on or 
off-treatment death are censored as follows:

Subjects that have completed study treatment are censored at the earliest of (date 
of study conclusion and date of study treatment stop + 7 days). 

Subjects that prematurely discontinued study treatment that attended the Week 52 
visit are censored at the earliest of (date of study conclusion and date of Week 52 + 
7 days).

Subjects that prematurely discontinued study treatment that withdrew from the 
study prior to Week 52 and have a survival status present are censored at the 
earliest of (date last known alive and projected Week 52 date + 7). 

Subjects that prematurely discontinued study treatment that withdrew from the 
study prior to Week 52 and do not have a survival status present or that have a 
post-study death reported are censored at the earliest of (date of study conclusion  
and projected Week 52 date + 7).
11.5.3.6.
BDI/TDI
BDI/TDI 
General

The BDI focal score will be calculated as the sum of the ratings recorded for each of the three 
individual scales (Functional Impairment, Magnitude of Task, and Magnitude of Effort). Each of 
these scales has five possible scores ranging from 0 to 4 (with lower scores indicating more 
impairment), with the range of the BDI focal score 0 to 12. If a score is missing for any of the 
three scales, then the BDI focal score will be set to missing.  BDI is assessed at baseline (Day 
1).

The TDI focal score will be calculated as the sum of the ratings recorded for each of the three 
individual scales (Functional Impairment, Magnitude of Task, and Magnitude of Effort). Each of 
these scales has a possible score ranging from -6 (major deterioration) to +6 (major 
improvement). TDI focal score is calculated as the sum of the three individual scores and then 
 
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BDI/TDI 
divided by 2 (so the range of the TDI focal score is -9 to +9). If a score is missing for any of the 
three scales, then the TDI focal score will be set to missing.

If the language of the TDI conducted at a visit is different to the language for the BDI, all TDI 
scores at that visit and subsequent visits will be set to missing.

If there is more than one response to a question at a visit or duplicate questionnaires, the BDI 
or TDI score for that visit will be set to missing.
Categorization of TDI Focal Score 

Full categorization of TDI focal score for categorical summary is as follows:
‘major improvement ’ defined as a score of ≥7 to ≤9
‘moderate improvement’ defined as a score of ≥4 to <7 
‘minor improvement’ defined as a score of ≥1 to <4
‘no change’ defined as a score of > -1 to < 1
‘minor deterioration’ defined as a score of > -4 to ≤ -1,
‘moderate deterioration’ defined as a score of >-7 to ≤-4 
‘major deterioration’ defined as a score of ≥-9 to ≤-7
Responder Status according to TDI Focal Score

A subject will be considered a responder if the on-treatment TDI focal score was at least 1 unit.

A subject will be considered a non-responder if their on-treatment TDI focal score was less than 
1 unit.

Missing data will be handled as detailed in Section 11.6.

For subjects who are responders at a particular visit, response will be further classified as 
moderate if the TDI focal score is 4 and <7 and as major if the TDI focal score is 7.
11.5.3.7.
eDiary
Calculation of Daily eDiary Endpoints
General

Subjects were instructed to complete the daily eDiary in the morning prior to taking any 
study treatment. 

Number of occasions of rescue salbutamol use and number of nighttime awakenings were 
collected in the daily eDiary.

The Yes/No question of “Did your respiratory symptoms stop you performing your usual 
activities in the last 24 hours?” were also collected in the eDiary. 

The table below shows which daily eDiary records are used to calculate the daily eDiary 
endpoints for each analysis time period. Any diary data collected in the post-treatment 
phase of the study will not be slotted. See Section 11.3.3 for details on the assignment of 
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Calculation of Daily eDiary Endpoints
Daily Record
Analysis Time Period
Beginning Timepoint 
(day)
Ending Timepoint
(day)
-13
1
Week -1 (Baseline)
2
29
Weeks 1 – 4
30
57
Weeks 5 – 8
58
85
Weeks 9 – 12
86
113
Weeks 13 – 16
114
141
Weeks 17 – 20
142
169
Weeks 21 – 24
170
197
Weeks 25 – 28
198
225
Weeks 29 – 32
226
253
Weeks 33 – 36
254
281
Weeks 37 – 40
282
309
Weeks 41 – 44
310
337
Weeks 45 – 48
338
365
Weeks 49 – 52
Note: There is no Day 0.  Any records with actual day>365 will not be assigned to a time period.
Note: Daily eDiary records that were not assigned to a time period will not be used in calculation of daily eDiary endpoints.

For a subject to be counted in any time period (except for baseline where at least 7 days non-
missing entries are required) for a given endpoint they must have at least one diary entry 
recorded for that endpoint during that time period.

Any daily eDiary data that were collected post-study treatment discontinuation will be excluded 
from analysis, including four weekly period data summaries.

If a subject has more than one daily eDiary record for any given day, the worst case response on 
that day for each endpoint will be used in the summaries and analyses. i.e. the maximum number 
of occasions of rescue use reported will be counted for the day in question and used to 
determine if it was a recue-free day; the maximum number of nighttime awakenings will be 
counted for the day in question; symptoms stopped usual activities = ‘Yes’ will be used as the 
worst case over symptoms stopped usual activities = ‘No’.    
eDiary Endpoints

The mean number of occasions of rescue use per day, percentage of rescue-free days, mean 
number of nighttime awakenings per night and percentage of days symptoms stopped usual 
activities will be calculated for each subject during the four weekly periods defined above.
11.5.3.8.
EQ-5D-5L
EQ-5D-5L
If the language of the EQ-5D-5L conducted at a post-baseline visit is different to the language 
used at baseline, the EQ-5D-5L scores for that visit and all subsequent visits will be set to 
 
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missing.
If there is more than one response to a question at a visit or duplicate questionnaires, the EQ-
5D-5L health state and utility score for that visit will be set to missing.
11.5.3.9.
Healthcare Resource Utilization
Healthcare Resource Utilization
The total number of visits for each type of healthcare contact (home visits (day), home visits 
(night), office/practice visits, urgent care/outpatient clinic visits, emergency room visits) and 
number of days in intensive care and number of days in general hospital wards will be calculated 
by summing the respective visits and number of days.  This will also be calculated for each 
contact type (COPD exacerbations, COPD not-exacerbation, other healthcare contact).
11.5.4.
Safety
11.5.4.1.
Exposure
Exposure
Exposure and Post-treatment Duration

Duration of exposure to study treatment is calculated as: 
o
treatment stop date – treatment start date +1

Duration of post-treatment time spent on study is calculated as: 
o
study conclusion date – treatment stop date

Duration of  total time spent on study is calculated as: 
o
study conclusion date – treatment start date + 1
Exposure Categories

The following exposure categories will be derived:
≥1 day, ≥4 weeks, ≥8 weeks, ≥12 weeks, ≥16 weeks, ≥20 weeks, ≥24 weeks, ≥28 weeks, 
≥32 weeks, ≥36 weeks, ≥40 weeks, ≥44 weeks, ≥48 weeks and ≥52 weeks.  An additional 
category of 51-53 weeks will also be summarized.

For post-treatment duration, the following categories will be derived:
0 days, 1-7 days, >7 days 
11.5.4.2.
Adverse Events
Adverse Events
Adverse Event Rate

The event rate per thousand subject-years will be displayed on most AE data displays listed in 
Section 11.12 (including summaries of AESIs and Serious Adverse Reports). Event rate per 
thousand subject-years will be calculated as the number of events x 1000 divided by the at risk 
period during the time-period of interest as defined in Section 11.5.1.5.2.
 
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Adverse Events of Special Interest (AESI)

AESI have been defined as AEs which have specified areas of interest for FF, VI or UMEC or 
the overall COPD population. The following table presents the AESI groups.  Groups which are
not SMQs are made up of a selection of preferred terms (PTs) defined by GSK. The complete 
list, including the PTs which contribute to each of the groups will be provided by Global Clinical 
Safety and Pharmacovigilance (GCSP) using the MedDRA version current at the time of 
reporting.  This will be finalized prior to unblinding.
AESI Group
AESI Subgroup
Sub-SMQ
Adrenal suppression
Anticholinergic syndrome (SMQ)
Asthma/bronchospasm (SMQ)
Cardiovascular effects
Cardiac arrhythmia
Arrhythmia related investigations, 
signs and symptoms (SMQ)
Bradyarrhythmia terms, 
nonspecific (SMQ)
Conduction defects (SMQ)
Disorders of sinus node function 
(SMQ)
Cardiac arrhythmia terms, 
nonspecific (SMQ)
Supraventricular tachyarrhythmias 
(SMQ)
Tachyarrhythmia terms, 
nonspecific (SMQ)
Ventricular tachyarrhythmias 
(SMQ)
Cardiac failure (SMQ)
Ischaemic heart disease (SMQ)
Hypertension (SMQ)
Central nervous system 
haemorrhages and 
cerebrovascular conditions (SMQ)
Ocular effects
Glaucoma (SMQ)
Lens disorder (SMQ)
Decreased bone mineral density 
and associated fractures
Effects on potassium
Gastrointestinal obstruction 
(SMQ)
Hyperglycaemia/new onset 
diabetes mellitus (SMQ)
Hypersensitivity
Local steroid effects
Pneumonia 
Lower Respiratory Tract Infection 
(LRTI) excluding pneumonia
Tremor
Urinary retention
 
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Adverse Events Considered of Interest in the Elderly

AEs considered of interest in the elderly will be summarized by age category and overall for each 
treatment group.

SMQs or PTs for these groupings are provided below.
AE Grouping
SMQ, PT or System Organ Class 
(SOC)
Any AE
Serious AE
 Results in death
 Life-threatening
 Hospitalization/prolongs existing hospitalization
 Results in disability/incapacity
 Congenital anomaly/birth defect
 Other (medically significant)
 Possible drug-induced liver injury
Adverse events leading to permanent discontinuation of study 
treatment or withdrawal from study
Psychiatric disorders
Psychiatric disorders (SOC)
Nervous system disorders
Nervous system disorders (SOC)
Accidents and injuries
Accidents and injuries (SMQ)
Cardiac disorders
Cardiac disorders (SOC)
Vascular disorders
Vascular disorders (SOC)
Cerebrovascular disorders
Central nervous system vascular 
disorders (SMQ)
Infections and infestations
Infections and infestations (SOC)
Anticholinergic syndrome
Anticholinergic syndrome (SMQ)
Quality of life decreased
Quality of life decreased (PT)
Postural hypotension, Falls, Black outs/Syncope, Dizziness, Ataxia 
and Fractures
Postural hypotension (selected PTs*), 
Falls (PT), Black outs/Syncope 
(selected PTs*), Dizziness (selected 
PTs*), Ataxia (selected PTs*) and 
Fractures (selected PTs*)
* Preferred terms which contribute to each of the groups will be provided by GCSP using the MedDRA 
version current at the time of reporting.  This will be finalised prior to unblinding.
Association to Serious Adverse Reports
An event in the pneumonia AESI group is considered associated with an adjudicated Serious 
Adverse Report if the Serious Adverse Report was classified as ‘COPD exacerbation with evidence 
of pneumonia’ or ‘Pneumonia/respiratory tract infection without COPD exacerbation’ and the onset 
of the Serious Adverse Report is within -7 to +10 days of the onset of the pneumonia AESI.
11.5.4.3.
Bone Fracture
Bone Fracture 

Bone fracture event rate will be calculated in the same manner as AE rate.
Bone Fracture Incidents

If a subject suffers fractures in multiple locations with the same date of fracture, this is 
 
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Bone Fracture 
considered to be one fracture incident.

In the case of multiple fracture types (traumatic/non-traumatic) contributing to one fracture 
incident, the worst case fracture type (non-traumatic) will be assigned to the fracture incident. 
E.g. if a subject has a traumatic wrist fracture and a non-traumatic foot fracture on the same 
date, this will be considered to be one non-traumatic fracture incident. 

Bone fracture incident event rate will be calculated in the same manner as AE rate.
11.5.4.4.
Maximum/Minimum Post-Baseline and Worst-Case Post-Baseline
Maximum/Minimum Post-Baseline and Worst-Case Post-Baseline
Definition
Reporting Details
Maximum post-baseline
(QTcF, QTc B, PR interval, ECG 
heart rate, pulse rate, systolic 
BP, diastolic BP and laboratory 
tests)
Maximum on-treatment value over all time-points (including 
scheduled and unscheduled assessments)
Minimum post-baseline
(Diastolic BP and laboratory 
tests that do not have a lower 
limit = 0)
Minimum on-treatment value over all time-points (including 
scheduled and unscheduled assessments)
Worst case post-baseline
(ECG findings)
Including scheduled and unscheduled on-treatment 
assessments

‘Abnormal’ if any on-treatment assessment is 
evaluated as ‘Abnormal’

‘Unable to evaluate’ if all on-treatment assessments 
are ‘Unable to evaluate’

‘Normal’ if any on-treatment assessment is evaluated 
as ‘Normal’ and there are no on-treatment 
assessments evaluated as ‘Abnormal’
NOTES :

The treatment phase definitions specified in Section 11.3.3 will be used and only assessments within the on-
treatment period will be considered in assessment of minimum/maximum/worst-case post-baseline.

Assessment of minimum/maximum/worst-case post-baseline will include data from scheduled, unscheduled and 
study treatment discontinuation visits (if applicable), and will include the Week 4 pre-dose ECG for the Pre-dose 
ECG sub-population. Vital signs (pulse rate, systolic BP and diastolic BP) collected at an assessment associated 
with a pneumonia event will also be included in derivation of a ‘maximum/minimum post-baseline’ assessment.
The pneumonia event related assessments (e.g. vitals) dates will be assumed to be the same as the event date. 
11.5.4.5.
Laboratory Parameters
Laboratory Parameters

Non-quantifiable laboratory results will be treated as missing in summary displays.  However, 
the results will be listed as received (e.g. ‘<x’ or ‘>x’).

An ‘any visit post-baseline’ classification will be derived, in which subjects will be counted in the 
‘low’ and ‘high’ categories if they reported a low or high value (respectively) at any scheduled or 
 
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Laboratory Parameters
unscheduled on-treatment visit. 

Change from baseline values will be classified relative to the normal range as ‘to low’, ‘to 
normal or no change’ or ‘to high’. Subjects who do not change categories or move from out-of-
range to normal will be classified as ‘to normal or no change’.

An ‘any visit post-baseline’ change classification will be derived, in which subjects will be 
counted in the ‘to low’ and ‘to high’ categories if they reported a change from a ‘normal’ 
baseline to a value below or above the normal range (respectively) at any scheduled or 
unscheduled on-treatment visit. Subjects who did not report a change to a value outside the 
normal range at any visit after the start of study treatment will be counted in the ‘to normal or no 
change’ category. 
Multiple Measurements for Post-Baseline Visits for Safety

Subjects having both high and low values relative to normal ranges at post-baseline visits for 
safety parameters will be counted in both the high and low categories of the “any visit post-
baseline” row of related summary tables.
11.5.4.6.
ECG
ECG Event Rates

ECG Abnormality event rates will be calculated in the same manner as AE rate.
ECG Categories
QTcF and QTcF change from baseline results will be reported in categories as below
ECG Parameter
Units
Ranges
Lower
Upper
Absolute
Absolute QTcF Interval
msec
0
≤ 450
> 450
≤ 480
> 480
≤ 500
> 500
≤ 530
> 530
Change from Baseline
Change from Baseline QTcF
msec
<-60
≥-60
<-30
≥-30
<0
≥0
< 30
≥ 30
<60
≥ 60
 
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11.5.4.7.
Pneumonia
Pneumonia
Pneumonia Event Rates
Pneumonia event rates (based on the pneumonia eCRF form) will be calculated in the same 
manner as AE rate.
Association of Chest X-Ray with Pneumonia Event

Pneumonia is considered to be supported by a chest X-ray if there is an associated X-ray which 
shows the presence of infiltrates. A chest X-ray is considered associated with pneumonia if it is 
performed within the duration of the pneumonia or performed between -7 to +10 days
(inclusive) of the date of onset of pneumonia. 
11.5.4.8.
Time to First Event
Time to First Event

The time to the first event will be calculated as (onset date of first event – date of start of 
treatment + 1).

Subjects will be represented from their Day 1 date to the start date of their first event or date of 
censoring. 

Subjects that have not experienced an event are censored at the earliest of their date of 
treatment stop + 1 day or date of death.
Time to First Composite Event 

The time to first composite event will be calculated as the minimum event onset date of all 
components of the composite endpoint.
11.5.4.9.
MACE
MACE
MACE Event Rates
MACE event rates will be calculated in the same manner as AE rate.
Broad MACE criteria
Narrow MACE criteria
Ischaemic heart disease SMQ:

Myocardial infarction SMQ (excluding 
fatalities)

Other ischemic heart disease SMQ 
(excluding fatalities)
-Myocardial infarction PT (excluding fatalities)
-Acute myocardial infarction PT (excluding 
fatalities)
Central nervous system haemorrhages and cerebrovascular conditions SMQ (excluding fatalities)
Adjudicated CV deaths
Note: Adjudication is performed for a serious adverse report (based on the event the adjudicators consider 
to be the primary medical event if the report includes several adverse events for an individual subject). 
Summaries for MACE will include any death adjudicated as from a CV cause and non-fatal events 
recorded in the eCRF. If, for example, a subject has an adjudicated CV death and a non-fatal myocardial 
infarction in the eCRF, they will be counted once in each category and once in the overall MACE count.
 
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11.6.
Appendix 6: Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank 
fields on the collection instrument:
o
These data will be indicated by the use of a “blank” in subject listing displays 
unless all data for a specific visit are missing in which case the visit is not 
displayed in the listing. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to 
be missing data and will be displayed as such.
o
Missing data will generally not be considered in the calculation of 
percentages (i.e., the denominator will not include subjects who have 
missing data at a given time point).
o
No imputation will be made for any missing numerical data, except in the
specified sensitivity analyses of the primary and secondary endpoints to 
assess the impact of missing data on study results.
Responder

Subjects with a missing baseline will have responder status as missing.

Subjects with missing on-treatment data and a subsequent non-missing on-
treatment scheduled assessment will not be considered a responder or non-
responder but will be left as missing.  

Subjects that have withdrawn from study treatment prior to the visit in question 
will be imputed as non-responders at all visits post-study treatment 
discontinuation where the assessment was expected to be performed 
(regardless of whether the subject has had a post-treatment assessment 
performed or not). This includes all visits up to and including Week 52.

Subjects with missing on-treatment data and no subsequent non-missing on-
treatment scheduled assessments will be imputed as non-responders.
11.6.1.
Missing or Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in subject listing displays.  

Dates which are completely missing will not be imputed, with the exception of 
the treatment stop date. Details for the imputation of the treatment stop date 
are provided in Section 11.5.1.2.
Concomitant 
Medications

Partial dates for any concomitant medications will be imputed using the 
following convention:  
O
If the partial date is a start date, a '01' will be used for the day and 'Jan' 
will be used for the month.
O
If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month.
O
If the imputed stop date results in a date that is after the date of death, the 
date of death will be used for the stop date of the medication.

The recorded partial date will be displayed in listings.
Adverse 

Any partial dates will be imputed using the following convention:
 
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Element
Reporting Detail
Events, 
Exacerbations, 
Pneumonia
O
If the partial date is a start date, a '01' will be used for the day and 'Jan' 
will be used for the month. 
O
However, if this imputation results in a date prior to Day 1 and the event 
could possibly have occurred during treatment from the partial 
information, then the Day 1 date will be assumed to be the start date. 
O
If it is not certain with the partial date/or no date at all which phase of the 
study the event started, it will then be considered to start on-treatment 
(worst case).
O
If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month.
O
If the imputed stop date results in a date that is after the date of death, the 
date of death will be used for the stop date.
O
For exacerbation data only; 
o
If the partial date pertains to a pre-treatment or off-treatment 
exacerbation then the imputation rules detailed above apply.  
Please note that having duplicate partial exacerbation start dates 
or end dates may result in overlapping exacerbations following 
imputation.  However, each exacerbation record will be counted 
as a unique exacerbation for summaries and analyses.  
o
For on-treatment exacerbations only, if the imputation rules 
detailed above result in overlapping exacerbations, end dates will 
be imputed as the day prior to the start of the next exacerbation.  
This is to ensure that all exacerbations are included appropriately 
in the Andersen-Gill analyses for the Time to Each on-treatment 
exacerbation endpoints.
O
The recorded partial date will be displayed in listings.  
Date of Death

Any partial date of death will be imputed using the following convention:
O
'01' will be used for the day and 'Jan' will be used for the month. 
O
However, if this imputation results in a date prior to a contact/assessment 
date reported in the eCRF (including adverse event dates, concomitant 
medication start/end dates), the maximum contact/assessment date will 
be assumed to be the date of death. 
O
The recorded partial date will be displayed in listings.
Date Last 
Known Alive

Any partial date last known alive from the survival status eCRF will be 
imputed using the following convention:
O
'01' will be used for the day and 'Jan' will be used for the month. 
O
However, if this imputation results in a date prior to a contact/assessment 
date reported in the eCRF (including adverse event dates, concomitant 
medication start/end dates), the maximum contact/assessment date will 
be assumed to be the date last known alive. 

The recorded partial date will be displayed in listings.
11.6.1.1.
Missing Data for Statistical Analysis
Details regarding the sensitivity analyses that will be performed for the primary and key 
secondary endpoints can be found in Section 7 & Section 8.  
 
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11.7.
Appendix 7: Multicenter Studies
11.7.1.
Geographical Region
Due to the large number of centers participating in this study, a geographical region will 
be used rather than adjusting for center in the statistical analyses.  The center grouping
will be created based on geographical region and number of randomized subjects in a 
country, in order to define groups of roughly similar size.  
Geographical Region
Countries
Western Europe 
Austria, Belgium, Czech Republic, Denmark, Finland, France, 
Germany, Netherlands, Norway, Poland, Romania, Spain, 
Sweden, United Kingdom
Eastern Europe
Israel, Russia, Turkey, Ukraine
Asia
China, Hong Kong, Japan, Korea, Philippines, Singapore, 
Thailand, Viet Nam
North America
Canada, Puerto Rico, United States
South America
Argentina, Brazil, Chile, Colombia, Peru
Other
Australia, New Zealand, South Africa
 
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11.8.
Appendix 8: Examination of Covariates, Subgroups & Other 
Strata
11.8.1.
Handling of Covariates, Subgroups & Other Strata
Covariates will be included in statistical analyses as detailed in the statistical model 
specifications in Section 7 and Section 8.
 
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11.9.
Appendix 9: Handling Multiple Comparisons and Multiplicity
The study has been powered at the 1% significance level in order to satisfy regulatory 
requirements of substantial evidence of efficacy for a single study. However, type I error 
is controlled at the 5% significance level.  
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 co-primary treatment comparisons (pairwise comparison of FF/UMEC/VI with 
FF/VI and FF/UMEC/VI with UMEC/VI for the annual rate of on-treatment 
moderate/severe exacerbations), both comparisons will be declared statistically 
significant if the unadjusted 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 unadjusted p-value is below 0.025. 
Pairwise comparisons of FF/UMEC/VI versus FF/VI and FF/UMEC/VI versus 
UMEC/VI will be performed for the secondary efficacy and other endpoints and for 
UMEC/VI vs. FF/VI on all endpoints. These comparisons will not be adjusted for 
multiplicity. If at least one of the co-primary treatment comparisons is considered 
statistically significant, inferences will be drawn from p-values for the treatment 
comparisons on secondary and other endpoints. If neither of the co-primary comparisons 
is considered statistically significant, testing on the secondary and other endpoints will be 
performed and presented for descriptive purposes only.
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, multiplicity across selected treatment 
comparisons and secondary endpoints 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. 
At least one endpoint must be statistically significant in the first block in order to make 
inferences in the second block.  As shown in Figure 1, at least one of endpoints S1a and 
S1b would need to be significant in order to make inferences for the S2a and S2b 
comparisons contained in the next block.
 
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Figure 1
Secondary endpoint hierarchy
Note that the reference level required to determine statistical significance for each block 
within the secondary hierarchy will depend on whether one or both comparisons were 
significant at the prior step:
Reference level for statistical significance based on unadjusted p-value for 
comparisons of FF/UMEC/VI versus FF/VI (all co-primary, block 1 and block 
2 endpoints) and FF/UMEC/VI versus UMEC/VI (co-primary and block 2 
endpoint)
Co-primary 
treatment 
comparisons
Both p<0.04
Both p<0.04
One p≥0.04 and 
one p<0.025
One p≥0.04 and 
one p<0.025
Block 1
Both p<0.04
One p≥0.04 and 
one p<0.025
Both p<0.008
One p≥0.008 
and one p<0.005
Block 2
Both p<0.05 or 
One p≥0.05 and 
one p<0.025
Both p<0.01 or 
One p≥0.01 and 
one p<0.005
Both p<0.008 or 
One p≥0.008 and 
one p<0.005
Both p<0.002 or 
One p≥0.002 
and one p<0.001
All further efficacy endpoints/treatment comparisons not in the above testing hierarchy 
will be considered statistically significant at the relevant reference level as detailed in 
Block 2 if at least one treatment comparison is considered to be statistically significant in 
Block 2.
 
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11.10.
Appendix 10: Model Checking and Diagnostics for 
Statistical Analysis
Model checking will only be performed for the primary analysis for each endpoint.  If the 
model assumptions are met for the primary analysis then we will assume that the model 
assumptions were also met for any subgroup analyses.
11.10.1.
Statistical Analysis Assumptions 
11.10.1.1. Negative Binomial Regression and Poisson Regression
Endpoint(s)

Annual rate of on-treatment moderate/severe exacerbations

Annual rate of on-treatment severe exacerbations

Annual rate of all on-treatment exacerbations (mild, moderate, severe)

Annual rate of on-treatment moderate exacerbations

Annual rate of on-treatment exacerbations requiring systemic/oral 
corticosteroids

Annual rate of on-treatment exacerbations requiring antibiotics
Analysis

Negative binomial regression

Poisson regression (moderate/severe exacerbations)

The fit of the regression models will be examined using “Q-Q” plots of the standardized 
residuals. Interpretation of these plots will be aided by the addition of simulated envelopes as 
proposed by Atkinson (Atkinson,1985).
11.10.1.2. Cox Proportional Hazards
Endpoint(s)

Time to first on-treatment moderate/severe exacerbation

Time to death from any cause (on-treatment) 

Time to first on-treatment severe exacerbation

Time to first on-treatment event in the pneumonia AESI group

Time to first on-treatment event in the pneumonia AESI group resulting in 
hospitalization, prolonged hospitalization or death

Time to first on-treatment event in the pneumonia AESI group or 
moderate/severe exacerbation

Time to first on-treatment event in the pneumonia AESI group resulting in 
hospitalization, prolonged hospitalization or death or severe exacerbation

Time to first on-treatment event in the pneumonia AESI group resulting in 
hospitalization, prolonged hospitalization or death or severe exacerbation or 
event in the CV AESI group resulting in hospitalization, prolonged 
hospitalization or death
Analysis

Cox’s proportional hazard model

The proportional hazards assumption will be examined by obtaining the Kaplan-Meier 
estimates of the survival function S(t) over time separately for each treatment group. In 
addition, the ln {-ln[S(t)]} plot will be produced.  
 
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11.10.1.3. Andersen-Gill
Endpoints

Time to onset of each on-treatment moderate/severe exacerbations

Time to onset of each severe exacerbation
Analysis

Andersen-Gill model for recurrent events

The proportional hazards assumption will be assessed by plotting the estimated log cumulative 
hazard function against the log of the time to event by treatment group. 
11.10.1.4. Mixed Model Repeated Measures
Endpoint(s)

Trough FEV1 

SGRQ total score 

Trough FVC

Post-bronchodilator FEV1

FEV1 reversibility

Post-bronchodilator FVC

TDI focal score

CAT score

Mean number of occasions of rescue use per day

Percentage of rescue-free days

Mean number of nighttime awakenings per night

Percentage of days symptoms stopped usual activities

Pulse rate

Systolic BP

Diastolic BP

QTcF
Analysis

MMRM

Distributional assumptions underlying the model used for analysis will be examined by 
obtaining a normal probability plot of the residuals and a plot of the residuals versus the fitted 
values (i.e. checking the normality assumption and constant variance assumption of the model 
respectively) to gain confidence that the model assumptions are reasonable. 
11.10.1.5. Generalized Linear Model
Endpoint(s)

Proportion of responders according to FEV1, SGRQ total score, CAT score, and 
TDI focal score
Analysis

Generalized linear model

Pearson residuals will be plotted by using PLOTS=PEARSONPANEL option for the model 
statement in SAS.
 
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11.10.1.6. Analysis of Covariance
Endpoint(s)

QTc(F), Trough FEV1 (Sensitivity), SGRQ Total Score(Sensitivity)
Analysis

ANCOVA

Distributional assumptions underlying the model used for analysis will be examined by 
obtaining a normal probability plot of the residuals and a plot of the residuals versus the fitted 
values (i.e. checking the normality assumption and constant variance assumption of the model 
respectively) to gain confidence that the model assumptions are reasonable
11.10.1.7. Logistic Regression
Endpoint(s)

Subject global rating of change in activity limitation

Subject global rating of change in COPD severity
Analysis

Logistic regression

.

The score test will be used to assess the proportional odds assumption.
 
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11.11.
Appendix 11: Abbreviations & Trademarks
11.11.1.
Abbreviations
Abbreviation
Description
ADAE
ADaM Dataset for Adverse Events
ADaM
Analysis Data Model
ADCM
ADaM Dataset for Concomitant Medications
AE
Adverse Event
AESI
Adverse Event of Special Interest
ASE
All Subjects Enrolled
ATC
Anatomical Therapeutic Chemical Classification
BDI
Baseline Dyspnea Index
BMI
Body Mass Index
BP
Blood Pressure
bpm
Beats Per Minute
CAT
COPD Assessment Test
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
COPD
Chronic Obstructive Pulmonary Disease
CRT
Case Report Tabulation
CSR
Clinical Study Report
CV
Cardiovascular
DBF
Database Freeze
DM
Data Management
DPI
Dry Powder Inhaler
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EOS
Eosinophil
EQ-5D-5L
EuroQol Questionnaire (five level)
FEV1
Forced Expiratory Volume in One Second
FF
Fluticasone Furoate
FVC
Forced Vital Capacity
GCSP
Global Clinical Safety and Pharmacovigilance
GLM
General Linear Model
GOLD
Global Initiative for Chronic Obstructive Lung Disease
GSK
GlaxoSmithKline
HRQoL
Health Related Quality of Life
IC
Informed Consent
ICF
Informed Consent Form
ICH
International Conference on Harmonization
ICS
Inhaled Corticosteroid
IDMC
Independent Data and Monitoring Committee
IDSL
Integrated Data Standards Library
ITT
Intent-To-Treat
IVRS
Interactive Voice Recognition System
 
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Abbreviation
Description
kg
Kilogram
KR
Kenward and Roger
L
Liter
LABA
Long-Acting Beta-Agonist
LAMA
Long-Acting Muscarinic Receptor Antagonist
LLN
Lower Limit of Normal
LRTI
Lower Respiratory Tract Infection
LS
Least-square
m
Meter
MACE
Major Adverse Cardiac Event
mcg
Microgram
MedDRA
Medical Dictionary for Regulatory Activities
mL
Milliliter
mmHg
Millimeters of Mercury 
MMRM
Mixed Model Repeated Measures
msec
Millisecond
NA
Not Applicable
NQ
Not Quantifiable 
PD
Protocol Deviation
PDE4
Phosphodiesterase-4
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PT
Preferred Term
QC
Quality Control
QTcF
QT interval corrected for heart rate by Fridericia’s formula
RAMOS
Randomization & Medication Ordering System 
RANDALL-
NG
GSK Randomization System – Next Generation
RAP
Reporting and Analysis Plan
RMC
Respiratory Medication Class
RTF
Rich Text Format
SAC
Statistical Analysis Complete
SAE
Serious Adverse Event
SDAC
Statistical Data Analysis Center
SDL
Source Data Lock
SDTM
Study Data Tabulation Model
SE
Standard Error
SGRQ
St. George’s Respiratory Questionnaire
SGRQ-C
SGRQ for COPD patients
SI
System Independent
SMQ
Standardized MedDRA Query
SOC
System Organ Class
TDI
Transitional Dyspnea Index
TFL
Tables, Figures & Listings 
TSCG
Tibco Spotfire Clinical Graphics software
 
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Abbreviation
Description
TTF
Time to First
ULN
Upper Limit of Normal
UMEC
Umeclidinium
VAS
Visual Analog Scale
VI
Vilanterol Trifenatate
11.11.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
CAT
SAS
ELLIPTA
TSCG
 
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11.12.
Appendix 12: List of Data Displays
11.12.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.01 to 1.xx
1.01 to 1.xx
Efficacy
2.001 to 2.xxx
2.01 to 2.xx
Safety
3.001 to 3.xxx
3.01 to 3.xx
Section
Listings
ICH Listings
1 to x
Other Listings
x+1 to z
11.12.2.
Deliverable
Delivery [Priority]
Description
SAC [1]
Final Statistical Analysis Complete.  These displays should be created 
first and will be provided to the clinical team as headline results.
SAC 
Final Statistical Analysis Complete.  These displays should be created 
once the high priority displays marked SAC [1] have been completed.
 
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11.12.3.
Study Population Tables
Study Population Tables
No.
Popu-
lation
Title
Deliverable
[Priority]
Subject Disposition
1.01
ASE
Summary of Study Populations and Reasons for Screen Failure
SAC
1.02
ITT
Summary of Attendance/Telephone Contact at Each Visit
SAC
1.03
ITT
Summary of Completion and Premature Discontinuation of Study 
Treatment
SAC
1.04
ITT
Summary of Study Completion and Withdrawal 
SAC
1.05
ASE
Summary of Number of Subjects Enrolled by Country
SAC
1.06
ASE
Summary of Number of Subjects Enrolled by Age Category
SAC
1.07
ITT
Summary of Number of Subjects by Geographical Region, Country and 
Center
SAC
1.08
ECG
Summary of Number of Subjects by Geographical Region, Country and 
Center
SAC
1.09
TDI
Summary of Number of Subjects by Geographical Region, Country and 
Center
SAC
1.10
ASE
Summary of Inclusion/Exclusion Criteria Deviations For Screen Failures
SAC
1.11
ITT
Summary of Inclusion/Exclusion Criteria Deviations 
SAC
1.12
ITT
Summary of Important Protocol Deviations
SAC
Demography
1.13
ITT
Summary of Demographic Characteristics
SAC [1]
1.14
ITT
Summary of Demographic Characteristics by Eosinophil Subgroup
SAC [1]
1.15
ECG
Summary of Demographic Characteristics 
SAC
1.16
TDI
Summary of Demographic Characteristics 
SAC
1.17
ITT
Summary of Demographic Characteristics by Country
SAC
1.18
ITT
Summary of Race and Racial Combinations
SAC
1.19
ITT
Summary of Race and Racial Combinations by Eosinophil Subgroup
SAC
1.20
ECG
Summary of Race and Racial Combinations
SAC
1.21
TDI
Summary of Race and Racial Combinations
SAC
Medical Conditions
1.22
ITT
Summary of Current Medical Conditions
SAC
1.23
ITT
Summary of Current Medical Conditions by Eosinophil Subgroup
SAC
1.24
ECG
Summary of Current Medical Conditions
SAC
1.25
ITT
Summary of Past Medical Conditions
SAC
1.26
ITT
Summary of Past Medical Conditions by Eosinophil Subgroup
SAC
1.27
ECG
Summary of Past Medical Conditions
SAC
1.28
ITT
Summary of Cardiovascular Risk Factors
SAC
1.29
ITT
Summary of Cardiovascular Risk Factors by Eosinophil Subgroup
SAC
1.30
ECG
Summary of Cardiovascular Risk Factors
SAC
1.31
ITT
Summary of Family History of Cardiovascular Risk Factors
SAC
1.32
ITT
Summary of Family History of Cardiovascular Risk Factors by Eosinophil 
Subgroup
SAC
1.33
ECG
Summary of Family History of Cardiovascular Risk Factors
SAC
1.34
ITT
Summary of Smoking History at Screening
SAC
1.35
ITT
Summary of Smoking History at Screening by Eosinophil Subgroup
SAC
1.36
ECG
Summary of Smoking History at Screening
SAC
 
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Study Population Tables
No.
Popu-
lation
Title
Deliverable
[Priority]
1.37
ITT
Summary of Smoking Status
SAC
1.38
ITT
Summary of Smoking Status by Eosinophil Subgroup
SAC
1.39
ECG
Summary of Smoking Status
SAC
1.40
ITT
Summary of Pneumonia Risk Factors at Screening
SAC
1.41
ITT
Summary of Pneumonia Risk Factors at Screening by Eosinophil 
Subgroup
SAC
Disease Characteristics
1.42
ITT
Summary of COPD Duration at Screening
SAC
1.43
ITT
Summary of COPD Duration at Screening by Eosinophil Subgroup
SAC
1.44
ITT
Summary of COPD Exacerbation History at Screening
SAC [1]
1.45
ITT
Summary of COPD Exacerbation History at Screening by Eosinophil 
Subgroup
SAC
1.46
ITT
Summary of COPD Exacerbation History at Screening by Country
SAC
1.47
ITT
Summary of COPD Exacerbation History Details at Screening
SAC
1.48
ITT
Summary of COPD Exacerbation History Details at Screening by 
Eosinophil Subgroup
SAC
1.49
ITT
Summary of COPD Exacerbation History Details at Screening by 
Country
SAC
1.50
ITT
Summary of Screening Lung Function
SAC [1]
1.51
ITT
Summary of Screening Lung Function by Eosinophil Subgroup
SAC
1.52
ITT
Summary of Screening Lung Function by Country
SAC
1.53
ITT
Summary of Reversibility and GOLD Grade (1-4) at Screening
SAC
1.54
ITT
Summary of Reversibility and GOLD Grade (1-4) at Screening by 
Eosinophil Subgroup
SAC
1.55
ITT
Summary of Reversibility and GOLD Grade (1-4) at Screening by 
Country
SAC
1.56
ITT
Summary of CAT Score at Screening
SAC
1.57
ITT
Summary of CAT Score at Screening by Eosinophil Subgroup
SAC
1.58
ITT
Summary of Shift in CAT Score Categories from Screening to Baseline
SAC
1.59
ITT
Summary of Shift in CAT Score Categories from Screening to Baseline 
by Eosinophil Subgroup
SAC
Pulse Oximetry
1.60
ITT
Summary of Percent Oxygen in Blood at Visit 2, Pre-Dose
SAC
Concomitant Medications
1.61
ITT
Summary of COPD Concomitant Medications Taken Prior to Screening
SAC
1.62
ITT
Summary of COPD Concomitant Medications Taken in the Run-in, 
Medications Given for Reasons other than an Exacerbation 
SAC
1.63
ITT
Summary of On-treatment COPD Concomitant Medications, Medications 
Given for Reasons other than an Exacerbation
SAC
1.64
ITT
Summary of Post-treatment COPD Concomitant Medications, 
Medications Given for Reasons other than an Exacerbation
SAC
1.65
ITT
Summary of On-treatment Concomitant Medications Given for an 
Exacerbation
SAC
1.66
ITT
Summary of Post-treatment Concomitant Medications Given for an 
Exacerbation
SAC
1.67
ITT
Summary of COPD Concomitant Medication Combinations Taken at 
Screening
SAC
 
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Study Population Tables
No.
Popu-
lation
Title
Deliverable
[Priority]
1.68
ITT
Summary of COPD Concomitant Medication Combinations Taken at 
Screening by Eosinophil Subgroup
SAC
1.69
ITT
Summary of COPD Concomitant Medication Combinations Taken at 
Screening by Country
SAC
1.70
ITT
Summary of COPD Concomitant Medication Combinations Taken at 
Treatment Discontinuation 
SAC
1.71
ITT
Summary of COPD Concomitant Medication Combinations Taken at 
Treatment Discontinuation for Those Subjects Providing Post-treatment 
Information
SAC
1.72
ITT
Summary of On-treatment Non-COPD Concomitant Medications
SAC
1.73
ITT
Summary of Post-treatment Non-COPD Concomitant Medications 
SAC
1.74
ITT
Summary of Influenza and Pneumonia Vaccination Taken at Any Time 
up to the End of Study Treatment 
SAC
Treatment Compliance
1.75
ITT
Summary of Treatment Compliance (%)
SAC
11.12.4.
Study Population Figures
Study Population figures
No.
Popu-
lation
Title
Deliverable
1.01
ITT
Kaplan-Meier Plot of Time to Premature Discontinuation of Study 
Treatment
SAC
1.02
ITT
Kaplan-Meier Plot of Time to Premature Discontinuation of Study 
Treatment – UMEC/VI and FF/VI treatment groups only
SAC
1.03
ITT
Kaplan-Meier Plot of Time to Study Withdrawal
SAC
1.04
ITT
Kaplan-Meier Plot of Time to Study Withdrawal– UMEC/VI and FF/VI 
treatment groups only
SAC
11.12.5.
Efficacy Tables
Efficacy: Tables
No.
Popul
ation
Title
Deliverable 
[Priority]
COPD Exacerbations – Primary Endpoint
2.001
ITT
Summary of On-treatment Moderate/Severe COPD Exacerbations
SAC
2.002
ITT
Summary of On-treatment Details of Moderate/Severe COPD 
Exacerbations
SAC
2.003
ITT
Summary of On-treatment Moderate/Severe COPD Exacerbations by 
Country
SAC
2.004
ITT
Analysis of On-treatment Moderate/Severe COPD Exacerbations -
Negative Binomial Model (Primary Analysis of the Primary Endpoint)
SAC [1]
2.005
ITT
Analysis of On-treatment Moderate/Severe COPD Exacerbations –
Poisson Model (Supportive Analysis of the Primary Endpoint)
SAC
2.006
ITT
P-values for Interactions of Treatment with Covariates for Negative
Binomial Analysis of On-treatment Moderate/Severe COPD 
Exacerbations (Supportive Analysis of the Primary Endpoint)
SAC
 
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Efficacy: Tables
No.
Popul
ation
Title
Deliverable 
[Priority]
2.007
ITT
Analysis of Moderate/Severe COPD Exacerbations - Negative Binomial 
Model, Analysis Including Off-treatment Data (Sensitivity Analysis of the 
Primary Endpoint)
SAC
2.008
ITT
Analysis of On-treatment Moderate/Severe COPD Exacerbations -
Negative Binomial Model, Imputing Data Following FF/UMEC/VI 
Discontinuation Using Jump to Reference Assumption (FF/VI as 
Reference) (Sensitivity Analysis of the Primary Endpoint)
SAC
2.009
ITT
Analysis of On-treatment Moderate/Severe COPD Exacerbations -
Negative Binomial Model, Imputing Data Following FF/UMEC/VI 
Discontinuation Using Jump to Reference Assumption (UMEC/VI as 
Reference) (Sensitivity Analysis of the Primary Endpoint)
SAC
2.010
ITT
Analysis of On and Off-treatment Moderate/Severe COPD Exacerbations 
- Negative Binomial Model, Imputing Data Following FF/UMEC/VI 
Discontinuation Using Jump to Reference Assumption (FF/VI as 
Reference) (Sensitivity Analysis of the Primary Endpoint)
SAC
2.011
ITT
Analysis of On and Off-treatment Moderate/Severe COPD Exacerbations 
- Negative Binomial Model, Imputing Data Following FF/UMEC/VI 
Discontinuation Using Jump to Reference Assumption (UMEC/VI as 
Reference) (Sensitivity Analysis of the Primary Endpoint)
SAC
COPD Exacerbations – Secondary Endpoints
2.012
ITT
Summary and Analysis of Time to First On-treatment Moderate/Severe 
COPD Exacerbation (Primary Analysis of Secondary Endpoint)
SAC [1]
2.013
ITT
Summary and Analysis of Time to First Moderate/Severe COPD 
Exacerbation Including Off-treatment Data (Sensitivity Analysis of 
Secondary Endpoint)
SAC
2.014
ITT
Summary and Analysis of Time to First On-treatment Moderate/Severe 
COPD Exacerbation or Premature Treatment Discontinuation (Sensitivity 
Analysis of Secondary Endpoint)
SAC
2.015
ITT
Summary of On-treatment Moderate/Severe COPD Exacerbations by 
Eosinophil Subgroup
SAC
2.016
ITT
Summary and Analysis of Time to First On-treatment Moderate/Severe 
COPD Exacerbation by Eosinophil Subgroup (Primary Analysis of 
Secondary Endpoint)
SAC
2.017
ITT
Analysis of On-treatment Moderate/Severe COPD Exacerbations by 
Eosinophil Subgroup - Negative Binomial Model (Primary Analysis of 
Secondary Endpoint)
SAC [1]
2.018
ITT
Summary of On-treatment Severe COPD Exacerbations 
SAC
2.019
ITT
Analysis of On-treatment Severe COPD Exacerbations - Negative 
Binomial Model (Primary Analysis of Secondary Endpoint)
SAC 
COPD Exacerbations – Other Efficacy Endpoints
2.020
ITT
Summary of Off-treatment Moderate/Severe COPD Exacerbations
SAC
2.021
ITT
Summary of On-treatment Mild/Moderate/Severe COPD Exacerbations
SAC
2.022
ITT
Analysis of On-treatment Mild/Moderate/Severe COPD Exacerbations -
Negative Binomial Model
SAC
2.023
ITT
Summary of On-treatment Moderate COPD Exacerbations
SAC
2.024
ITT
Analysis of On-treatment Moderate COPD Exacerbations - Negative 
Binomial Model
SAC
 
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118
Efficacy: Tables
No.
Popul
ation
Title
Deliverable 
[Priority]
2.025
ITT
Summary of On-treatment Moderate/Severe COPD Exacerbations 
Requiring Systemic/Oral Corticosteroids
SAC
2.026
ITT
Analysis of On-treatment Moderate/Severe COPD Exacerbations 
Requiring Systemic/Oral Corticosteroids – Negative Binomial Model
SAC
2.027
ITT
Summary of On-treatment  Moderate/Severe COPD Exacerbations 
Requiring Antibiotics
SAC
2.028
ITT
Analysis of On-treatment Moderate/Severe COPD Exacerbations 
Requiring Antibiotics – Negative Binomial Model
SAC
2.029
ITT
Summary of On-treatment Severe COPD Exacerbations by Eosinophil 
Subgroup
SAC
2.030
ITT
Analysis of On-treatment Severe COPD Exacerbations by Eosinophil 
Subgroup – Negative Binomial Model
SAC
2.031
ITT
Analysis of Time to Each On-treatment Moderate/Severe COPD 
Exacerbation
SAC
2.032
ITT
Analysis of Time to Each On-treatment Severe COPD Exacerbation
SAC
2.033
ITT
Summary and Analysis of Time to First On-treatment Severe COPD 
Exacerbation
SAC
2.034
ITT
Summary and Analysis of Time to First On-treatment Severe COPD 
Exacerbation by Eosinophil Subgroup
SAC
2.035
ITT
Summary and Analysis of Time to First On-treatment Mild/Moderate/ 
Severe COPD Exacerbation
SAC
2.036
ITT
Summary and Analysis of Time to First On-treatment Moderate COPD 
Exacerbation
SAC
2.037
ITT
Summary and Analysis of Time to First On-treatment Moderate/Severe 
COPD Exacerbation Requiring Systemic/Oral Corticosteroids
SAC
2.038
ITT
Summary and Analysis of Time to First On-treatment Moderate/Severe 
COPD Exacerbation Requiring Antibiotics
SAC
Spirometry – Secondary Endpoint
2.039
ITT
Summary of Baseline FEV1 (L)
SAC
2.040
ITT
Summary of Trough FEV1 (L)
SAC
2.041
ITT
Analysis of Trough FEV1 (L) (Primary Analysis of Secondary Endpoint)
SAC [1]
2.042
ITT
Analysis of Trough FEV1 (L) Imputing Data Following FF/UMEC/VI 
Discontinuation Using Jump to Reference Assumption (FF/VI as 
Reference) (Sensitivity Analysis of Secondary Endpoint)
SAC
2.043
ITT
Analysis of Trough FEV1 (L) Imputing Data Following FF/UMEC/VI 
Discontinuation Using Jump to Reference Assumption (UMEC/VI as 
Reference) (Sensitivity Analysis of Secondary Endpoint)
SAC
Spirometry – Other Efficacy Endpoints
2.044
ITT
Summary of Baseline Pre-bronchodilator FEV1 (L) by Eosinophil 
Subgroup
SAC
2.045
ITT
Summary of Trough FEV1 (L) by Eosinophil Subgroup
SAC
2.046
ITT
Analysis of Trough FEV1 (L) by Eosinophil Subgroup
SAC
2.047
ITT
Summary of Post-bronchodilator FEV1 (L)
SAC
2.048
ITT
Analysis of Post-bronchodilator FEV1 (L)
SAC
2.049
ITT
Summary and Analysis of Proportion of Subjects Obtaining at Least 
100mL Increase from Baseline in Trough FEV1
SAC
2.050
ITT
Summary and Analysis of Proportion of Subjects Obtaining at Least 
100mL Increase from Baseline in Trough FEV1 by Eosinophil Subgroup
SAC
 
2017N330297_00


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CTT116855
119
Efficacy: Tables
No.
Popul
ation
Title
Deliverable 
[Priority]
2.051
ITT
Summary of Baseline FEV1 Reversibility (mL)
SAC
2.052
ITT
Summary of FEV1 Reversibility (mL)
SAC
2.053
ITT
Analysis of FEV1 Reversibility (mL)
SAC
2.054
ITT
Summary of Baseline FVC (L)
SAC
2.055
ITT
Summary of Trough FVC (L)
SAC
2.056
ITT
Analysis  of Trough FVC (L)
SAC
2.057
ITT
Summary of Post-bronchodilator FVC (L)
SAC
2.058
ITT
Analysis of Post-bronchodilator FVC (L)
SAC
SGRQ – Secondary Endpoint
2.059
ITT
Summary of Baseline SGRQ Scores
SAC
2.060
ITT
Summary of SGRQ  Scores 
SAC
2.061
ITT
Analysis of SGRQ Total Score (Primary Analysis of Secondary Endpoint)
SAC [1]
2.062
ITT
Analysis of SGRQ Total Score Imputing Data Following FF/UMEC/VI 
Discontinuation Using Jump to Reference Assumption (FF/VI as 
Reference) (Sensitivity Analysis of Secondary Endpoint)
SAC
2.063
ITT
Analysis of SGRQ Total Score Imputing Data Following FF/UMEC/VI 
Discontinuation Using Jump to Reference Assumption (UMEC/VI as 
Reference) (Sensitivity Analysis of Secondary Endpoint)
SAC
SGRQ – Other Efficacy Endpoint
2.064
ITT
Summary of Baseline SGRQ Total Score by Eosinophil Subgroup
SAC
2.065
ITT
Summary of SGRQ Total Score by Eosinophil Subgroup
SAC
2.066
ITT
Analysis of SGRQ Total Score by Eosinophil Subgroup
SAC
2.067
ITT
Summary of SGRQ Total Score at Week 52 by Global Rating of Change 
in COPD Severity at Week 52, Combined Treatment Groups
SAC
2.068
ITT
Summary of SGRQ Total Score at Week 52 by Global Rating of Change 
in COPD Severity at Week 52 
SAC
2.069
ITT
Summary and Analysis of Proportion of Responders According to SGRQ 
Total Score
SAC [1]
2.070
ITT
Summary and Analysis of Proportion of Responders According to SGRQ 
Total Score by Eosinophil Subgroup
SAC
2.071
ITT
Summary and Analysis of Proportion of Moderate/Major Responders 
According to SGRQ Total Score
SAC
2.072
ITT
Summary and Analysis of Proportion of Major Responders According to 
SGRQ Total Score
SAC
BDI/TDI
2.073
TDI
Summary of BDI Focal Score
SAC
2.074
TDI
Summary of BDI Focal Score by Eosinophil Subgroup
SAC
2.075
TDI
Summary of TDI Focal Score 
SAC
2.076
TDI
Summary of TDI Focal Score by Eosinophil Subgroup
SAC
2.077
TDI
Analysis of TDI Focal Score
SAC
2.078
TDI
Analysis of TDI Focal Score by Eosinophil Subgroup
SAC
2.079
TDI
Summary of TDI Focal Score Categories of Improvement and 
Deterioration
SAC
2.080
TDI
Summary and Analysis of Proportion of Responders According to TDI 
Focal Score
SAC
2.081
TDI
Summary and Analysis of Proportion of Responders According to TDI 
Focal Score by Eosinophil Subgroup
SAC
 
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120
Efficacy: Tables
No.
Popul
ation
Title
Deliverable 
[Priority]
2.082
TDI
Summary and Analysis of Proportion of Moderate/Major Responders 
According to TDI Focal Score
SAC
2.083
TDI
Summary and Analysis of Proportion of Major Responders According to 
TDI Focal Score
SAC
All Cause Mortality
2.084
ITT
Summary of On-treatment Adjudicated Cause of Death 
SAC
2.085
ITT
Summary of On-treatment Adjudicated Cause of Death by Eosinophil 
Subgroup
SAC
2.086
ITT
Summary of Adjudicated Cause of Death Including Off-treatment Data
SAC
2.087
ITT
Summary of Adjudicated Cause of Death Including Off-treatment Data by 
Eosinophil Subgroup
SAC
2.088
ITT
Summary and Analysis of Time to On-treatment All Cause Mortality
SAC
2.089
ITT
Summary and Analysis of Time to All Cause Mortality Including Off-
treatment Data
SAC
CAT
2.090
ITT
Summary of Baseline CAT Score
SAC
2.091
ITT
Summary of Baseline CAT Score by Eosinophil Subgroup
SAC
2.092
ITT
Summary of CAT Score
SAC
2.093
ITT
Summary of CAT Score by Eosinophil Subgroup
SAC
2.094
ITT
Analysis of CAT Score
SAC
2.095
ITT
Analysis of CAT Score by Eosinophil Subgroup
SAC
2.096
ITT
Summary and Analysis of Proportion of Responders According to CAT 
Score 
SAC
2.097
ITT
Summary and Analysis of Proportion of Responders According to CAT 
Score by Eosinophil Subgroup
SAC
Subject Global Ratings
2.098
ITT
Summary of Subject Global Rating of Activity Limitation
SAC
2.099
ITT
Summary and Analysis of Subject Global Rating of Change in Activity 
Limitation
SAC
2.100
ITT
Summary of Subject Global Rating of COPD Severity
SAC
2.101
ITT
Summary and Analysis of Subject Global Rating of Change in COPD 
Severity
SAC
Daily Diary Assessments 
2.102
ITT
Summary of Mean Number of Occasions of Rescue Use per Day 
SAC
2.103
ITT
Analysis of Mean Number of Occasions of Rescue Use per Day by Four 
Weekly Period
SAC
2.104
ITT
Summary of Percentage of Rescue-Free Days
SAC
2.105
ITT
Analysis of Percentage of Rescue-Free Days by Four Weekly Period
SAC
2.106
ITT
Summary of Mean Number of Nighttime Awakenings per Night
SAC
2.107
ITT
Analysis of Mean Number of Nighttime Awakenings per Night by Four 
Weekly Period
SAC
2.108
ITT
Summary of Percentage of Days Symptoms Stopped Usual Activities
SAC
2.109
ITT
Analysis of Percentage of Days Symptoms Stopped Usual Activities by 
Four Weekly Period
SAC
EQ-5D-5L
2.110
ITT
Summary of EQ-5D-5L VAS Scores
SAC
2.111
ITT
Summary of EQ-5D-5L Utility Indices
SAC
 
2017N330297_00


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121
Efficacy: Tables
No.
Popul
ation
Title
Deliverable 
[Priority]
Healthcare Resource Utilization
2.112
ITT
Summary of Unscheduled Healthcare Resource Utilization
SAC
2.113
ITT
Summary of Unscheduled Healthcare Resource Utilization by Contact 
Type
SAC
Additional Sensitivity Analysis of Primary Endpoint (to be performed only if ≥2% of the ITT 
population are enrolled at sites that are withdrawn from the study due to concerns over protocol 
deviations)
2.114
ITT
Analysis of On-treatment Moderate/Severe COPD Exacerbations -
Negative Binomial Model, Excluding Subjects from Sites that were 
Withdrawn from the Study (Sensitivity Analysis of the Primary Endpoint)
11.12.6.
Efficacy Figures
Efficacy: Figures
No.
Popu-
lation
Title
Deliverable 
[Priority]
COPD Exacerbations – Primary Endpoint
2.01
ITT
Adjusted On-treatment Moderate/Severe COPD Exacerbation Rate 
Ratios 
SAC
2.02
ITT
Box Plot of On-treatment Moderate/Severe Annual Raw COPD 
Exacerbation Rates
SAC
2.03
ITT
Forest Plot of Adjusted On-treatment Moderate/Severe COPD 
Exacerbation Rate Ratios and Associated Sensitivity Analyses
SAC
COPD Exacerbations – Secondary Endpoints
2.04
ITT
Kaplan-Meier Plot of Time to First On-treatment Moderate/Severe 
COPD Exacerbation 
SAC
2.05
ITT
Kaplan-Meier Plot of Time to First On-treatment Moderate/Severe 
COPD Exacerbation – UMEC/VI and FF/VI treatment groups only
SAC
2.06
ITT
Hazard Ratios for Time to First On-treatment Moderate/Severe COPD 
Exacerbation
SAC
2.07
ITT
Kaplan-Meier Plot of Time to First Moderate/Severe COPD 
Exacerbation, Including Off-treatment Data
SAC
2.08
ITT
Kaplan-Meier Plot of Time to First Moderate/Severe COPD 
Exacerbation, Including Off-treatment Data – UMEC/VI and FF/VI 
treatment groups only
SAC
2.09
ITT
Forest Plot of Hazard Ratios for Time to First On-treatment 
Moderate/Severe COPD Exacerbation and Associated Sensitivity 
Analyses
SAC
 
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122
Efficacy: Figures
No.
Popu-
lation
Title
Deliverable 
[Priority]
2.10
ITT
Kaplan-Meier Plot of Time to First On-treatment Moderate/Severe 
COPD Exacerbation or Premature Treatment Discontinuation 
SAC
2.11
ITT
Kaplan-Meier Plot of Time to First On-treatment Moderate/Severe 
COPD Exacerbation or Treatment Discontinuation - UMEC/VI and FF/VI 
treatment groups only
SAC
2.12
ITT
Kaplan-Meier Plot of Time to First On-treatment Moderate/Severe 
COPD Exacerbation by Eosinophil Subgroup
SAC
2.13
ITT
Kaplan-Meier Plot of Time to First On-treatment Moderate/Severe 
COPD Exacerbation by Eosinophil Subgroup - UMEC/VI and FF/VI 
treatment groups only
SAC
2.14
ITT
Hazard Ratios for Time to First On-treatment Moderate/Severe COPD 
Exacerbation by Eosinophil Subgroup
SAC
2.15
ITT
Adjusted On-treatment Moderate/Severe COPD Exacerbation Rate 
Ratios by Eosinophil Subgroup
SAC
2.16
ITT
Adjusted On-treatment Severe COPD Exacerbation Rate Ratios
SAC
COPD Exacerbations – Other Endpoint
2.17
ITT
Kaplan-Meier Plot of Time to First On-treatment Mild/Moderate/Severe 
COPD Exacerbation
SAC
2.18
ITT
Kaplan-Meier Plot of Time to First On-treatment Mild/Moderate/Severe 
COPD Exacerbation- UMEC/VI and FF/VI treatment groups only
SAC
2.19
ITT
Kaplan-Meier Plot of Time to First On-treatment Moderate COPD 
Exacerbation
SAC
2.20
ITT
Kaplan-Meier Plot of Time to First On-treatment Moderate COPD 
Exacerbation- UMEC/VI and FF/VI treatment groups only
SAC
2.21
ITT
Kaplan-Meier Plot of Time to First On-treatment Moderate/Severe 
COPD Exacerbation Requiring Systemic/Oral Corticosteroids
SAC
2.22
ITT
Kaplan-Meier Plot of Time to First On-treatment Moderate/Severe 
COPD Exacerbation Requiring Systemic/Oral Corticosteroids- UMEC/VI 
and FF/VI treatment groups only
SAC
2.23
ITT
Kaplan-Meier Plot of Time to First On-treatment Moderate/Severe 
COPD Exacerbation Requiring Antibiotics
SAC
2.24
ITT
Kaplan-Meier Plot of Time to First On-treatment Moderate/Severe 
COPD Exacerbation Requiring Antibiotics- UMEC/VI and FF/VI 
treatment groups only
SAC
2.25
ITT
Kaplan-Meier Plot of Time to First On-treatment Severe COPD 
Exacerbation
SAC
2.26
ITT
Kaplan-Meier Plot of Time to First On-treatment Severe COPD 
Exacerbation- UMEC/VI and FF/VI treatment groups only
SAC
2.27
ITT
Kaplan-Meier Plot of Time to First On-treatment Severe COPD 
Exacerbation by Eosinophil Subgroup
SAC
2.28
ITT
Kaplan-Meier Plot of Time to First On-treatment Severe COPD 
Exacerbation by Eosinophil Subgroup- UMEC/VI and FF/VI treatment 
groups only
SAC
Spirometry – Secondary Endpoint
2.29
ITT
Least Squares Mean (95% CI) Change from Baseline in Trough FEV1 
(L)
SAC
 
2017N330297_00


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CTT116855
123
Efficacy: Figures
No.
Popu-
lation
Title
Deliverable 
[Priority]
2.30
ITT
Least Squares Mean (95% CI) Change from Baseline in Trough FEV1 
(L) – UMEC/VI and FF/VI treatment groups only
SAC
2.31
ITT
Least Squares Mean (95% CI) Treatment Difference in Change from 
Baseline in Trough FEV1 (L)
SAC
2.32
ITT
Forest Plot of Least Squares Mean (95% CI) Treatment Difference in 
Change from Baseline in Trough FEV1 (L) and Associated Sensitivity 
Analyses at Week 52
SAC
Spirometry – Other Efficacy Endpoints
2.33
ITT
Least Squares Mean (95% CI) Change from Baseline in Post-
bronchodilator FEV1 (L)
SAC
2.34
ITT
Least Squares Mean (95% CI) Change from Baseline in Post-
bronchodilator FEV1 (L) – UMEC/VI and FF/VI treatment groups only
SAC
2.35
ITT
Least Squares Mean (95% CI) Treatment Difference in Change from 
Baseline in Post-bronchodilator FEV1 (L)
SAC
2.36
ITT
Least Squares Mean (95% CI) Change from Baseline in Trough FVC (L)
SAC
2.37
ITT
Least Squares Mean (95% CI) Change from Baseline in Trough FVC (L) 
– UMEC/VI and FF/VI treatment groups only
SAC
2.38
ITT
Least Squares Mean (95% CI) Treatment Difference in Change from 
Baseline in Trough FVC (L)
SAC
2.39
ITT
Least Squares Mean (95% CI) Change from Baseline in Post-
bronchodilator FVC (L)
SAC
2.40
ITT
Least Squares Mean (95% CI) Change from Baseline in Post-
bronchodilator FVC (L) – UMEC/VI and FF/VI treatment groups only
SAC
2.41
ITT
Least Squares Mean (95% CI) Treatment Difference in Change from 
Baseline in Post-bronchodilator FVC (L)
SAC
SGRQ – Secondary Endpoint
2.42
ITT
Box Plot of Change from Baseline in SGRQ Total Score at Week 52
SAC
2.43
ITT
Empirical Distribution Function Plot of Change from Baseline in SGRQ 
Total Score at Week 52
SAC
2.44
ITT
Least Squares Mean (95% CI) Change from Baseline in SGRQ Total 
Score
SAC
2.45
ITT
Least Squares Mean (95% CI) Change from Baseline in SGRQ Total 
Score – UMEC/VI and FF/VI treatment groups only
SAC
2.46
ITT
Least Squares Mean (95% CI) Treatment Difference in Change from 
Baseline in SGRQ Total Score
SAC
2.47
ITT
Forest Plot of Least Squares Mean (95% CI) Treatment Difference in 
Change from Baseline in SGRQ Total Score and Associated Sensitivity 
Analyses at Week 52
SAC
SGRQ – Other Efficacy Endpoint
2.48
ITT
Box Plot of Change from Baseline in SGRQ Total Score at Week 52 by 
Global Rating of Change in COPD Severity at Week 52,  Combined 
Treatment Groups 
SAC
2.49
ITT
Box Plot of Change from Baseline in SGRQ Total Score at Week 52 by 
Global Rating of Change in COPD Severity at Week 52
SAC
All-Cause Mortality
2.50
ITT
Kaplan-Meier Plot of Time to On-treatment All Cause Mortality 
SAC
2.51
ITT
Kaplan-Meier Plot of Time to On-treatment All Cause Mortality –
UMEC/VI and FF/VI treatment groups only
SAC
 
2017N330297_00


CONFIDENTIAL
CTT116855
124
Efficacy: Figures
No.
Popu-
lation
Title
Deliverable 
[Priority]
2.52
ITT
Kaplan-Meier Plot of Time to All Cause Mortality Including Off-treatment 
Data 
SAC
2.53
ITT
Kaplan-Meier Plot of Time to All Cause Mortality Including Off-treatment 
Data – UMEC/VI and FF/VI treatment groups only
SAC
BDI/TDI
2.54
ITT
Least Squares Means (95% CI) TDI Focal Score
SAC
2.55
ITT
Least Squares Means (95% CI) TDI Focal Score – UMEC/VI and FF/VI 
treatment groups only
SAC
2.56
ITT
Least Squares Mean (95% CI) Treatment Difference in TDI Focal Score
SAC
CAT
2.57
ITT
Least Squares Mean (95% CI) Change from Baseline in CAT Score
SAC
2.58
ITT
Least Squares Mean (95% CI) Change from Baseline in CAT Score –
UMEC/VI and FF/VI treatment groups only
SAC
2.59
ITT
Least Squares Mean (95% CI) Treatment Difference in Change from 
Baseline in CAT Score
SAC
Daily Diary
2.60
ITT
Least Squares Mean (95% CI) Change from Baseline in Mean Number 
of Occasions of Rescue use per Day by Four Weekly Period
SAC
2.61
ITT
Least Squares Mean (95% CI) Change from Baseline in Mean Number 
of Occasions of Rescue use per Day by Four Weekly Period – UMEC/VI 
and FF/VI treatment groups only
SAC
2.62
ITT
Least Squares Mean (95% CI) Treatment Difference in Change from 
Baseline Mean Number of Occasions of Rescue Use per Day by Four 
Weekly Period
SAC
2.63
ITT
Least Squares Mean (95% CI) Change from Baseline in Percentage of 
Rescue-Free Days by Four Weekly Period
SAC
2.64
ITT
Least Squares Mean (95% CI) Change from Baseline in Percentage of 
Rescue-Free Days by Four Weekly Period – UMEC/VI and FF/VI 
treatment groups only 
SAC
2.65
ITT
Least Squares Mean (95% CI) Treatment Difference in Change from 
Baseline Percentage of Rescue-Free Days by Four Weekly Period
SAC
2.66
ITT
Least Squares Mean (95% CI) Change from Baseline in Mean Number 
of Nighttime Awakenings per Night by Four Weekly Period
SAC
2.67
ITT
Least Squares Mean (95% CI) Change from Baseline in Mean Number 
of Nighttime Awakenings per Night by Four Weekly Period – UMEC/VI 
and FF/VI treatment groups only
SAC
2.68
ITT
Least Squares Mean (95% CI) Treatment Difference in Change from 
Baseline Mean Number of Nighttime Awakenings per Night by Four 
Weekly Period
SAC
2.69
ITT
Least Squares Mean (95% CI) Change from Baseline in Percentage of 
Days Symptoms Stopped Usual Activities by Four Weekly Period
SAC
2.70
ITT
Least Squares Mean (95% CI) Change from Baseline in Percentage of 
Days Symptoms Stopped Usual Activities by Four Weekly Period –
UMEC/VI and FF/VI treatment groups only
SAC
2.71
ITT
Least Squares Mean (95% CI) Treatment Difference in Change from 
Baseline Percentage of Days Symptoms Stopped Usual Activities by 
Four Weekly Period
SAC
 
2017N330297_00


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125
11.12.7.
Safety Tables
Safety Tables
No.
Popu-
lation
Title
Deliverable
[Priority] 
Exposure
3.001
ITT
Summary of Study Treatment Exposure
SAC
3.002
ITT
Summary of Study Treatment Exposure by Eosinophil Subgroup
SAC
3.003
ITT
Summary of Post-treatment Duration on Study
SAC
3.004
ITT
Summary of Post-treatment Duration on Study by Eosinophil 
Subgroup
SAC
3.005
ITT
Summary of On- and Post-treatment Duration on Study
SAC
3.006
ITT
Summary of On- and Post-treatment Duration on Study by Eosinophil 
Subgroup
SAC
Adverse Events
3.007
ITT
Overview of On-treatment Adverse Events 
SAC
3.008
ITT
Summary  of On-treatment Adverse Events
SAC [1]
3.009
ITT
Summary  of On-treatment Adverse Events by Country
SAC
3.010
ITT
Summary of On-treatment Drug-related Adverse Events
SAC
3.011
ITT
Summary of On-treatment Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study
SAC
3.012
ITT
Summary of the 10 Most Frequent On-treatment Adverse Events in 
Each Treatment Group
SAC
3.013
ITT
Summary of On-treatment Common Non-serious Adverse Events 
Reported by 3% Or More of Subjects in Any Treatment Group
SAC
3.014
ITT
Summary of On-treatment Adverse Event Categories of Interest in 
the Elderly by Age
SAC
3.015
ASE
Relationship of Adverse Event System Organ Class, Preferred Term 
and Verbatim Text
SAC
Serious Adverse Events
3.016
ASE
Summary of Pre-treatment Serious Adverse Events 
SAC
3.017
ITT
Summary of Pre-treatment Serious Adverse Events 
SAC
3.018
ASE
Summary of Pre-treatment Fatal Serious Adverse Events 
SAC
3.019
ASE
Summary of Pre-treatment Serious Adverse Events Leading to 
Withdrawal from Study  
SAC
3.020
ITT
Summary of Subjects and Number of Occurrences of On-treatment 
Serious, Drug-related Serious, Fatal and Drug-related Serious 
Adverse Events
SAC
3.021
ITT
Summary of On-treatment Serious Adverse Events
SAC [1]
3.022
ITT
Summary of On-treatment Non-fatal Serious Adverse Events
SAC
3.023
ITT
Summary of On-treatment Fatal Serious Adverse Events
SAC [1]
3.024
ITT
Summary of On-treatment Drug-related Serious Adverse Events
SAC
 
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126
Safety Tables
No.
Popu-
lation
Title
Deliverable
[Priority] 
3.025
ITT
Summary of On-treatment Drug-related Fatal Serious Adverse 
Events
SAC
3.026
ITT
Summary of Post-treatment Serious Adverse Events 
SAC
3.027
ITT
Summary of Post-treatment Fatal Serious Adverse Events 
SAC
Adjudicated Serious Adverse Events
3.028
ITT
Summary of Adjudicated On-treatment Serious Adverse Reports
SAC
3.029
ITT
Summary of Adjudicated On-treatment Non-fatal Serious Adverse 
Reports
SAC
3.030
ITT
Summary of Adjudicated On-treatment Fatal Serious Adverse 
Reports
SAC
3.031
ITT
Summary of Adjudicated Post-treatment Serious Adverse Reports
SAC
3.032
ITT
Summary of Adjudicated Post-treatment Non-fatal Serious Adverse 
Reports
SAC
3.033
ITT
Summary of Adjudicated Post-treatment  Fatal Serious Adverse 
Reports
SAC
Adverse Events of Special Interest
3.034
ITT
Summary of On-treatment Adverse Events of Special Interest
SAC [1]
3.035
ITT
Summary of On-treatment Adverse Events of Special Interest by 
Eosinophil Subgroup
SAC
3.036
ITT
Summary and Analysis of Time to First On-treatment Event in the 
Pneumonia AESI Group
SAC
3.037
ITT
Summary and Analysis of Time to First On-treatment Event in the 
Pneumonia AESI Group by Eosinophil Subgroup
SAC
3.038
ITT
Summary of Pneumonia Risk Factors at Screening for Subjects with 
an Event in the Pneumonia AESI Group
SAC
3.039
ITT
Summary of Pneumonia Risk Factors at Screening for Subjects with 
an Event in the Pneumonia AESI Group by Eosinophil Subgoup
SAC
3.040
ITT
Summary and Analysis of Time to First On-treatment Event in the 
Cardiovascular AESI Group
SAC
3.041
ITT
Summary of Incidence of On-treatment Pneumonia AESI and 
Adjudicated Pneumonia
SAC
Serious Adverse Events of Special Interest
3.042
ITT
Summary of On-treatment Serious Adverse Events of Special 
Interest
SAC
3.043
ITT
Summary of On-treatment Fatal Serious Adverse Events of Special 
Interest
SAC
3.044
ITT
Summary and Analysis of Time to First On-treatment Event in the 
Pneumonia AESI Group Resulting in Hospitalization/Prolonged 
Hospitalization or Death
SAC
 
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127
Safety Tables
No.
Popu-
lation
Title
Deliverable
[Priority] 
3.045
ITT
Summary and Analysis of Time to First On-treatment Event in the 
Cardiovascular AESI Group Resulting in Hospitalization/Prolonged 
Hospitalization or Death 
SAC
MACE
3.046
ITT
Summary of On-treatment Major Adverse Cardiac Events (MACE) –
Narrow Definition
SAC
3.047
ITT
Summary of On-treatment Major Adverse Cardiac Events (MACE) –
Broad Definition
SAC
Pneumonia (eCRF Pneumonia Form)
3.048
ITT
Summary of On-treatment Pneumonia Incidence
SAC
3.049
ITT
Summary of On-treatment Details of Pneumonia
3.050
ITT
Summary of On-treatment Pneumonia Incidence Resulting in 
Hospitalization/Prolonged Hospitalization or Death
SAC
3.051
ITT
Summary of On-treatment Details of Pneumonia Resulting in 
Hospitalization/Prolonged Hospitalization or Death
SAC
Composite Endpoints
3.052
ITT
Summary and Analysis of Time to First On-treatment Event in the 
Pneumonia AESI Group or On-treatment Moderate/Severe COPD 
Exacerbation
SAC
3.053
ITT
Summary and Analysis of Time to First On-treatment Severe COPD 
Exacerbation or On-treatment Event in the Pneumonia AESI Group 
Resulting in Hospitalization/Prolonged Hospitalization or Death
SAC
3.054
ITT
Summary and Analysis of Time to First On-treatment Severe COPD 
Exacerbation or On-treatment Event in the Cardiovascular AESI 
Group Resulting in Hospitalization/Prolonged Hospitalization or 
Death or On-treatment Event in the Pneumonia AESI Group 
Resulting in Hospitalization/Prolonged Hospitalization or Death
SAC
Bone Fractures
3.055
ITT
Summary of On-treatment Bone Fractures
SAC
Radiography (Chest Imaging)
3.056
ITT
Summary of On-treatment Chest Imaging (X-ray or CT Scan)
SAC
Liver Event
3.057
ITT
Summary of Liver Monitoring/Stopping Event Reporting
SAC
3.058
ITT
Summary of Hepatobiliary Laboratory Abnormalities
SAC
Laboratory Parameters
3.059
ITT
Summary of Chemistry Data
SAC
3.060
ITT
Summary of Change from Baseline in Chemistry Data
SAC
3.061
ITT
Summary of Chemistry Data Outside the Normal Range
SAC
 
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128
Safety Tables
No.
Popu-
lation
Title
Deliverable
[Priority] 
3.062
ITT
Summary of Chemistry Changes from Baseline Relative to the 
Normal Range
SAC
3.063
ITT
Summary of Hematology Data
SAC
3.064
ITT
Summary of Change from Baseline in Hematology Data
SAC
3.065
ITT
Summary of Hematology Data Outside the Normal Range
SAC
3.066
ITT
Summary of Hematology Changes from Baseline Relative to the 
Normal Range
SAC
Vitals Signs
3.067
ITT
Summary of Vital Signs
SAC
3.068
ITT
Summary of Change from Baseline in Vital Signs
SAC
3.069
ITT
Analysis of Pulse Rate (bpm)
SAC
3.070
ITT
Analysis of Systolic Blood Pressure (mmHg)
SAC
3.071
ITT
Analysis of Diastolic Blood Pressure (mmHg)
SAC
ECGs
3.072
ITT
Summary of ECG Values
SAC
3.073
ECG
Summary of ECG Values 
SAC
3.074
ITT
Summary of Change from Baseline in ECG Values 
SAC
3.075
ECG
Summary of Change from Baseline in ECG Values 
SAC
3.076
ITT
Summary of ECG Findings
SAC
3.077
ECG
Summary of ECG Findings
SAC
3.078
ITT
Summary of ECG Findings Shifts from Baseline
SAC
3.079
ECG
Summary of ECG Findings Shifts from Baseline
SAC
3.080
ECG
Summary of ECG Findings Shifts from Pre-dose to Post-dose at 
Week 4
SAC
3.081
ITT
Summary of ECG Abnormalities
SAC
3.082
ECG
Summary of ECG Abnormalities
SAC
3.083
ITT
Summary of ECG Abnormalities >3% of Subjects in Any Treatment 
Group
SAC
3.084
ITT
Summary of QTc(F) (msec) Categories
SAC
3.085
ECG
Summary of QTc(F) (msec) Categories
SAC
3.086
ITT
Summary of Change From Baseline in QTc(F) (msec) Categories
SAC
3.087
ECG
Summary of Change From Baseline in QTc(F) (msec) Categories
SAC
3.088
ITT
Analysis of Post-dose QTc(F) (msec)
SAC
3.089
ECG
Analysis of Pre-dose QTc(F) (msec)
SAC
3.090
ECG
Summary of Change from Pre-dose to Post-Dose ECG Heart Rate at 
Week 4
SAC
 
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11.12.8.
Safety Figures
Safety Figures
No.
Popu-
lation
Title
Deliverable
[Priority] 
Exposure
3.01
ITT
Plot of Exposure to Study Treatment
SAC
Adverse Events of Special Interest
3.02
ITT
Kaplan-Meier Plot of Time to First On-treatment Event in the 
Pneumonia AESI Group
SAC 
3.03
ITT
Kaplan-Meier Plot of Time to First On-treatment Event in the 
Pneumonia AESI Group– UMEC/VI and FF/VI treatment groups only
SAC 
3.04
ITT
Kaplan-Meier Plot of Time to First On-treatment Event in the 
Cardiovascular AESI Group
SAC
3.05
ITT
Kaplan-Meier Plot of Time to First On-treatment Event in the 
Cardiovascular AESI Group– UMEC/VI and FF/VI treatment groups 
only
SAC
Serious Adverse Events of Special Interest
3.06
ITT
Kaplan-Meier Plot of Time to First On-treatment Event in the 
Pneumonia AESI Group Resulting in Hospitalization/Prolonged 
Hospitalization or Death
SAC
3.07
ITT
Kaplan-Meier Plot of Time to First On-treatment Event in the 
Pneumonia AESI Group Resulting in Hospitalization/Prolonged 
Hospitalization or Death– UMEC/VI and FF/VI treatment groups only
SAC
3.08
ITT
Kaplan-Meier Plot of Time to First On-treatment Event in the 
Cardiovascular AESI Group Resulting in Hospitalization/Prolonged 
Hospitalization or Death
SAC
3.09
ITT
Kaplan-Meier Plot of Time to First On-treatment Event in the 
Cardiovascular AESI Group Resulting in Hospitalization/Prolonged 
Hospitalization or Death– UMEC/VI and FF/VI treatment groups only
SAC
 
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130
Safety Figures
No.
Popu-
lation
Title
Deliverable
[Priority] 
Composite Endpoints
3.10
ITT
Kaplan-Meier Plot of Time to First On-treatment Event in the 
Pneumonia AESI Group or On-treatment Moderate/Severe COPD 
Exacerbation Composite
SAC
3.11
ITT
Kaplan-Meier Plot of Time to First On-treatment Event in the 
Pneumonia AESI Group or On-treatment Moderate/Severe COPD 
Exacerbation Composite– UMEC/VI and FF/VI treatment groups only
SAC
3.12
ITT
Kaplan-Meier Plot of Time to First On-treatment Severe COPD 
Exacerbation or On-treatment Event in the Pneumonia AESI Group
Resulting in Hospitalization/Prolonged Hospitalization or Death
SAC
3.13
ITT
Kaplan-Meier Plot of Time to First On-treatment Severe COPD 
Exacerbation or On-treatment Event in the Pneumonia AESI Group 
Resulting in Hospitalization/Prolonged Hospitalization or Death–
UMEC/VI and FF/VI treatment groups only
SAC
3.14
ITT
Kaplan-Meier Plot of Time to First On-treatment Severe COPD 
Exacerbation or On-treatment Event in the CV AESI Group Resulting 
in Hospitalization or Prolonged Hospitalization or Death or On-
treatment Event in the Pneumonia AESI Group Resulting in
Hospitalization/Prolonged Hospitalization or Death
SAC
3.15
ITT
Kaplan-Meier Plot of Time to First On-treatment Severe COPD 
Exacerbation or On-treatment Event in the CV AESI Group Resulting 
in Hospitalization or Prolonged Hospitalization or Death or On-
treatment Event in the Pneumonia AESI Group Resulting in 
Hospitalization/Prolonged Hospitalization or Death– UMEC/VI and 
FF/VI treatment groups only
SAC
3.16
ITT
Percentage of Subjects with an On-treatment Event in the 
Pneumonia AESI Group and Percentage of Subjects with an On-
treatment Moderate/Severe COPD Exacerbation
SAC
3.17
ITT
Percentage of Subjects with an On-treatment Event in the 
Pneumonia AESI Group and Percentage of Subjects with an On-
treatment Moderate/Severe COPD Exacerbation– UMEC/VI and 
FF/VI treatment groups only
SAC
Laboratory Parameters
3.18
ITT
Trellis Display of Maximum Post-baseline Liver Function Test Values, 
Versus Baseline Liver Function Test Values 
SAC
3.19
ITT
Scatter Plots of Maximum Post-baseline Versus Baseline For 
Chemistry Data
SAC
3.20
ITT
Box Plots of Change from Baseline to Maximum Post-baseline 
Values for Chemistry Data 
SAC
3.21
ITT
Scatter Plots of Minimum Post-baseline Versus Baseline For 
Chemistry Data
SAC
3.22
ITT
Box Plots of Change from Baseline to Minimum Post-baseline Values 
for Chemistry Data 
SAC
3.23
ITT
Scatter Plots of Maximum Post-baseline Versus Baseline For 
Hematology Data 
SAC
 
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131
Safety Figures
No.
Popu-
lation
Title
Deliverable
[Priority] 
3.24
ITT
Box Plots of Change from Baseline to Maximum Post-baseline 
Values for Hematology Data 
SAC
3.25
ITT
Scatter Plots of Minimum Post-baseline Versus Baseline For 
Hematology Data 
SAC
3.26
ITT
Box Plots of Change from Baseline to Minimum Post-baseline Values 
for Hematology Data
SAC
ECGs
3.27
ITT
Empirical Distribution Function Plot of Maximum Post-baseline QTcF 
(msec) 
SAC
3.28
ITT
Empirical Distribution Function Plot of Change from Baseline in 
Maximum Post-baseline QTcF (msec)
SAC
3.29
ECG
Empirical Distribution Function Plot of Maximum Post-baseline QTcF 
(msec) 
SAC
3.30
ECG
Empirical Distribution Function Plot of Change from Baseline in 
Maximum Post-baseline QTcF (msec)
SAC
 
2017N330297_00


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132
11.12.9.
ICH Listings
ICH : Listings
No.
Popu-
lation
Title
Deliverable
[Priority]
Study Population
1.
ASE
Listing of Reasons for Screen Failure
SAC
2.
ITT
Listing of Reasons for Study Withdrawal
SAC
3.
ITT
Listing of Reasons for Study Treatment Discontinuation
SAC
4.
ITT
Listing of Subjects for Whom the Treatment Blind was Broken during the 
Study
SAC
5.
ITT
Listing of Randomized and Actual Treatments
SAC
6.
ITT
Listing of Important Protocol Deviations
SAC
7.
ASE
Listing of Subjects with Inclusion and Exclusion Criteria Deviations for 
Screen Failures
SAC
8.
ITT
Listing of Subjects with Inclusion and Exclusion Criteria Deviations
SAC
9.
ITT
Listing of Subjects Excluded from the ITT Population
SAC
10.
ITT
Listing of Demographic Characteristics
SAC
11.
ITT
Listing of Race
SAC
12.
ITT
Listing of COPD Duration and Exacerbation History
SAC
Prior and Concomitant Medications
13.
ITT
Listing of COPD Concomitant Medications
SAC
COPD Exacerbations
14.
ITT
Listing of COPD Exacerbations
SAC
Spirometry
15.
ITT
Listing of Derived FEV1 (L) Endpoints
SAC
SGRQ
16.
ITT
Listing of SGRQ Domain Scores
SAC
Exposure
17.
ITT
Listing of Exposure and Post-treatment Duration on Study
SAC
Adverse Events
18.
ASE
Listing of All Adverse Events
SAC
 
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133
ICH : Listings
No.
Popu-
lation
Title
Deliverable
[Priority]
19.
ASE
Listing of Subject Numbers for Individual Adverse Events
SAC
20.
ASE
Listing of Fatal Serious Adverse Events
SAC
21.
ASE
Listing of Non-fatal Serious Adverse Events
SAC
22.
ASE
Listing of Reasons for Considering as a Serious Adverse Event
SAC
23.
ITT
Listing of Adverse Events leading to Withdrawal from the Study / 
Permanent Discontinuation of Study Treatment 
SAC
Liver Events
24.
ITT
Listing of Medical Conditions for Subjects with Liver Stopping Events
SAC
25.
ITT
Listing of Substance Use for Subjects with Liver Stopping Events
SAC
Laboratory Parameters
26.
ITT
Listing of Chemistry Values for Subjects with at Least One Value outside 
the Normal Range
SAC
27.
ITT
Listing of Hematology Values for Subjects with at Least One Value outside 
the Normal Range
SAC
12-Lead ECGs
28.
ITT
Listing of ECG Values for Subjects with Any Abnormal ECG Finding
SAC
29.
ITT
Listing of ECG Abnormalities 
SAC
 
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134
11.12.10. Non-ICH Listings
Non-ICH : Listings
No.
Popu-
lation
Title
Deliverable 
[Priority]
Study Population
30.
ASE
Listing of Study Treatment Misallocations
SAC
Spirometry
31.
ITT
Listing of Raw FEV1 (L) and FVC (L) Data
SAC
SGRQ
32.
ITT
Listing of SGRQ Individual Responses
SAC
 
2017N330297_00