Clinical trial NCT02729051
Conditions: Pulmonary Disease, Chronic Obstructive
Keywords: Chronic Obstructive Pulmonary Disease (COPD) fluticasone furoate/umeclidinium bromide/vilanterol (FF/UMEC/VI) Umeclidinium bromide (UMEC) Closed triple therapy Placebo Open triple therapy fluticasone furoate/vilanterol (FF/VI)
Sponsor: GlaxoSmithKline
Start date: 2016-06-29; Completion date: 2017-05-23
Enrollment: 1055 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This multicenter study will be conducted to compare the effect of FF/UMEC/VI with FF/VI plus UMEC on lung function after 24 weeks of treatment. This is a phase IIIB, 24-week, randomized, double-blind, parallel group multicenter study. This study will test the hypothesis that the difference in trough forced expiratory volume in one second (FEV1) between treatment groups is less than or equal to a pre-specified non-inferiority margin. Alternatively, this study will also test the hypothesis that the difference between treatment groups is greater than the margin. The triple therapy of FF/UMEC/VI in a single inhaler is being developed with the aim of providing a new treatment option for the management of advanced Global Initiative for Chronic Obstructive Lung Disease (GOLD) Group D COPD which will reduce the exacerbation frequency, allow for a reduced burden of polypharmacy, convenience, and improve lung function, health related quality of life (HRQoL) and symptom control over established dual/monotherapies. This study has a 2 week run in period where subjects will continue to have their existing COPD medications. At randomization, subjects will discontinue all existing COPD medications and will be assigned to treatment of FF/UMEC/VI, 100 microgram (mcg)/62.5 mcg/25 mcg and placebo or FF/VI, 100 mcg/25 mcg and UMEC, 62.5 mcg in a 1:1 ratio for 24 weeks. Subjects will have clinical visits at Pre-Screening (Visit 0), Screening (Visit 1), Randomization (Week 0, Visit 2), Week 4 (Visit 3), Week 12 (Visit 4) and Week 24 (Visit 5). A follow-up visit will be conducted at 1 week after the end of treatment period or after early withdrawal visit. Approximately, 1020 subjects will be enrolled in this study. There will be two pharmacokinetic (PK) groups (subset A and subset B). Approximately 120 subjects will be assigned to subset A and approximately 60 subjects will be assigned to subset B. The total duration of subject participation will be approximately 27 weeks, consisting of a 2-week run-in period, 24-week treatment period and a 1-week follow-up period.

Detailed description:

Arms: arm 1: Subjects will receive FF/UMEC/VI, 100 mcg/62.5 mcg/25 mcg and placebo inhalation powder via the dry powder inhaler (DPI), once daily in the morning. Subjects will also receive albuterol/salbutamol as a rescue medication when needed during the treatment period. arm 2: Subjects will receive FF/VI, 100 mcg/25 mcg and UMEC, 62.5 mcg inhalation powder via the DPI, once daily in the morning. Subjects will also receive albuterol/salbutamol as a rescue medication when needed during the treatment period.
Interventions: intervention 1: FF/UMEC/VI intervention 2: FF/VI intervention 3: UMEC intervention 4: Placebo intervention 5: Albuterol/salbutamol
Intervention descriptions: intervention 1: This intervention is provided in two strips. First strip contains FF blended with lactose. It is available as dry white powder, 100 mcg per blister. Second strip contains UMEC and VI blended with lactose and magnesium stearate. It is available as dry white powder, 62.5 mcg per blister UMEC, 25 mcg per blister VI. The intervention is inhaled via the DPI, once daily in the morning. DPI contains 30 doses (2 strips with 30 blisters per strip). intervention 2: This intervention is provided in two strips. First strip contains FF blended with lactose. It is available as dry white powder, 100 mcg per blister. Second strip contains VI blended with lactose and magnesium stearate. It is available as dry white powder, 25 mcg per blister. The intervention is inhaled via the DPI, once daily in the morning. DPI contains 30 doses (2 strips with 30 blisters per strip). intervention 3: This intervention is available in one strip. The strip contains UMEC blended with lactose and magnesium stearate. The formulation is available as dry white powder, 62.5 mcg per blister. The intervention is inhaled via the DPI, once daily in the morning. DPI contains 30 doses (1 strip with 30 blisters). intervention 4: This intervention is available in one strip. The strip contains lactose. The formulation is available as dry white powder. The intervention is inhaled via the DPI, once daily in the morning. DPI contains 30 doses (1 strip with 30 blisters). intervention 5: This is a rescue medication administered via metered-dose inhaler (MDI) with a spacer which will be used when needed during the study.

Protocol documents:
Prot_000.pdf: 
2015N261999_03
CONFIDENTIAL
The GlaxoSmithKline group of companies
200812
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A phase IIIB, 24-week randomised, double-blind study to 
compare ‘closed’ triple therapy (FF/UMEC/VI) with 'open' triple 
therapy (FF/VI + UMEC), in subjects with chronic obstructive 
pulmonary disease (COPD)
Compound Number:
GW642444+GSK573719+GW685698
Development Phase:
IIIB
Effective Date:
29-JUN-2016
Protocol Amendment Number:  03
Author (s):
 
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD


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


PPD
PPD
PPD


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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Potential Risk of 
Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Anticholinergic
effects
(including
Narrow angle 
glaucoma, bladder 
outflow obstruction 
and urinary 
retention)
There was one report of angle closure glaucoma (UMEC/VI 62.5/25 mcg) in 
the UMEC/VI development program in COPD. 
The incidence of urinary retention AESIs was low (<1%) in all treatment 
groups including placebo. Three PTs were reported for this AESI group: 
urinary hesitation, urinary retention, and urine flow decreased. No subjects 
had urinary retention AESIs in the placebo, UMEC 62.5 mcg group or UMEC 
125/25 mcg group. The PT of ‘urinary retention’ was reported by one subject 
each (<1%) in the UMEC/VI 62.5/25 mcg, VI 25 mcg and tiotropium treatment 
groups, with 2 subjects (<1%) reporting the event in the UMEC 125 mcg 
treatment group. One event of ‘urinary hesitation’ was reported in the UMEC 
125 mcg treatment group. No subjects in the Long-term Safety Study had an 
event in the urinary retention AESI group. None of the urinary retention AESIs 
reported were considered serious.
ICS has a similar class risk of glaucoma and elevated IOP; however these 
effects occur by a different mechanism that is not expected to be synergistic or 
additive when FF is used in combination with UMEC.
-
Patients with known narrow-angle 
glaucoma, prostatic hyperplasia or 
bladder outflow obstruction that in the 
opinion of the investigator 
contraindicates study participation or use 
of an inhaled anticholinergic, will be 
excluded from participating in the study.
-
Instream review of AE/SAE reports
Hypersensitivity
Clinical data from FF/VI
In the COPD placebo controlled studies (HZC102206/HZC102207), events 
related to hypersensitivity, such as pruritis and rash occurred at similar 
incidences in the active treatment groups (<1% to 2%) and placebo (<1%) and 
there appeared to be no increased risk of drug- associated hypersensitivity.  
-
As specified in Section 5.2 of the 
protocol, subjects with a history of 
allergy or hypersensitivity to lactose/milk 
protein or magnesium stearate, any 
corticosteroid, anticholinergic/muscarinic 
receptor antagonist, and/or beta2-


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


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


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


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


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


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


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


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9.
Abnormal Chest x-ray: Chest x-ray (posteroanterior and later) reveals evidence of 
pneumonia or a clinically significant abnormality not believed to be due to the 
presence of COPD, or another condition that would hinder the ability to detect an 
infiltrate on chest x-ray (e.g. significant cardiomegaly, pleural effusion or scarring). 
All subjects will have a chest x-ray at Screening (V1) [or historical radiograph or CT 
scan obtained within 3 months prior to Screening (V1). 
NOTES:

Subjects who have experienced pneumonia and/or moderate or severe COPD 
exacerbation within 3 months of Screening (V1) must provide a post 
pneumonia/exacerbation chest x-ray or have a chest x-ray conducted at 
Screening (V1). 

For sites in Germany: If a chest x-ray (or CT scan) within 3 months prior to 
Screening (V1) is not available, approval to conduct a diagnostic chest x-ray 
will need to be obtained  from the Federal Office for Radiation Protection (BfS).
10. Other diseases/abnormalities: Subjects with historical or current evidence of 
clinically significant cardiovascular, neurological, psychiatric, renal, hepatic, 
immunological, gastrointestinal, urogenital, nervous system, musculoskeletal, skin, 
sensory, endocrine (including uncontrolled diabetes or thyroid disease) or 
haematological abnormalities that are uncontrolled. Significant is defined as any 
disease that, in the opinion of the investigator, would put the safety of the subject at 
risk through participation, or which would affect the efficacy or safety analysis if the 
disease/condition exacerbated during the study.  
11. Unstable liver disease: ALT >2xULN; and bilirubin >1.5xULN (isolated bilirubin 
>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)
Current active liver or biliary disease (with the exception of Gilbert’s syndrome or 
asymptomatic gallstones or otherwise stable chronic liver disease per investigator 
assessment). 
NOTES: 

Stable chronic liver disease should generally be defined by the absence of 
ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or 
gastric varices, or persistent jaundice, or cirrhosis.

Chronic stable hepatitis B and C (e.g., presence of hepatitis B surface antigen 
(HBsAg) or positive hepatitis C antibody test result at screening or within 3 
months prior to first dose of study treatment) are acceptable if subject otherwise 
meets entry criteria.
12. Unstable or life threatening cardiac disease: subjects with any of the following at 
Screening (V1) would be excluded:

Myocardial infarction or unstable angina in the last 6 months 

Unstable or life threatening cardiac arrhythmia requiring intervention in the last 
3 months  

NYHA Class IV Heart failure 


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13. Abnormal and clinically significant 12-Lead ECG finding: Investigators will be 
provided with ECG reviews conducted by a centralized independent cardiologist to 
assist in evaluation of subject eligibility. The investigator will determine the clinical 
significance of each abnormal ECG finding in relation to the subject’s medical 
history and exclude subjects who would be at undue risk by participating in the trial. 
An abnormal and clinically significant finding that would preclude a subject from 
entering the trial is defined as a 12-lead tracing that is interpreted as, but not limited 
to, any of the following:

AF with rapid ventricular rate >120 BPM; 

sustained or nonsustained VT; 

Second degree heart block Mobitz type II and third degree heart block (unless 
pacemaker or defibrillator had been inserted)
14. Contraindications: A history of allergy or hypersensitivity to any corticosteroid, 
anticholinergic/muscarinic receptor antagonist, beta2-agonist, lactose/milk protein or 
magnesium stearate or a medical condition such as narrow-angle glaucoma, prostatic 
hypertrophy or bladder neck obstruction that, in the opinion of the investigator 
contraindicates study participation.
15. Cancer: Subjects with carcinoma that has not been in complete remission for at least 
3 years. Subjects who have had carcinoma in situ of the cervix, squamous cell 
carcinoma and basal cell carcinoma of the skin would not be excluded based on the 3 
year waiting period if the subject has been considered cured by treatment.
16. Oxygen therapy: Use of long-term oxygen therapy (LTOT) described as resting 
oxygen therapy >3L/min (Oxygen use 3L/min flow is not exclusionary.)
17. Medication prior to spirometry: Subjects who are medically unable to withhold 
their albuterol/salbutamol for the 4-hour period required prior to spirometry testing at 
each study visit.
18. Drug/alcohol abuse: Subjects with a known or suspected history of alcohol or drug 
abuse within the last 2 years.
19. Non-compliance: Subjects at risk of non-compliance, or unable to comply with the 
study procedures. Any infirmity, disability, or geographic location that would limit 
compliance for scheduled visits.
20. Questionable validity of consent: Subjects with a history of psychiatric disease, 
intellectual deficiency, poor motivation or other conditions that will limit the validity 
of informed consent to participate in the study.
21. Affiliation with investigator site: Study investigators, sub-investigators, study 
coordinators, employees of a participating investigator or study site, or immediate 
family members of the aforementioned that is involved with this study.
22. Inability to read: In the opinion of the investigator, any subject who is unable to 
read and/or would not be able to complete study related materials.


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


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


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


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


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


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


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


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


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
A Material Safety Data Sheet (MSDS)/equivalent document describing 
occupational hazards and recommended handling precautions either will be 
provided to the investigator, where this is required by local laws, or is available 
upon request from GSK.
6.7.
Compliance with Study Treatment Administration
When subjects are dosed at the site, they will receive study treatment under medical 
supervision.  The date and time of each dose administered in the clinic will be recorded in 
the source documents.  The dose of study treatment and study subject identification will 
be confirmed at the time of dosing by a member of the study site staff. When subjects 
self-administer study treatmentat home, compliance with study treatment will be assessed 
through querying the subject during the site visits and recording the number of doses 
remaining in the ELLIPTA in the eCRF.  A record of the number of ELLIPTAs 
dispensed to each subject must be maintained and reconciled with study treatment and 
compliance records.  Treatment start and stop dates will also be recorded in the eCRF. 
Study treatment non-compliance is defined as <80% or >120% over the 24-week 
treatment period. 
6.8.
Treatment of Study Treatment Overdose
An overdose is defined as a dose greater than the total doses described above which 
results in clinical signs and symptoms.  These should be recorded by the investigator on 
the AE/SAE pages.  In the event of an overdose of study treatment, the investigator 
should use clinical judgment in treating the overdose and contact the GSK medical 
monitor.
GSK is not recommending specific treatment guidelines for overdose and toxicity 
management. The investigator is advised to refer to the relevant document(s) for detailed 
information regarding warnings, precautions, contraindications, adverse events, and other 
significant data pertaining to the study drug being used in this study. Such documents 
may include, but not be limited to, the IB or equivalent document provided by GSK.
6.9.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because other treatment options are available.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific 
post-study treatment.
6.10.
Concomitant Medications and Non-Drug Therapies
All COPD medications used within approximately 3 months prior to Screening (V1) and 
during the study (including the post-treatment period) should be recorded in the eCRF. 


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


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influenza vaccines and pneumonia vaccines will be captured on the concomitant 
medication pages of the eCRF).

Allergy immunotherapy.

Antibiotics for short-term treatment (≤14 days) of acute infections. (Long term 
treatment with antibiotics is not allowed).

Systemic and ophthalmic beta-blockers. (Administer with caution as systemic 
beta-blockers block the pulmonary effect of beta-agonists, and may produce 
severe bronchospasm in patients with reversible obstructive airways disease. 
Cardioselective beta-blockers should be considered, although they also should be 
administered with caution).

Smoking cessation treatments. 

Cough suppressants. 

Tricyclic 
antidepressants 
and 
monoamine oxidase 
inhibitors 
(MAOIs). 
(Administer with extreme caution as they may potentiate the effects of beta-
agonists on the cardiovascular system, including QTc prolongation).

Diuretics.  (Caution is advised in the co-administration of beta-agonists with non-
potassium sparing diuretics as this may result in ECG changes and/or 
hypokalaemia).

Use of positive airway pressure for sleep apnoea.

Oral muscarinic antagonists for the treatment of overactive bladder are permitted 
but should be used with caution as they may exacerbate medical conditions that 
are contraindicated for anticholinergics (e.g., narrow angle glaucoma and bladder 
outflow obstruction).

CYP3A4 inhibitors  (Caution should be exercised when considering the 
coadministration of long-term ketoconazole and other known strong CYP3A4 
inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, 
lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, 
voriconazole)
because 
increased 
systemic 
corticosteroid 
and 
increased 
cardiovascular adverse effects may occur).
6.10.2.
Prohibited Medications and Non-Drug Therapies
Medications prohibited at specific time intervals prior to Visit 1 (and at any time during 
the study) are identified in the Exclusion Criteria (Section 5.2).  
NOTE: All COPD medications (except for rescue albuterol/salbutamol, mucolytics and 
oxygen) are prohibited during the randomised period of the study except during the 
treatment of a moderate/severe COPD exacerbation or pneumonia. In the event of an 
exacerbation or pneumonia, sites should attempt to follow protocol treatment guidelines 
(Section 12.7); however, treatment with any medication that the health care provider 
deems necessary is allowed.  Caution is advised in using a LABA or LAMA to treat a 
subject currently taking study treatment as these additional medications may increase the 
risk of overdose. If necessary the investigator or other health care personnel may stop the 


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


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


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


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


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7.2.
Screening and Critical Baseline Assessments
No study related procedures may be performed until the informed consent form has 
been signed by the subject.  A pre-screening visit may be required in order to administer 
the informed consent before any changes are made to the subject’s current medical 
regimen.  Selection and modification of the subject’s medications prior to study 
participation is based on the physician’s judgment according to sound medical practice, 
principles, and each subject’s needs.  A subject’s treatment must not be changed merely 
for the purpose of enabling the subject’s participation in the study.  The informed consent 
may be given at the Screening Visit (V1) if the subject does not take or has not taken any 
protocol excluded medications.  
During the pre-screening visit (V0) each subject will have the following procedures 
performed. The following demographic parameters will be captured: 

Year of birth, sex, race and ethnicity.

Concomitant medication review. 
The additional following critical baseline assessments will be conducted at Screening 
(V1):

Medical history including COPD history (comprised of COPD type [emphysema 
and/or chronic bronchitis]), smoking history, COPD exacerbations history, 
smoking status and previous and/or current medical conditions.

Concomitant Medications review (COPD concomitant medications in the 3 
months prior to Screening)

COPD exacerbation assessment (documented history of exacerbation(s) in the 12 
months prior to Screening)

Cardiovascular medical history/risk factors 

Inclusion/Exclusion criteria assessment

COPD Assessment Test (CAT)

Physical examination 

Pulse rate, blood pressure measurements 

12-lead ECG

Pre- and post-albuterol/salbutamol spirometry (reversibility) 

SAE assessment (if related to study participation)

Chest X-Ray [or historical radiograph obtained within 3 months prior to 
Screening (V1)]

Laboratory assessments (chemistry and hematology, hepatitis and pregnancy 
testing)


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


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


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


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


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


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


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
Single12-lead ECGs will be obtained at each time point during the study using an 
ECG machine that automatically calculates the heart rate and measures PR, QRS, 
QT, and QTc intervals.  
The investigator, a designated sub-investigator or other appropriately trained site 
personnel will be responsible for performing each 12-lead ECG. The Investigator must 
provide his/her dated signature on the original paper tracing, attesting to the authenticity 
of the ECG machine interpretation. 
All ECGs will be electronically transmitted to an independent cardiologist and evaluated. 
The independent cardiologist, blinded to treatment assignment, will be responsible for 
providing measurements of heart rate, QT intervals and an interpretation of all ECGs 
collected in this study. A hard copy of these results will be sent to the Investigator. The 
Investigator must provide his/her dated signature on the confirmed report, attesting to 
his/her review of the independent cardiologist’s assessment.
Details of the cardiac monitoring procedures will be provided by the centralised 
cardiology service provider.
7.4.5.
Vital Signs
Vital signs will be performed prior to conducting spirometry and prior to taking the 
morning dose of study treatment. Vital signs will be collected at Screening (V1), Week 4 
(V3), and Week 24 (V5) or at the Early Withdrawal Visit. Blood pressure (systolic and 
diastolic) and pulse rate will be measured in the sitting position after approximately 5 
minutes rest.  A single set of values will be collected and recorded in the source 
documentation and eCRF.
7.4.6.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 3, must be conducted in 
accordance with the Laboratory Manual, and Protocol Time and Events Schedule.
Laboratory requisition forms must be completed and samples must be clearly labelled 
with the subject number, protocol number, site/centre number, and visit date. Details for 
the preparation and shipment of samples will be provided by the laboratory and are 
detailed in the laboratory manual. Reference ranges for all safety parameters will be 
provided to the site by the laboratory responsible for the assessments.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the eCRF.
Refer to the SPM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
Haematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 3. 


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments
Phase III-IV liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and evaluate liver event aetiology (in alignment with the 
FDA premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Phase III-IV liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria - Liver Stopping Event
ALT-absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN  persists for 2 weeks
ALT 3xULN but <5xULN  persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot 
Monitor
ALT 5xULN but <8xULN and cannot be monitored weekly for 2 weeks
ALT 3xULN but <5xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to  liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue  study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries 
resolve , stabilize, or return to within baseline 
(see MONITORING below)

Viral hepatitis serology4

Only in those with underlying chronic 
hepatitis B at study entry (identified by 
positive hepatitis B surface antigen) 
quantitative hepatitis B DNA and hepatitis 
delta antibody5.

Blood sample for pharmacokinetic (PK) 
analysis, obtained within 72 hours after 
last dose6

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).


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
Do not restart/rechallenge subject with 
study treatment unless allowed per protocol 

If restart/rechallenge not allowed per 
protocol , permanently discontinue study 
treatment and may continue subject in the 
study for any protocol specified follow up 
assessments
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 
hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 
recommended
For All other criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24-
72 hrs 

Monitor subjects weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form
including acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG or gamma 
globulins).

Serum acetaminophen adduct HPLC 
assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with 
definite or likely acetaminophen use in the 
preceding week [James, 2009]). NOTE: 
not required in China

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease;complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants


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3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)   
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
5.
If hepatitis delta antibody assay cannot be performed,, it can be replaced with a PCR of hepatitis D RNA virus 
(where needed) [Le Gal, 2005].
6.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SPM.  
Phase III-IV liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 5xULN and <8xULN and bilirubin 
<2xULN without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 2 weeks.
OR
ALT 3xULN and <5xULN and bilirubin 
<2xULN without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks.

Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss subject 
safety. 

Subject can continue study treatment  

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above

If ALT decreases from ALT 5xULN and <8xULN to 
≥3xULN but <5xULN, continue to monitor liver 
chemistries weekly. 

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to within 
baseline.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.


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Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E.  Quantification 
of Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates 
Different Patterns of Virological Response to Interferon Therapy in Chronically Infected 
Patients.  J Clin Microbiol. 2005;43(5):2363–2369. 


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


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


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


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12.4.
Appendix 4: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.4.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE.  However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition 
of an AE or SAE.
Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 


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condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
12.4.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalisation for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires hospitalisation or prolongation of existing hospitalisation
NOTE:

In general, hospitalisation signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalisation are 
AEs.  If a complication prolongs hospitalisation or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalisation” occurred or was 
necessary, the AE should be considered serious.

Hospitalisation for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.


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
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.

Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation, or development of drug dependency 
or drug abuse
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.
12.4.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension


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


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


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or investigations, histopathological examinations or consultation with other health 
care professionals.

If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any post-mortem findings, 
including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
12.4.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the Medical Monitor or the SAE 
coordinator

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data

If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the Medical 
Monitor or the SAE coordinator by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
SAE reporting to GSK via paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the Medical Monitor or the SAE coordinator

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable, with a copy of the SAE data collection tool sent by 
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
Initial notification via the telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE receipt can be found at this beginning of the protocol on the 
Sponsor/Medical Monitor Contact Information page.


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


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12.5.2.
Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 2 
weeks of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, which will be 
forwarded to GSK.  Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of foetal status (presence 
or absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in Appendix 4 (Section 12.4.6). While the investigator is not obligated 
to actively seek this information in former study participants, he or she may learn of 
an SAE through spontaneous reporting.
Any female subject who becomes pregnant while participating 

will discontinue study treatment and be withdrawn from the study


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12.6.
Appendix 6 - Country Specific Requirements


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


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


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


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


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


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


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


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


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


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


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


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


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


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

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
200812
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for 200812: A phase IIIB, 24-
week randomised, double-blind study to compare ‘closed’ 
triple therapy (FF/UMEC/VI) with 'open' triple therapy 
(FF/VI + UMEC), in subjects with chronic obstructive 
pulmonary disease (COPD) 
Compound Number 
:
GSK2834425 (GW685698, GSK573719, GW642444)
Effective Date 
:
22-JUN-2017
Author’s Name and Functional Area: 
13-Jun-2017
Principal Statistician, Statistics and Programming (Clinical 
Statistics)
Manager, Statistics
13-Jun-2017
Approved by: 
22-JUN-2017
Director, Statistics and Programming (Clinical Statistics)
Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited
PPD
PPD
PPD


CONFIDENTIAL
200812
2
TABLE OF CONTENTS
PAGE
1.
REPORTING & ANALYSIS PLAN SYNPOSIS.........................................................5
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................7
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................7
2.2.
Study Objective(s) and Endpoint(s)...............................................................7
2.3.
Study Design ................................................................................................8
2.4.
Statistical Hypotheses.................................................................................10
3.
PLANNED ANALYSES ..........................................................................................10
3.1.
Final Analyses ............................................................................................10
4.
ANALYSIS POPULATIONS ...................................................................................11
4.1.
Protocol Deviations.....................................................................................12
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................13
5.1.
Handling of Missing Data............................................................................13
5.2.
Handling of Data from Additional Subset Populations .................................14
6.
STUDY POPULATION ANALYSES .......................................................................15
6.1.
Overview of Planned Analyses ...................................................................15
6.1.1.
Disposition...................................................................................16
6.1.2.
Concomitant Medications.............................................................16
6.1.3.
Treatment Compliance.................................................................17
6.1.4.
Disease Characteristics ...............................................................17
6.1.5.
Inhaler Malfunction ......................................................................17
7.
PRIMARY STATISTICAL ANALYSES....................................................................17
7.1.
Efficacy Analyses........................................................................................17
7.1.1.
Overview of Planned Efficacy Analyses .......................................17
7.1.1.1.
Spirometry data..........................................................18
7.1.2.
Planned Efficacy Statistical Analyses...........................................19
8.
SECONDARY STATISTICAL ANALYSES .............................................................21
8.1.
Other Efficacy Analyses..............................................................................21
8.1.1.
Overview of Planned Efficacy Analyses .......................................21
8.1.1.1.
St. George’s Respiratory Questionnaire for 
COPD Patients (SGRQ-C)..........................................22
8.1.1.2.
COPD Exacerbations .................................................22
8.1.1.3.
Baseline Dyspnea Index (BDI)/Transitional 
Dyspnea Index (TDI) Focal Score...............................22
8.1.2.
Planned Other Efficacy Statistical Analyses.................................23
8.1.2.1.
SGRQ Total Score......................................................23
8.1.2.2.
TDI .............................................................................23
8.1.2.3.
Proportion of Responders according to SGRQ 
Total Score and Responders according to TDI ...........23
8.1.2.4.
COPD Exacerbations .................................................24
8.2.
Safety Analyses..........................................................................................25
8.2.1.
Overview of Planned Analyses ....................................................25


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8.2.1.1.
Adverse Events of Special Interest.............................28
8.2.1.2.
Pneumonia .................................................................29
8.2.1.3.
Vital Signs ..................................................................29
8.2.1.4.
ECGs..........................................................................29
8.2.1.5.
Pregnancy..................................................................29
9.
REFERENCES.......................................................................................................30
10. APPENDICES........................................................................................................31
10.1.
Appendix 1: Protocol Deviation Management and Definitions for 
mPP Population..........................................................................................32
10.1.1.
Exclusion of Data from the ITT Analyses .....................................32
10.1.2.
Exclusions from mPP Population .................................................32
10.2.
Appendix 2: Time & Events.........................................................................34
10.3.
Appendix 3: Assessment Windows .............................................................37
10.4.
Appendix 4: Treatment States and Phases.................................................38
10.4.1.
Treatment Phase for Concomitant Medication Data.....................38
10.4.2.
Treatment Phase for Other Data..................................................39
10.5.
Appendix 5: Data Display Standards & Handling Conventions....................41
10.5.1.
Study Treatment & Sub-group Display Descriptors......................41
10.5.2.
Baseline Definition & Derivations .................................................41
10.5.2.1.
Baseline Definitions....................................................41
10.5.3.
Reporting Process & Standards...................................................42
10.6.
Appendix 6: Derived and Transformed Data ...............................................44
10.6.1.
General........................................................................................44
10.6.2.
Study Population..........................................................................44
10.6.3.
Safety ..........................................................................................49
10.6.4.
Efficacy and Health Outcomes.....................................................53
10.7.
Appendix 7: Premature Withdrawals & Handling of Missing Data ...............56
10.7.1.
Premature Withdrawals................................................................56
10.7.2.
Handling of Missing Data.............................................................56
10.7.2.1.
Handling of Missing or Partial Dates...........................57
10.7.2.2.
Handling of Missing Data for Statistical 
Analysis......................................................................57
10.8.
Appendix 8: Multicenter Studies..................................................................58
10.8.1.
Methods for Handling Centers .....................................................58
10.9.
Appendix 9: Examination of Covariates, Subgroups & Other Strata............59
10.9.1.
Handling of Covariates, Subgroups & Other Strata......................59
10.10. Appendix 10: Multiple Comparisons & Multiplicity .......................................60
10.10.1. Handling of Multiple Comparisons & Multiplicity...........................60
10.11. Appendix 11: Model Checking and Diagnostics for Statistical 
Analyses.....................................................................................................61
10.11.1. Statistical Analysis Assumptions..................................................61
10.12. Appendix 12: Abbreviations ........................................................................62
10.12.1. Trademarks .................................................................................63
10.13. Appendix 13: List of Data Displays..............................................................64
10.13.1. Data Display Numbering..............................................................64
10.13.2. Programming Note.......................................................................64
10.13.3. Study Population Tables..............................................................65
10.13.4. Study Population Figures.............................................................66
10.13.5. Efficacy Tables ............................................................................66
10.13.6. Efficacy Figures ...........................................................................67


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10.13.7. Safety Tables...............................................................................68
10.13.8. Safety Figures .............................................................................70
10.13.9. ICH Listings .................................................................................71
10.13.10.Non-ICH Listings..........................................................................72


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5
1.
REPORTING & ANALYSIS PLAN SYNPOSIS
Overview
Key Elements of the RAP
Purpose

This RAP details all planned analyses and outputs required for the final Clinical 
Study Report (CSR) of study 200812
Protocol

This RAP is based on the protocol amendment (Dated: 29-June-2016) of study 
200812 (GSK Document Number.  2015N261999_03) and eCRF Version 2.1
Primary 
Objective

To compare the effect of FF/UMEC/VI with FF/VI + UMEC on lung function after 
24 weeks of treatment in COPD subjects
Primary 
Endpoint

Change from baseline in trough FEV1 at Week 24 

The primary treatment comparison of FF/UMEC/VI with FF/VI+UMEC will be 
performed on trough FEV1 at Week 24, for the mPP Population.
Secondary 
Objectives

To compare the effects of FF/UMEC/VI with FF/VI + UMEC on health related 
quality of life and dyspnoea after 24 weeks of treatment

To compare the effect of FF/UMEC/VI with FF/VI + UMEC on time to first 
moderate or severe exacerbation during 24 weeks of treatment
Secondary 
Endpoints

Proportion of Responders based on the St George Respiratory Questionnaire 
(SGRQ) Total Score at Week 24

Change from baseline in SGRQ Total Score at Week 24

Proportion of Responders based on Transitional Dyspnoea Index (TDI) focal 
score at Week 24

TDI focal score at Week 24

Time to first moderate/severe exacerbation
Study 
Design

This is a phase IIIB, 24-week, randomised, double-blind, parallel group, 
multicenter study evaluating FF/UMEC/VI (100/62.5/25mcg) delivered via a 
single ELLIPTA (‘closed’ triple) plus matching placebo ELLIPTA versus FF/VI
(100/25mcg) + UMEC (62.5mcg) delivered via two ELLIPTAs (‘open’ triple), all 
taken once daily.  

Subjects will be randomized 1:1 to either FF/UMEC/VI or FF/VI+UMEC. The 
randomisation will be stratified based on long-acting bronchodilator usage 
during the run-in (none, one or two long-acting bronchodilators per day).

A study with 816 evaluable subjects for the primary analysis will have 90% 
power to determine non-inferiority of FF/UMEC/VI to FF/VI+UMEC based on 
trough FEV1 at Week 24 , an estimate of residual standard deviation (SD) for 
trough FEV1 at Week 24 of 220mL, at the one-sided 2.5% significance level 
when the margin of non-inferiority is 50mL and the true mean treatment 
difference is assumed to be 0mL.

Based on approximately 20% of subjects who are randomized discontinuing 
study treatment or being excluded from the mPP population at Week 24, 
approximately 1020 subjects will be randomised 
Planned 
Analyses

No interim analyses are planned for this study.


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6
Overview
Key Elements of the RAP

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 except for the identification of 
protocol deviation (PD) that require treatment details. The PD of taking 
incorrect treatment and treatment non-compliance (based on active treatment)
will be identified following DBF.
Analysis 
Populations

All Subjects Enrolled (ASE) population includes all subjects, for whom a record 
exists in the study database, including screen failures and any subject who was 
not screened but experienced an SAE between the date of informed consent 
and the planned date of the Screening visit. All Subjects Enrolled population 
(ASE) will be used for subject disposition, reason for withdrawal prior to 
randomisation, inclusion, exclusion and randomisation criteria deviations and 
SAEs for non randomised subjects. 

Intent-to-treat (ITT) population, which comprises all randomized subjects, 
excluding those who were randomized in error. A subject who is recorded as a 
screen or run-in failure and also randomized will be considered to be 
randomized in error.  Any other subject who receives a randomisation number 
will be considered to have been randomized. Intent-to-treat (ITT) population will 
be used for study population, efficacy and safety endpoints. 

Modified Per-Protocol (mPP) population includes all subjects in the ITT 
Population who do not have a full protocol deviation considered to impact 
efficacy.

Data following a moderate or severe COPD exacerbation or pneumonia 
will be excluded from analysis due to the potential impact of the 
exacerbation or the medications used to treat it

Subjects with partial protocol deviations considered to impact efficacy 
will be included in the mPP Population but will have their data excluded 
from analyses from the time of deviation onwards

mPP population will be used for the primary treatment comparison of 
the primary endpoint only.
Hypothesis
The null hypothesis is that the difference in trough FEV1 between treatment 
groups is less than or equal to a pre-specified non-inferiority margin -Δ: 
H0: T1 – T2 ≤-Δ
The alternative hypothesis is that the difference between treatment groups is 
greater than the margin.
H1: T1 – T2 > -Δ
where T1 and T2 are the treatment means for FF/UMEC/VI and FF/VI+UMEC,
respectively.
The non-inferiority margin has been set at 50mL, which is half the generally 
accepted minimal clinically important difference (MCID) for trough FEV1.
If the lower bound of the two-sided 95% confidence interval around the 


CONFIDENTIAL
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7
Overview
Key Elements of the RAP
(FF/UMEC/VI vs. FF/VI+UMEC) treatment difference is above -50mL then 
FF/UMEC/VI will be considered non-inferior to FF/VI+UMEC. 
Primary 
Analyses
The primary endpoint of change from baseline in trough FEV1 at Week 24 will be 
analyzed in the mPP population, using a mixed model repeated measures (MMRM) 
analysis, including trough FEV1 recorded at each of Week 4, 12 and 24. The model 
will include covariates of stratum (number of long-acting bronchodilators per day 
during the run-in, baseline FEV1, Visit, geographical region, treatment and Visit by 
baseline interaction. A Visit by treatment interaction term will also be included to 
allow treatment effects to be estimated at each visit separately. The variance-
covariance matrix will be assumed unstructured.
Other 
Efficacy 
Analyses
The MMRM analysis will be repeated for the ITT Population
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
There was one change to the originally planned statistical analysis specified in the 
protocol.
The Adherent population in the originally planned statistical analysis specified in the 
protocol is now referred to as the Modified Per Protocol (MPP) population. This is 
simply a change of the name of population. The definition remains the same.
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objective
Primary Endpoint

To compare the effect of FF/UMEC/VI 
with FF/VI + UMEC on lung function 
after 24 weeks of treatment

Change from baseline in trough FEV1 at Week 24
Other Endpoints

Change from baseline in trough FEV1 on Week 4 and 12

Change from baseline in trough FVC on Week 4,12 and 
24
Secondary Objective
Secondary Endpoint

To compare the effects of 
FF/UMEC/VI with FF/VI + UMEC on 
health related quality of life and 
dyspnoea after 24 weeks of treatment

To compare the effect of FF/UMEC/VI 
with FF/VI + UMEC on time to first 
moderate or severe exacerbation 

Proportion of Responders based on the St George 
Respiratory Questionnaire (SGRQ) Total Score at Week 
24

Change from baseline in SGRQ Total Score at Week 24

Proportion of Responders based on Transitional 
Dyspnoea Index (TDI) focal score at Week 24

TDI focal score at Week 24


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8
Objectives
Endpoints
during 24 weeks of treatment

Time to first moderate or severe exacerbation
Other Endpoints

Proportion of Responders based on the St George 
Respiratory Questionnaire (SGRQ) Total Score at Week 
12

Change from baseline in SGRQ Total Score at Week 12

Proportion of Responders based on TDI focal score at 
Week 12

TDI focal score at Week 12
PK

To compare the PK of FF, UMEC and 
VI when given as FF/UMEC/VI or 
FF/VI+UMEC in a subset of subjects

Population PK (in a subset of approximately 180 subjects) 
(note: Population PK analysis is subject to a separate 
RAP)
Safety

To compare the safety profile of
FF/UMEC/VI with FF/VI + UMEC over 
24 weeks of treatment

Incidence of adverse events

Incidence of adverse events of special interest

ECG measurements

Vital signs

Haematological and clinical chemistry parameters
2.3.
Study Design
Overview of Study Design and Key Features


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9
Overview of Study Design and Key Features
Design Features

This is a phase IIIB, 24-week, randomised, double-blind, parallel group, 
multicenter study evaluating FF/UMEC/VI  delivered via a single 
ELLIPTA (‘closed’ triple) plus matching placebo ELLIPTA versus FF/VI 
+ UMEC delivered via two ELLIPTAs (‘open’ triple), all taken once 
daily.  

Subjects will be randomized 1:1 to either FF/UMEC/VI or FF/VI+UMEC.
The randomisation will be stratified based on long-acting bronchodilator 
usage during the run-in (none, one or two long-acting bronchodilators 
per day).

Subjects will run-in on their existing COPD medications for 2 weeks and 
in addition will be provided with short acting albuterol/salbutamol to be 
used on an as-needed basis (rescue medication) throughout the study. 
Subjects will discontinue all existing COPD medications at the start of 
the randomised treatment period but may continue their study-supplied 
rescue albuterol/salbutamol.

A subject will be considered to have completed the study when they 
have completed all phases of the study including screening, run-in, the 
randomised treatment phase, and safety follow-up. Subjects who stop 
study treatment early will complete an Early Withdrawal Visit, followed 
by a Safety Follow-Up a week later and be withdrawn from the study.

Approximately 180 subjects, in selected sites, will be asked to 
participate in PK research. There will be two PK groups (subset A and 
subset B). Approximately 120 subjects will be assigned to subset A and 
approximately 60 subjects will be assigned to subset B. Subjects in 
subset A will provide a blood sample at two time-points at Week 12 (V4) 
and at Week 24 (V5). Subjects in subset B will provide bloodsamples at 
seven time points at Week 12 (V4).

A subset of subjects in selected countries (Russia, Japan and 
Germany) providing PK samples for subset A will also be asked to 
take part in a hair sample scalp & finger secretion PK Sub-Study. 
Hair sample scalp & finger secretion PK data is subject to a
separate RAP.
Dosing

The ELLIPTA contains 30 doses (FF/UMEC/VI, FF/VI, UMEC or 
placebo) and subjects will be instructed to administer one dose from 
each ELLIPTA once daily in the morning. 
Treatment 
Assignment

Following the run-in period, subjects who fulfil the randomisation criteria 
will be randomised (1:1) to one of the following double-blind treatment 
groups for 24 weeks:
FF/UMEC/VI 100/62.5/25mcg and placebo, both via the ELLIPTA once 
daily in the morning
or,
FF/VI 100/25mcg and UMEC 62.5mcg, both via the ELLIPTA once daily 
in the morning


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Overview of Study Design and Key Features

GSK RandAll NG used to generate randomisation schedules.

Country based randomisation for treatment allocation.

The randomisation is stratified based on long-acting bronchodilator 
usage during the run-in (none, one or two long-acting bronchodilators 
per day).
Interim Analysis

No interim analysis is planned for the study.
2.4.
Statistical Hypotheses
The primary objective of this study is to compare FF/UMEC/VI with FF/VI+UMEC in 
COPD subjects. The primary endpoint is change from baseline in trough FEV1 at Week 
24. The primary analysis is the comparison of this endpoint for FF/UMEC/VI vs. 
FF/VI+UMEC.
The null hypothesis is that the difference in change from baseline trough FEV1 between 
treatment groups is less than or equal to a pre-specified non-inferiority margin -Δ:
H0: T1 – T2 ≤ -Δ
The alternative hypothesis is that the difference between treatments is greater than the 
margin:
H1: T1 – T2 > -Δ 
where T1 and T2 are the treatment means for FF/UMEC/VI and FF/VI+UMEC, 
respectively.
The non-inferiority margin has been set at 50mL, which is half the generally accepted 
minimal clinically important difference (MCID) for trough FEV1.
If the lower bound of the two-sided 95% confidence interval around the (FF/UMEC/VI
vs. FF/VI+UMEC) treatment difference is above -50mL then FF/UMEC/VI will be 
considered non-inferior to FF/VI+UMEC. 
3.
PLANNED ANALYSES
3.1.
Final Analyses
No interim analysis is planned for this study. The final planned analyses will be 
performed after the completion of the following sequential steps (for this Clinical Data 
Interchange Standards Consortium [CDISC] study):
1.
All subjects have completed the study or been withdrawn as defined in the protocol.
2.
All required database cleaning activities have been completed and final database 
release (SDL) has been declared by Data Management on System Independent (SI) 
datasets.


CONFIDENTIAL
200812
11
3.
SI data to SDTM data conversion has completed by Conversion Service and quality 
control of SDTM has completed by DM.
4.
Study is unblinded by Clinical Statistician in Randall NG.
5.
Clinical Programmer extracts unblinded randomization and container codes from 
Randall NG and SMS2000 file from SMS2000 and then unblinds relevant SDTM 
datasets (Example: DM, EX, SE, PC etc) as per Clinical Statistics & Programming 
Study and Subject Treatment Unblinding Guideline document.
6.
Database freeze on SDTM datasets has been declared by DM.
Note: following database frozen (i.e., treatment unblinding), protocol deviations for 
subject received incorrect treatment and for non-compliance based on active treatment 
will be identified and flagged as PP exclusionary. These protocol deviations will be 
flagged as PP exclusionary in ADaM DV dataset.
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
All Subjects 
Enrolled (ASE)

All subjects for whom a record exists in the 
study database, including screen failures and 
any subject who was not screened but 
experienced an SAE between the date of 
informed consent and the planned date of the 
Screening visit.

Subject Disposition

Reason for 
withdrawal prior to 
randomisation

Inclusion, exclusion 
and randomisation 
criteria deviations

SAEs for non-
randomised 
subjects
Intent-to-Treat
(ITT)

All randomized subjects, excluding those who 
were randomized in error. A subject who is 
recorded as a screen or run-in failure and also 
randomized will be considered to be 
randomized in error. Any other subject who 
receives a randomization number will be 
considered to have been randomized.

Study Population

Efficacy

Health-related 
Quality of Life

Inhaler 
Assessments

Safety
Modified Per 
Protocol (mPP)

All subjects in the ITT Population who do not 
have a full protocol deviation considered to 
impact efficacy.

Data following a moderate/severe COPD 
exacerbation or pneumonia will be excluded 
from analysis due to the potential impact of the 
exacerbation or the medications used to treat it

Subjects with partial protocol deviations 
considered to impact efficacy will be included 

Primary treatment 
comparison of the 
primary endpoint 
only


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Population
Definition / Criteria
Analyses Evaluated
in the mPP Population but will have their data 
excluded from analyses from the time of 
deviation onwards.
NOTES :  Please refer to Appendix 13: List of Data Displays which details the population to be used for each displays 
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

Important protocol deviations (including deviations related to study 
inclusion/exclusion criteria, conduct of the trial, patient management or patient 
assessment) will be summarised and listed.

Exclusions from the mPP analysis population will also be summarised and listed. 
(Please refer to Appendix 1: Protocol Deviation Management and Definitions for
mPP Population).

Protocol deviations will be tracked by the study team throughout the conduct of the 
study in accordance with the Protocol Deviation Management Plan.
o
Data will be reviewed prior to SDTM DBF to ensure all important deviations and 
deviations which may lead to exclusion from the analysis are captured and 
categorised on the protocol deviations dataset. 
o
This dataset will be the basis for the summaries and listings of protocol 
deviations.

Subjects who received an incorrect container will be captured as an important 
protocol deviation. Whether or not the incorrect container contains incorrect 
treatment will be identified following DBF in the Analysis Data Model (ADaM) 
dataset. Overall treatment non-compliance based on active treatment will also be 
identified following DBF and will be flagged as PP exclusionary in ADaM DV 
dataset. 

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 eCRF.

A listing of any treatment misallocations will be produced for the ASE Population.


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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS
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
10.1
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population
10.2
Appendix 2: Time & Events
10.3
Appendix 3: Assessment Windows
10.4
Appendix 4: Treatment States and Phases
10.5
Appendix 5: Data Display Standards & Handling Conventions
10.6
Appendix 6: Derived and Transformed Data
10.7
Appendix 7: Premature Withdrawals & Handling of Missing Data
10.8
Appendix 8: Multicenter Studies
10.9
Appendix 9: Examination of Covariates, Subgroups & Other Strata
10.10
Appendix 10: Multiple Comparisons & Multiplicity
10.11
Appendix 11: Model Checking and Diagnostics for Statistical Analyses.
10.12
Appendix 12: Abbreviations & Trade Marks
10.13
Appendix 13: List of Data Displays
5.1.
Handling of Missing Data
The primary estimand for this study is a ‘de jure’ estimand.  The primary analysis will 
use an ‘MPP’ population, using only data collected on-treatment and excluding data 
following protocol deviation or other event considered to impact the primary efficacy 
endpoint of change from baseline in trough FEV1 (as detailed in Section 10.1.2).  This
will evaluate the treatment difference if all subjects had taken the treatment as directed in 
the protocol which is considered the appropriate estimand for a determination of non-
inferiority.
All data excluded from the primary efficacy analysis will be assumed to be missing at 
random.  The sensitivity of the results to this assumption will be investigated by use of a 
‘tipping point’ analysis as described in Section 7.1.2.  This will evaluate various 
assumptions for the mean change from baseline in trough FEV1 for data excluded from 
the primary analysis, including scenarios where the response to treatment on 
FF/UMEC/VI is worse than that on FF/VI + UMEC and vice versa.
An alternative estimand will be evaluated.  This will use the ITT population using all data 
collected on-treatment, for the change from baseline in trough FEV1.  (No off-treatment 


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data for trough FEV1 were collected in this study.)  All missing data will be assumed to 
be missing at random.  This will evaluate the treatment difference in all randomized 
subjects, regardless of adherence to the protocol but assuming the treatment effect for 
subjects who discontinued treatment was similar to that for those who completed 
treatment.
5.2.
Handling of Data from Additional Subset Populations
Approximately 180 subjects, in selected sites, will be asked to participate in the PK 
analysis. There will be two PK groups (subset A and subset B). Approximately 120 
subjects will be assigned to subset A and approximately 60 subjects will be assigned to 
subset B. Subjects in subset A will provide a blood sample at two time-points at Week 12 
(V4) and at Week 24 (V5). Subjects in subset B will provide blood samples at seven time 
points at Week 12 (V4).
Population PK analysis population (including subjects provided blood PK samples from 
this study and other studies in Closed Triple Program) will be described in a separate 
RAP. 
A subset of subjects in selected countries (Russia, Japan and Germany) providing PK 
samples for subset A will also be asked to take part in a hair sample scalp & finger 
secretion PK Sub-Study.  Separate analysis populations will be defined for the hair 
sample scalp & finger PK and analysis will be described in a separate RAP.


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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Analyses
The study population analyses generally will be based on the ITT population unless 
otherwise specified. Displays which use the ASE population or mPP population are 
identified below.
Table 2 provides an overview of the planned study population analyses, with the detailed 
list of data displays being presented in Section 10.13.
Table 2
Overview of Planned Study Population Analyses
Display Type
Data Displays Generated
Table
Figure
Listing
Subject Disposition
Study Populations and Reasons for Screen/Run-in
Failures 
Y1
Y
Attendance at Clinic Visits 
Y
Study Treatment Status
Y
Y
End of Study Record
Y
Y2
Y
Number of Subjects  
Y3
Inclusion and Exclusion Criteria Deviations
Y4
Y4
Important Protocol Deviations 
Y
Y
Exclusion from Modified Per Protocol Population
Y
Y
Reasons for study withdrawal
Y
Demography
Demographic Characteristics
Y5,7
Y
Race and Racial Combination
Y7
Y
Medical Conditions 
Medical Conditions (Current/Past )
Y
Y
Cardiovascular Risk Factors
Y
Family History of Cardiovascular Risk Factors
Y
Y
Smoking History at Screening
Y
Y
Smoking Status
Y
Y
Disease Characteristics
COPD Exacerbation History
Y
Y
Screening Lung Function 
Y5,7
Y
Reversibility and GOLD Grade(1-4) at Screening
Y7
Y 
CAT Score at Screening
Y
Y
Concomitant Medications
COPD Medications 
Y6
Y
COPD Medication Combination at Screening
Y7
Non-COPD Medications
Y8
Y
Relationship between ATC Level1/Ingredient/Verbatim 
Text for Non-COPD Medications
Y
Long-acting Bronchodilator Usage Per Day During 
Run-in (Randomisation Strata)
Y7,9
Y


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Display Type
Data Displays Generated
Table
Figure
Listing
Treatment Compliance
Treatment Compliance
Y
Y
Study Population Listings
Randomized and Actual Treatments
Y
Treatment Blind Broken During Study
Y
Treatment Misallocations
Y
Randomisation Strata (Derived and from eCRF)
Y
Percent Oxygen in Blood 
Y
Inhaler Malfunction
Y
NOTES :
Y = Yes display generated.
1.
ASE population
2.
Kaplan-Meier plot  
3.
By country (ASE population); by age category (ASE population); by geographical region, country and centre 
(ITT population)
4.
Screen failures (ASE population) and ITT population separately
5.
Repeat by country (ITT population)
6.
Run-in/On-treatment/Post-treatment and Given for Reasons other than an Exacerbation, given for an 
exacerbation, separately 
7.
ITT population and mPP population separately
8.
On-treatment and Post-treatment, separately
9.
None, one or two long acting bronchodilator
6.1.1.
Disposition
The study population summary will show the number of subjects overall who were 
enrolled, the number of pre-screen failures, the number of screen and run-in failures and 
the number with each reason for screen or run-in failure, the number of subjects in each 
treatment group and overall who were randomized, in the ITT population and the number 
of subjects in the mPP population.
The end of study record summary shows 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 shows 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 discontinuation.
6.1.2.
Concomitant Medications
COPD concomitant medications that have been stopped prior to Screening and non-
COPD concomitant medications that have been stopped prior to randomization will be 
listed and not be included in any summary tables. 
Non-COPD medication tables will report by Anatomical Therapeutic Chemical (ATC) 
level 1 and ingredient.  COPD medication tables will report by respiratory medication 
class (RMC) and ingredient (See Section 10.6.2).


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Multi-ingredient medications will be presented according to their combination ATC 
classification rather than the classification 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 will be presented.
The number of long-acting bronchodilator used per day during the run-in (none, one or 
two long-acting bronchodilators per day) will be summarised.
6.1.3.
Treatment Compliance
Treatment compliance will be determined as discussed in Section 10.6.2.  Note that the 
ELLIPTA inhaler used to dispense FF/UMEC/VI, FF/VI, UMEC or placebo has a 
counter that shows exactly the number of doses remaining. Compliance will be calculated 
based on the count recored on the dose counter and will be calculated overall and 
separately for each ELLIPTA inhaler (the inhaler contains FF/UMEC/VI or FF/VI and 
the inhaler contains placebo or UMEC).
6.1.4.
Disease Characteristics
The screening lung function summary will include pre-bronchodilator and post-
salbutamol 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).
6.1.5.
Inhaler Malfunction
Device malfunction occurs during the study will be recorded in eCRF with container 
numbers. This data will be listed.
7.
PRIMARY STATISTICAL ANALYSES
7.1.
Efficacy Analyses
7.1.1.
Overview of Planned Efficacy Analyses
The primary efficacy analyses for change from baseline in Trough FEV1 will be on the
mPP population. All outputs produced for the primary endpoint will be repeated on the 
ITT population.
Table 3 provides an overview of the planned efficacy analyses for Trough FEV1, with 
full details of data displays being presented in Section 10.13, List of Data Displays.
Other endpoints of trough FEV1 at Weeks 4 and 12, and trough FVC at Weeks 4, 12 and 
24 are also included in this section as they are related to the primary endpoint.


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Table 3
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
Spirometry
Baseline FEV1
Y1
Y2
Trough FEV1 
(MMRM analysis)
Y1
Y1
Y2
Y1
Y4
Y1
Y4,5
Y2
Trough FVC
Y3
Y2
Y3
Y2
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.
For mPP population and ITT population, separately.
2.
ITT population only and include a flag for mPP population.
3.
ITT population only
4.
MPP population only
5.
empirical distribution function plot
7.1.1.1.
Spirometry data
Spirometry is assessed pre-treatment on Week 0, and pre-dose at Weeks 4, 12 and 24.
Spirometry data including FEV1 and FVC will be transferred from the vendor to GSK.  
When spirometry has been performed but the reading was unacceptable, a record in the 
database will indicate that the spirometry was performed but all data will be missing and 
will not be included in listings or summary displays.
The definition of baseline FEV1 and FVC is in Section 10.5.2.1 and of trough FEV1 and 
FVC is in Section 10.6.4.  


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7.1.2.
Planned Efficacy Statistical Analyses
Primary Statistical Analyses
Endpoint(s)
o
Trough FEV1
Model Specification
o
The primary endpoint of change from baseline in trough FEV1 will be analyzed in the mPP
population, using a mixed model repeated measures (MMRM) analysis, including trough FEV1 
recorded at each of Week 4, 12 and 24. The model will include covariates of baseline FEV1, 
stratum (number of long-acting bronchodilators per day during the run-in), Visit, geographical 
region, treatment and Visit by baseline interaction. A Visit by treatment interaction term will also 
be included to allow treatment effects to be estimated at each visit separately. 
o
The variance-covariance matrix will be assumed unstructured.
o
Two models will be fitted; one with a response variable of trough FEV1, and one with a 
response variable of change from baseline in trough FEV1.
Handling of Missing Data for Analysis
o
No data were collected for subjects who prematurely discontinued study treatment.  All missing 
and excluded data will be assumed to be Missing at Random (MAR). Sensitivity analyses to 
investigate the impact of this assumption will be conducted as described below.
Model Checking & Diagnostics
o
Refer to Appendix 11: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation
o
Least Square (LS) mean and LS mean change from baseline with their corresponding standard 
errors (SEs) will be presented for each treatment by Visit, together with estimated treatment 
differences (FF/UMEC/VI vs. FF/VI+UMEC) and the corresponding 95% confidence intervals 
(CIs). 
o
A plot of LS means change from baseline and 95% CIs from the model will be generated for 
each treatment by Visit.
Example SAS Code
proc mixed data=<dataset>;
class treatment visit cengroup stratum subjid;
model endpoint=baseline stratum visit cengroup treatment visit*baseline 
visit*treatment / ddfm=kr;
repeated visit/ subject=subjid type=un;
lsmeans visit*treatment / cl diff e om=OMdset at (baseline)=(&blm.);
ods output lsmeans=lsmeans;
ods output diffs=diffs;
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.
Sensitivity and Supportive Statistical Analyses
o
The above will be repeated for the ITT population. LS mean and LS mean change from 


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Sensitivity and Supportive Statistical Analyses
baseline with their corresponding SEs will be presented for each treatment by Visit, together 
with estimated treatment differences and the corresponding 95% CIs. 
o
A “tipping point” sensitivity analysis of trough FEV1 at Week 24 will be conducted for the mPP
Population. This will explore the impact of missing data by using differing assumptions 
regarding the mean treatment effect in subjects who discontinue study treatment or have data 
excluded from the mPP Population analyses. Mean treatment effects investigated will range 
from a change from baseline of -150mL to +150mL in increments of 50mL.  For each value of 
the assumed mean change from baseline on FF/UMEC/VI, the full range of values for the 
assumed mean change from baseline for FF/VI+UMEC will be investigated; thus including
scenarios where subjects who discontinue FF/UMEC/VI have a lower treatment effect than 
those who discontinue FF/VI+UMEC and vice versa. The analysis results will be used to 
explore the conditions under which the conclusion of non-inferiority no longer holds.
o
For each subject with missing or excluded data at Week 24, a value will be imputed based 
on a random draw from a normal distribution with mean equal to the corresponding 
assumed mean change from baseline and standard deviation taken from the observed 
change from baseline data for the combined treatment arms at the Week 24 visit. Data for 
subjects with missing baseline values will not be imputed.  Analysis of the complete Week 
24 dataset will be carried out using an ANCOVA model with covariates of treatment group,
stratum (number of long-acting bronchodilators per day during the run-in), geographical 
region and baseline. 
o
The seed will be set using the following SAS code: 
data seed1;
   number=round(10000*ranuni(0),1);
   output;
run;
proc print;
run;
The seeds generated and assigned to each analysis will be documented separately prior 
to DBF.
A table will be produced displaying the 95% CI for the treatment difference at Week 24 
under the above assumptions for the mean changes from baseline for each of the 
treatment arms.

Interactions between treatment and other factors will be investigated as follows by adding 
interaction terms to the specified model:
o
An assessment of whether the effect of treatment on trough FEV1 is modified by number 
of long-acting bronchodilators per day during the run-in, geographic region, or baseline will 
be made by fitting separate repeated measures models, identical to the primary analysis 
models described above but also including additional terms as described below.
o
For the factors of number of long-acting bronchodilators per day during the run-in and 


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Sensitivity and Supportive Statistical Analyses
geographical region, the primary analysis model will be used with additional terms for the 
factor by treatment by Visit interaction. The p-value for the treatment by factor interaction 
at Week 24 will be obtained using contrast statements. If that p-value is ≥ 0.10 the 
interaction will be considered not significant. If the p-value is < 0.10, further investigation 
will be performed, for example running the analysis by each stratum or geographic region.
o
For baseline FEV1, the primary analysis model will be used with additional terms for the 
baseline value by treatment by Visit interaction. The p-value for the treatment by baseline 
interaction at Week 24 will be obtained using contrast statements. If that p-value is ≥ 0.10 
the interaction will be considered not significant. If the p-value is < 0.10, further 
investigation will be performed, for example running the analysis by dichotomous 
categories of baseline values (values above and below the median).
8.
SECONDARY STATISTICAL ANALYSES
8.1.
Other Efficacy Analyses
8.1.1.
Overview of Planned Efficacy Analyses
The other efficacy analyses will be based on the ITT population, unless otherwise 
specified.
Table 4 provides an overview of the planned efficacy analyses, with further details of 
data displays being presented in Section 10.13, List of Data Displays.
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
SGRQ
Baseline SGRQ 
Scores
Y
Y
SGRQ Domain Scores
Y
Y
Y
SGRQ Total Score 
(MMRM Analysis)
Y
Y
Y
Y
Y
Y
Y2
Y
Proportion of 
Responders according 
to SGRQ Total Score
Y
Y
Y
Baseline Dyspnea Index (BDI)/Transitional Dyspnea Index (TDI) 
BDI
Y
Y
TDI
Y
Y
Y
Y
Proportion of 
Responders according 
to TDI Focal Score
Y
Y
Y
COPD Exacerbations
Exacerbation 
Occurrence and 
Details
Y1
Y


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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
Time to First On-
treatment 
Moderate/Severe 
Exacerbation
Y
Y3
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.
Number and percent reporting COPD exacerbation and summary of details regarding the exacerbation. 
Repeat for post-treatment exacerbations.
2.
empirical distribution function plot
3.
Kaplan -Meier Plot
8.1.1.1.
St. George’s Respiratory Questionnaire for COPD Patients (SGRQ-C)
The SGRQ-C is completed at Week 0, Week 12, and Week 24.  The calculation for the 
SGRQ-C, including how to handle missing values, is detailed in the SGRQ-C manual 
(Jones, 2016).  The conversion of the SGRQ-C scores to SGRQ scores is as described in 
the manual and as detailed in Section 10.6.4.
Subjects will be classified as responders/non-responders based on SGRQ total score as 
described in Section 10.6.4
8.1.1.2.
COPD Exacerbations
The definition of moderate and severe exacerbations is provided in Section 10.6.4.  The 
definition of on- and post-treatment exacerbations is provided in Section 10.4.2.
For summary of on-treatment COPD exacerbations, details of the event to be summarized 
include the number and percent of subjects reporting an exacerbation (any severity, mild, 
moderate, severe and moderate/severe), number and percent subjects with each number 
of moderate/severe exacerbations (0, 1, ≥2), outcome, severity, duration, whether 
treatment with systemic or oral steroids was required, whether treatment with antibiotics 
was required, whether hospitalization was required, and whether the exacerbation 
resulted in a visit to the emergency room.  Post-treatment exacerbations will be similarly 
summarized. The total number of exacerbations will be included.  For derivation of time 
to first on treatment moderate or severe exacerbation, see Section 10.6.4.
8.1.1.3.
Baseline Dyspnea Index (BDI)/Transitional Dyspnea Index (TDI) Focal 
Score
BDI is assessed at Week 0.  TDI is assessed at Week 12 and Week 24.    The BDI and 
TDI focal scores [Mahler, 2004] will be calculated as shown in Section 10.6.4.


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8.1.2.
Planned Other Efficacy Statistical Analyses
8.1.2.1.
SGRQ Total Score
Secondary Statistical Analyses
Endpoint(s)
o
SGRQ total score 
Model Specification, Model Checking & Diagnostics, Model Results Presentation
o
Same as for trough FEV1, see Section 7.1.2
o
Visit includes week 12 and 24.
8.1.2.2.
TDI
Secondary Statistical Analyses
Endpoints

TDI focal score
Model Specification, Checking, Results Presentation and SAS code

Same as for trough FEV1, see Section 7.1.2

BDI will be used in place of baseline.

Visit includes week 12 and 24.
8.1.2.3.
Proportion of Responders according to SGRQ Total Score and
Responders according to TDI
Endpoints

Proportion of Responders according to SGRQ total score

Proportion of  Responders according to TDI
Model Specification

Generalized Linear Mixed Model

Terms in the model: 
  Dependent Variable: Response (Yes/No)  
  Categorical  :  treatment group, stratum, geographical region, visit
  Continuous  :  Baseline (for SGRQ total score) or BDI
  Interaction   :   baseline*Visit, treatment*Visit
  Repeated    :   Visit

The model will be fit with an unstructured variance-covariance matrix

One single model to include all visits 
o
SGRQ:  include Week 12 and 24  
o
TDI: include Week 12 and 24
Handling of Missing Data for Analysis

Subjects with missing on-treatment data and a subsequent non-missing on-treatment 
scheduled assessment will not be considered as a responder/non-responder but will be left as 
missing.

Subjects that have withdrawn from the study prior to the visit in question will be imputed as 


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non-responders at all visits post-withdrawal where the assessment was expected to be 
performed.

Refer to Appendix 11: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

Number and percentage of responders and non-responders for each treatment at each Week 

Odds ratio for comparison between FF/UMEC/VI and FF/VI+UMEC  with associated 95% CI 
Example SAS Code
proc glimmix data=filename ;
    class treatment stratum visitnum subjid centgroup;
    model respond(event="1") = treatment base stratum visitnum centgrp visitnum*base 
                                  visitnum*treatment 
           / dist=binary link=logit ddfm=kr solution;
    lsmeans visitnum*treatment / cl diff or om ; 
     random visitnum / subject=subjid residual type=un;
    ods output diffs=differs;
run;
8.1.2.4.
COPD Exacerbations
Secondary Statistical Analyses
Endpoints

Time to first on-treatment moderate/severe COPD exacerbation
Model Specification

Cox’s proportional hazards model
Terms in the model:
Dependent variable: time to first on-treatment moderate/severe exacerbation 
Categorical: treatment group, gender, exacerbation history (0, 1, >=2 moderate/severe 
exacerbations in the last 12 month at screening), smoking status (screening), stratum and 
geographical region. 
Continuous: % predicted FEV1 at Baseline

Use the ‘exact’ method for handling ties. (If the analysis will not run using the ‘exact’ 
method, then the ‘Efron’ method for handling ties will be used instead.)  
Handling of Missing Data for Analysis

Subjects who withdrew from the study prior to experiencing a COPD exacerbation will be 
considered censored at random.
Model Checking & Diagnostics

Refer to Appendix 11: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

Hazard ratio for comparison between FF/UMEC/VI and FF/VI+UMEC  with associated 95% CI 
Example SAS Code


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25
Secondary Statistical Analyses
proc phreg data=<dataset> ;
model timeto1*eventflag(0)=treatment fevpred stratum cengroup smokehis
hxf_exac / risklimits ties=exact;
run;
Secondary Statistical Analyses
Endpoints

Time to first on-treatment moderate/severe COPD exacerbation 
Model Specification  
o
A Kaplan-Meier analysis will also be performed for figure showing Kaplan-Meier survivor 
functions of the proportion of subjects with a first exacerbation over time for each treatment 
group separately plotted on the same figure. 
Example SAS code
proc lifetest data=destin outsurv=survest;  
  time timeto1*eventflag(0);
  strata treatment;
run;
Model Results Presentation
o
Probability of having an event, 95% CI and first quartile time to exacerbation (estimate of the 
time at which 25% of subjects in each treatment group would have had an exacerbation)
o
Figure showing Kaplan-Meier survivor functions of the proportion of subjects with a first 
exacerbation over time for each treatment group separately plotted on the same figure. 
8.2.
Safety Analyses
8.2.1.
Overview of Planned Analyses
The safety analyses generally will be based on the ITT population.  
Table 5 provides an overview of the planned analyses, with the detailed list of data 
displays being presented in Section 10.13. 
Table 5
Overview of Planned Safety Analyses
Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
Exposure 
Exposure Data
Y
Y
Y
Adverse Events (AEs)
Overview of  On-
Treatment AEs
Y
On-Treatment AEs
Y10
Post-Treatment AEs
Y
On-Treatment Drug-
Related AEs
Y
Pre-Treatment SAEs
Y1,2


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Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
On-Treatment SAEs
Y
Post-Treatment SAEs
Y
On-Treatment Fatal 
SAEs
Y
On-Treatment Drug-
Related SAEs
Y
Pre-Treatment SAEs 
Leading to Withdrawal 
from Study
Y1
On-Treatment AEs 
Leading to Withdrawal 
from Study
Y
On-Treatment AEs of 
Special Interest
Y
On-Treatment SAEs of 
Special Interest
Y
Relationship of AE 
System Organ Class, 
Preferred Term and 
Verbatim Text
Y1
On-treatment Common 
Non-Serious AEs (3% 
or More of Subjects in 
Any Treatment Group) 
Y
10 Most Frequent On-
treatment Adverse 
Event in Each 
Treatment Group 
Y
On-treatment 
Adverse Events by 
System Organ Class 
and Maximum 
Intensity
Y
Subject Numbers for 
Individual AEs
Y1
All AEs
Y1
Non-Fatal Serious AEs
Y1
Fatal AEs
Y1
AEs Leading to 
Withdrawal from Study
Y
Subject Numbers for 
On-Treatment AEs of 
Special Interest
Y
Reasons for 
Considering as a 
Serious Adverse 
Event
Y


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Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
Pneumonia 
On-Treatment 
Pneumonias Incidence
Y9
Y3
Details of on-treatment
Pneumonia
Y9
Y3
Post-Treatment 
Pneumonias Incidence
Y9
Y3
Details of Post-
treatment Pneumonia
Y9
Y3
Bone Fractures
On-Treatment Bone 
Fractures
Y
Y3
Post-Treatment Bone 
Fractures
Y
Y3
Radiography (Chest Imaging including X-Rays and CT Scan)
On-Treatment Chest 
Imaging
Y
Y3
Post-Treatment Chest 
Imaging
Y
Y3
Liver Events
Medical conditions 
for subjects with liver 
stopping events
Y
Liver Event Results 
and Time of Event 
Relative to Treatment
Y
Liver Event Substance 
Use
Y
Liver Event Information 
for RUCAM Score
Y
Liver Biopsy Details
Y
Liver Imaging Details
Y
On Treatment Laboratory Parameters
Liver Function Tests
Y6
Chemistry Values for 
Subjects with at Least 
One Value Outside the 
Normal Range
Y
Chemistry Data
Y
Y4
Y
Y5
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 
Y


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Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
Normal Range
Hematology Data
Y
Y4
Y
Y5
Hematology Data 
Outside the Normal 
Range
Y
Hematology Changes 
from Baseline Relative 
to the Normal Range
Y
On Treatment Vital Signs
Vital Sign Data (Pulse 
Rate, Sys BP, Dia BP)
Y
Y
Y
12-Lead ECGs
ECG Values
Y
Y7
Y
Y8
ECG Findings
Y
ECG Findings Shifts  
from Baseline
Y
QTcF Categories
Y
Y
ECG Abnormalities
Y
Y7
Y8
ECG Abnormalities 
Occurring in at least 
3% of Subjects in 
Either Treatment 
Group
Y
Maximum Post-
Baseline QTcF
Y8
Y8
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.
ASE Population 
2.
ITT Population
3.
Combined listing for on-treatment and post-treatment.
4.
Separate box plots of change from baseline in maximum and minimum post-baseline values
5.
Separate scatter plots for maximum and minimum post-baseline versus baseline divided by ULN for maximum and 
LLN for minimum 
6.
Trellis Display of Maximum Post-baseline Liver Function Test Values Versus Baseline Liver Function Test Values
7.
Listing of data only for subjects with any abnormal ECG finding.
8.
Empirical Distribution Function Plot
9.
Pneumonia are the cases recorded in Pneumonia Details CRF form
10. Repeat for by country
11. Trellis plot baseline vs post baseline
8.2.1.1.
Adverse Events of Special Interest
Adverse events (AEs) 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 Affairs (MedDRA) Queries (SMQs) and 
other groupings for AESI is provided in Section 10.6.3. 


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8.2.1.2.
Pneumonia
Summaries of pneumonia will include data from the Pneumonia Details CRF form.  
8.2.1.3.
Vital Signs
Vital signs are collected at Screening (Visit 1) and pre-dose at Week 4, Week 24 or at the 
Early Withdrawal Visit.  Vital signs collected at Early Withdrawal and at the onset of a 
pneumonia event will be included in ‘minimum/maximum post-baseline’ (see Section 
10.6.3 for the definition) summaries but will not be summarized separately.
8.2.1.4.
ECGs
12-Lead ECGs are collected at Screening (Visit 1) and approximately 15-45 min after 
dosing at Week 24  or at the Early Withdrawal Visit.  All ECG data present in the 
database will be considered valid and will be reported (even if the ECG had a technical 
error). ECGs collected at Study Treatment Discontinuation will be included in summary 
of ECG finding where ‘worst case post-baseline’ summarized but will not be summarized 
separately.
8.2.1.5.
Pregnancy
Any pregnancies reported during the study will be summarized in case narratives. Any 
pregnancy complication or elective termination of a pregnancy for medical reasons will 
be recorded as an AE or SAE and included in summaries and listings of AEs/SAEs.


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9.
REFERENCES
Aguis R and Kintz P (2010) Drug and alcohol testing in hair, collection and analysis. 
European workplace drug testing society, version 1.0, 1-18
Barbosa, J, Faria, J, Carvalho, F, Pedro, M, Queiros, O, Moreira, R and Dinis-Oliveira RJ 
(2013) Hair as an alternative matrix in bioanalysis. Bioanalysis 5 (8): 
GlaxoSmithKline Document Number 2015N261999_03, 200812, A phase IIIB, 24-week 
randomised, double-blind study to compare ‘closed’ triple therapy (FF/UMEC/VI) with 
'open' triple therapy (FF/VI + UMEC), in subjects with chronic obstructive pulmonary 
disease (COPD), 26-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.
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.
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


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10.
APPENDICES
Section
Appendix
RAP Section 4 : Analysis Populations
Section 10.1
Appendix 1: Protocol Deviation Management and Definitions for mPP Population
RAP Section 5 : General Considerations for Data Analyses & Data Handling Conventions
Section 10.2
Appendix 2: Time and Events
Section 10.3
Appendix 3: Assessment Windows
Section 10.4
Appendix 4: Treatment States & Phases
Section 10.5
Appendix 5: Data Display Standards & Handling Conventions

Study Treatment & Sub-group Display Descriptors

Baseline Definitions & Derivations

Reporting Process & Standards
Section 10.6
Appendix 6: Derived and Transformed Data

General, Study Population & Safety

Efficacy
Section 10.7
Appendix 7: Premature Withdrawals & Handling of Missing Data

Premature Withdrawals

Handling of Missing Data
Section 10.8
Appendix 8: Multicentre Studies

Laboratory Values

ECG

Vital Signs
Section 10.9
Appendix 9: Examination of Covariates and Subgroups
Section 10.10
Appendix 10: Multiple Comparisons and Multiplicity
Section 10.11
Appendix 11: Model Checking and Diagnostics for Statistical Analyses
Other RAP Appendices
Section 10.12
Appendix 12: Abbreviations & Trade Marks
Section 10.13
Appendix 13: List of Data Displays


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10.1.
Appendix 1: Protocol Deviation Management and Definitions
for mPP Population
10.1.1.
Exclusion of Data from the ITT Analyses
In general, all data recorded for subjects who were randomised (excluding those 
randomised in error) will be included in ITT analyses. The following will result in 
exclusion of data from ITT analyses:
Spirometry data are excluded from ITT analyses if the actual time of assessment is after 
the time of dosing on that day or if albuterol/salbutamol was used within 4h of the
assessment on that day.
10.1.2.
Exclusions from mPP Population
The full list of protocol deviations collected on the eCRF is in the PDMP.
The mPP Population is the primary analysis population, comprising all subjects from ITT 
population with the exception of:
o
Full exclusion: subjects who have a full protocol deviation considered to 
impact primary endpoint (trough FEV1)

Eligibility criteria (those that impacts primary endpoint as listed in 
PDMP, Appendix 2) not met 

Treatment non-compliance (overall compliance <80% or >120% over 
the 24-week treatment period, based on active treatment)

Randomisation criteria not met
Pneumonia or moderate/severe COPD exacerbation during run-
in
Any change to COPD maintenance medications (including 
dosage and regimen) during the run-in
Antibiotics for respiratory tract infections during the run-in
o
Partial exclusion: subjects who have a protocol deviation considered to impact 
primary endpoint. Trough FEV1 assessments collected after the incidence of 
the protocol deviation will be excluded from primary analysis. 

Subject received incorrect container which contains incorrect study 
treatment.

Subjects took prohibited medication during treatment period, as 
detailed in PDMP Appendix 3 Prohibited Medication. 


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o
Partial exclusion: other events (not a protocol deviation) considered to impact 
the primary endpoint. Trough FEV1 assessments collected on or after the 
event start date will be excluded from primary analysis. 

Subjects had a moderate/severe COPD exacerbation 

Subjects had pneumonia.

Subjects who were unblinded by GCSP due to safety concerns.
Note: Subjects who received incorrect treatment and non-compliance based on active 
treatment will be identified as important PDs and flagged as PP exclusionary following 
treatment unblinding. These PDs will be flagged as PP exclusionary in ADaM DV dataset 
and will be included in summary of exclusion from mPP population table.


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10.2.
Appendix 2: Time & Events
Protocol Activity
Pre-
Screen Screen
Treatment
Follow Up
Visit 0
Pre-
screen
Visit 1 
Screening
Visit 2
Randomisation 
Visit 
3
Visit 
4
Visit 5
Early 
Withdrawal 
Visit
Safety
Follow-
up 
Contact
Study Week
Week -2
Week 0
Week 
4
Week 
12
Week 
24
1 week 
Fw-up
Window
-3/+8d
-
4/+2d -8/+6d -8/+6d
-1/+4d
Written Informed Consent a
X
X
Genetic Informed Consent b
X
X
Demography c
X
X
Medical History, including 
cardiovascular history
X
COPD and Exacerbation 
History
X
Concomitant Medication 
Assessment
X
X
X
X
X
X
X
X
Inclusion/Exclusion Criteria
X
Randomisation Criteria
X
Smoking History
X
Smoking status
X
X
X
Smoking Cessation 
Counselling
X
X
X
Register Visit in IRT/ RAMOS 
NG d
X
X
X
X
X
X
Reversibility Testing e
X
Spirometry
Xf
Xf
Xf
Xf
Device training and 
registration
X
X
Exacerbation Assessment
X
X
X
X
X
X
X
SGRQ-C g
X
X
X
BDI g
X
TDI g
X
X
CAT g
X
eDevice close out h
X
X
X
Physical examination i
X
X
X
Adverse Events Assessment
X
X
X
X
X
X
X
Vital signs j
X
X
X
X
ECG
X
Xk
Xk
Chest X-ray l
X
Pulse oximetry m
X
Blood draw for PK 
Xn
Xo
Blood Draw for Genetics 
research 
Xp


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Protocol Activity
Pre-
Screen Screen
Treatment
Follow Up
Visit 0
Pre-
screen
Visit 1 
Screening
Visit 2
Randomisation 
Visit 
3
Visit 
4
Visit 5
Early 
Withdrawal 
Visit
Safety
Follow-
up 
Contact
Study Week
Week -2
Week 0
Week 
4
Week 
12
Week 
24
1 week 
Fw-up
Window
-3/+8d
-
4/+2d -8/+6d -8/+6d
-1/+4d
Haematology/biochemistry q
X
X
X
Urine Pregnancy Test r
X
X
X
X
X
Hepatitis B and C tests 
X
Dispense study treatment
X
X
X
Administer study treatment in 
clinic s
X
X
X
X
X
Assess study treatment 
compliance
X
X
X
X
Collect study treatment
X
X
X
X
Dispense 
albuterol/salbutamol
X
X
X
X
Collect albuterol/salbutamol
X
X
X
X
X
Issue/review paper diary t
X
X
X
X
X
X


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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.
The IRT will be used for randomisation, emergency unblinding and study treatment supply management (Please 
refer RAMOS NG IRT manual for more information)
e.
At Screening Visit 1 both pre and post-bronchodilator spirometry will be conducted. Pre-bronchodilator spirometry 
will be performed prior to the subject taking their morning dose of their usual COPD treatment, between 6am and 
11am and after withholding rescue albuterol/salbutamol for ≥4 hours.
f.
At Visits 2-5 (and the Early Withdrawal Visit), pre-bronchodilator spirometry will be performed prior to taking the 
morning dose of study treatment, between 6am and 11am and after withholding rescue albuterol/salbutamol for 
≥4 hours.   
g.
Patient reported assessments should be conducted in the following order and before other study assessments: 
SGRQ-C, BDI/TDI. 
h.
Close out eDevice for any subject who fails to randomize, withdraws early, or completes Visit 5.
i.
Physical examination may include height, weight, blood pressure, temperature, heart rate.
j.
Vital signs must be performed prior to spirometry and prior to taking morning dose of study mediation.
k.
ECG to be obtained 15 - 45 minutes post-dose at treatment Visit 5 and Early Withdrawal Visit (if possible).If a 
subject is not dosed at Early Withdrawal, then an ECG can be taken at any time during the visit
l.
Chest X-ray (PA and lateral) is required at Screening (or historical x-ray obtained within 3 months prior to 
Screening) and at anytime there is a suspected pneumonia or a mod/severe exacerbation.
m.
Pulse oximetry must be performed at V2 and anytime there is a suspected pneumonia or a moderate or severe 
exacerbation.
n.
PK subset A: PK samples of 120 subjects at selected sites, to be obtained at two time points at Visit 4: pre-dose 
and in the window 5 to15 minutes post-dose.
PK subset B: PK samples of 60 subjects at selected sites, to be obtained and Visit 4: pre-dose, 5-15min, 45-
90min, 2.5-4h, 6-8h, 10-12h, 23-24h post-dose. 
o.
PK subset A: PK samples of 120 subjects at selected sites, to be obtained at two time points at Visit 5: 5 to 15 
minutes post–dose and 45 to 90 minutes post-dose.
p.
The genetics blood sample should be taken at V5 or at any visit after Randomisation (V2). 
q.
Haematology and chemistry panels will include liver chemistry, and potassium and glucose levels.
r.
All female subjects of child bearing potential will have a urine pregnancy test at each visit except Visits 2 and 
follow-up.
s.
Subjects must withhold their morning dose of study treatment at each clinic visit and not take their study treatment 
dose until instructed to do so by study staff.
t.
Subjects will be issued a paper diary, at screening and other clinic visits (if required) in order to note any changes 
to concomitant medications and/or incidence of adverse events that may have occurred between clinic visits. 


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10.3.
Appendix 3: Assessment Windows
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 Early Withdrawal 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. 


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10.4.
Appendix 4: 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 of data up to Week 24 will consider all scheduled and unscheduled 
measurements that have been assigned a treatment phase of ‘On-treatment’. 
10.4.1.
Treatment Phase for 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. Calculation of stratum, i.e. long-acting bronchodilator 
usage per day during the run-in (none, one or two long-acting bronchodilators per day),
will also be based on the COPD medication taken on the day of the screening visit. If the 
calculated stratum is different to the randomized stratum, the calculated stratum will be 
used as a covariate in all analyses, but both values will be listed.  Treatment phases for 
summaries of COPD and non-COPD concomitant medications will be defined as follows: 
Definition
Treatment Phase
Run-in
On-
treatment
Post-
treatment
Subject did not take study treatment (e.g, run-in 
failures) and conmed stop date > date of 
Screening or variable that asks if conmed is on-
going (refer hereafter as goingmed) is “yes”
Y
(Conmed start date<treatment start date or 
variable that asks if medication taken prior to 
study is ”yes”(refer hereafter as priormed)) and 
date of Screening < conmed stop date 
<treatment start date
Y
(Conmed start date<treatment start date or 
priormed is yes) and  treatment start 
dateconmed stop datetreatment stop date 
Y
Y
(Conmed start date<treatment start date or 
priormed is yes) and  (conmed stop 
date>treatment stop date or goingmed is “yes”)
Y
Y
Y
(Treatment start dateconmed start 
date<treatment stop date and treatment start 
dateconmed stop datetreatment stop date) 
or (Treatment start date=conmed start 
date=conmed stop date=treatment stop date)
Y
([Treatment start dateconmed start 
date<treatment stop date] or [Treatment start 
date=conmed start date=treatment stop date]) 
and(conmed stop date>treatment stop date or 
Y
Y


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Definition
Treatment Phase
Run-in
On-
treatment
Post-
treatment
goingmed is Yes)
Conmed start≥treatment stop date and 
treatment start date ≠ treatment stop date
Y
NOTES: 

A concomitant medication will be classed in every period of the study in which it was taken (e.g., run-in, on-
treatment or post-treatment).  

See Section 10.7.2.1 for handling of partial dates.

If the study treatment stop date is missing, it will be imputed as described in Section 10.6.1.

Medications that stopped prior to Screening will not be assigned a treatment phase and will not be 
summarized.
10.4.2.
Treatment Phase for Other Data
Treatment phases for assessments scheduled at a set time will be defined according to the 
planned relative time of the assessment.
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, pre-treatment and on-treatment
and post-treatment phases will be defined as below:
Treatment Phase
Definition
Pre-treatment
Event onset date/time or assessment date/time < treatment start date/time.  
On-treatment 
Treatment start date/time ≤ event onset date/time or assessment date/time ≤ 
treatment stop date + 1 day, or any event/assessment with a missing or 
partial onset date unless there is evidence it was not on-treatment.
Post-treatment
Event onset date/time or assessment date/time treatment stop date + 2  
and event onset date/time or assessment date/time ≤ study conclusion date
Note: the study conclusion date reflects the safety F/U contact for study 
treatment completers. 
For all events and assessments (with the exception of concomitant medications) where 
time is not recorded, the pre-treatment, on-treatment and post-treatment phases will be 
defined as below:


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Treatment Phase
Definition
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 day or any event/assessment with a missing or partial onset date 
unless there is evidence it was not on-treatment.
Post-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.


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10.5.
Appendix 5: Data Display Standards & Handling 
Conventions
10.5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting 
Code
Description
Description
Order [1]
1
FF/UMEC/VI 
100mcg/62.5mcg/25mcg + Placebo
FF/UMEC/VI 100/62.5/25
1
2
FF/VI 100mcg/25mcg + UMEC 
62.5mcg
FF/VI 100/25 + UMEC 62.5
2
NOTES:
1.
Order represents treatments being presented in TFL, as appropriate.
10.5.2.
Baseline Definition & Derivations
10.5.2.1.
Baseline Definitions
Parameter
Study Assessments Collected prior to dosing
Baseline 
Definition
Screening
  Week 0  (Pre-Dose)
Efficacy
Trough FEV1, 
Trough FVC
X
X
Week 0 pre-dose.
SGRQ total and 
domain scores
X
Week 0 pre-dose
Safety 
Vitals, Labs, ECGs
X
Most recent 
individual value 
prior to first dose 
(generally 
Screening but could 
be a test repeat).
NOTES :

Unless otherwise specified, the baseline definitions specified in Section 10.5.2.1 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.


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10.5.3.
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/mid200812/final
QC Spreadsheet
: /arenv/arwork/gsk2834425/mid200812/documents
Analysis Datasets 

Analysis datasets will be created according to CDISC standards (SDTM Implementation Guide 
Version 3.1.3 or higher & AdaM Implementation Guide Version 1.0 or higher).

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

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:
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 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 data based on the raw data collected.

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.

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 on the eCRF.


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Reporting Standards

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. 
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 drug dosing will be shown in listings (refer to 
IDSL Statistical Principle 5.05.1).
o
Unscheduled or unplanned readings will be presented within the subject’s listings. 
Unscheduled Visits

Unscheduled visits will not be included in summary tables except as part of a ‘worst case post-
baseline’ assessment.

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous data
Refer to IDSL Statistical Principle 6.06.1
Categorical data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.


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10.6.
Appendix 6: Derived and Transformed Data
10.6.1.
General
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
Study Treatment  Stop Date
If overall treatment stop date is missing it will be imputed as follows:

For subjects who attended an Early Withdrawal visit, use the date of the Early Withdrawal
visit

For subjects who attended the last on-treatment visit, use the Visit 5 (Week 24) date

For subjects who died and did not attend an Early Withdrawal visit or the last on-treatment 
visit, use the date of death

For all other subjects, use the last recorded exposure start or stop date
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 5.

A subject is considered to have completed the study if they either attended Visit 5 or had a 
phone contact at Visit 5.
10.6.2.
Study Population
Demographics
Age

Age will be calculated based on the Pre-screening visit date

Birth date will be imputed as follows:

Any subject with a missing day will have this imputed as day ‘15’. 

Any subject with a missing date and month will have this imputed as ‘30JUN’.

Birth date will be presented in listings as ‘YYYY’. 
Age Category 
Age categories are based on age at Pre-screening and are defined as:

≤64 years

65-74 years, 

75-84 years

≥85 years


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Demographics
Body Mass Index

Calculated as weight (kg) / [height (m)]2
Subject Disposition
Subject Withdrawal 

For Kaplan-Meier plots of subject withdrawal over time, censoring will be performed as follows:
For subject withdrawal, subjects are represented from their Week 0 date to the date of early 
withdrawal from the study. Subjects that completed the study are censored at the earliest of the 
date of completion and day 168.
Smoking Status 
At Screening, subjects who were identified as former smokers but who last smoked within 6 
months prior to Screening will be re-classified as current smokers prior to summarizing. Subject 
listings will include original and re-classified status.
Compliance

ELLIPTA™ inhaler A contains FF/UMEC/VI (for subjects in FF/UMEC/VI treatment group) or 
FF/VI (for subjects in FF/VI+UMEC treatment group) and has container number with prefix 3.

ELLIPTA™ inhaler B contains placebo (for subjects in FF/UMEC/VI treatment group) or UMEC 
(for subjects in FF/VI+UMEC treatment group) and has container number with prefix 4.

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 and for that
inhaler.

Number of doses of study drug taken by each subject from each inhaler = Dose counter start-
dose counter stop.

Compliance are calculated as follows:

Compliance for Ellipta inhaler A =(dose counter start – dose counter stop for inhaler A) x 
100 / (exposure stop date – exposure start date +1)

Compliance for Ellipta Inhaler B=(dose counter start – dose counter stop for Inhaler B) x 
100 / (exposure stop date – exposure start date +1)

Overall Compliance = (compliance for Inhaler A + compliance for inhaler B with active 
treatment)/2. That is: 
O
For subject in FF/UMEC/VI treatment group, Overall Compliance = compliance for 
Inhaler A  
O
For subject in FF/VI + UMEC treatment group, Overall Compliance = (compliance 
for Inhaler A + compliance for inhaler B)/2

Overall compliance and compliance for each inhaler 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 


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Subject Disposition
compliance will still be calculated using data from all containers received and overall exposure 
start and stop dates.
Long-acting Bronchodilator Usage During the Run-in (Randomisation Stratum) 
Randomization stratum, long-acting bronchodilator usage during the run-in,  will be derived based
on the RMC classification and will be grouped into the following 3 categories:

None

One long-acting bronchodilator per day

Two long-acting bronchodilators per day
Long-acting bronchodilator is defined as any COPD medication in Respiratory Medication Class  
(MRC) under ‘Long-acting beta-2 agonist – Group 2’ or ‘Long-acting beta-2 agonist – Group 3’ or 
‘Long-acting anticholinergic’.
Based on RAMOS NG record, the number of subjects used none long-acting bronchodilator during 
run-in is very small (ie. <1% of randomized subjects).  Therefore, the combined stratum with 2 
categories will be used in the statistical analysis, ie, none and one long-acting bronchodilator per 
day will be combined into one category in analysis. 
Ranodmisation stratum is also collected at randomization in RAMOS NG. Both randomization 
stratum (derived and collected) will be listed.
Medical Conditions and Concomitant Medications
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 at screening.  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
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


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Medical Conditions and Concomitant Medications

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 will be grouped into the following 
categories based on the RMC classification:

ICS

LABA

LAMA

Xanthine

PDE4 Inhibitors

Any combination of the above

Other

None


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Medical Conditions and Concomitant Medications
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

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. 
o
Moderate COPD exacerbations are defined as exacerbations that required treatment with 
systemic/oral corticosteroids and/or antibiotics (not involving hospitalization).
o
Severe COPD exacerbations are defined as exacerbations that required in-patient 
hospitalization.

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).


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Medical Conditions and Concomitant Medications
COPD Assessment Test (CAT) at Screening
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.
The CAT score at screening will be summarized.
CAT Category 
Subject will be classified into the following CAT category based on the CAT score at Screening:

CAT <10

CAT≥10
The CAT category at screening will be summarised
Baseline Lung Function
Reversibility
The reversibility to salbutamol status of a subject is calculated at Screening and is based on the 
difference (absolute change and % change) between a subject’s pre-salbutamol assessment of 
FEV1 and their post-salbutamol assessment FEV1 and is defined as follows:

Reversible, if they had a difference in FEV1 of ≥12% and ≥ 200 mL, or

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:

GOLD Grade 1 (Mild):  percent predicted FEV1 80%

GOLD Grade 2 (Moderate): 50%percent predicted FEV1 < 80%

GOLD Grade 3 (Severe):  30%percent predicted FEV1 < 50%

GOLD Grade 4 (Very Severe): percent predicted FEV1 < 30%
10.6.3.
Safety
Exposure
Exposure Duration
Duration of exposure to study treatment is calculated as:

treatment stop date – treatment start date +1.


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Exposure
Exposure Duration
Exposure Categories

For the ITT population, the following exposure categories will be derived:
≥1 day, ≥4 weeks, ≥8 weeks, ≥12 weeks, ≥16 weeks, ≥20 weeks and ≥24 weeks
Adverse Events
AEs of Special Interest

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.
AE of special interest group
AE special interest 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)


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Hyperglycaemia/new onset diabetes 
mellitus (SMQ)
Hypersensitivity
Local steroid effects
Pneumonia
LRTI excluding pneumonia
Tremor
Urinary retention
Bone Fracture Incidents
If a subject suffers fractures in multiple locations with the same date of fracture, this is considered to 
be one fracture incident.
All bone fractures will be reported; and separately by traumatic and non-traumatic bone fractures.
Maximum/Minimum Post-Baseline and Worst-Case Post-Baseline
Definition
Reporting Details
Maximum post-baseline; 
(QTcF, QTcB, PR interval, ECG 
heart rate, pulse rate, systolic 
BP, diastolic BP and laboratory 
tests.)
Maximum on-treatment value over all timepoints.
Minimum post-baseline; 
(Diastolic BP and laboratory 
tests that do not have a lower 
limit = 0.)
Minimum on-treatment value over all timepoints. 
Worst case post-baseline
(ECG findings)

‘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 10.4.2 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). Vital signs (heart rate, systolic blood pressure and diastolic 
blood pressure) collected at an assessment associated with a pneumonia event will also be included in derivation 
of a ‘minimum/maximum post-baseline’ assessment.
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 at any scheduled or 


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Laboratory Parameters
unscheduled on-treatment visit during the treatment phase being summarized (see Section 
10.4.1 for the definition of treatment phases). 

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 during the treatment phase being summarized (see Section 
10.4.1 for the definition of treatment phases). 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 “Any visit post-
baseline” row of related summary tables. 
ECG
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


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ECG
Change from Baseline
Change from Baseline QTcF
msec
<-60
≥-60
<-30
≥-30
<0
≥0
< 30
≥ 30
<60
≥ 60
Association of Chest Imaging (X-ray or CT scan) with Pneumonia Event

A chest X-ray is considered associated with pneumonia if it is performed within -7 to +14 days 
of the date of onset of pneumonia or the date of resolution, whichever the latter. Pneumonia is 
considered to be supported by a chest X-ray if there is an associated X-ray which shows the 
presence of infiltrates.

Details of pneumonia events are collected on the Pneumonia Details eCRF page. As there may 
not be a one-to-one correspondence between these events and pneumonia AESI events, a 
cross-tabulation will be provided for the association of pneumonia AESI events and those 
recorded on the Pneumonia Details eCRF page.
10.6.4.
Efficacy and Health Outcomes
Spirometry
Predicted FEV1, Predicted FVC, Absolute and Percent Reversibility in FEV1,  Percent 
Predicted FEV1, Percent Predicted FVC, and Pre-salbutamol and Post-salbutamol FEV1/FVC 
Ratio

These derived items will be delivered in a dataset from the vendor for central spirometry, 
except for post-salbutamol FEV1/FVC ratio, and no recalculation will be performed.  Post-
salbutamol FEV1/FVC ratio will be calculated as the ratio of post-salbutamol FEV1 and FVC 
values.
Trough 

The trough value for FEV1 and FVC at Weeks 4, 12 and 24 is the value of the pre-dose 
assessment.

If the actual time of assessment is after the time of dosing on that day, the value for FEV1 and 
FVC will not be used.

Change from baseline in trough FEV1 and FVC will be calculated. 


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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).

The details for how to score the SGRQ-C are outlined in the SGRQ-C manual (Jones, 2016).  
This includes details on how to handle missing data.

SGRQ-C domain and total score 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, 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 a considered a responder according to SGRQ total score if their on-treatment 
SGRQ total score has decreased at least 4 units from 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.

Missing data will be handled as detailed in Section 10.7.2
COPD Exacerbations

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 
o
Moderate: required treatment with systemic/oral corticosteroids and/or antibiotics (not 
involving hospitalization)
o
Severe: required in-patient hospitalization

The duration of the exacerbation will be calculated as (exacerbation resolution date or date of 
death - exacerbation onset date + 1).

The time to the 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 Week 0 date to the earliest of the event or censoring.  
For 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.
Association to Chest Imaging (X-ray or CT Scan)

A chest X-ray or CT scan is considered associated with a moderate/severe exacerbation if it is 
performed within 0 to +14 days of the exacerbation start date.


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SAC 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, Magnitude of Effort). Each of 
these scales has five possible scores ranging from 0 to 4 (with lower scores indicating more 
impairment), so the range of the BDI focal score is 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 (Week 
0).

The SAC 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, Magnitude of Effort). Each of 
these scales has a possible score ranging from -6 to +6 . SAC TDI focal score is calculated as 
the sum of the three individual scores and then 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 SAC TDI focal score will be 
set to missing.

If the language of the SAC TDI conducted at a visit is different to the language for the BDI, all 
TDI scores at that visit and all subsequent visits will be set to missing
Responder Status according to SAC TDI Focal Score

A subject will be a responder if the on-treatment SAC TDI focal score was at least 1 unit at that 
visit.

A subject will be considered a non-responder if their on-treatment SAC TDI focal score was less 
than 1 unit.

Missing data will be handled as detailed in Section 10.7.2


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10.7.
Appendix 7: Premature Withdrawals & Handling of Missing 
Data
10.7.1.
Premature Withdrawals
Element
Reporting Detail
General

For reporting purposes, subject study completion (i.e. as specified in the 
protocol) was defined as 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 up to visit 5 and 
safety follow-up visit. Withdrawn subjects will not be replaced in the study.

All available data from subjects who were withdrawn from the study will be 
listed and all available planned data will be included in summary tables and 
figures, unless otherwise specified.
Vitals/Lab/ECG

Vitals/Lab/ECG data collected as part of the early withdrawal at a scheduled
visit, or at a standalone EW visit will be used in the summary of absolute 
values and change from baseline as part of the ‘minimum post baseline’,
‘minimum change from baseline’, ‘maximum post-baseline’ and ‘maximum 
change from baseline’ for diastolic and ‘maximum post-baseline’ and 
‘maximum change from baseline’ for pulse rate and systolic blood pressure
10.7.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank 
fields on the collection instrument :
o
These data will be indicated by the use of a “blank” in subject listing 
displays. Unless all data for a specific visit are missing in which case the 
data is excluded from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to 
be missing data and should be displayed as such.
o
No imputation will be made for any missing numerical data, except in the 
sensitivity analysis of the primary endpoint to assess the impact of missing 
data on study results.  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).
Responder

Subjects with a missing baseline will have responder status as missing.

Subjects with missing post-baseline data and a subsequent non-missing 
assessment will not be considered a responder or non-responder but will be left 
as missing.  

Subjects with a baseline but all missing post-baseline data will be considered a 
non-responder at all time points.


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10.7.2.1.
Handling of 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 around imputation of the treatment stop date 
are provided in Section 10.6.1
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.

The recorded partial date will be displayed in listings.
Adverse 
Events, 
Exacerbation,  
Pneumonia

Any partial dates 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 However, if these results in a date prior to Week 0 and the event could 
possibly have occurred during treatment from the partial information, 
then the Week 0 date will be assumed to be the start date. 
O The event 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 The recorded partial date will be displayed in listings.
10.7.2.2.
Handling of Missing Data for Statistical Analysis
A “tipping point” sensitivity analysis of trough FEV1 at Week 24 will be conducted for 
the mPP Population. This will explore the impact of missing data by using differing 
assumptions regarding the mean treatment effect in subjects who discontinue study 
treatment or have data excluded from the mPP Population analyses. Further details are 
given Section 7.1.2.  


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10.8.
Appendix 8: Multicenter Studies
10.8.1.
Methods for Handling Centers
It is likely that many centers will enroll a very small number of subjects and so rather 
than adjusting for center in the statistical analyses, a geographical region will be used in 
analyses where specified.  The center group will be created based on geographical region 
and number of randomized subjects in a country, in order to define groups of roughly 
similar size.  The table below shows (most up to date) the numbers in each reagion and 
the breakdown by stratum. 
Region
Countries
Number of subjects
in each region
Number of subjects
in each strata and 
each region
Europe 1
Russia, Poland 
Romania
398
0:               9
1:           195
>=2:       194
Europe 2
France, Germany, 
Italy, Spain
252
0:             15
1:             75
>=2:       162
Asia
Australia, Japan, 
S. Korea
215
0:               6
1:             49
>=2:       160
America
Argentina, 
Mexico
194
0:               3
1:            139
>=2:          52


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10.9.
Appendix 9: Examination of Covariates, Subgroups & Other 
Strata
10.9.1.
Handling of Covariates, Subgroups & Other Strata

Randomisation is stratified based on long-acting bronchodilator usage during the 
run-in (none, one or two long-acting bronchodilators per day). The stratum (with 
none and one combined into the same category based on derived strata) will be fitted 
as a covariate in all statistical models. 

Other covariates will be included for specific analyses as detailed in model 
specifications in Section 7 and Section 8.
  


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10.10.
Appendix 10: Multiple Comparisons & Multiplicity
10.10.1.
Handling of Multiple Comparisons & Multiplicity
Treatment comparisons will not be adjusted for multiplicity.  No p-values for treatment 
comparisons will be displayed.


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10.11.
Appendix 11: Model Checking and Diagnostics for 
Statistical Analyses
10.11.1.
Statistical Analysis Assumptions
Endpoints

Trough FEV1 

SGRQ total score 

TDI focal score
Analysis
MMRM

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.  
O In the event the model fails to run using the KR method, then the residual method 
will be used instead.

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. 
Endpoints

Proportion of responders according to SGRQ total score, TDI focal score
Analysis

Generalized Linear Model

Computation of confidence intervals for the odds ratios is based on the individual Wald 
tests 

FF/VI+UMEC will be used as the reference level for treatment

Pearson residuals will be plotted by using PLOTS=PEARSONPANEL option for the model 
statement in SAS.
Endpoints

Time to first on-treatment moderate/severe COPD exacerbation

Analysis

Cox’s proportional hazard method

The proportional hazards assumption for this method of analysis will be examined by 
obtaining the Kaplan-Meier estimates of the survival function S(t) over time separately for 
treatment group.  Under the assumption of proportional hazard between the treatment 
groups,  ln{−ln[S(t)]} for the two groups should be parallel to each other and the distance 
between them constant. If the curves are approximately parallel, then the proportional 
hazard assumption is not violated. If these curves cross each other or diverge greatly from 
the assumption of parallel lines, then the assumption is not met.


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10.12.
Appendix 12: Abbreviations
ADaM
Analysis Data Model
AE
Adverse Event
AESI
Adverse Event of Special Interest
ASE
All Subjects Enrolled
ATC
Anatomical Therapeutic Chemical Classification
BDI
Baseline Dyspnoea Index
BMI
Body Mass Index
BP
Blood Pressure
Bpm
Beats Per Minute
CAT
COPD Assessment Test
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Intervals
COPD
Chronic Obstructive Pulmonary Disease
CRT
Case Report Tabulation
CSR
Clinical Study Report
CRF
Case Report Form
CV
Cardiovascular
DBF
Database Freeze
DM
Data Management
DPI
Dry Powder Inhaler
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
FEV1
Forced Expiratory Volume in One Second
FF
Fluticasone Furoate 
FVC
Forced Vital Capacity
GCSP
Global Clinical Safety and Pharmacovigilance
GSK
GlaxoSmithKline
GSK573719
Umeclidinium (UMEC)
GW642444
Vilanterol Trifenatate (VI)
GW685698
Fluticasone Furoate (FF)
HRQoL
Health Related Quality of Life
IB
Investigator Brochure
ICS
Inhaled Corticosteroid
IDMC
Independent Data Monitoring Committee
ITT
Intent-to-Treat
LABA
Long Acting Beta-Agonist
LAMA
Long-acting Muscarinic Receptor Antagonists
MACE
Major Adverse Cardiac Event
mcg
Microgram
mL
Milliliter
MMRM
Mixed Models Repeated Measures
mPP
Modified Per-Protocol
PD
Protocol Deviation
PDMP
Protocol Deviation Management Plan


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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
RAMOS
Randomization & Medication Ordering System 
RANDALL-NG
GSK Randomization System – Next Generation
RAP
Reporting and Analysis Plan
RMC
Respiratory Medication Class
SABAs
Short-acting 2-adrenergic receptor agonists
SAE
Serious Adverse Event
SD
Standard Deviation
SDL
Source Data Lock
SDTM
Study Data Tabulation Model
SE
Standard Error
SGRQ
St Georges Respiratory Questionnaire
SGRQ-C
SGRQ for COPD patients
SI
System Independent
SMQ
Standardized MedDRA Query
SOC
System Organ Class
TDI
Transitional Dyspnoea Index 
TFL
Tables, Figures & Listings 
TSCG
Tibco Spotfire Clinical Graphics software
UMEC
Umeclidinium
VI
Vilanterol Trifenatate
10.12.1.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
ELLIPTA
SAS
CAT and COPD Assessment Test


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10.13.
Appendix 13: List of Data Displays
10.13.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.41
1.1 
Efficacy
2.1 to 2.24
2.1 to 2.10
Safety
3.1 to 3.47
3.1 to 3.14
Section
Listings
ICH Listings
1 to 17
Other Listings
17 to 50
10.13.2.
Programming Note
Unless otherwise stated all listings will be produced by country, treatment, center, and 
subject.   Present Country as a subheading/by variable in listing.  In addition, where 
applicable, listings will include a flag to indicate if the record is on-treatment or post-
treatment and a flag to indicate if the subject is in the mPP population. 


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10.13.3.
Study Population Tables
Study Population Tables
No.
Populatio
n
Title
Deliverable 
Subject Disposition
1.1.
ASE
Summary of Subject Populations and Reason for Screen/Run-in 
Failure 
SAC
1.2.
ITT
Summary of Attendance at Each Visit
SAC
1.3.
ITT
Summary of Completion and Premature Discontinuation of Study 
Treatment
SAC
1.4.
ITT
Summary of Study Completion and Withdrawal 
SAC
1.5.
ASE
Summary of Number of Subjects Enrolled By Country
SAC
1.6.
ASE
Summary of Age ranges
SAC
1.7.
ITT
Summary of Number of Subjects By Geographical Region, Country 
and Center
SAC
1.8.
MPP 
Summary of Number of Subjects By Geographical Region, Country 
and Center
SAC
1.9.
ASE
Summary of Inclusion/Exclusion Criteria Deviations For Screen 
Failures
SAC
1.10.
ITT
Summary of Inclusion/Exclusion Criteria Deviations 
SAC
1.11.
ITT
Summary of Important Protocol Deviations
SAC
1.12.
ITT
Summary of Exclusions from Modified Per Protocol Population
SAC
Demography
1.13.
ITT
Summary of Demographic Characteristics
SAC
1.14.
MPP
Summary of Demographic Characteristics
SAC
1.15.
ITT
Summary of Demographic Characteristics by Country
SAC
1.16.
ITT
Summary of Race and Racial Combinations
SAC
1.17.
MPP
Summary of Race and Racial Combinations
SAC
Medical Conditions
1.18.
ITT
Summary of Current Medical Conditions
SAC
1.19.
ITT
Summary of Past Medical Conditions
SAC
1.20.
ITT
Summary of Cardiovascular Risk Factors
SAC
1.21.
ITT
Summary of Family History of Cardiovascular Risk Factors
SAC
1.22.
ITT
Summary of Smoking History at Screening
SAC
Disease Characteristics
1.23.
ITT
Summary of COPD Exacerbation History at Screening
SAC
1.24.
ITT
Summary of Screening Lung Function
SAC
1.25.
MPP
Summary of Screening Lung Function
SAC
1.26.
ITT
Summary of Screening Lung Function by Country
SAC
1.27.
ITT
Summary of Reversibility and GOLD Grade (1-4) at Screening
SAC
1.28.
MPP
Summary of Reversibility and GOLD Grade (1-4) at Screening
SAC
1.29.
ITT
Summary of CAT Score and CAT Category at Screening
SAC
Concomitant Medications
1.30.
ITT
Summary of Long-acting Bronchodilator Usage during the Run-in 
(Randomization Strata)
SAC
1.31.
MPP
Summary of Long-acting Bronchodilator Usage during the Run-in 
(Randomization Strata)
SAC
1.32.
ITT
Summary of COPD Concomitant Medication Combinations Taken at 
Screening
SAC


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Study Population Tables
No.
Populatio
n
Title
Deliverable 
1.33.
ITT
Summary of COPD Concomitant Medications Taken in the Run-in, 
Medications Given for Reasons other than an Exacerbation
SAC
1.34.
ITT
Summary of On-Treatment COPD Concomitant Medications, 
Medications Given for Reasons other than an Exacerbation
SAC
1.35.
ITT
Summary of Post-Treatment COPD Concomitant Medications, 
Medications Given for Reasons other than an Exacerbation
SAC
1.36.
ITT
Summary of Concomitant Medications Taken in the Run-in Given for 
An Exacerbation
SAC
1.37.
ITT
Summary of On-Treatment Concomitant Medications Given for an 
Exacerbation
SAC
1.38.
ITT
Summary of Post-Treatment Concomitant Medications Given For an 
Exacerbation
SAC
1.39.
ITT
Summary of On-Treatment Non-COPD Concomitant Medications
SAC
1.40.
ITT
Summary of Post-Treatment Non-COPD Concomitant Medications 
SAC
Treatment Compliance
1.41.
ITT
Summary of Treatment Compliance (%)
SAC
10.13.4.
Study Population Figures
Study Population figures
No.
Populatio
n
Title
Deliverable 
1.1.
ITT
Kaplan-Meier Plot of Time to Study Withdrawal
SAC
10.13.5.
Efficacy Tables
Efficacy: Tables
No.
Populatio
n
Title
Deliverable 
Spirometry
2.1
ITT
Summary of Baseline FEV1 (L)
SAC
2.2
MPP
Summary of Baseline FEV1 (L)
SAC
2.3.
ITT
Summary of Baseline FEV1 (L) by Country
SAC
2.4.
ITT
Summary of Trough FEV1 (L) 
SAC
2.5.
MPP
Summary of Trough FEV1 (L) 
SAC
2.6.
ITT
Summary of Trough FEV1 (L) by Country
SAC
2.7.
ITT
Analysis of Trough FEV1 (L) 
SAC 
2.8.
MPP
Analysis of Trough FEV1 (L) 
SAC 
2.9.
ITT
Significance Levels for Interactions of Treatment with Number of 
Long-acting Bronchodilators per Day During the Run-in,
Geographical Region, and Baseline for Analysis of Trough FEV1 (L) 
SAC
2.10.
mPP
Significance Levels for Interactions of Treatment with Number of 
Long-acting Bronchodilators per Day During the Run-in,
Geographical Region, and Baseline for Analysis of Trough FEV1 (L) 
SAC


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Efficacy: Tables
No.
Populatio
n
Title
Deliverable 
2.11.
MPP
Trough FEV1 (L)  Tipping Point Sensitivity Analysis: 95%CIs  after 
Imputing Varying Week 24 Mean Change from Baseline Trough 
FEV1 (L)
SAC
2.12.
ITT
Summary of Baseline FVC (L)
SAC
2.13.
ITT
Summary of Trough FVC (L) 
SAC
SGRQ
2.14.
ITT
Summary of Baseline SGRQ Scores
SAC
2.15.
ITT
Summary of SGRQ  Scores 
SAC
2.16.
ITT
Analysis of SGRQ Total Score 
SAC 
2.17.
ITT
Summary and Analysis of Proportion of Responders According to 
SGRQ Total Score 
SAC
COPD Exacerbations
2.18.
ITT
Summary of On-Treatment COPD Exacerbations  
SAC
2.19.
ITT
Summary of Post-Treatment COPD Exacerbations
SAC
2.20.
ITT
Summary and Analysis of Time to First On-treatment Moderate or 
Severe Exacerbation (days)  
SAC
SACBDI/TDI
2.21.
ITT
Summary of SAC BDI Focal Score
SAC
2.22.
ITT
Summary of SAC TDI Focal Score  
SAC
2.23.
ITT
Analysis of SAC TDI Focal Score   
SAC
2.24.
ITT
Summary and Analysis of Proportion of Responders According to 
SAC TDI Focal Score  
SAC
10.13.6.
Efficacy Figures
Efficacy: Figures
No.
Populatio
n
Title
Deliverable 
Spirometry
2.1
ITT
Box Plot of Change from Baseline in Trough FEV1 (L) at Week 24
SAC
2.2
MPP
Box Plot of Change from Baseline in Trough FEV1 (L) at Week 24 
SAC
2.3
ITT
Empirical Distribution Function Plot of Change from Baseline in 
Trough FEV1 (L) at Week 24
SAC
2.4
MPP
Empirical Distribution Function Plot of Change from Baseline in 
Trough FEV1 (L) at Week 24
SAC
2.5
ITT
Least Squares Mean (95% CI) Change from Baseline in Trough 
FEV1 (L)  
SAC
2.6
MPP
Least Squares Mean (95% CI) Change from Baseline in Trough 
FEV1 (L)  
SAC
SGRQ
2.7
ITT
Least Squares Mean (95% CI) Change from Baseline in SGRQ Total 
Score  
SAC
2.8
ITT
Empirical Distribution Function Plot of Change from Baseline in 
SGRQ Total Score at Week 24
SAC
COPD Exacerbations
2.9
ITT
Kaplan-Meier Plot of Time to First Moderate/Severe COPD 
Exacerbation (Days)   
SAC


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Efficacy: Figures
No.
Populatio
n
Title
Deliverable 
BDI/TDI
2.10
ITT
Least Squares Means (95% CI) TDI Focal Score 
SAC
10.13.7.
Safety Tables
Safety Tables
No.
Population
Title
Deliverable 
Exposure
3.1
ITT
Summary of Exposure 
SAC
Adverse Events
3.2
ITT
Overview of On-Treatment Adverse Events 
SAC
3.3
ITT
Summary  of On-Treatment Adverse Events
SAC
3.4
ITT
Summary  of On-Treatment Adverse Events by Country
SAC
3.5
ITT
Summary  of Post -Treatment Adverse Events 
SAC 
3.6
ITT
Summary of On-treatment Drug-Related Adverse Events   
SAC
3.7
ITT
Summary of Serious Adverse Events (Serious, Drug-Related 
Serious, Fatal and Drug-Related Serious) by System Organ Class 
and Preferred Term (Number of Subjects and Occurrences)
SAC
3.8
ITT
Summary of On-treatment Serious Adverse Events 
SAC
3.9
ITT
Summary of On-treatment Fatal Serious Adverse Events 
SAC
3.10
ASE
Summary of Pre-treatment Serious Adverse Events 
SAC
3.11
ITT
Summary of Pre-treatment Serious Adverse Events 
SAC
3.12
ASE
Summary of Pre-treatment Serious Adverse Events Leading to 
Withdrawal from Study  
SAC
3.13
ITT
Summary of On-treatment  Drug-Related  Serious Adverse Events   
SAC
3.14
ITT
Summary of On-treatment Drug-Related Fatal Serious Adverse 
Events 
SAC
3.15
ITT
Summary of On-treatment Adverse Events Leading to Permanent 
Discontinuation of Study Drug or Withdrawal from Study 
SAC
3.16
ITT
Summary of On-treatment Adverse Events of Special Interest 
SAC
3.17
ITT
Summary of On-treatment Serious Adverse Events of Special 
Interest 
SAC
3.18
ASE
Relationship of Adverse Event System Organ Class, Preferred Term 
and Verbatim Text
SAC
3.19
ITT
Summary of On-Treatment Common (>=3% in Either Treatment 
Group) Non-serious Adverse Events by System Organ Class 
and Preferred Term (Number of Subjects and Occurrences)
SAC
3.20
ITT
Summary of the 10 Most Frequent On-treatment Adverse events in 
each Treatment Group 
SAC


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Safety Tables
No.
Population
Title
Deliverable 
3.21
ITT
Summary of On-Treatment Adverse Events by System Organ 
Class and Maximum Intensity
SAC
Pneumonia
3.22
ITT
Summary of On-treatment Pneumonias  Incidence
SAC
3.23
ITT
Summary of On-treatment Details of Pneumonia
SAC
3.24
ITT
Summary of Post-treatment Pneumonias
SAC
3.25
ITT
Summary of Post-treatment Details of Pneumonia
SAC
Bone Fractures
3.26
ITT
Summary of On-treatment Bone Fractures
SAC
3.27
ITT
Summary of Post-treatment Bone Fractures
SAC
Radiography (Chest Imaging : X-Rays or CT Scan)
3.28
ITT
Summary of  On-treatment Chest Imaging (X-Ray or CT Scan 
SAC
3.29
ITT
Summary of Post-treatment Chest Imaging (X-Ray or CT Scan)
SAC
Laboratory Parameters
3.30
ITT
Summary of Chemistry Data 
SAC
3.31
ITT
Summary of Change from Baseline in Chemistry Data 
SAC
3.32
ITT
Summary of Chemistry Data Outside the Normal Range 
SAC
3.33
ITT
Summary of Chemistry Changes from Baseline Relative to the 
Normal Range 
SAC
3.34
ITT
Summary of Hematology Data 
SAC
3.35
ITT
Summary of Change from Baseline in Hematology Data 
SAC
3.36
ITT
Summary of Hematology Data Outside the Normal Range 
SAC
3.37
ITT
Summary of Hematology Changes from Baseline Relative to the 
Normal Range 
SAC
Vitals Signs
3.38
ITT
Summary of Vital Signs 
SAC
3.39
ITT
Summary of Change from Baseline Vital Signs 
SAC
ECGs
3.40
ITT
Summary of ECG Values 
SAC
3.41
ITT
Summary of Change from Baseline in ECG Values 
SAC
3.42
ITT
Summary of QTc(F) (msec) Categories 
SAC
3.43
ITT
Summary of Change From Baseline in QTc(F) (msec) Categories 
SAC
3.44
ITT
Summary of ECG Findings 
SAC
3.45
ITT
Summary of ECG Findings Shifts from Baseline 
SAC
3.46
ITT
Summary of ECG Abnormalities  
SAC


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Safety Tables
No.
Population
Title
Deliverable 
3.47
ITT
Summary of ECG Abnormalities Occurring in at Least 3% of Subjects 
in Either Treatment Group 
SAC
10.13.8.
Safety Figures
Safety : Figures
No.
Popula
tion
Title
Deliverable 
Exposure
3.1
ITT
Plot of Exposure to Study Drug
SAC
Laboratory Parameters
3.4
ITT
Trellis Display of Maximum Post-baseline Liver Function Test Values, 
Versus Baseline Liver Function Test Values 
SAC
3.5
ITT
Scatter Plots of Maximum Post-baseline Versus Baseline For Chemistry 
Data 
SAC
3.6
ITT
Box Plots of Change from Baseline to Maximum Post-baseline Values for 
Chemistry Data 
SAC
3.7
ITT
Scatter Plots of Minimum Post-baseline Versus Baseline For Chemistry 
Data 
SAC
3.8
ITT
Box Plots of Change from Baseline to Minimum Post-baseline Values for 
Chemistry Data 
SAC
3.9
ITT
Scatter Plots of Maximum Post-baseline Versus Baseline For Hematology 
Data 
SAC
3.10
ITT
Box Plots of Change from Baseline to Maximum Post-baseline Values for 
Hematology Data 
SAC
3.11
ITT
Scatter Plots of Minimum Post-baseline Versus Baseline For Hematology 
Data 
SAC
3.12
ITT
Box Plots of Change from Baseline to Minimum Post-baseline Values for 
Hematology Data 
SAC
12-Lead ECGs
3.13
ITT
Empirical Distribution Function Plot of Maximum Post-baseline QTcF 
(msec) 
SAC
3.14
ITT
Empirical Distribution Function Plot of Change from Baseline in Maximum 
Post-baseline QTcF (msec)
SAC


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10.13.9.
ICH Listings
ICH : Listings
No.
Popul
ation
Title
Deliverable 
Study population
1.
ITT
Listing of Randomized and Actual Treatments
SAC
2.
ITT
Listing of Study Treatment Discontinuation Record
SAC
3.
ITT
Listing of Reasons for Study Withdrawal
SAC
4.
ASE
Listing of Subjects with Inclusion and Exclusion Criteria Deviations for 
Screen Failures
SAC
5.
ITT
Listing of Subjects with Inclusion and Exclusion Criteria Deviations
SAC
6.
ITT
Listing of Subjects for Whom the Treatment Blind was Broken during the 
Study
SAC
7.
ITT
Listing of Demographic Characteristics
SAC
8.
ITT
Listing of Race
SAC
Spirometry
9.
ITT
Listing of Raw FEV1 (L)  and FVC (L) Data
SAC
Exposure
10.
ITT
Listing of Exposure 
SAC
Adverse Events
11.
ASE
Listing of Subject Numbers for Individual Adverse Events
SAC
12.
ASE
Listing of All Adverse Events
SAC
13.
ASE
Listing of Non-Fatal Serious Adverse Events
SAC
14.
ASE
Listing of Fatal Adverse Events
SAC
15.
ITT
Listing of Adverse Events leading to Withdrawal from the Study
SAC


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ICH : Listings
No.
Popul
ation
Title
Deliverable 
Laboratory Parameters
16.
ITT
Listing of Chemistry Values for Subjects with at Least One Value outside the 
Normal Range
SAC
17.
ITT
Listing of Hematology Values for Subjects with at Least One Value outside 
the Normal Range
SAC
10.13.10. Non-ICH Listings
Non-ICH : Listings
No.
Popula
tion
Title
Deliverable 
Study Population
18.
ASE
Listing of Reason for Screen/Run-in  Failure
SAC
19.
ITT
Listing of Important Protocol Deviations
SAC
20.
ITT
Listing of Exclusion from Modified Per Protocol Population
SAC
21.
ASE
Listing of Study Treatment Misallocations
SAC
22.
ITT
Listing of Screening Lung Function, Reversibility Status, GOLD Grade and
CAT Score
SAC
23.
ITT
Listing of Medical Conditions
SAC
24.
ITT
Listing of Family History of Cardiovascular Risk Factors
SAC
25.
ITT
Listing of COPD Exacerbation History
SAC
26.
ITT
Listing of Smoking History and Smoking Status
SAC
27.
ITT
Listing of Percent Oxygen in Blood 
SAC
28.
ITT
Listing of COPD Concomitant Medications
SAC
29.
ITT
Listing of Non-COPD Concomitant Medications
SAC
30.
ITT
Listing of Randomisation Strata (Derived and from eCRF)
SAC
31.
ITT
Relationship between ATC Level 1, Ingredient and Verbatim Text for Non-
COPD Medications
SAC
32.
ITT
Listing of Treatment Compliance Data
SAC


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Non-ICH : Listings
No.
Popula
tion
Title
Deliverable 
Adverse Events
33.
ITT
Listing of Subject Numbers for On-Treatment Adverse Events of Special 
Interest
SAC
34.
ITT
Listing of Reasons for Considering as a Serious Adverse Event
SAC
COPD Exacerbations
35.
ITT
Listing of COPD Exacerbations
SAC
SGRQ
36.
ITT
Listing of SGRQ Scores
SAC
BDI/TDI
37.
ITT
Listing of BDI/TDI Focal Scores
SAC
CAT
38.
ITT
Listing of CAT Scores
SAC
Pneumonia Incidence
39.
ITT
Listing of Pneumonia Data
SAC
Bone Fractures
40.
ITT
Listing of Bone Fracture Data
SAC
Chest Imaging (X-Rays or CT Scan)
41.
ITT
Listing of Chest Imaging (X-Ray or CT Scan) Data
SAC
Liver Events
42.
ITT
Listing of Liver Event Results and Time of Event Relative to Treatment
SAC
43.
ITT
Listing of Medical Conditions for Subjects with Liver Stopping Events
SAC
44.
ITT
Listing of Substance Use for Subjects with Liver Stopping Events
SAC
45.
ITT
Listing of Liver Event Information for RUCAM Score
SAC
46.
ITT
Listing of Liver Biopsy Details
SAC
47.
ITT
Listing of Liver Imaging Details
SAC


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Non-ICH : Listings
No.
Popula
tion
Title
Deliverable 
12-Lead ECGs
48.
ITT
Listing of ECG Values for Subjects with Any Abnormal ECG Finding
SAC
49.
ITT
Listing of ECG Abnormalities 
SAC
Inhaler malfunctions
50.
ITT
Listing of Inhaler Malfunctions
SAC