A 24-week Treatment, Multi-center, Randomized, Double-blind, Double-dummy, Parallel Group Study to Compare Umeclidinium/Vilanterol, Umeclidinium, and Salmeterol in Subjects With Chronic Obstructive Pulmonary Disease (COPD)
Phase: PHASE4
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: GlaxoSmithKline

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The GlaxoSmithKline group of companies
201749
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TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A 24-week treatment, multi-center, randomized, double-blind, 
double-dummy, parallel group study to compare 
Umeclidinium/Vilanterol, Umeclidinium, and Salmeterol in 
subjects with chronic obstructive pulmonary disease (COPD)
Compound Number:
GSK2592356
Development Phase:
IV
Effective Date:
18-APR-2017
Protocol Amendment Number:  03
Author (s):
 
 
 
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited
 
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Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2016N277425_00
2016-SEP-13
Original
2016N277425_01
2017-FEB-07
Amendment No. 1
This protocol amendment was created to make the following changes:
Regulatory Agency Identifying Number(s):  A typographical error in the EudraCT no. 
corrected. IND no. added
Section 4.1and Section 4.4: Typographical errors and inconsistencies corrected
Inconsistencies between Section 4.4, Section 7.3.1.5 and Section 7.1revised
Section 7.1 Time and Events table:
Un-intentional deletion of the (“x”) were added to confirm that concomitant medications 
should be reviewed at every clinic visit was corrected.
Increased the visit window 
Typographical error and inconsistencies corrected as described in Appendix 9, Section 
12.9.
Section 7.2.2 Critical procedures performed at Screening (Visit 1): To clarify that height 
and weight are collected at V1 “Height and weight” added
Section 7.3.2 Spirometry: “At Screening, before the morning dose of usual COPD 
medication(s)” added.
Section 7.3.7:  Physical activity monitor (study subset)
Inconsistency between Section 1, Section 4.1 and Section 7.3.7 revised
2016N277425_02
2017-FEB-21
Amendment No. 2 Canada 
ONLY
This protocol amendment was created to comply with Health Canada guidelines.  They
require pharmaceutical manufacturers to expeditiously report domestic cases of unusual 
failure in efficacy (UFIE) for new drugs to the Marketed Health Products Directorate 
(MHPD) within 15 days of first notification.
Changes were made to Section 7.4.1 and Appendix 4.
2016N277425_03
2017-APR-18
Amendment No. 3
This protocol amendment was created to make the following changes:

Clarifications concerning study design, stratification, permitted and prohibited COPD 
medications, stopping criteria, visit windows, chest x-rays performed in the context of 
the protocol and site professional expertise

Rate of COPD exacerbations from tertiary endpoints to exploratory endpoints

Addition of an inclusion criterion specific to France

Integration of Canadian Amendment 2

Correction of typographical errors and inconsistencies
 
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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
Fax 
Number
Site Address
Primary 
Medical 
Monitor 
Cell: 
Cell: 
Fax: 
GlaxoSmithKline
Stockley Park 
West, 1-3 
Ironbridge Road, 
Heathrow, 
Uxbridge, 
Middlesex, UB11 
1BT, United 
Kingdom
Secondary 
Medical 
Monitor
MD
Telphone:
Cell:  
Fax:  
GlaxoSmithKline
Stockley Park 
West, 1-3 
Ironbridge Road, 
Heathrow, 
Uxbridge, 
Middlesex, UB11 
1BT, United 
Kingdom
SAE 
contact  
information 
Telephone: 
Cell: 
GlaxoSmithKline
RTP, 5 Moore Dr, 
Research 
Triangle Park, NC 
27709, United 
States
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(s):  IND no. 106616 and 104479, and EudraCT 
no. 2016-002513-22
 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol 201749
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date
 
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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 201749......................................................10
2.
INTRODUCTION....................................................................................................16
2.1.
Study Rationale ..........................................................................................16
2.2.
Brief Background ........................................................................................16
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................17
4.
STUDY DESIGN ....................................................................................................19
4.1.
Overall Design ............................................................................................19
4.2.
Treatment Arms and Duration.....................................................................21
4.3.
Type and Number of Subjects.....................................................................22
4.4.
Design Justification.....................................................................................22
4.5.
Dose Justification........................................................................................22
4.6.
Benefit: Risk Assessment ...........................................................................22
4.6.1.
Risk Assessment .........................................................................23
4.6.2.
Benefit Assessment.....................................................................26
4.6.3.
Overall Benefit: Risk Conclusion..................................................26
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............26
5.1.
Inclusion Criteria.........................................................................................26
5.2.
Exclusion Criteria........................................................................................28
5.3.
Randomization Criteria ...............................................................................31
5.4.
Screening/Baseline/Run-in Failures............................................................32
5.5.
Withdrawal/Stopping Criteria.......................................................................32
5.5.1.
Withdrawal from the Study...........................................................32
5.5.2.
Reason for Study Withdrawal.......................................................33
5.5.3.
Liver Chemistry Stopping Criteria ................................................34
5.5.3.1.
Study Treatment Restart or Rechallenge....................35
5.6.
Follow-up contact........................................................................................35
5.7.
Subject and Study Completion....................................................................35
6.
STUDY TREATMENT ............................................................................................35
6.1.
Investigational Product and Other Study Treatment....................................35
6.2.
Medical Devices..........................................................................................37
6.3.
Treatment Assignment................................................................................38
6.4.
Planned Dose Adjustments.........................................................................38
6.5.
Blinding.......................................................................................................39
6.6.
Packaging and Labeling..............................................................................39
6.7.
Preparation/Handling/Storage/Accountability..............................................39
6.7.1.
Study Treatment Return...............................................................40
6.8.
Compliance with Study Treatment Administration.......................................40
6.9.
Treatment of Study Treatment Overdose....................................................41
6.10.
Treatment after the End of the Study ..........................................................41
6.11.
Concomitant Medications and Non-Drug Therapies....................................41
6.11.1.
Permitted Medications and Non-Drug Therapies..........................42
6.11.2.
Prohibited Medications and Non-Drug Therapies.........................43
 
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7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................43
7.1.
Time and Events Table...............................................................................44
7.2.
Screening and Critical Baseline Assessments ............................................47
7.2.1.
Pre-screening Visit.......................................................................47
7.2.2.
Critical procedures performed at Screening (Visit 1)....................47
7.2.2.1.
Albuterol/Salbutamol Reversibility Assessment ..........48
7.2.3.
Critical procedures performed at first treatment Visit 
(Baseline V2)...............................................................................48
7.3.
Efficacy Assessments.................................................................................49
7.3.1.
HRQoL assessments: Completion of PRO questionnaires 
in the Electronic Diary..................................................................49
7.3.1.1.
Self Administered Computerised Baseline 
Dyspnea Index/Transitional Dyspnea Index 
(SAC BDI/TDI)............................................................49
7.3.1.2.
SGRQ-C.....................................................................50
7.3.1.3.
COPD Assessment Test (CAT) ..................................50
7.3.1.4.
EXACT and the Evaluating Respiratory 
Symptoms- COPD (E-RS: COPD)..............................51
7.3.1.5.
Subject Global Rating of COPD Severity and 
Global Rating of Change in COPD .............................51
7.3.2.
Spirometry ...................................................................................51
7.3.3.
Inspiratory capacity (IC)...............................................................52
7.3.4.
COPD Exacerbation ....................................................................53
7.3.5.
Clinically important deterioration (CID).........................................53
7.3.6.
Rescue albuterol/salbutamol use.................................................54
7.3.7.
Physical activity monitor (study subset) .......................................54
7.4.
Safety .........................................................................................................54
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........54
7.4.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................55
7.4.1.2.
Method of Detecting AEs and SAEs ...........................55
7.4.1.3.
Follow-up of AEs and SAEs........................................55
7.4.1.4.
Pneumonia Events .....................................................56
7.4.1.5.
Cardiovascular and Death Events ..............................56
7.4.1.6.
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ................56
7.4.1.7.
Regulatory Reporting Requirements for SAEs............56
7.4.1.8.
Additional Adverse Event (AE) Reporting 
Requirements for Canadian investigators...................57
7.4.2.
Pregnancy ...................................................................................57
7.4.3.
Medical Device Incidents (Including Malfunctions).......................57
7.4.4.
Electrocardiogram (ECG).............................................................57
7.5.
Genetics .....................................................................................................58
8.
DATA MANAGEMENT ...........................................................................................58
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................58
9.1.
Hypotheses.................................................................................................58
9.2.
Sample Size Considerations.......................................................................59
9.2.1.
Sample Size Sensitivity................................................................59
9.2.2.
Sample Size Re-estimation or Adjustment...................................60
9.3.
Data Analysis Considerations .....................................................................60
 
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9.3.1.
Analysis Populations....................................................................60
9.3.2.
Interim Analysis ...........................................................................60
9.4.
Key Elements of Analysis Plan ...................................................................60
9.4.1.
Primary Analyses.........................................................................61
9.4.2.
Other Analyses ............................................................................62
10. STUDY GOVERNANCE CONSIDERATIONS........................................................62
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............62
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................62
10.3.
Quality Control (Study Monitoring) ..............................................................63
10.4.
Quality Assurance.......................................................................................64
10.5.
Study and Site Closure ...............................................................................64
10.6.
Records Retention......................................................................................64
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................65
11. REFERENCES.......................................................................................................66
12. APPENDICES........................................................................................................69
12.1.
Appendix 1: Abbreviations and Trademarks................................................69
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................71
12.3.
Appendix 3: Genetic Research ...................................................................73
12.4.
Appendix 4: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................76
12.4.1.
Definition of Adverse Events........................................................76
12.4.2.
Definition of Serious Adverse Events...........................................77
12.4.3.
Definition of Cardiovascular Events .............................................79
12.4.4.
Recording of AEs and SAEs ........................................................79
12.4.5.
Evaluating AEs and SAEs............................................................80
12.4.6.
Reporting of SAEs to GSK...........................................................81
12.5.
Appendix 5: COPD Exacerbation Identification, Categorization and 
Treatment Guidelines..................................................................................83
12.5.1.
Guidelines for Identifying COPD Exacerbations...........................83
12.5.2.
COPD Exacerbation Severity.......................................................84
12.5.3.
Treatment of COPD Exacerbations..............................................84
12.5.4.
Guidelines for Treatment with Corticosteroids..............................84
12.5.5.
Guidelines for Treatment with Antibiotics .....................................85
12.5.6.
Onset and Resolution of COPD Exacerbations............................85
12.5.7.
Guideline for assessing multiple mild exacerbations ....................85
12.5.8.
Guideline for assessing exacerbations that increase in 
severity ........................................................................................85
12.6.
Appendix 6: Definition of and Procedures for Documenting Medical 
Device Incidents .........................................................................................86
12.6.1.
Definitions of a Medical Device Incident.......................................86
12.6.2.
Documenting Medical Device Incidents .......................................87
12.7.
Appendix 7: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in FRP and Collection of Pregnancy Information.......................88
12.7.1.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) ..............88
12.7.2.
Collection of Pregnancy Information ............................................88
 
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12.8.
Appendix 8: Country Specific Requirements...............................................90
12.9.
Appendix 9: Protocol changes ....................................................................91
12.9.1.
Protocol Amendment 1 ................................................................91
12.9.2.
Country-specific Protocol Amendment 2 for Canada....................97
12.9.3.
Protocol Amendment 3 ................................................................99
 
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1.
PROTOCOL SYNOPSIS FOR STUDY 201749
Rationale
The primary purpose of this study is to demonstrate improvements in lung function in 
subjects treated with Umeclidinium/Vilanterol (UMEC/VI) compared with Umeclidinium 
(UMEC) for 24 weeks.  A further important aspect of the study is to evaluate the effect of
UMEC/VI, UMEC, and salmeterol with respect to health-related quality of life (HRQoL), 
measured through patient reported outcomes (PROs) questionnaires, and lung function.  
Additional assessments to further evaluate other measures of chronic obstructive 
pulmonary disease (COPD) efficacy and symptoms control will be performed.
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary

To compare the effect of UMEC/VI 
(62.5/25 mcg once daily) with UMEC 
(62.5 mcg once daily) on lung function

Change from baseline in trough Forced 
Expiratory Volume in One Second 
(FEV1) at week 24 
Secondary

To compare UMEC/VI (62.5/25 mcg 
once daily), UMEC (62.5 mcg once 
daily) with salmeterol (50 mcg twice 
daily) on patient reported outcomes 
(PROs) 

Change from baseline in self 
administered computerised (SAC) 
transient dyspnea index (TDI) 

Percentage of TDI responders 
according to SAC TDI score.  A 
responder is defined as a ≥1 unit 
improvement in SAC TDI score 

Assessment of respiratory daily 
symptoms over 24 weeks using 
Evaluating Respiratory Symptoms-
COPD (E-RS) and its subscales 
(breathlessness, cough and sputum and 
chest symptoms) 

Percentage of E-RS responders
according to E-RS score (defined as 
reduction in E-RS score of 2 or 3.35 
units) from baseline

Change from baseline in St George’s 
Respiratory Questionnaire (SGRQ-C)

Percentage of responders according to 
SGRQ-C total score (defined as a 4 
point or greater reduction from 
 
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Objectives
Endpoints
baseline) 

Change from baseline in COPD 
assessment test (CAT)

Percentage of responders according to 
CAT (defined as a 2 unit improvement 
in score from baseline)
Other

To compare UMEC/VI (62.5/25 mcg 
once daily), UMEC (62.5 mcg once 
daily) with salmeterol (50 mcg twice 
daily) on other COPD efficacy measures 

Time to first mild, moderate or severe 
exacerbation

Time to moderate or severe 
exacerbation

Time to severe exacerbations

Time to clinically important 
deterioration (CID) composite endpoint 

Time to clinically important 
deterioration composite endpoint 
excluding FEV1

Rescue albuterol/salbutamol use, 
(percentage of rescue-free days and 
mean number of Inhalations/day) 
captured by the electronic diary 
(eDiary) over 24 weeks

Inspiratory capacity (IC)

Full Vital capacity (FVC) 

Change from baseline in trough FEV1

Change from baseline in global 
impression of disease severity 
 
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Objectives
Endpoints
Safety

To evaluate safety and tolerability of 
UMEC/VI (62.5/25 mcg once daily), 
UMEC (62.5 mcg once daily) and 
salmeterol 50 mcg twice daily)

Incidence of adverse events
Exploratory

To explore the effect of UMEC/VI 
(62.5/25 mcg once daily), UMEC 
(62.5 mcg once daily) with salmeterol 
(50 mcg twice daily) on rate of COPD 
exacerbation

Rate of mild, moderate or severe
exacerbations

Rate of moderate or severe 
exacerbation

To compare albuterol/salbutamol use 
captured in the eDiary with the 
electronic metered dose inhaler (eMDI) 
device 

Rescue albuterol/salbutamol use, 
(percentage of rescue-free days and 
mean number of Inhalations/day) 
captured by the eMDI device over 24 
weeks as data allow

To explore the effect of UMEC/VI 
(62.5/25 mcg once daily), UMEC (62.5 
mcg once daily) with salmeterol (50 
mcg twice daily) on physical activity

Change from baseline in physical 
activity 

To investigate the CID composite 
endpoint ability to predict short term 
outcomes 

To compare physical activity levels, 
ER-S, rescue medication use, 
exacerbations and mortality in subjects 
with and without a CID
Overall Design
This is a multi-centre, randomized, double blind, double dummy, 3-arm parallel group 
study.  Eligible subjects will be randomized in a ratio of 1:1:1 to UMEC/VI inhalation 
powder (62.5/25 mcg once daily) administered via the ELLIPTA™dry powder inhaler 
(DPI) or UMEC (62.5 mcg once daily) administered via the ELLIPTA DPI or salmeterol 
(50 mcg twice daily (BID)) administered via the DISKUS™DPI.
There will be a total of 5 clinic visits and one follow-up phone call (Visit 6). A pre-
screening visit (Visit 0) may be required in order to administer the informed consent 
before any changes are made to the subject’s current medication regimen. If no changes 
in medication are required, V0 (pre-screening) and V1 (screening) may be conducted on 
the same day. Inhaled long-acting muscarinic antagonist (LAMA) or long-acting beta2-
agonist (LABA) and/or albuterol/salbutamol as needed (rescue medication) are not 
exclusionary prior to Screening or during the run-in. 
Eligible subjects at Screening Visit 1 will be current or former smokers, at least 6 weeks 
ICS and ICS/LABA free with an FEV1 post-albuterol/salbutamol of ≥30% to ≤80% 
predicted normal and a FEV1/FVC <0.7 and a CAT score ≥10. 
 
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Subjects using inhaled LAMA or LABA medication must withhold their morning dose 
prior to Screening spirometry. Subjects who meet all other eligibility criteria at Screening 
will enter a run-in period for 4 weeks. During the run-in period, subjects will continue 
with their inhaled LAMA or LABA.  In addition, subjects will be provided with short 
acting albuterol/salbutamol as needed for relief of COPD symptoms (rescue medication) 
throughout the study.
Subjects who experience a moderate or severe COPD exacerbation during the run-in 
period will be deemed run-in failures.  Subjects who experience a mild COPD 
exacerbation, defined as worsening of symptoms that requires no treatment with 
antibiotics or steroids and is self managed by the patient by an increase of inhaled rescue 
medication will be able to continue in the study based on the judgment of the investigator 
and agreement of the sponsor’s medical monitor.
At the randomization Visit 2 (Day 1), those subjects who successfully complete the run-
in period, as well as meet the other pre-defined eligibility and randomization criteria, will 
be randomized to one of the 3 treatment arms for 24 weeks.
In addition, a subset of subjects (approximately 150 per treatment arm) will undergo 
assessment of their physical activity measured through a physical activity monitor 
(Actigraph GT9X) worn for 7 days from Screening (Visit 1), for 7 days from 
Randomisation (Visit 2), 7 days from Visit 3, and for 7 days prior to last clinic Visit 
(Visit 5). 
The occurrence of adverse events (AEs) will be evaluated throughout the study beginning 
at Visit 2 (Day 1) and until the follow-up contact (Visit 6).  Serious adverse events 
(SAEs) will be collected over the same time period as AEs.  However, any SAEs 
assessed as related to study participation (e.g., study treatment, protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK concomitant 
medication, will be recorded from the time a subject consents to participate in the study 
up to and including any follow up contact.
All subjects will be given an electronic diary (eDiary) for use during the run-in, and the 
treatment period to complete PRO questionnaires, record COPD daily symptoms and the 
time they take their COPD medications.  Daily rescue medication usage (number of 
inhalations taken in the last 24 h) will also be captured in the eDiary.  In addition, and in 
some countries, rescue medication use will also be captured by the use of electronic 
metered dose inhaler (eMDI).
At Screening Visit 1, all subjects must be trained on the proper use of their existing 
COPD medications inhalation devices and instructed to strictly adhere to and record the 
time they take their COPD medications in the eDiary.
At the randomization Visit 2, all subjects must be trained on the proper use of the 
ELLIPTA and DISKUS inhalation devices and instructed to strictly adhere to and record 
the time they take their study medications in the eDiary.
All subjects must be trained on the correct use of the eDiary and instructed to complete 
the eDiary during the run-in and treatment period.
 
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Subjects will be considered to have completed the study upon completion of the Follow–
Up contact by telephone.
There are no plans to routinely provide any of the study treatments for compassionate use 
following study completion as the study treatment are commercially available.
Treatment Arms and Duration
Subjects will be stratified based on long-acting bronchodilator usage during the run-in 
(none or one long-acting bronchodilator per day) and randomized in a ratio of 1:1:1 to 
either 

UMEC/VI 62.5/25 mcg once daily via ELLIPTA + placebo twice daily via 
DISKUS

UMEC 62.5 mcg once daily via ELLIPTA + placebo twice daily via DISKUS

Salmeterol 50 mcg twice daily via DISKUS + placebo once daily via ELLIPTA
 
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Study schematic
*Subjects may
continue the use of inhaled LAMAs or LABAs
and/or
study provided 
albuterol/salbutamol as needed (rescue medication) during the run-in while adhering to the 
withholding of other COPD medications detailed in the Exclusion Criteria.
Type and Number of Subjects
Approximately 3232 subjects will be screened, such that 2424 subjects will be 
randomized and approximately 2181 evaluable subjects complete the study. 
Analysis
The primary purpose of this study is to demonstrate improvements in lung function for 
subjects treated with UMEC/VI compared with UMEC for 24 weeks.
The primary endpoint is change from baseline in trough FEV1 at Week 24.
The null hypothesis is no difference between treatment groups (H0: μT – μS = 0), with 
the alternative hypothesis that there is a difference between treatment groups (H1: μT –
μS ≠0), where μT is the mean change from baseline for UMEC/VI and μS is the mean 
change from baseline for UMEC. 
The primary endpoint of mean change from baseline in trough FEV1 at the end of Week 
24 will be analysed using Mixed Models repeated Measures (MMRM) analysis. The 
MMRM analysis will include measurements at Treatment Weeks 4, 12 and 24. Treatment 
group (a categorical variable) will be fitted as the explanatory variable with appropriate 
pre-defined variables, stratum (number of bronchodilators per day during run-in) and 
baseline values, fitted as covariates. Visit (nominal) will be fitted as a categorical variable 
and visit-by-baseline and visit-by-treatment interaction terms will be included to allow 
treatment effects to be estimated at each visit separately.  The variance covariance matrix 
 
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will be assumed to be unstructured (based on previous experience no issues are expected 
with fitting models with this matrix structure). 
The estimated treatment differences between UMEC/VI versus UMEC for each endpoint 
will be presented with the 95% confidence intervals for the difference and the p-value. 
2.
INTRODUCTION
2.1.
Study Rationale
Chronic obstructive pulmonary disease (COPD) is associated with poor health-related 
quality of life (HRQoL).  Pharmacologic therapy is used to improve lung function, reduce 
symptoms, frequency and severity of exacerbations, and improve patients HRQoL
[GOLD, 2015].  Umeclidinium/Vilanterol (UMEC/VI 62.5/25 mcg) is indicated for the 
maintenance treatment of COPD that contain long-acting muscarinic antagonist (LAMA) 
and long-acting beta2-agonist (LABA) bronchodilators.  Umeclidinium (UMEC) is 
indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients 
with COPD.  Salmeterol has long been used for symptoms management of COPD.  
However, a direct comparison of these maintenance therapies has not been conducted 
with respect to HRQoL.
The primary purpose of this study is to demonstrate improvements in lung function for 
subjects treated with UMEC/VI compared with UMEC for 24 weeks.  The effect of
UMEC/VI, UMEC, and salmeterol with respect to patient HRQoL measured through 
patient reported outcomes (PROs) questionnaires, symptoms and lung function will also 
be evaluated.
2.2.
Brief Background
COPD is characterized by an airflow limitation which is not fully reversible, usually 
progressive and accompanied by a chronic cough, sputum production and dyspnea which 
can be a major cause of disability and anxiety associated with the disease [Maleki-Yazdi, 
2014]
Furthermore, acute exacerbations contribute to the overall severity of disease as these 
episodes are accompanied by worsened symptoms and are associated with increased 
decline in lung function and mortality [Wedzicha, 2013; Schmidt, 2014].
Pharmacologic therapy is used to improve lung function, reduce symptoms, reduce the 
frequency and severity of exacerbations, and also to improve health status and exercise 
tolerance.  Maintenance treatment is recommended primarily through the use of LABAs 
or LAMAs.  COPD treatment guidelines recommend an incremental approach to 
pharmacological treatment as the disease state worsens, involving the use of 
combinations of drug classes with different or complementary mechanisms [GOLD, 
2015]. 
UMEC/VI inhalation powder is a combination of UMEC (umeclidinium bromide), a 
LAMA, and VI (Vilanterol), a LABA, delivered via the ELLIPTA dry powder inhaler 
 
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(DPI). UMEC/VI at a dose of 62.5/25mcg once-daily is marketed in the United States 
(US) and Europe under the trade name ANORO™ELLIPTA.  
UMEC (62.5 mcg) inhalation powder is marketed in the United States (US) and Europe 
under the trade name INCRUSE™ELLIPTA.  UMEC (62.5mcg) is indicated as a 
maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD.  
UMEC (62.5 mcg) improves forced expiratory volume in one second (FEV1), dyspnea 
and HRQoL whether used as monotherapy [Trivedi, 2014; Feldman, 2016] or as an add 
on to fluticasone propionate and vilanterol (FF/VI) [Siler, 2015].  Salmetrol (50 mcg) 
DISKUS is a long-acting broncholdilator that has long been used for the maintenance 
treatment of COPD [Tashkin, 2010].
Clinically important deterioration (CID) is a novel, exploratory composite endpoint 
which assesses individual deteriorations in lung function and in patient PROs defined by 
the accepted minimal clinically important difference (MCID), as well as the incidence of 
moderate to severe exacerbations [Singh, 2016], (Section 7.3.5).  CID will be analysed to 
determine whether UMEC/VI (62.5/25mcg) therapy provides greater clinical stability as 
compared with UMEC and salmeterol monotherapies. 
3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary

To compare the effect of UMEC/VI 
(62.5/25 mcg once daily) with UMEC 
(62.5 mcg once daily) on lung function

Change from baseline in trough Forced 
Expiratory Volume in One Second 
(FEV1) at week 24 
Secondary

To compare UMEC/VI (62.5/25 mcg 
once daily), UMEC (62.5 mcg once 
daily) with salmeterol (50 mcg twice 
daily) on patient reported outcomes 
(PROs) 

Change from baseline in self 
administered computerised (SAC) 
transient dyspnea index (TDI) 

Percentage of TDI responders 
according to SAC TDI score.  A 
responder is defined as a ≥1 unit 
improvement in SAC TDI score 

Assessment of respiratory daily 
symptoms over 24 weeks using 
Evaluating Respiratory Symptoms-
COPD (E-RS) and its subscales 
(breathlessness, cough and sputum and 
chest symptoms) 

Percentage of E-RS responders 
according to E-RS score (defined as 
reduction in E-RS score of 2 or 3.35 
units) from baseline
 
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Objectives
Endpoints

Change from baseline in St George’s 
Respiratory Questionnaire (SGRQ-C)

Percentage of responders according to 
SGRQ-C total score (defined as a 4 
point or greater reduction from 
baseline) 

Change from baseline in COPD 
assessment test (CAT)

Percentage of responders according to 
CAT (defined as a 2 unit improvement 
in score from baseline)
Other

To compare UMEC/VI (62.5/25 mcg 
once daily), UMEC (62.5 mcg once 
daily) with salmeterol (50 mcg twice 
daily) on other COPD efficacy measures 

Time to first mild, moderate or severe 
exacerbation

Time to moderate or severe 
exacerbation

Time to severe exacerbations

Time to clinically important 
deterioration (CID) composite endpoint 

Time to clinically important 
deterioration composite endpoint 
excluding FEV1

Rescue albuterol/salbutamol use, 
(percentage of rescue-free days and 
mean number of Inhalations/day) 
captured by the electronic diary 
(eDiary) over 24 weeks

Inspiratory capacity (IC)

Full Vital capacity (FVC) 

Change from baseline in trough FEV1

Change from baseline in global 
impression of disease severity 
 
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Objectives
Endpoints
Safety

To evaluate safety and tolerability of 
UMEC/VI (62.5/25 mcg once daily), 
UMEC (62.5 mcg once daily) and 
salmeterol 50

mcg twice daily)

Incidence of adverse events
Exploratory

To explore the effect of UMEC/VI 
(62.5/25 mcg once daily), UMEC 
(62.5 mcg once daily) with salmeterol 
(50 mcg twice daily) on rate of COPD 
exacerbation

Rate of mild, moderate or severe 
exacerbations

Rate of moderate or severe 
exacerbation

To compare albuterol/salbutamol use 
captured in the eDiary with the 
electronic metered dose inhaler (eMDI) 
device 

Rescue albuterol/salbutamol use, 
(percentage of rescue-free days and 
mean number of Inhalations/day) 
captured by the eMDI device over 24 
weeks as data allow

To explore the effect of UMEC/VI 
(62.5/25 mcg once daily), UMEC (62.5 
mcg once daily) with salmeterol (50 
mcg twice daily) on physical activity

Change from baseline in physical 
activity 

To investigate the CID composite 
endpoint ability to predict short term 
outcomes 

To compare physical activity levels, 
ER-S, rescue medication use, 
exacerbations and mortality in subjects 
with and without a CID
4.
STUDY DESIGN
4.1.
Overall Design
This is a multi-centre, randomized, double blind, double-dummy, 3-arm parallel group 
study.  Eligible subjects will be randomized in a ratio of 1:1:1 to UMEC/VI inhalation 
powder (62.5/25 mcg once daily) administered via the ELLIPTA™dry powder inhaler, or 
UMEC (62.5 mcg once daily) administered via the ELLIPTA™or salmeterol (50 mcg 
BID) administered via the DISKUS. 
There will be a total of 5 clinic visits and one follow-up phone call (Visit 6). A pre-
screening visit (Visit 0) may be required in order to administer the informed consent 
before any changes are made to the subject’s current medication regimen. If no changes 
in medication are required, V0 (pre-screening) and V1 (screening) may be conducted on 
the same day. Inhaled long-acting muscarinic antagonist (LAMA) or long-acting beta2-
agonist (LABA) and/or albuterol/salbutamol as needed (rescue medication) are not 
exclusionary prior to Screening or during the run-in. 
 
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Eligible subjects at Screening Visit 1 will be current or former smokers, at least 6 weeks 
ICS and ICS/LABA free with an FEV1 post-albuterol/salbutamol of ≥30% to ≤80% 
predicted normal and a FEV1/FVC <0.7 and a CAT score ≥10.
Subjects using inhaled LAMA or LABA medication must withhold their morning dose 
prior to Screening spirometry. Subjects who meet all other eligibility criteria at Screening
will enter a run-in period for 4 weeks. During the run-in period, subjects will continue 
with their inhaled LAMA or LABA medication.  In addition, subjects will be provided 
with short acting albuterol/salbutamol as needed for relief of COPD symptoms (rescue 
medication) throughout the study. 
Subjects who experience a moderate or severe COPD exacerbation during the run-in 
period will be deemed run-in failures.  Subjects who experience a mild COPD 
exacerbation, defined as worsening of symptoms that requires no treatment with 
antibiotics or steroids and is self managed by the patient by an increase of inhaled rescue 
medication, (Appendix 5), will be able to continue in the study based on the judgment of 
the investigator and agreement of the sponsor’s medical monitor.
At the randomization Visit 2 (Day 1), those subjects who successfully complete the run-
in period as well as meet the other pre-defined eligibility and randomization criteria will 
be randomized to one of the 3 treatment arms for 24 weeks.
In addition, a subset of subjects (approximately 150 per treatment arm) will undergo 
assessment of their physical activity measured through a physical activity monitor 
(Actigraph GT9X) worn for 7 days from Screening (Visit 1), for 7 days from 
Randomisation (Visit 2), 7 days from Visit 3, and for 7 days prior to last clinic Visit 
(Visit 5).
The occurrence of adverse events (AEs) will be evaluated throughout the study beginning 
at Visit 2 (Day 1) and until the follow-up contact (Visit 6).  Serious adverse events 
(SAEs) will be collected over the same time period as AEs.  However, any SAEs 
assessed as related to study participation (e.g., study treatment, protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK concomitant 
medication, will be recorded from the time a subject consents to participate in the study 
up to and including any follow up contact (Appendix 4). 
All subjects will be given an electronic diary (eDiary) for use during the run-in, and the 
treatment period to complete PRO questionnaires, record COPD daily symptoms, any 
medical problems experienced during the study and the time they take their COPD 
medications.  Daily rescue medication usage (number of inhalations taken in the last 24h) 
will also be captured in the eDiary.  In addition, and in some countries, rescue medication 
use will also be captured by the use of electronic metered dose inhaler (eMDI).
At Screening Visit 1, all subjects must be trained on the proper use of their existing 
COPD medications inhalation devices and instructed to strictly adhere to and record the 
time they take their COPD medications in the eDiary.
 
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At the randomization Visit 2, all subjects must be trained on the proper use of the 
ELLIPTA and DISKUS inhalation devices and instructed to strictly adhere to and record 
the time they take their study medications in the eDiary.
All subjects must be trained on the correct use of the eDiary and instructed to complete 
the eDiary during the run-in and treatment period.
Subjects will be considered to have completed the study upon completion of the follow –
up contact by telephone.
There are no plans to routinely provide any of the study treatments for compassionate use 
following study completion as the study treatment are commercially available.
The study design schematic is illustrated in Figure 1
Figure 1
Study Schematic
*Subjects may continue the use of inhaled LAMAs or LABAs and/or study provided 
albuterol/salbutamol as needed (rescue medication) during the run-in while adhering to the 
withholding of other COPD medications detailed in the Exclusion Criteria.
4.2.
Treatment Arms and Duration
Subjects will be stratified based on long-acting bronchodilator usage during the run-in 
(none or one long-acting bronchodilator per day) and randomized in a ratio of 1:1:1 to 
either

UMEC/VI 62.5/25 mcg once daily via ELLIPTA + placebo twice daily via 
DISKUS

UMEC 62.5 mcg once daily via ELLIPTA + placebo twice daily via DISKUS

Salmeterol 50 mcg twice daily via DISKUS + placebo once daily via ELLIPTA
 
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The total duration of subject participation in the study will be approximately 29 to 35
weeks consisting of 6 weeks pre-screening if necessary, 4 weeks run-in, 24 week 
treatment and one week follow-up. 
4.3.
Type and Number of Subjects
Approximately 3232 will be screened globally in approximately 240 sites such that 
approximately 2424 subjects will be randomized and approximately 2181 evaluable 
subjects complete the study. 
4.4.
Design Justification
A randomized, double blinded, parallel group study is a standard, well-established design 
to evaluate the efficacy and safety of an investigational drug.  A salmeterol arm is 
included to allow a comparison to be made between UMEC/VI, UMEC with salmeterol, 
a standard practice treatment.
The double-dummy design is appropriate when drugs are of different appearance or 
different administration regimen which is appropriate in this study where the inhalers 
used have a different appearance and used once daily and twice daily.
The European Medicines Agency (EMA) COPD Guidelines suggest that duration of 12 to 
24 weeks is considered adequate for assessment of response of COPD symptoms to 
treatment intervention with bronchodilators (EMA COPD guidelines, 2012). 
The primary endpoint is trough FEV1 at week 24. This endpoint is generally considered to 
be a robust, well established and an objective means to show the efficacy of a 
bronchodilator [Dahl, 2010; Feldman, 2010]. 
Other endpoints such SAC TDI, E-RS, SGRQ-C, CAT, Subject Global Rating of Change 
in global impression of disease severity are captured to allow responder analyses and to 
provide comparative data on PROs between the treatment groups. 
4.5.
Dose Justification
This study is intended to evaluate the efficacy of marketed doses of UMEC/VI 
(62.5/25mcg once daily), UMEC (62.5 mcg once daily) and salmeterol (50mcg twice 
daily) that are approved for the maintenance treatment of COPD, with respect to PRO 
measures.
4.6.
Benefit: Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
UMEC/VI and UMEC can be found in the investigator’s brochures (IB) 
[GlaxoSmithKline Document Number RM2009/00437/07] and [GlaxoSmithKline 
Document Number RM2006/00835/09] and in the label information sheets. The current 
safety profile for UMEC (62.5mcg) and the UMEC/VI (62.5/25mcg) based on data 
available to date, is comparable with other LABAs and LAMAs.  Summary safety data 
can also be found in the information sheet for salmeterol [Serevent product information, 
2003].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
Investigational Product (IP) [UMEC/VI] 
Severe milk protein allergy
Anoro contains Lactose monohydrate (which contains milk 
protein) as an excipient.
Exclusion criteria have been set for subjects with milk 
protein allergy.
Cardiovascular effects such as cardiac arrhythmias e.g.
supraventricular tachycardia and extrasystoles.
Class effects associated with LABAs and LAMA containing 
therapy. The clinical significance of these arrhythmias is 
unknown. Clinical experience with UMEC/VI to date in 
completed studies did not show any association with major 
cardiovascular events. 
Data available in the product label for UMEC/VI 
Exclusion criteria have been set for subjects with 
uncontrolled or severe cardiovascular disease according to 
the principal investigation’s (PI) opinion where the potential 
risk may outweigh the benefit. The PI should also 
determine the clinical significance of abnormal ECG 
findings at screening and exclude subjects who would be 
at undue risk by participating in the trial.  Patients with the 
following abnormalities will be excluded from participation:  
atrial fibrillation with rapid ventricular rate >120bpm, 
sustained or nonsustained ventricular tachycardia, or 
second degree heart block Mobitz type II or third degree 
heart block (unless pacemaker or defibrillator had been 
inserted). 
Beta agonists and risk of asthma-related death
Long-acting beta agonists such as vilanterol when used 
alone may increase the risk of asthma-related death.  A 
placebo-controlled trial with another LABA (salmeterol) 
showed an increase in asthma-related deaths in subjects 
receiving salmeterol.  This finding with salmeterol is 
considered a class effect of all LABAs, including vilanterol. 
Data are not available to determine whether the rate of death 
in patients with COPD is increased by LABA.
Subjects with a current diagnosis of asthma are excluded 
from participation in the study.
Paradoxical bronchospasm
As with other inhaled medicines, UMEC/VI can produce 
paradoxical bronchospasm which may be life threatening.
If paradoxical bronchospasm occurs following dosing with 
UMEC/VI, this treatment should be discontinued 
immediately and alternative therapy should be instituted. 
Use in patients with narrow-angle glaucoma or urinary 
retention
No association has been found to date, in completed studies 
with UMEC/VI or UMEC monotherapy, on glaucoma or 
urinary retention.  However, glaucoma or urinary retention 
Exclusion criterion states that subjects with medical 
conditions such as narrow-angle glaucoma, prostatic 
hypertrophy, or bladder neck obstruction should only be 
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
have been observed with other antimuscarinic agents, and 
could potentially be due to the pharmacology.
included if, in the opinion of the principal investigator, the 
benefit outweighs the risk.
Use of beta blockers
Beta-adrenergic blockers may weaken or antagonize the 
effect of beta2-agonists such as vilanterol.
The study permitted medications and non drug therapies 
section states that concomitant administration with beta-
blockers is only permitted if, in the Investigator’s opinion, 
the likely benefit outweighs the potential risk.
Pregnancy
There is no experience to date of pregnancy during the use 
of UMEC/VI.
The study inclusion criteria ensures that female subjects of 
child bearing potential must have a negative pregnancy 
test at screening, and agree to a reliable contraceptive 
method, used consistently and correctly (i.e. in accordance 
with the approved product label and the instructions of the 
physician for the duration of the study). Exclusion criteria 
include Pregnancy: Women who are pregnant or lactating
or are planning on becoming pregnant during the study.
Severe hepatic impairment
UMEC/VI has not been studied in severe hepatic impairment.
Exclusion criterion states that subjects severe hepatic 
impairment should only be included if, in the opinion of the 
study physician, the benefit outweighs the risk.
Investigational product (IP) [UMEC]
Cardiovascular effects such as cardiac arrhythmia, e.g. 
atrial fibrillation and tachycardia
A potential class effect associated
with anti-muscarinic therapies. Data available to date in the 
IB for UMEC [GlaxoSmithKline Document Number 
RM2006/00835/09
Screening electrocardiogram (ECG) criteria to exclude 
subjects potentially at risk 
Narrow-angle glaucoma, urinary retention
A class effect associated with anti-muscarinic therapies.
Data available in the IB for UMEC [GlaxoSmithKline 
Document Number RM2006/00835/09
Exclusion criterion states that subjects with medical 
conditions such as narrow-angle glaucoma, prostatic 
hypertrophy, or bladder neck obstruction should only be 
included if, in the opinion of the study physician, the benefit 
outweighs the risk.
Paradoxical bronchospasm that may be life threatening
Known effect associated with inhalation therapy
A short-acting inhaled bronchodilator 
(albuterol/salbutamol) will be provided for use as needed 
throughout the study. The investigators will be instructed to 
assess subject’s condition to determine their eligibility to 
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
continue in the study and the need for alternative therapy.
Severe hepatic impairment
UMEC has not been studied in severe hepatic impairment.
Exclusion criterion states that subjects with severe hepatic 
impairment should only be included if, in the opinion of the 
study physician, the benefit outweighs the risk.
Pregnancy/Lactation
There is no experience to date of pregnancy during the use 
of UMEC.
The study inclusion criteria ensure that female subjects 
enrolled, who are of Child bearing potential, have a 
negative pregnancy test at screening, and agree to a 
reliable contraceptive method, used consistently and 
correctly (i.e. in accordance with the approved product 
label and the instructions of the physician for the duration 
of the study). Exclusion criteria states - Pregnancy: 
Women who are pregnant or lactating or are planning on 
becoming pregnant during the study.
Study Procedures
Spirometry procedures
This may cause difficulty breathing, changes in pulse rate 
and blood pressure, coughing, wheezing, chest tightness or 
fainting.
Subjects will be monitored during the procedure for these 
effects and spirometry will be discontinued should these 
occur.
ECG lead placement
This may cause skin irritation.
It may be necessary to have small patches (about a 
centimetre in diameter) of hair on the chest shaved to 
properly attach electrodes to the chest. 
Blood sampling procedure (optional pharmacogenetic 
blood sample)
Giving blood may make subjects feel faint, or experience 
mild pain, bruising, irritation or redness at the site. In rare 
cases, they may get an infection
Subjects will be monitored during the blood draw for these 
effects and should call their study doctor if any of these 
effects do not resolve
Other 
Side effects of rescue albuterol/salbutamol. Adverse 
events seen in clinical studies to date are however 
consistent for the beta2-adrenergic class of compounds
Class effects associated with short acting beta-agonists 
(SABAs)
Subjects should call their study doctor if they experience 
any of these symptoms
 
 
 
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4.6.2.
Benefit Assessment
Subjects will receive single or combination of long-acting bronchodilator therapies 
approved for maintenance treatment of COPD.  Participating subjects in this study will 
contribute to the process of further characterizing the benefit of these long-acting 
bronchodilators with respect to PROs and symptoms in the treatment of COPD.
Specific benefits associated with the study design and procedures include the following:

Subjects will receive treatments approved for the treatment of COPD that have 
been shown to be effective in the population under study

All subjects will receive albuterol/salbutamol for use “as needed” for relief of 
COPD symptoms

The combination of study procedures of spirometry, CAT, SGRQ, TDI, E-RS will 
provide the study subjects with a comprehensive evaluation of their symptoms, 
health status and COPD disease severity. Subjects will also be monitored 
throughout the study for any worsening of COPD symptoms or decline in general 
health.  Finally smoking cessation counselling will also be provided.
4.6.3.
Overall Benefit: Risk Conclusion
Taking into account the measures taken to minimize risk to subjects participating in this 
study, the potential risks identified in association with UMEC/VI, UMEC, salmeterol and 
with study procedures are justified by the anticipated benefits from active treatments that 
may be afforded to patients with COPD.
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 IBs, [GlaxoSmithKline 
Document Number RM2006/00835/09], [GlaxoSmithKline Document Number 
RM2009/00437/07] and product labels.
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
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.
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
 
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AGE
1.
40 years or older at date of signing informed consent
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2.
Outpatient with a diagnosis of COPD in accordance with the definition of the 
American Thoracic Society/European Respiratory Society (ATS/ERS) [Celli, 2004]. 
3.
FEV1: Persistent airflow limitations as indicated by:  A pre and post-
albuterol/salbutamol FEV1/FVC ratio of <0.70 and a post-albuterol/salbutamol FEV1
of ≥30% to ≤80% predicted normal values at Screening Visit 1.  Predicted values 
will be based upon the ERS Global Lung Function Initiative [Quanjer, 2012].
4.
CAT score:  A CAT score of ≥10 at Screening Visit 1
Smoking History
5.
Current or former cigarette smokers with a history of cigarette smoking of 10 
pack-years [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 both equal 10 pack-years)].  Former smokers are defined as those who have 
stopped smoking for at least 6 months prior to Visit 1.  Pipe and/or cigar use cannot 
be used to calculate pack-year history.
SEX
6.
Male and female subjects are eligible to participate in the study
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 must be tested.  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.  
 
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Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status 
prior to study enrolment.
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) (Appendix 7) from 30 days prior to the first dose of 
study medication and until [at least five terminal half-lives OR until any continuing 
pharmacologic effect has ended, whichever is longer] after the last dose of study 
medication and completion of the follow-up visit.
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.
INFORMED CONSENT
7.
Capable of giving signed informed consent prior to study participation, which 
includes compliance with the requirements and restrictions listed in the consent form 
and in this protocol.
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION 
1.
Asthma:  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).
2.
Alpha-antitrypsin deficiency: Subjects with known α1-antitrypsin deficiency as 
the underlying cause of COPD
3.
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.
4.
Unstable liver disease: 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). 

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 or within 3 months prior to 
first dose of study treatment) are acceptable if subject otherwise meets entry 
 
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criteria
5.
Unstable or life threatening cardiac disease: Investigational Product should be 
used with caution in subjects with severe cardiovascular disease.  In the opinion 
of the investigator, use should only be considered if the benefit is likely to 
outweigh the risk in conditions such as:

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
6.
12 Lead ECG: 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. Subjects with the 
following abnormalities are excluded from participation in the study:

Atrial fibrillation with rapid ventricular rate >120 bpm

Sustained or non-sustained ventricular tachycardia

Second degree heart block Mobitz type II or third degree heart block (unless 
pacemaker or defibrillator had been inserted)
7.
Antimuscarinic effects:  Subjects with medical conditions such as narrow-angle 
glaucoma, urinary retention, prostatic hypertrophy, or bladder neck obstruction 
should be excluded unless, in the opinion of the study physician, the benefit 
outweighs the risk.
8.
Other disease abnormalities: Any subject who is considered unlikely to survive 
the duration of the study period or has any rapidly progressing disease or 
immediate life-threatening illness (e.g. cancer). In addition, any subject who has 
any other condition (e.g. neurological condition) that is likely to affect respiratory 
function should not be included in the study.
9.
Hospitalization: Hospitalization for COPD or pneumonia within 12 weeks prior 
to Visit 1. Pneumonia and/or moderate COPD exacerbation that has not 
resolved at least 14 days prior to Screening Visit 1 and at least 30 days following 
the last dose of oral/systemic corticosteroids (if applicable). 
10.
Inhaled corticosteroids (ICS): Had received ICS or ICS/LABA for the treatment 
of COPD in the 6 weeks prior to Screening Visit 1
11.
Exacerbation: Had >1 moderate exacerbation in the 12 months prior to 
Screening Visit 1, or one severe exacerbation requiring hospitalisation in the 12 
months prior Screening Visit 1.
12.
Other respiratory tract infections that have not resolved at least 7 days prior to 
Screening V1.
13.
Lung Resection: Subjects with lung volume reduction surgery (including 
procedures such as endobronchial valves) within the 12 months prior to Screening 
V1.
14.
Oxygen: Use of long-term oxygen therapy (LTOT) described as resting oxygen 
 
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therapy >3L/min at screening required to maintain adequate oxygenation (e.g. 
SaO2 >90%). (Oxygen use ≤3L/min flow is not exclusionary, and patients may 
adjust oxygen levels up or down as needed during the study.)
CONCOMITANT MEDICATIONS
15.
Medications prior to Screening: Use of the following medications according to 
the following defined time intervals prior to Screening (Visit 1) or during the 
study:
Medication
No use within the 
following time intervals 
prior to Screening and
thereafter at any time 
during the study
Inhaled corticosteroids (ICS)
6 weeks
Depot corticosteroids
12 weeks
Systemic, oral or parenteral corticosteroidsa
6 weeks
Antibiotics (for lower respiratory tract infection)
6 weeks
Phosphodiesterase 4 (PDE4) Inhibitor (e.g roflumilast)
14 days
LABA/Inhaled Corticosteroid (ICS) combination products 
6 weeks
LABA/LAMA combination products
2 weeks
Theophyllines
48 hours
Oral beta2-agonists
     Long-acting
     Short-acting
48 hours
12 hours
Inhaled short acting beta2-agonistsb
4 hours
Inhaled short-acting anticholinergics
4 hours
Inhaled short-acting anticholinergic/short-acting beta2-agonist 
combination products
4 hours
Any other investigational medication
30 days or within 5 drug 
half-lives (whichever is 
longer)
a-
Corticosteroids are allowed for the treatment of COPD exacerbations during the double-blind treatment
phase of the study. Localized corticosteroid injections (e.g., intra-articular and epidural) are permitted.
b-
Use of study provided albuterol/salbutamol is permitted during the study, except in the 4-hour period prior to 
spirometry testing
16.
Medication prior to spirometry: Unable to withhold albuterol/salbutamol for 
the 4 hour period required prior to spirometry testing at each study visit. Unable 
to withhold morning dose of subject’s inhaled LABA or LAMA COPD 
medication prior to spirometry testing at Screening Visit (Visit 1).
17.
Maintenance use of short-acting bronchodilators:  Regular use (prescribed for 
daily/ regular use, not for as-needed use) of short-acting bronchodilators (e.g. 
albuterol/salbutamol).
RELEVANT HABITS
18.
Drug or alcohol abuse: A known or suspected history of alcohol or drug abuse 
within 2 years prior to Screening Visit 1 that in the opinion of the investigator 
 
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would prevent the subject from completing the study procedures.
CONTRAINDICATIONS 
19.
Any history of allergy or hypersensitivity to any anticholinergic/muscarinic 
receptor antagonist, sympathomimetic, lactose/milk protein or magnesium 
stearate.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
20.
Pulmonary Rehabilitation program: Participation in the acute phase of a 
pulmonary rehabilitation program within 4 weeks prior to Screening Visit 1.  
Subjects who are in the maintenance phase of a pulmonary rehabilitation program 
are not excluded.
21.
Affiliation with investigator sites: Is an investigator, sub-investigator, study 
coordinator, employee of a participating investigator or study site, or immediate 
family member of the aforementioned that is involved in 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 questionnaires on the electronic diary.
Subjects who fail to meet inclusion and exclusion criteria at the Screening Visit 1 will be 
considered screen failures and cannot be re-screened.
5.3.
Randomization Criteria
In order to be randomized to one of the 3 treatment arms at Visit 2, subjects must have 
completed the run-in period and must have fulfilled all inclusion and exclusion criteria 
described in Section 5.1 and Section 5.2. In addition to the following:
REQUIRED CRITERIA FOR RANDOMIZATION AND TREATMENT
1. COPD Exacerbation: Subjects must not have experienced a moderate or severe 
COPD exacerbation or a lower respiratory tract infection during run-in or at Day 1 
(Visit 2) inclusive.  A moderate exacerbation is defined as worsening of symptoms of 
COPD requiring the use of antibiotics or systemic corticosteroids.  A severe 
exacerbation is defined as worsening symptoms of COPD requiring hospitalization.
2. CAT score:  A CAT score of ≥10 at Visit 2
3. Prohibited Medications: No use of any prohibited medications during the run-in 
period or at Visit 2, including any ICS or ICS/LABA combination. Subject’s inhaled 
LABA or LAMA medication morning dose must be withheld and discontinued at 
Visit 2.
4. Any change to COPD medications: Including dosage and regimen during the run-in
5. Completion of electronic diary: Must have completed the electronic diary for at 
least 80% of days during the run-in period
 
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Subjects who do not meet the required criteria for randomization at Visit 2 will not be 
randomized.
5.4.
Screening/Baseline/Run-in Failures
Pre-screen, screen and run-in failures are defined as follows: 

Pre-screening failures: A subject, who is assigned a subject number at the Pre-
screening Visit 0 but does not have any Screening Visit 1 procedures, will be 
considered a pre-screen failure.

Screening failures: Those subjects that complete at least one Screening Visit 1 
procedure but do not enter the run-in period.

Run-in failures: Those subjects that enter the run-in period but are not randomized 
to any of the study treatment arms.
Subjects who are pre-screen, screen and run-in failure will be recorded in the eCRF.  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 to be recorded in eCRF including demography, screen failure details, eligibility 
criteria, and serious adverse events (Section 7.4.1). 
5.5.
Withdrawal/Stopping Criteria
5.5.1.
Withdrawal from the Study
Subjects may be withdrawn from the study at any time by the Investigator if it is 
considered to be detrimental for them to continue in the study.  Reasons for withdrawal 
from study treatment can include: an AE, clinically significant abnormality, lack of 
efficacy, sponsor terminated study, pregnancy, or for any other reason. 
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. 
A reason for the withdrawal from the study must be captured in the electronic case report 
form (eCRF).
Stopping Criteria
A subject must be withdrawn from the study, in consultation with the medical monitor 
and principal investigator, if any of the following stopping criteria are met:

Liver Chemistry: Meets any of the Liver chemistry stopping criteria (See Section 
5.5.3)
Note: clinical laboratory assessments are not required for this study. However, 
laboratory samples may be taken for liver event analysis, if clinically indicated by 
the study investigator.

Pregnancy:  Positive pregnancy test (see Appendix 7)
 
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
Unstable or life threatening cardiac events: myocardial infarction, hospitalization 
for unstable angina, stroke, and other cardiovascular events considered life- or 
intensively health-threatening by the study physician.

COPD Exacerbations: Subjects with two moderate or one severe COPD 
exacerbation during the study.

Withdrawal from study treatment requires withdrawal from the study.

Non-Compliance with Study treatment: Subjects’ compliance with study treatment 
will be assessed at each study visit. Subjects who are non-compliant should be re-
educated on the requirement for treatment compliance. Every effort will be made to 
keep subjects in the study and to re-educate those subjects who continue to be non-
compliant.  Subjects who continue to be non-compliant after multiple visit 
assessments may be permanently discontinued after consultation with the GSK 
clinical team. 

Non-Compliance with eDiary:  Subjects must be compliant in completing their 
eDiary between each pair of on-treatment visits.  Subjects who are non-compliant 
should be re-educated on the requirement for daily diary entry compliance. Subjects 
who continue to be non-compliant after multiple visit assessments may be 
permanently discontinued after consultation with the GSK clinical team.
Subjects withdrawn from study treatment will not be replaced. 
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”. 
5.5.2.
Reason for Study Withdrawal
The primary reason for study withdrawal will be recorded in the eCRF. When a subject 
withdraws consent, the investigator must document the reason (if specified by the 
subject) in the eCRF. 
The primary reason for study withdrawal may include:
Adverse event
 
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Lost to follow-up
Withdrew consent
o
subject relocated
o
frequency of visits
o
burden of procedures
o
other (specify)
Protocol deviation
Lack of efficacy
COPD exacerbation
Study closed/terminated
Subject reached protocol-defined stopping criteria
Pregnancy
Investigator discretion
5.5.3.
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
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.
5.5.3.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed.
5.6.
Follow-up contact
A safety follow-up contact (Visit 6) should be conducted 73 days following the 
completion of Visit 5 or the Early Withdrawal Visit, if applicable. 
The following procedures will be performed:

AE/SAE assessment

COPD exacerbation assessment

Concomitant medication assessment limited to any medications used to treat a 
COPD exacerbation or SAE (if applicable)

Pregnancy information (if applicable)
Subjects who have successfully completed all on-treatment randomized visits will be 
discharged from the study upon completion of the safety follow-up contact.
5.7.
Subject and Study Completion
A subject will be considered to have completed the study if he/she receives study 
treatment at Visit 5 (Week 24) and completes the follow-up contact Visit 6.
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.
The contents of the label will be in acaccordance with all applicable regulatory 
requirements.
Under normal conditions of handling and administration, investigational product is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to avoid 
direct eye or skin contact and the generation of aerosols or mists. Notify the monitor of 
any unintentional occupational exposure.  A Material Safety Data Sheet (MSDS) 
describing the occupational hazards and recommended handling precautions will be 
 
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provided to site staff if required by local laws or will otherwise be available from GSK 
upon request.
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 authorised site staff.  Investigational product must 
be dispensed or administered only to subjects enrolled in the study and in accordance 
with the protocol.
GlaxoSmithKline (GSK) will provide the study treatments for use in this study. 
The following study medications will be used in this study:

UMEC/VI 62.5/ 25mcg administered via ELLIPTA

UMEC 62.5 mcg administered via ELLIPTA

Salmeterol 50 mcg administered via DISKUS

Placebo via ELLIPTA

Placebo via DISKUS
Subjects will be instructed to take one dose of medication each morning from the 
ELLIPTA (one inhalation equals one dose), and one dose in the morning and one in the 
evening from the DISKUS.  Subject instructions and details on how to use the ELLIPTA 
and DISKUS are provided in the study reference manual (SRM).
A description of the UMEC/VI investigational product administered via the ELLIPTA is 
provided below in Table 1. The ELLIPTA will contain two, double-foil, laminate, blister 
strips.  The ELLIPTA will provide a total of 30 doses (60 blisters) and will deliver, when 
actuated, the contents of a single blister simultaneously from each of the two blister 
strips. 
The DISKUS will provide a total of 60 doses and will deliver, when actuated, the 
contents of a single blister.
A description of the UMEC investigational product administered via the ELLIPTA is 
provided below in Table 2. A description of placebo inhalation powder via ELLIPTA is 
shown in Table 3.  A description of salmeterol 50mcg and placebo via DISKUS are 
shown in Table 4 and Table 5 respectively.
Table 1
Description of UMEC/VI Inhalation Powder via ELLIPTA
Formulation
First strip
Second strip
Umeclidinium bromide blended with 
lactose monohydrate and 
magnesium stearate1
Vilanterol trifenatate blended with 
lactose monohydrate and magnesium 
stearate2
Dosage Form
ELLIPTA Inhaler with 30 doses (2 strips with 30 blisters per strip)
Unit Dose Strengths
62.5 mcg
25 mcg
Physical description
White powder
White powder
Route of Administration
Inhaled
1.
Magnesium stearate 0.6% w/w of total drug product
2.
Magnesium stearate 1.0% w/w of total drug product
 
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Table 2
Description of UMEC Inhalation Powder via ELLIPTA
Formulation
First strip
Umeclidinium bromide blended with lactose monohydrate and 
magnesium stearate1
Dosage Form
ELLIPTA Inhaler with 30 doses (1 strip with 30 blisters) 
Unit Dose Strengths
62.5mcg 
Physical description
Dry white powder
Route of Administration
Inhaled
1.
Magnesium stearate 0.6% w/w of total drug product
Table 3
Description of Placebo Inhalation powder via ELLIPTA
Formulation
First strip
Second strip
Lactose monohydrate blended with 
magnesium stearate1
Lactose monohydrate blended with 
magnesium stearate2
Dosage Form
ELLIPTA Inhaler with 30 doses (2 strips with 30 blisters per strip)
Unit Dose Strengths
Not applicable
Not applicable
Physical description
Dry white powder
Dry white powder
Route of Administration
Inhaled
1.
Magnesium stearate 0.6% w/w of total drug product
2.
Magnesium stearate 1% w/w of total drug product
Table 4
Description of salmeterol Inhalation powder via DISKUS
Formulation
First strip
Salmeterol Xinafoate blended with lactose monohydrate
Dosage Form
Diskus Inhaler with 60 doses (1 strip with 60 blisters per strip)
Unit Dose Strengths
50 mcg
Physical description
White powder
Route of Administration
Inhaled
Table 5
Description of Placebo inhalation powder via DISKUS
Formulation
Lactose monohydrate 
Dosage Form
Diskus Inhaler with 60 doses (1 strip with 60 blisters per strip)
Unit Dose Strengths
Not Applicable
Physical description
White powder
Route of Administration
Inhaled
Albuterol/salbutamol via metered-dose-inhaler (MDI) will be issued for reversibility 
testing at Visit 1.  Albuterol/salbutamol MDI for as needed (prn) use will be issued 
throughout the study.  Albuterol/salbutamol will be sourced from local commercial stock 
if appropriate.  
6.2.
Medical Devices
The eMDI devices are provided by GSK and are used in this study to electronically 
record rescue medication usage.  They have US FDA 510(K) clearance to market (Class 
 
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II device) and EU CE marketing (Class I device). Description of the eMDI and its use 
will be provided in the SRM.
6.3.
Treatment Assignment
Subjects who meet the randomization criteria will be assigned to one of the 3 study 
treatments in accordance with the randomization schedule generated by Clinical 
Statistics, prior to the start of the study, using validated internal software.
Once a randomization number is assigned to a subject, it cannot be reassigned to any 
other subject in the study.
This study will utilize RAMOS NG, which will provide a means for central 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 RAMOS NG to randomize subjects is provided in the SRM.
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.  On the other days during the treatment period 
(i.e. “non-clinic days”), subjects will be instructed to self-administer their study treatment 
in the morning and evening. Subjects should enter the time they take their study treatment 
in the eDiary. 
Subjects will be randomly assigned to one of the blinded study treatment regimens in 
equal proportion (ratio of 1:1:1):

UMEC/VI 62.5/25 mcg once daily via ELLIPTA + placebo twice daily via 
DISKUS

UMEC 62.5 mcg once daily via ELLIPTA + placebo twice daily via DISKUS

Salmeterol 50 mcg twice daily via DISKUS + placebo once daily via ELLIPTA
The randomisation will be stratified based on long-acting bronchodilator usage during 
the run-in (none or one long-acting bronchodilator per day).
Study treatment/investigational product will be dispensed at Visits 2, 3 and 4. 
In order to ensure subjects have sufficient doses of study treatment, they must return to 
clinic within 30 days from V2 and 60 days from V3 respectively (see Time and event 
table Section 7.1). 
Used study drug and rescue medication will be collected at Visits 3, 4 and 5 or at the 
Early Withdrawal Visit. 
6.4.
Planned Dose Adjustments
No dose adjustment is allowed for this study
 
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6.5.
Blinding
This will be a double-blind double dummy study 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. 

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. 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.
6.6.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.7.
Preparation/Handling/Storage/Accountability
No special preparation of the study treatment is required.

The investigator or designee must confirm appropriate temperature conditions 
have been maintained during transit for all study treatment received and any 
discrepancies are reported and resolved before use of the study treatment.

Only subjects enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment.  All study 
treatments must be stored in a secure environmentally controlled and monitored 
(manual or automated) area in accordance with the 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).  
 
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
Further guidance and information for final disposition of unused study treatment 
are provided in the SRM. 
All ELLIPTA DPI study treatment should be stored up to 25C (77F).  Each 
ELLIPTA DPI contains 30 doses and is packaged in a foil pouch with a desiccant 
sachet and stored in a carton. The inhaler should not be used for more than 30 days 
after opening the foil.  The sites must maintain a daily temperature log for the 
investigational product. 
Salmeterol DISKUS should be stored up to 25 C. 
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.

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.
6.7.1.
Study Treatment Return
All used and unused ELLIPTA and DISKUS inhalers 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 SRM.
Study treatment will be collected at Visit 3, 4 and 5 or at the Early Withdrawal Visit, if 
applicable. 
For any ELLIPTA or DISKUS inhaler that fails to function properly, the subject should 
return to the clinic as soon as possible to obtain a new inhaler.  The site will contact the 
RAMOS NG 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 
RAMOS NG
In addition, any ELLIPTA that fails to function properly must be identified and returned 
to GSK for testing. 
6.8.
Compliance with Study Treatment Administration
When subjects self-administer study treatment(s) at home, compliance with study 
treatment(s) will be assessed through querying the subject during the site visits and 
through study drug compliance assessed at Visits 2, 3, 4 and 5 documented in the source 
documents and eCRF.  A record of the number of ELLIPTA and DISKUS dispensed and 
the number of doses inhaled by each subject must be maintained and reconciled with 
study treatment and compliance records.  Treatment start and stop dates, including dates 
for treatment delays if any will also be recorded in the eCRF.
 
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Compliance with the ELLIPTA inhaler will be determined by reviewing the dose counter 
on the ELLIPTA.  Compliance with the study DISKUS will be determined by reviewing 
the dose counter on the DISKUS.  Subjects should be ≥80% to ≤120% compliant on 
taking study medication between each pair of on-treatment visits.  Subjects who fall 
outside this range should be re-educated on treatment compliance by their site. This re-
education should be documented in the subject’s source document.  If medication 
compliance repeatedly falls outside of acceptable ranges, the study sponsor/site monitor 
must be contacted to discuss subject eligibility for continued participation in the study.
6.9.
Treatment of Study Treatment Overdose
An overdose is defined as a dose greater than the total doses described in Section 6.1 and 
Section 6.8 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 medication, 
the investigator should use clinical judgment in treating the overdose and contact the 
study 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 may not be limited to, the approved product label for salmeterol 
albuterol, UMEC and UMEC/VI or equivalent document provided by GSK.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the subject.
6.10.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study, since the study treatments are commercially available.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, post-study treatment. 
6.11.
Concomitant Medications and Non-Drug Therapies
All COPD medications used within 30 days prior to Pre-Screening (Visit 0) and onwards 
should be recorded in the eCRF including any changes in medications.  Beginning at 
Visit 1 and throughout the rest of the study, all medications should be recorded in the 
eCRF including any changes.  Study provided albuterol/salbutamol and double-blinded 
study drug should not be recorded in the eCRF.  The minimum requirement includes but 
is not limited to drug name, dose, route and the dates of administration.  Medications 
initiated after completion of Visit 5 or the Early Withdrawal Visit will not be recorded in 
the eCRF, with the exception of those used to treat a COPD exacerbation or SAE that 
occurs between Visit 5 (or the Early Withdrawal Visit) and the follow-up contact at Visit 
6.
 
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6.11.1.
Permitted Medications and Non-Drug Therapies
The following relevant medications are permitted during this study:

Study-provided albuterol/salbutamol for use as relief medication throughout the 
run-in and treatment periods 

Mucolytics such as acetylcysteine

Medications for rhinitis (e.g. intranasal corticosteroids, antihistamines, cromolyn, 
nedocromil, nasal decongestants)

Influenza vaccine

pneumococcal vaccine

Antibiotics for short term treatment (14 days) of acute infections including  
COPD exacerbations

Systemic corticosteroids for short term (14 consecutive days)  treatment of 
COPD exacerbations 

As-needed supplemental oxygen use provided it is ≤3L/min flow at rest at 
screening.  Patients may adjust oxygen levels as needed during the study.

Pulmonary rehabilitation program in maintenance phase

Smoking cessation treatment, including a stable regimen of nicotine replacement

Use of positive airway pressure/non-invasive ventilation for sleep apnea/sleep 
disordered breathing (e.g. CPAP, BiPAP) 

Localized corticosteroid injections (e.g., intra-articular and epidural)

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)

Immunotherapy injections

Topical or ophthalmic corticosteroids

Over-the counter (OTC) cough suppressants

Tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs). Administer 
with caution as they may potentiate the effect of beta-agonists on the vascular 
system

Diuretics. Caution is advised in the co-administration of beta agonists with non-
potassium sparing diuretics

Allergy vaccination

All medications for other disorders as long as the dose remains constant whenever 
possible and their use would not be expected to affect lung function
 
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6.11.2.
Prohibited Medications and Non-Drug Therapies
Use of the medications listed in Table 6 is not permitted during the study
Table 6
Prohibited Medications and Non-Drug Therapies
Medication
Depot corticosteroids
Systemic, oral or parenteral corticosteroids1
Inhaled corticosteroids (ICS)2
Antibiotics >14 days
LABA/ICS combination products
PDE4 inhibitor (e.g. roflumilast)
Inhaled long acting beta2-agonists (LABA, e.g. salmeterol, formoterol, indacaterol, vilanterol)3
Long-acting muscarinic antagonists (LAMA, e.g. tiotropium, aclidinium, glycopyrronium, umeclidinium)3
LAMA/LABA combination products except for study drugs
Theophyllines
Oral beta2-agonists
Inhaled short acting beta2-agonists4
Inhaled short-acting anticholinergics
Inhaled short-acting anticholinergic/short-acting beta2-agonist combination products
Any other investigational medication
1
Except for the treatment of COPD exacerbations during the study. Localized corticosteroid injections (e.g., 
intra-articular and epidural) are permitted.
2
Except if during the study use of ICS is deemed necessary for the treatment of subjects’ exacerbation. 
3
Except for study drug
4
Use of study provided albuterol/salbutamol is permitted during the study, except in the 4-hour period prior to 
spirometry testing. 
The following medications or treatments are also not allowed during the study:

Use of long-term oxygen therapy (LTOT) described as resting oxygen therapy 
>3L/min only at screening. Oxygen may be titrated to any level deemed necessary 
during the study.

Regular use (prescribed for daily/ regular use, not for as-needed use) of short-
acting bronchodilators (e.g. albuterol/salbutamol)

Initiation of pulmonary rehabilitation during the study.
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 Section 7.1, are essential and required for study 
conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table Section 7.1
 
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7.1.
Time and Events Table
Blinded Treatment
Visit
Pre-
screen1
0
Screen/ 
Run-in
1
Rando-
mization 
2
3
4
5
EW 
Visit 2
Telephone Follow up 
contact 
6
Week
-10 to -4
-4
0
4
12
24
Day
-70 to -28
-28
1
28
84
168
7 days after V5 or EW 
Visit
Window
-7/+2 days 
-7/+2 days
-7/+2 
days
-7/+2 days
-7/+2 days
-7/+2 days
3 days
Screen/Baseline
Informed consent
X
Demography
X
Medical/COPD history
X
Smoking history/status
X
Smoking cessation counselling
X
Concomitant medication assessment
X
X
X
X
X
X
X
X
Height and weight
X
Cardiovascular History/family history of premature CV 
disease])
X
Screening spirometry (including post bronchodilator 
testing)3
X
CAT questionnaire
X
X
Verify Inclusion/Exclusion Criteria
X
Training on use of inhalers
X
X
Training on use of eDiary and eMDI
X
X
Verify randomization Criteria
X
Register Visit in InForm
X
X
X
X
X
X
X
X
Register Visit in RAMOS NG
X
X
X
X
X
X
X
X
 
 
 
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Blinded Treatment
Visit
Pre-
screen1
0
Screen/ 
Run-in
1
Rando-
mization 
2
3
4
5
EW 
Visit 2
Telephone Follow up 
contact 
6
Week
-10 to -4
-4
0
4
12
24
Day
-70 to -28
-28
1
28
84
168
7 days after V5 or EW 
Visit
Window
-7/+2 days 
-7/+2 days
-7/+2 
days
-7/+2 days
-7/+2 days
-7/+2 days
3 days
Efficacy/HRQoL assessments
Spirometry, including pre-dose FEV1, trough  FEV1 and 
inspiratory capacity
X
X
X
X
SAC BDI questionnaire 4
X
SAC TDI questionnaire 4
X
X
X
SGRQ-C questionnaire 4
X
X
X
X
CAT questionnaire 4
X
X
X
X
X
EXACT/ER-S: COPD 5
Patient Global Rating of COPD severity
X
X
X
X
Patient Global Rating of Change in COPD
X
X
X
Safety assessments
Adverse events/Serious adverse events 6
X
X
X
X
X
X
X
X
COPD exacerbation assessment
X
X
X
X
X
X
X
X
12-Lead ECG
X
Urine pregnancy test 7
X
X
X
X
Pharmacogenetic sample8
                                          X
Medication/Supplies
Dispense rescue albuterol/slabutamol. Dispense MDI9
X
X
X
X
X
Assess COPD medication compliance10 during run-in
X
Dispense eDiary
X
Assess compliance with eDiary during run-in 
X
Collect rescue albuterol/slabutamol. 
X
X
X
X
X
Collect eDiary
X
X
Dispense study treatment11
X
X
X
 
 
 
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Blinded Treatment
Visit
Pre-
screen1
0
Screen/ 
Run-in
1
Rando-
mization 
2
3
4
5
EW 
Visit 2
Telephone Follow up 
contact 
6
Week
-10 to -4
-4
0
4
12
24
Day
-70 to -28
-28
1
28
84
168
7 days after V5 or EW 
Visit
Window
-7/+2 days 
-7/+2 days
-7/+2 
days
-7/+2 days
-7/+2 days
-7/+2 days
3 days
Collect study treatment
X
X
X
X
Assess study treatment compliance during treatment10
X
X
X
X
Study sub-set
Physical activity monitor12
X
X
X
X
Collect Physical activity monitor
X
X
1.
Pre-screen Visit 0 must be completed prior to Screening Visit1. It can be completed 6 weeks prior or on the same day of V1, if no wash out of exclusionary medications is 
required. 
2.
Early Withdrawal Visit: Subjects that withdraw should return to the clinic as soon as possible to complete the Early Withdrawal Visit procedures.
3.
Spirometry at screening should be performed as described in (Section 7.2.2.1). 
4.
SAC BDI, SAC TDI, SGRQ-C, CAT questionnaires will be completed at clinic visits and in the eDiary
5.
EXACT/ER-S: COPD is completed daily in the eDiary approximately 2 hours before bed-time, starting on Day 1 of the run-in period.
6.
For the start date of collecting AEs and SAEs see (Appendix 4)
7.
Pregnancy test: for females for child bearing potential only.
8.
Pharmacogenetic sample may be drawn at visit 2 or any visit after.
9.
Rescue medication use to be recorded in the eDiary daily and in some sites in the eDiary and the eMDI
10. Sites are requested to call subjects every 2 weeks to remind them to take study treatment regularly and to record the time of the morning and evening dose in the eDiary.
11. In order to ensure subjects have sufficient doses of study treatment, they must return to clinic within 30 days from V2 and within 60 days from V3 respectively.
12. The Actigraph GT9X should be worn for 7 days from Visit 1, for 7 days from Visit 2, for 7 days from Visit 3 and for 7 days prior to Visit 5.
 
 
 
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7.2.
Screening and Critical Baseline Assessments
7.2.1.
Pre-screening Visit
During the Pre-screening Visit, the study designated personnel must provide informed 
consent to the study participant.  Subjects can perform the Pre-screening Visit (Visit 0) 
up to 6 weeks prior to or on the same day as the Screening Visit (Visit 1) if subject does 
not take or has not taken any protocol excluded medications.
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.  A subject number will be assigned at the time the 
informed consent form (ICF) is signed. No study related procedures may be 
performed until the informed consent form document has been signed by the 
subject.  
Once the informed consent is signed and if required, changes can be made to the subject’s 
current medication regimen. The investigator should exercise clinical judgment, and is 
discouraged from changing medications only for the purpose of the clinical study. 
During the pre-screening Visit 0, the following information is collected:

Demographic parameters: year of birth, gender, race and ethnicity

Concomitant medications review

COPD exacerbation assessment
From the pre-screening visit onwards concomitant medications, exacerbations and SAEs 
(considered as related to study participation) must be reported
7.2.2.
Critical procedures performed at Screening (Visit 1)
The following critical assessments will be conducted at Visit 1:

Cardiovascular medical history/risk factors (as detailed in the eCRF) will be
assessed at screening

Medical history including COPD (including date of diagnosis and COPD type 
(emphysema and/or chronic bronchitis), smoking history, COPD exacerbation 
history, smoking status and previous and/or current medical conditions) 

Concomitant medication review (COPD and non COPD medications in the 3 
months prior to Screening).

Height and weight

12-Lead ECG. (Note: ECG is performed at screening Visit 1 to test for eligibility 
only. See Section 7.4.4).
 
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
Urine pregnancy test if applicable

Train subject on the use of eDiary

COPD assessment test (CAT) and patient global rating of COPD severity in 
eDiary

Pre- and post-albuterol/salbutamol spirometry (reversibility, see Section 7.2.2.1)

Inclusion/Exclusion criteria assessment

Review exacerbations, AEs, (SAEs if related to study participation)

Train subject on the proper use of their COPD medication inhalation devices

Instruct subject to take their COPD medications as instructed and to enter the time 
they take their medication in the eDiary

Dispense rescue medication
Medical history will be assessed as related to the inclusion/exclusion criteria listed in 
Section 5.1 and Section 5.2.
Assessment of subject’s health status will be made at screening using CAT.  PRO 
questionnaires should be completed by subjects before any other assessments at a clinic 
visit, in the order specified in Section 7.3.1
7.2.2.1.
Albuterol/Salbutamol Reversibility Assessment
At Visit 1, both pre- and post-albuterol/salbutamol spirometry will be obtained to 
determine subject eligibility.  Reversibility assessment should be performed as follows:

Perform pre-bronchodilator spirometry and record FEV1 and FVC

Subject to self-administer 4 Inhalations (4X100g) of albuterol/salbutamol MDI

Perform post-bronchodilator spirometry and record FEV1 and FVC approximately 
10 to 30 minutes after albuterol/salbutamol administration
The results of the spirometry must meet the ATS/ERS criteria [Miller, 2005] for 
the subject to continue in the study.
7.2.3.
Critical procedures performed at first treatment Visit (Baseline 
V2)

Review and assess  compliance with subject’s COPD medications during the run-
in period

Review and assess compliance with completing the eDiary during the run-in 
period

Review AEs, SAEs and exacerbations
 
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
Urine pregnancy test, if applicable

Baseline dyspnea Index, BDI, patient global rating of COPD severity, patient 
global rating of change in COPD, SGRQ-C and CAT questionnaires in eDiary

Review randomization criteria (Section 5.3)

Register and randomize subject in RAMOS NG

Pre-dose spirometry; IC and FEV1

Train subject on the proper use of ELLIPTA and DISKUS inhalers

Dispense study medication

Dispense rescue medication

Optional pharmacogentic sample can be collected at V2 or any visit after.
7.3.
Efficacy Assessments
7.3.1.
HRQoL assessments: Completion of PRO questionnaires in the 
Electronic Diary
All subjects will be completing PRO questionnaires in the eDiary. 
It is requested that questionnaires are completed before any procedures are performed on 
the subject. 
All questionnaires will be completed using the eDiary at clinic and at home.  Adequate 
time should be allowed to complete all items of the questionnaires and the questionnaires 
must be reviewed by the investigator or designated study staff for completeness and, if 
necessary, the subject must be encouraged to complete any missing items. Where more 
than one questionnaire is to be completed at a visit the order should be as follows:
1. Baseline dyspnea index (Visit 2) then Transient dyspnea index at subsequent 
visits
2. Patient global rating of COPD severity and global rating of change in COPD
3. St George’s respiratory questionnaire
4. COPD Assessment Test 
Instructions for completing the questionnaires can be found in the SRM.
7.3.1.1.
Self Administered Computerised Baseline Dyspnea Index/Transitional 
Dyspnea Index (SAC BDI/TDI)
The BDI is used to measure the severity of dyspnea in patients at baseline. The TDI 
measures changes in the patient’s dyspnea from baseline.  The self-administered 
computerized version of the BDI/TDI (SAC BDI/TDI)[Mahler, 2004] is used to measure 
severity of dyspnea in patients at baseline (SAC BDI) on Day 1 (Visit 2) of treatment and 
change from the baseline (SAC TDI) at Week 4, 12 and 24 (Visits 3, 4 and 5).  The 
 
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scores in both indexes depend on ratings for three different categories: functional 
impairment; magnitude of task, and magnitude of effort. SAC BDI/TDI should be 
completed before performing spirometry. 
The SAC BDI/TDI was developed to address issues of potential bias in the interviewer 
administered (original) BDI/TDI [Mahler, 1984].  The SAC BDI/TDI provides a 
standardized approach to the measurement of dyspnea, equivalent to the original 
BDI/TDI with advantages over the interviewer method for grading dyspnea in patients 
with COPD by standardizing the process for each patient and eliminating individual 
judgment required by the interviewers when completing the original BDI/TDI. This also 
removes the need for the same investigator to conduct all interviews with a subject based 
on the patient’s responses. SAC TDI provides a continuous measure of change in dyspnea 
using a visual analogue scale to record responses. 
Details for the completion of the SAC BDI/TDI are provided in the SRM.
7.3.1.2.
SGRQ-C
The St George’s Respiratory Questionnaire-Chronic Obstructive Pulmonary Disease 
specific (SGRQ-C) will be completed by subjects at Randomisation (V2, Day 1), at Week 
4, 12 and 24.
The SGRQ-C [Meguro, 2007] is a well established, disease-specific questionnaire.  It was 
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, 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 scores 
equivalent to the SGRQ instrument [Meguro, 2007].  
7.3.1.3.
COPD Assessment Test (CAT)
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.
The CAT will be completed in the eDiary by subjects at Screening Visit 1 and 
Randomisation Visit 2 to assess their eligibility to enter the study.  CAT is also 
completed at Weeks 4, 12 and 24.  Additional instructions for completion of the CAT are 
provided in the SRM.
 
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7.3.1.4.
EXACT and the Evaluating Respiratory Symptoms- COPD (E-RS: 
COPD)
EXACT-PRO is a 14 item patient reported outcome instrument designed to capture 
information on the occurrence, frequency, severity, and duration of exacerbations of 
disease in patients with COPD [Leidy, 2011].  EXACT captures information on the 
severity of the respiratory and systemic manifestations of a COPD exacerbation as 
reported by the patient.  The instrument is to be completed daily (typically 2 hrs before 
bedtime) using the electronic diary.  The daily recording of information allows an 
assessment of the underlying day to day variability of a patient's symptoms and facilitates 
the detection of symptom worsening indicative of a COPD exacerbation.  The total score 
for EXACT ranges from 0-100.  The entire instrument is intended to be completed in 
about 3 minutes or less (typically the time required for completion decreases as the 
patient becomes more familiar with the tool and the electronic diary).
The E-RS: COPD consists of 11 items from the 14 item EXACT instrument [Leidy, 
2014].  E-RS: COPD is intended to capture information related to the respiratory 
symptoms of COPD, i.e. breathlessness, cough, sputum production, chest congestion and 
chest tightness.  The E-RS: COPD has a scoring range of 0-40 higher scores indicate 
more severe symptoms.
Three subscales of the E-RS are used to describe different symptoms; dyspnea, cough and 
sputum and chest symptoms.
The EXACT questionnaire will be completed by subjects in the eDiary, at home every 
night throughout the entire study, starting from Screening V1 
7.3.1.5.
Subject Global Rating of COPD Severity and Global Rating of Change 
in COPD
Subjects will complete the Global Rating of COPD Severity at Randomization Visit 2 
and visits 3, 4 and 5.  This single global question will ask subjects to rate their severity of 
COPD on a four point scale (mild, moderate, severe, and very severe).
This question should be used immediately before the patient completes other visit 
specific questionnaires but after completion of SAC TDI questionnaire. 
Subjects will also complete a Global Rating of Change in COPD (overall disease) 
question at Visits 3, 4 and 5.  Response options will be on a 7 point Likert scale ranging 
from much better to much worse.  Completing the question at each Visit allows for early 
detection of response as well as continued response.
7.3.2.
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 standardized spirometry equipment provided by an external vendor.
All subjects will have spirometry performed at Screening to assess eligibility (see Section 
7.2.2.1) and at Visits 2, 3, 4 and 5 during the treatment period.
 
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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 (i.e. a plateau in the volume time curve) and be free from 
artifacts due to cough, early termination, poor effort, obstructed mouthpiece, equipment 
malfunction, or other reasons [Miller, 2005].
The largest FEV1 and FVC from the 3 acceptable efforts should be recorded, even if they 
do not come from the same effort.
Spirometry for FEV1 and FVC assessments that is not obtained as follows will be 
considered a protocol deviation:

Started between 6:00AM and 11:00AM.

After withholding albuterol/salbutamol (all visits) for ≥4 hours

At Screening Visit 1, after wash out of medications as specified in the exclusion 
criteria in Section 5.2 (Concomitant Medications).

At Screening Visit 1, before subject’s morning dose of inhaled LABA or LAMA
COPD medication

At Visit 2 after withholding the morning dose of inhaled LABA or LAMA COPD 
medication and prior to administration of study medication

At Visit 3, 4 and 5 after withholding the morning dose of study treatment.

Pre dose assessment performed prior to dosing.
Subjects should refrain from smoking for 1 hour prior to each pulmonary function test.
Trough FEV1 measurements for UMEC/VI or UMEC on Weeks 4, 12 and 24 (Visits 3, 4 
and 5) should be performed 23 hours and 24 hours after the previous day’s dose of study 
medication recorded in the eDiary. This will also provide trough FEV1 measurements for 
the evening dose of salmeterol. 
7.3.3.
Inspiratory capacity (IC)
Inspiratory capacity (IC) is the volume of gas that can be taken into the lungs in a normal 
and full inhalation. Starting from the resting inspiratory position it is equal to the tidal 
volume plus the inspiratory reserve volume.  IC has been widely used to assess static and 
dynamic hyperinflation in patients with COPD.
IC will be measured by spirometry prior to forced manoeuvres pre-dose at Visits 2 (30 
and 5 min prior to dosing) and at trough at Visits 3, 4, and 5 (23 and 24 hrs post dosing 
on the previous day). For IC determination the average of at least three acceptable 
manoeuvres should be recorded.  Subjects should be tested while sitting, relaxed and 
wearing a nose clip.  They should be asked to breathe regularly for several breaths until 
the end-expiratory lung volume is stable (this usually requires at least three tidal 
manoeuvres) then urged to take a deep breath to Total Lung Capacity (TLC) with no 
hesitation.
 
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Spirometry for IC determination done in conjunction with FEV1 and FVC assessments 
that is not obtained as follows will be considered a protocol deviation:

Started between 6:00AM and 11:00AM.

After withholding albuterol/salbutamol (all visits) ≥4 hours 

At Visit 2 after discontinuation of run-in LABA or LAMA COPD medication and 
prior to administration of study medication

At Visit 3, 4 and 5 after withholding the morning dose of study drug 
7.3.4.
COPD Exacerbation
A mild exacerbation is defined as worsening of symptoms that require no treatment with 
antibiotics or steroids, and is self managed by the patient by an increase of inhaled rescue 
medications. A moderate COPD exacerbation is defined as worsening symptoms of 
COPD that require treatment with oral/systemic corticosteroids and/or antibiotics. A 
severe exacerbation is defined as worsening symptoms of COPD that require in-patient 
hospitalization or emergency room for longer than 24 hrs. 
If a subject experiences a mild, moderate or severe COPD exacerbation, the COPD 
exacerbation page of the eCRF should be completed. COPD exacerbations should not be 
recorded as an AE, unless they meet the definition of a SAE. Details of COPD 
exacerbation identification, categorization and treatment guidelines are described in 
Appendix 5.
Subjects who experience a mild exacerbation during the run-in period will not be 
withdrawn from the study. However, subjects who experience moderate or severe 
exacerbation during the run-in period will be withdrawn from the study and will not be 
allowed to be re-screened. 
Subjects, who experience a mild, moderate or severe exacerbation during the treatment 
period, will not be withdrawn from the study unless the investigator or GSK medical 
monitor thinks it is best for the patient to withdraw from the study.
Signs and symptoms of COPD included on the electronic diary cards will not be 
considered AEs and will not be recorded in the eCRF.
The time period for collection of COPD exacerbations will be from the Pre-Screening 
(Visit 0) until completion of the follow-up contact.  If a subject experiences a COPD 
exacerbation from the time the ICF is signed until randomization, summary information 
(yes/no status question) will be collected in the eCRF. COPD exacerbations after 
randomization through follow-up will be recorded on the COPD exacerbation page of the 
eCRF.
7.3.5.
Clinically important deterioration (CID)
Clinically important deterioration (CID) is a composite endpoint defined as:
 
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
A decrease of  100 mL from baseline in trough FEV1

A deterioration in HRQoL defined as 4 units increase from baseline in 
SGRQ

The occurrence of an on-treatment moderate/severe COPD exacerbation
In addition, this study will explore CAT and TDI PROs as part of the composite 
endpoint.
7.3.6.
Rescue albuterol/salbutamol use
Subjects will record the number of daily albuterol/salbutemol puffs they use in the 
eDiary.  In addition, in some countries and selected sites the number of puffs will be 
collected through the eMDI device (Section 6.2) 
7.3.7.
Physical activity monitor (study subset)
Physical activity limitation is a common feature of COPD and its measures are highly 
related to the degree of disease severity [Watz, 2009]. 
Reduced physical activity levels in COPD is associated with increased morbidity and 
mortality, sustained disability, depression, and social and physical isolation [Shu-Yi, 
2014; Gimeno, 2014] 
Improved activity has been identified as an important factor that may modify morbidity 
and mortality in COPD [Moy, 2012].
The Actigraph GT9X physical activity monitor will be used to measure levels of activity. 
The activity monitor will be worn by up to approximately 150 subjects per treatment arm 
for 7 days from Screening (Visit 1), for 7 days from Randomisation (Visit 2), 7 days from 
Visit 3 (Week 4) and for 7 days prior to Week 24 (Visit 5).
There will be 4 assessment periods, including a screening assessment in order to provide 
a reliable estimate of habitual physical activity. Each subject will be given an activity 
monitor and instruction leaflet at the start of each assessment period. Further details of 
distribution, operation and retrieval of the monitors will be provided in the SRM.
7.4.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1)
Safety endpoint includes:

Incidence of adverse events
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 4.
 
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The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
7.4.1.1.
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 7.4.1.3), at the timepoints 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 CRF.

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 12.4.4 to Section 12.4.6)
7.4.1.2.
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?
7.4.1.3.
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). 
 
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7.4.1.4.
Pneumonia Events
Investigators will be required to fill out a pneumonia event specific eCRF within one 
week of when the pneumonia AE/SAE(s) is first reported. 
7.4.1.5.
Cardiovascular and Death Events
For any cardiovascular events detailed in (Section 12.4.3) and all deaths, whether or not 
they are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF 
will be required to be completed. These sections include questions regarding 
cardiovascular (including sudden cardiac death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
7.4.1.6.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
The following disease related events (DREs) are common in subjects with COPD and can 
be serious/life threatening:

COPD exacerbation
COPD exacerbations are associated with the disease to be studied and will not be 
recorded as AEs unless the exacerbation meets the definition of a ‘serious’ AE. 
Exacerbations that meet the definition of ‘serious’ AEs will be recorded on the 
appropriate eCRF section and should be reported to GSK for all subjects regardless of 
whether or not they are randomized to study medication. Signs and symptoms of COPD 
included on the electronic diary will not be considered AEs and will not be recorded in 
the eCRF
7.4.1.7.
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.
 
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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.
7.4.1.8.
Additional Adverse Event (AE) Reporting Requirements for Canadian 
investigators
Health Canada requires pharmaceutical manufacturers to expeditiously report domestic 
cases of unusual failure in efficacy (UFIE) for new drugs to the Marketed Health 
Products Directorate (MHPD) within 15 days of first notification. This regulation applies 
to marketed drugs, and used as directed per the Canadian prescribing information, 
including those drugs used in Phase IV (non CTA filed) clinical trials.  
Adverse event (AE): Any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment. An AE can therefore 
be any unfavourable and unintended sign (including an abnormal laboratory finding) 
symptom or disease (new or exacerbated) temporally associated with the use of a 
Medicinal Product. For a marketed Medicinal Product, this can also include failure 
to produce expected benefits (i.e. lack of efficacy, with or without an adverse event), 
In order for GSK to comply this Canadian regulatory requirement, Canadian investigators 
are required to collect, record and report lack of efficacy events as per the table in 
Appendix 4 Section 12.4.1.  
All paper forms are required to be faxed to GSK Canada’s Drug Safety department at 
 within 24 hrs of first awareness.
7.4.2.
Pregnancy

Details of all pregnancies in female subjects will be collected after the start of 
Screening and until the follow-up contact. 

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 7.
7.4.3.
Medical Device Incidents (Including Malfunctions)
Procedures for documenting medical device incidents are provided in Appendix 6.
7.4.4.
Electrocardiogram (ECG)
A Single 12-lead ECG will be obtained at Screening using an ECG machine provided by 
the investigational site that automatically calculates the heart rate and measures PR, QRS, 
QT, and QTc intervals.
 
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The 12-lead ECG measurement and rhythm strip (10 seconds) will be obtained before 
spirometry testing. ECG measurement should be obtained after subjects have rested for 
approximately 5 minutes then the subjects should be placed in the supine position for the
ECG measurements.  An ECG is only required at Screening Visit 1 for eligibility 
assessment only. 
The investigator, a designated sub-investigator, or other appropriately trained site 
personnel will be responsible for performing and interpreting the 12-lead ECG at 
Screening Visit 1. The investigator must provide his/her dated signature on the original 
paper tracing, attesting to the authenticity of the ECG machine interpretation. 
7.5.
Genetics
Information regarding genetic research is included in Appendix 3
8.
DATA MANAGEMENT

For this study subject data will be entered into GSK defined CRFs, 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.  

CRFs (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 purpose of this study is to demonstrate improvements in lung function for 
subjects treated with UMEC/VI compared with UMEC for 24 weeks. 
The primary endpoint is change from baseline in trough FEV1 at Week 24.
The null hypothesis is no difference between treatment groups (H0: μT – μS = 0), with 
the alternative hypothesis that there is a difference between treatment groups (H1: μT –
μS ≠0), where μT is the mean change from baseline for UMEC/VI and μS is the mean 
change from baseline for UMEC. 
 
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9.2.
Sample Size Considerations
The primary endpoint is change from baseline in trough FEV1 at Week 24. As an 
important aim of the study is to compare UMEC/VI, UMEC and salmeterol with respect 
to HRQoL the sample size has been calculated to provide sufficient power for the 
comparison of the primary and secondary endpoint TDI, at Week 24.  
The sample size calculations use a two-sided 5% significance level and an estimate of 
between subject standard deviation for TDI of 2.94 units.  The estimate of SD is based on 
DB2113373 [Donohue, 2013], a study which consisted of treatment arms of UMEC/VI 
62.5/25, UMEC 62.5 VI (Vilanterol) 25mcg and placebo and is the value at Day 168 in a 
subgroup of subjects who were ICS free at screening.  Based on these data, 727 evaluable 
subjects per treatment arm will be required to provide 90% power to detect a statistically 
significant difference if the true difference is 0.5 units, ½ the MCID, between UMEC/VI 
and UMEC. The smallest observed effect predicted to result in a statistically significant 
difference between treatment groups is 0.31 units.
With this number of evaluable subjects per arm, the study will have >99% power 
assuming a true treatment difference of 80mL between UMEC/VI and UMEC for trough 
FEV1 at 24 weeks at the two-sided 5% significance level. This calculation uses a SD for 
trough FEV1 of 240mL, based on prior results for trials comparing dual bronchodilators 
versus single bronchodilators (Donohue, 2013; Bateman, 2013). The smallest observed 
effect predicted to result in a statistically significant difference between treatment groups 
is 25mL. 
In order to account a for a 10% withdrawal rate, approximately 808 subjects per 
treatment arm will be randomised.
9.2.1.
Sample Size Sensitivity
The assumption of a SD of 2.94 units for the TDI total score is based on estimates from 
previous studies. The following table presents the power achieved with the proposed 
sample size of 727 randomised subjects per arm, should the assumption around the SD of 
the data change. 
The actual assumptions used in the sample size calculation are shaded.
Endpoint 
Between 
subject SD
Treatment Difference
Power
TDI
2.54
0.5
96%
2.74
0.5
94%
2.94
0.5
90%
3.14
0.5
86%
3.34
0.5
81%
 
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9.2.2.
Sample Size Re-estimation or Adjustment
No sample size re-estimation is planned for this study. 
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 and received at least 
one dose of study medication. 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.

Displays will be based on the treatment to 
which the subject was randomized.

Study Population

Efficacy

Safety
Intent-to-
treat ICS 
free (ITT 
ICS free)

All subjects in the ITT Population who have 
not received ICS.

Study Population

Efficacy

Safety
9.3.2.
Interim Analysis
No interim analysis is planned for the study.
9.4.
Key Elements of Analysis Plan
Treatment Comparisons
The primary treatment comparison of UMEC/VI with UMEC will be performed on the 
ITT population.
 
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The other treatment comparisons of UMEC/VI and UMEC with Salmeterol will be 
performed on the ITT population and ITT ICS free population.
9.4.1.
Primary Analyses
The treatment comparison of primary interest will be UMEC/VI versus UMEC for the 
primary endpoint of change from baseline in trough FEV1 at Week 24. The primary 
analyses will be performed using a mixed model repeated measures (MMRM) analysis 
and will be based on a two-sided hypothesis testing approach on the ITT Population. 
In order to account for multiplicity across treatment comparisons and endpoints, a step-
down closed testing procedure will be applied whereby inference for secondary and other 
endpoints or treatment comparisons are dependent upon statistical significance having 
been achieved for the primary comparison. If the primary comparison is significant i.e. 
the associated p-value for UMEC/VI versus UMEC for change from baseline in trough 
FEV1 at Week 24 is below 0.05, this will allow inference of treatment comparisons 
(UMEC/VI versus UMEC on all other endpoints, and UMEC/VI versus Salmeterol and 
UMEC versus Salmeterol on all endpoints including the primary endpoint), which will be 
declared statistically significant if the associated p-value is below 0.05.  
There will be 2 analyses one for one for the German Federal Joint Committee (G-BA) 
and one for the rest of the world (ROW).
The step-down closed testing procedure only applies to the ROW.  For the G-BA 
statistical inference for secondary and other endpoints or treatment comparisons will not 
be conditional on achieving statistical significance of the primary comparison.  
The primary endpoint of mean change from baseline in trough FEV1 at the end of Week 
24 and secondary endpoint change from baseline in TDI score at Week 24 will both be 
analysed using MMRM analysis. The MMRM analysis for change from baseline in 
trough FEV1 and TDI will include measurements at Treatment Weeks 4, 12 and 24. 
Treatment group (a categorical variable) will be fitted as the explanatory variable with 
appropriate pre-defined variables, stratum (number of bronchodilators per day during 
run-in) and baseline values, fitted as covariates. Visit (nominal) will be fitted as a 
categorical variable and visit-by-baseline and visit-by-treatment interaction terms will be 
included to allow treatment effects to be estimated at each visit separately. The variance 
covariance matrix will be assumed to be unstructured (based on previous experience no 
issues are expected with fitting models with this matrix structure). 
While missing data are not explicitly imputed in the primary MMRM analyses, there is 
an underlying assumption that the data are missing at random. 
The estimated treatment differences between UMEC/VI versus UMEC for each endpoint 
will be presented with the 95% confidence intervals for the difference and the p-value. 
Full details of the analyses to be performed on all primary endpoints will be given in the 
RAP.
 
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9.4.2.
Other Analyses
The MMRM analysis will be repeated for the ITT ICS free population. Estimated 
differences between UMEC/VI or UMEC and Salmeterol will be presented together with 
95% confidence intervals (CIs) for the difference and p-values.
Secondary and other efficacy endpoints and treatment comparisons will be adjusted for 
multiplicity as per Section 9.4.1.
Full details of the analyses to be performed on the other efficacy endpoints will be given 
in the RAP.
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. 
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.
Study site Investigators will be selected to participate in the 201749 study based upon 
their pulmonology expertise and knowledge of the protocol defined patient population 
and associated required study assessments.
 
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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 
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 eCRF
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
 
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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.  

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.  
 
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
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.
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 randomization 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.
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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.
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, P., 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
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. 
Leidy NK, Sexton CC, Jones PW, Notte SM. et al. Measuring respiratory symptoms in 
clinical trials of COPD: reliability and validity of a daily diary. Thorax 2014; 69:5 424-
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Leidy NK, Wilcox TK, Jones PW, Roberts L, Powers JH, Sethi S. Standardizing 
measurement of chronic obstructive pulmonary disease exacerbations. Reliability and 
validity of a patient-reported diary. Am J Respir Crit Care Med 2011; 183:323-329 
Mahler DA, Ward J, Fierro-Carrion G, et al. Development of self-administered versions 
of modified baseline and transition dyspnea indexes in COPD. J COPD 2004; 165–172
Mahler DA, Weinberg DH, Wells CK, Feinstein AR. The measurement of dyspnea. 
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Maleki-Yazdi MR, Kaelin T, Richard N, Zvarich M, Church A. Efficacy and safety of 
umeclidinium/vilanterol 62.5/25 mcg and tiotropium 18 mcg in chronic obstructive 
pulmonary disease: results of a 24-week, randomized, controlled trial. Respiratory 
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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
CAT
COPD Assessment Test
CI
Confidence Intervals
CID
Clinically important deterioration 
COPD
Chronic Obstructive Pulmonary Disease
CPK
Creatine phosphokinase
CRF
Case Report Form
CV
Cardiovascular
DPI
Dry Powder Inhaler
DRE
Disease Related Event
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eDiary
Electronic Diary
eMDI
Electronic Metered Dose Inhaler
E-RS
Evaluating Respiratory Symptoms- COPD  Tool
ERS
European Respiratory Society
FEV₁
Forced Expiratory Volume in One Second
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GOLD
Global Initiative for Chronic Obstructive Lung Disease
GSK
GlaxoSmithKline
IB
Investigator Brochure
ICF
Informed Consent Form
ICS
Inhaled Corticosteroid
IEC
Independent Ethics Committee
IP
Investigational product
INR
International normalized ratio
IRT
Interactive Response Technology
ITT
Intent-to-Treat
IUD
Intrauterine Device
IUS
Intrauterine System
LABA
Long Acting Beta-Agonist
LAMA
Long-acting Muscarinic Receptor Antagonists
LDH
Lactate dehydrogenase
LTOT
Long Term Oxygen Therapy
 
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mcg
Microgram
MCID
Minimal Clinically Important Difference
MDI
Metered Dose Inhaler
mL
Milliliter
mMRC
Modified Medical Research Council
MMRM
Mixed Models Repeated Measures
MSDS
Material Safety Data Sheet
NYHA
New York Heart Association
OTC
Over the Counter
PGx
Pharmacogenetic
PIL
Patient Information Leaflet
PK
Pharmacokinetic
PP
Per Protocol
prn
As required
QTc
QT interval corrected for heart rate
RAP
Reporting and Analysis Plan
SABA
Short Acting Beta-Agonist
SAE
Serious Adverse Event
SD
Standard Deviation
SmPC
Summary of Product Characteristics
SRT
Safety Review Team
TDI
Transition Dyspnea Index
RAMOS NG
Randomization and medication ordering system new 
generation
ULN
Upper Limit of Normal
UMEC
Umeclidinium (GSK573719)
UMEC/VI
Umeclidinium & Vilanterol as a fixed dose combination
VI
Vilanterol Trifenate 
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
ANORO
E-RS
DISKUS
EXCACT
ELLIPTA
INCRUSE
SEREVENT
 
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12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments
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 normal 
ranges. baseline (see MONITORING below)

Do not restart/rechallenge subject with 
study treatment. 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 

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 a week after last 
dose6

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form
including acetaminophen, herbal 
 
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Liver Chemistry Stopping Criteria - Liver Stopping Event
liver event follow up assessments within  24 
hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to 
within normal ranges.

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 normal ranges.
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
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 SRM.  
 
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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 etiology 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 any concomitant medicines;

COPD susceptibility, severity, and progression of 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.
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.
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.  
 
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
A 6 ml blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. 
A blood sample is collected at the baseline visit, after the subject has been 
randomized and 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 being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA 
sample is retained

Discontinue participation in the genetic research and destroy the genetic DNA 
sample 
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. 
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis. 
 
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
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.
 
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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. Reporting Specific to Canada: For a 
marketed medicinal product, this can also include failure to produce expected 
benefits (i.e. lack of efficacy, with or without associated signs or symptoms or 
clinical sequelae).

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).

Excluding Canada, "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.

Reporting Specific to Canada: "Lack of efficacy" or "failure of expected 
pharmacological action" will be reported as an AE or SAE as per the table below
 
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Adverse 
Event 
criteria
Electronic case record 
form (eCRF) only
Paper form only
Electronic case 
record form 
(eCRF) + Paper 
form
Non serious 
Non drug related lack of 
efficacy reports with 
associated signs or 
symptoms or clinical 
sequelae 
Drug related lack of 
efficacy reports 
without associated 
signs or symptoms or 
clinical sequelae.
Drug related lack 
of efficacy with 
associated signs or 
symptoms or 
clinical sequelae  
Serious
Non drug related lack of 
efficacy reports with 
associated signs or 
symptoms or clinical 
sequelae 
Drug related lack of 
efficacy reports 
without associated 
signs or symptoms or 
clinical sequelae. 
Drug related lack 
of efficacy reports 
with associated 
signs or symptoms 
or clinical sequelae
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 
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., hospitalization 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:
 
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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 hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization 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 hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption
e.
Is a congenital anomaly/birth defect
f.
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 hospitalization 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 hospitalization, 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.
 
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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

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 electronic CRF and/or paper form as applicable. 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.
 
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
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 
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
 
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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 
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

Reporting Specific to Canada: For lack of efficacy reports, the paper form will be 
used to submit to GSK as per the table in Section 12.4.1 above. 

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

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 
 
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Monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
 
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12.5.
Appendix 5: COPD Exacerbation Identification, 
Categorization and Treatment Guidelines
12.5.1.
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 usage in their 
daily eDiary 

If the subject seeks emergency/acute care for worsening respiratory symptoms, 
he/she should request the caring Health Care Provider (HCP) to contact the 
Investigator as soon as possible.
Subjects with worsening respiratory symptoms will be classified as having:

A mild/moderate/severe exacerbation and/or pneumonia
OR

A Lower Respiratory Tract Infection (LRTI)
 
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
Background variability of COPD

A non-respiratory related disease

Other respiratory related disease
12.5.2.
COPD Exacerbation Severity
Each COPD exacerbation will be categorized based on severity as follows:
Moderate:  Worsening symptoms of COPD that require treatment with 
oral/systemic corticosteroids and/or antibiotics.
Severe: Worsening symptoms of COPD that require treatment with in-patient 
hospitalization or 24 hrs in the emergency room.
Chest X-Ray for pneumonia and/or moderate/severe exacerbation is not mandated but 
can be performed if required by the investigator as part of standard care of subjects.
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.
12.5.3.
Treatment of COPD Exacerbations
All medications used for the treatment of exacerbations must be recorded in the source 
documents and the exacerbation page of the eCRF.  All sites should follow the protocol 
treatment guidelines (as outlined below), but any medications deemed medically 
necessary may be used to treat a COPD exacerbation. However, caution is advised in 
using a LABA or LAMA to treat a subject currently taking IP as these additional 
medications may increase the risk of overdose. If necessary the PI or other health care 
personnel may stop the subject’s IP temporarily in order to treat the COPD exacerbation.
12.5.4.
Guidelines for Treatment with Corticosteroids
If in the opinion of the Investigator/treating physician the exacerbation is severe enough 
to warrant the need for oral or systemic corticosteroids (with or without antibiotics) the 
following guidelines should be used.

The duration of treatment with oral/systemic corticosteroids should be 14 days 
(dose and type according to local practice) 

The duration of treatment with oral/systemic corticosteroids should not exceed 14 
days unless approval is given by the sponsor or representative

Any course of oral/systemic corticosteroids started within 7 days of finishing a 
previous course will be considered as treatment for a single exacerbation
 
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12.5.5.
Guidelines for Treatment with Antibiotics
If there is evidence of respiratory infection that in the opinion of the Investigator or 
treating physician warrants the need for antibiotics the following guidelines should be 
followed:

The duration of treatment with antibiotics should not exceed 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 
12.5.6.
Onset and Resolution of COPD Exacerbations
For each mild, moderate and severe exacerbation, the date of onset and the date of 
resolution will be recorded in the study source documents and eCRF.
The date of onset is the first day (of at least 2 consecutive days) of worsening symptoms 
of COPD as described in Section 12.5.1.
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.
12.5.7.
Guideline for assessing multiple mild exacerbations
Two mild exacerbations can be combined into one, per the Investigator’s judgement, if a 
subject’s diary reveals that the two mild COPD exacerbations are separated by no more 
than three exacerbation free days.
12.5.8.
Guideline for assessing exacerbations that increase in severity
If an exacerbation starts off as mild, but becomes moderate or severe or starts off as 
moderate and becomes severe, the exacerbation should be captured as one exacerbation 
and classified by its highest level of severity.
 
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12.6.
Appendix 6: Definition of and Procedures for Documenting 
Medical Device Incidents
12.6.1.
Definitions of a Medical Device Incident
The detection and documentation procedures described in this protocol apply to all GSK 
medical devices provided for use in the study (see Section 6.2 for the list of GSK medical 
devices).
Medical Device Incident Definition:

Incident – Any malfunction or deterioration in the characteristics and/or performance 
of a device, as well as any inadequacy in the labeling or the instructions for use 
which, directly or indirectly, might lead to or might have led to the death of a 
patient/user/other persons or to a serious deterioration in their state of health.

Not all incidents lead to death or serious deterioration in health.  The non-occurrence 
of such a result might have been due to other fortunate circumstances or to the 
intervention of health care personnel.
It is sufficient that:

an incident associated with a device happened and

the incident was such that, if it occurred again, might lead to death or a serious 
deterioration in health.

A serious deterioration in state of health can include:

life-threatening illness

permanent impairment of body function or permanent damage to a body structure

a condition necessitating medical or surgical intervention to prevent one of the 
above 

fetal distress, fetal death or any congenital abnormality or birth defects
Examples of incidents

a patient, user, care giver or professional is injured as a result of a medical device 
failure or its misuse

a patient’s treatment is interrupted or compromised by a medical device failure

misdiagnosis due to medical device failure leads to inappropriate treatment

a patient’s health deteriorates due to medical device failure
 
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12.6.2.
Documenting Medical Device Incidents
Medical Device Incident Documenting:

Any medical device incident occurring during the study will be documented in the 
subject’s medical records, in accordance with the investigator’s normal clinical 
practice, and on the appropriate form.

For incidents fulfilling the definition of an AE or an SAE, the appropriate AE/SAE 
CRF page will be completed as described in Appendix 4.

The form will be completed as thoroughly as possible and signed by the investigator 
before transmittal to GSK.

It is very important that the investigator provides his/her assessment of causality to 
the medical device provided by GSK at the time of the initial report, and describes 
any corrective or remedial actions taken to prevent recurrence of the incident.

A remedial action is any action other than routine maintenance or servicing of a 
device where such action is necessary to prevent recurrence of an incident. This 
includes any amendment to the design to prevent recurrence.
 
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12.7.
Appendix 7: Modified List of Highly Effective Methods for 
Avoiding Pregnancy in FRP and Collection of Pregnancy 
Information
12.7.1.
Modified List of Highly Effective Methods for Avoiding Pregnancy 
in Females of Reproductive Potential (FRP)
The list does not apply to FRP with same sex partners or for subjects who are and will 
continue to be abstinent from penile-vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyle. Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.
1.
Contraceptive subdermal implant
2.
Intrauterine device or intrauterine system
3.
Combined estrogen and progestogen oral contraceptive [Hatcher, 2011]
4.
Injectable progestogen [Hatcher, 2011]
5.
Contraceptive vaginal ring [Hatcher, 2011]
6.
Percutaneous contraceptive patches [Hatcher, 2011]
7.
Male partner sterilization 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, 2011]. The documentation on male sterility can come from the site 
personnel’s: review of subject’s medical records, medical examination and/or semen 
analysis, or medical history interview provided by her or her partner.
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
12.7.2.
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 fetal status (presence or 
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.
 
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
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. 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 be withdrawn from the study
 
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12.8.
Appendix 8: Country Specific Requirements
In Canada only, additions were made to Section 7.4.1 and Appendix 4 to comply with 
Health Canada guidelines concerning the requirement of pharmaceutical manufacturers to 
expeditiously report domestic cases of unusual failure in efficacy (UFIE) for new drugs 
to the Marketed Health Products Directorate (MHPD) within 15 days of first notification.
 
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12.9.
Appendix 9: Protocol changes
Revision History
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2016-SEP-13
Original
2016N277425_01
2017-FEB-07
Amendment No. 1
2016N277425_02
2017-FEB-21
Amendment No. 2 Canada 
only
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2017-APR-18
Amendment No. 3
12.9.1.
Protocol Amendment 1
Scope:
This amendment applies to all sites
Protocol Changes for Amendment No.1 are summarised below.
Strike through text refers to deleted text and underlined refers to added text.
Protocol Changes:
Title
Rationale for change:  Correct a typographical error in the title: Umeclidimium to 
Umeclidinium
Regulatory Agency Identifying Number(s):  
Rationale for change:  To correct a typographical error of the EudraCT no. and add an 
IND no.
Revised text: EudraCT no 2016-002513-226, 2016-002513-22 , IND no. 104479
 
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Section 1
Overall Design
Rationale for change: To Correct a typographical error in the last paragraph.
Revised text: Salmeterol, salbutamol
“This is a multi-centre, randomized, double blind, double-dummy, 3-arm parallel group 
study.  Eligible subjects will be stratified based on long-acting bronchodilator usage 
during the run-in (none, one or 2 long-acting bronchodilators per day) and randomized in 
a ratio of 1:1:1 to UMEC/VI inhalation powder (62.5/25 mcg once daily) administered 
via the ELLIPTA inhaler, or UMEC (62.5 mcg once daily) administered via the 
ELLIPTA or salmeterol (50 mcg BID) administered via the DISKUS. 
There will be a total of 5 clinic visits and one follow-up phone call (Visit 6). The Pre-
screening Visit (Visit 0) can occur on the same day as the Screening Visit (Visit 1) if 
subject does not take or has not taken any excluded protocol medications, but must be 
completed prior to initiating any Visit 1 procedures. 
Subjects, who meet all the eligibility criteria at Screening, will enter a run-in period for 4 
weeks in order to continue to assess the subject’s eligibility for the study. During the run-
in period subjects will continue with their inhaled COPD medications (excluding ICS and 
any exclusionary medications).  In addition, subjects will be provided with short acting 
albuterol/salmeterol salbutamol to be used on as needed basis for relief of COPD 
symptoms (rescue medication) throughout the study”. 
Section 4.4 Design justification: To be consistent with Section 7.3.1.5 and Section 7.1 
the wording has been updated.
Rationale for change: Ensure consistency with Section 7.3.1.5 and Section 7.1 the 
wording has been changed in paragraph 5.
Revised text: “Other endpoints such SAC TDI, E-RS, SGRQ-C, CAT, Subject Global 
Rating of COPD Severity and Change in Global Rating impression of Change in COPD  
disease severity are captured to allow responder analyses and to provide comparative data 
on PROs between the treatment groups”. 
Section 7.1 Time and Event table
Rationale for change; to:
Correct an un-intentional deletion of the (“x”) in some cells and confirm that concomitant 
medications should be reviewed at every clinic visit.
Increase the visit window from 2 days to -7/+2
Ensure consistency of wording between Section 7.2 and Table 7.1. “Written” was deleted
Include height and weight at Screening and correct errors in foot note no.11
“In order to ensure subjects have sufficient doses of study treatment, they must return to 
clinic within 30 days from V2 and within 60 and 90 days from V3 and V4 respectively”
 
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Blinded Treatment
Visit
Pre-
screen1
0
Screen/ 
Run-in
1
Rando-
mization 
2
3
4
5
EW 
Visit 2
Telephone Follow up 
contact 
6
Week
-6 to -4
-4
0
4
12
24
Day
42 2
-7/+2 
days 
prior 
Visit 1
28 2
-7/+2 days 
prior Visit 
2
12 -7/+2 
days
28 2 -7/+2 
days 
84 2 
days
168 2 -7/+2 
days
72 3 days after V5 
or EW Visit
Screen/Baseline
Written Informed consent
X
Demography
X
Medical/COPD history
X
Smoking history/status
X
Smoking cessation counselling
X
Concomitant medication assessment
X
X
X
X
X
X
X
X
Height and weight
X
Cardiovascular History/family history of premature CV 
disease])
X
Screening spirometry (including post bronchodilator 
testing)3
X
CAT questionnaire
X
X
Verify Inclusion/Exclusion Criteria
X
Training on use of inhalers
X
X
Training on use of eDiary and eMDI
X
X
Verify randomization Criteria
X
Register Visit in InForm
X
X
X
X
X
X
X
X
Register Visit in RAMOS NG
X
X
X
X
X
X
X
X
 
 
 
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Blinded Treatment
Visit
Pre-
screen1
0
Screen/ 
Run-in
1
Rando-
mization 
2
3
4
5
EW 
Visit 2
Telephone Follow up 
contact 
6
Week
-6 to -4
-4
0
4
12
24
Day
42 2
-7/+2 
days 
prior 
Visit 1
28 2
-7/+2 days 
prior Visit 
2
12 -7/+2 
days
28 2 -7/+2 
days 
84 2 
days
168 2 -7/+2 
days
72 3 days after V5 
or EW Visit
Efficacy/HRQoL assessments
Spirometry, including pre-dose FEV1, trough  FEV1 and 
inspiratory capacity
X
X
X
X
SAC BDI questionnaire 4
X
SAC TDI questionnaire 4
X
X
X
SGRQ-C questionnaire 4
X
X
X
X
CAT questionnaire 4
X
X
X
X
X
EXACT/ER-S: COPD 5
Patient Global Rating of COPD severity
X
X
X
X
Patient Global Rating of Change in COPD
X
X
X
Safety assessments
Adverse events/Serious adverse events 6
X
X
X
X
X
X
X
X
COPD exacerbation assessment
X
X
X
X
X
X
X
X
12-Lead ECG
X
Urine pregnancy test 7
X
X
X
X
Pharmacogenetic sample8
                                           X
Medication/Supplies
Dispense rescue albuterol/slabutamol. Dispense MDI9
X
X
X
X
X
Assess COPD medication compliance10 during run-in
X
Dispense eDiary
X
Assess compliance with eDiary during run-in 
X
Collect rescue albuterol/slabutamol. 
X
X
X
X
X
Collect eDiary
X
X
Dispense study treatment11
X
X
X
 
 
 
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Blinded Treatment
Visit
Pre-
screen1
0
Screen/ 
Run-in
1
Rando-
mization 
2
3
4
5
EW 
Visit 2
Telephone Follow up 
contact 
6
Week
-6 to -4
-4
0
4
12
24
Day
42 2
-7/+2 
days 
prior 
Visit 1
28 2
-7/+2 days 
prior Visit 
2
12 -7/+2 
days
28 2 -7/+2 
days 
84 2 
days
168 2 -7/+2 
days
72 3 days after V5 
or EW Visit
Collect study treatment
X
X
X
X
Assess study treatment compliance during treatment10
X
X
X
X
Study sub-set
Physical activity monitor12
X
X
X
X
Collect Physical activity monitor
X
X
1.
Pre-screen Visit 0 must be completed prior to Screening Visit1. It can be completed 2 weeks prior or on the same day of V1, if no wash out of exclusionary medications is 
required. 
2.
Early Withdrawal Visit: Subjects that withdraw should return to the clinic as soon as possible to complete the Early Withdrawal Visit procedures.
3.
Spirometry at screening should be performed as described in (Section 7.2.2.1). 
4.
SAC BDI, SAC TDI, SGRQ-C, CAT questionnaires will be completed at clinic visits and in the eDiary
5.
EXACT/ER-S: COPD is completed daily in the eDiary approximately 2 hours before bed-time, starting on Day 1 of the run-in period.
6.
For the start date of collecting AEs and SAEs see (Appendix 4)
7.
Pregnancy test: for females for child bearing potential only.
8.
Pharmacogenetic sample may be drawn at visit 2 or any visit after.
9.
Rescue medication use to be recorded in the eDiary daily and in some sites in the eDiary and the eMDI
10. Sites are requested to call subjects every 2 weeks to remind them to take study treatment regularly and to record the time of the morning and evening dose in the eDiary.
11. In order to ensure subjects have sufficient doses of study treatment, they must return to clinic within 30 days from V2 and within 60 and 90 days from V3 and V4 respectively.
12. The Actigraph GT9X should be worn for 7 days from Visit 1, for 7 days from Visit 2, for 7 days from Visit 3 and for 7 days prior to Visit 5.
 
 
 
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Section 7.2.2 Critical procedures performed at Screening (Visit 1)
Rationale for change:  To clarify that height and weight are collected at V1
Revised text: “Height and weight”
Section 7.3.2 Spirometry
Rationale for change:  To further clarify that spirometry at Screening Visit 1 should be 
performed before subject inhales their usual morning COPD medication(s) a bullet point 
was added. “At Screening Visit 1, before the morning dose of usual COPD medications”
Revised text:
“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 standardized spirometry equipment provided by an external vendor.
All subjects will have spirometry performed at Screening to assess eligibility (see Section 
7.2.2.1) and at Visits 2, 3, 4 and 5 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 (i.e. a plateau in the volume time curve) and be free from 
artifacts due to cough, early termination, poor effort, obstructed mouthpiece, equipment 
malfunction, or other reasons [Miller, 2005].
The largest FEV1 and FVC from the 3 acceptable efforts should be recorded, even if they 
do not come from the same effort.
Spirometry for FEV1 and FVC assessments that is not obtained as follows will be 
considered a protocol deviation:

Started between 6:00AM and 11:00AM.

After withholding albuterol/salbutamol (all visits) for ≥4 hours

At Screening Visit 1, after wash out of medications as specified in the exclusion 
criteria in Section 5.2 (Concomitant Medications).

At Screening Visit 1, before the morning dose of usual COPD medications

At Visit 2 after discontinuing inhaled COPD medications and prior the first dose 
of study treatment 

At Visit 3, 4 and 5 after withholding the morning dose of study treatment.

Pre dose assessment performed prior dosing.
Subjects should refrain from smoking for 1 hour prior to each pulmonary function test.
Trough FEV1 measurements for UMC/VI or UMEC on Weeks 4, 12 and 24 (Visits 3, 4 
and 5) should be performed 23 hours and 24 hours after the previous day’s dose of study 
medication recorded in the eDiary. This will also provide trough FEV1 measurements for 
the evening dose of salmeterol”. 
 
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8.
Physical activity monitor (study subset)
Rationale for changes: Ensure consistency of the wording between Section 1 and 
Section 4.1 “overall design” and Section 7.3.7.
per treatment arm added to paragraph 4.
Revised Text: 
Physical activity monitor (study subset)
“Physical activity limitation is a common feature of COPD and its measures are highly 
related to the degree of disease severity [Watz, 2009]. 
Reduced physical activity levels in COPD is associated with increased morbidity and 
mortality, sustained disability, depression, and social and physical isolation [Shu-Yi, 
2014; Gimeno, 2014] 
Improved activity has been identified as an important factor that may modify morbidity 
and mortality in COPD [Moy, 2012].
The Actigraph GT9X physical activity monitor will be used to measure levels of activity. 
The activity monitor will be worn by up to approximately 150 subjects per treatment arm 
for 7 days from Screening (Visit 1), for 7 days from Randomisation (Visit 2), 7 days from 
Visit 3 (Week 4) and for 7 days prior to Week 24 (Visit 5).
There will be 4 assessment periods, including a screening assessment in order to provide 
a reliable estimate of habitual physical activity. Each subject will be given an activity 
monitor and instruction leaflet at the start of each assessment period. Further details of 
distribution, operation and retrieval of the monitors will be provided in the SRM”.
12.9.2.
Country-specific Protocol Amendment 2 for Canada
Amendment 02 applies to Canada only. The purpose of Amendment 2 is to comply with 
Health Canada guidelines. They state that all events associated with lack of efficacy of 
marketed investigational products must be documented and reported.
Strike through text refers to deleted text and underlined refers to added text.
Section 7.4.1 Adverse Events (AE) and serious Adverse Events (SAEs)
Rationale for change: A new Section added to include information related to 
documenting events related to lack of efficacy.
Revised text: 
“7.4.1.8 Additional Adverse Event (AE) Reporting Requirements for Canadian 
investigators
Health Canada requires pharmaceutical manufacturers to expeditiously report domestic 
cases of unusual failure in efficacy (UFIE) for new drugs to the Marketed Health 
Products Directorate (MHPD) within 15 days of first notification. This regulation applies 
to marketed drugs, and used as directed per the Canadian prescribing information,
including those drugs used in Phase IV (non CTA filed) clinical trials.  
Adverse event (AE): Any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment. An AE can therefore
 
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be any unfavourable and unintended sign (including an abnormal laboratory finding) 
symptom or disease (new or exacerbated) temporally associated with the use of a 
Medicinal Product. For a marketed Medicinal Product, this can also include failure 
to produce expected benefits (i.e. lack of efficacy, with or without an adverse event), 
In order for GSK to comply this Canadian regulatory requirement, Canadian investigators 
are required to collect, record and report lack of efficacy events as per the table in 
Appendix 4 Section 12.4.1”.  
All paper forms are required to be faxed to GSK Canada’s Drug Safety department at 
 within 24 hrs of first awareness.
Appendix 4, Section 12.4.1 
Rationale for change: To add a small table about reporting of AEs.
Revised text. The table below was added.
Adverse 
Event 
criteria
Electronic case record 
form (eCRF) only
Paper form only
Electronic case 
record form 
(eCRF) + Paper 
form
Non serious 
Non drug related lack of 
efficacy reports with 
associated signs or 
symptoms or clinical 
sequelae 
Drug related lack of 
efficacy reports 
without associated 
signs or symptoms or 
clinical sequelae.
Drug related lack 
of efficacy with 
associated signs or 
symptoms or 
clinical sequelae  
Serious
Non drug related lack of 
efficacy reports with 
associated signs or 
symptoms or clinical 
sequelae 
Drug related lack of 
efficacy reports 
without associated 
signs or symptoms or 
clinical sequelae. 
Drug related lack 
of efficacy reports 
with associated 
signs or symptoms 
or clinical sequelae 
Appendix 4, Section 12.4.4, second bullet point
Revised text: 
The investigator will then record all relevant information regarding an AE/SAE in the 
electronic CRF “and/or paper form as applicable”.  Added
Section 12.4.6, second bullet point
Revised text: 
“For lack of efficacy reports the paper form will be used to submit to GSK as per the
table in Section 12.4.1 above”. Added
 
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12.9.3.
Protocol Amendment 3
Protocol changes for Amendment 03, from protocol changes to amendment 02 (21-
Feb-2014)
Scope: This amendment applies to all sites
Amendment 03 Summary and Rationale
Strike through text refers to deleted text and underlined refers to added text.
List of Specific Changes
Section 1 Objective(s)/Endpoint(s) and Section 3 Objective(s)/Endpoint(s)
Rationale for change: Rate of COPD exacerbations endpoints from tertiary to 
exploratory due to stopping criteria. 
Revised text:
Exploratory

To explore the effect of UMEC/VI 
(62.5/25 mcg once daily), UMEC 
(62.5 mcg once daily) with salmeterol 
(50 mcg twice daily) on rate of COPD 
exacerbation

Rate of mild, moderate or severe 
exacerbations

Rate of moderate or severe 
exacerbation
Section 1. Overall Design
Rationale for change: To clarify study design and content of section to agree with 
Section 4.1
Revised text: 
There will be a total of 5 clinic visits and one follow-up phone call (Visit 6). A pre-
screening visit (Visit 0) may be required in order to administer the informed consent 
before any changes are made to the subject’s current medication regimen. If no changes 
in medication are required, V0 (pre-screening) and V1 (screening) may be conducted on 
the same day. Inhaled long-acting muscarinic antagonist (LAMA) or long-acting beta2-
agonist (LABA) and/or albuterol/salbutamol as needed (rescue medication) are not 
exclusionary prior to Screening or during the run-in.
Eligible subjects at Screening Visit 1 will be current or former smokers, at least 6 weeks 
ICS and ICS/LABA free with an FEV1 post-albuterol/salbutamol of ≥30% to ≤80% 
predicted normal and a FEV1/FVC <0.7 and a CAT score ≥10. 
Subjects using inhaled LAMA or LABA medication must withhold their morning dose 
prior to Screening spirometry. Subjects who meet all other eligibility criteria at Screening 
will enter a run-in period for 4 weeks. During the run-in period, subjects will continue 
with their inhaled LAMA or LABA.  In addition, subjects will be provided with short 
acting albuterol/salbutamol as needed for relief of COPD symptoms (rescue medication) 
 
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throughout the study.Eligible subjects at Screening will enter a run-in period for 4 weeks 
during which they continue taking their inhaled COPD medications (excluding ICS and 
any exclusionary medications).  In addition, subjects will be provided with short acting 
albuterol/salbutamol to be used on as needed basis (rescue medication) throughout the 
study.
Subjects who experience a moderate or severe COPD exacerbation during the run-in 
period will be deemed run-in failures.  Subjects who experience a mild COPD 
exacerbation, defined as worsening of symptoms that requires no treatment with 
antibiotics or steroids and is self managed by the patient by an increase of inhaled rescue 
medication will be able to continue in the study based on the judgment of the investigator 
and agreement of the sponsor’s medical monitor. Subjects experiencing a mild 
exacerbation, defined as worsening of symptoms that requires no treatment with 
antibiotics or steroids and is self managed by the patient by an increase of inhaled rescue 
medication, will be allowed to continue in the study.
At the randomization Visit 2 (Day 1), those subjects who successfully complete the run-
in period as well as meet the other pre-defined eligibility and randomization criteria will 
discontinue their inhaled COPD medications and will be randomized to one of the 
3 treatment arms for 24 weeks.
All subjects will be given an eDiary for use during the run-in, and treatment period to 
complete PRO questionnaires and record medical problems experienced during the study.  
Subjects will be performing slow and forced spirometry at specific visits.
There will be a total of 5 clinic visits and one follow-up phone call (Visit 6).  The total 
duration of subject participation in the study will be approximately 29 to 31 weeks 
consisting of 2 weeks pre-screening if necessary, 4 weeks run-in, 24 week treatment and 
one week Follow-Up. 
In addition, a subset of subjects up to 150 (approximately 150 per treatment arm) will 
undergo assessment of their physical activity measured through a physical activity 
monitor (Actigraph GT9X) worn for 7 days from Screening (Visit 1), for 7 days from 
Randomisation (Visit 2), 7 days from Visit 3, and for 7 days prior to last clinic Visit 
(Visit 5).
The occurrence of adverse events (AEs) will be evaluated throughout the study beginning 
at Visit 2 (Day 1) and until the follow-up contact (Visit 6).  Serious adverse events 
(SAEs) will be collected over the same time period as AEs.  However, any SAEs 
assessed as related to study participation (e.g., study treatment, protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK concomitant 
medication, will be recorded from the time a subject consents to participate in the study 
up to and including any follow up contact.
All subjects will be given an electronic diary (eDiary) for use during the run-in, and the 
treatment period to complete PRO questionnaires, record COPD daily symptoms and the 
time they take their COPD medications.  Daily rescue medication usage (number of 
inhalations taken in the last 24 h) will also be captured in the eDiary.  In addition, and in 
 
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some countries, rescue medication use will also be captured by the use of electronic 
metered dose inhaler (eMDI).
At Screening Visit 1, all subjects must be trained on the proper use of their existing 
COPD medications inhalation devices and instructed to strictly adhere to and record the 
time they take their COPD medications in the eDiary.
At the randomization Visit 2, all subjects must be trained on the proper use of the 
ELLIPTA and DISKUS inhalation devices and instructed to strictly adhere to and record 
the time they take their study medications in the eDiary.
All subjects must be trained on the correct use of the eDiary and instructed to complete 
the eDiary during the run-in and treatment period.
There are no plans to routinely provide any of the study treatments for compassionate use 
following study completion as the study treatment are commercially available.
Section 1. Treatment Arms and Duration
Rationale for change: clarify stratification and treatment arms
Revised text: Subjects will be stratified based on long-acting bronchodilator usage 
during the run-in (none or one or 2 long-acting bronchodilators per day) and randomized 
in a ratio of 1:1:1 to either

UMEC/VI 62.5/25 mcg once daily via ELLIPTA + placebo twice daily via 
DISKUS

UMEC 62.5 mcg once daily via ELLIPTA + placebo twice daily via DISKUS

Salmeterol 50 mcg twice daily via DISKUS + placebo once daily via ELLIPTA
Rationale for change: Clarify permitted and prohibited Screening and run-in COPD 
medications
Revised text: *Subjects may continue the use of inhaled LAMAs or LABAs and/or study 
provided albuterol/salbutamol as needed (rescue medication). Inhaled COPD medications 
including LABAs, LAMAs or LABA/LAMA combination products are allowed in run-in. ICS alone 
or in combination with a bronchodilator or any exclusionary medications are not allowed.
Section 4.1 Study Design
Rationale for change: To clarify study design
Revised text:
This is a multi-centre, randomized, double blind, double-dummy, 3-arm parallel group 
study.  Eligible subjects will be stratified based on long-acting bronchodilator usage 
during the run-in (none, one or 2 long-acting bronchodilators per day) and randomized in 
a ratio of 1:1:1 to UMEC/VI inhalation powder (62.5/25 mcg once daily) administered 
via the ELLIPTA™dry powder inhaler, or UMEC (62.5 mcg once daily) administered via 
the ELLIPTA™or salmeterol (50 mcg BID) administered via the DISKUS.
 
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A pre-screening visit (Visit 0) may be required in order to administer the informed 
consent before any changes are made to the subject’s current medication regimen. If no 
changes in medication are required, V0 (pre-screening) and V1 (screening) may be 
conducted on the same day. Inhaled long-acting muscarinic antagonist (LAMA) or long-
acting beta2-agonist (LABA) medications are not exclusionary prior to Screening or 
during the run-in. The Pre-screening Visit (Visit 0) can occur on the same day as the 
Screening Visit (Visit 1) if subject does not take or has not taken any excluded protocol 
medications, but must be completed prior to initiating any Visit 1 procedures.
Eligible subjects at Screening Visit 1 will be current or former smokers, at least 6 weeks 
ICS and ICS/LABA free with an FEV1 post-albuterol/salbutamol of ≥30% to ≤80% 
predicted normal and a FEV1/FVC <0.7 and a CAT score ≥10.
Subjects using inhaled LAMA or LABA medication must withhold their morning dose 
prior to Screening spirometry. Subjects who meet all other eligibility criteria at Screening 
will enter a run-in period for 4 weeks. in order to continue to assess the subject’s 
eligibility for the study During the run-in period, subjects will continue with their inhaled 
COPD medications (excluding ICS and any exclusionary medications) their inhaled 
LAMA or LABA medication.  In addition, subjects will be provided with short acting 
albuterol/salbutamol to be used on as needed basis for relief of COPD symptoms (rescue 
medication) throughout the study.
At the randomization Visit 2 (Day 1) those subjects who successfully complete the run-in 
period as well as meet the other pre-defined eligibility and randomization criteria will
discontinue their inhaled COPD medications and will be randomized to one of the 3 
treatment arms for 24 weeks.
In addition, a subset of subjects up to 150 (approximately 150 per treatment arm) will 
undergo assessment of their physical activity measured through a physical activity 
monitor (Actigraph GT9X) worn for 7 days from Screening (Visit 1), for 7 days from 
Randomisation (Visit 2), 7 days from Visit 3, and for 7 days prior to last clinic Visit 
(Visit 5).
During the run-in and treatment period, subjects will be completing PRO questionnaires 
in the eDiary and performing slow and forced spirometry at specific clinic visits.
Concurrent use of COPD maintenance medications including LAMAs, LABAs, oral beta-
agonists, theophyllines, inhaled corticosteroids, inhaled corticosteroids and LABA 
combination and phosphodiesterase 4 inhibitors will not be allowed during the study 
(Section 6.11.2) . 
*Subjects may continue the use of inhaled LAMAs or LABAs and/or study provided 
albuterol/salbutamol as needed (rescue medication) during the run-in while adhering to the 
withholding of other COPD medications detailed in the Exclusion Criteria. Inhaled COPD 
medications including LABAs, LAMAs or LABA/LAMA combination products are allowed in run-in. 
ICS alone or in combination with a bronchodilator or any exclusionary medications are not 
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Section 4.2 Treatment Arms and Duration
Rationale for change: clarify stratification and treatment arms
Revised text: Subjects will be stratified based on long-acting bronchodilator usage 
during the run-in (none or one or 2 long-acting bronchodilators per day) and randomized 
in a ratio of 1:1:1 to either

UMEC/VI 62.5/25 mcg once daily via ELLIPTA + placebo twice daily via 
DISKUS

UMEC 62.5 mcg once daily via ELLIPTA + placebo twice daily via DISKUS

Salmeterol 50 mcg twice daily via DISKUS + placebo once daily via ELLIPTA
Section 4.2 Type and Number of Subjects
Rationale for change: clarify number of sites
Revised text:
Approximately 3232 will be screened globally in approximately 240 205 sites such that 
approximately 2424 subjects will be randomized and approximately 2181 evaluable 
subjects complete the study.
Section 5.1 Inclusion Criteria
Rationale for change: Addition of inclusion criterion specific to France 
Revised text: 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.
Rationale for change: typo
40 years or older at date of signing informed consent at Screening Visit 1
Section 5.2 Exclusion Criteria
Rationale for change: typo 
Revised text: Pneumonia and/or moderate or severe COPD exacerbation 
Rationale for change: clarify prohibited Screening and run-in COPD medications
Revised text:
15. Medications prior to Screening: Use of the following medications according to the 
following defined time intervals prior to Screening (Visit 1) or during the study:
Medication
No use within the 
following time intervals 
prior to Screening and 
thereafter at any time 
during the study
Inhaled corticosteroids (ICS)
6 weeks
Depot corticosteroids
12 weeks
Systemic, oral or parenteral corticosteroidsa
6 weeks
Antibiotics (for lower respiratory tract infection)b
6 weeks
Phosphodiesterase 4 (PDE4) Inhibitor (e.g roflumilast)
14 days
 
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LABA/Inhaled Corticosteroid (ICS) combination products 
6 weeks
LABA/LAMA combination products
2 weeks
Theophyllines
48 hours
Oral beta2-agonists
     Long-acting
     Short-acting
48 hours
12 hours
Inhaled short acting beta2-agonistsb
4 hours
Inhaled short-acting anticholinergics
4 hours
Inhaled short-acting anticholinergic/short-acting beta2-agonist 
combination products
4 hours
Any other investigational medication
30 days or within 5 drug 
half-lives (whichever is 
longer)
a-
Corticosteroids are allowed for the treatment of COPD exacerbations during the double-blind treatment 
phase of the study. Localized corticosteroid injections (e.g., intra-articular and epidural) are permitted.
b-
Use of study provided albuterol/salbutamol is permitted during the study, except in the 4-hour period prior to 
spirometry testing
2. Medication prior to spirometry: Unable to withhold albuterol/salbutamol for the 
4 hour period required prior to spirometry testing at each study visit. Unable to 
withhold morning dose of subject’s inhaled LABA or LAMA COPD medication prior 
to spirometry testing at Screening Visit (Visit 1). 
Section 5.3 Randomization Criteria
Rationale for change: clarification of prohibited medications at randomization
Revised text: Prohibited Medications: No use of any prohibited medications during the 
run-in period or at Visit 2, including any ICS or ICS/LABA combination. Subject’s 
inhaled LABA or LAMA medication morning dose must be withheld and discontinued at 
Visit 2.
Section 5.5.1. Withdrawal from the Study
Rationale for change: Clarify stopping criteria for withdrawal 
Revised text:
Stopping Criteria
A subject will also must be withdrawn from the study, in consultation with the medical 
monitor and principal investigator, if any of the following stopping criteria are met:

Unstable or life threatening cardiac events: myocardial infarction, hospitalization 
for unstable angina, stroke, and other cardiovascular events considered life- or 
intensively health-threatening by the study physician.

COPD Exacerbations: Subjects with two moderate or one severe COPD 
exacerbation during the study.

Withdrawal from study treatment requires withdrawal from the study.
 
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
Non-Compliance with Study treatment: Subjects’ compliance with study treatment 
will be assessed at each study visit. Subjects who are non-compliant should be re-
educated on the requirement for treatment compliance. Every effort will be made to 
keep subjects in the study and to re-educate those subjects who continue to be non-
compliant.  Subjects who continue to be non-compliant after multiple visit 
assessments may be permanently discontinued after consultation with the GSK 
clinical team. 

Non-Compliance with eDiary:  Subjects must be compliant in completing their 
eDiary between each pair of on-treatment visits.  Subjects who are non-compliant 
should be re-educated on the requirement for daily diary entry compliance. Subjects 
who continue to be non-compliant after multiple visit assessments may be 
permanently discontinued after consultation with the GSK clinical team.
Note: Withdrawal from study treatment requires withdrawal from the study.
Section 5.6. Follow-up contact
Rationale for change: typo
Revised text: A safety follow-up contact (Visit 6) should be conducted 72 3days
Section 6.3 Treatment Assignment
Rationale for change: clarify stratification
Revised text: The randomisation will be stratified based on long-acting bronchodilator
usage during the run-in (none or, one or 2 long-acting bronchodilators per day).
In order to ensure subjects have sufficient doses of study treatment, they must return to 
clinic within 30 days from V2 and 60 and 90 days from V3 and V4
Section 7.1 Time and Events Table
Rationale for change: clarify Visit windows and correct typo concerning Pre-screen 
window
Revised text:
Blinded Treatment
Visit
Pre-
screen1
0
Screen/ Run-in
1
Rando-
mization 2
3
4
5
EW 
Visit 
2
Telephone 
Follow up 
contact 
6
Week
-10 -6 to -4
-4
0
4
12
24
Day
-70 to -28
42
-7/+2 days 
prior to 
Visit 1
-28-7/+2 days 
prior to Visit 2
1  -7/+2 
days
28  -
7/+2 
days
84  -
7/+2 
days
168  
-7/+2 
days
73 days 
after V5 or 
EW Visit
Window
-7/+2 days 
-7/+2 days
-7/+2 days
-7/+2 
days
-7/+2 
days
-7/+2 
days
3 days
 
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Section 7.1 Time and Events Table
Rationale for change: Correct inconsistency of pre-screen window to Medication 
withhold periods defined in the Exclusion Criteria
Revised text:
1.
Pre-screen Visit 0 must be completed prior to Screening Visit1. It can be completed 26 weeks prior or on the 
same day of V1, if no wash out of exclusionary medications is required. 
Section 7.2.1 Pre-screen Visit
Rationale for change: Correct inconsistency of pre-screen window to Medication 
withhold periods defined in the Exclusion Criteria
Revised text: Subjects can perform the Pre-screening Visit (Visit 0) up to 2 6 weeks 
prior to or on the same day as the Screening Visit (Visit 1) if subject does not take or has 
not taken any protocol excluded medications.
Section 7.3.1.2 SGRQ-C
Rationale for change: typo
Revised text: The St George’s Respiratory Questionnaire-Chronic Obstructive 
Pulmonary Disease specific (SGRQ-C) will be completed by subjects at Randomisation 
(V2, Day 1), at Week 4, 12 and 24 or at Early Withdrawal Visit (Where applicable). 
Section 7.3.1.5  Subject Global Rating of COPD Severity and Global Rating of 
Change in COPD
Rationale for change: typo
Revised text: Subjects will complete the Global Rating of COPD Severity at 
Randomization Visit 2 and visits 3, 4 and 5 or Early Withdrawal Visit.
Subjects will also complete a Global Rating of Change in COPD (overall disease) 
question at Visits 3, 4 and 5 or Early Withdrawal Visit.
Section 7.3.2  Spirometry
Rationale for change: clarify instructions of COPD medication use prior to Spirometry
Revised text:

At Screening Visit 1, before the subject’s morning dose of usual inhaled LABA or 
LAMA COPD medications

At Visit 2 after withholding the morning dose of inhaled LABA or LAMA COPD 
medication and prior to administration of study medication after discontinuing 
inhaled COPD medication medications and prior the first dose of study treatment
Section 7.3.3  Inspiratory capacity (IC)
Rationale for change: clarify instructions of COPD medication use prior to IC maneuver 
 
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Revised text:

At Visit 2 after discontinuation of run-in LABA or LAMA COPD medication and 
prior to administration of study medication

At Visit 3, 4 and 5 after withholding the morning dose of study drug 
Section 10.2 Regulatory and Ethical Considerations, Including the Informed 
Consent Process
Rationale for change: Clarifications concerning site professional expertise
Revised text: Study site Investigators will be selected to participate in the 201749 study 
based upon their pulmonology expertise and knowledge of the protocol defined patient 
population and associated required study assessments.
Section 12.4.1 Defining of Adverse Events
Rationale for change: Integration of Canadian Amendment 2 into main protocol
Revised text: Reporting Specific to Canada: For a marketed medicinal product, this 
can also include failure to produce expected benefits (i.e. lack of efficacy, with or without 
associated signs or symptoms or clinical sequelae).

Excluding Canada, "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.

Reporting Specific to Canada: "Lack of efficacy" or "failure of expected 
pharmacological action" will be reported as an AE or SAE as per the table below
Adverse 
Event 
criteria
Electronic case record 
form (eCRF) only
Paper form only
Electronic case 
record form 
(eCRF) + Paper 
form
Non serious 
Non drug related lack of 
efficacy reports with 
associated signs or 
symptoms or clinical 
sequelae 
Drug related lack of 
efficacy reports 
without associated 
signs or symptoms or 
clinical sequelae.
Drug related lack 
of efficacy with 
associated signs or 
symptoms or 
clinical sequelae  
Serious
Non drug related lack of 
efficacy reports with 
associated signs or 
symptoms or clinical 
sequelae 
Drug related lack of 
efficacy reports 
without associated 
signs or symptoms or 
clinical sequelae. 
Drug related lack 
of efficacy reports 
with associated 
signs or symptoms 
or clinical sequelae 
 
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Section 12.4.6 Reporting of SAEs to GSK
Rationale for change: Integration of Canadian Amendment 2 into main protocol
Revised text: Reporting Specific to Canada: For lack of efficacy reports, the paper 
form will be used to submit to GSK as per the table in Section 12.4.1 above.
Section 12.5.2 COPD Exacerbation Severity
Rationale for change: clarify chest x-rays performed in the context of the protocol
Revised text: Every effort should be made to conduct a chest x-ray within 48 hours 
of identification of a moderate or severe exacerbation. Chest X-Ray for pneumonia 
and/or moderate/severe exacerbation is not mandated but can be performed if required by 
the investigator as part of standard care of subjects.
Section 12.8 Appendix 8: Country Specific Requirements
Rationale for change: Integration of Canadian Amendment 2 into main protocol
Revised text: In Canada only, additions were made to Section 7.4.1 and Appendix 4 to
comply with Health Canada guidelines concerning the requirement of pharmaceutical 
manufacturers to expeditiously report domestic cases of unusual failure in efficacy 
(UFIE) for new drugs to the Marketed Health Products Directorate (MHPD) within 
15 days of first notification.
No country specific requirements exist.
 
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201749
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A 24-week treatment, multi-center, randomized, double-blind, 
double-dummy, parallel group study to compare 
Umeclidinium/Vilanterol, Umeclidinium, and Salmeterol in 
subjects with chronic obstructive pulmonary disease (COPD)
Compound Number:
GSK2592356
Development Phase:
IV
Effective Date:
21-FEB-2017
Protocol Amendment Number:  02
Author (s):
 
 
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2016N277425_00
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Original
2016N277425_01
2017-FEB-07
Amendment No. 1
This protocol amendment was created to make the following changes:
Regulatory Agency Identifying Number(s):  A typographical error in the EudraCT no. 
corrected. IND no. added
Section 4.1and Section 4.4: Typographical errors and inconsistencies corrected
Inconsistencies between Section 4.4, Section 7.3.1.5 and Section 7.1revised
Section 7.1 Time and event table:
Un-intentional deletion of the (“x”) were added to confirm that concomitant medications 
should be reviewed at every clinic visit was corrected.
Increased the visit window 
Typographical error and inconsistencies corrected as described in Appendix 9, Section 
12.9.
Section 7.2.2 Critical procedures performed at Screening (Visit 1): To clarify that height 
and weight are collected at V1 “Height and weight” added
Section 7.3.2 Spirometry: “At Screening, before the morning dose of usual COPD 
medication(s)” added.
Section 7.3.7:  Physical activity monitor (study subset)
Inconsistency between Section 1, Section 4.1 and Section 7.3.7 revised
2016N277425_02
2017-FEB-21
Amendment No. 2
This protocol amendment was created to comply with Health Canada guidelines. They
require pharmaceutical manufacturers to expeditiously report domestic cases of unusual 
failure in efficacy (UFIE) for new drugs to the Marketed Health Products Directorate 
(MHPD) within 15 days of first notification.
Changes were made to Section 7.4.1 and Appendix 4.
 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol 201749
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date
 
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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 201749........................................................9
2.
INTRODUCTION....................................................................................................14
2.1.
Study Rationale ..........................................................................................14
2.2.
Brief Background ........................................................................................14
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................15
4.
STUDY DESIGN ....................................................................................................17
4.1.
Overall Design ............................................................................................17
4.2.
Treatment Arms and Duration.....................................................................19
4.3.
Type and Number of Subjects.....................................................................20
4.4.
Design Justification.....................................................................................20
4.5.
Dose Justification........................................................................................20
4.6.
Benefit: Risk Assessment ...........................................................................20
4.6.1.
Risk Assessment .........................................................................21
4.6.2.
Benefit Assessment.....................................................................24
4.6.3.
Overall Benefit: Risk Conclusion..................................................24
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............24
5.1.
Inclusion Criteria.........................................................................................24
5.2.
Exclusion Criteria........................................................................................26
5.3.
Randomization Criteria ...............................................................................29
5.4.
Screening/Baseline/Run-in Failures............................................................29
5.5.
Withdrawal/Stopping Criteria.......................................................................30
5.5.1.
Withdrawal from the Study...........................................................30
5.5.2.
Reason for Study Withdrawal.......................................................31
5.5.3.
Liver Chemistry Stopping Criteria ................................................31
5.5.3.1.
Study Treatment Restart or Rechallenge....................32
5.6.
Follow-up contact........................................................................................32
5.7.
Subject and Study Completion....................................................................33
6.
STUDY TREATMENT ............................................................................................33
6.1.
Investigational Product and Other Study Treatment....................................33
6.2.
Medical Devices..........................................................................................35
6.3.
Treatment Assignment................................................................................35
6.4.
Planned Dose Adjustments.........................................................................36
6.5.
Blinding.......................................................................................................36
6.6.
Packaging and Labeling..............................................................................37
6.7.
Preparation/Handling/Storage/Accountability..............................................37
6.7.1.
Study Treatment Return...............................................................38
6.8.
Compliance with Study Treatment Administration.......................................38
6.9.
Treatment of Study Treatment Overdose....................................................38
6.10.
Treatment after the End of the Study ..........................................................39
6.11.
Concomitant Medications and Non-Drug Therapies....................................39
6.11.1.
Permitted Medications and Non-Drug Therapies..........................39
6.11.2.
Prohibited Medications and Non-Drug Therapies.........................40
 
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7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................41
7.1.
Time and Events Table...............................................................................42
7.2.
Screening and Critical Baseline Assessments ............................................45
7.2.1.
Pre-screening Visit.......................................................................45
7.2.2.
Critical procedures performed at Screening (Visit 1)....................45
7.2.2.1.
Albuterol/Salbutamol Reversibility Assessment ..........46
7.2.3.
Critical procedures performed at first treatment Visit 
(Baseline V2)...............................................................................46
7.3.
Efficacy Assessments.................................................................................47
7.3.1.
HRQoL assessments: Completion of PRO questionnaires 
in the Electronic Diary..................................................................47
7.3.1.1.
Self Administered Computerised Baseline 
Dyspnea Index/Transitional Dyspnea Index 
(SAC BDI/TDI)............................................................47
7.3.1.2.
SGRQ-C.....................................................................48
7.3.1.3.
COPD Assessment Test (CAT) ..................................48
7.3.1.4.
EXACT and the Evaluating Respiratory 
Symptoms- COPD (E-RS: COPD)..............................49
7.3.1.5.
Subject Global Rating of COPD Severity and 
Global Rating of Change in COPD .............................49
7.3.2.
Spirometry ...................................................................................49
7.3.3.
Inspiratory capacity (IC)...............................................................50
7.3.4.
COPD Exacerbation ....................................................................51
7.3.5.
Clinically important deterioration (CID).........................................51
7.3.6.
Rescue albuterl/salbutamol use...................................................52
7.3.7.
Physical activity monitor (study subset) .......................................52
7.4.
Safety .........................................................................................................52
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........52
7.4.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................53
7.4.1.2.
Method of Detecting AEs and SAEs ...........................53
7.4.1.3.
Follow-up of AEs and SAEs........................................53
7.4.1.4.
Pneumonia Events .....................................................54
7.4.1.5.
Cardiovascular and Death Events ..............................54
7.4.1.6.
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ................54
7.4.1.7.
Regulatory Reporting Requirements for SAEs............54
7.4.1.8.
Additional Adverse Event (AE) Reporting 
Requirements for Canadian investigators...................55
7.4.2.
Pregnancy ...................................................................................55
7.4.3.
Medical Device Incidents (Including Malfunctions).......................55
7.4.4.
Electrocardiogram (ECG).............................................................55
7.5.
Genetics .....................................................................................................56
8.
DATA MANAGEMENT ...........................................................................................56
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................56
9.1.
Hypotheses.................................................................................................56
9.2.
Sample Size Considerations.......................................................................57
9.2.1.
Sample Size Assumptions ...........................................................57
9.2.2.
Sample Size Sensitivity................................................................57
9.2.3.
Sample Size Re-estimation or Adjustment...................................58
 
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9.3.
Data Analysis Considerations .....................................................................58
9.3.1.
Analysis Populations....................................................................58
9.3.2.
Interim Analysis ...........................................................................58
9.4.
Key Elements of Analysis Plan ...................................................................58
9.4.1.
Primary Analyses.........................................................................59
9.4.2.
Other Analyses ............................................................................60
10. STUDY GOVERNANCE CONSIDERATIONS........................................................60
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............60
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................60
10.3.
Quality Control (Study Monitoring) ..............................................................61
10.4.
Quality Assurance.......................................................................................61
10.5.
Study and Site Closure ...............................................................................62
10.6.
Records Retention......................................................................................62
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................63
11. REFERENCES.......................................................................................................64
12. APPENDICES........................................................................................................67
12.1.
Appendix 1: Abbreviations and Trademarks................................................67
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................69
12.3.
Appendix 3: Genetic Research ...................................................................71
12.4.
Appendix 4: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................74
12.4.1.
Definition of Adverse Events........................................................74
12.4.2.
Definition of Serious Adverse Events...........................................75
12.4.3.
Definition of Cardiovascular Events .............................................76
12.4.4.
Recording of AEs and SAEs ........................................................77
12.4.5.
Evaluating AEs and SAEs............................................................77
12.4.6.
Reporting of SAEs to GSK...........................................................79
12.5.
Appendix 5: COPD Exacerbation Identification, Categorization and 
Treatment Guidelines..................................................................................80
12.5.1.
Guidelines for Identifying COPD Exacerbations...........................80
12.5.2.
COPD Exacerbation Severity.......................................................81
12.5.3.
Treatment of COPD Exacerbations..............................................81
12.5.4.
Guidelines for Treatment with Corticosteroids..............................81
12.5.5.
Guidelines for Treatment with Antibiotics .....................................82
12.5.6.
Onset and Resolution of COPD Exacerbations............................82
12.5.7.
Guideline for assessing multiple mild exacerbations ....................82
12.5.8.
Guideline for assessing exacerbations that increase in 
severity ........................................................................................82
12.6.
Appendix 6: Definition of and Procedures for Documenting Medical 
Device Incidents .........................................................................................83
12.6.1.
Definitions of a Medical Device Incident.......................................83
12.6.2.
Documenting Medical Device Incidents .......................................84
12.7.
Appendix 7: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in FRP and Collection of Pregnancy Information.......................85
12.7.1.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) ..............85
 
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12.7.2.
Collection of Pregnancy Information ............................................85
12.8.
Appendix 8: Country Specific Requirements...............................................87
12.9.
Appendix 9: protocol changes.....................................................................88
 
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1.
PROTOCOL SYNOPSIS FOR STUDY 201749
Rationale
The primary purpose of this study is to demonstrate improvements in lung function in 
subjects treated with Umeclidinium/Vilanterol (UMEC/VI) compared with Umeclidinium 
(UMEC) for 24 weeks.  A further important aspect of the study is to evaluate the effect of
UMC/VI, UMEC, and salmeterol with respect to health-related quality of life (HRQoL), 
measured through patient reported outcomes (PROs) questionnaires, and lung function.  
Additional assessments to further evaluate other measures of chronic obstructive 
pulmonary disease (COPD) efficacy and symptoms control will be performed.
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary

To compare the effect of UMEC/VI 
(62.5/25 mcg once daily) with UMEC 
(62.5 mcg once daily) on lung function

Change from baseline in trough Forced 
Expiratory Volume in One Second 
(FEV1) at week 24 
Secondary

To compare UMEC/VI (62.5/25 mcg 
once daily), UMEC (62.5 mcg once 
daily) with salmeterol (50 mcg twice 
daily) on patient reported outcomes 
(PROs) 

Change from baseline in self 
administered computerised (SAC) 
transient dyspnea index (TDI) 

Percentage of TDI responders 
according to SAC TDI score.  A 
responder is defined as a ≥1 unit 
improvement in SAC TDI score 

Assessment of respiratory daily 
symptoms over 24 weeks using 
Evaluating Respiratory Symptoms-
COPD (E-RS) and its subscales 
(breathlessness, cough and sputum and 
chest symptoms) 

Percentage of E-RS responders 
according to E-RS score (defined as 
reduction in E-RS score of 2 or 3.35 
units) from baseline

Change from baseline in St George’s 
Respiratory Questionnaire (SGRQ-C)

Percentage of responders according to 
SGRQ-C total score (defined as a 4 
point or greater reduction from 
 
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Objectives
Endpoints
baseline) 

Change from baseline in COPD 
assessment test (CAT)

Percentage of responders according to 
CAT (defined as a 2 unit improvement 
in score from baseline)
Other

To compare UMEC/VI (62.5/25 mcg 
once daily), UMEC (62.5 mcg once 
daily) with salmeterol (50 mcg twice 
daily) on other COPD efficacy measures 

Rate of mild, moderate or severe 
exacerbations

Time to first mild, moderate or severe 
exacerbation

Rate of moderate or severe 
exacerbation

Time to moderate or severe 
exacerbation

Time to severe exacerbations

Time to clinically important 
deterioration (CID) composite endpoint 

Time to clinically important 
deterioration composite endpoint 
excluding FEV1

Rescue albuterol/salbutamol use, 
(percentage of rescue-free days and 
mean number of Inhalations/day) 
captured by the electronic diary 
(eDiary) over 24 weeks

Inspiratory capacity (IC)

Full Vital capacity (FVC) 

Change from baseline in trough FEV1

Change from baseline in global 
impression of disease severity 
 
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Objectives
Endpoints
Safety

To evaluate safety and tolerability 
of UMEC/VI (62.5/25 mcg once 
daily), UMEC (62.5mcg once daily) 
and salmeterol 50mcg twice daily)

Incidence of adverse events
Exploratory

To compare albuterol/salbutamol 
use captured in the eDiary with the 
electronic metered dose inhaler 
(eMDI) device 

Rescue albuterol/salbutamol use, 
(percentage of rescue-free days and 
mean number of Inhalations/day) 
captured by the eMDI device over 24 
weeks as data allow

To explore the effect of UMEC/VI 
(62.5/25 mcg once daily), UMEC 
(62.5 mcg once daily) with 
salmeterol (50 mcg twice daily) on 
physical activity

Change from baseline in physical 
activity 

To investigate the CID composite 
endpoint ability to predict short 
term outcomes 

To compare physical activity levels, 
ER-S, rescue medication use, 
exacerbations and mortality in subjects 
with and without a CID
Overall Design
This is a multi-centre, randomized, double blind, double dummy, 3-arm parallel group 
study.  Eligible subjects will be randomized in a ratio of 1:1:1 to UMEC/VI inhalation 
powder (62.5/25 mcg once daily) administered via the ELLIPTA™dry powder inhaler 
(DPI), or UMEC (62.5 mcg once daily) administered via the ELLIPTA DPI or salmeterol 
(50 mcg twice daily (BID)) administered via the DISKUS™DPI.
Eligible subjects at Screening will enter a run-in period for 4 weeks during which they 
continue taking their inhaled COPD medications (excluding ICS and any exclusionary 
medications).  In addition, subjects will be provided with short acting 
albuterol/salbutamol to be used on as needed basis (rescue medication) throughout the 
study. 
Subjects who experience a moderate or severe COPD exacerbation during the run-in 
period will be deemed run-in failures.  Subjects experiencing a mild exacerbation, 
defined as worsening of symptoms that requires no treatment with antibiotics or steroids 
and is self managed by the patient by an increase of inhaled rescue medication, will be 
allowed to continue in the study.
At the randomization Visit 2 (Day 1) those subjects who successfully complete the run-in 
period as well as meet the other pre-defined eligibility and randomization criteria will 
discontinue their inhaled COPD medications and will be randomized to one of the 3 
treatment arms for 24 weeks.
 
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All subjects will be given an eDiary for use during the run-in, and treatment period to 
complete PRO questionnaires and record medical problems experienced during the study.  
Subjects will be performing slow and forced spirometry at specific visits.
In addition, a subset of subjects up to 150 per treatment arm will undergo assessment of 
their physical activity measured through a physical activity monitor (Actigraph GT9X) 
worn for 7 days from Screening (Visit 1), for 7 days from Randomisation (Visit 2), 7 
days from Visit 3, and for 7 days prior to last clinic Visit (Visit 5). 
There will be a total of 5 clinic visits and one follow-up phone call (Visit 6).  The total 
duration of subject participation in the study will be approximately 29 to 31 weeks 
consisting of 2 weeks pre-screening if necessary, 4 weeks run-in, 24 week treatment and 
one week Follow-Up. 
Subjects will be considered to have completed the study upon completion of the Follow–
Up contact by telephone.
Treatment Arms and Duration
Subjects will be stratified based on long-acting bronchodilator usage during the run-in 
(none, one or 2 long-acting bronchodilators per day) and randomized in a ratio of 1:1:1 to 
either 

UMEC/VI inhalation powder (62.5/25 mcg once daily) administered via the 
ELLIPTA DPI) or 

UMEC (62.5 mcg once daily) administered via the ELLIPTA DPI or 

Salmeterol (50 mcg BID) administered via DISKUS 
 
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Study schematic
*Inhaled COPD medications including LABAs, LAMAs or LABA/LAMA combination products are 
allowed in run-in. ICS alone or in combination with a bronchodilator or any exclusionary 
medications are not allowed.
Type and Number of Subjects
Approximately 3232 subjects will be screened, such that 2424 subjects will be 
randomized and approximately 2181 evaluable subjects complete the study. 
Analysis
The primary purpose of this study is to demonstrate improvements in lung function for 
subjects treated with UMEC/VI compared with UMEC for 24 weeks.
The primary endpoint is change from baseline in trough FEV1 at Week 24.
The null hypothesis is no difference between treatment groups (H0: μT – μS = 0), with 
the alternative hypothesis that there is a difference between treatment groups (H1: μT –
μS ≠0), where μT is the mean change from baseline for UMEC/VI and μS is the mean 
change from baseline for UMEC. 
The primary endpoint of mean change from baseline in trough FEV1 at the end of Week 
24 will be analysed using Mixed Models repeated Measures (MMRM) analysis. The 
MMRM analysis will include measurements at Treatment Weeks 4, 12 and 24. Treatment 
group (a categorical variable) will be fitted as the explanatory variable with appropriate 
pre-defined variables, stratum (number of bronchodilators per day during run-in) and 
baseline values, fitted as covariates. Visit (nominal) will be fitted as a categorical variable 
and visit-by-baseline and visit-by-treatment interaction terms will be included to allow 
treatment effects to be estimated at each visit separately.  The variance covariance matrix 
 
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will be assumed to be unstructured (based on previous experience no issues are expected 
with fitting models with this matrix structure). 
The estimated treatment differences between UMEC/VI versus UMEC for each endpoint 
will be presented with the 95% confidence intervals for the difference and the p-value. 
2.
INTRODUCTION
2.1.
Study Rationale
Chronic obstructive pulmonary disease (COPD) is associated with poor health-related 
quality of life (HRQoL).  Pharmacologic therapy is used to improve lung function, reduce 
symptoms, frequency and severity of exacerbations, and improve patients HRQoL
[GOLD, 2015].  Umeclidinium/Vilanterol (UMEC/VI 62.5/25 mcg) is indicated for the 
maintenance treatment of COPD that contain long-acting muscarinic antagonist (LAMA) 
and long-acting beta2-agonist (LABA) bronchodilators.  Umeclidinium (UMEC) is 
indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients 
with COPD.  Salmeterol has long been used for symptoms management of COPD.  
However, a direct comparison of these maintenance therapies has not been conducted 
with respect to HRQoL.
The primary purpose of this study is to demonstrate improvements in lung function for 
subjects treated with UMEC/VI compared with UMEC for 24 weeks.  The effect of
UMC/VI, UMEC, and salmeterol with respect to patient HRQoL measured through 
patient reported outcomes (PROs) questionnaires, symptoms and lung function will also 
be evaluated.
2.2.
Brief Background
COPD is characterized by an airflow limitation which is not fully reversible, usually 
progressive and accompanied by a chronic cough, sputum production and dyspnea which 
can be a major cause of disability and anxiety associated with the disease [Maleki-Yazdi, 
2014]
Furthermore, acute exacerbations contribute to the overall severity of disease as these
episodes are accompanied by worsened symptoms and are associated with increased 
decline in lung function and mortality [Wedzicha, 2013; Schmidt, 2014].
Pharmacologic therapy is used to improve lung function, reduce symptoms, reduce the 
frequency and severity of exacerbations, and also to improve health status and exercise 
tolerance.  Maintenance treatment is recommended primarily through the use of LABAs 
or LAMAs.  COPD treatment guidelines recommend an incremental approach to 
pharmacological treatment as the disease state worsens, involving the use of 
combinations of drug classes with different or complementary mechanisms [GOLD, 
2015]. 
UMEC/VI inhalation powder is a combination of UMEC (umeclidinium bromide), a 
LAMA, and VI (Vilanterol), a LABA, delivered via the ELLIPTA dry powder inhaler 
 
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(DPI). UMEC/VI at a dose of 62.5/25mcg once-daily is marketed in the United States 
(US) and Europe under the trade name ANORO™ELLIPTA.  
UMEC (62.5 mcg) inhalation powder is marketed in the United States (US) and Europe 
under the trade name INCRUSE™ELLIPTA.  UMEC (62.5mcg) is indicated as a 
maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD.  
UMEC (62.5 mcg) improves forced expiratory volume in one second (FEV1), dyspnea 
and HRQoL whether used as monotherapy [Trivedi, 2014; Feldman, 2016] or as an add 
on to fluticasone propionate and vilanterol (FF/VI) [Siler, 2015].  Salmetrol (50 mcg) 
DISKUS is a long-acting broncholdilator that has long been used for the maintenance 
treatment of COPD [Tashkin, 2010].
Clinically important deterioration (CID) is a novel, exploratory composite endpoint 
which assesses individual deteriorations in lung function and in patient PROs defined by 
the accepted minimal clinically important difference (MCID), as well as the incidence of 
moderate to severe exacerbations [Singh, 2016], (Section 7.3.5).  CID will be analysed to 
determine whether UMEC/VI (62.5/25mcg) therapy provides greater clinical stability as 
compared with UMEC and salmeterol monotherapies. 
3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary

To compare the effect of UMEC/VI 
(62.5/25 mcg once daily) with UMEC 
(62.5 mcg once daily) on lung function

Change from baseline in trough Forced 
Expiratory Volume in One Second 
(FEV1) at week 24 
Secondary

To compare UMEC/VI (62.5/25 mcg 
once daily), UMEC (62.5 mcg once 
daily) with salmeterol (50 mcg twice 
daily) on patient reported outcomes 
(PROs) 

Change from baseline in self 
administered computerised (SAC) 
transient dyspnea index (TDI) 

Percentage of TDI responders 
according to SAC TDI score.  A 
responder is defined as a ≥1 unit 
improvement in SAC TDI score 

Assessment of respiratory daily 
symptoms over 24 weeks using 
Evaluating Respiratory Symptoms-
COPD (E-RS) and its subscales 
(breathlessness, cough and sputum and 
chest symptoms) 

Percentage of E-RS responders 
according to E-RS score (defined as 
reduction in E-RS score of 2 or 3.35 
units) from baseline
 
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Objectives
Endpoints

Change from baseline in St George’s 
Respiratory Questionnaire (SGRQ-C)

Percentage of responders according to 
SGRQ-C total score (defined as a 4 
point or greater reduction from 
baseline) 

Change from baseline in COPD 
assessment test (CAT)

Percentage of responders according to 
CAT (defined as a 2 unit improvement 
in score from baseline)
Other

To compare UMEC/VI (62.5/25 mcg 
once daily), UMEC (62.5 mcg once 
daily) with salmeterol (50 mcg twice 
daily) on other COPD efficacy measures 

Rate of mild, moderate or severe 
exacerbations

Time to first mild, moderate or severe 
exacerbation

Rate of moderate or severe 
exacerbation

Time to moderate or severe 
exacerbation

Time to severe exacerbations

Time to clinically important 
deterioration (CID) composite endpoint

Time to clinically important 
deterioration composite endpoint 
excluding FEV1

Rescue albuterol/salbutamol use, 
(percentage of rescue-free days and 
mean number of Inhalations/day) 
captured by the electronic diary 
(eDiary) over 24 weeks

Inspiratory capacity (IC)

Full Vital capacity (FVC) 
 
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Objectives
Endpoints

Change from baseline in trough FEV1

Change from baseline in global 
impression of disease severity 
Safety

To evaluate safety and tolerability 
of UMEC/VI (62.5/25 mcg once 
daily), UMEC (62.5mcg once daily) 
and salmeterol (50mcg twice daily)

Incidence of adverse events
Exploratory

To compare albuterol/salbutamol 
use captured in the eDiary with the 
electronic metered dose inhaler 
(eMDI) device 

Rescue albuterol/salbutamol use, 
(percentage of rescue-free days and 
mean number of Inhalations/day) 
captured by the eMDI device over 24 
weeks as data allow

To explore the effect of UMEC/VI 
(62.5/25 mcg once daily), UMEC 
(62.5 mcg once daily) with 
salmeterol (50 mcg twice daily) on 
physical activity

Change from baseline in physical
activity 

To investigate the CID composite 
endpoint ability to predict short 
term outcomes 

To compare physical activity levels, 
ER-S, rescue medication use, 
exacerbations and mortality in subjects 
with and without a CID
4.
STUDY DESIGN
4.1.
Overall Design
This is a multi-centre, randomized, double blind, double-dummy, 3-arm parallel group 
study.  Eligible subjects will be stratified based on long-acting bronchodilator usage 
during the run-in (none, one or 2 long-acting bronchodilators per day) and randomized in 
a ratio of 1:1:1 to UMEC/VI inhalation powder (62.5/25 mcg once daily) administered 
via the ELLIPTA inhaler, or UMEC (62.5 mcg once daily) administered via the 
ELLIPTA or salmeterol (50 mcg BID) administered via the DISKUS. 
There will be a total of 5 clinic visits and one follow-up phone call (Visit 6). The Pre-
screening Visit (Visit 0) can occur on the same day as the Screening Visit (Visit 1) if 
subject does not take or has not taken any excluded protocol medications, but must be 
completed prior to initiating any Visit 1 procedures. 
Subjects, who meet all the eligibility criteria at Screening, will enter a run-in period for 4 
weeks in order to continue to assess the subject’s eligibility for the study. During the run-
in period subjects will continue with their inhaled COPD medications (excluding ICS and 
 
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any exclusionary medications).  In addition, subjects will be provided with short acting 
albuterol/salbutamol to be used on as needed basis for relief of COPD symptoms (rescue 
medication) throughout the study. 
Subjects who experience a moderate or severe COPD exacerbation during the run-in 
period will be deemed run-in failures.  Subjects who experience a mild COPD 
exacerbation, defined as worsening of symptoms that requires no treatment with 
antibiotics or steroids and is self managed by the patient by an increase of inhaled rescue 
medication, (Appendix 5), will be able to continue in the study based on the judgment of 
the investigator and agreement of the sponsor’s medical monitor.
At the randomization Visit 2 (Day 1) those subjects who successfully complete the run-in 
period as well as meet the other pre-defined eligibility and randomization criteria will 
discontinue their inhaled COPD medications and will be randomized to one of the 3 
treatment arms for 24 weeks.
During the run-in and treatment period, subjects will be completing PRO questionnaires 
in the eDiary and performing slow and forced spirometry at specific clinic visits.
In addition, a subset of subjects up to 150 per treatment arm will undergo assessment of 
their physical activity measured through a physical activity monitor (Actigraph GT9X) 
worn for 7 days from Screening (Visit 1), for 7 days from Randomisation (Visit 2), 7 
days from Visit 3, and for 7 days prior to last clinic Visit (Visit 5). 
Concurrent use of COPD maintenance medications including LAMAs, LABAs, oral beta-
agonists, theophyllines, inhaled corticosteroids, inhaled corticosteroids and LABA 
combination and phosphodiesterase 4 inhibitors will not be allowed during the study 
(Section 6.11.2) . 
The occurrence of adverse events (AEs) will be evaluated throughout the study beginning 
at Visit 2 (Day 1) and until the follow-up contact (Visit 6).  Serious adverse events 
(SAEs) will be collected over the same time period as AEs.  However, any SAEs 
assessed as related to study participation (e.g., study treatment, protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK concomitant 
medication, will be recorded from the time a subject consents to participate in the study 
up to and including any follow up contact (Appendix 4). 
All subjects will be given an electronic diary (eDiary) for use during the run-in, and the 
treatment period to complete PRO questionnaires, record COPD daily symptoms, any 
medical problems experienced during the study and the time they take their COPD 
medications.  Daily rescue medication usage (number of inhalations taken in the last 24h) 
will also be captured in the eDiary.  In addition, and in some countries, rescue medication 
use will also be captured by the use of electronic metered dose inhaler (eMDI).
At Screening Visit 1, all subjects must be trained on the proper use of their existing 
COPD medications inhalation devices and instructed to strictly adhere to and record the 
time they take their COPD medications in the eDiary.
 
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At the randomization Visit 2, all subjects must be trained on the proper use of the
ELLIPTA and DISKUS inhalation devices and instructed to strictly adhere to and record 
the time they take their study medications in the eDiary.
All subjects must be trained on the correct use of the eDiary and instructed to complete 
the eDiary during the run-in and treatment period.
Subjects will be considered to have completed the study upon completion of the follow –
up contact by telephone.
There are no plans to routinely provide any of the study treatments for compassionate use 
following study completion as the study treatment are commercially available.
The study design schematic is illustrated in Figure 1
Figure 1
Study Schematic
*Inhaled COPD medications including LABAs, LAMAs or LABA/LAMA combination products are 
allowed in run-in. ICS alone or in combination with a bronchodilator or any exclusionary 
medications are not allowed.
4.2.
Treatment Arms and Duration
Subjects will be stratified based on long-acting bronchodilator usage during the run-in 
(none, one or 2 long-acting bronchodilators per day) and randomized in a ratio of 1:1:1 to 
either

UMEC/VI inhalation powder (62.5/25 mcg once daily) administered via the 
ELLIPTA DPI) or 

UMEC (62.5 mcg once daily) administered via the ELLIPTA DPI or 

Salmeterol (50 mcg BID) administered via DISKUS
 
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The total duration of subject participation in the study will be approximately 29 to 
31 weeks consisting of 2 weeks pre-screening if necessary, 4 weeks run-in, 24 
week treatment and one week follow-up.
4.3.
Type and Number of Subjects
Approximately 3232 will be screened globally in approximately 205 sites such that 
approximately 2424 subjects will be randomized and approximately 2181 evaluable 
subjects complete the study. 
4.4.
Design Justification
A randomized, double blinded, parallel group study is a standard, well-established design 
to evaluate the efficacy and safety of an investigational drug.  A salmeterol arm is 
included to allow a comparison to be made between UMEC/VI, UMEC with salmeterol, 
a standard practice treatment.
The double-dummy design is appropriate when drugs are of different appearance or 
different administration regimen which is appropriate in this study where the inhalers 
used have a different appearance and used once daily and twice daily.
The European Medicines Agency (EMA) COPD Guidelines suggest that duration of 12 to 
24 weeks is considered adequate for assessment of response of COPD symptoms to 
treatment intervention with bronchodilators (EMA COPD guidelines, 2012). 
The primary endpoint is trough FEV1 at week 24. This endpoint is generally considered to 
be a robust, well established and an objective means to show the efficacy of a 
bronchodilator [Dahl, 2010; Feldman, 2010]. 
Other endpoints such SAC TDI, E-RS, SGRQ-C, CAT, Subject Global Rating of Change 
in global impression of disease severity are captured to allow responder analyses and to 
provide comparative data on PROs between the treatment groups. 
4.5.
Dose Justification
This study is intended to evaluate the efficacy of marketed doses of UMEC/VI 
(62.5/25mcg once daily), UMEC (62.5 mcg once daily) and salmeterol (50mcg twice 
daily) that are approved for the maintenance treatment of COPD, with respect to PRO 
measures.
4.6.
Benefit: Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
UMEC/VI and UMEC can be found in the investigator’s brochures (IB) 
[GlaxoSmithKline Document Number RM2009/00437/07] and [GlaxoSmithKline 
Document Number RM2006/00835/09] and in the label information sheets. The current 
safety profile for UMEC (62.5mcg) and the UMEC/VI (62.5/25mcg) based on data 
available to date, is comparable with other LABAs and LAMAs.  Summary safety data 
can also be found in the information sheet for salmeterol [Serevent product information, 
2003].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
Investigational Product (IP) [UMEC/VI] 
Severe milk protein allergy
Anoro contains Lactose monohydrate (which contains milk 
protein) as an excipient.
Exclusion criteria have been set for subjects with milk 
protein allergy.
Cardiovascular effects such as cardiac arrhythmias e.g.
supraventricular tachycardia and extrasystoles.
Class effects associated with LABAs and LAMA containing 
therapy. The clinical significance of these arrhythmias is 
unknown. Clinical experience with UMEC/VI to date in 
completed studies did not show any association with major 
cardiovascular events. 
Data available in the product label for UMEC/VI 
Exclusion criteria have been set for subjects with 
uncontrolled or severe cardiovascular disease according to 
the principal investigation’s (PI) opinion where the potential 
risk may outweigh the benefit. The PI should also 
determine the clinical significance of abnormal ECG 
findings at screening and exclude subjects who would be 
at undue risk by participating in the trial.  Patients with the 
following abnormalities will be excluded from participation:  
atrial fibrillation with rapid ventricular rate >120bpm, 
sustained or nonsustained ventricular tachycardia, or 
second degree heart block Mobitz type II or third degree 
heart block (unless pacemaker or defibrillator had been 
inserted). 
Beta agonists and risk of asthma-related death
Long-acting beta agonists such as vilanterol when used 
alone may increase the risk of asthma-related death.  A 
placebo-controlled trial with another LABA (salmeterol) 
showed an increase in asthma-related deaths in subjects 
receiving salmeterol.  This finding with salmeterol is 
considered a class effect of all LABAs, including vilanterol. 
Data are not available to determine whether the rate of death 
in patients with COPD is increased by LABA.
Subjects with a current diagnosis of asthma are excluded 
from participation in the study.
Paradoxical bronchospasm
As with other inhaled medicines, UMEC/VI can produce 
paradoxical bronchospasm which may be life threatening.
If paradoxical bronchospasm occurs following dosing with 
UMEC/VI, this treatment should be discontinued 
immediately and alternative therapy should be instituted. 
Use in patients with narrow-angle glaucoma or urinary 
retention
No association has been found to date, in completed studies 
with UMEC/VI or UMEC monotherapy, on glaucoma or 
urinary retention.  However, glaucoma or urinary retention 
Exclusion criterion states that subjects with medical 
conditions such as narrow-angle glaucoma, prostatic 
hypertrophy, or bladder neck obstruction should only be 
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
have been observed with other antimuscarinic agents, and 
could potentially be due to the pharmacology.
included if, in the opinion of the principal investigator, the 
benefit outweighs the risk.
Use of beta blockers
Beta-adrenergic blockers may weaken or antagonize the 
effect of beta2-agonists such as vilanterol.
The study permitted medications and non drug therapies 
section states that concomitant administration with beta-
blockers is only permitted if, in the Investigator’s opinion, 
the likely benefit outweighs the potential risk.
Pregnancy
There is no experience to date of pregnancy during the use 
of UMEC/VI.
The study inclusion criteria ensures that female subjects of 
child bearing potential must have a negative pregnancy 
test at screening, and agree to a reliable contraceptive 
method, used consistently and correctly (i.e. in accordance 
with the approved product label and the instructions of the 
physician for the duration of the study). Exclusion criteria 
include Pregnancy: Women who are pregnant or lactating 
or are planning on becoming pregnant during the study.
Severe hepatic impairment
UMEC/VI has not been studied in severe hepatic impairment.
Exclusion criterion states that subjects severe hepatic 
impairment should only be included if, in the opinion of the 
study physician, the benefit outweighs the risk.
Investigational product (IP) [UMEC]
Cardiovascular effects such as cardiac arrhythmia, e.g. 
atrial fibrillation and tachycardia
A potential class effect associated
with anti-muscarinic therapies. Data available to date in the
IB for UMEC [GlaxoSmithKline Document Number 
RM2006/00835/09
Screening electrocardiogram (ECG) criteria to exclude 
subjects potentially at risk 
Narrow-angle glaucoma, urinary retention
A class effect associated with anti-muscarinic therapies.
Data available in the IB for UMEC [GlaxoSmithKline 
Document Number RM2006/00835/09
Exclusion criterion states that subjects with medical 
conditions such as narrow-angle glaucoma, prostatic 
hypertrophy, or bladder neck obstruction should only be 
included if, in the opinion of the study physician, the benefit 
outweighs the risk.
Paradoxical bronchospasm that may be life threatening
Known effect associated with inhalation therapy
A short-acting inhaled bronchodilator 
(albuterol/salbutamol) will be provided for use as needed 
throughout the study. The investigators will be instructed to 
assess subject’s condition to determine their eligibility to 
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
continue in the study and the need for alternative therapy.
Severe hepatic impairment
UMEC has not been studied in severe hepatic impairment.
Exclusion criterion states that subjects with severe hepatic 
impairment should only be included if, in the opinion of the 
study physician, the benefit outweighs the risk.
Pregnancy/Lactation
There is no experience to date of pregnancy during the use 
of UMEC.
The study inclusion criteria ensure that female subjects 
enrolled, who are of Child bearing potential, have a 
negative pregnancy test at screening, and agree to a 
reliable contraceptive method, used consistently and 
correctly (i.e. in accordance with the approved product 
label and the instructions of the physician for the duration 
of the study). Exclusion criteria states - Pregnancy: 
Women who are pregnant or lactating or are planning on 
becoming pregnant during the study.
Study Procedures
Spirometry procedures
This may cause difficulty breathing, changes in pulse rate 
and blood pressure, coughing, wheezing, chest tightness or 
fainting.
Subjects will be monitored during the procedure for these 
effects and spirometry will be discontinued should these 
occur.
ECG lead placement
This may cause skin irritation.
It may be necessary to have small patches (about a 
centimetre in diameter) of hair on the chest shaved to 
properly attach electrodes to the chest. 
Blood sampling procedure (optional pharmacogenetic 
blood sample)
Giving blood may make subjects feel faint, or experience 
mild pain, bruising, irritation or redness at the site. In rare 
cases, they may get an infection
Subjects will be monitored during the blood draw for these 
effects and should call their study doctor if any of these 
effects do not resolve
Other 
Side effects of rescue albuterol/salbutamol. Adverse 
events seen in clinical studies to date are however 
consistent for the beta2-adrenergic class of compounds
Class effects associated with short acting beta-agonists 
(SABAs)
Subjects should call their study doctor if they experience 
any of these symptoms
 
 
 
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4.6.2.
Benefit Assessment
Subjects will receive single or combination of long-acting bronchodilator therapies 
approved for maintenance treatment of COPD.  Participating subjects in this study will 
contribute to the process of further characterizing the benefit of these long-acting 
bronchodilators with respect to PROs and symptoms in the treatment of COPD.
Specific benefits associated with the study design and procedures include the following:

Subjects will receive treatments approved for the treatment of COPD that have 
been shown to be effective in the population under study

All subjects will receive albuterol/salbutamol for use “as needed” for relief of 
COPD symptoms

The combination of study procedures of spirometry, CAT, SGRQ, TDI, E-RS will 
provide the study subjects with a comprehensive evaluation of their symptoms, 
health status and COPD disease severity. Subjects will also be monitored 
throughout the study for any worsening of COPD symptoms or decline in general 
health.  Finally smoking cessation counselling will also be provided.
4.6.3.
Overall Benefit: Risk Conclusion
Taking into account the measures taken to minimize risk to subjects participating in this 
study, the potential risks identified in association with UMEC/VI, UMEC, salmeterol and 
with study procedures are justified by the anticipated benefits from active treatments that 
may be afforded to patients with COPD.
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 IBs, [GlaxoSmithKline 
Document Number RM2006/00835/09], [GlaxoSmithKline Document Number 
RM2009/00437/07] and product labels.
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
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE
1.
40 years or older at date of signing informed consent at Screening Visit 1
 
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TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2.
Outpatient with a diagnosis of COPD in accordance with the definition of the 
American Thoracic Society/European Respiratory Society (ATS/ERS) [Celli, 2004]. 
3.
FEV1: Persistent airflow limitations as indicated by:  A pre and post-
albuterol/salbutamol FEV1/FVC ratio of <0.70 and a post-albuterol/salbutamol FEV1
of ≥30% to ≤80% predicted normal values at Screening Visit 1.  Predicted values 
will be based upon the ERS Global Lung Function Initiative [Quanjer, 2012].
4.
CAT score:  A CAT score of ≥10 at Screening Visit 1
Smoking History
5.
Current or former cigarette smokers with a history of cigarette smoking of 10 
pack-years [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 both equal 10 pack-years)].  Former smokers are defined as those who have 
stopped smoking for at least 6 months prior to Visit 1.  Pipe and/or cigar use cannot 
be used to calculate pack-year history.
SEX
6.
Male and female subjects are eligible to participate in the study
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 must be tested.  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.
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 
 
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Reproductive Potential (FRP) (Appendix 7) from 30 days prior to the first dose of 
study medication and until [at least five terminal half-lives OR until any continuing 
pharmacologic effect has ended, whichever is longer] after the last dose of study 
medication and completion of the follow-up visit.
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.
INFORMED CONSENT
7.
Capable of giving signed informed consent prior to study participation, which 
includes compliance with the requirements and restrictions listed in the consent form 
and in this protocol.
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION 
1.
Asthma:  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).
2.
Alpha-antitrypsin deficiency: Subjects with known α1-antitrypsin deficiency as 
the underlying cause of COPD
3.
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.
4.
Unstable liver disease: 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). 

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 or within 3 months prior to 
first dose of study treatment) are acceptable if subject otherwise meets entry 
criteria
5.
Unstable or life threatening cardiac disease: Investigational Product should be 
used with caution in subjects with severe cardiovascular disease.  In the opinion 
of the investigator, use should only be considered if the benefit is likely to 
 
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outweigh the risk in conditions such as:

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
6.
12 Lead ECG: 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. Subjects with the 
following abnormalities are excluded from participation in the study:

Atrial fibrillation with rapid ventricular rate >120 bpm

Sustained or non-sustained ventricular tachycardia

Second degree heart block Mobitz type II or third degree heart block (unless 
pacemaker or defibrillator had been inserted)
7.
Antimuscarinic effects:  Subjects with medical conditions such as narrow-angle 
glaucoma, urinary retention, prostatic hypertrophy, or bladder neck obstruction 
should be excluded unless, in the opinion of the study physician, the benefit 
outweighs the risk.
8.
Other disease abnormalities: Any subject who is considered unlikely to survive 
the duration of the study period or has any rapidly progressing disease or 
immediate life-threatening illness (e.g. cancer). In addition, any subject who has 
any other condition (e.g. neurological condition) that is likely to affect respiratory 
function should not be included in the study.
9.
Hospitalization: Hospitalization for COPD or pneumonia within 12 weeks prior 
to Visit 1. 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). 
10.
Inhaled corticosteroids (ICS): Had received ICS or ICS/LABA for the treatment 
of COPD in the 6 weeks prior to Screening Visit1
11.
Exacerbation: Had >1 moderate exacerbation in the 12 months prior Screening 
Visit1, or one severe exacerbation requiring hospitalisation in the 12 months prior 
Screening Visit 1.
12.
Other respiratory tract infections that have not resolved at least 7 days prior to 
Screening V1.
13.
Lung Resection: Subjects with lung volume reduction surgery (including 
procedures such as endobronchial valves) within the 12 months prior to Screening 
V1.
14.
Oxygen: Use of long-term oxygen therapy (LTOT) described as resting oxygen 
therapy >3L/min at screening required to maintain adequate oxygenation (e.g. 
SaO2 >90%). (Oxygen use ≤3L/min flow is not exclusionary, and patients may 
adjust oxygen levels up or down as needed during the study.)
 
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CONCOMITANT MEDICATIONS
1. Medications prior to Screening: Use of the following medications according to 
the following defined time intervals prior to Screening (Visit 1):
Medication
No use within the 
following time intervals 
prior to Screening
Inhaled corticosteroids (ICS)
6 weeks
Depot corticosteroids
12 weeks
Systemic, oral or parenteral corticosteroidsa
6 weeks
Antibiotics (for lower respiratory tract infection)
6 weeks
Phosphodiesterase 4 (PDE4) Inhibitor (e.g roflumilast)
14 days
LABA/Inhaled Corticosteroid (ICS) combination products 
6 weeks
Theophyllines
48 hours
Oral beta2-agonists
     Long-acting
     Short-acting
48 hours
12 hours
Inhaled short acting beta2-agonistsb
4 hours
Inhaled short-acting anticholinergics
4 hours
Inhaled short-acting anticholinergic/short-acting beta2-agonist 
combination products
4 hours
Any other investigational medication
30 days or within 5 drug 
half-lives (whichever is 
longer)
a-
Localized corticosteroid injections (e.g., intra-articular and epidural) are permitted.
b-
Use of study provided albuterol/salbutamol is permitted during the study, except in the 4-hour period prior to 
spirometry testing
2. Medication prior to spirometry: Unable to withhold albuterol/salbutamol for 
the 4 hour period required prior to spirometry testing at each study visit.
3. Maintenance use of short-acting bronchodilators:  Regular use (prescribed for 
daily/ regular use, not for as-needed use) of short-acting bronchodilators (e.g. 
albuterol/salbutamol).
RELEVANT HABITS
1. Drug or alcohol abuse: A known or suspected history of alcohol or drug abuse 
within 2 years prior to Screening Visit 1 that in the opinion of the investigator would 
prevent the subject from completing the study procedures.
CONTRAINDICATIONS 
1. Any history of allergy or hypersensitivity to any anticholinergic/muscarinic 
receptor antagonist, sympathomimetic, lactose/milk protein or magnesium stearate.
 
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DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
1. Pulmonary Rehabilitation program: Participation in the acute phase of a 
pulmonary rehabilitation program within 4 weeks prior to Screening Visit 1.  Subjects 
who are in the maintenance phase of a pulmonary rehabilitation program are not 
excluded.
2. Affiliation with investigator sites: Is an investigator, sub-investigator, study 
coordinator, employee of a participating investigator or study site, or immediate 
family member of the aforementioned that is involved in this study
3. Inability to read: In the opinion of the investigator, any subject who is unable to read 
and/or would not be able to complete questionnaires on the electronic diary.
Subjects who fail to meet inclusion and exclusion criteria at the Screening Visit 1 will be 
considered screen failures and cannot be re-screened.
5.3.
Randomization Criteria
In order to be randomized to one of the 3 treatment arms at Visit 2, subjects must have 
completed the run-in period and must have fulfilled all inclusion and exclusion criteria 
described in Section 5.1 and Section 5.2. In addition to the following:
REQUIRED CRITERIA FOR RANDOMIZATION AND TREATMENT
1. COPD Exacerbation: Subjects must not have experienced a moderate or severe 
COPD exacerbation or a lower respiratory tract infection during run-in or at Day 1 
(Visit 2) inclusive.  A moderate exacerbation is defined as worsening of symptoms of 
COPD requiring the use of antibiotics or systemic corticosteroids.  A severe 
exacerbation is defined as worsening symptoms of COPD requiring hospitalization.
2. CAT score:  A CAT score of ≥10 at Visit 2
3. Prohibited Medications: No use of any prohibited medications during the run-in 
period or at Visit 2, including any ICS or ICS/LABA combination
4. Any change to COPD medications: Including dosage and regimen during the run-in
5. Completion of electronic diary: Must have completed the electronic diary for at 
least 80% of days during the run-in period
Subjects who do not meet the required criteria for randomization at Visit 2 will not be 
randomized.
5.4.
Screening/Baseline/Run-in Failures
Pre-screen, screen and run-in failures are defined as follows: 

Pre-screening failures: A subject, who is assigned a subject number at the Pre-
screening Visit 0 but does not have any Screening Visit 1 procedures, will be 
considered a pre-screen failure.
 
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
Screening failures: Those subjects that complete at least one Screening Visit 1 
procedure but do not enter the run-in period.

Run-in failures: Those subjects that enter the run-in period but are not 
randomized to any of the study treatment arms.
Subjects who are pre-screen, screen and run-in failure will be recorded in the eCRF.  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 to be recorded in eCRF including demography, screen failure details, eligibility 
criteria, and serious adverse events (Section 7.4.1). 
5.5.
Withdrawal/Stopping Criteria
5.5.1.
Withdrawal from the Study
Subjects may be withdrawn from the study at any time by the Investigator if it is 
considered to be detrimental for them to continue in the study.  Reasons for withdrawal 
from study treatment can include: an AE, clinically significant abnormality, lack of 
efficacy, sponsor terminated study, pregnancy, or for any other reason. 
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. 
A reason for the withdrawal from the study must be captured in the electronic case report 
form (eCRF).
A subject will also be withdrawn from the study, in consultation with the medical 
monitor and principal investigator, if any of the following stopping criteria are met:

Liver Chemistry: Meets any of the Liver chemistry stopping criteria (See Section 
5.5.3)
Note: clinical laboratory assessments are not required for this study. However, 
laboratory samples may be taken for liver event analysis, if clinically indicated by 
the study investigator.

Pregnancy:  Positive pregnancy test (see Appendix 7)
Subjects withdrawn from study treatment will not be replaced. 
Note: Withdrawal from study treatment requires withdrawal from the study.
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. 
 
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
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”. 
5.5.2.
Reason for Study Withdrawal
The primary reason for study withdrawal will be recorded in the eCRF. When a subject 
withdraws consent, the investigator must document the reason (if specified by the 
subject) in the eCRF. 
The primary reason for study withdrawal may include:
Adverse event
Lost to follow-up
Withdrew consent
o
subject relocated
o
frequency of visits
o
burden of procedures
o
other (specify)
Protocol deviation
Lack of efficacy
COPD exacerbation
Study closed/terminated
Subject reached protocol-defined stopping criteria
o
Liver event
Pregnancy
Investigator discretion
5.5.3.
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
 
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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*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 2.
5.5.3.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed.
5.6.
Follow-up contact
A safety follow-up contact (Visit 6) should be conducted 72 days following the 
completion of Visit 5 or the Early Withdrawal Visit, if applicable. 
The following procedures will be performed:

AE/SAE assessment

COPD exacerbation assessment

Concomitant medication assessment limited to any medications used to treat a 
COPD exacerbation or SAE (if applicable)

Pregnancy information (if applicable)
Subjects who have successfully completed all on-treatment randomized visits will be 
discharged from the study upon completion of the safety follow-up contact.
 
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5.7.
Subject and Study Completion
A subject will be considered to have completed the study if he/she receives study 
treatment at Visit 5 (Week 24) and completes the follow-up contact Visit 6.
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.
The contents of the label will be in acaccordance with all applicable regulatory 
requirements.
Under normal conditions of handling and administration, investigational product is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to avoid 
direct eye or skin contact and the generation of aerosols or mists. Notify the monitor of 
any unintentional occupational exposure.  A Material Safety Data Sheet (MSDS) 
describing the occupational hazards and recommended handling precautions will be 
provided to site staff if required by local laws or will otherwise be available from GSK 
upon request.
Investigational product must be stored in a secure area under the appropriate physical 
conditions for the product.  Access to and administration of the investigational product 
will be limited to the investigator and authorised site staff.  Investigational product must 
be dispensed or administered only to subjects enrolled in the study and in accordance 
with the protocol.
GlaxoSmithKline (GSK) will provide the study treatments for use in this study. 
The following study medications will be used in this study:
UMEC/VI 62.5/ 25mcg administered via ELLIPTA
UMEC 62.5 mcg administered via ELLIPTA

Salmeterol 50 mcg administered via DISKUS

Placebo via ELLIPTA

Placebo via DISKUS
Subjects will be instructed to take one dose of medication each morning from the 
ELLIPTA (one inhalation equals one dose), and one dose in the morning and one in the 
evening from the DISKUS).  Subject instructions and details on how to use the ELLIPTA 
and DISKUS are provided in the study reference manual (SRM).
 
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A description of the UMEC/VI investigational product administered via the ELLIPTAis 
provided below in Table 1. The ELLIPTA will contain two, double-foil, laminate, blister 
strips.  The ELLIPTA will provide a total of 30 doses (60 blisters) and will deliver, when 
actuated, the contents of a single blister simultaneously from each of the two blister 
strips. 
The DISKUS will provide a total of 60 doses and will deliver, when actuated, the 
contents of a single blister.
A description of the UMEC investigational product administered via the ELLIPTA is 
provided below in Table 2. A description of placebo inhalation powder via ELLIPTA is 
shown in Table 3.  A description of salmeterol 50mcg and placebo via DISKUS are 
shown in Table 4 and Table 5 respectively.
Table 1
Description of UMEC/VI Inhalation Powder via ELLIPTA
Formulation
First strip
Second strip
Umeclidinium bromide blended with 
lactose monohydrate and 
magnesium stearate1
Vilanterol trifenatate blended with 
lactose monohydrate and magnesium 
stearate2
Dosage Form
ELLIPTA Inhaler with 30 doses (2 strips with 30 blisters per strip)
Unit Dose Strengths
62.5 mcg
25 mcg
Physical description
White powder
White powder
Route of Administration
Inhaled
1.
Magnesium stearate 0.6% w/w of total drug product
2.
Magnesium stearate 1.0% w/w of total drug product
Table 2
Description of UMEC Inhalation Powder via ELLIPTA
Formulation
First strip
Umeclidinium bromide blended with lactose monohydrate and 
magnesium stearate1
Dosage Form
ELLIPTA Inhaler with 30 doses (1 strip with 30 blisters) 
Unit Dose Strengths
62.5mcg 
Physical description
Dry white powder
Route of Administration
Inhaled
1.
Magnesium stearate 0.6% w/w of total drug product
Table 3
Description of Placebo inhalation powder via ELLIPTA
Formulation
First strip
Second strip
Lactose monohydrate blended with 
magnesium stearate1
Lactose monohydrate blended with 
magnesium stearate2
Dosage Form
ELLIPTA Inhaler with 30 doses (2 strips with 30 blisters per strip)
Unit Dose Strengths
Not applicable
Not applicable
Physical description
Dry white powder
Dry white powder
Route of Administration
Inhaled
1.
Magnesium stearate 0.6% w/w of total drug product
2.
Magnesium stearate 1% w/w of total drug product
 
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Table 4
Description of salmeterol Inhalation powder via DISKUS
Formulation
First strip
Salmeterol Xinafoate blended with lactose monohydrate
Dosage Form
Diskus Inhaler with 60 doses (1 strip with 60 blisters per strip)
Unit Dose Strengths
50 mcg
Physical description
White powder
Route of Administration
Inhaled
Table 5
Description of Placebo inhalation powder via DISKUS
Formulation
Lactose monohydrate 
Dosage Form
Diskus Inhaler with 60 doses (1 strip with 60 blisters per strip)
Unit Dose Strengths
Not Applicable
Physical description
White powder
Route of Administration
Inhaled
Albuterol/salbutamol via metered-dose-inhaler (MDI) will be issued for reversibility 
testing at Visit 1.  Albuterol/salbutamol MDI for as needed (prn) use will be issued 
throughout the study.  Albuterol/salbutamol will be sourced from local commercial stock 
if appropriate.  
6.2.
Medical Devices
The eMDI devices are provided by GSK and are used in this study to electronically 
record rescue medication usage.  They have US FDA 510(K) clearance to market (Class 
II device) and EU CE marking (Class I device). Description of the eMDI and its use will 
be provided in the SRM.
6.3.
Treatment Assignment
Subjects who meet the randomization criteria will be assigned to one of the 3 study 
treatments in accordance with the randomization schedule generated by Clinical 
Statistics, prior to the start of the study, using validated internal software.
Once a randomization number is assigned to a subject, it cannot be reassigned to any 
other subject in the study.
This study will utilize RAMOS NG, which will provide a means for central 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 RAMOS NG to randomize subjects is provided in the SRM.
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.  On the other days during the treatment period 
(i.e. “non-clinic days”), subjects will be instructed to self-administer their study treatment 
 
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in the morning and evening. Subjects should enter the time they take their study treatment 
in the eDiary. 
Subjects will be randomly assigned to one of the blinded study treatment regimens in 
equal proportion (ratio of 1:1:1):

UMEC/VI 62.5/25 mcg once daily via ELLIPTA + placebo twice daily via 
DISKUS

UMEC 62.5 mcg once daily via ELLIPTA + placebo twice daily via DISKUS

Salmeterol 50 mcg twice daily via DISKUS + placebo once daily via ELLIPTA
The randomisation will be stratified based on long-acting bronchodilator usage during 
the run-in (none, one or 2 long-acting bronchodilators per day). 
Study treatment/investigational product will be dispensed at Visits 2, 3 and 4. 
In order to ensure subjects have sufficient doses of study treatment, they must return to 
clinic within 30 days from V2, 60 and 90 days from V3 and V4 respectively (see Time 
and event table Section 7.1). 
Used study drug and rescue medication will be collected at Visits 3, 4 and 5 or at the 
Early Withdrawal Visit. 
6.4.
Planned Dose Adjustments
No dose adjustment is allowed for this study
6.5.
Blinding
This will be a double-blind double dummy study 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. 

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 
 
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A subject will be withdrawn if the subject’s treatment code is unblinded by the 
investigator or treating physician. 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.
6.6.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.7.
Preparation/Handling/Storage/Accountability
No special preparation of the study treatment is required.

The investigator or designee must confirm appropriate temperature conditions 
have been maintained during transit for all study treatment received and any 
discrepancies are reported and resolved before use of the study treatment.

Only subjects enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment.  All study 
treatments must be stored in a secure environmentally controlled and monitored 
(manual or automated) area in accordance with the 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 SRM. 
All ELLIPTA DPI study treatment should be stored up to 25C (77F).  Each All 
ELLIPTA DPI contains 30 doses and is packaged in a foil pouch with a desiccant 
sachet and stored in a carton. The inhaler should not be used for more than 30 days 
after opening the foil.  The sites must maintain a daily temperature log for the 
investigational product. 
Salmeterol DISKUS should be stored up to 25 C. 
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.

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.
 
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6.7.1.
Study Treatment Return
All used and unused ELLIPTA and DISKUS inhalers 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 SRM.
Study treatment will be collected at Visit 3, 4 and 5 or at the Early Withdrawal Visit, if 
applicable. 
For any ELLIPTA or DISKUS inhaler that fails to function properly, the subject should 
return to the clinic as soon as possible to obtain a new inhaler.  The site will contact the 
RAMOS NG 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 
RAMOS NG
In addition, any ELLIPTA that fails to function properly must be identified and returned 
to GSK for testing. 
6.8.
Compliance with Study Treatment Administration
When subjects self-administer study treatment(s) at home, compliance with study 
treatment(s) will be assessed through querying the subject during the site visits and 
through study drug compliance assessed at Visits 2, 3, 4 and 5 documented in the source 
documents and eCRF.  A record of the number of ELLIPTA and DISKUS dispensed and 
the number of doses inhaled by each subject must be maintained and reconciled with 
study treatment and compliance records.  Treatment start and stop dates, including dates 
for treatment delays if any will also be recorded in the eCRF.
Compliance with the ELLIPTA inhaler will be determined by reviewing the dose counter 
on the ELLIPTA.  Compliance with the study DISKUS will be determined by reviewing 
the dose counter on the DISKUS.  Subjects should be ≥80% to ≤120% compliant on 
taking study medication between each pair of on-treatment visits.  Subjects who fall 
outside this range should be re-educated on treatment compliance by their site. This re-
education should be documented in the subject’s source document.  If medication 
compliance repeatedly falls outside of acceptable ranges, the study sponsor/site monitor 
must be contacted to discuss subject eligibility for continued participation in the study.
6.9.
Treatment of Study Treatment Overdose
An overdose is defined as a dose greater than the total doses described in Section 6.1 and 
Section 6.8 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 medication, 
the investigator should use clinical judgment in treating the overdose and contact the 
study 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 
 
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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 may not be limited to, the approved product label for salmeterol 
albuterol, UMEC and UMEC/VI or equivalent document provided by GSK.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the subject.
6.10.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study, since the study treatments are commercially available.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, post-study treatment. 
6.11.
Concomitant Medications and Non-Drug Therapies
All COPD medications used within 30 days prior to Pre-Screening (Visit 0) and onwards 
should be recorded in the eCRF including any changes in medications.  Beginning at 
Visit 1 and throughout the rest of the study, all medications should be recorded in the 
eCRF including any changes.  Study provided albuterol/salbutamol and double-blinded 
study drug should not be recorded in the eCRF.  The minimum requirement includes but 
is not limited to drug name, dose, route and the dates of administration.  Medications 
initiated after completion of Visit 5 or the Early Withdrawal Visit will not be recorded in 
the eCRF, with the exception of those used to treat a COPD exacerbation or SAE that 
occurs between Visit 5 (or the Early Withdrawal Visit) and the follow-up contact atVisit 
6.
6.11.1.
Permitted Medications and Non-Drug Therapies
The following relevant medications are permitted during this study:

Study-provided albuterol/salbutamol for use as relief medication throughout the 
run-in and treatment periods 

Mucolytics such as acetylcysteine

Medications for rhinitis (e.g. intranasal corticosteroids, antihistamines, cromolyn, 
nedocromil, nasal decongestants)

Influenza vaccine

pneumococcal vaccine

Antibiotics for short term treatment (14 days) of acute infections including  
COPD exacerbations

Systemic corticosteroids for short term (14 consecutive days)  treatment of 
COPD exacerbations 
 
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
As-needed supplemental oxygen use provided it is ≤3L/min flow at rest at 
screening.  Patients may adjust oxygen levels as needed during the study.

Pulmonary rehabilitation program in maintenance phase

Smoking cessation treatment, including a stable regimen of nicotine replacement

Use of positive airway pressure/non-invasive ventilation for sleep apnea/sleep 
disordered breathing (e.g. CPAP, BiPAP) 

Localized corticosteroid injections (e.g., intra-articular and epidural)

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)

Immunotherapy injections

Topical or ophthalmic corticosteroids

Over-the counter (OTC) cough suppressants

Tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs). Administer 
with caution as they may potentiate the effect of beta-agonists on the vascular 
system

Diuretics. Caution is advised in the co-administration of beta agonists with non-
potassium sparing diuretics

Allergy vaccination

All medications for other disorders as long as the dose remains constant whenever 
possible and their use would not be expected to affect lung function
6.11.2.
Prohibited Medications and Non-Drug Therapies
Use of the medications listed in Table 6 is not permitted during the study
 
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Table 6
Prohibited Medications and Non-Drug Therapies
Medication
Depot corticosteroids
Systemic, oral or parenteral corticosteroids1
Inhaled corticosteroids (ICS)2
Antibiotics >14 days
LABA/ICS combination products
PDE4 inhibitor (e.g. roflumilast)
Inhaled long acting beta2-agonists (LABA, e.g. salmeterol, formoterol, indacaterol, vilanterol)
Long-acting muscarinic antagonists (LAMA, e.g. tiotropium, aclidinium, glycopyrronium, umeclidinium3)
LAMA/LABA combination products except for study drugs
Theophyllines
Oral beta2-agonists
Inhaled short acting beta2-agonists4
Inhaled short-acting anticholinergics
Inhaled short-acting anticholinergic/short-acting beta2-agonist combination products
Any other investigational medication
1
Except for the treatment of COPD exacerbations during the study. Localized corticosteroid injections (e.g., 
intra-articular and epidural) are permitted.
2
Except if during the study use of ICS is deemed necessary for the treatment of subjects’ exacerbation. 
3
Expect for study drug
4
Use of study provided albuterol/salbutamol is permitted during the study, except in the 4-hour period prior to 
spirometry testing. 
The following medications or treatments are also not allowed during the study:

Use of long-term oxygen therapy (LTOT) described as resting oxygen therapy 
>3L/min only at screening. Oxygen may be titrated to any level deemed necessary 
during the study.

Regular (prescribed for daily/regular use, not for as-needed use) therapy with 
albuterol/salbutamol.

Initiation of pulmonary rehabilitation during the study.
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 Section 7.1, are essential and required for study 
conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table Section 7.1
 
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7.1.
Time and Events Table
Blinded Treatment
Visit
Pre-
screen1
0
Screen/ 
Run-in
1
Rando-
mization 
2
3
4
5
EW 
Visit 2
Telephone Follow up 
contact 
6
Week
-6 to -4
-4
0
4
12
24
Day
42 -7/+2 
days 
prior 
Visit 1
28  -7/+2 
days prior 
Visit 2
1 -7/+2 
days
28  -7/+2 
days 
84  -7/+2 
days
168  -7/+2 
days
73 days after V5 or 
EW Visit
Screen/Baseline
Written informed consent
X
Demography
X
Medical/COPD history
X
Smoking history/status
X
Smoking cessation counselling
X
Concomitant medication assessment
X
X
X
X
X
X
X
X
Height and weight
X
Cardiovascular History/family history of premature CV 
disease])
X
Screening spirometry (including post bronchodilator 
testing)3
X
CAT questionnaire
X
X
Verify Inclusion/Exclusion Criteria
X
Training on use of inhalers
X
X
Training on use of eDiary and eMDI
X
X
Verify randomization Criteria
X
Register Visit in InForm
X
X
X
X
X
X
X
X
Register Visit in RAMOS NG
X
X
X
X
X
X
X
X
 
 
 
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Blinded Treatment
Visit
Pre-
screen1
0
Screen/ 
Run-in
1
Rando-
mization 
2
3
4
5
EW 
Visit 2
Telephone Follow up 
contact 
6
Week
-6 to -4
-4
0
4
12
24
Day
42 -7/+2 
days 
prior 
Visit 1
28  -7/+2 
days prior 
Visit 2
1 -7/+2 
days
28  -7/+2 
days 
84  -7/+2 
days
168  -7/+2 
days
73 days after V5 or 
EW Visit
Efficacy/HRQoL assessments
Spirometry, including pre-dose FEV1, trough  FEV1 and 
inspiratory capacity
X
X
X
X
SAC BDI questionnaire 4
X
SAC TDI questionnaire 4
X
X
X
SGRQ-C questionnaire 4
X
X
X
X
CAT questionnaire 4
X
X
X
X
X
EXACT/ER-S: COPD 5
Patient Global Rating of COPD severity
X
X
X
X
Patient Global Rating of Change in COPD
X
X
X
Safety assessments
Adverse events/Serious adverse events 6
X
X
X
X
X
X
X
X
COPD exacerbation assessment
X
X
X
X
X
X
X
X
12-Lead ECG
X
Urine pregnancy test 7
X
X
X
X
Pharmacogenetic sample8
                                          X
Medication/Supplies
Dispense rescue albuterol/slabutamol. Dispense MDI9
X
X
X
X
X
Assess COPD medication compliance10 during run-in
X
Dispense eDiary
X
Assess compliance with eDiary during run-in 
X
Collect rescue albuterol/slabutamol. 
X
X
X
X
X
Collect eDiary
X
X
Dispense study treatment11
X
X
X
Collect study treatment
X
X
X
X
 
 
 
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Blinded Treatment
Visit
Pre-
screen1
0
Screen/ 
Run-in
1
Rando-
mization 
2
3
4
5
EW 
Visit 2
Telephone Follow up 
contact 
6
Week
-6 to -4
-4
0
4
12
24
Day
42 -7/+2 
days 
prior 
Visit 1
28  -7/+2 
days prior 
Visit 2
1 -7/+2 
days
28  -7/+2 
days 
84  -7/+2 
days
168  -7/+2 
days
73 days after V5 or 
EW Visit
Assess study treatment compliance during treatment10
X
X
X
X
Study sub-set
Physical activity monitor12
X
X
X
X
Collect Physical activity monitor
X
X
1.
Pre-screen Visit 0 must be completed prior to Screening Visit1. It can be completed 2 weeks prior or on the same day of V1, if no wash out of exclusionary medications is 
required. 
2.
Early Withdrawal Visit: Subjects that withdraw should return to the clinic as soon as possible to complete the Early Withdrawal Visit procedures.
3.
Spirometry at screening should be performed as described in (Section 7.2.2.1). 
4.
SAC BDI, SAC TDI, SGRQ-C, CAT questionnaires will be completed at clinic visits and in the eDiary
5.
EXACT/ER-S: COPD is completed daily in the eDiary approximately 2 hours before bed-time, starting on Day 1 of the run-in period.
6.
For the start date of collecting AEs and SAEs see (Appendix 4)
7.
Pregnancy test: for females for child bearing potential only.
8.
Pharmacogenetic sample may be drawn at visit 2 or any visit after.
9.
Rescue medication use to be recorded in the eDiary daily and in some sites in the eDiary and the eMDI
10. Sites are requested to call subjects every 2 weeks to remind them to take study treatment regularly and to record the time of the morning and evening dose in the eDiary.
11. In order to ensure subjects have sufficient doses of study treatment, they must return to clinic within 30 days from V2 and within 60 days from V3 respectively.
12. The Actigraph GT9X should be worn for 7 days from Visit 1, for 7 days from Visit 2, for 7 days from Visit 3 and for 7 days prior to Visit 5.
 
 
 
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7.2.
Screening and Critical Baseline Assessments
7.2.1.
Pre-screening Visit
During the Pre-screening Visit, the study designated personnel must provide informed 
consent to the study participant.  Subjects can perform the Pre-screening Visit (Visit 0) 
up to 2 weeks prior to or on the same day as the Screening Visit (Visit 1) if subject does 
not take or has not taken any protocol excluded medications.
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.  A subject number will be assigned at the time the 
informed consent form (ICF) is signed. No study related procedures may be 
performed until the informed consent form document has been signed by the 
subject.  
Once the informed consent is signed and if required, changes can be made to the subject’s 
current medication regimen. The investigator should exercise clinical judgment, and is 
discouraged from changing medications only for the purpose of the clinical study. 
During the pre-screening Visit 0, the following information is collected:

Demographic parameters: year of birth, gender, race and ethnicity

Concomitant medications review

COPD exacerbation assessment
From the pre-screening visit onwards concomitant medications, exacerbations and SAEs 
(considered as related to study participation) must be reported
7.2.2.
Critical procedures performed at Screening (Visit 1)
The following critical assessments will be conducted at Visit 1:

Cardiovascular medical history/risk factors (as detailed in the eCRF) will be 
assessed at screening

Medical history including COPD (including date of diagnosis and COPD type 
(emphysema and/or chronic bronchitis), smoking history, COPD exacerbation 
history, smoking status and previous and/or current medical conditions) 

Concomitant medication review (COPD and non COPD medications in the 3 
months prior to Screening).

Height and weight

12-Lead ECG. (Note: ECG is performed at screening Visit 1 to test for eligibility 
only. See Section 7.4.4).
 
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
Urine pregnancy test if applicable

Train subject on the use of eDiary

COPD assessment test (CAT) and patient global rating of COPD severity in 
eDiary

Pre- and post-albuterol/salbutamol spirometry (reversibility, see Section 7.2.2.1)

Inclusion/Exclusion criteria assessment

Review exacerbations, AEs, (SAEs if related to study participation)

Train subject on the proper use of their COPD medication inhalation devices

Instruct subject to take their COPD medications as instructed and to enter the time 
they take their medication in the eDiary

Dispense rescue medication
Medical history will be assessed as related to the inclusion/exclusion criteria listed in 
Section 5.1 and Section 5.2.
Assessment of subject’s health status will be made at screening using CAT.  PRO 
questionnaires should be completed by subjects before any other assessments at a clinic 
visit, in the order specified in Section 7.3.1
7.2.2.1.
Albuterol/Salbutamol Reversibility Assessment
At Visit 1, both pre- and post-albuterol/salbutamol spirometry will be obtained to 
determine subject eligibility.  Reversibility assessment should be performed as follows:

Perform pre-bronchodilator spirometry and record FEV1 and FVC

Subject to self-administer 4 Inhalations (4X100g) of albuterol/salbutamol MDI

Perform post-bronchodilator spirometry and record FEV1 and FVC approximately 
10 to 30 minutes after albuterol/salbutamol administration
The results of the spirometry must meet the ATS/ERS criteria [Miller, 2005] for 
the subject to continue in the study.
7.2.3.
Critical procedures performed at first treatment Visit (Baseline 
V2)

Review and assess  compliance with subject’s COPD medications during the run-
in period

Review and assess compliance with completing the eDiary during the run-in 
period

Review AEs, SAEs and exacerbations
 
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
Urine pregnancy test, if applicable

Baseline dyspnea Index, BDI, patient global rating of COPD severity, patient 
global rating of change in COPD, SGRQ-C and CAT questionnaires in eDiary

Review randomization criteria (Section 5.3)

Register and randomize subject in RAMOS NG

Pre-dose spirometry; IC and FEV1

Train subject on the proper use of ELLIPTA and DISKUS inhalers

Dispense study medication

Dispense rescue medication

Optional pharmacogentic sample can be collected at V2 or any visit after.
7.3.
Efficacy Assessments
7.3.1.
HRQoL assessments: Completion of PRO questionnaires in the 
Electronic Diary
All subjects will be completing PRO questionnaires in the eDiary. 
It is requested that questionnaires are completed before any procedures are performed on 
the subject. 
All questionnaires will be completed using the eDiary at clinic and at home.  Adequate 
time should be allowed to complete all items of the questionnaires and the questionnaires 
must be reviewed by the investigator or designated study staff for completeness and, if 
necessary, the subject must be encouraged to complete any missing items. Where more 
than one questionnaire is to be completed at a visit the order should be as follows:
1. Baseline dyspnea index (Visit 2) then Transient dyspnea index at subsequent 
visits
2. Patient global rating of COPD severity and global rating of change in COPD
3. St George’s respiratory questionnaire
4. COPD Assessment Test 
Instructions for completing the questionnaires can be found in the SRM.
7.3.1.1.
Self Administered Computerised Baseline Dyspnea Index/Transitional 
Dyspnea Index (SAC BDI/TDI)
The BDI is used to measure the severity of dyspnea in patients at baseline. The TDI 
measures changes in the patient’s dyspnea from baseline.  The self-administered 
computerized version of the BDI/TDI (SAC BDI/TDI)[Mahler, 2004] is used to measure 
severity of dyspnea in patients at baseline (SAC BDI) on Day 1 (Visit 2) of treatment and 
change from the baseline (SAC TDI) at Week 4, 12 and 24 (Visits 3, 4 and 5).  The 
 
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scores in both indexes depend on ratings for three different categories: functional 
impairment; magnitude of task, and magnitude of effort. SAC BDI/TDI should be 
completed before performing spirometry. 
The SAC BDI/TDI was developed to address issues of potential bias in the interviewer 
administered (original) BDI/TDI [Mahler, 1984].  The SAC BDI/TDI provides a 
standardized approach to the measurement of dyspnea, equivalent to the original 
BDI/TDI with advantages over the interviewer method for grading dyspnea in patients 
with COPD by standardizing the process for each patient and eliminating individual 
judgment required by the interviewers when completing the original BDI/TDI. This also 
removes the need for the same investigator to conduct all interviews with a subject based 
on the patient’s responses. SAC TDI provides a continuous measure of change in dyspnea 
using a visual analogue scale to record responses. 
Details for the completion of the SAC BDI/TDI are provided in the SRM.
7.3.1.2.
SGRQ-C
The St George’s Respiratory Questionnaire-Chronic Obstructive Pulmonary Disease 
specific (SGRQ-C) will be completed by subjects at Randomisation (V2, Day 1), at Week 
4, 12 and 24 or at the Early Withdrawal Visit (where applicable).
The SGRQ-C [Meguro, 2007] is a well established, disease-specific questionnaire.  It was 
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, 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 scores 
equivalent to the SGRQ instrument [Meguro, 2007].  
7.3.1.3.
COPD Assessment Test (CAT)
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.
The CAT will be completed in the eDiary by subjects at Screening Visit 1 and 
Randomisation Visit 2 to assess their eligibility to enter the study.  CAT is also 
completed at Weeks 4, 12 and 24.  Additional instructions for completion of the CAT are 
provided in the SRM.
 
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7.3.1.4.
EXACT and the Evaluating Respiratory Symptoms- COPD (E-RS: 
COPD)
EXACT-PRO is a 14 item patient reported outcome instrument designed to capture 
information on the occurrence, frequency, severity, and duration of exacerbations of 
disease in patients with COPD [Leidy, 2011].  EXACT captures information on the 
severity of the respiratory and systemic manifestations of a COPD exacerbation as 
reported by the patient.  The instrument is to be completed daily (typically 2 hrs before 
bedtime) using the electronic diary.  The daily recording of information allows an 
assessment of the underlying day to day variability of a patient's symptoms and facilitates 
the detection of symptom worsening indicative of a COPD exacerbation.  The total score 
for EXACT ranges from 0-100.  The entire instrument is intended to be completed in 
about 3 minutes or less (typically the time required for completion decreases as the 
patient becomes more familiar with the tool and the electronic diary).
The E-RS: COPD consists of 11 items from the 14 item EXACT instrument [Leidy, 
2014].  E-RS: COPD is intended to capture information related to the respiratory 
symptoms of COPD, i.e. breathlessness, cough, sputum production, chest congestion and 
chest tightness.  The E-RS: COPD has a scoring range of 0-40 higher scores indicate 
more severe symptoms.
Three subscales of the E-RS are used to describe different symptoms; dyspnea, cough and 
sputum and chest symptoms.
The EXACT questionnaire will be completed by subjects in the eDiary, at home every 
night throughout the entire study, starting from Screening V1 
7.3.1.5.
Subject Global Rating of COPD Severity and Global Rating of Change 
in COPD
Subjects will complete the Global Rating of COPD Severity at Randomization Visit 2 
and visits 3, 4 and 5 or Early Withdrawal Visit.  This single global question will ask 
subjects to rate their severity of COPD on a four point scale (mild, moderate, severe, and 
very severe).
This question should be used immediately before the patient completes other visit 
specific questionnaires but after completion of SAC TDI questionnaire. 
Subjects will also complete a Global Rating of Change in COPD (overall disease) 
question at Visits 3, 4 and 5 or Early Withdrawal Visit.  Response options will be on a 7 
point Likert scale ranging from much better to much worse.  Completing the question at 
each Visit allows for early detection of response as well as continued response.
7.3.2.
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 standardized spirometry equipment provided by an external vendor.
 
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All subjects will have spirometry performed at Screening to assess eligibility (see Section 
7.2.2.1) and at Visits 2, 3, 4 and 5 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 (i.e. a plateau in the volume time curve) and be free from 
artifacts due to cough, early termination, poor effort, obstructed mouthpiece, equipment 
malfunction, or other reasons [Miller, 2005].
The largest FEV1 and FVC from the 3 acceptable efforts should be recorded, even if they 
do not come from the same effort.
Spirometry for FEV1 and FVC assessments that is not obtained as follows will be 
considered a protocol deviation:

Started between 6:00AM and 11:00AM.

After withholding albuterol/salbutamol (all visits) for ≥4 hours

At Screening Visit 1, after wash out of medications as specified in the exclusion 
criteria in Section 5.2 (Concomitant Medications).

At Screening Visit 1, before the morning dose of usual COPD medications

At Visit 2 after discontinuing inhaled COPD medications and prior the first dose 
of study treatment 

At Visit 3, 4 and 5 after withholding the morning dose of study treatment.

Pre dose assessment performed prior dosing.
Subjects should refrain from smoking for 1 hour prior to each pulmonary function test.
Trough FEV1 measurements for UMC/VI or UMEC on Weeks 4, 12 and 24 (Visits 3, 4 
and 5) should be performed 23 hours and 24 hours after the previous day’s dose of study 
medication recorded in the eDiary. This will also provide trough FEV1 measurements for 
the evening dose of salmeterol. 
7.3.3.
Inspiratory capacity (IC)
Inspiratory capacity (IC) is the volume of gas that can be taken into the lungs in a normal 
and full inhalation. Starting from the resting inspiratory position it is equal to the tidal 
volume plus the inspiratory reserve volume.  IC has been widely used to assess static and 
dynamic hyperinflation in patients with COPD.
IC will be measured by spirometry prior to forced manoeuvres pre-dose at Visits 2 (30 
and 5 min prior to dosing) and at trough at Visits 3, 4, and 5 (23 and 24 hrs post dosing 
on the previous day). For IC determination the average of at least three acceptable 
manoeuvres should be recorded.  Subjects should be tested while sitting, relaxed and 
wearing a nose clip.  They should be asked to breathe regularly for several breaths until 
the end-expiratory lung volume is stable (this usually requires at least three tidal 
manoeuvres) then urged to take a deep breath to Total Lung Capacity (TLC) with no 
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Spirometry for IC determination done in conjunction with FEV1 and FVC assessments 
that is not obtained as follows will be considered a protocol deviation:

Started between 6:00AM and 11:00AM.

After withholding albuterol/salbutamol (all visits) ≥4 hours 

At Visit 2 after discontinuation of run-in medication

At Visit 3, 4 and 5 after withholding the morning dose of study drug 
7.3.4.
COPD Exacerbation
A mild exacerbation is defined as worsening of symptoms that require no treatment with 
antibiotics or steroids, and is self managed by the patient by an increase of inhaled rescue 
medications. A moderate COPD exacerbation is defined as worsening symptoms of 
COPD that require treatment with oral/systemic corticosteroids and/or antibiotics. A 
severe exacerbation is defined as worsening symptoms of COPD that require in-patient 
hospitalization or emergency room for longer than 24 hrs. 
If a subject experiences a mild, moderate or severe COPD exacerbation, the COPD 
exacerbation page of the eCRF should be completed. COPD exacerbations should not be 
recorded as an AE, unless they meet the definition of a SAE. Details of COPD 
exacerbation identification, categorization and treatment guidelines are described in 
Appendix 5.
Subjects who experience a mild exacerbation during the run-in period will not be 
withdrawn from the study. However, Subjects who experience moderate or severe 
exacerbation during the run-in period will be withdrawn from the study and will not be 
allowed to be re-screened. 
Subjects who experience a mild, moderate or severe exacerbation during the treatment 
period, will not be withdrawn from the study unless the investigator or GSK medical 
monitor think it is best for the patient to withdraw from the study.
Signs and symptoms of COPD included on the electronic diary cards will not be 
considered AEs and will not be recorded in the eCRF.
The time period for collection of COPD exacerbations will be from the Pre-Screening 
(Visit 0) until completion of the follow-up contact.  If a subject experiences a COPD 
exacerbation from the time the ICF is signed until randomization, summary information 
(yes/no status question) will be collected in the eCRF. COPD exacerbations after
randomization through follow-up will be recorded on the COPD exacerbation page of the 
eCRF.
7.3.5.
Clinically important deterioration (CID)
Clinically important deterioration (CID) is a composite endpoint defined as:

A decrease of  100 mL from baseline in trough FEV1
 
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
A deterioration in HRQoL defined as 4 units increase from baseline in 
SGRQ

The occurrence of an on-treatment moderate/severe COPD exacerbation
In addition, this study will explore CAT and TDI PROs as part of the composite 
endpoint.
7.3.6.
Rescue albuterl/salbutamol use
Subjects will record the number of daily albuterol/salbutemol puffs they use in the 
eDiary.  In addition, in some countries and selected sites the number of puffs will be 
collected through the eMDI device (Section 6.2) 
7.3.7.
Physical activity monitor (study subset)
Physical activity limitation is a common feature of COPD and its measures are highly 
related to the degree of disease severity [Watz, 2009]. 
Reduced physical activity levels in COPD is associated with increased morbidity and 
mortality, sustained disability, depression, and social and physical isolation [Shu-Yi, 
2014; Gimeno, 2014] 
Improved activity has been identified as an important factor that may modify morbidity 
and mortality in COPD [Moy, 2012].
The Actigraph GT9X physical activity monitor will be used to measure levels of activity. 
The activity monitor will be worn by up to approximately 150 subjects per treatment arm 
for 7 days from Screening (Visit 1), for 7 days from Randomisation (Visit 2), 7 days from 
Visit 3 (Week 4) and for 7 days prior to Week 24 (Visit 5).
There will be 4 assessment periods, including a screening assessment in order to provide 
a reliable estimate of habitual physical activity. Each subject will be given an activity 
monitor and instruction leaflet at the start of each assessment period. Further details of 
distribution, operation and retrieval of the monitors will be provided in the SRM.
7.4.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1)
Safety endpoint includes:

Incidence of adverse events
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 4.
 
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The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
7.4.1.1.
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 7.4.1.3), at the timepoints 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 CRF.

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 12.4.4 to Section 12.4.6)
7.4.1.2.
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?
7.4.1.3.
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). 
 
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7.4.1.4.
Pneumonia Events
Investigators will be required to fill out a pneumonia event specific eCRF within one 
week of when the pneumonia AE/SAE(s) is first reported. 
7.4.1.5.
Cardiovascular and Death Events
For any cardiovascular events detailed in (Section 12.4.3) and all deaths, whether or not 
they are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF 
will be required to be completed. These sections include questions regarding 
cardiovascular (including sudden cardiac death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
7.4.1.6.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
The following disease related events (DREs) are common in subjects with COPD and can 
be serious/life threatening:

COPD exacerbation
COPD exacerbations are associated with the disease to be studied and will not be 
recorded as AEs unless the exacerbation meets the definition of a ‘serious’ AE. 
Exacerbations that meet the definition of ‘serious’ AEs will be recorded on the 
appropriate eCRF section and should be reported to GSK for all subjects regardless of 
whether or not they are randomized to study medication. Signs and symptoms of COPD 
included on the electronic diary will not be considered AEs and will not be recorded in 
the eCRF
7.4.1.7.
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.
 
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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.
7.4.1.8.
Additional Adverse Event (AE) Reporting Requirements for Canadian 
investigators
Health Canada requires pharmaceutical manufacturers to expeditiously report domestic 
cases of unusual failure in efficacy (UFIE) for new drugs to the Marketed Health 
Products Directorate (MHPD) within 15 days of first notification. This regulation applies 
to marketed drugs, and used as directed per the Canadian prescribing information, 
including those drugs used in Phase IV (non CTA filed) clinical trials.  
Adverse event (AE): Any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment. An AE can therefore 
be any unfavourable and unintended sign (including an abnormal laboratory finding) 
symptom or disease (new or exacerbated) temporally associated with the use of a 
Medicinal Product. For a marketed Medicinal Product, this can also include failure 
to produce expected benefits (i.e. lack of efficacy, with or without an adverse event), 
In order for GSK to comply this Canadian regulatory requirement, Canadian investigators 
are required to collect, record and report lack of efficacy events as per the table in 
Appendix 4 Section12.4.1.  
All paper forms are required to be faxed to GSK Canada’s Drug Safety department at 
 within 24 hrs of first awareness.
7.4.2.
Pregnancy

Details of all pregnancies in female subjects will be collected after the start of 
Screening and until the follow-up contact. 

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 7.
7.4.3.
Medical Device Incidents (Including Malfunctions)
Procedures for documenting medical device incidents are provided in Appendix 6.
7.4.4.
Electrocardiogram (ECG)
A Single 12-lead ECG will be obtained at Screening using an ECG machine provided by 
the investigational site that automatically calculates the heart rate and measures PR, QRS, 
QT, and QTc intervals.
 
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The 12-lead ECG measurement and rhythm strip (10 seconds) will be obtained before 
spirometry testing. ECG measurement should be obtained after subjects have rested for 
approximately 5 minutes then the subjects should be placed in the supine position for the 
ECG measurements.  An ECG is only required at Screening Visit 1 for eligibility 
assessment only. 
The investigator, a designated sub-investigator, or other appropriately trained site 
personnel will be responsible for performing and interpreting the 12-lead ECG at 
Screening Visit 1. The investigator must provide his/her dated signature on the original 
paper tracing, attesting to the authenticity of the ECG machine interpretation. 
7.5.
Genetics
Information regarding genetic research is included in Appendix 3
8.
DATA MANAGEMENT

For this study subject data will be entered into GSK defined CRFs, 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.  

CRFs (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 purpose of this study is to demonstrate improvements in lung function for 
subjects treated with UMEC/VI compared with UMEC for 24 weeks. 
The primary endpoint is change from baseline in trough FEV1 at Week 24.
The null hypothesis is no difference between treatment groups (H0: μT – μS = 0), with 
the alternative hypothesis that there is a difference between treatment groups (H1: μT –
μS ≠0), where μT is the mean change from baseline for UMEC/VI and μS is the mean 
change from baseline for UMEC. 
 
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9.2.
Sample Size Considerations
The primary endpoint is change from baseline in trough FEV1 at Week 24. As an 
important aim of the study is to compare UMEC/VI, UMEC and salmeterol with respect 
to HRQoL the sample size has been calculated to provide sufficient power for the 
comparison of the primary and secondary endpoint TDI, at Week 24.  
The sample size calculations use a two-sided 5% significance level and an estimate of 
between subject standard deviation for TDI of 2.94 units.  The estimate of SD is based on 
DB2113373 [Donohue, 2013], a study which consisted of treatment arms of UMEC/VI 
62.5/25, UMEC 62.5 VI (Vilanterol) 25mcg and placebo and is the value at Day 168 in a 
subgroup of subjects who were ICS free at screening.  Based on these data, 727 evaluable 
subjects per treatment arm will be required to provide 90% power to detect a statistically 
significant difference if the true difference is 0.5 units, ½ the MCID, between UMEC/VI 
and UMEC. The smallest observed effect predicted to result in a statistically significant 
difference between treatment groups is 0.31 units.
With this number of evaluable subjects per arm, the study will have >99% power 
assuming a true treatment difference of 80mL between UMEC/VI and UMEC for trough 
FEV1 at 24 weeks at the two-sided 5% significance level. This calculation uses a SD for 
trough FEV1 of 240mL, based on prior results for trials comparing dual bronchodilators 
versus single bronchodilators (Donohue, 2013; Bateman, 2013). The smallest observed 
effect predicted to result in a statistically significant difference between treatment groups 
is 25mL. 
In order to account a for a 10% withdrawal rate, approximately 808 subjects per 
treatment arm will be randomised.
9.2.1.
Sample Size Assumptions
9.2.2.
Sample Size Sensitivity
The assumption of a SD of 2.94 units for the TDI total score is based on estimates from 
previous studies. The following table presents the power achieved with the proposed 
sample size of 727 randomised subjects per arm, should the assumption around the SD of 
the data change. 
The actual assumptions used in the sample size calculation are shaded.
Endpoint 
Between 
subject SD
Treatment Difference
Power
TDI
2.54
0.5
96%
2.74
0.5
94%
2.94
0.5
90%
3.14
0.5
86%
3.34
0.5
81%
 
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9.2.3.
Sample Size Re-estimation or Adjustment
No sample size re-estimation is planned for this study. 
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 and received at least 
one dose of study medication. 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.

Displays will be based on the treatment to 
which the subject was randomized.

Study Population

Efficacy

Safety
Intent-to-
treat ICS 
free (ITT 
ICS free)

All subjects in the ITT Population who have 
not received ICS.

Study Population

Efficacy

Safety
9.3.2.
Interim Analysis
No interim analysis is planned for the study.
9.4.
Key Elements of Analysis Plan
Treatment Comparisons
The primary treatment comparison of UMEC/VI with UMEC will be performed on the 
ITT population.
 
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The other treatment comparisons of UMEC/VI and UMEC with Salmeterol will be 
performed on the ITT population and ITT ICS free population.
9.4.1.
Primary Analyses
The treatment comparison of primary interest will be UMEC/VI versus UMEC for the 
primary endpoint of change from baseline in trough FEV1 at Week 24. The primary 
analyses will be performed using a mixed model repeated measures (MMRM) analysis 
and will be based on a two-sided hypothesis testing approach on the ITT Population. 
In order to account for multiplicity across treatment comparisons and endpoints, a step-
down closed testing procedure will be applied whereby inference for secondary and other 
endpoints or treatment comparisons are dependent upon statistical significance having 
been achieved for the primary comparison. If the primary comparison is significant i.e. 
the associated p-value for UMEC/VI versus UMEC for change from baseline in trough 
FEV1 at Week 24 is below 0.05, this will allow inference of treatment comparisons 
(UMEC/VI versus UMEC on all other endpoints, and UMEC/VI versus Salmeterol and 
UMEC versus Salmeterol on all endpoints including the primary endpoint), which will be 
declared statistically significant if the associated p-value is below 0.05.  
There will be 2 analyses one for one for the German Federal Joint Committee (G-BA) 
and one for the rest of the world (ROW).
The step-down closed testing procedure only applies to the ROW.  For the G-BA 
statistical inference for secondary and other endpoints or treatment comparisons will not 
be conditional on achieving statistical significance of the primary comparison.  
The primary endpoint of mean change from baseline in trough FEV1 at the end of Week 
24 and secondary endpoint change from baseline in TDI score at Week 24 will both be 
analysed using MMRM analysis. The MMRM analysis for change from baseline in 
trough FEV1 and TDI will include measurements at Treatment Weeks 4, 12 and 24. 
Treatment group (a categorical variable) will be fitted as the explanatory variable with 
appropriate pre-defined variables, stratum (number of bronchodilators per day during 
run-in) and baseline values, fitted as covariates. Visit (nominal) will be fitted as a 
categorical variable and visit-by-baseline and visit-by-treatment interaction terms will be 
included to allow treatment effects to be estimated at each visit separately. The variance 
covariance matrix will be assumed to be unstructured (based on previous experience no 
issues are expected with fitting models with this matrix structure). 
While missing data are not explicitly imputed in the primary MMRM analyses, there is 
an underlying assumption that the data are missing at random. 
The estimated treatment differences between UMEC/VI versus UMEC for each endpoint 
will be presented with the 95% confidence intervals for the difference and the p-value. 
Full details of the analyses to be performed on all primary endpoints will be given in the 
RAP.
 
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9.4.2.
Other Analyses
The MMRM analysis will be repeated for the ITT ICS free population. Estimated 
differences between UMEC/VI or UMEC and Salmeterol will be presented together with 
95% confidence intervals (CIs) for the difference and p-values.
Secondary and other efficacy endpoints and treatment comparisons will be adjusted for 
multiplicity as per Section 9.4.1.
Full details of the analyses to be performed on the other efficacy endpoints will be given 
in the RAP.
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. 
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:
 
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
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 
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 eCRF
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 
 
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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.  

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, 
 
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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.
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 randomization 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.
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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
CAT
COPD Assessment Test
CI
Confidence Intervals
CID
Clinically important deterioration 
COPD
Chronic Obstructive Pulmonary Disease
CPK
Creatine phosphokinase
CRF
Case Report Form
CV
Cardiovascular
DPI
Dry Powder Inhaler
DRE
Disease Related Event
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eDiary
Electronic Diary
eMDI
Electronic Metered Dose Inhaler
E-RS
Evaluating Respiratory Symptoms- COPD  Tool
ERS
European Respiratory Society
FEV₁
Forced Expiratory Volume in One Second
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GOLD
Global Initiative for Chronic Obstructive Lung Disease
GSK
GlaxoSmithKline
IB
Investigator Brochure
ICF
Informed Consent Form
ICS
Inhaled Corticosteroid
IEC
Independent Ethics Committee
IP
Investigational product
INR
International normalized ratio
IRT
Interactive Response Technology
ITT
Intent-to-Treat
IUD
Intrauterine Device
IUS
Intrauterine System
LABA
Long Acting Beta-Agonist
LAMA
Long-acting Muscarinic Receptor Antagonists
LDH
Lactate dehydrogenase
LTOT
Long Term Oxygen Therapy
 
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mcg
Microgram
MCID
Minimal Clinically Important Difference
MDI
Metered Dose Inhaler
mL
Milliliter
mMRC
Modified Medical Research Council
MMRM
Mixed Models Repeated Measures
MSDS
Material Safety Data Sheet
NYHA
New York Heart Association
OTC
Over the Counter
PGx
Pharmacogenetic
PIL
Patient Information Leaflet
PK
Pharmacokinetic
PP
Per Protocol
prn
As required
QTc
QT interval corrected for heart rate
RAP
Reporting and Analysis Plan
SABA
Short Acting Beta-Agonist
SAE
Serious Adverse Event
SD
Standard Deviation
SmPC
Summary of Product Characteristics
SRT
Safety Review Team
TDI
Transition Dyspnea Index
RAMOS NG
Randomization and medication ordering system new 
generation
ULN
Upper Limit of Normal
UMEC
Umeclidinium (GSK573719)
UMEC/VI
Umeclidinium & Vilanterol as a fixed dose combination
VI
Vilanterol Trifenate 
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
ANORO
E-RS
DISKUS
EXCACT
ELLIPTA
INCRUSE
SEREVENT
 
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12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments
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 normal 
ranges. baseline (see MONITORING below)

Do not restart/rechallenge subject with 
study treatment. 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 

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 a week after last 
dose6

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form
including acetaminophen, herbal 
 
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Liver Chemistry Stopping Criteria - Liver Stopping Event
liver event follow up assessments within  24 
hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to 
within normal ranges.

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 normal ranges.
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
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 SRM.  
 
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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 etiology 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 any concomitant medicines;

COPD susceptibility, severity, and progression of 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.
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.
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.  
 
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
A 6 ml blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. 
A blood sample is collected at the baseline visit, after the subject has been 
randomized and 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 being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA 
sample is retained

Discontinue participation in the genetic research and destroy the genetic DNA 
sample 
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. 
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis. 
 
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
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.
 
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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. For a marketed medicinal product, this 
can also include failure to produce expected benefits (i.e. lack of efficacy, with or 
without associated signs or symptoms or clinical sequelae).

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" will be reported 
as an AE or SAE as per the table below
Adverse 
Event 
criteria
Electronic case record 
form (eCRF) only
Paper form only
Electronic case 
record form 
(eCRF) + Paper 
form
Non serious 
Non drug related lack of 
efficacy reports with 
associated signs or 
symptoms or clinical 
Drug related lack of 
efficacy reports 
without associated 
signs or symptoms or 
Drug related lack 
of efficacy with 
associated signs or 
symptoms or 
 
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sequelae 
clinical sequelae.
clinical sequelae  
Serious
Non drug related lack of 
efficacy reports with 
associated signs or 
symptoms or clinical 
sequelae 
Drug related lack of 
efficacy reports 
without associated 
signs or symptoms or 
clinical sequelae. 
Drug related lack 
of efficacy reports 
with associated 
signs or symptoms 
or clinical sequelae
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 
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., hospitalization 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 hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization 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 hospitalization are 
 
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AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption
e.
Is a congenital anomaly/birth defect
f.
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 hospitalization 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 hospitalization, 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
 
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
Valvulopathy

Pulmonary hypertension

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 electronic CRF and/or paper form as applicable. 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:
 
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
Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
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.
 
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
The investigator is obligated to assist.  This may include additional laboratory tests 
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

For lack of efficacy reports, the paper form will be used to submit to GSK as per the 
table in Section 12.4.1 above. 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

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 by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
 
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12.5.
Appendix 5: COPD Exacerbation Identification, 
Categorization and Treatment Guidelines
12.5.1.
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 usage in their 
daily eDiary 

If the subject seeks emergency/acute care for worsening respiratory symptoms, 
he/she should request the caring Health Care Provider (HCP) to contact the 
Investigator as soon as possible.
Subjects with worsening respiratory symptoms will be classified as having:

A mild/moderate/severe exacerbation and/or pneumonia
OR

A Lower Respiratory Tract Infection (LRTI)
 
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
Background variability of COPD

A non-respiratory related disease

Other respiratory related disease
12.5.2.
COPD Exacerbation Severity
Each COPD exacerbation will be categorized based on severity as follows:
Moderate:  Worsening symptoms of COPD that require treatment with 
oral/systemic corticosteroids and/or antibiotics.
Severe: Worsening symptoms of COPD that require treatment with in-patient 
hospitalization or 24 hrs in the emergency room.
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.
12.5.3.
Treatment of COPD Exacerbations
All medications used for the treatment of exacerbations must be recorded in the source 
documents and the exacerbation page of the eCRF.  All sites should follow the protocol 
treatment guidelines (as outlined below), but any medications deemed medically 
necessary may be used to treat a COPD exacerbation. However, caution is advised in 
using a LABA or LAMA to treat a subject currently taking IP as these additional 
medications may increase the risk of overdose. If necessary the PI or other health care 
personnel may stop the subject’s IP temporarily in order to treat the COPD exacerbation.
12.5.4.
Guidelines for Treatment with Corticosteroids
If in the opinion of the Investigator/treating physician the exacerbation is severe enough 
to warrant the need for oral or systemic corticosteroids (with or without antibiotics) the 
following guidelines should be used.

The duration of treatment with oral/systemic corticosteroids should be 14 days 
(dose and type according to local practice) 

The duration of treatment with oral/systemic corticosteroids should not exceed 14 
days unless approval is given by the sponsor or representative

Any course of oral/systemic corticosteroids started within 7 days of finishing a 
previous course will be considered as treatment for a single exacerbation
 
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12.5.5.
Guidelines for Treatment with Antibiotics
If there is evidence of respiratory infection that in the opinion of the Investigator or 
treating physician warrants the need for antibiotics the following guidelines should be 
followed:

The duration of treatment with antibiotics should not exceed 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 
12.5.6.
Onset and Resolution of COPD Exacerbations
For each mild, moderate and severe exacerbation, the date of onset and the date of 
resolution will be recorded in the study source documents and eCRF.
The date of onset is the first day (of at least 2 consecutive days) of worsening symptoms 
of COPD as described in Section 12.5.1.
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.
12.5.7.
Guideline for assessing multiple mild exacerbations
Two mild exacerbations can be combined into one, per the Investigator’s judgement, if a 
subject’s diary reveals that the two mild COPD exacerbations are separated by no more 
than three exacerbation free days.
12.5.8.
Guideline for assessing exacerbations that increase in severity
If an exacerbation starts off as mild, but becomes moderate or severe or starts off as 
moderate and becomes severe, the exacerbation should be captured as one exacerbation 
and classified by its highest level of severity.
 
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12.6.
Appendix 6: Definition of and Procedures for Documenting 
Medical Device Incidents
12.6.1.
Definitions of a Medical Device Incident
The detection and documentation procedures described in this protocol apply to all GSK 
medical devices provided for use in the study (see Section 6.2 for the list of GSK medical 
devices).
Medical Device Incident Definition:

Incident – Any malfunction or deterioration in the characteristics and/or performance 
of a device, as well as any inadequacy in the labeling or the instructions for use 
which, directly or indirectly, might lead to or might have led to the death of a 
patient/user/other persons or to a serious deterioration in their state of health.

Not all incidents lead to death or serious deterioration in health.  The non-occurrence 
of such a result might have been due to other fortunate circumstances or to the 
intervention of health care personnel.
It is sufficient that:

an incident associated with a device happened and

the incident was such that, if it occurred again, might lead to death or a serious 
deterioration in health.

A serious deterioration in state of health can include:

life-threatening illness

permanent impairment of body function or permanent damage to a body structure

a condition necessitating medical or surgical intervention to prevent one of the 
above 

fetal distress, fetal death or any congenital abnormality or birth defects
Examples of incidents

a patient, user, care giver or professional is injured as a result of a medical device 
failure or its misuse

a patient’s treatment is interrupted or compromised by a medical device failure

misdiagnosis due to medical device failure leads to inappropriate treatment

a patient’s health deteriorates due to medical device failure
 
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12.6.2.
Documenting Medical Device Incidents
Medical Device Incident Documenting:

Any medical device incident occurring during the study will be documented in the 
subject’s medical records, in accordance with the investigator’s normal clinical 
practice, and on the appropriate form.

For incidents fulfilling the definition of an AE or an SAE, the appropriate AE/SAE 
CRF page will be completed as described in Appendix 4.

The form will be completed as thoroughly as possible and signed by the investigator 
before transmittal to GSK.

It is very important that the investigator provides his/her assessment of causality to 
the medical device provided by GSK at the time of the initial report, and describes 
any corrective or remedial actions taken to prevent recurrence of the incident.

A remedial action is any action other than routine maintenance or servicing of a 
device where such action is necessary to prevent recurrence of an incident. This 
includes any amendment to the design to prevent recurrence.
 
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12.7.
Appendix 7: Modified List of Highly Effective Methods for 
Avoiding Pregnancy in FRP and Collection of Pregnancy 
Information
12.7.1.
Modified List of Highly Effective Methods for Avoiding Pregnancy 
in Females of Reproductive Potential (FRP)
The list does not apply to FRP with same sex partners or for subjects who are and will 
continue to be abstinent from penile-vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyle. Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.
1.
Contraceptive subdermal implant
2.
Intrauterine device or intrauterine system
3.
Combined estrogen and progestogen oral contraceptive [Hatcher, 2011]
4.
Injectable progestogen [Hatcher, 2011]
5.
Contraceptive vaginal ring [Hatcher, 2011]
6.
Percutaneous contraceptive patches [Hatcher, 2011]
7.
Male partner sterilization 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, 2011]. The documentation on male sterility can come from the site 
personnel’s: review of subject’s medical records, medical examination and/or semen 
analysis, or medical history interview provided by her or her partner.
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
12.7.2.
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 fetal status (presence or 
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.
 
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
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. 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 be withdrawn from the study
 
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12.8.
Appendix 8: Country Specific Requirements
No country-specific requirements exist.
 
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12.9.
Appendix 9: protocol changes
Revision History
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Original
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Amendment No. 1
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Amendment No. 2 Canada 
only
Protocol Amendment 1
Scope:
This amendment applies to all sites
Protocol Changes for Amendment No.1 are summarised below.
Strike through text refers to deleted text and underlined refers to added text.
Protocol Changes:
Title
Rationale for change:  Correct a typographical error in the title: Umeclidimium to 
Umeclidinium
Regulatory Agency Identifying Number(s):  
Rationale for change:  To correct a typographical error of the EudraCT no. and add an 
IND no.
Revised text: EudraCT no 2016-002513-226, 2016-002513-22 , IND no. 104479
 
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Section 1
Overall Design
Rationale for change: To Correct a typographical error in the last paragraph.
Revised text: Salmeterol, salbutamol
“This is a multi-centre, randomized, double blind, double-dummy, 3-arm parallel group 
study.  Eligible subjects will be stratified based on long-acting bronchodilator usage 
during the run-in (none, one or 2 long-acting bronchodilators per day) and randomized in 
a ratio of 1:1:1 to UMEC/VI inhalation powder (62.5/25 mcg once daily) administered 
via the ELLIPTA inhaler, or UMEC (62.5 mcg once daily) administered via the 
ELLIPTA or salmeterol (50 mcg BID) administered via the DISKUS. 
There will be a total of 5 clinic visits and one follow-up phone call (Visit 6). The Pre-
screening Visit (Visit 0) can occur on the same day as the Screening Visit (Visit 1) if 
subject does not take or has not taken any excluded protocol medications, but must be 
completed prior to initiating any Visit 1 procedures. 
Subjects, who meet all the eligibility criteria at Screening, will enter a run-in period for 4 
weeks in order to continue to assess the subject’s eligibility for the study. During the run-
in period subjects will continue with their inhaled COPD medications (excluding ICS and 
any exclusionary medications).  In addition, subjects will be provided with short acting 
albuterol/salmeterol salbutamol to be used on as needed basis for relief of COPD 
symptoms (rescue medication) throughout the study”. 
Section 4.4 Design justification: To be consistent with Section 7.3.1.5 and Section 7.1 
the wording has been updated.
Rationale for change: Ensure consistency with Section 7.3.1.5 and Section 7.1 the 
wording has been changed in paragraph 5.
Revised text: “Other endpoints such SAC TDI, E-RS, SGRQ-C, CAT, Subject Global 
Rating of COPD Severity and Change in Global Rating impression of Change in COPD  
disease severity are captured to allow responder analyses and to provide comparative data 
on PROs between the treatment groups”. 
Section 7.1 Time and Event table
Rationale for change; to:
Correct an un-intentional deletion of the (“x”) in some cells and confirm that concomitant 
medications should be reviewed at every clinic visit.
Increase the visit window from 2 days to -7/+2
Ensure consistency of wording between Section 7.2 and Table 7.1. “Written” was deleted
Include height and weight at Screening and correct errors in foot note no.11
“In order to ensure subjects have sufficient doses of study treatment, they must return to 
clinic within 30 days from V2 and within 60 and 90 days from V3 and V4 respectively”
 
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Blinded Treatment
Visit
Pre-
screen1
0
Screen/ 
Run-in
1
Rando-
mization 
2
3
4
5
EW 
Visit 2
Telephone Follow up 
contact 
6
Week
-6 to -4
-4
0
4
12
24
Day
42 2
-7/+2 
days 
prior 
Visit 1
28 2
-7/+2 days 
prior Visit 
2
12 -7/+2
days
28 2 -7/+2 
days 
84 2 
days
168 2 -7/+2 
days
72 3 days after V5 
or EW Visit
Screen/Baseline
Written Informed consent
X
Demography
X
Medical/COPD history
X
Smoking history/status
X
Smoking cessation counselling
X
Concomitant medication assessment
X
X
X
X
X
X
X
X
Height and weight
X
Cardiovascular History/family history of premature CV 
disease])
X
Screening spirometry (including post bronchodilator 
testing)3
X
CAT questionnaire
X
X
Verify Inclusion/Exclusion Criteria
X
Training on use of inhalers
X
X
Training on use of eDiary and eMDI
X
X
Verify randomization Criteria
X
Register Visit in InForm
X
X
X
X
X
X
X
X
Register Visit in RAMOS NG
X
X
X
X
X
X
X
X
 
 
 
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Blinded Treatment
Visit
Pre-
screen1
0
Screen/ 
Run-in
1
Rando-
mization 
2
3
4
5
EW 
Visit 2
Telephone Follow up 
contact 
6
Week
-6 to -4
-4
0
4
12
24
Day
42 2
-7/+2 
days 
prior 
Visit 1
28 2
-7/+2 days 
prior Visit 
2
12 -7/+2
days
28 2 -7/+2 
days 
84 2 
days
168 2 -7/+2 
days
72 3 days after V5 
or EW Visit
Efficacy/HRQoL assessments
Spirometry, including pre-dose FEV1, trough  FEV1 and 
inspiratory capacity
X
X
X
X
SAC BDI questionnaire 4
X
SAC TDI questionnaire 4
X
X
X
SGRQ-C questionnaire 4
X
X
X
X
CAT questionnaire 4
X
X
X
X
X
EXACT/ER-S: COPD 5
Patient Global Rating of COPD severity
X
X
X
X
Patient Global Rating of Change in COPD
X
X
X
Safety assessments
Adverse events/Serious adverse events 6
X
X
X
X
X
X
X
X
COPD exacerbation assessment
X
X
X
X
X
X
X
X
12-Lead ECG
X
Urine pregnancy test 7
X
X
X
X
Pharmacogenetic sample8
                                          X
Medication/Supplies
Dispense rescue albuterol/slabutamol. Dispense MDI9
X
X
X
X
X
Assess COPD medication compliance10 during run-in
X
Dispense eDiary
X
Assess compliance with eDiary during run-in 
X
Collect rescue albuterol/slabutamol. 
X
X
X
X
X
Collect eDiary
X
X
Dispense study treatment11
X
X
X
 
 
 
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Blinded Treatment
Visit
Pre-
screen1
0
Screen/ 
Run-in
1
Rando-
mization 
2
3
4
5
EW 
Visit 2
Telephone Follow up 
contact 
6
Week
-6 to -4
-4
0
4
12
24
Day
42 2
-7/+2 
days 
prior 
Visit 1
28 2
-7/+2 days 
prior Visit 
2
12 -7/+2
days
28 2 -7/+2 
days 
84 2 
days
168 2 -7/+2 
days
72 3 days after V5 
or EW Visit
Collect study treatment
X
X
X
X
Assess study treatment compliance during treatment10
X
X
X
X
Study sub-set
Physical activity monitor12
X
X
X
X
Collect Physical activity monitor
X
X
1.
Pre-screen Visit 0 must be completed prior to Screening Visit1. It can be completed 2 weeks prior or on the same day of V1, if no wash out of exclusionary medications is 
required. 
2.
Early Withdrawal Visit: Subjects that withdraw should return to the clinic as soon as possible to complete the Early Withdrawal Visit procedures.
3.
Spirometry at screening should be performed as described in (Section 7.2.2.1). 
4.
SAC BDI, SAC TDI, SGRQ-C, CAT questionnaires will be completed at clinic visits and in the eDiary
5.
EXACT/ER-S: COPD is completed daily in the eDiary approximately 2 hours before bed-time, starting on Day 1 of the run-in period.
6.
For the start date of collecting AEs and SAEs see (Appendix 4)
7.
Pregnancy test: for females for child bearing potential only.
8.
Pharmacogenetic sample may be drawn at visit 2 or any visit after.
9.
Rescue medication use to be recorded in the eDiary daily and in some sites in the eDiary and the eMDI
10. Sites are requested to call subjects every 2 weeks to remind them to take study treatment regularly and to record the time of the morning and evening dose in the eDiary.
11. In order to ensure subjects have sufficient doses of study treatment, they must return to clinic within 30 days from V2 and within 60 and 90 days from V3 and V4 respectively.
12. The Actigraph GT9X should be worn for 7 days from Visit 1, for 7 days from Visit 2, for 7 days from Visit 3 and for 7 days prior to Visit 5.
 
 
 
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Section 7.2.2 Critical procedures performed at Screening (Visit 1)
Rationale for change:  To clarify that height and weight are collected at V1
Revised text: “Height and weight”
Section 7.3.2 Spirometry
Rationale for change:  To further clarify that spirometry at Screening Visit 1 should be 
performed before subject inhales their usual morning COPD medication(s) a bullet point 
was added. “At Screening Visit 1, before the morning dose of usual COPD medications”
Revised text:
“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 standardized spirometry equipment provided by an external vendor.
All subjects will have spirometry performed at Screening to assess eligibility (see Section 
7.2.2.1) and at Visits 2, 3, 4 and 5 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 (i.e. a plateau in the volume time curve) and be free from 
artifacts due to cough, early termination, poor effort, obstructed mouthpiece, equipment 
malfunction, or other reasons [Miller, 2005].
The largest FEV1 and FVC from the 3 acceptable efforts should be recorded, even if they 
do not come from the same effort.
Spirometry for FEV1 and FVC assessments that is not obtained as follows will be 
considered a protocol deviation:

Started between 6:00AM and 11:00AM.

After withholding albuterol/salbutamol (all visits) for ≥4 hours

At Screening Visit 1, after wash out of medications as specified in the exclusion 
criteria in Section 5.2 (Concomitant Medications).

At Screening Visit 1, before the morning dose of usual COPD medications

At Visit 2 after discontinuing inhaled COPD medications and prior the first dose 
of study treatment 

At Visit 3, 4 and 5 after withholding the morning dose of study treatment.

Pre dose assessment performed prior dosing.
Subjects should refrain from smoking for 1 hour prior to each pulmonary function test.
Trough FEV1 measurements for UMC/VI or UMEC on Weeks 4, 12 and 24 (Visits 3, 4 
and 5) should be performed 23 hours and 24 hours after the previous day’s dose of study 
medication recorded in the eDiary. This will also provide trough FEV1 measurements for 
the evening dose of salmeterol”. 
 
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8.
Physical activity monitor (study subset)
Rationale for changes: Ensure consistency of the wording between Section 1 and 
Section 4.1 “overall design” and Section 7.3.7.
per treatment arm added to paragraph 4.
Revised Text: 
Physical activity monitor (study subset)
“Physical activity limitation is a common feature of COPD and its measures are highly 
related to the degree of disease severity [Watz, 2009]. 
Reduced physical activity levels in COPD is associated with increased morbidity and 
mortality, sustained disability, depression, and social and physical isolation [Shu-Yi, 
2014; Gimeno, 2014] 
Improved activity has been identified as an important factor that may modify morbidity 
and mortality in COPD [Moy, 2012].
The Actigraph GT9X physical activity monitor will be used to measure levels of activity. 
The activity monitor will be worn by up to approximately 150 subjects per treatment arm 
for 7 days from Screening (Visit 1), for 7 days from Randomisation (Visit 2), 7 days from 
Visit 3 (Week 4) and for 7 days prior to Week 24 (Visit 5).
There will be 4 assessment periods, including a screening assessment in order to provide 
a reliable estimate of habitual physical activity. Each subject will be given an activity 
monitor and instruction leaflet at the start of each assessment period. Further details of 
distribution, operation and retrieval of the monitors will be provided in the SRM”.
Country-specific Protocol Amendment 2 for Canada
Amendment 02 applies to Canada only. The purpose of Amendment 2 is to comply with 
Health Canada guidelines. They sate that all events associated with lack of efficacy of 
marketed investigational products must be documented and reported.
Strike through text refers to deleted text and underlined refers to added text.
Section 7.4.1 Adverse Events (AE) and serious Adverse Events (SAEs)
Rationale for change: A new Section added to include information related to 
documenting events related to lack of efficacy.
Revised text: 
“7.4.1.8 Additional Adverse Event (AE) Reporting Requirements for Canadian 
investigators
Health Canada requires pharmaceutical manufacturers to expeditiously report domestic 
cases of unusual failure in efficacy (UFIE) for new drugs to the Marketed Health 
Products Directorate (MHPD) within 15 days of first notification. This regulation applies 
to marketed drugs, and used as directed per the Canadian prescribing information, 
including those drugs used in Phase IV (non CTA filed) clinical trials.  
Adverse event (AE): Any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment. An AE can therefore
 
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be any unfavourable and unintended sign (including an abnormal laboratory finding) 
symptom or disease (new or exacerbated) temporally associated with the use of a 
Medicinal Product. For a marketed Medicinal Product, this can also include failure 
to produce expected benefits (i.e. lack of efficacy, with or without an adverse event), 
In order for GSK to comply this Canadian regulatory requirement, Canadian investigators 
are required to collect, record and report lack of efficacy events as per the table in 
Appendix 4 Section 12.4.1”.  
All paper forms are required to be faxed to GSK Canada’s Drug Safety department at 
 within 24 hrs of first awareness.
Appendix 4, Section 12.4.1 
Rationale for change: To add a small table about reporting of AEs.
Revised text. The table below was added.
Adverse 
Event 
criteria
Electronic case record 
form (eCRF) only
Paper form only
Electronic case 
record form 
(eCRF) + Paper 
form
Non serious 
Non drug related lack of 
efficacy reports with 
associated signs or 
symptoms or clinical 
sequelae 
Drug related lack of 
efficacy reports 
without associated 
signs or symptoms or 
clinical sequelae.
Drug related lack 
of efficacy with 
associated signs or 
symptoms or 
clinical sequelae  
Serious
Non drug related lack of 
efficacy reports with 
associated signs or 
symptoms or clinical 
sequelae 
Drug related lack of 
efficacy reports 
without associated 
signs or symptoms or 
clinical sequelae. 
Drug related lack 
of efficacy reports 
with associated 
signs or symptoms 
or clinical sequelae 
Appendix 4, Section 12.4.4, second bullet point
Revised text: 
The investigator will then record all relevant information regarding an AE/SAE in the 
electronic CRF “and/or paper form as applicable”.  Added
Section 12.4.6, second bullet point
Revised text: 
“For lack of efficacy reports the paper form will be used to submit to GSK as per the
table in Section 12.4.1 above”. Added
 
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TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A 24-week treatment, multi-center, randomized, double-blind, 
double-dummy, parallel group study to compare 
Umeclidinium/Vilanterol, Umeclidinium, and Salmeterol in 
subjects with chronic obstructive pulmonary disease (COPD)
Compound Number:
GSK2592356
Development Phase:
IV
Effective Date:
07-FEB-2017
Protocol Amendment Number:  01
Author (s):
 
 
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2016N277425_00
2016-SEP-13
Original
2016N277425_01
2017-FEB-07
Amendment No. 1
This protocol amendment was created to make the following changes:
Regulatory Agency Identifying Number(s):  A typographical error in the EudraCT no.
corrected. IND no. added
Section 4.1 and Section 4.4: Typographical errors and inconsistencies corrected
Inconsistencies between Section 4.4, Section 7.3.1.5 and Section 7.1 revised
Section 7.1 Time and event table:
Un-intentional deletion of the (“x”) were added to confirm that concomitant medications 
should be reviewed at every clinic visit was corrected.
Increased the visit window 
Typographical error and inconsistencies corrected as described in Appendix 9, Section 
12.9.
Section 7.2.2 Critical procedures performed at Screening (Visit 1): To clarify that height 
and weight are collected at V1 “Height and weight” added
Section 7.3.2 Spirometry: “At Screening, before the morning dose of usual COPD 
medication(s)” added.
Section 7.3.7: Physical activity monitor (study subset)
Inconsistency between Section 1, Section 4.1 and Section 7.3.7 revised
 
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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
Fax 
Number
Site Address
Primary 
Medical 
Monitor 
Telephone: 
Cell: 
Fax:
GlaxoSmithKline
Stockley Park 
West, 1-3 
Ironbridge Road, 
Heathrow, 
Uxbridge, 
Middlesex, UB11 
1BT, United 
Kingdom
Secondary 
Medical 
Monitor
MD
Telphone:
Cell:  
Fax:  
GlaxoSmithKline
Stockley Park 
West, 1-3 
Ironbridge Road, 
Heathrow, 
Uxbridge, 
Middlesex, UB11 
1BT, United 
Kingdom
SAE 
contact  
information 
Telephone: 
Cell:
Fax:
GlaxoSmithKline
Stockley Park 
West, 1-3 
Ironbridge Road, 
Heathrow, 
Uxbridge, 
Middlesex, UB11 
1BT, United 
Kingdom
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 
 
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person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.   
Regulatory Agency Identifying Number(s):  IND no. 106616 and 104479, and EudraCT 
no. 2016-002513-22
 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 201749
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date
 
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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 201749......................................................10
2.
INTRODUCTION....................................................................................................15
2.1.
Study Rationale ..........................................................................................15
2.2.
Brief Background ........................................................................................15
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................16
4.
STUDY DESIGN ....................................................................................................18
4.1.
Overall Design ............................................................................................18
4.2.
Treatment Arms and Duration.....................................................................20
4.3.
Type and Number of Subjects.....................................................................21
4.4.
Design Justification.....................................................................................21
4.5.
Dose Justification........................................................................................21
4.6.
Benefit: Risk Assessment ...........................................................................21
4.6.1.
Risk Assessment .........................................................................22
4.6.2.
Benefit Assessment.....................................................................25
4.6.3.
Overall Benefit: Risk Conclusion..................................................25
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............25
5.1.
Inclusion Criteria.........................................................................................25
5.2.
Exclusion Criteria........................................................................................27
5.3.
Randomization Criteria ...............................................................................30
5.4.
Screening/Baseline/Run-in Failures............................................................30
5.5.
Withdrawal/Stopping Criteria.......................................................................31
5.5.1.
Withdrawal from the Study...........................................................31
5.5.2.
Reason for Study Withdrawal.......................................................32
5.5.3.
Liver Chemistry Stopping Criteria ................................................32
5.5.3.1.
Study Treatment Restart or Rechallenge....................33
5.6.
Follow-up contact........................................................................................33
5.7.
Subject and Study Completion....................................................................34
6.
STUDY TREATMENT ............................................................................................34
6.1.
Investigational Product and Other Study Treatment....................................34
6.2.
Medical Devices..........................................................................................36
6.3.
Treatment Assignment................................................................................36
6.4.
Planned Dose Adjustments.........................................................................37
6.5.
Blinding.......................................................................................................37
6.6.
Packaging and Labeling..............................................................................38
6.7.
Preparation/Handling/Storage/Accountability..............................................38
6.7.1.
Study Treatment Return...............................................................39
6.8.
Compliance with Study Treatment Administration.......................................39
6.9.
Treatment of Study Treatment Overdose....................................................39
6.10.
Treatment after the End of the Study ..........................................................40
6.11.
Concomitant Medications and Non-Drug Therapies....................................40
6.11.1.
Permitted Medications and Non-Drug Therapies..........................40
6.11.2.
Prohibited Medications and Non-Drug Therapies.........................41
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................42
 
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7.1.
Time and Events Table...............................................................................43
7.2.
Screening and Critical Baseline Assessments ............................................46
7.2.1.
Pre-screening Visit.......................................................................46
7.2.2.
Critical procedures performed at Screening (Visit 1)....................46
7.2.2.1.
Albuterol/Salbutamol Reversibility Assessment ..........47
7.2.3.
Critical procedures performed at first treatment Visit 
(Baseline V2)...............................................................................47
7.3.
Efficacy Assessments.................................................................................48
7.3.1.
HRQoL assessments: Completion of PRO questionnaires 
in the Electronic Diary..................................................................48
7.3.1.1.
Self Administered Computerised Baseline 
Dyspnea Index/Transitional Dyspnea Index 
(SAC BDI/TDI)............................................................48
7.3.1.2.
SGRQ-C.....................................................................49
7.3.1.3.
COPD Assessment Test (CAT) ..................................49
7.3.1.4.
EXACT and the Evaluating Respiratory 
Symptoms- COPD (E-RS: COPD)..............................50
7.3.1.5.
Subject Global Rating of COPD Severity and 
Global Rating of Change in COPD .............................50
7.3.2.
Spirometry ...................................................................................50
7.3.3.
Inspiratory capacity (IC)...............................................................51
7.3.4.
COPD Exacerbation ....................................................................52
7.3.5.
Clinically important deterioration (CID).........................................52
7.3.6.
Rescue albuterl/salbutamol use...................................................53
7.3.7.
Physical activity monitor (study subset) .......................................53
7.4.
Safety .........................................................................................................53
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........53
7.4.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................54
7.4.1.2.
Method of Detecting AEs and SAEs ...........................54
7.4.1.3.
Follow-up of AEs and SAEs........................................54
7.4.1.4.
Pneumonia Events .....................................................55
7.4.1.5.
Cardiovascular and Death Events ..............................55
7.4.1.6.
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ................55
7.4.1.7.
Regulatory Reporting Requirements for SAEs............55
7.4.2.
Pregnancy ...................................................................................56
7.4.3.
Medical Device Incidents (Including Malfunctions).......................56
7.4.4.
Electrocardiogram (ECG).............................................................56
7.5.
Genetics .....................................................................................................56
8.
DATA MANAGEMENT ...........................................................................................56
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................57
9.1.
Hypotheses.................................................................................................57
9.2.
Sample Size Considerations.......................................................................57
9.2.1.
Sample Size Assumptions ...........................................................58
9.2.2.
Sample Size Sensitivity................................................................58
9.2.3.
Sample Size Re-estimation or Adjustment...................................58
9.3.
Data Analysis Considerations .....................................................................58
9.3.1.
Analysis Populations....................................................................58
9.3.2.
Interim Analysis ...........................................................................59
 
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9.4.
Key Elements of Analysis Plan ...................................................................59
9.4.1.
Primary Analyses.........................................................................59
9.4.2.
Other Analyses ............................................................................60
10. STUDY GOVERNANCE CONSIDERATIONS........................................................61
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............61
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................61
10.3.
Quality Control (Study Monitoring) ..............................................................62
10.4.
Quality Assurance.......................................................................................62
10.5.
Study and Site Closure ...............................................................................62
10.6.
Records Retention......................................................................................63
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................64
11. REFERENCES.......................................................................................................65
12. APPENDICES........................................................................................................68
12.1.
Appendix 1: Abbreviations and Trademarks................................................68
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................70
12.3.
Appendix 3: Genetic Research ...................................................................73
12.4.
Appendix 4: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................76
12.4.1.
Definition of Adverse Events........................................................76
12.4.2.
Definition of Serious Adverse Events...........................................77
12.4.3.
Definition of Cardiovascular Events .............................................78
12.4.4.
Recording of AEs and SAEs ........................................................79
12.4.5.
Evaluating AEs and SAEs............................................................79
12.4.6.
Reporting of SAEs to GSK...........................................................81
12.5.
Appendix 5: COPD Exacerbation Identification, Categorization and 
Treatment Guidelines..................................................................................82
12.5.1.
Guidelines for Identifying COPD Exacerbations...........................82
12.5.2.
COPD Exacerbation Severity.......................................................83
12.5.3.
Treatment of COPD Exacerbations..............................................83
12.5.4.
Guidelines for Treatment with Corticosteroids..............................83
12.5.5.
Guidelines for Treatment with Antibiotics .....................................84
12.5.6.
Onset and Resolution of COPD Exacerbations............................84
12.5.7.
Guideline for assessing multiple mild exacerbations ....................84
12.5.8.
Guideline for assessing exacerbations that increase in 
severity ........................................................................................84
12.6.
Appendix 6: Definition of and Procedures for Documenting Medical 
Device Incidents .........................................................................................85
12.6.1.
Definitions of a Medical Device Incident.......................................85
12.6.2.
Documenting Medical Device Incidents .......................................86
12.7.
Appendix 7: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in FRP and Collection of Pregnancy Information.......................87
12.7.1.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) ..............87
12.7.2.
Collection of Pregnancy Information ............................................87
12.8.
Appendix 8: Country Specific Requirements...............................................89
12.9.
Appendix 9: protocol changes.....................................................................90
 
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1.
PROTOCOL SYNOPSIS FOR STUDY 201749
Rationale
The primary purpose of this study is to demonstrate improvements in lung function in 
subjects treated with Umeclidinium/Vilanterol (UMEC/VI) compared with Umeclidinium 
(UMEC) for 24 weeks.  A further important aspect of the study is to evaluate the effect of
UMC/VI, UMEC, and salmeterol with respect to health-related quality of life (HRQoL), 
measured through patient reported outcomes (PROs) questionnaires, and lung function.  
Additional assessments to further evaluate other measures of chronic obstructive 
pulmonary disease (COPD) efficacy and symptoms control will be performed.
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary

To compare the effect of UMEC/VI 
(62.5/25 mcg once daily) with UMEC 
(62.5 mcg once daily) on lung function

Change from baseline in trough Forced 
Expiratory Volume in One Second 
(FEV1) at week 24 
Secondary

To compare UMEC/VI (62.5/25 mcg 
once daily), UMEC (62.5 mcg once 
daily) with salmeterol (50 mcg twice 
daily) on patient reported outcomes 
(PROs) 

Change from baseline in self 
administered computerised (SAC) 
transient dyspnea index (TDI) 

Percentage of TDI responders 
according to SAC TDI score.  A 
responder is defined as a ≥1 unit 
improvement in SAC TDI score 

Assessment of respiratory daily 
symptoms over 24 weeks using 
Evaluating Respiratory Symptoms-
COPD (E-RS) and its subscales 
(breathlessness, cough and sputum and 
chest symptoms) 

Percentage of E-RS responders 
according to E-RS score (defined as 
reduction in E-RS score of 2 or 3.35 
units) from baseline

Change from baseline in St George’s 
Respiratory Questionnaire (SGRQ-C)

Percentage of responders according to 
SGRQ-C total score (defined as a 4 
point or greater reduction from 
 
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Objectives
Endpoints
baseline) 

Change from baseline in COPD 
assessment test (CAT)

Percentage of responders according to 
CAT (defined as a 2 unit improvement 
in score from baseline)
Other

To compare UMEC/VI (62.5/25 mcg 
once daily), UMEC (62.5 mcg once 
daily) with salmeterol (50 mcg twice 
daily) on other COPD efficacy measures 

Rate of mild, moderate or severe 
exacerbations

Time to first mild, moderate or severe 
exacerbation

Rate of moderate or severe 
exacerbation

Time to moderate or severe 
exacerbation

Time to severe exacerbations

Time to clinically important 
deterioration (CID) composite endpoint 

Time to clinically important 
deterioration composite endpoint 
excluding FEV1

Rescue albuterol/salbutamol use, 
(percentage of rescue-free days and 
mean number of Inhalations/day) 
captured by the electronic diary 
(eDiary) over 24 weeks

Inspiratory capacity (IC)

Full Vital capacity (FVC) 

Change from baseline in trough FEV1

Change from baseline in global 
impression of disease severity 
 
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Objectives
Endpoints
Safety

To evaluate safety and tolerability 
of UMEC/VI (62.5/25 mcg once 
daily), UMEC (62.5mcg once daily) 
and salmeterol 50mcg twice daily)

Incidence of adverse events
Exploratory

To compare albuterol/salbutamol 
use captured in the eDiary with the 
electronic metered dose inhaler 
(eMDI) device 

Rescue albuterol/salbutamol use, 
(percentage of rescue-free days and 
mean number of Inhalations/day) 
captured by the eMDI device over 24 
weeks as data allow

To explore the effect of UMEC/VI 
(62.5/25 mcg once daily), UMEC 
(62.5 mcg once daily) with 
salmeterol (50 mcg twice daily) on 
physical activity

Change from baseline in physical 
activity 

To investigate the CID composite 
endpoint ability to predict short 
term outcomes 

To compare physical activity levels, 
ER-S, rescue medication use, 
exacerbations and mortality in subjects 
with and without a CID
Overall Design
This is a multi-centre, randomized, double blind, double dummy, 3-arm parallel group 
study.  Eligible subjects will be randomized in a ratio of 1:1:1 to UMEC/VI inhalation 
powder (62.5/25 mcg once daily) administered via the ELLIPTA® dry powder inhaler 
(DPI), or UMEC (62.5 mcg once daily) administered via the ELLIPTA DPI or salmeterol 
(50 mcg twice daily (BID)) administered via the DISKUS® DPI.
Eligible subjects at Screening will enter a run-in period for 4 weeks during which they 
continue taking their inhaled COPD medications (excluding ICS and any exclusionary 
medications).  In addition, subjects will be provided with short acting 
albuterol/salbutamol to be used on as needed basis (rescue medication) throughout the 
study. 
Subjects who experience a moderate or severe COPD exacerbation during the run-in 
period will be deemed run-in failures.  Subjects experiencing a mild exacerbation, 
defined as worsening of symptoms that requires no treatment with antibiotics or steroids 
and is self managed by the patient by an increase of inhaled rescue medication, will be 
allowed to continue in the study.
At the randomization Visit 2 (Day 1) those subjects who successfully complete the run-in 
period as well as meet the other pre-defined eligibility and randomization criteria will 
discontinue their inhaled COPD medications and will be randomized to one of the 3 
treatment arms for 24 weeks.
 
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All subjects will be given an eDiary for use during the run-in, and treatment period to 
complete PRO questionnaires and record medical problems experienced during the study.  
Subjects will be performing slow and forced spirometry at specific visits.
In addition, a subset of subjects up to 150 per treatment arm will undergo assessment of 
their physical activity measured through a physical activity monitor (Actigraph GT9X) 
worn for 7 days from Screening (Visit 1), for 7 days from Randomisation (Visit 2), 7 
days from Visit 3, and for 7 days prior to last clinic Visit (Visit 5). 
There will be a total of 5 clinic visits and one follow-up phone call (Visit 6).  The total 
duration of subject participation in the study will be approximately 29 to 31 weeks 
consisting of 2 weeks pre-screening if necessary, 4 weeks run-in, 24 week treatment and 
one week Follow-Up. 
Subjects will be considered to have completed the study upon completion of the Follow–
Up contact by telephone.
Treatment Arms and Duration
Subjects will be stratified based on long-acting bronchodilator usage during the run-in 
(none, one or 2 long-acting bronchodilators per day) and randomized in a ratio of 1:1:1 to 
either 

UMEC/VI inhalation powder (62.5/25 mcg once daily) administered via the 
ELLIPTA DPI) or 

UMEC (62.5 mcg once daily) administered via the ELLIPTA DPI or 

Salmeterol (50 mcg BID) administered via DISKUS 
 
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Study schematic
*Inhaled COPD medications including LABAs, LAMAs or LABA/LAMA combination products are 
allowed in run-in. ICS alone or in combination with a bronchodilator or any exclusionary 
medications are not allowed.
Type and Number of Subjects
Approximately 3232 subjects will be screened, such that 2424 subjects will be 
randomized and approximately 2181 evaluable subjects complete the study. 
Analysis
The primary purpose of this study is to demonstrate improvements in lung function for 
subjects treated with UMEC/VI compared with UMEC for 24 weeks.
The primary endpoint is change from baseline in trough FEV1 at Week 24.
The null hypothesis is no difference between treatment groups (H0: μT – μS = 0), with 
the alternative hypothesis that there is a difference between treatment groups (H1: μT –
μS ≠0), where μT is the mean change from baseline for UMEC/VI and μS is the mean 
change from baseline for UMEC. 
The primary endpoint of mean change from baseline in trough FEV1 at the end of Week 
24 will be analysed using Mixed Models repeated Measures (MMRM) analysis. The 
MMRM analysis will include measurements at Treatment Weeks 4, 12 and 24. Treatment 
group (a categorical variable) will be fitted as the explanatory variable with appropriate 
pre-defined variables, stratum (number of bronchodilators per day during run-in) and 
baseline values, fitted as covariates. Visit (nominal) will be fitted as a categorical variable 
and visit-by-baseline and visit-by-treatment interaction terms will be included to allow 
treatment effects to be estimated at each visit separately.  The variance covariance matrix 
 
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will be assumed to be unstructured (based on previous experience no issues are expected 
with fitting models with this matrix structure). 
The estimated treatment differences between UMEC/VI versus UMEC for each endpoint 
will be presented with the 95% confidence intervals for the difference and the p-value. 
2.
INTRODUCTION
2.1.
Study Rationale
Chronic obstructive pulmonary disease (COPD) is associated with poor health-related 
quality of life (HRQoL).  Pharmacologic therapy is used to improve lung function, reduce 
symptoms, frequency and severity of exacerbations, and improve patients HRQoL
[GOLD, 2015].  Umeclidinium/Vilanterol (UMEC/VI 62.5/25 mcg) is indicated for the 
maintenance treatment of COPD that contain long-acting muscarinic antagonist (LAMA) 
and long-acting beta2-agonist (LABA) bronchodilators.  Umeclidinium (UMEC) is 
indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients 
with COPD.  Salmeterol has long been used for symptoms management of COPD.  
However, a direct comparison of these maintenance therapies has not been conducted 
with respect to HRQoL.
The primary purpose of this study is to demonstrate improvements in lung function for 
subjects treated with UMEC/VI compared with UMEC for 24 weeks.  The effect of
UMC/VI, UMEC, and salmeterol with respect to patient HRQoL measured through 
patient reported outcomes (PROs) questionnaires, symptoms and lung function will also 
be evaluated.
2.2.
Brief Background
COPD is characterized by an airflow limitation which is not fully reversible, usually 
progressive and accompanied by a chronic cough, sputum production and dyspnea which 
can be a major cause of disability and anxiety associated with the disease [Maleki-Yazdi, 
2014]
Furthermore, acute exacerbations contribute to the overall severity of disease as these 
episodes are accompanied by worsened symptoms and are associated with increased 
decline in lung function and mortality [Wedzicha, 2013; Schmidt, 2014].
Pharmacologic therapy is used to improve lung function, reduce symptoms, reduce the 
frequency and severity of exacerbations, and also to improve health status and exercise 
tolerance.  Maintenance treatment is recommended primarily through the use of LABAs 
or LAMAs.  COPD treatment guidelines recommend an incremental approach to 
pharmacological treatment as the disease state worsens, involving the use of 
combinations of drug classes with different or complementary mechanisms [GOLD, 
2015]. 
UMEC/VI inhalation powder is a combination of UMEC (umeclidinium bromide), a 
LAMA, and VI (Vilanterol), a LABA, delivered via the ELLIPTA dry powder inhaler 
 
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(DPI). UMEC/VI at a dose of 62.5/25mcg once-daily is marketed in the United States 
(US) and Europe under the trade name ANORO® ELLIPTA.  
UMEC (62.5 mcg) inhalation powder is marketed in the United States (US) and Europe 
under the trade name INCRUSE® ELLIPTA.  UMEC (62.5mcg) is indicated as a 
maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD.  
UMEC (62.5 mcg) improves forced expiratory volume in one second (FEV1), dyspnea 
and HRQoL whether used as monotherapy [Trivedi, 2014; Feldman, 2016] or as an add 
on to fluticasone propionate and vilanterol (FF/VI) [Siler, 2015].  Salmetrol (50 mcg) 
DISKUS is a long-acting broncholdilator that has long been used for the maintenance 
treatment of COPD [Tashkin, 2010].
Clinically important deterioration (CID) is a novel, exploratory composite endpoint 
which assesses individual deteriorations in lung function and in patient PROs defined by 
the accepted minimal clinically important difference (MCID), as well as the incidence of 
moderate to severe exacerbations [Singh, 2016], (Section 7.3.5).  CID will be analysed to 
determine whether UMEC/VI (62.5/25mcg) therapy provides greater clinical stability as 
compared with UMEC and salmeterol monotherapies. 
3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary

To compare the effect of UMEC/VI 
(62.5/25 mcg once daily) with UMEC 
(62.5 mcg once daily) on lung function

Change from baseline in trough Forced 
Expiratory Volume in One Second 
(FEV1) at week 24 
Secondary

To compare UMEC/VI (62.5/25 mcg 
once daily), UMEC (62.5 mcg once 
daily) with salmeterol (50 mcg twice 
daily) on patient reported outcomes 
(PROs) 

Change from baseline in self 
administered computerised (SAC) 
transient dyspnea index (TDI) 

Percentage of TDI responders 
according to SAC TDI score.  A 
responder is defined as a ≥1 unit 
improvement in SAC TDI score 

Assessment of respiratory daily 
symptoms over 24 weeks using 
Evaluating Respiratory Symptoms-
COPD (E-RS) and its subscales 
(breathlessness, cough and sputum and 
chest symptoms) 

Percentage of E-RS responders 
according to E-RS score (defined as 
reduction in E-RS score of 2 or 3.35 
units) from baseline
 
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Objectives
Endpoints

Change from baseline in St George’s 
Respiratory Questionnaire (SGRQ-C)

Percentage of responders according to 
SGRQ-C total score (defined as a 4 
point or greater reduction from 
baseline) 

Change from baseline in COPD 
assessment test (CAT)

Percentage of responders according to 
CAT (defined as a 2 unit improvement 
in score from baseline)
Other

To compare UMEC/VI (62.5/25 mcg 
once daily), UMEC (62.5 mcg once 
daily) with salmeterol (50 mcg twice 
daily) on other COPD efficacy measures 

Rate of mild, moderate or severe 
exacerbations

Time to first mild, moderate or severe 
exacerbation

Rate of moderate or severe 
exacerbation

Time to moderate or severe 
exacerbation

Time to severe exacerbations

Time to clinically important 
deterioration (CID) composite endpoint 

Time to clinically important 
deterioration composite endpoint 
excluding FEV1

Rescue albuterol/salbutamol use, 
(percentage of rescue-free days and 
mean number of Inhalations/day) 
captured by the electronic diary 
(eDiary) over 24 weeks

Inspiratory capacity (IC)

Full Vital capacity (FVC) 
 
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Objectives
Endpoints

Change from baseline in trough FEV1

Change from baseline in global 
impression of disease severity 
Safety

To evaluate safety and tolerability 
of UMEC/VI (62.5/25 mcg once 
daily), UMEC (62.5mcg once daily) 
and salmeterol (50mcg twice daily)

Incidence of adverse events
Exploratory

To compare albuterol/salbutamol 
use captured in the eDiary with the 
electronic metered dose inhaler 
(eMDI) device 

Rescue albuterol/salbutamol use, 
(percentage of rescue-free days and 
mean number of Inhalations/day) 
captured by the eMDI device over 24 
weeks as data allow

To explore the effect of UMEC/VI 
(62.5/25 mcg once daily), UMEC 
(62.5 mcg once daily) with 
salmeterol (50 mcg twice daily) on 
physical activity

Change from baseline in physical 
activity 

To investigate the CID composite 
endpoint ability to predict short 
term outcomes 

To compare physical activity levels, 
ER-S, rescue medication use, 
exacerbations and mortality in subjects 
with and without a CID
4.
STUDY DESIGN
4.1.
Overall Design
This is a multi-centre, randomized, double blind, double-dummy, 3-arm parallel group 
study.  Eligible subjects will be stratified based on long-acting bronchodilator usage 
during the run-in (none, one or 2 long-acting bronchodilators per day) and randomized in 
a ratio of 1:1:1 to UMEC/VI inhalation powder (62.5/25 mcg once daily) administered 
via the ELLIPTA inhaler, or UMEC (62.5 mcg once daily) administered via the 
ELLIPTA or salmeterol (50 mcg BID) administered via the DISKUS. 
There will be a total of 5 clinic visits and one follow-up phone call (Visit 6). The Pre-
screening Visit (Visit 0) can occur on the same day as the Screening Visit (Visit 1) if 
subject does not take or has not taken any excluded protocol medications, but must be 
completed prior to initiating any Visit 1 procedures. 
Subjects, who meet all the eligibility criteria at Screening, will enter a run-in period for 4 
weeks in order to continue to assess the subject’s eligibility for the study. During the run-
in period subjects will continue with their inhaled COPD medications (excluding ICS and 
 
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any exclusionary medications).  In addition, subjects will be provided with short acting 
albuterol/salbutamol to be used on as needed basis for relief of COPD symptoms (rescue 
medication) throughout the study. 
Subjects who experience a moderate or severe COPD exacerbation during the run-in 
period will be deemed run-in failures.  Subjects who experience a mild COPD 
exacerbation, defined as worsening of symptoms that requires no treatment with 
antibiotics or steroids and is self managed by the patient by an increase of inhaled rescue 
medication, (Appendix 5), will be able to continue in the study based on the judgment of 
the investigator and agreement of the sponsor’s medical monitor.
At the randomization Visit 2 (Day 1) those subjects who successfully complete the run-in 
period as well as meet the other pre-defined eligibility and randomization criteria will 
discontinue their inhaled COPD medications and will be randomized to one of the 3 
treatment arms for 24 weeks.
During the run-in and treatment period, subjects will be completing PRO questionnaires 
in the eDiary and performing slow and forced spirometry at specific clinic visits.
In addition, a subset of subjects up to 150 per treatment arm will undergo assessment of 
their physical activity measured through a physical activity monitor (Actigraph GT9X) 
worn for 7 days from Screening (Visit 1), for 7 days from Randomisation (Visit 2), 7 
days from Visit 3, and for 7 days prior to last clinic Visit (Visit 5). 
Concurrent use of COPD maintenance medications including LAMAs, LABAs, oral beta-
agonists, theophyllines, inhaled corticosteroids, inhaled corticosteroids and LABA 
combination and phosphodiesterase 4 inhibitors will not be allowed during the study 
(Section 6.11.2) . 
The occurrence of adverse events (AEs) will be evaluated throughout the study beginning 
at Visit 2 (Day 1) and until the follow-up contact (Visit 6).  Serious adverse events 
(SAEs) will be collected over the same time period as AEs.  However, any SAEs 
assessed as related to study participation (e.g., study treatment, protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK concomitant 
medication, will be recorded from the time a subject consents to participate in the study 
up to and including any follow up contact (Appendix 4). 
All subjects will be given an electronic diary (eDiary) for use during the run-in, and the 
treatment period to complete PRO questionnaires, record COPD daily symptoms, any 
medical problems experienced during the study and the time they take their COPD 
medications.  Daily rescue medication usage (number of inhalations taken in the last 24h) 
will also be captured in the eDiary.  In addition, and in some countries, rescue medication 
use will also be captured by the use of electronic metered dose inhaler (eMDI).
At Screening Visit 1, all subjects must be trained on the proper use of their existing 
COPD medications inhalation devices and instructed to strictly adhere to and record the 
time they take their COPD medications in the eDiary.
 
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At the randomization Visit 2, all subjects must be trained on the proper use of the 
ELLIPTA and DISKUS inhalation devices and instructed to strictly adhere to and record 
the time they take their study medications in the eDiary.
All subjects must be trained on the correct use of the eDiary and instructed to complete 
the eDiary during the run-in and treatment period.
Subjects will be considered to have completed the study upon completion of the follow –
up contact by telephone.
There are no plans to routinely provide any of the study treatments for compassionate use 
following study completion as the study treatment are commercially available.
The study design schematic is illustrated in Figure 1
Figure 1
Study Schematic
*Inhaled COPD medications including LABAs, LAMAs or LABA/LAMA combination products are 
allowed in run-in. ICS alone or in combination with a bronchodilator or any exclusionary 
medications are not allowed.
4.2.
Treatment Arms and Duration
Subjects will be stratified based on long-acting bronchodilator usage during the run-in 
(none, one or 2 long-acting bronchodilators per day) and randomized in a ratio of 1:1:1 to 
either

UMEC/VI inhalation powder (62.5/25 mcg once daily) administered via the 
ELLIPTA DPI) or 

UMEC (62.5 mcg once daily) administered via the ELLIPTA DPI or 

Salmeterol (50 mcg BID) administered via DISKUS
 
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The total duration of subject participation in the study will be approximately 29 to 
31 weeks consisting of 2 weeks pre-screening if necessary, 4 weeks run-in, 24 
week treatment and one week follow-up. 
4.3.
Type and Number of Subjects
Approximately 3232 will be screened globally in approximately 205 sites such that 
approximately 2424 subjects will be randomized and approximately 2181 evaluable 
subjects complete the study. 
4.4.
Design Justification
A randomized, double blinded, parallel group study is a standard, well-established design 
to evaluate the efficacy and safety of an investigational drug.  A salmeterol arm is 
included to allow a comparison to be made between UMEC/VI, UMEC with salmeterol, 
a standard practice treatment.
The double-dummy design is appropriate when drugs are of different appearance or 
different administration regimen which is appropriate in this study where the inhalers 
used have a different appearance and used once daily and twice daily.
The European Medicines Agency (EMA) COPD Guidelines suggest that duration of 12 to 
24 weeks is considered adequate for assessment of response of COPD symptoms to 
treatment intervention with bronchodilators (EMA COPD guidelines, 2012). 
The primary endpoint is trough FEV1 at week 24. This endpoint is generally considered to 
be a robust, well established and an objective means to show the efficacy of a 
bronchodilator [Dahl, 2010; Feldman, 2010]. 
Other endpoints such SAC TDI, E-RS, SGRQ-C, CAT, Subject Global Rating of Change 
in global impression of disease severity are captured to allow responder analyses and to 
provide comparative data on PROs between the treatment groups. 
4.5.
Dose Justification
This study is intended to evaluate the efficacy of marketed doses of UMEC/VI 
(62.5/25mcg once daily), UMEC (62.5 mcg once daily) and salmeterol (50mcg twice 
daily) that are approved for the maintenance treatment of COPD, with respect to PRO 
measures.
4.6.
Benefit: Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
UMEC/VI and UMEC can be found in the investigator’s brochures (IB) 
[GlaxoSmithKline Document Number RM2009/00437/07] and [GlaxoSmithKline 
Document Number RM2006/00835/09] and in the label information sheets. The current 
safety profile for UMEC (62.5mcg) and the UMEC/VI (62.5/25mcg) based on data 
available to date, is comparable with other LABAs and LAMAs.  Summary safety data 
can also be found in the information sheet for salmeterol [Serevent product information,
2003].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
Investigational Product (IP) [UMEC/VI] 
Severe milk protein allergy
Anoro contains Lactose monohydrate (which contains milk 
protein) as an excipient.
Exclusion criteria have been set for subjects with milk 
protein allergy.
Cardiovascular effects such as cardiac arrhythmias e.g.
supraventricular tachycardia and extrasystoles.
Class effects associated with LABAs and LAMA containing 
therapy. The clinical significance of these arrhythmias is 
unknown. Clinical experience with UMEC/VI to date in 
completed studies did not show any association with major 
cardiovascular events. 
Data available in the product label for UMEC/VI 
Exclusion criteria have been set for subjects with 
uncontrolled or severe cardiovascular disease according to 
the principal investigation’s (PI) opinion where the potential 
risk may outweigh the benefit. The PI should also 
determine the clinical significance of abnormal ECG 
findings at screening and exclude subjects who would be 
at undue risk by participating in the trial.  Patients with the 
following abnormalities will be excluded from participation:  
atrial fibrillation with rapid ventricular rate >120bpm, 
sustained or nonsustained ventricular tachycardia, or 
second degree heart block Mobitz type II or third degree 
heart block (unless pacemaker or defibrillator had been 
inserted). 
Beta agonists and risk of asthma-related death
Long-acting beta agonists such as vilanterol when used 
alone may increase the risk of asthma-related death.  A 
placebo-controlled trial with another LABA (salmeterol) 
showed an increase in asthma-related deaths in subjects 
receiving salmeterol.  This finding with salmeterol is 
considered a class effect of all LABAs, including vilanterol. 
Data are not available to determine whether the rate of death 
in patients with COPD is increased by LABA.
Subjects with a current diagnosis of asthma are excluded 
from participation in the study.
Paradoxical bronchospasm
As with other inhaled medicines, UMEC/VI can produce 
paradoxical bronchospasm which may be life threatening.
If paradoxical bronchospasm occurs following dosing with 
UMEC/VI, this treatment should be discontinued 
immediately and alternative therapy should be instituted. 
Use in patients with narrow-angle glaucoma or urinary 
retention
No association has been found to date, in completed studies 
with UMEC/VI or UMEC monotherapy, on glaucoma or 
urinary retention.  However, glaucoma or urinary retention 
Exclusion criterion states that subjects with medical 
conditions such as narrow-angle glaucoma, prostatic 
hypertrophy, or bladder neck obstruction should only be 
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
have been observed with other antimuscarinic agents, and 
could potentially be due to the pharmacology.
included if, in the opinion of the principal investigator, the 
benefit outweighs the risk.
Use of beta blockers
Beta-adrenergic blockers may weaken or antagonize the 
effect of beta2-agonists such as vilanterol.
The study permitted medications and non drug therapies 
section states that concomitant administration with beta-
blockers is only permitted if, in the Investigator’s opinion, 
the likely benefit outweighs the potential risk.
Pregnancy
There is no experience to date of pregnancy during the use 
of UMEC/VI.
The study inclusion criteria ensures that female subjects of 
child bearing potential must have a negative pregnancy 
test at screening, and agree to a reliable contraceptive 
method, used consistently and correctly (i.e. in accordance 
with the approved product label and the instructions of the 
physician for the duration of the study). Exclusion criteria 
include Pregnancy: Women who are pregnant or lactating 
or are planning on becoming pregnant during the study.
Severe hepatic impairment
UMEC/VI has not been studied in severe hepatic impairment.
Exclusion criterion states that subjects severe hepatic 
impairment should only be included if, in the opinion of the 
study physician, the benefit outweighs the risk.
Investigational product (IP) [UMEC]
Cardiovascular effects such as cardiac arrhythmia, e.g. 
atrial fibrillation and tachycardia
A potential class effect associated
with anti-muscarinic therapies. Data available to date in the 
IB for UMEC [GlaxoSmithKline Document Number 
RM2006/00835/09
Screening electrocardiogram (ECG) criteria to exclude 
subjects potentially at risk 
Narrow-angle glaucoma, urinary retention
A class effect associated with anti-muscarinic therapies.
Data available in the IB for UMEC [GlaxoSmithKline 
Document Number RM2006/00835/09
Exclusion criterion states that subjects with medical 
conditions such as narrow-angle glaucoma, prostatic 
hypertrophy, or bladder neck obstruction should only be 
included if, in the opinion of the study physician, the benefit 
outweighs the risk.
Paradoxical bronchospasm that may be life threatening
Known effect associated with inhalation therapy
A short-acting inhaled bronchodilator 
(albuterol/salbutamol) will be provided for use as needed 
throughout the study. The investigators will be instructed to 
assess subject’s condition to determine their eligibility to 
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
continue in the study and the need for alternative therapy.
Severe hepatic impairment
UMEC has not been studied in severe hepatic impairment.
Exclusion criterion states that subjects with severe hepatic 
impairment should only be included if, in the opinion of the 
study physician, the benefit outweighs the risk.
Pregnancy/Lactation
There is no experience to date of pregnancy during the use 
of UMEC.
The study inclusion criteria ensure that female subjects 
enrolled, who are of Child bearing potential, have a 
negative pregnancy test at screening, and agree to a 
reliable contraceptive method, used consistently and 
correctly (i.e. in accordance with the approved product 
label and the instructions of the physician for the duration 
of the study). Exclusion criteria states - Pregnancy: 
Women who are pregnant or lactating or are planning on 
becoming pregnant during the study.
Study Procedures
Spirometry procedures
This may cause difficulty breathing, changes in pulse rate 
and blood pressure, coughing, wheezing, chest tightness or 
fainting.
Subjects will be monitored during the procedure for these 
effects and spirometry will be discontinued should these 
occur.
ECG lead placement
This may cause skin irritation.
It may be necessary to have small patches (about a 
centimetre in diameter) of hair on the chest shaved to 
properly attach electrodes to the chest. 
Blood sampling procedure (optional pharmacogenetic 
blood sample)
Giving blood may make subjects feel faint, or experience 
mild pain, bruising, irritation or redness at the site. In rare 
cases, they may get an infection
Subjects will be monitored during the blood draw for these 
effects and should call their study doctor if any of these 
effects do not resolve
Other 
Side effects of rescue albuterol/salbutamol. Adverse 
events seen in clinical studies to date are however 
consistent for the beta2-adrenergic class of compounds
Class effects associated with short acting beta-agonists 
(SABAs)
Subjects should call their study doctor if they experience 
any of these symptoms
 
 
 
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4.6.2.
Benefit Assessment
Subjects will receive single or combination of long-acting bronchodilator therapies 
approved for maintenance treatment of COPD.  Participating subjects in this study will 
contribute to the process of further characterizing the benefit of these long-acting 
bronchodilators with respect to PROs and symptoms in the treatment of COPD.
Specific benefits associated with the study design and procedures include the following:

Subjects will receive treatments approved for the treatment of COPD that have 
been shown to be effective in the population under study

All subjects will receive albuterol/salbutamol for use “as needed” for relief of 
COPD symptoms

The combination of study procedures of spirometry, CAT, SGRQ, TDI, E-RS will 
provide the study subjects with a comprehensive evaluation of their symptoms, 
health status and COPD disease severity. Subjects will also be monitored 
throughout the study for any worsening of COPD symptoms or decline in general 
health.  Finally smoking cessation counselling will also be provided.
4.6.3.
Overall Benefit: Risk Conclusion
Taking into account the measures taken to minimize risk to subjects participating in this 
study, the potential risks identified in association with UMEC/VI, UMEC, salmeterol and 
with study procedures are justified by the anticipated benefits from active treatments that 
may be afforded to patients with COPD.
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 IBs, [GlaxoSmithKline 
Document Number RM2006/00835/09], [GlaxoSmithKline Document Number 
RM2009/00437/07] and product labels.
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
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE
1.
40 years or older at date of signing informed consent at Screening Visit 1
 
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TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2.
Outpatient with a diagnosis of COPD in accordance with the definition of the 
American Thoracic Society/European Respiratory Society (ATS/ERS) [Celli, 2004]. 
3.
FEV1: Persistent airflow limitations as indicated by:  A pre and post-
albuterol/salbutamol FEV1/FVC ratio of <0.70 and a post-albuterol/salbutamol FEV1
of ≥30% to ≤80% predicted normal values at Screening Visit 1.  Predicted values 
will be based upon the ERS Global Lung Function Initiative [Quanjer, 2012].
4.
CAT score:  A CAT score of ≥10 at Screening Visit 1
Smoking History
5.
Current or former cigarette smokers with a history of cigarette smoking of 10 
pack-years [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 both equal 10 pack-years)].  Former smokers are defined as those who have 
stopped smoking for at least 6 months prior to Visit 1.  Pipe and/or cigar use cannot 
be used to calculate pack-year history.
SEX
6.
Male and female subjects are eligible to participate in the study
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 must be tested.  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.
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 
 
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Reproductive Potential (FRP) (Appendix 7) from 30 days prior to the first dose of 
study medication and until [at least five terminal half-lives OR until any continuing 
pharmacologic effect has ended, whichever is longer] after the last dose of study 
medication and completion of the follow-up visit.
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.
INFORMED CONSENT
7.
Capable of giving signed informed consent prior to study participation, which 
includes compliance with the requirements and restrictions listed in the consent form 
and in this protocol.
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION 
1.
Asthma:  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).
2.
Alpha-antitrypsin deficiency: Subjects with known α1-antitrypsin deficiency as 
the underlying cause of COPD
3.
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.
4.
Unstable liver disease: 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). 

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 or within 3 months prior to 
first dose of study treatment) are acceptable if subject otherwise meets entry 
criteria
5.
Unstable or life threatening cardiac disease: Investigational Product should be 
used with caution in subjects with severe cardiovascular disease.  In the opinion 
of the investigator, use should only be considered if the benefit is likely to 
 
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outweigh the risk in conditions such as:

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
6.
12 Lead ECG: 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. Subjects with the 
following abnormalities are excluded from participation in the study:

Atrial fibrillation with rapid ventricular rate >120 bpm

Sustained or non-sustained ventricular tachycardia

Second degree heart block Mobitz type II or third degree heart block (unless 
pacemaker or defibrillator had been inserted)
7.
Antimuscarinic effects:  Subjects with medical conditions such as narrow-angle 
glaucoma, urinary retention, prostatic hypertrophy, or bladder neck obstruction 
should be excluded unless, in the opinion of the study physician, the benefit 
outweighs the risk.
8.
Other disease abnormalities: Any subject who is considered unlikely to survive 
the duration of the study period or has any rapidly progressing disease or 
immediate life-threatening illness (e.g. cancer). In addition, any subject who has 
any other condition (e.g. neurological condition) that is likely to affect respiratory 
function should not be included in the study.
9.
Hospitalization: Hospitalization for COPD or pneumonia within 12 weeks prior 
to Visit 1. 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). 
10.
Inhaled corticosteroids (ICS): Had received ICS or ICS/LABA for the treatment 
of COPD in the 6 weeks prior to Screening Visit1
11.
Exacerbation: Had >1 moderate exacerbation in the 12 months prior Screening 
Visit1, or one severe exacerbation requiring hospitalisation in the 12 months prior 
Screening Visit 1.
12.
Other respiratory tract infections that have not resolved at least 7 days prior to 
Screening V1.
13.
Lung Resection: Subjects with lung volume reduction surgery (including 
procedures such as endobronchial valves) within the 12 months prior to Screening 
V1.
14.
Oxygen: Use of long-term oxygen therapy (LTOT) described as resting oxygen 
therapy >3L/min at screening required to maintain adequate oxygenation (e.g. 
SaO2 >90%). (Oxygen use ≤3L/min flow is not exclusionary, and patients may 
adjust oxygen levels up or down as needed during the study.)
 
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CONCOMITANT MEDICATIONS
1. Medications prior to Screening: Use of the following medications according to 
the following defined time intervals prior to Screening (Visit 1):
Medication
No use within the 
following time intervals 
prior to Screening
Inhaled corticosteroids (ICS)
6 weeks
Depot corticosteroids
12 weeks
Systemic, oral or parenteral corticosteroidsa
6 weeks
Antibiotics (for lower respiratory tract infection)
6 weeks
Phosphodiesterase 4 (PDE4) Inhibitor (e.g roflumilast)
14 days
LABA/Inhaled Corticosteroid (ICS) combination products 
6 weeks
Theophyllines
48 hours
Oral beta2-agonists
     Long-acting
     Short-acting
48 hours
12 hours
Inhaled short acting beta2-agonistsb
4 hours
Inhaled short-acting anticholinergics
4 hours
Inhaled short-acting anticholinergic/short-acting beta2-agonist 
combination products
4 hours
Any other investigational medication
30 days or within 5 drug 
half-lives (whichever is 
longer)
a-
Localized corticosteroid injections (e.g., intra-articular and epidural) are permitted.
b-
Use of study provided albuterol/salbutamol is permitted during the study, except in the 4-hour period prior to 
spirometry testing
2. Medication prior to spirometry: Unable to withhold albuterol/salbutamol for 
the 4 hour period required prior to spirometry testing at each study visit.
3. Maintenance use of short-acting bronchodilators:  Regular use (prescribed for 
daily/ regular use, not for as-needed use) of short-acting bronchodilators (e.g. 
albuterol/salbutamol).
RELEVANT HABITS
1. Drug or alcohol abuse: A known or suspected history of alcohol or drug abuse 
within 2 years prior to Screening Visit 1 that in the opinion of the investigator would 
prevent the subject from completing the study procedures.
CONTRAINDICATIONS 
1. Any history of allergy or hypersensitivity to any anticholinergic/muscarinic 
receptor antagonist, sympathomimetic, lactose/milk protein or magnesium stearate.
 
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DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
1. Pulmonary Rehabilitation program: Participation in the acute phase of a 
pulmonary rehabilitation program within 4 weeks prior to Screening Visit 1.  Subjects 
who are in the maintenance phase of a pulmonary rehabilitation program are not 
excluded.
2. Affiliation with investigator sites: Is an investigator, sub-investigator, study 
coordinator, employee of a participating investigator or study site, or immediate 
family member of the aforementioned that is involved in this study
3. Inability to read: In the opinion of the investigator, any subject who is unable to read 
and/or would not be able to complete questionnaires on the electronic diary.
Subjects who fail to meet inclusion and exclusion criteria at the Screening Visit 1 will be 
considered screen failures and cannot be re-screened.
5.3.
Randomization Criteria
In order to be randomized to one of the 3 treatment arms at Visit 2, subjects must have 
completed the run-in period and must have fulfilled all inclusion and exclusion criteria 
described in Section 5.1 and Section 5.2. In addition to the following:
REQUIRED CRITERIA FOR RANDOMIZATION AND TREATMENT
1. COPD Exacerbation: Subjects must not have experienced a moderate or severe 
COPD exacerbation or a lower respiratory tract infection during run-in or at Day 1 
(Visit 2) inclusive.  A moderate exacerbation is defined as worsening of symptoms of 
COPD requiring the use of antibiotics or systemic corticosteroids.  A severe 
exacerbation is defined as worsening symptoms of COPD requiring hospitalization.
2. CAT score:  A CAT score of ≥10 at Visit 2
3. Prohibited Medications: No use of any prohibited medications during the run-in 
period or at Visit 2, including any ICS or ICS/LABA combination
4. Any change to COPD medications: Including dosage and regimen during the run-in
5. Completion of electronic diary: Must have completed the electronic diary for at 
least 80% of days during the run-in period
Subjects who do not meet the required criteria for randomization at Visit 2 will not be 
randomized.
5.4.
Screening/Baseline/Run-in Failures
Pre-screen, screen and run-in failures are defined as follows: 

Pre-screening failures: A subject, who is assigned a subject number at the Pre-
screening Visit 0 but does not have any Screening Visit 1 procedures, will be 
considered a pre-screen failure.
 
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
Screening failures: Those subjects that complete at least one Screening Visit 1 
procedure but do not enter the run-in period.

Run-in failures: Those subjects that enter the run-in period but are not 
randomized to any of the study treatment arms.
Subjects who are pre-screen, screen and run-in failure will be recorded in the eCRF.  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 to be recorded in eCRF including demography, screen failure details, eligibility 
criteria, and serious adverse events (Section 7.4.1). 
5.5.
Withdrawal/Stopping Criteria
5.5.1.
Withdrawal from the Study
Subjects may be withdrawn from the study at any time by the Investigator if it is 
considered to be detrimental for them to continue in the study.  Reasons for withdrawal 
from study treatment can include: an AE, clinically significant abnormality, lack of 
efficacy, sponsor terminated study, pregnancy, or for any other reason. 
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. 
A reason for the withdrawal from the study must be captured in the electronic case report 
form (eCRF).
A subject will also be withdrawn from the study, in consultation with the medical 
monitor and principal investigator, if any of the following stopping criteria are met:

Liver Chemistry: Meets any of the Liver chemistry stopping criteria (See Section 
5.5.3)
Note: clinical laboratory assessments are not required for this study. However, 
laboratory samples may be taken for liver event analysis, if clinically indicated by 
the study investigator.

Pregnancy:  Positive pregnancy test (see Appendix 7)
Subjects withdrawn from study treatment will not be replaced. 
Note: Withdrawal from study treatment requires withdrawal from the study.
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. 
 
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
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”. 
5.5.2.
Reason for Study Withdrawal
The primary reason for study withdrawal will be recorded in the eCRF. When a subject 
withdraws consent, the investigator must document the reason (if specified by the 
subject) in the eCRF. 
The primary reason for study withdrawal may include:
Adverse event
Lost to follow-up
Withdrew consent
o
subject relocated
o
frequency of visits
o
burden of procedures
o
other (specify)
Protocol deviation
Lack of efficacy
COPD exacerbation
Study closed/terminated
Subject reached protocol-defined stopping criteria
o
Liver event
Pregnancy
Investigator discretion
5.5.3.
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
 
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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*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 2.
5.5.3.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed.
5.6.
Follow-up contact
A safety follow-up contact (Visit 6) should be conducted 72 days following the 
completion of Visit 5 or the Early Withdrawal Visit, if applicable. 
The following procedures will be performed:

AE/SAE assessment

COPD exacerbation assessment

Concomitant medication assessment limited to any medications used to treat a 
COPD exacerbation or SAE (if applicable)

Pregnancy information (if applicable)
Subjects who have successfully completed all on-treatment randomized visits will be 
discharged from the study upon completion of the safety follow-up contact.
 
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5.7.
Subject and Study Completion
A subject will be considered to have completed the study if he/she receives study 
treatment at Visit 5 (Week 24) and completes the follow-up contact Visit 6.
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.
The contents of the label will be in acaccordance with all applicable regulatory 
requirements.
Under normal conditions of handling and administration, investigational product is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to avoid 
direct eye or skin contact and the generation of aerosols or mists. Notify the monitor of 
any unintentional occupational exposure.  A Material Safety Data Sheet (MSDS) 
describing the occupational hazards and recommended handling precautions will be 
provided to site staff if required by local laws or will otherwise be available from GSK 
upon request.
Investigational product must be stored in a secure area under the appropriate physical 
conditions for the product.  Access to and administration of the investigational product 
will be limited to the investigator and authorised site staff.  Investigational product must 
be dispensed or administered only to subjects enrolled in the study and in accordance 
with the protocol.
GlaxoSmithKline (GSK) will provide the study treatments for use in this study. 
The following study medications will be used in this study:
UMEC/VI 62.5/ 25mcg administered via ELLIPTA
UMEC 62.5 mcg administered via ELLIPTA

Salmeterol 50 mcg administered via DISKUS

Placebo via ELLIPTA

Placebo via DISKUS
Subjects will be instructed to take one dose of medication each morning from the 
ELLIPTA (one inhalation equals one dose), and one dose in the morning and one in the 
evening from the DISKUS).  Subject instructions and details on how to use the ELLIPTA 
and DISKUS are provided in the study reference manual (SRM).
 
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A description of the UMEC/VI investigational product administered via the ELLIPTAis 
provided below in Table 1. The ELLIPTA will contain two, double-foil, laminate, blister 
strips.  The ELLIPTA will provide a total of 30 doses (60 blisters) and will deliver, when 
actuated, the contents of a single blister simultaneously from each of the two blister 
strips. 
The DISKUS will provide a total of 60 doses and will deliver, when actuated, the 
contents of a single blister.
A description of the UMEC investigational product administered via the ELLIPTA is 
provided below in Table 2. A description of placebo inhalation powder via ELLIPTA is 
shown in Table 3.  A description of salmeterol 50mcg and placebo via DISKUS are 
shown in Table 4 and Table 5 respectively.
Table 1
Description of UMEC/VI Inhalation Powder via ELLIPTA
Formulation
First strip
Second strip
Umeclidinium bromide blended with 
lactose monohydrate and 
magnesium stearate1
Vilanterol trifenatate blended with 
lactose monohydrate and magnesium 
stearate2
Dosage Form
ELLIPTA Inhaler with 30 doses (2 strips with 30 blisters per strip)
Unit Dose Strengths
62.5 mcg
25 mcg
Physical description
White powder
White powder
Route of Administration
Inhaled
1.
Magnesium stearate 0.6% w/w of total drug product
2.
Magnesium stearate 1.0% w/w of total drug product
Table 2
Description of UMEC Inhalation Powder via ELLIPTA
Formulation
First strip
Umeclidinium bromide blended with lactose 
monohydrate and magnesium stearate1
Dosage Form
ELLIPTA Inhaler with 30 doses (1 strip with 30 blisters) 
Unit Dose Strengths
62.5mcg 
Physical description
Dry white powder
Route of Administration
Inhaled
1.
Magnesium stearate 0.6% w/w of total drug product
Table 3
Description of Placebo inhalation powder via ELLIPTA
Formulation
First strip
Second strip
Lactose monohydrate blended with 
magnesium stearate1
Lactose monohydrate blended with 
magnesium stearate2
Dosage Form
ELLIPTA Inhaler with 30 doses (2 strips with 30 blisters per strip)
Unit Dose Strengths
Not applicable
Not applicable
Physical description
Dry white powder
Dry white powder
Route of Administration
Inhaled
1.
Magnesium stearate 0.6% w/w of total drug product
2.
Magnesium stearate 1% w/w of total drug product
 
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Table 4
Description of salmeterol Inhalation powder via DISKUS
Formulation
First strip
Salmeterol Xinafoate blended with 
lactose monohydrate
Dosage Form
Diskus Inhaler with 60 doses (1 strip 
with 60 blisters per strip)
Unit Dose Strengths
50 mcg
Physical description
White powder
Route of Administration
Inhaled
Table 5
Description of Placebo inhalation powder via DISKUS
Formulation
Lactose monohydrate 
Dosage Form
Diskus Inhaler with 60 doses (1 strip 
with 60 blisters per strip)
Unit Dose Strengths
Not Applicable
Physical description
White powder
Route of Administration
Inhaled
Albuterol/salbutamol via metered-dose-inhaler (MDI) will be issued for reversibility 
testing at Visit 1.  Albuterol/salbutamol MDI for as needed (prn) use will be issued 
throughout the study.  Albuterol/salbutamol will be sourced from local commercial stock 
if appropriate.  
6.2.
Medical Devices
The eMDI devices are provided by GSK and are used in this study to electronically 
record rescue medication usage.  They have US FDA 510(K) clearance to market (Class 
II device) and EU CE marking (Class I device). Description of the eMDI and its use will 
be provided in the SRM.
6.3.
Treatment Assignment
Subjects who meet the randomization criteria will be assigned to one of the 3 study 
treatments in accordance with the randomization schedule generated by Clinical 
Statistics, prior to the start of the study, using validated internal software.
Once a randomization number is assigned to a subject, it cannot be reassigned to any 
other subject in the study.
This study will utilize RAMOS NG, which will provide a means for central 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 RAMOS NG to randomize subjects is provided in the SRM.
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 
 
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instructed to do so by clinic personnel.  On the other days during the treatment period 
(i.e. “non-clinic days”), subjects will be instructed to self-administer their study treatment 
in the morning and evening. Subjects should enter the time they take their study treatment 
in the eDiary. 
Subjects will be randomly assigned to one of the blinded study treatment regimens in 
equal proportion (ratio of 1:1:1):

UMEC/VI 62.5/25 mcg once daily via ELLIPTA + placebo twice daily via 
DISKUS

UMEC 62.5 mcg once daily via ELLIPTA + placebo twice daily via DISKUS

Salmeterol 50 mcg twice daily via DISKUS + placebo once daily via ELLIPTA
The randomisation will be stratified based on long-acting bronchodilator usage during 
the run-in (none, one or 2 long-acting bronchodilators per day). 
Study treatment/investigational product will be dispensed at Visits 2, 3 and 4. 
In order to ensure subjects have sufficient doses of study treatment, they must return to 
clinic within 30 days from V2, 60 and 90 days from V3 and V4 respectively (see Time 
and event table Section 7.1). 
Used study drug and rescue medication will be collected at Visits 3, 4 and 5 or at the 
Early Withdrawal Visit. 
6.4.
Planned Dose Adjustments
No dose adjustment is allowed for this study
6.5.
Blinding
This will be a double-blind double dummy study 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. 

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. 
 
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
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. 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.
6.6.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.7.
Preparation/Handling/Storage/Accountability
No special preparation of the study treatment is required.

The investigator or designee must confirm appropriate temperature conditions 
have been maintained during transit for all study treatment received and any 
discrepancies are reported and resolved before use of the study treatment.

Only subjects enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment.  All study 
treatments must be stored in a secure environmentally controlled and monitored 
(manual or automated) area in accordance with the 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 SRM. 
All ELLIPTA DPI study treatment should be stored up to 25C (77F).  Each All 
ELLIPTA DPI contains 30 doses and is packaged in a foil pouch with a desiccant 
sachet and stored in a carton. The inhaler should not be used for more than 30 days 
after opening the foil.  The sites must maintain a daily temperature log for the 
investigational product. 
Salmeterol DISKUS should be stored up to 25 C. 
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.

A Material Safety Data Sheet (MSDS)/equivalent document describing 
occupational hazards and recommended handling precautions either will be 
 
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provided to the investigator, where this is required by local laws, or is available 
upon request from GSK.
6.7.1.
Study Treatment Return
All used and unused ELLIPTA and DISKUS inhalers 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 SRM.
Study treatment will be collected at Visit 3, 4 and 5 or at the Early Withdrawal Visit, if 
applicable. 
For any ELLIPTA or DISKUS inhaler that fails to function properly, the subject should 
return to the clinic as soon as possible to obtain a new inhaler.  The site will contact the 
RAMOS NG 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 
RAMOS NG
In addition, any ELLIPTA that fails to function properly must be identified and returned 
to GSK for testing. 
6.8.
Compliance with Study Treatment Administration
When subjects self-administer study treatment(s) at home, compliance with study 
treatment(s) will be assessed through querying the subject during the site visits and 
through study drug compliance assessed at Visits 2, 3, 4 and 5 documented in the source 
documents and eCRF.  A record of the number of ELLIPTA and DISKUS dispensed and 
the number of doses inhaled by each subject must be maintained and reconciled with 
study treatment and compliance records.  Treatment start and stop dates, including dates 
for treatment delays if any will also be recorded in the eCRF.
Compliance with the ELLIPTA inhaler will be determined by reviewing the dose counter 
on the ELLIPTA.  Compliance with the study DISKUS will be determined by reviewing 
the dose counter on the DISKUS.  Subjects should be ≥80% to ≤120% compliant on 
taking study medication between each pair of on-treatment visits.  Subjects who fall 
outside this range should be re-educated on treatment compliance by their site. This re-
education should be documented in the subject’s source document.  If medication 
compliance repeatedly falls outside of acceptable ranges, the study sponsor/site monitor 
must be contacted to discuss subject eligibility for continued participation in the study.
6.9.
Treatment of Study Treatment Overdose
An overdose is defined as a dose greater than the total doses described in Section 6.1 and 
Section 6.8 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 medication, 
the investigator should use clinical judgment in treating the overdose and contact the 
study Medical Monitor. 
 
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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 may not be limited to, the approved product label for salmeterol 
albuterol, UMEC and UMEC/VI or equivalent document provided by GSK.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the subject.
6.10.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study, since the study treatments are commercially available.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, post-study treatment. 
6.11.
Concomitant Medications and Non-Drug Therapies
All COPD medications used within 30 days prior to Pre-Screening (Visit 0) and onwards 
should be recorded in the eCRF including any changes in medications.  Beginning at 
Visit 1 and throughout the rest of the study, all medications should be recorded in the 
eCRF including any changes.  Study provided albuterol/salbutamol and double-blinded 
study drug should not be recorded in the eCRF.  The minimum requirement includes but 
is not limited to drug name, dose, route and the dates of administration.  Medications 
initiated after completion of Visit 5 or the Early Withdrawal Visit will not be recorded in 
the eCRF, with the exception of those used to treat a COPD exacerbation or SAE that 
occurs between Visit 5 (or the Early Withdrawal Visit) and the follow-up contact atVisit 
6.
6.11.1.
Permitted Medications and Non-Drug Therapies
The following relevant medications are permitted during this study:

Study-provided albuterol/salbutamol for use as relief medication throughout the 
run-in and treatment periods 

Mucolytics such as acetylcysteine

Medications for rhinitis (e.g. intranasal corticosteroids, antihistamines, cromolyn, 
nedocromil, nasal decongestants)

Influenza vaccine

pneumococcal vaccine

Antibiotics for short term treatment (14 days) of acute infections including  
COPD exacerbations

Systemic corticosteroids for short term (14 consecutive days)  treatment of 
COPD exacerbations 
 
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
As-needed supplemental oxygen use provided it is ≤3L/min flow at rest at 
screening.  Patients may adjust oxygen levels as needed during the study.

Pulmonary rehabilitation program in maintenance phase

Smoking cessation treatment, including a stable regimen of nicotine replacement

Use of positive airway pressure/non-invasive ventilation for sleep apnea/sleep 
disordered breathing (e.g. CPAP, BiPAP) 

Localized corticosteroid injections (e.g., intra-articular and epidural)

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)

Immunotherapy injections

Topical or ophthalmic corticosteroids

Over-the counter (OTC) cough suppressants

Tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs). Administer 
with caution as they may potentiate the effect of beta-agonists on the vascular 
system

Diuretics. Caution is advised in the co-administration of beta agonists with non-
potassium sparing diuretics

Allergy vaccination

All medications for other disorders as long as the dose remains constant whenever 
possible and their use would not be expected to affect lung function
6.11.2.
Prohibited Medications and Non-Drug Therapies
Use of the medications listed in Table 6 is not permitted during the study
 
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Table 6
Prohibited Medications and Non-Drug Therapies
Medication
Depot corticosteroids
Systemic, oral or parenteral corticosteroids1
Inhaled corticosteroids (ICS)2
Antibiotics >14 days
LABA/ICS combination products
PDE4 inhibitor (e.g. roflumilast)
Inhaled long acting beta2-agonists (LABA, e.g. salmeterol, formoterol, indacaterol, vilanterol)
Long-acting muscarinic antagonists (LAMA, e.g. tiotropium, aclidinium, glycopyrronium, umeclidinium3)
LAMA/LABA combination products except for study drugs
Theophyllines
Oral beta2-agonists
Inhaled short acting beta2-agonists4
Inhaled short-acting anticholinergics
Inhaled short-acting anticholinergic/short-acting beta2-agonist combination products
Any other investigational medication
1
Except for the treatment of COPD exacerbations during the study. Localized corticosteroid injections (e.g., 
intra-articular and epidural) are permitted.
2
Except if during the study use of ICS is deemed necessary for the treatment of subjects’ exacerbation. 
3
Expect for study drug
4
Use of study provided albuterol/salbutamol is permitted during the study, except in the 4-hour period prior to 
spirometry testing. 
The following medications or treatments are also not allowed during the study:

Use of long-term oxygen therapy (LTOT) described as resting oxygen therapy 
>3L/min only at screening. Oxygen may be titrated to any level deemed necessary 
during the study.

Regular (prescribed for daily/regular use, not for as-needed use) therapy with 
albuterol/salbutamol.

Initiation of pulmonary rehabilitation during the study.
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 Section 7.1, are essential and required for study 
conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table Section 7.1
 
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7.1.
Time and Events Table
Blinded Treatment
Visit
Pre-
screen1
0
Screen/ 
Run-in
1
Rando-
mization 
2
3
4
5
EW 
Visit 2
Telephone Follow up 
contact 
6
Week
-6 to -4
-4
0
4
12
24
Day
42 -7/+2
days 
prior 
Visit 1
28 -7/+2 
days prior 
Visit 2
1 -7/+2 
days
28 -7/+2 
days 
84 -7/+2 
days
168 -7/+2
days
73 days after V5 or 
EW Visit
Screen/Baseline
Written informed consent
X
Demography
X
Medical/COPD history
X
Smoking history/status
X
Smoking cessation counselling
X
Concomitant medication assessment
X
X
X
X
X
X
X
X
Height and weight
X
Cardiovascular History/family history of premature CV 
disease])
X
Screening spirometry (including post bronchodilator 
testing)3
X
CAT questionnaire
X
X
Verify Inclusion/Exclusion Criteria
X
Training on use of inhalers
X
X
Training on use of eDiary and eMDI
X
X
Verify randomization Criteria
X
Register Visit in InForm
X
X
X
X
X
X
X
X
Register Visit in RAMOS NG
X
X
X
X
X
X
X
X
 
 
 
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Blinded Treatment
Visit
Pre-
screen1
0
Screen/ 
Run-in
1
Rando-
mization 
2
3
4
5
EW 
Visit 2
Telephone Follow up 
contact 
6
Week
-6 to -4
-4
0
4
12
24
Day
42 -7/+2
days 
prior 
Visit 1
28 -7/+2 
days prior 
Visit 2
1 -7/+2 
days
28 -7/+2 
days 
84 -7/+2 
days
168 -7/+2
days
73 days after V5 or 
EW Visit
Efficacy/HRQoL assessments
Spirometry, including pre-dose FEV1, trough  FEV1 and 
inspiratory capacity
X
X
X
X
SAC BDI questionnaire 4
X
SAC TDI questionnaire 4
X
X
X
SGRQ-C questionnaire 4
X
X
X
X
CAT questionnaire 4
X
X
X
X
X
EXACT/ER-S: COPD 5
Patient Global Rating of COPD severity
X
X
X
X
Patient Global Rating of Change in COPD
X
X
X
Safety assessments
Adverse events/Serious adverse events 6
X
X
X
X
X
X
X
X
COPD exacerbation assessment
X
X
X
X
X
X
X
X
12-Lead ECG
X
Urine pregnancy test 7
X
X
X
X
Pharmacogenetic sample8
                                          X
Medication/Supplies
Dispense rescue albuterol/slabutamol. Dispense MDI9
X
X
X
X
X
Assess COPD medication compliance10 during run-in
X
Dispense eDiary
X
Assess compliance with eDiary during run-in 
X
Collect rescue albuterol/slabutamol. 
X
X
X
X
X
Collect eDiary
X
X
Dispense study treatment11
X
X
X
Collect study treatment
X
X
X
X
 
 
 
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Blinded Treatment
Visit
Pre-
screen1
0
Screen/ 
Run-in
1
Rando-
mization 
2
3
4
5
EW 
Visit 2
Telephone Follow up 
contact 
6
Week
-6 to -4
-4
0
4
12
24
Day
42 -7/+2
days 
prior 
Visit 1
28 -7/+2 
days prior 
Visit 2
1 -7/+2 
days
28 -7/+2 
days 
84 -7/+2 
days
168 -7/+2
days
73 days after V5 or 
EW Visit
Assess study treatment compliance during treatment10
X
X
X
X
Study sub-set
Physical activity monitor12
X
X
X
X
Collect Physical activity monitor
X
X
1.
Pre-screen Visit 0 must be completed prior to Screening Visit1. It can be completed 2 weeks prior or on the same day of V1, if no wash out of exclusionary medications is 
required. 
2.
Early Withdrawal Visit: Subjects that withdraw should return to the clinic as soon as possible to complete the Early Withdrawal Visit procedures.
3.
Spirometry at screening should be performed as described in (Section 7.2.2.1). 
4.
SAC BDI, SAC TDI, SGRQ-C, CAT questionnaires will be completed at clinic visits and in the eDiary
5.
EXACT/ER-S: COPD is completed daily in the eDiary approximately 2 hours before bed-time, starting on Day 1 of the run-in period.
6.
For the start date of collecting AEs and SAEs see (Appendix 4)
7.
Pregnancy test: for females for child bearing potential only.
8.
Pharmacogenetic sample may be drawn at visit 2 or any visit after.
9.
Rescue medication use to be recorded in the eDiary daily and in some sites in the eDiary and the eMDI
10. Sites are requested to call subjects every 2 weeks to remind them to take study treatment regularly and to record the time of the morning and evening dose in the eDiary.
11. In order to ensure subjects have sufficient doses of study treatment, they must return to clinic within 30 days from V2 and within 60 days from V3 respectively.
12. The Actigraph GT9X should be worn for 7 days from Visit 1, for 7 days from Visit 2, for 7 days from Visit 3 and for 7 days prior to Visit 5.
 
 
 
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7.2.
Screening and Critical Baseline Assessments
7.2.1.
Pre-screening Visit
During the Pre-screening Visit, the study designated personnel must provide informed 
consent to the study participant.  Subjects can perform the Pre-screening Visit (Visit 0) 
up to 2 weeks prior to or on the same day as the Screening Visit (Visit 1) if subject does 
not take or has not taken any protocol excluded medications.
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.  A subject number will be assigned at the time the 
informed consent form (ICF) is signed. No study related procedures may be 
performed until the informed consent form document has been signed by the 
subject.  
Once the informed consent is signed and if required, changes can be made to the subject’s 
current medication regimen. The investigator should exercise clinical judgment, and is 
discouraged from changing medications only for the purpose of the clinical study. 
During the pre-screening Visit 0, the following information is collected:

Demographic parameters: year of birth, gender, race and ethnicity

Concomitant medications review

COPD exacerbation assessment
From the pre-screening visit onwards concomitant medications, exacerbations and SAEs 
(considered as related to study participation) must be reported
7.2.2.
Critical procedures performed at Screening (Visit 1)
The following critical assessments will be conducted at Visit 1:

Cardiovascular medical history/risk factors (as detailed in the eCRF) will be 
assessed at screening

Medical history including COPD (including date of diagnosis and COPD type 
(emphysema and/or chronic bronchitis), smoking history, COPD exacerbation 
history, smoking status and previous and/or current medical conditions) 

Concomitant medication review (COPD and non COPD medications in the 3 
months prior to Screening).

Height and weight

12-Lead ECG. (Note: ECG is performed at screening Visit 1 to test for eligibility 
only. See Section 7.4.4).
 
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
Urine pregnancy test if applicable

Train subject on the use of eDiary

COPD assessment test (CAT) and patient global rating of COPD severity in 
eDiary

Pre- and post-albuterol/salbutamol spirometry (reversibility, see Section 7.2.2.1)

Inclusion/Exclusion criteria assessment

Review exacerbations, AEs, (SAEs if related to study participation)

Train subject on the proper use of their COPD medication inhalation devices

Instruct subject to take their COPD medications as instructed and to enter the time 
they take their medication in the eDiary

Dispense rescue medication
Medical history will be assessed as related to the inclusion/exclusion criteria listed in 
Section 5.1 and Section 5.2.
Assessment of subject’s health status will be made at screening using CAT.  PRO 
questionnaires should be completed by subjects before any other assessments at a clinic 
visit, in the order specified in Section 7.3.1
7.2.2.1.
Albuterol/Salbutamol Reversibility Assessment
At Visit 1, both pre- and post-albuterol/salbutamol spirometry will be obtained to 
determine subject eligibility.  Reversibility assessment should be performed as follows:

Perform pre-bronchodilator spirometry and record FEV1 and FVC

Subject to self-administer 4 Inhalations (4X100g) of albuterol/salbutamol MDI

Perform post-bronchodilator spirometry and record FEV1 and FVC approximately 
10 to 30 minutes after albuterol/salbutamol administration
The results of the spirometry must meet the ATS/ERS criteria [Miller, 2005] for 
the subject to continue in the study.
7.2.3.
Critical procedures performed at first treatment Visit (Baseline 
V2)

Review and assess  compliance with subject’s COPD medications during the run-
in period

Review and assess compliance with completing the eDiary during the run-in 
period

Review AEs, SAEs and exacerbations
 
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
Urine pregnancy test, if applicable

Baseline dyspnea Index, BDI, patient global rating of COPD severity, patient 
global rating of change in COPD, SGRQ-C and CAT questionnaires in eDiary

Review randomization criteria (Section 5.3)

Register and randomize subject in RAMOS NG

Pre-dose spirometry; IC and FEV1

Train subject on the proper use of ELLIPTA and DISKUS inhalers

Dispense study medication

Dispense rescue medication

Optional pharmacogentic sample can be collected at V2 or any visit after.
7.3.
Efficacy Assessments
7.3.1.
HRQoL assessments: Completion of PRO questionnaires in the 
Electronic Diary
All subjects will be completing PRO questionnaires in the eDiary. 
It is requested that questionnaires are completed before any procedures are performed on 
the subject. 
All questionnaires will be completed using the eDiary at clinic and at home.  Adequate 
time should be allowed to complete all items of the questionnaires and the questionnaires 
must be reviewed by the investigator or designated study staff for completeness and, if 
necessary, the subject must be encouraged to complete any missing items. Where more 
than one questionnaire is to be completed at a visit the order should be as follows:
1. Baseline dyspnea index (Visit 2) then Transient dyspnea index at subsequent 
visits
2. Patient global rating of COPD severity and global rating of change in COPD
3. St George’s respiratory questionnaire
4. COPD Assessment Test 
Instructions for completing the questionnaires can be found in the SRM.
7.3.1.1.
Self Administered Computerised Baseline Dyspnea Index/Transitional 
Dyspnea Index (SAC BDI/TDI)
The BDI is used to measure the severity of dyspnea in patients at baseline. The TDI 
measures changes in the patient’s dyspnea from baseline.  The self-administered 
computerized version of the BDI/TDI (SAC BDI/TDI)[Mahler, 2004] is used to measure 
severity of dyspnea in patients at baseline (SAC BDI) on Day 1 (Visit 2) of treatment and 
change from the baseline (SAC TDI) at Week 4, 12 and 24 (Visits 3, 4 and 5).  The 
 
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scores in both indexes depend on ratings for three different categories: functional 
impairment; magnitude of task, and magnitude of effort. SAC BDI/TDI should be 
completed before performing spirometry. 
The SAC BDI/TDI was developed to address issues of potential bias in the interviewer 
administered (original) BDI/TDI [Mahler, 1984].  The SAC BDI/TDI provides a 
standardized approach to the measurement of dyspnea, equivalent to the original 
BDI/TDI with advantages over the interviewer method for grading dyspnea in patients 
with COPD by standardizing the process for each patient and eliminating individual 
judgment required by the interviewers when completing the original BDI/TDI. This also 
removes the need for the same investigator to conduct all interviews with a subject based 
on the patient’s responses. SAC TDI provides a continuous measure of change in dyspnea 
using a visual analogue scale to record responses. 
Details for the completion of the SAC BDI/TDI are provided in the SRM.
7.3.1.2.
SGRQ-C
The St George’s Respiratory Questionnaire-Chronic Obstructive Pulmonary Disease 
specific (SGRQ-C) will be completed by subjects at Randomisation (V2, Day 1), at Week 
4, 12 and 24 or at the Early Withdrawal Visit (where applicable).
The SGRQ-C [Meguro, 2007] is a well established, disease-specific questionnaire.  It was 
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, 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 scores 
equivalent to the SGRQ instrument [Meguro, 2007].  
7.3.1.3.
COPD Assessment Test (CAT)
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.
The CAT will be completed in the eDiary by subjects at Screening Visit 1 and 
Randomisation Visit 2 to assess their eligibility to enter the study.  CAT is also 
completed at Weeks 4, 12 and 24.  Additional instructions for completion of the CAT are 
provided in the SRM.
 
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7.3.1.4.
EXACT and the Evaluating Respiratory Symptoms- COPD (E-RS: 
COPD)
EXACT-PRO is a 14 item patient reported outcome instrument designed to capture 
information on the occurrence, frequency, severity, and duration of exacerbations of 
disease in patients with COPD [Leidy, 2011].  EXACT captures information on the 
severity of the respiratory and systemic manifestations of a COPD exacerbation as 
reported by the patient.  The instrument is to be completed daily (typically 2 hrs before 
bedtime) using the electronic diary.  The daily recording of information allows an 
assessment of the underlying day to day variability of a patient's symptoms and facilitates 
the detection of symptom worsening indicative of a COPD exacerbation.  The total score 
for EXACT ranges from 0-100.  The entire instrument is intended to be completed in 
about 3 minutes or less (typically the time required for completion decreases as the 
patient becomes more familiar with the tool and the electronic diary).
The E-RS: COPD consists of 11 items from the 14 item EXACT instrument [Leidy, 
2014].  E-RS: COPD is intended to capture information related to the respiratory 
symptoms of COPD, i.e. breathlessness, cough, sputum production, chest congestion and 
chest tightness.  The E-RS: COPD has a scoring range of 0-40 higher scores indicate 
more severe symptoms.
Three subscales of the E-RS are used to describe different symptoms; dyspnea, cough and 
sputum and chest symptoms.
The EXACT questionnaire will be completed by subjects in the eDiary, at home every 
night throughout the entire study, starting from Screening V1 
7.3.1.5.
Subject Global Rating of COPD Severity and Global Rating of Change 
in COPD
Subjects will complete the Global Rating of COPD Severity at Randomization Visit 2 
and visits 3, 4 and 5 or Early Withdrawal Visit.  This single global question will ask 
subjects to rate their severity of COPD on a four point scale (mild, moderate, severe, and 
very severe).
This question should be used immediately before the patient completes other visit 
specific questionnaires but after completion of SAC TDI questionnaire. 
Subjects will also complete a Global Rating of Change in COPD (overall disease) 
question at Visits 3, 4 and 5 or Early Withdrawal Visit.  Response options will be on a 7 
point Likert scale ranging from much better to much worse.  Completing the question at 
each Visit allows for early detection of response as well as continued response.
7.3.2.
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 standardized spirometry equipment provided by an external vendor.
 
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All subjects will have spirometry performed at Screening to assess eligibility (see Section 
7.2.2.1) and at Visits 2, 3, 4 and 5 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 (i.e. a plateau in the volume time curve) and be free from 
artifacts due to cough, early termination, poor effort, obstructed mouthpiece, equipment 
malfunction, or other reasons [Miller, 2005].
The largest FEV1 and FVC from the 3 acceptable efforts should be recorded, even if they 
do not come from the same effort.
Spirometry for FEV1 and FVC assessments that is not obtained as follows will be 
considered a protocol deviation:

Started between 6:00AM and 11:00AM.

After withholding albuterol/salbutamol (all visits) for ≥4 hours

At Screening Visit 1, after wash out of medications as specified in the exclusion 
criteria in Section 5.2 (Concomitant Medications).

At Screening Visit 1, before the morning dose of usual COPD medications

At Visit 2 after discontinuing inhaled COPD medications and prior the first dose 
of study treatment 

At Visit 3, 4 and 5 after withholding the morning dose of study treatment.

Pre dose assessment performed prior dosing.
Subjects should refrain from smoking for 1 hour prior to each pulmonary function test.
Trough FEV1 measurements for UMC/VI or UMEC on Weeks 4, 12 and 24 (Visits 3, 4 
and 5) should be performed 23 hours and 24 hours after the previous day’s dose of study 
medication recorded in the eDiary. This will also provide trough FEV1 measurements for 
the evening dose of salmeterol. 
7.3.3.
Inspiratory capacity (IC)
Inspiratory capacity (IC) is the volume of gas that can be taken into the lungs in a normal 
and full inhalation. Starting from the resting inspiratory position it is equal to the tidal 
volume plus the inspiratory reserve volume.  IC has been widely used to assess static and 
dynamic hyperinflation in patients with COPD.
IC will be measured by spirometry prior to forced manoeuvres pre-dose at Visits 2 (30 
and 5 min prior to dosing) and at trough at Visits 3, 4, and 5 (23 and 24 hrs post dosing 
on the previous day). For IC determination the average of at least three acceptable 
manoeuvres should be recorded.  Subjects should be tested while sitting, relaxed and 
wearing a nose clip.  They should be asked to breathe regularly for several breaths until 
the end-expiratory lung volume is stable (this usually requires at least three tidal 
manoeuvres) then urged to take a deep breath to Total Lung Capacity (TLC) with no 
hesitation.
 
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Spirometry for IC determination done in conjunction with FEV1 and FVC assessments 
that is not obtained as follows will be considered a protocol deviation:

Started between 6:00AM and 11:00AM.

After withholding albuterol/salbutamol (all visits) ≥4 hours 

At Visit 2 after discontinuation of run-in medication

At Visit 3, 4 and 5 after withholding the morning dose of study drug 
7.3.4.
COPD Exacerbation
A mild exacerbation is defined as worsening of symptoms that require no treatment with 
antibiotics or steroids, and is self managed by the patient by an increase of inhaled rescue 
medications. A moderate COPD exacerbation is defined as worsening symptoms of 
COPD that require treatment with oral/systemic corticosteroids and/or antibiotics. A 
severe exacerbation is defined as worsening symptoms of COPD that require in-patient 
hospitalization or emergency room for longer than 24 hrs. 
If a subject experiences a mild, moderate or severe COPD exacerbation, the COPD 
exacerbation page of the eCRF should be completed. COPD exacerbations should not be 
recorded as an AE, unless they meet the definition of a SAE. Details of COPD 
exacerbation identification, categorization and treatment guidelines are described in 
Appendix 5.
Subjects who experience a mild exacerbation during the run-in period will not be 
withdrawn from the study. However, Subjects who experience moderate or severe 
exacerbation during the run-in period will be withdrawn from the study and will not be 
allowed to be re-screened. 
Subjects who experience a mild, moderate or severe exacerbation during the treatment 
period, will not be withdrawn from the study unless the investigator or GSK medical 
monitor think it is best for the patient to withdraw from the study.
Signs and symptoms of COPD included on the electronic diary cards will not be 
considered AEs and will not be recorded in the eCRF.
The time period for collection of COPD exacerbations will be from the Pre-Screening 
(Visit 0) until completion of the follow-up contact.  If a subject experiences a COPD 
exacerbation from the time the ICF is signed until randomization, summary information 
(yes/no status question) will be collected in the eCRF. COPD exacerbations after
randomization through follow-up will be recorded on the COPD exacerbation page of the 
eCRF.
7.3.5.
Clinically important deterioration (CID)
Clinically important deterioration (CID) is a composite endpoint defined as:

A decrease of  100 mL from baseline in trough FEV1
 
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
A deterioration in HRQoL defined as 4 units increase from baseline in 
SGRQ

The occurrence of an on-treatment moderate/severe COPD exacerbation
In addition, this study will explore CAT and TDI PROs as part of the composite 
endpoint.
7.3.6.
Rescue albuterl/salbutamol use
Subjects will record the number of daily albuterol/salbutemol puffs they use in the 
eDiary.  In addition, in some countries and selected sites the number of puffs will be 
collected through the eMDI device (Section 6.2) 
7.3.7.
Physical activity monitor (study subset)
Physical activity limitation is a common feature of COPD and its measures are highly 
related to the degree of disease severity [Watz, 2009]. 
Reduced physical activity levels in COPD is associated with increased morbidity and 
mortality, sustained disability, depression, and social and physical isolation [Shu-Yi, 
2014; Gimeno, 2014] 
Improved activity has been identified as an important factor that may modify morbidity 
and mortality in COPD [Moy, 2012].
The Actigraph GT9X physical activity monitor will be used to measure levels of activity. 
The activity monitor will be worn by up to approximately 150 subjects per treatment arm
for 7 days from Screening (Visit 1), for 7 days from Randomisation (Visit 2), 7 days from 
Visit 3 (Week 4) and for 7 days prior to Week 24 (Visit 5).
There will be 4 assessment periods, including a screening assessment in order to provide 
a reliable estimate of habitual physical activity. Each subject will be given an activity 
monitor and instruction leaflet at the start of each assessment period. Further details of 
distribution, operation and retrieval of the monitors will be provided in the SRM.
7.4.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1)
Safety endpoint includes:

Incidence of adverse events
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 4.
 
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The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
7.4.1.1.
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 7.4.1.3), at the timepoints 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 CRF.

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 12.4.4 to Section 12.4.6)
7.4.1.2.
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?
7.4.1.3.
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). 
 
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7.4.1.4.
Pneumonia Events
Investigators will be required to fill out a pneumonia event specific eCRF within one 
week of when the pneumonia AE/SAE(s) is first reported. 
7.4.1.5.
Cardiovascular and Death Events
For any cardiovascular events detailed in (Section 12.4.3) and all deaths, whether or not 
they are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF 
will be required to be completed. These sections include questions regarding 
cardiovascular (including sudden cardiac death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
7.4.1.6.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
The following disease related events (DREs) are common in subjects with COPD and can 
be serious/life threatening:

COPD exacerbation
COPD exacerbations are associated with the disease to be studied and will not be 
recorded as AEs unless the exacerbation meets the definition of a ‘serious’ AE. 
Exacerbations that meet the definition of ‘serious’ AEs will be recorded on the 
appropriate eCRF section and should be reported to GSK for all subjects regardless of 
whether or not they are randomized to study medication. Signs and symptoms of COPD 
included on the electronic diary will not be considered AEs and will not be recorded in 
the eCRF
7.4.1.7.
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.
 
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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.
7.4.2.
Pregnancy

Details of all pregnancies in female subjects will be collected after the start of 
Screening and until the follow-up contact. 

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 7.
7.4.3.
Medical Device Incidents (Including Malfunctions)
Procedures for documenting medical device incidents are provided in Appendix 6.
7.4.4.
Electrocardiogram (ECG)
A Single 12-lead ECG will be obtained at Screening using an ECG machine provided by 
the investigational site that automatically calculates the heart rate and measures PR, QRS, 
QT, and QTc intervals.
The 12-lead ECG measurement and rhythm strip (10 seconds) will be obtained before 
spirometry testing. ECG measurement should be obtained after subjects have rested for 
approximately 5 minutes then the subjects should be placed in the supine position for the 
ECG measurements.  An ECG is only required at Screening Visit 1 for eligibility 
assessment only. 
The investigator, a designated sub-investigator, or other appropriately trained site 
personnel will be responsible for performing and interpreting the 12-lead ECG at 
Screening Visit 1. The investigator must provide his/her dated signature on the original 
paper tracing, attesting to the authenticity of the ECG machine interpretation. 
7.5.
Genetics
Information regarding genetic research is included in Appendix 3
8.
DATA MANAGEMENT

For this study subject data will be entered into GSK defined CRFs, 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.
 
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
Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated 
medication dictionary, GSKDrug.  

CRFs (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 purpose of this study is to demonstrate improvements in lung function for 
subjects treated with UMEC/VI compared with UMEC for 24 weeks. 
The primary endpoint is change from baseline in trough FEV1 at Week 24.
The null hypothesis is no difference between treatment groups (H0: μT – μS = 0), with 
the alternative hypothesis that there is a difference between treatment groups (H1: μT –
μS ≠0), where μT is the mean change from baseline for UMEC/VI and μS is the mean 
change from baseline for UMEC. 
9.2.
Sample Size Considerations
The primary endpoint is change from baseline in trough FEV1 at Week 24. As an 
important aim of the study is to compare UMEC/VI, UMEC and salmeterol with respect 
to HRQoL the sample size has been calculated to provide sufficient power for the 
comparison of the primary and secondary endpoint TDI, at Week 24.  
The sample size calculations use a two-sided 5% significance level and an estimate of 
between subject standard deviation for TDI of 2.94 units.  The estimate of SD is based on 
DB2113373 [Donohue, 2013], a study which consisted of treatment arms of UMEC/VI 
62.5/25, UMEC 62.5 VI (Vilanterol) 25mcg and placebo and is the value at Day 168 in a 
subgroup of subjects who were ICS free at screening.  Based on these data, 727 evaluable 
subjects per treatment arm will be required to provide 90% power to detect a statistically 
significant difference if the true difference is 0.5 units, ½ the MCID, between UMEC/VI 
and UMEC. The smallest observed effect predicted to result in a statistically significant 
difference between treatment groups is 0.31 units.
With this number of evaluable subjects per arm, the study will have >99% power 
assuming a true treatment difference of 80mL between UMEC/VI and UMEC for trough 
FEV1 at 24 weeks at the two-sided 5% significance level. This calculation uses a SD for 
trough FEV1 of 240mL, based on prior results for trials comparing dual bronchodilators 
versus single bronchodilators (Donohue, 2013; Bateman, 2013). The smallest observed 
effect predicted to result in a statistically significant difference between treatment groups 
is 25mL. 
 
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In order to account a for a 10% withdrawal rate, approximately 808 subjects per 
treatment arm will be randomised.
9.2.1.
Sample Size Assumptions
9.2.2.
Sample Size Sensitivity
The assumption of a SD of 2.94 units for the TDI total score is based on estimates from 
previous studies. The following table presents the power achieved with the proposed 
sample size of 727 randomised subjects per arm, should the assumption around the SD of 
the data change. 
The actual assumptions used in the sample size calculation are shaded.
Endpoint 
Between 
subject SD
Treatment Difference
Power
TDI
2.54
0.5
96%
2.74
0.5
94%
2.94
0.5
90%
3.14
0.5
86%
3.34
0.5
81%
9.2.3.
Sample Size Re-estimation or Adjustment
No sample size re-estimation is planned for this study. 
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 
 
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Population
Definition / Criteria
Analyses Evaluated
subjects
Intent-to-
treat (ITT)

All randomized subjects, excluding those who 
were randomized in error and received at least 
one dose of study medication. 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.

Displays will be based on the treatment to 
which the subject was randomized.

Study Population

Efficacy

Safety
Intent-to-
treat ICS 
free (ITT 
ICS free)

All subjects in the ITT Population who have 
not received ICS.

Study Population

Efficacy

Safety
9.3.2.
Interim Analysis
No interim analysis is planned for the study.
9.4.
Key Elements of Analysis Plan
Treatment Comparisons
The primary treatment comparison of UMEC/VI with UMEC will be performed on the 
ITT population.
The other treatment comparisons of UMEC/VI and UMEC with Salmeterol will be 
performed on the ITT population and ITT ICS free population.
9.4.1.
Primary Analyses
The treatment comparison of primary interest will be UMEC/VI versus UMEC for the 
primary endpoint of change from baseline in trough FEV1 at Week 24. The primary 
analyses will be performed using a mixed model repeated measures (MMRM) analysis 
and will be based on a two-sided hypothesis testing approach on the ITT Population. 
In order to account for multiplicity across treatment comparisons and endpoints, a step-
down closed testing procedure will be applied whereby inference for secondary and other 
endpoints or treatment comparisons are dependent upon statistical significance having 
been achieved for the primary comparison. If the primary comparison is significant i.e. 
the associated p-value for UMEC/VI versus UMEC for change from baseline in trough 
FEV1 at Week 24 is below 0.05, this will allow inference of treatment comparisons 
(UMEC/VI versus UMEC on all other endpoints, and UMEC/VI versus Salmeterol and 
UMEC versus Salmeterol on all endpoints including the primary endpoint), which will be 
declared statistically significant if the associated p-value is below 0.05.  
 
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There will be 2 analyses one for one for the German Federal Joint Committee (G-BA) 
and one for the rest of the world (ROW).
The step-down closed testing procedure only applies to the ROW.  For the G-BA 
statistical inference for secondary and other endpoints or treatment comparisons will not 
be conditional on achieving statistical significance of the primary comparison.  
The primary endpoint of mean change from baseline in trough FEV1 at the end of Week 
24 and secondary endpoint change from baseline in TDI score at Week 24 will both be 
analysed using MMRM analysis. The MMRM analysis for change from baseline in 
trough FEV1 and TDI will include measurements at Treatment Weeks 4, 12 and 24. 
Treatment group (a categorical variable) will be fitted as the explanatory variable with 
appropriate pre-defined variables, stratum (number of bronchodilators per day during 
run-in) and baseline values, fitted as covariates. Visit (nominal) will be fitted as a 
categorical variable and visit-by-baseline and visit-by-treatment interaction terms will be 
included to allow treatment effects to be estimated at each visit separately. The variance 
covariance matrix will be assumed to be unstructured (based on previous experience no 
issues are expected with fitting models with this matrix structure). 
While missing data are not explicitly imputed in the primary MMRM analyses, there is 
an underlying assumption that the data are missing at random. 
The estimated treatment differences between UMEC/VI versus UMEC for each endpoint 
will be presented with the 95% confidence intervals for the difference and the p-value. 
Full details of the analyses to be performed on all primary endpoints will be given in the 
RAP.
9.4.2.
Other Analyses
The MMRM analysis will be repeated for the ITT ICS free population. Estimated 
differences between UMEC/VI or UMEC and Salmeterol will be presented together with 
95% confidence intervals (CIs) for the difference and p-values.
Secondary and other efficacy endpoints and treatment comparisons will be adjusted for 
multiplicity as per Section 9.4.1.
Full details of the analyses to be performed on the other efficacy endpoints will be given 
in the RAP.
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. 
 
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Deaths and SAEs will be documented in case narrative format. 
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 eCRF
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.  

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 
 
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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 randomization 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.
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James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
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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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spirometry.  Eur Respir J.  2005;26: 319-338.
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umeclidinium added to fluticasone furoate/vilanterol in chronic obstructive pulmonary 
disease: Results of two randomized studies.  Respir Med. 2015; 109:1155-63
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clinically important deteriorations in COPD with umeclidinium/vilanterol. Int’l J of 
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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
CAT
COPD Assessment Test
CI
Confidence Intervals
CID
Clinically important deterioration 
COPD
Chronic Obstructive Pulmonary Disease
CPK
Creatine phosphokinase
CRF
Case Report Form
CV
Cardiovascular
DPI
Dry Powder Inhaler
DRE
Disease Related Event
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eDiary
Electronic Diary
eMDI
Electronic Metered Dose Inhaler
E-RS
Evaluating Respiratory Symptoms- COPD  Tool
ERS
European Respiratory Society
FEV₁
Forced Expiratory Volume in One Second
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GOLD
Global Initiative for Chronic Obstructive Lung Disease
GSK
GlaxoSmithKline
IB
Investigator Brochure
ICF
Informed Consent Form
ICS
Inhaled Corticosteroid
IEC
Independent Ethics Committee
IP
Investigational product
INR
International normalized ratio
IRT
Interactive Response Technology
ITT
Intent-to-Treat
IUD
Intrauterine Device
IUS
Intrauterine System
LABA
Long Acting Beta-Agonist
LAMA
Long-acting Muscarinic Receptor Antagonists
LDH
Lactate dehydrogenase
LTOT
Long Term Oxygen Therapy
 
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mcg
Microgram
MCID
Minimal Clinically Important Difference
MDI
Metered Dose Inhaler
mL
Milliliter
mMRC
Modified Medical Research Council
MMRM
Mixed Models Repeated Measures
MSDS
Material Safety Data Sheet
NYHA
New York Heart Association
OTC
Over the Counter
PGx
Pharmacogenetic
PIL
Patient Information Leaflet
PK
Pharmacokinetic
PP
Per Protocol
prn
As required
QTc
QT interval corrected for heart rate
RAP
Reporting and Analysis Plan
SABA
Short Acting Beta-Agonist
SAE
Serious Adverse Event
SD
Standard Deviation
SmPC
Summary of Product Characteristics
SRT
Safety Review Team
TDI
Transition Dyspnea Index
RAMOS NG
Randomization and medication ordering system new 
generation
ULN
Upper Limit of Normal
UMEC
Umeclidinium (GSK573719)
UMEC/VI
Umeclidinium & Vilanterol as a fixed dose combination
VI
Vilanterol Trifenate 
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
ANORO
E-RS
DISKUS
EXCACT
ELLIPTA
INCRUSE
SEREVENT
 
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12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments
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 normal 
ranges. baseline (see MONITORING below)

Do not restart/rechallenge subject with 
study treatment. Permanently discontinue 
study treatment and may continue subject 
in the study for any protocol specified follow 
up assessments

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 a week after last 
dose6

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
 
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Liver Chemistry Stopping Criteria - Liver Stopping Event
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 normal ranges.

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 normal ranges.
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
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 
 
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approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.  
 
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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 etiology 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 any concomitant medicines;

COPD susceptibility, severity, and progression of 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.
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.
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.  
 
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
A 6 ml blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. 
A blood sample is collected at the baseline visit, after the subject has been 
randomized and 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 being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA 
sample is retained

Discontinue participation in the genetic research and destroy the genetic DNA 
sample 
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. 
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis. 
 
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
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.
 
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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., hospitalization 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 hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization 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 hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
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 hospitalization 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 hospitalization, 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 
and not interfering with everyday activities.
 
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
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 
or investigations, histopathological examinations or consultation with other health 
 
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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

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 by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
 
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12.5.
Appendix 5: COPD Exacerbation Identification, 
Categorization and Treatment Guidelines
12.5.1.
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 usage in their 
daily eDiary 

If the subject seeks emergency/acute care for worsening respiratory symptoms, 
he/she should request the caring Health Care Provider (HCP) to contact the 
Investigator as soon as possible.
Subjects with worsening respiratory symptoms will be classified as having:

A mild/moderate/severe exacerbation and/or pneumonia
OR

A Lower Respiratory Tract Infection (LRTI)
 
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
Background variability of COPD

A non-respiratory related disease

Other respiratory related disease
12.5.2.
COPD Exacerbation Severity
Each COPD exacerbation will be categorized based on severity as follows:
Moderate:  Worsening symptoms of COPD that require treatment with 
oral/systemic corticosteroids and/or antibiotics.
Severe: Worsening symptoms of COPD that require treatment with in-patient 
hospitalization or 24 hrs in the emergency room.
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.
12.5.3.
Treatment of COPD Exacerbations
All medications used for the treatment of exacerbations must be recorded in the source 
documents and the exacerbation page of the eCRF.  All sites should follow the protocol 
treatment guidelines (as outlined below), but any medications deemed medically 
necessary may be used to treat a COPD exacerbation. However, caution is advised in 
using a LABA or LAMA to treat a subject currently taking IP as these additional 
medications may increase the risk of overdose. If necessary the PI or other health care 
personnel may stop the subject’s IP temporarily in order to treat the COPD exacerbation.
12.5.4.
Guidelines for Treatment with Corticosteroids
If in the opinion of the Investigator/treating physician the exacerbation is severe enough 
to warrant the need for oral or systemic corticosteroids (with or without antibiotics) the 
following guidelines should be used.

The duration of treatment with oral/systemic corticosteroids should be 14 days 
(dose and type according to local practice) 

The duration of treatment with oral/systemic corticosteroids should not exceed 14 
days unless approval is given by the sponsor or representative

Any course of oral/systemic corticosteroids started within 7 days of finishing a 
previous course will be considered as treatment for a single exacerbation
 
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12.5.5.
Guidelines for Treatment with Antibiotics
If there is evidence of respiratory infection that in the opinion of the Investigator or 
treating physician warrants the need for antibiotics the following guidelines should be 
followed:

The duration of treatment with antibiotics should not exceed 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 
12.5.6.
Onset and Resolution of COPD Exacerbations
For each mild, moderate and severe exacerbation, the date of onset and the date of 
resolution will be recorded in the study source documents and eCRF.
The date of onset is the first day (of at least 2 consecutive days) of worsening symptoms 
of COPD as described in Section 12.5.1.
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.
12.5.7.
Guideline for assessing multiple mild exacerbations
Two mild exacerbations can be combined into one, per the Investigator’s judgement, if a 
subject’s diary reveals that the two mild COPD exacerbations are separated by no more 
than three exacerbation free days.
12.5.8.
Guideline for assessing exacerbations that increase in severity
If an exacerbation starts off as mild, but becomes moderate or severe or starts off as 
moderate and becomes severe, the exacerbation should be captured as one exacerbation 
and classified by its highest level of severity.
 
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12.6.
Appendix 6: Definition of and Procedures for Documenting 
Medical Device Incidents
12.6.1.
Definitions of a Medical Device Incident
The detection and documentation procedures described in this protocol apply to all GSK 
medical devices provided for use in the study (see Section 6.2 for the list of GSK medical 
devices).
Medical Device Incident Definition:

Incident – Any malfunction or deterioration in the characteristics and/or performance 
of a device, as well as any inadequacy in the labeling or the instructions for use 
which, directly or indirectly, might lead to or might have led to the death of a 
patient/user/other persons or to a serious deterioration in their state of health.

Not all incidents lead to death or serious deterioration in health.  The non-occurrence 
of such a result might have been due to other fortunate circumstances or to the 
intervention of health care personnel.
It is sufficient that:

an incident associated with a device happened and

the incident was such that, if it occurred again, might lead to death or a serious 
deterioration in health.

A serious deterioration in state of health can include:

life-threatening illness

permanent impairment of body function or permanent damage to a body structure

a condition necessitating medical or surgical intervention to prevent one of the 
above 

fetal distress, fetal death or any congenital abnormality or birth defects
Examples of incidents

a patient, user, care giver or professional is injured as a result of a medical device 
failure or its misuse

a patient’s treatment is interrupted or compromised by a medical device failure

misdiagnosis due to medical device failure leads to inappropriate treatment

a patient’s health deteriorates due to medical device failure
 
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12.6.2.
Documenting Medical Device Incidents
Medical Device Incident Documenting:

Any medical device incident occurring during the study will be documented in the 
subject’s medical records, in accordance with the investigator’s normal clinical 
practice, and on the appropriate form.

For incidents fulfilling the definition of an AE or an SAE, the appropriate AE/SAE 
CRF page will be completed as described in Appendix 4.

The form will be completed as thoroughly as possible and signed by the investigator 
before transmittal to GSK.

It is very important that the investigator provides his/her assessment of causality to 
the medical device provided by GSK at the time of the initial report, and describes 
any corrective or remedial actions taken to prevent recurrence of the incident.

A remedial action is any action other than routine maintenance or servicing of a 
device where such action is necessary to prevent recurrence of an incident. This 
includes any amendment to the design to prevent recurrence.
 
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12.7.
Appendix 7: Modified List of Highly Effective Methods for 
Avoiding Pregnancy in FRP and Collection of Pregnancy 
Information
12.7.1.
Modified List of Highly Effective Methods for Avoiding Pregnancy 
in Females of Reproductive Potential (FRP)
The list does not apply to FRP with same sex partners or for subjects who are and will 
continue to be abstinent from penile-vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyle. Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.
1.
Contraceptive subdermal implant
2.
Intrauterine device or intrauterine system
3.
Combined estrogen and progestogen oral contraceptive [Hatcher, 2011]
4.
Injectable progestogen [Hatcher, 2011]
5.
Contraceptive vaginal ring [Hatcher, 2011]
6.
Percutaneous contraceptive patches [Hatcher, 2011]
7.
Male partner sterilization 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, 2011]. The documentation on male sterility can come from the site 
personnel’s: review of subject’s medical records, medical examination and/or semen 
analysis, or medical history interview provided by her or her partner.
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
12.7.2.
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 fetal status (presence or 
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.
 
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
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. 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

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12.8.
Appendix 8: Country Specific Requirements
No country-specific requirements exist.
 
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12.9.
Appendix 9: protocol changes
Scope:
This amendment applies to all sites
Protocol Changes for Amendment No.1 are summarised below.
Strike through text refers to deleted text and underlined refers to added text.
Protocol Changes:
Title
Rationale for change:  Correct a typographical error in the title: Umeclidimium to 
Umeclidinium
Regulatory Agency Identifying Number(s):  
Rationale for change:  To correct a typographical error of the EudraCT no. and add an 
IND no.
Revised text: EudraCT no 2016-002513-226, 2016-002513-22 , IND no. 104479
 
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Section 1
Overall Design
Rationale for change: To Correct a typographical error in the last paragraph.
Revised text: Salmeterol, salbutamol
“This is a multi-centre, randomized, double blind, double-dummy, 3-arm parallel group 
study.  Eligible subjects will be stratified based on long-acting bronchodilator usage 
during the run-in (none, one or 2 long-acting bronchodilators per day) and randomized in 
a ratio of 1:1:1 to UMEC/VI inhalation powder (62.5/25 mcg once daily) administered 
via the ELLIPTA inhaler, or UMEC (62.5 mcg once daily) administered via the 
ELLIPTA or salmeterol (50 mcg BID) administered via the DISKUS. 
There will be a total of 5 clinic visits and one follow-up phone call (Visit 6). The Pre-
screening Visit (Visit 0) can occur on the same day as the Screening Visit (Visit 1) if 
subject does not take or has not taken any excluded protocol medications, but must be 
completed prior to initiating any Visit 1 procedures. 
Subjects, who meet all the eligibility criteria at Screening, will enter a run-in period for 4 
weeks in order to continue to assess the subject’s eligibility for the study. During the run-
in period subjects will continue with their inhaled COPD medications (excluding ICS and 
any exclusionary medications).  In addition, subjects will be provided with short acting 
albuterol/salmeterol salbutamol to be used on as needed basis for relief of COPD 
symptoms (rescue medication) throughout the study”. 
Section 4.4 Design justification: To be consistent with Section 7.3.1.5 and Section 7.1 
the wording has been updated.
Rationale for change: Ensure consistency with Section 7.3.1.5 and Section 7.1 the 
wording has been changed in paragraph 5.
Revised text: “Other endpoints such SAC TDI, E-RS, SGRQ-C, CAT, Subject Global 
Rating of COPD Severity and Change in Global Rating impression of Change in COPD  
disease severity are captured to allow responder analyses and to provide comparative data 
on PROs between the treatment groups”. 
Section 7.1 Time and Event table
Rationale for change; to:
Correct an un-intentional deletion of the (“x”) in some cells and confirm that concomitant 
medications should be reviewed at every clinic visit.
Increase the visit window from 2 days to -7/+2
Ensure consistency of wording between Section 7.2 and table 7.1. “Written” was deleted
Include height and weight at Screening and correct errors in foot note no.11
“In order to ensure subjects have sufficient doses of study treatment, they must return to 
clinic within 30 days from V2 and within 60 and 90 days from V3 and V4 respectively”
 
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Blinded Treatment
Visit
Pre-
screen1
0
Screen/ 
Run-in
1
Rando-
mization 
2
3
4
5
EW 
Visit 2
Telephone Follow up 
contact 
6
Week
-6 to -4
-4
0
4
12
24
Day
42 2
-7/+2 
days 
prior 
Visit 1
28 2
-7/+2 days 
prior Visit 
2
12 -7/+2 
days
28 2 -7/+2 
days 
84 2 
days
168 2 -7/+2 
days
72 3 days after V5 
or EW Visit
Screen/Baseline
Written Informed consent
X
Demography
X
Medical/COPD history
X
Smoking history/status
X
Smoking cessation counselling
X
Concomitant medication assessment
X
X
X
X
X
X
X
X
Height and weight
X
Cardiovascular History/family history of premature CV 
disease])
X
Screening spirometry (including post bronchodilator 
testing)3
X
CAT questionnaire
X
X
Verify Inclusion/Exclusion Criteria
X
Training on use of inhalers
X
X
Training on use of eDiary and eMDI
X
X
Verify randomization Criteria
X
Register Visit in InForm
X
X
X
X
X
X
X
X
Register Visit in RAMOS NG
X
X
X
X
X
X
X
X
 
 
 
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Blinded Treatment
Visit
Pre-
screen1
0
Screen/ 
Run-in
1
Rando-
mization 
2
3
4
5
EW 
Visit 2
Telephone Follow up 
contact 
6
Week
-6 to -4
-4
0
4
12
24
Day
42 2
-7/+2 
days 
prior 
Visit 1
28 2
-7/+2 days 
prior Visit 
2
12 -7/+2 
days
28 2 -7/+2 
days 
84 2 
days
168 2 -7/+2 
days
72 3 days after V5 
or EW Visit
Efficacy/HRQoL assessments
Spirometry, including pre-dose FEV1, trough  FEV1 and 
inspiratory capacity
X
X
X
X
SAC BDI questionnaire 4
X
SAC TDI questionnaire 4
X
X
X
SGRQ-C questionnaire 4
X
X
X
X
CAT questionnaire 4
X
X
X
X
X
EXACT/ER-S: COPD 5
Patient Global Rating of COPD severity
X
X
X
X
Patient Global Rating of Change in COPD
X
X
X
Safety assessments
Adverse events/Serious adverse events 6
X
X
X
X
X
X
X
X
COPD exacerbation assessment
X
X
X
X
X
X
X
X
12-Lead ECG
X
Urine pregnancy test 7
X
X
X
X
Pharmacogenetic sample8
                                           X
Medication/Supplies
Dispense rescue albuterol/slabutamol. Dispense MDI9
X
X
X
X
X
Assess COPD medication compliance10 during run-in
X
Dispense eDiary
X
Assess compliance with eDiary during run-in 
X
Collect rescue albuterol/slabutamol. 
X
X
X
X
X
Collect eDiary
X
X
Dispense study treatment11
X
X
X
 
 
 
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Blinded Treatment
Visit
Pre-
screen1
0
Screen/ 
Run-in
1
Rando-
mization 
2
3
4
5
EW 
Visit 2
Telephone Follow up 
contact 
6
Week
-6 to -4
-4
0
4
12
24
Day
42 2
-7/+2 
days 
prior 
Visit 1
28 2
-7/+2 days 
prior Visit 
2
12 -7/+2 
days
28 2 -7/+2 
days 
84 2 
days
168 2 -7/+2 
days
72 3 days after V5 
or EW Visit
Collect study treatment
X
X
X
X
Assess study treatment compliance during treatment10
X
X
X
X
Study sub-set
Physical activity monitor12
X
X
X
X
Collect Physical activity monitor
X
X
1.
Pre-screen Visit 0 must be completed prior to Screening Visit1. It can be completed 2 weeks prior or on the same day of V1, if no wash out of exclusionary medications is 
required. 
2.
Early Withdrawal Visit: Subjects that withdraw should return to the clinic as soon as possible to complete the Early Withdrawal Visit procedures.
3.
Spirometry at screening should be performed as described in (Section 7.2.2.1). 
4.
SAC BDI, SAC TDI, SGRQ-C, CAT questionnaires will be completed at clinic visits and in the eDiary
5.
EXACT/ER-S: COPD is completed daily in the eDiary approximately 2 hours before bed-time, starting on Day 1 of the run-in period.
6.
For the start date of collecting AEs and SAEs see (Appendix 4)
7.
Pregnancy test: for females for child bearing potential only.
8.
Pharmacogenetic sample may be drawn at visit 2 or any visit after.
9.
Rescue medication use to be recorded in the eDiary daily and in some sites in the eDiary and the eMDI
10. Sites are requested to call subjects every 2 weeks to remind them to take study treatment regularly and to record the time of the morning and evening dose in the eDiary.
11. In order to ensure subjects have sufficient doses of study treatment, they must return to clinic within 30 days from V2 and within 60 and 90 days from V3 and V4 respectively.
12. The Actigraph GT9X should be worn for 7 days from Visit 1, for 7 days from Visit 2, for 7 days from Visit 3 and for 7 days prior to Visit 5.
 
 
 
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Section 7.2.2 Critical procedures performed at Screening (Visit 1)
Rationale for change:  To clarify that height and weight are collected at V1
Revised text: “Height and weight”
Section 7.3.2 Spirometry
Rationale for change:  To further clarify that spirometry at Screening Visit 1 should be 
performed before subject inhales their usual morning COPD medication(s) a bullet point 
was added. “At Screening Visit 1, before the morning dose of usual COPD medications”
Revised text:
“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 standardized spirometry equipment provided by an external vendor.
All subjects will have spirometry performed at Screening to assess eligibility (see Section 
7.2.2.1) and at Visits 2, 3, 4 and 5 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 (i.e. a plateau in the volume time curve) and be free from 
artifacts due to cough, early termination, poor effort, obstructed mouthpiece, equipment 
malfunction, or other reasons [Miller, 2005].
The largest FEV1 and FVC from the 3 acceptable efforts should be recorded, even if they 
do not come from the same effort.
Spirometry for FEV1 and FVC assessments that is not obtained as follows will be 
considered a protocol deviation:

Started between 6:00AM and 11:00AM.

After withholding albuterol/salbutamol (all visits) for ≥4 hours

At Screening Visit 1, after wash out of medications as specified in the exclusion 
criteria in Section 5.2 (Concomitant Medications).

At Screening Visit 1, before the morning dose of usual COPD medications

At Visit 2 after discontinuing inhaled COPD medications and prior the first dose 
of study treatment 

At Visit 3, 4 and 5 after withholding the morning dose of study treatment.

Pre dose assessment performed prior dosing.
Subjects should refrain from smoking for 1 hour prior to each pulmonary function test.
Trough FEV1 measurements for UMC/VI or UMEC on Weeks 4, 12 and 24 (Visits 3, 4 
and 5) should be performed 23 hours and 24 hours after the previous day’s dose of study 
 
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medication recorded in the eDiary. This will also provide trough FEV1 measurements for 
the evening dose of salmeterol”. 
7.3.7
Physical activity monitor (study subset)
Rationale for changes: Ensure consistency of the wording between Section 1 and 
Section 4.1 “overall design” and Section 7.3.7.
per treatment arm added to paragraph 4.
Revised Text: 
Physical activity monitor (study subset)
“Physical activity limitation is a common feature of COPD and its measures are highly 
related to the degree of disease severity [Watz, 2009]. 
Reduced physical activity levels in COPD is associated with increased morbidity and 
mortality, sustained disability, depression, and social and physical isolation [Shu-Yi, 
2014; Gimeno, 2014] 
Improved activity has been identified as an important factor that may modify morbidity 
and mortality in COPD [Moy, 2012].
The Actigraph GT9X physical activity monitor will be used to measure levels of activity. 
The activity monitor will be worn by up to approximately 150 subjects per treatment arm 
for 7 days from Screening (Visit 1), for 7 days from Randomisation (Visit 2), 7 days from 
Visit 3 (Week 4) and for 7 days prior to Week 24 (Visit 5).
There will be 4 assessment periods, including a screening assessment in order to provide 
a reliable estimate of habitual physical activity. Each subject will be given an activity 
monitor and instruction leaflet at the start of each assessment period. Further details of 
distribution, operation and retrieval of the monitors will be provided in the SRM”.
 
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TITLE PAGE
Division:  Worldwide Development
Information Type: Clinical Protocol
Title:
A 24-week treatment, multi-center, randomized, double-blind, 
double-dummy, parallel group study to compare 
Umeclidinium/Vilanterol, Umeclidimium, and Salmeterol in 
subjects with chronic obstructive pulmonary disease (COPD)
Compound Number:
GSK2592356
Development Phase
IV
Effective Date:
13-SEP-2016
Author(s):
 
 
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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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
Fax 
Number
Site Address
Primary 
Medical 
Monitor 
Telephone:
Cell:
Fax:
GlaxoSmithKline
Stockley Park 
West, 1-3 
Ironbridge Road, 
Heathrow, 
Uxbridge, 
Middlesex, UB11 
1BT, United 
Kingdom
Secondary 
Medical 
Monitor
MD
Telphone:
Cell:  
Fax:  
GlaxoSmithKline
Stockley Park 
West, 1-3 
Ironbridge Road, 
Heathrow, 
Uxbridge, 
Middlesex, UB11 
1BT, United 
Kingdom
SAE 
contact  
information 
Telephone: 
Cell: 
Fax:
GlaxoSmithKline
Stockley Park 
West, 1-3 
Ironbridge Road, 
Heathrow, 
Uxbridge, 
Middlesex, UB11 
1BT, United 
Kingdom
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 
 
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person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.   
Regulatory Agency Identifying Number(s): IND no. 106616 and EudraCT no. 2016-
002513-226
 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE

I confirm agreement to conduct the study in compliance with the protocol.

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
 
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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 201749........................................................9
2.
INTRODUCTION....................................................................................................15
2.1.
Study Rationale ..........................................................................................15
2.2.
Brief Background ........................................................................................15
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................16
4.
STUDY DESIGN ....................................................................................................18
4.1.
Overall Design ............................................................................................18
4.2.
Treatment Arms and Duration.....................................................................20
4.3.
Type and Number of Subjects.....................................................................21
4.4.
Design Justification.....................................................................................21
4.5.
Dose Justification........................................................................................21
4.6.
Benefit: Risk Assessment ...........................................................................21
4.6.1.
Risk Assessment .........................................................................22
4.6.2.
Benefit Assessment.....................................................................25
4.6.3.
Overall Benefit: Risk Conclusion..................................................25
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............25
5.1.
Inclusion Criteria.........................................................................................25
5.2.
Exclusion Criteria........................................................................................27
5.3.
Randomization Criteria ...............................................................................30
5.4.
Screening/Baseline/Run-in Failures............................................................30
5.5.
Withdrawal/Stopping Criteria.......................................................................31
5.5.1.
Withdrawal from the Study...........................................................31
5.5.2.
Reason for Study Withdrawal.......................................................32
5.5.3.
Liver Chemistry Stopping Criteria ................................................32
5.5.3.1.
Study Treatment Restart or Rechallenge....................33
5.6.
Follow-up contact........................................................................................33
5.7.
Subject and Study Completion....................................................................34
6.
STUDY TREATMENT ............................................................................................34
6.1.
Investigational Product and Other Study Treatment....................................34
6.2.
Medical Devices..........................................................................................36
6.3.
Treatment Assignment................................................................................36
6.4.
Planned Dose Adjustments.........................................................................37
6.5.
Blinding.......................................................................................................37
6.6.
Packaging and Labeling..............................................................................38
6.7.
Preparation/Handling/Storage/Accountability..............................................38
6.7.1.
Study Treatment Return...............................................................39
6.8.
Compliance with Study Treatment Administration.......................................39
6.9.
Treatment of Study Treatment Overdose....................................................39
6.10.
Treatment after the End of the Study ..........................................................40
6.11.
Concomitant Medications and Non-Drug Therapies....................................40
6.11.1.
Permitted Medications and Non-Drug Therapies..........................40
6.11.2.
Prohibited Medications and Non-Drug Therapies.........................41
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................42
 
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7.1.
Time and Events Table...............................................................................43
7.2.
Screening and Critical Baseline Assessments ............................................46
7.2.1.
Pre-screening Visit.......................................................................46
7.2.2.
Critical procedures performed at Screening (Visit 1)....................46
7.2.2.1.
Albuterol/Salbutamol Reversibility Assessment ..........47
7.2.3.
Critical procedures performed at first treatment Visit 
(Baseline V2)...............................................................................47
7.3.
Efficacy Assessments.................................................................................48
7.3.1.
HRQoL assessments: Completion of PRO questionnaires 
in the Electronic Diary..................................................................48
7.3.1.1.
Self Administered Computerised Baseline 
Dyspnea Index/Transitional Dyspnea Index 
(SAC BDI/TDI)............................................................48
7.3.1.2.
SGRQ-C.....................................................................49
7.3.1.3.
COPD Assessment Test (CAT) ..................................49
7.3.1.4.
EXACT and the Evaluating Respiratory 
Symptoms- COPD (E-RS: COPD)..............................49
7.3.1.5.
Subject Global Rating of COPD Severity and 
Global Rating of Change in COPD .............................50
7.3.2.
Spirometry ...................................................................................50
7.3.3.
Inspiratory capacity (IC)...............................................................51
7.3.4.
COPD Exacerbation ....................................................................52
7.3.5.
Clinically important deterioration (CID).........................................52
7.3.6.
Rescue albuterl/salbutamol use...................................................53
7.3.7.
Physical activity monitor (study subset) .......................................53
7.4.
Safety .........................................................................................................53
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........53
7.4.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................53
7.4.1.2.
Method of Detecting AEs and SAEs ...........................54
7.4.1.3.
Follow-up of AEs and SAEs........................................54
7.4.1.4.
Pneumonia Events .....................................................54
7.4.1.5.
Cardiovascular and Death Events ..............................55
7.4.1.6.
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ................55
7.4.1.7.
Regulatory Reporting Requirements for SAEs............55
7.4.2.
Pregnancy ...................................................................................56
7.4.3.
Medical Device Incidents (Including Malfunctions).......................56
7.4.4.
Electrocardiogram (ECG).............................................................56
7.5.
Genetics .....................................................................................................56
8.
DATA MANAGEMENT ...........................................................................................56
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................57
9.1.
Hypotheses.................................................................................................57
9.2.
Sample Size Considerations.......................................................................57
9.2.1.
Sample Size Assumptions ...........................................................58
9.2.2.
Sample Size Sensitivity................................................................58
9.2.3.
Sample Size Re-estimation or Adjustment...................................58
9.3.
Data Analysis Considerations .....................................................................58
9.3.1.
Analysis Populations....................................................................58
9.3.2.
Interim Analysis ...........................................................................59
 
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9.4.
Key Elements of Analysis Plan ...................................................................59
9.4.1.
Primary Analyses.........................................................................59
9.4.2.
Other Analyses ............................................................................60
10. STUDY GOVERNANCE CONSIDERATIONS........................................................61
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............61
10.2.
Regulatory and Ethical Considerations, Including the Informed
Consent Process ........................................................................................61
10.3.
Quality Control (Study Monitoring) ..............................................................62
10.4.
Quality Assurance.......................................................................................62
10.5.
Study and Site Closure ...............................................................................62
10.6.
Records Retention......................................................................................63
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................64
11. REFERENCES.......................................................................................................65
12. APPENDICES........................................................................................................68
12.1.
Appendix 1: Abbreviations and Trademarks................................................68
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................70
12.3.
Appendix 3: Genetic Research ...................................................................73
12.4.
Appendix 4: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................76
12.4.1.
Definition of Adverse Events........................................................76
12.4.2.
Definition of Serious Adverse Events...........................................77
12.4.3.
Definition of Cardiovascular Events .............................................78
12.4.4.
Recording of AEs and SAEs ........................................................79
12.4.5.
Evaluating AEs and SAEs............................................................79
12.4.6.
Reporting of SAEs to GSK...........................................................81
12.5.
Appendix 5: COPD Exacerbation Identification, Categorization and 
Treatment Guidelines..................................................................................82
12.5.1.
Guidelines for Identifying COPD Exacerbations...........................82
12.5.2.
COPD Exacerbation Severity.......................................................83
12.5.3.
Treatment of COPD Exacerbations..............................................83
12.5.4.
Guidelines for Treatment with Corticosteroids..............................83
12.5.5.
Guidelines for Treatment with Antibiotics .....................................84
12.5.6.
Onset and Resolution of COPD Exacerbations............................84
12.5.7.
Guideline for assessing multiple mild exacerbations ....................84
12.5.8.
Guideline for assessing exacerbations that increase in 
severity ........................................................................................84
12.6.
Appendix 6: Definition of and Procedures for Documenting Medical 
Device Incidents .........................................................................................85
12.6.1.
Definitions of a Medical Device Incident.......................................85
12.6.2.
Documenting Medical Device Incidents .......................................86
12.7.
Appendix 7: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in FRP and Collection of Pregnancy Information.......................87
12.7.1.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) ..............87
12.7.2.
Collection of Pregnancy Information ............................................87
12.8.
Appendix 8: Country Specific Requirements...............................................89
 
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1.
PROTOCOL SYNOPSIS FOR STUDY 201749
Rationale
The primary purpose of this study is to demonstrate improvements in lung function in 
subjects treated with Umeclidinium/Vilanterol (UMEC/VI) compared with Umeclidinium 
(UMEC) for 24 weeks.  A further important aspect of the study is to evaluate the effect of
UMC/VI, UMEC, and salmeterol with respect to health-related quality of life (HRQoL),
measured through patient reported outcomes (PROs) questionnaires, and lung function.  
Additional assessments to further evaluate other measures of chronic obstructive 
pulmonary disease (COPD) efficacy and symptoms control will be performed.
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary

To compare the effect of UMEC/VI 
(62.5/25 mcg once daily) with UMEC 
(62.5 mcg once daily) on lung function

Change from baseline in trough Forced 
Expiratory Volume in One Second 
(FEV1) at week 24 
Secondary

To compare UMEC/VI (62.5/25 mcg 
once daily), UMEC (62.5 mcg once 
daily) with salmeterol (50 mcg twice 
daily) on patient reported outcomes 
(PROs) 

Change from baseline in self 
administered computerised (SAC) 
transient dyspnea index (TDI) 

Percentage of TDI responders 
according to SAC TDI score.  A 
responder is defined as a ≥1 unit 
improvement in SAC TDI score 

Assessment of respiratory daily 
symptoms over 24 weeks using 
Evaluating Respiratory Symptoms-
COPD (E-RS) and its subscales 
(breathlessness, cough and sputum and 
chest symptoms) 

Percentage of E-RS responders 
according to E-RS score (defined as 
reduction in E-RS score of 2 or 3.35 
units) from baseline

Change from baseline in St George’s 
Respiratory Questionnaire (SGRQ-C)

Percentage of responders according to 
SGRQ-C total score (defined as a 4 
point or greater reduction from 
 
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Objectives
Endpoints
baseline) 

Change from baseline in COPD 
assessment test (CAT)

Percentage of responders according to 
CAT (defined as a 2 unit improvement 
in score from baseline)
Other

To compare UMEC/VI (62.5/25 mcg 
once daily), UMEC (62.5 mcg once 
daily) with salmeterol (50 mcg twice 
daily) on other COPD efficacy measures 

Rate of mild, moderate or severe 
exacerbations

Time to first mild, moderate or severe 
exacerbation

Rate of moderate or severe 
exacerbation

Time to moderate or severe 
exacerbation

Time to severe exacerbations

Time to clinically important 
deterioration (CID) composite endpoint 

Time to clinically important 
deterioration composite endpoint 
excluding FEV1

Rescue albuterol/salbutamol use, 
(percentage of rescue-free days and 
mean number of Inhalations/day) 
captured by the electronic diary 
(eDiary) over 24 weeks

Inspiratory capacity (IC)

Full Vital capacity (FVC) 

Change from baseline in trough FEV1

Change from baseline in global 
impression of disease severity 
 
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Objectives
Endpoints
Safety

To evaluate safety and tolerability 
of UMEC/VI (62.5/25 mcg once 
daily), UMEC (62.5mcg once daily)
and salmeterol 50mcg twice daily)

Incidence of adverse events
Exploratory

To compare albuterol/salbutamol 
use captured in the eDiary with the 
electronic metered dose inhaler 
(eMDI) device 

Rescue albuterol/salbutamol use, 
(percentage of rescue-free days and 
mean number of Inhalations/day) 
captured by the eMDI device over 24 
weeks as data allow

To explore the effect of UMEC/VI 
(62.5/25 mcg once daily), UMEC 
(62.5 mcg once daily) with 
salmeterol (50 mcg twice daily) on 
physical activity

Change from baseline in physical 
activity 

To investigate the CID composite 
endpoint ability to predict short 
term outcomes 

To compare physical activity levels, 
ER-S, rescue medication use, 
exacerbations and mortality in subjects 
with and without a CID
Overall Design
This is a multi-centre, randomized, double blind, double dummy, 3-arm parallel group 
study.  Eligible subjects will be randomized in a ratio of 1:1:1 to UMEC/VI inhalation 
powder (62.5/25 mcg once daily) administered via the ELLIPTA® dry powder inhaler
(DPI), or UMEC (62.5 mcg once daily) administered via the ELLIPTA DPI or salmeterol 
(50 mcg twice daily (BID)) administered via the DISKUS® DPI.
Eligible subjects at Screening will enter a run-in period for 4 weeks during which they
continue taking their inhaled COPD medications (excluding ICS and any exclusionary 
medications).  In addition, subjects will be provided with short acting 
albuterol/salmeterol to be used on as needed basis (rescue medication) throughout the 
study. 
Subjects who experience a moderate or severe COPD exacerbation during the run-in 
period will be deemed run-in failures. Subjects experiencing a mild exacerbation, 
defined as worsening of symptoms that requires no treatment with antibiotics or steroids 
and is self managed by the patient by an increase of inhaled rescue medication, will be 
allowed to continue in the study.
At the randomization Visit 2 (Day 1) those subjects who successfully complete the run-in 
period as well as meet the other pre-defined eligibility and randomization criteria will 
discontinue their inhaled COPD medications and will be randomized to one of the 3 
treatment arms for 24 weeks.
 
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All subjects will be given an eDiary for use during the run-in, and treatment period to 
complete PRO questionnaires and record medical problems experienced during the study.  
Subjects will be performing slow and forced spirometry at specific visits.
In addition, a subset of subjects up to 150 per treatment arm will undergo assessment of 
their physical activity measured through a physical activity monitor (Actigraph GT9X) 
worn for 7 days from Screening (Visit 1), for 7 days from Randomisation (Visit 2), 7 
days from Visit 3, and for 7 days prior to last clinic Visit (Visit 5). 
There will be a total of 5 clinic visits and one follow-up phone call (Visit 6).  The total 
duration of subject participation in the study will be approximately 29 to 31 weeks 
consisting of 2 weeks pre-screening if necessary, 4 weeks run-in, 24 week treatment and 
one week Follow-Up. 
Subjects will be considered to have completed the study upon completion of the Follow–
Up contact by telephone.
Treatment Arms and Duration
Subjects will be stratified based on long-acting bronchodilator usage during the run-in 
(none, one or 2 long-acting bronchodilators per day) and randomized in a ratio of 1:1:1 to 
either

UMEC/VI inhalation powder (62.5/25 mcg once daily) administered via the 
ELLIPTA DPI) or 

UMEC (62.5 mcg once daily) administered via the ELLIPTA DPI or 

Salmeterol (50 mcg BID) administered via DISKUS 
 
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Study schematic
*Inhaled COPD medications including LABAs, LAMAs or LABA/LAMA combination products are 
allowed in run-in. ICS alone or in combination with a bronchodilator or any exclusionary 
medications are not allowed.
Type and Number of Subjects
Approximately 3232 subjects will be screened, such that 2424 subjects will be 
randomized and approximately 2181 evaluable subjects complete the study. 
Analysis
The primary purpose of this study is to demonstrate improvements in lung function for 
subjects treated with UMEC/VI compared with UMEC for 24 weeks.
The primary endpoint is change from baseline in trough FEV1 at Week 24.
The null hypothesis is no difference between treatment groups (H0: μT – μS = 0), with 
the alternative hypothesis that there is a difference between treatment groups (H1: μT –
μS ≠0), where μT is the mean change from baseline for UMEC/VI and μS is the mean 
change from baseline for UMEC. 
The primary endpoint of mean change from baseline in trough FEV1 at the end of Week 
24 will be analysed using Mixed Models repeated Measures (MMRM) analysis. The 
MMRM analysis will include measurements at Treatment Weeks 4, 12 and 24. Treatment 
group (a categorical variable) will be fitted as the explanatory variable with appropriate 
pre-defined variables, stratum (number of bronchodilators per day during run-in) and 
baseline values, fitted as covariates. Visit (nominal) will be fitted as a categorical variable 
and visit-by-baseline and visit-by-treatment interaction terms will be included to allow 
treatment effects to be estimated at each visit separately. The variance covariance matrix 
 
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will be assumed to be unstructured (based on previous experience no issues are expected 
with fitting models with this matrix structure). 
The estimated treatment differences between UMEC/VI versus UMEC for each endpoint 
will be presented with the 95% confidence intervals for the difference and the p-value. 
 
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2.
INTRODUCTION
2.1.
Study Rationale
Chronic obstructive pulmonary disease (COPD) is associated with poor health-related 
quality of life (HRQoL).  Pharmacologic therapy is used to improve lung function, reduce 
symptoms, frequency and severity of exacerbations, and improve patients HRQoL
[GOLD, 2015]. Umeclidinium/Vilanterol (UMEC/VI 62.5/25 mcg) is indicated for the 
maintenance treatment of COPD that contain long-acting muscarinic antagonist (LAMA) 
and long-acting beta2-agonist (LABA) bronchodilators. Umeclidinium (UMEC) is 
indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients 
with COPD. Salmeterol has long been used for symptoms management of COPD. 
However, a direct comparison of these maintenance therapies has not been conducted 
with respect to HRQoL.
The primary purpose of this study is to demonstrate improvements in lung function for 
subjects treated with UMEC/VI compared with UMEC for 24 weeks.  The effect of
UMC/VI, UMEC, and salmeterol with respect to patient HRQoL measured through 
patient reported outcomes (PROs) questionnaires, symptoms and lung function will also 
be evaluated.
2.2.
Brief Background
COPD is characterized by an airflow limitation which is not fully reversible, usually 
progressive and accompanied by a chronic cough, sputum production and dyspnea which 
can be a major cause of disability and anxiety associated with the disease [Maleki-Yazdi,
2014]
Furthermore, acute exacerbations contribute to the overall severity of disease as these 
episodes are accompanied by worsened symptoms and are associated with increased 
decline in lung function and mortality [Wedzicha, 2013; Schmidt, 2014].
Pharmacologic therapy is used to improve lung function, reduce symptoms, reduce the 
frequency and severity of exacerbations, and also to improve health status and exercise 
tolerance.  Maintenance treatment is recommended primarily through the use of LABAs
or LAMAs. COPD treatment guidelines recommend an incremental approach to 
pharmacological treatment as the disease state worsens, involving the use of 
combinations of drug classes with different or complementary mechanisms [GOLD, 
2015]. 
UMEC/VI inhalation powder is a combination of UMEC (umeclidinium bromide), a 
LAMA, and VI (Vilanterol), a LABA, delivered via the ELLIPTA® dry powder inhaler 
(DPI). UMEC/VI at a dose of 62.5/25mcg once-daily is marketed in the United States 
(US) and Europe under the trade name ANORO® ELLIPTA®.
UMEC (62.5 mcg) inhalation powder is marketed in the United States (US) and Europe 
under the trade name INCRUSE® ELLIPTA®.  UMEC (62.5mcg) is indicated as a 
maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD.
UMEC (62.5 mcg) improves forced expiratory volume in one second (FEV1), dyspnea 
 
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and HRQoL whether used as monotherapy [Trivedi, 2014; Feldman, 2016] or as an add 
on to fluticasone propionate and vilanterol (FF/VI) [Siler, 2015]. Salmetrol (50 mcg)
DISKUS® is a long-acting broncholdilator that has long been used for the maintenance 
treatment of COPD [Tashkin, 2010].
Clinically important deterioration (CID) is a novel, exploratory composite endpoint 
which assesses individual deteriorations in lung function and in patient PROs defined by 
the accepted minimal clinically important difference (MCID), as well as the incidence of 
moderate to severe exacerbations [Singh, 2016], (Section 7.3.5). CID will be analysed to 
determine whether UMEC/VI (62.5/25mcg) therapy provides greater clinical stability as 
compared with UMEC and salmeterol monotherapies.
3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary

To compare the effect of UMEC/VI 
(62.5/25 mcg once daily) with UMEC 
(62.5 mcg once daily) on lung function

Change from baseline in trough Forced 
Expiratory Volume in One Second 
(FEV1) at week 24 
Secondary

To compare UMEC/VI (62.5/25 mcg 
once daily), UMEC (62.5 mcg once 
daily) with salmeterol (50 mcg twice 
daily) on patient reported outcomes 
(PROs) 

Change from baseline in self 
administered computerised (SAC) 
transient dyspnea index (TDI) 

Percentage of TDI responders 
according to SAC TDI score.  A 
responder is defined as a ≥1 unit 
improvement in SAC TDI score 

Assessment of respiratory daily 
symptoms over 24 weeks using 
Evaluating Respiratory Symptoms-
COPD (E-RS) and its subscales 
(breathlessness, cough and sputum and 
chest symptoms) 

Percentage of E-RS responders 
according to E-RS score (defined as 
reduction in E-RS score of 2 or 3.35 
units) from baseline

Change from baseline in St George’s 
Respiratory Questionnaire (SGRQ-C)

Percentage of responders according to 
SGRQ-C total score (defined as a 4 
point or greater reduction from 
 
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Objectives
Endpoints
baseline) 

Change from baseline in COPD 
assessment test (CAT)

Percentage of responders according to 
CAT (defined as a 2 unit improvement 
in score from baseline)
Other

To compare UMEC/VI (62.5/25 mcg 
once daily), UMEC (62.5 mcg once 
daily) with salmeterol (50 mcg twice 
daily) on other COPD efficacy measures 

Rate of mild, moderate or severe 
exacerbations

Time to first mild, moderate or severe 
exacerbation

Rate of moderate or severe 
exacerbation

Time to moderate or severe 
exacerbation

Time to severe exacerbations

Time to clinically important 
deterioration (CID) composite endpoint 

Time to clinically important 
deterioration composite endpoint 
excluding FEV1

Rescue albuterol/salbutamol use, 
(percentage of rescue-free days and 
mean number of Inhalations/day) 
captured by the electronic diary 
(eDiary) over 24 weeks

Inspiratory capacity (IC)

Full Vital capacity (FVC) 

Change from baseline in trough FEV1

Change from baseline in global 
impression of disease severity 
 
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Objectives
Endpoints
Safety

To evaluate safety and tolerability 
of UMEC/VI (62.5/25 mcg once 
daily), UMEC (62.5mcg once daily)
and salmeterol (50mcg twice daily)

Incidence of adverse events
Exploratory

To compare albuterol/salbutamol 
use captured in the eDiary with the 
electronic metered dose inhaler 
(eMDI) device 

Rescue albuterol/salbutamol use, 
(percentage of rescue-free days and 
mean number of Inhalations/day) 
captured by the eMDI device over 24 
weeks as data allow

To explore the effect of UMEC/VI 
(62.5/25 mcg once daily), UMEC 
(62.5 mcg once daily) with 
salmeterol (50 mcg twice daily) on 
physical activity

Change from baseline in physical 
activity 

To investigate the CID composite 
endpoint ability to predict short 
term outcomes 

To compare physical activity levels, 
ER-S, rescue medication use, 
exacerbations and mortality in subjects 
with and without a CID
4.
STUDY DESIGN
4.1.
Overall Design
This is a multi-centre, randomized, double blind, double-dummy, 3-arm parallel group 
study.  Eligible subjects will be stratified based on long-acting bronchodilator usage 
during the run-in (none, one or 2 long-acting bronchodilators per day) and randomized in 
a ratio of 1:1:1 to UMEC/VI inhalation powder (62.5/25 mcg once daily) administered 
via the ELLIPTA inhaler, or UMEC (62.5 mcg once daily) administered via the 
ELLIPTA or salmeterol (50 mcg BID) administered via the DISKUS.
There will be a total of 5 clinic visits and one follow-up phone call (Visit 6). The Pre-
screening Visit (Visit 0) can occur on the same day as the Screening Visit (Visit 1) if 
subject does not take or has not taken any excluded protocol medications, but must be 
completed prior to initiating any Visit 1 procedures. 
Subjects, who meet all the eligibility criteria at Screening, will enter a run-in period for 4 
weeks in order to continue to assess the subject’s eligibility for the study. During the run-
in period subjects will continue with their inhaled COPD medications (excluding ICS and 
any exclusionary medications). In addition, subjects will be provided with short acting 
albuterol/salmeterol to be used on as needed basis for relief of COPD symptoms (rescue 
medication) throughout the study. 
 
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Subjects who experience a moderate or severe COPD exacerbation during the run-in 
period will be deemed run-in failures. Subjects who experience a mild COPD 
exacerbation, defined as worsening of symptoms that requires no treatment with 
antibiotics or steroids and is self managed by the patient by an increase of inhaled rescue 
medication, (Appendix 5), will be able to continue in the study based on the judgment of 
the investigator and agreement of the sponsor’s medical monitor.
At the randomization Visit 2 (Day 1) those subjects who successfully complete the run-in 
period as well as meet the other pre-defined eligibility and randomization criteria will 
discontinue their inhaled COPD medications and will be randomized to one of the 3 
treatment arms for 24 weeks.
During the run-in and treatment period, subjects will be completing PRO questionnaires
in the eDiary and performing slow and forced spirometry at specific clinic visits.
In addition, a subset of subjects up to 150 per treatment arm will undergo assessment of 
their physical activity measured through a physical activity monitor (Actigraph GT9X) 
worn for 7 days from Screening (Visit 1), for 7 days from Randomisation (Visit 2), 7 
days from Visit 3, and for 7 days prior to last clinic Visit (Visit 5). 
Concurrent use of COPD maintenance medications including LAMAs, LABAs, oral beta-
agonists, theophyllines, inhaled corticosteroids, inhaled corticosteroids and LABA 
combination and phosphodiesterase 4 inhibitors will not be allowed during the study
(Section 6.11.2) . 
The occurrence of adverse events (AEs) will be evaluated throughout the study beginning 
at Visit 2 (Day 1) and until the follow-up contact (Visit 6).  Serious adverse events 
(SAEs) will be collected over the same time period as AEs. However, any SAEs 
assessed as related to study participation (e.g., study treatment, protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK concomitant 
medication, will be recorded from the time a subject consents to participate in the study 
up to and including any follow up contact (Appendix 4). 
All subjects will be given an electronic diary (eDiary) for use during the run-in, and the 
treatment period to complete PRO questionnaires, record COPD daily symptoms, any 
medical problems experienced during the study and the time they take their COPD 
medications. Daily rescue medication usage (number of inhalations taken in the last 24h)
will also be captured in the eDiary. In addition, and in some countries, rescue medication 
use will also be captured by the use of electronic metered dose inhaler (eMDI).
At Screening Visit 1, all subjects must be trained on the proper use of their existing 
COPD medications inhalation devices and instructed to strictly adhere to and record the 
time they take their COPD medications in the eDiary.
At the randomization Visit 2, all subjects must be trained on the proper use of the 
ELLIPTA and DISKUS inhalation devices and instructed to strictly adhere to and record 
the time they take their study medications in the eDiary.
 
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All subjects must be trained on the correct use of the eDiary and instructed to complete 
the eDiary during the run-in and treatment period.
Subjects will be considered to have completed the study upon completion of the follow –
up contact by telephone.
There are no plans to routinely provide any of the study treatments for compassionate use 
following study completion as the study treatment are commercially available.
The study design schematic is illustrated in Figure 1
Figure 1
Study Schematic
*Inhaled COPD medications including LABAs, LAMAs or LABA/LAMA combination products are 
allowed in run-in. ICS alone or in combination with a bronchodilator or any exclusionary 
medications are not allowed.
4.2.
Treatment Arms and Duration
Subjects will be stratified based on long-acting bronchodilator usage during the run-in 
(none, one or 2 long-acting bronchodilators per day) and randomized in a ratio of 1:1:1 to 
either

UMEC/VI inhalation powder (62.5/25 mcg once daily) administered via the 
ELLIPTA DPI) or 

UMEC (62.5 mcg once daily) administered via the ELLIPTA DPI or 

Salmeterol (50 mcg BID) administered via DISKUS
The total duration of subject participation in the study will be approximately 29 to 
31 weeks consisting of 2 weeks pre-screening if necessary, 4 weeks run-in, 24 
week treatment and one week follow-up. 
 
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4.3.
Type and Number of Subjects
Approximately 3232 will be screened globally in approximately 205 sites such that 
approximately 2424 subjects will be randomized and approximately 2181 evaluable 
subjects complete the study.
4.4.
Design Justification
A randomized, double blinded, parallel group study is a standard, well-established design 
to evaluate the efficacy and safety of an investigational drug. A salmeterol arm is 
included to allow a comparison to be made between UMEC/VI, UMEC with salmeterol, 
a standard practice treatment.
The double-dummy design is appropriate when drugs are of different appearance or 
different administration regimen which is appropriate in this study where the inhalers 
used have a different appearance and used once daily and twice daily.
The European Medicines Agency (EMA) COPD Guidelines suggest that duration of 12 to 
24 weeks is considered adequate for assessment of response of COPD symptoms to 
treatment intervention with bronchodilators (EMA COPD guidelines, 2012).
The primary endpoint is trough FEV1 at week 24. This endpoint is generally considered to 
be a robust, well established and an objective means to show the efficacy of a 
bronchodilator [Dahl, 2010; Feldman, 2010].
Other endpoints such SAC TDI, E-RS, SGRQ-C, CAT, Subject Global Rating of Change 
in global impression of disease severity are captured to allow responder analyses and to 
provide comparative data on PROs between the treatment groups. 
4.5.
Dose Justification
This study is intended to evaluate the efficacy of marketed doses of UMEC/VI 
(62.5/25mcg once daily), UMEC (62.5 mcg once daily) and salmeterol (50mcg twice 
daily) that are approved for the maintenance treatment of COPD, with respect to PRO
measures.
4.6.
Benefit: Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
UMEC/VI and UMEC can be found in the investigator’s brochures (IB)
[GlaxoSmithKline Document Number RM2009/00437/07] and [GlaxoSmithKline 
Document Number RM2006/00835/09] and in the label information sheets. The current 
safety profile for UMEC (62.5mcg) and the UMEC/VI (62.5/25mcg) based on data 
available to date, is comparable with other LABAs and LAMAs.  Summary safety data 
can also be found in the information sheet for salmeterol [Serevent product information
2003].The following section outlines the risk assessment and mitigation strategy for this 
protocol: 6
 
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4.6.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [UMEC/VI] 
Severe milk protein allergy
Anoro contains Lactose monohydrate (which contains milk 
protein) as an excipient.
Exclusion criteria have been set for subjects with milk 
protein allergy.
Cardiovascular effects such as cardiac arrhythmias e.g.
supraventricular tachycardia and extrasystoles.
Class effects associated with LABAs and LAMA containing 
therapy. The clinical significance of these arrhythmias is 
unknown. Clinical experience with UMEC/VI to date in 
completed studies did not show any association with major 
cardiovascular events. 
Data available in the product label for UMEC/VI 
Exclusion criteria have been set for subjects with 
uncontrolled or severe cardiovascular disease according to 
the principal investigation’s (PI) opinion where the potential 
risk may outweigh the benefit. The PI should also 
determine the clinical significance of abnormal ECG 
findings at screening and exclude subjects who would be
at undue risk by participating in the trial.  Patients with the 
following abnormalities will be excluded from participation:  
atrial fibrillation with rapid ventricular rate >120bpm, 
sustained or nonsustained ventricular tachycardia, or 
second degree heart block Mobitz type II or third degree 
heart block (unless pacemaker or defibrillator had been 
inserted). 
Beta agonists and risk of asthma-related death
Long-acting beta agonists such as vilanterol when used 
alone may increase the risk of asthma-related death.  A 
placebo-controlled trial with another LABA (salmeterol) 
showed an increase in asthma-related deaths in subjects 
receiving salmeterol.  This finding with salmeterol is 
considered a class effect of all LABAs, including vilanterol. 
Data are not available to determine whether the rate of death 
in patients with COPD is increased by LABA.
Subjects with a current diagnosis of asthma are excluded 
from participation in the study.
Paradoxical bronchospasm
As with other inhaled medicines, UMEC/VI can produce 
paradoxical bronchospasm which may be life threatening.
If paradoxical bronchospasm occurs following dosing with 
UMEC/VI, this treatment should be discontinued 
immediately and alternative therapy should be instituted. 
Use in patients with narrow-angle glaucoma or urinary 
retention
No association has been found to date, in completed studies 
with UMEC/VI or UMEC monotherapy, on glaucoma or 
urinary retention.  However, glaucoma or urinary retention 
Exclusion criterion states that subjects with medical 
conditions such as narrow-angle glaucoma, prostatic 
hypertrophy, or bladder neck obstruction should only be 
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
have been observed with other antimuscarinic agents, and 
could potentially be due to the pharmacology.
included if, in the opinion of the principal investigator, the 
benefit outweighs the risk.
Use of beta blockers
Beta-adrenergic blockers may weaken or antagonize the 
effect of beta2-agonists such as vilanterol.
The study permitted medications and non drug therapies 
section states that concomitant administration with beta-
blockers is only permitted if, in the Investigator’s opinion, 
the likely benefit outweighs the potential risk.
Pregnancy
There is no experience to date of pregnancy during the use 
of UMEC/VI.
The study inclusion criteria ensures that female subjects of 
child bearing potential must have a negative pregnancy 
test at screening, and agree to a reliable contraceptive 
method, used consistently and correctly (i.e. in accordance 
with the approved product label and the instructions of the 
physician for the duration of the study). Exclusion criteria 
include Pregnancy: Women who are pregnant or lactating 
or are planning on becoming pregnant during the study.
Severe hepatic impairment
UMEC/VI has not been studied in severe hepatic impairment.
Exclusion criterion states that subjects severe hepatic 
impairment should only be included if, in the opinion of the 
study physician, the benefit outweighs the risk.
Investigational product (IP) [UMEC]
Cardiovascular effects such as cardiac arrhythmia, e.g.
atrial fibrillation and tachycardia
A potential class effect associated
with anti-muscarinic therapies. Data available to date in the 
IB for UMEC [GlaxoSmithKline Document Number 
RM2006/00835/09
Screening electrocardiogram (ECG) criteria to exclude 
subjects potentially at risk 
Narrow-angle glaucoma, urinary retention
A class effect associated with anti-muscarinic therapies.
Data available in the IB for UMEC [GlaxoSmithKline
Document Number RM2006/00835/09
Exclusion criterion states that subjects with medical 
conditions such as narrow-angle glaucoma, prostatic 
hypertrophy, or bladder neck obstruction should only be 
included if, in the opinion of the study physician, the benefit 
outweighs the risk.
Paradoxical bronchospasm that may be life threatening
Known effect associated with inhalation therapy
A short-acting inhaled bronchodilator 
(albuterol/salbutamol) will be provided for use as needed 
throughout the study. The investigators will be instructed to 
assess subject’s condition to determine their eligibility to 
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
continue in the study and the need for alternative therapy.
Severe hepatic impairment
UMEC has not been studied in severe hepatic impairment.
Exclusion criterion states that subjects with severe hepatic 
impairment should only be included if, in the opinion of the 
study physician, the benefit outweighs the risk.
Pregnancy/Lactation
There is no experience to date of pregnancy during the use 
of UMEC.
The study inclusion criteria ensure that female subjects 
enrolled, who are of Child bearing potential, have a 
negative pregnancy test at screening, and agree to a 
reliable contraceptive method, used consistently and 
correctly (i.e. in accordance with the approved product 
label and the instructions of the physician for the duration 
of the study). Exclusion criteria states - Pregnancy: 
Women who are pregnant or lactating or are planning on 
becoming pregnant during the study.
Study Procedures
Spirometry procedures
This may cause difficulty breathing, changes in pulse rate 
and blood pressure, coughing, wheezing, chest tightness or 
fainting.
Subjects will be monitored during the procedure for these 
effects and spirometry will be discontinued should these 
occur.
ECG lead placement
This may cause skin irritation.
It may be necessary to have small patches (about a 
centimetre in diameter) of hair on the chest shaved to 
properly attach electrodes to the chest. 
Blood sampling procedure (optional pharmacogenetic 
blood sample)
Giving blood may make subjects feel faint, or experience 
mild pain, bruising, irritation or redness at the site. In rare 
cases, they may get an infection
Subjects will be monitored during the blood draw for these 
effects and should call their study doctor if any of these 
effects do not resolve
Other 
Side effects of rescue albuterol/salbutamol. Adverse 
events seen in clinical studies to date are however 
consistent for the beta2-adrenergic class of compounds
Class effects associated with short acting beta-agonists
(SABAs)
Subjects should call their study doctor if they experience 
any of these symptoms
 
 
 
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4.6.2.
Benefit Assessment
Subjects will receive single or combination of long-acting bronchodilator therapies 
approved for maintenance treatment of COPD.  Participating subjects in this study will 
contribute to the process of further characterizing the benefit of these long-acting 
bronchodilators with respect to PROs and symptoms in the treatment of COPD.
Specific benefits associated with the study design and procedures include the following:

Subjects will receive treatments approved for the treatment of COPD that have 
been shown to be effective in the population under study

All subjects will receive albuterol/salbutamol for use “as needed” for relief of 
COPD symptoms

The combination of study procedures of spirometry, CAT, SGRQ, TDI, E-RS will 
provide the study subjects with a comprehensive evaluation of their symptoms,
health status and COPD disease severity. Subjects will also be monitored 
throughout the study for any worsening of COPD symptoms or decline in general 
health. Finally smoking cessation counselling will also be provided.
4.6.3.
Overall Benefit: Risk Conclusion
Taking into account the measures taken to minimize risk to subjects participating in this 
study, the potential risks identified in association with UMEC/VI, UMEC, salmeterol and 
with study procedures are justified by the anticipated benefits from active treatments that 
may be afforded to patients with COPD.
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 IBs, [GlaxoSmithKline
Document Number RM2006/00835/09], [GlaxoSmithKline Document Number 
RM2009/00437/07] and product labels.
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
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE
1.
40 years or older at date of signing informed consent at Screening Visit 1
 
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TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2.
Outpatient with a diagnosis of COPD in accordance with the definition of the 
American Thoracic Society/European Respiratory Society (ATS/ERS) [Celli, 2004]. 
3.
FEV1: Persistent airflow limitations as indicated by:  A pre and post-
albuterol/salbutamol FEV1/FVC ratio of <0.70 and a post-albuterol/salbutamol FEV1
of ≥30% to ≤80% predicted normal values at Screening Visit 1.  Predicted values 
will be based upon the ERS Global Lung Function Initiative [Quanjer, 2012].
4.
CAT score:  A CAT score of ≥10 at Screening Visit 1
Smoking History
5.
Current or former cigarette smokers with a history of cigarette smoking of 10 
pack-years [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 both equal 10 pack-years)].  Former smokers are defined as those who have 
stopped smoking for at least 6 months prior to Visit 1.  Pipe and/or cigar use cannot 
be used to calculate pack-year history.
SEX
6.
Male and female subjects are eligible to participate in the study
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 must be tested.  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.
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 
 
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Reproductive Potential (FRP) (Appendix 7) from 30 days prior to the first dose of 
study medication and until [at least five terminal half-lives OR until any continuing 
pharmacologic effect has ended, whichever is longer] after the last dose of study 
medication and completion of the follow-up visit.
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.
INFORMED CONSENT
7.
Capable of giving signed informed consent prior to study participation, which 
includes compliance with the requirements and restrictions listed in the consent form 
and in this protocol.
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION 
1.
Asthma:  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).
2.
Alpha-antitrypsin deficiency: Subjects with known α1-antitrypsin deficiency as 
the underlying cause of COPD
3.
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.
4.
Unstable liver disease: 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). 

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 or within 3 months prior to 
first dose of study treatment) are acceptable if subject otherwise meets entry 
criteria
5.
Unstable or life threatening cardiac disease: Investigational Product should be 
used with caution in subjects with severe cardiovascular disease.  In the opinion 
of the investigator, use should only be considered if the benefit is likely to 
 
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outweigh the risk in conditions such as:

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
6.
12 Lead ECG: 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. Subjects with the 
following abnormalities are excluded from participation in the study:

Atrial fibrillation with rapid ventricular rate >120 bpm

Sustained or non-sustained ventricular tachycardia

Second degree heart block Mobitz type II or third degree heart block (unless 
pacemaker or defibrillator had been inserted)
7.
Antimuscarinic effects: Subjects with medical conditions such as narrow-angle 
glaucoma, urinary retention, prostatic hypertrophy, or bladder neck obstruction 
should be excluded unless, in the opinion of the study physician, the benefit 
outweighs the risk.
8.
Other disease abnormalities: Any subject who is considered unlikely to survive 
the duration of the study period or has any rapidly progressing disease or 
immediate life-threatening illness (e.g. cancer). In addition, any subject who has 
any other condition (e.g. neurological condition) that is likely to affect respiratory 
function should not be included in the study.
9.
Hospitalization: Hospitalization for COPD or pneumonia within 12 weeks prior 
to Visit 1. 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). 
10.
Inhaled corticosteroids (ICS): Had received ICS or ICS/LABA for the treatment 
of COPD in the 6 weeks prior to Screening Visit1
11.
Exacerbation: Had >1 moderate exacerbation in the 12 months prior Screening 
Visit1, or one severe exacerbation requiring hospitalisation in the 12 months prior 
Screening Visit 1.
12.
Other respiratory tract infections that have not resolved at least 7 days prior to 
Screening V1.
13.
Lung Resection: Subjects with lung volume reduction surgery (including 
procedures such as endobronchial valves) within the 12 months prior to Screening 
V1.
14.
Oxygen: Use of long-term oxygen therapy (LTOT) described as resting oxygen 
therapy >3L/min at screening required to maintain adequate oxygenation (e.g.
SaO2 >90%). (Oxygen use ≤3L/min flow is not exclusionary, and patients may 
adjust oxygen levels up or down as needed during the study.)
 
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CONCOMITANT MEDICATIONS
1. Medications prior to Screening: Use of the following medications according to 
the following defined time intervals prior to Screening (Visit 1):
Medication
No use within the 
following time intervals 
prior to Screening
Inhaled corticosteroids (ICS)
6 weeks
Depot corticosteroids
12 weeks
Systemic, oral or parenteral corticosteroidsa
6 weeks
Antibiotics (for lower respiratory tract infection)
6 weeks
Phosphodiesterase 4 (PDE4) Inhibitor (e.g roflumilast)
14 days
LABA/Inhaled Corticosteroid (ICS) combination products 
6 weeks
Theophyllines
48 hours
Oral beta2-agonists
     Long-acting
     Short-acting
48 hours
12 hours
Inhaled short acting beta2-agonistsb
4 hours
Inhaled short-acting anticholinergics
4 hours
Inhaled short-acting anticholinergic/short-acting beta2-agonist 
combination products
4 hours
Any other investigational medication
30 days or within 5 drug 
half-lives (whichever is 
longer)
a-
Localized corticosteroid injections (e.g., intra-articular and epidural) are permitted.
b-
Use of study provided albuterol/salbutamol is permitted during the study, except in the 4-hour period prior to 
spirometry testing
2. Medication prior to spirometry: Unable to withhold albuterol/salbutamol for 
the 4 hour period required prior to spirometry testing at each study visit.
3. Maintenance use of short-acting bronchodilators:  Regular use (prescribed for 
daily/ regular use, not for as-needed use) of short-acting bronchodilators (e.g. 
albuterol/salbutamol).
RELEVANT HABITS
1. Drug or alcohol abuse: A known or suspected history of alcohol or drug abuse 
within 2 years prior to Screening Visit 1 that in the opinion of the investigator would 
prevent the subject from completing the study procedures.
CONTRAINDICATIONS 
1. Any history of allergy or hypersensitivity to any anticholinergic/muscarinic 
receptor antagonist, sympathomimetic, lactose/milk protein or magnesium stearate.
 
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DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
1. Pulmonary Rehabilitation program: Participation in the acute phase of a 
pulmonary rehabilitation program within 4 weeks prior to Screening Visit 1.  Subjects 
who are in the maintenance phase of a pulmonary rehabilitation program are not 
excluded.
2. Affiliation with investigator sites: Is an investigator, sub-investigator, study 
coordinator, employee of a participating investigator or study site, or immediate 
family member of the aforementioned that is involved in this study
3. Inability to read: In the opinion of the investigator, any subject who is unable to read 
and/or would not be able to complete questionnaires on the electronic diary.
Subjects who fail to meet inclusion and exclusion criteria at the Screening Visit 1 will be 
considered screen failures and cannot be re-screened.
5.3.
Randomization Criteria
In order to be randomized to one of the 3 treatment arms at Visit 2, subjects must have 
completed the run-in period and must have fulfilled all inclusion and exclusion criteria 
described in Section 5.1 and Section 5.2. In addition to the following:
REQUIRED CRITERIA FOR RANDOMIZATION AND TREATMENT
1. COPD Exacerbation: Subjects must not have experienced a moderate or severe 
COPD exacerbation or a lower respiratory tract infection during run-in or at Day 1 
(Visit 2) inclusive.  A moderate exacerbation is defined as worsening of symptoms of 
COPD requiring the use of antibiotics or systemic corticosteroids.  A severe 
exacerbation is defined as worsening symptoms of COPD requiring hospitalization.
2. CAT score:  A CAT score of ≥10 at Visit 2
3. Prohibited Medications: No use of any prohibited medications during the run-in 
period or at Visit 2, including any ICS or ICS/LABA combination
4. Any change to COPD medications: Including dosage and regimen during the run-in
5. Completion of electronic diary: Must have completed the electronic diary for at 
least 80% of days during the run-in period
Subjects who do not meet the required criteria for randomization at Visit 2 will not be 
randomized.
5.4.
Screening/Baseline/Run-in Failures
Pre-screen, screen and run-in failures are defined as follows: 

Pre-screening failures: A subject, who is assigned a subject number at the Pre-
screening Visit 0 but does not have any Screening Visit 1 procedures, will be 
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
Screening failures: Those subjects that complete at least one Screening Visit 1 
procedure but do not enter the run-in period.

Run-in failures: Those subjects that enter the run-in period but are not 
randomized to any of the study treatment arms.
Subjects who are pre-screen, screen and run-in failure will be recorded in the eCRF.  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 to be recorded in eCRF including demography, screen failure details, eligibility 
criteria, and serious adverse events (Section 7.4.1). 
5.5.
Withdrawal/Stopping Criteria
5.5.1.
Withdrawal from the Study
Subjects may be withdrawn from the study at any time by the Investigator if it is 
considered to be detrimental for them to continue in the study.  Reasons for withdrawal 
from study treatment can include: an AE, clinically significant abnormality, lack of 
efficacy, sponsor terminated study, pregnancy, or for any other reason. 
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. 
A reason for the withdrawal from the study must be captured in the electronic case report 
form (eCRF).
A subject will also be withdrawn from the study, in consultation with the medical 
monitor and principal investigator, if any of the following stopping criteria are met:

Liver Chemistry: Meets any of the Liver chemistry stopping criteria (See Section 
5.5.3)
Note: clinical laboratory assessments are not required for this study. However, 
laboratory samples may be taken for liver event analysis, if clinically indicated by 
the study investigator.

Pregnancy: Positive pregnancy test (see Appendix 7)
Subjects withdrawn from study treatment will not be replaced.
Note: Withdrawal from study treatment requires withdrawal from the study.
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. 
 
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
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”. 
5.5.2.
Reason for Study Withdrawal
The primary reason for study withdrawal will be recorded in the eCRF. When a subject 
withdraws consent, the investigator must document the reason (if specified by the 
subject) in the eCRF. 
The primary reason for study withdrawal may include:
Adverse event
Lost to follow-up
Withdrew consent
o
subject relocated
o
frequency of visits
o
burden of procedures
o
other (specify)
Protocol deviation
Lack of efficacy
COPD exacerbation
Study closed/terminated
Subject reached protocol-defined stopping criteria
o
Liver event
o
Pregnancy
Investigator discretion
5.5.3.
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
 
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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*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 2.
5.5.3.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed.
5.6.
Follow-up contact
A safety follow-up contact (Visit 6) should be conducted 72 days following the 
completion of Visit 5 or the Early Withdrawal Visit, if applicable. 
The following procedures will be performed:

AE/SAE assessment

COPD exacerbation assessment

Concomitant medication assessment limited to any medications used to treat a 
COPD exacerbation or SAE (if applicable)

Pregnancy information (if applicable)
Subjects who have successfully completed all on-treatment randomized visits will be 
discharged from the study upon completion of the safety follow-up contact.
 
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5.7.
Subject and Study Completion
A subject will be considered to have completed the study if he/she receives study 
treatment at Visit 5 (Week 24) and completes the follow-up contact Visit 6.
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.
The contents of the label will be in acaccordance with all applicable regulatory 
requirements.
Under normal conditions of handling and administration, investigational product is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to avoid 
direct eye or skin contact and the generation of aerosols or mists. Notify the monitor of 
any unintentional occupational exposure.  A Material Safety Data Sheet (MSDS) 
describing the occupational hazards and recommended handling precautions will be 
provided to site staff if required by local laws or will otherwise be available from GSK 
upon request.
Investigational product must be stored in a secure area under the appropriate physical 
conditions for the product.  Access to and administration of the investigational product 
will be limited to the investigator and authorised site staff.  Investigational product must 
be dispensed or administered only to subjects enrolled in the study and in accordance 
with the protocol.
GlaxoSmithKline (GSK) will provide the study treatments for use in this study. 
The following study medications will be used in this study:
UMEC/VI 62.5/ 25mcg administered via ELLIPTA
UMEC 62.5 mcg administered via ELLIPTA

Salmeterol 50 mcg administered via DISKUS

Placebo via ELLIPTA

Placebo via DISKUS
Subjects will be instructed to take one dose of medication each morning from the 
ELLIPTA (one inhalation equals one dose), and one dose in the morning and one in the 
evening from the DISKUS). Subject instructions and details on how to use the ELLIPTA
and DISKUS are provided in the study reference manual (SRM).
 
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A description of the UMEC/VI investigational product administered via the ELLIPTAis 
provided below in Table 1. The ELLIPTA will contain two, double-foil, laminate, blister 
strips.  The ELLIPTA will provide a total of 30 doses (60 blisters) and will deliver, when 
actuated, the contents of a single blister simultaneously from each of the two blister 
strips. 
The DISKUS will provide a total of 60 doses and will deliver, when actuated, the
contents of a single blister.
A description of the UMEC investigational product administered via the ELLIPTA is 
provided below in Table 2. A description of placebo inhalation powder via ELLIPTA is 
shown in Table 3. A description of salmeterol 50mcg and placebo via DISKUS are 
shown in Table 4 and Table 5 respectively.
Table 1
Description of UMEC/VI Inhalation Powder via ELLIPTA
Formulation
First strip
Second strip
Umeclidinium bromide blended with 
lactose monohydrate and 
magnesium stearate1
Vilanterol trifenatate blended with 
lactose monohydrate and magnesium 
stearate2
Dosage Form
ELLIPTA Inhaler with 30 doses (2 strips with 30 blisters per strip)
Unit Dose Strengths
62.5 mcg
25 mcg
Physical description
White powder
White powder
Route of Administration
Inhaled
1.
Magnesium stearate 0.6% w/w of total drug product
2.
Magnesium stearate 1.0% w/w of total drug product
Table 2
Description of UMEC Inhalation Powder via ELLIPTA
Formulation
First strip
Umeclidinium bromide blended with lactose 
monohydrate and magnesium stearate1
Dosage Form
ELLIPTA Inhaler with 30 doses (1 strip with 30 blisters) 
Unit Dose Strengths
62.5mcg 
Physical description
Dry white powder
Route of Administration
Inhaled
1.
Magnesium stearate 0.6% w/w of total drug product
Table 3
Description of Placebo inhalation powder via ELLIPTA
Formulation
First strip
Second strip
Lactose monohydrate blended with 
magnesium stearate1
Lactose monohydrate blended with 
magnesium stearate2
Dosage Form
ELLIPTA Inhaler with 30 doses (2 strips with 30 blisters per strip)
Unit Dose Strengths
Not applicable
Not applicable
Physical description
Dry white powder
Dry white powder
Route of Administration
Inhaled
1.
Magnesium stearate 0.6% w/w of total drug product
2.
Magnesium stearate 1% w/w of total drug product
 
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Table 4
Description of salmeterol Inhalation powder via DISKUS
Formulation
First strip
Salmeterol Xinafoate blended with 
lactose monohydrate
Dosage Form
Diskus Inhaler with 60 doses (1 strip 
with 60 blisters per strip)
Unit Dose Strengths
50 mcg
Physical description
White powder
Route of Administration
Inhaled
Table 5
Description of Placebo inhalation powder via DISKUS
Formulation
Lactose monohydrate 
Dosage Form
Diskus Inhaler with 60 doses (1 strip 
with 60 blisters per strip)
Unit Dose Strengths
Not Applicable
Physical description
White powder
Route of Administration
Inhaled
Albuterol/salbutamol via metered-dose-inhaler (MDI) will be issued for reversibility 
testing at Visit 1.  Albuterol/salbutamol MDI for as needed (prn) use will be issued 
throughout the study.  Albuterol/salbutamol will be sourced from local commercial stock 
if appropriate.  
6.2.
Medical Devices
The eMDI devices are provided by GSK and are used in this study to electronically 
record rescue medication usage.  They have US FDA 510(K) clearance to market (Class 
II device) and EU CE marking (Class I device). Description of the eMDI and its use will 
be provided in the SRM.
6.3.
Treatment Assignment
Subjects who meet the randomization criteria will be assigned to one of the 3 study 
treatments in accordance with the randomization schedule generated by Clinical 
Statistics, prior to the start of the study, using validated internal software.
Once a randomization number is assigned to a subject, it cannot be reassigned to any 
other subject in the study.
This study will utilize RAMOS NG, which will provide a means for central 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 RAMOS NG to randomize subjects is provided in the SRM.
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 
 
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instructed to do so by clinic personnel.  On the other days during the treatment period 
(i.e. “non-clinic days”), subjects will be instructed to self-administer their study treatment 
in the morning and evening. Subjects should enter the time they take their study treatment 
in the eDiary.
Subjects will be randomly assigned to one of the blinded study treatment regimens in 
equal proportion (ratio of 1:1:1):

UMEC/VI 62.5/25 mcg once daily via ELLIPTA + placebo twice daily via 
DISKUS

UMEC 62.5 mcg once daily via ELLIPTA + placebo twice daily via DISKUS

Salmeterol 50 mcg twice daily via DISKUS + placebo once daily via ELLIPTA
The randomisation will be stratified based on long-acting bronchodilator usage during 
the run-in (none, one or 2 long-acting bronchodilators per day). 
Study treatment/investigational product will be dispensed at Visits 2, 3 and 4. 
In order to ensure subjects have sufficient doses of study treatment, they must return to 
clinic within 30 days from V2, 60 and 90 days from V3 and V4 respectively (see Time 
and event table Section 7.1). 
Used study drug and rescue medication will be collected at Visits 3, 4 and 5 or at the 
Early Withdrawal Visit.
6.4.
Planned Dose Adjustments
No dose adjustment is allowed for this study
6.5.
Blinding
This will be a double-blind double dummy study 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. 

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. 
 
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
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. 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.
6.6.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.7.
Preparation/Handling/Storage/Accountability
No special preparation of the study treatment is required.

The investigator or designee must confirm appropriate temperature conditions 
have been maintained during transit for all study treatment received and any 
discrepancies are reported and resolved before use of the study treatment.

Only subjects enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment.  All study 
treatments must be stored in a secure environmentally controlled and monitored 
(manual or automated) area in accordance with the 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 SRM.
All ELLIPTA DPI study treatment should be stored up to 25C (77F).  Each All 
ELLIPTA DPI contains 30 doses and is packaged in a foil pouch with a desiccant 
sachet and stored in a carton. The inhaler should not be used for more than 30 days 
after opening the foil.  The sites must maintain a daily temperature log for the 
investigational product. 
Salmeterol DISKUS should be stored up to 25 C. 
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.

A Material Safety Data Sheet (MSDS)/equivalent document describing 
occupational hazards and recommended handling precautions either will be 
 
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provided to the investigator, where this is required by local laws, or is available 
upon request from GSK.
6.7.1.
Study Treatment Return
All used and unused ELLIPTA and DISKUS inhalers 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 SRM.
Study treatment will be collected at Visit 3, 4 and 5 or at the Early Withdrawal Visit, if 
applicable. 
For any ELLIPTA or DISKUS inhaler that fails to function properly, the subject should 
return to the clinic as soon as possible to obtain a new inhaler.  The site will contact the 
RAMOS NG 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 
RAMOS NG
In addition, any ELLIPTA that fails to function properly must be identified and returned 
to GSK for testing. 
6.8.
Compliance with Study Treatment Administration
When subjects self-administer study treatment(s) at home, compliance with study 
treatment(s) will be assessed through querying the subject during the site visits and
through study drug compliance assessed at Visits 2, 3, 4 and 5 documented in the source 
documents and eCRF.  A record of the number of ELLIPTA and DISKUS dispensed and 
the number of doses inhaled by each subject must be maintained and reconciled with 
study treatment and compliance records.  Treatment start and stop dates, including dates 
for treatment delays if any will also be recorded in the eCRF.
Compliance with the ELLIPTA inhaler will be determined by reviewing the dose counter 
on the ELLIPTA. Compliance with the study DISKUS will be determined by reviewing 
the dose counter on the DISKUS.  Subjects should be ≥80% to ≤120% compliant on 
taking study medication between each pair of on-treatment visits. Subjects who fall 
outside this range should be re-educated on treatment compliance by their site. This re-
education should be documented in the subject’s source document. If medication 
compliance repeatedly falls outside of acceptable ranges, the study sponsor/site monitor 
must be contacted to discuss subject eligibility for continued participation in the study.
6.9.
Treatment of Study Treatment Overdose
An overdose is defined as a dose greater than the total doses described in Section 6.1 and
Section 6.8 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 medication, 
the investigator should use clinical judgment in treating the overdose and contact the 
study Medical Monitor. 
 
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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 may not be limited to, the approved product label for salmeterol 
albuterol, UMEC and UMEC/VI or equivalent document provided by GSK.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the subject.
6.10.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study, since the study treatments are commercially available.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, post-study treatment.
6.11.
Concomitant Medications and Non-Drug Therapies
All COPD medications used within 30 days prior to Pre-Screening (Visit 0) and onwards 
should be recorded in the eCRF including any changes in medications. Beginning at 
Visit 1 and throughout the rest of the study, all medications should be recorded in the 
eCRF including any changes. Study provided albuterol/salbutamol and double-blinded 
study drug should not be recorded in the eCRF. The minimum requirement includes but 
is not limited to drug name, dose, route and the dates of administration. Medications 
initiated after completion of Visit 5 or the Early Withdrawal Visit will not be recorded in 
the eCRF, with the exception of those used to treat a COPD exacerbation or SAE that 
occurs between Visit 5 (or the Early Withdrawal Visit) and the follow-up contact atVisit 
6.
6.11.1.
Permitted Medications and Non-Drug Therapies
The following relevant medications are permitted during this study:

Study-provided albuterol/salbutamol for use as relief medication throughout the 
run-in and treatment periods 

Mucolytics such as acetylcysteine

Medications for rhinitis (e.g. intranasal corticosteroids, antihistamines, cromolyn, 
nedocromil, nasal decongestants)

Influenza vaccine

pneumococcal vaccine

Antibiotics for short term treatment (14 days) of acute infections including  
COPD exacerbations

Systemic corticosteroids for short term (14 consecutive days)  treatment of 
COPD exacerbations 
 
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
As-needed supplemental oxygen use provided it is ≤3L/min flow at rest at 
screening. Patients may adjust oxygen levels as needed during the study.

Pulmonary rehabilitation program in maintenance phase

Smoking cessation treatment, including a stable regimen of nicotine replacement

Use of positive airway pressure/non-invasive ventilation for sleep apnea/sleep 
disordered breathing (e.g. CPAP, BiPAP)

Localized corticosteroid injections (e.g., intra-articular and epidural)

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)

Immunotherapy injections

Topical or ophthalmic corticosteroids

Over-the counter (OTC) cough suppressants

Tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs). Administer 
with caution as they may potentiate the effect of beta-agonists on the vascular 
system

Diuretics. Caution is advised in the co-administration of beta agonists with non-
potassium sparing diuretics

Allergy vaccination

All medications for other disorders as long as the dose remains constant whenever 
possible and their use would not be expected to affect lung function
6.11.2.
Prohibited Medications and Non-Drug Therapies
Use of the medications listed in Table 6 is not permitted during the study
 
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Table 6
Prohibited Medications and Non-Drug Therapies
Medication
Depot corticosteroids
Systemic, oral or parenteral corticosteroids1
Inhaled corticosteroids (ICS)2
Antibiotics >14 days
LABA/ICS combination products
PDE4 inhibitor (e.g. roflumilast)
Inhaled long acting beta2-agonists (LABA, e.g. salmeterol, formoterol, indacaterol, vilanterol)
Long-acting muscarinic antagonists (LAMA, e.g. tiotropium, aclidinium, glycopyrronium, umeclidinium3)
LAMA/LABA combination products except for study drugs
Theophyllines
Oral beta2-agonists
Inhaled short acting beta2-agonists4
Inhaled short-acting anticholinergics
Inhaled short-acting anticholinergic/short-acting beta2-agonist combination products
Any other investigational medication
1
Except for the treatment of COPD exacerbations during the study. Localized corticosteroid injections (e.g., 
intra-articular and epidural) are permitted.
2
Except if during the study use of ICS is deemed necessary for the treatment of subjects’ exacerbation.
3
Expect for study drug
4
Use of study provided albuterol/salbutamol is permitted during the study, except in the 4-hour period prior to 
spirometry testing. 
The following medications or treatments are also not allowed during the study:

Use of long-term oxygen therapy (LTOT) described as resting oxygen therapy 
>3L/min only at screening. Oxygen may be titrated to any level deemed necessary 
during the study.

Regular (prescribed for daily/regular use, not for as-needed use) therapy with 
albuterol/salbutamol.

Initiation of pulmonary rehabilitation during the study.
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 Section 7.1, are essential and required for study 
conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table Section 7.1
 
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7.1.
Time and Events Table
Blinded Treatment
Visit
Pre-
screen1
0
Screen/ 
Run-in
1
Rando-
mizatio
n 2
3
4
5
EW 
Visit 2
Telephone Follow up 
contact 
6
Week
-6 to -4
-4
0
4
12
24
Day
42 2
days 
prior 
Visit 1
28 2 days 
prior Visit 2
12
days
28 2
days 
84 2
days
168 2
days
72 days after V5 or 
EW Visit
Screen/Baseline
Written informed consent
X
Demography
X
Medical/COPD history
X
Smoking history/status
X
Smoking cessation counselling
X
Concomitant medication assessment
X
X
Cardiovascular History/family history of premature CV 
disease])
X
Screening spirometry (including post bronchodilator testing)3
X
CAT questionnaire
X
X
Verify Inclusion/Exclusion Criteria
X
Training on use of inhalers
X
X
Training on use of eDiary and eMDI
X
X
Verify randomization Criteria
X
Register Visit in InForm
X
X
X
X
X
X
X
X
Register Visit in RAMOS NG
X
X
X
X
X
X
X
X
 
 
 
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Blinded Treatment
Visit
Pre-
screen1
0
Screen/ 
Run-in
1
Rando-
mizatio
n 2
3
4
5
EW 
Visit 2
Telephone Follow up 
contact 
6
Week
-6 to -4
-4
0
4
12
24
Day
42 2
days 
prior 
Visit 1
28 2 days 
prior Visit 2
12
days
28 2
days 
84 2
days
168 2
days
72 days after V5 or 
EW Visit
Efficacy/HRQoL assessments
Spirometry, including pre-dose FEV1, trough  FEV1 and 
inspiratory capacity
X
X
X
X
SAC BDI questionnaire 4
X
SAC TDI questionnaire 4
X
X
X
SGRQ-C questionnaire 4
X
X
X
X
CAT questionnaire 4
X
X
X
X
X
EXACT/ER-S: COPD 5
Patient Global Rating of COPD severity
X
X
X
X
Patient Global Rating of Change in COPD
X
X
X
Safety assessments
Adverse events/Serious adverse events 6
X
X
X
X
X
X
X
X
COPD exacerbation assessment
X
X
X
X
X
X
X
X
12-Lead ECG
X
Urine pregnancy test 7
X
X
X
X
Pharmacogenetic sample8
                                           X
Medication/Supplies
Dispense rescue albuterol/slabutamol. Dispense MDI9
X
X
X
X
X
Assess COPD medication compliance10during run-in
X
Dispense eDiary
X
Assess compliance with eDiary during run-in 
X
Collect rescue albuterol/slabutamol. 
X
X
X
X
X
Collect eDiary
X
X
Dispense study treatment11
X
X
X
Collect study treatment
X
X
X
X
 
 
 
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Blinded Treatment
Visit
Pre-
screen1
0
Screen/ 
Run-in
1
Rando-
mizatio
n 2
3
4
5
EW 
Visit 2
Telephone Follow up 
contact 
6
Week
-6 to -4
-4
0
4
12
24
Day
42 2
days 
prior 
Visit 1
28 2 days 
prior Visit 2
12
days
28 2
days 
84 2
days
168 2
days
72 days after V5 or 
EW Visit
Assess study treatment compliance during treatment10
X
X
X
X
Study sub-set
Physical activity monitor12
X
X
X
X
Collect Physical activity monitor
X
X
1.
Pre-screen Visit 0 must be completed prior to Screening Visit1. It can be completed 2 weeks prior or on the same day of V1, if no wash out of exclusionary medications is 
required. 
2.
Early Withdrawal Visit: Subjects that withdraw should return to the clinic as soon as possible to complete the Early Withdrawal Visit procedures.
3.
Spirometry at screening should be performed as described in (Section 7.2.2.1). 
4.
SAC BDI, SAC TDI, SGRQ-C, CAT questionnaires will be completed at clinic visits and in the eDiary
5.
EXACT/ER-S: COPD is completed daily in the eDiary approximately 2 hours before bed-time, starting on Day 1 of the run-in period.
6.
For the start date of collecting AEs and SAEs see (Appendix 4)
7.
Pregnancy test: for females for child bearing potential only.
8.
Pharmacogenetic sample may be drawn at visit 2 or any visit after.
9.
Rescue medication use to be recorded in the eDiary daily and in some sites in the eDiary and the eMDI
10. Sites are requested to call subjects every 2 weeks to remind them to take study treatment regularly and to record the time of the morning and evening dose in the eDiary.
11. In order to ensure subjects have sufficient doses of study treatment, they must return to clinic within 30 days from V2 and within 60 and 90 days from V3 and V4 respectively
12. The Actigraph GT9X should be worn for 7 days from Visit 1, for 7 days from Visit 2, for 7 days from Visit 3 and for 7 days prior to Visit 5.
 
 
 
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7.2.
Screening and Critical Baseline Assessments
7.2.1.
Pre-screening Visit
During the Pre-screening Visit, the study designated personnel must provide informed 
consent to the study participant.  Subjects can perform the Pre-screening Visit (Visit 0) 
up to 2 weeks prior to or on the same day as the Screening Visit (Visit 1) if subject does 
not take or has not taken any protocol excluded medications.
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.  A subject number will be assigned at the time the 
informed consent form (ICF) is signed. No study related procedures may be 
performed until the informed consent form document has been signed by the 
subject.  
Once the informed consent is signed and if required, changes can be made to the subject’s 
current medication regimen. The investigator should exercise clinical judgment, and is 
discouraged from changing medications only for the purpose of the clinical study. 
During the pre-screening Visit 0, the following information is collected:

Demographic parameters: year of birth, gender, race and ethnicity

Concomitant medications review

COPD exacerbation assessment
From the pre-screening visit onwards concomitant medications, exacerbations and SAEs 
(considered as related to study participation) must be reported
7.2.2.
Critical procedures performed at Screening (Visit 1)
The following critical assessments will be conducted at Visit 1:

Cardiovascular medical history/risk factors (as detailed in the eCRF) will be 
assessed at screening

Medical history including COPD (including date of diagnosis and COPD type 
(emphysema and/or chronic bronchitis), smoking history, COPD exacerbation 
history, smoking status and previous and/or current medical conditions) 

Concomitant medication review (COPD and non COPD medications in the 3
months prior to Screening).

12-Lead ECG. (Note: ECG is performed at screening Visit 1 to test for eligibility 
only. See Section 7.4.4).

Urine pregnancy test if applicable
 
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
Train subject on the use of eDiary

COPD assessment test (CAT) and patient global rating of COPD severity in 
eDiary

Pre- and post-albuterol/salbutamol spirometry (reversibility, see Section 7.2.2.1)

Inclusion/Exclusion criteria assessment

Review exacerbations, AEs, (SAEs if related to study participation)

Train subject on the proper use of their COPD medication inhalation devices

Instruct subject to take their COPD medications as instructed and to enter the time 
they take their medication in the eDiary

Dispense rescue medication
Medical history will be assessed as related to the inclusion/exclusion criteria listed in 
Section 5.1 and Section 5.2.
Assessment of subject’s health status will be made at screening using CAT. PRO
questionnaires should be completed by subjects before any other assessments at a clinic 
visit, in the order specified in Section 7.3.1
7.2.2.1.
Albuterol/Salbutamol Reversibility Assessment
At Visit 1, both pre- and post-albuterol/salbutamol spirometry will be obtained to
determine subject eligibility.  Reversibility assessment should be performed as follows:

Perform pre-bronchodilator spirometry and record FEV1 and FVC

Subject to self-administer 4 Inhalations (4X100g) of albuterol/salbutamol MDI

Perform post-bronchodilator spirometry and record FEV1 and FVC approximately 
10 to 30 minutes after albuterol/salbutamol administration
The results of the spirometry must meet the ATS/ERS criteria [Miller, 2005] for 
the subject to continue in the study.
7.2.3.
Critical procedures performed at first treatment Visit (Baseline 
V2)

Review and assess  compliance with subject’s COPD medications during the run-
in period

Review and assess compliance with completing the eDiary during the run-in 
period

Review AEs, SAEs and exacerbations

Urine pregnancy test, if applicable
 
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
Baseline dyspnea Index, BDI, patient global rating of COPD severity, patient 
global rating of change in COPD, SGRQ-C and CAT questionnaires in eDiary

Review randomization criteria (Section 5.3)

Register and randomize subject in RAMOS NG

Pre-dose spirometry; IC and FEV1

Train subject on the proper use of ELLIPTA and DISKUS inhalers

Dispense study medication

Dispense rescue medication

Optional pharmacogentic sample can be collected at V2 or any visit after.
7.3.
Efficacy Assessments
7.3.1.
HRQoL assessments: Completion of PRO questionnaires in the 
Electronic Diary
All subjects will be completing PRO questionnaires in the eDiary. 
It is requested that questionnaires are completed before any procedures are performed on 
the subject. 
All questionnaires will be completed using the eDiary at clinic and at home. Adequate 
time should be allowed to complete all items of the questionnaires and the questionnaires 
must be reviewed by the investigator or designated study staff for completeness and, if 
necessary, the subject must be encouraged to complete any missing items. Where more 
than one questionnaire is to be completed at a visit the order should be as follows:
1. Baseline dyspnea index (Visit 2) then Transient dyspnea index at subsequent 
visits
2. Patient global rating of COPD severity and global rating of change in COPD
3. St George’s respiratory questionnaire
4. COPD Assessment Test
Instructions for completing the questionnaires can be found in the SRM.
7.3.1.1.
Self Administered Computerised Baseline Dyspnea Index/Transitional 
Dyspnea Index (SAC BDI/TDI)
The BDI is used to measure the severity of dyspnea in patients at baseline. The TDI 
measures changes in the patient’s dyspnea from baseline.  The self-administered 
computerized version of the BDI/TDI (SAC BDI/TDI)[Mahler, 2004] is used to measure 
severity of dyspnea in patients at baseline (SAC BDI) on Day 1 (Visit 2) of treatment and 
change from the baseline (SAC TDI) at Week 4, 12 and 24 (Visits 3, 4 and 5).  The 
scores in both indexes depend on ratings for three different categories: functional 
 
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impairment; magnitude of task, and magnitude of effort. SAC BDI/TDI should be 
completed before performing spirometry. 
The SAC BDI/TDI was developed to address issues of potential bias in the interviewer 
administered (original) BDI/TDI [Mahler, 1984].  The SAC BDI/TDI provides a 
standardized approach to the measurement of dyspnea, equivalent to the original 
BDI/TDI with advantages over the interviewer method for grading dyspnea in patients 
with COPD by standardizing the process for each patient and eliminating individual 
judgment required by the interviewers when completing the original BDI/TDI. This also 
removes the need for the same investigator to conduct all interviews with a subject based 
on the patient’s responses. SAC TDI provides a continuous measure of change in dyspnea 
using a visual analogue scale to record responses. 
Details for the completion of the SAC BDI/TDI are provided in the SRM.
7.3.1.2.
SGRQ-C
The St George’s Respiratory Questionnaire-Chronic Obstructive Pulmonary Disease 
specific (SGRQ-C) will be completed by subjects at Randomisation (V2, Day 1), at Week 
4, 12 and 24 or at the Early Withdrawal Visit (where applicable).
The SGRQ-C [Meguro, 2007] is a well established, disease-specific questionnaire.  It was
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, 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 scores 
equivalent to the SGRQ instrument [Meguro, 2007].  
7.3.1.3.
COPD Assessment Test (CAT)
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.
The CAT will be completed in the eDiary by subjects at Screening Visit 1 and 
Randomisation Visit 2 to assess their eligibility to enter the study. CAT is also 
completed at Weeks 4, 12 and 24. Additional instructions for completion of the CAT are 
provided in the SRM.
7.3.1.4.
EXACT and the Evaluating Respiratory Symptoms- COPD (E-RS:
COPD)
EXACT-PRO is a 14 item patient reported outcome instrument designed to capture 
information on the occurrence, frequency, severity, and duration of exacerbations of 
 
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disease in patients with COPD [Leidy, 2011]. EXACT captures information on the 
severity of the respiratory and systemic manifestations of a COPD exacerbation as 
reported by the patient. The instrument is to be completed daily (typically 2 hrs before 
bedtime) using the electronic diary. The daily recording of information allows an 
assessment of the underlying day to day variability of a patient's symptoms and facilitates 
the detection of symptom worsening indicative of a COPD exacerbation. The total score 
for EXACT ranges from 0-100. The entire instrument is intended to be completed in 
about 3 minutes or less (typically the time required for completion decreases as the 
patient becomes more familiar with the tool and the electronic diary).
The E-RS: COPD consists of 11 items from the 14 item EXACT instrument [Leidy, 
2014].  E-RS: COPD is intended to capture information related to the respiratory 
symptoms of COPD, i.e. breathlessness, cough, sputum production, chest congestion and 
chest tightness. The E-RS: COPD has a scoring range of 0-40 higher scores indicate 
more severe symptoms.
Three subscales of the E-RS are used to describe different symptoms; dyspnea, cough and 
sputum and chest symptoms.
The EXACT questionnaire will be completed by subjects in the eDiary, at home every 
night throughout the entire study, starting from Screening V1 
7.3.1.5.
Subject Global Rating of COPD Severity and Global Rating of Change 
in COPD
Subjects will complete the Global Rating of COPD Severity at Randomization Visit 2
and visits 3, 4 and 5 or Early Withdrawal Visit. This single global question will ask 
subjects to rate their severity of COPD on a four point scale (mild, moderate, severe, and 
very severe).
This question should be used immediately before the patient completes other visit 
specific questionnaires but after completion of SAC TDI questionnaire. 
Subjects will also complete a Global Rating of Change in COPD (overall disease) 
question at Visits 3, 4 and 5 or Early Withdrawal Visit.  Response options will be on a 7 
point Likert scale ranging from much better to much worse. Completing the question at 
each Visit allows for early detection of response as well as continued response.
7.3.2.
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 standardized spirometry equipment provided by an external vendor.
All subjects will have spirometry performed at Screening to assess eligibility (see Section 
7.2.2.1) and at Visits 2, 3, 4 and 5 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 
 
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start of test and end of test (i.e. a plateau in the volume time curve) and be free from 
artifacts due to cough, early termination, poor effort, obstructed mouthpiece, equipment 
malfunction, or other reasons [Miller, 2005].
The largest FEV1 and FVC from the 3 acceptable efforts should be recorded, even if they 
do not come from the same effort.
Spirometry for FEV1 and FVC assessments that is not obtained as follows will be 
considered a protocol deviation:

Started between 6:00AM and 11:00AM.

After withholding albuterol/salbutamol (all visits) for ≥4 hours

At Screening Visit 1, after wash out of medications as specified in the exclusion 
criteria in Section 5.2 (Concomitant Medications).

At Visit 2 after discontinuing inhaled COPD medications and prior the first dose 
of study treatment

At Visit 3, 4 and 5 after withholding the morning dose of study treatment.

Pre dose assessment performed prior dosing.
Subjects should refrain from smoking for 1 hour prior to each pulmonary function test.
Trough FEV1 measurements for UMC/VI or UMEC on Weeks 4, 12 and 24 (Visits 3, 4 
and 5) should be performed 23 hours and 24 hours after the previous day’s dose of study 
medication recorded in the eDiary. This will also provide trough FEV1 measurements for 
the evening dose of salmeterol. 
7.3.3.
Inspiratory capacity (IC)
Inspiratory capacity (IC) is the volume of gas that can be taken into the lungs in a normal 
and full inhalation. Starting from the resting inspiratory position it is equal to the tidal 
volume plus the inspiratory reserve volume. IC has been widely used to assess static and 
dynamic hyperinflation in patients with COPD.
IC will be measured by spirometry prior to forced manoeuvres pre-dose at Visits 2 (30 
and 5 min prior to dosing) and at trough at Visits 3, 4, and 5 (23 and 24 hrs post dosing 
on the previous day). For IC determination the average of at least three acceptable 
manoeuvres should be recorded. Subjects should be tested while sitting, relaxed and 
wearing a nose clip. They should be asked to breathe regularly for several breaths until 
the end-expiratory lung volume is stable (this usually requires at least three tidal 
manoeuvres) then urged to take a deep breath to Total Lung Capacity (TLC) with no 
hesitation.
Spirometry for IC determination done in conjunction with FEV1 and FVC assessments 
that is not obtained as follows will be considered a protocol deviation:

Started between 6:00AM and 11:00AM.

After withholding albuterol/salbutamol (all visits) ≥4 hours 
 
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
At Visit 2 after discontinuation of run-in medication

At Visit 3, 4 and 5 after withholding the morning dose of study drug 
7.3.4.
COPD Exacerbation
A mild exacerbation is defined as worsening of symptoms that require no treatment with 
antibiotics or steroids, and is self managed by the patient by an increase of inhaled rescue 
medications. A moderate COPD exacerbation is defined as worsening symptoms of 
COPD that require treatment with oral/systemic corticosteroids and/or antibiotics. A 
severe exacerbation is defined as worsening symptoms of COPD that require in-patient 
hospitalization or emergency room for longer than 24 hrs. 
If a subject experiences a mild, moderate or severe COPD exacerbation, the COPD 
exacerbation page of the eCRF should be completed. COPD exacerbations should not be 
recorded as an AE, unless they meet the definition of a SAE. Details of COPD 
exacerbation identification, categorization and treatment guidelines are described in
Appendix 5.
Subjects who experience a mild exacerbation during the run-in period will not be 
withdrawn from the study. However, Subjects who experience moderate or severe 
exacerbation during the run-in period will be withdrawn from the study and will not be 
allowed to be re-screened. 
Subjects who experience a mild, moderate or severe exacerbation during the treatment 
period, will not be withdrawn from the study unless the investigator or GSK medical 
monitor think it is best for the patient to withdraw from the study.
Signs and symptoms of COPD included on the electronic diary cards will not be 
considered AEs and will not be recorded in the eCRF.
The time period for collection of COPD exacerbations will be from the Pre-Screening 
(Visit 0) until completion of the follow-up contact.  If a subject experiences a COPD 
exacerbation from the time the ICF is signed until randomization, summary information 
(yes/no status question) will be collected in the eCRF. COPD exacerbations after 
randomization through follow-up will be recorded on the COPD exacerbation page of the 
eCRF.
7.3.5.
Clinically important deterioration (CID)
Clinically important deterioration (CID) is a composite endpoint defined as:

A decrease of  100 mL from baseline in trough FEV1

A deterioration in HRQoL defined as 4 units increase from baseline in 
SGRQ

The occurrence of an on-treatment moderate/severe COPD exacerbation
In addition, this study will explore CAT and TDI PROs as part of the composite 
endpoint.
 
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7.3.6.
Rescue albuterl/salbutamol use
Subjects will record the number of daily albuterol/salbutemol puffs they use in the 
eDiary. In addition, in some countries and selected sites the number of puffs will be 
collected through the eMDI device (Section 6.2) 
7.3.7.
Physical activity monitor (study subset)
Physical activity limitation is a common feature of COPD and its measures are highly 
related to the degree of disease severity [Watz, 2009]. 
Reduced physical activity levels in COPD is associated with increased morbidity and 
mortality, sustained disability, depression, and social and physical isolation [Shu-Yi,
2014; Gimeno, 2014] 
Improved activity has been identified as an important factor that may modify morbidity 
and mortality in COPD [Moy, 2012].
The Actigraph GT9X physical activity monitor will be used to measure levels of activity. 
The activity monitor will be worn by up to approximately 150 subjects for 7 days from 
Screening (Visit 1), for 7 days from Randomisation (Visit 2), 7 days from Visit 3 (Week 
4) and for 7 days prior to Week 24 (Visit 5).
There will be 4 assessment periods, including a screening assessment in order to provide 
a reliable estimate of habitual physical activity. Each subject will be given an activity 
monitor and instruction leaflet at the start of each assessment period. Further details of 
distribution, operation and retrieval of the monitors will be provided in the SRM.
7.4.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1)
Safety endpoint includes:

Incidence of adverse events
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 4.
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
7.4.1.1.
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 
 
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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 7.4.1.3), at the timepoints 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 CRF.

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 12.4.4 to Section 12.4.6)
7.4.1.2.
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?
7.4.1.3.
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).
7.4.1.4.
Pneumonia Events
Investigators will be required to fill out a pneumonia event specific eCRF within one 
week of when the pneumonia AE/SAE(s) is first reported. 
 
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7.4.1.5.
Cardiovascular and Death Events
For any cardiovascular events detailed in (Section 12.4.3) and all deaths, whether or not 
they are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF 
will be required to be completed. These sections include questions regarding 
cardiovascular (including sudden cardiac death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
7.4.1.6.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
The following disease related events (DREs) are common in subjects with COPD and can 
be serious/life threatening:

COPD exacerbation
COPD exacerbations are associated with the disease to be studied and will not be 
recorded as AEs unless the exacerbation meets the definition of a ‘serious’ AE. 
Exacerbations that meet the definition of ‘serious’ AEs will be recorded on the 
appropriate eCRF section and should be reported to GSK for all subjects regardless of 
whether or not they are randomized to study medication. Signs and symptoms of COPD 
included on the electronic diary will not be considered AEs and will not be recorded in 
the eCRF
7.4.1.7.
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.
 
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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.
7.4.2.
Pregnancy

Details of all pregnancies in female subjects will be collected after the start of 
Screening and until the follow-up contact.

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 7.
7.4.3.
Medical Device Incidents (Including Malfunctions)
Procedures for documenting medical device incidents are provided in Appendix 6.
7.4.4.
Electrocardiogram (ECG)
A Single 12-lead ECG will be obtained at Screening using an ECG machine provided by 
the investigational site that automatically calculates the heart rate and measures PR, QRS, 
QT, and QTc intervals.
The 12-lead ECG measurement and rhythm strip (10 seconds) will be obtained before 
spirometry testing. ECG measurement should be obtained after subjects have rested for 
approximately 5 minutes then the subjects should be placed in the supine position for the 
ECG measurements. An ECG is only required at Screening Visit 1 for eligibility 
assessment only. 
The investigator, a designated sub-investigator, or other appropriately trained site 
personnel will be responsible for performing and interpreting the 12-lead ECG at 
Screening Visit 1. The investigator must provide his/her dated signature on the original 
paper tracing, attesting to the authenticity of the ECG machine interpretation. 
7.5.
Genetics
Information regarding genetic research is included in Appendix 3
8.
DATA MANAGEMENT

For this study subject data will be entered into GSK defined CRFs, 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.  
 
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
CRFs (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 purpose of this study is to demonstrate improvements in lung function for 
subjects treated with UMEC/VI compared with UMEC for 24 weeks. 
The primary endpoint is change from baseline in trough FEV1 at Week 24.
The null hypothesis is no difference between treatment groups (H0: μT – μS = 0), with 
the alternative hypothesis that there is a difference between treatment groups (H1: μT –
μS ≠0), where μT is the mean change from baseline for UMEC/VI and μS is the mean 
change from baseline for UMEC. 
9.2.
Sample Size Considerations
The primary endpoint is change from baseline in trough FEV1 at Week 24. As an 
important aim of the study is to compare UMEC/VI, UMEC and salmeterol with respect 
to HRQoL the sample size has been calculated to provide sufficient power for the 
comparison of the primary and secondary endpoint TDI, at Week 24.  
The sample size calculations use a two-sided 5% significance level and an estimate of 
between subject standard deviation for TDI of 2.94 units.  The estimate of SD is based on 
DB2113373 [Donohue, 2013], a study which consisted of treatment arms of UMEC/VI 
62.5/25, UMEC 62.5 VI (Vilanterol) 25mcg and placebo and is the value at Day 168 in a 
subgroup of subjects who were ICS free at screening.  Based on these data, 727 evaluable 
subjects per treatment arm will be required to provide 90% power to detect a statistically 
significant difference if the true difference is 0.5 units, ½ the MCID, between UMEC/VI 
and UMEC. The smallest observed effect predicted to result in a statistically significant 
difference between treatment groups is 0.31 units.
With this number of evaluable subjects per arm, the study will have >99% power 
assuming a true treatment difference of 80mL between UMEC/VI and UMEC for trough 
FEV1 at 24 weeks at the two-sided 5% significance level. This calculation uses a SD for 
trough FEV1 of 240mL, based on prior results for trials comparing dual bronchodilators 
versus single bronchodilators (Donohue, 2013; Bateman, 2013). The smallest observed 
effect predicted to result in a statistically significant difference between treatment groups 
is 25mL. 
In order to account a for a 10% withdrawal rate, approximately 808 subjects per 
treatment arm will be randomised.
 
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9.2.1.
Sample Size Assumptions
9.2.2.
Sample Size Sensitivity
The assumption of a SD of 2.94 units for the TDI total score is based on estimates from 
previous studies. The following table presents the power achieved with the proposed 
sample size of 727 randomised subjects per arm, should the assumption around the SD of 
the data change. 
The actual assumptions used in the sample size calculation are shaded.
Endpoint 
Between 
subject SD
Treatment Difference
Power
TDI
2.54
0.5
96%
2.74
0.5
94%
2.94
0.5
90%
3.14
0.5
86%
3.34
0.5
81%
9.2.3.
Sample Size Re-estimation or Adjustment
No sample size re-estimation is planned for this study. 
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-
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subjects
 
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Population
Definition / Criteria
Analyses Evaluated
Intent-to-
treat (ITT)

All randomized subjects, excluding those who 
were randomized in error and received at least 
one dose of study medication. 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.

Displays will be based on the treatment to 
which the subject was randomized.

Study Population

Efficacy

Safety
Intent-to-
treat ICS 
free (ITT 
ICS free)

All subjects in the ITT Population who have 
not received ICS.

Study Population

Efficacy

Safety
9.3.2.
Interim Analysis
No interim analysis is planned for the study.
9.4.
Key Elements of Analysis Plan
Treatment Comparisons
The primary treatment comparison of UMEC/VI with UMEC will be performed on the 
ITT population.
The other treatment comparisons of UMEC/VI and UMEC with Salmeterol will be 
performed on the ITT population and ITT ICS free population.
9.4.1.
Primary Analyses
The treatment comparison of primary interest will be UMEC/VI versus UMEC for the 
primary endpoint of change from baseline in trough FEV1 at Week 24. The primary 
analyses will be performed using a mixed model repeated measures (MMRM) analysis 
and will be based on a two-sided hypothesis testing approach on the ITT Population. 
In order to account for multiplicity across treatment comparisons and endpoints, a step-
down closed testing procedure will be applied whereby inference for secondary and other 
endpoints or treatment comparisons are dependent upon statistical significance having 
been achieved for the primary comparison. If the primary comparison is significant i.e. 
the associated p-value for UMEC/VI versus UMEC for change from baseline in trough 
FEV1 at Week 24 is below 0.05, this will allow inference of treatment comparisons 
(UMEC/VI versus UMEC on all other endpoints, and UMEC/VI versus Salmeterol and 
UMEC versus Salmeterol on all endpoints including the primary endpoint), which will be 
declared statistically significant if the associated p-value is below 0.05.  
 
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There will be 2 analyses one for one for the German Federal Joint Committee (G-BA) 
and one for the rest of the world (ROW).
The step-down closed testing procedure only applies to the ROW.  For the G-BA 
statistical inference for secondary and other endpoints or treatment comparisons will not 
be conditional on achieving statistical significance of the primary comparison.  
The primary endpoint of mean change from baseline in trough FEV1 at the end of Week 
24 and secondary endpoint change from baseline in TDI score at Week 24 will both be 
analysed using MMRM analysis. The MMRM analysis for change from baseline in 
trough FEV1 and TDI will include measurements at Treatment Weeks 4, 12 and 24. 
Treatment group (a categorical variable) will be fitted as the explanatory variable with 
appropriate pre-defined variables, stratum (number of bronchodilators per day during 
run-in) and baseline values, fitted as covariates. Visit (nominal) will be fitted as a 
categorical variable and visit-by-baseline and visit-by-treatment interaction terms will be 
included to allow treatment effects to be estimated at each visit separately. The variance 
covariance matrix will be assumed to be unstructured (based on previous experience no 
issues are expected with fitting models with this matrix structure). 
While missing data are not explicitly imputed in the primary MMRM analyses, there is 
an underlying assumption that the data are missing at random. 
The estimated treatment differences between UMEC/VI versus UMEC for each endpoint 
will be presented with the 95% confidence intervals for the difference and the p-value. 
Full details of the analyses to be performed on all primary endpoints will be given in the 
RAP.
9.4.2.
Other Analyses
The MMRM analysis will be repeated for the ITT ICS free population. Estimated 
differences between UMEC/VI or UMEC and Salmeterol will be presented together with 
95% confidence intervals (CIs) for the difference and p-values.
Secondary and other efficacy endpoints and treatment comparisons will be adjusted for 
multiplicity as per Section 9.4.1.
Full details of the analyses to be performed on the other efficacy endpoints will be given 
in the RAP.
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. 
 
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Deaths and SAEs will be documented in case narrative format. 
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 eCRF
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.  

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 
 
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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 randomization 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.
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Chen H, Yu KD, Xu GZ. Association between Variant Y402H in Age-Related Macular 
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umeclindinium/vilanterol 62.5/25mcg in COPD.  Respir Med 2013; 107: 1538-1546.
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EMA/CHMP/48353572 , 2012.
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Gorin MB. Genetic insights into age-related macular degeneration: Controversies 
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James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
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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, P., 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
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. 
Leidy NK, Sexton CC, Jones PW, Notte SM. et al. Measuring respiratory symptoms in 
clinical trials of COPD: reliability and validity of a daily diary. Thorax 2014; 69:5 424-
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Leidy NK, Wilcox TK, Jones PW, Roberts L, Powers JH, Sethi S. Standardizing 
measurement of chronic obstructive pulmonary disease exacerbations. Reliability and 
validity of a patient-reported diary. Am J Respir Crit Care Med 2011; 183:323-329 
Mahler DA, Ward J, Fierro-Carrion G, et al. Development of self-administered versions 
of modified baseline and transition dyspnea indexes in COPD. J COPD 2004; 165–172
Mahler DA, Weinberg DH, Wells CK, Feinstein AR. The measurement of dyspnea. 
Contents, inter-observer agreement, and physiologic correlates of two new clinical 
indexes. Chest 1984, 85: 751-758.
Maleki-Yazdi MR, Kaelin T, Richard N, Zvarich M, Church A. Efficacy and safety of 
umeclidinium/vilanterol 62.5/25 mcg and tiotropium 18 mcg in chronic obstructive 
pulmonary disease: results of a 24-week, randomized, controlled trial. Respiratory 
medicine. 2014;108:1752-60.
Maltais F, Singh S, Donald AC, Crater G, Church A, Goh AH, Riley JH. Effects of a 
combination of umeclidinium/vilanterol on exercise endurance in patients with chronic 
obstructive pulmonary disease: two randomized, double-blind clinical trials. Ther Adv 
Respir Dis. 2014;8:169-81.
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, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright 
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spirometry.  Eur Respir J.  2005;26: 319-338.
Moy ML, Weston NA, Wilson EJ, Hess ML, Richardson CR. A pilot study of an Internet 
walking program and pedometer in COPD. Respir Med. 2012;106:1342-50. 
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Global Lung Function Initiative.  Multi-ethnic reference values for spirometry for the 3-
95 year age range: the global lung function 2012 equations. Eur Respir J, 2012; 40: 
1324–1343.
Schmidt SA, Johansen MB, Olsen M et al. The impact of exacerbation frequency on 
mortality following acute exacerbation of COPD: a registry-based cohort study. B Med J. 
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Shu-Yi Liao, Roberto Benzo et al. Physical Activity Monitoring in Patients with Chronic 
Obstructive Pulmonary Disease. Journal of the COPD Foundation 2014; 1: 155-165
Siler T, Kerwin E, Sousa A, Donald A, Rehan A, Church A, Efficacy and safety of 
umeclidinium added to fluticasone furoate/vilanterol in chronic obstructive pulmonary 
disease: Results of two randomized studies.  Respir Med. 2015; 109:1155-63
Singh D, Maleki-Yazdi MR, Tombs L, Iqbal A, Fahy WA, Naya I. Prevention of 
clinically important deteriorations in COPD with umeclidinium/vilanterol. Int’l J of 
COPD, 2016; 11:1413-1424
Tashkin DP, Fabbri LM. Long acting beta-agonists in the management of chronic 
obstructive pulmonary disease: Current and future agents.  Respir Research, 2010; 11: 
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randomised, placebo-controlled study.  Eur Respir J. 2014; 43: 72–81.
Watz H, Waschki B, Meyer T, Magnussen H: Physical activity in patients with COPD. 
Eur Respir J 2009, 33:262–272.
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frequent exacerbator phenotype in chronic obstructive pulmonary disease. BMC 
Medicine, 2013; 11:181
 
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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
CAT
COPD Assessment Test
CI
Confidence Intervals
CID
Clinically important deterioration 
COPD
Chronic Obstructive Pulmonary Disease
CPK
Creatine phosphokinase
CRF
Case Report Form
CV
Cardiovascular
DPI
Dry Powder Inhaler
DRE
Disease Related Event
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eDiary
Electronic Diary
eMDI
Electronic Metered Dose Inhaler
E-RS
Evaluating Respiratory Symptoms- COPD  Tool
ERS
European Respiratory Society
FEV₁
Forced Expiratory Volume in One Second
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GOLD
Global Initiative for Chronic Obstructive Lung Disease
GSK
GlaxoSmithKline
IB
Investigator Brochure
ICF
Informed Consent Form
ICS
Inhaled Corticosteroid
IEC
Independent Ethics Committee
IP
Investigational product
INR
International normalized ratio
IRT
Interactive Response Technology
ITT
Intent-to-Treat
IUD
Intrauterine Device
IUS
Intrauterine System
LABA
Long Acting Beta-Agonist
LAMA
Long-acting Muscarinic Receptor Antagonists
LDH
Lactate dehydrogenase
LTOT
Long Term Oxygen Therapy
 
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mcg
Microgram
MCID
Minimal Clinically Important Difference
MDI
Metered Dose Inhaler
mL
Milliliter
mMRC
Modified Medical Research Council
MMRM
Mixed Models Repeated Measures
MSDS
Material Safety Data Sheet
NYHA
New York Heart Association
OTC
Over the Counter
PGx
Pharmacogenetic
PIL
Patient Information Leaflet
PK
Pharmacokinetic
PP
Per Protocol
prn
As required
QTc
QT interval corrected for heart rate
RAP
Reporting and Analysis Plan
SABA
Short Acting Beta-Agonist
SAE
Serious Adverse Event
SD
Standard Deviation
SmPC
Summary of Product Characteristics
SRT
Safety Review Team
TDI
Transition Dyspnea Index
RAMOS NG
Randomization and medication ordering system new 
generation
ULN
Upper Limit of Normal
UMEC
Umeclidinium (GSK573719)
UMEC/VI
Umeclidinium & Vilanterol as a fixed dose combination
VI
Vilanterol Trifenate 
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
ANORO
E-RS
DISKUS
EXCACT
ELLIPTA
INCRUSE
SEREVENT
 
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12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments
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 normal 
ranges. baseline (see MONITORING below)

Do not restart/rechallenge subject 
with study treatment. Permanently 
discontinue study treatment and may 
continue subject in the study for any 
protocol specified follow up assessments

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 a week after last 
dose6

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
 
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Liver Chemistry Stopping Criteria - Liver Stopping Event
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 normal ranges.

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 normal ranges.
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
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 
 
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approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.  
 
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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 etiology 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 any concomitant medicines;

COPD susceptibility, severity, and progression of 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.
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.
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.  
 
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
A 6 ml blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. 
A blood sample is collected at the baseline visit, after the subject has been 
randomized and 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 being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA 
sample is retained

Discontinue participation in the genetic research and destroy the genetic DNA 
sample 
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. 
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis. 
 
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
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.
 
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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., hospitalization 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 hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization 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 hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
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 hospitalization 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 hospitalization, 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 
and not interfering with everyday activities.
 
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
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 
or investigations, histopathological examinations or consultation with other health 
 
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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

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 by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
 
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12.5.
Appendix 5: COPD Exacerbation Identification, 
Categorization and Treatment Guidelines
12.5.1.
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 usage in their 
daily eDiary 

If the subject seeks emergency/acute care for worsening respiratory symptoms, 
he/she should request the caring Health Care Provider (HCP) to contact the 
Investigator as soon as possible.
Subjects with worsening respiratory symptoms will be classified as having:

A mild/moderate/severe exacerbation and/or pneumonia
OR

A Lower Respiratory Tract Infection (LRTI)
 
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
Background variability of COPD

A non-respiratory related disease

Other respiratory related disease
12.5.2.
COPD Exacerbation Severity
Each COPD exacerbation will be categorized based on severity as follows:
Moderate:  Worsening symptoms of COPD that require treatment with 
oral/systemic corticosteroids and/or antibiotics.
Severe: Worsening symptoms of COPD that require treatment with in-patient 
hospitalization or 24 hrs in the emergency room.
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.
12.5.3.
Treatment of COPD Exacerbations
All medications used for the treatment of exacerbations must be recorded in the source 
documents and the exacerbation page of the eCRF.  All sites should follow the protocol 
treatment guidelines (as outlined below), but any medications deemed medically 
necessary may be used to treat a COPD exacerbation. However, caution is advised in 
using a LABA or LAMA to treat a subject currently taking IP as these additional 
medications may increase the risk of overdose. If necessary the PI or other health care 
personnel may stop the subject’s IP temporarily in order to treat the COPD exacerbation.
12.5.4.
Guidelines for Treatment with Corticosteroids
If in the opinion of the Investigator/treating physician the exacerbation is severe enough 
to warrant the need for oral or systemic corticosteroids (with or without antibiotics) the 
following guidelines should be used.

The duration of treatment with oral/systemic corticosteroids should be 14 days 
(dose and type according to local practice) 

The duration of treatment with oral/systemic corticosteroids should not exceed 14 
days unless approval is given by the sponsor or representative

Any course of oral/systemic corticosteroids started within 7 days of finishing a 
previous course will be considered as treatment for a single exacerbation
 
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12.5.5.
Guidelines for Treatment with Antibiotics
If there is evidence of respiratory infection that in the opinion of the Investigator or 
treating physician warrants the need for antibiotics the following guidelines should be 
followed:

The duration of treatment with antibiotics should not exceed 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 
12.5.6.
Onset and Resolution of COPD Exacerbations
For each mild, moderate and severe exacerbation, the date of onset and the date of 
resolution will be recorded in the study source documents and eCRF.
The date of onset is the first day (of at least 2 consecutive days) of worsening symptoms 
of COPD as described in Section 12.5.1.
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.
12.5.7.
Guideline for assessing multiple mild exacerbations
Two mild exacerbations can be combined into one, per the Investigator’s judgement, if a 
subject’s diary reveals that the two mild COPD exacerbations are separated by no more 
than three exacerbation free days.
12.5.8.
Guideline for assessing exacerbations that increase in severity
If an exacerbation starts off as mild, but becomes moderate or severe or starts off as 
moderate and becomes severe, the exacerbation should be captured as one exacerbation 
and classified by its highest level of severity.
 
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12.6.
Appendix 6: Definition of and Procedures for Documenting 
Medical Device Incidents
12.6.1.
Definitions of a Medical Device Incident
The detection and documentation procedures described in this protocol apply to all GSK 
medical devices provided for use in the study (see Section 6.2 for the list of GSK medical 
devices).
Medical Device Incident Definition:

Incident – Any malfunction or deterioration in the characteristics and/or performance 
of a device, as well as any inadequacy in the labeling or the instructions for use 
which, directly or indirectly, might lead to or might have led to the death of a 
patient/user/other persons or to a serious deterioration in their state of health.

Not all incidents lead to death or serious deterioration in health.  The non-occurrence 
of such a result might have been due to other fortunate circumstances or to the 
intervention of health care personnel.
It is sufficient that:

an incident associated with a device happened and

the incident was such that, if it occurred again, might lead to death or a serious 
deterioration in health.

A serious deterioration in state of health can include:

life-threatening illness

permanent impairment of body function or permanent damage to a body structure

a condition necessitating medical or surgical intervention to prevent one of the 
above 

fetal distress, fetal death or any congenital abnormality or birth defects
Examples of incidents

a patient, user, care giver or professional is injured as a result of a medical device 
failure or its misuse

a patient’s treatment is interrupted or compromised by a medical device failure

misdiagnosis due to medical device failure leads to inappropriate treatment

a patient’s health deteriorates due to medical device failure
 
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12.6.2.
Documenting Medical Device Incidents
Medical Device Incident Documenting:

Any medical device incident occurring during the study will be documented in the 
subject’s medical records, in accordance with the investigator’s normal clinical 
practice, and on the appropriate form.

For incidents fulfilling the definition of an AE or an SAE, the appropriate AE/SAE 
CRF page will be completed as described in Appendix 4.

The form will be completed as thoroughly as possible and signed by the investigator 
before transmittal to GSK.

It is very important that the investigator provides his/her assessment of causality to 
the medical device provided by GSK at the time of the initial report, and describes 
any corrective or remedial actions taken to prevent recurrence of the incident.

A remedial action is any action other than routine maintenance or servicing of a 
device where such action is necessary to prevent recurrence of an incident. This 
includes any amendment to the design to prevent recurrence.
 
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12.7.
Appendix 7: Modified List of Highly Effective Methods for 
Avoiding Pregnancy in FRP and Collection of Pregnancy 
Information
12.7.1.
Modified List of Highly Effective Methods for Avoiding Pregnancy 
in Females of Reproductive Potential (FRP)
The list does not apply to FRP with same sex partners or for subjects who are and will 
continue to be abstinent from penile-vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyle. Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.
1.
Contraceptive subdermal implant
2.
Intrauterine device or intrauterine system
3.
Combined estrogen and progestogen oral contraceptive [Hatcher, 2011]
4.
Injectable progestogen [Hatcher, 2011]
5.
Contraceptive vaginal ring [Hatcher, 2011]
6.
Percutaneous contraceptive patches [Hatcher, 2011]
7.
Male partner sterilization 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, 2011]. The documentation on male sterility can come from the site 
personnel’s: review of subject’s medical records, medical examination and/or semen 
analysis, or medical history interview provided by her or her partner.
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
12.7.2.
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 fetal status (presence or 
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.
 
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
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. 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 be withdrawn from the study
 
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12.8.
Appendix 8: Country Specific Requirements
No country-specific requirements exist.
 
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