A Randomized, Open-Label, 8-Week Cross-Over Study to Compare Umeclidinium/Vilanterol With Tiotropium/Olodaterol Once-Daily 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
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TITLE PAGE
Division:  Worldwide Development
Information Type: Clinical Protocol
Title:
A Randomized, Open-Label, 8-Week Cross-Over Study to 
Compare Umeclidinium/Vilanterol with Tiotropium/Olodaterol 
Once-Daily in Subjects with Chronic Obstructive Pulmonary 
Disease (COPD)
Compound Number:
GSK573719+GW642444
Development Phase
IV
Effective Date:
29-MAR-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
 
Stockley Park 
West, 1-3 
Ironbridge 
Road, 
Uxbridge, 
Middlesex, 
UB11 1BT, 
United 
Kingdom
Secondary 
Medical 
Monitor
 
980 Great 
West Road, 
Brentford, 
Middlesex, 
TW8 9GS, 
United 
Kingdom
SAE 
contact  
information 
TBD
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 106616 and EudraCT 2016-000585-36
 
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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 204990........................................................8
2.
INTRODUCTION....................................................................................................10
2.1.
Study Rationale ..........................................................................................10
2.2.
Brief Background ........................................................................................11
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................11
4.
STUDY DESIGN ....................................................................................................12
4.1.
Overall Design ............................................................................................12
4.2.
Treatment Arms and Duration.....................................................................14
4.3.
Type and Number of Subjects.....................................................................14
4.4.
Design Justification.....................................................................................14
4.5.
Dose Justification........................................................................................15
4.6.
Benefit:Risk Assessment ............................................................................15
4.6.1.
Risk Assessment .........................................................................16
4.6.2.
Benefit Assessment.....................................................................18
4.6.3.
Overall Benefit:Risk Conclusion...................................................18
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............18
5.1.
Inclusion Criteria.........................................................................................18
5.2.
Exclusion Criteria........................................................................................21
5.3.
Screening/Baseline/Run-in Failures............................................................24
5.4.
Randomization Criteria ...............................................................................25
5.5.
Withdrawal/Stopping Criteria.......................................................................25
5.5.1.
Study Specific Withdrawal Criteria ...............................................25
5.5.2.
Reasons for Study Withdrawal.....................................................26
5.5.3.
Early Withdrawal Visit ..................................................................26
5.6.
Follow-up Contact.......................................................................................27
5.7.
Subject and Study Completion....................................................................27
6.
STUDY TREATMENT ............................................................................................27
6.1.
Investigational Product and Other Study Treatment....................................27
6.2.
Medical Devices..........................................................................................29
6.3.
Treatment Assignment................................................................................29
6.4.
Blinding.......................................................................................................30
6.5.
Packaging and Labelling.............................................................................30
6.6.
Preparation/Handling/Storage/Accountability..............................................30
6.6.1.
Storage........................................................................................30
6.6.2.
Study Medication Return..............................................................31
6.7.
Compliance with Study Treatment Administration.......................................31
6.8.
Treatment of Study Treatment Overdose....................................................31
6.9.
Treatment after the End of the Study ..........................................................32
6.10.
Concomitant Medications and Non-Drug Therapies....................................32
6.10.1.
Permitted Medications and Non-Drug Therapies..........................32
6.10.2.
Prohibited Medications and Non-Drug Therapies.........................33
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................34
7.1.
Time and Events Table...............................................................................35
 
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7.2.
Screening and Critical Baseline Assessments ............................................39
7.2.1.
Modified Medical Research Council (mMRC) Dyspnea 
Scale ...........................................................................................40
7.2.2.
12-Lead ECG...............................................................................40
7.3.
Efficacy.......................................................................................................41
7.3.1.
Spirometry ...................................................................................41
7.3.2.
Albuterol/Salbutamol Reversibility Assessment ...........................41
7.3.3.
Inspiratory Capacity (IC) ..............................................................42
7.4.
Electronic Diary...........................................................................................42
7.4.1.
EXACT and the Evaluating Respiratory Symptoms- COPD 
(E-RS; COPD) .............................................................................42
7.4.2.
Supplemental Albuterol/Salbutamol Use......................................43
7.4.3.
COPD Assessment Test (CAT)....................................................43
7.4.4.
Inhaler questionnaires..................................................................44
7.4.4.1.
Inhaler Ease of Use....................................................44
7.4.4.2.
Inhaler Errors..............................................................44
7.4.5.
Any Medical Problems Experienced and any Medications 
used to Treat those Medical Problems.........................................44
7.5.
Safety .........................................................................................................45
7.5.1.
COPD Exacerbations...................................................................45
7.5.2.
Adverse Events (AE), Serious Adverse Events (SAEs) and 
sentinel events.............................................................................45
7.5.2.1.
Time period and Frequency for collecting AE 
and SAE information...................................................45
7.5.2.2.
Method of Detecting AEs and SAEs ...........................46
7.5.2.3.
Follow-up of AEs and SAEs........................................46
7.5.2.4.
Cardiovascular Events................................................46
7.5.2.5.
Pneumonia Events .....................................................47
7.5.2.6.
Death Events..............................................................47
7.5.2.7.
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ................47
7.5.2.8.
Regulatory Reporting Requirements for SAEs............47
7.5.3.
Pregnancy ...................................................................................48
7.5.4.
Liver Chemistry Stopping Criteria ................................................48
7.5.5.
Medical Device Incidents (Including Malfunctions).......................50
7.5.6.
Physical Exams ...........................................................................50
8.
DATA MANAGEMENT ...........................................................................................50
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................50
9.1.
Hypotheses.................................................................................................50
9.2.
Sample Size Considerations.......................................................................51
9.2.1.
Sample Size Assumptions ...........................................................51
9.2.2.
Sample Size Sensitivity................................................................51
9.2.3.
Sample Size Re-estimation or Adjustment...................................52
9.3.
Data Analysis Considerations .....................................................................52
9.3.1.
Analysis Populations....................................................................52
9.3.2.
Interim Analysis ...........................................................................53
9.4.
Key Elements of Analysis Plan ...................................................................53
9.4.1.
Efficacy Analyses.........................................................................54
9.4.2.
Safety Analyses...........................................................................55
 
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10. STUDY GOVERNANCE CONSIDERATIONS........................................................55
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............55
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................55
10.3.
Quality Control (Study Monitoring) ..............................................................56
10.4.
Quality Assurance.......................................................................................57
10.5.
Study and Site Closure ...............................................................................57
10.6.
Records Retention......................................................................................57
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................58
11. REFERENCES.......................................................................................................59
12. APPENDICES........................................................................................................61
12.1.
Appendix 1 – Abbreviations and Trademarks..............................................61
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................63
12.2.1.
Prompt Reporting of Serious Adverse Events and Other 
Events to GSK.............................................................................66
12.3.
Appendix 3: Liver Safety – Study Treatment Restart or Rechallenge 
Guidelines...................................................................................................68
12.4.
Appendix 4: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................69
12.4.1.
Definition of Adverse Events........................................................69
12.4.2.
Definition of Serious Adverse Events...........................................70
12.4.3.
Definition of Sentinel Events ........................................................71
12.4.4.
Definition of Cardiovascular Events .............................................72
12.4.5.
Recording of AEs and SAEs ........................................................72
12.4.6.
Evaluating AEs and SAEs............................................................73
12.4.7.
Reporting of SAEs to GSK...........................................................74
12.5.
Appendix 5: Definition of and Procedures for Documenting Medical 
Device Incidents .........................................................................................76
12.5.1.
Definitions of a Medical Device Incident.......................................76
12.5.2.
Documenting Medical Device Incidents .......................................77
12.6.
Appendix 6: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in FRP and Collection of Pregnancy Information.......................78
12.6.1.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) ..............78
12.6.2.
Collection of Pregnancy Information ............................................78
12.7.
Appendix 7  - Country Specific Requirements.............................................80
 
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1.
PROTOCOL SYNOPSIS FOR STUDY 204990
Rationale
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary

To compare the effect of UMEC/VI 
62.5/25mcg with TIO/OLO 5/5mcg once daily 
on lung function in subjects with moderate 
COPD over 8 weeks of treatment.

Trough FEV1 at Week 8
Others

To compare the effect of UMEC/VI 
62.5/25mcg with TIO/OLO 5 /5mcg  on other 
measures of efficacy and measures of health-
related quality of life 

Proportion of responders according to FEV1
(a responder is defined as a ≥100mL change 
in Trough FEV1 from baseline) at Week 8

Rescue albuterol/salbutamol use 
(percentage of rescue-free days and mean 
number of Inhalations/day) captured in e 
diary

Trough FEV1, at Week 4

Trough FVC at Weeks 4 and 8

Trough IC at Weeks 4 and 8

COPD Assessment Test (CAT) score at 
Weeks 4 and 8

Proportion of responders according to CAT 
(defined as a ≥1 unit improvement in score 
from baseline) at Weeks 4 and 8

Time to clinically important deterioration
composite endpoint 

Inhaler ease of use

Inhaler errors

Assessment of respiratory daily symptoms 
over Weeks 1-8 using Evaluating Respiratory 
Symptoms- COPD (E-RS)  and its subscales 
(breathlessness, cough and sputum and 
chest symptoms)

Exploratory

To compare the effect of UMEC/VI 
62.5/25 mcg with TIO/OLO 5 /5mcg  on other 
measures of efficacy and measures of health-
related quality of life

Rescue albuterol/salbutamol use (percentage 
of rescue-free days and mean number of 
Inhalations/day) over Weeks 1-8 using eMDI
as data allow
Safety
To evaluate safety and tolerability of UMEC/VI 
62.5/25 mcg and TIO/OLO 5/5mcg

Incidence of adverse events

Incidence of COPD exacerbations
 
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Overall Design
This is a multicentre, randomized, open label, 2 period crossover complete block design 
study.
Eligible subjects will be randomised to receive a sequence consisting of 
umeclidinium/vilanterol (UMEC/VI) inhalation powder [62.5/25mcg once-daily] 
administered as 1 inhalation once-daily from the Ellipta Inhaler and tiotropium/olodaterol 
(TIO/OLO) 5/5mcg inhalation spray administered as inhalation of 2 inhalations once-
daily from the Respimat inhaler.  Each treatment sequence will be 8 weeks.
Study Schematic
R=Randomization
Treatment Arms and Duration

UMEC/VI 62.5/25mcg (as 1 inhalation from the ELLIPTA inhaler)

TIO/OLO 5/5mcg (as inhalation of 2 inhalations of 2.5/2.5mcg each from the 
Respimat inhaler)
All treatments will be administered once-daily in the morning for 8 weeks.
The total duration of subject participation in the study will be approximately 22 weeks
consisting of approximately 2 week run-in, two 8 week treatment periods separated by 
approximately 3 week washout and approximately 1 week follow-up.
Type and Number of Subjects
Approximately 338 subjects with moderate COPD will be screened to achieve 220
randomised and 168 evaluable subjects in the per protocol (PP) population.
 
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Analysis
The null hypothesis is that the difference in trough FEV1 between treatment groups is less 
than or equal to a pre-specified non-inferiority margin Δ:
H0: T1 – T2 ≤ Δ
The alternative hypothesis is that the difference between treatment groups is greater than 
the margin.
H1: T1 – T2 > Δ
Where T1 and T2 are the treatment means for UMEC/VI 62.5/25mcg and TIO/OLO
5/5mcg, respectively.
The non-inferiority margin has been set at -50mL for trough FEV1, consistent with 
previous studies evaluating long-acting bronchodilators for non-inferiority on lung 
function measures [Ichinose, 2010; Agustí, 2014].
If the lower bound of the 95% confidence interval around the (UMEC/VI vs. TIO/OLO) 
treatment difference is above -50mL then UMEC/VI will be considered non-inferior to 
TIO/OLO.
If the lower bound of the 95% confidence interval around the (UMEC/VI 62.5/25mcg vs.
TIO/OLO 5/5mcg) treatment difference is above 0 then UMEC/VI 62.5/25mcg will be 
considered superior to TIO/OLO 5/5mcg.
The primary endpoint of trough FEV1 at Week 8 will be analysed using a repeated 
measures model including data recorded at each of Week 4 and Week 8 for the PP 
population. Treatment group (categorical) will be fitted as the explanatory variable, with
period baseline, mean baseline, period, and visit fitted as covariates.  Visit (nominal) will 
be fitted as a categorical variable and visit by period baseline, visit by mean baseline and 
visit by treatment interaction terms will be included. Treatment effects will be estimated 
at each visit separately. The variance-covariance matrix will be assumed unstructured. 
2.
INTRODUCTION
2.1.
Study Rationale
UMEC/VI and TIO/OLO are both fixed dose combinations indicated for the maintenance 
treatment chronic obstructive pulmonary disease (COPD) that contain long-acting 
muscarinic antagonist (LAMA) and long-acting beta2-agonist (LABA) bronchodilators.  
Both are delivered via unique inhalers. The efficacy and safety of UMEC/VI and 
TIO/OLO have been well characterized with respect to placebo and their respective 
component medications. However, a direct comparison of these two combinations has not 
been conducted to further characterize their relative efficacy and safety profiles.
 
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The purpose of this study is to compare the efficacy and safety of UMEC/VI with 
TIO/OLO when used in subject with moderate COPD. Additional assessments to 
evaluate inhaler errors and study-subject rated inhaler ease of use will be conducted.
2.2.
Brief Background
COPD is a common preventable and treatable disease characterized by persistent airflow 
limitation that is usually progressive and associated with an enhanced chronic 
inflammatory response in the airways and the lung to noxious particles or gases. COPD is 
characterised by symptoms of chronic and progressive breathlessness/ dyspnea, cough 
and sputum production which can be a major cause of disability and anxiety associated 
with the disease [Mannino, 2007].
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 long 
acting bronchodilators with long acting formulations of either beta2-receptor agonists or 
muscarinic receptor antagonists. 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 of action 
[Celli, 2004; GOLD, 2015]. As disease progresses from mild to moderate, regular 
treatment with one or more long-acting bronchodilators is recommended.
UMEC/VI Inhalation Powder is a combination of UMEC, a LAMA, and VI, a LABA,
delivered via the ELLIPTA dry powder inhaler. 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®. 
TIO/OLO is a combination of TIO, a LAMA, and OLO, a LABA, delivered via the 
Respimat inhaler. TIO/OLO at a dose of 5/5mcg once-daily is marketed under the trade 
name Stiolto Respimat.in the United States (US) and Spiolto Respimat in Europe.  For 
ease Stiolto will be used hereafter in this protocol. 
Both combinations are indicated for the maintenance treatment of COPD.
3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary

To compare the effect of UMEC/VI 
62.5/25 mcg with TIO/OLO 5/5mcg once daily 
on lung function in subjects with moderate 
COPD over 8 weeks of treatment.

Clinic visit trough FEV1 at Week 8
Others

To compare the effect of UMEC/VI 
62.5/25 mcg with TIO/OLO 5 /5mcg on other 
measures of efficacy and measures of health-
related quality of life 

Proportion of responders according to FEV1
(a responder is defined as a ≥100mL change 
in Trough FEV1 from baseline) at Week 8

Rescue albuterol/salbutamol use (percentage 
 
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Objectives
Endpoints
of rescue-free days and mean number of 
Inhalations/day) captured in e diary

Trough FEV1 at Week 4

Trough FVC at Weeks 4 and 8

Trough IC at Weeks 4 and 8 

COPD Assessment Test (CAT) score at 
Weeks 4 and 8

Proportion of responders according to CAT 
(defined as a 1 unit improvement in score 
from baseline) at Weeks 4 and 8

Time to clinically important deterioration
composite endpoint

Inhaler ease of use

Inhaler errors

Assessment of respiratory daily symptoms 
over Weeks 1-8 using Evaluating Respiratory 
Symptoms - COPD (E-RS) and its subscales 
(breathlessness, cough and sputum and 
chest symptoms)
Exploratory

To compare the effect of UMEC/VI 
62.5/25 mcg with TIO/OLO 5 /5mcg  on other 
measures of efficacy and measures of health-
related quality of life

Rescue albuterol/salbutamol use (percentage 
of rescue-free days and mean number of 
Inhalations/day) over Weeks 1-8 using eMDI
as data allow
Safety
To evaluate safety and tolerability of  UMEC/VI 
62.5/25 mcg and TIO/OLO 5/5mcg

Incidence of adverse events (AEs)

Incidence of COPD exacerbations
4.
STUDY DESIGN
4.1.
Overall Design
This is a multicentre, randomized, open label, 2 period cross-over, complete block design
study.
Eligible subjects will be randomised to receive a sequence consisting of UMEC/VI 
62.5/25 mcg once-daily administered as 1 inhalation once-daily from the Ellipta Inhaler 
and TIO/OLO 5/5mcg inhalation spray administered as inhalation of 2 inhalations once-
daily from the Respimat inhaler.  Each treatment sequence will be 8 weeks.
There will be up to 8 clinic visits conducted on an outpatient basis (Figure 1).
 
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Figure 1
Study Schematic
R=Randomization
At Pre-Screen (Visit 0), subjects will provide consent for participation in the study by 
signing the Informed Consent Form (ICF), prior to undertaking any study procedures, and 
a review of their demography, medical history, concomitant medications, and a COPD 
exacerbation assessment will be performed. Once the ICF is signed, subjects will receive 
a subject identifier. Pre-screening and Screening may occur on the same day, if 
appropriate. Subjects who meet the eligibility criteria at Screening (Visit 1) will complete 
a run-in period of approximately 2 weeks followed by two 8-week treatment periods that 
are separated by a washout of approximate 3 weeks. A follow-up phone call for adverse 
event and COPD exacerbation assessment will be conducted approximately 1 week after 
the last clinic visit or early withdrawal.
At Visits 2 and 5, pre-dose (baseline) spirometry for each treatment period will be 
obtained prior to administration of the first dose of study medication for the treatment 
period. Trough spirometry will be obtained during each treatment period after 4 weeks 
(Visits 3 and 6) and 8 weeks (Visits 4 and 7). Health status will be evaluated using the 
COPD Assessment Test (CAT) at screening (Visit 1), baseline (Visit 2 and 5) and after 4 
weeks (Visits 3 and 6) and 8 weeks (Visits 4 and 7) of treatment.
Concurrent use of COPD maintenance medications including LAMAs, LABAs, oral beta-
agonists, theophyllines, inhaled corticosteroids, and phosphodiesterase 4 inhibitors will 
not be allowed during the study and, if applicable, will be washed out prior to study 
entry.
The occurrence of adverse events will be evaluated throughout the study beginning at 
Day 1 (Visit 2) and until the follow up contact. Serious adverse events (SAEs) will be 
collected over the same time period as for adverse events (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. Assessment of COPD exacerbations will be 
obtained at all study visits.
 
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Albuterol/salbutamol will be provided to subjects to use on an as needed basis for relief 
of COPD symptoms throughout the run-in, washout and treatment periods
All subjects will be given an electronic diary for use during the run-in, washout and 
treatment periods to record daily questionnaires,  any medical problems experienced 
during the study and any medication taken for those medical problems.
Daily rescue medication usage (number of inhalations taken in the last 24h) will also be 
captured in the eDiary and by the use of electronic inhaler (eMDI) as data allows.  
For determination of subject disposition, subjects will be considered to have completed 
the study upon completion of Visit 7. There are no plans to routinely provide any of the 
study treatments for compassionate use following study completion.
4.2.
Treatment Arms and Duration

UMEC/VI 62.5/ 25mcg (as 1 inhalation from the ELLIPTA inhaler)

TIO/OLO 5/5mcg (as 2 inhalations of 2.5/2.5mcg each from the Respimat inhaler)
All treatments will be administered once-daily in the morning for 8 weeks.
The total duration of subject participation in the study will be approximately 22 weeks
consisting of a approximately 2 week run-in, two 8 week treatment periods separated by 
approximately 3 week washout and an approximately 1 week follow-up.
4.3.
Type and Number of Subjects
Approximately 338 subjects will be screened and, assuming 35% of these will not be 
eligible for randomization; approximately 220 subjects will be randomized.  Based on a 
dropout rate of 15%, approximately 186 subjects will be included in the ITT population.  
Approximately 168 subjects will be evaluable in the PP population (based on a 10% 
protocol deviation rate).
4.4.
Design Justification
A randomized, cross-over study is a standard, well-established design to evaluate the 
efficacy and safety of two active drugs and each patient receives both medicines and acts 
as their own control. A complete block design will allow for within-subject treatment 
comparisons which will reduce variability in the response as each subject acts as their 
own control.
The 3-week washout between the two treatment periods is considered sufficient to enable 
washout of the effects of UMEC/VI and OLO/TIO on lung function measures. In two 
exercise studies previously conducted by GSK (DB2114417 and DB2114418), there was 
no evidence of a treatment by period interaction which suggests no evidence of carry 
over.
The open label design is appropriate as placebo Respimat from Boehringer Inglehiem 
(BI) is not available to allow a double-dummy design and the Ellipta and Respimat 
inhalers differ in appearance. The open-label design will have a negligible effect on the 
 
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spirometric data.  Pulmonary function testing is an objective physiologic assessment that 
provides consistent, reproducible results provided adequate measures are used to ensure 
standardization of testing procedures.  Well-qualified research sites with expertise in 
pulmonary function testing will be used, and a centralized spirometry vendor will provide 
standardized equipment and site training and provide quality assessment of each 
spirometry test based on accepted international lung function testing guidelines.  
Additionally, individuals performing the testing procedures will be blinded to the 
administered treatment
While the FDA and EMA guidance for trials assessing bronchodilators in patients with 
COPD recommend 12 weeks of treatment, the wealth of data with Anoro Ellipta and 
Stiolto Respimat support that treatment duration of 8 weeks is considered adequate for 
assessing FEV1 changes in response to the long-acting bronchodilators under study.  
Treatment response was shown to reach steady-state after 4 weeks in previous large scale 
parallel-group studies conducted over 6 months [Donohue, 2013; Decramer, 2014; 
Maleki-Yazdi, 2014] and after 6 weeks in two 12-week cross over studies [Maltais, 
2014]. Similar steady state findings were obtained in the primary efficacy studies 
conducted over 6 months for Stiolto Respimat [Buhl, 2015].
The PP population will be used for the treatment comparison of the primary endpoint of 
trough FEV1 at Week 8 for non-inferiority and superiority.  
The margin of non-inferiority is -50mL and the true mean treatment difference is 
assumed to be 0mL.  The non-inferiority margin of -50mL has been chosen which is 
consistent with the non-inferiority margins used for trough FEV1 or 0 to 24 hour 
weighted mean FEV1 in previous studies comparing long-acting bronchodilators or long-
acting bronchodilator/ICS combinations [Ichinose, 2010; Agustí, 2014]. Therefore, if the 
lower confidence interval (2.5% one-sided significance level) of the statistical testing 
should fall above -50mL then UMEC/VI may be deemed to be statistically non-inferior to 
OLO/TIO.
If non-inferiority is observed, the testing procedure will continue to examine statistical 
superiority.  Superiority of UMEC/VI over OLO/TIO would be claimed provided the 
lower bound of the 95% confidence interval is above 0 for the treatment difference and a 
treatment difference of approximately 50mL is obtained.
4.5.
Dose Justification
This study is intended to evaluate doses of UMEC/VI (62.5/25mcg once-daily) and 
TIO/OLO (5/5mcg once-daily) that are approved for the maintenance treatment of COPD 
and are therefore most relevant to prescribers and other health care profiles to more fully 
understanding the comparative efficacy and safety of the medications under study.
4.6.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
UMEC/VI can be found in the product label, in the Investigator’s Brochure and in the 
label information sheet. Summary safety data can also be found in the labels for 
TIO/OLO and for albuterol/salbutamol.
 
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The following section outlines the risk assessment and mitigation strategy for this 
protocol.
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 causal association has been 
found to date, in completed studies 
with UMEC/VI or UMEC 
monotherapy, on glaucoma or urinary 
Exclusion criterion states that 
subjects with medical conditions such 
as narrow-angle glaucoma, prostatic 
hypertrophy, or bladder neck 
 
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Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
retention.  However, glaucoma or 
urinary retention have been observed 
with other antimuscarinic agents, and 
could potentially be due to the 
pharmacology.
obstruction should only be 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.
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. 
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 have the potential to receive the combination long-acting bronchodilator 
therapies UMEC/VI and TIO/OLO for COPD which may provide benefit to the subjects 
to improve airflow obstruction.  Subjects who participate in this study will contribute to 
the process of further characterizing the benefit of these long-acting bronchodilator 
combinations for 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 for use “as needed” for relief of COPD 
symptoms

The combination of study procedures of spirometry, physical examination and 
COPD Assessment Test (CAT) will provide the study subjects with a 
comprehensive evaluation of their health and COPD disease severity. Subjects 
will also be monitored throughout the study to see if their disease and general 
health worsens. 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 and TIO/OLO 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 products or other study 
treatment that may impact subject eligibility is provided in the IB, 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:
[1] Type of subject: 
Outpatient.
[2] Informed Consent:
A signed and dated written informed consent prior to study participation
 
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[3] AGE
Subjects 40 years of age or older at Visit 1
[4] Gender
Male and female subjects are eligible to participate in the study.
At the discretion of the study investigator and in alignment with local country acceptable 
criteria, a female is eligible to enter and participate in the study 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:
Non-reproductive potential (i.e., physiologically incapable of becoming pregnant, 
including any female who is post-menopausal or surgically sterile) defined as:
Pre-menopausal females with one of the following:

Documented tubal ligation

Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral or tubal occlusion 

Hysterectomy

Documented Bilateral Oophorectomy
Postmenopausal defined as 12 months of spontaneous amenorrhea in questionable 
cases a blood sample with simultaneous follicle stimulating hormone (FSH) and 
estradiol levels consistent with menopause (refer to laboratory reference ranges for 
confirmatory levels).  Females on hormone replacement therapy (HRT) and whose 
menopausal status is in doubt will be required to use one of the highly effective 
contraception methods if they wish to continue their HRT during the study.  
Otherwise, they must discontinue HRT to allow confirmation of post-menopausal
status prior to study enrolment.
OR
Reproductive potential, has a negative pregnancy test at screening, and agrees to 
one of the methods below in the GSK Modified List of Highly Effective Methods for 
Avoiding Pregnancy in Females of Reproductive Potential (FRP) requirements from 
methods used consistently and correctly (i.e., in accordance with the local approved 
product label and per study investigator discretion and the instructions of the 
physician from 30 days prior to the first dose of study medication and until to follow-
up contact):
GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in Females 
of Reproductive Potential (FRP)
This list does not apply to FRP with same sex partners, when this is their preferred and 
usual lifestyle or for subjects who are and will continue to be abstinent from penile-
vaginal intercourse on a long term and persistent basis.

Contraceptive subdermal implant that meets the SOP effectiveness criteria 
including a <1% rate of failure per year, as stated in the product label
 
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
Intrauterine device or intrauterine system that meets the SOP effectiveness criteria 
including a <1% rate of failure per year, as stated in the product label [Hatcher, 
2007a]

Oral Contraceptive, either combined or progestogen alone 

Injectable progestogen 

Contraceptive vaginal ring

Percutaneous contraceptive patches 

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.  

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.
[5] Diagnosis:
A diagnosis of COPD in accordance with the definition by the American Thoracic 
Society/European Respiratory Society [Celli, 2004].
[6] Smoking History:
Current or former cigarette smokers with a history of cigarette smoking of 10 pack-
years [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.
[7] Severity of Disease: 
A pre and post-albuterol/salbutamol FEV1/FVC ratio of <0.70 and a post-
albuterol/salbutamol FEV1 of 70% to ≥ 50 % of predicted normal values at Visit 1. 
Predicted values will be based upon the ERS Global Lung Function Initiative [Quanjer, 
2012].  
[8] Dyspnea:
A score of ≥2 on the Modified Medical Research Council Dyspnea Scale (mMRC) at 
Visit 1.
 
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5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
[1]  Pregnancy:
Women who are pregnant or lactating or are planning on becoming pregnant during the 
study.
[2]  Asthma:  
A current diagnosis of asthma.  (Subjects with a prior history of asthma are eligible if 
they have a current diagnosis of COPD, which is the primary cause of their respiratory 
symptoms).
[3]  Other Respiratory Disorders:
α1-antitrypsin deficiency: Subjects with α1-antitrypsin deficiency as the underlying 
cause of COPD
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]  Other Diseases/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.
[5]  Severe Hepatic Impairment: 
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). 
Notes: 

Stable chronic liver disease should generally be defined by the absence of 
ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or 
gastric varices, or persistent jaundice, or cirrhosis.

Chronic stable hepatitis B and C (e.g., presence of hepatitis B surface antigen 
(HBsAg) or positive hepatitis C antibody test result at screening or within 3 
months prior to first dose of study treatment) are acceptable if subject otherwise 
meets entry criteria
 
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[6]  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
[7]  Contraindications: 
Any history of allergy or hypersensitivity to any anticholinergic/muscarinic receptor 
antagonist, sympathomimetic, lactose/milk protein or magnesium stearate.
[8]  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.
[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). 
Other respiratory tract infections that have not resolved at least 7 days prior to 
Screening (V1).
[10]  Lung Resection:  
Subjects with lung volume reduction surgery (including procedures such as 
endobronchial valves) within the 12 months prior to Screening (V1).
[11]  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 
 
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participation in the study:

Atrial fibrillation with rapid ventricular rate >120 bpm

Sustained or nonsustained ventricular tachycardia

Second degree heart block Mobitz type II or third degree heart block (unless 
pacemaker or defibrillator had been inserted)
[12]  Medication Prior to Spirometry:  
Unable to withhold albuterol/salbutamol for the 4 hour period required prior to 
spirometry testing at each study visit.
[13]  Medications Prior to Screening:  
Use of the following medications according to the following defined time intervals prior 
to Screening (Visit 1):
Medication
Time interval
Depot corticosteroids
12 weeks
Systemic, oral or parenteral corticosteroids1
6 weeks
Antibiotics (for lower respiratory tract infection)
6 weeks
LABA/Inhaled Corticosteroid (ICS) combination products 
30 days
ICS
30 days
Phosphodiesterase 4 (PDE4) Inhibitor (roflumilast)
14 days
Inhaled long acting beta2 agonists (LABAs):
-salmeterol, formoterol
-olodaterol, indacaterol, vilanterol
48 hours
14 days
Long-acting muscarinic antagonists (LAMAs): tiotropium, 
aclidinium, glycopyrronium, umeclidinium
7 days
LAMA/LABA combination products 
Apply whichever mono 
component has the longest 
washout
Theophyllines
48 hours
Oral beta2-agonists
     Long-acting
     Short-acting
48 hours
12 hours
Inhaled short acting beta2-agonists2
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)
1.
Localized corticosteroid injections (e.g., intra-articular and epidural) are permitted.
2.
Use of study provided albuterol/salbutamol is permitted during the study, except in the 4-hour period prior to 
spirometry testing
[14]  Oxygen: 
Use of long-term oxygen therapy (LTOT) described as resting oxygen therapy >3L/min 
at screening. (Oxygen use ≤3L/min flow is not exclusionary, and patients may adjust 
oxygen levels as needed during the study.)
 
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[15]  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).
[16]  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.
[17]  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.
[18]  Affiliation with Investigator Site:  
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.
[19]  Inability to Read: 
In the opinion of the investigator, any subject who is unable to read and/or would not be 
able to complete a questionnaire.
Subjects who fail to meet inclusion and exclusion criteria at the Screening Visit will be 
considered screen failures and cannot be re-screened.
5.3.
Screening/Baseline/Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized. Data for screening failure will be collected in source 
documentation at the site and will be transmitted to GSK. In order to ensure transparent 
reporting of screen failure subjects, meet the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements, and respond to queries from Regulatory 
authorities, a minimal set of screen failure information is required including 
Demography, Screen Failure details, Eligibility Criteria, and Serious Adverse Events
related to study participation or concomitant medication.
 
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5.4.
Randomization Criteria
Subjects must meet the following randomisation criteria at Day 1 (Visit 2), in order to be 
randomised to study medication:
1. COPD Exacerbation: 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. Prohibited Medications: No use of any prohibited medications during the run-in 
period or at Visit 2.
5.5.
Withdrawal/Stopping Criteria
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as 
soon as possible. 

The site must counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or should 
continue in the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and if necessary a certified letter to the subject’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be 
considered to have withdrawn from the study with a primary reason of “Lost to 
Follow-up”. 
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons. If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records. 
5.5.1.
Study Specific Withdrawal Criteria
A subject must be withdrawn from the study if any of the following criteria are met:

Pregnancy: Positive pregnancy test

Liver Chemistry: Meets any of the protocol-defined liver chemistry stopping 
criteria as defined in Section 7.5.4.  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.
 
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5.5.2.
Reasons for Study Withdrawal
The primary reason for study withdrawal will be recorded in the eCRF. When a subject 
withdraws consent, the investigator must document the reason (if specified by the 
subject) in the eCRF. The primary reason for study withdrawal (and sub-reason, if 
applicable) will be categorized as:

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
o
COPD exacerbations

Study closed/terminated

Subject reached protocol-defined stopping criteria
o
Liver event
o
Pregnancy

Investigator discretion
5.5.3.
Early Withdrawal Visit
The definition of an early subject withdrawal from the study will be any subject who is 
randomized to blinded medication and, for any reason, is withdrawn prior to completion 
of the Visit 7 procedures.
A subject may voluntarily discontinue participation in the study at any time.  The 
investigator may also, at his/her discretion; discontinue the subject from participating in 
the study at any time.  In addition, the investigator must make every effort to have the 
subject return to the clinic as soon as possible after discontinuation of study drug for an 
Subjects that withdraw from the study should return to the clinic return to the clinic as 
soon as possible after discontinuation of study drug for an Early Withdrawal Visit.  At the 
Early Withdrawal Visit, the following evaluations and procedures should be completed 
and recorded in the eCRF as required:

Concomitant medication assessment

Adverse event assessment
 
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
COPD exacerbation assessment

Physical examination (recorded in source documents only)

Collect/review electronic diary  

Collect used study medication (blinded study medication and rescue 
albuterol/salbutamol)

Assess compliance with investigational product

Urine pregnancy test for females of childbearing potential 

Inhaler ease of use questionnaire

Smoking status and smoking cessation counseling

Contact the RAMOS IRT to report subject’s early withdrawal from the study
A follow-up contact as described in Section 5.6 should be conducted 5 to 10 days 
following completion of the Early Withdrawal Visit.
5.6.
Follow-up Contact
A safety follow-up contact should be conducted 73 days following the completion of 
Visit 7 or the Early Withdraw 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
For determination of subject disposition, subjects will be considered to have completed 
the study upon completion of Visit 7.
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 
 
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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 investigational product for use in this study. 
The following study medications will be used in this study:

UMEC/VI 62.5/ 25mcg administered via ELLIPTA

TIO/OLO 5/5mcg administered via Respimat
Subjects will be instructed to take one dose of medication each morning from either the
ELLIPTA (one inhalation to equal one dose) or the Respimat (inhalation of two
inhalations to equal one dose.) Subject instructions and details on how to use the
ELLIPTA and Respimat are provided in the SPM.
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 DPI 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. 
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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GSK will also supply commercial stock TIO/OLO Inhalation Spray delivered via 
Respimat as manufactured by Boehringer Ingelheim (Headquarters in Ingelheim, 
Germany). Each actuation from the Respimat inhaler delivers 3.124mcg tiotropium 
bromide monohydrate (equivalent to 2.5mcg tiotropium) and 2.736mcg olodaterol 
hydrochloride (equivalent to 2.5mcg olodaterol) from the mouthpiece. Each TIO/OLO 
carton will contain a Respimat cartridge as an aluminum cylinder with a tamper 
protection seal on the cap and a Respimat inhaler. The Respimat inhaler is a cylindrical 
shaped inhaler with a gray colored body and a clear base. The clear base is removed to 
insert the cartridge. The Respimat contains a dose counter and will provide 60 metered 
inhalations
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.  If not available or not appropriate locally, GSK will source centrally.  
6.2.
Medical Devices
Subject to availability, medical devices (eMDI devices) are being provided by GSK for 
use in this study.  These devices, which are fitted on to albuterol/salbutamol MDI to 
electronically record rescue medication usage, have US FDA 510(K) clearance to market
(Class II device) and EU CE marking (Class I device).
6.3.
Treatment Assignment
Subjects will be assigned to study treatment in accordance with the randomization 
schedule generated by Clinical Statistics, prior to the start of the study, using validated 
internal software.
Subjects who meet the eligibility criteria will be randomly assigned to one of the 
following sequences shown in Table 2 in equal proportion:
Table 2
Treatment Sequences
Sequence
Period 1
Period 2
1
UMEC/VI Inhalation Powder 62.5/25mcg, 
(as 1 inhalation) administered once daily via 
the Ellipta inhaler 
8 weeks
TIO/OLO 5/5mcg, (as 2 inhalations of 
2.5/2.5mcg per inhalation) administered 
once daily via Respimat
8 weeks
2
TIO/OLO 5/5mcg, (as 2 inhalations of 
2.5/2.5mcg per inhalation) administered 
once daily via Respimat
8 weeks
UMEC/VI Inhalation Powder 62.5/25mcg, 
(as 1 inhalation) administered once daily via 
the Ellipta inhaler 
8weeks
Once a randomization number is assigned to a subject it cannot be reassigned to any other 
subject in the study. 
 
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The duration of treatment for each subject in each period is 8 weeks.  On the morning of 
each clinic study visit, subjects will refrain from taking their morning dose of study 
medication 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 medication each morning.
During the washout period, subjects will discontinue use of the study medication and will 
continue use of study provided albuterol to manage breakthrough symptoms. 
Additionally, short-acting anticholinergics will be allowed for use during the washout 
periods.
This study will utilize an IVR/IWR 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 IVR/IWR to register and randomize subjects is provided in the SPM.
6.4.
Blinding
This is an open label study with no blinding of IP due to lack of availability of placebo 
Respimat.
6.5.
Packaging and Labelling
The contents of the label will be in accordance with all applicable regulatory 
requirements and will be mentioned in the SPM.
6.6.
Preparation/Handling/Storage/Accountability
No special preparation of study treatment is required.
6.6.1.
Storage
All Ellipta DPI study medication 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. 
The TIO/OLO should be stored at 25C (77F). Avoid freezing. 
Sites must maintain a daily temperature log for the investigational products.
Investigational product must be stored in a secure area under the appropriate physical
conditions for the product.  Access to and administration of the investigational product 
will be limited to the investigator and authorized site staff.  Details of study medication 
administration oversight are provided in the SPM.  Investigational product must be 
dispensed or administered only to subjects enrolled in the study and in accordance with 
the protocol.
 
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6.6.2.
Study Medication Return
All used and unused Ellipta DPIs, and Respimat 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 SPM.
All study medication will be collected at Visit 4 and 7 or at the IP discontinuation visit, if 
applicable.
For any Ellipta DPI or Respimat 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 
IVRS IRT to obtain a new treatment pack number for the subject and dispense a new 
study medication kit from the site’s investigational product supply as instructed by the 
IVR/IWR
In addition, any Ellipta DPI that fails to function properly must be identified and returned 
to GSK for testing.  Details of the failure will be documented in the eCRF.
6.7.
Compliance with Study Treatment Administration
Study drug administration at clinic visits will be observed by study personnel to ensure 
the proper administration of study drug.  Subject compliance with UMEC/VI (one 
inhalation per day equals one dose) will be assessed at the appropriate Week 4 and Week 
8 clinic visits by reviewing the dose counter on the Ellipta inhaler. Subject compliance
with TIO/OLO will be assessed at the appropriate Week 4 and Week 8 clinic visits by
reviewing the number of inhalations/day (2 inhalations/day to equal one dose) as 
recorded in the eDiary. 
If study medication compliance with either inhaler is determined to be < 80% or > 120%, 
the subject must be re-educated on proper dosing per protocol.  This re-education should 
be documented in the subject’s source document.  Overall compliance with either inhaler 
during an entire period that is not within the range of be >=80% and <=120% will be 
identified as a protocol deviation. Subjects with overall compliance not within the range 
of be >=80% and <=120% during the first treatment period will be allowed to continue in 
the study provided re-education on proper dosing is provided.
6.8.
Treatment of Study Treatment Overdose
An overdose is defined as a dose greater than the total doses described above which 
results in clinical signs and symptoms.  These should be recorded by the investigator on 
the AE/SAE pages.  In the event of an overdose of study 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 
 
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significant data pertaining to the study drug being used in this study. Such documents 
may include, but not be limited to, the approved product label for TIO/OLO, albuterol 
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.
6.9.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because the indication being studied is not life threatening or seriously debilitating 
and/or other treatment options are available.  
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific 
post-study treatment.
6.10.
Concomitant Medications and Non-Drug Therapies
All COPD medications used within 30 days prior to Visit 0 and onwards should be 
recorded in the eCRF including any changes. Beginning at Screening (Visit 1) and 
throughout the rest of the study, all non-COPD medications should be recorded in the 
eCRF including any changes. The minimum requirement includes but is not limited to 
drug name, dose, route and the dates of administration. Study provided 
albuterol/salbutamol and study drug should not be recorded in the eCRF.  Medications 
initiated after completion of Visit 7 will not be recorded in the eCRF, with the exception 
of those used to treat a COPD exacerbation or SAE that occurs between Visit 7 and the 
follow-up contact.
6.10.1.
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 

Short-acting inhaled muscarinic antagonists during washout period only, provided 
they are washed out for 4 hours prior to Visit 5

Mucolytics such as acetylcysteine

Medications for rhinitis (e.g. intranasal corticosteroids, antihistamines, cromolyn, 
nedocromil, nasal decongestants)

Influenza vaccine

Pneumonia vaccine

Antibiotics for short term treatment (14 days) of acute infections including  
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
Systemic corticosteroids for short term (14 consecutive days)  treatment of 
COPD exacerbations 

As-needed oxygen use (i.e. 12 hours per day)

Pulmonary rehabilitation program in maintenance phase

Smoking cessation treatment, including a stable regimen of nicotine replacement

Use of positive airway pressure for sleep apnea 

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
6.10.2.
Prohibited Medications and Non-Drug Therapies
Use of the medications listed in Table 3 is not permitted during the study.
Table 3
Prohibited Medications
Medication
Depot corticosteroids
Systemic, oral or parenteral corticosteroids1
Antibiotics >14 days
LABA/ICS combination products
ICS 
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, umeclidinium)
LAMA/LABA combination products except for study drugs
Theophyllines
Oral beta2-agonists
Inhaled short acting beta2-agonists2
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
Use of study provided albuterol/salbutamol is permitted during the study, except in the 4-hour period 
prior to spirometry testing. Inhaled short-acting anticholinergics are allowed during the washout period 
and must be discontinued for 4 hours prior to Visit 5
 
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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 at screening. 

Regular (prescribed for daily/regular use, not for as-needed use) therapy with 
albuterol/salbutamol.

Initiation of pulmonary rehabilitation during the study.
Acetaminophen should not be used in patients with acute viral hepatitis.
7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.
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
Screen/Run-in
Treatment 1
Wash-
Out
Treatment 2
Post-Treatment
Visit
0
Prescreen1
1
(Screen)
2
(Rand)
3
4
5
6
7
EW Visit2
Follow up 
Contact11
Treatment Day 
14 3
days 
prior to 
Visit 2 
1
3
days
28
3 days 
56
3 days 
21 days
3 days
1
21 3
days
after V4
28
3 days 
after V5
56
3 days 
after V5
7 3days 
after V7 or 
EW Visit
Week
-1
N/A
4
8
N/A
4
8
Screen / 
Baseline
Written informed consent
X
Demography
X
Medical/COPD history
X
Smoking history/status
X
X
X
Smoking cessation 
counselling
X
X
X
Verify 
Inclusion/exclusion 
criteria
X
Concomitant medication 
assessment
X
X
X
X
X
X
X
X
X
X
X
Verify Randomization 
criteria
X
Physical examination 
X
X
X
Screening 12-Lead ECG
X
Screening spirometry 
(including post-
bronchodilator testing)3
X
mMRC dyspnea scale
X
Training on use of 
inhalers13
X
X
Training in the use of 
eDiary and eMDI
X
Register visit IVRS
X
X
X
X
X
X
X
X
X
X
X
 
 
 
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Screen/Run-in
Treatment 1
Wash-
Out
Treatment 2
Post-Treatment
Visit
0
Prescreen1
1
(Screen)
2
(Rand)
3
4
5
6
7
EW Visit2
Follow up 
Contact11
Treatment Day 
14 3
days 
prior to 
Visit 2 
1
3
days
28
3 days 
56
3 days 
21 days
3 days
1
21 3
days
after V4
28
3 days 
after V5
56
3 days 
after V5
7 3days 
after V7 or 
EW Visit
Week
-1
N/A
4
8
N/A
4
8
Efficacy/
Inhaler 
Evaluations
Pre dose Spirometry
(FEV1, FVC and IC)4
X
X
Trough Spirometry 
(FEV1, FVC and IC)5
X
X
X
X
CAT12
X
X
X
X
X
X
X
EXACT-PRO (14 item 
questionnaire)
Inhaler Ease of use 
assessment
X
X
Inhaler Errors 
assessment13
X
X
Safety
Adverse event 
assessment6
X
X
X
X
X
X
X
X
X
X
COPD exacerbation 
assessment
X
X
X
X
X
X
X
X
X
X
X
Urine pregnancy test7
X
X
X
X
X
Observed dose in clinic14
X
X
Medication/
Supplies
Dispense rescue 
albuterol/salbutamol8 
with eMDI
X
X
X
X
X
X
X
Collect rescue 
albuterol/salbutamol9 
with eMDI
X
X
X
X
X
X
X
Dispense period 1 study 
medication
X
X
 
 
 
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Screen/Run-in
Treatment 1
Wash-
Out
Treatment 2
Post-Treatment
Visit
0
Prescreen1
1
(Screen)
2
(Rand)
3
4
5
6
7
EW Visit2
Follow up 
Contact11
Treatment Day 
14 3
days 
prior to 
Visit 2 
1
3
days
28
3 days 
56
3 days 
21 days
3 days
1
21 3
days
after V4
28
3 days 
after V5
56
3 days 
after V5
7 3days 
after V7 or 
EW Visit
Week
-1
N/A
4
8
N/A
4
8
Collect period 1 study 
medication
X
X
Dispense period 2 study 
medication
X
X
Collect period 2 study 
medication
X
X
Assess drug 
compliance10
X
X
X
X
X
Dispense eDiary
X
Collect eDiary
X
X
1.
Pre-screen Visit must be completed prior to or on the same day as Screening Visit.
2.
Early Withdrawal Visit: Subjects that withdraw should return to the clinic as soon as possible for the Early Withdrawal Visit.
3.
Spirometry at screening for FEV₁ and FVC assessments to be conducted as follows: pre-bronchodilator testing followed by post-albuterol/salbutamol testing. Post-
albuterol/salbutamol testing conducted 10 to 30 minutes after subject self-administration of 4 Inhalations of albuterol/ salbutamol.  IC will not be obtained at Screening.
4.
Spirometry: On Day 1 of each period (Visits 2 and 5 respectively), pre-dose IC, FEV₁, and FVC measurements should be conducted 30 minutes and 5 minutes prior to dosing.
5.
Trough IC, FEV₁, and FVC measurements on Weeks 4 and 8 of each treatment period should be done 23 hours and 24 hours after the previous day’s dose of study medication.
6.
Adverse events and Serious Adverse Events to be collected from the start of study drug (Visit 2) until the follow-up contact. However, any serious adverse events assessed as 
related to study participation or related to a GSK concomitant medication will be recorded from the time of consent. Subjects will use eDiary to record any medical problems 
experienced during the study and any medication taken for those medical problems
7.
Pregnancy test: for females for child bearing potential only.
8.
After Visit 1, albuterol/salbutamol to be used and dispensed on an as-needed basis. Use in inhalations/day to be recorded daily by subjects using the ePro.
9.
Collect albuterol/salbutamol: as required (all rescue medication should be collected at Visit 7 or the Early Withdrawal Visit).
10. Compliance with UMEC/VI will be determined by reviewing the dose counter on the Ellipta inhaler. Compliance with the TIO/OLO will be determined by reviewing the number of 
inhalations/day (2 inhalations/day to equal one dose) as recorded in the e Diary.
11. The follow-up contact will be by telephone 5 to 10 days after V7 or the Early Withdrawal Visit.
 
 
 
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12. CAT will be performed at the site on the eDiary.
13. For first dosing of each treatment period the subject will follow the patient information sheet under the observation of the site staff. Before the subject leaves the clinic the site staff 
will make sure the subject is shown a training video on the use of the inhaler and they will make sure the inhaler is correctly loaded.  
14. Dosing by the subject will be observed in the clinic and corrected if necessary.  Retraining by showing the training video to take place if dosing not correct.  PI to make sure inhaler 
loader appropriately loaded before subject leaves the clinic.
EW= Early withdrawal
Rand = Randomization
 
 
 
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7.2.
Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors (as detailed in the CRF) will be assessed at 
screening.
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5.  
Reported Outcomes questionnaires should be completed by subjects before any other 
assessment at a clinic visit, in the order specified.
No study related procedures may be performed until the informed consent form 
document has been signed by the subject.  A pre-screening visit may be required in 
order to administer the informed consent before any changes are made to the subject’s 
current medication regimen. The investigator should exercise clinical judgment, and is 
discouraged from changing medications only for the purposes of the clinical study. The 
informed consent must be signed before any changes are made to the subject’s current 
medication regimen. The informed consent may be given at the screening visit if the 
subject does not take or has not taken any prohibited medications defined by the protocol.  
During the pre-screening visit (Visit 0); each subject will have the following information 
collected:

Demographic history (including gender, ethnic origin, race and year of birth)

Concomitant medication review

COPD exacerbation assessment

Cardiovascular medical history/risk factors
The additional following critical baseline assessments will be conducted at Visit 1:

Medical history including COPD (compromised of 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) 

Inclusion/Exclusion criteria assessment

Concomitant medication review (COPD concomitant medications in the 3 months 
prior to Screening)

Pre- and post-albuterol/salbutamol spirometry (reversibility)

Physical examination 

12-Lead ECG

Urine pregnancy test if applicable
 
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
SAE assessment (if related to study participation)

mMRC dyspnea scale

CAT
Assessment of subject’s health status will be made at screening using CAT.  Patient 
Reported Outcomes questionnaires must be completed by subjects before any other 
assessment at each clinic visit, in the order specified. mMRC should be performed prior 
to CAT at screening as it is an inclusion criterion.
7.2.1.
Modified Medical Research Council (mMRC) Dyspnea Scale
At screening the subject’s degree of dyspnea to different levels of activity will be rated 
on the five point mMRC scale. The mMRC, administered by an interviewer, asks subjects 
to rate how breathless they are using a 0-4 point scale.
The mMRC, administered by an interviewer, asks subjects to rate how breathless they are 
on a 5-point scale as follows:

0 = not troubled by breathlessness except with strenuous exercise

1 = troubled by shortness of breath when hurrying on the level or walking up a 
slight hill

2 = Walks slower than people of the same age on the level because of 
breathlessness or has to stop for breath when walking at own pace on the level

3 = stops for breath after walking about 100 yards or after a few minutes on the 
level

4 = too breathless to leave the house or breathless when dressing or undressing
7.2.2.
12-Lead ECG
ECG measurements will be obtained with equipment provided by the investigation site. A 
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. 
ECGs are only required at Visit 1 (Screening) only for eligibility assessment. 
The investigator, a designated sub-investigator, or other appropriately trained site 
personnel will be responsible for performing and interpreting the 12-lead ECG at Visit 1 
(Screening). The investigator must provide his/her dated signature on the original paper 
tracing, attesting to the authenticity of the ECG machine interpretation. 
 
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7.3.
Efficacy
7.3.1.
Spirometry
Spirometry measurements will be obtained using spirometry equipment that meets or
exceeds the minimal performance recommendations of the ATS [Miller, 2005]. All sites
will use standardized spirometry equipment provided by an external vendor.
All subjects will have spirometry performed at Screening and at Visits 2, 3, 4, 5, 6, and 7
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) ≥4 hours and after withholding
short-acting inhaled anticholinergics taken during washout for ≥4 hours prior to 
Visit 5

At Visit 1, after withholding COPD medications as specified in the exclusion 
criteria in Section 5.

At Visit 3 and 6 after withholding the morning dose of study drug (note study 
drug will not be administered at visits 4 and 7). 

Pre dose assessments performed prior dosing
Subjects should refrain from smoking for 1 hour prior to each pulmonary function test.
On Day 1 of each treatment period (Visits 2 and 5 respectively), pre-dose spirometry
measurements should be conducted 30 minutes and 5 minutes prior to dosing. Trough
measurements on Weeks 4 (Visits 3 and 6) and Week 8 (Visits 4 and 7) of each treatment 
period should be done 23 hours and 24 hours after the previous day’s dose of study 
medication. Any trough FEV1 measurement collected outside 22.0-25.0 hours after the 
previous day’s dose will be considered protocol deviations with data exclusion from the 
Per Protocol population analysis of trough FEV1.
7.3.2.
Albuterol/Salbutamol Reversibility Assessment
At Visit 1, both pre- and post-albuterol/salbutamol spirometry will be obtained to 
determine subject eligibility. Failure to obtain both pre- and post- post-
albuterol/salbutamol spirometry at Visit 1 will be considered a protocol deviation. 
Bronchodilator responsiveness testing will be completed as follows: Following pre-
albuterol/salbutamol spirometry (three acceptable spirometry efforts), the subject will 
 
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self-administer 4 Inhalations of albuterol/salbutamol MDI. Three acceptable spirometry 
efforts should be obtained approximately 10 to 30 minutes after albuterol/salbutamol 
administration.
7.3.3.
Inspiratory Capacity (IC)
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; 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 and 5
(30 and 5 min prior to dosing) and at trough at Visits 3, 4, 6 and 7 (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 TLC (Total Lung Capacity) 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 and after withholding
short-acting inhaled anticholinergics taken during washout for ≥4 hours prior to 
Visit 5

At Visit 3 after withholding the morning dose of study drug (note study drug will 
not be administered at visits 4 and 7). 
7.4.
Electronic Diary
Electronic diary will be used to collect the following: E-RS, rescue use, CAT and 
Inhaler questionnaires and potential medical problems.
7.4.1.
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 
 
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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.
7.4.2.
Supplemental Albuterol/Salbutamol Use
Subjects should be instructed that study-provided albuterol/salbutamol should be used on 
an ‘as-needed’ basis only.  
Rescue medication will be captured in the electronic Diary as well as eMDI as data allow.  
Details on how to place the eMDI on the MDI is described in the SPM.
Rescue inhaler use will be captured each day (during run-in, washout and treatment 
periods) by means of an eDiary and if available and possible in an eMDI device . The 
eDiary will be used as the primary analysis measure.   eMDI attaches to the actual MDI 
inhaler and that gets activated every time there is an actuation. The device should be 
attached to the MDI inhaler at the first subject visit. If the subject requires a replacement 
rescue inhaler the eMDI device can be transferred from the old inhaler to the new on. 
This should be performed at the study site by the Investigator or designee.
Use of rescue albuterol/salbutamol should not be recorded as a concomitant medication 
in the eCRF.
The following Clinic visit Questionnaires will also be collected on the electronic 
diary:
7.4.3.
COPD Assessment Test (CAT)
COPD-related health status will be assessed using the CAT at Visit 1 for subject 
characterisation and then Visits 2, 3, 4, 5, 6 and Visit 7.
The COPD Assessment Test (CAT) is a patient-completed instrument designed to 
provide a simple and reliable measure of health status in COPD. The CAT is designed to 
measure overall COPD-related health status for the assessment and long-term follow-up 
of individual patients.  The instrument consists of eight items; each formatted as a 
semantic six-point differential scale, and is completed by the patient [Jones, 2009; Jones, 
2012].
CAT will be completed at each visit on the eDiary. Additional instructions for 
completion of the CAT are provided in the SPM.
CAT evaluations must be performed before any other visit procedures.
 
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7.4.4.
Inhaler questionnaires
7.4.4.1.
Inhaler Ease of Use
An investigator (or designee)-administered questionnaire will be completed at Visits 2
and 5, or Early Withdrawal if applicable, to determine the ease of use of the ELLIPTA
and Respimat. Six questions will be asked and the subject will be required to select only 
one response for each question.
A sample of the inhaler ease of use questionnaire is included in the SPM. Additional
instructions for completion of this questionnaire are provided in the SPM.
7.4.4.2.
Inhaler Errors
Inhaler errors will be assessed using the Inhalers Errors Checklist at Visit 2 and Visit 5 to 
assess the critical and overall (critical and non-critical) errors made by subjects with the 
ELLIPTA and Respimat inhalers. 
The investigator (or designee)-administered inhaler errors checklist is based on the steps
listed in the Patient Information Leaflets (PIL) for each inhaler.  The proportion of 
subjects reported by the investigator or designee as making at least one critical error 
(defined as an error that is most likely to result in no or only minimal medication being 
inhaled) or overall error (includes a critical and non-critical error) will be evaluated in 
this study.
The inhaler errors checklist will be administered by the investigator or designee.
At Visit 2 and 5, the subject will prepare his or her inhaler for first use and  self-
administer their first dose of the study medication in the clinic under the supervision of 
the investigator or designee.  The subject will simply follow the instructions in the patient 
information leaflet without prior instruction on the day.  Any errors (critical or non-
critical) made by the subject while using the inhaler will be recorded by the investigator 
or designee. If the subject makes no errors, this will also be recorded.  Any errors (critical 
or non-critical) made by the subject while using the inhaler will be recorded by the
investigator or designee. If the subject makes no errors, this will also be recorded. The 
investigator or designee will demonstrate the correct use of the inhaler to the subject and 
will make sure the inhaler is loaded properly before the subject leaves the clinic.
Additional instructions for completion of the inhaler errors checklist are provided in the 
SPM.
7.4.5.
Any Medical Problems Experienced and any Medications used to 
Treat those Medical Problems
Signs and symptoms of COPD included on the electronic diary card will not be 
considered AEs and will not be collected in the eCRF.
 
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7.5.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).  
Safety endpoints include the following:

Incidence of COPD exacerbations

Incidence of adverse events
7.5.1.
COPD Exacerbations
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. 
If a subject experiences a moderate or severe COPD exacerbation, the COPD 
exacerbation page of the eCRF should be completed. COPD exacerbations should not be 
recorded as an Adverse Event, unless they meet the definition of a Serious Adverse 
Event.
Subjects who experience a moderate or severe exacerbation during the run-in period will 
be withdrawn from the study and will not be allowed to be re-screened. 
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. COPD exacerbations after randomization 
through follow-up will be recorded on the COPD exacerbation page of the eCRF.
7.5.2.
Adverse Events (AE), Serious Adverse Events (SAEs) and 
sentinel events
The definitions of an AE or SAE and sentinel event can be found in Section 12.4.
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE.
7.5.2.1.
Time period and Frequency for collecting AE and SAE information

AEs will be collected from the start of study treatment and until the follow up 
contact.  

AEs and SAEs will be collected at the time points specified in the Time and Events 
Table (Section 7.1).
 
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
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.

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. 

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in.

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 
Section 7.5.2.1
7.5.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact?” 

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?” 
7.5.2.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs and non-serious AEs of special interest 
(as defined in Section 7.5.2) 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).
7.5.2.4.
Cardiovascular Events
Investigators will be required to fill out event specific data collection tools for the 
following AEs and SAEs:  

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

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
Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularisation
This information should be recorded in the specific cardiovascular eCRF within one week 
of when the AE/SAE(s) are first reported.
7.5.2.5.
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. 
7.5.2.6.
Death Events
In addition, all deaths will require a specific death data collection tool to be completed.  
The death data collection tool includes questions regarding cardiovascular (including 
sudden cardiac death) and non-cardiovascular death.
This information should be recorded in the specific death eCRF within one week of when 
the death is first reported.
7.5.2.7.
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.
7.5.2.8.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK or designee of SAEs and non-serious AEs 
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 
 
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regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.5.3.
Pregnancy

Any pregnancy that occurs during study participation must be reported using a 
clinical trial pregnancy form.  To ensure subject safety, each pregnancy must be 
reported to GSK within 2 weeks of learning of its occurrence.  The pregnancy 
must be followed up to determine outcome (including premature termination) and 
status of mother and child.  Pregnancy complications and elective terminations for 
medical reasons must be reported as an AE or SAE.  Spontaneous abortions must 
be reported as an SAE.

Any SAE occurring in association with a pregnancy, brought to the investigator’s 
attention after the subject has completed the study and considered by the 
investigator as possibly related to the study treatment, must be promptly reported 
to GSK.

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 6.
7.5.4.
Liver Chemistry Stopping Criteria
A protocol-defined liver chemistry stopping criteria and increased monitoring algorithm 
is provided in Figure 2.
 
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Figure 2
Phase III/Phase IV Liver Stopping and Increased Monitoring 
Algorithm
Liver Safety Required Actions and Follow up Assessments Section can be found in
Appendix 2
Phase III-IV Liver Chemistry Increased Monitoring Algorithm with Continued 
Therapy for ALT 3xULN but <8xULN
Liver Safety Required Actions and Follow up Assessments Section can be found in
Appendix 2
Note: This study does not require laboratory assessments, therefore the liver chemistry
criteria apply to any laboratory assessments obtained outside of the protocol-specified 
safety evaluations.
Continue Study Treatment 
Discontinue Study Treatment 
Plus 
Bilirubin≥2x
ULN (>35% 
direct) or plus
INR>1.5, if 
measured*
Possible  
Hy’s Law
ALT≥3xULN
ALT
≥8xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
No
Yes
Yes
Yes
No
No
No
See algorithm 
for continued 
therapy with 
increased liver 
chemistry 
monitoring
Yes
*INR value not applicable to subjects on anticoagulants 
ALT 
≥3xULN 
but 
<8xULN
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
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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7.5.5.
Medical Device Incidents (Including Malfunctions)
Procedures for Documenting Medical Device Incidents are provided in Appendix 5
7.5.6.
Physical Exams
A complete physical examination will be performed at Visit 1 screening and at Visit 7 or 
Early Withdrawal Visit if appropriate. 
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).
8.
DATA MANAGEMENT

For this study subject data will be entered into GSK defined electronic case report 
forms (eCRFs), transmitted electronically to GSK or designee and combined with 
data provided from other sources in a validated data system.  

Management of clinical data will be performed in accordance with applicable 
GSK standards and data cleaning procedures to ensure the integrity of the data, 
e.g., removing errors and inconsistencies in the data.

Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated 
medication dictionary, GSKDrug.  

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 objective of this study is to compare UMEC/VI 62.5/25 mcg with TIO/OLO
5/5 mcg in moderate COPD subjects. The primary endpoint is trough FEV1 at Week 8. 
The primary analysis is the comparison of this endpoint for UMEC/VI 62.5/25 mcg vs.
TIO/OLO 5/5 mcg.  
The null hypothesis is that the difference in trough FEV1 between treatment groups is less 
than or equal to a pre-specified non-inferiority margin Δ:
H0: T1 – T2 ≤ Δ
The alternative hypothesis is that the difference between treatment groups is greater than 
the margin.
H1: T1 – T2 > Δ
 
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where T1 and T2 are the treatment means for UMEC/VI 62.5/25 mcg and TIO/OLO 5/5 
mcg, respectively.
The non-inferiority margin has been set at -50mL, which is consistent with the non-
inferiority margins used for trough FEV1 or 0 to 24 hour weighted mean FEV1 in 
previous studies comparing long-acting bronchodilators or long-acting 
bronchodilator/ICS combinations [Ichinose, 2010; Vogelmeier, 2010; Agustí, 2014].
If the lower bound of the 95% confidence interval around the (UMEC/VI 62.5/25 mcg vs.
TIO/OLO 5/5 mcg) treatment difference is above -50mL then UMEC/VI 62.5/25 mcg
will be considered non-inferior to TIO/OLO 5/5 mcg.
If the lower bound of the 95% confidence interval around the (UMEC/VI 62.5/25 mcg vs.
TIO/OLO 5/5 mcg) treatment difference is above 0 then UMEC/VI 62.5/25 mcg will be 
considered superior to TIO/OLO 5/5 mcg.
9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
The sample size calculations use a one-sided 2.5% significance level and an estimate of 
within-subject standard deviation (SD) for trough FEV1 of 140 ml.  The estimate of SD is 
based on a mixed model repeated measures (MMRM) analyses of two previous cross-
over studies in COPD subjects evaluating trough FEV1 at Week 2. The observed SD from 
these studies (133ml in DB2116132 and 113ml in DB2116133) has been increased to 
allow for additional variability that may be observed during an 8 week treatment period. 
A study with 168 evaluable subjects for the primary analysis on the per-protocol (PP)
population will have 90% power to detect non-inferiority of UMEC/VI to TIO/OLO
based on trough FEV1 at Week 8, when the margin of non-inferiority is -50mL and the 
true mean treatment difference is assumed to be 0mL.
It is estimated that approximately 10% of subjects who will provide a Week 8 assessment 
will be excluded from the PP population, which would require 186 subjects with a Week 
8 assessment in the ITT population.  Allowing for a 15% withdrawal rate, a total of 220 
subjects will be randomised.
9.2.2.
Sample Size Sensitivity
The within-subject SD of 140 ml for trough FEV1 used for the sample size calculations 
was based on two previous cross-over responder studies in COPD subjects evaluating 
trough FEV1 at Week 2.  If the standard deviation observed in this study is different from 
the estimated value used in the sample size calculation, the power to determine non-
inferiority based on trough FEV1 at Week 8 will be affected. Table 4 illustrates the power 
which would be obtained with various standard deviations, assuming the number of
evaluable subjects remains constant at 168 and the non-inferiority margin is -50 mL. 
 
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Table 4
Impact on Power of Different Estimates of Standard Deviation for 
Trough FEV1
Within-subject SD (mL)
Power for Margin of -50 mL
100
>99%
120
97%
140
90%
160
81%
180
72%
If the within subject SD increased to 180 mL, the study would have 72% power to 
conclude non-inferiority based on a margin of -50 mL. If the SD were 100 mL then the 
study would have >99% power to conclude non-inferiority.
Based on a within subject SD of 140 mL and a sample size of 168 evaluable PP subjects, 
the lower confidence bound for the treatment difference would be greater than 0 at an 
observed treatment difference of 30 mL [detectable effect].
Based on a within subject SD of 140 mL and a sample size of 186 ITT subjects, the study 
would conclude superiority (i.e. lower confidence bound > 0) with a treatment difference
of 29mL [detectable effect]. 
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
Three subject populations will be identified.
The All Subjects Enrolled Population will comprise all subjects for whom a record 
exists on the study database, including screen failures and any subject who was not 
screened but experienced a serious adverse event (SAE) between the date of informed 
consent and the planned date of the Screening Visit. This population will be used for 
reporting subject disposition, reasons for withdrawal prior to randomization, and 
inclusion, exclusion and randomization criteria deviations and SAEs for non-randomised
subjects.
The Intent-to-treat (ITT) Population will comprise all subjects randomized to treatment, 
excluding those who were randomized in error. A subject who is recorded as a screen or 
run-in failure and also randomized will be considered to be randomized in error.  Any 
other subject who receives a randomization number will be considered to have been 
randomized. Randomized subjects will be assumed to have received study medication 
unless definitive evidence to the contrary exists. Outcomes will be reported according to 
the randomized treatment allocation. This population will be the used for all efficacy and 
safety displays unless specified otherwise. 
 
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The Per Protocol (PP) Population will comprise all subjects in the ITT Population who 
do not have a full protocol deviation considered to impact efficacy. Receipt of a study 
treatment other than the randomised treatment will be considered a full protocol 
deviation. Subjects with partial protocol deviations considered to impact efficacy will be 
included in the PP Population but will have their data excluded from PP analyses from 
the time of deviation onwards. Subjects with time-point specific or period specific 
protocol deviations will be included in the PP population but will have the data affected 
excluded from PP analyses. The definition of full, partial, time-point specific and period 
specific deviations considered to impact efficacy will be included in the Reporting and 
Analysis Plan (RAP). This population will be used for the primary comparison between 
the treatments to determine NI.  It will also be used for the primary comparison between 
treatments to assess superiority, assuming that the primary analysis on the PP population 
supports the conclusion of NI.
9.3.2.
Interim Analysis
No interim analysis is planned.
9.4.
Key Elements of Analysis Plan
Since this is an 8 week non-inferiority study with two active comparators, the number of 
withdrawals is expected to be low. In particular, subjects who experience an exacerbation 
whilst in the study will be allowed to continue participating if possible. Furthermore, the 
primary comparison is non-inferiority on the per protocol population (a De Jure 
estimand) and inclusion of data from subjects post-withdrawal would likely bias the 
results towards a conclusion of non-inferiority. Hence data from subjects post-withdrawal 
will not be collected.  Where possible, data from subjects who withdraw prematurely 
from the study will be included in any relevant analyses. Specific details for inclusion 
will be detailed in the RAP, but in general the minimum data required will be a baseline 
evaluation and at least one on-treatment evaluation. Tipping Point analyses will however 
be conducted to assess robustness of conclusions.  Data collected during a clinic visit will 
be reported by the visit at which the data were collected and will not be excluded from 
any analysis for being collected outside of an assessment window.
For the purposes of analyses, a completed subject is defined as anyone completing the 
last treatment visit for each period (Visit 4 and 7).
It is anticipated that approximately 30 centres (worldwide) will participate in the study. 
Centres enrolling a small number of subjects may be pooled with another centre. All 
amalgamations will be finalised and documented in the RAP. These amalgamations will 
be used wherever region is incorporated into the analysis.
Baseline values for each endpoint will be those used from Visit 1 (screening) or pre-
treatment in period 1 at Visit 2 (randomisation) or pre-treatment in period 2 at Visit 5 and 
will be defined in the RAP.
 
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9.4.1.
Efficacy Analyses
All efficacy data will be summarized using means, SDs and ranges for continuous data 
and frequencies and percentages for categorical data.
Primary Endpoint
The primary endpoint of trough FEV1 at week 8 will be analysed using a repeated 
measures model including data recorded at each of Week 4 and Week 8 for the PP 
population. Treatment group (categorical) will be fitted as the explanatory variable, with 
period baseline, mean baseline, period, and visit fitted as covariates.  Visit (nominal) will 
be fitted as a categorical variable and visit by period baseline, visit by mean baseline and 
visit by treatment interaction terms will be included. Treatment effects will be estimated 
at each visit separately. The variance-covariance matrix will be assumed unstructured. 
Missing data are not imputed in this analysis; however, all non-missing data will be used 
within the analysis to estimate the treatment effect at Week 8.
Estimated treatment differences for UMEC/VI vs. TIO/OLO will be presented together 
with 95% confidence intervals (CIs) for the difference and p-values (for test of 
superiority).
The MMRM analysis of the primary endpoint will be repeated for the ITT Population
testing for superiority in order to ensure consistent results with those from the PP 
population.  These analyses will include data from protocol deviators.  In addition, a 
tipping point analysis will be carried out as a sensitivity analysis for the primary endpoint 
of trough FEV1 at Week 8 on the PP and ITT population in order to assess the impact of 
missing data.  Full details will be given in the RAP.
Other Endpoints
FVC and IC at Week 4 and Week 8 will be analysed separately using the same 
methodology as that for the primary endpoint.  The mean number of Inhalations of rescue 
medication per day for Weeks 1-2, 3-4, 5-6 and 7-8 will be analysed using a mixed model 
repeated measures analysis including covariates of period baseline, mean baseline, 
period, treatment, two-weekly period, two-weekly period by period baseline interaction
and two-weekly period by mean baseline interaction. The model will use all available 
values recorded during Weeks 1-2, 3-4, 5-6 and 7-8.  Missing data are not directly 
imputed in this analysis; however, all non-missing data for a subject will be used within 
the analysis to estimate the treatment effect for the mean number of Inhalations of rescue 
medication over Weeks 1-8.  Two models will be fitted; one with a response variable of 
mean number of Inhalations, and one with a response variable of change from baseline in 
mean number of Inhalations. The variance-covariance matrix will be assumed 
unstructured. 
Estimated treatment differences for UMEC/VI vs. TIO/OLO will be presented together 
with 95% confidence intervals (CIs) for the difference and p-values.
 
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The percentage of rescue-free days will be analysed similarly.  If the assumption for 
normality is not satisfied a non-parametric analysis will be used instead.  Full details will 
be given in the RAP.
The CAT endpoint at Week 4 and Week 8 will be analysed using an MMRM analysis as 
described for the primary endpoint of trough FEV1.
Responder analyses for trough FEV1 and CAT will be analysed using a logistic 
regression analysis for Week 4 and Week 8 separately.  Further details will be given in 
the RAP.
9.4.2.
Safety Analyses
AEs will be coded using the standard GSK dictionary, Medical Dictionary for Regulatory 
Activities (MedDRA), and grouped by body system. AEs with onset pre-treatment or 
during active treatment will be summarized separately. The number and percentage of 
subjects experiencing at least one AE of any type, AEs within each body system and AEs 
within each preferred term will be presented for each treatment group. Separate 
summaries will be provided for all AEs, drug related AEs, SAEs and AEs leading to 
withdrawal.
All SAEs will be tabulated and listed by treatment group. Deaths and SAEs will be 
documented in case narrative format.
The proportion of subjects experiencing a COPD exacerbation will be tabulated.
Full details of the analyses to be performed on all efficacy and 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.
 
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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 CRF 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.
REFERENCES
Agustí A, de Teresa L, De Backer W, Zvarich MT, Locantore N, Barnes N, Bourbeau J, 
Crim C. A comparison of the efficacy and safety of once-daily fluticasone 
furoate/vilanterol with twice-daily fluticasone propionate/salmeterol in moderate to very 
severe COPD. Eur Respir J. 2014;43:763-72.
Buhl R, Maltais F, Abrahams R, Bjermer L, Derom E, Ferguson G, Fležar M, Hébert J, 
McGarvey L, Pizzichini E, Reid J, Veale A, Grönke L, Hamilton A, Korducki L, Tetzlaff 
K, Waitere-Wijker S, Watz H, Bateman E. Tiotropium and olodaterol fixed-dose 
combination versus mono-components in COPD (GOLD 2-4). Eur Respir J. 
2015;45:969-79.
Celli BR, MacNee W. Standards for the diagnosis and treatment of patients with COPD: 
a summary of the ATS/ERS position paper. Eur Respir J. 2004; 23:932-946.
Decramer M, Anzueto A, Kerwin E, et al.  Efficacy and safety of umeclidinium plus 
vilanterol versus tiotropium, vilanterol, or umeclidinium monotherapies over 24 weeks in 
patients with chronic obstructive pulmonary disease: results from two multicenter, 
blinded, randomized controlled trials.  Lancet Respir Med 2014; 2: 474-86.
Donohue, JF, Maleki-Yazdi MR, Kilbride S, et al.  Efficacy and safety of once-daily 
umeclindinium/vilanterol 62.5/25mcg in COPD.  Respir Med 2013; 107: 1538-1546.
GOLD. Global Initiative for Chronic Obstructive Lung Disease [GOLD]. Global Strategy 
for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary 
Disease. Last Updated 2015. http://www.goldcopd.org.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, editors. 
Contraceptive Technology. 19th edition. New York: Ardent Media, 2007(a): 24. Table 3-
2.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, editors. 
Contraceptive Technology. 19th edition. New York: Ardent Media, 2007(b): 28.
Ichinose M, Fujimoto T, Fukuchi Y.  Tiotropium 5 mg via Respimat and 18 mg via 
HandiHaler; efficacy and safety in Japanese COPD patients.  Respiratory Medicine; 
2010:104, 228e236
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
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-
430
 
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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 
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.
Mannino DM, Buist AS. Global burden of COPD: risk factors, prevalence, and future 
trends. Lancet. 2007: 370:765-73
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright 
P, van der Grinten CPM, Gustafsson P, Jensen R, Johnson DC, MacIntyre N, McKay R, 
Navajas D, Pedersen OF, Pellegrino R, Viegi G, Wanger J.  Standardisation of 
spirometry.  Eur Respir J.  2005;26:319-338.
Quanjer P, Stanojevic S, Cole T, Baur X., Hall G, Enright P, et al. on behalf of the ERS 
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.
Vogelmeier C, Ramos-Barbon D, Jack D, Piggott S, Owen R, Higgins M, Kramer B; 
INTIME study investigators (INdacaterol & TIotropium: Measuring Efficacy).
Indacaterol provides 24-hour bronchodilation in COPD: a placebo-controlled blinded 
comparison with tiotropium. Respir Res. 2010;11:135.
 
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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
Time to 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- PRO
Evaluating respiratory Symptoms of COPD Tool
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
IE
Inhaler Errors
IEC
Independent Ethics Committee
IP
Investigational product
INR
International normalized ratio
IRB
Independent Review Board
IRT
Interactive Response Technology
ITT
Intent-to-Treat
IUD
Intrauterine Device
IUS
Intrauterine System
LABA
Long Acting Beta-Agonist
 
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LAMA
Long-acting Muscarinic Receptor Antagonists
LDH
Lactate dehydrogenase
LTOT
Long Term Oxygen Therapy
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
NI
non-inferiority margins
NYHA
New York Heart Association
TIO/OLO
Tiotropium/Olodaterol as fixed dose combination
OTC
Over the Counter
PDE
Phosphodiesterase
PGx
Pharmacogenetic
PIL
Patient Information Leaflet
PK
Pharmacokinetic
PP
Per Protocol
prn
As required
QTc
QT interval corrected for heart rate
QTc(F)
QT interval corrected for heart rate according to Fridericia 
formula
RAP
Reporting and Analysis Plan
RNA
Ribonucleic acid
SABA
Short Acting Beta-Agonist
SAE
Serious Adverse Event
SD
Standard Deviation
SmPC
Summary of Product Characteristics
SPM
Study Procedures Manual
SRT
Safety Review Team
TDI
Transition Dyspnea Index
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
Respimat
CAT
Stiolto
ELLIPTA
 
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12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments
Phase III-IV liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and evaluate liver event 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 stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria - Liver Stopping Event
ALT-absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN  persists for 2 weeks
ALT 3xULN but <5xULN  persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2 
ALT 3xULN and INR>1.5, if INR measured
Cannot 
Monitor
ALT 5xULN but <8xULN and cannot be monitored weekly for 2 weeks
ALT 3xULN but <5xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to  liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue  study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries 
resolve , stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge subject with 
study treatment unless allowed per protocol 
and GSK Medical Governance approval is 

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 
 
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granted (refer to Appendix 3)

If restart/rechallenge not  allowed or not 
granted, permanently discontinue study 
treatment and may continue subject in the 
study for any protocol specified follow up 
assessments
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 
hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 
recommended
For All other criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform
liver event follow up assessments within  24-
72 hrs 

Monitor subjects weekly until liver chemistries 
resolve, stabilize or return to within baseline
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form
including acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG or gamma 
globulins).

Serum acetaminophen adduct HPLC 
assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with 
definite or likely acetaminophen use in the 
preceding week [James, 2009]). NOTE: 
not required in China

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography)
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated will 
not apply to subjects receiving anticoagulants
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 
 
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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.  
Phase III-IV liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 5xULN and <8xULN and
bilirubin <2xULN without symptoms
believed to be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 2 weeks.
OR
ALT 3xULN and <5xULN and
bilirubin <2xULN without symptoms
believed to be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks.

Notify the GSK medical monitor within 24 hours
of learning of the abnormality to discuss subject 
safety. 

Subject can continue study treatment  

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above

If ALT decreases from ALT 5xULN and <8xULN 
to ≥3xULN but <5xULN, continue to monitor liver 
chemistries weekly. 

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to within 
baseline.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E.  Quantification 
of Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates 
Different Patterns of Virological Response to Interferon Therapy in Chronically Infected 
Patients.  J Clin Microbiol. 2005;43(5):2363–2369.
 
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12.2.1.
Prompt Reporting of Serious Adverse Events and Other Events 
to GSK
SAEs, cardiovascular, pneumonia, death events, pregnancies, medical device incidents,
non-serious AEs related to study treatment and liver function abnormalities meeting pre-
defined criteria will be reported promptly by the investigator to GSK as described in the 
following table once the investigator determines that the event meets the protocol 
definition for that event.
Initial Reports
Follow-up Information on a Previous 
Report
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours
“SAE” data 
collection tool
24 hours
Updated “SAE” 
data collection tool
Cardiovascular or 
Pneumonia and/or 
death event (s)4
Initial and 
follow up 
reports to be 
completed 
within one 
week of when 
the 
cardiovascular, 
Pneumonia 
and or death 
event (s) is 
reported 
“Cardiovascular 
(CV)”, 
“Pneumonia” 
and/or “death” 
event(s) data 
collection tool(s) if 
applicable
Initial and follow 
up reports to be 
completed within 
one week of when 
the cardiovascular 
event Pneumonia 
and/or death 
event (s) is 
reported
Updated “CV, 
Pneumonia,” and/or 
“death” event (s) 
data collection 
tool(s) if applicable
Medical Device 
Incident
24 hours
“Medical Device 
Incident Report 
Form”
24 hours
Updated “Medical 
Device Incident 
Report Form”
Pregnancy
2 weeks
“Pregnancy 
Notification Form”
2 weeks
“Pregnancy Follow-
up Form”
Non-serious adverse 
events related to 
study treatment
5 calendar 
days
“Adverse
Reaction” data 
collection tool
2 weeks
Updated “Adverse 
Reaction” data 
collection tool
Liver chemistry abnormalities for Phase I to IV:
ALT3xULN and
Bilirubin2xULN 
(>35% direct) (or 
ALT3xULN and
INR>1.5, if INR 
measured)1
24 hours2
“SAE” data 
collection tool.  
“Liver Event CRF” 
and “Liver 
Imaging” and/or 
“Liver Biopsy” 
CRFs, if 
applicable3
24 hours
Updated “SAE” 
data collection 
tool/“Liver Event” 
Documents3
 
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Initial Reports
Follow-up Information on a Previous 
Report
Type of Event
Time Frame
Documents
Time Frame
Documents
Remaining liver chemistry abnormalities Phase III to IV:
ALT8xULN; 
ALT3xULN with 
hepatitis or rash or 
3xULN and <5xULN 
that persists4 
weeks
24 hours2
“Liver Event” 
Documents 
(defined above) 3
24 hours
Updated “Liver 
Event” Documents3
ALT5xULN plus 
bilirubin <2xULN
24 hours2
“Liver Event” 
Documents 
(defined above) 
do not need 
completing unless 
elevations persist 
for 2 weeks or 
subject cannot be 
monitored weekly 
for 2 weeks3
24 hours
Updated “Liver 
Event” Documents, 
if applicable3
ALT5xULN and 
bilirubin <2xULN that 
persists 2 weeks
24 hours2
“Liver Event” 
Documents 
(defined above) 3
24 hours
Updated “Liver 
Event” Documents3
ALT3xULN and <5x 
ULN and bilirubin 
<2xULN
24 hours2
“Liver Event” 
Documents 
(defined above) 
do not need 
completing unless 
elevations persist 
for 4 weeks or 
subject cannot be 
monitored weekly 
for 4 weeks3
24 hours
Updated “Liver 
Event” Documents, 
if applicable3
1.
INR measurement is not required; if measured, the threshold value stated will not apply to patients receiving 
anticoagulants.
2.
GSK must be contacted at onset of liver chemistry elevations to discuss subject safety
3.
Liver Event Documents (i.e., “Liver Event CRF” and “Liver Imaging CRF” and/or “Liver Biopsy CRF”, as 
applicable) should be completed as soon as possible.
4.
The SRT (or Study Team, if there is no SRT) should determine the appropriate time frame, if one is needed, for 
completion of DRE CRF pages.
Procedures for documenting, transmitting and follow-up of medical device incidents 
along with the regulatory reporting requirements for medical devices are provided in the 
SPM.
 
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12.3.
Appendix 3: Liver Safety – Study Treatment Restart or 
Rechallenge Guidelines
Not applicable
 
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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.

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.  Also, "lack of efficacy" or 
"failure of expected pharmacological action" also constitutes 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 
 
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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 
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.
 
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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.

Refer to Appendix 2 for the required liver chemistry follow-up instructions
12.4.3.
Definition of Sentinel Events
A Sentinel Event is a GSK-defined SAE that is not necessarily drug-related but has been 
associated historically with adverse reactions for other drugs and is therefore worthy of 
heightened pharmacovigilance. Medical monitor review of all SAEs for possible Sentinel 
Events is mandated at GSK.  The GSK medical monitor may request additional clinical 
information on an urgent basis if a possible Sentinel Event is identified on SAE review.:
 
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The current GSK-defined Sentinel Events 

Acquired Long QT Syndrome

Agranulocytosis/Severe Neutropenia 

Anaphylaxis & Anaphylactoid Reactions 

Hepatotoxicity

Acute Renal Failure

Seizure

Stevens Johnson syndrome/Toxic epidermal necrosis
12.4.4.
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
12.4.5.
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 
 
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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.
12.4.6.
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.
 
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
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 
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.
12.4.7.
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 
 
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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.
SAE reporting to GSK via paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the Medical Monitor

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable, with a copy of the SAE data collection tool sent by 
overnight mail

Initial notification via the telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE receipt can be found at this beginning of the protocol on the 
Sponsor/Medical Monitor Contact Information page.
SAE reporting to GSK via PIMS

Facsimile transmission of the following PIMS listings for the corresponding subject 
is the preferred method to transmit SAE information to the Medical Monitor:
SAE listing
Demographic listing
Study treatment listing

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable, with a copy of all required information sent by overnight 
mail.

If the PIMS system is unavailable when the SAE occurs, the site will use the paper 
SAE form and fax that to the Medical Monitor. The site will enter the SAE data into 
PIMS as soon as the system becomes available.
 
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12.5.
Appendix 5: Definition of and Procedures for Documenting 
Medical Device Incidents
12.5.1.
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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12.5.2.
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 

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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12.6.
Appendix 6: Modified List of Highly Effective Methods for 
Avoiding Pregnancy in FRP and Collection of Pregnancy 
Information
12.6.1.
Modified List of Highly Effective Methods for Avoiding Pregnancy 
in Females of Reproductive Potential (FRP)
This list does not apply to FRP with same sex partners, when this is their preferred and 
usual lifestyle or for subjects who are and will continue to be abstinent from penile-
vaginal intercourse on a long term and persistent basis.

Contraceptive subdermal implant 

Intrauterine device or intrauterine system 

Oral Contraceptive, either combined or progestogen alone [Hatcher, 2007a] 

Injectable progestogen [Hatcher, 2007a]

Contraceptive vaginal ring [Hatcher, 2007a]

Percutaneous contraceptive patches [Hatcher, 2007a]

Male partner 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, 2007a].  

Male condom plus partner use of one of the contraceptive options below:
o
Contraceptive subdermal implant 
o
Intrauterine device or intrauterine system 
o
Oral Contraceptive, either combined or progestogen alone [Hatcher, 
2007a] Injectable progestogen [Hatcher, 2007a]
o
Contraceptive vaginal ring [Hatcher, 2007a]
o
Percutaneous contraceptive patches [Hatcher, 2007a]
This is an all inclusive list of those methods that meet the GSK definition of highly 
effective: having a failure rate of less than 1% per year when used consistently and, 
correctly and, when applicable, in accordance with the product label.  For non-product 
methods (e.g.  male sterility), the investigator determines what is consistent and correct 
use. The GSK definition is based on the definition provided by the ICH [ICH, M3 (R2) 
2009].
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.
12.6.2.
Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study
 
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
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.

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 discontinue study medication

Investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study.  This 
applies only to subjects who are randomized to receive study medication. 

After obtaining the necessary signed informed consent from the female partner 
directly, the investigator will record pregnancy information on the appropriate form 
and submit it to GSK within 2 weeks of learning of the partner’s pregnancy

Partner will also be followed to determine the outcome of the pregnancy.  
Information on the status of the mother and child will be forwarded to GSK. 

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date.  Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure.
 
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12.7.
Appendix 7 - Country Specific Requirements
No country-specific requirements exist.
 
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