Clinical trial NCT02799784
Conditions: Pulmonary Disease, Chronic Obstructive
Keywords: tiotropium COPD olodaterol Umeclidinium bromide efficacy vilanterol
Sponsor: GlaxoSmithKline
Start date: 2016-07-14; Completion date: 2017-04-27
Enrollment: 236 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The primary objective of this study is to assess the effect of umeclidinium/vilanterol (UMEC/VI) versus tiotropium/olodaterol (TIO/OLO) in subjects with moderated COPD.

This is a multicentre, randomized, open label, 2 period crossover complete block design study.

Eligible subjects, who complete a 2-week run-in period, will be randomized to receive a sequence consisting of UMEC/VI inhalation powder (62.5/25 microgram \[mcg\] once-daily \[QD\]) administered as 1 inhalation via the ELLIPTA® Inhaler and TIO/OLO 5/5 mcg inhalation spray administered as 2 inhalations via the RESPIMAT® inhaler, for 8 weeks each. This will be followed by a 3-week washout period and one-week follow-up period. The total duration of subject participation in the study will be approximately 22 weeks.

ELLIPTA is a registered trademark of the GlaxoSmithKline group of companies. RESPIMAT is a registered trademark of Boehringer Ingelheim.

Detailed description:

Arms: arm 1: Subjects will receive UMEC/VI 62.5/25 mcg (as one inhalation) administered QD via the ELLIPTA Inhaler for 8 weeks followed by a washout period of 3 weeks arm 2: Subjects will receive TIO/OLO 5/5 mcg (as 2 inhalations of 2.5/2.5 mcg per inhalation) administered QD via the RESPIMAT inhaler for 8 weeks followed by a washout period of 3 weeks
Interventions: intervention 1: UMEC/VI intervention 2: TIO/OLO intervention 3: Albuterol/salbutamol
Intervention descriptions: intervention 1: ELLIPTA dry powder inhaler (DPI) will contain a total of 30 doses. Each DPI will be comprised of two double-foil, laminate blister strips. Each blister of one strip will consist of 62.5 mcg of UMEC blended with lactose and magnesium stearate while each blister of other strip will consist of 25 mcg of VI blended with lactose and magnesium stearate. Each actuation of the DPI will deliver the contents of one blister from each strip simultaneously intervention 2: TIO/OLO inhalation spray will be supplied as an inhalation spray delivered using a RESPIMAT inhaler. Each actuation from the RESPIMAT inhaler delivers 3.124 mcg tiotropium bromide monohydrate (equivalent to 2.5 mcg tiotropium) and 2.736 mcg olodaterol hydrochloride (equivalent to 2.5 mcg olodaterol) intervention 3: Albuterol/salbutamol will be supplied as an inhalation spray via metered dose inhaler and will be issued for reversibility testing at Visit 1. Albuterol/salbutamol will be permitted throughout the study for use as-needed

Protocol documents:
Prot_000.pdf: 
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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:
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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.
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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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SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
204990
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for 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
:
GSK2592356 (GSK573719 + GW642444)
Effective Date 
:
26-MAY-2017
Description :

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 204990.

This RAP is intended to describe the planned efficacy and safety analyses required 
for the study.

This RAP will be provided to the study team members to convey the content of the 
final Statistical Analysis Complete (SAC) Deliverable.
Author’s Name and Functional Area: 
26-MAY-2017
Principal Statistician, Statistics (Clinical Statistics)
26-MAY-2017
Principal Statistician, Statistics (Clinical Statistics)
Approved by: 
26-MAY-2017
Director (Clinical Statistics)
Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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TABLE OF CONTENTS
PAGE
1.
REPORTING & ANALYSIS PLAN SYNPOSIS.........................................................5
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................8
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................8
2.2.
Study Objective(s) and Endpoint(s)...............................................................9
2.3.
Study Design ..............................................................................................10
2.4.
Statistical Hypotheses.................................................................................10
3.
PLANNED ANALYSES ..........................................................................................11
3.1.
Final Analyses ............................................................................................11
4.
ANALYSIS POPULATIONS ...................................................................................12
4.1.
Protocol Deviations.....................................................................................13
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................14
6.
STUDY POPULATION ANALYSES .......................................................................15
6.1.
Overview of Planned Analyses ...................................................................15
6.1.1.
Subject Disposition ......................................................................16
6.1.2.
Medical Conditions and Concomitant Medications.......................17
6.1.3.
Disease and Background Characteristics.....................................17
7.
PRIMARY STATISTICAL ANALYSES....................................................................18
7.1.
Efficacy Analyses........................................................................................18
7.1.1.
Overview of Planned Efficacy Analyses .......................................18
7.1.2.
Planned Efficacy Statistical Analyses...........................................19
8.
OTHER STATISTICAL ANALYSES .......................................................................22
8.1.
Other Efficacy Endpoints ............................................................................22
8.1.1.
Overview of Planned Efficacy Analyses .......................................22
8.1.2.
Planned Efficacy Statistical Analyses for Other Efficacy 
Endpoints.....................................................................................23
8.1.2.1.
Responder FEV1.........................................................23
8.1.2.2.
Trough FVC and IC ....................................................24
8.1.2.3.
Rescue Medication ..........................................................24
8.1.2.4.
CAT .............................................................................26
8.1.2.5.
E-RS............................................................................27
8.1.2.6.
Inhaler assessment summaries...........................................28
8.2.
Safety Analyses..........................................................................................30
8.2.1.
Overview of Planned Analyses ....................................................30
8.2.2.
Adverse Events............................................................................31
8.2.2.1.
Adverse Events of Special Interest.............................31
8.2.3.
COPD Exacerbations...................................................................32
8.2.4.
Liver Events.................................................................................32
9.
REFERENCES.......................................................................................................33
10. APPENDICES........................................................................................................34
 
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10.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................35
10.1.1.
Exclusions from Per Protocol Analysis.........................................35
10.2.
Appendix 2: Time & Events.........................................................................36
10.2.1.
Protocol Defined Time & Events ..................................................36
10.3.
Appendix 3: Assessment Windows .............................................................40
10.3.1.
Definitions of Assessment Windows for Analyses........................40
10.4.
Appendix 4: Treatment States and Phases.................................................41
10.4.1.
Treatment States .........................................................................41
10.4.1.1.
Treatment States for Concomitant Medication 
Data ...........................................................................41
10.4.1.2.
Treatment States for AE Data.....................................42
10.4.1.3.
Treatment States for COPD Exacerbation Data..........43
10.5.
Appendix 5: Data Display Standards & Handling Conventions....................44
10.5.1.
Study Treatment & Sequence Display Descriptors.......................44
10.5.2.
Baseline Definition & Derivations .................................................44
10.5.2.1.
Baseline Definitions....................................................44
10.5.2.2.
Derivations and Handling of Missing Baseline 
Data ...........................................................................46
10.5.3.
Reporting Process & Standards...................................................46
10.6.
Appendix 6: Derived and Transformed Data ...............................................48
10.6.1.
General........................................................................................48
10.6.2.
Study Population..........................................................................48
10.6.3.
Safety ..........................................................................................51
10.6.4.
Efficacy........................................................................................52
10.7.
Appendix 7: Premature Withdrawals & Handling of Missing Data ...............58
10.7.1.
Premature Withdrawals................................................................58
10.7.2.
Handling of Missing Data.............................................................58
10.7.2.1.
Handling of Missing Dates..........................................58
10.7.2.2.
Handling of Partial Dates............................................59
10.7.2.3.
Handling of Missing Data for Statistical 
Analysis......................................................................59
10.8.
Appendix 8: Multicenter Studies..................................................................60
10.8.1.
Methods for Handling Centres .....................................................60
10.9.
Appendix 9: Examination of Covariates, Subgroups & Other Strata............61
10.9.1.
Handling of Covariates.................................................................61
10.10. Appendix 10: Multiple Comparisons & Multiplicity .......................................62
10.10.1.
Handling of Multiple Comparisons & Multiplicity...........................62
10.11. Appendix 11: Model Checking and Diagnostics for Statistical 
Analyses.....................................................................................................63
10.12. Appendix 12 – Abbreviations & Trade Marks ..............................................64
10.12.1.
Abbreviations...............................................................................64
10.12.2.
Trademarks .................................................................................65
10.13. Appendix 13: List of Data Displays..............................................................66
10.13.1.
Data Display Numbering..............................................................66
10.13.2.
Mock Example Shell Referencing ................................................66
10.13.3.
Deliverable [Priority].....................................................................66
10.13.4.
Study Population Tables..............................................................67
10.13.5.
Efficacy Tables ............................................................................71
10.13.6.
Efficacy Figures ...........................................................................75
10.13.7.
Safety Tables...............................................................................77
10.13.8.
ICH Listings .................................................................................80
 
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10.13.9.
Non-ICH Listings..........................................................................82
 
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1.
REPORTING & ANALYSIS PLAN SYNPOSIS
Overview
Key Elements of the RAP
Purpose

This RAP details all planned analyses and outputs required for the final Clinical 
Study Report (CSR) of study 204990.
Protocol

This RAP is based on the original protocol (Dated: 29-Mar-2016) for study 
204990 [GlaxoSmithKline Document Number 2015N256437_00] and eCRF 
Version 1.2.
Primary 
Objective

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.
Primary 
Endpoint

Trough FEV1 at Week 8
Study 
Design

Multicentre, randomized, open-label, 2 period cross-over, complete block 
design study to evaluate the efficacy and safety of UMEC/VI 62.5/25mcg with 
TIO/OLO 5/5mcg when used in subjects with moderate COPD.

Eligible subjects will be randomized 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 puffs once-daily from the Respimat inhaler.  Each treatment 
period will be 8 weeks.

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 
62.5/25mcg to TIO/OLO 5/5mcg 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.
Based on 15% withdrawal rate and 10% exclusion rate from the PP population 
220 subjects will be randomized.
Planned 
Analyses

No interim analyses are planned.

All decisions regarding final analysis, as defined in this RAP document, will be 
made prior to Database Freeze (unblinding) of the study data.
Analysis 
Populations

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-randomized subjects.

The Intent-to-treat (ITT) Population will comprise all randomized subjects, 
excluding those who were randomized in error, who received at least one dose 
of study medication. A subject who is recorded as a screen or run-in failure and 
also randomized will be considered to be randomized in error.  Any other subject 
 
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Overview
Key Elements of the RAP
who receives a randomization number will be considered to have been 
randomized. Displays will be based on the treatment to which the subject was 
randomized. This population will be the used for all efficacy and safety displays 
unless specified otherwise. 

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 randomized 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. 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.

The Inhaler Naive (IN) population definition will comprise of all subjects in the 
ITT population who have not used either Ellipta or Respimat for 6 months prior to 
inhaler evaluation (Visit 2 or Visit 5). This population will be used for all Inhaler 
assessment displays unless stated otherwise.
Hypothesis

The null hypothesis is that the difference in trough FEV1 between treatment 
groups is less than or equal to a pre-specified non-inferiority margin Δ:
H0: T1 – T2 ≤ Δ
The alternative hypothesis is that the difference between treatment groups is 
greater than the margin.
H1: T1 – T2 > Δ
where T1 and T2 are the treatment means for 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 M, 2010; Vogelmeier C, 2010;  Agustí
A, 2014].

If the lower bound of the two-sided 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 
 
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Overview
Key Elements of the RAP
mcg.

If the lower bound of the two-sided 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.
Primary 
Analyses

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.
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 on conclusions of non-
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2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Any changes from the originally planned statistical analysis specified in the protocol 
GlaxoSmithKline Document Number 2015N256437_00 are outlined in Table 1.
Table 1
Changes to Protocol Defined Analysis Plan
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes

Time to clinically important 
deterioration composite endpoint

Time to clinically important 
deterioration composite 
endpoint will not be 
analysed

Study deemed too short to 
assess and SGRQ is not 
collected.

Proportion of responders 
according to CAT (defined as a 
1 unit improvement in score 
from baseline) at Weeks 4 and 8

Proportion of responders 
according to CAT (defined 
as a 2 unit improvement in 
score from baseline) at 
Weeks 4 and 8

Typographical error

ITT population definition

All randomized subjects, 
excluding those who were 
randomized in error. A subject 
who is recorded as a screen or 
run-in failure and also 
randomized will be considered to 
be randomized in error.  Any 
other subject who receives a 
randomization number will be
considered to have been 
randomized.
Displays will be based on the 
treatment to which the subject 
was randomized.

ITT population definition
now includes – received at 
least one dose of study 
medication.

All randomized subjects, 
excluding those who were 
randomized in error and 
received at least one dose 
of study medication. A 
subject who is recorded as 
a screen or run-in failure 
and also randomized will be 
considered to be 
randomized in error.  Any 
other subject who receives 
a randomization number will 
be considered to have been 
randomized. Displays will 
be based on the treatment 
to which the subject was 
randomized.

For consistency with prior 
GSK573719 + GW642444 
studies

No Inhaler Naive population 

Inhaler Naive population 
definition

All subjects in the ITT 
population who have not 
used either Ellipta or 
Respimat for 6 months prior 
to inhaler evaluation (Visit 2 

Population for Inhaler 
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Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes
or Visit 5). 

This population will be used 
for all Inhaler assessment 
displays unless stated 
otherwise.
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoint

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.

Trough FEV1 at Week 8
Other Efficacy Objectives
Other Efficacy Endpoints

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 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 
2 unit improvement in score from baseline) at Weeks 4 
and 8

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 Objectives
Exploratory Endpoints 

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 might using eMDI
Safety
Safety Endpoints

To evaluate safety and tolerability of  
UMEC/VI 62.5/25 mcg and TIO/OLO 
5/5mcg

Incidence of adverse events (AEs)

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2.3.
Study Design
Overview of Study Design and Key Features
Design
Features

Multicenter, randomized, open-label, 2 period complete block design cross-over study.
Dosing

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 puffs to equal one dose.), for 8 weeks in each treatment 
period.
Treatment 
Assignment

220 subjects equally randomized to two treatment sequences containing the two 
treatments UMEC/VI 62.5/25mcg and TIO/OLO 5/5 mcg.

GSK RandAll NG used to generate randomization schedules.

Centralised randomization using GSK RAMOS for treatment allocation.
Interim 
Analysis

No interim analysis is planned.
2.4.
Statistical Hypotheses
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 62.5/25 mcg and TIO/OLO 5/5 
mcg, respectively.
 
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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 M, 2010; Vogelmeier C, 2010; Agustí A, 
2014].
If the lower bound of the two-sided 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 two-sided 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.
P-values will be displayed in the analysis outputs in this study. Inference to be drawn
from these p-values will be as follows:

If the treatment comparison on the primary endpoint has a lower confidence limit
below the non-inferiority margin, non-inferiority is not demonstrated. No
inference will be drawn from p-values for treatment comparisons on any other
endpoints.

If the treatment comparison on the primary endpoint has a lower confidence limit 
above the non-inferiority margin but below 0, non-inferiority is established but 
the p-value cannot be used to give an indication of the strength of that non-
inferiority.  Note the p-value is for a test of superiority and not associated with a 
test for non-inferiority.  
Inference will be drawn from p-values for treatment comparisons on non lung-
function related endpoints (see below), which will be called statistically 
significant if <0.05. If the treatment comparison on the primary endpoint has a 
lower confidence limit above 0, superiority is established and the p-value can be 
used to give an indication of the strength of that superiority. Inference will be 
drawn from p-values for treatment comparisons on all other endpoints, which will 
be called statistically significant if <0.05.
The primary endpoint of trough FEV1 is considered independent of non lung function
‘other’ endpoints, defined as rescue medication use, CAT score, inhaler ease of use, 
inhaler errors, respiratory daily symptoms endpoints.  All other endpoints are lung 
function endpoints and are not considered to be independent from the primary endpoint 
of trough FEV1.
3.
PLANNED ANALYSES
3.1.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All subjects have completed the study as defined in the protocol.
 
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2.
All required database cleaning activities have been completed and final database 
release has been declared by Data Management.
3.
All decisions on exclusion of data from PP analyses based on the PDMP will be 
agreed prior to releasing the randomization codes (See Section 10.1 for details).
4.
All criteria for releasing the randomization codes have been met. 
5.
Randomization codes have been distributed according to RandAll NG procedures.
6.
Database freeze has been declared by Data Management.
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
All Subjects 
Enrolled (ASE)

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.

Displays for this population will not be split by 
treatment.

Subject disposition

Reasons for 
withdrawal prior to 
randomization

Inclusion/exclusion/ran
domization criteria 
deviations for non-
randomized subjects

SAEs for screen and 
run-in failures and 
randomized subjects
Intent-To-Treat 
(ITT)

All randomized subjects, excluding those who were 
randomized in error, who received at least one 
dose of study medication. A subject who is 
recorded as a screen or run-in failure and also 
randomized will be considered to be randomized in 
error.  Any other subject who receives a 
randomization number will be considered to have 
been randomized. 

Displays will be based on the treatment to which 
the subject was randomized.

Study population

Primary efficacy

Other efficacy

Safety
Per-Protocol (PP)

All subjects in the ITT Population who were not 
identified as full protocol deviators.

Subjects with partial protocol deviations considered 
to impact efficacy will be included in the PP 
Population but will have their data excluded from 
the PP analysis 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 the PP analysis.

Protocol deviations that would exclude subjects 
from the PP population or subject data from PP
analysis are defined in Appendix 1 (Protocol 
Deviation Management and Definition for Per-
Protocol Population).

The decision to exclude a subject from the PP

Primary efficacy
 
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Population
Definition / Criteria
Analyses Evaluated
population will be made prior to releasing the 
randomization codes.

Displays will be based on the treatment to which 
the subject was randomized.
Inhaler Naive (IN)

All subjects in the ITT population who have not 
used either Ellipta or Respimat for 6 months prior 
to inhaler evaluation (Visit 2 or Visit 5). 

This population will be used for all Inhaler 
assessment displays. 
NOTES : 

Please refer to Appendix 13: List of Data Displays which details the population to be used for each displays being 
generated.
4.1.
Protocol Deviations

Important protocol deviations (including deviations related to study 
inclusion/exclusion criteria, conduct of the trial, subject management or subject
assessment) will be summarised and listed.

Important deviations which result in exclusion from the PP population will also be 
summarised and listed. (Please refer to Appendix 1: Protocol Deviation Management 
and Definitions for Per Protocol Population).
o
Protocol deviations will be tracked by the study team throughout the conduct of 
the study in accordance with the Protocol Deviation Management Plan.
o
Data will be reviewed prior to releasing the randomization codes and freezing the 
database to ensure all important deviations and deviations which may lead to 
exclusion from the PP analysis are captured and categorised on the protocol 
deviations dataset. 
o
This dataset will be the basis for the summaries and listings of protocol 
deviations.

A separate summary and listing of all inclusion/exclusion criteria deviations will also 
be provided. This summary will be based on data as recorded on the 
inclusion/exclusion page of the eCRF.

A listing of any treatment misallocations will be produced for the ASE population.
 
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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS
Table 2 provides an overview of appendices within the RAP for outlining general 
considerations for data analyses and data handling conventions. 
Table 2
Overview of Appendices
Section
Component
10.1
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol Population
10.2
Appendix 2: Time & Events
10.3
Appendix 3: Assessment Windows
10.4
Appendix 4: Treatment States and Phases
10.5
Appendix 5: Data Display Standards & Handling Conventions
10.6
Appendix 6: Derived and Transformed Data
10.7
Appendix 7: Premature Withdrawals & Handling of Missing Data
10.8
Appendix 8: Multicenter Studies
10.9
Appendix 9: Examination of Covariates, Subgroups & Other Strata
10.10
Appendix 10: Multiple Comparisons & Multiplicity
10.11
Appendix 11: Model Checking and Diagnostics for Statistical Analyses.
 
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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Analyses
The study population analyses will be based on the ITT population, unless otherwise 
specified.
Table 3 provides an overview of the planned study population analyses, with full details 
of data displays being presented in Appendix 13: List of Data Displays.
Table 3
Overview of Planned Study Population Analyses
Display Type
Data Displays Generated
Table
Figure
Listing
Subject Disposition
Study Populations and Reasons for Screen Failures (ASE)
Y
Attendance at Each Clinic Visit
Y
End of Study Record
Y
Y
Treatment Completion
Y
Reasons for Subject Withdrawal from the Study During 
Each Period
Y
Reasons for Discontinuation of Treatment During Each 
Period
Y
Number of Subjects by Country and Centre
Y
Follow-up Contact
Y
Treatment
Randomized and Actual Treatments
Y
Overall Percentage Treatment Compliance
Y
Y
Subjects Who Discontinued Study Treatment
Y
Protocol Deviations
Important Protocol Deviations
Y
Y
Exclusions from Per Protocol Analyses
Y
Y
Inclusion/Exclusion/Randomization Criteria Deviations, 
ASE and ITT
Y
Y
Treatment Misallocations (ASE)
Y
Demography
Demographic Characteristics, ITT and PP (Note the listing 
will only be produced for ITT)
Y
Y
Race and Racial Combinations
Y
Race and Racial Combinations Details
Y
Y
Age group breakdown for the trial (ASE)
Y
Subject Number per Country (ASE)
Y
Medical Conditions and Concomitant Medications
Current/Past Medical Conditions
Y
Y
Family History of Cardiovascular Risk Factors
Y
Y
COPD Concomitant Medications Not Given for an 
Exacerbation (Pre-Run-in, During Run-in or Washout, On-
treatment, Post-treatment) (Only one listing required for all 
COPD medications)
Y
Y
 
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Display Type
Data Displays Generated
Table
Figure
Listing
COPD Concomitant Medications Given for an Exacerbation 
(On-treatment, During Washout, Post-treatment)
Y
Y
Non-COPD Concomitant Medications (On-treatment, Post-
treatment) (Only one listing required for all non-COPD 
medications)
Y
Y
Relationship Between Anatomical Therapeutic 
Classification (ATC) Level 1, Ingredient and Verbatim Text 
Non-COPD Concomitant Medications Only
Y
Disease and Background Characteristics
COPD History and COPD Exacerbation History (only one 
listing required)
Y
Y
Smoking History and Status
Y
Y
Screening Lung Function Test Results (listed as part of the 
Listing of FEV1)
Y
Y
GOLD Categories and Reversibility at Screening
Y
Y
Screening IC Results (listed as part of the Listing of IC)
Y
Y
mMRC Dyspnoea Scale at Screening
Y
Y
NOTES :

Y = Yes display generated.
6.1.1.
Subject Disposition
The number of subjects in the ASE population, the number and percentage of subjects 
who were pre-screen failures, who had exacerbations during the pre-screening period, 
who attended the screening visit and of those the number and percentage of subjects who
were screen failures with the reasons for failing or run-in failures with reasons for failing 
will be presented.  The number of subjects randomized and the number of subjects who 
were in the ITT population will be presented by treatment and overall. Of those in the 
ITT population the number and percentage of subjects who discontinued treatment and 
the number and percentage of subjects in the PP Population will be presented by 
treatment and overall.
The number and percentage of subjects who completed the study as planned as well 
subjects who stopped investigational product prematurely will be presented, along with 
the number and percentage of subjects who reported each primary and sub-reason for 
discontinuation of treatment.
The end of study record summary shows the number of subjects who completed the study 
as well as the number who withdrew early from the study along with reasons for early 
withdrawal. 
A summary of the number and percentage of subjects who entered, discontinued 
treatment and completed each period of the study will be displayed.  
A summary of reasons for withdrawal during each period (period 1, washout and period 
2) will be presented for each treatment. A summary of reasons for discontinuation of 
treatment during each period will also be produced.
 
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6.1.2.
Medical Conditions and Concomitant Medications
The number and percentage of subjects reporting each current medical condition will be 
presented for the overall population.  This table will include a category of ‘Any 
Cardiovascular Risk Factor’ and will present all medical conditions regardless of 
frequency.  The table will be repeated for past medical conditions.
Non-COPD medications will be summarised by Anatomical-Therapeutic-Chemical 
(ATC) level 1 and ingredient. Multi-ingredient medications will be presented according 
to their combination ATC classification rather than the classifications of the ingredients.
Respiratory Medication Class (RMC) will be provided by Data Management for each 
COPD concomitant medication.  COPD medications not given for an exacerbation, and 
medications given for an exacerbation, will be summarised by Respiratory Medication 
Class (RMC).
COPD and non-COPD medications will be listed separately. The COPD medications 
listing will indicate whether each medication was taken for an exacerbation. Both listings 
will indicate in which treatment state each medication was taken (Pre-Run-in, During 
Run-in, On-treatment, During Washout, Post-treatment).
A listing of the relationship between ATC Level 1, ingredient and verbatim text will be 
produced for non-COPD medications only.
6.1.3.
Disease and Background Characteristics
Pre- and post-salbutamol FEV1, FVC and FEV1/FVC ratio, post-salbutamol FEV1 as a 
percentage of predicted normal and FEV1 reversibility to salbutamol (expressed in mL 
and as a percentage) at Screening will be summarised by treatment and overall.
The number and percentage of subjects in each GOLD Grade 1-4, GOLD Category A-D 
using mMRC and GOLD Category A-D using CAT, and the number and percentage of 
subjects classified as Reversible/Non-reversible to salbutamol at Screening (defined in 
Section 10.6.2) will also be summarised by treatment and overall.
History of disease, along with smoking status and family history of cardiovascular 
disease will also be summarised by treatment and overall. 
 
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7.
PRIMARY STATISTICAL ANALYSES
7.1.
Efficacy Analyses
7.1.1.
Overview of Planned Efficacy Analyses
The primary efficacy analyses for the primary endpoint will be on the PP population. All
outputs produced for the primary endpoint will be repeated on the ITT population.
Further investigation will be done if the results from the PP analysis are not consistent 
with the results from the ITT analysis for the primary endpoint.  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 on conclusions of non-inferiority and superiority.  
Table 4 provides an overview of the planned efficacy analyses for the primary endpoint,
with full details of data displays being presented in Appendix 13: List of Data Displays.
Table 4
Overview of Planned Efficacy Analyses for the Primary Endpoint
Endpoint 
Change from Baseline [1]
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
Trough FEV1
Trough FEV1 at Week 
8 (ITT and PP 
population) 
Y
Y3
Y
Y2
Y
Tipping point on 
Trough FEV1 at Week 
8 (ITT and PP 
population)
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.

[1] Analysis and Summaries to include absolute values too.

2 Box plot and empirical distribution function plot for change from baseline.

3 Figures include all time points produced for change from baseline only. 
 
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7.1.2.
Planned Efficacy Statistical Analyses
Primary Statistical Analyses
Endpoint(s)

Trough FEV1 at Week 8 (results for trough FEV1 at Week 4 will be obtained from the same 
analysis)
Model Specification

Trough FEV1 at Week 8 will be analysed for the PP population using a mixed model repeated 
measures (MMRM) including data recorded at each of Week 4 and Week 8.

The following covariates will be included in the model: period baseline (the difference between 
a subject’s baseline in each treatment period and the mean overall baseline for that subject), 
mean baseline (the mean of the baselines in each of the two treatment periods), period, 
treatment, visit, visit by period baseline, visit by mean baseline and visit by treatment 
interactions, where visit is nominal Subject will be fitted as a random effect.

Two models will be fitted; one with a response variable of trough FEV1, and one with a 
response variable of change from baseline in trough FEV1.

An unstructured covariance structure for the R matrix will be used by specifying ‘type=UN’ on 
the REPEATED line.

The Kenward and Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used. If this 
method does not run, the residual method will be used instead.
Example SAS code
proc mixed data=start;
  class subject period treatment visit;
  model endpoint=period treatment visit mean_base period_base 
visit*period_base visit*mean_base visit*treatment /
ddfm=kr;
  random intercept / subject=subject;
  repeated visit / subject=subject*period type=un;
  lsmeans visit*treatment / cl diff e;   
  ods output lsmeans=lsmeans;
  ods output diffs=diffs;
run;
Model Checking & Diagnostics

Refer to Appendix 11: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

Least squares (LS) mean and LS mean changes from baseline with their corresponding 
standard errors (SEs) will be presented for each treatment by visit, together with estimated 
treatment differences (UMEC/VI 62.5/25 vs. TIO/OLO 5/5), corresponding 95% CIs and p-
values.

A plot of LS mean changes from baseline and 95% CIs for each treatment by visit will be 
generated.

The type III tests of fixed effects and the covariance parameter estimates from the model will 
be presented in two tables.
Summary Results Presentation

Summary of baseline FEV1 will be presented by treatment for all subjects.
 
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Primary Statistical Analyses

A box plot and an empirical distribution function plot of change from baseline in trough FEV1 at 
Week 8 will be produced.

Summary statistics for raw and change from baseline in trough FEV1 at each visit and for each 
treatment will be presented on the same table.
Sensitivity and Supportive Statistical Analyses

The analysis and results presentation will be repeated for the ITT population (with the 
exception of the box plot and empirical distribution function plot).

Sensitivity of the results to missing data will be assessed using Tipping Point Analysis for both 
the PP and ITT population.  Analysis of the primary endpoint at Week 8 will be run with missing 
data imputed under a variety of assumptions for the mean of the missing data. This will be 
done for both study arms separately. These analyses will allow for determination of the ‘tipping 
point(s)’ which is, the mean values for missing data that would cause a change in the 
conclusion of a)non-inferiority and b)superiority as assessed by the lower limit of the two-sided 
95% CI. Multiple- imputation will be used for imputing the Week 8 endpoint of interest for 
subjects who had missing on-treatment data at Week 8. 
For each imputation, a random draw will be made from a normal distribution with mean equal 
to the corresponding assumed mean change from baseline and standard deviation taken from 
the observed change from baseline data for the combined treatment arms at the Week 8 visit. 
Data for subjects with missing baseline values will not be imputed. Analysis of the complete 
Week 8 dataset will be carried out using an ANCOVA model with covariates of treatment group 
and baseline for that particular period (Note: not the period baseline) . 
Initially the same mean change from baseline will be assumed for subjects who withdrew from 
both treatment arms. The assumed values for the mean change from baseline at Week 8 will 
vary from -150mL to +150mL in increments of 50mL.
The analysis will be repeated assuming different mean changes from baseline for subjects who 
withdrew from each treatment arm.  For each value of the assumed mean change from 
baseline for subjects who withdrew from UMEC/VI, the full range of values for subjects who 
withdrew from TIO/OLO will be investigated.
Seeds for multiple imputation analyses will be set using the following SAS code: 
data seed1;
   number=round(10000*ranuni(0),1);
   output;
run;
proc print;
run;
The seeds generated and assigned to each analysis will be documented separately prior to 
DBF. A table will be produced displaying the two-sided 95% lower confidence limit of the Week 
 
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Sensitivity and Supportive Statistical Analyses
8 treatment differences under the above assumptions for the mean changes from baseline for 
each of the treatment arms

An assessment of whether the effect of treatment is modified by the interaction of 
Period
Period baseline
Mean baseline
will be made. Interactions with treatment will be investigated by fitting separate MMRM models 
with the same terms as the main model, and adding in treatment by factor by visit interaction. 
Contrast statements will be used to obtain the p-value for the treatment by factor interaction at 
Week 8. The interaction term will be tested at the 10% significance level.  If that p-value is 
>=0.10 the interaction will be considered not significant. If the p-value is <0.10, further 
investigation will be performed, for example running analysis by each level of the factor, or for 
subgroups above and below the median. This will  be assessed for the PP population. 
 
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8.
OTHER STATISTICAL ANALYSES
8.1.
Other Efficacy Endpoints
8.1.1.
Overview of Planned Efficacy Analyses
The other efficacy summaries and analyses will be based on the ITT population, unless 
otherwise specified.
Table 5 provides an overview of the planned efficacy analyses, with further details of 
data displays being presented in Appendix 13: List of Data Displays.
Table 5
Overview of Planned Efficacy Analyses
Endpoint 
Change from Baseline[1]
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
Responder FEV1
Proportion of 
responders according 
to FEV1 (a responder is 
defined as a ≥100mL 
change in Trough FEV1
from baseline) at Week
4 and 8 [2]
Y
Y
Y
Trough FVC and IC
Trough FVC 
Y
Y
Y
Y
Trough IC
Y
Y
Y
Y
Rescue medication
Mean number of puffs 
per day of rescue over 
the study duration 
(Weeks 1-8) captured 
using e-diary
Y
Y
Y
Percentage of rescue 
free days over the 
study duration (Weeks 
1-8) captured using e-
diary [2]
Y
Y
Y
Mean number of 
occurrences per day of 
rescue over the study 
duration (Weeks 1-8) 
captured using e-MDI
Y
Y
Percentage of rescue 
free days over the 
study duration (Weeks 
1-8) captured using e-
MDI [3]
Y
Y
CAT
CAT score
Y
Y
Y
Y
 
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Endpoint 
Change from Baseline[1]
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
Proportion of CAT 
responders [2]
Y
Y
Y
Inhaler assessments
Inhaler ease of use
Y
Y
Y
Inhaler errors
Y
Y
E-RS
E-RS
Y
Y
Y
Y
Proportion of E-RS 
responders [2]
Y
Y
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents TFL related to any displays of individual subject observed raw data.
1.
Analysis and Summaries to include absolute values too for all endpoints with the exception of Responder 
analysis
2.
Summary and analysis will be combined into a single display.
3.
Summary only
8.1.2.
Planned Efficacy Statistical Analyses for Other Efficacy 
Endpoints
8.1.2.1.
Responder FEV1
Statistical Analyses for Proportion of Trough FEV1 Responders
Endpoints

Proportion of responders according to FEV1 (a responder is defined as a ≥100mL change in 
Trough FEV1 from baseline)
Model Specification

At each visit, the proportion of subjects achieving a ≥100mL change in Trough FEV1 from 
baseline will be analysed using a generalised linear mixed model.

The following covariates will be included in the model: period baseline, mean baseline, period, 
treatment, visit, visit by period baseline, visit by mean baseline and visit by treatment 
interactions, where visit is nominal.
Example SAS code
proc glimmix data=start;
  class subject period treatment visit;
  model endpoint(descending)=period treatment visit mean_base period_base
visit*period_base visit*mean_base visit*treatment / dist=binary           
                                  link=logit ddfm=kr solution;
  random intercept / subject=subject;
  random visit / subject=subject*period residual type=un;
  lsmeans visit*treatment / diff;  
  ods output lsmeans=lsmeans;
  ods output diffs=diffs;
run;
 
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Statistical Analyses for Proportion of Trough FEV1 Responders

Note: The residual statement turns the random statement into a repeated statement
Model Checking & Diagnostics

Refer to Appendix 11: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

The odds ratio, 95% CI and p-value of UMEC/VI 62.5/25 vs. TIO/OLO 5/5 will be presented.
Summary Results Presentation

The number and percentage of responders and non-responders at each visit will be 
summarized on the same table as the analysis results detailed above.
8.1.2.2.
Trough FVC and IC
Statistical Analyses 
Endpoints

Trough FVC

Trough IC  
Model Specification

Trough FVC and Trough IC endpoints above will be analyzed using the same methodology as 
the primary analysis of trough FEV1 (detailed in Section 8.1.2.1) using all available FVC or IC 
data recorded at Weeks 4 and 8.  
Model Checking & Diagnostics

Refer to Appendix 11: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

Least squares (LS) mean and LS mean changes from baseline with their corresponding 
standard errors (SEs) will be presented for each treatment by visit, together with estimated 
treatment differences (UMEC/VI 62.5/25 vs. TIO/OLO 5/5), corresponding 95% CIs and p-
values.

A plot of LS mean changes from baseline and 95% CIs for each treatment by visit will be 
generated.
Summary Results Presentation

Summary of baseline FVC will be presented by treatment for all subjects.

Summary statistics for raw and change from baseline in trough FVC at each visit and for each 
treatment will be presented on the same table.

Summary of baseline IC will be presented by treatment for all subjects.

Summary statistics for raw and change from baseline in trough IC at each visit and for each 
treatment will be presented on the same table.
8.1.2.3.
Rescue Medication
Mean number of Puffs/Occurrences of Rescue Medication
Endpoints

Mean number of puffs per day of rescue medication over the study duration (Weeks1-8) 
captured using e-diary

Percentage of rescue-free days over the study duration (Weeks 1-8) captured using e-diary
 
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Mean number of Puffs/Occurrences of Rescue Medication

Mean number of occurences per day of rescue medication over the study duration (Weeks1-8) 
captured using e-MDI

Percentage of rescue-free days over the study duration (Weeks 1-8) captured using e-MDI
Model Specification for MMRM Analysis Weeks 1-8

Each endpoint derived for Weeks 1-2, 3-4, 5-6 and 7-8 will be analysed using a MMRM 
analysis using all available values recorded during Weeks 1-2, 3-4, 5-6 and 7-8.

The following covariates will be included in the model: 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 overall treatment effect will be estimated.

Two models will be fitted for each endpoint; one with a response variable of mean number of 
puffs/day or percentage of rescue-free days, and one with a response variable of the change 
from baseline.

An unstructured covariance structure for the R matrix will be used by specifying ‘type=UN’ on 
the REPEATED line.

The Kenward and Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used.
Example SAS code
proc mixed data=start;
  class subject period treatment 2wkperd;
  model endpoint=period treatment 2wkperd mean_base period_base 
2wkperd*period_base 2wkperd*mean_base /
ddfm=kr;
  random intercept / subject=subject;
  repeated 2wkperd / subject=subject*period type=un;
lsmeans treatment / cl diff e ;
  ods output lsmeans=lsmeans;
  ods output diffs=diffs;
run;
Model Checking & Diagnostics

Refer to Appendix 11: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

The LS mean and LS mean change from baseline over Weeks 1-8 with their corresponding 
SEs will be presented for each treatment, together with the estimated treatment difference 
(UMEC/VI 62.5/25 vs. TIO/OLO 5/5), corresponding 95% CI and p-value.

Percentage of rescue-free days will have LS mean with over Weeks 1-8 with their 
corresponding SEs will be presented for each treatment, together with the estimated treatment 
difference (UMEC/VI 62.5/25 vs. TIO/OLO 5/5), corresponding 95% CI and p-value.
Summary Results Presentation

The mean number of puffs of rescue medication per day at baseline, during each two weeks of 
treatment and over the entire 8-week treatment period will be summarized by treatment.  The 
change from baseline values will also be summarized by treatment, for each two weeks of 
treatment and the entire 8-week treatment period.

This will be repeated for percentage of rescue-free days.

Only the above summaries (not analysis) will be repeated for rescue medication 
 
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Mean number of Puffs/Occurrences of Rescue Medication
(albuterol/salbutamol) collected using eMDI.
Non-parametric analysis

If the assumption of normality is not satisfied (as seen in previous studies with similar design), 
a non-parametric analysis will be carried out.  Hodges Lehman estimates for the median 
treatment difference and 95% confidence interval based upon a Wilcoxon rank sum test will be 
used.  The p-value will be based on Van Elteren test, an extension to the Wilcoxon rank sum 
test for two group comparison.  
8.1.2.4.
CAT
Statistical Analyses for CAT Score
Endpoints

CAT Score 
Model Specification

CAT will be analyzed using a MMRM including data recorded at each of Week 4 and Week 8.

The following covariates will be included in the model: period baseline, mean baseline, period, 
treatment, visit, visit by period baseline, visit by mean baseline and visit by treatment 
interactions, where visit is nominal.  Subject will be fitted as a random effect.

Two models will be fitted; one with a response variable of CAT score, and one with a response 
variable of change from baseline in CAT score.
Example SAS code
proc mixed data=start;
  class subject period treatment visit;
  model endpoint=period treatment visit mean_base period_base 
visit*period_base visit*mean_base visit*treatment /
ddfm=kr;
  random intercept / subject=subject;
  repeated visit / subject=subject*period type=un;
  lsmeans visit*treatment / cl diff e;   
  ods output lsmeans=lsmeans;
  ods output diffs=diffs;
run;
Model Checking & Diagnostics

Refer to Appendix 11: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

Least squares (LS) mean and LS mean changes from baseline with their corresponding 
standard errors (SEs) will be presented for each treatment by visit, together with estimated 
treatment differences (UMEC/VI 62.5/25 vs. TIO/OLO 5/5), corresponding 95% CIs and p-
values.

A plot of LS mean changes from baseline and 95% CIs for each treatment by visit will be 
generated.
Summary Results Presentation

Summary of baseline CAT score will be presented by treatment for all subjects.

Summary statistics for raw and change from baseline in CAT score at each visit and for each 
treatment will be presented on the same table.
 
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Statistical Analyses for Proportion of CAT Responders
Endpoints

Proportion of Responders according to CAT
Model Specification

At each visit, the proportion of responders will be analysed using a generalised linear mixed 
model.

Please see Section 10.6.4 for details on responder definition. 

The following covariates will be included in the model: period baseline, mean baseline, period, 
treatment, visit, visit by period baseline, visit by mean baseline and visit by treatment 
interactions, where visit is nominal.

See Section 10.7.2 for details on how to handle missing data.
Example SAS code
proc glimmix data=start;
  class subject period treatment visit;
  model endpoint(descending)=period treatment visit mean_base period_base
visit*period_base visit*mean_base visit*treatment / dist=binary           
                                  link=logit ddfm=kr solution;
  random intercept / subject=subject;
  random visit / subject=subject*period residual type=un;
  lsmeans visit*treatment / diff;  
  ods output lsmeans=lsmeans;
  ods output diffs=diffs;
run;

Note: The residual statement turns the random statement into a repeated statement
Model Checking & Diagnostics

Refer to Appendix 11: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

The odds ratio, 95% CI and p-value of UMEC/VI 62.5/25 vs. TIO/OLO 5/5 will be presented.
Summary Results Presentation

The number and percentage of responders and non-responders at each visit will be 
summarized on the same table as the analysis results detailed above.
8.1.2.5. E-RS
Statistical Analyses for E-RS
Endpoints

Change from baseline in weekly mean scores for E-RS and its subscales (breathlessness, 
cough and sputum and chest symptoms)
Model Specification

E-RS endpoint above will be analyzed using similar methodology as the MMRM analysis of 
Trough FEV1 (detailed in Section 7.1.2) using all available data recorded from the EXACT-PRO 
questionnaire.

For E-RS and subscales, all weekly mean scores will be included in the analysis.
Model Checking & Diagnostics
 
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Statistical Analyses for E-RS

Refer to Appendix 11: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

Least squares (LS) mean and LS mean changes from baseline with their corresponding 
standard errors (SEs) will be presented for each treatment by weekly treatment period, 
together with estimated treatment differences (UMEC/VI 62.5/25 vs. TIO/OLO 5/5), 
corresponding 95% CIs and p-values.
Summary Results Presentation

The mean score at baseline and during each week of treatment will be summarized by 
treatment.  The change from baseline values will also be summarized by treatment, for each 
week of treatment.
Statistical Analysis of Proportion of Responders according to E-RS
Endpoints

Proportion of responders for E-RS and its subscales (breathlessness, cough and sputum and
chest symptoms)
Model Specification

For each mean weekly E-RS total score and subscales, the proportion of responders will be 
analyzed using similar methodology as the generalized linear mixed model analysis of Trough 
FEV1 responder (detailed in Section 8.1.2.1). 

Please see Section 10.6.4 for details on responder definitions. 

See Section 10.7.2 for details on how to handle missing data.
Model Checking & Diagnostics

Refer to Appendix 11: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

The odds ratio, 95% CI and p-value of UMEC/VI 62.5/25 vs. TIO/OLO 5/5 will be presented
Summary Results Presentation

The number and percentage of responders and non-responders at each visit will be 
summarized on the same table as the analysis results detailed above.
8.1.2.6.
Inhaler assessment summaries
Inhaler Error Assessment 
Endpoint

Percentage of subjects making at least one critical error 

Percentage of subjects making at least overall error 

See Section 10.6.4 for error derivation.
Summary of Results Presentation

Summarized by inhaler, response (at least one error critical and overall) using n and %.
Results will be presented by sequence and total.

The number and percent of subjects reporting each error for each individual question will also 
be presented (separate table for each inhaler).
 
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Statistical Analysis of Inhaler Ease of Use Assessment
Endpoints

Ease of use’ rating for the ELLIPTA DPI compared with the Respimat.
Model Specification

Each question will be analysed using the Cochran-Mantel-Haenszel test adjusted for country

The Cochran-Mantel-Haenszel test serves as a stratified approximation to Prescott’s test, a 
variation of a one-sample chi-square test that accounts for study inhaler sequence and 
difference in ease of use response [Prescott, 1981; Senn, 2002].  Homogeneity among country 
with respect difference in to ease of use will be assessed using a Breslow-Day test.  Results of 
this test will not be reported on the final data display.

See Section 10.6.4 for ease of use derivation.
Example SAS code

SAS code for stratified approximation to Prescott’s test for each preference question: 

ods output CMH = cmhi (where = (upcase(AltHypothesis) =: 'ROW MEAN SCORES') keep = 
AltHypothesis Prob) ;
proc freq data = pref_data ;
        tables country * seq * ease_ord / cmh ;
      run ;
      

SAS code for checking Breslow-Day Test for 2x2 
      proc freq data = pref_data (where = (ease_ord ne 0)) ;
        tables country * seq * ease_ord / cmh ;
Model Results Presentation

P-values will be presented for the comparison between inhalers on the summary table
Summary Results Presentation

Responses to the Ease of Use questionnaire will be summarised by inhaler, question/item
and type of responses for the IN population. 

The percentage preference (rated higher for Ellipta, rated higher for Respimat, rated the same) 
will be summarized on the same table as the analysis results detailed above. Results will be 
presented by question, sequence and total. 

An additional summary will be produced based on the difference between the ratings for
the two inhalers. The rating are coded as Very Easy=1, Easy=2, Neutral=3, Difficult=4,
Very Difficult=5. Therefore, the difference in rating will be ranged from -4 to 4. A
difference of -4 indicates a rating of ‘Very Easy’ for Ellipta and a ‘Very Difficult’ for
Other.
 
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8.2.
Safety Analyses
8.2.1.
Overview of Planned Analyses
The safety analyses will be based on the ITT population, unless otherwise specified.
Table 6 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 13: List of Data Displays.
Table 6
Overview of Planned Safety Analyses
Endpoint 
Absolute
Summary
Individual
T
F
F
L
Incidence of Adverse Events
Overview of On-treatment Adverse Events (AEs)
Y
On-treatment AEs 
Y
Post-treatment AEs
Y
Drug related On-treatment AEs
Y
Fatal On-treatment SAEs
Y
Fatal Post-treatment SAEs
Y
Fatal Drug related On-treatment SAEs
Y
Non-fatal On-treatment SAEs
Y
Non-fatal Post-treatment SAEs
Y
Non-fatal Drug related On-treatment SAEs
Y
10 Most Frequent On-treatment AEs on Each Treatment
Y
On-treatment AEs of Special Interest (AESI) (SOC will not be 
presented for this display)
Y
Pre-treatment Fatal SAEs, (ASE, total column only)
Y
Pre-treatment Non-fatal SAEs, (ASE, total column only)
Y
Pre-treatment AEs Leading to Withdrawal from the Study, (ASE, 
total column only)
Y
On-treatment AEs Leading to Permanent Discontinuation of Study 
Treatment or Withdrawal from the Study
Y
Relationship Between Primary System Organ Class, Preferred Term 
and Verbatim AE Text, 
Y
On-treatment Non-serious AEs reported by 3% or more subjects 
(before rounding) in any treatment group, EMA Requirement (ITT)
Y
Summary of Serious Adverse Events by Preferred Term Including 
Drug-related Status and Fatal Status (ITT)
EMA Requirement
Y
Subject Numbers for Each AE
Y
All AEs
Y
Non-fatal SAEs 
Y
Fatal SAEs 
Y
AEs Leading to Permanent Discontinuation of Study Treatment or 
Y
 
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Endpoint 
Absolute
Summary
Individual
T
F
F
L
Withdrawal from the Study
On-treatment Drug-related AEs
Y
Pulse Rate, Systolic Blood Pressure and Diastolic Blood Pressure
Y
On- treatment COPD Exacerbations
Y
Y
Post- treatment COPD Exacerbations
Y
Y
Exposure Data 
Y
Y
Potential DPI Inhaler Malfunctions
Y
Potential Chest X-ray Data
Y
All Other potential Pneumonia Data 
Y
Liver Events
Y
Virology
Y
Myocardial Infarction/Unstable Angina*
Y
Congestive Heart Failure*
Y
Arrhythmias*
Y
Valvulopathy*
Y
Pulmonary Hypertension*
Y
Cerebrovascular Events/Stroke and Transient Ischemic Attack*
Y
Peripheral Arterial Thromboembolism*
Y
Deep Venous Thrombosis/Pulmonary Embolism*
Y
Revascularisation*
Y
All cause deaths
Y
ECG
Y
*collected if cardiovascular event occurs
8.2.2.
Adverse Events
AE incidence will be summarised by treatment using the primary System Organ Class 
(SOC) and preferred term.  
The 10 most frequent on-treatment adverse events in each treatment summary will use 
the counts to determine the most frequent 10 events.  In case of ties in frequency all AEs 
for that frequency will be displayed.  On-treatment AEs experienced by 3 % (after 
rounding) or more of subjects in any treatment group will also be displayed (SOC will 
not be presented for this display.)
Classification of an AE as pre-, on- or post-treatment is provided in Section 10.4.1. All 
listings of AEs/SAEs will include an identification of the treatment state.
8.2.2.1.
Adverse Events of Special Interest
Adverse events (AEs) of special interest (AESI) have been defined as AEs which have 
specified areas of interest for UMEC, VI or for the COPD population. A list of 
Standardized Medical Dictionary for Regulatory Affairs (MedDRA) Queries (SMQs) and 
other groupings for AESI is provided in Section 10.6.3.
 
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8.2.3.
COPD Exacerbations
On- and post-treatment exacerbations will be summarized separately.
The definition of on- and post-treatment exacerbations is provided in Section 10.4.1.3.
The number and percentage of subjects reporting 0, 1, 2 or >2 COPD exacerbations, the 
total number of exacerbations, the number and percentage of subjects withdrawn due to 
an exacerbation and the number and percentage of subjects treated by oral/systemic 
corticosteroids, antibiotics or hospitalisation will also be presented. The number and 
percentage of exacerbations with each outcome category and each severity will be 
presented and the exacerbation duration will be summarised.
8.2.4.
Liver Events
Liver event information will be listed for all subjects who report a liver event, to include:

The time from the start of randomized study treatment to the liver event.

The information captured on the Liver Event Assessment Form which is used to 
calculate the Roussel Uclaf Causality Assessment Method score.

If liver biopsy was performed, the size of the biopsy and the recorded outcomes.

If liver imaging was performed, the recorded outcomes for the liver imaging 
assessment.
 
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9.
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.

Evidera. (2016).  Evaluating Respiratory Symptoms (E-RS™) in COPD (E-RS™: 
COPD)

GlaxoSmithKline Document Number 2015N256437_00 Study ID 204990. (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) Report Date 29-MAR-2016. 

GOLD. Global Initiative for Chronic Obstructive Lung Disease (Updated 2017). 
http://www.goldcopd.org.

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

Prescott, RS.  The comparison of success rates in cross-over trials in the presence of 
an order effect.  Appl Stat. 1981; 30:9-15.

Ratitch, B., O'Kelly, M. and Tosiello, R. (2013), Missing data in clinical trials: from 
clinical assumptions to statistical analysis using pattern mixture models. Pharmaceut. 
Statist., 12: 337–347. doi: 10.1002/pst.1549

Senn, Stephen.  Cross-over Trials in Clinical Research, 2nd ed.  Chichester:  John 
Wiley & Sons, Ltd, 2002.  pp 128-131, 202-203.

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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10.
APPENDICES
Section
Appendix
RAP Section 4 : Analysis Populations
Section 10.1
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population
RAP Section 5 : General Considerations for Data Analyses & Data Handling Conventions
Section 10.2
Appendix 2: Time & Events
Section 10.3
Appendix 3: Assessment Windows
Section 10.4
Appendix 4: Treatment States & Phases
Section 10.5
Appendix 5: Data Display Standards & Handling Conventions

Study Treatment & Sub-group Display Descriptors

Baseline Definitions & Derivations

Reporting Process & Standards
Section 10.6
Appendix 6: Derived and Transformed Data

General, Study Population & Safety

Efficacy
Section 10.7
Appendix 7: Premature Withdrawals & Handling of Missing Data

Premature Withdrawals

Handling of Missing Data
Section 10.8
Appendix 8: Multicentre Studies
Section 10.9
Appendix 9: Examination of Covariates and Subgroups
Section 10.10
Appendix 10: Multiple Comparisons and Multiplicity
Section 10.11
Appendix 11: Model Checking and Diagnostics for Statistical Analyses
Other RAP Appendices
Section 10.12
Appendix 12: Abbreviations & Trade Marks
Section 10.13
Appendix 13: List of Data Displays
 
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10.1.
Appendix 1: Protocol Deviation Management and Definitions
for Per Protocol Population
10.1.1.
Exclusions from Per Protocol Analysis
The full list of protocol deviations collected on the eCRF is in the PDMP.  This will 
include those that will also be excluded from the per protocol analyses.  
Concomitant medications will be reviewed for deviations from the time of informed 
consent through to the time of stopping study treatment.
Subjects with partial deviations will be excluded from PP analyses from the onset of the 
deviation onwards.  Subjects with time point specific or period specific deviations will 
have only the affected time point excluded from PP analyses.
 
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10.2.
Appendix 2: Time & Events
10.2.1.
Protocol Defined Time & Events
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
 
 
 
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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
Training in the use of 
eDiary and eMDI
X
Register visit IVRS
X
X
X
X
X
X
X
X
X
X
X
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
 
 
 
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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
Dispense period 1 study 
medication
X
X
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).
 
 
 
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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.
12. CAT will be performed at the site on the eDiary.
13. For first dosing of each treatment period the subject will follow the subject 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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10.3.
Appendix 3: Assessment Windows
10.3.1.
Definitions of Assessment Windows for Analyses
Data are generally reported according to the nominal time of clinic visits and assessments 
as specified in the protocol, and time windows for exclusion will not be defined.  For 
example, if a subject recorded values for the Week 4 (Day 28) visit that were actually 
made on the 21st day of treatment, they will be presented as Week 4 (Day 28) values in 
the summary tables.  
For the 23 and 24 h post-dose trough FEV1 measurements, a time window of 22.0-25.0 h 
is allowed for the actual time of an assessment relative to time of dosing on the previous 
day.  Values falling outside of this window will not be used in the PP analysis of the 
primary endpoint, but will still be included in all ITT analyses.
 
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10.4.
Appendix 4: Treatment States and Phases
10.4.1.
Treatment States
Assessments and events will be classified according to time of occurrence relative to the 
start and/or stop date of the study treatment.
10.4.1.1.
Treatment States for Concomitant Medication Data
The following rules will be used to classify a concomitant medication as being taken 
during one or more study treatment phases (pre-treatment, on-treatment and post-
treatment):
DATE RULES
PRETRT 
(Pre treatment)
DURTRT
(On treatment)
POSTTRT 
(Post treatment)
mststdt = .
Y
mststdt ^=.
AND
(cmstdt < mststdt OR cmprior = Y)
AND
cmendt <= mststdt
Y
mststdt ^=.
AND
(cmstdt < mststdt OR cmprior = Y) 
AND 
mststdt < cmendt <= mstendt
Y
Y
mststdt ^=.
AND
(cmstdt < mststdt OR cmprior = Y) 
AND 
(cmendt > mstendt OR cmongo = Y)
Y
Y
Y
mststdt ^= .
AND
mststdt <= cmstdt <= mstendt 
AND
mststdt <= cmendt <= mstendt
Y
mststdt ^= .
AND
mststdt <= cmstdt <= mstendt 
AND
(cmendt > mstendt OR cmongo = Y)
Y
Y
mststdt ^= .
AND
cmstdt>=mstendt
Y
cmstdt=start date of the concomitant medication, cmendt=end date of the concomitant 
medication, mststdt =start date of the study medication, mstendt =end date of the study 
medication
 
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The following SAS code will be used:
   if mststdt=. then do; 
     pretrt="Y"; durtrt='';  posttrt=''; 
   end;
   if mststdt ne . and (cmstdt2 < mststdt or cmprior='Y') and (cmendt2 <= mststdt) then do; 
     pretrt='Y'; durtrt='';  posttrt=''; 
   end;
   if mststdt ne . and (cmstdt2 < mststdt or cmprior='Y') and mststdt < cmendt2 <= mstendt then do; 
     pretrt='Y'; durtrt='Y'; posttrt=''; 
   end;
   if mststdt ne . and (cmstdt2 < mststdt or cmprior='Y') and (cmendt2 > mstendt or cmongo='Y') then do; 
     pretrt='Y'; durtrt='Y'; posttrt='Y'; 
   end;
   if mststdt ne . and mststdt <= cmstdt2 <= mstendt and mststdt <= cmendt2 <= mstendt then do; 
     pretrt='';  durtrt='Y'; posttrt=''; 
   end; 
   if mststdt ne . and mststdt <= cmstdt2 <= mstendt and (cmendt2 > mstendt or cmongo='Y') then do; 
     pretrt='';  durtrt='Y'; posttrt='Y'; 
   end;
   if mststdt ne . and cmstdt2 >= mstendt then do; 
     pretrt='';  durtrt='';  posttrt='Y'; 
   end;
10.4.1.2.
Treatment States for AE Data
Classification of an AE as pre-, on- or post-treatment will be made with reference to the 
study treatment start and stop dates for each period and the AE onset date. If the AE onset 
date is missing or partial then the AE will be considered on-treatment unless there is 
evidence to the contrary (e.g. the month of the onset date is present and is less than the 
month of the first dose of study treatment). AEs with onset on the day after the last day of 
treatment will be considered on-treatment. Other AEs with onset during the wash-out or 
follow-up periods, or following IP discontinuation will be considered post-treatment but 
will be assigned to the treatment received in the previous period. AEs with missing or 
partial onset dates which are not classified will be included in listings only. AEs reported 
by subjects who did not receive treatment will be considered pre-treatment.
Treatment State
Definition
Pre-Treatment
AE Onset Date < First Study Treatment Start Date
On-Treatment
If AE onset date is on or after treatment start date & on or before treatment stop date.
Study Treatment Start Date  ≤ AE Start Date ≤ Study Treatment Stop Date + 1 day 
Post-Treatment
If AE onset date is after the treatment stop date plus 1 day.
AE Start Date > Study Treatment Stop Date + 1 day
Onset Time  
Since 1st Dose 
(Days)
If Treatment Start Date ˃  AE Onset Date: = AE Onset Date - Treatment Start Date
If Treatment Start Date ≤ AE Onset Date: = AE Onset Date - Treatment Start Date +1
Missing otherwise.
Duration (Days) 
AE Resolution Date – AE Onset Date + 1
Drug-related
If relationship is marked ‘YES’ on [Inform/CRF OR value is missing].
NOTES: 

If the study treatment stop date is missing then the AE will be considered to be On-Treatment.
 
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10.4.1.3.
Treatment States for COPD Exacerbation Data
Classification of a COPD exacerbation as having onset on- or post-treatment will be 
made with reference to the study treatment start and stop dates and the exacerbation onset 
date. If the exacerbation onset date is missing or partial then the exacerbation will be 
considered on-treatment unless there is evidence to the contrary (e.g. the month of the 
onset date is present and is less than the month of the first dose of study medication). 
Exacerbations with onset on the day after the last day of a treatment will be considered 
on-treatment. Other exacerbations with onset during a washout or follow-up period, or 
following IP discontinuation will be considered post-treatment but will be assigned to the 
treatment received in the previous period. Exacerbations which are not considered on- or 
post-treatment or which are reported by subjects who did not receive treatment will be 
included in listings only. The duration of the exacerbation will be calculated as 
(exacerbation resolution date or date of death - exacerbation onset date + 1).
Treatment State
Definition
On-Treatment
If onset date is on or after treatment start date & on or before treatment stop date.
Study Treatment Start Date  ≤ Start Date ≤ Study Treatment Stop Date + 1 day
Post-Treatment
If AE onset date is after the treatment stop date.
Start Date > Study Treatment Stop Date +1 day
 
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10.5.
Appendix 5: Data Display Standards & Handling 
Conventions
10.5.1.
Study Treatment & Sequence Display Descriptors
Treatment Descriptions
RandAll NG
Data Displays for Reporting 
Code
Description
Description
Order [1]
3
UMEC/VI 62.5/25 mcg
UMEC/VI 62.5/25 
1
4
TIO/OLO 5/5 mcg
TIO/OLO 5/5 
2
NOTES:
1.
Order represents treatments being presented in TFL, as appropriate.
Sequence Descriptions
Data Displays for Reporting 
Period 1
Period 2
Description
UMEC/VI 62.5/25
TIO/OLO 5/5
UMEC/VI 62.5/25_TIO/OLO 5/5
TIO/OLO 5/5
UMEC/VI 62.5/25
TIO/OLO 5/5_UMEC/VI 62.5/25
10.5.2.
Baseline Definition & Derivations
10.5.2.1.
Baseline Definitions
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
latest pre-dose assessment. 
Baseline definitions are applicable to each period.
Parameter
Study Assessments
Considered As Baseline
Baseline Used in Data Display
Day 1 (Pre-Dose)
FEV1 and FVC
Trough FEV1 and 
FVC
X
Mean value (30 min and 5 min pre-dose) 
recorded before dosing on Day 1 of each 
period. If one of the values is missing then the 
baseline will be the single remaining value
IC
Trough IC 
X
Mean value (30 min and 5 min pre-dose) 
recorded before dosing on Day 1 of each 
period. If one of the values is missing then the 
baseline will be the single remaining value
Rescue Use
Mean Number of 
Puffs of Rescue 
X
The total puffs of rescue for each day will be 
calculated as number of salbutamol puffs. If 
 
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Parameter
Study Assessments
Considered As Baseline
Baseline Used in Data Display
Day 1 (Pre-Dose)
Medication Per Day 
and Percentage of 
Rescue-free Days 
Over Weeks 1-8
captured using e-
diary
the number of puffs is missing then the total 
puffs will be set to missing for that day.
Provided at least half the days within the 
summary period have non-missing values the 
baseline is calculated over the duration stated 
below:
Period 1: Values recorded between the latest 
of (7 days prior to Visit 2 and the day of Visit 
1) and the Day before Visit 2
Period 2: Values recorded between the latest 
of (7 days prior to Visit 5 and the day of Visit 
4) and the Day before Visit 5.
Mean Number of 
Occurrences of 
Rescue Medication 
Per Day and 
Percentage of 
Rescue-free Days 
Over Weeks 1-8 
captured using e-
MDI
X
The total occurrences, defined as >1 puff 
within a 2 minute time window, of rescue for 
each day will be calculated. 
Baseline is calculated over the duration 
stated below:
Period 1: Values recorded between the latest 
of (7 days prior to Visit 2 and the day of Visit 
1) and the Day before Visit 2
Period 2: Values recorded between the latest 
of (7 days prior to Visit 5 and the day of Visit 
4) and the Day before Visit 5.
Where entries of occurrences are not present
the number of occurrences is assumed to be 
0. 
CAT
CAT
X
Value recorded before dosing on Day 1 of 
each period
E-RS
E-RS
X
Provided at least 4 days are non-missing, the 
baseline is calculated as the average of 
measurements over the duration stated 
below:
Period 1: Values recorded between the latest 
of (7 days prior to Visit 2 and the day of Visit 
1) and the Day before Visit 2
Period 2: Values recorded between the latest 
of (7 days prior to Visit 5 and the day of Visit 
4) and the Day before Visit 5.
 
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For FEV1 and FVC, IC, rescue use, CAT and E-RS analyses:

Mean (subject level) baseline is defined as the mean of the baselines in each period 
for each subject.

Period baseline is defined as the difference between the baseline and mean baseline 
for each period and each subject.
10.5.2.2.
Derivations and Handling of Missing Baseline Data
Definition
Reporting Details
Change from Baseline
= Post-Dose Visit Value – Baseline
Percentage Change from Baseline
= ((Post-Dose Visit Value – Baseline)/Baseline)*100
NOTES :

Unless otherwise specified, the baseline definitions specified in Section 10.5.2.1 Baseline Definitions will be used 
for derivations for endpoints / parameters and indicated on summaries and listings.

Unless otherwise stated, if baseline data is missing no derivation will be performed and will be set to missing.
10.5.3.
Reporting Process & Standards
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
: uk1salx00175
HARP Area
: gsk573719_gw642444/mid204990/final
QC Spreadsheet
: gsk573719_gw642444/mid204990/final/qc
Analysis Datasets 

Analysis datasets will be created according to Legacy GSK A&R dataset standards.
Generation of RTF Files

RTF files will be generated for all tables in the final reporting effort.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated:
o
4.03 to 4.23: General Principles
o
5.01 to 5.08: Principles Related to Data Listings
o
6.01 to 6.11: Principles Related to Summary Tables
o
7.01 to 7.13: Principles Related to Graphics 
Formats

All data will be reported according to the treatment to which the subject was randomized unless 
otherwise stated.

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (dp) will be adopted for 
reporting of data based on the raw data collected.
 
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Reporting Standards

Numeric data will be reported to the precision collected on the eCRF.

The reported precision from non-eCRF sources will follow the IDSL statistical principles but 
may be adjusted to a clinically interpretable number of dp.

Mean number of rescue puffs/day, percentage of rescue-free days, E-RS and CAT will have a 
min and max to 1 dp and then follow IDSL standards for reporting other summary statistics.

FEV1, FVC, and IC will have a min and max to 2 dp and then follow IDSL standards for 
reporting other summary statistics.

Odds Ratios will be reported to 2dp.
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses :

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to 
IDSL Statistical Principle 5.05.1).

Unscheduled and Early Withdrawal assessments will be presented within the subject’s 
listings. 
Unscheduled Visits

Unscheduled visits will not be included in summary tables.

Unscheduled visits will not be included in figures.

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.
 
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10.6.
Appendix 6: Derived and Transformed Data
10.6.1.
General
Study Day

Calculated as the number of days from start date of treatment:

Ref Date = Missing                             → Study Day = Missing 

Ref Date < 1st Treatment Start Date   → Study Day = Ref Date – 1st Treatment Start Date    

Ref Date ≥ 1st Treatment Start Date   → Study Day = Ref Date – (1st Treatment Start 
Date) + 1    
Period Study Day

For period 1, period day will be the same as study day. For period 2, period day will be
calculated as (Ref Date – 2nd Treatment Start Date + 1).
10.6.2.
Study Population
Demographics
Age

GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed 
as follows:
o
Any subject with a missing day will have this imputed as day ‘15’. 
o
Any subject with a missing date and month will have this imputed as ‘30th June’.

Birth date will be presented in listings as ‘YYYY’.

Age will be calculated based on the Pre-screening visit date.
Body Mass Index (BMI)

Calculated as Weight (kg) / [Height (m)2]
Reversibility
Reversibility

A subject’s responsiveness to salbutamol at Screening will be classified as ‘Reversible’ or ‘Non-
reversible’ based on the difference between their pre-salbutamol assessment of FEV1 and their 
post-salbutamol assessment of FEV1 as follows:

Reversible, if they had a difference in FEV1 of ≥ 12 % and ≥ 200 mL, or

Non-reversible, if they had a difference in FEV1 of < 200 mL or a ≥ 200 mL difference that 
was < 12 % of the pre-salbutamol FEV1.  
GOLD Classifications
GOLD Grade 1-4

Subjects will be classified into Global Initiative for Chronic Obstructive Lung Disease (GOLD) 
(GOLD, 2017 Grades 1-4 using the post-salbutamol percent predicted FEV1 assessment at 
Screening (Visit 1):
o
GOLD Grade 1 (Mild):  Percent Predicted FEV1 ≥ 80%
 
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o
GOLD Grade 2 (Moderate): 50% ≤ Percent Predicted FEV1 < 80%
o
GOLD Grade 3 (Severe):  30% ≤ Percent Predicted FEV1 < 50%
o
GOLD Grade 4 (Very Severe): Percent Predicted FEV1 < 30% 
GOLD Category A-D (Using mMRC)

Subjects will be classified into GOLD (mMRC) Categories A-D as follows: 
A. Low risk, less symptoms: mMRC <2 and <2 exacerbations in the past year and no 
exacerbation leading to hospitalisation in the past year 
B. Low risk, more symptoms: mMRC ≥2 and <2 exacerbations in the past year and no 
exacerbation leading to hospitalisation in the past year 
C. High risk, less symptoms: mMRC <2 and (≥2 exacerbations in the past year or ≥1 
exacerbation leading to hospitalisation in the past year)
D. High risk, more symptoms: mMRC ≥2 and (≥2 exacerbations in the past year or ≥1 
exacerbation leading to hospitalisation in the past year)
GOLD Category A-D (Using CAT)

Subjects will be classified into GOLD (CAT) Categories A-D as follows: 
A. Low risk, less symptoms: CAT <10 and <2 exacerbations in the past year and no 
exacerbation leading to hospitalisation in the past year 
B. Low risk, more symptoms: CAT ≥10 and <2 exacerbations in the past year and no 
exacerbation leading to hospitalisation in the past year 
C. High risk, less symptoms: CAT <10 and (≥2 exacerbations in the past year or ≥1 
exacerbation leading to hospitalisation in the past year)
D. High risk, more symptoms: CAT ≥10 and (≥2 exacerbations in the past year or ≥1 
exacerbation leading to hospitalisation in the past year)
Compliance
Overall Compliance

For randomized treatments dispensed from the Ellipta DPI, the number of doses of study 
treatment taken by each subject from each inhaler will be calculated from the dose counter start 
and stop counts for each inhaler used.  If a dose counter start count is missing then it will be 
assumed to be 30.  If all dose counter stop counts are non-missing for a treatment period then 
the percentage compliance for that period will be calculated as:
Compliance = sum of all (dose counter start – dose counter stop) x 100
                                (exposure stop date – exposure start date +1)
For randomized treatments dispensed from the Respimat, the number of doses of study 
treatment taken by each subject will be calculated from the dose counter start and stop counts 
for each inhaler used.  If a dose counter start count is missing then it will be assumed to be 60.  
If all dose counter stop counts are non-missing for a treatment period then the percentage 
compliance for that period will be calculated as:
Compliance = sum of all (dose counter start – dose counter stop) x 100
                              2 x (exposure stop date – exposure start date +1)
 
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Compliance

If any dose counter stop in a treatment period is missing then the treatment compliance will be
set to missing for that period.

Overall compliance in each period will be categorised as follows:
< 80 %
≥80 % to < 95 %
≥95 % to ≤105 %
>105 % to ≤120 %
       >120 %.
 
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10.6.3.
Safety
Adverse Events
AEs of Special Interest

AEs of special interest have been defined as AEs which have specified areas of interest for 
UMEC or VI or the overall COPD population. Groups which are not SMQs are made up of a 
selection of preferred terms (PTs) defined by GSK. The complete list, including the preferred 
terms which contribute to each of the groups will be provided by Global Clinical Safety and 
Pharmacovigilance (GCSP) using the MedDRA version at the time of reporting.  This will be 
finalised prior to randomization codes being released.
Special Interest AE Group/
Subgroup
SMQ Group
Cardiovascular effects/
Cardiac Arrhythmia
Cardiovascular effects/
Cardiac Failure
Cardiac failure (SMQ)
Cardiovascular effects/
Cardiac Ischaemia 
Ischaemic heart disease (SMQ)
Cardiovascular effects/
Hypertension
Hypertension (SMQ)
Cardiovascular effects/
Stroke
Central nervous system haemorrhages and 
cerebrovascular conditions (SMQ)
Pneumonia
LRTI excluding pneumonia
Ocular effects (antimuscarinic)
Glaucoma (SMQ)
Paradoxical bronchospasm
Asthma/bronchospasm
Urinary retention
Extent of Exposure
Exposure Duration

Number of days of exposure to study drug in each period will be calculated based on the 
formula:  
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 1

If a subject’s overall exposure stop date in that period is missing it will be assumed to be the 
 
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Extent of Exposure
latest recorded exposure start or stop date in that period.

If a subject’s overall exposure start date is missing then it will be assumed to be their Day 1 visit 
date from that period.

If a subject received a treatment other than the randomized treatment during the study, the 
exposure will still be calculated based on overall exposure start and stop dates in each period.

If the dose counter start=dose counter stop then it will be assumed that no doses were taken 
from that container.
Exposure Categories

The following exposure categories will be derived:
1-27 days, >27-55 days, >55 days
10.6.4.
Efficacy
Spirometry
Trough 

The trough value for FEV1, FVC and IC at each of Week 4 and Week 8 is calculated from the 
values at the assessments made 23 h and 24 h after dosing on the previous day.  

If the actual time of an assessment is after the time of dosing on the current day, the value will 
not be used in the calculation of trough for the PP population.  

For the PP population, a value will additionally be excluded from the trough FEV1 calculation if 
the assessment is outside the time window of 22.0-25.0 h after dosing on the previous day.  

If one of the values is missing or excluded then the trough will be the single remaining value; 
otherwise the trough will be the mean of the two values.
Proportion of responders according to FEV1

A subject will be a considered a responder according to trough FEV1 if their trough FEV1 value 
has increased by at least 100mL from baseline.  

A subject will be considered a non-responder if their trough FEV1 value has decreased, has not 
changed, or has increased by less than 100mL compared to baseline.

Missing data will be handled as detailed in Section 10.7.2
Calculation of Daily eDiary endpoints
General
Subjects were instructed to complete the daily eDiary in the evening (typically at bedtime).  
The parameters collected include rescue use and EXACT-PRO scores.

The tables below show which daily eDiary records are used to calculate the daily eDiary 
parameters for each period.  Any diary data collected in the post-treatment phase of the study 
will not be slotted. See Section 10.4.1.1 for details on the assignment of treatment phases.
To be used for rescue medication:
 
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Calculation of Daily eDiary endpoints
Period
First day
Last day
Period 1 Baseline 
Latest of (7 days before Visit 2 
(Day 1) and day of Visit 1 
(Screening))
Day before Visit 2 (Day 1)
Period 1 Week 1-2
Period study day 1 (day of 
Visit 2)
Period study day 14
Period 1 Week 3-4
Period study day 15
Period study day 28
Period 1 Week 5-6
Period study day 29
Period study day 42
Period 1 Week 7-8
Period study day 43
Earliest of (Period study day 55
and day before Visit 4)
Period 1 Week 1-8
Period study day 1 (day of 
Visit 2)
Earliest of (Period study day 55
and day before Visit 4)
Period 2 Baseline 
Latest of (7 days before Visit 5
(Day 1) and day of Visit 4)
Day before Visit 5 (Day 1)
Period 2 Week 1-2
Period study day 1 (day of 
Visit 5)
Period study day 14
Period 2 Week 3-4
Period study day 15
Period study day 28
Period 2 Week 5-6
Period study day 29
Period study day 42
Period 2 Week 7-8
Period study day 43
Earliest of (Period study day 55
and day before Visit 7)
Period 2 Week 1-8
Period study day 1 (day of
Visit 5)
Earliest of (Period study day 55
and day before Visit 7)
To be used for E-RS:
Period
First day
Last day
Period 1 Baseline 
Latest of (7 days before Visit 2 
(Day 1) and day of Visit 1 
(Screening))
Day before Visit 2 (Day 1)
Period 1 Week 1
Period study day 1 (day of 
Visit 2)
Period study day 7
Period 1 Week 2
Period study day 8
Period study day 14
Period 1 Week 3
Period study day 15
Period study day 21
Period 1 Week 4
Period study day 22
Period study day 28
Period 1 Week 5
Period study day 29
Period study day 35
Period 1 Week 6
Period study day 36
Period study day 42
Period 1 Week 7
Period study day 43
Period study day 49
Period 1 Week 8
Period study day 50
Earliest of (Period study day 55 
and day before Visit 4)
 
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Calculation of Daily eDiary endpoints
Period 2 Baseline 
Latest of (7 days before Visit 5
(Day 1) and day of Visit 4)
Day before Visit 5 (Day 1)
Period 2 Week 1
Period study day 1 (day of 
Visit 5)
Period study day 7
Period 2 Week 2
Period study day 8
Period study day 14
Period 2 Week 3
Period study day 15
Period study day 21
Period 2 Week 4
Period study day 22
Period study day 28
Period 2 Week 5
Period study day 29
Period study day 35
Period 2 Week 6
Period study day 36
Period study day 42
Period 2 Week 7
Period study day 43
Period study day 49
Period 2 Week 8
Period study day 50
Earliest of (Period study day 55 
and day before Visit 7)
Mean Number of Puffs and Percentage Rescue Free Days via e-diary

For rescue use, ‘day’ refers to the period between one record of rescue use and the next.

A rescue-free day is defined as a day where the total puffs is 0.

For each summary period, the mean number of puffs per day and the percentage of rescue free 
days, will be calculated, using the number of days with non-missing values for the endpoint as 
denominator.

Rescue use will be summarised over the periods defined above.

For a subject to be counted in any time period (except for baseline where at at least half the 
days within the summary period are required) for a given endpoint they must have at least one 
diary entry recorded for that endpoint during that time period.
Mean Number of Occurrences and Percentage Rescue Free Days via e-MDI

A rescue-free day is defined as a day where the total number of puffs is missing.

Occurrence is defined as >1 puff within a 2 minute time window.

For each summary period, the mean number of occurrences per day and the percentage of 
rescue free days, will be calculated, using last dose-first dose+1 as denominator.

Rescue use will be summarised over the periods defined above.
EXACT PRO
EXACT Respiratory Symptoms

The EXACT-PRO (Evidera, 2016) is a 14-item daily diary (typically completed at bedtime).  The 
daily E-RS total score (and subscales) will be computed according to the E-RS in COPD user 
manual [Evidera, 2016]. 

The weekly mean scores for E-RS, and the subscales RS-Breathlessness, RS-Cough and 
Sputum, and RS-Chest Symptoms will be calculated as the mean of the daily scores in the 
weekly intervals defined above.

Mean weekly score = (sum of daily scores/# diary days completed). If fewer than 4 days of data 
are available in any 7-day period, a mean weekly score should not be calculated. If fewer than 3 
days worth of data are available in the 6-day period (day 50 to day 55) then a mean weekly 
score should not be calculated.
 
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Calculation of Daily eDiary endpoints
E-RS Responder

E-RS Total Score Responder: on-treatment weekly mean change from baseline E-RS total 
score ≤ -2

E-RS Total Score Non-responder: on-treatment  weekly mean change from baseline E-RS total 
score > -2

E-RS Breathlessness Responder: on-treatment weekly mean change from baseline E-RS
Breathlessness subscale score ≤ -1

E-RS Breathlessness Non-responder: on-treatment weekly mean change from baseline E-RS
Breathlessness subscale score > -1

E-RS Cough Responder: on-treatment weekly mean change from baseline E-RS Cough & 
Sputum subscale score ≤ -0.7

E-RS Cough Non-responder: on-treatment weekly mean change from baseline E-RS Cough & 
Sputum subscale score > -0.7

E-RS Cough & Sputum Responder: on-treatment weekly mean change from baseline E-RS
Chest Symptoms subscale score ≤ -0.7

E-RS Cough & Sputum Non-responder: on-treatment weekly mean change from baseline E-RS
Chest Sypmtoms subscale score > -0.7
CAT
CAT Score

The CAT consists of eight items each formatted as a six-point differential scale: 0 (no impact) to 
5 (high impact). A CAT score will be calculated by summing the non-missing scores on the eight 
items.  The score can have values ranging from 0 to 40. 

If one item is missing, then the score for that item is set as the average of the non-missing 
items. If more than one item is missing, then the CAT score will be set to missing. 

If the language of the CAT conducted at a post-baseline visit is different to the language used at 
baseline, the CAT score for that visit and all subsequent visits will be set to missing
CAT Responder

A subject will be a responder if their on-treatment CAT score has decreased at least 2 units 
from baseline CAT total score.

A subject will be considered a non-responder if their on-treatment CAT score has decreased by 
less than 2 units, has not changed, or has increased compared to baseline.

Missing data will be handled as detailed in Section 10.7.2.
 
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Inhaler Assessment
Ease of Use

Ease of Use questionnaire consists of 5 ordinal responses: very easy (1), easy (2), neutral (3), 
difficult (4) and very difficult (5), for each question. ‘Very easy’ is considered as the highest 
rating while ‘very difficult’ is considered as the lowest rating. Subjects answer each question 
regarding to ELLIPTA inhaler and ‘Other’ inhaler, respectively. 
An ordinal variable (ease_ord) will be derived to based on the ease of use rating for each 
inhaler and based on the sequence of inhaler use. This variable will be used in the statistical 
analysis for ease of use data. 

If the sequence of inhaler use is ELLIPTA inhaler in 1st period and RESPMIMAT inhaler in 2nd 
period, then for each ease of use question
ease_ord = -1, if subject’s ease of use rating for ELLIPTA inhaler is higher
ease_ord = 1, if subject’s ease of use rating for RESPMIMAT inhaler is higher
ease_ord = 0, if subject’s ease of use rating are the same with both inhalers

If the sequence of inhaler use is RESPMIMAT inhaler in 1st period and ELLIPTA inhaler in 2nd 
period, then for each preference question
ease_ord = 1, if subject’s ease of use rating for ELLIPTA inhaler is higher
ease_ord = -1, if subject’s ease of use rating for RESPMIMAT inhaler is higher
ease_ord = 0, if subject’s ease of use rating are the same with both inhalers
Critical Error Variable

Whether a subject had at least one critical error and at least one overall error (critical and non-
critical) will be derived for each inhaler.

Table below shows critical errors in bold. 

Responses in ( ) indicate an error. 
Respimat
Preparation for first use
(0 = No)  1 = Yes
Keep cap close. Press safety catch and 
pull off clear base
(0 = No)  1 = Yes
Cap still closed. Insert narrow end of 
cartridge into inhaler and gently push 
against a firm surface to ensure that it 
has gone all the way in
(0 = No)  1 = Yes
Cap still closed. Replace clear base 
(0 = No)  1 = Yes
Cap still closed. Turn clear base in 
direction of the arrows on the label 
until you hear a click 
(0 = No) 1 = Yes
Flip cap open until it clicks into open 
position
(0 = No) 1 = Yes
 
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Critical Error Variable
Point inhaler towards ground and 
press dose release button. Close cap 
and repeat steps 4-6 until the mist is 
visible. Then repeat steps 4-6 another 
3 times before use
(0 = No) 1 = Yes
Exhaled directly into mouthpiece
0 = No (1 = Yes)
No seal by the lips round the 
mouthpiece during the inhalation
0 = No (1 = Yes)
Daily Use
0 = No 1 = Yes
(*Not applicable to derived 
errors as question not 
appropriate to study design )
Keep cap closed. Turn clear base in 
direction of the arrows on the label 
until you hear a click
(0 = No) 1 = Yes
Flip cap open until it clicks into open 
position 
(0 = No) 1 = Yes
Breathe out slowly and fully then close 
your lips around mouthpiece 
(0 = No) 1 = Yes
While taking in a slow deep breath 
press dose release button ; keep 
breathing in slowly 
(0 = No) 1 = Yes
Close cap
(0 = No) 1 = Yes
Ellipta
Failed to open cover 
0 = No (1 = Yes)
Shook the device upside down after 
dose preparation
0 = No (1 = Yes)
No exhalation before an inhalation
0 = No (1 = Yes)
Exhaled directly into mouthpiece
0 = No (1 = Yes)
No seal by the lips round the 
mouthpiece during the inhalation
0 = No (1 = Yes)
Inhalation manoeuvre:
-
long
-
steady
-
deep
0 = No (1 = Yes)
Blocked air inlet during inhalation 
manoeuvre
0 = No (1 = Yes)
Did not hold breath
0 = No (1 = Yes)
Did not close the device 
(Note:  this is an error but one which 
does not affect the medication that is 
inhaled)
0 = No (1 = Yes)
 
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10.7.
Appendix 7: Premature Withdrawals & Handling of Missing
Data
10.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion is defined as attendance at Visit 7. 

Withdrawn subjects were not replaced in the study.

All available data from subjects who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, 
unless otherwise specified.
10.7.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank 
fields on the collection instrument :
o
These data will be indicated by the use of a “blank” in subject listing displays 
unless all data for a specific visit are missing in which case the visit is not 
displayed in the listing. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to 
be missing data and should be displayed as such.
o
No imputation will be made for any missing numerical data, except in the 
sensitivity analysis of primary endpoints to assess the impact of missing 
data on study results.  Missing data will generally not be considered in the 
calculation of percentages (i.e., the denominator will not include subjects 
who have missing data at a given time point).
10.7.2.1.
Handling of Missing Dates
Element
Reporting Detail
General
Partial dates will be displayed as captured in subject listing displays.
Responder

Subjects with a missing baseline will have responder status as missing.

Subjects with missing post-baseline data and a subsequent non-missing 
scheduled assessment will not be considered a responder or non-responder but 
will be left as missing.  

Subjects with a missing post-baseline assessment with no subsequent non-
missing assessments will be considered a non-responder for that and all 
subsequent time points.

Subjects with a baseline but all missing post-baseline data will be considered a 
non-responder at all time points.
 
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Element
Reporting Detail
Adverse 
Events

The eCRF allows for the possibility of partial dates (i.e., only month and year) to 
be recorded for AE start and end dates; that is, the day of the month may be 
missing. In such a case, the following conventions will be applied for calculating 
the time to onset and the duration of the event:
o
Missing Start Day: First of the month will be used unless this is before the 
period start date of study treatment; in this case the study treatment period
start date will be used and hence the event is considered On-treatment as 
per Appendix 4: Treatment States.
o
Missing Stop Day: Last day of the month will be used, unless this is after the 
period stop date of study treatment; in this case the study treatment period
stop date will be used.

Completely missing start or end dates will remain missing, with no imputation 
applied. Consequently, time to onset and duration of such events will be 
missing.
10.7.2.2.
Handling of Partial Dates
Element
Reporting Detail
Concomitant 
Medications

Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will 
be used for the month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month.

The recorded partial date will be displayed in listings.
Adverse 
Events

Any partial dates for adverse events will be raised to data management. If the 
full date cannot be ascertained, the following assumptions will be made:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will 
be used for the month. 
o
However, if these results in a date prior to Week 1 Day 1 of the respective 
period and the event could possibly have occurred during treatment from 
the partial information, then the pWeek 1 Day 1 date for the respective 
period will be assumed to be the start date. 
o
The AE will then be considered to start on-treatment (worst case).
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month 
unless this is after the period stop date of study treatment; in this case the 
period study treatment stop date will be used.

The recorded partial date will be displayed in listings.
10.7.2.3.
Handling of Missing Data for Statistical Analysis
For analysis of trough FEV1 at Week 8, sensitivity analyses will be produced using tipping point 
methodology (Ratitch, 2013).  These methods are detailed in Section 7.1.2.
 
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10.8.
Appendix 8: Multicenter Studies
10.8.1.
Methods for Handling Centres

This study will be randomized centrally.  

Results will be presented for all centres combined; centre will not be accounted for in 
statistical analyses. 
 
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10.9.
Appendix 9: Examination of Covariates, Subgroups & Other 
Strata
10.9.1.
Handling of Covariates

Consistency of treatment effect across covariates fitted in the primary efficacy endpoint 
analysis models will be examined by fitting separate models to examine treatment by period 
baseline, treatment by mean baseline and treatment by period interactions.

No formal statistical analysis of sub-groups of the study population will be performed.

The interaction terms will be tested at the 10% significance level. Significant interactions 
(<0.10) will be investigated further, for example running the analysis by each category. 
Continuous covariates may be grouped into dichotomous categories (values above and below 
median).
 
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10.10.
Appendix 10: Multiple Comparisons & Multiplicity
10.10.1.
Handling of Multiple Comparisons & Multiplicity
See Section 2.4 for details on inferences that can be drawn on primary and ‘other’ endpoints for 
non-inferiority and superiority.
 
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10.11.
Appendix 11: Model Checking and Diagnostics for 
Statistical Analyses
Distributional assumptions underlying the model used for analyses using MMRM (non binary data) 
will be examined by obtaining a normal probability plot of the residuals and a plot of the residuals 
versus the fitted values (i.e. checking the normality assumption and constant variance assumption 
of the model respectively) to gain confidence that the model assumptions are reasonable.
 
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10.12.
Appendix 12 – Abbreviations & Trade Marks
10.12.1.
Abbreviations
Abbreviation
Description
AE
Adverse Event
A&R
Analysis and Reporting 
ASE
All Subjects Enrolled
ATC
Anatomical-Therapeutic-Chemical
CAT
COPD Assessment Test
CI
Confidence Interval
CS
Clinical Statistics
CSR
Clinical Study Report
CTR
Clinical Trial Register
DOB
Date of Birth
DP
Decimal Places
DPI
Dry Powder Inhaler
eCRF
Electronic Case Record Form
E-RS
EXACT Respiratory Symptoms
FEV1
Forced Expiratory Volume in One Second
FVC
Forced Vital Capacity
GOLD
Global Initiative for Chronic Obstructive Lung Disease
IC
Inspiratory Capacity
ICH
International Conference on Harmonisation
ICS
Inhaled Corticosteroid
IDSL
Integrated Data Standards Library
IMMS
International Modules Management System
IP
Investigational Product
ITT
Intent-To-Treat
GUI
Guidance
KR
Kenwood Roger
LS
Least squares
mMRC
Modified Medical Research Council
MMRM
Mixed Model Repeated Measures
PD
Protocol Deviation
PDMP
Protocol Deviation Management Plan
PP
Per Protocol
QC
Quality Control
RAP
Reporting & Analysis Plan
RAMOS
Randomization & Medication Ordering System 
SAC
Statistical Analysis Complete
SAE
Serious Adverse Event
SE
Standard Error
SOP
Standard Operation Procedure
TA
Therapeutic Area
 
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Abbreviation
Description
TFL
Tables, Figures & Listings 
GSK
GlaxoSmithKline
UMEC
Umeclidinium Bromide
VI
Vilanterol
10.12.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
ELLIPTA
SAS
 
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10.13.
Appendix 13: List of Data Displays
10.13.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.40
Efficacy
2.1 to 2.48
2.1 to 2.13
Safety
3.1 to 3.23
Section
Listings
ICH Listings
1 to 17
Other Listings
18 to 32
10.13.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in a separate document.
Section
Figure
Table
Listing
Study Population
SP_Fn
SP_Tn
SP_Ln
Efficacy
E_Fn
E_Tn
E_Ln
Safety
S_Fn
S_Tn
S_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL / TST ID / Example Shell’ or ‘Programming Notes’ column using 
the reference convention detailed in this table.
10.13.3.
Deliverable [Priority]
Delivery
Description
SAC
Final Statistical Analysis Complete
 
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10.13.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliver-able 
Subject Disposition
1.1.
ASE
Summary of Subject Populations and Reasons for Screen 
Failures
SAC
1.2.
ITT
Summary of Attendance at Each Clinic Visit
SAC
1.3.
ITT
Summary of Completion and Premature Discontinuation of 
Study Treatment
SAC
1.4.
ITT
Summary of Study Completion and Withdrawal
SAC
1.5.
ITT
Summary of Subject Discontinuation at Each Period
SAC
1.6.
ITT
Summary of Subject Withdrawal at Each Period
SAC
1.7.
ITT
Summary of Reasons for Discontinuation of Treatment at 
End of Each Period
SAC
1.8.
ITT
Summary of Reasons for Withdrawal at End of Each 
Period
SAC
1.9.
ITT
IDSL – NS3
Summary of Number of Subjects by Country and Centre
Replace ‘Centre ID’ header 
with ‘Investigator  at Centre’       
SAC
Protocol Deviations
1.10.
ASE
IDSL – IE2
Summary of Inclusion/ Exclusion/ Randomization Criteria 
Deviations for Screen or Run-in failures
Include ‘Number of Screen or 
Run-in Failures’ row at the top 
of the table.  This is to be 
used as the denominator for 
the % calculations. 
SAC
1.11.
ITT
IDSL – IE1
Summary of Inclusion/ Exclusion/ Randomization Criteria 
Deviations for Intent-to-treat
SAC
 
 
 
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Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliver-able 
1.12.
ITT
SP_T09 (DV1A)
Summary of Important Protocol Deviations 
SAC
1.13.
ITT
SP_T10
Summary of Exclusions from the Per Protocol Analysis
SAC
Demography
1.14.
ITT
IDSL - DM1
Summary of Demographic Characteristics, Intent-to-treat
SAC
1.15.
PP
IDSL - DM1
Summary of Demographic Characteristics, Per Protocol
SAC
1.16.
ITT
IDSL - DM5
Summary of Race and Racial Combinations
SAC
1.17.
ITT
IDSL – DM6
Summary of Race and Racial Combination Details
SAC
1.18.
ASE
EMA Table 1
Summary of Number of Subjects Enrolled by Country
EMA Reporting Package. 
Macro: EMA_COUNTRY
SAC
1.19.
ASE
EMA Table 2
Summary of Number of Subjects Enrolled by Age Category
EMA Reporting Package. 
Macro: EMA_AGEGRP
SAC
Medical Condition & Concomitant Medications
1.20.
ITT
IDSL – MH4
Summary of Current Medical Conditions
SAC
1.21.
ITT
IDSL – MH4
Summary of Past Medical Conditions
SAC
1.22.
ITT
SP_T11
Summary of Family History of Cardiovascular Risk Factors 
at Screening
SAC
1.23.
ITT
SP_T12
Summary of COPD History at Screening
SAC
1.24.
ITT
SP_T13
Summary of COPD Exacerbation History at Screening
SAC
1.25.
ITT
IDSL-SU1
Summary of Smoking History at Screening
Using Years Smoked, 
Cigarettes/Day and Smoking 
Pack Years
SAC
 
 
 
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Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliver-able 
1.26.
ITT
SP_T14
Summary of Smoking Status at Screening
SAC
1.27.
ITT
SP_T15
Summary of COPD Concomitant Medications Not Given for 
a COPD Exacerbation Taken Before Run-in
SAC
1.28.
ITT
SP_T15
Summary of COPD Concomitant Medications Not Given for 
a COPD Exacerbation Taken During Run-in or Washout
Display treatments instead of 
total
SAC
1.29.
ITT
SP_T15
Summary of COPD Concomitant Medications Not Given for 
a COPD Exacerbation Taken On-treatment
Display treatments instead of 
total
SAC
1.30.
ITT
SP_T15
Summary of COPD Concomitant Medications Not Given for 
a COPD Exacerbation Taken Post-treatment
1.31.
ITT
SP_T15
Summary of  Concomitant Medications Given for a COPD 
Exacerbation Taken On-treatment
Display treatments instead of 
total
SAC
1.32.
ITT
SP_T15
Summary of  Concomitant Medications Given for a COPD 
Exacerbation Taken During Washout
Display treatments instead of 
total
1.33.
ITT
SP_T15
Summary of  Concomitant Medications Given for a COPD 
Exacerbation Taken Post-treatment
1.34.
ITT
IDSL – CM1
Summary of Non-COPD Concomitant Medications Taken 
On-treatment
Display ATC and ingredient by 
treatments
SAC
1.35.
ITT
IDSL – CM1
Summary of Non-COPD Concomitant Medications Taken 
Post-treatment
Display ATC and ingredient by 
total
SAC
Baseline Severity
1.36.
ITT
Summary of Screening Lung Function Test Results
SAC
1.37.
ITT
Summary of GOLD Grade 1-4, GOLD mMRC Category A-
D, GOLD CAT Category A-D and Reversibility at Screening 
SAC
1.38.
ITT
Summary of Screening IC Results
SAC
 
 
 
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Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliver-able 
1.39.
ITT
Summary of mMRC Dyspnoea Scale at Screening
SAC
Treatment
1.40.
ITT
Summary of Overall Percentage Treatment Compliance
SAC
 
 
 
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10.13.5.
Efficacy Tables
Efficacy: Tables
No.
Population
IDSL / TST ID / Example 
Shell
Title
Programming Notes
Deliver-able 
Spirometry
2.1.
PP
E_T01
Summary of Baseline FEV1 (L), Per Protocol
SAC
2.2.
PP
E_T02
Summary of Trough FEV1 (L), Per Protocol
SAC
2.3.
PP
E_T03
Analysis of Trough FEV1 (L), Per Protocol
SAC
2.4.
PP
E_T04
Covariance Parameter Estimates for Repeated 
Measures Analysis of Trough FEV1 (L), Per 
Protocol
SAC
2.5.
PP
E_T05
Type III Tests of Fixed Effects for Repeated 
Measures Analysis of Trough FEV1 (L), Per 
Protocol
SAC
2.6.
PP
E_T06
Significance Levels for Interactions of Treatment 
with Period, Period Baseline and Mean Baseline for 
Trough FEV1 (L), Per Protocol
SAC
2.7.
ITT
E_T01
Summary of Baseline FEV1 (L), Intent-to-treat
SAC
2.8.
ITT
E_T02
Summary of Trough FEV1 (L), Intent-to-treat
SAC
2.9.
ITT
E_T03
Analysis of Trough FEV1 (L), Intent-to-treat
SAC
ITT
E_T04
Covariance Parameter Estimates for Repeated 
Measures Analysis of Trough FEV1 (L), Intent-to-
treat
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / TST ID / Example 
Shell
Title
Programming Notes
Deliver-able 
2.10.
ITT
E_T05
Type III Tests of Fixed Effects for Repeated 
Measures Analysis of Trough FEV1 (L), Intent-to-
treat
SAC
2.11.
ITT
E_T08
Summary and Analysis of Proportion of 
Responders according to FEV1 (L)
SAC
2.12.
PP
Analysis of Trough FEV1 (L) , Tipping Point 
Sensitivity Analysis, Per Protocol
SAC
2.13.
ITT
Analysis of Trough FEV1 (L) , Tipping Point 
Sensitivity Analysis, Intent-to-treat
SAC
2.14.
ITT
E_T01
Summary of Baseline FVC (L)
SAC
2.15.
ITT
E_T02
Summary of Trough FVC (L)
SAC
2.16.
ITT
E_T03
Analysis of Trough FVC (L)
SAC
IC 
2.17.
ITT
E_T01
Summary of Baseline IC (L) 
SAC
2.18.
ITT
E_T02
Summary of Trough IC (L) 
SAC
2.19.
ITT
E_T03
Analysis of Trough IC (L)
SAC
Rescue Medication
2.20.
ITT
E_T09
Summary of Mean Number of Puffs of Rescue 
Medication per Day using e-diary
SAC 
2.21.
ITT
E_T10
Analysis of Mean Number of Puffs of Rescue 
Medication per Day over Weeks 1-8 using e-diary
SAC 
2.22.
ITT
E_T11
Summary of Percentage Rescue-free Days using e-
diary
SAC 
2.23.
ITT
E_T12
Analysis of Percentage Rescue-free Days over 
SAC 
 
 
 
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Efficacy: Tables
No.
Population
IDSL / TST ID / Example 
Shell
Title
Programming Notes
Deliver-able 
Weeks 1-8 using e-diary
2.24.
ITT
E_T09
Summary of Mean Number of Puffs of Rescue 
Medication per Day using eMDI
SAC 
2.25.
ITT
E_T11
Summary of Percentage Rescue-free Days using 
eMDI
SAC 
CAT
2.26.
ITT
E_T02
Summary of CAT Score
Include baseline
SAC 
2.27.
ITT
E_T03
Analysis of CAT Score
SAC 
2.28.
ITT
E_T08
Summary and Analysis of Proportion of Responders 
According to CAT
SAC
E-RS
2.29.
ITT
E_T02
Summary of Weekly Mean E-RS Total Score
SAC 
2.30.
ITT
E_T02
Summary of Weekly Mean E-RS - Breathlessness 
Score
SAC
2.31.
ITT
E_T02
Summary of Weekly Mean E-RS - Cough and 
Sputum Score
SAC
2.32.
ITT
E_T02
Summary of Weekly Mean E-RS - Chest Score
SAC
2.33.
ITT
E_T03
Analysis of Weekly Mean E-RS Total Score
SAC 
2.34.
ITT
E_T03
Analysis of Weekly Mean E-RS - Breathlessness 
Score
SAC
2.35.
ITT
E_T03
Analysis of Weekly Mean E-RS - Cough and 
Sputum Score
SAC
2.36.
ITT
E_T03
Analysis of Weekly Mean E-RS - Chest Score
SAC
2.37.
ITT
E_T08
Summary and Analysis of Proportion of Responders 
According to E-RS Total Score
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / TST ID / Example 
Shell
Title
Programming Notes
Deliver-able 
2.38.
ITT
E_T08
Summary and Analysis of Proportion of Responders 
According to E-RS Breathlessness Score
2.39.
ITT
E_T08
Summary and Analysis of Proportion of Responders 
According to E-RS Cough and Sputum Score
SAC
2.40.
ITT
E_T08
Summary and Analysis of Proportion of Responders 
According to E-RS Chest Score
SAC
Inhaler Ease of use
2.41.
IN
(example 200301)
Summary of Ease of Use Questionnaire
SAC 
2.42.
IN
(example 200301)
Summary and Analysis of Ease of Use Rating
Present by sequence and 
total
SAC
2.43.
IN
(example 200301)
Summary of Ease of Use Rating
Present by sequence and 
total (example 200301)
Inhaler Errors
2.44.
IN
(example 200301)
Summary of Errors for the ELLIPTA Inhaler
Raw questionnaire data 
SAC 
2.45.
IN
(example 200301)
Summary of Errors for the Respimat Inhaler
Raw questionnaire data 
SAC 
2.46.
IN
(example 200301)
Summary of Number of Subjects with at least One 
Error
Include critical and overall. 
Present by sequence and 
total 
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10.13.6.
Efficacy Figures
Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming 
Notes
Deliver-able
Spirometry
2.1.
PP
E_F01
Box Plot of Change from Baseline in Trough FEV1 (L) at 
Week 8, Per Protocol
SAC
2.2.
PP
E_F02
Empirical Distribution Function Plot of Change from 
Baseline in Trough FEV1 (L) at Week 8, Per Protocol
SAC
2.3.
PP
E_F03
Least Squares Mean Change from Baseline (95% CI) in 
Trough FEV1 (L), Per Protocol
SAC
2.4.
ITT
E_F01
Box Plot of Change from Baseline in Trough FEV1 (L) at 
Week 8, Intent-to-treat
SAC
2.5.
ITT
E_F02
Empirical Distribution Function Plot of Change from 
Baseline in Trough FEV1 (L) at Week 8, Intent-to-treat
SAC
2.6.
ITT
E_F03
Least Squares Mean Change from Baseline (95% CI) in 
Trough FEV1 (L), Intent-to-treat
SAC
2.7.
ITT
E_F03
Least Squares Mean Change from Baseline (95% CI) in 
Trough FVC (L)
SAC
IC
2.8.
ITT
E_F03
Least Squares Mean Change from Baseline (95% CI) in 
Trough IC (L)
SAC
CAT
2.9.
ITT
E_F03
Least Squares Mean Change from Baseline (95% CI) in 
CAT Score
SAC
 
 
 
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Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming 
Notes
Deliver-able
E-RS
2.10.
ITT
E_F03
Least Squares Mean (95% CI) Change from Baseline in 
Weekly Mean E-RS Total Score
SAC
2.11.
ITT
E_F03
Least Squares Mean (95% CI) Change from Baseline in 
Weekly Mean E-RS Breathlessness Score
SAC
2.12.
ITT
E_F03
Least Squares Mean (95% CI) Change from Baseline in 
Weekly Mean E-RS Cough and Sputum Score
SAC
2.13.
ITT
E_F03
Least Squares Mean (95% CI) Change from Baseline in 
Weekly Mean E-RS Chest Score
SAC
 
 
 
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10.13.7.
Safety Tables
Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliver-able 
Adverse Events
3.1.
ITT
S_T01
Overview of Adverse Events
SAC
3.2.
ITT
S_T02 (AE1)
Summary of On-treatment Adverse Events
SAC
3.3.
ITT
S_T02 (AE1)
Summary of Post-treatment Adverse Events
Include footnote ‘Note: AEs 
with onset during the 
washout or follow-up period 
or following IP 
discontinuation are 
considered post-treatment 
and have been assigned to 
the treatment previously 
received.’
SAC
3.4.
ITT
S_T02 (AE1)
Summary of On-treatment Adverse Events Reported by 3% 
(after rounding) or More Subjects in Any Treatment 
SAC
3.5.
ITT
S_T02 (AE1)
Summary of the 10 Most Frequent On-treatment Adverse 
Events in Each Treatment 
Count most frequent number 
of events, not subjects and 
%. Sort by descending total 
incidence (sum of number of 
subjects with event).
SAC
3.6.
ITT
S_T02 (AE1)
Summary of On-treatment Drug Related Adverse Events
SAC
3.7.
ASE
S_T02 (AE1)
Summary of Pre-treatment Fatal Serious Adverse Events
SAC
3.8.
ITT
S_T02 (AE1)
Summary of On-treatment Fatal Serious Adverse Events
SAC
3.9.
ITT
S_T02 (AE1)
Summary of Post-treatment Fatal Serious Adverse Events
Include footnote ‘Note: AEs 
with onset during the 
washout or follow-up period 
or following IP 
SAC
 
 
 
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Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliver-able 
discontinuation are
considered post-treatment 
and have been assigned to 
the treatment previously 
received.’
3.10.
ITT
S_T02 (AE1)
Summary of On-treatment Drug-related Fatal Serious 
Adverse Events
SAC
3.11.
ASE
S_T02 (AE1)
Summary of Pre-treatment Non-fatal Serious Adverse Events
SAC
3.12.
ITT
S_T02 (AE1)
Summary of On-treatment Non-fatal Serious Adverse Events
SAC
3.13.
ITT
S_T02 (AE1)
Summary of Post-treatment Non-fatal Serious Adverse 
Events
Include footnote ‘Note: AEs 
with onset during the 
washout or follow-up period 
or following IP 
discontinuation are 
considered post-treatment 
and have been assigned to 
the treatment previously 
received.’
SAC
3.14.
ITT
S_T02 (AE1)
Summary of On-treatment Drug-related Non-fatal Serious 
Adverse Events
SAC
3.15.
ITT
S_T03
Summary of On-treatment Adverse Events of Special Interest
SAC
3.16.
ITT
S_T02 (AE1)
Summary of On-treatment Adverse Events Leading to 
Permanent Discontinuation of Study Treatment or Withdrawal 
from the Study
SAC
3.17.
ASE
S_T02 (AE1)
Summary of Pre-treatment Adverse Events Leading 
Withdrawal from the Study
SAC
3.18.
ASE
IDSL -AE2
Relationship between Adverse Event System Organ Class, 
Preferred Term and Verbatim Text
SAC
 
 
 
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Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliver-able 
3.19.
ASE
EMA Table 3
Summary of Non-serious Adverse Events > 3% (before 
rounding) in any treatment
EMA Reporting Package
Macro: EMA_AE
SAC
3.20.
ASE
Standard EMA 
output
Summary of On-treatment Adverse Events Categories 
by Age Subgroup
EMA Reporting Package
Macro: EMA_AE
SAC
COPD exacerbations
3.21.
ITT
S_T04
Summary of On-treatment COPD Exacerbations
SAC
3.22.
ITT
S_T04
Summary of Post-treatment COPD Exacerbations
Include footnote ‘Note: 
Exacerbations with onset 
during the washout or follow-
up period or following IP 
discontinuation are 
considered post-treatment 
and have been assigned to 
the treatment previously 
received.’
SAC
Extent of Exposure
3.23.
ITT
S_T05
Summary of Exposure
SAC
 
 
 
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10.13.8.
ICH Listings
For all listings replace ‘Centre ID’/‘Inv. ID’ header with ‘Investigator at Centre’/’Inv. at Centre’.  The CENTREID variable should be used for this.
ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
Study Population: Subject Disposition
1.
ITT
IDSL_
ES2
Listing of Reasons for Withdrawal
SAC
Study Population: Protocol Deviations
2.
ITT
Listing of Important Protocol Deviations
SAC
3.
ASE
IDSL – IE3
Listing of Inclusion/ Exclusion/ Randomization Criteria 
Deviations
SAC
Study Population: Treatment
4.
ITT
IDSL – TA1
Listing of Randomized and Actual Treatments
SAC
Study Population: Demography
5.
ITT
IDSL – DM2
Listing of Demographic Characteristics
Include BMI as the optional 
measurement.  In addition, 
include a country column 
as the first sort variable.  A 
flag will be included to 
identify those subjects in 
the PP population.
SAC
6.
ITT
IDSL – DM9
Listing of Race
Include a country column 
as the first sort variable.
SAC
7.
ITT
Listing of Screening Lung Function Tests
SAC
 
 
 
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ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
Efficacy: Spirometry and IC
8.
ITT
Listing of Raw FEV1 (L) and FVC (L) Data
Flags will be included to: 1. 
identify those subjects in 
the PP population; 
SAC
9.
ITT
Listing of Raw IC (L) Data
SAC
Safety: Adverse Events
10.
ASE
IDSL_
AE7
Listing of Subject Numbers for Individual Adverse Events
SAC
11.
ASE
IDSL_
AE8
Listing of All Adverse Events
Additional columns 
detailing questions for SAE 
variables will need to be 
added.  
SAC
12.
ASE
IDSL_
AE8
Listing of Non-fatal Serious Adverse Events
Additional columns 
detailing questions for SAE 
variables will need to be 
added.  
SAC
13.
ASE
IDSL_
AE8
Listing of Fatal Serious Adverse Events
Additional columns 
detailing questions for SAE 
variables will need to be 
added.  
SAC
14.
ASE
IDSL_
AE8
Listing of Adverse Events leading to Discontinuation of 
Study Treatment or Withdrawal from the Study
Additional columns 
detailing questions for SAE 
variables will need to be 
added.  
SAC
15.
ITT
IDSL_
AE8
Listing of On-treatment Drug-related AEs
Additional columns 
detailing questions for SAE 
variables will need to be 
added.  
SAC
 
 
 
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82
ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
Safety: Extent of Exposure
16.
ITT
Listing of Exposure 
SAC
Safety: DPI Malfunctions
17.
ITT
Listing of Potential DPI Inhaler Malfunctions
SAC
10.13.9.
Non-ICH Listings
For all listings replace ‘Centre ID’/‘Inv. ID’ header with ‘Investigator at Centre’/’Inv. at Centre’.  The CENTREID variable should be used for this.
Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
Study Population: Subject Disposition
18.
ASE
IDSL -
ES2
Listing of Reasons for Withdrawal – Subjects Randomized but 
Not in the ITT Population
SAC
19.
ITT
Listing of the Follow-up Contact
SAC
Study Population: Protocol Deviations
20.
ITT
Listing of Exclusions from the Per-protocol Analysis
SAC
 
 
 
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83
Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
21.
ITT
IDSL – TA1
Listing of Treatment Misallocations
Change Centre ID to 
Investigator ID: xxxxxx
And also 
Investigator at Centre: 
xxxxxx
SAC
Study Population: Treatment
22.
ITT
Listing of Overall Percentage Treatment Compliance
SAC
23.
ITT
SP_L1
Listing of Subjects Who Discontinued Study Treatment
SAC
Study Population: Medical Conditions & Concomitant Medications
24.
ITT
IDSL – MH2
Listing of Medical Conditions
SAC
25.
ITT
Listing of Family History of Cardiovascular Risk Factors
SAC
26.
ITT
Listing of COPD History
SAC
27.
ITT
Listing of Smoking History and Smoking Status
SAC
28.
ITT
IDSL_
CM2
Listing of COPD Concomitant Medications
SAC
29.
ITT
IDSL_
CM2
Listing of non-COPD Concomitant Medications
SAC
30.
ITT
IDSL – CM6
Relationship between ATC Level 1, Ingredient and Verbatim 
Text for Non-COPD Medications
SAC
 
 
 
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84
Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
Study Population: Baseline Severity
31.
ITT
Listing of GOLD Grade/Categories and Reversibility
SAC
32.
ITT
Listing of mMRC Dyspnoea Scale at Screening
SAC
Efficacy: Spirometry and IC
33.
ITT
Listing of Derived FEV1 (L)
SAC
34.
ITT
Listing of Derived FVC (L)
SAC
35.
ITT
Listing of Derived IC (L)
SAC
Efficacy: eDiary endpoints
36.
ITT
Listing of Derived Rescue Endpoints
SAC
37.
ITT
Listing of E-RS Scores
SAC
38.
ITT
Listing of Derived E-RS Scores
SAC
QoL: CAT
39.
ITT
Listing of CAT Scores
SAC
Inhaler Assessments
40.
ITT
Listing of Errors on ELLIPTA Inhaler 
Indicate IN pop flag
SAC
41.
ITT
Listing of Errors on Respimat Inhaler 
Indicate IN pop flag
SAC
42.
ITT
Listing of Derived Error Data
Indicate IN pop flag
SAC
43.
ITT
Listing of Ease of Use Questionnaire Data
Indicate IN pop flag
SAC
 
 
 
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CONFIDENTIAL
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85
Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
Safety
44.
ITT
IDSL_
VS4
Listing of Vital Signs
SAC
45.
ITT
Listing of ECG Values
Just list screening values
SAC
46.
ITT
Listing of COPD Exacerbations
SAC
Safety: Pneumonia
47.
ITT
IDSL_
VS4
Listing of Chest X-ray Data
SAC
48.
ITT
Listing of all Pneumonia Data
SAC
Safety: Liver Events
49.
ITT
IDSL_
VS4
Listing of Liver Events
SAC
50.
ITT
Listing of Virology
SAC
 
 
 
2017N327578_00


CONFIDENTIAL
204990
86
Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
Safety: Cardiovascular Events
51.
ITT
IDSL_
VS4
Listing of Myocardial infarction/unstable angina
SAC
52.
ITT
Listing of Congestive heart failure
SAC
53.
ITT
IDSL_
VS4
Listing of Arrhythmias
SAC
54.
ITT
Listing of Valvulopathy
SAC
55.
ITT
IDSL_
VS4
Listing of Pulmonary hypertension
SAC
56.
ITT
Listing of Cerebrovascular events/stroke and transient ischemic 
attack
SAC
57.
ITT
Listing of Peripheral arterial thromboembolism
SAC
58.
ITT
IDSL_
VS4
Listing of Deep venous thrombosis/pulmonary embolism
SAC
59.
ITT
Listing of Revascularisation
SAC
60.
ITT
IDSL_
VS4
Listing of All cause deaths
SAC
 
 
 
2017N327578_00