Conditions: Pulmonary Disease, Chronic Obstructive
Keywords: FF/VI/UMEC TRELEGY ELLIPTA COPD Effectiveness
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 3109
Healthy volunteers: no

Brief summary:
The primary purpose of this study is to assess the effectiveness of TRELEGY ELLIPTA relative to non-ELLIPTA Multiple Inhaler Triple Therapies (MITT) for Chronic Obstructive Pulmonary Disease (COPD) control within the usual clinical practice setting. The study will be conducted once TRELEGY ELLIPTA has been approved in the countries in which the study will be conducted and is available commercially. This is a randomized, open-label, effectiveness, phase 4 study of 24 weeks' duration in COPD subjects to evaluate TRELEGY ELLIPTA (fluticasone furoate \[FF\]/vilanterol \[VI\]/umeclidinium bromide \[UMEC\]: 100 microgram \[mcg\]/62.5 mcg/25 mcg) inhalation powder taken once daily using a single ELLIPTA inhaler compared with any non-ELLIPTA MITT in the usual care setting. Effectiveness of TRELEGY ELLIPTA will be assessed by comparing proportion of COPD Assessment Test (CAT) responders at Week 24 between two treatment groups. TRELEGY and ELLIPTA are trademarks of GlaxoSmithKline (GSK) group of companies. The study will enroll approximately 3000 subjects.

Detailed description:

Arms:
arm 1: Eligible subjects will receive a blended combination of FF in the first strip (100 mcg per blister) and UMEC/VI in second strip (62.5 mcg UMEC per blister and 25 mcg VI per blister), a single inhalation once daily in the morning in the same TRELEGY ELLIPTA Dry Powder Inhaler (DPI) via inhalation route for a period of 24 weeks. Study treatment may be augmented with other prescribed COPD medications such as including rescue medications, which will be prescribed and obtained according to usual practice. arm 2: Eligible subjects will receive the ICS/LAMA/LABA products twice daily and dosing regimens as prescribed by their physician for a period of 24 weeks. Study treatment may be augmented with other prescribed COPD medications such as including rescue medications, which will be prescribed and obtained according to usual practice.

Interventions: intervention 1: FF/UMEC/VI intervention 2: Inhaled Corticosteroid intervention 3: LAMA intervention 4: LABA intervention 5: COPD rescue medications
Intervention descriptions: intervention 1: FF is a dry white powder containing 100 mcg GW685698 blended with lactose in one blister in the first strip of the DPI. UMEC/VI is a dry white powder containing 62.5 mcg of UMEC and 25 mcg of VI per blister, both blended together with lactose and magnesium stearate in the second strip of the DPI. intervention 2: Inhaled Corticosteroid (ICS) as prescribed by the physician. intervention 3: LAMA as prescribed by the physician. intervention 4: LABA as prescribed by the physician. intervention 5: Rescue medications for COPD will be prescribed and obtained according to usual practice.

Protocol document:
Prot_000.pdf: 
2017N321744_02
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TITLE PAGE
Protocol Title: The Clinical Effectiveness of Fluticasone Furoate/Umeclidinium 
Bromide/Vilanterol in a Single Inhaler (TRELEGYTM ELLIPTATM) when Compared 
with Non-ELLIPTA Multiple Inhaler Triple Therapies in COPD Patients within a Usual
Care Setting.
Protocol Number: 206854/Amendment 02
Short Title: INTREPID: INvestigation of TRELEGY Effectiveness: Usual PractIce 
Design
Compound Number:
GSK2834425(GSK573719+GW642444+GW685698)
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information: Can be found in the Study 
Reference Manual
Regulatory Agency Identifying Number(s): EudraCT number 2017-004369-29
Approval Date:28-SEP-2018
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.
Unauthorised copying or use of this information is prohibited.
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 2
28-Sep-2018
Amendment 1
15-Feb-2018
Original Protocol
06-Nov-2017
Amendment 2 28-SEP-2018
Overall Rationale for the Amendment 02:
The purpose of the amendment is to:
Include wording for collection of a historical eosinophil count, whole blood count 
and % eosinophils, which will be used to provide further characterisation of the 
patient population enrolled in the study.
Clarify information pertaining to the reporting of GSK Medical 
Device/Drug/Device combinations incidents.
 
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Section # and 
Name
Description of Change
Brief Rationale
2
Schedule of 
activities
Addition of requirement to 
collect the most recent
historical eosinophil count 
data. 
There is increasing evidence to 
suggest that eosinophil levels are 
predictive of response to inhaled 
corticosteroids.  Collection of 
eosinophil data will allow more 
complete characterisation of the 
patient population included in the 
study and support data interpretation.
3.2.1 and 3.2.2
Risk Mitigation
Changed source of safety 
information used by the 
Investigator for Trelegy from 
the Summary of patient 
characteristics to the 
Investigator Brochure.
To be consistent across the asset the 
decision was made to use the 
Investigator Brochure as the 
Reference Safety Information (RSI)
as there are countries where Trelegy 
is still not licensed and are unable to 
use the SmPC as the RSI.
5.5
Data Collection
Addition of requirement to 
collect the most recent 
historical eosinophil count 
data 
There is increasing evidence to 
suggest that eosinophil levels are 
predictive of response to inhaled 
corticosteroids. Collection of 
eosinophil data will allow more 
complete characterisation of the 
patient population included in the 
study and support data interpretation.
9.4
Rationale for collection of 
historical eosinophil counts, 
whole blood count and % 
eosinophils
There is increasing evidence to 
suggest that eosinophil levels are 
predictive of response to inhaled 
corticosteroids.
9.6
Treatment of 
overdose
Changed source of safety 
information used by the 
Investigator for Trelegy from 
the Summary of patient 
characteristics to the 
Investigator Brochure.
To be consistent across the asset the 
decision was made to use the 
Investigator Brochure as the 
Reference Safety Information (RSI) 
as there are countries where Trelegy 
is still not licensed and are unable to 
use the SmPC as the RSI.
9.7.1
GSK Medical 
Device
GSK 
Drug/Device 
combinations 
To provide clarity on the 
reporting requirements and 
what a drug/device 
combination is.
As this study is using commercial 
supply of investigational products, 
the reporting requirements around 
drug/device products is different
from that of clinical supplies This 
has been clarified
 
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Section # and 
Name
Description of Change
Brief Rationale
incidents
7.6.1
Medications
Changed source of safety 
information used by the 
Investigator for Trelegy from 
the Summary of patient 
characteristics to the 
Investigator Brochure.
To be consistent across the asset the 
decision was made to use the 
Investigator Brochure as the 
Reference Safety Information (RSI) 
as there are countries where Trelegy 
is still not licensed and are unable to 
use the SmPC as the RSI.
References 
Addition of references to 
provide background to 
eosinophil data collection
Provide reader with additional 
sources.
Overall Rationale for the Amendment 01: The purpose of the amendment is to include 
wording for reporting of unusual failure in efficacy for new drugs as required by the 
Canadian Marketed Health Products Directorate. This will permit the inclusion of Canada 
as a potential study country. Changes have also been made to enable collection of both 
pre- and post-bronchodilator FEV1 from the spirometry subgroup at baseline. This will 
permit reversibility assessment and definition of the study subpopulation.
A consenting visit has been added to the schedule of activities, this will allow sites who 
are assessing lung function to have more flexibility in scheduling. 
Other protocol updates include guidance on recording participant participation in 
pulmonary rehabilitation; the reporting requirements for medical device incidents and 
inhaler malfunction; some editing for clarity/ consistency and corrections of 
typographical errors. 
 
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Section # and 
Name
Description of Change
Brief Rationale
12.3.1
Additional 
Adverse Event 
(AE) Reporting 
Requirements 
for Canadian 
investigators
Addition of Health Canada 
requirements for reporting of 
unusual failure in efficacy for 
new drugs to the Marketed 
Health Products Directorate 
Potential addition of Canada as a 
study country
9 Study 
Assessments and 
Procedures
9.1.2 Lung 
Function
Change to allow collection of 
both pre-and post-
bronchodilator spirometry at 
Visit 1
Assessment of reversibility and 
definition of study population
7 Treatments 
7.6 Concomitant 
Therapy
Collection of participant 
pulmonary rehabilitation 
programme details
Use of a pulmonary rehabilitation 
programme may impact the primary 
outcome. We will collect details of 
any pulmonary rehabilitation 
programme to permit analysis of this
impact.
9.6 Safety 
Assessments
Wording added to describe the 
reporting requirements for 
medical devices and defective 
inhalers
To provide sites with clarity
2 Schedule of 
Activities
Consenting Visit 0 added
The maximum time allowed 
between consent, screening 
and randomisation set to 6 
weeks 
To provide sites with flexibility, 
clarity and consistency
Throughout
Editing for clarity/ consistency 
and corrections of 
typographical errors.
Minor, therefore have not been 
summarised
 
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TABLE OF CONTENTS
PAGE
1.
SYNOPSIS.............................................................................................................10
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................13
3.
INTRODUCTION....................................................................................................21
3.1.
Background and Rationale..........................................................................21
3.2.
Benefit/Risk Assessment ............................................................................22
3.2.1.
Risk Assessment .........................................................................22
3.2.2.
Risk Mitigation .............................................................................22
3.2.3.
Benefit Assessment.....................................................................22
3.2.4.
Overall Benefit: Risk Conclusion..................................................23
4.
OBJECTIVES AND OUTCOMES...........................................................................24
5.
STUDY DESIGN ....................................................................................................26
5.1.
Eligibility criteria..........................................................................................26
5.1.1.
Screen Failures............................................................................27
5.2.
Study Treatment .........................................................................................27
5.2.1.
Treatment Change.......................................................................27
5.3.
Study Visits and Usual Care .......................................................................28
5.4.
Study Procedures .......................................................................................28
5.4.1.
COPD Assessment Test (CAT)....................................................28
5.4.2.
Spirometry ...................................................................................29
5.4.3.
Assessment of Errors in the Use of Study Treatment 
Inhalers........................................................................................29
5.4.4.
Participant Treatment and Study Satisfaction 
Questionnaire ..............................................................................29
5.4.5.
Health Related Quality of Life Questionnaire ...............................29
5.5.
Data Collection ...........................................................................................29
5.5.1.
Exploratory Electronic Health Record (EHR) Data 
Collection.....................................................................................30
5.6.
Number of Participants ...............................................................................30
5.7.
Participant and Study Completion...............................................................30
5.8.
Scientific Rationale for Study Design ..........................................................30
5.9.
Dose Justification........................................................................................31
6.
STUDY POPULATION...........................................................................................31
6.1.
Inclusion Criteria.........................................................................................32
6.2.
Exclusion Criteria........................................................................................32
6.3.
Screen Failures...........................................................................................34
7.
TREATMENTS.......................................................................................................34
7.1.
Treatments Administered............................................................................34
7.2.
Method of Treatment Assignment ...............................................................35
7.3.
Blinding.......................................................................................................35
7.4.
Preparation/Handling/Storage/Accountability..............................................35
7.5.
Treatment Compliance................................................................................35
7.6.
Concomitant Therapy..................................................................................35
7.6.1.
Medications .................................................................................36
 
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7.6.2.
Non-Drug Therapies ....................................................................37
7.7.
Treatment after the End of the Study ..........................................................37
8.
DISCONTINUATION CRITERIA.............................................................................37
8.1.
Discontinuation of Study .............................................................................37
8.2.
Discontinuation of Study Treatment ............................................................38
8.3.
Withdrawal from the Study..........................................................................38
8.4.
Lost to Follow Up........................................................................................39
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................40
9.1.
Effectiveness Assessments ........................................................................40
9.1.1.
The COPD Assessment Test (CAT):............................................40
9.1.2.
Lung Function..............................................................................41
9.1.2.1.
Reversibility Testing ...................................................42
9.1.3.
Assessment of Errors in the Use of Inhaler(s)..............................42
9.2.
Other Assessments ....................................................................................43
9.2.1.
Clinically Important Deterioration .................................................43
9.2.2.
COPD Exacerbations...................................................................43
9.2.3.
Healthcare Resource Utilisation...................................................43
9.3.
Exploratory Assessments ...........................................................................44
9.3.1.
Participant Treatment and Study Satisfaction 
Questionnaire ..............................................................................44
9.3.2.
Health Related Quality of Life Questionnaire ...............................44
9.4.
Other ..........................................................................................................44
9.5.
Adverse Events...........................................................................................44
9.5.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................45
9.5.2.
Method of Detecting AEs and SAEs.............................................46
9.5.3.
Follow-up of AEs and SAEs.........................................................46
9.5.4.
Regulatory Reporting Requirements for SAEs .............................46
9.5.5.
Cardiovascular and Death Events................................................46
9.5.6.
Pneumonia ..................................................................................47
9.5.7.
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as SAEs...............................................47
9.5.8.
Pregnancy ...................................................................................48
9.6.
Treatment of Overdose...............................................................................48
9.7.
Safety Assessments ...................................................................................48
9.7.1.
Medical Devices...........................................................................48
9.7.2.
Drug/Device Combination Products .............................................49
9.8.
Pharmacokinetics .......................................................................................50
9.9.
Pharmacodynamics ....................................................................................50
9.10.
Genetics .....................................................................................................50
9.11.
Biomarkers .................................................................................................50
10. STATISTICAL CONSIDERATIONS........................................................................50
10.1.
Hypotheses.................................................................................................50
10.2.
Sample Size Determination ........................................................................51
10.2.1.
Primary Outcome.........................................................................51
10.2.2.
Secondary Outcomes ..................................................................52
10.2.2.1.
FEV1 ..........................................................................52
10.2.2.2.
Critical Errors..............................................................52
10.2.3.
Sample Size Sensitivity................................................................53
 
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10.3.
Populations for Analyses ............................................................................54
10.4.
Statistical Analyses.....................................................................................55
10.4.1.
Effectiveness Analyses................................................................55
10.4.2.
Safety Analyses...........................................................................56
10.4.3.
Other Analyses ............................................................................57
10.4.4.
Interim Analyses ..........................................................................57
11. REFERENCES.......................................................................................................58
12. APPENDICES........................................................................................................60
12.1.
Appendix 1: Abbreviations and Trademarks................................................60
12.2.
Appendix 2: Study Governance Considerations..........................................63
12.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................67
12.3.1.
Additional Adverse Event (AE) Reporting Requirements 
for Canadian investigators ...........................................................72
12.4.
Appendix 4: Collection of Pregnancy Information........................................74
12.5.
Appendix 5 COPD Exacerbation Identification, Categorisation and 
Treatment Guidelines..................................................................................76
12.5.1.
Guidelines for Identifying COPD Exacerbations...........................76
12.5.2.
COPD Exacerbation Severity.......................................................77
12.5.3.
Treatment of COPD Exacerbations..............................................77
12.5.4.
Guidelines for Treatment with Corticosteroids..............................77
12.5.5.
Guidelines for Treatment with Antibiotics .....................................77
12.5.6.
Onset and Resolution of COPD Exacerbations............................77
12.5.7.
Guideline for assessing multiple exacerbations............................78
12.5.8.
Guideline for assessing exacerbations that increase in 
severity ........................................................................................78
12.6.
Appendix 6: Summary of Risks...................................................................79
12.7.
Appendix 7: Inhaler Specific Errors.............................................................84
12.8.
Appendix 8: Protocol Amendment History...................................................97
 
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1.
SYNOPSIS
Protocol Title: The Clinical Effectiveness of Fluticasone Furoate/Umeclidinium 
Bromide/ Vilanterol in a Single Inhaler (TRELEGYTM ELLIPTATM) when Compared 
with Non-ELLIPTA Multiple Inhaler Triple Therapies in COPD Patients within a Usual 
Care Setting.
Short Title: INTREPID: INvestigation of TRELEGY Effectiveness: usual PractIce 
Design
Rationale: The highly-controlled conditions of a randomised clinical trial (RCT) remove 
factors that influence and differentiate the use of medicines in everyday clinical practice. 
Effectiveness data generated in the broader population observed in an everyday clinical 
setting is increasingly being recognised as important in complementing data derived from 
the pivotal Phase III safety and efficacy studies.
The primary purpose of this study is to assess the effectiveness of TRELEGY ELLIPTA 
relative to non-ELLIPTA Multiple Inhaler Triple Therapies (MITT) for Chronic 
Obstructive Pulmonary Disease (COPD) control within the usual clinical practice setting.
The study will be conducted once TRELEGY ELLIPTA has been approved in the 
countries in which the study will be conducted and is available commercially. 
Objectives and Primary and Secondary Outcomes:
Objective
Outcome
Primary
To compare the effectiveness of 
TRELEGY ELLIPTA with non-ELLIPTA 
MITT for the impact of COPD on 
wellbeing and daily life after 24 weeks’ 
treatment.
Proportion of responders based on the 
COPD Assessment Test (CAT) at week 24. 
Response defined as change from baseline 
of CAT score 2 at 24 weeks.
Secondary (subgroup of participants)
To compare the effectiveness of 
TRELEGY ELLIPTA with non-ELLIPTA 
MITT on lung function after 24 weeks’ 
treatment.
Change from baseline in Forced Expiratory 
Volume in one second (FEV1) at 24 weeks
(subgroup of participants).
To compare critical errors made by study 
participants using the ELLIPTA inhaler
with participants using selected non-
ELLIPTA MITT after 24 weeks’ treatment.
Percentage of participants making at least 1 
critical error in inhalation technique at 24 
weeks. (subgroup of participants)
 
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Overall Design:
This is a randomised, open-label, effectiveness, phase IV study of 24 weeks’ duration in 
COPD patients to evaluate TRELEGY ELLIPTA [FF/UMEC/VI: 
100mcg/62.5mcg/25mcg] inhalation powder taken once daily using a single ELLIPTA 
inhaler compared with any non-ELLIPTA MITT in the usual care setting. 
To reflect usual care as closely as possible, only 2 study visits are required: these are at 
screening/randomisation (Visit 1) and at the end of the study after 24 weeks of treatment 
(Visit 2) or at early withdrawal (EW). At the investigators discretion, it is acceptable to 
invite the participant to a consenting visit (Visit 0) prior to Visit 1.
During the 24-week treatment period (between the two study visits), participants should 
receive usual clinical care, according to physician’s discretion, in line with local COPD 
care guidelines. After starting a new treatment, the physician should, at their discretion, 
ascertain participant well-being within a time-frame acceptable for the participants needs.
The participants will complete the COPD Assessment Test (CAT; V1 and Visit 2/EW 
Visit), a Health-Related Quality of Life Questionnaire (HRQoL; V1 and Visit 2/EW 
Visit) and a Participant Treatment and Study Satisfaction Questionnaire (Visit 2/EW 
Visit). A subgroup will be assessed for lung function and for inhaler error assessment.
The investigator will record serious adverse events (SAEs), study treatment related 
adverse events (AEs) and AEs that lead to withdrawal from study treatment. The 
investigator will also record moderate and severe exacerbation events, COPD related 
healthcare resource use, change in medication since the last scheduled or unscheduled 
visit/contact, historical eosinophil counts, whole blood count and % eosinophils.
Eligibility
Patients enrolled into the study must have the following

A clinical diagnosis of COPD with a score of ≥10 on the CAT prior to 
randomisation.
 
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
At least one moderate or severe exacerbation during the 3 years prior to 
randomisation, documented in medical notes.

Continuous use of non-ELLIPTA MITT or dual therapy prior to randomisation. 
Continuous use is defined as at least 60 days’ prescription cover during the prior 
16 weeks.
Dual therapy is defined as:

Long-acting β2-agonist used in combination with long-acting muscarinic 
antagonist (LABA/LAMA)
or

Inhaled corticosteroid used in combination with long-acting β2-agonist 
(ICS/LABA).
NOTE: Patients who are currently receiving dual therapy must be considered by their 
physician to require a step-up to triple therapy. The reason for the physician decision 
to step-up to triple therapy must be documented.
Study Treatment

Patients who consent to join the study and who meet eligibility criteria will be 
randomised to receive 24 weeks’ prescription cover for one of the following: 
o
TRELEGY ELLIPTA 
o
non-ELLIPTA MITT.

Randomisation will be stratified by prior therapy. 

For the duration of the study, participants should remain on the treatment to which 
they are randomised. If this is not possible, then at the investigator’s discretion, 
the participant may change treatment to a preferred alternative treatment. If the 
preferred alternative treatment is, in the opinion of the treating physician, 
unsuitable for the participant, then treatment can be changed to a non-preferred 
alternative. A change in study treatment should not result in withdrawal from the 
study. All participants should remain in the study and complete the 24-week Visit. 
If this is not possible then an EW visit should be completed.

In line with usual care, physicians will ensure that participants receive training on 
the correct use of COPD maintenance treatment inhaler(s) at randomisation and
whenever a treatment change is prescribed.
Number of Participants:
The target enrolment is 3000 participants randomised equally between the two treatment 
arms. It is estimated that approximately 3400 participants will be screened in order to 
randomise 3000. 
 
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2.
SCHEDULE OF ACTIVITIES (SOA)
PROCEDURE *
TREATMENT PERIOD
NOTES
VISIT 0
Consenting
VISIT 1
Screening
& 
Randomisation
Usual care /
contact for 
COPD related 
event or serious 
adverse event 
Early
Withdrawal
(EW) Visit
VISIT 2
The following sequence of events must be followed 
1.ICF, 2. Screening, 3. Randomisation. All three may 
occur on the same day with no more than 6 weeks 
between ICF and screening and no more than 6 weeks 
between screening and randomisation.
Study week
1
After week 1 and 
before Visit 2
After week 1 
and before 
Visit 2
24 (21 
days)
EW Visit should only be conducted if the participant 
discontinues from participating in the study. Participants 
withdrawing from study treatment but remaining in the 
study should continue to Visit 2.
Informed consent 
form (ICF)
X
ICF must be signed before any study procedures/ 
assessments 
Inclusion and 
exclusion criteria
X
Recheck clinical status before randomisation and/or 1st 
prescription for study treatment
Demography
X
Height and weight
X
Medical history: past 
and current medical 
conditions 
X
This includes family history of premature CV disease.
 
 
 
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PROCEDURE *
TREATMENT PERIOD
NOTES
VISIT 0
Consenting
VISIT 1
Screening
& 
Randomisation
Usual care /
contact for 
COPD related 
event or serious 
adverse event 
Early
Withdrawal
(EW) Visit
VISIT 2
The following sequence of events must be followed 
1.ICF, 2. Screening, 3. Randomisation. All three may 
occur on the same day with no more than 6 weeks 
between ICF and screening and no more than 6 weeks 
between screening and randomisation.
Study week
1
After week 1 and 
before Visit 2
After week 1 
and before 
Visit 2
24 (21 
days)
EW Visit should only be conducted if the participant 
discontinues from participating in the study. Participants 
withdrawing from study treatment but remaining in the 
study should continue to Visit 2.
Historical eosinophil 
count. whole blood 
count, % eosinophils
X
X
Most recent historical eosinophil measure taken within 
the previous 36 months prior to patients consenting 
visit. (Visit 1 or Visit 0 whichever is applicable)
o
An absolute number of eosinophils 
and the % of eosinophils out of the 
total WBC
o
White Blood Cell count (WBC)
Chronic Obstructive 
Pulmonary Disease 
(COPD) and 
Exacerbation history 
X
The number of moderate/ severe exacerbations in the 12 
months prior to V1 will be collected.
Randomisation
X
 
 
 
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PROCEDURE *
TREATMENT PERIOD
NOTES
VISIT 0
Consenting
VISIT 1
Screening
& 
Randomisation
Usual care /
contact for 
COPD related 
event or serious 
adverse event 
Early
Withdrawal
(EW) Visit
VISIT 2
The following sequence of events must be followed 
1.ICF, 2. Screening, 3. Randomisation. All three may 
occur on the same day with no more than 6 weeks 
between ICF and screening and no more than 6 weeks 
between screening and randomisation.
Study week
1
After week 1 and 
before Visit 2
After week 1 
and before 
Visit 2
24 (21 
days)
EW Visit should only be conducted if the participant 
discontinues from participating in the study. Participants 
withdrawing from study treatment but remaining in the 
study should continue to Visit 2.
COPD assessment 
test
(CAT)
X
X
X
CAT must be completed prior to randomization and 
prior to any other study procedures. Participants who 
have changed or discontinued treatment will remain in 
the study and complete CAT assessment at the Visit 
2/EW Visit.
COPD
Exacerbation 
assessment
X
X
X
Moderate and severe exacerbations that occur between 
V1 and V2 will be recorded. 
COPD related 
healthcare resource 
use assessment
X
X
X
Details 
of 
primary 
healthcare 
contacts, 
known 
secondary care contacts and all COPD related 
medication use that occurs between V1 and V2 will be 
recorded in the eCRF.
Assessment of 
inhaler errors 
(subgroup only)
X
X
 
 
 
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PROCEDURE *
TREATMENT PERIOD
NOTES
VISIT 0
Consenting
VISIT 1
Screening
& 
Randomisation
Usual care /
contact for 
COPD related 
event or serious 
adverse event 
Early
Withdrawal
(EW) Visit
VISIT 2
The following sequence of events must be followed 
1.ICF, 2. Screening, 3. Randomisation. All three may 
occur on the same day with no more than 6 weeks 
between ICF and screening and no more than 6 weeks 
between screening and randomisation.
Study week
1
After week 1 and 
before Visit 2
After week 1 
and before 
Visit 2
24 (21 
days)
EW Visit should only be conducted if the participant 
discontinues from participating in the study. Participants 
withdrawing from study treatment but remaining in the 
study should continue to Visit 2.
Spirometry for lung 
function 
(subgroup only)
X
X
X
Spirometry should be performed before the day’s dose 
of usual care or study medication. 
The assessment is pre-and post-salbutamol at Visit 1 
and pre-salbutamol at Visit 2 /EW Visit. It should be 
started between approximately 6:00 am and 12:00 pm
The most recent use of COPD maintenance inhaler/ 
study treatment should be noted. 
Participant treatment 
& study satisfaction 
questionnaire
X
X
Health Related 
Quality of Life 
Questionnaire 
(HRQoL)
X
X
X
 
 
 
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PROCEDURE *
TREATMENT PERIOD
NOTES
VISIT 0
Consenting
VISIT 1
Screening
& 
Randomisation
Usual care /
contact for 
COPD related 
event or serious 
adverse event 
Early
Withdrawal
(EW) Visit
VISIT 2
The following sequence of events must be followed 
1.ICF, 2. Screening, 3. Randomisation. All three may 
occur on the same day with no more than 6 weeks 
between ICF and screening and no more than 6 weeks 
between screening and randomisation.
Study week
1
After week 1 and 
before Visit 2
After week 1 
and before 
Visit 2
24 (21 
days)
EW Visit should only be conducted if the participant 
discontinues from participating in the study. Participants 
withdrawing from study treatment but remaining in the 
study should continue to Visit 2.
Review of study 
treatment related 
Adverse Events (AE) 
X
X
X
X
Clinical judgment should be used to determine whether 
there is a relationship between study treatment and each 
occurrence of each AE/SAE.
Study treatment related adverse events must be recorded 
from V1. 
Where a causality relationship is determined, this must 
be recorded as a study treatment related AE.
AEs not related to either study treatment or 
withdrawal from study treatment are not recorded, 
unless classified as serious adverse events. 
Refer to Appendix 3 for definitions of AEs, SAEs and 
guidelines on assessment of causality by investigator
 
 
 
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PROCEDURE *
TREATMENT PERIOD
NOTES
VISIT 0
Consenting
VISIT 1
Screening
& 
Randomisation
Usual care /
contact for 
COPD related 
event or serious 
adverse event 
Early
Withdrawal
(EW) Visit
VISIT 2
The following sequence of events must be followed 
1.ICF, 2. Screening, 3. Randomisation. All three may 
occur on the same day with no more than 6 weeks 
between ICF and screening and no more than 6 weeks 
between screening and randomisation.
Study week
1
After week 1 and 
before Visit 2
After week 1 
and before 
Visit 2
24 (21 
days)
EW Visit should only be conducted if the participant 
discontinues from participating in the study. Participants 
withdrawing from study treatment but remaining in the 
study should continue to Visit 2.
Review of Adverse 
Events (AE) that 
lead to withdrawal 
from study treatment
X
X
X
X
All AEs that lead to withdrawal from study treatment, 
whether judged related to study treatment or not, should 
be recorded.
The participant should be encouraged to remain in the 
study for collection of effectiveness and safety data.
All AEs that lead to withdrawal from the study whilst 
the participant is on study treatment, whether judged 
related to study treatment or not, should be recorded.
 
 
 
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PROCEDURE *
TREATMENT PERIOD
NOTES
VISIT 0
Consenting
VISIT 1
Screening
& 
Randomisation
Usual care /
contact for 
COPD related 
event or serious 
adverse event 
Early
Withdrawal
(EW) Visit
VISIT 2
The following sequence of events must be followed 
1.ICF, 2. Screening, 3. Randomisation. All three may 
occur on the same day with no more than 6 weeks 
between ICF and screening and no more than 6 weeks 
between screening and randomisation.
Study week
1
After week 1 and 
before Visit 2
After week 1 
and before 
Visit 2
24 (21 
days)
EW Visit should only be conducted if the participant 
discontinues from participating in the study. Participants 
withdrawing from study treatment but remaining in the 
study should continue to Visit 2.
SAE review
X
X
X
X
X
SAEs that are related to study participation or to GSK 
products are collected from the time of consent to 
randomisation. All other SAEs are recorded from the 
time of randomisation.
Clinical judgment should be used to determine the 
relationship 
between 
study 
treatment 
and 
each 
occurrence of each AE/SAE.
Where a causality relationship is determined, this must 
be recorded as a study treatment related SAE.
Refer to Appendix 3 for definitions of AEs, SAEs and 
guidelines on assessment of causality by investigator.
Details of 
randomised study 
treatment and any 
study treatment 
changes
X
X
X
X
Reason for change in treatment, details and date of new 
treatment should be recorded.
 
 
 
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PROCEDURE *
TREATMENT PERIOD
NOTES
VISIT 0
Consenting
VISIT 1
Screening
& 
Randomisation
Usual care /
contact for 
COPD related 
event or serious 
adverse event 
Early
Withdrawal
(EW) Visit
VISIT 2
The following sequence of events must be followed 
1.ICF, 2. Screening, 3. Randomisation. All three may 
occur on the same day with no more than 6 weeks 
between ICF and screening and no more than 6 weeks 
between screening and randomisation.
Study week
1
After week 1 and 
before Visit 2
After week 1 
and before 
Visit 2
24 (21 
days)
EW Visit should only be conducted if the participant 
discontinues from participating in the study. Participants 
withdrawing from study treatment but remaining in the 
study should continue to Visit 2.
Details of medicine 
and therapy taken for 
respiratory and other 
selected conditions 
X
X
X
X
* The timing and number of planned study assessments, including assessments may be altered during the study based on newly 
available data.
 
 
 
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3.
INTRODUCTION
3.1.
Background and Rationale
COPD guidelines advocate the use of one or more long-acting bronchodilators (long-
acting muscarinic receptor antagonists (LAMA) or long-acting β2-adrenergic receptor 
agonists (LABA) in addition to inhaled corticosteroids (ICS) for patients who continue to 
have advanced COPD with significant symptoms and are at a high risk of exacerbations
[GOLD, 2013]. Population based studies of COPD treatment patterns demonstrate that 
Multiple Inhaler Triple Therapy (MITT), an ICS/LAMA/LABA combination, is already 
widely used in the clinical management of COPD [Price, 2014, Landis, 2017].
GlaxoSmithKline (GSK) has developed a once-daily triple therapy [Fluticasone Furoate
(FF)/ Umeclidinium (UMEC)/ Vilanterol (VI) (100mcg/62.5mcg/25mcg)] in a single 
inhaler (TRELEGY ELLIPTA). TRELEGY ELLIPTA provides a new treatment option 
for the management of patients with advanced COPD with the aim of reducing
exacerbation frequency and burden of polypharmacy, improving lung function, health 
related quality of life and symptom control, while providing a more convenient treatment 
option for patients compared with established dual/monotherapies.
It is acknowledged that double-blind randomised clinical trials (RCT) conducted for 
registration purposes enrol a more selected patient population than is expected to be 
prescribed the medication post-approval and treated in normal clinical practice. 
Traditional, randomised controlled trials often exclude or withdraw participants who do 
not achieve a certain level of compliance with the investigational product. Participants
may also be excluded because of their age, the severity of their disease, or the presence of 
comorbidities which would exclude them from entry to registration trials [Herland, 
2005]. The highly-controlled conditions of an RCT remove factors that influence and 
differentiate the use of medicines in everyday clinical practice. Thus, safety and 
effectiveness data generated in the broader population observed in an everyday clinical 
setting are increasingly being recognised as important in complementing data derived 
from the pivotal Phase III safety and efficacy studies [Kardos, 2016]. The Salford Lung 
Study (SLS) was designed to evaluate the effectiveness and safety of the once-daily 
inhaled combination of fluticasone furoate and vilanterol (fluticasone furoate–vilanterol) 
as compared with existing maintenance therapy in a broad population of patients with 
COPD receiving usual care [Vestbo, 2016]. This study will build on the learnings from 
SLS to permit the unobtrusive assessment of effectiveness outcomes and safety 
monitoring, blended into routine clinical care.
The primary purpose of this study is to meet this need by assessing the effectiveness of 
TRELEGY ELLIPTA relative to non-ELLIPTA MITT within the usual clinical practice 
setting. The study will be conducted once TRELEGY ELLIPTA has been approved in the 
countries in which the study will be conducted and is available commercially. 
 
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3.2.
Benefit/Risk Assessment
3.2.1.
Risk Assessment 
TRELEGY ELLIPTA
More detailed information about the known and expected risks and reasonably expected 
adverse events of TRELEGY ELLIPTA are described in the Investigator Brochure. To 
supplement this, the study risk assessment is outlined in Appendix 6 and the following 
section outlines the risk mitigation strategy for this study.
Multiple Inhaler Triple Therapy (MITT)
In this study, MITT will be used in line with the recommendations provided in the 
product label. The most common drug-related adverse reactions for the components of 
MITT are associated with anti-cholinergic therapy, β2-agonists and inhaled 
corticosteroids. These are of the same drug class as TRELEGY ELLIPTA and so have a 
similar profile of undesirable effects (see Appendix 6). Please refer to the package insert 
for precise information on the risks of using the individual components of MITT. 
Other COPD Maintenance Therapy
If other COPD maintenance therapy is prescribed at the physician’s direction, these 
should be used in line with the recommendations provided in the product label. Please 
refer to the package insert for precise information on the risks of using the individual 
components. 
3.2.2.
Risk Mitigation 
TRELEGY ELLIPTA and MITT

Investigators are informed of the risks for Trelegy in the Investigator Brochure.

Patients with known hypersensitivity to the study treatment, excipients or 
components will be excluded from the study.
3.2.3.
Benefit Assessment
COPD guidelines advocate the use of one or more long-acting bronchodilators (LAMA or
LABA) in addition to ICS as therapy treatment option for the most advanced patients 
with significant symptoms and a high risk of exacerbations [GOLD, 2017].
Benefits of MITT have been shown in published studies which assessed the use of MITT
in moderate-severe COPD patients. These studies reported improvements in lung 
function, health related quality of life, hospitalisation rates and rescue medication use, 
compared to dual therapy (ICS/LABA) or LAMA alone [Lipson, 2017, Aaron, 2007, 
Cazzola, 2007, Hanania, 2012, Jung, 2012, Welte, 2009]. These studies also showed that 
the number and type of reported AEs were generally similar with administration of dual 
or monotherapy doses for periods of up to one year, and were mostly related to their 
pharmacological mode of action. 
Patients enrolled in this study will receive either TRELEGY ELLIPTA or a non-
ELLIPTA MITT. Based on available data with the components ICS, LAMA and LABA, 
 
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it is expected that patients will potentially derive clinical benefit from this combination of 
study treatments.
In a disease where polypharmacy is common, the TRELEGY ELLIPTA, once-daily 
combination has the potential to optimise bronchodilator therapy, improve patient 
adherence to therapy and, as a result, improve overall disease management in COPD 
patients.
3.2.4.
Overall Benefit: Risk Conclusion
The clinical development programmes for TRELEGY ELLIPTA demonstrated a 
favourable benefit/risk for patients with COPD. This has led to approval and marketing of 
TRELEGY ELLIPTA for a COPD indication in a number of countries around the world.
Current risks that have been identified for these therapeutic classes are based on the 
known pharmacology of the individual components: ICS, LAMA and LABA. These 
include key risks of pneumonia and bone disorders/fractures from ICS-containing 
combinations, and the risk of adverse cardiovascular effects from LAMA/LABA-
containing combinations. However, the associated benefit/risk profiles for both arms of 
the study are similar because the three active components are of the same therapeutic 
class. 
Participants enrolled onto the study will be receiving medication of therapeutic classes 
which are available for prescription. At enrolment, the treating physician has already 
made the decision that the benefit/risk for this triple combination therapy is appropriate
for these patients. 
Participants will be monitored according to usual care at their physician’s discretion with 
adverse events recorded as described in Section 9.5. The potential benefit of this new 
therapy in patients with moderate to severe COPD supports the conduct of this study to 
collect effectiveness data from a clinical practice setting.
 
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4.
OBJECTIVES AND OUTCOMES
Objectives
Outcomes
Primary
To compare the effectiveness of 
TRELEGY ELLIPTA with non-ELLIPTA 
MITT for the impact of COPD on 
wellbeing and daily life after 24 weeks’ 
treatment. 
Proportion of responders based on the 
COPD Assessment Test (CAT) at week 24. 
Response defined as change from baseline 
of CAT score 2 at 24 weeks.
Secondary
To compare the effectiveness of 
TRELEGY ELLIPTA with non-ELLIPTA 
MITT on lung function after 24 weeks’
treatment.
Change from baseline in FEV1 at 24 weeks 
(in a subset of participants).
To compare critical errors (CE) made by 
study participants using the ELLIPTA 
inhaler with participants using selected 
non-ELLIPTA MITT after 24 weeks’
treatment.
Percentage of participants making at least 1 
critical error in inhalation technique at 24 
weeks (in a subset of participants).
Other
To compare TRELEGY ELLIPTA with 
inhaled non-ELLIPTA MITT for a 
clinically important deterioration (CID)
Proportion of responders who experience
CID.
CID is a composite outcome defined as any 
one of the following events:

100 mL reduction from baseline in
FEV1 at 24 weeks.

An exacerbation (requiring treatment 
with antibiotics and/or systemic 
steroids or hospitalisation)

2 units change (increase) from baseline 
in CAT score at 24 weeks.
 
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Objectives
Outcomes
To quantify the incidence, rate and time to 
first moderate/severe COPD exacerbation 
for study participants on TRELEGY 
ELLIPTA compared with participants on 
non-ELLIPTA MITT. 

Annualised rate of moderate/severe 
exacerbations (defined as: requiring 
treatment with antibiotics and/or 
systemic steroids or hospitalisation).

Time to first moderate /severe 
exacerbation (defined as: requiring
treatment with one or more of the 
following: antibiotics, systemic 
steroids, hospitalisation).
To compare the effectiveness of 
TRELEGY ELLIPTA with non-ELLIPTA 
MITT for COPD-related Healthcare 
Resource Utilisation (HCRU). 
The frequency of COPD related HCRU
including: 

Primary healthcare contacts. 

COPD related medication.

Hospital admissions, outpatient 
appointments and A&E 
attendances.
Exploratory: frequency of HCRU 
assessed using electronic health 
records.
Exploratory
To assess the data for correlation between 
critical errors and clinical outcomes
Numerical correlation of CE with CAT, 
moderate/ severe exacerbations and FEV1.
To describe the patient study experience 
Participant Treatment and Study 
Satisfaction Questionnaire at 24 weeks/ 
EW Visit.
To describe the change from baseline in 
patient Health Related Quality of Life
Health Related Quality of Life 
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Objectives
Outcomes
Safety
To compare safety for study participants 
using the ELLIPTA inhaler with 
participants using non-ELLIPTA MITT 
after 24 weeks’ treatment.

All serious adverse events

Study treatment related adverse events

Adverse events that lead to withdrawal 
from study treatment
5.
STUDY DESIGN
Figure 1
Study Schematic 
This is a randomised, open-label, effectiveness, phase IV study of 24 weeks’ duration in
COPD patients to evaluate TRELEGY ELLIPTA [FF/UMEC/VI: 
100mcg/62.5mcg/25mcg] inhalation powder taken once daily using a single ELLIPTA
inhaler compared with any non-ELLIPTA MITT in the usual care setting. 
Patients who meet the study entry criteria will be invited to join the study by their 
physician. Those who give their informed consent will be assessed for eligibility.
5.1.
Eligibility criteria
Patients enrolled into the study must have the following.

A clinical diagnosis of COPD with a score of ≥10 on the COPD Assessment Test 
(CAT) prior to randomisation.

At least one moderate or severe exacerbation during the 3 years prior to 
randomisation, documented in medical notes.

Continuous use of non-ELLIPTA MITT or dual therapy prior to randomisation. 
Continuous use is defined as at least 60 days’ prescription cover during the prior 
16 weeks.
 
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Dual therapy is defined as:

Long-acting β2-agonist used in combination with long-acting muscarinic 
antagonist (LABA/LAMA).
or

Inhaled corticosteroid used in combination with long-acting β2-agonist 
(ICS/LABA)
NOTE: Patients who are currently receiving dual therapy must be considered by their 
physician to require a step- up to triple therapy. The reason for the physician decision 
to step-up to triple therapy must be documented.
Full details of inclusion/ exclusion criteria are listed in Section 6.
5.1.1.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical trial 
but are never subsequently randomised. The reason for screen failure will be recorded in 
the electronic case report form (eCRF).
5.2.
Study Treatment

Study treatment is defined as the COPD maintenance therapy that the patient is 
prescribed whilst enrolled in the study from randomisation to the Visit 2 /EW 
visit.

Patients meeting eligibility criteria will be randomised to receive 24 weeks’
prescription cover for one of the following:
o
TRELEGY ELLIPTA
o
non-ELLIPTA MITT

Participants should remain on the treatment to which they are randomised. 

However, the prescribed COPD maintenance therapy (i.e. study treatment) may 
change for an individual participant as described in Section 5.2.1.

In line with usual care, physicians should ensure that participants receive training 
on the correct use of COPD maintenance treatment inhalers at randomisation and
whenever there is a study treatment change.
5.2.1.
Treatment Change
For the duration of the study, participants should remain on the treatment to which they 
are randomised. If this is not possible, then at physician’s discretion, they may change 
treatment to a preferred alternative treatment.

The preferred alternative treatment for patients randomised to TRELEGY 
ELLIPTA is any MITT or any single inhaler triple therapy. 

The preferred alternative treatment for patients randomised to non-ELLIPTA 
MITT is an alternative non-ELIPTA MITT or any other non-ELLIPTA COPD 
maintenance therapy.
 
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If the preferred alternative treatment is, in the opinion of the treating physician, 
unsuitable for the participant, then treatment can be changed to a non-preferred 
alternative.
Any change in study treatment must be recorded. The reason for this change should also 
be recorded.
A change in COPD maintenance treatment should not result in withdrawal from the 
study. All participants should remain in the study and complete Visit 2. If this is not 
possible then an early withdrawal visit should be completed.
5.3.
Study Visits and Usual Care
To reflect usual care as closely as possible, only 2 study visits are required: these are at 
screening/randomisation (Visit 1) and at the end of the study after 24 weeks of treatment
or at early withdrawal (Visit 2/EW Visit). At the investigators discretion, it is acceptable 
to invite the participant to a consenting visit (Visit 0) prior to Visit 1. The gaps between 
each activity must be no more than 6 weeks.
During the 24-week treatment period (between the two study visits), participants should 
receive usual clinical care, according to physician’s discretion, in line with local COPD 
care guidelines. After starting a new treatment, the physician should, at their discretion, 
ascertain participant well-being within a time-frame acceptable for the participants needs.
The participants will complete the CAT (V1 and Visit 2/EW Visit), a Health-Related
Quality of Life Questionnaire (V1 and Visit 2/EW Visit) and a Participant Treatment and 
Study Satisfaction Questionnaire (Visit 2/EW Visit). A subgroup will be assessed for 
lung function and for inhaler error assessment.
The investigator will record moderate and severe COPD exacerbation events (on the 
exacerbation page of the eCRF). With respect to COPD exacerbation SAEs, only a subset 
of these will be collected (on the SAE page of the eCRF; see Section 9.5.7).
5.4.
Study Procedures
Full details of study procedures are given Section 9: Study Assessments and Procedures
5.4.1.
COPD Assessment Test (CAT)
CAT should be completed prior to randomisation and at Visit 2 /EW Visit. The CAT is 
required for all participants. It is a simple 8-item validated questionnaire to assess the 
impact of COPD on wellbeing and daily life. 
If a participant does not present as expected for their final study visit (on study 
completion or withdrawal), every attempt should be made to encourage them to attend as 
soon as possible.
In very exceptional circumstances, when the participant is not able to attend for a Visit 
2/EW Visit, the CAT assessment, together with a safety assessment may be carried out 
 
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via a domiciliary visit/telephone call within 21 days of final study/early withdrawal visit 
date. The type of contact used for the CAT assessment must be recorded.
5.4.2.
Spirometry
In a subgroup of approximately 1520 participants, spirometry will be measured at 
randomisation and at the Visit 2/EW Visit. If, in the opinion of the investigator, a 
participant has a pre-existing condition that makes them unable to perform spirometry, 
then this should be clearly documented. 
5.4.3.
Assessment of Errors in the Use of Study Treatment Inhalers
In line with usual care, at the start of the study, and whenever participants are issued with 
a prescription for a new study COPD maintenance treatment, the physician (or delegate) 
should, at their discretion, train the participant on the correct use of their inhaler(s).
All participants who are offered spirometry should also have an assessment of inhaler
errors provided that an appropriate error checklist is available for the study medication 
they are using for COPD maintenance therapy at Visit 2/EW. A critical error (CE) is 
defined as an error that is most likely to result in no, or significantly reduced, medication 
being inhaled. If participants are unable to perform spirometry they may still participate 
in the CE assessment.
5.4.4.
Participant Treatment and Study Satisfaction Questionnaire
At Visit 2/EW Visit, participants will complete a short treatment and study satisfaction 
questionnaire.
5.4.5.
Health Related Quality of Life Questionnaire
At enrolment and at Week 24/EW Visit, participants will complete a short HRQoL 
questionnaire.
5.5.
Data Collection
In addition to the details of study procedures and patient reported outcomes, data 
collection in the study eCRF will include the following

All SAEs.

Study treatment related AEs (see Appendix 3 for guidelines on assessment of 
causality by investigator).

AEs which lead to withdrawal from study treatment.

Details of moderate and severe COPD exacerbation events including medications 
given.

Reason for change in study treatment

Healthcare resource use associated with COPD related medical encounters 
including medication prescribed for treatment of respiratory conditions.

Historical blood eosinophils
 
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5.5.1.
Exploratory Electronic Health Record (EHR) Data Collection
Following patient consent, in some countries which have suitable systems, healthcare 
resource utilisation data will be electronically transmitted from electronic health records 
to a third party who will transfer anonymised data to GSK for exploratory analysis. 
Data captured from electronic health records will be considered exploratory only and is 
not intended to be relied upon in assessing the study outcomes or for monitoring or 
otherwise managing the participant’s care. 
Data sources and data flow will be clearly defined in the Data Management Plan. The 
data collected will be the subject of a supplementary analysis plan.
5.6.
Number of Participants
The target enrolment is 3000 participants randomised equally between the two treatment 
arms. This assumes a study drop-out rate of 13.5% i.e., the study will have 2594 
participants who attend the Visit 2 and are still on their initially randomised treatment 
(1297 per arm). It is estimated that approximately 3400 participants will be screened in 
order to randomise 3000. 
5.7.
Participant and Study Completion
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the last visit at Week 24.
The end of the study is defined as the date of the last visit of the last participant in the 
study.
5.8.
Scientific Rationale for Study Design
Although the intention of this study is to assess TRELEGY ELLIPTA in a minimally 
interventional routine clinical care setting, a randomised parallel group design has been 
chosen to provide the most robust evidence of clinical effectiveness. 
Randomisation provides some control for potential bias, e.g. time (disease progression) 
and study effects. A study effect was observed in the usual care arm of the triple therapy 
subgroup within the Salford Lung Study (SLS); annualised exacerbation rates decreased 
substantially following randomisation although the patient’s treatment remained 
unchanged [Vestbo, 2016].
Comparison of randomised parallel groups will enable a fair assessment of the 
effectiveness of TRELEGY ELLIPTA relative to non-ELLIPTA MITT.
The study population is intended to be broad and reflect COPD patients with advanced 
symptomatic disease who their physician may consider to be suitable for triple therapy.
The primary focus of this study is COPD control measured by the CAT questionnaire 
which is recommended in the most recent Global COPD Strategy Document for
assessment of COPD health status impairment [GOLD, 2017]. CAT is meaningful to 
 
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patients as a patient-reported outcome measure which assesses the impact of COPD on 
their daily lives and helpful to Health Care Professionals (HCPs) to inform patient 
management. It has also been shown to be of significant interest and relevance to payers 
in recent (unpublished) research conducted by GSK. CAT is a minimally interventional 
measure which will be assessed only at randomisation, and at the end of study (Visit 
2/EW Visit).
The CAT data will be supported by secondary outcomes of lung function and inhaler 
error use errors in a subgroup of patients, but no additional study visits have been 
included to support these outcomes: thus, maintaining the routine-care nature of the 
study. Exacerbations and healthcare resource use data is of key interest to payers and will 
be included in the study as descriptive outcomes.
The duration of the study is 24 weeks, when all primary and secondary outcomes can be 
assessed adequately and there is less potential for treatment switching than in a longer 
study. Maintenance of the patient’s randomised treatment regimen during the study is at 
the discretion of the treating physician. Change in COPD maintenance treatment 
represents a potential challenge to the assessment of the true treatment effect. This is 
because the decision to change treatment could be directly influenced by the patient’s 
outcome. The study will collect outcomes relating to treatment changes in order to better 
understand switch patterns and reasons for treatment changes.
There will be no protocol defined study visits other than at the start and finish of the 24-
week treatment period in order to minimise study effects and create conditions which are 
as similar as possible to everyday clinical practice. Study visits and non-routine clinic 
assessments have a potential impact on factors which can differentiate treatments in usual 
clinical practice, e.g. treatment adherence [Chen, 2015].
The minimal patient assessment and monitoring planned for this study is suitable for 
investigation of this approved medicine, which has been in clinical use for some time as 
two separate inhalers containing the same medicines.
5.9.
Dose Justification
The FF/UMEC/VI (100/62.5/25mcg) dose was studied in the phase III clinical trial 
programme and is the licensed dose in the countries in which the study will be conducted. 
The dose of the non-ELLIPTA MITT and all other COPD medications will be prescribed 
as the approved doses within the licence.
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
 
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6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
1.
Informed Consent: Capable of giving signed informed consent as described in 
Appendix 2 which includes compliance with the requirements and restrictions listed 
in the informed consent form (ICF) and in this protocol.
2.
COPD Diagnosis: Patients with a documented physician diagnosis of COPD.
3.
Severity of COPD symptoms: A score of ≥10 on the COPD Assessment Test
(CAT) at screening.
4.
History of Exacerbations. Patients who have a history of treatment with 
systemic/oral corticosteroids, antibiotics and/or hospitalisation for at least one COPD 
exacerbation in the 3 years prior to randomisation. This will be captured through 
patient recall and/or medical records and must be documented in patients notes. 
Prior use of systemic/oral corticosteroids and/or antibiotics alone does not qualify as 
an exacerbation history unless the use was associated with treatment of worsening 
symptoms of COPD.
5.
Existing COPD Maintenance Treatment. Patients currently receiving one of the 
non-ELLIPTA maintenance therapies listed below who have been prescribed it 
continually for at least 16 weeks prior to randomisation.
Continuous prescription is defined as a minimum of 60 days’ prescription cover 
during the prior 16 weeks.
The non -ELLIPTA maintenance therapy must be one of the following 

ICS in combination with LAMA and LABA (MITT)

LAMA and LABA used in combination as a dual therapy

LABA and ICS used in combination as a dual therapy
NOTE: patients who are currently on a dual maintenance therapy for COPD must be 
considered by their physician to require a step-up to triple therapy. The reason for the 
physician decision to step-up must be documented.
Patients who are receiving only COPD medication on an ‘as required’ basis are not 
eligible.
6.
Age and Sex: Participants must be aged 40 years of age at the time of signing the 
informed consent.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
1. Women of child bearing potential as defined in Appendix 4. This includes women 
who are pregnant or lactating or are planning on becoming pregnant during the study.
 
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2. Medical Conditions: Patients with any life-threatening condition i.e. low probability, 
in the opinion of the investigator, of 6-month survival due to severity of COPD or co-
morbid condition. 
3. Patients with unstable COPD. Patients with resolution of an exacerbation less than 
2 weeks prior to Visit 1, must not be randomised. Patients may be rescreened 2 weeks 
after resolution of exacerbation (exacerbation is defined as: requiring treatment with 
antibiotics and/or systemic steroids or hospitalisation).
4. Other diseases/abnormalities: Patients with historical or current evidence of 
uncontrolled or clinically significant disease. Significant is defined as any disease 
that, in the opinion of the investigator, would put the safety of the participant at risk 
through participation, or which would affect the effectiveness or safety analysis if the 
disease/condition exacerbated during the study
5. Hypersensitivity: A history of allergy or hypersensitivity to any corticosteroid, 
anticholinergic/muscarinic receptor antagonist, β2-agonist, lactose/milk protein or 
magnesium stearate or a medical condition such as narrow-angle glaucoma, prostatic 
hypertrophy or bladder neck obstruction that, in the opinion of the investigator
contraindicates study participation.
6. Prior/Concomitant Therapy with Oral Corticosteroid. Patients who, in the 
opinion of the treating investigator, are chronic users of oral corticosteroids for
respiratory or other indications (if unsure discuss with the medical monitor prior to 
screening).
Chronic use is defined as more than 14 days’ continuous use during the 12 weeks 
prior to Visit 1.
7. Participants currently participating in any interventional clinical study.
Participants taking any investigational drug treatment within 30 days prior to Visit 1
or within five half-lives (t½) of the prior investigational study (whichever is the 
longer of the two).
 
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6.3.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomised to study treatment. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography and screen failure details.
Individuals who do not initially meet the criteria for participation in this study (screen 
failure) may be rescreened. Rescreened participants should be assigned a new subject 
number.
7.
TREATMENTS
Study treatment is defined as any investigational treatment(s) or marketed product(s)
intended to be administered to a study participant according to the study protocol.
7.1.
Treatments Administered
All study treatments will be sourced from commercial supply. Participants randomised to 
TRELEGY ELLIPTA will receive the following investigational product (see Table 1) 
and should inhale once from the ELLIPTA at the same time each day for the duration of 
the 24-week treatment period:
Table 1
Description of Inhalation Powder in TRELEGY ELLIPTA
TRELEGY ELLIPTA Dry Powder Inhaler (DPI)
FF/UMEC/VI 
First strip 
Second strip 
GW685698 (FF) blended 
with lactose
GW642444 (VI) and GSK573719 
(UMEC) blended with lactose and 
magnesium stearate
Dosage Form 
ELLIPTA DPI with 30 doses (2 strips with 30 blisters per strip)
Unit Dose Strengths 
100 mcg per blister
25 mcg per blister GW642444,
62.5 mcg per blister GSK573719
Physical description 
Dry white powder
Dry white powder
Route of 
Administration 
Inhaled
Participants randomised to non-ELLIPTA MITT will receive the ICS/LAMA/LABA
products and dosing regimens as prescribed by their physician. 
Study treatment may be augmented with other prescribed COPD medications such as
including rescue medications, which will be prescribed and obtained according to usual 
practice.
 
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At the physician’s discretion, participants recruited into the study will be instructed on 
the proper use of the inhaler(s) to which they have been randomised. 
7.2.
Method of Treatment Assignment
A participant will be assigned a subject number at the time the informed consent is 
signed. Once a subject number is assigned to a participant it cannot be reassigned to any
other participant in the study.
All participants will be centrally randomised using an Interactive Web Response System 
(IWRS). Before the study is initiated, the log in information and directions for the IWRS 
will be provided to each site. Once a randomisation number is assigned to a participant it 
cannot be reassigned to any other participant in the study.
A country based randomisation schedule will be generated by Clinical Statistics, prior to 
the start of the study and using validated internal software.
Participants will be randomised (1:1) to receive a prescription for one of the following 
study treatment regimens: 

TRELEGY ELLIPTA once daily in the morning
or

Non- ELLIPTA MITT twice daily treatment
The randomisation will be stratified based on previous treatment (ICS/LABA or 
LABA/LAMA or ICS/LAMA/LABA). The recruitment of ICS/LABA and 
LABA/LAMA will be capped at a combined total of approximately 50% at a country 
level.
The duration of treatment for each participant is 24 weeks.
7.3.
Blinding
Blinding procedures will not be used in this open label study
7.4.
Preparation/Handling/Storage/Accountability
Study treatment will be prescribed to the participant by the site as a licensed product. 
Handling and storage will be as per normal pharmacy practice. No study treatment 
accountability will be performed.
7.5.
Treatment Compliance
No measures, outside of usual care, will be taken to ensure and document treatment 
compliance.
7.6.
Concomitant Therapy
Any medication or vaccine for the treatment of a respiratory condition that the participant 
receives at the time of consent or receives during the study should be recorded along 
with:

dates of administration including start and end dates
 
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
dosage information including dose and frequency
7.6.1.
Medications
There are no prohibited medications. Participants should be prescribed medications at the 
physician’s discretion according to usual care, with reference to the Investigator Brochure 
for potential interactions. 
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
Treatment for COPD
COPD exacerbations should be treated at physician’s discretion as per usual practice. 
Medications used may include:

Antibiotics prescribed for an exacerbation.

Treatment with systemic corticosteroid (tablets, suspension or injection) for a limited 
period as described in Appendix 5.

A physician-advised change in SABA use (i.e. routinely scheduled versus as needed 
use).

Leukotriene receptor antagonists (LTRAs) and leukotriene modifiers.

Oral theophylline.

Mucolytics such as Acetylcysteine.

Any COPD medication deemed medically necessary for the short-term treatment 
(≤14days) of a moderate/severe COPD exacerbation or pneumonia
Guidance / caution is provided in relation to use of the following:

Systemic and ophthalmic beta-blockers: Administer with caution as systemic 
beta-blockers block the pulmonary effect of beta-agonists and may produce severe 
bronchospasm in patients with reversible obstructive airways disease. Cardio-
selective beta-blockers should be considered, although they also should be 
administered with caution.

Tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs): 
Administer with extreme caution as they may potentiate the effects of beta-
agonists on the cardiovascular system, including QTc prolongation.

Diuretics: Caution is advised in the co-administration of beta-agonists with non-
potassium sparing diuretics as this may result in hypokalemia and/or ECG 
changes.

CYP3A4 inhibitors: Caution should be exercised when considering the 
coadministration of long-term ketoconazole and other known strong CYP3A4
inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole,
lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin,
 
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voriconazole) because increased systemic corticosteroid and increased
cardiovascular adverse effects may occur.
7.6.2.
Non-Drug Therapies
Pulmonary Rehabilitation
At physician’s discretion, it is preferable to defer starting a course of pulmonary 
rehabilitation until after the end of the study.
Details of any pulmonary rehabilitation programme which starts or stops either during the 
8 weeks prior to Visit 1 or during the study should be captured in the eCRF.
Oxygen therapy is permitted.
Continuous Positive Airway Pressure (CPAP)
At the physician’s discretion, it is preferable to defer commencing CPAP for the 
treatment of obstructive sleep apnoea during the 6 weeks prior to enrolment. 
Details of CPAP treatment should be captured in the eCRF.
7.7.
Treatment after the End of the Study
There is no plan to continue to provide study treatment following the end of the study. At 
the end of the study, the choice of COPD maintenance treatment is at the discretion and 
clinical judgment of the physician.
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study

GSK reserves the right to suspend or prematurely discontinue this study at any 
time for reasons including, but not limited to, safety or ethical issues. For 
multicentre 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.

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.

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 
 
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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 Independent Review 
Board/Independent Ethics Committee (IRB/IEC) promptly and provide the reason 
for the suspension or premature discontinuation.

Participants who are found to be pregnant during the conduct of the study should 
be withdrawn from the study.
8.2.
Discontinuation of Study Treatment
For the duration of the study, participants should remain on the treatment to which they 
are randomised. 
If deemed necessary by the treating physician, the participant may change to a preferred
alternative COPD maintenance therapy as listed in Table 2.
Table 2
Preferred Alternative COPD maintenance therapy
Note: alternatives treatment should only be prescribed when participant cannot continue
the treatment to which they were randomised at Visit 1.
Treatment at randomisation
Permitted Treatment change 
TRELEGY ELLIPTA
Any therapy for COPD including
1.any MITT 
2.any single inhaler triple therapy
Any non-ELLIPTA MITT
1.Any non-ELLIPTA MITT
2. Any non-ELLIPTA therapy for COPD, excluding 
single inhaler triple therapy
Participants who are prescribed a preferred alternative COPD maintenance treatment 
should still be encouraged to continue in the study to collect all data including at Visit 2. 
Those who discontinue from the study should complete the EW Visit.
Participants who are prescribed COPD maintenance treatment which is not a preferred 
alternative should still be encouraged to continue in the study to collect all data including 
at Visit 2. Those who discontinue from the study should complete the EW visit.
8.3.
Withdrawal from the Study

Participants that permanently stop study treatment are not required to 
withdraw from the study. If for any reason a participant must permanently stop 
 
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their study treatment, every effort should be made by the Investigator/delegate to 
keep the participant in the study to collect important effectiveness and safety 
data. Alternative treatment options are described in Section 8.2, Table 2

A participant may withdraw from the study 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.

Refer to the SoA for data to be collected at the time of study discontinuation and
follow-up and for any further evaluations that need to be completed.
8.4.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she fails to return for the Visit 2
and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for the 
Visit 2:

The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible.

Before a participant is deemed lost to follow up, the investigator/ delegate must 
make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record.

If a participant is unable to attend for the end of study visit or EW visit, the CAT 
assessment may be carried out via a telephone call from the study site within 21 
days of the planned study visit.

Should the participant be completely unreachable, 21 days after the planned 
study visit, he/she will be considered to have withdrawn from the study with a 
primary reason of lost to follow-up. 
 
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9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA. 

Protocol waivers or exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management and 
obtained before signing of ICF may be utilised for screening or baseline purposes 
provided the procedure met the protocol-specified definition.
9.1.
Effectiveness Assessments
9.1.1.
The COPD Assessment Test (CAT):
The CAT questionnaire should be completed prior to randomisation and before any 
procedures or assessments are performed to avoid influencing the participant’s response. 
To avoid biasing responses, the participant should not be told the results of any 
diagnostic tests prior to completing the CAT questionnaire. It is recommended that the 
questionnaires be administered at the same time of day at both Visit 1 and 2.
The CAT will be completed by participants on paper prior to randomisation (Visit 1) and 
at Visit 2 before any other scheduled assessments.
In very exceptional circumstances, when the participant is not able to attend for a Visit 2, 
the CAT assessment, together with a safety assessment may be carried out via a 
domiciliary visit/telephone call within 21 days of final study visit date. This must be 
noted in the eCRF.
The COPD Assessment Test [Jones, 2009, Jones, 2012] is a validated, short and simple
patient completed questionnaire which has been developed for use in routine clinical
practice to measure the health status of patients with COPD. The CAT is an 8-item
questionnaire suitable for completion by all patients diagnosed with COPD. When
completing the questionnaire, participants rate their experience on a 6-point scale, 
ranging from 0 (no impairment) to 5 (maximum impairment) with a scoring range of 0-
40. Higher scores indicate greater disease impact.
Adequate time must be allowed to complete all items on the questionnaires; the 
questionnaires must be reviewed for completeness and, if necessary, the participant
should be encouraged to complete any missing assessments or items.
 
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Further instructions for completing the questionnaires can be found in the Study
Reference Manual (SRM).
9.1.2.
Lung Function
Lung function will be obtained using spirometry equipment that meets or exceeds the 
minimal performance recommendations of the ATS [Miller, 2005]. All sites will use 
standardised spirometry equipment provided by an external vendor. 
For FEV1 and FVC determination, at least 3 acceptable spirometry efforts (with no more 
than 8) should be obtained. Acceptable spirometry efforts should have a satisfactory start 
of test and end of test (e.g. a plateau in the volume-time curve) and be free from artefacts 
due to cough, early termination, poor effort, obstructed mouthpiece, equipment 
malfunction, or other reasons [Miller, 2005].
To facilitate pre-dose spirometry, participants should be encouraged to time their COPD 
maintenance therapy so that they are due for their next dose at the time of the study visit, 
which should be in the morning. 
At Visit 1 and 2, Spirometry, should be measured prior to the day’s dose of usual care/ 
study treatment. At Visit 1 pre- and post-salbutamol spirometry should be measured to 
assess reversibility (see Section 9.1.2.1). At Visit 2/ EW Visit, only pre-salbutamol 
spirometry will be measured.
The largest FEV1 and FVC from the 3 acceptable efforts should be recorded, even if they 
do not come from the same effort.
Spirometry should be performed as follows:

Started between approximately 6:00am and 12:00pm.

After completing the CAT.

Before the assessment of inhaler errors (critical errors).

After withholding short-acting beta-agonists/anti-cholinergic for 4 hours

At Visit 1 before the morning dose of usual COPD medication.

At Visit 2/ EW Visit before the morning dose of study COPD maintenance 
treatment.

The participant’s position during spirometry measurements (sitting or standing) 
should be consistent for both study visits.
If it is not possible to withhold usual care/study treatment and/or short-acting beta-
agonists or anti-cholinergic for ≥4 hours, then spirometry will still be measured and 
recorded. The most recent use of COPD maintenance treatment/ study treatment should
be recorded.
 
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The spirometry equipment must be used according to vendor guidelines. Further details 
regarding the spirometry procedures are provided in the SRM and the manual provided 
by the spirometry vendor.
Participants who are unable to perform spirometry may still have an inhaler error 
assessment and will not be excluded from the study.
9.1.2.1.
Reversibility Testing
Reversibility testing should be completed as follows:  Following pre-salbutamol 
spirometry (three acceptable spirometry efforts), the participant should self-administer 
salbutamol.  Three acceptable spirometry efforts should be obtained approximately 10 to 
15 minutes after salbutamol administration.
9.1.3.
Assessment of Errors in the Use of Inhaler(s)
At the start of the study, and whenever participants are issued with a prescription for a 
new COPD maintenance therapy, the physician (or delegate) will, at their discretion, train
the participant on the correct use of their inhaler(s). 
All participants who have spirometry measured should also have an assessment of inhaler 
errors performed where an appropriate error checklist is available for the study treatment 
they are using at Visit 2/EW Visit. If participants are unable to perform spirometry they 
may still participate in the inhaler errors assessment.
The errors listed will be aligned with the correct use information from the respective 
Patient Information Leaflets (PILs), in a checklist for each inhaler and these will be 
provided to investigators for scoring errors during the assessment.
The critical and overall errors per inhaler and how these have been defined are described 
in Appendix 7. If a suitable checklist is not available for study treatment, the participant 
will not have an error assessment. For participants who are on multiple inhaler therapy, 
checklists must be available for both inhalers in order for error assessment to proceed.
The errors made during the demonstration by participants are defined as “noncritical”, 
when the dose may not be affected, but the participant has demonstrated improper use of 
their inhaler, as per the checklist. A critical error is defined as an error that is most likely 
to result in no or significantly reduced medication being inhaled.
Assessment of Inhaler Error in Use
For the assessment, participants will be asked to demonstrate inhaler use when taking 
their regular dose of medication. Participants who have not withheld prescribed study 
medication must not perform an inhaler error assessment. Any errors (critical or non-
critical) made by the participant while using the inhaler will be recorded by the 
investigator or delegate during the assessment on the checklist provided. If the participant 
makes no errors, this will also be recorded by the investigator/delegate. 
If the participant makes any error in the use of the inhaler, the investigator/delegate will 
provide instruction in the correct use to the participant. 
 
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Where applicable, participants who use multiple inhalers should be tested on each inhaler 
consecutively according to their usual practice. 
The checklists will be provided in the Study Reference Manual.
9.2.
Other Assessments
9.2.1.
Clinically Important Deterioration
CID is a composite outcome which assesses individual deteriorations in lung function and 
CAT (as defined by the accepted minimal clinically important difference) as well as the 
incidence of exacerbation (requiring treatment with antibiotics and/or systemic steroids or 
hospitalisation). For this study, it will be defined as follows:

100 mL reduction from baseline in FEV1 at 24 weeks.

An exacerbation (requiring treatment with antibiotics and/or systemic steroids or 
hospitalisation)

2 units change (increase) from baseline in CAT score at 24 weeks.
9.2.2.
COPD Exacerbations
Moderate and severe COPD exacerbation data will be collected from medical records and 
patient recall in the eCRF by the investigator and study-site personnel for all participants. 
A moderate or severe exacerbation is defined as worsening COPD symptoms that 
required systemic corticosteroids and/or antibiotics or hospitalisation. Use of antibiotics 
alone does not qualify as an exacerbation unless the use is associated with treatment of 
worsening symptoms of COPD, such as increased dyspnoea, sputum volume, or sputum 
purulence (colour). See Appendix 5 for Exacerbation Identification, Categorisation and 
Treatment Guidelines.
9.2.3.
Healthcare Resource Utilisation
Primary and available secondary healthcare resource utilisation data including 
prescriptions associated with COPD related medical encounters will be collected in the 
eCRF by the investigator and study-site personnel for all participants.
In addition, visits and contacts that are due to a moderate or severe COPD exacerbation 
will be assessed and recorded.
The data collected will include:

Primary healthcare contacts for COPD related care and treatment

Medication for COPD related treatment.

Hospital admissions, outpatient appointments and A&E attendances relating to 
COPD care.
Protocol-mandated procedures, tests, and encounters are excluded.
 
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9.3.
Exploratory Assessments
9.3.1.
Participant Treatment and Study Satisfaction Questionnaire 
A short questionnaire will be provided to the participant on paper for completion. This 
will then be transferred by site staff or the investigator into the eCRF.
9.3.2.
Health Related Quality of Life Questionnaire
A short HRQoL questionnaire will be provided to the participant on paper for 
completion. This will then be transferred by site staff or the investigator into the eCRF.
9.4.
Other
Eosinophil count
Eosinophils are increasingly being recognised as important biomarkers to predict which 
patients with COPD may respond to inhaled steroids.  There is growing evidence, 
(Pascoe, 2018, Greulich, 2018, Brusselle, 2018) that patients with higher eosinophils 
have a better response to inhaled steroids (ICS) and this may be incorporated in 
guidelines about who should receive ICS in the near future.  Gathering eosinophil data 
for subjects taking part in this study will help to further define the study COPD patient 
population, whether they would meet future guideline recommendations for ICS and also 
offers the opportunity to gain this information in normal clinical practice.
A new blood test is not required on patients entering the study, as the intention is to keep 
interventions to a minimum, in this clinical effectiveness study. It is likely that most 
patients will have had a full blood count in the last three years, which will have included 
eosinophil measurement.  Where available, peripheral blood eosinophil levels/percentage 
of count and WBC counts will be collected using the historical value closest to the 
patients consenting visit, (V0/V1) and no later than 36 months prior to the patients first 
study visit.
9.5.
Adverse Events
At scheduled and unscheduled visits for COPD related care, the following information 
will be collected and recorded in the eCRF:

All SAEs

Treatment related AEs

AEs that lead to withdrawal from study treatment.
The definitions of an AE or SAE can be found in Appendix 3. 
 
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In addition, from the above safety data, the investigator will be instructed to fill the eCRF 
for Cardiovascular effects events and Pneumonia events (see Section 9.5.5 and Section
9.5.6).
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an SAE or study treatment related AE. The 
investigator remains responsible for reporting and following up AEs that are serious, or 
considered related to the study treatment or to participation in the study, or that caused 
the participant to discontinue the study treatment (see Section 8). 
There may be situations in which 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 before the 
initial transmission of the SAE data to GSK.
Canadian Specific Reporting Requirements
In order for GSK to comply with Health Canada requirement, Canadian investigators are 
required to record drug related lack of efficacy events. A lack of efficacy is the failure to 
produce expected benefits. 
Lack of efficacy" or "failure of expected pharmacological action" will be reported on a 
paper form as an AE or SAE as described in Section 12.3.1: Additional AE reporting 
requirements for Canadian Investigators.
9.5.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs that are considered related to study participation or considered related 
to any GSK product will be collected from the signing of the ICF until 
randomisation.

All other SAEs will be collected from randomisation until completion of the 
Visit 2/EW Visit at the time points specified in the SoA (Section 2).

All study treatment related AEs and AEs that lead to withdrawal from study 
treatment will be collected from randomisation until completion of the Visit 
2/EW Visit at the time points specified in the SoA (Section 2).

All SAEs will be recorded and reported to the sponsor or designee within 24 
hours of the investigator becoming aware of the event, as indicated in Appendix
3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available.

Investigators are not obligated to actively seek AEs or SAEs in former study 
participants, after the study end. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the 
study, and he/she considers the event to be reasonably related to the study 
treatment or study participation, the investigator must promptly notify the 
sponsor.
 
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
The method of recording, evaluating, and assessing causality of AEs and SAEs
and the procedures for completing and transmitting SAE reports are provided in
Appendix 3.
9.5.2.
Method of Detecting AEs and SAEs
Care must be taken not to introduce bias when detecting AE and/or SAE. Open-ended 
and non-leading verbal questioning of the participant is the preferred method to inquire 
about AE occurrence. 
9.5.3.
Follow-up of AEs and SAEs
After the initial SAE, study treatment related AE or AE leading to withdrawal report, the 
investigator is required to proactively follow each participant at subsequent 
visits/contacts. All SAEs and AEs which are study treatment related, will be followed 
until the event is resolved, stabilised, otherwise explained, or the participant is lost to 
follow-up (as defined in Section 8.4). Further information on follow-up procedures is 
given in Appendix 3.
9.5.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are 
met. 

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study treatment 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
IRB/ IEC, and investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or 
other specific safety information e.g., summary or listing of SAE from the 
sponsor, will review and then file it and will notify the IRB/IEC, if appropriate 
according to local requirements.
9.5.5.
Cardiovascular and Death Events
For all SAEs, deaths, treatment related AEs and AEs that lead to withdrawal from study 
drug, the cardiovascular events detailed in Appendix 3 must be reported. For these events 
the specific Cardiovascular (CV) and Death sections of the eCRF will be required to be 
completed. These sections include questions regarding cardiovascular (including sudden 
cardiac death) and non-cardiovascular death. 
The CV eCRFs are presented as queries in response to reporting of certain CV Medical 
Dictionary for Regulatory Activities (MedDRA) terms. The CV information should be 
 
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recorded in the specific cardiovascular section of the eCRF within one week of receipt of 
a CV Event data query prompting its completion.
The Death eCRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
9.5.6.
Pneumonia
For all pneumonia events, which are SAEs, treatment related AEs or AEs that lead to 
withdrawal from study treatment, the pneumonia section of the eCRF should be 
completed with the details that are available to the investigator.
The investigators and site staff should remain vigilant for the possible development of 
pneumonia in patients with COPD as the clinical features of such infections overlap with 
the symptoms of COPD exacerbations.
Risk factors for pneumonia in patients with COPD receiving ICS/LABA include current 
smokers, patients with a history of prior pneumonia, patients with a body mass index < 
25 kg/m2 and patients with an FEV1 < 50% predicted.
For all suspected cases of pneumonia, Investigators are strongly encouraged to confirm 
the diagnosis (this includes obtaining a chest x-ray) and to initiate appropriate therapy as 
promptly as possible. 
9.5.7.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
COPD Exacerbation is a disease related events (DREs), common in participants with 
COPD and can be serious/life threatening.
Moderate and severe COPD exacerbation events will be recorded on the Exacerbation 
page in the participant’s eCRF.
Because exacerbations are typically associated with the disease under study, an 
exacerbation will not be reported according to the standard process for expedited 
reporting of SAEs to GSK unless the event meets the following criteria:

The event is, in the investigator’s opinion, of greater intensity, frequency, or 
duration than expected for the individual participant, or

The investigator considers that there is a reasonable possibility that the event 
was related to treatment with the investigational product. Please refer to 
Appendix 3 for guidelines on assessment of causality by investigator
NOTE: If either of the above conditions apply, then the event must be recorded and 
reported as an SAE in addition to reporting as an exacerbation.
 
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9.5.8.
Pregnancy
Women of Child Bearing Potential are excluded from this study. If a female participant 
becomes pregnant whilst enrolled in the study, the participant must withdraw from the 
study and should be followed up until the pregnancy outcome. Refer to Appendix 4 for 
further detail.
9.6.
Treatment of Overdose
An overdose is defined as a dose greater than the total doses which results in clinical 
signs and symptoms. These should be recorded by the investigator on the AE/SAE pages. 
In the event of an overdose of study treatment, the investigator should use clinical 
judgment in treating the overdose and contact the GSK medical monitor. GSK is not 
recommending specific treatment guidelines for overdose and toxicity management. The 
investigator is advised to refer to the relevant document(s) for detailed information 
regarding warnings, precautions, contraindications, AEs, and other significant data 
pertaining to the study treatment being used in this study. Such documents may include, 
but not be limited to, the PIL/Investigator Brochure or equivalent document. In the event 
of an overdose, the treating investigator should:

Contact the medical monitor immediately.

Closely monitor the participant for AE/SAE and laboratory abnormalities until study 
treatment can no longer be detected systemically.

Document the quantity of the excess dose as well as the duration of the overdosing in 
the eCRF.
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 
participant.
9.7.
Safety Assessments
All SAEs that are considered related to study participation or considered related to a GSK 
product will be collected from the time of consent.
All other SAEs, treatment related AEs and AEs that lead to withdrawal from study drug 
will be collected from randomisation. These events will be collected, where available, 
during the 24-week period of usual care when the participant is seen for COPD related 
usual care visits. This information may be supplemented from available medical records
and patient recall.
Planned time points for safety assessments are provided in the SoA.
9.7.1.
Medical Devices
A medical device is any instrument, apparatus, appliance, material or other article, 
whether used alone or in combination, including the software intended by its 
manufacturer to be used specifically for diagnostic and/or therapeutic purposes and
necessary for its proper application, intended by the manufacturer to be used for human
beings for any of the following:
 
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
Diagnosis, prevention, monitoring, treatment or alleviation of disease.

Diagnosis, monitoring, treatment, alleviation of or compensation for an injury or

Handicap;

investigation, replacement or modification of the anatomy or of a physiological

process;

control of conception;
and which does not achieve its principal intended action in or on the human body by 
pharmacological, immunological or metabolic means, but which may be assisted in its 
function by such means (Medical Device Definition from European Union Council
Directive 007/47/EC dated 5 Sept 2007).
Medical devices approved for use in Europe bear a European Conformity (CE) mark; 
otherwise, they are considered investigational devices. 
Examples of GSK medical devices include, but are not limited to: metered dose inhaler, 
auto-injector, inhalation spacers, measuring cups, measuring spoons, paediatric oral 
syringes, dry powder inhalers
Medical devices (spacers/holding chambers) are being provided by GSK for use in this 
study by a subgroup of participants. 
A medical device incident is any malfunction or deterioration in the characteristics and/or 
performance of a device, as well as any inadequacy in the labelling or the instructions for 
use which, directly or indirectly might lead to or might have led to the death of a patient, 
or user or of other persons or to a serious deterioration in their state of health.
GSK medical device incidents, including those resulting from malfunctions of the device, 
must be reported. 
9.7.2.
Drug/Device Combination Products
Not all delivery systems are considered “medical devices”. However, some GSK 
investigational products are considered “drug/device combination products” and incidents 
of device malfunction must be reported to GSK from the investigative site. Examples of 
GSK drug/device combination products include, but are not limited to: albiglutide 
lyophylized pen injector, albiglutide liquid autoinjector, ELLIPTA (nDPI) inhaler, and 
Breezhaler inhaler. 
GSK must be notified if any GSK device or Drug/Device combination product fails to 
function properly. Incidents should be reported as a device malfunction and not as a 
safety event. 
It is possible for a reportable safety event to occur at the same time as a device 
malfunction. Safety events are reported as described in Section 9.5
If a device malfunction is reported to the investigator site, the following process should 
be followed: 
 
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
report the malfunction  

as this study uses commercial supply, the GSK Customer Complaints Form will 
be used.

arrange for a new device to be provided if not already done so by a pharmacy/ 
prescription 
Non-GSK medical device incidents should be reported to the appropriate manufacturer as 
per usual local practice.
9.8.
Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study.
9.9.
Pharmacodynamics
Pharmacodynamics parameters are not evaluated in this study.
9.10.
Genetics
Genetics are not evaluated in this study.
9.11.
Biomarkers
Biomarkers are not evaluated in this study.
10.
STATISTICAL CONSIDERATIONS
10.1.
Hypotheses
The primary objective of this study is to evaluate the effectiveness of TRELEGY 
ELLIPTA versus non-ELLIPTA MITT in COPD patients in a pragmatic setting over 24 
weeks. The study will provide evidence to support HCP and payer discussions that 
TRELEGY ELLIPTA is more effective on CAT improvement than non-ELLIPTA MITT 
in a patient population representative of everyday clinical practice.
The primary effectiveness outcome is the proportion of CAT responders at Visit 2 and the 
primary treatment comparison is TRELEGY ELLIPTA versus non-ELLIPTA MITT for 
all participants.
In addition, other exploratory treatment comparisons of TRELEGY ELLIPTA with non-
ELLIPTA MITT will be performed for the prior treatment stratification levels of 
ICS/LABA/LAMA, ICS/LABA and LABA/LAMA separately for the primary outcome
only.
The null hypothesis is that there is no difference in the proportion of CAT responders at 
Visit 2 between TRELEGY ELLIPTA and non-ELLIPTA MITT:
H0: T1 – T2 = 0
 
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The alternative hypothesis is that there is a difference between treatment groups:
H1: T1 – T2 ≠ 0
where T1 and T2 are, the treatment means for TRELEGY ELLIPTA and non-ELLIPTA 
MITT respectively.
10.2.
Sample Size Determination
10.2.1.
Primary Outcome
The sample size is based on the proportion of CAT responders for the comparison of 
TRELEGY ELLIPTA with non-ELLIPTA MITT. 
A recent effectiveness study conducted by GSK (HZC115151) included a cohort of 
participants who were on triple (ICS+LABA+LAMA) therapy at baseline, who were 
subsequently randomised to continue with this therapy (‘usual care’) or to switch to 
FF/VI + LAMA therapy. The proportion of CAT responders at 12 months in the ‘usual 
care’ arm was 35% and the odds ratio for being a responder vs. a non-responder for 
FF/VI+LAMA vs. usual care was 1.68. 
CAT and St George’s Respiratory Questionnaire (SGRQ) responder data from a RCT of 
FF/UMEC/VI generally demonstrated lower odds ratios for triple vs. dual therapy and in 
addition some participants will be stepping up from ICS/LABA or LABA/LAMA, so a 
lower value of 1.3 has been assumed for sample size calculations.
For the sample size calculation for this study, the proportion of CAT responders in the 
non-ELLIPTA MITT arm at Visit 2 is assumed to be 35%. Assuming the true odds ratio 
between treatments is 1.3 (i.e. proportion of responders on FF/UMEC/VI is 41%), a 
sample size of 1297 participants per arm would provide 90% power to reject the null 
hypothesis at the two-sided 5% significance level. Calculation performed using PASS 12 
sample size software [Hintze, 2013]. 
In the HZC115151 study, 88% of participants were included in the analysis of CAT 
responders at 12 months, and RCT data from a recently completed study with 
FF/UMEC/VI indicated low levels of dropout between 6 and 12 months [Lipson, 2017]. 
For some estimands missing data may be treated as missing, and hence assuming a 
similar level of dropout (13.5%), a total of 3000 participants are required to be 
randomised. Missing assumptions will be explored within the estimand framework which 
will be provided in more detail in the Reporting & Analysis Plan (RAP).
Participants will be randomised in a 1:1 proportion to the TRELEGY ELLIPTA and non-
ELLIPTA MITT arms, respectively.
The randomisation schedule will be stratified based on previous treatment. The 
stratification levels will be one of ICS/LABA, LABA/LAMA or ICS/LAMA/LABA.
 
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10.2.2.
Secondary Outcomes
10.2.2.1.
FEV1
Estimated values for the residual standard deviation (SD) for trough FEV1 observed in 
RCTs have been around 250 ml. As this study is a pragmatic study with minimal 
intervention carried out in normal clinical practice and participants may not be able to 
provide a true trough FEV1 measurement it is expected that the variability of the data 
will be higher.
Using an estimated residual SD of 300 mL, a two-sided significance threshold of 5% and 
90% power, and assuming a true treatment difference of 50mL, the study would need to 
obtain FEV1 data for a minimum of 757 participants per treatment arm to detect a 
statistically significant difference between TRELEGY ELLIPTA and non-ELLIPTA 
MITT Figure 2.
Figure 2
FEV1 Sample Size vs Assumed True Treatment Difference
10.2.2.2.
Critical Errors
There is limited data available on CEs made by patients following 24 weeks of inhaler 
use.
A range of CE rates (participants with at least one CE) were explored for each of the 
treatment groups. Using conservative rates of 10% on ELLIPTA and 20% on non-
ELLIPTA MITT 266 participants in each treatment group would be required to provide 
90% power to reject the null hypothesis at a two-sided 5% significance level. The CE rate 
within the non-ELLIPTA MITT treatment group would include participants who had an 
error on one inhaler only as well as those who had an error on both inhalers.
 
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Given that not all participants in the non-ELLIPTA MITT arm may be on inhaler 
combinations for which error checklists in both inhalers are available, there may be fewer 
participants in the non-ELLIPTA MITT arm and thus more than 266 participants may be 
assessed in the ELLIPTA treatment arm in order to ensure we have 266 participants in 
the non-ELLIPTA MITT arm.
Additionally, in order to enable further exploratory treatment comparisons between 
specific inhalers, the aim will be to obtain at least 500 participants per treatment arm with 
error assessments performed.
10.2.3.
Sample Size Sensitivity
If the CAT response rate in the non-ELLIPTA MITT treatment arm is different from the 
value of 35% or the assumed true odds ratio used in the sample size calculation, the 
power to detect a difference in the response rates between the treatment arms will be 
affected.
Figure 3 illustrates the effect on power for varying non-ELLIPTA MITT CAT response 
rate assumptions and odds ratio values for the comparison. The sample size and two-
sided significance threshold of 5% remain fixed.
 
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Figure 3
CAT Power and Odds Ratio
It should be noted that a trial can run to its conclusion and deliver a significant p-value
for an effect smaller than the one we nominally powered for (assuming the assumptions 
underlying the sample size calculation are correct). In this case, based on a nominal true 
odds ratio of 1.3, a response rate of 35% on the non-ELLIPTA MITT arm and a sample 
size of 1297 evaluable participants per arm, we would see a p=0.05 with an odds ratio of 
1.172 and p<0.05 for odds ratios >1.172.
10.3.
Populations for Analyses
For purposes of analysis, the following populations are defined in Table 3. 
Table 3
Definitions of Analysis Populations 
Population
Definition / Criteria
All Subjects Enrolled 
(ASE)
All participants for whom a record exists in the study 
database, including screen failures. 
Intent-to-treat (ITT)
All randomised participants, excluding those who were 
randomised in error. A participant who is recorded as a screen 
failure and also randomised will be considered to be 
randomised in error. Any other participant who receives a 
randomisation number will be considered to have been 
randomised.
Displays will be based on the treatment to which the 
participant was randomised unless otherwise stated.
FEV1 Population
All members of the ITT population for whom an FEV1
assessment was planned.
 
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Population
Definition / Criteria
CE Population
All members of the ITT population for whom a CE
assessment was planned. Note that participants within selected 
centres performing inhaler assessments who are not on an 
inhaler for which an error checklist is available will not be 
included in this population.
10.4.
Statistical Analyses
10.4.1.
Effectiveness Analyses
The primary comparison of interest for the all effectiveness outcomes is TRELEGY 
ELLIPTA compared to non-ELLIPTA MITT. However, for each outcome, different 
estimands may be explored depending on the scientific question of interest. These will be 
detailed in the RAP.
Table 4
Statistical Analysis Methods for key Outcomes
Outcome
Statistical Analysis Methods
Primary
The primary outcome of proportion of CAT responders at Visit 2 will be 
analysed for the ITT population using a logistic regression model with 
treatment as an explanatory variable and baseline CAT score, number of 
exacerbations in the prior year, prior medication use strata and country 
included as covariates. All recorded data up to the time of study 
withdrawal will be included in analysis. The primary estimand of interest 
will be defined in the RAP. Consideration will be given on how to handle 
participants in the analysis who discontinue study medication, receive 
alternative medications, who fail to provide a CAT response or who 
discontinue from the study. In some of these scenarios participants may 
provide data after these events, in others subsequent data may be missing. 
These situations will be further investigated using sensitivity analysis to 
the primary estimand of interest or using alternative estimands on the 
primary outcome. Further details will be provided in the RAP. 
Secondary
Inference will only be made on the secondary outcomes if the primary 
analysis achieves significance. Otherwise results will be for descriptive 
purposes only.
FEV1:
FEV1 will only be collected at a subset of centres.
The secondary outcome of change from baseline in FEV1 at Visit 2 will 
 
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Outcome
Statistical Analysis Methods
be analysed for the ITT population using an analysis of covariance model 
with treatment as an explanatory variable and baseline FEV1, prior 
medication use strata and country included as covariates.
Critical Errors:
Inhaler error assessments will only be performed at a subset of centres.
The secondary outcome of percentage of participants making at least one 
CE at Visit 2 will be analysed for the ITT population using a logistic 
regression model with treatment as an explanatory variable. Country and 
prior medication use strata will be included in the model if possible.
The odds ratio, 95% CI and p-value will be presented for the comparison 
between TRELEGY ELLIPTA and non-ELLIPTA MITT. It will be based 
on a two-sided hypothesis testing approach of superiority.
For the non-ELLIPTA MITT arm all inhalers for which error checklists 
are available will be considered. Any participant in the non-ELLLIPTA 
MITT arm using an inhaler for which no error checklist is available will 
not be considered for CE assessment.
Estimands may be defined in order to take into account participants who 
have changed their study treatment during the study. These will be 
detailed further in the RAP.
Exploratory
Exploratory analyses relating to HCRU outcomes obtained from the EHR 
database will be described in a supplementary RAP and reported 
independently of the main RAP.
Full details of the analyses to be performed on the primary and other effectiveness
outcomes will be given in the RAP.
10.4.2.
Safety Analyses
SAEs will be coded using the standard GSK dictionary, MedDRA, and grouped by 
system organ class. The number and percentage of participants experiencing at least one 
SAE of any type, SAEs within each system organ class and SAEs within each preferred 
term will be presented for each treatment group. Separate summaries will be provided for 
all SAEs, study treatment related SAEs, fatal SAEs and SAEs leading to withdrawal. 
Deaths and SAEs will be documented in case narrative format.
All safety analyses will be performed on the ITT population. Further consideration may 
be given to cases where participants have changed treatment.
 
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Similar summaries will be performed for Adverse Drug Reactions (ADRs).
10.4.3.
Other Analyses
All other analyses will be described in the RAP.
10.4.4.
Interim Analyses
No interim analyses are planned.
 
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11.
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Tiotropium in Combination with Placebo, Salmeterol, or Fluticasone–Salmeterol for 
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Brusselle G, Pavord ID, Landis S, Pascoe S, Lettis S, Morjaria N, Barnes N, Hilton E, 
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Chen LF, Vander Weg MW, Hofmann DA, Reisinger HS. The Hawthorne Effect in 
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Global Strategy for the Diagnosis, Management and Prevention of COPD, Global 
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Greulich T, Franz Vogelmeier C. The Lancet Respiratory Medicine. Blood eosinophils as 
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Jones, PW., Harding, G., Wiklund, I., Berry, P., Tabberer, M., Yu, R., Leidy, N. ‘Tests of 
the Responsiveness of the Chronic Obstructive Pulmonary Disease (COPD) Assessment 
Test (CAT) Following Acute Exacerbation and Pulmonary ehabilitation.’ Chest. 2012. 
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Jung KS, Park HY, Park SY, Kim SK, Kim YK, Shim JJ et al. Comparison of tiotropium 
plus fluticasone propionate/salmeterol with tiotropium in COPD: A randomised 
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Kardos P, Worsley S, Singh D, Román-Rodríguez M, Newby DE, Müllerová H. 
Randomised controlled trials and real-world observational studies in evaluating 
cardiovascular safety of inhaled bronchodilator therapy in COPD. International Journal of 
Chronic Obstructive Pulmonary Disease. 2016. 11(1) Pages 2885—2895 
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Landis SH, Wurst K, Le HV, Bonar K, Punekar YS. Can Assessment of Disease Burden 
Prior to Changes in Initial COPD Maintenance Treatment Provide Insight into Remaining 
Unmet Needs? A Retrospective Database Study in UK Primary Care. COPD. 2017. 
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Lipson DA; Barnacle H, Birk R, Brealey N, Locantore N, Lomas DA, Ludwig-Sengpiel 
A , Mohindra R, Tabberer M, Zhu C_Q, and Pascoe SJ. FULFIL Trial: Once-Daily Triple 
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Miller MR, Hankinson J, Odencrantz J, Standardisation of spirometry. Eur Respir J. 
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Hutton, C, Ashton V, Stewart R, Bichel, K, Management of COPD in the UK primary-
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Pascoe S, Pavord I, Hinds D, Locantore N, Barnes N. The association between blood 
eosinophils and risk and treatment outcome in COPD is not dichotomised. The Lancet 
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Crawford, J, Frith, L Harvey, C, Svedsater, H, Woodcock, A Effectiveness of Fluticasone 
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September 29, 2016 DOI: 10.1056/NEJMoa1608033
Welte, T Miravitlles M, Hernandez P, Eriksson G, Peterson S, Polanowski T, Kessler R. 
Efficacy and Tolerability of Budesonide/Formoterol Added to Tiotropium in Patients 
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2009.180:741–750. 
 
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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
ADR
Adverse Drug Reaction
AE
Adverse Event
AESI
Adverse Event of Special Interest
ATS
American Thoracic Society
CAT
COPD Assessment Test
CE
Critical Errors
CFR
Code of Federal Regulation
CI
Confidence Intervals
CID
Clinically Important Deterioration
CIOMS
Council for International Organizations of Medical Sciences
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic Obstructive Pulmonary Disease
CPAP
Continuous Positive Airway Pressure
CRF
Case Report Form
CSR
Clinical Study Report
CV
Cardiovascular
DRE
Disease Related Events
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EHR
Electronic Health Record
EW
Early Withdrawal
EXT
Extension
FEV1
Forced Expiratory Volume in One Second
FF
Fluticasone Furoate 
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GSK
GlaxoSmithKline
GSK573719
Umeclidinium (UMEC)
GW642444
Vilanterol Trifenatate (VI)
GW685698
Fluticasone Furoate (FF)
HCP
Health Care Provider
HCRU
Health Care Resource Use
HIPPA
Health Insurance Portability and Accountability Act
HR
Heart Rate
HRQoL
Health Related Quality of Life
ICF
Informed Consent Form
ICH
International Conference of Harmonization
ICS
Inhaled Corticosteroid
IEC
Independent Ethics Committee
IRB
Independent Review Board
 
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IRT
Interactive Response
Technology
ITT
Intent-to-Treat
IUD
Intrauterine Device
IUS
Intrauterine System
LABA
Long-acting 2 Agonist
LAMA
Long-acting Muscarinic Receptor Antagonist
LRTI
Lower Respiratory Tract Infection
LTRA
Leukotriene Receptor Antagonists
MACE
Major Adverse Cardiac Event
MAO
Monoamine Oxidase Inhibitors
mcg
Microgram
MedDRA
Medical dictionary for Regulatory Activities
MHDP
Marketed Health Products Directorate
MITT
Multiple Inhaler Triple Therapy
MMRM
Mixed Models Repeated Measures
MSDS
Material Safety Data Sheet
PIL
Patient Information Leaflet
PK
Pharmacokinetic
PRAC
Pharmacovigilance Risk Assessment Committee
prn
As required
RAP
Reporting and Analysis Plan
RAMOS NG
Participant Randomisation & Dispensing IT System
RCT
Randomised Clinical Trial
SABA
Short-acting 2-adrenergic receptor agonist
SAE
Serious Adverse Event
SD
Standard Deviation
SGRQ
St Georges Respiratory Questionnaire
SmPC
Summary of Product Characteristics
SoA
Schedule of Activities
SRM
Study Reference Manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
TOC
Table of Contents
UFIE
Unusual Failure in Efficacy
UMEC
Umeclidinium
VI
Vilanterol Trifenatate
WOCBP
Woman of Childbearing Potential
 
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Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
ELLIPTA
SAS
TRELEGY
 
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12.2.
Appendix 2: Study Governance Considerations
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines [ICH, 2009]

Applicable laws and regulations

The protocol, protocol amendments, ICF, and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 

Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/IEC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
Financial Disclosure
If required, investigators and sub-investigators will provide the sponsor with sufficient, 
accurate financial information as requested to allow the sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate regulatory 
authorities.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorised representative and answer all 
questions regarding the study. 

Participants must be informed that their participation is voluntary. Participants 
or their legally authorised representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
 
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ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study centre. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorised person obtaining the informed consent 
must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorised representative. 
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorised personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results.
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicentre studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
 
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Dissemination of Clinical Study Data
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report (CSR). 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 participants, as 
appropriate.
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.
Data Quality Assurance

Participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g., EHR). 
The investigator is responsible for verifying that data entries are accurate and 
correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorised site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
CSR/ equivalent summary unless local regulations or institutional policies 
require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the 
sponsor. 
 
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Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available.

Definition of what constitutes source data can be found in the SRM.
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study treatment development
 
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12.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
SAEs, study treatment related AEs and AEs that lead to withdrawal from study treatment
will be reported in this study.
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study treatment, whether or not considered related to the 
study treatment.

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 study treatment.
Events Meeting the AE Definition 
Study treatment related events or AEs that lead to withdrawal from study treatment 
will be reported if they meet the following definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., electrocardiogram (ECG), radiological scans, vital 
signs measurements), including those that worsen from baseline, considered 
clinically significant in the medical and scientific judgment of the investigator (i.e., 
not related to progression of underlying disease).

New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug 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 it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses 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. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfil the definition of an AE 
or SAE. (Refer to Section 12.3.1 for specific requirements for Canadian 
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Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’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 
participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which 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.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalisation for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant 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 inpatient hospitalisation or prolongation of existing hospitalisation
In general, hospitalisation signifies that the participant 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 investigator’s office or 
outpatient setting. Complications that occur during hospitalisation are AE. If a 
complication prolongs hospitalisation or fulfils any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalisation” occurred, or was necessary, the 
AE should be considered serious.
Hospitalisation for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
 
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d.
Results in persistent disability/incapacity

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, diarrhoea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with 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 SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalisation but may 
jeopardise the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation, or development of drug dependency 
or drug abuse.
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 that satisfy the criteria in Section 9.2.

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularisation
 
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Recording AE and SAE
AE 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) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to one of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilised for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least one of the predefined 
outcomes as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
each occurrence of each AE/SAE.

A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
 
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administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in 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 in which 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 before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other HCPs.

If a participant dies during participation in the study or during a recognised follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology, if any.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.
Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper SAE data collection tool (see next section).

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The investigator or medically-qualified sub-investigator must show evidence within 
 
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the eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hours of SAE 
entry into the eCRF.

After the study is completed at a given site, the electronic data collection tool 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 participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor by telephone.

Contacts for SAE reporting can be found in the SRM.
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 or courier service.

Initial notification via 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 reporting can be found in the SRM.
12.3.1.
Additional Adverse Event (AE) Reporting Requirements for 
Canadian investigators
Health Canada requires pharmaceutical manufacturers to expeditiously report domestic 
cases of unusual failure in efficacy (UFIE) for new drugs to the Marketed Health 
Products Directorate (MHPD) within 15 days of first notification. This regulation applies 
to marketed drugs, and used as directed per the Canadian prescribing information, 
including those drugs used in Phase IV (non-CTA filed) clinical trials.  
In order for GSK to comply with this Health Canada requirement, Canadian investigators 
are required to record drug related lack of efficacy events. A lack of efficacy is the failure 
to produce expected benefits. 
Lack of efficacy" or "failure of expected pharmacological action" will be reported on a 
paper form as an AE or SAE as described in Table 5.
All paper forms are required to be faxed to GSK Canada’s Drug Safety department at 
within 24 hrs of first awareness.
 
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Table 5
CANADA ONLY: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Event
1.Adverse 
Event 
criteria
2.All countries 
including Canada: 
Electronic case record 
form (eCRF) only
3.Canada only: Paper 
form only
4.Canada only: 
Electronic case 
record form 
(eCRF) AND 
Paper form
Non-serious
AEs considered related 
to study treatment and 
AEs leading to 
withdrawal from the 
study or from treatment
Drug related lack of 
efficacy reports 
without associated 
signs or symptoms or 
clinical sequelae.
Drug related lack 
of efficacy with
associated signs or 
symptoms or 
clinical sequelae  
Serious
All SAEs
Drug related lack of 
efficacy reports 
without associated 
signs or symptoms or 
clinical sequelae. 
Drug related lack 
of efficacy reports 
with associated 
signs or symptoms 
or clinical sequelae 
 
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12.4.
Appendix 4: Collection of Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below).
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of participant’s 
medical records, medical examination, or medical history interview.
3. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. 

Females on HRT must have physician confirmation of postmenopausal status 
prior to study enrolment.
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK.

Generally, follow-up will not be required for longer than 6 to 8 weeks beyond the 
estimated delivery date.

Any termination of pregnancy will be reported, regardless of foetal status (presence 
or absence of anomalies) or indication for procedure. 

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. 
 
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
A spontaneous abortion is always considered to be an SAE and will be reported as 
such.

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in Appendix 3. 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 participant who becomes pregnant while participating will be withdrawn 
from the study.
 
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12.5.
Appendix 5 COPD Exacerbation Identification, 
Categorisation and Treatment Guidelines
12.5.1.
Guidelines for Identifying COPD Exacerbations
The following are symptoms used to ascertain an exacerbation of COPD:
Worsening of two or more of the following major symptoms for at least two consecutive
days:

Dyspnea

Sputum volume

Sputum purulence (colour)
OR
Worsening of any one major symptom together with any one of the following minor
symptoms for at least two consecutive days:

Sore throat

Colds (nasal discharge and/or nasal congestion)

Fever (oral temperature > 37.5 °C) without other cause

Increased cough

Increased wheeze
Participants who experience worsening COPD symptoms for greater than 24 hours might 
choose one of the following courses of action:

Use prescribed medication (rescue pack) and inform their physician or study 
investigator at the next health care contact.

Contact a health care provider for COPD related care.

Participants with worsening respiratory symptoms will be classified as having:
A mild/moderate/severe exacerbation and/or pneumonia
OR

A Lower Respiratory Tract Infection (LRTI)

Background variability of COPD

A non-respiratory related disease

Other respiratory related disease
 
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12.5.2.
COPD Exacerbation Severity
Each COPD exacerbation will be categorised based on severity as follows:
Moderate: Worsening symptoms of COPD that require treatment with systemic
corticosteroids and/or antibiotics.
Severe: Worsening symptoms of COPD that require treatment with in-patient
hospitalisation.
Details of an exacerbation should be recorded in the exacerbation page of the eCRF.
However, exacerbations should not be recorded in the AE section of the eCRF unless
they meet the definition of an SAE. 
Use of antibiotics for the treatment of upper or lower respiratory tract infections will not
be considered a COPD exacerbation unless the participant experiences worsening 
symptoms of COPD which match the definition of an exacerbation as given above.
12.5.3.
Treatment of COPD Exacerbations
All medications used for the treatment of exacerbations should be recorded in the source
documents and the exacerbation page of the eCRF. All sites should follow the protocol
treatment guidelines (as outline below), but any medications deemed medically necessary
may be used to treat a COPD exacerbation. However, caution is advised in using a LABA
or LAMA to treat a participant currently taking study treatment as these additional
medications may increase the risk of overdose. If necessary, the investigator or other
health care personnel may stop the participants study treatment temporarily in order to 
treat the COPD exacerbation.
12.5.4.
Guidelines for Treatment with Corticosteroids

Any course of systemic corticosteroids started within 7 days of finishing a previous 
course will be considered as treatment for a single exacerbation.
12.5.5.
Guidelines for Treatment with Antibiotics

Use of antibiotics for the treatment of upper or lower respiratory tract infections is 
not considered a COPD exacerbation unless the participant experiences worsening of 
symptoms of COPD.
12.5.6.
Onset and Resolution of COPD Exacerbations
For each moderate and severe exacerbation, the date of onset and the date of
resolution will be recorded in the study source documents and eCRF.
The date of onset is the first day (of at least 2 consecutive days) of worsening symptoms
of COPD.
The date of resolution should be based on when the treating investigator or participant 
determines that the COPD symptoms have returned to pre-exacerbation levels or to a new
baseline. In determining this resolution date, consideration should be given to participant
valuation.
 
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12.5.7.
Guideline for assessing multiple exacerbations
Two exacerbations can be combined into one, per the investigator’s judgement, if two 
mild COPD exacerbations are separated by no more than three exacerbation free days.
12.5.8.
Guideline for assessing exacerbations that increase in severity
If an exacerbation starts off as mild, but becomes moderate or severe or starts off as
moderate and becomes severe, the exacerbation should be captured as one exacerbation
and classified by its highest level of severity.
 
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12.6.
Appendix 6: Summary of Risks
Summary of Data/Rationale for Risk for FF/UMEC/VI
Identified risk of 
clinical significance
Pneumonia in patients 
with COPD
Pneumonia is a class 
concern for any ICS-
containing product for 
the treatment of COPD
In a study (CTT116853) in 1810 randomised COPD patients 
treated with FF/UMEC/VI or budesonide/formoterol 
(BUD/FOR) for up to 24 weeks (ITT population), or up to 52 
weeks (subset of 430 patients; extension (EXT) population), 
the incidence of events in the pneumonia adverse event of 
special interest (AESI) group was 2.2% and 0.8% for 
FF/UMEC/VI and BUD/FOR respectively in the ITT 
population, and 1.9% and 1.8% for FF/UMEC/VI and 
BUD/FOR respectively in the EXT population. There was 
one fatal case of pneumonia in a patient who received 
FF/UMEC/VI.
The incidence of pneumonia with FF/UMEC/VI in this study 
was in line with the incidence of pneumonia seen in 24 week 
studies with FF/VI (<1-2% with FF/VI 100/25) and less than 
that observed in 52 week exacerbation studies with FF/VI (6% 
with FF/VI 100/25) [Dransfield, 2013]. Similarly, the 
incidence of pneumonia with FF/UMEC/VI was less than that 
observed in a 12-month exacerbation trial with BUD/FOR 
(6.4%) [Sharafkhaneh, 2012]. Prior studies with FF/VI have 
demonstrated risk factors associated with a higher risk of 
pneumonia in patients with COPD (e.g., advanced age, poor 
lung function, low BMI, current smoking, and a prior history 
of pneumonia) [Crim, 2009]. These risk factors were present 
in some patients with pneumonia in study CTT116853 with 
FF/UMEC/VI, however, the low number of pneumonia events 
reported in the study precludes drawing any definite 
conclusions about risk factors. These risk factors should be
taken into consideration when using an ICS in patients with 
COPD. Pneumonia risk will be important in the benefit-risk 
assessment for FF/UMEC/VI in COPD patients, hence a 
robust risk mitigation strategy is being proposed.
The Pharmacovigilance Risk Assessment Committee (PRAC)
recently conducted an Article 31 review to evaluate the risk of 
pneumonia with use of ICSs in patients with COPD. The 
PRAC review confirmed that COPD patients treated with 
inhaled corticosteroids are at increased risk of pneumonia; 
however, the Committee’s view was that the benefits of ICSs 
continue to outweigh their risks. The PRAC also looked 
whether there were any differences in the risk of pneumonia 
between these products, and did not find conclusive evidence 
 
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Summary of Data/Rationale for Risk for FF/UMEC/VI
of such difference
Potential risk of 
clinical significance
Decreased bone mineral 
density and associated 
fractures.
Reduction in bone 
density, and the 
subsequent risk of 
fractures, is a known 
potential risk with 
corticosteroids.
There may be a modest increase in risk of fracture among 
patients with COPD treated with ICS; but, the results are not 
consistent across individual studies [Christensson, 2008, 
Lehouck, 2011, Weldon, 2009].
In study CTT116853, the incidence of events in the decreased 
bone mineral density and associated fractures AESI group was 
low, with an incidence of 0.4% and 0.7% in the FF/UMEC/VI 
and BUD/FOR treatment groups respectively in the ITT 
population up to 24 weeks, and 0.5% in both treatment groups 
in the EXT Population up to 52 weeks. The majority of the 
fractures in both treatment groups were traumatic in nature.
Serious Cardiovascular 
effects on heart rate 
(HR), blood pressure, 
QT interval, potentially
leading to cardiac 
arrhythmia
Cardiovascular (CV) 
effects are a potential 
class effect associated 
with anti-muscarinic and 
beta agonist therapies
In the COPD population, there is a high prevalence of 
concurrent CV disease and the prevalence of CV co-
morbidities increases with worsening severity of COPD.
In study CTT116853, approximately two-thirds of all 
participants reported CV risk factors at baseline. In this study, 
cardiovascular effects were the most frequently reported 
AESI, with a similar incidence between FF/UMEC/VI and 
BUD/FOR treatment groups in the ITT population up to 24 
weeks (4.3% and 5.2% respectively) and the EXT population 
up 52 weeks (8.6% and 10% respectively). Within subgroups 
of cardiovascular effects, hypertension was reported most 
frequently and with a numerically higher incidence with 
BUD/FOR (2.3%) compared with FF/UMEC/VI (1.3%) in the 
ITT population up to 24 weeks, but with a similar incidence in 
the EXT population up to 52 weeks (0.9 to 1.0% across 
treatment groups). Cardiac arrhythmias were reported the next 
most frequently and occurred with an incidence of 1.2% in 
both treatment groups in the ITT Population up to 24 weeks, 
and with an incidence of 1.9% and 3.6% in the FF/UMEC/VI 
and BUD/FOR groups in the EXT population up to 52 weeks.
The incidence of serious events in the cardiovascular effects 
AESI was low, with an incidence of 1.0% and 1.1% in the 
FF/UMEC/VI and BUD/FOR groups respectively in the ITT 
population to 24 weeks, and 2.9% and 1.4% in the 
FF/UMEC/VI and BUD/FOR groups respectively in the EXT 
population to 52 weeks. The absolute numbers of fatal events 
in cardiovascular effects AESI was low in the study, despite 
the study enrolling participants with a number of CV 
comorbidities at baseline.
 
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Summary of Data/Rationale for Risk for FF/UMEC/VI
A pre-specified Major Adverse Cardiac Event (MACE) 
analysis was conducted in CTT116853, with broad MACE 
defined as: Ischemic Heart Disease SMQ excluding fatalities, 
plus Central Nervous System Haemorrhages and 
Cerebrovascular Conditions SMQ excluding fatalities, plus 
adjudicated cardiovascular deaths. The narrow MACE 
definition included only the preferred terms of Myocardial 
ischaemia and Acute myocardial infarction in place of the 
Ischaemic Heart Disease SMQ. Overall, the absolute number 
of MACE events using either the broad or narrow definition 
was low both in the ITT population up to 24 weeks and EXT 
population up to 52 weeks. No clinically relevant differences 
were observed between FF/UMEC/VI and BUD/FOR based 
on narrow and broad MACE analysis both in the ITT 
population to 24 weeks and EXT population to 52 weeks.
In study CTT116853, there were no emerging number of CV 
comorbidities at baseline.
A pre-specified Major Adverse Cardiac Event (MACE) 
analysis was conducted in CTT116853, with broad MACE 
defined as: Ischemic Heart Disease SMQ excluding fatalities, 
plus Central Nervous System Haemorrhages and 
Cerebrovascular Conditions SMQ excluding fatalities, plus 
adjudicated cardiovascular deaths. The narrow MACE 
definition included only the preferred terms of Myocardial 
ischaemia and Acute myocardial infarction in place of the 
Ischaemic Heart Disease SMQ. Overall, the absolute number 
of MACE events using either the broad or narrow definition 
was low both in the ITT population up to 24 weeks and EXT 
population up to 52 weeks. No clinically relevant differences 
were observed between FF/UMEC/VI and BUD/FOR based 
on narrow and broad MACE analysis both in the ITT 
population to 24 weeks and EXT population to 52 weeks.
In study CTT116853, there were no emerging signals from 
vital signs, ECGs, or Holter data.
Missing information
Safety in pregnancy and 
lactation
There is a low incidence of pregnancy in the COPD 
population due to their age. There were no reports of 
pregnancy in the COPD patients enrolled in the CTT116853 
and 200109/200110 studies with FF/UMEC/VI.
Due to the high risk to the foetus of uncontrolled COPD in 
pregnant women, a discussion on the benefit of continuing 
therapy will need to occur with the patient and the prescribing 
 
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Summary of Data/Rationale for Risk for FF/UMEC/VI
physician.
Safety in severe hepatic 
impairment
Patients with severe hepatic impairment were studied as part 
of FF/VI development program but not in the UMEC/VI 
development program. It was agreed with European 
Medicines Agency (EMA; Follow-up Scientific Advice 
meeting) that no additional/repeat studies in subjects with 
hepatic impairment would be required as part of FF/UMEC/VI 
development program. 
Due to lack of data with UMEC in severe hepatic impairment, 
safety in this subgroup of subjects would be included as 
missing information in this FF/UMEC/VI Risk Management 
Plan.
References
Brusselle G, Pavord ID, Landis S, Pascoe S, Lettis S, Morjaria N, Barnes N, Hilton E, 
Blood eosinophil levels as a biomarker in COPD, Respiratory Medicine (2018), doi: 
10.1016/j.rmed.2018.03.016
Christensson C, Thoren A, Lindberg B. Safety of inhaled budesonide: clinical 
manifestations of systemic corticosteroid-related adverse effects. Drug Safety. 
2008;31:965-988.
Crim C, Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, et al. Pneumonia 
risk in COPD patients receiving inhaled corticosteroids alone or in combination: TORCH 
study results. EUR Respier J 2009;34(2):641-647.
De Bisschop MB, Bellou A. Anaphylaxis. Current Opinion in Critical Care. 
2012;18(4):308-317.
Dransfield MT, Bourbeau J, Jones PW, Hanania NA, Mahler DA, Vestbo J, et al. Once-
daily inhaled fluticasone furoate and vilanterol versus vilanterol only for prevention of 
exacerbations of COPD: two replicate double-blind, parallel-group, randomised 
controlled trials. Lancet Respir Med 2013;1:210-223.
Lehouck A, Boonen S, Decramer M, Janssens W. COPD, bone metabolism, and 
osteoporosis. Chest. 2011;139:648-657.
Niggemann B, Beyer K. Factors augmenting allergic reactions. Allergy. 
2014;69(12):1582-1587.
Packe GE, Cayton RM, Mashhoudi N. Nebulised ipratropium bromide and salbutamol 
causing closed-angle glaucoma. Lancet. 1984;22:691.
 
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Sharafkhaneh A, Southard JG, Goldman M, Uryniak T, Martin UJ. Effect of 
budesonide/formorterol pMDI on COPD exacerbations: A double-blind, randomised 
study. Respir Med 2012;106(2):257-268.
Steve Pascoe, Ian Pavord, David Hinds, Nicolas Locantore, Neil Barnes. The association 
between blood eosinophils and risk and treatment outcome in COPD is not dichotomised 
The Lancet Respiratory Medicine. 2018: doi: 10.1016/S2213-2600(18)30137-1.
Timm Greulich, Claus Franz Vogelmeier. Blood eosinophils as a marker of eosinophilic 
exacerbations in COPD. The Lancet Respiratory Medicine. 2018: doi: 10.1016/S2213-
2600(18)30095-X.
Weldon D. The effects of corticosteroids on bone growth and bone density. Ann. Allergy 
Asthma Immunol. 2009;103:3-11.
 
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12.7.
Appendix 7: Inhaler Specific Errors 
There are no universally agreed checklists that define CEs and over all errors for specific 
inhalers. The checklist and identification of CEs have been developed by GSK based 
upon:

A review of the PIL for each inhaler and the steps defined therein for correct use. 

The available literature which is exhaustive for a number of the commonly used
inhalers.

Review of these errors with a group of external inhaler experts.
The CE checklists are therefore, as robust as possible. Furthermore, GSK uses selected 
sites with trained assessors to ensure as much consistency as possible in the valuation of 
errors in study participants.
Checklist of instructions for correct use will be based on the steps listed in the 
PIL/package insert for each inhaler. Some of the steps outlined in the PILs/package 
inserts require several actions to be identified and checked by the investigator.
CEs are identified as underlined in the list below. A CE is defined as
an error that is most likely to result in no or significantly reduced medication being
inhaled. These errors will be captured in a checklist provided for assessment of inhaler
use.
Note: Checklists which may be used to assess inhaler errors are listed below. These 
checklists may be updated as new information becomes available using the stringent 
procedure described above. New checklists may be utilised in the study as and when they 
are developed for use, with appropriate training material available.
Inhaler Errors Checklist: ELLIPTA
PIL  
Step
PIL Wording
(ELLIPTA June 2016)
Error
(Underlined text 
indicates a critical 
error)
Completed 
Correctly
Not 
Completed 
Correctly
2
Prepare a dose
Wait to open the cover until you are 
ready to take your dose. 
Do not shake the inhaler.
• Slide the cover down until you hear 
a click.
Failed to open cover
Shook the device 
after dose 
preparation
3
Inhale your medicine
• While holding the inhaler away from 
your mouth, breathe out as far as is 
comfortable.
Do not breathe out into the inhaler.
No exhalation before 
an inhalation
Exhaled directly into 
mouthpiece
 
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PIL  
Step
PIL Wording
(ELLIPTA June 2016)
Error
(Underlined text 
indicates a critical 
error)
Completed 
Correctly
Not 
Completed 
Correctly
• Put the mouthpiece between your 
lips, and close your lips firmly around 
it.
Do not block the air vent with your 
fingers.
• Take one long, steady, deep breath 
in. Hold this breath for as long as 
possible (at least 3-4 seconds).
• Remove the inhaler from your 
mouth.
• Breathe out slowly and gently.
No seal by the lips 
round the 
mouthpiece during 
the inhalation
Inhalation 
manoeuvre was not:
- long
- steady
- deep
Blocked air inlet 
during inhalation 
manoeuvre
Did not hold breath 
4
• Close the inhaler 
Did not close the 
device (Note: this is 
an error but one 
which does not affect 
the medication that is 
inhaled)
Other comments:
 
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Inhaler Errors Checklist: Generic MDI
PIL  
Step
PIL Wording
(Generic MDI March 2015)
Error
(Underlined  
text indicates 
a critical 
error)
Completed 
Correctly
Not
Completed 
Correctly
2
• Remove the mouthpiece cover/cap
Failed to 
remove cap.
3
Shake the inhaler 4-5 times to ensure 
that:
• Any loose objects are removed
• The contents of the inhaler are evenly 
mixed
Did not shake 
the device.
4
• Hold the inhaler upright with your 
thumb on the base, below the 
mouthpiece. 
• Breathe out as far as is comfortable.
• Do not breathe in again yet.
Did not inhale 
within 5 
seconds of 
shaking the 
device.
No exhalation 
before 
inhalation.
5
• Place the mouthpiece in your mouth 
between your teeth.
•Close your lips around it.
•Do not bite.
Failed to place 
device in 
mouth.
6
• Breathe in through your mouth.
• Just after starting to breathe in, press 
down on the top of the canister to 
release a puff of medicine.
• Do this while still breathing in slowly 
and deeply.
Inhalation 
manoeuvre 
was not:
- slow
- deep (Note: 
if it lasts for 
<2 seconds, 
then it is too 
fast)
No dose 
actuated 
during an 
inhalation 
manoeuvre.
Dose 
coordination 
so poor that 
patient is 
likely to have 
received no 
dose or only 
received 
minimal dose.
 
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PIL  
Step
PIL Wording
(Generic MDI March 2015)
Error
(Underlined  
text indicates 
a critical 
error)
Completed 
Correctly
Not
Completed 
Correctly
Dose 
coordination 
was sup-
optimal but 
patient likely 
to have 
received some 
dose.
7
• Hold your breath, take the inhaler from 
your mouth and your finger from the top 
of the inhaler.
•Continue holding your breath for a few 
seconds, or as long as is comfortable.
Did not hold 
breath
8
• If your doctor has told you to take two 
puffs, wait about half a minute before 
taking another puff by repeating steps 3 
to 7
More than one 
dose actuation 
during 
inhalation 
procedure
9
• After use always replace the 
mouthpiece cover straight away to keep 
dust out. Replace the cover by firmly 
pushing and clicking into position
NOT REQUIRED
Other comments:
 
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Inhaler Errors Checklist: Seebri Breezhaler
PIL  
Step
PIL Wording
(Seebri Breezhaler October 2015)
Error
(Underlined  text 
indicates a critical 
error)
Completed 
Correctly
Not 
Completed 
Correctly
1
Remove the cap
NOT REQUIRED
2
Open inhaler
•Hold the base of the inhaler firmly and tilt 
the mouthpiece. This opens the inhaler
NOT REQUIRED
3
Prepare capsule
• Separate one of the blisters from the 
blister card by tearing along the 
perforation. Take one blister and peel away 
the protective backing to expose the 
capsule.
•Do not push capsule through foil.
NOT REQUIRED
4
Remove a capsule
• Capsules should always be stored in the 
blister and only removed immediately 
before use. With dry hands, remove 
capsule from the blister.
• Do not swallow the capsule.
Failed to remove 
capsule
5
Insert capsule
• Place the capsule into the capsule 
chamber.
• Never place a capsule directly into the 
mouthpiece.
Failed to insert 
capsule into the 
chamber
6
Close the Inhaler
• Close the inhaler until you hear a “click”.
Did not completely 
close device capsule 
chamber (heard click 
when satisfactory)
 
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PIL  
Step
PIL Wording
(Seebri Breezhaler October 2015)
Error
(Underlined  text 
indicates a critical 
error)
Completed 
Correctly
Not 
Completed 
Correctly
7
Pierce the capsule:
• Hold the inhaler upright with the 
mouthpiece pointing up.
• Pierce the capsule by firmly pressing 
together both side buttons at the same time.
Do this only once.
• You should hear a “click” as the capsule 
is being pierced.
Did not pierce the 
capsule and failed to 
release piercing 
buttons fully before 
inhalation (HCP to 
check that capsule was 
pierced and that 
piercing buttons were 
released)
8
Release the side buttons fully,
Shook the device after 
dose preparation
9 
Breathe out:
• Before placing the mouthpiece in your 
mouth, breathe out fully
Do not blow into the mouthpiece 
Exhaled directly into 
the mouthpiece
10
Inhale the medicine:
• To breathe the medicine deeply into your 
airways:
• Hold the inhaler as shown in the picture.
The side buttons should be facing left and 
right. Do not press the side buttons.
• Place the mouthpiece in your mouth and 
close your lips firmly around it.
• Breathe in rapidly but steadily, as deeply 
as you can. 
Do not press the side buttons.
No seal by the lips 
round the mouthpiece 
during the inhalation
Inhalation manoeuvre 
was not:
-Rapid
-Steady
-Deep
11
If you do not hear a whirring noise:
The capsule may be stuck in the capsule 
chamber. If this happens:
• Open the inhaler and carefully loosen the 
capsule by tapping the base of the inhaler.
Do not press the side buttons.
Capsule did not rattle
Blocked air inlet 
during inhalation 
manoeuvre
 
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PIL  
Step
PIL Wording
(Seebri Breezhaler October 2015)
Error
(Underlined  text 
indicates a critical 
error)
Completed 
Correctly
Not 
Completed 
Correctly
• Inhale the medicine again by repeating 
steps 9 and 10.
12
Hold breath:
After you have inhaled the medicine:
• Hold your breath for at least 5-10 seconds 
or as long as you comfortably can while 
taking the inhaler out of your mouth.
• Then breathe out.
• Open the inhaler to see if any powder is 
left in the capsule.
Did not hold breath
13
If there is powder left in the capsule:
• Close the inhaler.
• Repeat steps 9 to 12.
Did not check inside 
the capsule chamber if 
powder was left / did 
not make a second 
inhalation
Other comments:
 
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Inhaler Errors Checklist: Seretide Diskus
PIL  
Step
PIL Wording
(Seretide DISKUS March 2015)
Error
(Underlined  text 
indicates a critical 
error)
Completed 
Correctly
Not 
Completed 
Correctly
1
• Hold the outer case in one hand and put 
thumb of your other hand on the thumbgrip.
• Push your thumb away from you as far as it 
will go
• You will hear a click. This will open a 
small hole in the mouthpiece
Failed to open cover
2
• Hold your inhaler with the mouthpiece 
towards you (you can hold it in either your 
right or left hand).
• Slide the lever away from you as far as it 
will go (you will hear a click). This places 
dose in the mouthpiece.
Lever is not pushed 
back
Shook the device after 
dose preparation
3
• Hold the inhaler away from your mouth, 
breathe out as far as is comfortable.
• Do not breathe into the inhaler.
No exhalation before 
an inhalation
Exhaled directly into 
mouthpiece
4
• Put the mouthpiece between your lips.
• Breathe in, steadily and deeply through the 
inhaler, not through your nose.
• Remove the inhaler from your mouth.
• Hold your breath for about 10 seconds or 
for as long as is comfortable
• Breathe out slowly.
No seal by the lips 
round the mouthpiece 
during the inhalation
Inhalation manoeuvre 
was not:
- steady
- deep
Did not hold breath 
5
After use, rinse your mouth with water and 
spit it out, and/or brush your teeth. 
NOT REQUIRED
6
• To close the inhaler, slide the thumbgrip 
back towards you, as far as it will go. You 
will hear a click.
Did not close the 
device (Note: this is an 
error but one which 
does not affect the 
medication that is 
inhaled)
 
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PIL  
Step
PIL Wording
(Seretide DISKUS March 2015)
Error
(Underlined  text 
indicates a critical 
error)
Completed 
Correctly
Not 
Completed 
Correctly
Other comments:
 
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Inhaler Errors Checklist: Spiriva Handihaler
PIL  
Step
PIL Wording
(Spiriva HandiHaler November 2014)
Error
(Underlined  text 
indicates a critical 
error)
Completed 
Correctly
Not 
Completed 
Correctly
3
• Remove capsule from blister pack (only 
immediately before use, see blister handling) 
and place it in the centre chamber, as 
illustrated. 
It does not matter which way the capsule is 
placed in the chamber.
Failed to remove 
capsule
Failed to insert capsule 
into the chamber
4
• Close the mouthpiece firmly until you hear 
a click, leaving the dust cap open.
Did not completely 
close device capsule 
chamber (heard click 
when satisfactory)
5
• Hold the inhaler device with the 
mouthpiece upwards and press the piercing 
button completely in only once, and release
This makes holes in the capsule and allows 
the medication to be released when you 
breathe in.
Did not pierce the 
capsule (HCP should 
check capsule was 
pierced)
Shook the device after 
dose preparation
6
• Breathe out completely.
• Please avoid breathing into the mouthpiece 
at any time
No exhalation before 
an inhalation
Exhaled directly into 
mouthpiece
7
• Raise the inhaler to your mouth and close 
your lips tightly around the mouthpiece.
• Keep your head in an upright position and 
breathe in slowly and deeply but at a rate 
sufficient to hear or feel the capsule vibrate. 
• Breathe until your lungs are full; then hold 
your breath as long as comfortable and at the 
same time take the inhaler out of your 
mouth.
• Resume normal breathing. Repeat steps 6 
and 7 once, in order to empty capsule 
completely.
No seal by the lips 
round the mouthpiece 
during the inhalation
Inhalation manoeuvre 
was not:
- slow
- deep
Capsule did not rattle
Blocked air inlet 
during inhalation 
manoeuvre
Did not hold breath
Did not check inside 
the capsule chamber if 
powder was left/ did 
 
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PIL  
Step
PIL Wording
(Spiriva HandiHaler November 2014)
Error
(Underlined  text 
indicates a critical 
error)
Completed 
Correctly
Not 
Completed 
Correctly
not make second 
inhalation
Other Comments:
 
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Inhaler Errors Checklist: Symbicort Turbohaler
PIL  
Step
PIL Wording
(Symbicort Turbuhaler October 2015)
Error
(Underlined  text 
indicates a critical 
error)
Completed 
Correctly
Not 
Completed 
Correctly
1
• Unscrew the cover and lift it off.
You may hear a rattling sound
Failed to remove cap
2
• Hold your Inhaler upright with the red grip 
at the bottom.
Did not hold device 
upright (± 45° OK) 
during dose 
preparation
3
• Do not hold the mouthpiece when you load 
your inhaler. To load your inhaler with a 
dose, turn the red grip as far as it will go in 
one direction. Then turn it as far as it will go
in the other direction (it does not matter 
which way you turn it first).
• You should hear a click sound. Your 
inhaler is now loaded and ready to use. Only 
load your inhaler when you need to use it.
Base not twisted fully 
backwards and 
forwards, no click 
heard
Device tipped 
downwards after dose 
preparation
Shook the device after 
dose preparation
4
• Hold your inhaler away from your mouth. 
Breathe out gently (as far as is comfortable).
• Do not breathe out through your inhaler
No exhalation before 
inhalation
Exhaled directly into 
mouthpiece
5
• Place the mouthpiece gently between your 
teeth. Close your lips.
• Breathe in as deeply and as hard as you can 
through your mouth. Do not chew or bite on 
the mouthpiece.
No seal by the lips 
round the mouthpiece 
during inhalation
Inhalation manoeuvre 
was not:
- forceful 
- deep
Note to HCP: it is 
important that the 
inhalation is forceful 
and deep from the start 
for this inhaler
Blocked air inlet 
during inhalation 
manoeuvre
 
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PIL  
Step
PIL Wording
(Symbicort Turbuhaler October 2015)
Error
(Underlined  text 
indicates a critical 
error)
Completed 
Correctly
Not 
Completed 
Correctly
6
• Remove the inhaler from your mouth.
• Breathe out gently.
The amount of medicine that is inhaled is 
very small. This means you may not be able 
to taste it after inhalation. If you have 
followed instructions, you can still be 
confident that you have inhaled the dose and 
the medicine is now in your lungs.
Did not hold breath
7
• If you are to take a second inhalation, 
repeat steps 2 to 6.
NOT REQUIRED
8 + 
9
• Replace cover tightly after use
Did not close the 
device (Note: this is an 
error but one which 
does not affect the 
medication that is 
inhaled)
Other comments:
 
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12.8.
Appendix 8: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).
DOCUMENT HISTORY
Document
Date of Issue
Amendment 2
28-Sep-2018
Amendment 1
15-Feb-2018
Original Protocol
06-Nov-2017
 
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SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
206854
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for study 206854: The Clinical 
Effectiveness of Fluticasone Furoate/Umeclidinium Bromide/ 
Vilanterol in a Single Inhaler (TRELEGYTM ELLIPTATM) 
when Compared with Non-ELLIPTA Multiple Inhaler Triple 
Therapies in COPD Patients within a Usual Care Setting.
Compound Number 
:
GSK2834425 (GW685698+GSK573719+GW642444)
Effective Date 
:
30-Oct-2019
Description:

The purpose of this document is to describe the planned analyses and output to be 
included in the Clinical Study Report (CSR) for study 206854 (INTREPID: 
INvestigation of TRELEGY Effectiveness: Usual PractIce Design). 

This RAP is intended to describe the effectiveness and safety analyses required for 
the study. 

This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable.
RAP Author(s):
Author
Statistician, Clinical Statistics
Copyright 2019 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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
RAP Team Review Confirmations (Method: E- mail):
Reviewer
Date
16-Oct-2019
Statistics Leader, Clinical Statistics
14-Oct-2019
Programming Manager, Clinical Programming
13-Oct-2019
RW Clinical Development Director (CIL)
14-Oct-2019
Clinical Development Physician (MM)
14-Oct-2019
RW Clinical Study Manager (OSL)
15-Oct-2019
Principal Clinical Data Manager (DQL)
15-Oct-2019
Safety Scientist, SERM, Safety and Medical Governance
14-Oct-2019
Global Medical Director, COPD, Respiratory
15-Oct-2019
Director, Patient Reported Outcomes, VEO

Clinical Statistics & Clinical Programming Line Approvals (Method: Pharma 
TMF eSignature):
Approver
Date
29-Oct-2019
Senior Statistics Director, Clinical Statistics
30-Oct-2019
Programming Manager, Clinical Programming
(Delegated to 
, Director Clinical Programming, 
Statistical Programming & Governance)
 
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TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................7
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................7
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................7
2.2.
Study Objective(s) and Endpoint(s)...............................................................8
2.3.
Study Design ..............................................................................................10
2.4.
Statistical Hypotheses / Statistical Analyses ...............................................11
3.
PLANNED ANALYSES ..........................................................................................12
3.1.
Interim Analyses .........................................................................................12
3.2.
Final Analyses ............................................................................................12
4.
ANALYSIS POPULATIONS ...................................................................................12
4.1.
Protocol Deviations.....................................................................................13
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................14
5.1.
Study Treatment & Sub-group Display Descriptors.....................................14
5.2.
Baseline Definitions ....................................................................................14
5.3.
Multicentre Studies .....................................................................................14
5.4.
Examination of Covariates, Other Strata and Subgroups............................15
5.4.1.
Examination of Subgroups...........................................................15
5.5.
Multiple Comparisons and Multiplicity .........................................................16
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................16
6.
STUDY POPULATION ANALYSES .......................................................................17
6.1.
Overview of Planned Study Population Analyses........................................17
7.
EFFECTIVENESS ANALYSES ..............................................................................18
7.1.
Primary Effectiveness Analyses..................................................................18
7.1.1.
COPD Assessment Test (CAT) Score .........................................18
7.1.1.1.
Endpoint / Variables ...................................................18
7.1.1.2.
Summary Measure .....................................................18
7.1.1.3.
Population of Interest..................................................18
7.1.1.4.
Strategy for Intercurrent (Post-Randomisation) 
Events ........................................................................18
7.1.1.5.
Statistical Analyses / Methods ....................................20
7.1.1.5.1.
Statistical Methodology 
Specification ...........................................20
7.2.
Secondary Effectiveness Analyses .............................................................22
7.2.1.
Forced Expiratory Volume in 1 Second (FEV1) ............................22
7.2.1.1.
Endpoint / Variables ...................................................23
7.2.1.2.
Summary Measure .....................................................23
7.2.1.3.
Population of Interest..................................................23
7.2.1.4.
Strategy for Intercurrent (Post-Randomisation) 
Events ........................................................................23
7.2.1.5.
Statistical Analyses / Methods ....................................24
 
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7.2.1.5.1.
Statistical Methodology 
Specification ...........................................24
7.2.2.
Trough FEV1................................................................................25
7.2.2.1.
Endpoint / Variables ...................................................25
7.2.2.2.
Summary Measure .....................................................26
7.2.2.3.
Population of Interest..................................................26
7.2.2.4.
Strategy for Intercurrent (Post-Randomisation) 
Events ........................................................................26
7.2.2.5.
Statistical Analyses / Methods ....................................27
7.2.2.5.1.
Statistical Methodology 
Specification ...........................................27
7.2.3.
Critical Errors (CE).......................................................................27
7.2.3.1.
Endpoint / Variables ...................................................27
7.2.3.2.
Summary Measure .....................................................28
7.2.3.3.
Population of Interest..................................................28
7.2.3.4.
Strategy for Intercurrent (Post-Randomisation) 
Events ........................................................................28
7.2.3.5.
Statistical Analyses / Methods ....................................29
7.2.3.5.1.
Statistical Methodology 
Specification ...........................................29
7.3.
Other Effectiveness Analyses .....................................................................32
7.3.1.
Clinically Important Deterioration (CID)........................................32
7.3.1.1.
Endpoint / Variables ...................................................32
7.3.1.2.
Summary Measure .....................................................32
7.3.1.3.
Population of Interest..................................................32
7.3.1.4.
Strategy for Intercurrent (Post-Randomisation) 
Events ........................................................................32
7.3.1.5.
Statistical Analyses / Methods ....................................34
7.3.1.5.1.
Statistical Methodology 
Specification ...........................................34
7.3.2.
Clinically Important Deterioration (Analyses of 
Components)...............................................................................34
7.3.2.1.
100 mL Reduction from Baseline in Trough 
FEV1 at 24 weeks.......................................................35
7.3.2.1.1.
Endpoint / Variables................................35
7.3.2.1.2.
Summary Measure .................................35
7.3.2.1.3.
Population of Interest..............................35
7.3.2.1.4.
Strategy for Intercurrent (Post-
Randomisation) Events...........................35
7.3.2.1.5.
Statistical Analyses / Methods ................36
7.3.2.2.
2 Units Change (Increase) from Baseline in 
CAT Score at 24 Weeks .............................................37
7.3.2.2.1.
Endpoint / Variables................................37
7.3.2.2.2.
Summary Measure .................................37
7.3.2.2.3.
Population of Interest..............................37
7.3.2.2.4.
Strategy for Intercurrent (Post-
Randomisation) Events...........................37
7.3.2.2.5.
Statistical Analysis / Methods .................39
7.3.3.
Annualised Rate of Moderate/Severe Exacerbations ...................40
7.3.4.
Time to first Moderate/Severe Exacerbation ................................40
7.3.5.
Healthcare Resource Utilisation (HCRU) .....................................41
7.4.
Exploratory Effectiveness Analyses ............................................................41
 
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7.4.1.
Association of Critical Errors with CAT, Moderate/ Severe 
Exacerbations FEV1 and FVC......................................................41
7.4.2.
Patient Study Experience.............................................................42
7.4.3.
Health Related Quality of Life Questionnaire (HRQoL) ................42
8.
SAFETY ANALYSES .............................................................................................43
8.1.
Adverse Events Analyses ...........................................................................43
8.2.
Adverse Events of Special Interest Analyses..............................................44
8.3.
Other Safety Analyses ................................................................................44
9.
REFERENCES.......................................................................................................45
10. APPENDICES........................................................................................................46
10.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................46
10.1.1.
Exclusions from Per Protocol Population .....................................46
10.2.
Appendix 2: Schedule of Activities ..............................................................47
10.2.1.
Protocol Defined Schedule of Events...........................................47
10.3.
Appendix 3: Assessment Windows .............................................................54
10.4.
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................55
10.4.1.
Study Phases ..............................................................................55
10.4.1.1.
Study Phases for Assessments ..................................55
10.4.1.2.
Study Phases for Concomitant Medication .................55
10.4.1.3.
Study Phases for COPD Exacerbations......................56
10.4.2.
Treatment Emergent Flag for Adverse Events/Serious 
Adverse Events............................................................................57
10.5.
Appendix 5: Data Display Standards & Handling Conventions....................58
10.5.1.
Reporting Process .......................................................................58
10.5.2.
Reporting Standards....................................................................58
10.6.
Appendix 6: Derived and Transformed Data ...............................................60
10.6.1.
General........................................................................................60
10.6.2.
Study Population..........................................................................60
10.6.3.
Effectiveness ...............................................................................65
10.6.4.
Safety ..........................................................................................71
10.7.
Appendix 7: Reporting Standards for Missing Data.....................................72
10.7.1.
Premature Withdrawals................................................................72
10.7.2.
Handling of Missing Data.............................................................72
10.7.2.1.
Handling of Missing and Partial Dates ........................76
10.8.
Appendix 8: Abbreviations & Trade Marks ..................................................78
10.8.1.
Abbreviations...............................................................................78
10.8.2.
Trademarks .................................................................................79
10.9.
Appendix 9: List of Data Displays ...............................................................80
10.9.1.
Data Display Numbering..............................................................80
10.9.2.
Mock Example Shell Referencing ................................................80
10.9.3.
Deliverables.................................................................................80
10.9.4.
Study Population Tables..............................................................81
10.9.5.
Study Population Figures.............................................................86
10.9.6.
Effectiveness Tables....................................................................87
10.9.7.
Effectiveness Figures...................................................................95
10.9.8.
Safety Tables...............................................................................96
10.9.9.
ICH Listings ...............................................................................100
 
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10.9.10. Non-ICH Listings........................................................................102
10.9.11. Patient Profile Listings ...............................................................104
10.10. Appendix 10: Example Mock Shells for Data Displays ..............................105
 
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1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report (CSR) for study 206854 for Protocol:
Revision Chronology:
2017N321744_00
06-NOV-2017
Original
2017N321744_01
15-FEB-2018
Amendment 1
2017N321744_02
28-SEP-2018
Amendment 2
Note that in line with the Protocol, this RAP will use the term “Participant” (except 
Appendix 9: List of Data Displays), while all data displays (Tables, Figures & Listings)
produced as part of the planned dry-run and the Statistical Analysis Complete (SAC), 
will use the term “Subject” which reflects GSK Data Display Standards terminology.
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Changes from the originally planned statistical analysis specified in the original protocol 
(Dated: 06-NOV-2017), protocol amendment 1 (Dated: 15-FEB-2018) and protocol 
amendment 2 (Dated 28-SEP-2018) 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
Other Endpoint: Proportion of 
responders who experience CID. 
(Section 2.2)
Other Endpoint: Proportion of 
participants who experience CID. 
The CID is a negative 
outcome and so the use of 
word “responder” may be 
misleading. Wording has been 
updated in the RAP to avoid 
misinterpretation.
Exploratory Endpoint: Numerical 
correlation of CE with CAT, 
moderate/severe exacerbations 
and FEV1 (Section 2.2)
Exploratory Endpoint: Association 
of CE with CAT score, moderate/
severe exacerbations, FEV1 and 
FVC
No formal statistical analysis 
was planned for this 
exploratory endpoint. 
Association between the 
endpoints will be investigated 
through graphical 
representation of the data and 
data summarisation 
(frequency tables as defined 
in Section 7.4.1)
Analysis Populations - FEV1: 
All members of the ITT population 
for whom an FEV1 assessment was 
planned.
Analysis Populations - FEV1: 
All members of the ITT population 
for whom a spirometry assessment 
was performed at any of Visit 1 or 
Change of population 
definition to be consistent with 
the information collected in 
the study eCRF. 
 
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Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes
Visit 2.
Note: If at least a single record 
exists in the electronic spirometry 
data provided for a participant then 
this constitutes evidence that 
spirometry measurements were 
taken (or attempted to be taken).
The FEV1 value may still be 
missing.
Analysis Populations - CE: 
All members of the ITT population 
for whom a critical error 
assessment was planned. Note that 
participants within selected centres 
performing inhaler assessments 
who are not on an inhaler for which 
an error checklist is available will 
not be included in this population.
Analysis Populations - CE: 
All members of the ITT population 
for whom a critical error assessment 
was performed at Visit 2. 
Note: Participants within selected 
centres performing inhaler 
assessments who are not on an 
inhaler for which an error checklist 
is available will not be included in 
this population. Also, participants 
who are on more than one device 
must perform an assessment for all 
devices to be included in the 
population.
Change of population 
definition to be consistent with 
the information collected in 
the study eCRF.
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints
To compare the effectiveness of 
TRELEGY ELLIPTA with non-ELLIPTA 
MITT for the impact of COPD on wellbeing 
and daily life after 24 weeks’ treatment
Proportion of responders based on the COPD Assessment 
Test (CAT) at week 24. Response defined as change from 
baseline of CAT score ≥2 at 24 weeks
Secondary Objectives
Secondary Endpoints
To compare the effectiveness of 
TRELEGY ELLIPTA with non-ELLIPTA 
MITT on lung function after 24 weeks’ 
treatment
Change from baseline in FEV1 at 24 weeks (in a subset of 
participants)
To compare critical errors (CE) made by 
study participants using the ELLIPTA 
inhaler with participants using selected 
non-ELLIPTA MITT after 24 weeks’ 
treatment
Percentage of participants making at least 1 critical error in 
inhalation technique at 24 weeks (in a subset of participants)
Other Objectives
Other Endpoints
To compare TRELEGY ELLIPTA with 
inhaled non-ELLIPTA MITT for a clinically 
Proportion of participants who experience CID. CID is a 
composite outcome defined as any one of the following 
 
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Objectives
Endpoints
important deterioration (CID)
events:
100 mL reduction from baseline in FEV1 at 24 weeks
An exacerbation (requiring treatment with antibiotics 
and/or systemic steroids or hospitalisation)
2 units change (increase) from baseline in CAT score 
at 24 weeks
To quantify the incidence, rate and time to 
first moderate/severe COPD exacerbation 
for study participants on TRELEGY 
ELLIPTA compared with participants on 
non-ELLIPTA MITT

Annualised rate of moderate/severe exacerbations 
(defined as: requiring treatment with antibiotics and/or 
systemic steroids or hospitalisation).

Time to first moderate /severe exacerbation (defined as: 
requiring treatment with one or more of the following: 
antibiotics, systemic steroids, hospitalisation)
To compare the effectiveness of 
TRELEGY ELLIPTA with non-ELLIPTA 
MITT for COPD-related Healthcare 
Resource Utilisation (HCRU)
The frequency of COPD related HCRU including:
Primary healthcare contacts.
COPD related medication.
Hospital admissions, outpatient appointments and 
A&E attendances.
Exploratory: frequency of HCRU assessed using electronic 
health records.
Exploratory Objectives
Exploratory Endpoints
To assess the data for correlation between 
critical errors and clinical outcomes
Association of CE with CAT score, moderate/ severe 
exacerbations FEV1and FVC
To describe the participant study 
experience
Participant Treatment and Study Satisfaction Questionnaire at 
24 weeks/EW Visit.
To describe the change from baseline in 
patient Health Related Quality of Life
Health Related Quality of Life Questionnaire
Safety Objectives
Safety Endpoints
To compare safety for study participants 
using the ELLIPTA inhaler with 
participants using non-ELLIPTA MITT after 
24 weeks’ treatment

All serious adverse events

Study treatment related adverse events

Adverse events that lead to withdrawal from study 
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2.3.
Study Design
Overview of Study Design and Key Features
Design 
Features
This is a phase IV, randomised, open-label, effectiveness, study of 24 weeks duration in 
COPD patients to evaluate TRELEGY ELLIPTA [FF/UMEC/VI: 100mcg/62.5mcg/25mcg] 
inhalation powder taken once daily using a single ELLIPTA inhaler compared with any 
non-ELLIPTA Multiple Inhaler Triple Therapy (MITT) in the usual care setting. 
Participants who meet the study entry criteria will be invited to join the study by their 
physician. Those who give their informed consent will be assessed for eligibility. 
Study treatment is defined as the COPD maintenance therapy that the patient is 
prescribed whilst enrolled in the study from randomisation to the 24 week/EW visit. 
Patients meeting eligibility criteria will be randomised to receive 24 weeks prescription 
cover for one of the following: 

TRELEGY ELLIPTA 

non-ELLIPTA MITT 
Participants should remain on the treatment to which they are randomised. If this is not 
possible, then at the investigator’s discretion, the participant may change treatment to a 
preferred alternative treatment (see Protocol, Section 5.2.1). If the preferred alternative 
treatment is, in the opinion of the treating physician, unsuitable for the participant, then 
treatment can be changed to a non-preferred alternative. A change in study treatment 
should not result in withdrawal from the study. All participants should remain in the study 
and complete the 24-week visit. If this is not possible then an EW visit should be 
completed.
Dosing
TRELEGY ELLIPTA: FF/UMEC/VI: 100mcg/62.5mcg/25mcg once daily (QD).
Non-ELLIPTA MITT: ICS/LAMA/LABA products and dosing regimens as prescribed by 
their physician twice daily.
Time & 
Events
Appendix 2: Schedule of Activities
 
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Overview of Study Design and Key Features
Treatment 
Assignment
A participant will be assigned a subject number at the time the informed consent is signed 
in accordance with the randomisation schedule. Once a subject number is assigned to a 
participant it cannot be reassigned to any other participant in the study. The randomisation 
schedule will be generated using RANDALL NG and all participants will be centrally 
randomised using an Interactive Web Response System (IWRS), RAMOS NG.
Randomisation (1:1) will be stratified by the “Prior Treatment Therapy” (treatment the 
participants receive prior to screening; ICS/LABA or LAMA/LABA or ICS/LAMA/LABA) with 
dynamic blocking allocation by Country.
Interim 
Analysis
No interim analysis is planned.
2.4.
Statistical Hypotheses / Statistical Analyses
The primary objective of this study is to evaluate the effectiveness of TRELEGY 
ELLIPTA versus non-ELLIPTA MITT in COPD patients in a pragmatic setting over 24 
weeks. The study will provide evidence to support HCP and payer discussions that 
TRELEGY ELLIPTA is more effective on CAT improvement than non-ELLIPTA MITT 
in a patient population representative of everyday clinical practice.
The primary effectiveness outcome is the proportion of CAT responders at week 24 
(Visit 2) and the primary treatment comparison is TRELEGY ELLIPTA versus non-
ELLIPTA MITT for
all participants.
In addition, other exploratory treatment comparisons of TRELEGY ELLIPTA with non-
ELLIPTA MITT will be performed for the prior treatment stratification levels of ICS/ 
LABA/LAMA, ICS/LABA and LABA/LAMA separately for the primary outcome
only.
The null hypothesis is that there is no difference in the proportion of CAT responders at
week 24 between TRELEGY ELLIPTA and non-ELLIPTA MITT:
H0: T1 – T2 = 0
The alternative hypothesis is that there is a difference between treatment groups:
H1: T1 – T2 ≠ 0
where T1 and T2 are, the treatment means for TRELEGY ELLIPTA and non-ELLIPTA 
MITT respectively.
 
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3.
PLANNED ANALYSES
3.1.
Interim Analyses
There are no interim analyses planned. 
3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All participants have completed the study as defined in the protocol.
2.
All required database cleaning activities have been completed and final database 
release (DBR) has been declared by Data Management.
3.
All criteria for unblinding the randomisation codes have been met. 
4.
Randomisation codes have been distributed according to RandAll NG
procedures.
5.
Database freeze (DBF) has been declared by Data Management.
This is an effectiveness study that collects data differently to a traditional clinical trial 
and also allows participants’ Investigational Product (IP) to be modified during the study. 
The trial design (open label) and the ways the study medication data are recorded in the 
datasets means that steps must be taken to ensure that Statistics and Programming (S&P)
remain blinded to study investigator prescribing of study medication until the S&P 
unblinding (i.e., review of unblinded datasets) takes place at DBR. Formal unblinding via 
RandALL will occur immediately prior to DBF, per standard practice. Details on the 
blinding strategy are included in the Blinding Strategy Charter. 
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses 
Evaluated
All Subjects 
Enrolled (ASE)
All participants for whom a record exists in the study database, 
including screen failures.
Study Population
Intent-to-Treat 
(ITT)
All randomised participants, excluding those who were randomised in 
error. A participant who is recorded as a screen failure and also 
randomised will be considered to be randomised in error. Any other 
participant who receives a randomisation number will be considered to 
have been randomised. Displays will be based on the treatment to 
which the participant was randomised unless otherwise stated.
Study Population
Primary, 
Exploratory and 
Other 
Effectiveness 
Safety
FEV1
All members of the ITT population for whom a spirometry assessment 
was performed at any of Visit 1 or Visit 2.
Note: If at least a single record exists in the electronic spirometry data 
provided for a participant then this constitutes evidence that spirometry 
measurements were taken (or attempted to be taken). The FEV1 value 
Secondary 
Effectiveness 
 
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Population
Definition / Criteria
Analyses 
Evaluated
may still be missing.
CE
All members of the ITT population for whom a critical error assessment 
was performed at Visit 2. 
Note: Participants within selected centres performing inhaler 
assessments who are not on an inhaler for which an error checklist is 
available will not be included in this population. Also, participants who 
are on more than one device must perform an assessment for all 
devices to be included in the population.
Secondary 
Effectiveness 
Refer to Appendix 9: List of Data Displays which details the population used for each display.
4.1.
Protocol Deviations
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed.
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan (PDMP)
o Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations 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 Electronic Case Report Form (eCRF).
A listing of any treatment misallocations will be produced for the ITT population.
 
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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting
Code
Description
Description
Order in TLF
1
Ellipta FF/UMEC/VI 100mcg/62.5mcg/25mcg 
QD
FF/UMEC/VI 100/62.5/25
1
2
Non-Ellipta Multiple Inhaler Triple Therapy 
(MITT) Usual Care
Non-Ellipta MITT 
2
Treatment comparisons will be displayed as follows using the descriptors as specified:

FF/UMEC/VI 100/62.5/25 vs Non-Ellipta MITT
5.2.
Baseline Definitions
For all endpoints, the baseline value will be the value recorded at Visit 1 (Screening & 
Randomisation). 
For the primary endpoint, baseline COPD Assessment Test (CAT) score will be the CAT 
score recorded at the CAT assessment at Visit 1. Note that for cases where a CAT 
assessment was not performed at Visit 1 as per Protocol and a historical CAT score was 
recorded in the eCRF by the Investigator instead, if the date of the historical CAT 
assessment was more than 14 days prior to Visit 1, then the baseline CAT score data will 
be considered as missing for the participant and will not be included in the analyses of the 
primary endpoint.
For the secondary endpoints of FEV1 and Trough FEV1, baseline FEV1 and baseline
Trough FEV1 will be the pre-bronchodilator FEV1 and pre-bronchodilator Trough FEV1
value recorded from the spirometry performed at Visit 1, respectively. 
If multiple pre-bronchodilator FEV1 or Trough FEV1 records exist for a participant at 
Visit 1, the latest record that is on or prior to the randomised treatment start date will be 
considered as baseline (see Section 10.6.3). 
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing.
5.3.
Multicentre Studies
In this multicentre global study, enrolment will be presented by country and investigative 
site, unless otherwise specified.
 
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5.4.
Examination of Covariates, Other Strata and Subgroups
The list of covariates and other strata to be used in statistical analyses is as described in 
table below, unless otherwise specified in Section 7.
Category
Details
Strata
The study randomisation will be stratified based on the treatment the participants receive 
prior to screening:

ICS/LABA,

LABA/LAMA or

ICS/LAMA/LABA
Covariates
Primary endpoint of CAT score:

Baseline CAT score

Number of exacerbations in the prior year (categorical, see Section 10.6.2)

Prior medication use strata (actual strata, see Section 10.6.2)

Country
Secondary endpoint of FEV1:

Baseline FEV1 score

Prior medication use strata (actual strata, see Section 10.6.2)

Country

Timing of Spirometry (see Section 7.2.1.5.1)
Secondary endpoint of Trough FEV1:

Baseline Trough FEV1 score

Prior medication use strata (actual strata, see Section 10.6.2)

Country
Secondary endpoint of Critical Errors:

Country

Prior medication use strata (actual strata, see Section 10.6.2)
Other endpoint of proportion of participants who experience a CID:

Country

Prior medication use strata (actual strata, see Section 10.6.2)

Baseline Trough FEV1 

Baseline CAT score

Number of exacerbations in the prior year (categorical, see Section 10.6.2)
Consideration will be given around other exploratory covariates for the study endpoints in a 
supplementary RAP. 
5.4.1.
Examination of Subgroups
No subgroups are considered in this RAP. Consideration of subgroups to be used in 
descriptive summaries and statistical analyses will be given in a supplementary RAP. 
 
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5.5.
Multiple Comparisons and Multiplicity
There is a single primary endpoint and treatment comparison, so no adjustment for 
multiplicity is required for the primary effectiveness comparison.
With regards to the secondary, other and exploratory endpoints, inference will only be 
made if the primary analysis achieves significance. Inference for secondary, other or 
exploratory endpoints will then be made at the 5% significance level. Otherwise results 
will be for descriptive purposes only.
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
10.3
Appendix 3: Assessment Windows
10.4
Appendix 4: Study Phases and Treatment Emergent Adverse Events
10.5
Appendix 5: Data Display Standards & Handling Conventions
10.6
Appendix 6: Derived and Transformed Data
10.7
Appendix 7: Reporting Standards for Missing Data
 
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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the Intent-to-Treat (ITT) population (as 
defined in Section 4), unless otherwise specified.
Study population analyses including descriptive statistics of participant’s disposition, 
protocol deviations, demographic and baseline characteristics, prior and concomitant 
medications, and exposure will be based on GSK Core Data Standards.  Details of the 
planned displays are presented in Appendix 9: List of Data Displays.
In addition, Section 10.6.2 includes details with regards to derivation of data for the study 
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7.
EFFECTIVENESS ANALYSES
7.1.
Primary Effectiveness Analyses
7.1.1.
COPD Assessment Test (CAT) Score
CAT score data are collected at Visit 1 (prior to randomisation) and at Visit 2/ EW visit. 
If participants are not able to attend the clinic visit at Visit 1, CAT assessment data can be 
collected at a domiciliary visit instead. If participants are not able to attend the clinic visit 
at Visit 2, CAT assessment can be performed at a domiciliary visit or at a telephone call. 
Visit 1 or Visit 2 CAT score data collected at a domiciliary visit will be used in the 
statistical analysis and will also be included in data summaries and listings.
Visit 2 CAT score data collected at a telephone call, will not be considered for use in the 
statistical analyses, unless otherwise stated. This data will not be included in data 
summaries but will be included in listings.
CAT score data collected during assessments that are considered as EW assessments, will 
not be considered for use within the statistical analyses, unless otherwise stated. CAT 
score data collected during EW assessments will be included in data summaries and 
listings.
7.1.1.1.
Endpoint / Variables
The primary endpoint will be the proportion of responders based on CAT at week 24 
(Visit 2). 
7.1.1.2.
Summary Measure
The summary measure used for the treatment comparison will be an Odds Ratio (OR) and 
a 95% CI. 
7.1.1.3.
Population of Interest 
The analysis will be based on the Intent-to-Treat (ITT) population (as defined in Section 
4), unless otherwise specified.
7.1.1.4.
Strategy for Intercurrent (Post-Randomisation) Events
The list of intercurrent events/events leading to missing data that may occur during 
the study and may affect the estimation of the treatment effect are:

Randomised Treatment Discontinuation: participants may discontinue 
randomised COPD maintenance therapy and continue in the study without being 
prescribed another COPD maintenance therapy. This is considered an intercurrent 
event.

Randomised Treatment Modification: participants may discontinue randomised 
COPD maintenance therapy and get prescribed another COPD maintenance 
therapy during the study. This is considered an intercurrent event.
 
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
Pulmonary Rehabilitation: participants may change pulmonary rehabilitation
status during the study. E.g., Participant considered to be undergoing pulmonary 
rehabilitation at Visit 1 but stopped during the study and so no longer on 
pulmonary rehabilitation at Visit 2. See Section 10.6.3 for definition of pulmonary 
rehabilitation status at Visit 1 and at Visit 2.  This is considered an intercurrent 
event.

Oxygen Therapy: If participants start oxygen therapy during the study and they 
have not had another oxygen therapy prior to the study start, this is considered as 
an intercurrent event. If participants start oxygen therapy during the study but 
they have recorded another oxygen therapy prior to the study start, this is not 
considered as an intercurrent event.

Early Withdrawal from Study: participants may prematurely withdraw from the 
study which results in missing endpoint data.

Week 24 CAT Score not Available (other reasons than EW): CAT score at 
week 24 (Visit 2) may not be available for other reasons (not EW).
The strategies for handling these events for this endpoint are described in Table 2.
Table 2
Strategies for handling intercurrent events/events leading to 
missing data for the primary endpoint of proportion of CAT 
responders at week 24
Intercurrent Events 
Missing Data
Estimand
Randomised 
Treatment 
Discontinuatio
n 
Randomise
d Treatment 
Modificatio
n
Pulmonary 
Rehabilitatio
n 
Oxygen 
Therapy 
Study 
Withdrawal 
Week 24 
CAT Score 
not 
Available
Treatment 
Policy x 
Composit
e
Week 24 CAT 
score data to be 
used in the 
analysis 
regardless of the 
intercurrent event 
of randomised 
treatment 
discontinuation.
(Treatment 
Policy)
If participants 
modify their 
randomised 
treatment 
during the 
study, they 
will be 
considered as 
non-
responders 
for the week 
24 CAT score. 
(Composite)
If participants
change 
pulmonary 
rehabilitation 
status during 
the study, they 
will be 
considered as 
non-responders 
for the week 24 
CAT score.
(Composite)
If 
participants 
start 
oxygen 
therapy 
during the 
study and 
they have 
not had 
another 
oxygen 
therapy 
prior to the 
study start, 
they will be 
considered 
as non-
responders 
for the 
week 24 
CAT score.
(Composite
)
Missing week 
24 CAT score 
data will be 
imputed 
based on the 
randomised 
treatment arm 
characteristics
. This 
assumes 
MAR. See 
details in 
Section 
10.7.2.
Missing week 
24 CAT score 
data will be
imputed 
based on the 
randomised 
treatment arm 
characteristics
. This 
assumes 
MAR. See 
details in 
Section 
10.7.2.
 
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This primary estimand for the primary endpoint of week 24 CAT score will assess the 
randomised treatment effect, handling differently each of the intercurrent events/events 
leading to missing data described in Table 2 above.
7.1.1.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 9: List of Data Displays and
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints /variables defined in Section 7.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
7.1.1.5.1.
Statistical Methodology Specification
Endpoint / Variables
Proportion of responders based on the COPD Assessment Test (CAT) score at week 24 (Visit 2). For 
definition of CAT responders, see Section 10.6.3.
Model Specification
The primary endpoint of proportion of CAT responders at week 24 will be analysed for the ITT Population 
using a logistic regression model with treatment as an explanatory variable and baseline CAT score
(continuous), number of exacerbations in the prior year (categorical, see Section 10.6.2), prior medication 
use strata (categorical, see Section 10.6.2) and country (categorical) included as covariates.
Interaction Testing: 
For the primary estimand, interactions between treatment and other factors will be investigated as follows by 
adding interaction terms to the model defined above. 
Separate models will be fitted to investigate the effect of treatment by covariate interactions: (i) with the 
addition of an interaction term for Treatment by Baseline CAT score, (ii) with addition of interaction term for 
Treatment by Number of Exacerbations in the Prior Year, (iii) with addition of interaction term for Treatment 
by Prior Medication Use Strata, (iv) with addition of interaction term for Treatment by Country. Note: The 
logistic regression model described for the primary analysis above will be used, with the addition of each 
specific interaction term. No multiple imputation will be performed for missing week 24 CAT score data.
The p-value for each interaction test will be presented. If any interaction p-value is less than 0.10 further 
investigations will be carried out, for example running the analysis by each category of the subgroup. Any 
outputs from interaction investigation will also be presented.
Model Results Presentation
The odds ratio, 95% CI and p-value will be presented for the comparison between treatment arms. It will be 
based on a two-sided hypothesis testing approach of superiority. 
Model Checking & Diagnostics
For the primary estimand, the model assumptions will be assessed by performing a logistic regression 
analysis using the primary estimand model specified in the Model Specification section above. No multiple 
imputation will be performed for the missing CAT score data at week 24. The Pearson residuals from this 
 
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analysis will be plotted.
Supportive Analyses
Additional supportive estimands will be defined for the primary endpoint of CAT score. The 
variable/endpoint, the summary measure and the population of interest for the supportive estimands will be 
as defined in Section 7.1.1.1, Section 7.1.1.2 and Section 7.1.1.3, respectively. The strategies for handling 
the intercurrent events/events leading to missing data for each of these supportive estimands are as 
described below:
Supportive Estimand I (Treatment Policy x Composite): 
Intercurrent Events
Missing data
Estimand 
Randomised 
Treatment 
Discontinuation
Randomised 
Treatment 
Modification
Pulmonary 
Rehabilitation
Oxygen 
Therapy
Study 
Withdrawal 
Week 24 
CAT Score 
not 
Available
Treatment 
Policy x 
Composite
Week 24 CAT 
score data to be 
used in the 
analysis 
regardless of the 
intercurrent event 
of randomised 
treatment 
discontinuation.
(Treatment 
Policy)
Week 24 
CAT score 
data to be 
used in the 
analysis 
regardless of 
the 
intercurrent 
event of 
randomised 
treatment 
modification.
(Treatment 
Policy)
Week 24 CAT 
score data to 
be used in the 
analysis 
regardless of 
the intercurrent 
event of 
change of 
pulmonary 
rehabilitation 
status during 
the study.
(Treatment
Policy)
Week 24 
CAT score 
data to be 
used in the 
analysis 
regardless 
of the 
intercurrent 
event of 
start 
oxygen 
therapy 
during the 
study.
(Treatment 
Policy)
If 
participants 
prematurely 
withdraw 
from study, 
they will be 
considered 
as non-
responders 
for the week 
24 CAT 
score.
(Composite)
If week 24 
CAT score 
data are 
missing for 
other 
reasons than 
EW, 
participants 
will be 
considered 
as non-
responders 
for the week 
24 CAT 
score.
(Composite)
Supportive Estimand I, will use the actual values of the week 24 CAT score, regardless of whether the 
intercurrent events described in the table above occurred in the study. A more conservative approach for the 
missing data will be followed, where participants with missing week 24 CAT score (because of EW or other 
reasons) will be considered as non-responders (composite strategy). 
Supportive Estimand II (Treatment Policy x Composite): 
Intercurrent Events
Missing data
Estimand 
Randomised 
Treatment 
Discontinuatio
n
Randomise
d Treatment 
Modification
Pulmonary 
Rehabilitatio
n
Oxygen 
Therapy
Study 
Withdrawal 
Week 24 CAT 
Score not 
Available
Treatment 
Policy x 
Composit
e
Week 24 CAT 
score data to be 
used in the 
analysis 
regardless of the 
intercurrent 
event of 
randomised 
treatment 
discontinuation.
If participants 
modify their 
randomised 
treatment 
during the 
study, they 
will be 
considered 
as non-
responders 
Week 24 CAT 
score data to 
be used in the 
analysis 
regardless of 
the 
intercurrent 
event of 
change of 
pulmonary 
Week 24 
CAT score 
data to be 
used in the 
analysis 
regardless 
of the 
intercurren
t event of 
start 
Missing week 
24 CAT score 
data will be 
imputed based 
on the
randomised 
treatment arm 
characteristics
. This 
assumes 
Missing week 
24 CAT score 
data will be 
imputed based 
on the 
randomised 
treatment arm 
characteristics
. This 
assumes 
 
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(Treatment 
Policy)
for the week 
24 CAT 
score.
(Composite)
rehabilitation 
status during 
the study.
(Treatment 
Policy)
oxygen 
therapy 
during the 
study.
(Treatment 
Policy)
MAR. See 
details in 
Section 
10.7.2.
MAR. See 
details in 
Section 
10.7.2.
Supportive Estimand II, will use the actual values of the week 24 CAT score, regardless of whether the 
intercurrent events of randomised treatment discontinuation, change of pulmonary rehabilitation status or 
start of oxygen therapy have occurred during the study, but a composite strategy will be followed for the 
intercurrent event of randomised treatment modification. This is to assess the effect of the intercurrent event 
of randomised treatment modification on the estimate of the treatment effect. The same imputation 
approach as the one used for the primary estimand (Section 7.1.1.4) will be performed for missing CAT 
score data at week 24.
Supportive Estimand III (Hypothetical): 
Intercurrent Events
Missing data
Estimand 
Randomised 
Treatment 
Discontinuation
Randomised 
Treatment 
Modification
Pulmonary 
Rehabilitation
Oxygen 
Therapy
Study 
Withdrawal 
Week 24 
CAT Score 
not 
Available
Hypothetical
Ignore actual 
week 24 CAT 
score record. 
Assume is 
missing at 
random (MAR) 
and impute week 
24 CAT score as 
what would have 
been if 
participant would 
not have 
discontinued 
from randomised 
study treatment.
Ignore actual 
week 24 CAT 
score. 
Assume is 
MAR and 
impute week 
24 CAT score 
as what 
would have 
been if 
participant 
would not 
have 
modified the
randomised 
treatment.
Ignore actual 
week 24 CAT 
score. Assume 
is MAR and 
impute week 
24 CAT score 
as what would 
have been if 
participant 
would not have 
changed 
pulmonary 
rehabilitation 
status.
Ignore 
actual 
week 24 
CAT score. 
Assume is 
MAR and 
impute 
week 24 
CAT score 
as what 
would have 
been if 
participant 
would not 
have 
started 
oxygen 
therapy.
Missing 
week 24 
CAT score 
data will be 
imputed 
assuming is 
MAR and 
impute 
values as 
what would 
have been if 
participant 
would not 
have 
withdrawn 
early from 
study.
Missing 
week 24 
CAT score 
data will be 
imputed 
assuming is 
MAR and 
impute 
week 24 
CAT score 
as what 
would have 
been if 
participant 
had an 
available 
CAT score 
at week 24.
Supportive Estimand III, will assess the treatment effect that would have been observed in a hypothetical 
scenario where no participants experienced the intercurrent events/events leading to missing data described 
in table above. This method fits a Bayesian normal repeated measures model and then imputes missing 
week 24 CAT scores assuming that the data is missing at random (i.e. that the participant continues to be 
treated with their randomised treatment). The imputed and “real”/ available data will be analysed and 
summarised using Rubin’s rules. See details in Section 10.7.2.
7.2.
Secondary Effectiveness Analyses
7.2.1.
Forced Expiratory Volume in 1 Second (FEV1)
Spirometry data are collected at Visit 1 (pre and post-salbutamol) and at Visit 2/ EW visit 
(only pre-salbutamol). If participants are not able to attend the scheduled clinic visit at 
 
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Visit 1/ Visit 2 to perform the spirometry assessment, the Visit 1/ Visit 2 spirometry 
assessment can be performed at a domiciliary visit. 
Spirometry data collected at a domiciliary visit will be used in the secondary statistical 
analyses of FEV1, unless otherwise stated. This data will also be included in data 
summaries and listings. 
Spirometry data collected during assessments that are considered as EW assessments or 
have been inadvertently collected during the study and do not qualify as Visit 1/ Visit 2 
spirometry, will not be considered for use within the statistical analyses, unless otherwise 
stated. Spirometry data collected at EW assessments will be included in data summaries 
and listings. Spirometry data inadvertently collected in the study that do not qualify as 
Visit 1/ Visit 2 spirometry will not be included in data summaries but will be included in 
listings.
7.2.1.1.
Endpoint / Variables
Change from baseline in FEV1 at 24 weeks. 
7.2.1.2.
Summary Measure
The summary measure will be the adjusted mean treatment differences.
7.2.1.3.
Population of Interest 
The analysis will be based on the FEV1 population (as defined in Section 4), unless 
otherwise specified.
7.2.1.4.
Strategy for Intercurrent (Post-Randomisation) Events
The list of intercurrent events/events leading to missing data that may occur during 
the study and may affect the estimation of the treatment effect are:

Randomised Treatment Discontinuation: participants may discontinue 
randomised COPD maintenance therapy and continue in the study without being
prescribed another COPD maintenance therapy. This is considered an intercurrent 
event.

Randomised Treatment Modification: participants may discontinue randomised 
COPD maintenance therapy and get prescribed another COPD maintenance 
therapy during the study. This is considered an intercurrent event.

Pulmonary Rehabilitation: participants may change pulmonary rehabilitation 
status during the study. E.g., Participant considered to be undergoing pulmonary 
rehabilitation at Visit 1 but stopped during the study and so no longer on 
pulmonary rehabilitation at Visit 2. See Section 10.6.3 for definition of pulmonary 
rehabilitation status at Visit 1 and at Visit 2. This is considered an intercurrent 
event.

Oxygen Therapy: If participants start oxygen therapy during the study and they 
have not had another oxygen therapy prior to the study start, this is considered as 
an intercurrent event. If participants start oxygen therapy during the study but 
 
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they have recorded another oxygen therapy prior to the study start, this is not 
considered as an intercurrent event.

Early withdrawal from Study: participants may prematurely withdraw from the 
study which results in missing endpoint data.

Week 24 FEV1 Data not Available (other reasons than EW): FEV1 data at 
week 24 (Visit 2) may not be available for other reasons (not EW).
The strategies for handling these events for this endpoint are described in Table 3.
Table 3
Strategies for handling intercurrent events/events leading to 
missing data for the secondary endpoint of change from baseline in 
FEV1 at week 24
Intercurrent Events
Missing data
Estimand 
Randomised 
Treatment 
Discontinuation
Randomised 
Treatment 
Modification
Pulmonary 
Rehabilitation
Oxygen 
Therapy
Study 
Withdrawal
Week 24 
FEV1 not 
Available
Treatment 
Policy
Week 24 FEV1
data to be used in 
the analysis 
regardless of the 
intercurrent event 
of randomised 
treatment 
discontinuation.
(Treatment 
Policy)
Week 24 FEV1
data to be used 
in the analysis 
regardless of 
the intercurrent 
event of 
randomised 
treatment 
modification.
(Treatment 
Policy)
Week 24 FEV1
data to be 
used in the 
analysis 
regardless of 
the 
intercurrent 
event of 
change of 
pulmonary 
rehabilitation 
status during 
the study. 
(Treatment 
Policy)
Week 24 
FEV1 data to 
be used in 
the analysis 
regardless 
of the 
intercurrent 
event of 
start of 
oxygen 
therapy 
during the 
study.
(Treatment 
Policy)
Missing 
week 24 
FEV1 data 
will be 
imputed 
based on 
the 
randomised 
treatment 
arm. 
Assumes 
MAR. See 
details in 
Section 
10.7.2.
Missing week 
24 FEV1 data 
will be 
imputed 
based on the 
randomised 
treatment 
arm. Assumes 
MAR. See 
details in 
Section 
10.7.2.
This primary estimand for the secondary endpoint of FEV1 will assess the randomised 
treatment effect regardless of whether the intercurrent events/events leading to missing 
data described in Table 3 above have occurred in the study.
7.2.1.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 9: List of Data Displays and
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints/variables defined in Section 7.2.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
7.2.1.5.1.
Statistical Methodology Specification
Endpoint / Variables
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Model Specification
The secondary endpoint of change from baseline in FEV1 at week 24 will be analysed for the FEV1
population using an analysis of covariance (ANCOVA) model with treatment as an explanatory variable and 
baseline FEV1(continuous), prior medication use strata (categorical, see Section 10.6.2) and country
(categorical) included as covariates.
An additional covariate “Timing of Spirometry” (categorical) indicating when the spirometry assessment was 
performed (i.e., pre/post maintenance COPD therapy) at Visit 1 and Visit 2 will be defined. All possible 
combinations for timing of spirometry at Visit 1 and Visit 2 will form the levels of the covariate: 
1
Visit 1: Pre-COPD maintenance therapy dose – Visit 2: Pre-COPD 
maintenance therapy dose
2
Visit 1: Pre-COPD maintenance therapy dose – Visit 2: Post-COPD 
maintenance therapy dose
3
Visit 1: Post-COPD maintenance therapy dose – Visit 2: Pre-COPD 
maintenance therapy dose
4
Visit 1: Post-COPD maintenance therapy dose – Visit 2: Post-COPD 
maintenance therapy dose
Interaction between Treatment and Timing of Spirometry will be checked. If the interaction p-value is less 
than 0.10 then the estimate of the treatment effect will be based on the model that includes baseline FEV1, 
prior medication use strata, country and the timing of spirometry as covariates as well as the interaction 
term treatment by timing of spirometry. If the interaction p-value is not less than 0.10 then the estimate of 
the treatment effect will be based on the model which will only include baseline FEV1, prior medication use 
strata, country and the timing of spirometry as covariates.
Model Results Presentation
Adjusted Least-square (LS) means and LS mean change from baseline values for each treatment group will 
be presented with their associated standard errors as well as 95% CIs. The estimated treatment difference 
along with corresponding standard error, 95% CI and p-value will be presented.
Model Checking & Diagnostics
For the primary estimand, distributional assumptions underlying the model used for analysis will be 
examined. An ANCOVA analysis will be performed using the primary estimand model specified in the Model 
Specification section above. No multiple imputation will be performed for the missing week 24 FEV1 data. 
The 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, will be produced. 
7.2.2.
Trough FEV1
Spirometry data will be used in the statistical analyses in the same way as described in 
Section 7.2.1.
7.2.2.1.
Endpoint / Variables
Change from baseline in Trough FEV1 at 24 weeks. Trough FEV1 is defined in Section 
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7.2.2.2.
Summary Measure
The summary measure will be the adjusted mean treatment differences.
7.2.2.3.
Population of Interest
The analysis will be based on participants included in the FEV1 population (as defined in 
Section 4), who also managed to withhold COPD maintenance treatment at both Visit 1 
and Visit 2 spirometry assessment (see also Section 10.6.3 for definition of Trough 
FEV1), unless otherwise specified.
7.2.2.4.
Strategy for Intercurrent (Post-Randomisation) Events
The list of intercurrent events/events leading to missing data that may occur during 
the study and may affect the estimation of the treatment effect are as described in Section 
7.2.1.4.
The strategies for handling these events for this endpoint are described in Table 4.
Table 4
Strategies for handling intercurrent events/events leading to 
missing data for the secondary endpoint of change from baseline in 
Trough FEV1 at week 24
Intercurrent Events
Missing data
Estimand 
Randomised 
Treatment 
Discontinuation
Randomised 
Treatment 
Modification
Pulmonary 
Rehabilitation
Oxygen 
Therapy
Study 
Withdrawal
Week 24 FEV1
not Available
Treatment 
Policy
Week 24 Trough 
FEV1 data to be 
used in the 
analysis 
regardless of the 
intercurrent 
event of 
randomised 
treatment 
discontinuation.
(Treatment 
Policy)
Week 24 
Trough FEV1
data to be 
used in the 
analysis 
regardless of
the 
intercurrent 
event of 
randomised 
treatment 
modification.
(Treatment 
Policy)
Week 24 
Trough FEV1
data to be 
used in the 
analysis 
regardless of 
the 
intercurrent 
event of 
change of 
pulmonary 
rehabilitation 
status during 
the study.
(Treatment 
Policy)
Week 24 
Trough FEV1
data to be 
used in the 
analysis 
regardless of 
the intercurrent 
event of start 
of oxygen 
therapy during 
the study.
(Treatment 
Policy)
Missing week 
24 Trough 
FEV1 data 
will be 
imputed 
based on the 
randomised 
treatment 
arm. 
Assumes 
MAR. See 
details in 
Section 
10.7.2.
Missing week 
24 Trough 
FEV1 data will 
be imputed 
based on the 
randomised 
treatment arm. 
Assumes 
MAR. See 
details in 
Section 10.7.2.
The primary estimand for the secondary endpoint of Trough FEV1 will assess the 
randomised treatment effect regardless of whether the intercurrent events/events leading 
to missing data described in Table 4 have occurred in the study.
 
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7.2.2.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 9: List of Data Displays and
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints/variables defined in Section 7.2.2.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
7.2.2.5.1.
Statistical Methodology Specification
Endpoint / Variables
Change from baseline in Trough FEV1 at 24 weeks.
Model Specification
The secondary endpoint of change from baseline in Trough FEV1 at week 24 will be analysed for the FEV1
population using an analysis of covariance (ANCOVA) model with treatment as an explanatory variable and 
baseline Trough FEV1(continuous), prior medication use strata (categorical, see Section 10.6.2) and 
country (categorical) included as covariates.
Model Results Presentation
Adjusted Least-square (LS) means and LS mean change from baseline values for each treatment group will 
be presented with their associated standard errors as well as 95% CIs. The estimated treatment difference 
along with corresponding standard error, 95% CI and p-value will be presented.
Model Checking & Diagnostics
For the primary estimand, distributional assumptions underlying the model used for analysis will be 
examined. An ANCOVA analysis will be performed using the primary estimand model specified in the Model 
Specification section above. No multiple imputation will be performed for the missing week 24 Trough FEV1
data. The 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, will be produced. 
7.2.3.
Critical Errors (CE)
Inhaler error assessment data is collected at a clinic visit at Visit 2/ EW visit. Inhaler 
error data collected during assessments considered as EW assessments, will not be 
considered for use within the statistical analyses, unless otherwise stated. Inhaler error 
assessment data collected during EW assessments will be included in data summaries and 
listings.
7.2.3.1.
Endpoint / Variables
Percentage of participants making at least one critical error in inhalation technique at 24 
weeks.
 
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7.2.3.2.
Summary Measure
The summary measure used for the treatment comparison will be an Odds Ratio (OR) and 
a 95% CI. 
7.2.3.3.
Population of Interest 
The analysis will be based on participants in the Critical Error (CE) population (as 
defined in Section 4), unless otherwise specified.
7.2.3.4.
Strategy for Intercurrent (Post-Randomisation) Events
The following intercurrent events/events leading to missing data are considered for 
the secondary endpoint of critical errors:

Randomised Treatment Modification: participants may discontinue randomised 
COPD maintenance therapy and get prescribed another COPD maintenance 
therapy during the study. The three following scenarios are considered after the 
intercurrent event of randomised treatment modification:
a)
New COPD maintenance therapy uses the same devices as randomised 
COPD maintenance therapy and error assessments are performed on these 
new devices.
b)
New COPD maintenance therapy uses different devices to randomised 
COPD maintenance therapy, but devices that are assessed in the study 
(checklists available) and for which error assessments are performed.
c)
New COPD maintenance therapy uses devices which are not being assessed 
in this study (no checklists available) and thus no error assessment is 
available at week 24 (Visit 2).

Early Withdrawal from Study: participants may prematurely withdraw from the 
study and so no actual week 24 (Visit 2) inhaler error assessment is performed.

Week 24 Inhaler Error Assessment Data not Available (other reasons than 
EW), e.g., participants on multiple inhalers may have missed performing the 
assessment on the secondary device at week 24 (Visit 2); participant may miss a 
component of a device assessment and all other question responses indicate 
correct use.
The strategies for handling these events for this endpoint are described in Table 5.
 
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Table 5
Strategies for handling intercurrent events/events leading to 
missing data for the secondary endpoint of percentage of 
participants making at least 1 critical error in inhalation technique at 
week 24
Intercurrent Events
Missing data
Estimand 
Randomised Treatment Modification
Study Withdrawal
Week 24 Inhaler Error 
Assessment Data not 
Available
Hypothetical
For the purposes of this secondary 
endpoint analysis any inhaler error 
assessment data following randomised 
treatment modification event and falling 
under scenario a, will be included in the 
analysis. Any error assessment data 
following randomised treatment 
modification and falling under scenario b 
or c, will be treated as missing (See also 
Section 10.6.3).
If participant
prematurely withdraw 
from study, no 
imputation will be 
performed for the 
missing actual week 24 
inhaler error data.
If week 24 inhaler error 
data are not available (for 
other reasons than EW) 
no imputation will be 
performed. 
The primary estimand of the secondary endpoint of critical errors will assess the 
treatment effect that would have been observed in a hypothetical scenario where no 
participant experienced the intercurrent events/events leading to missing data described in
Table 5.
7.2.3.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 9: List of Data Displays and
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints/variables defined in Section 7.2.3.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
7.2.3.5.1.
Statistical Methodology Specification
Endpoint / Variables
Percentage of participants making at least one critical error in inhalation technique at 24 weeks.
Model Specification
The secondary endpoint of percentage of participants making at least one critical error at week 24 will be 
analysed for the CE population using a logistic regression model with treatment as an explanatory variable. 
Country (categorical) and prior medication use strata (categorical, see Section 10.6.2) will be included as 
covariates in the model.
For the non-ELLIPTA MITT arm all devices for which we have error checklists will be considered. Any 
participant in the non-ELLIPTA MITT arm using a device for which we have no error checklist will not be 
considered for critical error assessment.
Model Results Presentation
 
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The odds ratio, 95% CI and p-value will be presented for the comparison between treatment arms. It will be 
based on a two-sided hypothesis testing approach of superiority.
Model Checking & Diagnostics
For the primary estimand, the model assumptions will be assessed by plotting the Pearson residuals from 
this analysis.
Supportive Analyses
A supportive estimand will be defined for the secondary endpoint of CE. The variable/endpoint, the 
summary measure and population of interest for the supportive estimands will be as defined in Section 
7.2.3.1, Section 7.2.3.2 and Section 7.2.3.3, respectively. The strategies for handling the intercurrent 
events/events leading to missing data for this supportive estimand are as described below:
Supportive Estimand (Treatment Policy)
Intercurrent Events
Missing data
Estimand 
Randomised Treatment 
Modification
Study Withdrawal
Week 24 Inhaler Error 
Assessment Data not 
Available
Treatment 
Policy
All available inhaler error assessment 
data collected at week 24 (Visit 2) will 
be included in the analysis, 
regardless of the inhaler device the 
participants used at the week 24 
assessment following the randomised 
treatment modification event.
(Treatment Policy)
If participant prematurely 
withdrew from study, no 
imputation will be performed 
for the missing actual week 24 
(Visit 2) inhaler error data. 
Note: If participant prematurely 
withdrew from study and an 
inhaler error assessment was 
performed at an EW visit, 
available EW data will be used 
in the analysis. 
If week 24 inhaler error 
data are not available 
(for other reasons than 
EW) no imputation will 
be performed.
Supportive Estimand of the secondary endpoint of critical errors will assess the randomised treatment effect 
regardless of whether the intercurrent events/events leading to missing data described in the table above 
have occurred in the study.
Exploratory Analyses
In addition, further exploratory treatment comparisons between the individual inhalers assessed in the study 
will be performed, if there are at least 100 participants who performed an inhaler error assessment for each 
of the individual inhalers assessed in the study. The inhaler comparisons to be assessed are:
Ellipta vs Diskus
Ellipta vs MDI[1]
Ellipta vs Breezhaler
Ellipta vs Turbuhaler
Ellipta vs Handihaler
Ellipta vs Genuair
[1] This is for participants whose COPD maintenance therapy is administered via an MDI. Rescue 
medications administered via an MDI are not included.
o For each of these exploratory comparisons the variable/endpoint and the summary measure will be as 
defined in Sections 7.2.3.1 and Section 7.2.3.2. 
o The population of interest will be participants from the ITT population (as defined in Section 4) with 
available critical error assessment data on any of the following devices: Ellipta, Breezhaler, Handihaler, 
 
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MDI, Turbuhaler, Genuair. Note: Participants whose COPD maintenance treatment is administered via 
multiple inhalers not all of which have an inhaler error checklist available in the study, but an inhaler 
error assessment was still performed for any of those that are assessed in the study, then these 
participants will be included in the population and the available inhaler error data will be use in the 
analysis (see also Section 10.6.3).
o Intercurrent Events: The inhaler error data at week 24 will be used regardless of the device the 
participants used at the week 24 (Visit 2) assessment following the randomised treatment modification 
event (Treatment Policy).
o Handling Missing Data: Events leading to missing data (e.g., study withdrawal), will be handled as 
described in Section 7.2.3.4, Table 5. This exploratory estimand will assess the device effect on
participants who remain in the study and provide inhaler error data in any of the devices assessed in the 
study (i.e., devices for which a checklist is available). 
o Model Specification: The percentage of participants making at least one critical error at week 24 will be 
analysed for each inhaler comparison separately, using a logistic regression model with device type as 
an explanatory variable. Country (categorical) and prior medication use strata (categorical, see Section 
10.6.2) will be included as covariates in the model.
 
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7.3.
Other Effectiveness Analyses
7.3.1.
Clinically Important Deterioration (CID)
For the endpoint of CID, CAT score data and spirometry data collected at domiciliary 
visits or at a telephone call (i.e., for CAT at Visit 2) will be used in the statistical analyses 
as described in Sections 7.1.1 and Section 7.2.1, respectively. CAT score data and
spirometry data collected at EW assessments, will be used within the statistical analyses, 
unless otherwise stated. Spirometry data inadvertently collected in the study that do not 
qualify as Visit 1/ Visit 2/ EW visit spirometry will not be included in the statistical 
analyses.
7.3.1.1.
Endpoint / Variables
Proportion of participants who experience Clinically Important Deterioration (CID). CID 
is a composite outcome defined in Section 10.6.3.
7.3.1.2.
Summary Measure
The summary measure used for the treatment comparison will be an Odds Ratio (OR) and 
a 95% CI. 
7.3.1.3.
Population of Interest 
The analysis will be based on the FEV1 population (as defined in Section 4), unless 
otherwise specified.
7.3.1.4.
Strategy for Intercurrent (Post-Randomisation) Events
The list of intercurrent events/events leading to missing data that may occur during 
the study and may affect the estimation of the treatment effect are:
Randomised Treatment Discontinuation: participants may discontinue 
randomised COPD maintenance therapy and continue in the study without being
prescribed another COPD maintenance therapy. This is considered and intercurrent 
event.
Randomised Treatment Modification: participants may discontinue randomised 
COPD maintenance therapy and get prescribed another COPD maintenance therapy 
during the study. This is considered an intercurrent event.
Pulmonary Rehabilitation: participants may change pulmonary rehabilitation 
status during the study. E.g., Participant considered to be undergoing pulmonary 
rehabilitation at Visit 1 but stopped during the study and so no longer on pulmonary 
rehabilitation at Visit 2. See Section 10.6.3 for definition of pulmonary 
rehabilitation status at Visit 1 and at Visit 2. This is considered an intercurrent 
event.
Oxygen Therapy: If participants start oxygen therapy during the study and they 
have not had another oxygen therapy prior to the study start, this is considered as an 
 
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intercurrent event. If participants start oxygen therapy during the study but they 
have recorded another oxygen therapy prior to the study start, this is not considered 
as an intercurrent event.
Early Withdrawal from Study: participants may prematurely withdraw from the 
study which results in missing endpoint data.
Week 24 CAT Score Data not Available (other reasons than EW): CAT score at 
week 24 (Visit 2) may not be available for other reasons (not EW).
Week 24 FEV1 Data not Available (other reasons than EW): Trough FEV1 data 
at week 24 (Visit 2) may not be available for other reasons (not EW).
The strategies for handling these events for this endpoint are described in Table 6.
Table 6
Strategies for handling intercurrent events/events leading to 
missing data for the endpoint of proportion of participants who 
experience CID
Intercurrent Events
Missing data
Estimand 
Randomised 
Treatment 
Discontinuatio
n
Randomise
d 
Treatment 
Modificatio
n
Pulmonary 
Rehabilitatio
n
Oxygen 
Therapy
Study 
Withdraw
al
Week 24 
Trough 
FEV1 not 
Available
Week 24 
CAT not 
Available
Treatmen
t Policy x 
Composit
e
Week 24 
Trough FEV1
data, CAT
score data and 
on-study 
Exacerbation 
data to be used 
in the analysis 
regardless of 
the intercurrent 
event of 
randomised 
treatment 
discontinuation. 
(Treatment 
Policy)
Week 24 
Trough 
FEV1 data, 
CAT score
data and 
on-study 
Exacerbatio
n data to be 
used in the 
analysis 
regardless 
of the 
intercurrent 
event of 
randomised 
treatment 
modification
. (Treatment 
Policy)
Trough FEV1
data, CAT
score data 
and on-study 
Exacerbation 
data to be 
used in the
analysis 
regardless of 
the 
intercurrent 
event of 
change of 
pulmonary 
rehabilitation 
status during 
the study.
(Treatment 
Policy)
If 
participant
s start 
oxygen 
therapy 
during the 
study and 
they have 
not had 
another 
oxygen 
therapy 
prior to the 
study start, 
they will be 
considered 
as meeting 
the criteria 
for CID. 
(Composit
e)
Missing 
week 24 
Trough 
FEV1 and 
CAT score
data will 
be imputed 
based on 
the 
randomise
d 
treatment 
arm. 
Assumes 
MAR. See 
details in 
Section 
10.7.2.
Note: EW 
data will 
be 
included in 
the 
analysis.
Missing 
week 24 
Trough 
FEV1 data 
will be 
imputed 
based on 
the 
randomise
d 
treatment 
arm. 
Assumes 
MAR. See 
details in 
Section 
10.7.2.
Missing 
week 24 
CAT score 
data will 
be 
imputed 
based on 
the 
randomise
d 
treatment 
arm. 
Assumes 
MAR. See 
details in 
Section 
10.7.2.
This primary estimand for the endpoint of proportion of participants who experience CID 
will assess the randomised treatment effect, handling differently each of the intercurrent 
events/events leading to missing data described in Table 6 above. 
 
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7.3.1.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 9: List of Data Displays and
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints /variables defined in Section 7.3.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
7.3.1.5.1.
Statistical Methodology Specification
Endpoint / Variables
Proportion of participants who experience a CID. CID is a composite outcome defined in Section 10.6.3.
Model Specification
The endpoint of proportion of participants who experience a CID will be analysed for the FEV1 population 
using a logistic regression model with treatment as an explanatory variable and baseline Trough FEV1
(continuous), baseline CAT score (continuous), number of exacerbations in the prior year (categorical, see 
Section 10.6.2), prior medication use strata (categorical, see Section 10.6.2) and country (categorical)
included as covariates.
Model Results Presentation
The odds ratio, 95% CI and p-value will be presented for the comparison between treatment arms. It will be 
based on a two-sided hypothesis testing approach of superiority.
Model Checking & Diagnostics
For the primary estimand, the model assumptions will be assessed by performing a logistic regression 
analysis using the primary estimand model specified in the Model Specification section above. No multiple 
imputation will be performed for the missing CAT score data or the missing Trough FEV1 data at week 24. 
The Pearson residuals from this analysis will be plotted.
Sensitivity Analyses
A sensitivity analysis will be performed for the estimand defined in Sections 7.3.1.1 to Section 7.3.1.4, using 
the same model specified for the primary analysis described in the Model Specification section above, but 
excluding the number of exacerbations in the prior year (categorical) from the list of covariates. 
Model Specification: The proportion of participants who experience a CID will be analysed for the FEV1
population using a logistic regression model with treatment as an explanatory variable and baseline Trough 
FEV1 (continuous), baseline CAT score (continuous), prior medication use strata (categorical, see Section 
10.6.2) and country (categorical) included as covariates.
7.3.2.
Clinically Important Deterioration (Analyses of Components)
Trough FEV1 data will be used in the analyses as described in Section 7.3.1.
 
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7.3.2.1.
100 mL Reduction from Baseline in Trough FEV1 at 24 weeks
7.3.2.1.1.
Endpoint / Variables
Proportion of participants who experience a 100 mL reduction from baseline in Trough 
FEV1 at 24 weeks.
7.3.2.1.2.
Summary Measure
The summary measure used for the treatment comparison will be an Odds Ratio (OR) and 
a 95% CI. 
7.3.2.1.3.
Population of Interest
The analysis will be based on the FEV1 population (as defined in Section 4), unless 
otherwise specified.
7.3.2.1.4.
Strategy for Intercurrent (Post-Randomisation) Events
The list of intercurrent events/events leading to missing data that may occur during 
the study and may affect the estimation of the treatment effect are:

Randomised Treatment Discontinuation: participants may discontinue 
randomised COPD maintenance therapy and continue in the study without being
prescribed another COPD maintenance therapy. This is considered an intercurrent 
event.

Randomised Treatment Modification: participants may discontinue randomised 
COPD maintenance therapy and get prescribed another COPD maintenance 
therapy during the study. This is considered an intercurrent event.

Pulmonary Rehabilitation: participants may change pulmonary rehabilitation 
status during the study. E.g., Participant considered to be undergoing pulmonary 
rehabilitation at Visit 1 but stopped during the study and so no longer on 
pulmonary rehabilitation at Visit 2. See Section 10.6.3 for definition of pulmonary 
rehabilitation status at Visit 1 and at Visit 2. This is considered an intercurrent 
event.

Oxygen Therapy: If participants start oxygen therapy during the study and they 
have not had another oxygen therapy prior to the study start, this is considered as 
an intercurrent event. If participants start oxygen therapy during the study but 
they have recorded another oxygen therapy prior to the study start, this is not 
considered as an intercurrent event.

Early Withdrawal from Study: participants may prematurely withdraw from the 
study which results in missing endpoint data.

Week 24 Trough FEV1 Data not Available (other reasons than EW): Trough 
FEV1 data at week 24 (Visit 2) may not be available for other reasons (not EW).
The strategies for handling these events for this endpoint are described in Table 7.
 
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Table 7
Strategies for handling intercurrent events/events leading to 
missing data for the endpoint of proportion of participants who 
experience a 100mL reduction from baseline in Trough FEV1 at week
24
Intercurrent Events
Missing data
Estimand 
Randomised 
Treatment 
Discontinuation
Randomised 
Treatment 
Modification
Pulmonary 
Rehabilitation
Oxygen 
Therapy
Study 
Withdrawal
Week 24 
Trough FEV1 
not Available
Treatment 
Policy x 
Composite
Week 24 Trough 
FEV1 data to be 
used in the 
analysis 
regardless of the 
intercurrent 
event of 
randomised 
treatment 
discontinuation.
(Treatment 
Policy)
Week 24 
Trough FEV1
data to be 
used in the 
analysis 
regardless of 
the 
intercurrent 
event of 
randomised 
treatment 
modification.
(Treatment 
Policy)
Week 24 
Trough FEV1
data to be 
used in the 
analysis 
regardless of 
the 
intercurrent 
event of 
change of 
pulmonary 
rehabilitation 
status during 
the study.
(Treatment 
Policy)
If 
participants 
start oxygen 
therapy 
during the 
study and 
they have 
not had 
another 
oxygen 
therapy 
prior to the 
study start, 
they will be 
considered 
as having 
experienced 
a 100mL
reduction 
from 
baseline in 
Trough 
FEV1.
(Composite)
Missing week 
24 Trough 
FEV1 data will 
be imputed 
based on the 
randomised 
treatment 
arm. Assumes 
MAR. See 
details in 
Section 
10.7.2.
Note: Trough 
FEV1 data 
collected at 
EW visits will 
be included in 
the analysis.
Missing week 
24 Trough 
FEV1 data will 
be imputed 
based on the 
randomised 
treatment arm. 
Assumes MAR.
See details in 
Section 10.7.2.
This primary estimand for the endpoint of proportion of participants who experience a 
100mL reduction from baseline in Trough FEV1 at 24 weeks, will assess the randomised 
treatment effect, handling differently each of the intercurrent events/events leading to 
missing data described in Table 7 above. 
7.3.2.1.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 9: List of Data Displays and
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints /variables defined in Section 7.3.2.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
 
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Statistical Methodology Specification
Endpoint / Variables
Proportion of participants who experience a 100 mL reduction from baseline in Trough FEV1 at 24 weeks.
Model Specification
The endpoint of proportion of participants who experience a 100 mL reduction from baseline in Trough FEV1
at 24 weeks will be analysed for the FEV1 population using a logistic regression model with treatment as an 
explanatory variable and baseline Trough FEV1 (continuous), prior medication use strata (categorical, see 
Section 10.6.2) and country (categorical) included as covariates.
Model Results Presentation
The odds ratio, 95% CI and p-value will be presented for the comparison between treatment arms. It will be 
based on a two-sided hypothesis testing approach of superiority.
Model Checking & Diagnostics
For the primary estimand, the model assumptions will be assessed by performing a logistic regression 
analysis using the primary estimand model specified in the Model Specification section above. No multiple 
imputation will be performed for the missing Trough FEV1 data at week 24. The Pearson residuals from this 
analysis will be plotted.
7.3.2.2.
2 Units Change (Increase) from Baseline in CAT Score at 24 Weeks
7.3.2.2.1.
Endpoint / Variables
Proportion of participants who experience a 2-unit change (increase) from baseline in 
CAT score at 24 weeks.
7.3.2.2.2.
Summary Measure
The summary measure used for the treatment comparison will be an Odds Ratio (OR) and 
a 95% CI. 
7.3.2.2.3.
Population of Interest
The analysis will be based on the FEV1 population (as defined in Section 4), unless 
otherwise specified.
7.3.2.2.4.
Strategy for Intercurrent (Post-Randomisation) Events
The list of intercurrent events/events leading to missing data that may occur during 
the study and may affect the estimation of the treatment effect are:

Randomised Treatment Discontinuation: participants may discontinue randomised 
COPD maintenance therapy and continue in the study without being prescribed 
another COPD maintenance therapy. This is considered an intercurrent event.

Randomised Treatment Modification: participants may discontinue randomised 
COPD maintenance therapy and get prescribed another COPD maintenance therapy 
during the study. This is considered an intercurrent event.
 
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
Pulmonary Rehabilitation: participants may change pulmonary rehabilitation status 
during the study. E.g., Participant considered to be pulmonary rehabilitation at Visit 
1 but stopped during the study and so no longer on pulmonary rehabilitation at Visit 
2. See Section 10.6.3 for definition of pulmonary rehabilitation status at Visit 1 and 
at Visit 2. This is considered an intercurrent event.

Oxygen Therapy: If participants start oxygen therapy during the study and they 
have not had another oxygen therapy prior to the study start, this is considered as an 
intercurrent event. If participants start oxygen therapy during the study but they have 
recorded another oxygen therapy prior to the study start, this is not considered as an 
intercurrent event.

Early Withdrawal from Study: participants may prematurely withdraw from the 
study which results in missing endpoint data. 

Week 24 CAT Score not Available (other reasons than EW): CAT score at week 
24 (Visit 2) may not be available for other reasons (not EW).
The strategies for handling these events for this endpoint are described in Table 8.
Table 8
Strategies for handling intercurrent events/events leading to 
missing data for the endpoint of proportion of participants who 
experience a 2-unit change (increase) from baseline in CAT score at 
week 24
Intercurrent Events
Missing data
Estimand 
Randomised 
Treatment 
Discontinuation
Randomised 
Treatment 
Modification
Pulmonary 
Rehabilitation
Oxygen 
Therapy
Study 
Withdrawal
Week 24 CAT 
not Available
Treatment 
Policy x 
Composite
Week 24 CAT 
score data to be 
used in the 
analysis 
regardless of the 
intercurrent 
event of 
randomised 
treatment 
discontinuation.
(Treatment 
Policy)
Week 24 
CAT score 
data to be 
used in the 
analysis 
regardless of 
the 
intercurrent 
event of 
randomised 
treatment 
modification.
(Treatment 
Policy)
Week 24 CAT
score data to 
be used in the 
analysis 
regardless of 
the 
intercurrent 
event of 
change of 
pulmonary 
rehabilitation 
status during 
the study.
(Treatment 
Policy)
If 
participants 
start oxygen 
therapy 
during the 
study and 
they have 
not had 
another 
oxygen 
therapy 
prior to the 
study start, 
they will be 
considered 
as having 
experienced 
a 2 unit 
increase 
from 
baseline in 
CAT score.
(Composite)
Missing week 
24 CAT score 
data will be 
imputed based 
on the 
randomised 
treatment arm 
characteristics. 
This assumes 
MAR. See 
details in 
Section 10.7.2.
Note: CAT 
score data 
collected at EW 
visits will be 
included in the 
analysis.
Missing week 
24 CAT score 
data will be 
Imputed based 
on the 
randomised 
treatment arm 
characteristics. 
This assumes 
MAR. See 
details in 
Section 
10.7.2.
 
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This primary estimand for the endpoint of proportion of participants who experience a 2-
unit change (increase) from baseline in CAT score at 24 weeks, will assess the 
randomised treatment effect, handling differently each of the intercurrent events/events 
leading to missing data described in Table 8 above. 
7.3.2.2.5.
Statistical Analysis / Methods
Details of the planned displays are provided in Appendix 9: List of Data Displays and
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints /variables defined in Section 7.3.2.2.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
 
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Statistical Methodology Specification
Endpoint / Variables
Proportion of participants who experience a 2-unit change (increase) from baseline in CAT score at 24 
weeks.
Model Specification
The endpoint of proportion of participants who experience a 2-unit change (increase) from baseline in CAT 
score at 24 weeks, will be analysed for the FEV1 population using a logistic regression model with treatment 
as an explanatory variable and baseline CAT score (continuous), prior medication use strata (categorical, 
see Section 10.6.2) and country (categorical) included as covariates.
Model Results Presentation
The odds ratio, 95% CI and p-value will be presented for the comparison between treatment arms. It will be 
based on a two-sided hypothesis testing approach of superiority.
Model Checking & Diagnostics
For the primary estimand, the model assumptions will be assessed by performing a logistic regression 
analysis using the primary estimand model specified in the Model Specification section above. No multiple 
imputation will be performed for the missing CAT score data at week 24. The Pearson residuals from this 
analysis will be plotted.
7.3.3.
Annualised Rate of Moderate/Severe Exacerbations
No formal statistical analysis is planned for the endpoint of the annualised rate of 
moderate/severe exacerbations and thus no estimands are defined for this endpoint. For 
derivation of the annualised rate see Section 10.6.3.
Unless otherwise specified, the annualised rate of on-randomised treatment 
moderate/severe exacerbations as well as the annualised rate of on-study moderate/severe 
exacerbations will be summarised by the randomised treatment group using descriptive 
statistics (n, mean, SD, median, min, max), based on the Intent-to-Treat (ITT) population
(as defined in Section 4). The COPD exacerbation data will be listed.
Details of the planned displays are provided in Appendix 9: List of Data Displays and
will be based on GSK data standards and statistical principles.
7.3.4.
Time to first Moderate/Severe Exacerbation
No formal statistical analysis is planned for the endpoint of the time to first 
moderate/severe exacerbation and thus no estimands are defined for this endpoint. 
Unless otherwise specified, the time to first on-randomised treatment moderate/severe 
exacerbations as well as the time to first on-study moderate/severe exacerbations will be 
summarised by the randomised treatment group, based on the Intent-to-Treat (ITT) 
population (as defined in Section 4), using Kaplan Meir Estimates.
The probability of having a moderate/severe exacerbation with a 95% CI for each 
treatment group and the median time to event will be presented. Kaplan-Meier curves
 
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will also be presented showing the probability of having an event over time for each 
randomised treatment group separately plotted on the same figure. 
Details of the planned displays are provided in Appendix 9: List of Data Displays and
will be based on GSK data standards and statistical principles.
7.3.5.
Healthcare Resource Utilisation (HCRU) 
Analyses relating to HCRU outcomes obtained from the Electronic Health Record (EHR)
database will be described in a supplementary RAP and reported independently of this 
RAP.
As part of this RAP, the number of participants who had unscheduled (routine COPD 
care not included) COPD related healthcare contacts (e.g., deteriorating COPD) and the 
number of contacts by type (e.g., telephone calls, physician office/practice visits etc) will 
be summarised by the randomised treatment group.
All available HCRU data collected during the study will be summarised, including data 
from participants who prematurely withdrew from study. 
7.4.
Exploratory Effectiveness Analyses
7.4.1.
Association of Critical Errors with CAT, Moderate/ Severe 
Exacerbations FEV1 and FVC
No formal statistical analysis is planned for this exploratory endpoint. The association of 
critical errors with CAT score at week 24 and the association of critical errors with FEV1
and FVC at week 24 will be graphically presented. In addition, the association of critical 
errors with change from baseline in CAT score at week 24 and the association of critical 
errors with change from baseline in FEV1 and change from baseline in FVC at week 24 
will be graphically presented. This will be based on participants in the CE population 
whose COPD maintenance treatment is administered via inhalers all of which have an 
inhaler error checklist available in the study.
The association of critical errors with CAT response (i.e., responder vs non-responder) at 
week 24 will be summarised in a frequency table. In addition, the association of critical 
errors with on-randomised treatment moderate/severe exacerbations as well as the 
association of critical errors with on-study moderate/severe exacerbations will be 
summarised in a frequency table. See also Section 10.6.3.
The CAT score data, spirometry data (i.e., FEV1 and FVC) and critical error data 
collected at week 24 (Visit 2) will be used for this exploratory endpoint as described in 
Section 7.1.1, Section 7.2.1 and Section 7.2.3, respectively.
Details of the planned displays are provided in Appendix 9: List of Data Displays and
will be based on GSK data standards and statistical principles.
 
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7.4.2.
Patient Study Experience
No formal statistical analysis is planned for the endpoint of Participant Treatment and 
Study Satisfaction Questionnaire at 24 weeks/ EW Visit.
The participant responses to the Treatment and Study Satisfaction Questionnaire at 24 
weeks/ EW Visit will be summarised by the randomised treatment group and listed, based 
on the Intent-to-Treat (ITT) population (as defined in Section 4), unless otherwise 
specified. Frequency of the response categories (“Strongly Agree” to “Strongly 
Disagree”) will be presented for each question by randomised treatment group. See also 
Section 10.6.3.
Details of the planned displays are provided in Appendix 9: List of Data Displays and
will be based on GSK data standards and statistical principles.
7.4.3.
Health Related Quality of Life Questionnaire (HRQoL)
No formal statistical analysis is planned for the endpoint of Health Related Quality of 
Life Questionnaire (HRQoL).
The HRQoL data from each visit (Visit 1 and Visit 2) will be summarised by the 
randomised treatment group and listed, based on the Intent-to-Treat (ITT) population, 
unless otherwise specified. For the numerical questions of the questionnaire (Item 2, 3, 
and 4, see Section 10.6.3) data will be summarised using descriptive statistics (n, mean, 
SD, median, min, max). For Item 1 of the questionnaire, the frequency of the categories 
selected at each visit (Visit 1 and Visit 2) will be summarised. 
HRQoL data collected at an EW visit will also be included in the summaries and listings. 
Details of the planned displays are provided in Appendix 9: List of Data Displays and
will be based on GSK data standards and statistical principles.
 
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8.
SAFETY ANALYSES
The safety analyses will be based on the Intent-to-Treat (ITT) population (as defined in 
Section 4), unless otherwise specified.
8.1.
Adverse Events Analyses
AEs not related to either study treatment or withdrawal from study treatment are not 
recorded, unless classified as serious adverse events.
Adverse events analyses including the descriptive statistics of Serious Adverse Events 
(SAEs), study treatment related AEs and AEs that lead to withdrawal from study 
treatment will be based on GSK Core Data Standards. The details of the planned displays 
are provided in Appendix 9: List of Data Displays.
Serious adverse events (SAEs) associated with study participation or related to any GSK 
product, will be collected from the point of informed consent until randomisation. All 
SAEs will be collected from randomisation until completion of the Visit 2/ EW Visit, at 
the time points specified in the Schedule of Activities (SoA) in Section 10.2. Treatment 
related AEs and AEs leading to study treatment withdrawal, will be collected from 
randomisation until completion of Visit 2/EW Visit, at the time points specified in the 
SoA in Section 10.2. All SAEs, and relevant AEs will be summarised and displayed by 
randomised treatment group. The onset dates of the SAEs/relevant AEs relative to the 
randomised treatment start and stop dates will be used to determine in which period an 
AE occurs.
The AE/SAE text recorded in the eCRF will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA), and will be reported using the primary System Organ 
Class (SOC) and Preferred Term (PT). The number of participants with one or more 
events of any type will be calculated. Results will be displayed in the order of decreasing 
frequency, both across SOC and within SOC. A SOC will not be included if no 
SAEs/AEs in that SOC are reported. If the total incidence for any two or more AEs is 
equal, the events will be presented in alphabetical order. 
Adverse events and Serious Adverse Events will also be listed, with SOC, event (PT), 
treatment group, number of participants with the event, and specific participant numbers. 
Demographic details (e.g., age, sex and race), as well as details of the individual AEs, 
will also be included in these listings. Listings will be sorted within participant by the 
date of onset of the AE.
Note that moderate and severe COPD exacerbation events will be recorded on the 
Exacerbation page in the participant’s eCRF. Because exacerbations are typically 
associated with the disease under study, an exacerbation will not be reported according to 
the standard process for expedited reporting of SAEs to GSK unless the event meets any 
of the criteria defined in Section 9.5.7 of the Protocol.
Details of the SAE/AE summaries and listings are presented in Appendix 9: List of Data
Displays.
 
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8.2.
Adverse Events of Special Interest Analyses
A comprehensive list of MedDRA terms based on clinical review will be used to identify 
each type of event. Changes to the MedDRA dictionary may occur between the start of 
the study and the time of reporting. Furthermore, emerging data from on-going studies 
may highlight additional adverse events of special interest. Therefore, the list of terms to 
be used for each event of interest and the specific events of interest will be based on the 
safety review team (SRT) agreements in place at the time of reporting. 
Serious Adverse Events of Special Interest (SAESI) will be summarised by the 
randomised treatment arms and by the class of medication taken at the time of the event. 
SAESI will also be listed. The details of the planned displays are provided in Appendix 9:
List of Data Displays.
Table in Section 10.6.4 presents the groups of Serious Adverse Events of Special Interest 
(SAESI). Groups which are not standardized MedDRA queries (SMQs) comprise a 
selection of PTs defined by GSK. The complete list, including the PTs that contribute to 
each of the groups, will be provided by GCSP using the MedDRA version current at the 
time of reporting. This list will be finalized prior to unblinding the database.
8.3.
Other Safety Analyses
Any pregnancies reported during the study will be summarised in case narratives. Any 
pregnancy complication or elective termination of a pregnancy for medical reasons 
should be recorded as an AE or SAE and included in summaries and listings of 
AEs/SAEs.
 
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9.
REFERENCES
GlaxoSmithKline Document Number 2017N321744_00, Study ID 206854. The Clinical 
Effectiveness of Fluticasone Furoate/Umeclidinium Bromide/Vilanterol in a Single 
Inhaler (TRELEGYTM ELLIPTATM) when Compared with Non-ELLIPTA Multiple 
Inhaler Triple Therapies in COPD Patients within a Usual Care Setting. Effective Date 
06-NOV-2017. 
GlaxoSmithKline Document Number 2017N321744_01 (Amendment 1), Study ID 
206854. The Clinical Effectiveness of Fluticasone Furoate/Umeclidinium 
Bromide/Vilanterol in a Single Inhaler (TRELEGYTM ELLIPTATM) when Compared 
with Non-ELLIPTA Multiple Inhaler Triple Therapies in COPD Patients within a Usual 
Care Setting. Effective Date 15-FEB-2018. 
GlaxoSmithKline Document Number 2017N321744_02 (Amendment 2), Study ID 
206854. The Clinical Effectiveness of Fluticasone Furoate/Umeclidinium 
Bromide/Vilanterol in a Single Inhaler (TRELEGYTM ELLIPTATM) when Compared 
with Non-ELLIPTA Multiple Inhaler Triple Therapies in COPD Patients within a Usual 
Care Setting. Effective Date 28-SEP-2018. 
Global Strategy for the Diagnosis, Management and Prevention of COPD, Global 
Initiative for Chronic Obstructive Lung Disease (GOLD) 2017. Available from: 
http://goldcopd.org.
 
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10.
APPENDICES
10.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
10.1.1.
Exclusions from Per Protocol Population
A per protocol (PP) population is not defined for this study therefore there are no criteria 
leading to exclusion from a per protocol population.  All deviations will be managed 
during the study according to the PDMP.
 
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10.2.
Appendix 2: Schedule of Activities
10.2.1.
Protocol Defined Schedule of Events
PROCEDURE *
TREATMENT PERIOD
NOTES
VISIT 0
Consenting
VISIT 1
Screening
& 
Randomisation
Usual care / 
contact for 
COPD related 
event or serious 
adverse event 
Early
Withdrawal
(EW) Visit
VISIT 2
The following sequence of events must be followed 
1.ICF, 2. Screening, 3. Randomisation. All three may 
occur on the same day with no more than 6 weeks 
between ICF and screening and no more than 6 weeks 
between screening and randomisation. 
Study week
1
After week 1 and 
before Visit 2
After week 1 
and before 
Visit 2
24 (21 
days)
EW Visit should only be conducted if the participant 
discontinues from participating in the study. Participants 
withdrawing from study treatment but remaining in the 
study should continue to Visit 2.
Informed consent 
form (ICF)
X
ICF must be signed before any study procedures/ 
assessments 
Inclusion and 
exclusion criteria
X
Recheck clinical status before randomisation and/or 1st 
prescription for study treatment
Demography
X
Height and weight
X
Medical history: past 
and current medical 
conditions 
X
This includes family history of premature CV disease.
 
 
 
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PROCEDURE *
TREATMENT PERIOD
NOTES
VISIT 0
Consenting
VISIT 1
Screening
& 
Randomisation
Usual care / 
contact for 
COPD related 
event or serious 
adverse event 
Early
Withdrawal
(EW) Visit
VISIT 2
The following sequence of events must be followed 
1.ICF, 2. Screening, 3. Randomisation. All three may 
occur on the same day with no more than 6 weeks 
between ICF and screening and no more than 6 weeks 
between screening and randomisation. 
Study week
1
After week 1 and 
before Visit 2
After week 1 
and before 
Visit 2
24 (21 
days)
EW Visit should only be conducted if the participant 
discontinues from participating in the study. Participants 
withdrawing from study treatment but remaining in the 
study should continue to Visit 2.
Historical eosinophil 
count. whole blood 
count, % eosinophils
X
X
Most recent historical eosinophil measure taken within
the previous 36 months prior to patients consenting
visit. (Visit 1 or Visit 0 whichever is applicable)

An absolute number of eosinophils and the % of 
eosinophils out of the total WBC

White Blood Cell count (WBC)
Chronic Obstructive 
Pulmonary Disease 
(COPD) and 
Exacerbation history 
X
The number of moderate/ severe exacerbations in the 12 
months prior to V1 will be collected.
Randomisation
X
COPD assessment 
test (CAT)
X
X
X
CAT must be completed prior to randomisation and 
prior to any other study procedures. Participants who 
have changed or discontinued treatment will remain in 
the study and complete CAT assessment at the Visit 
2/EW Visit.
COPD Exacerbation 
assessment
X
X
X
Moderate and severe exacerbations that occur between 
V1 and V2 will be recorded. 
 
 
 
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PROCEDURE *
TREATMENT PERIOD
NOTES
VISIT 0
Consenting
VISIT 1
Screening
& 
Randomisation
Usual care / 
contact for 
COPD related 
event or serious 
adverse event 
Early
Withdrawal
(EW) Visit
VISIT 2
The following sequence of events must be followed 
1.ICF, 2. Screening, 3. Randomisation. All three may 
occur on the same day with no more than 6 weeks 
between ICF and screening and no more than 6 weeks 
between screening and randomisation. 
Study week
1
After week 1 and 
before Visit 2
After week 1 
and before 
Visit 2
24 (21 
days)
EW Visit should only be conducted if the participant 
discontinues from participating in the study. Participants 
withdrawing from study treatment but remaining in the 
study should continue to Visit 2.
COPD related 
healthcare resource 
use assessment
X
X
X
Details 
of 
primary 
healthcare 
contacts, 
known 
secondary care contacts and all COPD related 
medication use that occurs between V1 and V2 will be 
recorded in the eCRF.
Assessment of 
inhaler errors 
(subgroup only)
X
X
Spirometry for lung 
function (subgroup 
only)
X
X
X
Spirometry should be performed before the day’s dose 
of usual care or study medication. 
The assessment is pre-and post-salbutamol at Visit 1 
and pre-salbutamol at Visit 2 /EW Visit. It should be 
started between approximately 6:00 am and 12:00 pm
The most recent use of COPD maintenance inhaler/ 
study treatment should be noted. 
Participant treatment 
& study satisfaction 
questionnaire
X
X
 
 
 
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PROCEDURE *
TREATMENT PERIOD
NOTES
VISIT 0
Consenting
VISIT 1
Screening
& 
Randomisation
Usual care / 
contact for 
COPD related 
event or serious 
adverse event 
Early
Withdrawal
(EW) Visit
VISIT 2
The following sequence of events must be followed 
1.ICF, 2. Screening, 3. Randomisation. All three may 
occur on the same day with no more than 6 weeks 
between ICF and screening and no more than 6 weeks 
between screening and randomisation. 
Study week
1
After week 1 and 
before Visit 2
After week 1 
and before 
Visit 2
24 (21 
days)
EW Visit should only be conducted if the participant 
discontinues from participating in the study. Participants 
withdrawing from study treatment but remaining in the 
study should continue to Visit 2.
Health Related 
Quality of Life 
Questionnaire 
(HRQoL)
X
X
X
Review of study 
treatment related 
Adverse Events (AE) 
X
X
X
X
Clinical judgment should be used to determine whether 
there is a relationship between study treatment and each 
occurrence of each AE/SAE.
Study treatment related adverse events must be recorded 
from V1. 
Where a causality relationship is determined, this must 
be recorded as a study treatment related AE.
AEs not related to either study treatment or 
withdrawal from study treatment are not recorded, 
unless classified as serious adverse events. 
Refer to Protocol Amendment 2, Appendix 3 for 
definitions of AEs, SAEs and guidelines on assessment 
of causality by investigator
 
 
 
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PROCEDURE *
TREATMENT PERIOD
NOTES
VISIT 0
Consenting
VISIT 1
Screening
& 
Randomisation
Usual care / 
contact for 
COPD related 
event or serious 
adverse event 
Early
Withdrawal
(EW) Visit
VISIT 2
The following sequence of events must be followed 
1.ICF, 2. Screening, 3. Randomisation. All three may 
occur on the same day with no more than 6 weeks 
between ICF and screening and no more than 6 weeks 
between screening and randomisation. 
Study week
1
After week 1 and 
before Visit 2
After week 1 
and before 
Visit 2
24 (21 
days)
EW Visit should only be conducted if the participant 
discontinues from participating in the study. Participants 
withdrawing from study treatment but remaining in the 
study should continue to Visit 2.
Review of Adverse 
Events (AE) that 
lead to withdrawal 
from study treatment
X
X
X
X
All AEs that lead to withdrawal from study treatment, 
whether judged related to study treatment or not, should 
be recorded.
The participant should be encouraged to remain in the 
study for collection of effectiveness and safety data.
All AEs that lead to withdrawal from the study whilst 
the participant is on study treatment, whether judged 
related to study treatment or not, should be recorded.
 
 
 
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PROCEDURE *
TREATMENT PERIOD
NOTES
VISIT 0
Consenting
VISIT 1
Screening
& 
Randomisation
Usual care / 
contact for 
COPD related 
event or serious 
adverse event 
Early
Withdrawal
(EW) Visit
VISIT 2
The following sequence of events must be followed 
1.ICF, 2. Screening, 3. Randomisation. All three may 
occur on the same day with no more than 6 weeks 
between ICF and screening and no more than 6 weeks 
between screening and randomisation. 
Study week
1
After week 1 and 
before Visit 2
After week 1 
and before 
Visit 2
24 (21 
days)
EW Visit should only be conducted if the participant 
discontinues from participating in the study. Participants 
withdrawing from study treatment but remaining in the 
study should continue to Visit 2.
SAE review
X
X
X
X
X
SAEs that are related to study participation or to GSK 
products are collected from the time of consent to 
randomisation. All other SAEs are recorded from the 
time of randomisation.
Clinical judgment should be used to determine the 
relationship 
between 
study 
treatment 
and 
each 
occurrence of each AE/SAE.
Where a causality relationship is determined, this must 
be recorded as a study treatment related SAE.
Refer to Protocol Amendment 2, Appendix 3 for 
definitions of AEs, SAEs and guidelines on assessment 
of causality by investigator.
Details of 
randomised study 
treatment and any 
study treatment 
changes
X
X
X
X
Reason for change in treatment, details and date of new 
treatment should be recorded.
 
 
 
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PROCEDURE *
TREATMENT PERIOD
NOTES
VISIT 0
Consenting
VISIT 1
Screening
& 
Randomisation
Usual care / 
contact for 
COPD related 
event or serious 
adverse event 
Early
Withdrawal
(EW) Visit
VISIT 2
The following sequence of events must be followed 
1.ICF, 2. Screening, 3. Randomisation. All three may 
occur on the same day with no more than 6 weeks 
between ICF and screening and no more than 6 weeks 
between screening and randomisation. 
Study week
1
After week 1 and 
before Visit 2
After week 1 
and before 
Visit 2
24 (21 
days)
EW Visit should only be conducted if the participant 
discontinues from participating in the study. Participants 
withdrawing from study treatment but remaining in the 
study should continue to Visit 2.
Details of medicine 
and therapy taken for 
respiratory and other 
selected conditions 
X
X
X
X
* The timing and number of planned study assessments, including assessments may be altered during the study based on newly available 
data.
 
 
 
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10.3.
Appendix 3: Assessment Windows
Clinic visits/phone calls are scheduled to take place as specified in the protocol and the 
Schedule of Activities table in Appendix 2: Schedule of Activities. All participants
should remain in the study and complete the week 24 visit. If this is not possible then an 
early withdrawal visit should be completed.
If a participant withdraws early from the study and provides early withdrawal 
assessments (CAT, FEV1, Inhaler errors), then consideration is given as to how/if these 
data are used. This is defined under the estimand framework in the appropriate analysis 
methodology sections (Section 7).
 
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10.4.
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events
10.4.1.
Study Phases
10.4.1.1.
Study Phases for Assessments
Assessments will be classified according to the time of occurrence relative to the study 
treatment (i.e., randomised treatment) start/stop date.
Study Phase
Definition
Pre-randomised 
Treatment 
Assessment < Study Treatment Start Date
On-randomised 
Treatment
Study Treatment Start Date ≤ Assessment ≤ Study Treatment Stop Date + 1
Post-randomised 
Treatment 
(Assessment > Study Treatment Stop Date + 1) and (Assessment ≤ Study Conclusion 
Date)
Note: Participants can prematurely discontinue from the randomised treatment or 
modify their randomised treatment at any time during the study, at the Investigator’s 
discretion. Any assessment performed after the randomised treatment stop day + 1 and 
before the study conclusion date will be considered as “Post-randomised Treatment”. 
Post-Study
Assessment > Study Conclusion Date 
Note: this post-study data will not be included in any summaries or analyses (but will be 
listed).
10.4.1.2.
Study Phases for Concomitant Medication
Any medication or vaccine for the treatment of a respiratory condition that the participant 
receives at the time of consent or receives during the study are collected. 
Classification of the prior/concomitant medication is described in Table 9.
Table 9
Classification of prior/concomitant medication
Pre-randomised 
Treatment
On-randomised 
treatment
Post randomised 
treatment
(a)
xx
Randomised Treatment Start Date
Randomised Treatment Stop Date
(b)
x
x
(c)
x

x
(d)
x-x
(e)
x
x
(f)
x--x
(g)
?x
(h)*
?
x
(i)*
?

x
(j)**
x

?
(k)**
x
?
(l)
x-?
(m)***
?

?
 
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x = start/stop date of prior/concomitant medication
? = missing start/stop date of prior/concomitant medication
* If a medication is stopped on-randomised treatment or post-randomised treatment and no start date is recorded it will 
be assumed that the medication was ongoing from the pre-randomised treatment phase
** If a medication is started pre-randomised treatment or on-randomised treatment and no stop date is recorded then 
usage will be assumed to be ongoing for the remainder of the study
*** If a medication has no start or stop date it will be assumed that the medication was ongoing from the pre-
randomised treatment phase to the post-randomised treatment phase
Medications which start/stop on the same day as the randomised treatment start or 
randomised treatment stop date respectively, will be classed as on-randomised treatment.
Partial dates for concomitant medications (if present) will be imputed as described in 
Section 10.7.2.1 prior to the classification of the medications as described in Table 9.
Medications that start after the date of study conclusion (i.e., Concomitant Medication 
Start Date > Study Conclusion Date), will be classified as “Post-Study”. This post-study 
data will not be included in any summaries or analyses but will be listed.
Medications will be grouped based on the Respiratory Medication Class (RMC) (see 
Section 10.6.2) and sorted in descending order of total incidence for Respiratory Class 
and in descending order of total incidence for the ingredient within each Respiratory 
Class. If the total incidence for any two or more ingredients is equal, the ingredients will
be presented in alphabetical order.
10.4.1.3.
Study Phases for COPD Exacerbations
COPD exacerbations will be classified according to the time of occurrence relative to the 
study treatment (i.e., randomised treatment) start/stop date.
Study Phase
Definition
Pre-randomised 
Treatment 
COPD Exacerbation < Study Treatment Start Date
On-randomised 
Treatment
Study Treatment Start Date ≤ COPD Exacerbation ≤ Study Treatment Stop Date + 1
Note: If Prior Medication Stop Date = Randomised Treatment Start Date (date overlap) 
and COPD Exacerbation starts on that day, the COPD exacerbation will be considered 
as “On-randomised Treatment”.
Post-randomised 
Treatment 
(COPD Exacerbation > Study Treatment Stop Date + 1) and (COPD Exacerbation ≤ 
Study Conclusion Date)
Note: Participants can prematurely discontinue from the randomised treatment or 
modify their randomised treatment at any time during the study, at the Investigator’s 
discretion. Any exacerbation occurring after the randomised treatment stop day + 1 and 
prior to the study conclusion date will be considered as “Post-randomised Treatment”. 
On-Study
Randomisation Date ≤ COPD Exacerbation ≤ Latest of (Study Conclusion Date or 
Study Withdrawal Date)
Post-Study
COPD Exacerbation > Study Conclusion Date 
 
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Study Phase
Definition
Note: this post-study data will not be included in any summaries or analyses (but will be 
listed).
10.4.2.
Treatment Emergent Flag for Adverse Events/Serious Adverse 
Events
Adverse Events/Serious Adverse Events will be classified according to the time of 
occurrence relative to the study treatment (i.e., randomised treatment) start/stop date.
Study Phase
Definition
Pre-randomised 
Treatment
AE/SAE Start Date < Study Treatment Start Date
On-randomised 
Treatment 
Study Treatment Start Date ≤ AE/SAE Start Date ≤ Study Treatment Stop Date + 1
Note: If Prior Medication Stop Date = Randomised Treatment Start Date (date overlap) 
and AE/SAE starts on that day, the AE/SAE will be considered as “On-randomised 
Treatment”.
Post-randomised 
Treatment
AE/SAE Start Date > Study Treatment Stop Date + 1
Note: Participants can prematurely discontinue from the randomised treatment or 
modify their randomised treatment at any time during the study, at the Investigator’s 
discretion. Any AE/ SAEs reported after the randomised treatment stop day +1 and 
prior to the study conclusion date will be considered as “Post-randomised Treatment”.
On-Study
Randomisation Date ≤ AE/SAE Start Date ≤ Latest of (Study Conclusion Date or Study 
Withdrawal Date)
Onset Time Since 
Study Treatment 
Start Date (days)
Time since first dose will be derived as followed:

If Study Treatment Start Date or AE/SAE Start Date is missing => missing

If Study Treatment Start date > AE/SAE Start Date => AE/SAE Start Date – Study 
Treatment Start Date

If Study Treatment Start Date ≤ AE/SAE Start Date => AE/SAE Start Date – Study 
Treatment Start Date + 1
Duration (Days) 
AE/SAE Resolution Date – AE/SAE Onset Date + 1
Drug-related
If relationship is marked ‘YES’.
 
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10.5.
Appendix 5: Data Display Standards & Handling 
Conventions
10.5.1.
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
: uk1salx00175
HARP Compound
: /arenv/arprod/gsk2834425/206854
Analysis Datasets 

Analysis datasets will be created according to Legacy GSK Analysis & Reporting (A&R) dataset 
standards. 
Generation of RTF Files

Rich Text Format (RTF) files will be generated for all Table displays for this reporting effort.
10.5.2.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):
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 
Note: All data displays (Tables, Figures & Listings) produced as part of the Statistical Analysis Complete 
(SAC), will use the term “Subject” which reflects GSK Data Display Standards terminology.
Formats

All data will be reported according to the treatment the participant was randomised to unless otherwise 
stated.

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected, unless otherwise stated.

Numeric data will be reported at 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’s.
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.

Actual time will be used for calculation of times to event and Kaplan-Meier plots.

Reporting for Data Listings: 

Planned and actual time relative to study start date will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).
Unscheduled Visits

Unscheduled visits will not be included in summary tables and/or figures.
 
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
All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.
 
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10.6.
Appendix 6: Derived and Transformed Data
10.6.1.
General
Study Day

Calculated as the number of days from Treatment Start Date (i.e., Randomised Treatment Start Date):

Reference Date = Missing                      → Study Day = Missing 

Reference Date < Treatment Start Date → Study Day = Reference Date –Treatment Start Date

Reference Data ≥ Treatment Start Date → Study Day = Reference Date – (Treatment Start Date) 
+ 1    
Randomised Treatment Start/Stop Date

Randomised treatment start date will be defined as the earliest treatment start date and randomised 
treatment stop date will be defined as the latest treatment stop date as captured in the “Study 
Treatment” (CONMEDS_CR_1) eCRF form.
Missing or partial randomised treatment stop dates will be handled as described in Section 10.7.2.1.
10.6.2.
Study Population
Disposition
Time to Study Withdrawal/ Treatment Discontinuation
For Kaplan-Meier plots of study withdrawal over time and discontinuation from study treatment over time, 
censoring will be performed as follows:

For study withdrawal, participants are represented from the date of start of the randomised treatment
to the date of early withdrawal from the study (or date of death). Participants that completed the study 
are censored at the earliest of the date of completion and Day 169.

For discontinuation from study treatment, participants are represented from the date of start of the 
study randomised treatment to the date of discontinuation from study randomised treatment (or date of 
death). Participants that complete study randomised treatment are censored at the earliest of their 
study randomised treatment stop date and Day 169.
Demographics
Age
In accordance with GSK policy, only year of birth is collected in the eCRF. In order to estimate 
participant’s age, a complete birthdate will be estimated by using the year recorded in the eCRF and 
assigning month and day values of ’30JUN.’
Age, in whole years, will be calculated based on the Screening Visit date.
Birth date will be presented in listings as ‘YYYY.’
Completely missing dates of birth will remain as missing with no imputation applied. Consequently, the 
age of the participant will not be calculated and will remain missing.
Age Categories 
Age categories are based on age at Screening and are defined as:
 
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Demographics

≤64 years

65-74 years

75-84 years

≥85 years
Body Mass Index (BMI)
BMI will be calculated in the eCRF as Weight (kg) / Height (m)2.
Race
High-level Food and Drug Administration (FDA) race categories and designated Asian subcategories are:

American Indian or Alaska Native

Asian
o Central/South Asian Heritage
o Japanese Heritage/East Asian Heritage/South East Asian Heritage
o Mixed Asian Heritage (only required if data exists)

Black or African American

Native Hawaiian or other Pacific Islander

White
These categories and subcategories will be summarised along with all combinations of high-level 
categories which exist in the data. All five of the high-level race categories and the Asian subcategories 
must appear on the display even if there are no participants in a particular category, but combinations that 
do not exist in the data do not need to be represented. Combinations will be represented as the 
concatenation of the high-level category terms, e.g., “White & Asian”. The designated Asian subcategories 
will not be summarised as combinations with other categories.
In addition, the standard race categories collected per IDSL will be summarized along with categories for 
mixed race. The categories are: 

American Indian or Alaska Native

Asian - Central/South Asian Heritage

Asian – East Asian Heritage

Asian – Japanese Heritage

Asian – South East Asian Heritage

Black/African American

Native Hawaiian or other Pacific Islander

White – Arabic/North African Heritage

White – White/Caucasian/European Heritage

Mixed Asian Race

Mixed White Race

Multiple
“Mixed Asian Race” is only used if more than one Asian category is selected, but no non-Asian races. 
Similarly, “Mixed White Race” is only used if both of the White categories are selected, and no non-White 
races. If multiple races of different types are selected, then the overall “Multiple” category is used.
A participant will only be represented in a single category. A participant who selects a combination of races 
will be counted as “Mixed Asian Race,” “Mixed White Race,” or “Multiple,” but not in each of the constituent 
terms. Therefore, the counts will add up to the total number of participants with a response.
 
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Demographics
Age Ranges
For the Summary of Age Ranges, the following ranges will be presented, as per the European Medicines 
Agency (EMA) clinical trial results disclosure requirements:

Adults (18-64)

≥65-84 years

≥85 years
Extent of Exposure and Post-randomised Treatment Study Duration

Number of days of exposure to randomised treatment will be calculated based on the formula:  
[ Randomised Treatment Stop Date – Randomised Treatment Start Date ] + 1
Participants who were randomised but did not report a randomised treatment start date will be 
categorised as having zero days of exposure. 

Duration of post-randomised treatment time spent in the study will be calculated as:
[ Study Conclusion Date – Randomised Treatment Stop Date ]

Duration of total time spent in the study will be calculated as:
[ Study Conclusion Date – Randomisation Date ] + 1
The following exposure categories will also be presented: 
≥ 1 day, ≥ 4 weeks, ≥ 8 weeks, ≥ 12 weeks, ≥16 weeks, ≥ 20 weeks, ≥ 24 weeks, 23-25 weeks
Medical Conditions and Concomitant Medications
COPD Exacerbation History
COPD exacerbations occurring in the past 12 months prior to Screening reported on the Exacerbation 
History eCRF form will be categorized as 0, 1, ≥2.
The number of COPD exacerbations reported in the past 12 months will be summarised according to the 
categories: 1) moderate COPD exacerbations, 2) severe COPD exacerbations, and 3) moderate/severe 
COPD exacerbations.
Moderate COPD exacerbations: defined as exacerbations that required treatment with oral/systemic 
corticosteroids and/or antibiotics (not involving hospitalization).
Severe COPD exacerbations: defined as exacerbations that required in-patient hospitalization.
Moderate/Severe COPD exacerbations: defined as the total number of moderate and severe COPD 
exacerbations.
COPD Concomitant Medications

COPD concomitant medications will be grouped into the following Respiratory Medication Classes 
(RMC) based on pre-defined code lists derived from Anatomical Therapeutic Chemical (ATC) 
 
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Medical Conditions and Concomitant Medications
classifications:
o
Androgens and estrogens
o
Anti-IgE, Anti-IL5
o
Anticholinergic
o
Antiinfectives (antibiotics, antiseptics)
o
Antimycotics
o
Antivirals
o
Beta-2 agonists
o
Corticosteroid – inhaled
o
Corticosteroid – depot
o
Corticosteroid – systemic oral parenteral and intra-articular
o
Corticosteroid – other
o
Leukotriene receptor antagonist
o
Long-acting anticholinergic
o
Long-acting beta-2 agonist – Group 2 (once per day)
o
Long-acting beta-2 agonist – Group 3 (twice per day)
o
Mucolytics
o
Nedocromil or cromolyn sodium
o
Oxygen
o
PDE4 inhibitors
o
Short-acting anticholinergic
o
Short-acting beta-2 agonist
o
Xanthine
o
Other COPD medication
Actual Prior Medication Use Strata
The actual prior medication use strata will be defined from the CONMEDS form of the CRF using the COPD 
maintenance medications taken prior to Randomisation.
Historical Eosinophils Data
Historical Haematology data of White Blood Cell (WBC) and Eosinophils data will be collected at Visit 2. 
This data will be summarised by the randomised treatment groups (using descriptive statistics) and will be 
listed. Eosinophils data will also be categorised as described below and summarised by the randomised 
treatment groups:

< 0.15 10^9/L

≥ 0.15 10^9/L
Screening Lung Function
Reversibility
A participant’s status as reversible to salbutamol is calculated at Screening and is based on the difference 
(absolute change and % change) between a participant’s pre-salbutamol assessment of FEV1 and their 
post-salbutamol assessment of FEV1 and is defined as follows:

Reversible, if the difference in FEV1 is ≥ 12% and ≥ 200 mL, or

Non-reversible, if the difference in FEV1 is < 200 mL or, the difference is ≥ 200 mL and is < 12 % 
of the pre-salbutamol FEV1
If a participant was not able to provide both a pre-salbutamol and post-salbutamol assessment, then the 
 
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Screening Lung Function
reversibility status will be missing.
GOLD Grade 1-4 
Participants will be classified into Global Initiative on Obstructive Lung Disease (GOLD) Grades 1-4 using 
the post-salbutamol percent predicted FEV1 assessment at Screening [GOLD, 2017]:

GOLD Grade 1 (Mild): percent predicted FEV1 80%

GOLD Grade 2 (Moderate): 50% percent predicted FEV1 < 80%

GOLD Grade 3 (Severe): 30% percent predicted FEV1 < 50%

GOLD Grade 4 (Very Severe): percent predicted FEV1 < 30%
If a participant was not able to provide post-salbutamol assessment, then the GOLD Grade will be missing.
FEV1/FVC ratio at Screening
Using the lung function data from the PFT dataset, the following additional calculations will be performed: 

Pre-bronchodilator FEV1/FVC ratio will be calculated as: 
[ Pre-bronchodilator FEV1/FVC (%) ] / 100

Post-bronchodilator FEV1/FVC ratio will be calculated as: 
[ Post-bronchodilator FEV1 / Post-bronchodilator FVC ]
Pre and post-bronchodilator FEV1/FVC ratio at Screening will be summarised. 
Cardiovascular Risk Factors
Participants with at least one of the following current or past medical conditions at Screening will be classed 
as having a cardiovascular (CV) risk factor.

Coronary artery disease

Myocardial infarction

Arrhythmia

Congestive heart failure

Hypertension

Cerebrovascular accident

Diabetes mellitus

Hypercholesterolemia
The number of CV risk factors at Screening (0, 1, or ≥ 2) will be derived.
 
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10.6.3.
Effectiveness
Intercurrent Events
Pulmonary Rehabilitation Status at Visit 1 and Visit 2
For the Pulmonary Rehabilitation, the following information is collected in the eCRF at Visit 1 and Visit 2:
V1, Q1: Is the subject currently on a Pulmonary rehabilitation program?
V1, Q2: Has the subject started a Pulmonary rehabilitation program within the last 8 weeks prior to Visit 1?
V1, Q3: Has the subject stopped a Pulmonary rehabilitation program within the last 8 weeks prior to Visit
1?
V2, Q1: Is the subject currently on a Pulmonary rehabilitation program?
V2, Q2: Has the subject started a Pulmonary rehabilitation program since Visit 1?
V2, Q3: Has the subject stopped a Pulmonary rehabilitation program since Visit 1?
The Pulmonary Rehabilitation status for a participant at Visit 1 or Visit 2 can be defined as: a) “On 
Pulmonary Rehabilitation” or b) “Not on Pulmonary Rehabilitation”.

Visit 1: In order for a participant to be considered as “Not on Pulmonary Rehabilitation” at Visit 1, the 
participant should not be currently on a Pulmonary Rehabilitation program at Visit 1 (i.e., All Visit 1 
questions should be answered with a “No”).

Visit 2: In order for a participant to be considered as “Not on Pulmonary Rehabilitation” at Visit 2, the 
participant should not be currently on a Pulmonary Rehabilitation program at Visit 2 (i.e., All Visit 2 
questions should be answered with a “No” and also not considered on Pulmonary Rehabilitation at 
Visit 1).
Primary Endpoint
COPD Assessment Test (CAT)


For the Effectiveness analysis of CAT score:
If the language of the CAT assessed at week 24 (Visit 2) is different from the language used at baseline 
(Visit 1), the CAT score at the week 24 (Visit 2) will be set to missing.
With regards to the primary endpoint analyses, a participant will be considered as a responder according 
to the CAT score if their week 24 (Visit 2) CAT score has decreased at least 2 units from the baseline 
CAT score. A participant will be considered as a non-responder if their week 24 (Visit 2) CAT score has 
 
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decreased by less than 2 units, has not changed, or has increased compared to the baseline CAT score. 
Baseline CAT score is as defined in Section 5.2.

Ways of handling missing week 24 CAT score data are included in Section 7.1.1 as part of the 
estimands defined for this endpoint.
Secondary Endpoint
Multiple Lung Function Tests

If there are multiple spirometry tests recorded for a participant at Visit 1, the data from the latest test that 
is on or prior to the treatment start date will be considered in the planned data summaries and statistical 
analyses. 

If there are multiple spirometry tests recorded for a participant at Visit 2, the data from the latest test 
prior to study conclusion date will be considered for the planned data summaries and statistical 
analyses. 
All lung function test data will be listed.
Trough FEV1
For the spirometry assessment at Visit 1 and Visit 2, the following information is collected in the PFT 
dataset:
Q1: Please select the class of COPD maintenance treatment (Options: 9=ICS+LABA+LAMA; 
10=LABA+LAMA; 12=ICS+LABA; 13=LABA; 14=LAMA)
Q2: (Goes with Q1) How long since the patient took their last dose of COPD maintenance treatment? 
(Options: 12=0 to 4 hours; 13=4 to 8 hours; 14=8 to 12 hours; 15=12 to 16 hours; 16=16 to 24 hours; 17=24 
hours)
Q3: Please select the class of COPD maintenance treatment. If no additional maintenance to that provided 
in Q1 then please select “Not applicable”. (Options: 9=ICS+LABA+LAMA; 10=LABA+LAMA; 12=ICS+LABA; 
13=LABA; 14=LAMA; “Not applicable”)
Q4: (Goes with Q3) How long since the patient took their last dose of COPD maintenance treatment? 
Please select “Not applicable” if “Not applicable” selected in Q3. (Options: 12=0 to 4 hours; 13=4 to 8 hours; 
14=8 to 12 hours; 15=12 to 16 hours; 16=16 to 24 hours; 17=24 hours; “Not applicable”)
Trough FEV1 will be defined as the FEV1 value recorded while participants have withheld the COPD 
maintenance treatment. 

For COPD maintenance treatments taken once-daily, FEV1 will be considered as Trough if the 
participant withheld the LABA and LAMA components of the maintenance treatment for at least 16 hours 
(category 16=16-24 hours or 17=24 hours selected in Q2 and Q4 (if applicable))

For COPD maintenance treatments taken twice-daily, FEV1 will be considered as Trough if the 
participant withheld the LABA and LAMA components of the maintenance treatment for at least 8 hours 
(category 14=8-12 hours, 15=12-16 hours, 16=16-24 hours or 17=24 hours selected in Q2 and Q4 (if 
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Note:
o If information is missing for some of the components of the maintenance COPD medication but 
available for the rest of the components, it will be assumed that the missing information is the same as 
the available information (e.g., if participant is on ICS + LABA + LAMA (MITT) and the LABA 
component was Trough but there is no information available for the LAMA component, then it will be 
assumed that LAMA component was also Trough. Similarly, if LABA component was recorded as non-
Trough). Reminder: we do not consider the ICS as a monotherapy component for the definition of the 
Trough FEV1. 
o If information is completely missing for all components of the maintenance COPD medication, it will be 
assumed that the FEV1 is not Trough.
o The maintenance COPD medication frequencies will be identified by linking the medication class 
selected at the PFT eCRF form with the medications listed in the Study Treatment eCRF form.
Critical Errors

For the primary estimand of the secondary endpoint of critical errors (Section 7.2.3.4, Table 5), if
participants modify their COPD maintenance therapy during the study the following scenarios are 
considered: 
a)
If the new therapy uses the same device(s) as the randomised COPD maintenance therapy, and 
error assessments are performed on these new device(s), this data will be used in the analysis.
b)
If the new therapy uses different device(s) to the randomised COPD maintenance therapy, but they 
are device(s) that are assessed in the study (checklists available) and for which error assessments 
are performed, then this data will be set to missing.
c)
If the new COPD maintenance therapy uses device(s) which are not being assessed in this study 
(no checklists available) then no error assessment is available at week 24 (Visit 2) and so this data 
is expected to be missing.

For the supportive estimand of the secondary endpoint of critical errors, if participants modify their 
COPD maintenance therapy during the study the inhaler error data will be used regardless of whether 
the participant remained on the same device(s) after modifying the randomised treatment. 

According to the protocol, if participant is using more than one inhaler for the administration of the COPD 
maintenance therapy and inhaler error checklists are not available in the study for all the inhalers, then 
an inhaler error assessment should not be performed at Visit 2 by the participant. However, in the 
situation that an inhaler error assessment has been carried out for any of those inhalers for which a 
checklist is available, the data will not be used in the primary analyses (primary estimand) or the 
supportive analysis (supportive estimand) but they will be used in the exploratory analysis of the 
individual inhaler comparisons (Section 7.2.3.5.1). 

In the situation where a participant may miss a component of a device assessment and one or more of 
the other question responses (critical error) indicate an error was made, then the missing value has no 
additional impact on the response outcome as participant will be considered as having at least one
critical error. In the situation where a participant may miss a component of a device assessment and all 
other responses to question indicate no error made, then the response to this endpoint (i.e., participant 
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
More details around ways of handling missing week 24 CE data are included in Section 7.2.3 as part of 
the estimands defined for this endpoint.
Other Endpoints
Clinically Important Deterioration (CID)
CID is a composite outcome defined as any one of the following events:
1.
100 mL reduction from baseline in FEV1 at 24 weeks. Note: Baseline Trough FEV1 will be 
considered for this component. 
2.
An exacerbation (requiring treatment with antibiotics and/or systemic steroids or hospitalisation)
3.
2 units change (increase) from baseline in CAT score at 24 weeks
Note: Point 1 can only be considered for participants who are part of the FEV1 population (as defined in 
Section 4).
Ways of handling missing data in the analyses are included in Section 7.3.1 and Section 7.3.2 as part of the 
estimands defined for this endpoint.
For the listing of the CID data, the CID response flag will be defined as:

If any of the three CID criteria defined above has been met, the participant will be considered as 
having experienced CID regardless of if the response to the other criteria is missing.

If the response to any of the three CID criteria defined above is missing and the other criteria have 
not been met, then the CID response will be set to missing. 
Note: The CID analyses incorporates multiple imputation for missing CAT score and missing Trough FEV1
data as described in Section 7.3.1.4.
Time to First Moderate/Severe Exacerbation

Individual exacerbations are collected in the eCRF by the Investigator during the study.
COPD exacerbations will be classified as pre-randomised treatment, on-randomised treatment, post-
randomised treatment, and on-study or post-study as described in Section 10.4.1.3. Also, exacerbation 
severity is defined in Section 10.6.1.

The time to first exacerbation based only on on-randomised treatment data will be calculated as:
[ First On-randomised Treatment Exacerbation Onset Date – Randomised Treatment Start Date ] + 1
Participants will be represented from the date of start of the randomised treatment to the start date of 
their first on-randomised treatment exacerbation or date of censoring. Participants that have not 
experienced an on-randomised treatment exacerbation are censored at the earliest of the randomised 
treatment stop date + 1 or the date of death.

The time to first on-study exacerbation will be calculated as:
[ First Exacerbation Onset Date – Randomisation Date ] + 1
 
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Exacerbations reported during the on-study phase will be considered (see Section 10.4.1.3 for details of 
assigning study phase).
Participants will be represented from the day they were randomised in the study to the start date of their 
first exacerbation or date of censoring. Participants that have not experienced an on-study exacerbation 
are censored at the earliest of the study conclusion date or the date of death.
Annualised Rate of Moderate/Severe Exacerbations

The annualized rate of on-randomised treatment exacerbations will be calculated as:
[ Number of Exacerbations / Time on Randomised Treatment (in days) ] x 365.25
where: 
Number of Exacerbations:
Number of On-randomised Treatment Moderate/Severe 
Exacerbations for each Participant
Time on Randomised 
Treatment:
[ earliest of (Randomised Treatment End Date + 1 or Date of Death 
or Study Conclusion Date) - Randomised Treatment Start Date ] +1

The annualized rate of on-study exacerbations will be calculated as:
[ Number of Exacerbations / Time on Study (in days) ] x 365.25
where: 
Number of Exacerbations:
Number of On-Study Moderate/Severe Exacerbations for each 
Participant
Time on Study:
[ earliest of (Study Conclusion Date or Study Withdrawal Date) -
Randomisation Date ] +1
Exploratory Endpoints
Association of CE with CAT, moderate/ severe exacerbations, FEV1 and FVC

Association of CE with CAT score: 
o A box-plot of the number of critical errors and the CAT score at week 24 will be populated. The 
number of errors (classified as: 0 errors; 1 error; ≥2 errors) will be presented on the x-axis and the 
week 24 CAT score (continuous) will be presented in the y-axis.
o A box-plot of the number of critical errors and the change from baseline in CAT score at week 24 will 
be populated. The number of errors (classified as: 0 errors; 1 error; ≥ 2 errors) will be presented on 
the x-axis and the change from baseline in CAT score at week 24 (continuous) will be presented in 
the y-axis. 
o The number of critical errors (classified as: 0 errors; 1 error; ≥ 2 errors) and the CAT response at 
week 24 (classified as: Responders, Non-responders) will also be summarised in a frequency table. 

Association of CE with FEV1: 
o A box-plot of the number of critical errors and the FEV1 at week 24 will be populated. The number of 
 
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errors (classified as: 0 errors; 1 error; ≥2 errors) will be presented on the x-axis and the week 24
FEV1 (continuous) will be presented in the y-axis.
o A box-plot of the number of critical errors and the change from baseline in FEV1 at week 24 will be 
populated. The number of errors (classified as: 0 errors; 1 error; ≥ 2 errors) will be presented on the 
x-axis and the change from baseline in FEV1 at week 24 (continuous) will be presented in the y-axis.

Association of CE with FVC: 
o A box-plot of the number of critical errors and the FVC at week 24 will be populated. The number of 
errors (classified as: 0 errors; 1 error; ≥2 errors) will be presented on the x-axis and the week 24
FVC (continuous) will be presented in the y-axis.
o A box-plot of the number of critical errors and the change from baseline in FVC at week 24 will be 
populated. The number of errors (classified as: 0 errors; 1 error; ≥ 2 errors) will be presented on the 
x-axis and the change from baseline in FVC at week 24 (continuous) will be presented in the y-axis.

Association of CE with Moderate/Severe Exacerbations:
The number of critical errors (classified as: 0 errors; 1 error; ≥2 errors) and the number of exacerbations 
(classified as: 0 exacerbations; 1 exacerbation; ≥2 exacerbations), will be summarised in a three-way 
frequency table. One frequency table for the on-randomised treatment moderate/severe exacerbations 
and one for the on-study moderate/severe exacerbations.
Participant Treatment and Study Satisfaction Questionnaire
The Participant Treatment and Study Satisfaction Questionnaire include the following items:




Data will be summarized and listed as described in Section 7.4.2.
Health Related Quality of Life Questionnaire
The Health Related Quality of Life Questionnaire includes the following items:




Data will be summarised and listed as described in Section 7.4.3. 
 
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protected by third party copyright laws and therefore have been excluded.
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are 
protected by third party copyright laws and therefore have been excluded.
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are 
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10.6.4.
Safety
Serious Adverse Events
Serious Adverse Events of Special Interest
SAESI have been defined as SAEs which have specified areas of interest for FF, VI or UMEC or the overall 
COPD population. The following table presents the SAESI groups. Groups which are not SMQs are made up of 
a selection of preferred terms (PTs) defined by GSK. The complete list, including the PTs which contribute to 
each of the groups will be provided by Global Clinical Safety and Pharmacovigilance (GCSP) using the 
MedDRA version current at the time of reporting. This will be finalized prior to unblinding.
SAESI Group
SAESI Subgroup
Sub-SMQ
Cardiovascular effects
Cardiac arrhythmia
Arrhythmia related investigations, 
signs and symptoms (SMQ)
Bradyarrhythmia terms, 
nonspecific (SMQ)
Conduction defects (SMQ)
Disorders of sinus node function 
(SMQ)
Cardiac arrhythmia terms, 
nonspecific (SMQ)
Supraventricular tachyarrhythmias 
(SMQ)
Tachyarrhythmia terms, 
nonspecific (SMQ)
Ventricular tachyarrhythmias 
(SMQ)
Cardiac failure (SMQ)
Ischaemic heart disease (SMQ)
Hypertension (SMQ)
Central nervous system 
haemorrhages and 
cerebrovascular conditions (SMQ)
Decreased bone mineral density 
and associated fractures
Pneumonia
Infective pneumonia SMQ 
(Narrow)
Lower Respiratory Tract Infection 
(LRTI) excluding pneumonia SMQ 
(Narrow)
For the planned summary of SAESI by class of medication:

For the SAESI group of Pneumonia, events will be allocated to the treatment the participant was 
taking for the majority of the 28 days prior to the onset of the event. If the event occurred within 28 days 
of Randomisation, only the treatment taken post Randomisation is considered for the treatment 
allocation. For all other special interest groups, events are allocated to the treatment the participant was 
taking on the day of onset of the event.

For SAESI group of Pneumonia, a participant will be considered at risk for a given treatment up until 
28 days after the stop date of this treatment.
 
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10.7.
Appendix 7: Reporting Standards for Missing Data
10.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Participant study completion (i.e., as specified in the protocol) is defined as completion 
of the week 24 study visit (Visit 2). 

Participant treatment completion is defined as no premature discontinuation or 
modification of the randomised COPD maintenance treatment at any time prior to 
formal study completion. 

Withdrawn participants were not replaced in the study.

ICH-required data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in relevant summary tables and figures, 
unless otherwise specified. 

Withdrawal visits will be slotted as per Appendix 3: Assessment Windows or will be
summarised as withdrawal visits.
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 participant listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such.
Handling of missing data in the statistical analyses of the primary, secondary or other endpoints (i.e., CID), 
is described in Section 7 as part of the estimands framework. When multiple imputation is the suggested 
method for handling missing data, then the imputation will follow the steps described below.
Element
Reporting Detail
Week 24 
CAT
For the Primary Estimand and the Supportive Estimand II defined in Section 7.1.1.4 and 
Section 7.1.1.5.1, respectively, missing week 24 CAT score data will be imputed as 
described below:
1. In the original analysis dataset (Dataset A), a flag variable for each intercurrent event 
identified for the endpoint will be created, which will indicate the participants for which 
the intercurrent event has occurred.
2. If a participant has reported at least one intercurrent event for which a “composite” 
strategy is suggested, the continuous endpoint data (if available) for that participant 
will be set to missing. All participants remain in one dataset which will be used for the 
imputation.
3. First step of the imputation will be to run an imputation model (parameter-estimation 
model) to get pseudo-independent samples from the joint posterior distribution for the 
linear predictor parameters (“betas” associated with treatment, baseline CAT score 
(continuous), number of exacerbations in the prior year (categorical), prior medication 
 
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use strata (categorical) and country (categorical)) and the covariance parameters.
4. Next step is to impute the missing endpoint data (as continuous data) by constructing 
endpoint estimates from the samples. This will be done assuming that the data is 
missing-at-random (MAR) i.e., based on the randomised treatment arm characteristics. 
A sufficient number of m samples (imputations) will be used to ensure that the final 
estimates are consistent and independent of any seeds used in the sampling process. 
Note that the participants with an intercurrent event for which a composite strategy is 
planned, will technically also have their “missing” continuous data imputed but this will 
be ignored. Also, note that participants with missing baseline CAT score (or any other 
missing covariates) will not be included in the analysis as they will not have a change 
from baseline.
5. There will be m imputed sets of data for analysis.
6. For each set of data, a binary response variable indicating responders and non-
responders based on the change from baseline CAT score at week 24 (Visit 2) will be 
created for each participant. Note that the imputed continuous data for those 
participants flagged as having a composite intercurrent event should be set back to 
missing and the response status defined as “non-response” by definition (composite 
strategy).
7. A univariate logistic regression analysis will be performed for each set of data as 
described in Section 7.1.1.5.1.
8. The “m” results from the analyses of each set of data are combined using Rubin’s 
formulae [Rubin, 1987]. (Note: model estimates should be combined on the model 
scale rather than the exponentiated [odds ratio] scale and then turned into an odds 
ratio by exponentiating).
Note: This approach will also be used for the imputation of missing CAT score data for the 
analysis of 2 Units Change (Increase) from Baseline in CAT score at 24 weeks (CID 
analysis of components, Section 7.3.2.2), adjusting for the covariates specified for this
analysis (i.e., baseline CAT, prior medication use strata and country) and for the imputation 
of missing Trough FEV1 data for the analysis of 100mL reduction in Trough FEV1 at 24 
weeks (analysis of CID components, Section 7.3.2.1), adjusting for the covariates specified 
for these analyses (i.e., baseline Trough FEV1, prior medication use strata and country.
For the Supportive Estimand III (Hypothetical) defined in Section 7.1.1.5.1, week 24 CAT 
score data will be imputed as described below:
1. In the original analysis dataset (Dataset A), a flag variable for each intercurrent event 
identified for the endpoint will be created, which will indicate the participants for which 
the intercurrent event has occurred.
2. For participants who have reported any of the intercurrent events identified for the 
endpoint, their response (if available) after the occurrence of the event (i.e., week 24 
(Visit 2) CAT score) will be set to missing (Dataset B). All missing week 24 (Visit 2) 
CAT score values (those originally missing and those set to missing) will be imputed. 
Dataset B will be used for the imputation. 
3. First step of the imputation will be to run an imputation model (parameter-estimation 
model) to get pseudo-independent samples from the joint posterior distribution for the 
linear predictor parameters (“betas” associated with treatment, baseline CAT score 
 
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(continuous), number of exacerbations in the prior year (categorical), prior medication 
use strata (categorical) and country (categorical)) and the covariance parameters.
4. Next step is to impute the missing endpoint data (as continuous data) by constructing 
endpoint estimates from the samples. This will be done assuming that the data is 
missing-at-random (MAR) i.e. based on the randomised treatment arm characteristics. 
A sufficient number of m samples (imputations) will be used to ensure that the final 
estimates are consistent and independent of any seeds used in the sampling process.
5. There will be m imputed sets of data for analysis.
6. For each set of data for analysis, a binary response variable indicating the responders 
and non-responders based on the change from baseline CAT score at week 24 (Visit 
2) will be created for each participant.
7. A univariate logistic regression analysis will be performed for each “new” analysis 
dataset as described in RAP Section 7.1.1.5.1.
8. The “m” results from the analyses of each dataset are combined using Rubin’s 
formulae [Rubin, 1987]. (Note: model estimates should be combined on the model 
scale rather than the exponentiated [odds ratio] scale and then turned into an odds 
ratio by exponentiating).
Week 24 
FEV1/ 
Trough FEV1
For the estimands defined in Sections 7.2.1 (FEV1 analysis) and Section 7.2.2 (Trough 
FEV1 analysis), missing week 24 FEV1/Trough FEV1 data will be imputed as described 
below:
1. In the original analysis dataset (Dataset A), a flag variable for each intercurrent event 
identified for the endpoint will be created, which will indicate the participants for which 
the intercurrent event has occurred.
2. Note that for the intercurrent events defined for these endpoints, no composite strategy 
is planned so Dataset A will be used as it is for the imputation.
3. First step of the imputation will be to run an imputation model (parameter-estimation 
model) to get pseudo-independent samples from the joint posterior distribution for the 
linear predictor parameters (“betas” associated with treatment, baseline FEV1/Trough 
FEV1 score (continuous), prior medication use strata (categorical), country 
(categorical) and timing of spirometry (categorical – only for the FEV1 analysis)) and 
the covariance parameters.
4. Next step is to impute the missing endpoint data (as continuous data) by constructing 
endpoint estimates from the samples. This will be done assuming that the data is 
missing-at-random (MAR) i.e. based on the randomised treatment arm characteristics. 
A sufficient number of m samples (imputations) will be used to ensure that the final 
estimates are consistent and independent of any seeds used in the sampling process.  
Note that participants with missing FEV1/Trough FEV1 at Visit 1 (or any other missing 
covariates) will not be included in the analysis as they will not have a change from 
baseline.
5. There will be m imputed sets of data for analysis.
6. For each set of data, a univariate ANCOVA analysis will be performed for each set of
 
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data as described in Section 7.2.1.5.1 (FEV1 analysis) and Section 7.2.2.5.1 (Trough 
FEV1 analysis).
7. The “m” results from the analyses of each set of data are combined using Rubin’s 
formulae [Rubin, 1987].
CID
For the estimand defined in Section 7.3.1.4, missing week 24 CAT score data and/or 
missing week 24 Trough FEV1 data will be imputed as described below:
1. In the original analysis dataset (Dataset A), a flag variable for each intercurrent event 
identified for the endpoint will be created, which will indicate the participants for which 
the intercurrent event has occurred.
2. If a participant has reported at least one intercurrent event for which a “composite” 
strategy is suggested, the continuous week 24 Trough FEV1 data and the CAT score 
data for that participant (if available) will be set to missing. All participants remain in 
the one dataset which will be used for the imputation.
3. For each of the following components of the CID endpoint: a) CAT score and b) 
Trough FEV1, first step of the imputation will be to run an imputation model (parameter-
estimation model) to get pseudo-independent samples from the joint posterior 
distribution for the linear predictor parameters (“betas” associated with treatment,
baseline Trough FEV1 (continuous), baseline CAT score (continuous), number of 
exacerbations in the prior year (categorical), prior medication use strata (categorical) 
and country (categorical)) and the covariance parameters. Note: Missing exacerbation 
data will not be imputed. 
4. For each of the components of the CID mentioned in the previous step (CAT score and 
Trough FEV1) next step is to impute the missing data (CAT score and Trough FEV1
data) as continuous data by constructing endpoint estimates from the samples. This 
will be done assuming that the data is missing-at-random (MAR) i.e. based on the 
randomised treatment arm characteristics. A sufficient number of m samples 
(imputations) will be used to ensure that the final estimates are consistent and 
independent of any seeds used in the sampling process. Note that the participants with 
an intercurrent event for which a composite strategy is planned, will technically also 
have their “missing” continuous data imputed but this will be ignored. Also, note that 
participants with missing CAT score at Visit 1 or missing Trough FEV1 data at Visit 1 
(or any other missing covariates) will not be included in the analysis as they will not 
have a change from baseline.
5. There will be m imputed sets of data for analysis.
6. For each set of data, a binary response variable indicating participants who experience 
CID and those who do not (as defined in Section 10.6.3) will be created for each 
participant. Note that the imputed continuous data for those participants flagged as 
having a composite intercurrent event, should be set back to missing and the response 
status defined as “non-response” by definition (composite strategy).
7. A univariate logistic regression analysis will be performed for each set of data as 
described in Section 7.3.1.5.1.
8. The “m” results from the analyses of each set of data are combined using Rubin’s 
formulae [Rubin, 1987]. (Note: model estimates should be combined on the model 
 
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scale rather than the exponentiated [odds ratio] scale and then turned into an odds 
ratio by exponentiating).
10.7.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in participant listing displays.
Randomised 
Treatment 
Stop Date

If participant remained on the randomised treatment throughout the study (i.e., no 
randomised treatment discontinuation or randomised treatment modification) and has a 
missing or partial randomised treatment stop date, then the randomised treatment stop
date will be imputed in the following way: 
o
If the date is completely missing, it will be imputed as the latest of Study
Conclusion Date/ Visit 2 Date
o
If partial date is available (only month and year available), then the day will be 
imputed as the earliest of [the Last Day of the Month or the Study Conclusion Date/ 
Visit 2 Date]
o
If a partial date is available (only year available), then the day and month will be 
imputed as the earliest of [the Last Day of the Year or the Study Conclusion Date/ 
Visit 2 Date]

If participant has discontinued from randomised treatment or modified randomised 
treatment during the study or discontinued from study (Early Withdrawal) and has a 
missing or partial randomised treatment stop date, then the randomised treatment stop 
date will be imputed in the following way:
o
If the date is completely missing, it will be imputed as the Day Prior to the Start 
Date of the Modified Maintenance Treatment 
o
If a partial date is available (only month and year available), then the day will be 
imputed as the earliest of [the Last Day of the Month or the Day Prior to the Start 
Date of the Modified Maintenance Treatment]
o
If a partial date is available (only year available), then the day and month will be 
imputed as the earliest of [the Last Day of the Year or the Day Prior to the Start 
Date of the Modified Maintenance Treatment]

In the special situation where, a participant has discontinued from randomised 
treatment or modified randomised treatment during the study or discontinued from 
study (Early Withdrawal) and has a missing or partial randomised treatment stop date, 
but the start date of the modified maintenance treatment is also missing or partial, then 
the randomised treatment stop date and the modified randomised treatment start date 
will be imputed in the following way:
o
If partial dates are available (only month and year available), and Visit 2 or
Conclusion Date (if Visit 2 Date not available or Visit 2 Date = Conclusion Date) is 
in the same month, then the Modified Treatment Start Date will be imputed as the 
Day Prior to Visit 2/ Conclusion Date and the Randomised Treatment Stop Date as 
the Day Prior to the Imputed Modified Treatment Stop Date.
E.g., 
Date
Original Date
Imputed Date
Randomised Treatment Stop Date
--Apr-2019
22-Apr-2019
Modified Treatment Start Date
--Apr-2019
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Element
Reporting Detail
Visit 2 Date
24-Apr-2019
N/A
For the scenario above, same rule will apply if one of the two dates are completely 
missing but the other is partial or if both dates are completely missing. 
o
If partial dates are available (only month and year available), and Visit 2 or
Conclusion Date (if Visit 2 date not available or Visit 2 Date = Conclusion Date) is 
not in the same month, then the Modified Treatment Start Date will be imputed as 
the Last Day of the Month (of the partial date) and the Randomised Treatment Stop 
Date as the Day Prior to the Imputed Modified Treatment Stop Date.
E.g., 
Date
Original Date
Imputed Date
Randomised Treatment Stop Date
--Apr-2019
29-Apr-2019
Modified Treatment Start Date
--Apr-2019
30-Apr-2019
Visit 2 Date
10-May-2019
N/A
For the scenario above, if the Randomised Treatment Stop Date is partial and the 
Modified Treatment Start Date dates is completely missing, then the Randomised 
Treatment Stop Date will be imputed as the last day of the month (of the partial 
date) and the Modified Treatment Start Date as the Day After the Imputed 
Randomised Treatment Stop Date.
Adverse
Events/ 
Serious 
Adverse 
Events

The eCRF does not allow for the possibility of partial dates to be recorded for AE/SAE 
start and end dates.

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.
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.
 
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10.8.
Appendix 8: Abbreviations & Trade Marks
10.8.1.
Abbreviations
Abbreviation
Description
AE
Adverse Event
A&R
Analysis and Reporting 
CAT
COPD Assessment Test
CDISC
Clinical Data Interchange Standards Consortium
CE
Critical Error
CI
Confidence Interval
CID
Clinically Important Deterioration
CIL
Clinical Investigation Lead
COPD
Chronic Obstructive Pulmonary Disease
CSR
Clinical Study Report
CV
Cardiovascular
DBF
Database Freeze
DBR
Database Release
DP
Decimal Places
DQL
Data Quality Lead
eCRF
Electronic Case Record Form
EHR
Electronic Health Record
EMA
European Medicines Agency
EW
Early Withdrawal
FDA
Food and Drug Administration
FEV1
Forced Expiratory Volume in 1 Second
FVC
Forced Vital Capacity
GOLD
Global Initiative on Obstructive Lung Disease
GSK
GlaxoSmithKline
HCP
Health Care Provider
HCRU
Healthcare Resource Utilisation
HRQoL
Health Related Quality of Life Questionnaire 
ICH
International Conference on Harmonization
IDSL
Integrated Data Standards Library
IP
Investigational Product
IWRS
Interactive Web Response System
ITT
Intent-To-Treat
MAR
Missing at Random
MDI
Metered Dose Inhaler
MITT
Multiple Inhaler Triple Therapy
MM
Medical Monitor
OSL
Operational Study Lead
PDMP
Protocol Deviation Management Plan
PFT
Pulmonary Function Test
PP
Per Protocol
 
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Abbreviation
Description
RAP
Reporting & Analysis Plan
RAMOS
Randomization & Medication Ordering System 
RW
Real World
SAC
Statistical Analysis Complete
SERM
Safety Evaluation and Risk Management
SOP
Standard Operation Procedure
TA
Therapeutic Area
TFL
Tables, Figures & Listings 
VEO
Value Evidence and Outcomes
10.8.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
CAT
BREEZHALER
DISKUS
GENUAIR 
ELLIPTA
HANDIHALER
RAMOS NG 
SAS
RANDALL NG
TURBUHALER
TRELEGY
 
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10.9.
Appendix 9: List of Data Displays
10.9.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.n
1.1 to 1.n
Effectiveness
2.1 to 2.n
2.1 to 2.n
Safety
3.1 to 3.n
N/A
Section
Listings
ICH Listings
1 to x
Other Listings
x+1 to y
10.9.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 10: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Effectiveness
EFF_Fn
EFF_Tn
EFF_Ln
Safety
-
SAFE_Tn
SAFE_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL / Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’
10.9.3.
Deliverables
Delivery 
Description
SAC 
Final Statistical Analysis Complete
 
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10.9.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
ASE
Non-Standard
Summary of Subject Populations and Reasons for Screen 
Failure
SAC
1.2.
ITT
Non-Standard
Summary of Attendance at Each Visit by Visit Type
See IMPACT 1.02.
For Visit 1, Visit type will be: 1) 
Patient usual care site; 2) Referral 
site; 3) Home visit. For Visit 2, Visit 
type will be the ones defined for 
Visit 1 with the addition of 4) 
Telephone Visit.
Present EW visit separately using 
the Visit type categories defined for 
Visit 2.
SAC
1.3.
FEV1
Non-Standard
Summary of Attendance at Each Visit by Visit Type
As for Table 1.2.
SAC
1.4.
CE
Non-Standard
Summary of Attendance at Each Visit by Visit Type
As for Table 1.2.
SAC
1.5.
ITT
SD1
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment
SAC
1.6.
FEV1
SD1
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment
SAC
1.7.
CE
SD1
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment
SAC
 
 
 
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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.8.
ITT
ES1
Summary of Study Status and Reasons for Study Withdrawal 
SAC
1.9.
FEV1
ES1
Summary of Study Status and Reasons for Study Withdrawal 
SAC
1.10.
CE
ES1
Summary of Study Status and Reasons for Study Withdrawal 
SAC
1.11.
ITT
Non-Standard
Summary of Prior Medication Use Strata
SAC
1.12.
ASE
Non-Standard
Summary of Number of Subjects by Country
Based on IDSL NS1 but display 
presented only by Country (not by 
Centre ID and Investigator ID). Only 
Total column is required. 
SAC
1.13.
ITT
NS1
Summary of Number of Subjects by Country and Centre
SAC
1.14.
ASE
IE1
Summary of Inclusion/Exclusion Criteria Deviations for Screen 
Failures 
SAC
1.15.
ITT
IE1
Summary of Inclusion/Exclusion Criteria Deviations 
SAC
Protocol Deviation
1.16.
ITT
DV1
Summary of Important Protocol Deviations
SAC
Demographic and Baseline Characteristics
1.17.
ASE
DM11
Summary of Age Ranges
As per IDSL DM11 but also see 
Section 10.6.2.
SAC
1.18.
ITT
DM1
Summary of Demographic Characteristics
As per IDSL DM1 but also see 
Section 10.6.2.
SAC
1.19.
FEV1
DM1
Summary of Demographic Characteristics
As per IDSL DM1 but also see 
Section 10.6.2.
SAC
1.20.
CE
DM1
Summary of Demographic Characteristics
As per IDSL DM1 but also see 
Section 10.6.2.
SAC
 
 
 
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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.21.
ITT
DM1
Summary of Demographic Characteristics by Country
SAC
1.22.
ITT
DM1
Summary of Demographic Characteristics by Prior Medication 
Use Strata
SAC
1.23.
ITT
DM5
Summary of Race and Racial Combinations
As per IDSL DM5 but also see 
Section 10.6.2.
SAC
Medical Conditions
1.24.
ITT
MH4
Summary of Current Medical Conditions
SAC
1.25.
ITT
MH4
Summary of Past Medical Conditions
SAC
1.26.
ITT
Non-Standard
Summary of Cardiovascular Risk Factors
SAC
1.27.
ITT
FH1
Summary of Family History of Cardiovascular Risk Factors
SAC
Disease Characteristics
1.28.
ITT
Non-Standard
Summary of COPD Duration at Screening
SAC
1.29.
ITT
Non-Standard
Summary of COPD Exacerbation History at Screening
SAC
1.30.
FEV1
Non-Standard
Summary of Lung Function at Screening
Table will include all available 
Screening data regardless of visit 
type (e.g., domiciliary visit etc). It 
will also include historical CAT 
score data (more than 14 days prior 
to V1 - not flagged as baseline).
SAC
1.31.
FEV1
Non-Standard
Summary of Reversibility and GOLD Grade (1–4) at Screening
See Section 10.6.2.
SAC
1.32.
FEV1
Non-Standard
Summary of PIFR (L/min) at Screening
SAC
1.33.
ITT
Non-Standard
Summary of CAT Score and CAT Category at Screening
CAT categories: CAT < 10 and CAT 
≥ 10.
SAC
1.34.
ITT
Non-Standard
Summary of Historical Eosinophils Data
See Section 10.6.2.
SAC
 
 
 
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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Prior and Concomitant Medications
1.35.
ITT
Non-Standard
Summary of Pre-randomised Treatment Respiratory 
Concomitant Medications Excluding those Taken for an 
Exacerbation
Non-Standard but based on IDSL 
CM1. RMC classification to be 
used. 
SAC
1.36.
ITT
Non-Standard
Summary of On-randomised Treatment Respiratory 
Concomitant Medications Excluding those Taken for an 
Exacerbation
Non-Standard but based on IDSL 
CM1. RMC classification to be 
used. Randomised COPD 
Maintenance Therapy will not be 
included in this summary. 
SAC
1.37.
ITT
Non-Standard
Summary of Post-randomised Treatment Respiratory 
Concomitant Medication Excluding those Taken for an 
Exacerbation
Non-Standard but based on IDSL 
CM1. RMC classification to be 
used.
SAC
1.38.
ITT
Non-Standard
Summary of Pre-randomised Treatment COPD Concomitant 
Medications Taken for an Exacerbation
Non-Standard but based on IDSL 
CM1. RMC classification to be 
used.
SAC
1.39.
ITT
Non-Standard
Summary of On-randomised Treatment COPD Concomitant 
Medications Taken for an Exacerbation
Non-Standard but based on IDSL 
CM1. RMC classification to be 
used.
SAC
1.40.
ITT
Non-Standard
Summary of Post-randomised Treatment COPD Concomitant 
Medications Taken for an Exacerbation
Non-Standard but based on IDSL 
CM1. RMC classification to be 
used.
SAC
1.41.
ITT
Non-Standard
Summary of Respiratory Concomitant Medication Combinations 
Taken at Screening Excluding Those Taken for an Exacerbation 
Non-Standard but based on IDSL 
CM1. RMC classification to be 
used. See IMPACT Table 1.67.
SAC
 
 
 
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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.42.
ITT
Non-Standard
Summary of Respiratory Concomitant Medication Taken at 
Treatment Discontinuation Excluding Those Taken for an 
Exacerbation
Non-Standard but based on IDSL 
CM1. RMC classification to be 
used. See IMPACT Table 1.70.
SAC
Treatment Exposure
1.43.
ITT
Non-Standard
Summary of Treatment Exposure
Exposure to Randomised 
Treatment.
Also present the total time in study 
post-randomised treatment and the 
total time spent on-study.
See 207609 Table 3.1.
SAC
1.44.
ITT
Non-Standard
Summary of Unique Treatment Paths
See study HZC115151, Table 1.34
(only bottom segment is required).
SAC
Intercurrent Events
1.45.
ITT
Non-Standard
Summary of Intercurrent Events
SAC
1.46.
FEV1
Non-Standard
Summary of Intercurrent Events
SAC
1.47.
CE
Non-Standard
Summary of Intercurrent Events
SAC
 
 
 
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10.9.5.
Study Population Figures
Study Population Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.1.
ITT
Non-Standard
Kaplan-Meier Plot of Time to Premature Discontinuation of 
Study Treatment 
SAC
1.2.
ITT
Non-Standard
Kaplan-Meier Plot of Time to Study Withdrawal
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10.9.6.
Effectiveness Tables
Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Primary Endpoint
2.1.
ITT
Non-Standard
Summary of CAT Score
Summary at each visit (Baseline 
CAT, Week 24 and Change from 
Baseline – separate out EW visit).
SAC
2.2.
ITT
Non-Standard
Summary and Analysis of the Percentage of Responders 
According to the CAT Score at Week 24 (Primary Estimand -
Treatment Policy x Composite)
Include Footnote:
“Note: A Treatment policy strategy 
was used for the intercurrent event 
of Randomised Treatment 
Discontinuation. For the intercurrent 
events of Randomised Treatment 
Modification, change of Pulmonary 
Rehabilitation status and start of 
Oxygen Therapy, a Composite 
strategy was used.”
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.3.
ITT
Non-Standard
Summary and Analysis of the Percentage of Responders 
According to the CAT Score at Week 24 (Supportive Estimand I-
Treatment Policy x Composite)
Include Footnote:
“Note: A Treatment policy strategy 
was used for the intercurrent event 
of Randomised Treatment 
Discontinuation, Randomised 
Treatment Modification, change of 
Pulmonary Rehabilitation status and 
start of Oxygen Therapy. Subjects 
who prematurely discontinue from 
study and subjects with missing 
Visit 2 (Week 24) CAT score (for
other reason) are considered as 
non-responders”.
SAC
2.4.
ITT
Non-Standard
Summary and Analysis of the Percentage of Responders 
According to the CAT Score at Week 24 (Supportive Estimand 
II– Treatment Policy x Composite)
Include Footnote:
“Note: A Treatment policy strategy 
was used for the intercurrent events 
of Randomised Treatment 
Discontinuation, change of 
Pulmonary Rehabilitation status and 
start of Oxygen Therapy. For the 
intercurrent event of Randomised 
Treatment Modification, a 
Composite strategy was used.”.
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.5.
ITT
Non-Standard
Summary and Analysis of the Percentage of Responders 
According to the CAT Score at Week 24 (Supportive Estimand 
III– Hypothetical)
Include Footnote:
“Note: A Hypothetical strategy was 
used for the intercurrent events of 
Randomised Treatment 
Discontinuation, Randomised 
Treatment Modification, change of 
Pulmonary Rehabilitation status and 
start of Oxygen Therapy.”.
SAC
2.6.
ITT
Non-Standard
P-values for Interactions of Treatment with Covariates for 
Analysis of the Percentage of Responders According to the CAT 
Score at Week 24 (Primary Estimand - Treatment Policy x 
Composite)
The p-value for each interaction test 
will be presented. If any interaction 
p-value is less than 0.10 further 
investigations will be carried out, for 
example running the analysis by 
each category of the subgroup. Any 
output from interaction investigation
will also be presented in additional 
displays.
SAC
Secondary Endpoints
2.7.
FEV1
Non-Standard
Summary of FEV1
Summary at each visit (Baseline 
FEV1, Week 24 and Change from 
Baseline – separate out EW visit).
SAC
2.8.
FEV1
Non-Standard
Summary of Trough FEV1
Summary at each visit (Baseline 
Trough FEV1, Week 24 and 
Change from Baseline – separate 
out EW visit).
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.9.
FEV1
Non-Standard
Analysis of Change from Baseline in FEV1 at Week 24 (Primary 
Estimand – Treatment Policy)
Include Footnote:
“Note: A Treatment Policy strategy 
was used for the intercurrent events 
of Randomised Treatment 
Discontinuation, Randomised 
Treatment Modification, change of 
Pulmonary Rehabilitation status and 
start of Oxygen Therapy.”.
SAC
2.10.
FEV1
Non-Standard
Analysis of Change from Baseline in Trough FEV1 at Week 24 
(Primary Estimand – Treatment Policy)
Include Footnote:
“Note: A Treatment Policy strategy 
was used for the intercurrent events 
of Randomised Treatment 
Discontinuation, Randomised 
Treatment Modification, change of 
Pulmonary Rehabilitation status and 
start of Oxygen Therapy.”.
SAC
2.11.
CE
Non-Standard
Summary of Critical and Overall Errors 
Each inhaler presented on different 
page. Frequency for each error type 
to be presented for each inhaler. 
Flag with “[1]” the error types which
are considered as critical errors and 
include relevant footnote.
Include footnote: “All inhalers apart 
from the Ellipta inhaler are used in 
combination with at least one other 
inhaler by the subjects.”.
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.12.
CE
Non-Standard
Analysis of the Percentage of Subjects Making at Least One 
Critical Error at Week 24 (Primary Estimand – Hypothetical)
Include Footnote:
“Note: A Hypothetical strategy was 
used for the intercurrent event of
Randomised Treatment 
Modification.”.
SAC
2.13.
CE
Non-Standard
Analysis of the Percentage of Subjects Making at Least One 
Critical Error at Week 24 (Supportive Estimand – Treatment 
Policy)
Include Footnote:
“Note: A Treatment Policy strategy 
was used for the intercurrent event
of Randomised Treatment 
Modification.”.
SAC
2.14.
ITT
Non-Standard
Analysis of the Percentage of Subjects Making at Least One 
Critical Error at Week 24 Ellipta vs Comparator Device
(Exploratory Estimand – Treatment Policy)
Exploratory analysis to be 
performed if at least 100 
subjects/arm perform an inhaler 
assessment. Comparison of 
inhalers: Ellipta vs Diskus; Ellipta vs 
Breezhaler; Ellipta vs Handihaler; 
Ellipta vs MDI; Ellipta vs Turbuhaler; 
Ellipta vs Genuair to be presented 
in each page. 
SAC
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.15.
FEV1
Non-Standard
Summary and Analysis of the Percentage of Subjects Who 
Experience Clinically Important Deterioration (Primary Estimand 
– Treatment Policy x Composite)
Include Footnote:
“Note: A Treatment Policy strategy 
was used for the intercurrent events 
of Randomised Treatment 
Discontinuation, Randomised 
Treatment Modification and change 
of Pulmonary Rehabilitation status. 
For the intercurrent event of start of 
Oxygen Therapy, a Composite 
strategy was used.”.
SAC
2.16.
FEV1
Non-Standard
Summary and Analysis of the Percentage of Subjects Who 
Experience Clinically Important Deterioration (Sensitivity 
Analysis – Treatment Policy x Composite Estimand)
Same estimand as in Table 2.15,
excluding the number of 
exacerbations in the prior year from 
the list of covariates in the model.
SAC
2.17.
FEV1
Non-Standard
Summary and Analysis of the Percentage of Subjects Who 
Experience a 100 mL Reduction from Baseline in Trough FEV1 
at 24 Weeks (Primary Estimand – Treatment Policy x 
Composite)
Include Footnote:
“Note: A Treatment Policy strategy 
was used for the intercurrent events 
of Randomised Treatment 
Discontinuation, Randomised 
Treatment Modification and change 
of Pulmonary Rehabilitation status. 
For the intercurrent event of start of 
Oxygen Therapy, a Composite 
strategy was used.”.
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.18.
FEV1
Non-Standard
Summary and Analysis of the Percentage of Subjects Who 
Experience a 2-unit Change (Increase) from Baseline in CAT 
Score at 24 Weeks (Primary Estimand – Treatment Policy x 
Composite)
Include Footnote:
“Note: A Treatment Policy strategy 
was used for the intercurrent events 
of Randomised Treatment 
Discontinuation, Randomised 
Treatment Modification and change 
of Pulmonary Rehabilitation status. 
For the intercurrent event of start of 
Oxygen Therapy, a Composite 
strategy was used.”.
SAC
2.19.
ITT
Non-Standard
Summary of On-randomised Treatment Moderate/Severe COPD 
Exacerbations 
SAC
2.20.
ITT
Non-Standard
Summary of On-Study Moderate/Severe COPD Exacerbations 
SAC
2.21.
ITT
Non-Standard
Summary of Annualised Rate of On-Study Moderate/Severe 
Exacerbations
SAC
2.22.
ITT
Non-Standard
Kaplan Meir Estimates of Time to First On-randomised 
Treatment Moderate/Severe COPD Exacerbations
Just at Day 169.
SAC
2.23.
ITT
Non-Standard
Kaplan Meir Estimates of Time to First On-Study 
Moderate/Severe COPD Exacerbations
Just at Day 169.
SAC
2.24.
ITT
Non-Standard
Summary of Unscheduled COPD Related Healthcare Contacts
SAC
Exploratory Endpoints
2.25.
CE
Non-Standard
Association of Number of Critical Errors and CAT Response at 
Week 24 
Frequency table. Categories as 
described in Section 10.6.3.
SAC
2.26.
CE
Non-Standard
Association of Number of Critical Errors and On-randomised 
Treatment Moderate/Severe Exacerbations 
A 3-way frequency table. 
Categories as described in Section 
10.6.3.
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.27.
CE
Non-Standard
Association of Number of Critical Errors and On-Study 
Moderate/Severe Exacerbations
A 3-way frequency table. 
Categories as described in Section 
10.6.3.
SAC
2.28.
ITT
Non-Standard
Summary of Subject Treatment and Study Satisfaction 
Questionnaire Responses at Week 24/ EW Visit
SAC
2.29.
ITT
Non-Standard
Summary of Health Related Quality of Life Questionnaire 
Responses
Summary at each Visit.
SAC
 
 
 
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10.9.7.
Effectiveness Figures
Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Primary Endpoint
2.1.
ITT
Non-Standard
Box-plot of Change from baseline in CAT Score at Week 24
See Section 10.6.3.
SAC
Other Endpoints
2.2.
ITT
Non-Standard
Kaplan Meir Plot for Time to First On-randomised Treatment 
Moderate/Severe Exacerbation
SAC
2.3.
ITT
Non-Standard
Kaplan Meir Plot for Time to On-Study First Moderate/Severe 
Exacerbation
SAC
Exploratory Endpoints
2.4.
CE
Non-Standard
Box-plot of Association of Critical Errors with CAT Score at 
Week 24
See Section 10.6.3.
SAC
2.5.
CE
Non-Standard
Box-plot of Association of Critical Errors with Change from 
Baseline in CAT Score at Week 24
See Section 10.6.3.
SAC
2.6.
CE
Non-Standard
Box-plot of Association of Critical Errors with FEV1 at Week 24
See Section 10.6.3.
SAC
2.7.
CE
Non-Standard
Box-plot of Association of Critical Errors with Change from 
Baseline in FEV1 at Week 24
See Section 10.6.3.
SAC
2.8.
CE
Non-Standard
Box-plot of Association of Critical Errors with FVC at Week 24
See Section 10.6.3.
SAC
2.9.
CE
Non-Standard
Box-plot of Association of Critical Errors with Change from 
Baseline in FVC at Week 24
See Section 10.6.3.
SAC
 
 
 
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10.9.8.
Safety Tables
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
[Priority]
Adverse Events (AEs)
3.1.
ITT
Non-Standard
Summary of Adverse Events Overview
byval: On-randomised Treatment, 
Post-randomised Treatment.
Include Footnote: 
“Note: Only treatment related AEs 
and AEs that lead to withdrawal 
from study treatment and Serious 
AEs are collected and 
summarised.”.
SAC 
3.2.
ITT
AE1
Summary of Pre-randomised Treatment Adverse Events by 
System Organ Class and Preferred Term
Same comments as for 3.1.
Based on IDSL AE1 presenting also 
rates.
SAC 
3.3.
ITT
AE1
Summary of On-randomised Treatment Adverse Events by 
System Organ Class and Preferred Term
Same comments as for 3.1.
Based on IDSL AE1 presenting also 
rates.
SAC 
 
 
 
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
[Priority]
3.4.
ITT
AE1
Summary of Post-randomised Treatment Adverse Events by 
System Organ Class and Preferred Term
Same comments as for 3.1.
Based on IDSL AE1 presenting also 
rates.
SAC 
3.5.
ITT
AE1
Summary of On-Study Adverse Events by System Organ Class 
and Preferred term
Same comments as for 3.1.
Based on IDSL AE1 presenting also 
rates.
SAC
3.6.
ITT
AE1
Summary of On-randomised Treatment Drug-related Adverse 
Events by System Organ Class and Preferred Term
Based on IDSL AE1 presenting also 
rates.
SAC 
3.7.
ITT
AE1
Summary of Post-randomised Treatment Drug-related Adverse 
Events by System Organ Class and Preferred Term
Based on IDSL AE1 presenting also 
rates.
SAC 
3.8.
ITT
AE1
Summary of On-randomised Treatment Adverse Events Leading 
to Permanent Discontinuation of Study Treatment or Withdrawal 
from Study by System Organ Class and Preferred Term
Based on IDSL AE1 presenting also 
rates.
SAC
3.9.
ITT
AE15
Summary of Common (>=1% in Either Treatment Group) On-
randomised Treatment Non-serious Adverse Events by System 
Organ Class and Preferred Term (Number of Subjects and 
Occurrences)
Include Footnote: 
“Note: Only treatment related AEs 
and AEs that lead to withdrawal 
from study treatment are 
summarised.”.
SAC
Serious and Other Significant Adverse Events
3.10.
ITT
AE16
Summary of On-randomised Treatment Serious Adverse Events 
by System Organ Class and Preferred Term (Number of 
Subjects and Occurrences)
SAC 
 
 
 
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
[Priority]
3.11.
ASE
AE1
Summary of Pre-randomised Treatment Serious Adverse Events 
by System Organ Class and Preferred Term
Based on IDSL AE1 presenting also 
rates.
SAC
3.12.
ITT
AE1
Summary of Pre-randomised Treatment Serious Adverse Events 
by System Organ Class and Preferred Term
Based on IDSL AE1 presenting also 
rates.
SAC
3.13.
ITT
AE1
Summary of On-randomised Treatment Serious Adverse Events 
by System Organ Class and Preferred Term
Based on IDSL AE1 presenting also 
rates.
SAC
3.14.
ITT
AE1
Summary of Post-randomised Treatment Serious Adverse 
Events by System Organ Class and Preferred Term
Based on IDSL AE1 presenting also 
rates.
SAC
3.15.
ITT
AE1
Summary of On-Study Serious Adverse Events by System 
Organ Class and Preferred Term
Based on IDSL AE1 presenting also 
rates.
SAC
3.16.
ITT
AE1
Summary of On-randomised Treatment Serious Adverse Events 
Leading to Permanent Discontinuation of Study Treatment or 
Withdrawal from Study by System Organ Class and Preferred 
Term
Based on IDSL AE1 presenting also 
rates.
SAC
3.17.
ITT
AE1
Summary of On-randomised Treatment Fatal Serious Adverse 
Events by System Organ Class and Preferred Term
Based on IDSL AE1 presenting also 
rates.
SAC
3.18.
ITT
AE1
Summary of Post-randomised Treatment Fatal Serious Adverse 
Events by System Organ Class and Preferred Term
Based on IDSL AE1 presenting also 
rates.
SAC
3.19.
ITT
Non-Standard
Summary of On-Study Fatal Serious Adverse Events by Class of 
Medication
SAC
3.20.
ITT
AE1
Summary of Pre-randomised Treatment Serious Adverse Events 
Leading to Withdrawal from Study by System Organ Class and 
Preferred Term
Based on IDSL AE1 presenting also 
rates.
SAC
3.21.
ITT
AE1
Summary of On-randomised Treatment Drug-Related Serious 
Adverse Events by System Organ Class and Preferred Term
Based on IDSL AE1 presenting also 
rates.
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
[Priority]
3.22.
ITT
AE1
Summary of On-randomised Treatment Drug-Related Fatal 
Serious Adverse Events by System Organ Class and Preferred 
Term
Based on IDSL AE1 presenting also 
rates.
SAC
3.23.
ITT
AE3
Summary of Common (>=1% in Either Treatment Group) On-
randomised Treatment Serious Adverse Events by Preferred 
Term
Present by PT (not SOC).
SAC
3.24.
ITT
Non-Standard
Summary of On-randomised Treatment Serious Adverse Events 
of Special Interest
Based on IDSL AE1 but present by 
Special Interest (SI) Group, SI 
Subgroup, Sub-SMQ and PT. Also, 
present rates.
SAC
3.25.
ITT
Non-Standard
Summary of Post-randomised Treatment Serious Adverse 
Events of Special Interest
Based on IDSL AE1 but present by 
Special Interest (SI) Group, SI 
Subgroup, Sub-SMQ and PT. Also,
present rates.
SAC
3.26.
ITT
Non-Standard
Summary of On-Study Serious Adverse Events of Special 
Interest by Class of Medication
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10.9.9.
ICH Listings
All ICH listings will be presented by Country, unless otherwise specified.
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.
ASE
ES7
Listing of Reasons for Screen Failure
SAC
2.
ITT
TA1
Listing of Randomised and Actual Treatments
SAC
3.
ITT
TA1
Listing of Randomised and Actual Prior Medication Use Strata
SAC
4.
ITT
SD2
Listing of Reasons for Study Treatment Discontinuation
SAC
5.
ITT
ES2
Listing of Reasons for Study Withdrawal
SAC
Protocol Deviations
6.
ITT
DV2
Listing of Important Protocol Deviations
SAC
7.
ASE
IE3
Listing of Subjects with Inclusion/Exclusion Criteria Deviations 
for Screen Failures
SAC
8.
ITT
IE3
Listing of Subjects with Inclusion/Exclusion Criteria Deviations
SAC
Demographic and Baseline Characteristics
9.
ITT
DM2
Listing of Demographic Characteristics
SAC
10.
ITT
DM9
Listing of Race
SAC
Prior and Concomitant Medications
11.
ITT
Non-Standard
Listing of Respiratory Concomitant Medications
Including flag to indicate those 
taken for an exacerbation (COPD).
SAC
Treatment Exposure
12.
ITT
Non-Standard
Listing of Exposure Data
SAC
 
 
 
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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events
13.
ASE
AE8
Listing of All Adverse Events
Include Footnote: 
“Note: Only treatment related AEs 
and AEs that lead to withdrawal 
from study treatment and Serious 
AEs are collected and listed.”.
SAC
14.
ASE
AE7
Listing of Subject Numbers for Individual Adverse Events
Footnote from Listing 13 is 
applicable to this display.
Listing not presented by Country.
SAC
Serious and Other Significant Adverse Events
15.
ASE
AE8
Listing of Fatal Serious Adverse Events
SAC
16.
ASE
AE8
Listing of Non-Fatal Serious Adverse Events
SAC
17.
ASE
AE14
Listing of Reasons for Considering as a Serious Adverse Event
SAC
18.
ASE
AE8
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment
SAC
19.
ITT
AE8
Listing of Serious Adverse Events of Special Interest
SAC
 
 
 
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10.9.10.
Non-ICH Listings
All Non-ICH listings will be presented by Country, unless otherwise specified.
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Study Population
20.
ITT
Non-Standard
Listing of Study Treatment Misallocations
Similar to IDSL TA1.
SAC
21.
ITT
Non-Standard
Listing of Randomised Treatment and Randomised Treatment 
Modifications
SAC
22.
ITT
MH2
Listing of Medical Conditions
SAC
23.
ITT
Non-Standard
Listing of Family History of Cardiovascular Risk Factors
SAC
24.
ITT
Non-Standard
Listing of COPD Exacerbation History
SAC
25.
ITT
CM6
Relationship between ATC Level 1, Ingredient and Verbatim 
Text for Non-Respiratory Medications
SAC
26.
ITT
Non-Standard
Listing of f Historical Eosinophils Data
SAC
Effectiveness
27.
ITT
Non-Standard
Listing of CAT Scores
SAC
28.
FEV1
Non-Standard
Listing of Lung Function Data
Listing will also include PIFR data.
SAC
29.
ITT
Non-Standard
Listing of Inhaler Critical and Overall Errors
SAC
30.
FEV1
Non-Standard
Listing of Clinically Important Deterioration Data
SAC
31.
ITT
Non-Standard
Listing of COPD Exacerbations
SAC
32.
ITT
Non-Standard
Listing of Participant Treatment and Study Satisfaction 
Questionnaire Responses
SAC
 
 
 
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Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
33.
ITT
Non-Standard
Listing of Health Related Quality of Life Questionnaire (HRQoL) 
Responses
SAC
Safety
34.
ITT
Non-Standard
SAE Terms of Special Interest
Listing not presented by Country.
SAC
35.
ITT
AE7
Listing of Subject Numbers for On-randomised Treatment 
Serious Adverse Events of Special Interest
Listing not presented by Country.
SAC
 
 
 
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10.9.11.
Patient Profile Listings
Patient Profile: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
[Priority]
Study Population
36.
ITT
Non-Standard
Listing of Arrhythmias
Include information required by 
IDSL standards.
SAC
37.
ITT
Non-Standard
Listing of Congestive Heart Failure
Include information required by 
IDSL standards.
SAC
38.
ITT
Non-Standard
Listing of Cerebrovascular Events/ Stroke/ Transient Ischemic 
Attack
Include information required by 
IDSL standards.
SAC
39.
ITT
Non-Standard
Listing of Deep Vein Thrombosis/ Pulmonary Embolism
Include information required by 
IDSL standards.
SAC
40.
ITT
Non-Standard
Listing of Myocardial Infarction/ Unstable Angina
Include information required by 
IDSL standards.
SAC
41.
ITT
Non-Standard
Listing of Peripheral Arterial Thromboembolism
Include information required by 
IDSL standards.
SAC
42.
ITT
Non-Standard
Listing of Pulmonary Hypertension
Include information required by 
IDSL standards.
SAC
43.
ITT
Non-Standard
Listing of Revascularisation
Include information required by 
IDSL standards.
SAC
44.
ITT
Non-Standard
Listing of Valvulopathy
Include information required by 
IDSL standards.
SAC
 
 
 
2019N418769_00


CONFIDENTIAL
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105
10.10.
Appendix 10: Example Mock Shells for Data Displays
The data display shells are contained in separate documents and are available upon request.
 
 
 
2019N418769_00