The Clinical Effectiveness of Fluticasone Furoate/Umeclidinium Bromide/Vilanterol in a Single Inhaler (TRELEGY™ ELLIPTA™) When Compared With Non-ELLIPTA Multiple Inhaler Triple Therapies in COPD Patients Within a Usual Care Setting
Phase: PHASE4
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: GlaxoSmithKline

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GlaxoSmithKline group of companies
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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 
Questionnaire
 
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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.
REFERENCES
Aaron SD, Vandemheen KL, Fergusson D, Maltais F, Bourbeau J, Goldstein R, et al. 
Tiotropium in Combination with Placebo, Salmeterol, or Fluticasone–Salmeterol for 
Treatment of Chronic Obstructive Pulmonary Disease A Randomised Trial. Ann Intern 
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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: 
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Cazzola M, Ando F, Santus P, Ruggeri P, Marco F, Sanduzzi A, Smato M. A pilot study 
to assess the effects of combining fluticasone propionate/salmeterol and tiotropium on the 
airflow obstruction of patients with severe to-very severe COPD. Pul. Pharm. & 
Therapeu. 2007. 20:556–561.
Chen LF, Vander Weg MW, Hofmann DA, Reisinger HS. The Hawthorne Effect in 
Infection Prevention and Epidemiology. Infect Control Hosp Epidemiol. 2015. 
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Global Strategy for the Diagnosis, Management and Prevention of COPD, Global 
Initiative for Chronic Obstructive Lung Disease (GOLD) 2013. Available from: 
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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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Hanania NA, Crater GD, Morris AN, Emmett AH, O'Dell DM, Niewoehner DE. Benefits 
of adding fluticasone propionate/salmeterol to tiotropium in moderate to severe COPD. 
Respir Med. 2012;106(1):91-101.
Herland K, Akselsen JP, Skjønsberg OH, Bjermer L.How representative are clinical 
study patients with asthma or COPD for a larger "real life" population of patients with 
obstructive lung disease? Respir Med. 2005 Jan; 99(1):11-9.
Hintze, J. PASS 12. NCSS, LLC. Kaysville, Utah, USA. 2013.www.ncss.com.
International Conference of Harmonisation [ICH] of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 2009. Guidance on nonclinical 
safetystudies for the conduct of human clinical trials and marketing authorization for 
pharmaceuticals M3(R2).
Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Kline Leidy N. Development and 
first validation of the COPD Assessment Test. Eur Respir J. 2009. 34(3):648-54.
 
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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. 
142 134-140.
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 
controlled study. Resp. Med. .2012. 106: 382-389. doi:10.1016/j.rmed.2011.09.004.
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. 
14(1):80-85.
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 
Therapy in Patients with Chronic Obstructive Pulmonary Disease. American Journal of 
Respiratory and Critical Care Medicine 2017. 196(4):438-446. 
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Miller MR, Hankinson J, Odencrantz J, Standardisation of spirometry. Eur Respir J. 
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Price D, West D, Bruseelle G, Gruffydd-Jones, K, Jones, R, Miravitlles M, Rossi A, 
Hutton, C, Ashton V, Stewart R, Bichel, K, Management of COPD in the UK primary-
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2014. 9 889–905
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 
Respiratory Medicine. 2018: doi: 10.1016/S2213-2600(18)30137-1.
Vestbo,J, Leather, D, Diar Bakerly, N, New, J, Gibson, M, McCorkindale, S, Collier, S, 
Crawford, J, Frith, L Harvey, C, Svedsater, H, Woodcock, A Effectiveness of Fluticasone 
Furoate–Vilanterol for COPD in Clinical Practice. N Engl J Med 2016. 375:1253-1260 
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 
with Chronic Obstructive Pulmonary Disease. Am. J. Respir. Crit.Care Med. 
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 
investigators)
 
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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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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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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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