An Open-label, Low Interventional Clinical Study Investigating Error Rates (Critical and Overall) Prior to Any Retraining in Correct Use of the ELLIPTA Dry Powder Inhaler (DPI) Compared to Other DPIs Including; DISKUS, Turbuhaler, HandiHaler and Breezhaler as a Monotherapy or in Combination, in Adult Patients With Chronic Obstructive Pulmonary Disease (COPD)
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: GlaxoSmithKline

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TITLE PAGE
Protocol Title: An open-label, low interventional clinical study investigating error rates 
(critical and overall) prior to any retraining in correct use of the ELLIPTA dry powder 
inhaler (DPI) compared to other DPIs including; DISKUS, Turbuhaler, HandiHaler and 
Breezhaler as a monotherapy or in combination, in adult patients with Chronic 
Obstructive Pulmonary Disease (COPD).
Protocol Number: 204981
Short Title: A low interventional clinical study comparing error rates (critical and 
overall); between the ELLIPTA dry powder inhaler (DPI) and other DPIs, prior to any 
retraining in correct use, and as prescribed to treat COPD patients.
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): N/A
Approval Date: 24-JAN-2017
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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TABLE OF CONTENTS
PAGE
1.
SYNOPSIS...............................................................................................................6
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................10
3.
INTRODUCTION....................................................................................................12
3.1.
Study Rationale ..........................................................................................12
3.2.
Background ................................................................................................12
3.3.
Benefit/Risk Assessment ............................................................................13
3.3.1.
Risk Assessment .........................................................................14
3.3.2.
Benefit Assessment.....................................................................14
3.3.3.
Overall Benefit: Risk Conclusion..................................................14
4.
OBJECTIVES AND ENDPOINTS...........................................................................15
5.
STUDY DESIGN ....................................................................................................16
5.1.
Overall Design ............................................................................................16
5.2.
Number of Participants ...............................................................................21
5.3.
Participant and Study Completion...............................................................21
5.4.
Scientific Rationale for Study Design ..........................................................21
5.5.
Dose Justification........................................................................................21
6.
STUDY POPULATION...........................................................................................22
6.1.
Inclusion Criteria.........................................................................................22
6.2.
Exclusion Criteria........................................................................................22
6.3.
Lifestyle Restrictions...................................................................................23
6.3.1.
Meals and Dietary Restrictions ....................................................23
6.3.2.
Activity .........................................................................................23
6.4.
Screen Failures...........................................................................................23
7.
TREATMENTS.......................................................................................................24
7.1.
Treatments Administered............................................................................24
7.1.1.
Medical Devices...........................................................................24
7.2.
Method of Treatment Assignment ...............................................................24
7.3.
Blinding.......................................................................................................24
7.4.
Preparation/Handling/Storage/Accountability..............................................24
7.5.
Treatment Compliance................................................................................24
7.6.
Concomitant Therapy..................................................................................24
7.7.
Treatment after the End of the Study ..........................................................25
8.
DISCONTINUATION CRITERIA.............................................................................26
8.1.
Discontinuation of Study Treatment ............................................................26
8.1.1.
Liver Chemistry Stopping Criteria ................................................26
8.1.2.
QTc Stopping Criteria ..................................................................26
8.2.
Withdrawal from the Study..........................................................................26
8.3.
Lost to Follow Up........................................................................................26
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................27
9.1.
Efficacy Assessments.................................................................................27
 
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9.1.1.
Assessment of Errors in Use of DPI(s).........................................27
9.1.2.
Other Study assessments............................................................28
9.1.2.1.
Arthritis, Visual Impairment and Neurological 
Disorders....................................................................28
9.1.2.2.
Age and Education .....................................................28
9.1.2.3.
Time on current DPI and time since last trained .........28
9.1.2.4.
Level of control and exacerbation history....................29
9.2.
Adverse Events...........................................................................................29
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................29
9.2.2.
Method of Detecting AEs and SAEs.............................................29
9.2.3.
Follow-up of AEs and SAEs.........................................................29
9.2.4.
Regulatory Reporting Requirements for SAEs .............................30
9.2.5.
Cardiovascular and Death Events................................................30
9.3.
Safety Assessments ...................................................................................30
9.4.
Pharmacokinetics .......................................................................................30
9.5.
Pharmacodynamics ....................................................................................31
9.6.
Genetics .....................................................................................................31
9.7.
Biomarkers .................................................................................................31
9.8.
Health Economics OR Medical Resource Utilisation and Health 
Economics..................................................................................................31
10. STATISTICAL CONSIDERATIONS........................................................................32
10.1.
Hypotheses.................................................................................................32
10.2.
Sample Size Determination ........................................................................32
10.3.
Populations for Analyses ............................................................................33
10.4.
Statistical Analyses.....................................................................................33
10.4.1.
Efficacy Analyses.........................................................................33
10.4.2.
Safety Analyses...........................................................................34
10.4.3.
Other Analyses ............................................................................35
10.4.4.
Interim Analyses ..........................................................................35
11. REFERENCES.......................................................................................................36
12. APPENDICES........................................................................................................38
12.1.
Appendix 1: Abbreviations and Trademarks................................................38
12.2.
Appendix 2: Inhaler specific errors for the inhalers used in this study .........39
12.3.
Appendix 3: Study Governance Considerations..........................................53
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................57
12.5.
Appendix 5: Protocol Amendment History...................................................63
 
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LIST OF FIGURES
PAGE
Figure 1 
Study Schematic ..............................................................................17
Figure 2
Comparisons....................................................................................20
Figure 3
Outline of study procedure and evaluation of errors in DPI 
use process......................................................................................28
LIST OF TABLES
PAGE
Table 1 
Treatment Groups ............................................................................16
 
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1.
SYNOPSIS
Protocol Title: An open-label, low interventional clinical study investigating error rates 
(critical and overall) prior to any retraining in correct use of the ELLIPTA dry powder 
inhaler (DPI) compared to other DPIs including; DISKUS, Turbuhaler, HandiHaler and 
Breezhaler as a monotherapy or in combination, in adult patients with Chronic 
Obstructive Pulmonary Disease (COPD).
Short Title: A low interventional clinical study comparing error rates (critical and 
overall); between the ELLIPTA dry powder inhaler (DPI) and other DPIs, prior to any 
retraining in correct use, and as prescribed to treat COPD patients.
Rationale: This study will investigate error rates for the ELLIPTA DPI, alone or in 
combination, when compared to a number of other DPIs (DISKUS, Turbuhaler, 
HandiHaler and Breezhaler) and combinations of these, as prescribed to COPD patients. 
This study will aim to provide clinical evidence in COPD patients that the minimal 
number of steps required to correctly use the ELLIPTA DPI results in fewer errors made 
by participants. The study will also assess if this lower error rate is then better maintained 
over time, following any required re-training in correct use.
Objectives and Endpoints: The objectives and endpoints for the study are listed in the 
table below. 
 
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Objectives
Endpoints
Primary
To compare the number of COPD patients 
making critical errors when using their current
prescribed inhaled medication, at V1 and prior 
to any re-training in correct use.
The percentage of participants making at least 
one critical error at V1 for each DPI tested.
Secondary
To compare the number of COPD patients 
making overall errors, when using their current
prescribed inhaled medication at V1 and prior 
to any re-training in correct use.
The percentage of participants making at least 
one overall error at V1 for each DPI tested.
To compare the number of COPD patients 
making critical and overall errors, when using 
their current prescribed inhaled medication at 
V2 (week 6).

The percentage of participants making 
at least one critical error at V2 for each 
DPI tested. 

The percentage of participants making 
at least one overall error at V2 for each 
DPI tested.
Exploratory
To explore, across all DPIs tested, if any 
association between critical errors, and key 
patients characteristics including:

Age.

Educational Status.

Co-Morbidities (Arthritis (upper limbs), 
Neurological Disorders & Visual 
impairment).

Time on current DPI(s).

Time since last trained on DPI(s).

Level of control (COPD Assessment 
Test (CAT) and Exacerbation History).
Exploration of these characteristics will be 
investigated using a logistic regression model on 
the primary endpoint of, the percentage of 
participants making at least one critical error at 
V1 for each inhaler tested, including each of 
these factors as terms in the model.

Age obtained from Demography.

Educational status from time in full time 
education.

Co-morbidities will be documented as 
relevant to DPI use.

Time on current DPI(s) and time since 
last trained will be documented 
categorically; however time on current 
DPI(s) will be included in the primary 
analysis model.

Level of control will be assessed by:
o COPD Assessment Test.
o Exacerbation History (Previous 
1 year and required treatment 
with antibiotics and/or steroids).
Overall Design:
This is an open-label, low interventional study which does not involve administration of 
treatment nor placebo. The analysed population will be the Intent to Treat (ITT) 
population, which is defined as all patients who have demonstrated use in their primary 
DPI from one or more of the prescribed DPIs listed below.
 
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Screened and confirmed COPD patients will attend the clinic for two visits, where they 
will demonstrate the use of their prescribed DPI. This will investigate the relative ability 
of COPD patients to use their prescribed DPI. Participants will demonstrate DPI use over 
two visits, approximately 6 weeks apart. Their demonstration of DPI use at Visit 1 (V1)
will serve as the primary end-point in this study. Visit 2 (V2) will serve as the secondary 
end-point, where their ability to maintain the correct use of their prescribed DPI will be 
examined. 
Participants taking part in the study must be using one of the listed DPIs as their primary 
treatment (the term ‘primary treatment’ is explained in detail in Section 5.1):

ELLIPTA (RELVAR ELLIPTA™, ANORO ELLIPTA™or INCRUSE
ELLIPTA™)

Turbuhaler (Symbicort Turbuhaler)

DISKUS (Seretide DISKUS™)

HandiHaler. (Spiriva HandiHaler)

Breezhaler (Ultibro or Seebri Breezhaler)
Participant’s use of the above listed DPIs will be assessed for critical and overall errors. 
Following error assessment, participants will be instructed in correct use of their DPI(s) if 
they have made any errors during their visit, as they would in general/primary practice. If 
the participant has used a DPI correctly, they will not receive any instruction on correct 
use for that DPI, but will be informed of their correct use.
Within 6 weeks, plus or minus 7 days (deemed long enough to establish if any retraining 
is required, or if no training required, correct use is maintained), participants will attend 
the clinic for V2 and they will be reassessed for errors made during use of their DPI. Any 
changes in health and prescriptions will be captured. Upon completion of V2, the 
participant will be discharged from the study. This is detailed in Figure 1 below.
Figure 1
Study Schematic
 
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Number of Participants:
Sufficient patients with COPD will be screened in order to assure that each arm (outlined 
in Table 1) consists of 50 patients (A-I). Approximately 450 evaluable participants will 
complete the study.
Treatment Groups and Duration:
The duration of the study consists of two visits, approximately 6 weeks apart (± 7 days). 
Patients will continue to use their prescribed medication for the duration of the study. No 
active or placebo medication will be provided during the course of the study.
Table 1 below defines the treatments groups and treatment comparisons of interest 
depending on their prescribed treatment and whether they take a monotherapy or 
combination treatment to treat their COPD.
Table 1
Treatment Groups
Treatments
Combination DPI Treatment Groups 
Single DPI Treatment Groups 
ICS-LABA With
Spiriva HandiHaler (LAMA)
ICS-LABA With 
Incruse ELLIPTA™(LAMA)
Relvar ELLIPTA™(ICS/LABA)
A
G
Symbicort Turbuhaler (ICS/LABA)
B
H
Seretide DISKUS™(ICS/LABA)
C
I
Spiriva HandiHaler (LAMA)
D
Incruse ELLIPTA™ (LAMA)
E
Anoro ELLIPTA ™(LAMA/LABA)
Ultibro Breezhaler (LAMA/LABA)
F
Seebri Breezhaler (LAMA)
Any participant that is included because of a relevant treatment will also, if using a 
generic Ventolin Metered Dose Inhaler (MDI) for rescue treatment, have their rescue
therapy (MDI) errors also assessed during demonstration.
 
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2.
SCHEDULE OF ACTIVITIES (SOA)
Visit 0 
Screening 
Visit 1 
Baseline
Visit 2
Notes
Day 1 (Can 
occur on 
same day 
as V1)
Day 1 (Can 
occur on 
same day 
as V0)
Week 6 
7 days
Procedure
Screening (V0)
Completed prior to V1 
assessments.
Written informed consent
X
V0 can take place on 
the same day as V1. V1 
should be completed no 
later than 30 days after 
consent.
Participant demography
X
Age, height, weight, 
year of birth, sex, 
ethnicity and geographic 
ancestry will be 
recorded.
Medical/disease history 
including COPD, smoking 
and 
Arthritis/Ophthalmic/Neurolog
ical history
X
Participant will have a 
medical history of 
COPD, smoking history, 
time on current DPI(s), 
time since last trained 
on DPI(s) and any co-
morbidities that may 
affect correct use of DPI
recorded.
Exacerbation History
X
Exacerbation history for 
previous year recorded.
COPD diagnosis
X
Documented 
confirmation of COPD 
diagnosis from 
Physician.
Concomitant medication 
history including COPD 
therapy history
X
All current concomitant 
medication of relevance 
(Arthritic, Ophthalmic, 
Neurological
medications) or related 
to an AE will be 
recorded. A minimum 
COPD therapy history 
for the preceding 2 
years will be recorded.
 
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Visit 0 
Screening 
Visit 1 
Baseline
Visit 2
Notes
Inclusion/exclusion criteria
X
All criteria must be met 
prior to inclusion at V1.
Register the patient
X
To ensure the correct 
number of patients are 
included on each arm.
CAT Score
X
Take this for reference 
(exploratory).
Educational status 
X
No. of years spent in full 
time education.
Study Assessments (V1 
+V2)
Assess participant’s ability to 
correctly use their DPI(s) and 
MDI(s) with Checklists
X
X
No instruction provided 
by HCP before or during 
this assessment.
Correct use of DPI training
X
X
Train participants should 
they make errors during 
demonstration.
Adverse event/Serious 
adverse event assessment
X
X
Collected until 
completion of study.
Prescriptions and health 
review
X
X
Review changes in 
prescription and health 
between beginning and 
end of study.
 
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3.
INTRODUCTION
3.1.
Study Rationale
Please note that Turbohaler and ACCUHALER are the names commonly used within the 
United Kingdom for these DPIs. However, in other regions and for the purposes of this 
study, these DPIs are referred to as Turbuhaler and DISKUS respectively in this protocol. 
This study is designed to investigate error rates during the use of ELLIPTA DPI, alone or 
in combination, when compared to a number of other DPI types (DISKUS, Turbuhaler,
HandiHaler and Breezhaler) and combinations of these, as prescribed to COPD patients
during routine medical practice. This study aims to provide clinical evidence in COPD 
patients that the reduced number of steps required to use the ELLIPTA DPI could result 
in fewer errors made by participants, and therefore a more consistent treatment. The 
study will also assess if this reduced error rate is then better maintained over time, 
following any required instruction in correct use.
3.2.
Background
Chronic Obstructive Pulmonary Disease (COPD) is a progressive obstructive lung 
disease that is characterised by long-term poor airflow. The disease manifests when 
noxious particles or gases lead to a modification in a participant’s airways, resulting in 
the development of a chronic inflammatory response. This leads to increasing airflow 
limitation, breathlessness and other symptoms. Despite being both treatable and 
preventable, COPD remains one of the leading causes of morbidity and mortality 
worldwide. Despite recent advances in diagnosis and treatment, the economic and social 
burden of this disease is increasing [GOLD, 2017].
The goal of COPD treatment is to reduce or relieve symptoms, and reduce risk by 
preventing exacerbations. The result of which aims to improve both exercise tolerance 
and health status whilst, preventing disease progression and treating exacerbations, 
ultimately reducing mortality rates. The current treatment of COPD includes; smoking 
cessation, inhaled pharmacological therapy, primarily long and short term 
bronchodilators (2-agonists and anti-cholinergics) and inhaled corticosteroid, as well as 
other non-pharmacological interventions.
The current GOLD treatment guidelines assign COPD patients into four groups from A to 
D, depending on the severity of their symptoms and associated risk. Assignment usually 
incorporates both the patient’s degree of airflow limitation and exacerbation history.
Accordingly, patients belonging to Group A experience the fewest symptoms and are 
thus classified as low risk on the spectrum. These patients may only need a short acting 
bronchodilator as required to relieve symptoms. However, as the disease progresses, 
other inhaled therapies are required in combination in order to maintain airway control.
Such that COPD patients from Group D, whom have a high symptom burden, high risk of 
exacerbations and/or high airflow limitation, may require multiple inhaled therapies 
including: inhaled corticosteroids (ICS), long-acting 2-agonists (LABA) and long-acting 
muscarinic antagonists/anticholinergic agents (LAMA). When all three drugs are 
administered collectively, this is referred to as triple therapy.
 
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Currently, patients requiring triple therapy can be prescribed ICS/LABA and LAMA, or 
LABA/LAMA and ICS, from separate inhalers. The specific ICS/LABA/LAMA 
combination therapy prescribed will determine the variation in inhaler types (and thereby 
the inhalation techniques) and dosing regimens. Use of different inhaler devices, 
inhalation techniques and dosing regimens contributes to treatment complexity. This can
increase the potential for errors during inhaler use, thus reducing or precluding drug 
delivery to the site of action in the lungs [Cochrane M, 2000; van der Palen J, 1999]. 
Fixed-dose combination inhalers that minimise the number of inhalers required could 
simplify treatment, improve adherence, and reduce errors in inhaler use. An inhaler
which incorporates all three treatments consequently, has the potential to more aptly treat 
the disease [GOLD, 2017].
The ability of COPD patients to correctly use their prescribed inhaler(s) coupled with 
adequate training in inhaler technique are also critical factors involved in effective drug 
delivery [Bonini M, 2015; Melani A, 2011]. A review of inhaler use revealed that most 
common errors made by patients included; a failure to exhale before inhalation, failure to 
hold breath after inhalation, incorrect positioning of the inhaler, and failure to execute a 
forceful and deep inhalation. While these mistakes can be remedied by reading the 
Patient Information leaflet (PIL) or training by a nurse or physician, the reality is that 
inefficient inhaler technique can lead to reduced drug delivery and lung deposition may 
result in ineffective treatment of the disease [Lavorini F, 2008].
For any prescribed inhaler, it is thus imperative that the patient follows all the steps in the 
PIL correctly in order to ensure optimal drug delivery. Furthermore, given the time 
demands on healthcare professionals, the time required by a primary care nurse, 
physician, or a community pharmacist to train a patient in correct use of an inhaler(s) at 
the time of initial prescription, and for any subsequent retraining becomes important. 
Therefore, an inhaler which is simple to use and requires minimal time to train would be 
highly advantageous [Bonini M, 2015]. A simple inhaler, which requires fewer steps to 
deliver the active drug, may be preferred by a COPD patient. This has the potential to 
improve compliance, and may potentially impact the overall management of the disease
[Yun Kirby, 2015].
The ELLIPTA DPI has been designed to be simple for patients to use, and data supports 
that when using an ELLIPTA DPI COPD patients make fewer critical and overall errors
compared with other common DPIs tested [van der Palen J, 2016].The ELLIPTA DPI has 
also been shown to be preferred by patients for a number of reasons, including simplicity 
and the reduced number of steps required to receive therapy [van der Palen J, 2016]. The 
ELLIPTA DPI is already available to deliver a LABA/ICS combination (RELVAR
ELLIPTA™), LAMA (INCRUSE ELLIPTA™), and LAMA/LABA combination 
(ANORO ELLIPTA™). Accordingly, in other clinical studies, the benefit of a once daily,
triple therapy where all three active treatments are provided in one ELLIPTA DPI has
been assessed and is in review with regulatory agencies.
3.3.
Benefit/Risk Assessment
The safety profile of all inhalers used in this study is well characterised. Given the nature 
of the study, short duration of dosing and the fact that there is no change in dose from 
 
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what the participant would otherwise be taking, unexpected safety events are not 
anticipated to occur.
This study does not involve treatment with sponsor supplied active or placebo 
medication. Participants who meet the inclusion/exclusion criteria will continue their 
COPD medication as prescribed by their healthcare provider during their participation in 
the study. Participants should continue to follow up with their regular physician for their 
COPD healthcare during the study.
The study procedures include demonstration of the use of the participants prescribed 
inhaler(s) by the study participant. This will also include a subsequent instruction on 
correct use by site staff if correct use is not demonstrated as per the PIL.
Adverse events (AEs) and serious adverse events (SAEs) will be collected for the 
duration of the study.
3.3.1.
Risk Assessment
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Paradoxical 
bronchospasm, which 
may occur with an 
immediate increase in 
wheezing after
inhalation.
As with other inhalation therapy, 
paradoxical bronchospasm may occur with 
an immediate increase in wheezing after 
dosing. From post-marketing data, 
paradoxical bronchospasm has been 
reported at a frequency of <1/10,000 
including isolated reports [Nicklas, 1990].
This should be treated
immediately with a fast and short 
acting inhaled bronchodilator.
Investigators will be instructed to 
assess the participant’s condition 
to determine their eligibility to 
continue in the study and the
need for alternative therapy.
3.3.2.
Benefit Assessment
As there is no treatment provided concomitantly to the patient’s currently prescribed 
medication, no benefit to the participant is expected during this study. However, 
participants may improve their ability to use their DPI as a result of the training involved 
in this study.
3.3.3.
Overall Benefit: Risk Conclusion
The overall potential risk identified is minimal due to the nature of the study, in that no 
COPD medication, in addition to their already prescribed therapy is provided to 
participants.
 
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4.
OBJECTIVES AND ENDPOINTS
Further information on all endpoints described in this section is provided in Section 
10.4.1.
Objectives
Endpoints
Primary
To compare the number of COPD patients 
making critical errors when using their current
prescribed inhaled medication, at V1 and prior 
to any re-training in correct use.
The percentage of participants making at least 
one critical error at V1 for each DPI tested.
Secondary
To compare the number of COPD patients 
making overall errors, when using their current
prescribed inhaled medication at V1 and prior 
to any re-training in correct use.
The percentage of participants making at least 
one overall error at V1 for each DPI tested.
To compare the number of COPD patients 
making critical and overall errors, when using 
their current prescribed inhaled medication at 
V2 (week 6).

The percentage of participants making 
at least one critical error at V2 for each 
DPI tested.

The percentage of participants making 
at least one overall error at V2 for each 
DPI tested.
Exploratory
To explore, across all DPIs tested, if any 
association between critical errors, and key 
patients characteristics including:

Age.

Educational Status.

Co-Morbidities (Arthritis (upper limbs), 
Neurological Disorders & Visual 
impairment).

Time on current DPI(s).

Time since last trained on DPI(s).

Level of control (COPD Assessment 
Test (CAT) and Exacerbation History).
Exploration of these characteristics will be 
investigated using a logistic regression model on 
the primary endpoint of, the percentage of 
participants making at least one critical error at
V1 for each inhaler tested, including each of 
these factors as terms in the model. Further 
information about these factors is described in 
Section 9.1.2.

Age obtained from Demography.

Educational status from time in full time 
education.

Co-morbidities will be documented as 
relevant to DPI use.

Time on current DPI(s) and time since 
last trained will be documented 
categorically; however time on current 
DPI(s) will be included in the primary 
analysis model.

Level of control will be assessed by:
o COPD Assessment Test.
o Exacerbation History (Previous 
1 year and required treatment 
with antibiotics and/or steroids).
 
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5.
STUDY DESIGN
5.1.
Overall Design
This study will be conducted as an open-label, low-interventional study. COPD 
diagnosed participants will attend the clinic for the screening visit (V0) and subsequent 
assessment visit (V1). These visits may occur on the same day. They will need to 
withhold a dose of their prescribed inhaled medicine (maintenance) and bring all of their 
prescribed inhaled medicines (maintenance and rescue) with them during V1 and V2. 
Participants will be included in the study if they are prescribed any of the following DPIs
for maintenance treatment of their COPD: ELLIPTA (RELVAR ELLIPTA™, ANORO 
ELLIPTA™or INCRUSE ELLIPTA™), Turbuhaler (Symbicort Turbuhaler), DISKUS
(Seretide DISKUS™), HandiHaler (Spiriva HandiHaler), and Breezhaler (Ultibro or 
Seebri Breezhaler). 
Participants using any other inhalers not listed here to receive maintenance therapy are 
hereby excluded from participation. For the purposes of this study, these DPIs are defined 
as primary or secondary, depending on the total number of DPIs prescribed to the patient
and the method of combination treatment delivered as described below:

Participants prescribed therapy via a single DPI, in either a fixed dose combination 
LABA/ICS (ELLIPTA, Turbuhaler, DISKUS), a monotherapy LAMA (ELLIPTA, 
HandiHaler, Breezhaler), or a fixed dose combination LAMA/LABA (ELLIPTA, 
Breezhaler) would have that DPI considered as the primary DPI for analysis.

For participants receiving prescribed therapy via two of these types of DPI, the DPI
from which they receive LABA/ICS (ELLIPTA or Turbuhaler or DISKUS) will be 
considered the primary DPI for analysis, while the DPI from which they receive 
LAMA (HandiHaler or ELLIPTA) treatment will be considered secondary during 
analysis. 
Participants will be separated into nine different treatment groups (A-I) in this study 
depending on their prescribed COPD treatment, as is outlined in Table 1 below. Groups 
A-F include patients using a single DPI to treat their COPD. Groups G-I consist of 
patients who are prescribed two DPIs for treatment of their COPD. 
Table 1
Treatment Groups
Treatments
Combination DPI Treatment Groups 
Single DPI Treatment Groups
ICS-LABA With
Spiriva HandiHaler (LAMA)
ICS-LABA With 
Incruse ELLIPTA™(LAMA)
Relvar ELLIPTA™(ICS/LABA)
A
G
Symbicort Turbuhaler (ICS/LABA)
B
H
Seretide DISKUS™(ICS/LABA)
C
I
Spiriva HandiHaler (LAMA)
D
Incruse ELLIPTA™(LAMA)
E
 
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Treatments
Combination DPI Treatment Groups 
Single DPI Treatment Groups
ICS-LABA With
Spiriva HandiHaler (LAMA)
ICS-LABA With 
Incruse ELLIPTA™(LAMA)
Anoro ELLIPTA ™(LAMA/LABA)
Ultibro Breezhaler (LAMA/LABA)
F
Seebri Breezhaler (LAMA)
The use of all DPIs specified in this study will be assessed for both critical and overall
errors. After successful inclusion into the study, participants will have their maintenance 
DPI’s and relevant rescue therapy (MDI) errors (if used by patient) assessed at V1, 
receiving no training or information on technique from health clinic staff prior to that 
assessment. Following error assessment, if the participant has made any errors during 
their visit, they will be instructed on the correct use of their DPI(s) as they would in 
general/primary practice. If the participant uses their DPI correctly, they will not receive 
any instruction on correct use for that DPI, but will be informed of their correct use.
Other baseline information including demography, smoking history, symptom score 
(CAT), medical history, time on each DPI, time since last trained and educational 
information will be captured at this visit.
Within 6 weeks, plus or minus 7 days (deemed long enough to lose or forget training), 
participants will attend the clinic for V2 and will be reassessed for errors made during use 
of their DPI(s). Any changes in health and prescriptions will be captured at this visit. 
Upon completion of V2, participants will be discharged from the study. They will be 
referred to their GP for further training if they continue to demonstrate incorrect use of 
their prescribed DPI. This is detailed in Figure 1 below.
Figure 1
Study Schematic
 
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The primary endpoint for this study will be the percentage of participants making at least 
one critical error (critical error rate) during the use of their primary DPI. The 
comparisons that will be made between treatment groups are outlined in Figure 2 below
and are as follows:
Primary comparisons:
1. RELVAR ELLPITA DPI vs. any other ICS/LABA (Seretide DISKUS™or 
Symbicort Turbuhaler) DPI.

This comparison aims to compare critical error rates in the primary 
ICS/LABA DPIs.

Group A versus group B

Group A versus group C
2. INCRUSE ELLIPTA™or ANORO ELLIPTA™DPI vs. any other LAMA
(Spiriva HandiHaler or Seebri Breezhaler), or LAMA/LABA (Ultibro Breezhaler)
DPIs.

This comparison aims to compare critical error rates in the 
primary LAMA and LAMA/LABA DPIs.

Group E versus Group D

Group E versus Group F
Other comparisons:
3. RELVAR ELLIPTA™DPI vs. RELVAR ELLIPTA™with any other LAMA
(Spiriva HandiHaler or INCRUSE ELLIPTA™) DPI.

This aims to compare critical error rates in the primary DPI,
simulating a triple therapy from one DPI (ELLIPTA) against triple 
 
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therapy from two ELLIPTA DPIs, or from ELLIPTA DPI with any 
other LAMA DPI.

Group A versus Group G
4. RELVAR ELLIPTA™DPI vs. all ICS/LABA (Seretide DISKUS™, RELVAR 
ELLIPTA™or Symbicort Turbuhaler) DPIs with a LAMA (Spiriva HandiHaler, 
Seebri Breezhaler or INCRUSE ELLIPTA™) second DPI.

This aims to compare critical error rates in the primary DPI, 
simulating a triple therapy delivered in one ELLIPTA DPI against
a triple therapy from any two other DPIs used in the study.

Group A versus Group G+H+I
5. RELVAR ELLIPTA™DPI with or without a LAMA DPI (Spiriva HandiHaler, 
Seebri Breezhaler or INCRUSE ELLIPTA™) vs. any other ICS/LABA (Seretide 
DISKUS™or Symbicort Turbuhaler) DPI with or without a LAMA (Spiriva 
HandiHaler or Seebri Breezhaler) DPI.

This aims to compare critical error rates in the primary DPI,
simulating a triple therapy delivered in one ELLIPTA DPI or 
combination of DPIs against a triple therapy using any other 
ICS/LABA delivering primary DPI.
 
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
Group A+G versus B+H

Group A+G versus C+I
All comparisons investigated are outlined in Figure 2 below:
Figure 2
Comparisons
The secondary endpoints will be tested in the same way as the primary endpoints and will 
also involve the same comparisons, however it will assess the percentage of participants 
making at least one overall error at V1 for each DPI tested, or one critical and/or overall
error at V2 for each DPI tested. 
If the participant cannot demonstrate correct use by the end of V2, they will be referred to 
their General Practitioner (GP) for additional training.
 
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5.2.
Number of Participants
Sufficient patients with COPD will be screened to ensure that approximately 450
participants will be enrolled to achieve 50 evaluable participants per treatment group (A-
I). An evaluable participant is defined in the Intent-to-Treat population in Section 10.3.
If participants prematurely discontinue the study, additional replacement participants may
be recruited at the discretion of the Sponsor.
5.3.
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 scheduled procedure shown in the Schedule of 
Activities.
The end of the study is defined as the date of the last visit of the last participant in the 
study.
5.4.
Scientific Rationale for Study Design
The study design has been chosen in order to appropriately capture the ability of COPD 
patients to use their DPI in a low interventional setting. It involves an investigation of the 
error rate in the ELLIPTA DPI, alone or in combination, when compared to a number of 
other DPIs (DISKUS, Turbuhaler, HandiHaler and Breezhaler) and combinations of 
these, as prescribed to COPD patients. It will also investigate whether upon correction of 
these errors during retraining at V1, the patient after approximately 6 weeks at V2 
maintains correct use regardless of whether they were trained by the HCP or not. 
This information will aim to provide clinical evidence in COPD patients that the reduced 
number of steps required by the ELLIPTA DPI results in fewer errors made by the 
participants. It will also help determine the extent to which this reduced error rate is 
maintained over time after appropriate retraining in correct use, as would occur in a real 
world setting where patients are trained/retrained by a doctor (GP), nurse or pharmacist. 
5.5.
Dose Justification
Not applicable as no active treatment will be provided in this study
 
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6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
TYPE OF PARTICIPANT AND DIAGNOSIS
1. Participants with documented Physician’s diagnosis of COPD, and currently 
receiving maintenance therapy
2. Aged 40 years of age at inclusion.
3. Using one of the maintenance therapies of interest described in Table 1, for at least 3 
months prior to inclusion on the study.
SEX
4. Males or Females
INFORMED CONSENT
5. Capable of giving signed informed consent, which includes compliance with the 
requirements and restrictions listed in the consent form and in the protocol.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
CONCURRENT MEDICATIONS/MEDICAL HISTORY 
1. Asthma: Participants with a current diagnosis of asthma. Participants with a prior 
history of asthma are eligible if they have a current diagnosis of COPD.
RELEVANT HABITS
2. Drug/alcohol abuse: Participants with a known or suspected alcohol or drug abuse 
history at screening (V0) that in the opinion of the investigator could interfere with 
the participant’s proper completion of the protocol requirement.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
3. Investigational Product: Participants who have received an investigational drug 
and/or medical device within 30 days of entry into this study (Screening/V1), or 
within five half-lives of the investigational drug, whichever is longer.
4. Investigational Product: Participants who have been trained during participation in 
any device study in the 6 months prior to entry into this study.
 
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6.3.
Lifestyle Restrictions
There are no lifestyle restrictions.
6.3.1.
Meals and Dietary Restrictions
There are no meal or dietary restrictions.
6.3.2.
Activity
There are no restrictions on activity.
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently entered in the study. 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, screen failure details, eligibility criteria, and any serious adverse events 
(SAEs).
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened once. Rescreened participants should be assigned a new participant
number.
 
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7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol. The term ‘study treatment’ is used throughout the protocol, 
however it must be reiterated that there will not be any administration of a study 
treatment, neither placebo, nor investigational treatment during this study. Participants 
will be taking their own prescribed COPD treatment and dosage.
7.1.
Treatments Administered
This study does not involve the administration of any new treatments. It assesses the 
ability of the participant to use their currently prescribed treatment (DPI).
7.1.1.
Medical Devices

Medical devices (not manufactured by or for GSK) that will be used in this study are 
HandiHaler and Breezhaler.
7.2.
Method of Treatment Assignment
All participants will be assigned to their relative treatment groups based on their current 
prescribed treatment. Participants will be assigned in equal numbers to one of the nine 
groups tested in the study (A-I) based on the current medication that they are prescribed. 
The nine treatment groups are outlined in Table 1 and assignment of participants to their 
respective treatment arms will cease once the required number of participants has been 
reached.
7.3.
Blinding
This is an open label study, as the participants are providing their own prescribed 
medication for the duration of the study. There will be no blinding.
7.4.
Preparation/Handling/Storage/Accountability
As the study does not involve the administration of any new treatment and the patient 
will only be taking their prescribed medication, relevant instructions how to prepare, 
handle and store the medication will be outlined in detail in the respective PIL for the 
participants prescribed treatment.
7.5.
Treatment Compliance
Not applicable as the participant is not being provided any new treatment during this 
study
7.6.
Concomitant Therapy
A detailed history of previous and ongoing COPD medications, in particular any types of 
inhalers used to deliver these medications for the previous 24 months from V0 should be 
 
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recorded in order to correctly place the participant in the relevant treatment group. This is 
a three visit study unless V0 and V1 occur on the same day and patients should continue 
to take their medication as prescribed by their physician throughout the course of the 6 
week study.
However, any medication or vaccine of relevance to the study (Arthritis, Visual 
Impairment or Neurological Disorders) or prescribed for an AE experienced during the 
study that the participant is receiving at the time of enrolment or receives during the 
study must be recorded along with:

reason for use

dates of administration including start and end dates

dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
7.7.
Treatment after the End of the Study
Not applicable as there is no active treatment provided in this two visit study. Participants 
will be taking their prescribed medication for the duration of this study and will not 
receive any specific post-study treatments. 
 
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8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
Not applicable as the participants are not introduced to any new treatment(s).
8.1.1.
Liver Chemistry Stopping Criteria
Not applicable as the participants are not introduced to any new treatment(s).
8.1.2.
QTc Stopping Criteria
Not applicable as the participants are not introduced to any new treatment(s).
8.2.
Withdrawal from the Study

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, compliance or administrative reasons.

If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent.

Refer to the SoA for data to be collected at the time of the follow-up visit and 
for any further evaluations that need to be completed.
8.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
one of the scheduled visits 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 a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee 
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.

Should the participant continue to be unreachable, 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 summarised in the SoA.

Participant registration will be described in the Study Reference Manual (SRM).

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 the study.

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 criteria and was performed within 
the time frame defined in the SoA.
9.1.
Efficacy Assessments
9.1.1.
Assessment of Errors in Use of DPI(s)
Participants will be assessed on their use of their prescribed DPI. A checklist for each 
DPI will be provided to HCPs for scoring errors during the study conduct. The checklists 
will be provided in the Study Reference Manual and are located in Appendix 12.2.
The errors listed will be aligned with the correct use information from the respective DPI 
PILs, in the form of a checklist. The errors made during the demonstration by participants 
are defined as “critical”, when the participant receives a lesser/no dose, and “non-
critical”, when the dose may not be affected, but the participant has demonstrated 
improper use of their DPI, as per the PIL. The combination of all errors made will be 
described as overall errors.
At V1, participants will be asked to demonstrate use of their prescribed DPI and MDI if 
applicable. Any errors (critical or non-critical) made by the participant will be recorded 
by the HCP on the checklists provided in Appendix 2. If the participant makes no errors, 
this will also be recorded and reported back to the participant by the HCP. There will be 
no further assessment at this visit. However, if the participant makes any errors during the 
demonstration, the HCP will provide instruction on the correct use of their DPI. At V2, 
approximately 6 weeks after V1, the same exact procedure will be carried out. However, 
if the HCP deems the participant still unable to correctly use their prescribed DPI, after a 
third instruction, the participant should be referred to their GP for further assessment. 
This is illustrated below in Figure 3.
 
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Figure 3
Outline of study procedure and evaluation of errors in DPI use 
process
9.1.2.
Other Study assessments
9.1.2.1.
Arthritis, Visual Impairment and Neurological Disorders

This information will be collected via simple questions at the screening visit.
9.1.2.2.
Age and Education

Age will be collected from the participant’s demography information. Education 
information will include time in full time education. This will be documented as 
number of years in full time education, including primary, secondary and tertiary 
education.
9.1.2.3.
Time on current DPI and time since last trained

Time on current DPI will be determined categorically as described below:
o
3 months > x ≤6 months
o
6 months > x ≤1 year
o
1 year > x ≤ 2 years
o
2 years > x ≤ 3 years
o
x > 3 years

Time since last trained on DPI will be captured in the same way as time on 
current DPI; however, it will not be used as a term in the primary analysis model.
 
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9.1.2.4.
Level of control and exacerbation history

Level of control will be assessed at the screening visit (V0) and will include:
o
Participants will undertake the COPD assessment test (CAT) during V0 to 
determine their level of control
o
Participants will have their exacerbation history for the previous 1 year 
collected at V0.
9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 12.4.
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study,
or that caused the participant to discontinue the study (see Section 8).
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs and AEs will be collected from the signing of the ICF until the time 
point specified in the SoA (Section 2).

Medical occurrences that begin before obtaining informed consent will be 
recorded on the Medical History/Current Medical Conditions section of the case 
report form (CRF) not the AE section.

All SAEs will be recorded and reported to the sponsor or designee within 24 
hours, as indicated in Appendix 12.4. 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. 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.

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 12.4.
9.2.2.
Method of Detecting AEs and SAEs
Care will 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. 
9.2.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, will be followed until the event is 
resolved, stabilised, otherwise explained, or the participant is lost to follow-up (as 
 
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defined in Section 8.3). Further information on follow-up procedures is given in 
Appendix 4.
9.2.4.
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, 
Institutional Review Boards (IRB)/Independent Ethics Committees (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 eg, summary or listing of SAE) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.
9.2.5.
Cardiovascular and Death Events
For any cardiovascular events and all deaths, whether or not they are considered SAEs, 
specific Cardiovascular (CV) and Death sections of the CRF will be required to be 
completed. These sections include questions regarding cardiovascular (including sudden 
cardiac death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV Medical 
Dictionary of Regulatory Activities (MedDRA) terms. The CV information should be 
recorded in the specific cardiovascular section of the CRF within one week of receipt of a 
CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
9.3.
Safety Assessments
There are no mandated safety assessments, other than monitoring for AEs and SAEs and 
this is described in detail in Section 9.2.
9.4.
Pharmacokinetics
PK parameters are not evaluated in this study.
 
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9.5.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
9.6.
Genetics
Genetics are not evaluated in this study.
9.7.
Biomarkers
Biomarkers are not evaluated in this study.
9.8.
Health Economics OR Medical Resource Utilisation and 
Health Economics
Health Economics/Medical Resource Utilisation and Health Economics parameters are 
not evaluated in this study.
 
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10.
STATISTICAL CONSIDERATIONS
10.1.
Hypotheses
The primary purpose of this study is to assess the number of critical errors made by 
COPD patients for each DPI tested.
The primary endpoint of the study is the percentage of participants making at least one 
critical error (critical error rate) for each DPI at V1. This will be analysed using logistic 
regression and will be adjusted for the covariate of time on current DPI.
For each DPI comparison, the null hypotheses are no difference between DPIs:
H0: p1=p2
The alternative hypothesis is that there is a difference between DPIs:
HA: p1≠p2
The DPIs and treatment comparisons for this study are outlined in Section 5.1 and Table 
1.
10.2.
Sample Size Determination
The sample size calculation is based on the primary endpoint, the percentage of 
participants making at least one critical error in each primary DPI at V1.
Based on reported critical error rates [Molimard M, 2004] and results from study 
[NCT02184624, 200301], a critical error rate (i.e. the proportion of participants making 
at least one critical error using the DPI after reading the patient information leaflet) for 
each of the DPIs has been assumed. The rates in Molimard were generally lower than 
those seen in 200301 for those DPIs present in both, suggesting a difference between the 
reporting within those studies. The ELLIPTA DPI critical error rate has been assumed as 
5%, which is the lowest of the rates observed in the 200301 sub-studies. The rationale for 
choosing the lowest rate is the choice of critical error rate for the other DPIs is assumed 
to be 30%, based on the rates observed in Molimard (Accuhaler 11%; Turbohaler 32%), 
whereas in 200301 we observed higher rates of 44-48%.  
A total of 50 participants in each treatment/DPI group will provide > 94% power to show 
a statistically significant difference between the critical error rate of each of the paired 
treatment/DPI comparisons assuming a true critical error rate of 5% for the ELLIPTA 
DPI and 30% for each of the other DPIs.
A two-sided 5% significance level was assumed to test the difference between critical 
error rates for each of the treatment/DPI comparisons of interest. 
 
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10.3.
Populations for Analyses
The analysis population will be the Intent-to-treat population (ITT), defined as all 
participants who have demonstrated DPI use in their primary DPI. The ITT population 
will be used in all analysis for all endpoints.
Population
Description
All Participants Enrolled 
ASE 
All participants who sign the ICF and for whom a record exists in the 
study database, including screen failures and any participant who 
was not screened but experienced an SAE between the date of 
informed consent and the planned date of the screening visit.
Intent-To-Treat (ITT)
All participants who have been enrolled and demonstrated use of
their primary DPI.
Safety
This population will be the same as the Intent-To-Treat population
10.4.
Statistical Analyses
10.4.1.
Efficacy Analyses
Endpoint
Statistical Analysis Methods
Primary
The primary endpoint is the percentage of participants making at least one critical 
error when using the DPI which forms part of their current prescribed inhaled 
medication, at V1 prior to any re-training in correct use.
This endpoint will be analysed using logistic regression with treatment option as 
fixed effects and adjusting for the covariate of time on current DPI. The odds ratio, 
95% CI and p-value will be presented for the comparison between DPIs. It will be 
based on a two-sided hypothesis testing approach of superiority.
This analysis will be performed for each of the primary and other treatment 
comparisons detailed in Section 5.1 and Table 1.
For all formal treatment comparisons, the errors used are for the primary DPI 
within each treatment/DPI group.
Sensitivity analyses may be performed to take into account patients who have 
changed their medication during the study.  This will be detailed further in the 
RAP.
There will be no adjustment for multiple comparisons on multiple endpoints in the 
analysis.
Secondary
The following secondary endpoints will be analysed in the same way as for the 
primary endpoint and using the same treatment comparisons:
 
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Endpoint
Statistical Analysis Methods

The percentage of participants making at least one overall error at V1 for each 
DPI tested 

The percentage of participants making at least one critical error at V2 for each
DPI tested

The percentage of participants making at least one overall error at V2 for each 
DPI tested
For all formal statistical analyses where more than one DPI has been used, the 
comparison will be between the critical errors recorded on the primary DPI. Error 
rates will not be combined when dual DPIs are being used. 
There will be no adjustment for multiple comparisons on multiple endpoints in the 
analysis.
Exploratory
To explore, across all DPIs tested, if any association between critical errors, and 
key patients characteristics including:

Age.

Educational Status.

Co-Morbidities (Arthritis (upper limbs), Neurological & Visual Impairment)

Time on current DPI(s) (Note: This is already included in the primary 
analysis model, however the parameter may be used in further exploratory 
analyses).

Time since last trained on DPI(s) (collected but not used in the primary 
analysis model).

Level of control- CAT and Exacerbation History.
How these variables will be collected is described in Section 9.1.2.
Exploration of these characteristics will be investigated using a logistic regression 
model on the primary endpoint of the percentage of participants making at least 
one critical error at V1 for each DPI tested, including each of these factors as 
terms in the model.
10.4.2.
Safety Analyses
All safety analyses will be performed on the ITT Population. 
 
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Adverse events (AEs) will be coded using the standard GSK dictionary, Medical
Dictionary for Regulatory Activities (MedDRA), and grouped by body system. The 
number and percentage of participants experiencing at least one AE of any type, AEs 
within each body system and AEs within each preferred term will be presented for each 
treatment group. Separate summaries will be provided for all AEs, drug related AEs, fatal 
SAEs, non-fatal SAEs, AESIs and AEs leading to withdrawal.
Deaths and SAEs, if applicable, will be documented in case narrative format.
10.4.3.
Other Analyses
All other analyses will be described in the reporting and analysis plan.
10.4.4.
Interim Analyses
No interim analyses are planned.
 
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11.
REFERENCES
Bonini M, Usmani, O. The importance of inhaler devices in the treatment of COPD. 
COPD Research and Practice. 2015:1-9. 
Celli B, MacNee W. Standards for the diagnosis and treatment of patients with COPD: a 
summary of the ATS/ERS position paper. European Respiratory Journal. 2004;23:932-
46. 
Cochrane M, Bala M, Downs K, Mauskopf J, Ben-Joseph R. Inhaled Corticosteroids for 
Asthma Therapy: Patient Compliance, Devices, and Inhalation Technique. CHEST. 
2000;117:542-50. 
GlaxoSmithKline Document Number NCT02184624 Study ID 200301. An open-label 
study of inhaler device attributes investigating critical and overall errors, ease of use, and 
preference between a number of inhaler devices (ELLIPTA, Turbuhaler, HandiHaler, 
Breezhaler, MDI, and DISKUS) in adult participants with Chronic Obstructive 
Pulmonary Disease (COPD). Report Date 17-09-2015. 
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the 
diagnosis, management, and prevention of COPD (Updated 2016). , Available from 
http://www.goldcopd.org; 2017. . 
Komase Y, Asako A, Kobyashi A, Sharma R E. Ease-of-use preference for the 
ELLIPTA® dry powder inhaler over a commonly used single-dose capsule dry powder 
inhaler by inhalation device naïve Japanese volunteers aged 40 years or older. 
International Journal of COPD. 2014;9:1365-75. 
Lavorini F, Magnan A, Dubus J, Voshaar T, Corbetta L, Broeders M, Dekhuijzen R, 
Sanchis J, Viejo J, Barnes P, Corrigan C, Levy M, Crompton GK. Effect of incorrect use 
of dry powder inhalers on management of patients with asthma and COPD. Respiratory 
Medicine. 2008;102:593-604. 
Melani A, Bonavia M, Cilenti V, Cinti C, Lodi M, Martucci P. Inhaler mishandling 
remiains common in real life and is associated with reduced disease control. Respiratory 
Medicine. 2011;105:930-38. 
Molimard M, Rahierson C, Lignot S, Depont F, Abouelfath A, Moore N. Assessment of 
Handling of Inhaler Devices in Real Life: An Observational Study in 3811 Patients in 
Primary Care. Journal of Aerosol Medicine. 2004;16:249-54.
Nicklas R. A. Paradoxical bronchospasm associated with the use of inhaled bet agonists. 
Journal of Allergy and Clinical Immunology. 1990;85:959-964. 
van der Palen J, Klein J, van Herwaarden C, Zelhuis G, Seydel E. Multiple inhalers 
confuse asthma patients. European Respiratory Journal. 1999;14:1034-37. 
van der Palen J, Thomas M, Chrystyn H, Sharma R, Imber V , Zhu C-Q, Svedsater H. 
Training And Time To Achieve Correct Inhaler Use: A Comparison Between Inhalers In 
 
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Patients With COPD. American Journal of Respiratory and Critical Care Medicine. 
2016;193:A6811 (c). 
van der Palen J, Thomas M, Chrystyn H, Sharma R, Imber V, Zhu C-Q, Barnes N. 
Inhaler Errors After Reading The Patient Information Leaflet In Patients With COPD: A 
Comparison of Ellipta® With Five Other Inhaler Devices. American Journal of 
Respiratory and Critical Care Medicine. 2016;193:A6811 (a). 
van der Palen J, Thomas M, Chrystyn H, Sharma R, Svedsater H, Zhu C-Q, Barnes N. 
Inhaler Preference In Patients With COPD: A Comparison Of Ellipta® With Five Inhaler 
Devices. American Journal of Respiratory and Critical Care Medicine. 2016;193:A6813 
(b). 
Yun Kirby S, Zhu C-Q, Kerwin E, Stanford R, Georges G. A preference Study of Two 
Placebo Dry Powder Inhalers in Adults with COPD: ELLIPTA Dry Powder Inhaler (DPI) 
versus DISKUS DPI. COPD: Journal of Chronic Obstructive Pulmonary Disease. 
2015;13:167-175. 
 
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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
ASE
All Participants Enrolled
COPD
Chronic Obstructive Pulmonary Disease
CONSORT
Consolidated Standards of Reporting trials
CRF 
Case Report Form
CV
Cardiovascular
DPI
Dry Powder Inhaler
GP
General Practitioner
HCP
Healthcare professional
ICS
Inhaled Corticosteroids
IEC
Independent Ethics Committees
IRB
Institutional Review Boards
ITT
Intent-to-Treat
LABA
Long Acting 2-Agonist
LAMA
Long Acting Anticholinergic
MedRA
Medical Dictionary of Regulatory Activities
PIL
Patient instruction Leaflet
SABA
Short Acting 2-Adrenergic Agonist
SAE
Serious Adverse Effects
SAMA
Short Acting Muscarinic Antagonist
SoA
Schedule of Activities
SRM 
Study Reference Manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
ANORO ELLIPTA
Seebri Breezhaler
INCRUSE ELLIPTA
Spiriva HandiHaler
RELVAR ELLIPTA
Symbicort Turbuhaler
SERETIDE DISKUS
Ultibro Breezhaler
 
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12.2.
Appendix 2: Inhaler specific errors for the inhalers used in 
this study
There are no universally agreed checklists that define critical errors and overall errors for
specific inhalers. The checklist and critical errors for use in this study have been
developed by GSK for each inhaler 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 critical errors checklists are, therefore, as robust as possible. Furthermore, GSK has
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(s) for each inhaler. Some of the steps outlined in the
PIL(s) require several actions to be identified and checked by the HCP.
Critical Errors are identified in underlined text in the list below. A critical error is defined 
as an error that is most likely to result in no or significantly reduced medication being
inhaled. The specific errors outlined in these checklists will NOT change, however, their 
formatting or layout may change prior to use by the site.
 
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Protocol Identifier
204981
Participant Identifier
ELLIPTA (RELVAR, 
INCRUSE and ANORO
Checklist
Visit #
Date of Assessment:
DAY
MONTH
YEAR
Attempt Number:
PIL (1)
HCP (2)
HCP (3)
PIL  
Step
PIL Wording
(Relvar, Incruse and Anoro
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.
• 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 exhalation before 
an inhalation
Exhaled directly into 
mouthpiece
No seal by the lips 
round the 
mouthpiece during 
the inhalation
Inhalation 
manoeuvre was not :
- long
- steady
- deep
Blocked air inlet 
during inhalation 
manoeuvre
 
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PIL  
Step
PIL Wording
(Relvar, Incruse and Anoro
ELLIPTA™June 2016)
Error
(Underlined  text 
indicates a critical 
error)
Completed 
Correctly
Not 
Completed 
Correctly
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:
Staff Name – Print
Staff Signature
Date
 
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Protocol 
Identifier
204981
Participant Identifier
DISKUS Checklist
Visit #
Date of Assessment:
DAY
MONTH
YEAR
Attempt Number:
PIL (1)
HCP (2)
HCP (3)
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 
No seal by the lips 
round the mouthpiece 
during the inhalation
 
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PIL  
Step
PIL Wording
(Seretide DISKUS™March 2015)
Error
(Underlined  text 
indicates a critical 
error)
Completed 
Correctly
Not 
Completed 
Correctly
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.
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)
Other comments:
Staff Name – Print
Staff Signature
Date
 
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Protocol Identifier
204981
Participant Identifier
HandiHaler Checklist
Visit #
Date of Assessment:
DAY
MONTH
YEAR
Attempt Number:
PIL (1)
HCP (2)
HCP (3)
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. 
No seal by the lips 
round the mouthpiece 
during the inhalation
Inhalation manoeuvre 
was not :
- slow
 
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• 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.
- 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 
not make second 
inhalation
Other Comments:
Staff Name – Print
Staff Signature
Date
 
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Protocol Identifier
204981
Participant Identifier
Turbuhaler Checklist
Visit #
Date of Assessment:
DAY
MONTH
YEAR
Attempt Number:
PIL (1)
HCP (2)
HCP (3)
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 
No seal by the lips 
round the mouthpiece 
during inhalation
 
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bite on the mouthpiece.
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
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:
Staff Name – Print
Staff Signature
Date
 
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Protocol Identifier
204981
Participant Identifier
Breezhaler Checklist
Visit #
Date of Assessment:
DAY
MONTH
YEAR
Attempt Number:
PIL (1)
HCP (2)
HCP (3)
PIL  
Step
PIL Wording
(Seebri and Ultibro 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
 
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PIL  
Step
PIL Wording
(Seebri and Ultibro Breezhaler
October 2015)
Error
(Underlined  text 
indicates a critical 
error)
Completed 
Correctly
Not 
Completed 
Correctly
6
Close the Inhaler
• Close the inhaler until you hear a “click”.
Did not completely 
close device capsule 
chamber (heard click 
when satisfactorily)
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.
• Inhale the medicine again by repeating
steps 9 and 10.
Capsule did not rattle
Blocked air inlet during 
inhalation manoeuvre
12
Hold breath:
After you have inhaled the medicine:
• Hold your breath for at least 5-10 seconds
Did not hold breath
 
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PIL  
Step
PIL Wording
(Seebri and Ultibro Breezhaler
October 2015)
Error
(Underlined  text 
indicates a critical 
error)
Completed 
Correctly
Not 
Completed 
Correctly
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.
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:
Staff Name – Print
Staff Signature
Date
 
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Protocol Identifier
204981
Participant Identifier
Generic MDI Checklist
Visit #
Date of Assessment:
DAY
MONTH
YEAR
Attempt Number:
PIL (1)
HCP (2)
HCP (3)
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.
 
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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 so 
poor that patient is 
likely to have 
received no dose or 
only received minimal 
dose.
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:
Staff Name – Print
Staff Signature
Date
 
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12.3.
Appendix 3: 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 
Organisations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (eg, 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 IEC/IRB 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/EC

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
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. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
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. 
 
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
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, 
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. 

Participants who are rescreened are required to sign a new ICF.
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 multicenter 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. 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.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (eg, laboratory 
data). 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 
Clinical Study Report (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. 
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.
 
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
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 source data agreement 
or source data verification form.
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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12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
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 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present 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. 

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. Also, "lack of 
efficacy" or "failure of expected pharmacological action" constitutes an AE or SAE.
 
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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 (eg, 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 (eg, 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 physician’s office or 
outpatient setting. Complications that occur during hospitalization 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 (eg, 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:

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 (eg, 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 1 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 utilized 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 1 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.
 
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
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 
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 health care professionals.

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.

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.
 
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
The investigator or medically-qualified sub-investigator must show evidence within 
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.
 
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12.5.
Appendix 5: Protocol Amendment History
N/A
 
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