A Randomized, Open-label, Cross-over, Placebo Inhaler Study to Evaluate the Correct Use of ELLIPTA™ Dry Powder Inhaler (DPI) Compared to DISKUS™ DPI Used in Combination With HandiHaler DPI in Participants With Chronic Obstructive Pulmonary Disease (COPD)
Phase: PHASE4
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: GlaxoSmithKline

2016N305948_01
CONFIDENTIAL
GlaxoSmithKline group of companies
206901
1
TITLE PAGE
Protocol Title: A randomized, open-label, cross-over, placebo inhaler study to evaluate 
the correct use of ELLIPTA™dry powder inhaler (DPI) compared to DISKUS™DPI 
used in combination with HandiHaler DPI in participants with Chronic Obstructive
Pulmonary Disease (COPD).
Protocol Number: 206901/01
Short Title: A clinical study evaluating the correct use of the placebo ELLIPTA dry 
powder inhaler, in comparison to combinations of placebo dry powder inhalers used to 
provide fixed-dose combination triple therapy, in participants with COPD.
Compound Number:
GSK2834425 (GW685698+GSK573719+GW642444)
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): IND No. 114873
Approval Date: 17-MAY-2017
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 1               2016N305948_01     17-MAY-2017
Original Protocol          2016N305948_ 00     27-Feb-2017
Amendment 01 17-MAY-2017
Overall Rationale for the Amendment: Amendment 01 applies to all study centers 
participating in the 206901 study.  Amendment 01 was created to make the following 
changes: to extend the time a participant must not have used the ELLIPTA, DISKUS, or 
HandiHaler inhalers prior to Visit 1, to delete one of the withdrawal criteria, to add an 
exclusion criteria for participants that are only taking a SABA, and to add some 
clarification to the overall study design. Minor clerical errors are also being corrected.
The specific areas where changes were made to the protocol are listed below.  
SECTION # AND NAME
DESCRIPTION OF CHANGE
BRIEF RATIONALE
Section 1
Synopsis 
(2nd Secondary Objective)
and
Section 4
Objectives and Endpoints
(2nd Secondary Objective)
Original Text: To evaluate the 
relative proportions of critical 
errors for COPD participants 
using an ELLIPTA inhaler 
compared to those using a 
DISKUS and HandiHaler to 
receive their COPD 
medications.
New Text: To evaluate the 
relative proportions of critical 
errors for COPD participants 
using an ELLIPTA inhaler 
compared to those using a 
DISKUS + HandiHaler 
combination to receive their 
COPD medications.
Updated DISKUS 
and HandiHaler to 
DISKUS + 
HandiHaler 
combination for 
consistency.
Section 1
Synopsis
(Other Objectives and 
Endpoints)
Original Text:  Not Present
New Text:
Objective:

To evaluate whether 
more participants with 
Added additional 
“Other” objective/ 
endpoint to capture 
inhaler preference 
based upon inhaler 
regimen and 
number of steps 
needed to take the 
 
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SECTION # AND NAME
DESCRIPTION OF CHANGE
BRIEF RATIONALE
and
Section 4
Objectives and Endpoints
(Other)
COPD prefer the 
ELLIPTA inhaler to the 
DISKUS + HandiHaler 
combination inhalers 
regimen based on the 
number of steps needed 
to take the medication.
Endpoint:

Inhaler regimen 
preference based on the 
number of steps needed 
to take the medication.
medication.
Section 2
Schedule of Activities (SOA)
Procedures
Original Text:  Assess 
participant’s ability to correctly 
use the newly dispensed inhaler  
(following participant reading 
patient instruction leaflet (PIL) 
then demonstrating correct use)5
New Text:  Assess participant’s 
ability to correctly use the newly 
dispensed inhaler (s) (following
participant reading patient 
instruction leaflet (PIL) then 
demonstrating correct use)5
Added (s) to 
inhaler as there 
could be the 
possibility of 2 
inhalers being 
dispensed.
Section 2
Schedule of Activities (SOA)
Preference Questionnaire/Visit 3
Original Text:  Not Present
New Text:  Footnote 8 added:  
Safety assessments will be 
completed at the Early 
Withdrawal Visit: however, 
inhaler preference 
questionnaires will not be 
completed.
Added footnote to 
clarify that 
Preference 
Questionnaires 
will not be 
completed at the 
Early Withdrawal 
Visit as 
documented in 
Section 8.2.
Section 5.1 
Overall Design
(2rd paragraph from the end)
Original Text: Assessment of 
errors will be conducted by 
health care professionals trained 
in the correct inhaler use of 
three inhalers prior to the start of 
the study by face-to-face and 
videotaped instruction training 
Deleted face-to 
face training along 
with videotaped 
instruction.  
Training will be 
explained in the 
 
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SECTION # AND NAME
DESCRIPTION OF CHANGE
BRIEF RATIONALE
based on the checklist of errors. 
After randomization, 
participants will be asked to read 
the PIL of the first inhaler and 
then asked to demonstrate 
correct inhaler use, if they do 
not demonstrate correct use they 
will be instructed on correct use 
by the HCP.  A baseline 
assessment will be conducted 
when the participant is initially 
dispensed the inhaler and a 
second assessment will be 
conducted after each 28 day 
dosing period.  After 
demonstrating correct use at 
Visit 1, the participant will be 
sent home with the inhaler for 
the first 28 day treatment period.  
At Visit 2, two checklists shall 
be completed, the first checklist 
will be for the Day 28 
assessment of the first inhaler 
and the second checklist will be 
another baseline assessment for 
the second inhaler which has 
been dispensed.
New Text:  Assessment of errors 
will be conducted by health care 
professionals trained in the 
correct use of the three inhalers 
prior to the start of the study 
based on the checklist of errors.  
After randomization, 
participants will be asked to read 
the PIL of the first inhaler (s) 
and then asked to demonstrate 
correct inhaler use, if they do 
not demonstrate correct use they 
will be instructed verbally on 
correct use by the HCP.  A 
baseline assessment will be 
conducted when the participant 
is initially dispensed the inhaler 
(s) and a second assessment will 
be conducted after each 28 day 
SRM.
Clarified that this 
next attempt at 
training will be 
given verbally.
Added that the PIL 
will be sent home 
with the 
participant.
Added (s) to 
inhaler as there 
could be the 
possibility of 2 
inhalers being 
dispensed.
Deleted wording 
 
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SECTION # AND NAME
DESCRIPTION OF CHANGE
BRIEF RATIONALE
dosing period.  After 
demonstrating correct use at 
Visit 1, the participant will be 
sent home with the inhaler (s) 
and the PIL for the first 28 day 
treatment period.  At Visit 2, 
two checklists shall be 
completed, the first checklist 
will be for the Day 28 
assessment of the first inhaler (s) 
and the second checklist will be 
another baseline assessment for 
the second inhaler (s) dispensed.
Section 5.1 
Overall Design
(3rd paragraph from the end)
Original Text:  This study offers 
a design aimed at assessing the 
correct use and the number of 
errors made by the participant 
using each inhaler [after reading 
the instructions in the patient 
information leaflet and after 
healthcare professional (HCP) 
instruction] and participant 
preference of the inhalers. 
New Text:  This study offers a 
design aimed at assessing the 
correct use and the number of 
errors made by the participant 
using each inhaler [after reading 
the instructions in the patient 
information leaflet (PIL) and 
after 28 days of use] and 
participant preference of the 
inhalers. 
Clarified that the 
number of errors 
assessed for each 
inhaler will be 
addressed after the 
participant has 
read the PIL and 
after 28 days of 
use and not after 
verbal HCP 
instruction.
Added PIL 
abbreviation for 
the patient 
information leaflet.
Section 5.1
Overall Design
(last paragraph)
Original Text:  Either the 
ELLIPTA checklist or the 
DISKUS + HandiHaler 
combination checklist will be 
utilized after 28 days of 
treatment depending on the 
inhalers returned.  Individual 
checklist assessment of the 
DISKUS and the HandiHaler 
will not be assessed.  
Compliance with returned 
Clarified 
compliance with 
returned inhalers 
based upon the 
dose counters and 
capsules returned.
 
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SECTION # AND NAME
DESCRIPTION OF CHANGE
BRIEF RATIONALE
inhalers (based on the dose 
counter and remaining capsules) 
will also be assessed by study 
staff at Visits 2 and 3.  A 
Preference Questionnaire will 
also be administered and 
reviewed by study staff at Visit 
3 or the last clinic visit.
New Text:  Either the ELLIPTA 
checklist or the DISKUS + 
HandiHaler combination 
checklist will be utilized after 28 
days of treatment depending on 
the inhaler (s) returned.  
Individual checklist assessment 
of the DISKUS and the 
HandiHaler will not be assessed.  
Compliance with returned 
inhalers (based on the dose 
counter for the ELLIPTA and 
DISKUS and remaining 
capsules for the HandiHaler) 
will also be assessed by study 
staff at Visits 2 and 3.  A 
Preference Questionnaire will 
also be administered and 
reviewed by study staff at Visit 
3 or the last clinic visit.
Section 6.1
Inclusion Criteria
and
Section 6.2
Exclusion Criteria
Original Text:  Bulleted text
New Text:  Numbered text.  
Added numbers to formally 
bulleted text for both Inclusion 
(1-9) and Exclusion (1-13) 
Criteria
Added numbers to 
Inclusion and 
Exclusion Criteria 
to help capture 
potential Screen 
Failure reason in e-
CRF
Section 6.1
Inclusion Criteria
(Type of Participant and 
Original Text: Participants must 
have a diagnosis of COPD with 
a documented history of COPD 
for at least 6 months, in 
accordance with the definition 
by the American Thoracic 
Updated the time 
participants must 
have a documented 
history of COPD 
from 6 to 12 
 
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SECTION # AND NAME
DESCRIPTION OF CHANGE
BRIEF RATIONALE
Diagnosis)
Society/European Respiratory 
Society [Celli, 2004].  
New Text:  Participants must 
have a diagnosis of COPD with 
a documented history of COPD 
for at least 12 months, in 
accordance with the definition 
by the American Thoracic 
Society/European Respiratory 
Society [Celli, 2004].
months.
Section 6.1
Inclusion Criteria
(COPD Medications)
Original Text: All participants 
should be able to stay on their 
prescribed maintenance COPD 
treatment without change 
throughout the entire treatment 
period.   
New Text:  All participants 
should be able to stay on their 
prescribed maintenance COPD 
inhaler (s) without change 
throughout the entire treatment 
period.
Clarified that it’s 
the change in 
inhalers not 
treatment that 
should remain 
stable throughout 
the treatment 
period.
Section 6.2
Exclusion Criteria
(Prior/Concomitant COPD 
Therapy)
Original Text:  Participants must 
not have used the ELLIPTA, 
DISKUS, or HandiHaler 
inhalers in the 6 months prior to 
Visit 1.  
New Text:  Participants must not 
have used the ELLIPTA, 
DISKUS, or HandiHaler 
inhalers in the 12 months prior 
to Visit 1.
Extended the time 
a participant 
should be naive to 
inhaler use prior to 
Visit 1.
Section 6.2
Exclusion Criteria 
(Prior/Concomitant COPD 
Therapy)
Original Text:  Not Present 
New Text:  Participants must not 
be receiving only inhaled short-
acting beta-adrenergic agonists, 
i.e., albuterol as their daily 
COPD therapy (as needed [prn] 
Clarified that 
participants only 
taking SABAs are 
not eligible for the 
study
 
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SECTION # AND NAME
DESCRIPTION OF CHANGE
BRIEF RATIONALE
or regularly scheduled).
Section 6.2 
Exclusion Criteria
(Other Diseases/Abnormalities)
Original Text:   Historical or 
current evidence of clinically 
significant or rapidly 
progressing or unstable 
cardiovascular, neurological, 
cardiovascular, neurological, 
renal, hepatic, immunological, 
endocrine (including 
uncontrolled diabetes or thyroid 
disease) or hematological 
abnormalities that are 
uncontrolled.
New Text: Historical or current 
evidence of clinically significant 
or rapidly progressing or 
unstable cardiovascular, 
neurological, renal, hepatic, 
immunological, endocrine 
(including uncontrolled diabetes 
or thyroid disease) or 
hematological abnormalities that 
are uncontrolled.  
Deleted duplicate 
text.
Section 7.7
Concomitant Therapy
(First paragraph)
Original Text:  A detailed 
history of previous and ongoing 
COPD medications, in particular 
any types of inhalers used to 
deliver these medications for the 
previous 6 months from Visit 1, 
should be recorded in order to 
determine the participant’s 
inclusion in the study. 
New Text:  A detailed history of 
previous and ongoing COPD 
medications, in particular any 
types of inhalers used to deliver 
these medications for the 
previous 12 months from Visit 
1, should be recorded in order to 
determine the participant’s 
inclusion in the study.
Clarified the time 
for which previous 
and ongoing 
COPD medications 
will be captured 
prior to Visit 1.
 
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SECTION # AND NAME
DESCRIPTION OF CHANGE
BRIEF RATIONALE
Section 8.2 
Withdrawal/Stopping Criteria 
(first bullet)
Original Text:  Participant is not 
able to demonstrate correct use 
of the inhalers within two 
attempts at the dispensation 
visit.
New Text: Text deleted.
Participant will not 
be withdrawn after 
two attempts to 
demonstrate 
correct use.  There 
are no protocol 
specific number of 
attempts to 
demonstrate 
correct use.  
Verbal training 
should be given 
until correct use 
has been 
demonstrated prior 
to releasing the 
participant from 
the clinic.
Section 9.1.3
Other Endpoints
Original Text: Not Present 
New Text: Inhaler regimen 
preference based on the number 
of steps needed to take the 
medication
Added additional  
endpoint to capture 
inhaler preference 
based upon inhaler 
regimen and 
number of steps 
needed to take the 
medication.
Section 10.3
Populations for Analyses
(All Subjects Enrolled (ASE) –
Description)
Original Text: 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 a SAE between the 
date of informed consent and the 
planned date of the Screening 
visit. 
New Text: 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 a SAE between 
signing the informed consent 
Clarified the All 
Subjects Enrolled 
Population 
regarding when 
SAE information 
will be collected 
after signing the 
ICF and screening.
 
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SECTION # AND NAME
DESCRIPTION OF CHANGE
BRIEF RATIONALE
and screening.
Section 10.4.1
Efficacy Analyses
(Other Endpoint)
Original Text: Not Present 
New Text: Inhaler regimen 
preference based on the number 
of steps needed to take the 
medication
Added additional  
endpoint to capture 
inhaler preference 
based upon inhaler 
regimen and 
number of steps 
needed to take the 
medication.
 
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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS.............................................................................................................14
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................18
3.
INTRODUCTION....................................................................................................20
3.1.
Study Rationale ..........................................................................................20
3.2.
Background ................................................................................................20
3.3.
Benefit/Risk Assessment ............................................................................21
3.3.1.
Risk Assessment .........................................................................22
3.3.2.
Benefit Assessment.....................................................................23
3.3.3.
Overall Benefit: Risk Conclusion..................................................23
4.
OBJECTIVES AND ENDPOINTS...........................................................................23
5.
STUDY DESIGN ....................................................................................................25
5.1.
Overall Design ............................................................................................25
5.2.
Number of Participants ...............................................................................27
5.3.
Participant and Study Completion...............................................................27
5.4.
Scientific Rationale for Study Design ..........................................................27
5.5.
Dose Justification........................................................................................27
6.
STUDY POPULATION...........................................................................................28
6.1.
Inclusion Criteria.........................................................................................28
6.2.
Exclusion Criteria........................................................................................29
6.3.
Lifestyle Restrictions...................................................................................30
6.3.1.
Meals and Dietary Restrictions ....................................................30
6.3.2.
Activity .........................................................................................30
6.4.
Screen Failures...........................................................................................31
7.
TREATMENTS.......................................................................................................31
7.1.
Treatments Administered............................................................................31
7.1.1.
Medical Devices...........................................................................33
7.2.
Dose Modification .......................................................................................33
7.3.
Method of Treatment Assignment ...............................................................33
7.4.
Blinding.......................................................................................................33
7.5.
Preparation/Handling/Storage/Accountability..............................................34
7.6.
Treatment Compliance................................................................................34
7.7.
Concomitant Therapy..................................................................................34
7.8.
Treatment after the End of the Study ..........................................................35
8.
DISCONTINUATION CRITERIA.............................................................................35
8.1.
Discontinuation of Study Treatment ............................................................35
8.1.1.
Liver Chemistry Stopping Criteria ................................................35
8.1.2.
QTc Stopping Criteria ..................................................................35
8.1.3.
Temporary Discontinuation ..........................................................35
8.2.
Withdrawal/Stopping Criteria.......................................................................35
8.3.
Lost to Follow Up........................................................................................36
 
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9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................36
9.1.
Efficacy Assessments.................................................................................37
9.1.1.
Primary Endpoint .........................................................................37
9.1.2.
Secondary Endpoints...................................................................37
9.1.3.
Other Endpoints...........................................................................38
9.1.4.
Assessment of Preference...........................................................38
9.2.
Safety Assessments ...................................................................................38
9.2.1.
Adverse Events............................................................................38
9.2.1.1.
Time Period and Frequency for Collecting AE 
and SAE Information ..................................................38
9.2.1.2.
Method of Detecting AEs and SAEs ...........................39
9.2.1.3.
Follow-up of AEs and SAEs........................................39
9.2.1.4.
Regulatory Reporting Requirements for SAEs............39
9.2.2.
Cardiovascular and Death Events................................................40
9.2.3.
COPD Exacerbations...................................................................40
9.2.4.
Pregnancy ...................................................................................41
9.2.5.
Treatment of Overdose................................................................41
9.2.6.
Physical Examination...................................................................41
9.2.7.
Vital Signs....................................................................................41
9.2.8.
Electrocardiograms......................................................................41
9.2.9.
Clinical Safety Laboratory Assessments ......................................41
9.3.
Pharmacokinetics .......................................................................................42
9.4.
Pharmacodynamics ....................................................................................42
9.5.
Genetics .....................................................................................................42
9.6.
Biomarkers .................................................................................................42
9.7.
Health Economics OR Medical Resource Utilization and Health 
Economics..................................................................................................42
10. STATISTICAL CONSIDERATIONS........................................................................42
10.1.
Hypotheses.................................................................................................42
10.2.
Sample Size Determination ........................................................................43
10.3.
Populations for Analyses ............................................................................44
10.4.
Statistical Analyses.....................................................................................44
10.4.1.
Efficacy Analyses.........................................................................44
10.4.2.
Safety Analyses...........................................................................45
10.4.3.
Other Analyses ............................................................................46
10.4.4.
Interim Analyses ..........................................................................46
11. REFERENCES.......................................................................................................47
12. APPENDICES........................................................................................................48
12.1.
Appendix 1: Abbreviations and Trademarks................................................48
12.2.
Appendix 2: Study Governance Considerations..........................................50
12.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................54
12.4.
Appendix 4:  Collection of Pregnancy Information.......................................60
12.5.
Appendix 5: Protocol Amendment History...................................................61
 
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1.
SYNOPSIS
Protocol Title: A randomized, open-label, cross-over, placebo inhaler study to evaluate 
the correct use of ELLIPTA dry powder inhaler (DPI) compared to DISKUS DPI used in 
combination with HandiHaler DPI in participants with Chronic Obstructive Pulmonary 
Disease (COPD).
Short Title: A clinical study evaluating the correct use of the placebo ELLIPTA dry 
powder inhaler, in comparison to combinations of placebo dry powder inhalers used to 
provide fixed-dose combination triple therapy, in participants with COPD.
Rationale:  This study is designed to assess the benefits of delivering triple therapy using 
a single ELLIPTA™ DPI (fixed-dose combination triple therapy) versus delivering triple 
therapy using two different types of inhalers (open triple therapy) to participants with 
Chronic Obstructive Pulmonary Disease (COPD). It will assess correct inhaler use when 
using a single ELLIPTA™ DPI versus using combinations of commercially available and 
commonly used DPIs:  DISKUS™ used in combination with HandiHaler  This study will 
also assess critical errors and preference attributes for fixed-dose combination triple 
therapy as compared to the open triple therapy.
Objectives and Endpoints:  The objectives and endpoints for the study are listed in the 
table below.
Objective
Endpoint
Primary

To evaluate the relative proportions 
of COPD participants who correctly 
use an ELLIPTA inhaler compared to 
those who correctly use a DISKUS + 
HandiHaler combination to receive 
their COPD medications.

Comparison of the correct inhaler use 
as defined by the percentage of 
participants with zero errors after 28 
days of use.
Secondary

To evaluate the overall correct use of 
an ELLIPTA inhaler compared to the 
DISKUS + HandiHaler combination 
in COPD participants.

Number of errors by type for each 
inhaler after 28 days of use.

Number and change in errors per 
participant for each treatment group 
(V2 and V3) after 28 days of use.

Number and change in errors for each 
treatment group in participants with 
one or more errors after 28 days of 
use.
 
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Objective
Endpoint

To evaluate the relative proportions 
of critical errors for COPD 
participants using an ELLIPTA 
inhaler compared to those using a 
DISKUS + HandiHaler combination 
to receive their COPD medications.

Comparison of correct inhaler use as 
defined by the percentage of 
participants with zero critical errors 
after 28 days of use.
Other

To evaluate the impact of number of 
COPD maintenance inhalers on study 
inhaler errors (ELLIPTA and 
DISKUS + HandiHaler) after 28 days 
of use.

Comparison of correct inhalers use as 
defined by the percentage of 
participants with zero errors after 28 
days of use, including the number of 
prescribed maintenance inhalers as a 
covariate.

To evaluate the number of overall 
errors made by COPD participants 
after a participant has read the Patient 
Instruction Leaflet (PIL(s)).

The comparison of participants 
making zero errors after reading the 
PIL (s) at the start of each treatment 
period.

To evaluate the participant’s 
preference of these inhaler options 
based on how easy it was to tell how 
many doses were remaining.

Inhaler preference based on how easy 
it was to tell how many doses remain.

To evaluate inhaler preference of 
taking a regimen that was one inhaler, 
once a day versus multiple inhalers 
with a varied dosing regimen.

Inhaler dosing regimen preference.

To evaluate whether more 
participants with COPD prefer the 
ELLIPTA inhaler to the DISKUS + 
HandiHaler combination inhalers 
regimen based on the number of steps 
needed to take the medication.

Inhaler regimen preference based on 
the number of steps needed to take 
the medication.
Overall Design: This study will be conducted as a randomized, multi-center, open-label, 
cross-over study comparing placebo ELLIPTA (GSK) with placebo DISKUS (GSK) + 
HandiHaler [Boehringer Ingelheim (BI)] to assess correct inhaler use.  A sufficient 
number of participants with COPD will be randomized such that 216 participants 
complete the study.  Participants will continue taking their usual COPD maintenance 
treatment and rescue medications during the entire 56-day study period.
 
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This study has 3 visits and will be completed in approximately 56 days. 
Study Schematic:
Number of Participants:  Approximately 300 participants with COPD will be screened 
to ensure approximately 240 participants will be randomized, such that approximately 
216 evaluable participants complete the study.
Treatment Groups and Duration:  Duration is 3 clinical visits over approximately 56 
days.
There is no active treatment and participants will continue to take their own prescribed 
COPD maintenance and rescue medication during the entire 56-day study period.
The treatment groups are the following:

At Visit 1 (Day 1) approximately half of the participants will be randomized to 
receive a placebo ELLIPTA (QD) inhaler for use during the first 28 day treatment 
period.  The remaining half of the participants will receive a placebo DISKUS 
(BID) + placebo HandiHaler (QD) for use during the first 28 day treatment 
period.

At Visit 2 (Day 28) participants previously receiving the placebo DISKUS + 
placebo HandiHaler inhalers at Visit 1 will receive a placebo ELLIPTA (QD) 
inhaler for the second 28 day treatment period. Those participants initially 
receiving a placebo ELLIPTA inhaler at Visit 1 will receive a placebo DISKUS 
(BID) inhaler + a placebo HandiHaler (QD) inhaler for the second 28 day 
treatment period.

At Visit 3 (Day 56) after conducting their last correct inhaler use assessments, the 
participants will answer either preference questionnaire 1 or preference 
questionnaire 2 depending on their randomization schedule.
 
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Randomization 
Group
Sequence of Using the Inhalers
Preference 
Questionnaire 
Version
1st Period
2nd Period
A
ELLIPTA
DISKUS + 
HandiHaler
1
B
ELLIPTA
DISKUS + 
HandiHaler
2
C
DISKUS + 
HandiHaler
ELLIPTA
1
D
DISKUS + 
HandiHaler
ELLIPTA
2
Participants will use the assigned placebo inhaler, in each period to match the dose in the 
prescribing information for the medication that they match.  ELLIPTA DPI and 
HandiHaler DPI will both be taken as one inhalation, once daily.  DISKUS DPI will be 
taken as one inhalation, twice daily.
Study endpoints will be based on evaluation of participant’s correct use and preference 
questionnaires.
The aim of this study is to further evaluate the participant handling errors on ELLIPTA 
relative to a subset of other available inhalers.  The overall correct use of the GSK 
ELLIPTA relative to two other inhalers, a GSK DISKUS and the Boehringer Ingelheim 
HandiHaler shall be assessed.  Placebo inhalers are used to remove any bias due to 
treatment effect, avoid the need for wash-in/wash-out periods, and to avoid the need to
withhold or discontinue current COPD medications, which may affect the participant’s 
clinical status (improvement or decline) and perceptions.
 
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2.
SCHEDULE OF ACTIVITIES (SOA)
Procedures
Visit 0
Screening
(Can 
occur on 
same day 
as V1)
Visit 1 
Randomization
(Can occur on 
the same day 
as V0)
Visit 2
Assessment/ 
Cross-over
Visit 3
Last Visit/
End of 
Study/Early 
Withdrawal
Study Day
1
28 (2)
56 (2)
Screening/safety 
assessments
Written informed consent 
1
X
Participant demography
X
Medical/disease history 
including chronic 
obstructive pulmonary 
disease (COPD) history
X
Therapy history
X
Inclusion/exclusion 
criteria
X
Concomitant medication
X
X
X
Physical examination2
X
Vital signs2
X
Adverse events (AEs)/
Serious adverse event
(SAEs)3
X
X
X
Randomization 4
X
Study inhaler correct use 
and preference
Participant reviews written 
instructions on the correct 
use of the newly dispensed 
inhaler(s) 
X
X
Assess participant’s ability 
to correctly use the newly 
dispensed inhaler (s) 
(following participant 
reading patient instruction 
leaflet (PIL) then 
demonstrating correct 
use)5
X
X
Assess participant’s ability 
to correctly use the 
returned inhaler(s) without 
instruction6
X
X
 
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Procedures
Visit 0
Screening
(Can 
occur on 
same day 
as V1)
Visit 1 
Randomization
(Can occur on 
the same day 
as V0)
Visit 2
Assessment/ 
Cross-over
Visit 3
Last Visit/
End of 
Study/Early 
Withdrawal
Study Day
1
28 (2)
56 (2)
Assess compliance with 
the returned study 
inhaler(s) (based on the 
dose counter)
X
X
Preference Questionnaire
X8
Worksheets and 
medication
Dispense study inhaler(s)
X
X
Collect study inhaler(s)
X
X
Dispense Medical 
Problems/Medications 
Taken Worksheet 7
X
X
Collect and review 
Medical 
Problems/Medications 
Taken Worksheet 7
X
X
1.
Participants will be assigned a subject number at the time when the informed consent form (ICF) is signed at 
Visit 0 or Visit 1.  The ICF must be signed before any study procedures are conducted.  
2.
Results are recorded in the source documents only.
3.
Refer to protocol Section 9.2.1.1 for AE/SAE data collection period.
4.
Randomisation conducted if the Participant meets all study screening criteria.
5.
A health care professional trained on the inhalers will conduct the assessments at Visits 1 and 2, following 
dispensing of the appropriate inhaler (s) for the next dosing period.  
6.
A health care professional trained on the inhalers will conduct the assessments of the participant’s ability to 
correctly use the returned inhaler (s) at Visits 2 and 3 following return of the inhaler (s) used for the previous 
dosing period. This should be completed at Early Withdrawal Visit if a participant has taken one or more doses 
of the inhaler at home.
7.
Participants will record medical problems and medications taken on the Medical Problems/Medications Taken 
Worksheet between visits.
8.
Safety assessments will be completed at the Early Withdrawal Visit: however, inhaler preference questionnaires 
will not be completed.
 
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3.
INTRODUCTION
3.1.
Study Rationale
This study is designed to assess the benefits of delivering triple therapy using a single 
ELLIPTA™ Dry powder inhaler (DPI) (fixed-dose combination closed triple therapy) 
versus delivering triple therapy using two different types of inhalers (open triple therapy) 
to participants with Chronic Obstructive Pulmonary Disease (COPD).  It will assess 
correct inhaler use when using a single ELLIPTA™ DPI versus using combinations of 
commercially available and commonly used DPIs:  DISKUS™ used in combination with 
HandiHaler  This study will also assess critical errors and preference attributes for a 
fixed-dose triple therapy as compared to the multiple inhalers to receive triple therapy.
The cross-over design is chosen to allow participants to serve as their own control in their 
ability to use both the ELLIPTA and the DISKUS + HandiHaler inhalers.  Placebo 
inhalers will be used to remove any bias due to treatment effect.  The comparison of the 
ELLIPTA to the DISKUS + HandiHaler combination was chosen as this combination of 
inhalers is the most commonly prescribed triple combination in the  United States.  The 
28-day treatment period is consistent with other ELLIPTA correct use and critical errors 
studies.  Correct use will be evaluated with reference to the steps outlined in the 
manufacturer’s package insert for the inhalers.
3.2.
Background
Chronic Obstructive Pulmonary Disease (COPD) is a progressive disease of the airways.
Noxious particles or gases lead to a modification in patient’s airways which develop a
chronic inflammatory response to these environmental factors. This leads to increasing
airflow limitation, breathlessness and other symptoms. Despite being both treatable and
preventable, COPD is a leading cause of morbidity and mortality worldwide. The
economic and social burden of this disease has not been reduced and is increasing despite
advances in diagnosis and treatment. [GOLD, 2017]
The current treatment goals for COPD are to reduce and relieve symptoms and thereby
improve exercise tolerance and health status, whilst reducing risk by preventing disease
progression, preventing and treating exacerbations, and reducing mortality.
Smoking cessation, inhaled pharmacological therapy, primarily long and short term
bronchodilators (beta2-agonists and anticholinergics) and inhaled corticosteroids, and
other non-pharmacological interventions are currently used to achieve the treatment
goals.
The current GOLD treatment guidelines, place patients in 4 groups from A to D,
dependent on severity of symptoms and assessment of risk; with Group A patients having
the fewest symptoms and a low risk as assessed by degree of airflow limitation and/or
exacerbation history. COPD patients in Group A may just need a short acting
bronchodilator as needed to relieve symptoms. However, as disease progresses, other
inhaled therapies are added on to maintain control, such that COPD patients in Group D,
who have many symptoms and a high risk of exacerbations and/or high airflow
 
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limitation, may need multiple inhaled therapies (inhaled corticosteroids (ICS), long-
acting beta2-agonist (LABA) and long-acting anticholinergic (LAMA)).
Currently, patients requiring triple therapy can be prescribed ICS/LABA and LAMA in
separate inhalers. The specific ICS/LABA and LAMA prescribed determine whether the
inhaler types (and thereby the inhalation techniques) and the dosing regimens are similar
or different. Use of different inhaler types with different inhalation techniques and dosing
regimens can add to treatment complexity, and also increase the potential for errors in
inhaler use that reduce or preclude drug delivery to the site of action in the lungs
[Cochrane, 2000, Van Der Palen, 1999].   Fixed-dose combination inhalers that minimize
the number of inhalers required would simplify treatment, improve adherence, reduce 
errors in inhaler use, and potentially lead to better outcomes [GOLD, 2017].
The skill and ability of the COPD patient to use the prescribed inhaler/s correctly coupled
with adequate training in inhaler technique are also critical to ensure effective drug
delivery [Cochrane, 2000, Melani, 2011].  Critical errors made when using inhalers, 
which significantly reduce or completely inhibit drug delivery, have been identified for 
various inhalation devices [Van Der Palen, 2016].  Between 36 and 49% of patients with 
COPD perform critical inhaler errors with currently used inhalers [Van Der Palen, 2016]. 
For any prescribed inhaler, the patient needs to follow all the steps in the patient 
information leaflet correctly in order to ensure optimal drug delivery. In this regard, the 
time needed for a primary care nurse, physician, or a community pharmacist to train a 
patient in correct use of an inhaler at the time of initial prescription, and for any
subsequent retraining becomes important. Given the time demands on healthcare 
professionals, a device which is simple to use and requires minimal time to train would 
be desirable [Bonini, 2015]. Further, patients may prefer easy-to-use inhalers having 
fewer steps to deliver drug; this has the potential to improve compliance and thereby 
impact outcomes.
ELLIPTA™ DPI has been designed to be simple for patients to use. In COPD patients’
naïve to ELLIPTA and comparator inhalers, data has shown that patients make fewer 
critical and overall errors when using ELLIPTA as compared to other common DPIs 
tested [Van Der Palen, 2016(a)]. ELLIPTA DPI was also shown to be preferred by 
patients for a number of attributes, including number of steps and training time required 
to receive therapy [Van Der Palen, 2016(b), Van Der Palen, 2016(c), Komase, 2014]. 
ELLIPTA is already available to deliver a LABA/ICS combination (BREO ELLIPTA), 
LAMA(INCRUSE ELLIPTA), and LAMA/LABA combination (ANORO ELLIPTA).  A 
fixed-dose triple therapy (ICS/LAMA/LABA) is currently being assessed in clinical 
studies to deliver all 3 active treatments from a single ELLIPTA DPI.
3.3.
Benefit/Risk Assessment
This study involves the use of placebo inhalers (placebo ELLIPTA, placebo DISKUS, 
and placebo HandiHaler) that do not contain active treatments. The inhalers contain the 
excipients lactose and lactose blended with magnesium stearate.  Participants with known 
hypersensitivity to any of these or severe milk protein allergy that could contraindicate 
study participation are to be excluded from the study.  Participants who meet the 
inclusion/exclusion criteria will continue their COPD treatment as prescribed by their 
 
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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.
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 inhaling.
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.
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.
Allergic reaction due to 
hypersensitivity to placebo 
excipients.
The placebo inhalers and 
placebo capsules (for 
HandiHaler) contain the 
excipient lactose and 
lactose blended with 
magnesium stearate.  
There are known allergies 
to these ingredients.
Participants with a know 
hypersensitivity to any of 
these, or severe milk protein 
allergy that could 
contraindicate study 
participation are excluded 
from the study (Section 6.2).  
If an allergic reaction occurs, 
it should be treated 
immediately with a fast and 
short acting inhaled 
bronchodilator and other 
appropriate drugs used in 
allergic reactions (e.g. 
glucocorticosteroids, 
adrenalin) guided by the 
nature and severity of the 
allergic reaction.  
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.
 
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3.3.2.
Benefit Assessment
As this is a placebo study, no benefit to the participant is expected.  No active treatment 
is being administered.  The participant will continue to receive their own COPD therapy 
as prescribed.
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.
4.
OBJECTIVES AND ENDPOINTS
This study will compare correct inhaler use along with critical errors and participant 
preference of inhalers for fixed-dosed combination triple therapy from a single ELLIPTA 
inhaler versus triple therapy received from DISKUS in combination with HandiHaler.
Objectives
Endpoints
Primary

To evaluate the relative proportions 
of COPD participants who correctly 
use an ELLIPTA inhaler compared 
to those who correctly use a 
DISKUS + HandiHaler 
combination to receive their COPD 
medications.

Comparison of correct inhaler use as 
defined by the percentage of 
participants with zero errors after 28 
days of use.
Secondary

To evaluate the overall correct use 
of an ELLIPTA inhaler compared 
to the DISKUS + HandiHaler 
combination in COPD participants.

Number of errors by type for each 
inhaler after 28 days of use.

Number and change in errors per 
participant for each treatment group 
(V2 and V3) after 28 days of use.

Number and change in errors for each 
treatment group in participants with one 
or more errors after 28 days of use.

To evaluate the relative proportions 
of critical errors for COPD 

Comparison of correct inhaler use as 
defined by the percentage of 
 
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Objectives
Endpoints
participants using an ELLIPTA 
inhaler compared to those using a 
DISKUS + HandiHaler 
combination to receive their COPD 
medications.
participants with zero critical errors 
after 28 days of use.
Other

To evaluate the impact of number 
of COPD maintenance inhalers on 
study inhaler errors (ELLIPTA and 
DISKUS + HandiHaler) after 28 
days of use.

Comparison of correct inhalers use as 
defined by the percentage of 
participants with zero errors after 28 
days of use, including the number of 
prescribed maintenance inhalers as a 
covariate.

To evaluate the number of overall 
errors made by COPD participants 
after a participant has read the 
Patient Instruction Leaflet (PIL(s)).

The comparison of participants making 
zero errors after reading the PIL (s) at 
the start of each treatment period.

To evaluate the participant’s 
preference of these inhaler options 
based on how easy it was to tell 
how many doses were remaining.

Inhaler preference based on how easy 
it was to tell how many doses remain.

To evaluate inhaler preference of 
taking a regimen that was one 
inhaler, once a day versus multiple 
inhalers with a varied dosing 
regimen.

Inhaler dosing regimen preference.

To evaluate whether more 
participants with COPD prefer the 
ELLIPTA inhaler to the DISKUS + 
HandiHaler combination inhalers 
regimen based on the number of 
steps needed to take the medication.

Inhaler regimen preference based on 
the number of steps needed to take the 
medication.
 
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5.
STUDY DESIGN
5.1.
Overall Design
This study will be conducted as a randomized, multi-center, open-label, cross-over study 
comparing placebo ELLIPTA (GSK) with placebo DISKUS (GSK) + HandiHaler 
[Boehringer Ingelheim (BI)] to assess correct inhaler use.
This study has 3 visits and will be completed in approximately 56 days.  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.
There is no active treatment and participants will continue to take their own prescribed 
COPD maintenance medication and rescue medications during the entire 56-day study 
period.
The treatment groups are the following:

At Visit 1 (Day 1) half of the participants will be randomized to receive a placebo 
ELLIPTA (QD) inhaler for use during the first 28 day treatment period.  The 
remaining half of the participants will receive a placebo DISKUS (BID) + placebo 
HandiHaler (QD) for use during the first 28 day treatment period.

At Visit 2 (Day 28) participants previously receiving the placebo DISKUS + 
placebo HandiHaler inhalers at Visit 1 will receive a placebo ELLIPTA (QD) 
inhaler for the second 28 day treatment period. Those participants initially 
receiving a placebo ELLIPTA inhaler at Visit 1 will receive a placebo DISKUS 
(BID) inhaler + a placebo HandiHaler (QD) inhaler for the second 28 day 
treatment period.

At Visit 3 (Day 56) after conducting their last correct inhaler use assessments, 
participants will answer either preference questionnaire 1 or preference 
questionnaire 2 depending on their randomization schedule.
Randomization 
Group
Sequence of Using the Inhalers
Preference 
Questionnaire 
Version
1st Period
2nd Period
A
ELLIPTA
DISKUS + 
HandiHaler
1
B
ELLIPTA
DISKUS + 
HandiHaler
2
C
DISKUS + 
HandiHaler
ELLIPTA
1
D
DISKUS + 
HandiHaler
ELLIPTA
2
 
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This study offers a design aimed at assessing the correct use and the number of errors 
made by the participant using each inhaler [after reading the instructions in the patient 
information leaflet (PIL) and after 28 days of use] and participant preference of the 
inhalers. 
Assessment of errors will be conducted by health care professionals trained in the 
correct inhaler use of the three inhalers prior to the start of the study based on the 
checklist of errors.  After randomization, participants will be asked to read the PIL of 
the first inhaler (s) and then asked to demonstrate correct inhaler use, if they do not 
demonstrate correct use they will be instructed verbally on correct use by the HCP.  A 
baseline assessment will be conducted when the participant is initially dispensed the 
inhaler (s) and a second assessment will be conducted after each 28 day dosing 
period.  After demonstrating correct use at Visit 1, the participant will be sent home 
with the inhaler and the PIL for the first 28 day treatment period.  At Visit 2, two 
checklists shall be completed, the first checklist will be for the Day 28 assessment of 
the first inhaler (s) and the second checklist will be another baseline assessment for 
the second inhaler (s) dispensed.
A health care professional trained on the inhalers will assess the participant’s ability 
to correctly use the returned inhalers.  Either the ELLIPTA checklist or the DISKUS 
+ HandiHaler combination checklist will be utilized after 28 days of treatment
depending on the inhaler (s) returned.  Individual checklist assessment of the 
DISKUS and the HandiHaler will not be assessed.  Compliance with returned inhalers 
(based on the dose counter for the ELLIPTA and DISKUS and remaining capsules for 
the HandiHaler) will also be assessed by study staff at Visits 2 and 3.  A Preference 
Questionnaire will also be administered and reviewed by study staff at Visit 3 or the 
last clinic visit.
Overall Design:
Day 1: V1
Day 28: V2
               Day 56: V3
     
Day 1
       Day 28                                                        Day 56
Training Inhaler 1                              Training Inhaler 2                     Correct Use Inhaler 2
                                                         Correct Use Inhaler 1                             Preference
                       INHALER 1                                                    INHALER 2
 
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5.2.
Number of Participants
Approximately 300 participants with COPD will be screened to achieve 240 randomized 
and 216 evaluable participants for an estimated total of 108 participants per device 
sequence (not accounting for questionnaires, see Section 10.2).  Questionnaires will then 
be randomly assigned within each device sequence to give 54 per randomized treatment
group.
For the purpose of this study an evaluable participant is defined as a randomized 
participant who completed error assessments for both randomized treatment groups.
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
This study is designed to assess the benefits of delivering triple therapy using a single 
ELLIPTA  DPI (fixed-dose combination triple therapy) versus delivering triple therapy 
using two different types of inhalers (open triple therapy) to participants with COPD.  It 
will assess correct inhaler use when using a single ELLIPTA DPI versus using 
combinations of commercially available and commonly used DPIs:  DISKUS used in 
combination with HandiHaler.  This study will also assess critical errors (which 
significantly reduce or completely inhibit drug delivery), non-critical errors, and 
preference attributes for the fixed-dose combination triple therapy as compared to the 
open triple therapy.
The cross-over design is chosen to allow participants to serve as their own control in their 
ability to use both the ELLIPTA and the DISKUS + HandiHaler inhalers.  Placebo 
inhalers are used to remove any bias due to treatment effect.  The comparison of the 
ELLIPTA to the DISKUS + HandiHaler combination was chosen as this combination of 
inhalers is the most commonly prescribed triple combination in the  United States.  The 
28-day treatment period is consistent with other ELLIPTA correct use and critical errors 
studies.  Correct use will be evaluated with reference to the steps outlined in the 
manufacturer’s package insert for the inhalers.
This study highlights the need for participants using a new inhaler device to have 
adequate training and assessment at the time when starting a new treatment, for periodic 
review of training, and also the need to ensure that the proper inhaler is selected for the 
participant.
5.5.
Dose Justification
Not applicable as this is a placebo-only 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:
Informed Consent
1. Participants must be capable of giving signed informed consent as described in 
Appendix 3 which includes compliance with the requirements and restrictions 
listed in the informed consent form (ICF) and in this protocol.
Type of Participant and Diagnosis
2. Participants must have a diagnosis of COPD with a documented history of COPD 
for at least 12 months, in accordance with the definition by the American 
Thoracic Society/European Respiratory Society [Celli, 2004].
Age
3. Participants must be 40 years of age inclusive, at the time of signing the informed 
consent.
Gender
4. Males or Females. Females must not be pregnant or planning pregnancy during 
the study or not lactating (Appendix 4).
Disease Severity
5. Participants must have a documented post albuterol forced expiratory volume in 
one second (FEV1)/ forced vital capacity (FVC) ratio <0.70 and FEV1 70% of 
predicted obtained within two years of Visit 1.
Smoking History
6. Current or former (defined as participants who have quit smoking for at least 3 
months prior to Screening/Visit 1) cigarette smokers with a > 10 pack-year 
smoking history [Number of pack-years = (number of cigarettes per day ÷ 20) x 
number of years smoked (e.g., 10 pack-years is equal to 20 cigarettes per day for 
10 years, or 10 cigarettes per day for 20 years].
COPD Medications
7. All participants should be currently receiving maintenance treatment for COPD 
for at least 4 weeks prior to Randomization/Visit 1 and evaluated as unlikely to 
change COPD treatment within 4 weeks of Visit 1.
 
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8. All participants should be able to stay on their prescribed maintenance COPD 
inhaler (s) without change throughout the entire treatment period.
Other
9. Participants must be able to read, comprehend, and record information in English.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Participants must not have a current diagnosis of asthma.
Prior/Concomitant COPD Therapy
2. Participants must not have used the ELLIPTA, DISKUS, or HandiHaler inhalers 
in the 12 months prior to Visit 1.
3. Participants must not be receiving their current COPD medications with the 
ELLIPTA, DISKUS, or HandiHaler inhalers.
4. Participants must not be receiving only inhaled short-acting beta-adrenergic 
agonists, i.e., albuterol as their daily COPD therapy (as needed [prn] or regularly 
scheduled).
Exacerbations
5. Participants must not have experienced more than 1 COPD exacerbation which 
required hospitalization in the 12 months prior to Visit 1.
Alcohol and Drug Abuse
6. Participants must not have a known or suspected history of alcohol or drug abuse 
within the last 2 years.
History of Hypersensitivity
7. Participants must not have a history of hypersensitivity to any component of the 
study inhalers (e.g. lactose, magnesium stearate).  In addition, participants with a 
history of severe milk protein allergy that, in the opinion of the study physician, 
contraindicates participation will also be excluded.
Other Respiratory Disorders
8. Participants with other respiratory disorders, including active tuberculosis, active 
lung cancer, sarcoidosis, lung fibrosis, pulmonary hypertension, or pulmonary 
disease (including but not confined to asthma, bronchiectasis with the need for 
 
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treatment, cystic fibrosis, and bronchopulmonary dysplasia), interstitial lung 
diseases or other active pulmonary diseases.
Other Diseases/Abnormalities
            Participants with:
9. Historical or current evidence of clinically significant or rapidly progressing or 
unstable cardiovascular, neurological, renal, hepatic, immunological, endocrine 
(including uncontrolled diabetes or thyroid disease) or hematological 
abnormalities that are uncontrolled. Significant is defined as any disease that, in 
the opinion of the investigator, would put the safety of the participant at risk 
through participation, or which would affect the analysis if the disease/condition 
exacerbated during the study.
10. History of psychiatric disease, intellectual impairment, poor motivation or other 
conditions that will limit the validity of informed consent to participate in the 
study.
Compliance
11. Participants at risk of non-compliance, or unable to comply with the study 
procedures, or unable to continue their current medications.
Investigational Product
12. Participants who have received an investigational drug and/or medical 
device/inhaler within 30 days of entry into this study (Screening/Visit 1), or 
within five drug half-lives of the investigational drug, whichever is longer.
Affiliation with Investigator’s Site
13. Participants will not be eligible for this study if he/she is an immediate family 
member of the participating investigator, sub-investigator, study coordinator, or 
employee of the participating investigator.
6.3.
Lifestyle Restrictions
There are no lifestyle restrictions.
6.3.1.
Meals and Dietary Restrictions
There are no meals or dietary restrictions.
6.3.2.
Activity
There are no restrictions on activity.
 
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6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized.  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).
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.
GSK Clinical Trials Supplies will provide the placebo inhalers for use in this study 
together with placebo capsules where appropriate.  
7.1.
Treatments Administered
This study does not involve the administration of any new treatments.  It assesses the 
ability of the participants to use the placebo inhalers listed in the table below.
 
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Study Treatment 
Name:
ELLIPTA placebo 
DPI
DISKUS placebo 
DPI
HandiHaler DPI and 
placebo Capsules
Dosage formulation:
Placebo DPI 
with two strips 
with 30 blisters 
per strip. 
First strip
containing 
lactose
monohydrate 
and a second 
strip containing
lactose 
monohydrate
blended with 
magnesium 
stearate.
Placebo DPI with 
one blister strip 
containing 
lactose 
monohydrate.
DPI with placebo 
capsules containing 
lactose monohydrate.
Unit dose 
strength(s)/Dosage 
level(s):
NA
NA
NA
Route of 
Administration 
Oral inhalation 
(Inhalation 
Powder).
Oral inhalation 
(Inhalation 
Powder).
Oral inhalation (Inhalation 
Powder).
Dosing instructions:
As directed
As directed
As directed
Packaging and 
Labelling
Study Treatment 
will be provided in 
the appropriate 
container and will 
be labelled as 
required per 
country 
requirement.
Study Treatment 
will be provided in 
the appropriate 
container and will 
be labelled as 
required per 
country 
requirement.
Study Treatment will be 
provided in the 
appropriate container and 
will be labelled as 
required per country 
requirement.
Manufacturer
GSK
GSK
Boehringer Ingelheim
(HandiHaler); 
GSK/Catalent (placebo 
capsules)
 
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7.1.1.
Medical Devices
There are no medical devices utilized in this study.
7.2.
Dose Modification
There are no dose modifications.
7.3.
Method of Treatment Assignment
All participants will be centrally randomized using an Interactive Web Response System 
(IWRS).  Before the study is initiated, the log in information and directions for the IWRS 
will be provided to each site.  
Participants will be assigned in equal numbers to one of the following sequences.  The 
possible sequences are shown below:
Randomization 
Group
Sequence of Using the Inhalers
Preference 
Questionnaire 
Version
1st Period
2nd Period
A
ELLIPTA
DISKUS + 
HandiHaler
1
B
ELLIPTA
DISKUS + 
HandiHaler
2
C
DISKUS + 
HandiHaler
ELLIPTA
1
D
DISKUS + 
HandiHaler
ELLIPTA
2
Study treatments will be dispensed at the study visit summarized in the SoA.
7.4.
Blinding
This is an open-label study; however, the order of treatment and preference questionnaire 
answered by a participant will be assigned using an IWRS.  The site will contact the 
IWRS prior to study treatment administration for each participant.  The site will record 
the treatment assignment on the applicable case report form, if required.  Potential bias 
will be reduced by randomizing the order of treatment and the preference questionnaire 
version answered by the participants.
 
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7.5.
Preparation/Handling/Storage/Accountability

The investigator or designee must confirm appropriate temperature conditions 
have been maintained during transit for all study treatment received and any 
discrepancies are reported and resolved before use of the study treatment.

Only participants enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment. All study 
treatments must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions 
with access limited to the investigator and authorized site staff.

The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation, and final disposition records).

Further guidance and information for the final disposition of unused study 
treatment are provided in the Study Reference Manual. 

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  
7.6.
Treatment Compliance
Participants initially will receive study treatment at the clinical site where they will 
receive study treatment directly under supervision of the investigator or designee.
Compliance will be calculated from the dose counter on returned ELLIPTA and DISKUS 
inhalers after each 28 day treatment period.  HandiHaler compliance will be calculated 
from the number of capsules supplied and returned after 28 days of use.  For compliance 
calculations, study staff should document the number of remaining doses for each inhaler 
prior to the participant leaving the clinic.
7.7.
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 12 months from Visit 1, 
should be recorded in order to determine the participant’s inclusion in the study.
Participants should continue to take their usual COPD and other medication through the 
conduct of the 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
 
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The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
7.8.
Treatment after the End of the Study
There is no active treatment, placebo only, and participants will not receive any specific 
post study treatments.
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 there is no active treatment; all participants will receive placebo 
treatment only.
8.1.2.
QTc Stopping Criteria
Not applicable as there is no active treatment; all participants will receive placebo 
treatment only.
8.1.3.
Temporary Discontinuation
Not applicable as there is no active treatment; all participants will receive placebo 
treatment only.
8.2.
Withdrawal/Stopping Criteria
Any participant may voluntarily discontinue participation in this study at any time.  
Further, an investigator may, at their discretion, discontinue any participant from 
participating in the study at any time.  All investigators with discontinued participants 
from their sites will be required to make every effort to schedule those participants for an 
Early Withdrawal Visit as soon as possible.  Accordingly, the reasons for each 
participant’s withdrawal must be recorded in the case report form (CRF) and may include 
the following:  AE, consent withdrawn, lost to follow-up, protocol deviation, study 
closed/terminated, COPD exacerbation, and investigator’s discretion.  Specific regards 
should be given to distinguish withdrawals due to an AE, COPD exacerbation, and 
protocol deviation.  The occurrence of serious adverse event (SAE) that results in 
withdrawal will be recorded as withdraw due to “adverse event”.  
A participant will also be withdrawn from the study if they experience any of the 
following:

COPD exacerbation which requires hospitalization.
 
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
COPD exacerbation which requires emergency treatment, which would in the 
investigator’s judgement pose continued participation in this study as an 
unacceptable risk (i.e. unable to demonstrate correct use).

AE/SAE that would, in the investigator’s judgement, make continued 
participation in the study an unacceptable risk.

Use of any medication delivered by the ELLIPTA, DISKUS or HandiHaler 
inhalers (excluding placebo inhalers).

Participant reports becoming pregnant during the study.
If a participant is prematurely discontinued from the study, the investigator must make 
every effort to perform the assessments as specified in the SoA at an early withdrawal 
(EW) visit as soon as possible and then discontinue the participant from the study.
Safety assessments will be completed at the Early Withdrawal Visit: however, inhaler 
preference questionnaires will not be completed.  After completion of the Early 
Withdrawal Visit, participants will be discharged from the study.
8.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
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. 
9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA. 

Protocol waivers or exemptions are not allowed. 

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment.
 
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
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 (e.g., 
to confirm the diagnosis of COPD) and obtained before signing of ICF may be 
utilized for screening or baseline purposes provided the procedure met the protocol-
specified criteria and was performed within the time frame defined in the SoA.

Prior to randomization at Visit 1, all assessments to confirm inclusion into the study 
will be completed.  The details of these assessments are defined in the SoA.
9.1.
Efficacy Assessments
9.1.1.
Primary Endpoint
The aim of the study is to evaluate the percentage of participants which correctly use the 
ELLIPTA DPI compared to the DISKUS + HandiHaler DPIs after a 28 day treatment 
period.  “Correct Use” is defined as the percentage of participants with zero errors after 
28 days of use.
A checklist for correct use of each of the study medications has been developed based on 
the steps identified in the Patient Instruction Leaflets (PIL’s).  Following removal of the 
inhaler from the packaging, an eligible participant, after reading the PIL,  will be guided 
by a trained health care provider (HCP) to demonstrate correct use of the inhaler they 
have been assigned.  A baseline assessment will be conducted when the participant is 
initially dispensed the inhaler and a second assessment will be conducted after each 28 
day dosing period.  A trained HCP will complete the appropriate Correct Use Checklist(s) 
at each visit.  At visit 2, two checklists shall be completed, the first checklist will be for 
the Day 28 assessment of the first inhaler (s) and afterwards the second checklist will be 
another baseline assessment for the second inhaler (s) which has been dispensed.
9.1.2.
Secondary Endpoints
A number of additional secondary endpoints shall be evaluated based on the information 
collected in the Correct Use Checklists.  These include:

Number of errors by type for each inhaler after 28 days of use.

Number and change in errors per participant for each treatment group (V2, V3) 
after 28 days of use.

Number and change in errors for each treatment group in participants with one or 
more errors after 28 days of use.

Comparison of correct inhaler use as defined by the percentage of participants 
with zero critical errors after 28 days of use.
 
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9.1.3.
Other Endpoints
A number of additional other endpoints shall be evaluated based on the information 
collected in the Correct Use Checklists.  These include:

Comparison of correct inhaler use as defined by the percentage of participants 
with zero errors after 28 days of use, including the number of prescribed 
maintenance inhalers as a covariant.

The comparison of participants making zero errors after reading the PIL (s) at the 
start of each treatment period.

Inhaler preference based on how easy it was to tell how many doses remain.

Inhaler dosing regimen preference.

Inhaler regimen preference based on the number of steps needed to take the 
medication.
9.1.4.
Assessment of Preference
After completing the correct use assessment for all treatments, the HCP will have the 
participant complete the assigned preference questionnaire. This assessment should occur 
at Visit 3 (Last Visit/End of Study) (Day 56) after the participant has demonstrated their 
inhaler use.
9.2.
Safety Assessments
9.2.1.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 3.
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. 
9.2.1.1.
Time Period and Frequency for Collecting AE and SAE Information

All SAEs will be collected from the signing of the ICF until the time points 
specified in the SoA (Section 2).

All AEs will be collected from randomization until the time points specified in 
the SoA (Section 2).

Medical occurrences that begin before the start of study treatment but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the case report form (CRF) not the AE section.
 
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
All SAEs will be recorded and reported to the sponsor or designee within 24 
hours, as indicated in Appendix 3. The investigator will submit any updated 
SAE data to the sponsor within 24 hours of it being available.

Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. 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 3.
9.2.1.2.
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. 
9.2.1.3.
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, stabilized, otherwise explained, or the participant is lost to follow-up (as 
defined in Section 8.3). Further information on follow-up procedures is given in 
Appendix 3
9.2.1.4.
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 e.g., 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.
 
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9.2.2.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 3 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 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.
9.2.3.
COPD Exacerbations
A COPD exacerbation is defined as acute worsening of symptoms of COPD requiring the 
use of antibiotics, systemic corticosteroids or oral corticosteroids (tablets, suspension, or 
injection) and/or emergency treatment or hospitalization.
Participants who experience a COPD exacerbation during the treatment period may 
remain in the study and should continue to use their study inhaler if possible.  Treatment 
of COPD exacerbations with short-term antibiotics and systemic corticosteroids (less than 
or equal to 14 days) is permitted.
For worsening COPD symptoms/exacerbations requiring:

Emergency treatment the decision whether such a participant would continue in 
the study or be withdrawn would be determined per investigator discretion.  The 
Study Medical Monitor would be available to discuss any related questions with 
the investigator.

Hospitalization:  such a participant should be withdrawn from the study.
If a participant experiences a COPD exacerbation, the COPD exacerbation page of the 
eCRF should be completed.  COPD exacerbations should not be recorded as an Adverse 
Event, unless they meet the definition of a Serious Adverse Event and these SAEs will be 
recorded on the appropriate CRF section and should be reported to GSK for all 
participants.
The time period for collection of COPD exacerbations will be from Visit 1 and will end 
when Visit 3/Early Withdrawal visit has been completed.
Signs and symptoms of COPD will not be considered AEs and will not be recorded in the 
eCRF.
 
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9.2.4.
Pregnancy

Details of all pregnancies in female participants will be collected after the start of 
study treatment. 

If a pregnancy is reported, the investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4.

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Appendix 4. 
9.2.5.
Treatment of Overdose
There is no active treatment in this study, placebo only.
9.2.6.
Physical Examination
The following will be assessed at Visit 1 and recorded in the source documents:

A brief physical examination will include, at a minimum, assessments of the 
skin, lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
9.2.7.
Vital Signs
The following will be assessed at Visit 1 and recorded in the source documents:

Temperature, pulse rate, respiratory rate, and blood pressure will be assessed.

Blood pressure and pulse measurements will be assessed with a completely 
automated device. Manual techniques will be used only if an automated device 
is not available.

Blood pressure and pulse measurements should be preceded by at least 5 
minutes of rest for the participant in a quiet setting without distractions (e.g., 
television, cell phones).

Vital signs will be measured in a semi-supine position after 5 minutes rest and 
will include temperature, systolic and diastolic blood pressure, and pulse rate.
9.2.8.
Electrocardiograms
Electrocardiograms will not be conducted during the study.
9.2.9.
Clinical Safety Laboratory Assessments
Clinical safety laboratory assessments will not be conducted during the study.
 
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9.3.
Pharmacokinetics
PK parameters are not evaluated in this study.
9.4.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
9.5.
Genetics
Genetics are not evaluated in this study.
9.6.
Biomarkers
Biomarkers are not evaluated in this study.
9.7.
Health Economics OR Medical Resource Utilization and 
Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study.
10.
STATISTICAL CONSIDERATIONS
10.1.
Hypotheses
The primary purpose of this study is to assess the number of errors made by
COPD participants, for the ELLIPTA inhaler or DISKUS + HandiHaler inhalers 
combined after 28 days use. This is a superiority study.
The primary endpoint is the percentage of participants making zero errors on the 
ELLIPTA inhaler compared with the DISKUS + HandiHaler inhalers.
The null hypothesis is that there is no difference in the proportion of participants making 
zero errors on the ELLIPTA inhaler compared to the DISKUS + HandiHaler inhalers.
H0: PE – PD+H = 0
The alternative hypothesis is there is a difference in the proportion of participants making
zero errors on the ELLIPTA inhaler compared to the DISKUS + HandiHaler inhalers.
H1: PE – PD+H ≠ 0
 
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10.2.
Sample Size Determination
The sample size calculations for this study have been based on the primary endpoint, 
which is the percentage of participants making zero errors in each treatment group 
(ELLIPTA or DISKUS + HandiHaler) after 28 days use.
The estimates of inhaler errors were taken from the overall errors reported in the 200301 
study for each individual inhaler (ELLIPTA, DISKUS and HandiHaler) separately. 
Although this study is only assessing combined errors in the DISKUS + HandiHaler 
treatment group, individual inhaler errors were used to estimate the combined error rate 
in order to provide a conservative estimate. By doing this it assumes that participants, 
who made no errors on the DISKUS inhaler, would not make any errors of the 
HandiHaler inhaler and vice-versa.
As the 200301 study only had a single visit, no estimates were available for error rates 
over 28 days, however the study did provided estimates of participant errors after reading 
the PIL and after being instructed on correct use by a HCP up to three times. As 
participants will have the PIL for 28 days, and can be instructed by a HCP at the inhaler 
dispensing visit if necessary, both estimates of error rates along with a sensitivity analysis 
examining some of the potential error rates between were used to inform sample size 
calculations.
Using 10,000 simulations, a total of 216 participant (54 per treatment sequence) provide 
at least 90% power to show a statistically significance difference between the overall 
error rate of the ELLIPTA inhaler versus DISKUS + HandiHaler inhalers, for all of the 
paired treatment error rates shown in Table 1.
Table 1
Error rates of ELLIPTA vs. DISKUS + HandiHaler achievable with 
90% power, 5 % Type 1 error using a total of 216 participants 
ELLIPTA
Error Rate
DISKUS + HandiHaler
Error Rate
33%
>=50%
30%
>=47%
20%
>=35%
10%
>=23%
5%
>=15%
Conditional logistic regression and a two-sided 5% significance level were used as the 
analysis method for all simulations performed. As it is expected that some participants 
would drop out or change inhalers during the study, with 10% withdrawal it would be
 
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necessary to enrol 240 participants (60 per treatment sequence) to ensure there were 216 
participants with evaluable data at the end of the study.
For the purpose of this study an evaluable participant is defined as a randomized 
participant who completed error assessments for both randomized treatment groups.
10.3.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
All Subjects 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 a SAE 
between signing the informed consent and screening.
Intent-to-Treat (ITT)
All randomised participants, excluding those who were 
randomised in error, and did not have at least one error 
assessment at Visit 1.  A participant who is recorded as a 
screen failure or run-in failure and also randomised will be 
considered to be randomised in error. Any other participant 
who receives a randomisation number will be considered to 
have been randomised. This population will be analysed 
according to the treatment sequence the participants were 
randomised to, and not the treatment sequence they actually 
received.
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 
zero errors after 28 days use. 
This endpoint will be analysed using conditional logistic regression 
with participant as fixed strata, and treatment option and period as 
fixed effects. The odds ratio, 95% confidence interval (CI) and p-
value will be presented for the comparison between treatment 
options. It will be based on a two-sided hypothesis testing approach 
of superiority.
Secondary
The percentage of participants making at least one critical error after 
28 days use will be analysed using the same model as the primary 
 
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Endpoint
Statistical Analysis Methods
endpoint.
The impact of number of COPD maintenance inhalers will be 
analysed using the same model as the primary endpoint, but with 
number of maintenance inhalers as an additional covariate. 
The following secondary endpoints will be summarised only:

Number of errors by type for each treatment group after 28 
days of use.

Number and change in errors per participant for each 
treatment group (V2 and V3) after 28 days of use.

Number and change in errors for each inhaler in participants 
with one or more errors after 28 days of use.
Other
Analysis of the following other endpoints will be defined in the 
Reporting and Analysis Plan:

Comparison of correct inhalers use as defined by the 
percentage of participants with zero errors after 28 days of 
use, including the number of prescribed maintenance inhalers 
as a covariate.

The percentage of participants making at least one overall 
error after reading the PIL (s) at the start of each treatment 
period.

Inhaler preference based on how easy it was to tell how many 
doses remain.

Inhaler and dosing regimen preference.

Inhaler regimen preference based on the number of steps needed to 
take the medication.
10.4.2.
Safety Analyses
All safety analyses will be performed on the Safety Population. 
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 
AEs, non-fatal SAEs, AESIs and AEs leading to withdrawal.
Deaths and SAEs, if applicable, will be documented in case narrative format.
 
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10.4.3.
Other Analyses
Any other analysis will be documented in the Report and Analysis Plan.
10.4.4.
Interim Analyses
There will be no interim analyses with this study.
 
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11.
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Van Der Palen J, Thomas M, Chrystyn H, Sharma R, Imber V, Zhu C.-Q, et.al. Inhaler 
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Comparison Of Ellipta® With Five Inhaler Devices. Am J Respir Crit Care Med 193;
2016:A6811 (a).
Van Der Palen J, Thomas M, Chrystyn H, Sharma R, Svedsater H, Zhu C.-Q, et.al.
Inhaler Preference In Patients With COPD: A Comparison Of Ellipta® With Five Inhaler
Devices. Am J Respir Crit Care Med 193; 2016:A6813 (b).
Van Der Palen J, Thomas M, Chrystyn H, Sharma R, Imber V, Zhu C.-Q, et.al. Training 
And Time To Achieve Correct Inhaler Use: A Comparison Between Inhalers In Patients 
With COPD. Am J Respir Crit Care Med 193; 2016:A6811 (c).
Van Der Palen J, Thomas M, Chrystyn H, Sharma R, van der Valk Paul, Goosens M, 
et.al. A randomized open-label cross-over study of inhaler errors, preference and time to 
achieve correct inhaler use in patients with COPD or asthma: comparison of ELLIPTA 
with other inhaler devices.   Prim Care Resp Med (2016) 26, 16079.
 
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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
AE
Adverse Event
ASE
All Subjects Enrolled
BI
Boehringer Ingelheim
BID
Twice Daily
CI
Confidence Interval
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic Obstructive Pulmonary Disease
CRF
Case Report Form
CSR
Clinical Study Report
CV
Cardiovascular
DPI
Dry Powder Inhaler
EW
Early Withdrawal
FEV1
Forced Expiratory Volume in one Second
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GSK
GlaxoSmithKline
HCP
Healthcare Professional
ICF
Informed Consent Form
ICH
International Conference On Harmonisation
ICS
Inhaled Corticosteroids
IEC
Independent Ethics Committees
IRB
Institutional Review Boards
ITT
Intent-to-Treat
IWRS
Interactive Web Response System
LABA
Long-Acting Beta2-Agonist
LAMA
Long-Acting Anticholinergic
MedRA
Medical Dictionary of Regulatory Activities
PIL
Patient Instruction Leaflet
QD
Once Daily
SAE
Serious Adverse Event
SoA
Schedule of Activities
SUSAR
Suspected Unexpected Serious Adverse Reactions
 
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Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of 
companies
ANORO ELLIPTA
HandiHaler
BREO ELLIPTA
DISKUS
INCRUSE ELLIPTA
 
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12.2.
Appendix 2: Study Governance Considerations
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (e.g., advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Any amendments to the protocol will require 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 SAEs 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 authorized 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 authorized 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 center. 

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 authorized 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 authorized representative. 
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
Committees Structure
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
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 (e.g., 
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 authorized 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.

Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available.

Definition of what constitutes source data can be found in the Study Reference 
Manual.
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 
 
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completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study treatment development
 
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12.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
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 (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not related 
to progression of underlying disease).

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.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
 
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assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization 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 hospitalization or prolongation of existing hospitalization
In general, hospitalization 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 hospitalization or fulfils any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
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, diarrhea, influenza, 
 
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and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize 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 hospitalization, 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

Revascularization
Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.
 
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
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 sufficient 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.

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 
 
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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 recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology. 

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.
Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper SAE data collection tool (see next Section).

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The investigator or medically-qualified sub-investigator must show evidence within 
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 
 
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next Section) or to the medical monitor/SAE coordinator by telephone.

Contacts for SAE reporting can be found in Study Reference Manual.
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 or the SAE coordinator.

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 Study Reference Manual.
 
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12.4.
Appendix 4:  Collection of Pregnancy Information
Collection of Pregnancy Information
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date.  

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. 

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in Appendix 3. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 
Any female participant who becomes pregnant while participating  

Will be withdrawn from the study. 
 
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12.5.
Appendix 5: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).
 
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Protocol Title: A randomized, open-label, cross-over, placebo inhaler study to evaluate 
the correct use of ELLIPTA™dry powder inhaler (DPI) compared to DISKUS™DPI 
used in combination with HandiHaler™DPI in participants with Chronic Obstructive 
Pulmonary Disease (COPD)
Protocol Number: 206901
Short Title: A clinical study evaluating the correct use of the placebo ELLIPTA dry 
powder inhaler, in comparison to combinations of placebo dry powder inhalers used to 
provide fixed-dose combination triple therapy, in participants with COPD.
Compound Number:
GSK2834425 (GW685698+ GSK573719+GW642444)
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): IND No. 114873
Approval Date: 27-FEB-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...............................................................................................................5
2.
SCHEDULE OF ACTIVITIES (SOA).........................................................................9
3.
INTRODUCTION....................................................................................................11
3.1.
Study Rationale ..........................................................................................11
3.2.
Background ................................................................................................11
3.3.
Benefit/Risk Assessment ............................................................................12
3.3.1.
Risk Assessment .........................................................................13
3.3.2.
Benefit Assessment.....................................................................14
3.3.3.
Overall Benefit: Risk Conclusion..................................................14
4.
OBJECTIVES AND ENDPOINTS...........................................................................14
5.
STUDY DESIGN ....................................................................................................15
5.1.
Overall Design ............................................................................................15
5.2.
Number of Participants ...............................................................................17
5.3.
Participant and Study Completion...............................................................18
5.4.
Scientific Rationale for Study Design ..........................................................18
5.5.
Dose Justification........................................................................................18
6.
STUDY POPULATION...........................................................................................18
6.1.
Inclusion Criteria.........................................................................................19
6.2.
Exclusion Criteria........................................................................................20
6.3.
Lifestyle Restrictions...................................................................................21
6.3.1.
Meals and Dietary Restrictions ....................................................21
6.3.2.
Activity .........................................................................................21
6.4.
Screen Failures...........................................................................................21
7.
TREATMENTS.......................................................................................................22
7.1.
Treatments Administered............................................................................22
7.1.1.
Medical Devices...........................................................................24
7.2.
Dose Modification .......................................................................................24
7.3.
Method of Treatment Assignment ...............................................................24
7.4.
Blinding.......................................................................................................24
7.5.
Preparation/Handling/Storage/Accountability..............................................25
7.6.
Treatment Compliance................................................................................25
7.7.
Concomitant Therapy..................................................................................25
7.8.
Treatment after the End of the Study ..........................................................26
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
8.1.3.
Temporary Discontinuation ..........................................................26
8.2.
Withdrawal/Stopping Criteria.......................................................................26
8.3.
Lost to Follow Up........................................................................................27
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................27
 
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9.1.
Efficacy Assessments.................................................................................28
9.1.1.
Primary Endpoint .........................................................................28
9.1.2.
Secondary Endpoints...................................................................28
9.1.3.
Other Endpoints...........................................................................29
9.1.4.
Assessment of Preference...........................................................29
9.2.
Safety Assessments ...................................................................................29
9.2.1.
Adverse Events............................................................................29
9.2.1.1.
Time Period and Frequency for Collecting AE 
and SAE Information ..................................................29
9.2.1.2.
Method of Detecting AEs and SAEs ...........................30
9.2.1.3.
Follow-up of AEs and SAEs........................................30
9.2.1.4.
Regulatory Reporting Requirements for SAEs............30
9.2.2.
Cardiovascular and Death Events................................................30
9.2.3.
COPD Exacerbations...................................................................31
9.2.4.
Pregnancy ...................................................................................31
9.2.5.
Treatment of Overdose................................................................32
9.2.6.
Physical Examination...................................................................32
9.2.7.
Vital Signs....................................................................................32
9.2.8.
Electrocardiograms......................................................................32
9.2.9.
Clinical Safety Laboratory Assessments ......................................32
9.3.
Pharmacokinetics .......................................................................................32
9.4.
Pharmacodynamics ....................................................................................32
9.5.
Genetics .....................................................................................................33
9.6.
Biomarkers .................................................................................................33
9.7.
Health Economics OR Medical Resource Utilization and Health 
Economics..................................................................................................33
10. STATISTICAL CONSIDERATIONS........................................................................33
10.1.
Hypotheses.................................................................................................33
10.2.
Sample Size Determination ........................................................................33
10.3.
Populations for Analyses ............................................................................34
10.4.
Statistical Analyses.....................................................................................35
10.4.1.
Efficacy Analyses.........................................................................35
10.4.2.
Safety Analyses...........................................................................36
10.4.3.
Other Analyses ............................................................................36
10.4.4.
Interim Analyses ..........................................................................36
11. REFERENCES.......................................................................................................37
12. APPENDICES........................................................................................................38
12.1.
Appendix 1: Abbreviations and Trademarks................................................38
12.2.
Appendix 2: Study Governance Considerations..........................................40
12.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................44
12.4.
Appendix 4:  Collection of Pregnancy Information.......................................50
 
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1.
SYNOPSIS
Protocol Title: A randomized, open-label, cross-over, placebo inhaler study to evaluate 
the correct use of ELLIPTA dry powder inhaler (DPI) compared to DISKUS DPI used in 
combination with HandiHaler DPI in participants with Chronic Obstructive Pulmonary 
Disease (COPD).
Short Title: A clinical study evaluating the correct use of the placebo ELLIPTA dry 
powder inhaler, in comparison to combinations of placebo dry powder inhalers used to 
provide fixed-dose combination triple therapy, in participants with COPD.
Rationale:  This study is designed to assess the benefits of delivering triple therapy using 
a single ELLIPTA™ DPI (fixed-dose combination triple therapy) versus delivering triple 
therapy using two different types of inhalers (open triple therapy) to participants with 
Chronic Obstructive Pulmonary Disease (COPD).  It will assess correct inhaler use when 
using a single ELLIPTA™ DPI versus using combinations of commercially available and 
commonly used DPIs:  DISKUS™ used in combination with HandiHaler.  This study 
will also assess critical errors and preference attributes for fixed-dose combination triple 
therapy as compared to the open triple therapy.
Objectives and Endpoints:  The objectives and endpoints for the study are listed in the 
table below.
Objective
Endpoint
Primary

To evaluate the relative proportions 
of COPD participants who correctly 
use an ELLIPTA inhaler compared to 
those who correctly use a DISKUS +
HandiHaler combination to receive 
their COPD medications.

Comparison of the correct inhaler use 
as defined by the percentage of 
participants with zero errors after 28 
days of use.
Secondary

To evaluate the overall correct use of 
an ELLIPTA inhaler compared to the 
DISKUS + HandiHaler combination 
in COPD participants.

Number of errors by type for each 
inhaler after 28 days of use.

Number and change in errors per 
participant for each treatment group
(V2 and V3) after 28 days of use.

Number and change in errors for each 
treatment group in participants with 
one or more errors after 28 days of 
use.
 
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Objective
Endpoint

To evaluate the relative proportions 
of critical errors for COPD 
participants using an ELLIPTA 
inhaler compared to those using a 
DISKUS and HandiHaler to receive 
their COPD medications.

Comparison of correct inhaler use as 
defined by the percentage of 
participants with zero critical errors 
after 28 days of use.
Other

To evaluate the impact of number of 
COPD maintenance inhalers on study 
inhaler errors (ELLIPTA and 
DISKUS + HandiHaler) after 28 days 
of use.

Comparison of correct inhalers use as 
defined by the percentage of 
participants with zero errors after 28 
days of use, including the number of 
prescribed maintenance inhalers as a 
covariate.

To evaluate the number of overall 
errors made by COPD participants 
after a participant has read the Patient 
Instruction Leaflet (PIL(s)).

The comparison of participants
making zero errors after reading the 
PIL (s) at the start of each treatment 
period.

To evaluate the participant’s 
preference of these inhaler options 
based on how easy it was to tell how 
many doses were remaining.

Inhaler preference based on how easy 
it was to tell how many doses remain.

To evaluate inhaler preference of 
taking a regimen that was one inhaler, 
once a day versus multiple inhalers 
with a varied dosing regimen.

Inhaler dosing regimen preference.
Overall Design:  This study will be conducted as a randomized, multi-center, open-label, 
cross-over study comparing placebo ELLIPTA (GSK) with placebo DISKUS (GSK) + 
HandiHaler [Boehringer Ingelheim (BI)] to assess correct inhaler use. A sufficient 
number of participants with COPD will be randomized such that 216 participants 
complete the study.  Participants will continue taking their usual COPD maintenance 
treatment and rescue medications during the entire 56-day study period.
This study has 3 visits and will be completed in approximately 56 days.
 
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Study Schematic:
Number of Participants:  Approximately 300 participants with COPD will be screened 
to ensure approximately 240 participants will be randomized, such that approximately 
216 evaluable participants complete the study.
Treatment Groups and Duration:  Duration is 3 clinical visits over approximately 56
days.
There is no active treatment and participants will continue to take their own prescribed 
COPD maintenance and rescue medication during the entire 56-day study period.
The treatment groups are the following:

At Visit 1 (Day 1) approximately half of the participants will be randomized to 
receive a placebo ELLIPTA (QD) inhaler for use during the first 28 day treatment 
period.  The remaining half of the participants will receive a placebo DISKUS 
(BID) + placebo HandiHaler (QD) for use during the first 28 day treatment 
period.

At Visit 2 (Day 28) participants previously receiving the placebo DISKUS + 
placebo HandiHaler inhalers at Visit 1 will receive a placebo ELLIPTA (QD) 
inhaler for the second 28 day treatment period. Those participants initially 
receiving a placebo ELLIPTA inhaler at Visit 1 will receive a placebo DISKUS 
(BID) inhaler + a placebo HandiHaler (QD) inhaler for the second 28 day 
treatment period.

At Visit 3 (Day 56) after conducting their last correct inhaler use assessments, the 
participants will answer either preference questionnaire 1 or preference 
questionnaire 2 depending on their randomization schedule.
 
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Randomization 
Group
Sequence of Using the Inhalers
Preference 
Questionnaire
Version
1st Period
2nd Period
A
ELLIPTA
DISKUS + 
HandiHaler
1
B
ELLIPTA
DISKUS + 
HandiHaler
2
C
DISKUS + 
HandiHaler
ELLIPTA
1
D
DISKUS + 
HandiHaler
ELLIPTA
2
Participants will use the assigned placebo inhaler, in each period to match the dose in the 
prescribing information for the medication that they match.  ELLIPTA DPI and 
HandiHaler DPI will both be taken as one inhalation, once daily.  DISKUS DPI will be 
taken as one inhalation, twice daily.
Study endpoints will be based on evaluation of participant’s correct use and preference 
questionnaires.
The aim of this study is to further evaluate the participant handling errors on ELLIPTA 
relative to a subset of other available inhalers.  The overall correct use of the GSK 
ELLIPTA relative to two other inhalers, a GSK DISKUS and the Boehringer Ingelheim
HandiHaler shall be assessed.  Placebo inhalers are used to remove any bias due to 
treatment effect, avoid the need for wash-in/wash-out periods, and to avoid the need to 
withhold or discontinue current COPD medications, which may affect the participant’s 
clinical status (improvement or decline) and perceptions.
 
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2.
SCHEDULE OF ACTIVITIES (SOA)
Procedures
Visit 0
Screening
(Can 
occur on 
same day 
as V1)
Visit 1 
Randomization
(Can occur on 
the same day 
as V0)
Visit 2
Assessment/ 
Cross-over
Visit 3
Last Visit/
End of 
Study/Early 
Withdrawal
Study Day
1
28 (2)
56 (2)
Screening/safety 
assessments
Written informed consent 
1
X
Participant demography
X
Medical/disease history 
including chronic 
obstructive pulmonary 
disease (COPD) history
X
Therapy history
X
Inclusion/exclusion 
criteria
X
Concomitant medication
X
X
X
Physical examination2
X
Vital signs2
X
Adverse events (AEs)/
Serious adverse event
(SAEs)3
X
X
X
Randomization 4
X
Study inhaler correct use 
and preference
Participant reviews written 
instructions on the correct 
use of the newly dispensed 
inhaler(s) 
X
X
Assess participant’s ability 
to correctly use the newly 
dispensed inhaler 
(following participant 
reading patient instruction 
leaflet (PIL) then 
demonstrating correct 
use)5
X
X
Assess participant’s ability 
to correctly use the 
returned inhaler(s) without 
instruction6
X
X
 
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Procedures
Visit 0
Screening
(Can 
occur on 
same day 
as V1)
Visit 1 
Randomization
(Can occur on 
the same day 
as V0)
Visit 2
Assessment/ 
Cross-over
Visit 3
Last Visit/
End of 
Study/Early 
Withdrawal
Study Day
1
28 (2)
56 (2)
Assess compliance with 
the returned study 
inhaler(s) (based on the 
dose counter)
X
X
Preference Questionnaire
X
Worksheets and 
medication
Dispense study inhaler(s)
X
X
Collect study inhaler(s)
X
X
Dispense Medical 
Problems/Medications 
Taken Worksheet 7
X
X
Collect and review 
Medical 
Problems/Medications 
Taken Worksheet 7
X
X
1.
Participants will be assigned a subject number at the time when the informed consent form (ICF) is signed at 
Visit 0 or Visit 1.  The ICF must be signed before any study procedures are conducted.  
2.
Results are recorded in the source documents only.
3.
Refer to protocol Section 9.2.1.1 for AE/SAE data collection period.
4.
Randomisation conducted if the Participant meets all study screening criteria.
5.
A health care professional trained on the inhalers will conduct the assessments at Visits 1 and 2, following 
dispensing of the appropriate inhaler (s) for the next dosing period.  
6.
A health care professional trained on the inhalers will conduct the assessments of the participant’s ability to 
correctly use the returned inhaler (s) at Visits 2 and 3 following return of the inhaler (s) used for the previous 
dosing period. This should be completed at Early Withdrawal Visit if a participant has taken one or more doses 
of the inhaler at home.
7.
Participants will record medical problems and medications taken on the Medical Problems/Medications Taken 
Worksheet between visits.
 
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3.
INTRODUCTION
3.1.
Study Rationale
This study is designed to assess the benefits of delivering triple therapy using a single 
ELLIPTA™ Dry powder inhaler (DPI) (fixed-dose combination closed triple therapy) 
versus delivering triple therapy using two different types of inhalers (open triple therapy) 
to participants with Chronic Obstructive Pulmonary Disease (COPD).  It will assess 
correct inhaler use when using a single ELLIPTA™ DPI versus using combinations of 
commercially available and commonly used DPIs:  DISKUS™ used in combination with 
HandiHaler.  This study will also assess critical errors and preference attributes for a 
fixed-dose triple therapy as compared to the multiple inhalers to receive triple therapy.
The cross-over design is chosen to allow participants to serve as their own control in their 
ability to use both the ELLIPTA and the DISKUS + HandiHaler inhalers.  Placebo 
inhalers will be used to remove any bias due to treatment effect.  The comparison of the 
ELLIPTA to the DISKUS + HandiHaler combination was chosen as this combination of 
inhalers is the most commonly prescribed triple combination in the  United States.  The 
28-day treatment period is consistent with other ELLIPTA correct use and critical errors 
studies.  Correct use will be evaluated with reference to the steps outlined in the 
manufacturer’s package insert for the inhalers.
3.2.
Background
Chronic Obstructive Pulmonary Disease (COPD) is a progressive disease of the airways.
Noxious particles or gases lead to a modification in patient’s airways which develop a
chronic inflammatory response to these environmental factors. This leads to increasing
airflow limitation, breathlessness and other symptoms. Despite being both treatable and
preventable, COPD is a leading cause of morbidity and mortality worldwide. The
economic and social burden of this disease has not been reduced and is increasing despite
advances in diagnosis and treatment. [GOLD, 2017]
The current treatment goals for COPD are to reduce and relieve symptoms and thereby
improve exercise tolerance and health status, whilst reducing risk by preventing disease
progression, preventing and treating exacerbations, and reducing mortality.
Smoking cessation, inhaled pharmacological therapy, primarily long and short term
bronchodilators (beta2-agonists and anticholinergics) and inhaled corticosteroids, and
other non-pharmacological interventions are currently used to achieve the treatment
goals.
The current GOLD treatment guidelines, place patients in 4 groups from A to D,
dependent on severity of symptoms and assessment of risk; with Group A patients having
the fewest symptoms and a low risk as assessed by degree of airflow limitation and/or
exacerbation history. COPD patients in Group A may just need a short acting
bronchodilator as needed to relieve symptoms. However, as disease progresses, other
inhaled therapies are added on to maintain control, such that COPD patients in Group D,
who have many symptoms and a high risk of exacerbations and/or high airflow
 
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limitation, may need multiple inhaled therapies (inhaled corticosteroids (ICS), long-
acting beta2-agonist (LABA) and long-acting anticholinergic (LAMA)).
Currently, patients requiring triple therapy can be prescribed ICS/LABA and LAMA in
separate inhalers. The specific ICS/LABA and LAMA prescribed determine whether the
inhaler types (and thereby the inhalation techniques) and the dosing regimens are similar
or different. Use of different inhaler types with different inhalation techniques and dosing
regimens can add to treatment complexity, and also increase the potential for errors in
inhaler use that reduce or preclude drug delivery to the site of action in the lungs
[Cochrane, 2000, Van Der Palen, 1999].   Fixed-dose combination inhalers that minimize
the number of inhalers required would simplify treatment, improve adherence, reduce
errors in inhaler use, and potentially lead to better outcomes [GOLD, 2017].
The skill and ability of the COPD patient to use the prescribed inhaler/s correctly coupled
with adequate training in inhaler technique are also critical to ensure effective drug
delivery [Cochrane, 2000, Melani, 2011]. Critical errors made when using inhalers, 
which significantly reduce or completely inhibit drug delivery, have been identified for 
various inhalation devices [Van Der Palen, 2016].  Between 36 and 49% of patients with 
COPD perform critical inhaler errors with currently used inhalers [Van Der Palen, 2016].
For any prescribed inhaler, the patient needs to follow all the steps in the patient 
information leaflet correctly in order to ensure optimal drug delivery. In this regard, the 
time needed for a primary care nurse, physician, or a community pharmacist to train a 
patient in correct use of an inhaler at the time of initial prescription, and for any 
subsequent retraining becomes important. Given the time demands on healthcare 
professionals, a device which is simple to use and requires minimal time to train would 
be desirable [Bonini, 2015]. Further, patients may prefer easy-to-use inhalers having 
fewer steps to deliver drug; this has the potential to improve compliance and thereby 
impact outcomes.
ELLIPTA™DPI has been designed to be simple for patients to use. In COPD patients’
naïve to ELLIPTA and comparator inhalers, data has shown that patients make fewer 
critical and overall errors when using ELLIPTA as compared to other common DPIs 
tested [Van Der Palen, 2016(a)]. ELLIPTA DPI was also shown to be preferred by 
patients for a number of attributes, including number of steps and training time required 
to receive therapy [Van Der Palen, 2016(b), Van Der Palen, 2016(c), Komase, 2014]. 
ELLIPTA is already available to deliver a LABA/ICS combination (BREO ELLIPTA), 
LAMA(INCRUSE ELLIPTA), and LAMA/LABA combination (ANORO ELLIPTA). A 
fixed-dose triple therapy (ICS/LAMA/LABA) is currently being assessed in clinical 
studies to deliver all 3 active treatments from a single ELLIPTA DPI.
3.3.
Benefit/Risk Assessment
This study involves the use of placebo inhalers (placebo ELLIPTA, placebo DISKUS, 
and placebo HandiHaler) that do not contain active treatments. The inhalers contain the 
excipients lactose and lactose blended with magnesium stearate.  Participants with known 
hypersensitivity to any of these or severe milk protein allergy that could contraindicate 
study participation are to be excluded from the study.  Participants who meet the 
inclusion/exclusion criteria will continue their COPD treatment as prescribed by their 
 
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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.
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 inhaling.
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.
This should be treated 
immediately with a fast and 
short acting inhaled 
bronchodilator.  Investigators 
will be instructed to assess the 
participants’s condition to 
determine their eligibility to 
continue in the study and the 
need for alternative therapy.
Allergic reaction due to 
hypersensitivity to placebo 
excipients.
The placebo inhalers and 
placebo capsules (for 
HandiHaler) contain the 
excipient lactose and 
lactose blended with 
magnesium stearate.  
There are known allergies 
to these ingredients.
Participants with a know 
hypersensitivity to any of 
these, or severe milk protein 
allergy that could 
contraindicate study 
participation are excluded 
from the study (Section 6.2).  
If an allergic reaction occurs, 
it should be treated 
immediately with a fast and 
short acting inhaled 
bronchodilator and other 
appropriate drugs used in 
allergic reactions (e.g. 
glucocorticosteroids, 
adrenalin) guided by the 
nature and severity of the 
allergic reaction.  
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.
 
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3.3.2.
Benefit Assessment
As this is a placebo study, no benefit to the participant is expected.  No active treatment 
is being administered.  The participant will continue to receive their own COPD therapy 
as prescribed.
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.
4.
OBJECTIVES AND ENDPOINTS
This study will compare correct inhaler use along with critical errors and participant
preference of inhalers for fixed-dosed combination triple therapy from a single ELLIPTA 
inhaler versus triple therapy received from DISKUS in combination with HandiHaler.
Objectives
Endpoints
Primary

To evaluate the relative proportions 
of COPD participants who correctly 
use an ELLIPTA inhaler compared 
to those who correctly use a 
DISKUS + HandiHaler 
combination to receive their COPD 
medications.

Comparison of correct inhaler use as 
defined by the percentage of 
participants with zero errors after 28 
days of use.
Secondary

To evaluate the overall correct use 
of an ELLIPTA inhaler compared 
to the DISKUS + HandiHaler 
combination in COPD participants.

Number of errors by type for each 
inhaler after 28 days of use.

Number and change in errors per 
participant for each treatment group
(V2 and V3) after 28 days of use.

Number and change in errors for each 
treatment group in participants with one 
or more errors after 28 days of use.

To evaluate the relative proportions 
of critical errors for COPD 

Comparison of correct inhaler use as 
defined by the percentage of 
 
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Objectives
Endpoints
participants using an ELLIPTA 
inhaler compared to those using a 
DISKUS and HandiHaler to receive 
their COPD medications.
participants with zero critical errors 
after 28 days of use.
Other

To evaluate the impact of number 
of COPD maintenance inhalers on 
study inhaler errors (ELLIPTA and 
DISKUS + HandiHaler) after 28 
days of use.

Comparison of correct inhalers use as 
defined by the percentage of 
participants with zero errors after 28 
days of use, including the number of 
prescribed maintenance inhalers as a 
covariate.

To evaluate the number of overall 
errors made by COPD participants 
after a participant has read the 
Patient Instruction Leaflet (PIL(s)).

The comparison of participants making 
zero errors after reading the PIL (s) at 
the start of each treatment period.

To evaluate the participant’s 
preference of these inhaler options 
based on how easy it was to tell 
how many doses were remaining.

Inhaler preference based on how easy 
it was to tell how many doses remain.

To evaluate inhaler preference of 
taking a regimen that was one 
inhaler, once a day versus multiple 
inhalers with a varied dosing 
regimen.

Inhaler dosing regimen preference.
5.
STUDY DESIGN
5.1.
Overall Design
This study will be conducted as a randomized, multi-center, open-label, cross-over study 
comparing placebo ELLIPTA (GSK) with placebo DISKUS (GSK) + HandiHaler 
[Boehringer Ingelheim (BI)] to assess correct inhaler use.
This study has 3 visits and will be completed in approximately 56 days. 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.
 
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There is no active treatment and participants will continue to take their own prescribed 
COPD maintenance medication and rescue medications during the entire 56-day study 
period.
The treatment groups are the following:

At Visit 1 (Day 1) half of the participants will be randomized to receive a placebo 
ELLIPTA (QD) inhaler for use during the first 28 day treatment period.  The 
remaining half of the participants will receive a placebo DISKUS (BID) + placebo 
HandiHaler (QD) for use during the first 28 day treatment period.

At Visit 2 (Day 28) participants previously receiving the placebo DISKUS + 
placebo HandiHaler inhalers at Visit 1 will receive a placebo ELLIPTA (QD) 
inhaler for the second 28 day treatment period. Those participants initially 
receiving a placebo ELLIPTA inhaler at Visit 1 will receive a placebo DISKUS 
(BID) inhaler + a placebo HandiHaler (QD) inhaler for the second 28 day 
treatment period.

At Visit 3 (Day 56) after conducting their last correct inhaler use assessments, 
participants will answer either preference questionnaire 1 or preference 
questionnaire 2 depending on their randomization schedule.
Randomization 
Group
Sequence of Using the Inhalers
Preference 
Questionnaire 
Version
1st Period
2nd Period
A
ELLIPTA
DISKUS + 
HandiHaler
1
B
ELLIPTA
DISKUS + 
HandiHaler
2
C
DISKUS + 
HandiHaler
ELLIPTA
1
D
DISKUS + 
HandiHaler
ELLIPTA
2
This study offers a design aimed at assessing the correct use and the number of errors
made by the participant using each inhaler [after reading the instructions in the patient 
information leaflet and after healthcare professional (HCP) instruction] and 
participant preference of the inhalers.
Assessment of errors will be conducted by health care professionals trained in the 
correct inhaler use of three inhalers prior to the start of the study by face-to-face and 
 
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videotaped instruction training based on the checklist of errors.  After randomization, 
participants will be asked to read the PIL of the first inhaler and then asked to 
demonstrate correct inhaler use, if they do not demonstrate correct use they will be 
instructed on correct use by the HCP.  A baseline assessment will be conducted when 
the participant is initially dispensed the inhaler and a second assessment will be 
conducted after each 28 day dosing period.  After demonstrating correct use at Visit 
1, the participant will be sent home with the inhaler for the first 28 day treatment 
period.  At Visit 2, two checklists shall be completed, the first checklist will be for the 
Day 28 assessment of the first inhaler and the second checklist will be another 
baseline assessment for the second inhaler which has been dispensed.
A health care professional trained on the inhalers will assess the participant’s ability 
to correctly use the returned inhalers. Either the ELLIPTA checklist or the DISKUS 
+ HandiHaler combination checklist will be utilized after 28 days of treatment
depending on the inhalers returned.  Individual checklist assessment of the DISKUS 
and the HandiHaler will not be assessed.  Compliance with returned inhalers (based 
on the dose counter and remaining capsules) will also be assessed by study staff at 
Visits 2 and 3.  A Preference Questionnaire will also be administered and reviewed 
by study staff at Visit 3 or the last clinic visit.
Overall Design:
Day 1: V1
Day 28: V2
               Day 56: V3
     
Day 1
       Day 28                                                        Day 56
Training Inhaler 1                              Training Inhaler 2                     Correct Use Inhaler 2
                                                         Correct Use Inhaler 1                             Preference
5.2.
Number of Participants
Approximately 300 participants with COPD will be screened to achieve 240 randomized 
and 216 evaluable participants for an estimated total of 108 participants per device 
sequence (not accounting for questionnaires, see Section 10.2).  Questionnaires will then 
be randomly assigned within each device sequence to give 54 per randomized treatment 
group.
                       INHALER 1                                                    INHALER 2
 
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For the purpose of this study an evaluable participant is defined as a randomized 
participant who completed error assessments for both randomized treatment groups.
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
This study is designed to assess the benefits of delivering triple therapy using a single 
ELLIPTA DPI (fixed-dose combination triple therapy) versus delivering triple therapy 
using two different types of inhalers (open triple therapy) to participants with COPD.  It 
will assess correct inhaler use when using a single ELLIPTA DPI versus using 
combinations of commercially available and commonly used DPIs:  DISKUS used in 
combination with HandiHaler.  This study will also assess critical errors (which 
significantly reduce or completely inhibit drug delivery), non-critical errors, and 
preference attributes for the fixed-dose combination triple therapy as compared to the 
open triple therapy.
The cross-over design is chosen to allow participants to serve as their own control in their 
ability to use both the ELLIPTA and the DISKUS + HandiHaler inhalers.  Placebo 
inhalers are used to remove any bias due to treatment effect.  The comparison of the 
ELLIPTA to the DISKUS + HandiHaler combination was chosen as this combination of 
inhalers is the most commonly prescribed triple combination in the  United States.  The 
28-day treatment period is consistent with other ELLIPTA correct use and critical errors 
studies.  Correct use will be evaluated with reference to the steps outlined in the 
manufacturer’s package insert for the inhalers.
This study highlights the need for participants using a new inhaler device to have 
adequate training and assessment at the time when starting a new treatment, for periodic 
review of training, and also the need to ensure that the proper inhaler is selected for the 
participant.
5.5.
Dose Justification
Not applicable as this is a placebo-only study.
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
 
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6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Informed Consent

Participants must be capable of giving signed informed consent as described in 
Appendix 3 which includes compliance with the requirements and restrictions 
listed in the informed consent form (ICF) and in this protocol.
Type of Participant and Diagnosis

Participants must have a diagnosis of COPD with a documented history of COPD 
for at least 6 months, in accordance with the definition by the American Thoracic 
Society/European Respiratory Society [Celli, 2004].
Age

Participants must be 40 years of age inclusive, at the time of signing the informed 
consent.
Gender

Males or Females. Females must not be pregnant or planning pregnancy during 
the study or not lactating (Appendix 4).
Disease Severity

Participants must have a documented post albuterol forced expiratory volume in 
one second (FEV1)/ forced vital capacity (FVC) ratio <0.70 and FEV1 70% of 
predicted obtained within two years of Visit 1.
Smoking History

Current or former (defined as participants who have quit smoking for at least 3 
months prior to Screening/Visit 1) cigarette smokers with a > 10 pack-year 
smoking history [Number of pack-years = (number of cigarettes per day ÷ 20) x 
number of years smoked (e.g., 10 pack-years is equal to 20 cigarettes per day for 
10 years, or 10 cigarettes per day for 20 years].
COPD Medications

All participants should be currently receiving maintenance treatment for COPD
for at least 4 weeks prior to Randomization/Visit 1 and evaluated as unlikely to 
change COPD treatment within 4 weeks of Visit 1.

All participants should be able to stay on their prescribed maintenance COPD 
treatment without change throughout the entire treatment period.
 
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Other

Participants must be able to read, comprehend, and record information in English.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions

Participants must not have a current diagnosis of asthma.
Prior/Concomitant COPD Therapy

Participants must not have used the ELLIPTA, DISKUS, or HandiHaler inhalers 
in the 6 months prior to Visit 1.

Participants must not be receiving their current COPD medications with the 
ELLIPTA, DISKUS, or HandiHaler inhalers.
Exacerbations

Participants must not have experienced more than 1 COPD exacerbation which 
required hospitalization in the 12 months prior to Visit 1.
Alcohol and Drug Abuse

Participants must not have a known or suspected history of alcohol or drug abuse 
within the last 2 years.
History of Hypersensitivity

Participants must not have a history of hypersensitivity to any component of the 
study inhalers (e.g. lactose, magnesium stearate).  In addition, participants with a 
history of severe milk protein allergy that, in the opinion of the study physician, 
contraindicates participation will also be excluded.
Other Respiratory Disorders

Participants with other respiratory disorders, including active tuberculosis, active
lung cancer, sarcoidosis, lung fibrosis, pulmonary hypertension, or pulmonary 
disease (including but not confined to asthma, bronchiectasis with the need for 
treatment, cystic fibrosis, and bronchopulmonary dysplasia), interstitial lung 
diseases or other active pulmonary diseases.
 
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Other Diseases/Abnormalities
Participants with:

Historical or current evidence of clinically significant or rapidly progressing 
or unstable cardiovascular, neurological, cardiovascular, neurological, renal, 
hepatic, immunological, endocrine (including uncontrolled diabetes or thyroid 
disease) or hematological abnormalities that are uncontrolled. Significant is 
defined as any disease that, in the opinion of the investigator, would put the 
safety of the participant at risk through participation, or which would affect 
the analysis if the disease/condition exacerbated during the study.

History of psychiatric disease, intellectual impairment, poor motivation or 
other conditions that will limit the validity of informed consent to participate 
in the study.
Compliance

Participants at risk of non-compliance, or unable to comply with the study 
procedures, or unable to continue their current medications.
Investigational Product

Participants who have received an investigational drug and/or medical 
device/inhaler within 30 days of entry into this study (Screening/Visit 1), or 
within five drug half-lives of the investigational drug, whichever is longer.
Affiliation with Investigator’s Site

Participants will not be eligible for this study if he/she is an immediate family 
member of the participating investigator, sub-investigator, study coordinator, or 
employee of the participating investigator.
6.3.
Lifestyle Restrictions
There are no lifestyle restrictions.
6.3.1.
Meals and Dietary Restrictions
There are no meals 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 randomized. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
 
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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).
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.
GSK Clinical Trials Supplies will provide the placebo inhalers for use in this study 
together with placebo capsules where appropriate.  
7.1.
Treatments Administered
This study does not involve the administration of any new treatments.  It assesses the 
ability of the participants to use the placebo inhalers listed in the table below.
 
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Study Treatment 
Name:
ELLIPTA placebo 
DPI
DISKUS placebo 
DPI
HandiHaler DPI and 
placebo Capsules
Dosage formulation:
Placebo DPI 
with two strips 
with 30 blisters 
per strip. 
First strip
containing 
lactose
monohydrate 
and a second 
strip containing
lactose 
monohydrate
blended with 
magnesium
stearate.
Placebo DPI with 
one blister strip 
containing 
lactose 
monohydrate.
DPI with placebo 
capsules containing 
lactose monohydrate.
Unit dose 
strength(s)/Dosage 
level(s):
NA
NA
NA
Route of 
Administration 
Oral inhalation 
(Inhalation 
Powder).
Oral inhalation 
(Inhalation 
Powder).
Oral inhalation (Inhalation 
Powder).
Dosing instructions:
As directed
As directed
As directed
Packaging and 
Labelling
Study Treatment 
will be provided in 
the appropriate 
container and will 
be labelled as 
required per 
country 
requirement.
Study Treatment 
will be provided in 
the appropriate 
container and will 
be labelled as 
required per 
country 
requirement.
Study Treatment will be 
provided in the 
appropriate container and 
will be labelled as 
required per country 
requirement.
Manufacturer
GSK
GSK
Boehringer Ingelheim
(HandiHaler); 
GSK/Catalent (placebo 
capsules)
 
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7.1.1.
Medical Devices
There are no medical devices utilized in this study.
7.2.
Dose Modification
There are no dose modifications.
7.3.
Method of Treatment Assignment
All participants will be centrally randomized using an Interactive Web Response System 
(IWRS).  Before the study is initiated, the log in information and directions for the IWRS 
will be provided to each site.  
Participants will be assigned in equal numbers to one of the following sequences.  The 
possible sequences are shown below:
Randomization 
Group
Sequence of Using the Inhalers
Preference 
Questionnaire 
Version
1st Period
2nd Period
A
ELLIPTA
DISKUS + 
HandiHaler
1
B
ELLIPTA
DISKUS + 
HandiHaler
2
C
DISKUS + 
HandiHaler
ELLIPTA
1
D
DISKUS + 
HandiHaler
ELLIPTA
2
Study treatments will be dispensed at the study visit summarized in the SoA.
7.4.
Blinding
This is an open-label study; however, the order of treatment and preference questionnaire 
answered by a participant will be assigned using an IWRS.  The site will contact the 
IWRS prior to study treatment administration for each participant.  The site will record 
the treatment assignment on the applicable case report form, if required.  Potential bias 
will be reduced by randomizing the order of treatment and the preference questionnaire 
version answered by the participants.
 
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7.5.
Preparation/Handling/Storage/Accountability

The investigator or designee must confirm appropriate temperature conditions 
have been maintained during transit for all study treatment received and any 
discrepancies are reported and resolved before use of the study treatment.

Only participants enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment. All study 
treatments must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions 
with access limited to the investigator and authorized site staff.

The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation, and final disposition records).

Further guidance and information for the final disposition of unused study 
treatment are provided in the Study Reference Manual.

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  
7.6.
Treatment Compliance
Participants initially will receive study treatment at the clinical site where they will 
receive study treatment directly under supervision of the investigator or designee.
Compliance will be calculated from the dose counter on returned ELLIPTA and DISKUS 
inhalers after each 28 day treatment period.  HandiHaler compliance will be calculated 
from the number of capsules supplied and returned after 28 days of use.  For compliance 
calculations, study staff should document the number of remaining doses for each inhaler 
prior to the participant leaving the clinic.
7.7.
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 6 months from Visit 1, should 
be recorded in order to determine the participant’s inclusion in the study.
Participants should continue to take their usual COPD and other medication through the 
conduct of the 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
 
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The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
7.8.
Treatment after the End of the Study
There is no active treatment, placebo only, and participants will not receive any specific 
post study treatments.
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 there is no active treatment; all participants will receive placebo 
treatment only.
8.1.2.
QTc Stopping Criteria
Not applicable as there is no active treatment; all participants will receive placebo 
treatment only.
8.1.3.
Temporary Discontinuation
Not applicable as there is no active treatment; all participants will receive placebo 
treatment only.
8.2.
Withdrawal/Stopping Criteria
Any participant may voluntarily discontinue participation in this study at any time.  
Further, an investigator may, at their discretion, discontinue any participant from 
participating in the study at any time.  All investigators with discontinued participants
from their sites will be required to make every effort to schedule those participants for an 
Early Withdrawal Visit as soon as possible.  Accordingly, the reasons for each 
participant’s withdrawal must be recorded in the case report form (CRF) and may include 
the following:  AE, consent withdrawn, lost to follow-up, protocol deviation, study 
closed/terminated, COPD exacerbation, and investigator’s discretion.  Specific regards 
should be given to distinguish withdrawals due to an AE, COPD exacerbation, and 
protocol deviation.  The occurrence of serious adverse event (SAE) that results in 
withdrawal will be recorded as withdraw due to “adverse event”.  
A participant will also be withdrawn from the study if they experience any of the 
following:

Participant is not able to demonstrate correct use of the inhalers within two
attempts at the dispensation visit.

COPD exacerbation which requires hospitalization.
 
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
COPD exacerbation which requires emergency treatment, which would in the 
investigator’s judgement pose continued participation in this study as an 
unacceptable risk (i.e. unable to demonstrate correct use).

AE/SAE that would, in the investigator’s judgement, make continued 
participation in the study an unacceptable risk.

Use of any medication delivered by the ELLIPTA, DISKUS or HandiHaler 
inhalers (excluding placebo inhalers).

Participant reports becoming pregnant during the study.
If a participant is prematurely discontinued from the study, the investigator must make 
every effort to perform the assessments as specified in the SoA at an early withdrawal 
(EW) visit as soon as possible and then discontinue the participant from the study.
Safety assessments will be completed at the Early Withdrawal Visit: however, inhaler 
preference questionnaires will not be completed.  After completion of the Early 
Withdrawal Visit, participants will be discharged from the study.
8.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
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. 
9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA. 

Protocol waivers or exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment.
 
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
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 (e.g.,
to confirm the diagnosis of COPD) and obtained before signing of ICF may be 
utilized for screening or baseline purposes provided the procedure met the protocol-
specified criteria and was performed within the time frame defined in the SoA.

Prior to randomization at Visit 1, all assessments to confirm inclusion into the study 
will be completed.  The details of these assessments are defined in the SoA.
9.1.
Efficacy Assessments
9.1.1.
Primary Endpoint
The aim of the study is to evaluate the percentage of participants which correctly use the 
ELLIPTA DPI compared to the DISKUS + HandiHaler DPIs after a 28 day treatment 
period.  “Correct Use” is defined as the percentage of participants with zero errors after 
28 days of use.
A checklist for correct use of each of the study medications has been developed based on 
the steps identified in the Patient Instruction Leaflets (PIL’s).  Following removal of the 
inhaler from the packaging, an eligible participant, after reading the PIL, will be guided 
by a trained health care provider (HCP) to demonstrate correct use of the inhaler they 
have been assigned.  A baseline assessment will be conducted when the participant is 
initially dispensed the inhaler and a second assessment will be conducted after each 28 
day dosing period.  A trained HCP will complete the appropriate Correct Use Checklist(s) 
at each visit.  At visit 2, two checklists shall be completed, the first checklist will be for 
the Day 28 assessment of the first inhaler and afterwards the second checklist will be 
another baseline assessment for the second inhaler which has been dispensed.
9.1.2.
Secondary Endpoints
A number of additional secondary endpoints shall be evaluated based on the information 
collected in the Correct Use Checklists.  These include:

Number of errors by type for each inhaler after 28 days of use.

Number and change in errors per participant for each treatment group (V2, V3) 
after 28 days of use.

Number and change in errors for each treatment group in participants with one or 
more errors after 28 days of use.

Comparison of correct inhaler use as defined by the percentage of participants
with zero critical errors after 28 days of use.
 
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9.1.3.
Other Endpoints
A number of additional other endpoints shall be evaluated based on the information 
collected in the Correct Use Checklists.  These include:

Comparison of correct inhaler use as defined by the percentage of participants
with zero errors after 28 days of use, including the number of prescribed 
maintenance inhalers as a covariant.

The comparison of participants making zero errors after reading the PIL (s) at the 
start of each treatment period.

Inhaler preference based on how easy it was to tell how many doses remain.

Inhaler dosing regimen preference.
9.1.4.
Assessment of Preference
After completing the correct use assessment for all treatments, the HCP will have the 
participant complete the assigned preference questionnaire. This assessment should occur 
at Visit 3 (Last Visit/End of Study) (Day 56) after the participant has demonstrated their 
inhaler use.
9.2.
Safety Assessments
9.2.1.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 3.
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. 
9.2.1.1.
Time Period and Frequency for Collecting AE and SAE Information

All SAEs will be collected from the signing of the ICF until the time points
specified in the SoA (Section 2).

All AEs will be collected from randomization until the time points specified in 
the SoA (Section 2).

Medical occurrences that begin before the start of study treatment but after 
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 3. The investigator will submit any updated 
SAE data to the sponsor within 24 hours of it being available.
 
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
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 3.
9.2.1.2.
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. 
9.2.1.3.
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, stabilized, otherwise explained, or the participant is lost to follow-up (as 
defined in Section 8.3). Further information on follow-up procedures is given in 
Appendix 3
9.2.1.4.
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 e.g., 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.
9.2.2.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 3 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will 
 
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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 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.
9.2.3.
COPD Exacerbations
A COPD exacerbation is defined as acute worsening of symptoms of COPD requiring the 
use of antibiotics, systemic corticosteroids or oral corticosteroids (tablets, suspension, or 
injection) and/or emergency treatment or hospitalization.
Participants who experience a COPD exacerbation during the treatment period may 
remain in the study and should continue to use their study inhaler if possible.  Treatment 
of COPD exacerbations with short-term antibiotics and systemic corticosteroids (less than 
or equal to 14 days) is permitted.
For worsening COPD symptoms/exacerbations requiring:

Emergency treatment the decision whether such a participant would continue in 
the study or be withdrawn would be determined per investigator discretion.  The 
Study Medical Monitor would be available to discuss any related questions with 
the investigator.

Hospitalization:  such a participant should be withdrawn from the study.
If a participant experiences a COPD exacerbation, the COPD exacerbation page of the 
eCRF should be completed.  COPD exacerbations should not be recorded as an Adverse 
Event, unless they meet the definition of a Serious Adverse Event and these SAEs will be 
recorded on the appropriate CRF section and should be reported to GSK for all 
participants.
The time period for collection of COPD exacerbations will be from Visit 1 and will end 
when Visit 3/Early Withdrawal visit has been completed.
Signs and symptoms of COPD will not be considered AEs and will not be recorded in the 
eCRF.
9.2.4.
Pregnancy

Details of all pregnancies in female participants will be collected after the start of 
study treatment. 

If a pregnancy is reported, the investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4.
 
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
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Appendix 4. 
9.2.5.
Treatment of Overdose
There is no active treatment in this study, placebo only.
9.2.6.
Physical Examination
The following will be assessed at Visit 1 and recorded in the source documents:

A brief physical examination will include, at a minimum, assessments of the 
skin, lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
9.2.7.
Vital Signs
The following will be assessed at Visit 1 and recorded in the source documents:

Temperature, pulse rate, respiratory rate, and blood pressure will be assessed.

Blood pressure and pulse measurements will be assessed with a completely 
automated device. Manual techniques will be used only if an automated device 
is not available.

Blood pressure and pulse measurements should be preceded by at least 5 
minutes of rest for the participant in a quiet setting without distractions (e.g., 
television, cell phones).

Vital signs will be measured in a semi-supine position after 5 minutes rest and 
will include temperature, systolic and diastolic blood pressure, and pulse rate.
9.2.8.
Electrocardiograms
Electrocardiograms will not be conducted during the study.
9.2.9.
Clinical Safety Laboratory Assessments
Clinical safety laboratory assessments will not be conducted during the study.
9.3.
Pharmacokinetics
PK parameters are not evaluated in this study.
9.4.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
 
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9.5.
Genetics
Genetics are not evaluated in this study.
9.6.
Biomarkers
Biomarkers are not evaluated in this study.
9.7.
Health Economics OR Medical Resource Utilization and 
Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study.
10.
STATISTICAL CONSIDERATIONS
10.1.
Hypotheses
The primary purpose of this study is to assess the number of errors made by
COPD participants, for the ELLIPTA inhaler or DISKUS + HandiHaler inhalers 
combined after 28 days use. This is a superiority study.
The primary endpoint is the percentage of participants making zero errors on the
ELLIPTA inhaler compared with the DISKUS + HandiHaler inhalers.
The null hypothesis is that there is no difference in the proportion of participants making 
zero errors on the ELLIPTA inhaler compared to the DISKUS + HandiHaler inhalers.
H0: PE – PD+H = 0
The alternative hypothesis is there is a difference in the proportion of participants making 
zero errors on the ELLIPTA inhaler compared to the DISKUS + HandiHaler inhalers.
H1: PE – PD+H ≠0
10.2.
Sample Size Determination
The sample size calculations for this study have been based on the primary endpoint, 
which is the percentage of participants making zero errors in each treatment group 
(ELLIPTA or DISKUS + HandiHaler) after 28 days use.
The estimates of inhaler errors were taken from the overall errors reported in the 200301 
study for each individual inhaler (ELLIPTA, DISKUS and HandiHaler) separately. 
Although this study is only assessing combined errors in the DISKUS + HandiHaler 
treatment group, individual inhaler errors were used to estimate the combined error rate 
in order to provide a conservative estimate. By doing this it assumes that participants,
 
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who made no errors on the DISKUS inhaler, would not make any errors of the 
HandiHaler inhaler and vice-versa.
As the 200301 study only had a single visit, no estimates were available for error rates 
over 28 days, however the study did provided estimates of participant errors after reading 
the PIL and after being instructed on correct use by a HCP up to three times. As 
participants will have the PIL for 28 days, and can be instructed by a HCP at the inhaler
dispensing visit if necessary, both estimates of error rates along with a sensitivity analysis 
examining some of the potential error rates between were used to inform sample size 
calculations.
Using 10,000 simulations, a total of 216 participant (54 per treatment sequence) provide 
at least 90% power to show a statistically significance difference between the overall 
error rate of the ELLIPTA inhaler versus DISKUS + HandiHaler inhalers, for all of the 
paired treatment error rates shown in Table 1.
Table 1
Error rates of ELLIPTA vs. DISKUS + HandiHaler achievable with 
90% power, 5 % Type 1 error using a total of 216 participants
ELLIPTA
Error Rate
DISKUS + HandiHaler
Error Rate
33%
>=50%
30%
>=47%
20%
>=35%
10%
>=23%
5%
>=15%
Conditional logistic regression and a two-sided 5% significance level were used as the 
analysis method for all simulations performed. As it is expected that some participants
would drop out or change inhalers during the study, with 10% withdrawal it would be 
necessary to enrol 240 participants (60 per treatment sequence) to ensure there were 216 
participants with evaluable data at the end of the study.
For the purpose of this study an evaluable participant is defined as a randomized 
participant who completed error assessments for both randomized treatment groups.
10.3.
Populations for Analyses
For purposes of analysis, the following populations are defined:
 
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Population
Description
All Subjects 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 randomised participants, excluding those who were 
randomised in error, and did not have at least one error 
assessment at Visit 1.  A participant who is recorded as a 
screen failure or run-in failure and also randomised will be 
considered to be randomised in error. Any other participant
who receives a randomisation number will be considered to 
have been randomised. This population will be analysed 
according to the treatment sequence the participants were 
randomised to, and not the treatment sequence they actually 
received.
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 
zero errors after 28 days use. 
This endpoint will be analysed using conditional logistic regression 
with participant as fixed strata, and treatment option and period as 
fixed effects. The odds ratio, 95% confidence interval (CI) and p-
value will be presented for the comparison between treatment 
options. It will be based on a two-sided hypothesis testing approach 
of superiority.
Secondary
The percentage of participants making at least one critical error after 
28 days use will be analysed using the same model as the primary 
endpoint.
The impact of number of COPD maintenance inhalers will be 
analysed using the same model as the primary endpoint, but with 
number of maintenance inhalers as an additional covariate. 
The following secondary endpoints will be summarised only:

Number of errors by type for each treatment group after 28 
 
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Endpoint
Statistical Analysis Methods
days of use.

Number and change in errors per participant for each 
treatment group (V2 and V3) after 28 days of use.

Number and change in errors for each inhaler in participants
with one or more errors after 28 days of use.
Other
Analysis of the following other endpoints will be defined in the 
Reporting and Analysis Plan:

Comparison of correct inhalers use as defined by the 
percentage of participants with zero errors after 28 days of 
use, including the number of prescribed maintenance inhalers 
as a covariate.

The percentage of participants making at least one overall 
error after reading the PIL (s) at the start of each treatment 
period.

Inhaler preference based on how easy it was to tell how many 
doses remain.

Inhaler and dosing regimen preference.
10.4.2.
Safety Analyses
All safety analyses will be performed on the Safety Population. 
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
AEs, 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
Any other analysis will be documented in the Report and Analysis Plan.
10.4.4.
Interim Analyses
There will be no interim analyses with this study.
 
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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 BR, MacNee W. Standards of the diagnosis and treatment of patients with COPD: a
summary of the ATS/ERS position paper. Eur Respir J. 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;
117:542–550.
Global Initiative for Chronic Obstructive Lung Disease (GOLD 2017). Global strategy
for the diagnosis, management, and prevention of COPD (Updated 2017). Available
from http://www.goldcopd.org.
Komase Y, Asako A, Kobyyashi 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.
Melani A, Bonavia M, Cilenti V, Cinti C, Lodi M, Martucci P. Inhaler mishandling
remains common in real life and is associated with reduced disease control. Respiratory
Medicine (2011) 105, 930-938.
Van Der Palen J, Klein J, Van Herwaarden ,Zielhuis, Seydel E. Multiple inhalers confuse
asthma patients. Eur Respir J 1999; 14: 1034-1037.
Van Der Palen J, Thomas M, Chrystyn H, Sharma R, Imber V, Zhu C.-Q, et.al.
Inhaler Errors After Reading The Patient Information Leaflet In Patients With COPD: A
Comparison Of Ellipta® With Five Inhaler Devices. Am J Respir Crit Care Med 193;
2016:A6811 (a).
Van Der Palen J, Thomas M, Chrystyn H, Sharma R, Svedsater H, Zhu C.-Q, et.al.
Inhaler Preference In Patients With COPD: A Comparison Of Ellipta® With Five Inhaler
Devices. Am J Respir Crit Care Med 193; 2016:A6813 (b).
Van Der Palen J, Thomas M, Chrystyn H, Sharma R, Imber V, Zhu C.-Q, et.al.
Training And Time To Achieve Correct Inhaler Use: A Comparison Between Inhalers In
Patients With COPD. Am J Respir Crit Care Med 193; 2016:A6811 (c).
Van Der Palen J, Thomas M, Chrystyn H, Sharma R, van der Valk Paul, Goosens M, 
et.al. A randomized open-label cross-over study of inhaler errors, preference and time to 
achieve correct inhaler use in patients with COPD or asthma: comparison of ELLIPTA 
with other inhaler devices.   Prim Care Resp Med (2016) 26, 16079.
 
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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
AE
Adverse Event
ASE
All Subjects Enrolled
BI
Boehringer Ingelheim
BID
Twice Daily
CI
Confidence Interval
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic Obstructive Pulmonary Disease
CRF
Case Report Form
CSR
Clinical Study Report
CV
Cardiovascular
DPI
Dry Powder Inhaler
EW
Early Withdrawal
FEV1
Forced Expiratory Volume in one Second
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GSK
GlaxoSmithKline
HCP
Healthcare Professional
ICF
Informed Consent Form
ICH
International Conference On Harmonisation
ICS
Inhaled Corticosteroids
IEC
Independent Ethics Committees
IRB
Institutional Review Boards
ITT
Intent-to-Treat
IWRS
Interactive Web Response System
LABA
Long-Acting Beta2-Agonist
LAMA
Long-Acting Anticholinergic
MedRA
Medical Dictionary of Regulatory Activities
PIL
Patient Instruction Leaflet
QD
Once Daily
SAE
Serious Adverse Event
SoA
Schedule of Activities
SUSAR
Suspected Unexpected Serious Adverse Reactions
 
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Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of 
companies
ANORO ELLIPTA
HandiHaler
BREO ELLIPTA
DISKUS
INCRUSE ELLIPTA
 
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12.2.
Appendix 2: Study Governance Considerations
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (e.g., advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Any amendments to the protocol will require 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 SAEs 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 authorized 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 authorized 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 center. 

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 authorized 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 authorized representative. 
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
Committees Structure
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
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 (e.g., 
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 authorized 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.

Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available.

Definition of what constitutes source data can be found in the Study Reference 
Manual.
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 
 
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completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study treatment development
 
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12.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
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 (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not related 
to progression of underlying disease).

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.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
 
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assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization 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 hospitalization or prolongation of existing hospitalization
In general, hospitalization 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 hospitalization or fulfils any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
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, diarrhea, influenza, 
 
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and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize 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 hospitalization, 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

Revascularization
Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.
 
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
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 sufficient 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.

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 
 
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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 recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.
Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper SAE data collection tool (see next Section).

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The investigator or medically-qualified sub-investigator must show evidence within 
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 
 
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next Section) or to the medical monitor/SAE coordinator by telephone.

Contacts for SAE reporting can be found in Study Reference Manual.
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 or the SAE coordinator.

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 Study Reference Manual.
 
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12.4.
Appendix 4:  Collection of Pregnancy Information
Collection of Pregnancy Information
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date.  

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. 

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK
as described in Appendix 3. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 
Any female participant who becomes pregnant while participating  

Will be withdrawn from the study.
 
2018N356105_00