A Randomized, Multi-center, Open-label, Cross-over Study Comparing Critical Errors, Overall Errors, Training/Teaching Time, and Preference Attributes of the ELLIPTA Dry Powder Inhaler Versus the BREEZHALER Dry Powder Inhaler, in Adult Participants With Mild to Moderate Asthma
Phase: PHASE4
Conditions: Asthma
Sponsor: GlaxoSmithKline

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GlaxoSmithKline group of companies
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TITLE PAGE
Protocol Title: A randomized, multi-center, open-label, cross-over study comparing 
critical errors, overall errors, training/teaching time, and preference attributes of the 
ELLIPTA dry powder inhaler versus the BREEZHALER dry powder inhaler, in adult 
participants with mild to moderate asthma. 
Protocol Number: 213306
Compound Number 
or Name:
GSK2285997 
Brief Title: A comparison of critical errors, overall errors, training/teaching time, and 
preference attributes of the ELLIPTA versus BREEZHALER dry powder inhalers in 
adult participants with asthma.  
Study Phase: IV 
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Manufacturer: Placebo BREEZHALER,
Novartis International AG,
Ronda de Santa Maria, 158, 08210 
Barberà del Vallès, Barcelona, Spain
Approval Date: 05-JAN-2021
Copyright 2021 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.

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SPONSOR SIGNATORY:
Protocol Title: A randomized, multi-center, open-label, cross-over study comparing 
critical errors, overall errors, training/teaching time, and preference attributes of the 
ELLIPTA dry powder inhaler versus the BREEZHALER dry powder inhaler, in adult 
participants with mild to moderate asthma. 
Protocol Number: 213306
Compound Number 
or Name:
GSK2285997 
Dr. Soniya Mokashi
Global Medical Director-Respiratory
Date
Medical Monitor Name and Contact Information can be found in the Study Reference 
Manual

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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SUMMARY..........................................................................................6
1.1.
Synopsis.......................................................................................................6
1.2.
Schema ......................................................................................................10
1.3.
Schedule of Activities (SoA)........................................................................11
2.
INTRODUCTION....................................................................................................13
2.1.
Study Rationale ..........................................................................................13
2.2.
Background ................................................................................................13
2.3.
Benefit/Risk Assessment ............................................................................15
2.3.1.
Risk Assessment .........................................................................15
2.3.2.
Benefit Assessment.....................................................................16
2.3.3.
Overall Benefit: Risk Conclusion..................................................16
3.
OBJECTIVES AND ENDPOINTS AND ESTIMANDS.............................................16
4.
STUDY DESIGN ....................................................................................................19
4.1.
Overall Design ............................................................................................19
4.2.
Scientific Rationale for Study Design ..........................................................20
4.2.1.
Participant Input into Design ........................................................21
4.3.
Justification for Dose ..................................................................................21
4.4.
End of Study Definition ...............................................................................21
5.
STUDY POPULATION...........................................................................................21
5.1.
Inclusion Criteria.........................................................................................21
5.2.
Exclusion Criteria........................................................................................22
5.3.
Lifestyle Considerations..............................................................................22
5.4.
Screen Failures...........................................................................................23
5.5.
Criteria for Temporarily Delaying 
Enrollment/Randomization/Administration of Study Intervention 
Administration.............................................................................................23
6.
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY..............................23
6.1.
Study Intervention(s) Administered .............................................................23
6.1.1.
Medical Devices...........................................................................24
6.2.
Preparation/Handling/Storage/Accountability..............................................24
6.3.
Measures to Minimize Bias: Randomization and Blinding ...........................25
6.4.
Study Intervention Compliance ...................................................................25
6.5.
Dose Modification .......................................................................................26
6.6.
Continued Access to Study Intervention after the End of the Study ............26
6.7.
Treatment of Overdose...............................................................................26
6.8.
Concomitant Therapy..................................................................................26
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.....................................................................26
7.1.
Discontinuation of Study Intervention..........................................................26
7.2.
Participant Discontinuation/Withdrawal from the Study ...............................26
7.3.
Lost to Follow Up........................................................................................27
8.
STUDY ASSESSMENTS AND PROCEDURES .....................................................27

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8.1.
Efficacy Assessments.................................................................................27
8.1.1.
Assessment of errors in use of inhalers .......................................27
8.1.2.
Time taken to demonstrate correct use of the inhaler ..................29
8.1.3.
Assessment of ease-of-use .........................................................29
8.1.4.
Willingness to continue with the inhaler .......................................29
8.1.5.
Preference questionnaire.............................................................29
8.2.
Safety Assessments ...................................................................................29
8.2.1.
Pregnancy Testing.......................................................................29
8.3.
Serious Adverse Events (SAEs) and Other Safety Reporting......................30
8.3.1.
Time Period and Frequency for Collecting SAE, ADE, and 
SADE Information........................................................................30
8.3.2.
Method of Detecting SAEs, ADEs, and SADEs............................30
8.3.3.
Follow-up of SAEs and SADEs....................................................30
8.3.4.
Regulatory Reporting Requirements for SAEs/SADEs.................31
8.3.5.
Cardiovascular and Death Events................................................31
8.3.6.
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as SAEs...............................................31
8.3.7.
Adverse Events of Special Interest ..............................................32
8.3.8.
Medical Device Deficiencies ........................................................32
8.3.8.1.
Time Period for Detecting Medical Device 
Deficiencies................................................................32
8.3.8.2.
Follow-up of Medical Device Deficiencies...................32
8.3.8.3.
Prompt Reporting of Medical Device 
Deficiencies to Sponsor..............................................32
8.3.8.4.
Regulatory Reporting Requirements for 
Medical Device Incidents............................................33
8.4.
Pharmacokinetics .......................................................................................33
8.5.
Genetics and/or Pharmacogenomics ..........................................................33
8.6.
Biomarkers .................................................................................................33
8.7.
Immunogenicity Assessments.....................................................................33
8.8.
Health Economics OR Medical Resource Utilization and Health 
Economics..................................................................................................33
9.
STATISTICAL CONSIDERATIONS........................................................................33
9.1.
Statistical Hypotheses.................................................................................33
9.2.
Sample Size Determination ........................................................................34
9.3.
Analysis Sets..............................................................................................34
9.4.
Statistical Analyses.....................................................................................35
9.4.1.
Primary Endpoint .........................................................................35
9.4.2.
Secondary Endpoint(s) ................................................................36
9.4.3.
Safety Analysis ............................................................................41
9.5.
Interim Analysis ..........................................................................................41
10. SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS...............................................................................................42
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................42
10.1.1.
Regulatory and Ethical Considerations ........................................42
10.1.2.
Financial Disclosure.....................................................................43
10.1.3.
Informed Consent Process ..........................................................43
10.1.4.
Data Protection............................................................................43
10.1.5.
Data Quality Assurance ...............................................................44

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10.1.6.
Source Documents ......................................................................45
10.1.7.
Study and Site Start and Closure.................................................45
10.1.8.
Publication Policy.........................................................................46
10.2.
Appendix 2: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................47
10.2.1.
Definition of AE............................................................................47
10.2.2.
Definition of SAE..........................................................................47
10.2.3.
Definition of Cardiovascular Events .............................................48
10.2.4.
Recording and Follow-Up of SAE ................................................49
10.2.5.
eporting of SAE to GSK ...............................................................50
10.3.
Appendix 3 CRITICAL ERROR CHECKLISTS............................................52
10.3.1.
ELLIPTA Critical Error Checklist ..................................................52
10.3.2.
BREEZHALER Critical Error Checklist.........................................54
10.4.
Appendix 4: Ease of Use Questionnaires....................................................56
10.5.
Appendix 5. Willingness to continue with inhaler.........................................59
10.6.
Appendix 6: Preference Questionnaires......................................................60
10.7.
Appendix 7: ADEs, SADEs, and Device Deficiencies: Definition and 
Procedures for Recording, Evaluating, Follow-up, and Reporting in 
Medical Device Studies...............................................................................62
10.7.1.
Definition of ADE .........................................................................62
10.7.2.
Definition of SADE.......................................................................62
10.7.3.
Definition of Device Deficiency.....................................................63
10.7.4.
Recording and Follow-Up of ADE, SADEs, and Device 
Deficiencies .................................................................................63
10.7.5.
Reporting of SADEs.....................................................................65
10.7.6.
Reporting of Device Deficiencies .................................................66
10.8.
Appendix 8: Abbreviations and Definitions and Trademarks .......................67
11. REFERENCES.......................................................................................................69

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1.
PROTOCOL SUMMARY
1.1.
Synopsis
A randomized, multi-center, open-label, cross-over study comparing critical errors, 
overall errors, training/teaching time, and preference attributes of the ELLIPTA dry 
powder inhaler versus the BREEZHALER dry powder inhalers, in adult participants with 
mild to moderate asthma.
Brief Title: A comparison of critical errors, overall errors, training/ teaching time, and 
preference attributes of the ELLIPTA versus BREEZHALER dry powder inhalers in 
adult participants with asthma 
Rationale: Previous evidence has demonstrated that participants with chronic obstructive 
pulmonary disease (COPD) had significantly fewer critical errors (defined as an error that 
is most likely to result in no or significantly reduced medication being inhaled) with the 
ELLIPTA dry powder inhaler (DPI) than with the BREEZHALER DPI after only reading 
the patient information leaflet (PIL); however, the performance of the ELLIPTA DPI 
compared to the BREEZHALER DPI remains untested in asthma patients.  As many as 
25% of asthma patients have never received instruction on inhaler technique from a 
health-care professional (HCP) and therefore it is considered important that patients be 
prescribed an inhaler that is least prone to patient errors after the only instruction on 
technique received is via the reading of the patient information leaflet.  This study is 
designed therefore to provide data in asthma participants to assist HCPs in assessing the 
various attributes of the ELLIPTA and BREEZHALER DPIs, by comparing the 
incidence of critical and overall errors, patient preference, willingness to continue with 
the inhaler and time to correct use.
Objectives and Endpoints:
Primary objective
Endpoint
To compare the proportion of participants 
who make at least one critical error after 
reading the section on inhaler use in the 
patient information leaflets (PILs) for 
ELLIPTA and BREEZHALER inhalers
Participants who make at least one critical 
error after reading the section on inhaler use in 
the patient information leaflets (PILs).
Secondary Objectives
Endpoints
To compare the proportion of participants 
who still make at least one critical error after 
receiving further instruction from the 
Healthcare Professional (HCP) for ELLIPTA 
and BREEZHALER inhalers
Participants who still make at least one 
critical error after receiving further instruction 
(up to 3) from the HCP.

2 0 2 0 N 4 3 9 7 2 2 _ 0 0
C O N FI D E N TI A L
2 1 3 3 0 6
7
T o c o m pare t he pr o p orti o n of o verall err ors 
ma de b y t he partici pa nts aft er rea di n g t he PI L, 
a n d if necessar y, wit h a d diti o nal i nstr ucti o n 
fr o m t he H C P f or E L LI P T A a n d 
B R E E Z H A L E R i n halers

Partici pa nts w h o ma ke at least o ne o verall 
err or after rea di n g t he PI L.

Partici pa nts w h o still ma ke at least o ne 
o verall err or after recei vi n g f urt her 
i nstr ucti o n ( u p t o 3) fr o m t he H C P.
T o s u m marize t he n u m ber of err ors (critical 
a n d o verall) ma de o n eac h i n haler, wit h or 
wit h o ut f urt her H C P i nstr ucti o n.
N u m ber of e rr ors ma de after rea di n g t he 
PI L(s), a n d, if necessar y, after recei vi n g 
f urt her i nstr ucti o n fr o m t he H C P.
T o c o m pare t he pr o p orti o n of partici pa nts t hat 
re q uire f urt her i nstr ucti o n fr o m t he H C P t o 
de m o nstrate c orrect i n haler use f or E L LI P T A 
a n d B R E E Z H A L E R i n halers
Re q uiri n g f urt her i nstr ucti o n fr o m t he H C P t o 
de m o nstrate c orrect i n haler use.
T o c o m pare t he Trai ni n g/ Teac hi n g Ti me 
re q uire d t o de m o nstrate c orrect i n haler use f or 
E L LI P T A a n d B R E E Z H A L E R i n halers -

T he a m o u nt of ti me ta ke n t o de m o nstrate 
i n haler use wit h o ut H C P i nter ve nti o n 
( T 1). 

T he a m o u nt of ti me ta ke n t o be gi ve n 
i nstr ucti o n b y t he H C P ( u p t o 3 ti mes) o n 
use of t he i n haler a n d t o de m o nstrate 
i n haler use ( T 2).

T he t otal a m o u nt of ti me ta ke n t o 
de m o nstrate i n haler use ( T 1 + T 2).
T o c o m pare ease - of-use f or E L LI P T A a n d 
B R E E Z H A L E R i n halers
Ease - of-use fr o m q uesti o n nair e. T his will be 
gr o u pe d as eas y (
) or 
diffic ult 
. 
T he varia bles will i ncl u de:

Ease of use rati n g 

T elli n g h o w ma n y d oses are left i n 
i n haler

L ear ni n g h o w t o use t he i n haler

H a n dli n g t he i n haler

P re pari n g t he i n haler

H ol di n g t he i n haler w hile usi n g it
T o s u m mari ze ease - of-use f or E L LI P T A a n d 
B R E E Z H A L E R i n halers
Ease - of-use fr o m q uesti o n naire  
 
. T he 
varia bles will i ncl u de t he:

Ease of use rati n g 

Telli n g h o w ma n y d oses are left i n 
in haler 

Lear ni n g h o w t o use t he i n haler
C CI
C CI
C CI
C CI

2 0 2 0 N 4 3 9 7 2 2 _ 0 0
C O N FI D E N TI A L
2 1 3 3 0 6
8

Ha n dli n g t he i n haler

Pre pari n g t he i n haler

H ol di n g t he i n haler w hile usi n g it
T o c o m pare t he willi n g ness t o c o nti n ue wit h 
t he E L LI P T A a n d/ or B R E E Z H A L E R i n haler
Willi n g ness t o c o nti n ue wit h t he i n haler usi n g 
a vis ual a nal o g ue scale ( V A S) bet wee n 0 
t o 1 0 0
T o c o m pare prefere nce attri b utes f or 
E L LI P T A a n d B R E E Z H A L E R i n halers
I n haler prefere nce fr o m q uesti o n naire 
( E L LI P T A, B R E E Z HA L E R or n o 
prefere nce). T he varia bles will i ncl u de:

Preferre d i n haler, o verall. 

N u m ber of ste ps t o ta ke t he 
me dicati o n

Ti me nee de d t o ta ke t he me dicati o n

H o w eas y t he i n haler is t o use

Size of t he i n haler

C o mf ort of t he m o ut h piece

Ease of o pe ni n g t he i n haler
S afet y
T o e val uate t he safet y of t he E L LI P T A de vice 
a n d t he B R E E Z H A L E R de vice
I nci de nce of a d verse de vice effects 
( A D Es)/seri o us a d verse e ve nts 
( S A Es)/seri o us a d verse de vice effects 
( S A D Es).
T he pri mar y  esti ma n d is t he o d ds rati o bet wee n t he E L LI P T A i n haler a n d t he 
B R E E Z H A L E R i n haler i n partici pa nts wit h mil d t o m o derate ast h ma w h o ma ke at least 
o ne critical err or w hile de m o nstrati n g use of t he i n haler after rea di n g t he PI L(s) base d o n 
partici pa nts w h o were a ble t o atte m pt t o de m o nstrate t he u se of b ot h i n halers.
T he pri mar y  esti ma n d c o nsists of t he f oll o wi n g attri b utes :

I n h aler c o m p aris o n: E L LI P T A or B R E E Z H A L E R i n haler.

P o p ul ati o n: partici pa nts wit h mil d t o m o derate ast h ma dia g n osis w h o atte m pt 
de m o nstrati o n of b ot h i n halers.

V ari a ble: partici pa nts w h o ma ke at least o n e critical err or after rea di n g t he secti o n 
o n i n haler use i n t he PI L ( wit h o ut f urt her i nstr ucti o n).

P o p ul ati o n -s u m m ary me as ure: T he o d ds rati o bet wee n t he E L LI P T A a n d 
B R E E Z H A L E R i n halers.

I nterc urre nt eve nt: N ot atte m pti n g de m o nstrati o n of t he i n haler ( E L LI P T A or 
B R E E Z H A L E R). T his is a d dresse d i n t he p o p ulati o n attri b ute ( pri nci pal strat u m 
strate g y).
C CI
C CI
C CI

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A principal stratum strategy will be used to address the intercurrent event for participants 
who do not attempt demonstration of the inhaler (ELLIPTA or BREEZHALER). This 
means all participants randomized will fall into exactly one of the following four strata: 
1. S00: Stratum of randomized participants who attempt inhaler demonstration 
(ELLIPTA and BREEZHALER) independent of period.
2. S01: Stratum of randomized participants who attempt the demonstration of the 
BREEZHALER inhaler and do not attempt demonstration of the ELLIPTA 
inhaler independent of period.
3. S10: Stratum of randomized participants who attempt the demonstration of the 
ELLIPTA inhaler and do not complete demonstration of the BREEZHALER 
inhaler independent of period.
4. S11: Stratum of randomized participants who do not attempt inhaler 
demonstration (ELLIPTA and BREEZHALER) independent of period.
Comparisons made between the ELLIPTA and BREEZHALER inhaler will be based on 
those who fall in the S00 stratum.
All secondary estimands will use the same population, inhaler comparison and strategy 
for the intercurrent event as for the primary estimand. Secondary estimands for the 
proportion of participants who still make at least one critical error after receiving further 
HCP instruction, the proportion of participants who make at least one overall error after 
reading the PIL(s) and the proportion of participants who make at least one overall error 
after receiving further HCP instruction will use the same summary measure as for the 
primary estimand. Training/teaching time will be summarized using median time for each 
inhaler. 
Overall Design:
The study will be a randomized, multi-center, open label, placebo inhaler-handling study 
with a 2x2 complete block crossover design. The study involves two visits which can be 
completed on the same day: Visit 0 (V0) is for screening and informed consent while V1 
is for the inhaler assessment (V1). Visit 1 must be completed no later than 30 days after 
the initial consent at Visit 0. Eligible participants will be randomized to test either the 
ELLIPTA DPI followed by BREEZHALER DPI or BREEZHALER DPI followed by 
ELLIPTA DPI. After the critical and overall errors assessment has been completed for 
each inhaler, participants will complete the inhaler ease-of-use questionnaire and then be 
asked to complete a visual analogue scale (VAS) on their willingness to continue with the 
inhaler. Once participants have completed assessments for both inhalers, they will 
complete one of the two versions of the preference questionnaire in each of the two-
blocks
The population to be studied is participants aged 18 years and older with mild to 
moderate asthma who have been prescribed to use maintenance therapy with inhaled 
corticosteroids (ICS) or ICS/long acting β2-Agonist (LABA) for at least 12 weeks prior 
to study and naïve to both ELLIPTA and BREEZHALER DPI inhalers. Main exclusion 
criteria is concurrent diagnosis of COPD.

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Number of Participants: This study will randomly assign 114 adult participants with 
mild to moderate asthma
Brief Summary:
This is a randomized, multi-centre, open label, placebo inhaler-handling study with a 2x2 
complete block crossover design to study critical errors, overall errors, training/teaching 
time, ease-of-use and willingness to continue and preference attributes of two dry powder 
inhalers:  ELLIPTA and BREEZHALER. This study will randomly assign 114 adult 
asthma participants aged ≥18 years with mild to moderate asthma, naïve to both the DPI 
inhalers (ELLIPTA and BREEZHALER). Each participant will be randomized to one of 
the four groups: ELLIPTA followed by BREEZHALER or BREEZHALER followed by 
ELLIPTA and further refined by assignment of the preference questionnaire version. The 
study involves two visits which can be completed on the same day.
Intervention Groups and Duration:
The eligible participants will be randomized to receive either the ELLIPTA DPI followed 
by BREEZHALER DPI or BREEZHALER DPI followed by ELLIPTA DPI. As this is an 
inhaler use study, placebo inhalers will be utilised. 
Data Monitoring/ Other Committee: No
1.2.
Schema

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1.3.
Schedule of Activities (SoA)
Visit Number
V0
V1
Notes
Study Day
1
1
(or 2*)
*V0 can take place on the same day as 
V1. V1 should be completed no later 
than 30 days after V0.
Procedure:
Screening Assessments
Completed prior to randomization
Written informed consent
X
Participants must be randomized within 
30 days of providing written informed
consenta.
Participant demography
X
Age, year of birth, sex, ethnicity and 
geographic ancestry will be recorded
Medical/disease history including 
Asthma
X
Participant will have a medical history of 
asthma, confirmed by HCP
Concomitant asthma medication 
history
X
Current asthma concomitant medication 
will be recorded. 
Inclusion/exclusion criteria
Xb 
All criteria must be met prior to 
randomization at V1
Study Assessments
Completed once participants are 
confirmed as eligible 
Randomization
X
Randomized to inhaler order and 
preference questionnaires 
Assess the number of inhaler 
errors (critical and overall)c on 
each inhaler after reading the 
relevant section of the PIL for 
Inhaler tested
X
No instruction is provided by the HCP for 
this assessment.
Assess the number of inhaler 
errors (overall and critical)c on 
each inhaler after each of 3 
attempts following instruction by 
HCP
X
If a participant cannot show correct use 
after reading the inhaler use sections of 
the PIL (Attempt 1), then the HCP has up 
to 3 attempts to instruct the participant to 
attain this (Attempts 2-4).

2 0 2 0 N 4 3 9 7 2 2 _ 0 0
C O N FI D E N TI A L
2 1 3 3 0 6
1 2
Vi sit N u m b er
V 0
V 1
N ot e s
T e ac hi n g -Tr ai ni n g Ti m e f or e ac h 
i n h al er. 
X
T h e H C P will r ec or d

St art a n d e n d ti m e of p artici p a nt 
r e a di n g t h e PI L ( T 0)

St art a n d e n d ti m e of first 
d e m o nstr ati o n f oll o wi n g PI L 
r e a di n g ( T 1).

St art ti m e fr o m t h e first H C P 
i nstr ucti o n t o p artici p a nt 
d e m o nstr ati n g c orr ect us e ( u p t o 
3 att e m pts) ( T 2).
E as e -of -u s e q u esti o n n air e d
X
P artici p a nt will c o m pl et e e as e -of -u s e 
Q u esti o n n air e f or t h at i n h al er  
Willi n g n ess t o c o nti n u e V A S e
X
At t h e e n d of t h e ass ess m e nt f or e ac h 
i n h al er, p artici p a nt will b e ask e dt o 
i n dic at e t h eir willi n g n ess t o c o nti n u e wit h 
t h e d evic e usi n g a V A S b et w e e n 0
 t o 1 0 0
Pr ef er e nc e qu esti o n n air e f
X
P artici p a nt will c o m pl et e v ersi o n of 
p r ef er e nc e q u esti o n n air e t o w hic h t h ey 
h av e b e e n r a n d o miz e d.  
S A E/ A E ass ess m e nt
X
C oll ect e d u ntil c o m pl eti o n of fi n al st u dy 
ass ess m e nt at V 1.
a)
P artici p a nts c o ul d st art t h e r ec o ns e nt, scr e e ni n g a n d r a n d o miz ati o n pr oc e d ur es o nc e m or e if t h ey miss t h e 3 0 -d ay 
wi n d o w
b)
If Visit 1 is a s e p ar at e d ay t o t h e scr e e ni n g visit ( Visit 0), t h e i nv esti g at or s h o ul d c o nfir m t h at t h e p artici p a nt h as 
n ot us e d o n e of t h e i n h al ers of i nt er est (i. e. E L LI P T A or B R E E Z H A L E R) i n t h e ti m e b et w e e n V 0 a n d V 1 pri or t o 
r a n d o miz ati o n. If a n i n h al er h as b e e n us e d, t h e n t his w o ul d b e a scr e e n f ail.
c)
Ov er all a n d critic al err ors f or e ac h i n h al er ar e d efi n e d i n A p p e n dix 3
d)
E as e of us e q u esti o n n air e is i ncl u d e d i n A p p e n dix 4
e)
Willi n g n ess t o c o nti n u e V A S is i n A p p e n dix 5
f)
Pr ef er e nc e q u esti o n n air e is i ncl u d e d i n A p p e n dix 6

T he C o m pete nt A ut h orit y ( C A) a n d et hics c o m mittee ( E C) will be i nf or me d of a n y 
safety iss ues t hat c o nstit ute a s u bsta ntial a me n d me nt a n d re q uire alterati o n of t he 
safety m o nit ori n g sc he me or a me n d me nt of t he i nf or me d c o nse nt f or m (I C F). T he 
c ha n ges will be a p pr o ve d b y  t he C A a n d t he E C bef ore i m ple me ntati o n
C CI
C CI
C CI

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2.
INTRODUCTION
Inhaled medications (i.e., inhaled corticosteroids [ICSs], short-acting and long-acting β2-
adrenergic agonists [SABAs and LABAs, respectively] and long-acting anti-muscarinic 
antagonists [LAMA] are the cornerstone of asthma management [GINA, 2020]. Short-
acting bronchodilators (e.g. SABAs and short-acting muscarinic antagonists) are given as 
quick-relief medications to alleviate acute attacks, while ICS, and ICS/LABA ± LAMA 
combinations, which target the underlying inflammatory pathology of the disease and 
bronchoconstriction are given as regular maintenance therapy to control symptoms and 
reduce the risk of exacerbations [GINA, 2020]. 
In terms of inhalers, GINA advises to choose the most appropriate inhaler for patients 
and if there are several inhalers to choose from, to involve the patient in this choice 
[GINA, 2020]. GINA also recommends checking inhaler technique at every opportunity 
and to identify and correct any errors by demonstration of inhaler use before escalating 
the therapy. Assessing and understanding inhaler handling errors by patients is therefore 
key to maximising the therapeutic benefit of the medication and ensuring as good a 
control of their disease can be achieved.
2.1.
Study Rationale 
Previous evidence has demonstrated that participants with COPD had significantly fewer 
critical errors with ELLIPTA than with the BREEZHALER [van der Palen, 2016] when 
reading the patient information leaflet (PIL). However, its performance against 
BREEZHALER remains untested in asthma patients. As many as 25% patients have 
never received verbal inhaler technique instruction [Lavorini, 2008] and therefore it is 
important that patients should be prescribed an inhaler that is least prone to errors after 
only reading the patient information leaflet. This study is designed therefore to provide 
data in asthma participants to assist health-care professionals (HCPs) in assessing the 
various attributes of both inhalers, including critical and overall errors, time to correct 
use, ease-of-use questionnaire, willingness to continue with the inhaler and patient 
preference.
2.2.
Background
The importance of correct use of inhalers is emphasised by GINA for asthma patients 
[GINA, 2020] and by GOLD for patients with chronic obstructive pulmonary disease 
(COPD) [GOLD, 2020] by ensuring selection of the appropriate inhaler, demonstration of 
the inhaler and assessment of inhaler use is reviewed prior to escalating therapy.  Errors 
made by the patient can affect the amount of medication received and disease control so 
it is essential to ensure good inhaler technique. 
Comparison of inhaler techniques between asthma and COPD patients suggests 
inconsistencies with some observational studies demonstrating similar error rates [Arora, 
2014; Chorão, 2014; Takaku, 2017; Ocakli, 2018] and other studies demonstrating higher 
rates in COPD patients [Khassawneh, 2008; Melani, 2011] but when adjusting for age, 
inhaler and level of instruction, this difference disappeared [Melani, 2011].  Study 
designs often observational, in usual practice with patients being familiar with their 

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inhalers, in different geographical and socio-economic areas may account for the 
inconsistent effects. Old age [Arora, 2014; Chorão, 2014], lower socio-economic [Arora, 
2014] and educational levels [Arora, 2014; Chorão, 2014] and female gender [Chorão, 
2014] were risk factors for greater errors in inhaler handling.
The ELLIPTA DPI was developed to deliver various inhaled maintenance medications, 
including mono, dual and triple therapies, for the treatment of asthma and COPD. 
Participants with asthma or COPD make fewer critical errors (defined as an error that is 
most likely to result in no or significantly reduced medication being inhaled) and overall 
errors (any error in inhaler technique) with the ELLIPTA DPI than with other DPIs [van 
der Palen, 2016]. Furthermore, participant preference for the ELLIPTA DPI has been 
demonstrated previously versus other DPIs for many attributes, including ease of use and 
time to train [van der Palen, 2016].  The BREEZHALER DPI is also approved for use 
with a variety of inhaled mono- or combination-medications although has not yet been 
widely used by asthma patients. 
The present study involves the use of ELLIPTA and BREEZHALER DPI inhalers that 
contain placebo and not active treatments. Participants will continue to take their own 
prescribed asthma medication and other concomitant medication during the study.  
Participants should also follow-up with their regular physician for their asthma healthcare 
during the study.
The placebo inhaler for ELLIPTA and the placebo capsules for BREEZHALER contain 
the excipients lactose. Participants with a known hypersensitivity to these or severe milk 
protein allergy are excluded from the study (Section 5.2)

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2.3.
Benefit/Risk Assessment
2.3.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Intervention(s) 
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 from FF/VI, 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.
Allergic reaction due to hypersensitivity to 
placebo excipients.
The placebo inhalers and placebo capsules (for 
BREEZHALER) contain the excipient lactose.  
There are known allergies to this ingredient.
Participants with a known hypersensitivity to 
this, or severe milk protein allergy that could 
contraindicate study participation are excluded 
from the study (Section 5.2). If an allergic 
reaction occurs, it 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.

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2.3.2.
Benefit Assessment
As this is a placebo study, no benefit to the participant is expected. No active treatment is 
being administered. The participants will continue to receive their own asthma therapy as 
prescribed.
2.3.3.
Overall Benefit: Risk Conclusion
The overall potential risk identified is considered minimal due to the placebo nature of 
the study and the 1-day duration of inhaler assessments at Visit 1.
3.
OBJECTIVES AND ENDPOINTS AND ESTIMANDS
Primary objective
Endpoint
To compare the proportion of participants 
who make at least one critical error after 
reading the section on inhaler use in the 
patient information leaflets (PILs) for 
ELLIPTA and BREEZHALER inhalers.
Participants who make at least one critical 
error after reading the section on inhaler use 
in the patient information leaflets (PILs).
Secondary Objectives
Endpoints
To compare the proportion of participants 
who still make at least one critical error 
after receiving further instruction from the 
Healthcare Professional (HCP) for 
ELLIPTA and BREEZHALER inhalers.
Participants who still make at least one 
critical error after receiving further 
instruction (up to 3) from the HCP.
To compare the proportion of overall errors 
made by the participants after reading the 
PIL, and if necessary, with additional 
instruction from the HCP for ELLIPTA and 
BREEZHALER inhalers.

Participants who make at least one 
overall error after reading the PIL(s).

Participants who still make at least one 
overall error after receiving further 
instruction (up to 3) from the HCP.
To summarize the number of errors (critical 
and overall) made on each inhaler, with or 
without further HCP instruction.
Number of errors made after reading the 
PIL(s), and, if necessary, after receiving 
further instruction from the HCP.
To compare the proportion of participants 
that require further instruction from the 
HCP to demonstrate correct inhaler use for 
ELLIPTA and BREEZHALER inhalers.
Requiring further instruction from the HCP 
to demonstrate correct inhaler use.

2 0 2 0 N 4 3 9 7 2 2 _ 0 0
C O N FI D E N TI A L
2 1 3 3 0 6
1 7
T o c o m pare t he Trai ni n g/ Teac hi n g Ti me 
re q uire d t o de m o nstrate c orrect i n haler use 
f or E L LI P T A a n d B R E E Z H A L E R i n halers.

T he a m o u nt of ti me ta ke n t o 
de m o nstrate i n hale r use wit h o ut H C P 
i nter ve nti o n ( T 1). 

T he a m o u nt of ti me ta ke n t o be gi ve n 
i nstr ucti o n b y t he H C P ( u p t o 3 ti mes) 
o n use of t he i n haler a n d t o de m o nstrate 
i n haler use ( T 2).

T he t otal a m o u nt of ti me ta ke n t o 
de m o nstrate i n haler use ( T 1 + T 2).
T o c o m pare eas e- of-use f or E L LI P T A a n d 
B R E E Z H A L E R i n halers .
Ease - of-use fr o m q uesti o n naire . T his will be
gr o u pe d as eas y
) or 
diffic ult 
. 
T he varia bles will i ncl u de:

E ase of use rati n g 

T elli n g h o w ma n y d oses are left i n 
i n haler

L ear ni n g h o w t o use t he i n haler

H a n dli n g t he i n haler

P re pari n g t he i n haler

H ol di n g t he i n haler w hile usi n g it .
T o s u m mari ze ease - of-use f or E L LI P T A 
a n d B R E E Z H A L E R i n halers .
Ease - of-use fr o m q uesti o n naire 
 
 T he 
varia bles will i ncl u de t he:

Ease of use rati n g 

Telli n g h o w ma n y d oses are left i n 
I n haler 

Lear ni n g h o w t o use t he i n haler

Ha n dli n g t he i n haler

Pre pari n g t he i n haler

H ol di n g t he i n haler w hile usi n g it .
T o c o m pare t he willi n g ness t o c o nti n ue wit h 
t he E L LI P T A a n d/ or B R E E Z H A L E R 
i n haler.
Willi n g ness t o c o nti n ue wit h t he i n haler 
usi n g a vis ual a nal o g ue scale ( V A S) 
bet wee n 0
 t o 1 0 0
T o c o m pare prefere nce attri b utes f or 
E L LI P T A a n d B R E E Z H A L E R i n halers .
I n haler prefere nce fr o m q uesti o n naire 
( E L LI P T A, B R E E Z H A L E R or n o 
prefere nce). T he varia bles will i ncl u de:

Preferre d i n haler, o verall. 

N u m ber of ste ps t o ta ke t he 
me dicati o n
C CI
C CI
C CI
C CI
C CI
C CI

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
Time needed to take the medication

How easy the inhaler is to use

Size of the inhaler

Comfort of the mouthpiece

Ease of opening the inhaler.
Safety
To evaluate the safety of the ELLIPTA 
device and the BREEZHALER device.
Incidence of adverse device effects 
(ADEs)/serious adverse events 
(SAEs)/serious adverse device effects 
(SADEs).
The primary estimand is the odds ratio between the ELLIPTA inhaler and the 
BREEZHALER inhaler in participants with mild to moderate asthma who make at least 
one critical error while demonstrating use of the inhaler after reading the PIL(s) based on 
participants who were able to attempt to demonstrate the use of both inhalers.
The primary estimand consists of the following attributes:

Inhaler comparison: ELLIPTA or BREEZHALER inhaler.

Population: participants with mild to moderate asthma diagnosis who attempt 
demonstration of both inhalers.

Variable: participants who make at least one critical error after reading the section 
on inhaler use in the PIL (without further instruction).

Population-summary measure: The odds ratio between the ELLIPTA and 
BREEZHALER inhalers.

Intercurrent event: Not attempting demonstration of the inhaler (ELLIPTA or 
BREEZHALER). This is addressed in the population attribute (principal stratum 
strategy).
A principal stratum strategy will be used to address the intercurrent event for participants 
who do not attempt demonstration of the inhaler (ELLIPTA or BREEZHALER). This 
means all participants randomized will fall into exactly one of the following four strata: 
1. S00: Stratum of randomized participants who attempt inhaler demonstration 
(ELLIPTA and BREEZHALER) independent of period.
2. S01: Stratum of randomized participants who attempt the demonstration of the 
BREEZHALER inhaler and do not attempt demonstration of the ELLIPTA 
inhaler independent of period.
3. S10: Stratum of randomized participants who attempt the demonstration of the 
ELLIPTA inhaler and do not complete demonstration of the BREEZHALER 
inhaler independent of period.

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4. S11: Stratum of randomized participants who do not attempt inhaler 
demonstration (ELLIPTA and BREEZHALER) independent of period.
Comparisons made between the ELLIPTA and BREEZHALER inhaler will be based on 
those who fall in the S00 stratum.
All secondary estimands will use the same population, inhaler comparison and strategy 
for the intercurrent event as for the primary estimand. Secondary estimands for the 
proportion of participants who still make at least one critical error after receiving further 
HCP instruction, the proportion of participants who make at least one overall error after 
reading the PIL(s) and the proportion of participants who make at least one overall error 
after receiving further HCP instruction will use the same summary measure as for the 
primary estimand. Training/teaching time will be summarized using median time for each 
inhaler. 
4.
STUDY DESIGN
4.1.
Overall Design
The study will be a randomized, multi-center, open label, placebo study with a 2x2 
complete block crossover design. The study will have one visit (although there could 
be two visits with up to 30 days between the informed consent visit (V0) and the 
study intervention visit (V1).
Eligible participants with mild to moderate asthma will be randomized to test either 
the ELLIPTA DPI (containing placebo) followed by BREEZHALER DPI (with 
placebo capsules), or vice versa in each of the two blocks for the crossover study. 
Only participants who are naïve to both ELLIPTA and BREEZHALER inhaler will 
be included. 
Participants will demonstrate inhaler use for the first inhaler after reading the relevant 
sections of the PIL (Attempt 1). If the participant makes any errors, the investigator 
demonstrates the correct use of the inhaler by conducting a full demonstration as 
described in the relevant section of the PIL, and the participant will try inhaler use 
again (Attempt 2). If after the first demonstration by the investigator the participant 
continues to make errors, the investigator will demonstrate correct inhaler use to the 
participant up to two additional times (Attempts 3 & 4). 
Following each attempted use of the inhaler by the participant, the trained 
investigator will assess for and document any critical errors (i.e. defined as an error 
that is most likely to result in no or significantly reduced medication being inhaled) 
(See Appendix 3) and non-critical errors made by the participant. This process of 
error assessment will be used to assess for critical and non-critical errors made by the 
participant for both inhalers being tested. 
At the end of the assessment of the first inhaler, participants will be asked to.
complete the ease-of-use questionnaire for this device (Appendix 4) followed by 

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participant completion of the visual analogue scale (VAS) on their willingness to 
continue with this inhaler (Appendix 5).
Participants will be permitted up to a 30-minute break (if required) between 
completing the assessment of the first inhaler and commencing error assessments for 
the second inhaler. The second inhaler critical errors assessment follows the same 
sequence of testing as the first – (Attempts 1 is with no HCP instruction and Attempts 
2-4 are with HCP instruction as required).
Once the error assessment of the second inhaler has been completed the participant 
will complete the ease-of-use questionnaire for this device (Appendix 4) followed by 
participant completion of the VAS on their willingness to continue with this inhaler
(Appendix 5 ).
If required, another period of up to 30 min for a break would be allowed followed by 
the participant completing one of the two versions of the preference questionnaire
(Appendix 6), as per randomization sequence.
Two versions of the inhaler preference questionnaire (See Appendix 6) are provided 
to minimize any potential bias introduced from the order in which the inhalers are 
taken in relation to the order the inhalers are assessed by the participant in each 
questionnaire. The version of each questionnaire to be completed by each participant 
is determined by the sequence arm they are randomly assigned to at Visit 1 (see Table 
1).
Further details are available in the study schematic in Section 1.2 and the assessments 
to be performed are detailed in the schedule of activities (SOA) in Section 1.3 and in 
study assessments Section 8. 
4.2.
Scientific Rationale for Study Design

Assessment of critical errors from inhaler handling studies has been used in 
previous GSK studies using an open-label, cross-over, placebo treatment design 
[van der Palen, 2016 van der Palen, 2018].

In common with these previous studies, a cross-over design has been chosen for 
the present study. No carry-over effects were demonstrated when using this 
design previously [van der Palen, 2013]. This design also allows participants to 
act as their own control in assessing their ability to use both inhalers, as well as 
allowing for the screening visit (V0) and the Visit 1 to occur on the same day, 
thereby reducing the inconvenience to participants of multiple study site visits.  
Breaks of up to 30-minutes have been included in the design to allow a degree of 
flexibility for the participant.

The study will use placebo inhalers for all study assessments. This aims to remove 
bias from any perceived benefit a participant may have for a particular active 
treatment. There is also no need for participants to withhold any treatments they 
are receiving, and there will be no need for a washout period between the inhaler 
used in each Assessment Period.

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4.2.1.
Participant Input into Design
There was no participant engagement into the design.
4.3.
Justification for Dose
This is a placebo inhaler study so there is no active medication. 
4.4.
End of Study Definition
The end of the study is defined as the date of the last visit of the last participant in the 
study.
A participant is considered to have completed the study if he/she has completed the 
critical and overall error assessment for both inhalers, willingness to continue with 
inhaler question and both the questionnaires (preference and ease of use) in the study 
including the last scheduled procedure shown in the SoA (Section 1.3)
5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1.
Participant must be aged 18 years or older at the time of signing the informed 
consent.
Type of Participant and Disease Characteristics
2.
Participants who have a confirmed mild or moderate asthma diagnosis as per GINA, 
2020. 
3.
Participants must be on asthma maintenance therapy (ICS or ICS/LABA) for at least 
12 weeks prior to study participation. 
4.
Participants must be naïve to both the ELLIPTA and BREEZHALER inhalers 
If Visit 1 is a separate day from the screening visit (Visit 0), the investigator should 
confirm that the participant has not used one of the inhalers of interest 
(i.e. ELLIPTA or BREEZHALER) in the time between V0 and V1 prior to 
randomization. If an inhaler has been used, then this would be a screen fail. 

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V0 can take place on the same day as V1. V1 should be completed no later than 30 
days after consent.  Participants could start the reconsent, screening and 
randomization procedures once more if they miss the 30-day window.
5.
Male or female who are not pregnant or not planning a pregnancy during the study or 
not Lactating
Informed Consent
6.
Capable of giving signed informed consent as described in Section 10.1.3 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.
5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Concurrent diagnosis of COPD or other respiratory disorders including active 
tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary 
hypertension, interstitial lung diseases or other active pulmonary diseases.
2. History of hypersensitivity to any components of the study inhaler (e.g., lactose). 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.
3. Historical or current evidence of clinically significant or rapidly progressing or 
unstable 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.
Other Exclusions
4. Drug/alcohol abuse: Participants with a known or suspected alcohol or drug abuse,
which in the opinion of the investigator could interfere with the participant’s proper 
completion of the protocol requirement.
5. A participant 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, as well as employees of GSK or Novartis.
6. Inability to Read: In the opinion of the investigator, any participant who is unable to 
read and/or would not be able to complete a questionnaire and understand verbal 
instructions.
7. Medical and physical conditions that in the opinion of the investigator could impact 
the ability of the participant to manipulate the inhaler.
5.3.
Lifestyle Considerations
There are no lifestyle restrictions.

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5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized/entered in the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, any protocol deviations 
and any serious adverse events (SAEs).
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened one further time at the discretion of the investigator. Rescreened 
participants must be assigned a new participant number for every screening/rescreening 
event.
5.5.
Criteria for Temporarily Delaying 
Enrollment/Randomization/Administration of Study 
Intervention Administration 
The study involves two visits (V0 and V1), which can be completed on the same day. The 
assessments are completed on V1, which is when participants are randomized so this 
section is not applicable. 
6.
STUDY INTERVENTION(S) AND CONCOMITANT 
THERAPY
6.1.
Study Intervention(s) Administered
ARM Name
ELLIPTA Arm 
BREEZHALER Arm 
Intervention Name
Placebo ELLIPTA
Placebo
BREEZHALER
Type 
Dry Powder Inhaler 
Dry Powder Inhaler
Dose Formulation
Placebo composed of 
lactose
Placebo 
Unit Dose Strength(s)
N/A 
N/A
Dosage Level(s)
Placebo
Placebo
Route of Administration
For Oral Inhalation 
For Oral Inhalation 

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IMP and NIMP
NIMP
NIMP
Sourcing
GSK
Novartis
Packaging and Labelling
To be labelled in 
accordance to Regulatory 
Requirements 
To be labelled in accordance 
to Regulatory Requirements 
6.1.1.
Medical Devices

The GSK manufactured medical devices provided for use in this study is the 
ELLIPTA.

The other medical device (not manufactured by or for GSK provided for use in this 
study is the BREEZHALER (Novartis).

GSK medical device deficiencies, (including malfunction, use error and inadequate 
labelling) shall be documented, and reported by the investigator throughout the 
clinical investigation (see Section 8.3.8 ) and appropriately managed by the sponsor.
6.2.
Preparation/Handling/Storage/Accountability
1.
The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention.
2.
Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions 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.
3.
The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records).
4.
Further guidance and information for the final disposition of unused study 
intervention are provided in the study Reference Manual.

Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff.  

A Material Safety Data Sheet (MSDS)/equivalent document describing 
occupational hazards and recommended handling precautions either will be 
provided to the investigator, where this is required by local laws, or is available 
upon request from GSK.

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6.3.
Measures to Minimize Bias: Randomization and Blinding
This is an open-label study; however, the specific intervention to be taken by a 
participant will be assigned using an IVRS/IWRS. The site will contact the IVRS/IWRS 
prior to the start of study intervention administration for each participant. The site will 
record the intervention assignment on the applicable electronic case report form (eCRF), 
if required. Potential bias will be reduced by the following steps: by randomizing the 
order of intervention and the preference questionnaire versions that will be answered by 
the participants as per Table 1.
Table 1
Randomization Schedule
Sequence 
Arm
Part  1
Part  2
Preference Questionnaire
(versions)
A
ELLIPTA
BREEZHALER
1
B
ELLIPTA
BREEZHALER
2
C
BREEZHALER
ELLIPTA
1
D
BREEZHALER
ELLIPTA
2
6.4.
Study Intervention Compliance

The participant must use the inhaler under supervision of the investigator or designee, 
who will assess if there are any errors in the use of the inhaler. The intervention 
follows sequential hierarchical use of the inhaler
o
First Inhaler 

First use after reading inhaler use section of PIL (Attempt 1)

If Failed – Second use after first instruction by HCP (Attempt 2)

If Failed – Third use after second instruction by HCP (Attempt 3)

If Failed – fourth use after third instruction by HCP (Attempt 4)

If Failed – Recorded and no further intention with first inhaler 
o
Second Inhaler 

First use after reading inhaler use section of PIL (Attempt 1)

If Failed – Second use after first instruction by HCP (Attempt 2)

If Failed – Third use after second instruction by HCP (Attempt 3)

If Failed – fourth use after third instruction by HCP (Attempt 4)

If Failed – Recorded and no further intention

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6.5.
Dose Modification
This section is not applicable.
6.6.
Continued Access to Study Intervention after the End of the 
Study
This section is not applicable as no active treatments are being administered in the study.
6.7.
Treatment of Overdose
This section is not applicable as all participants will receive the placebo only.
6.8.
Concomitant Therapy
Any medication that the participant is receiving at the time of enrolment or receives 
during the study must be recorded along with:

reason for use

dosage information including dose and frequency
In case, the participants visit the site within the 30 days interval between the Visit 0 and 
Visit 1 for enrolment, the participants can continue to take their concomitant medications 
as per their routine therapy except the use of ELLIPTA and BREEZHALER inhalers.  
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
7.
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1.
Discontinuation of Study Intervention
This section is not applicable since discontinuation of study intervention corresponds to 
withdrawal from the study since each inhaler is only available on a single day.  
7.2.
Participant Discontinuation/Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request or 
may be withdrawn at any time at the discretion of the investigator for safety, 
behavioural, or compliance reasons. This is expected to be uncommon.

If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent.

If a participant withdraws during the interval between screening (V0) and Visit 1, 
there are no assessments that would need to be completed following withdrawal. 
A participant can also withdraw following randomization. In such cases, the 

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participant may be asked to provide the reason for discontinuation which needs to 
be documented. 
7.3.
Lost to Follow Up
This section is not applicable as the assessment visit (V1) occurs on a single day
8.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA (Section 1.3). 

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 intervention.

Adherence to the study design requirements, including those specified in the SoA 
(Section 1.3), is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that 
potential participants meet all eligibility criteria. The investigator will maintain a 
screening log to record details of all participants screened and to confirm 
eligibility or record reasons for screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management and 
obtained before signing of ICF may be 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 (Section 1.3).

Prior to randomization, at V1, all assessments to confirm inclusion at V0 will be 
completed. The details of these assessment are provided in the SoA (Section 1.3)
8.1.
Efficacy Assessments
8.1.1.
Assessment of errors in use of inhalers

Participants will be randomized to the order of inhaler as detailed in Table 1 and 
the sequence of questionnaire completion is indicated in the study Schema in 
Section 1.2. Participants will be provided with the relevant sections of the PIL, 
explaining the correct use for both inhalers. The critical and overall errors per 
inhaler and how these have been defined are outlined in Section 10.3 Appendix 3

The errors listed will be aligned with the correct use information from the 
respective PILs, in a checklist for each inhaler which will be provided to the 
HCPs for scoring errors during the study conduct.  The checklists to be completed 
by the investigator will be provided.
The steps required to assess participant errors in using the inhalers is illustrated in 
Figure 1 and summarized below:

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
Participants will demonstrate inhaler use after reading the use sections of the PIL 
which is provided to them by the investigator (Attempt 1). 

If the participant makes any errors according to the error checklists in Appendix 
3, the investigator demonstrates the correct use of the inhaler, and the participant 
will try inhaler use again (Attempt 2). If after the first demonstration the 
participant continues to make errors, the investigator will again demonstrate 
correct inhaler use to the participant prior to the participant trying again (Attempt 
3).  If the participant has still not demonstrated correct use, the HCP will again 
demonstrate correct use for the final time, followed by the final attempt for the 
participant to demonstrate use of the inhaler (Attempt 4). 

Following each attempted use of the inhaler by the participant, the trained 
investigator will assess for, and document, any critical errors (i.e., defined as an 
error that is most likely to result in no or significantly reduced medication being 
inhaled) and non-critical errors made by the participant. 

This process of error assessment will be used to assess for critical and non-critical 
errors made by the participant for both inhalers being tested. 

Participants will be permitted up to a 30-minute break between completing the 
assessment of the first inhaler and commencing error assessments for the second 
inhaler.
Figure 1
Assessment of errors for each inhaler

2 0 2 0 N 4 3 9 7 2 2 _ 0 0
C O N FI D E N TI A L
2 1 3 3 0 6
2 9
8. 1. 2.
Ti m e t a k e n t o d e m o n str at e c orr e ct u s e of t h e i n h al er
Ti me ta ke n t o c orrectl y use t he i n haler will be rec or de d as f oll o ws:

T 0: t he ti me ta ke n fr o m w he n t he partici pa nt starts t o rea d t he rele va nt secti o ns of 
t he PI L u ntil t he y c o m plete t he rea di n g a n d are rea d y t o start de m o nstrati o n of t he 
i n haler

T 1: t he ti me fr o m w he n t he partici pa nt starts t he de m o nstrati o n of t he i n haler after 
rea di n g t he PI L u ntil t he y  ha ve c o m plete d de m o nstrati o n of i n haler use 

T 2: t he ti me fr o m w he n t he i n vesti gat or starts t o i nstr uct t he partici pa nt u ntil 
c orrect use is de m o nstrate d ( u p t o ma x. 3 atte m pts)
o
T 2 i ncl u des t he ti me use d b y  t he i n vesti gat or f or re-i nstr ucti n g t he 
partici pa nts t hr o u g h o ut.

T 1 + T 2: t he ti me fr o m w he n t he partici pa nt starts t he de m o nstrati o n u ntil c orrect 
use is de m o nstrate d ( 4 atte m pts - o nce after t he rea di n g t he PI L a n d f oll o wi n g 
i nstr ucti o n fr o m i n vesti gat or u p t o 3 ti mes).
8. 1. 3.
A s s e s s m e nt of e a s e -of -u s e 
O nce t he err or assess me nt of eac h i n haler has bee n c o m plete d t h e partici pa nt will 
c o m plete t he ease of use q uesti o n naire f or t hat de vice (A p pe n di x 4 ). T his is a series of 6 
q uesti o ns w hic h t he partici pa nt is as ke d t o rate t heir ease of use e x perie nce wit h t he 
de vice.  T his is c o m plete d f or t he first de vice bef ore m o vi n g t o t he critical err ors 
assess me nt of t he sec o n d de vice. 
8. 1. 4.
Willi n g n e s s t o c o nti n u e wit h t h e i n h al er
After c o m pleti o n of t he critical err ors assess me nt f or eac h i n haler a n d t he ease of u se 
q uesti o n naire f or t hat i n haler , t he partici pa nt will als o be as ke d t he f oll o wi n g q uesti o n 
usi n g a vis ual a nal o g ue scale ( A p pe n di x 5 ): ‘O n a scale of 0
 t o 1 0 0 
, w o ul d y o u be willi n g t o c o nti n ue wit h t his i n haler?’ 
8. 1. 5.
Pr ef er e n c e q u e sti o n n air e
After c o m pleti n g t he err ors i n use assess me nt f or b ot h de vices, t he partici pa nts will 
c o m plete t he assi g ne d prefere nce q uesti o n naires ( A p pe n di x 6 ).
8. 2.
S af et y A s s e s s m e nt s
T here are n o safet y assess me nts wit hi n t his st u d y  e xce pt c ollecti o n of a d verse de vice 
e ve nts, seri o us a d verse de vice e ve n ts a n d seri o us a d verse e ve nts arisi n g fr o m t he use of 
t he i n haler. These will be dealt wit h as per S ecti o n 8. 3 .
8. 2. 1.
Pr e g n a n c y  T e sti n g 
Pre g na nc y  testi n g is n ot re q uire d d uri n g t he st u d y.
C CI
C CI

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8.3.
Serious Adverse Events (SAEs) and Other Safety Reporting
The definitions of adverse events (AE) or serious adverse events (SAEs) can be found in 
Section 10.2. In this study, only AEs which meet the seriousness criteria will be 
collected.  The method of recording, evaluating, and assessing causality of SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.2.
All device-related safety events (adverse device effects [ADEs] and serious adverse 
device effects [SADEs]) will be collected in this study.  Definitions of ADEs and SADEs, 
can be found in Section 10.7. Device deficiencies are covered in Section 10.7.
SAEs, ADEs and SADEs will be reported by the participant (or, when appropriate, by a 
caregiver, surrogate, or the participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an SAE, ADE and SADE and remain 
responsible for following up all SAEs and SADEs only.
8.3.1.
Time Period and Frequency for Collecting SAE, ADE, and SADE
Information

All SAEs, ADEs, and SADEs will be collected from consent until the time points 
specified in the SoA (Section 1.3).

Medical occurrences that begin before the start of study intervention but after 
obtaining informed consent will be recorded as Medical History/Current Medical 
Conditions.

All SAEs and SADEs will be recorded and reported to the sponsor or designee 
immediately and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 2. The investigator will submit any updated SAE/SADE data to the sponsor 
within 24 hours of it being available.

Investigators are not obligated to actively seek information on SAEs and SADEs after 
the conclusion of the study participation. However, if the investigator learns of any 
SAE/SADE, 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 
intervention or study participation, the investigator must promptly notify the sponsor.
8.3.2.
Method of Detecting SAEs, ADEs, and SADEs

Care will be taken not to introduce bias when detecting SAEs, ADEs, and/or 
SADEs. Open-ended and non-leading verbal questioning of the participant is the 
preferred method to inquire about SAE/ADE/SADE occurrence. 
8.3.3.
Follow-up of SAEs and SADEs
All SAEs/SADEs, will be followed until the event is resolved, stabilized, otherwise 
explained. Further information on follow-up procedures is given in Appendix 2.

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8.3.4.
Regulatory Reporting Requirements for SAEs/SADEs

Prompt notification by the investigator to the sponsor of an SAE/SADE is essential so 
that legal obligations and ethical responsibilities towards the safety of participants 
and the safety of a study intervention 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 intervention 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.

An investigator who receives an investigator safety report describing an SAE/SADE
or other specific safety information (e.g., summary or listing of SAEs/SADEs) from 
the sponsor will review Investigator’s Brochure and will notify the IRB/IEC, if 
appropriate according to local requirements.

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.

The complaint including labelling failure must be logged, processed and reported 
under the requirements of the Regulation (EU) 2017/745 Medical Device Regulation 
(MDR) Article 80(2) and GSK Medical Device Complaint Management System in 
accordance with ISO 13485 procedural requirements for ELLIPTA Device. While for 
BREEZHALER, the data must be reported under the requirements of the Regulation 
(EU) 2017/745 Medical Device Regulation (MDR) Article 80(2). Further details on 
reporting are included in the study reference manual.
8.3.5.
Cardiovascular and Death Events
For any cardiovascular events detailed in Section 10.2.3 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.
8.3.6.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
This section is not applicable

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8.3.7.
Adverse Events of Special Interest 
This section is not applicable
8.3.8.
Medical Device Deficiencies
Medical devices are being provided for use in this study. To fulfil regulatory reporting 
obligations worldwide, the investigator is responsible for the detection and 
documentation of events meeting the definitions of device deficiency that occur during 
the study with such devices. 
The definition of a Medical Device Deficiency can be found in Section 10.7 Appendix 7
of the protocol. 
8.3.8.1.
Time Period for Detecting Medical Device Deficiencies

Medical device deficiencies that result in an incident will be detected, 
documented, and reported during all periods of the study in which the medical 
device is used. 

If the investigator learns of any device deficiency at any time after a participant 
has been discharged from the study, and such device deficiency is considered 
reasonably related to a medical device provided for the study, the investigator will 
promptly notify the sponsor.

The method of documenting Medical Device Incidents is provided in Section 10.6
Appendix 6 .
8.3.8.2.
Follow-up of Medical Device Deficiencies

Follow-up applies to all participants, including those who discontinue study 
intervention or the study.

The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the deficiency.

New or updated information will be recorded on the originally completed form with 
all changes signed and dated by the investigator.
8.3.8.3.
Prompt Reporting of Medical Device Deficiencies to Sponsor

Device deficiencies will be reported to the sponsor within 24 hours after the 
investigator determines that the event meets the protocol definition of a device 
deficiency.

The Medical Device Deficiency Report Form will be sent to the sponsor 
electronically.  If electronic is unavailable, then paper reporting should be utilized.

The sponsor will be the contact for the receipt of device deficiency reports.

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8.3.8.4.
Regulatory Reporting Requirements for Medical Device Incidents

The investigator will promptly report all deficiencies occurring with any medical 
device provided for use in the study in order for the sponsor to fulfil the legal 
responsibility to notify appropriate regulatory authorities and other entities about 
certain safety information relating to medical devices being used in clinical studies.

The investigator, or responsible person according to local requirements (e.g., the head 
of the medical institution), will comply with the applicable local regulatory 
requirements relating to the reporting of device deficiencies to the IRB/IEC.
8.4.
Pharmacokinetics
Pharmacokinetic parameters are not being evaluated in this study.
8.5.
Genetics and/or Pharmacogenomics
Genetics are not being evaluated in this study.
8.6.
Biomarkers
Biomarkers will not be evaluated in this study.
8.7.
Immunogenicity Assessments
Immunogenicity assessments will not be performed
8.8.
Health Economics OR Medical Resource Utilization and 
Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study.
9.
STATISTICAL CONSIDERATIONS
9.1.
Statistical Hypotheses
The primary purpose of this study is to assess the number of critical errors (defined as an 
error that is most likely to result in no or significantly reduced medication being inhaled) 
made by asthma participants, after they have read the patient information leaflet(s) (PIL) 
for each inhaler. This is a superiority study.
The primary estimand is the odds ratio between the ELLIPTA and BREEZHALER
inhaler in participants with mild to moderate asthma who make at least one critical error 
while demonstrating use of the inhaler after reading the PIL(s) based on participants who 
were able to attempt to demonstrate the use of both inhalers.

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The null hypothesis is that there is no difference in the proportion of participants who 
make at least one critical error on the ELLIPTA inhaler compared with the 
BREEZHALER inhaler:
H0: PELLIPTA=PBREEZHALER
The alternative hypothesis is that there is a difference in the proportion of participants 
who make at least one critical error on the ELLIPTA inhaler compared with the 
BREEZHALER inhaler:
H1: PELLIPTA≠PBREEZHALER
This comparison will be tested at the two-sided 5% significance level.
9.2.
Sample Size Determination
A total of 114 participants will be randomly assigned to study intervention such that 
approximately 114 evaluable participants complete the study. 
The sample size for a 2x2 crossover study is based on the formula presented by Chow, 
2008 and Kung-Jong, 2016. To calculate the conditional odds ratio (via McNemar’s) the 
proportion of participants who have discordant pairs (those who had at least one critical 
error in one inhaler but not the other) was determined based on expert advice.  A panel of 
5 experts was convened to consider the evidence from previous studies of similar design
[van der Palen, 2016;van der Palen, 2018] and with consideration given to observational 
studies in the literature [Khassawneh, 2008; Melani, 2011; Arora, 2014; Chorão, 2014; 
Takaku, 2017; Ocakli, 2018]. A consensus view of the likely error rates that would be 
observed with the ELLIPTA and BREEZHALER devices was subsequently reached. 
A consensus was reached that the proportion of participants who make a critical error in 
the ELLIPTA inhaler and not on the BREEZHALER inhaler would be 6% and the 
proportion of patients who make a critical error in the BREEZHALER inhaler and not on 
the ELLIPTA inhaler would be 20%.
Based on the discordant proportions, an odds ratio of 0.3 was calculated and a standard 
deviation on the log odds ratio scale of 2.785 was calculated based on GSK study 200301 
[van der Palen, 2016. Based on these estimates and a two-sided Type I error rate of 5%, a 
total of 114 participants are required to provide 90% power. No withdrawals are expected
based on previous similarly designed studies. No correlation between periods is assumed 
and no carry over effect is assumed based on previous evidence [van der Palen, 2013]. 
Moreover, both inhalers will contain placebo and participants may have up to a 30-
minute break after demonstrating the first inhaler.
9.3.
Analysis Sets
For the purposes of analysis, the following analysis data sets are defined:

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Participant Analysis 
Set
Description
Screened
All participants screened and Signed ICF 
Randomized
All participants randomized
Performance Evaluable  
All participants who complete reading of the PIL(s) and 
attempt demonstration on both inhalers.
Safety
All randomized participants who complete (whether 
successful or unsuccessful) at least one inhalation with any 
study inhaler 
9.4.
Statistical Analyses
The statistical analysis plan will be finalized prior to data base lock (DBL) and it will 
include a more technical and detailed description of the statistical analyses described in 
this section. This section is a summary of the planned statistical analyses of the most 
important endpoints including primary and key secondary endpoints.
9.4.1.
Primary Endpoint
Objectives
Statistical Analysis Methods
Primary
Primary estimand
The proportion of participants who make at least one critical 
error in each inhaler (ELLIPTA or BREEZHALER) after 
reading the section on inhaler use in the PIL(s) assessed on the 
Day/Visit 1.
The primary treatment effect to be estimated will be the 
comparison of the ELLIPTA inhaler to the BREEZHALER 
inhaler.
The population will be participants with mild to moderate 
asthma who attempt demonstration of both inhalers.
The population-summary measure is an odds ratio.
The intercurrent event is participants who do not attempt 
demonstration of the inhaler (ELLIPTA or BREEZHALER). A 
principal stratum strategy will be used to address the intercurrent 
event. Participants will fall into exactly one of the following four 
strata: 
1. S00: Stratum of randomized participants who attempt 
inhaler demonstration (ELLIPTA and BREEZHALER) 
independent of period.

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Objectives
Statistical Analysis Methods
2. S01: Stratum of randomized participants who attempt 
the demonstration of the BREEZHALER inhaler and 
do not attempt demonstration of the ELLIPTA inhaler 
independent of period.
3. S10: Stratum of randomized participants who attempt 
the demonstration of the ELLIPTA inhaler and do not 
complete demonstration of the BREEZHALER inhaler 
independent of period.
4. S11: Stratum of randomized participants who do not 
attempt inhaler demonstration (ELLIPTA and 
BREEZHALER) independent of period.
The estimated treatment effect will be based on participants who 
fall in the S00 strata.
The comparison of ELLIPTA with BREEZHALER will be 
summarized by an odds ratio. The proportion of participants who 
make at least one critical error in each inhaler will be analysed 
using an exact conditional logistic regression model with 
participant as fixed strata with inhaler, and period as fixed 
effects. The odds ratio of ELLIPTA relative to BREEZHALER 
together with the 95% confidence interval and two-sided p-value 
will also be presented.
Superiority will be declared based on a significance level at the 
two-sided 5% level.
Sensitivity analysis
A sensitivity analysis will be performed using a generalised 
mixed effects model with a binomial family and log link with a 
random effect for participant ID and inhaler, period, age and sex 
as fixed effects. An unstructured variance-covariance matrix will 
be used.
9.4.2.
Secondary Endpoint(s)
Estimands for the secondary variables will use the same inhaler comparison, population 
and strategy for the intercurrent event as for the primary estimand. This means the 
estimated treatment effect comparing the ELLIPTA inhaler to the BREEZHALER inhaler 
will be based on the stratum of participants who were able to attempt demonstration on 
both inhalers. All comparisons will be made at the two-sided 5% significance level.
Objectives
Statistical analysis methods
To compare the 
proportion of 
participants who still 
make at least one 
critical error after 
Participants who still make at least one critical error after 
receiving further instruction (up to 3) from the HCP.
Participants receive further instruction if an error was made 
after reading the PIL.

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Objectives
Statistical analysis methods
receiving further 
instruction from the 
Healthcare 
Professional (HCP) 
for ELLIPTA and 
BREEZHALER 
inhalers

Variable: participants making at least one critical error
after the a) first instruction from the HCP (attempt 2), b) 
the second instruction from HCP (attempt 3) and c) third 
instruction from the HCP (attempt 4). 

Population-summary measure: The odds ratio of 
participants making at least one critical error between the 
ELLIPTA and BREEZHALER inhalers.
a) The denominator will include all participants who fall 
in the S00 stratum. Participants who do not receive the 
first HCP instruction are assumed to have zero critical 
errors.
b) The denominator for those that require a second further 
instruction will include all participants who fall in the 
S00 stratum. Participants who do not receive the second 
HCP instruction are assumed to have zero critical 
errors.
c) The denominator for those that require a third further 
instruction will include all participants who fall in the 
S00 stratum. Participants who do not receive the third 
HCP instruction are assumed to have zero critical 
errors.
The analysis method will be the same as for the primary 
endpoint.
Note: This model will only be fitted if there is sufficient data, 
otherwise summary statistics will be presented.
To compare the 
proportion of overall 
errors made by 
participants after 
reading the inhaler 
use sections of the 
PIL, and if necessary, 
with additional 
instruction from the 
HCP for ELLIPTA 
and BREEZHALER 
inhalers

Participants who make at least one overall error after 
reading the PIL(s) (Attempt 1).

Variable: participants who make at least one overall error 
after reading the PIL. 

Population-summary measure: The odds ratio between 
the ELLIPTA and BREEZHALER inhalers.
The analysis method will be the same as for the primary 
endpoint.
This will be repeated for the participants who still make at 
least one overall error after receiving further instruction (up to 
3) from the HCP. Participants receive further instruction if an 
error was made after reading the PIL.

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Objectives
Statistical analysis methods

Variable: participants who make at least one overall error
after the a) first instruction from the HCP (attempt 2), b) 
the second instruction from HCP (attempt 3) and c) third 
instruction from the HCP (attempt 4). 

Population-summary measure: The odds ratio of 
participants making at least one overall error.
a) The denominator will include all participants who fall 
in the S00 stratum. Participants who do not receive the 
first instruction by the HCP are assumed to have zero 
overall errors.
b) The denominator for those that require a second further 
instruction will include all participants who fall in the 
S00 stratum. Participants who do not receive the second 
HCP instruction are assumed to have zero overall 
errors.
c) The denominator for those that require a third further 
instruction will include all participants who fall in the 
S00 stratum. Participants who do not receive the third 
HCP instruction are assumed to have zero overall 
errors.
Note: the model will only be fitted for the endpoints where 
further instruction is required provided there is sufficient data, 
otherwise summary statistics will be presented.
To summarize the 
number of errors 
(critical and overall) 
made on each inhaler, 
with or without 
further HCP 
instruction.
Number of errors (critical and overall) made after reading the 
PIL(s), and, if necessary, after receiving further instruction 
from the HCP.

Variable: Critical and overall errors made with or without 
further HCP instruction.

Population-summary measure: The number of critical 
errors and overall errors made will be presented for each 
inhaler by instruction (0, 1, 2, 3).
To compare the 
proportion of 
participants that 
require further 
instruction from the 
HCP to demonstrate 
correct inhaler use for
ELLIPTA and 
BREEZHALER 
inhalers
Requiring further instruction from the HCP to demonstrate 
correct inhaler use:

Variable: participants who do or do not require further 
instruction from the HCP. 

Population-summary measure: The number and 
percentage of participants who require further instruction 
from the HCP will be summarized. 
A McNemar’s test will be performed comparing the 
proportion of requiring further instruction on the ELLIPTA

2 0 2 0 N 4 3 9 7 2 2 _ 0 0
C O N FI D E N TI A L
2 1 3 3 0 6
3 9
O bjecti ves
St atistic al a n al ysis met h o ds
i n haler vs. re q uiri n g f urt her i nstr ucti o n o n t he B R E E Z H A L E R
i n haler.
T o c o m pare t he 
Trai ni n g/ Teac hi n g 
Ti me re q uire d t o 
de m o nstrate c orrect 
i n haler use f or 
E L LI P T A a n d 
B R E E Z H A L E R 
i n halers
T he a m o u nt of ti me ta ke n t o de m o nstrate i n haler use wit h o ut 
H C P i nter ve nti o n ( T 1). 

V ari a ble: ti me ta ke n t o de m o nstrate i n haler use wit h o ut 
H C P i nter ve nti o n ( T 1).

P o p ul ati o n -s u m m ary me as ure: Me dia n ti me t o 
de m o nstrate i n haler use.
T he me dia n ti me will be ta ke n fr o m t he Ka pla n -Meier m o del.
A d diti o nall y , the mea n ( S D) , me dia n, mi ni m u m a n d ma xi m u m 
will als o be prese nte d f or partici pa nts w h o de m o nstrate c orrect 
i n haler use.
Partici pa nts w h o fail t o de m o nstrate t he c orrect use will be 
ce ns ore d at t he e n d of T 1.
T he a m o u nt of ti me ta ke n t o be gi ve n i nstr ucti o n b y  t he H C P 
( u p t o 3 ti mes) o n use of t he i n haler a n d t o de m o nstrate i n haler 
use ( T 2).

V ari a ble: ti me ta ke n t o be gi ve n i nstr ucti o n b y t he H C P 
( u p t o 3 ti mes) o n use of t he i n haler a n d de m o nstrate 
i n haler use ( T 2).

P o p ul ati o n -s u m m ary me as ure: Me dia n ti me t o 
de m o nstrate i n hale r use.
T he me dia n ti me will be ta ke n fr o m t he Ka pla n -Meier m o del.
A d diti o nall y , t he mea n ( S D), me dia n, mi ni m u m a n d ma xi m u m 
will als o be prese nte d f or partici pa nts w h o de m o nstrate c orrect 
i n haler use.

T h ose w h o de m o nstrate c orrect use after rea di n g t he PI L 
(a n d t heref ore d o n ot re q uire f urt her i nstr ucti o n) will be 
c o nsi dere d as de m o nstrati n g c orrect use at T 2 a n d ti me 
ta ke n t o de m o nstrate c orrect use will e q ual t o 0 mi n utes. 
T he t otal a m o u nt of ti me ta ke n t o de m o nstrate c orrect 
i n haler use u ntil c orrect de m o nstrati o n is o bser ve d
( T 1 + T 2). V ari a ble: t otal ti me ta ke n t o de m o nstrate i n haler 
use ( T 1 + T 2).

P o p ul ati o n -s u m m ary me as ure: Me dia n ti me a n d t o 
de m o nstrate i n haler use.
T he me dia n ti me will be ta ke n fr o m t he Ka pla n- Meier m o del.
A d diti o nall y , t he mea n ( S D), me dia n, mi ni m u m a n d ma xi m u m 
will als o be prese nte d f or partici pa nts w h o de m o nstrate c orrect 
i n haler use.
T o c o m pare ease - of-
use f or E L LI P T A a n d 

Ease - of- use prefere nce fr o m q uesti o n naire. T his will be 
gr o u pe d as e as y
or diffic ult
C CI
C CI

2 0 2 0 N 4 3 9 7 2 2 _ 0 0
C O N FI D E N TI A L
2 1 3 3 0 6
4 0
O bjecti ves
St atistic al a n al ysis met h o ds
B R E E Z H A L E R 
i n halers
, t hat is, h o w t he ease of use is 
rate d by t he partici pa nt.
o
V ari a ble: ease of use rati n g. 
o
P o p ul ati o n -s u m m ary me as ure: T he n u m ber a n d 
perce nta ge of partici pa nts w h o rate t he i n ha ler
eas y t o use . T o test w het her t he ease of use was 
eas y or diffic ult, a Mc Ne mar’s
test will be 
perf or me d.
T he p o p ulati o n -meas ure s u m mar y  defi ne d a b o ve will be t he 
sa me wa y f or t he f oll o wi n g varia bles as i n dicate d b y 
partici pa nts’ ease of use:

Telli n g h o w ma n y d oses are left i n i n haler

Lear ni n g h o w t o use t he i n haler

Ha n dli n g t he i n haler

Pre pari n g t he i n haler

H ol di n g t he i n haler w hile usi n g it
T o s u m marise ease -
of- use f or E L LI P T A 
a n d B R E E Z H A L E R 
i n halers

Ease - of- use prefere nce fr o m q uesti o n naire, t hat is, h o w t he 
ease of use is rate d
 
o
V ari a ble: ease of use rati n g. 
o
P o p ul ati o n -s u m m ary me as ure: T he n u m ber a n d 
perce nta ge of partici pa nt s w h o rate t he i n haler 
f or eac h cate g or y.
T he p o p ulati o n -meas ure s u m mar y  defi ne d a b o ve will be t he 
sa me wa y f or t he f oll o wi n g varia bles as i n dicate d b y 
partici pa nts’ ease of use:

Telli n g h o w ma n y d oses are left i n i n haler

Lear ni n g h o w t o use t he i n haler

Ha n dli n g t he i n haler

Pre pari n g t he i n haler

H ol di n g t he i n haler w hile usi n g it
T o c o m pare t he 
willi n g ness t o 
c o nti n ue wit h t he 
E L LI P T A a n d/ or 
B R E E Z H A L E R 
i n haler
Willi n g ness t o c o nti n ue wit h t he i n haler usi n g a V A S bet wee n 
0
t o 1 0 0

V ari a ble: Willi n g ness t o c o nti n ue wit h t he i n haler.

P o p ul ati o n s u m m ary me as ure:   T he mea n a n d sta n dar d 
de viati o n f or willi n g ness t o c o nti n ue wit h t he i n haler will 
be prese nte d f or eac h i n haler a n d a c o m paris o n ma de 
bet wee n t he i n halers ( E L LI P T A vs. B R E E Z H A L E R).
T he mea n ( S D), mi ni m u m a n d ma xi m u m will be prese nte d. A 
paire d t-test will be perf or me d c o m pari n g t he mea n 
C CI
C CI
C CI
C CI
C CI

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Objectives
Statistical analysis methods
willingness to continue with the ELLIPTA inhaler vs. the 
mean willingness to continue with the BREEZHALER inhaler.
To compare 
preference attributes 
for ELLIPTA and 
BREEZHALER 
inhalers
Participants who expressed a preference on attributes from the 
preference questionnaire.

Variable: preferred inhaler, overall. 

Population-summary measure: The number and 
percentage of participants who prefer the respective 
inhaler overall (ELLIPTA, BREEZHALER or no 
preference). A comparison will be made between 
the inhalers (ELLIPTA vs. BREEZHALER) using 
Prescott’s test, where participants who select “no 
preference” included as uninformative.
The population-summary measure defined above will be the 
same for the following variables as indicated by the 
participant’s preference:

Preference based on the number of steps to take the 
medication.

Preference based on the time needed to take the 
medication.

Preference based on how easy the inhaler is to use.

Preference based on the size of the inhaler.

Preference based on the comfort of the mouthpiece.

Preference based on the ease of opening the inhaler.
9.4.3.
Safety Analysis
All safety analyses will be performed on the safety analysis set. All ADEs will be 
summarized by each inhaler. Listings will be presented for SAEs and SADEs.
Deaths, SADEs and SAEs, if applicable, will be documented in case narrative format.
9.5.
Interim Analysis
No interim analyses are planned for this study.

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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
10.1.1.
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 and ISO 14155 
2020 guidelines 

Applicable laws and regulations

The protocol, protocol amendments, ICF, IB 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. 

Protocols and any substantial amendments to the protocol will require Central 
Ethics Committee (CEC) approval prior to initiation except for changes necessary 
to eliminate an immediate hazard to study participants.

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), ), European 
Medical Device Regulation 2017/745 for clinical device research, and all 
other applicable local regulations

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10.1.2.
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.
10.1.3.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study. 

Participants must be informed that their participation is voluntary. Participants 
will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, ISO 14155 Health 
Insurance Portability and Accountability Act (HIPAA), GDPR 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 
A participant who is rescreened is not required to sign another ICF if the rescreening 
occurs within (30) days from the previous ICF signature date.
GSK (alone or working with others) may use participant’s coded study data and other 
information to carry out this study; understand the results of this study; learn more about 
the study disease; publish the results of these research efforts 
10.1.4.
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 who will be required to give 
consent for their data to be used as described in the informed consent. 

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.

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
Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report.  The investigator 
will be provided reasonable access to statistical tables, figures, and relevant 
reports and will have the opportunity to review the complete study results at a 
GSK site or other mutually-agreeable location.

GSK will also provide all investigators who participated in the study with a 
summary of the study results and will tell the investigators what treatment their 
patients’ received.  The investigators are encouraged to share the summary results 
with the study participants, as appropriate.

Under the framework of the SHARE initiative, GSK intends to make anonymized 
participant-level data from this trial available to external researchers for scientific 
analyses or to conduct further research that can help advance medical science or 
improve patient care. This helps ensure the data provided by trial participants are 
used to maximum effect in the creation of knowledge and understanding. 
Requests for access may be made through www.clinicalstudydatarequest.com.

The procedures and timing for public disclosure of the protocol and results 
summary and for development of a manuscript for publication for this study will 
be in accordance with GSK Policy.

GSK intends to make anonymized patient-level data from this trial available to 
external researchers for scientific analyses or to conduct further research that can 
help advance medical science or improve patient care. This helps ensure the data 
provided by trial participants are used to maximum effect in the creation of 
knowledge and understanding
10.1.5.
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. 

Guidance on completion of CRFs will be provided in eCRF completion 
guidelines.

Quality tolerance limits (QTLs) will be pre-defined in the QTL plan to identify 
systematic issues that can impact participant safety and/or reliability of study 
results. These pre-defined parameters will be monitored during and at the end of 
the study and all deviations from the QTLs and remedial actions taken will be 
summarized in the clinical study report.

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

Monitoring details describing strategy including definition of study critical data 
items and processes (e.g., risk-based initiatives in operations and quality such as 
Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 

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noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

The sponsor assumes accountability for actions delegated to other individuals 
(e.g., Contract Research Organizations).

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. 
10.1.6.
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 and its origin can be found in [Source 
Data Acknowledgment].

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF.

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. 
10.1.7.
Study and Site Start and Closure
First Act of Recruitment
The study start date is the date on which the clinical study will be open for recruitment of 
participants.

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Study/Site Termination
GSK or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:
For study termination:

Discontinuation of further study intervention development
For site termination:

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 or no recruitment of participants (evaluated after a reasonable amount 
of time) by the investigator

If the study is prematurely terminated or suspended, the sponsor shall promptly 
inform the investigators, the IECs/IRBs, the regulatory authorities, and any 
contract research organization(s) used in the study of the reason for termination or 
suspension, as specified by the applicable regulatory requirements. The 
investigator shall promptly inform the participant and should assure appropriate 
participant therapy and/or follow-up
10.1.8.
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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10.2.
Appendix 2: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
10.2.1.
Definition of AE
AE Definition

AEs are defined below, however only AEs which meet the seriousness criteria (see
Section 10.2.2 ) will be collected in this study:

An AE is any untoward medical occurrence in a clinical study participant, 
temporally associated with the use of a study intervention, whether or not 
considered related to the study intervention.

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 intervention.
10.2.2.
Definition of SAE
An SAE is defined as any serious adverse event 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 admitted 
(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 
fulfills any other serious criteria, the event is serious. When in doubt as to 
whether “hospitalization” occurred or was necessary, the AE should be 
considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE.
d. Results in persistent or significant disability/incapacity

The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.

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
This definition is not intended to include experiences of relatively minor 
medical significance such as uncomplicated headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may 
interfere with or prevent everyday life functions but do not constitute a 
substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Is a suspected transmission of any infectious agent via an authorised medicinal 
product
g. Other situations:

Possible Hy’s Law case: ALT≥3xULN AND total bilirubin ≥2xULN (>35% 
direct bilirubin) or international normalized ratio (INR) >1.5 must be 
reported as SAE

Medical or scientific judgment should be exercised by the investigator in 
deciding whether SAE reporting is appropriate in other situations such as 
significant medical events that 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.
o
Examples of such events include invasive or malignant cancers, 
intensive treatment for allergic bronchospasm, blood dyscrasias,  
convulsions, or development of intervention dependency or 
intervention abuse.
10.2.3.
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 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

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10.2.4.
Recording and Follow-Up of SAE
SAE Recording

When an 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 SAE information.

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 required form.

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 SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each 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 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 intervention 
and each occurrence of each 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 intervention 
administration will be considered and investigated.

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
The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each SAE, the investigator must document in the medical notes that he/she has 
reviewed the SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of 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 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 submitted 
documents.

The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.
10.2.5.
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, then the site will use the paper SAE data 
collection tool (see next section) to report the event within 24 hours.

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 

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relationship of each SAE to IP/study participation (causality) within 72 hours of 
SAE entry into the eCRF.

After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor/SAE coordinator by telephone.

Contacts for SAE reporting can be found in the study reference manual .
SAE Reporting to GSK via Paper Data Collection Tool

Facsimile transmission of the SAE paper data collection tool 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 data collection tool within the designated reporting time 
frames.

Contacts for SAE reporting can be found in the study reference manual.

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10.3.
Appendix 3 CRITICAL ERROR CHECKLISTS
A critical error is defined as an error that is most likely to result in no or significantly 
reduced medication being inhaled. These errors will be captured in a checklist provided 
for HCP assessment of DPI use.
Please note, the critical error checklists are designed to record any errors that are 
made by the participant based on the patient information leaflet for each device.  
Any inadequacies of the medical devices that that fall under the definition of a 
device deficiency (as defined in Section 10.7 Appendix 7)  , must be reported 
separately as per Regulation (EU) 2017/745 Medical Device Regulation (MDR) 
Article 80(2).
10.3.1.
ELLIPTA Critical Error Checklist
Protocol Identifier
213306
Participant Identifier
ELLIPTA Checklist
Visit 1
Date of Assessment:
DAY
MONTH
YEAR
Attempt Number:
PIL (1)
HCP (2)
HCP (3)
PIL  
Step
PIL Wording
Error
(Underlined  text 
indicates a critical 
error)
Step 
Performed 
correctly
Step 
Performed 
Incorrectly
1
Prepare a dose
Wait to open the cover until you are ready to take 
your dose. 
Do not shake the inhaler.
• Slide the cover down until you hear a “click”.
Failed to open cover until 
click is heard
Intentionally shook the 
inhaler after dose 
preparation
2
Inhale your medicine
• While holding the inhaler away from your mouth, 
breathe out as far as is comfortable.
Do not breathe out into the inhaler.
No exhalation before an 
inhalation
Exhaled directly into 
mouthpiece
HCP(4)

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• Put the mouthpiece between your lips and close 
your lips firmly around it.
Do not block the air vent with your fingers.
• Take one long, steady, deep breath in. Hold this 
breath for as long as possible (at least 3-4 
seconds).
• Remove the inhaler from your mouth.
• Breathe out slowly and gently.
No seal created by lips 
around the mouthpiece 
during the inhalation
Inhalation manoeuvre 
was NOT:
- long
- steady
- deep
Blocked air inlet during 
inhalation manoeuvre
Did not hold breath 
3
Close the inhaler and rinse your mouth.
Did not close the inhaler 
(Note: this is an error but 
one which does not 
affect the medication that 
is inhaled)
Did not rinse mouth out 
with water (Note: this is 
an error but one which 
does not affect the 
medication that is 
inhaled)
Other comments:

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10.3.2.
BREEZHALER Critical Error Checklist
Protocol Identifier
Participant Identifier
BREEZHALER checklist 
213306
Visit #
Date of Assessment:
Attempt Number:
PIL
Step
PIL Wording
Error
(Underlined text 
indicates a 
critical error)
Complete
d 
Correctly
Not 
Complete
d 
Correctly
1
Prepare a dose
Pull off cap.
Failed to pull off cap 
2
Open inhaler
Tilt the mouthpiece to open the inhaler
Failed to open inhaler
3
Remove a capsule
   Remove capsule from blister pack.
Failed to remove 
capsule from 
blister pack
4
Insert capsule
Place the capsule into the capsule 
chamber.
Failed to insert 
capsule into the 
chamber
5
Close the Inhaler
  Close the inhaler until you hear a“click”.
Failed to close the inhaler 
(heard 'click’ when 
satisfactory)
6
Pierce the capsule:
Pierce the capsule with the mouthpiece pointing 
up and firmly pressing together both sides until 
you hear a “click” and release the side buttons 
fully
Failed to pierce capsule 
and failed to release the 
piercing buttons 
Intentionally shook the 
inhaler after preparation
HCP (4)

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7
Breathe out fully
While holding the inhaler away from your mouth, 
breathe out as far as is comfortable.
Do not breathe out into the Inhaler.
No exhalation before 
inhalation
Exhaled directly into 
mouthpiece
8
Inhale medicine deeply
Put the mouthpiece between your lips, and close 
your lips firmly around it.
Do not press the side buttons
• Take in one rapid and deep breath, sufficient to 
hear or feel the capsule. 
No seal created by the 
lips round the 
mouthpiece during 
inhalation
Pressed the side 
buttons while inhaling 
through the mouthpiece
Inhalation maneuver
was not:
-Rapid
-Deep
9
As you breathe, the capsule should make a 
whirring noise
• If there is no whirring noise, loosen 
the capsule by tapping the base of 
inhaler and repeat step 7 and 8.
Capsule did not whirr
10
Hold this breath for up to 5 secs
• Remove the inhaler from your mouth.
Failed to hold breath 
11
Check capsule chamber is empty
Open the capsule to check it is empty
If powder remains in capsule, close the inhaler 
and repeat steps 7-12
Did not check the capsule 
chamber
Failed to repeat inhalation 
when powder remained in 
the capsule
12
Close the inhaler and replace the cap
Did not close the inhaler 
and close the cap
Other comments:

2 0 2 0 N 4 3 9 7 2 2 _ 0 0
C O N FI D E N TI A L
2 1 3 3 0 6
5 6
1 0. 4.
A p p e n di x 4 : E a s e of U s e Q u e sti o n n air e s
E L LI P T A
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y t hir d 
p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

2 0 2 0 N 4 3 9 7 2 2 _ 0 0
C O N FI D E N TI A L
2 1 3 3 0 6
5 7
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y t hir d 
p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

2 0 2 0 N 4 3 9 7 2 2 _ 0 0
C O N FI D E N TI A L
2 1 3 3 0 6
5 8
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y t hir d 
p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

2 0 2 0 N 4 3 9 7 2 2 _ 0 0
C O N FI D E N TI A L
2 1 3 3 0 6
5 9
1 0. 5.
A p p e n di x 5. Willi n g n e s s t o c o nti n u e wit h i n h al er 
T he i n vesti gat or will as k y o u t he f oll o wi n g q uesti o n:
O n a scale of 0
t o 1 0 0
 w o ul d y o u be t o c o nti n ue wit h 
t his i n haler. Ple ase mar k o n t he li ne h o w willi n g y o u w o ul d be t o c o nti n ue wit h t his 
i n haler. 
C CI
C CI
C CI
C CI

2 0 2 0 N 4 3 9 7 2 2 _ 0 0
C O N FI D E N TI A L
2 1 3 3 0 6
6 0
1 0. 6.
A p p e n di x 6 : Pr ef er e n c e Q u e sti o n n air e s
Versi o n 1 - Se q ue nce A ( E L LI P T A B R E E Z H A L E R) a n d Se q ue nce C 
( B R E E Z H A L E R E L LIP T A)
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y t hir d 
p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

2 0 2 0 N 4 3 9 7 2 2 _ 0 0
C O N FI D E N TI A L
2 1 3 3 0 6
6 1
Versi o n 2 - Se q ue nce B ( E L LI P T A B R E E Z H A L E R) a n d Se q ue nce D 
( B R E E Z H A L E R E L LIP T A)
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y 
t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

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10.7.
Appendix 7: ADEs, SADEs, and Device Deficiencies: 
Definition and Procedures for Recording, Evaluating, 
Follow-up, and Reporting in Medical Device Studies

The definitions and procedures detailed in this appendix are in accordance with 
ISO 14155 and European Medical Device Regulation (MDR) 2017/745 for 
clinical device research (if applicable). 

Both the investigator and the sponsor will comply with all local medical device 
reporting requirements for medical devices.

The detection and documentation procedures described in this protocol apply to 
all GSK medical devices provided for use in the study (see Section 6.1.1 for the 
list of GSK medical devices).
10.7.1.
Definition of ADE
ADE Definition 

An adverse device effect (ADE) is an AE related to the use of an investigational 
medical device. This definition includes any AE resulting from insufficient or 
inadequate instructions for use, deployment, implantation, installation, or 
operation, or any malfunction of the investigational medical device as well as any 
event resulting from use error or from intentional misuse of the investigational 
medical device.
10.7.2.
Definition of SADE 
A SADE is any serious ADE that:
a.
Led to death 
b.
Led to serious deterioration in the health of the participant, that either resulted in:

A life-threatening illness or injury. 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.

A permanent impairment of a body structure or a body function.

Inpatient or prolonged hospitalization. Planned hospitalization for a pre-existing 
condition, or a procedure required by the protocol, without serious deterioration in 
health, is not considered an SADE.

Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function
c.
Led to fetal distress, fetal death or a congenital abnormality or birth defect
d.
Is a suspected transmission of any infectious agent via a medicinal product

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Definition

A SADE is defined as an adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event.

Any device deficiency that might have led to an SAE/SADE if appropriate action 
had not been taken, intervention had not occurred, or circumstances had been less 
fortunate.
10.7.3.
Definition of Device Deficiency
Device Deficiency Definition

A device deficiency is an inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safety, or performance. Device deficiencies 
include malfunctions, use errors, and information supplied by the manufacturer.
10.7.4.
Recording and Follow-Up of ADE, SADEs, and Device 
Deficiencies
ADE, SADE, and Device Deficiency Recording

When an ADE/SADE/device deficiency occurs, it is the responsibility of the 
investigator to review all documentation (e.g., hospital progress notes, laboratory 
reports, and diagnostics reports) related to the event.

The investigator will then record all relevant ADE/SADE device deficiency
information in the participant’s medical records, in accordance with the 
investigator’s normal clinical practice, and on the appropriate form.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to the medical monitor or SAE coordinator in lieu of completion 
of the ADE/SADE/device deficiency form.

There may be instances when copies of medical records for certain cases are 
requested by the medical monitor. 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 the medical monitor.

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 ADE/ SADE.

For device deficiencies, it is very important that the investigator describes any 
corrective or remedial actions taken to prevent recurrence of the deficiency.
o
A remedial action is any action other than routine maintenance or servicing of 
a medical device where such action is necessary to prevent recurrence of a 

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device deficiency. This includes any amendment to the device design to 
prevent recurrence.
Assessment of Intensity

The investigator will make an assessment of intensity for each ADE/ SADE/ device 
deficiency reported during the study and assign it to one of the following 
categories: 

Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An ADE that is assessed 
as severe should not be confused with an SADE. Severe is a category used for 
rating the intensity of an event; both ADEs and SADEs 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 SADE, not when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each ADE/SADE/device deficiency

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 intervention 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB), in his/her 
assessment.

For each ADE/SADE/device deficiency, the investigator must document in the 
medical notes that he/she has reviewed the ADE/SADE/device deficiency and has 
provided an assessment of causality.

There may be situations in which an SADE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for every 
event before the initial transmission of the SADE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SADE follow-up report with the updated causality 
assessment.

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
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of SADE/device deficiency

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 SADE/ device deficiency 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 SADE data to GSK within 24 hours of 
receipt of the information.
10.7.5.
Reporting of SADEs
SADE Reporting to GSK via an Electronic Data Collection Tool

The primary mechanism for reporting an SADE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable, then the site will use the paper SADE data 
collection tool (see next table) in order to report the event within 24 hours.

The site will enter the SADE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the electronic data collection tool will 
be taken offline to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SADE from a study participant or receives 
updated data on a previously reported SADE after the electronic data collection 
tool has been taken off-line, then the site can report this information on a paper 
SADE form (see next section) or to the GSK medical monitor/SAE coordinator by 
telephone.

Contacts for SADE reporting can be found in the study reference manual.
SADE Reporting to GSK via Paper Data CollectionTool

Facsimile transmission of the SADE data collection tool is the preferred method to 
transmit this information to the GSK medical monitor or the SAE coordinator.

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
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SADE paper 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 SADE paper data collection tool within the designated 
reporting time frames.

Contacts for SADE reporting can be found in the study reference manual.
10.7.6.
Reporting of Device Deficiencies

Device Deficiency Reporting to GSK 

NOTE: There are additional reporting obligations for medical device deficiencies 
that are potentially related to SAEs/SADEs that must fulfill the legal responsibility 
to notify appropriate regulatory authorities and other entities about certain safety 
information relating to medical devices being used in clinical studies. 

Any device deficiency that is associated with an SAE/SADE must be reported to 
GSK within 24 hours after the investigator determines that the event meets the 
definition of a device deficiency.

GSK will review all device deficiencies and determine and document in writing 
whether they could have led to an SAE/SADE. These device deficiencies will be 
reported to the regulatory authorities and IRBs/IECs as required by national 
regulations.

Contacts for SAE/SADE reporting can be found in the study reference manual.

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10.8.
Appendix 8: Abbreviations and Definitions and Trademarks
ADE
Adverse Device Effects
AE
Adverse Event
CONSORT
Consolidated Standards of Reporting trials
COPD
Chronic Obstructive Pulmonary Disease
CRF
Case Report Form
DPI
Dry Powder Inhaler
GINA
Global Initiative for Asthma
HCP
Healthcare professional
ICS
Inhaled Corticosteroids
IEC
Independent Ethics Committees
IRB
Institutional Review Boards
LABA
Long Acting β2-Agonist
LAMA
Long Acting Anticholinergic
MedDRA 
Medical Dictionary of Regulatory 
Activities
PIL 
Patient instruction Leaflet
QTL
Quality Tolerance Limits
SABA 
Short Acting α2-Adrenergic Agonist
SADE
Serious Adverse Device Effects
SAE
Serious Adverse Events
SAMA
Short Acting Muscarinic Antagonist
SoA
Schedule of Activities
SRM 
Study Reference Manual

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SUSAR 
Suspected Unexpected Serious Adverse 
Reactions
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
ELLIPTA
BREEZHALER
SAS
WinNonlin

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11.
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