Clinical trial NCT03380429
Conditions: Asthma
Keywords: Connected Inhaler System Metered Dose Inhaler ELLIPTA RELVAR/BREO Dry Powder Inhaler Salbutamol Asthma
Sponsor: GlaxoSmithKline
Start date: 2018-01-31; Completion date: 2019-01-24
Enrollment: 437 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
GlaxoSmithKline (GSK) in collaboration with Propeller Health has developed a sensor, which can clip on to the ELLIPTA® dry powder inhaler (DPI) and monitor the time and date that the ELLIPTA DPI cover is fully opened and closed. Additionally, a sensor will be attached to the rescue medication metered dose inhaler (MDI). The data from both sensors will be fed back to the subject via an application (app) on smart phone and will be reviewed by the subject's health care professional (HCP) via an online dashboard. The sensors, app, dashboard and systems to provide data comprise the CIS. This study will be the first to evaluate the effect of CIS on adherence to maintenance therapy in subjects with uncontrolled asthma. This is an open-label, randomized, parallel group study in asthmatic subjects currently on a fixed dose inhaled corticosteroid (ICS)/long-acting beta 2 agonist (LABA) maintenance therapy. Eligible subjects will receive RELVAR®/BREO® maintenance therapy via ELLIPTA DPI and salbutamol rescue medication via MDI with sensors attached to both inhalers during the run-in period, which may last for up to 3 months. Eligible subjects will then be randomized into five treatment arms depending on whether the data, from RELVAR/BREO ELLIPTA or RELVAR/BREO ELLIPTA and salbutamol MDI, is fed back to the subject or subject and HCP, or not at all. The treatment period for the study is approximately 6 months and there will be a follow-up period one week post last visit. The total duration of a subject in the study will be approximately 9 months. RELVAR, BREO and ELLIPTA are registered trademarks of GlaxoSmithKline group of companies.

Detailed description:

Arms: arm 1: Eligible subjects will receive RELVAR/BREO maintenance therapy via ELLIPTA DPI and salbutamol rescue medication via MDI with sensors attached to both inhalers. Information from sensor attached to RELVAR/BREO ELLIPTA will be fed back to the subject via an app on smart phone and to the subject's HCP via an online dashboard. arm 2: Eligible subjects will receive RELVAR/BREO maintenance therapy via ELLIPTA DPI and salbutamol rescue medication via MDI with sensors attached to both inhalers. Information from sensor attached to RELVAR/BREO ELLIPTA will be fed back to the subject via an app on smart phone. arm 3: Eligible subjects will receive RELVAR/BREO maintenance therapy via ELLIPTA DPI and salbutamol rescue medication via MDI with sensors attached to both inhalers. Information from sensors attached to RELVAR/BREO ELLIPTA and salbutamol MDI will be fed back to both subject and HCP. The data will be fed back to the subject through an app and to HCP through an online dashboard. arm 4: Eligible subjects will receive RELVAR/BREO maintenance therapy via ELLIPTA DPI and salbutamol rescue medication via MDI with sensors attached to both inhalers. Information from sensors attached to RELVAR/BREO ELLIPTA and salbutamol MDI will be fed back to subject through an app. arm 5: Eligible subjects will receive RELVAR/BREO maintenance therapy via ELLIPTA DPI and salbutamol rescue medication via MDI with sensors attached to both inhalers. Subjects will be provided with a home hub through which their data will be uploaded during the study but the subjects and their HCP will not be able to view the data.
Interventions: intervention 1: RELVAR/BREO intervention 2: Salbutamol intervention 3: Smart phone app intervention 4: HCP Dashboard intervention 5: Sensors
Intervention descriptions: intervention 1: RELVAR/BREO will be available at doses of 100/25 micrograms (µg) and 200/25 µg to be administered via ELLIPTA DPI. Subjects will be administered one inhalation of RELVAR/BREO once daily. intervention 2: Salbutamol will be available at a dose of 100 µg to be administered via MDI. Subjects will be administered salbutamol as and when required. intervention 3: Subjects will be required to download an app associated with sensor on their smartphone. The sensors attached to the inhalers will be connected to the smartphone via Bluetooth. intervention 4: The information from sensors will be reviewed by the HCP via an online dashboard. intervention 5: Clip-on sensors will be fitted to electronically record the actuation data.

Protocol documents:
Prot_000.pdf: 
2016N307903_01
CONFIDENTIAL
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TITLE PAGE
Protocol Title: An open label, randomised, parallel group clinical study to evaluate the 
effect of the Connected Inhaler System (CIS) on adherence to Relvar/Breo ELLIPTA 
therapy, in asthmatic subjects with poor control.
Protocol Number: 207040/ Amendment 01
Short Title: A clinical study to evaluate the effect of the Connected Inhaler System (CIS) 
on adherence to maintenance therapy in poorly controlled asthmatic patients.
Compound Number:
GW685698+GW642444 (GSK2285997)
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information can be found in the Study Reference 
Manual
Regulatory Agency Identifying Number(s): EUDRACT: 2017-002266-45, IND 
077855
Approval Date: 10-SEP-2018
Copyright 2018 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.


PPD
PPD


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
Document
Date
Amendment 01
10-SEP-2018
Original Protocol
22-JUN-2017
Amendment 01 10-SEP-2018
Overall Rationale for the Amendment:
Following scientific advice from regulatory agencies, a much faster study recruitment 
time than expected and a much lower than expected subject dropout rate, GSK have 
reassessed the rationale for the planned interim analysis and sample size re-estimation, 
which was planned for the study. The primary aim of this amendment is to remove the 
current requirement to perform the interim analysis and any subsequent need to include 
further subjects that followed that.
Also, the Benefit/Risk Assessment section has been amended to align with the updated 
EU-RMP.
Some other text changes to clarify protocol have been made as well as typographical 
corrections throughout.
Section # and Name
Description of Change
Brief Rationale
1. Synopsis
Deletion/amendment of
text in these sections
Requirement for the interim 
analysis and sample size re-
estimation to be removed from 
study protocol.
5.1 Overall Design
5.2 Number of Subjects
5.4. Scientific Rationale for Study 
Design
7.5. Method of Treatment 
Assignment
11.2.3. Sample Size Re-
estimation
11.4.4. Interim Analyses
2.0. Schedule of Activities
SOA table updated to 
align with Section 9.2.1
Requirement to collect protocol 
defined safety events from start of 
run-in and once a subject has 
begun treatment with Relvar/Breo 
added to table and notes.


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Section # and Name
Description of Change
Brief Rationale
3.3 Benefit/Risk Assessment
Removal of Potential 
Risks from this section to 
align with the latest RMP 
and updated Pneumonia 
risk with HZA115150 
(SLS asthma) data
EU-RMP has been updated and 
version 10 approved in 
accordance with GVP module V, 
revision 2. Now aligns with the 
latest RMP and has been updated
the Pneumonia risk with 
HZA115150 (SLS asthma) data.
1.0 Synopsis (*) and
4.0. Objectives and Endpoints
Deletion of Prescriptions 
Filled, from health care 
utilisation endpoints
This data will be reported as part 
of demography.
*Addition of ACT 
composite endpoint-
Percentage of patients 
who have either an ACT 
total score of ≥ 20 or an 
increase from baseline 
of ≥ 3 in ACT total score 
at Month 6 (Visit 10)
To align ACT endpoint with other 
clinical studies.
Correction to Asthma 
Symptom Utility Index 
(ASUI) endpoint
Changes to ASUI endpoint to 
correct measure and direction of 
improvement.
Correction to BMQ 
endpoint
To include the multiple endpoints
that the BMQ PRO has.
5.1 Overall Design 
Clarification of Early 
Withdrawal
Clarify that patients who have 
discontinued the CIS but not 
Relvar/Breo ELLIPTA are 
encouraged to stay in the study.
7.9. Concomitant Therapy
Text amended
Clarify which asthma maintenance 
medication is collected in eCRF.
8.0. Discontinuation Criteria
Text amended.
To clarify which treatment 
(Relvar/Breo) withdrawal would 
lead to a subject’s withdrawal
from study.
9.1.3.6 Beliefs in Medicine 
Questionnaire (BMQ)
Text amended
Clarified that the BMQ also 
comprises a General Benefit 
scale.


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Section # and Name
Description of Change
Brief Rationale
9.1.3.8. Exit Interviews
Text amended
To allow, for logistical reasons, 
the Exit Interview to be 
conducted, by phone, off -site
within 14 days of V11.
9.2.6.1. Asthma Exacerbations
Text amended
To clarify definition for severe 
asthma exacerbation.
9.5. Biomarkers
Text amended
To clarify the period a subject 
must withhold rescue and 
ICS/LABA prior to FeNO and PEF 
assessments.
9.7. Prescription Record for 
Asthma Maintenance Medication
Text amended
To clarify which asthma 
maintenance medication 
Prescription Records are collected 
in the eCRF.
Minor corrections of typographical errors throughout.


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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS...............................................................................................................9
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................13
3.
INTRODUCTION....................................................................................................17
3.1.
Study Rationale ..........................................................................................17
3.2.
Background ................................................................................................18
3.3.
Benefit/Risk Assessment ............................................................................20
3.3.1.
Risk assessment for Relvar/Breo 100/25mcg and 
200/25mcg...................................................................................20
3.3.2.
Overall Benefit: Risk Conclusion..................................................24
4.
OBJECTIVES AND ENDPOINTS...........................................................................24
5.
STUDY DESIGN ....................................................................................................28
5.1.
Overall Design ............................................................................................28
5.2.
Number of Subjects ....................................................................................32
5.3.
Subject and Study Completion....................................................................32
5.4.
Scientific Rationale for Study Design ..........................................................32
5.5.
Dose Justification........................................................................................33
6.
STUDY POPULATION...........................................................................................33
6.1.
Inclusion Criteria.........................................................................................33
6.2.
Exclusion Criteria........................................................................................35
6.3.
Lifestyle Restrictions...................................................................................36
6.4.
Screen, Run-in and Randomisation Failures...............................................36
7.
TREATMENTS.......................................................................................................36
7.1.
Treatments Administered............................................................................37
7.2.
Relvar/Breo Dose Guidance: ......................................................................38
7.3.
Medical Devices..........................................................................................38
7.4.
Dose Modification .......................................................................................38
7.5.
Method of Treatment Assignment ...............................................................39
7.6.
Blinding.......................................................................................................39
7.7.
Preparation/Handling/Storage/Accountability..............................................39
7.8.
Treatment Compliance................................................................................40
7.9.
Concomitant Therapy..................................................................................40
7.10.
Prohibited Concomitant Medication.............................................................41
7.11.
Treatment after the End of the Study ..........................................................41
8.
DISCONTINUATION CRITERIA.............................................................................41
8.1.
Discontinuation of Study Treatment ............................................................42
8.1.1.
Liver Chemistry Stopping Criteria ................................................42
8.1.2.
QTc Stopping Criteria ..................................................................43
8.2.
Withdrawal from the Study..........................................................................43
8.3.
Lost to Follow Up........................................................................................44


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9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................44
9.1.
Efficacy Assessments.................................................................................45
9.1.1.
Primary, Secondary and Other Adherence Measures ..................45
9.1.2.
Secondary Efficacy Endpoints .....................................................45
9.1.2.1.
Asthma Control Test...................................................45
9.1.2.2.
Rescue Medication Use..............................................45
9.1.3.
Questionnaires and Interviews.....................................................45
9.1.3.1.
Asthma Control Test (ACT) ........................................46
9.1.3.2.
Asthma Symptom Utility Index (ASUI) ........................46
9.1.3.3.
St Georges Respiratory Questionnaire (SGRQ) .........46
9.1.3.4.
Patient Activation Measure (PAM)..............................47
9.1.3.5.
Medication Adherence Report Scale for 
Asthma (MARS-A), 10-item questionnaire..................47
9.1.3.6.
Beliefs in Medicine Questionnaire (BMQ). ..................47
9.1.3.7.
Exit Questionnaire ......................................................48
9.1.3.8.
Exit Interviews ............................................................48
9.2.
Serious Adverse Events (SAE), Non-Serious Adverse Events that 
leads to withdrawal and Non Serious Adverse Drug Reactions 
(ADR) .........................................................................................................49
9.2.1.
Time Period and Frequency for Collecting AE, ADR and 
SAE Information...........................................................................49
9.2.2.
Method of Detecting AEs, ADRs and SAEs .................................50
9.2.3.
Follow-up of AEs, ADRs and SAEs..............................................50
9.2.4.
Regulatory Reporting Requirements for SAEs .............................50
9.2.5.
Cardiovascular and Death Events................................................51
9.2.6.
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as SAEs...............................................51
9.2.6.1.
Asthma Exacerbations................................................51
9.2.7.
Pregnancy ...................................................................................52
9.2.8.
Medical Device Incidents (Including Malfunctions).......................52
9.3.
Treatment of Overdose...............................................................................52
9.4.
Screening and Safety Assessments............................................................52
9.4.1.
Physical Examinations.................................................................53
9.4.2.
Vital Signs....................................................................................53
9.4.3.
Clinical Safety Laboratory Assessments ......................................53
9.5.
Biomarkers .................................................................................................53
9.5.1.
FeNO in breath ............................................................................53
9.5.2.
Peak Expiratory Flow (PEF).........................................................54
9.6.
Prescription Record for Asthma Maintenance Medication...........................54
9.7.
Medical Resource Utilisation and Health Economics ..................................54
10. DATA MANAGEMENT ...........................................................................................55
11. STATISTICAL CONSIDERATIONS........................................................................55
11.1.
Hypothesis..................................................................................................55
11.2.
Sample Size Determination ........................................................................56
11.2.1.
Sample Size Assumptions ...........................................................56
11.2.2.
Sample Size Sensitivity................................................................56
11.3.
Populations for Analyses ............................................................................57
11.4.
Statistical Analyses.....................................................................................57
11.4.1.
Adherence Analyses....................................................................58
11.4.2.
Safety Analyses...........................................................................60


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11.4.3.
Other Analyses ............................................................................60
12. REFERENCES.......................................................................................................61
13. APPENDICES........................................................................................................65
13.1.
Appendix 1: Abbreviations and Trademarks................................................65
13.2.
Appendix 2: Study Governance Considerations..........................................67
13.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................71
13.4.
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................77
13.5.
Appendix 5: Liver Safety: Required Actions, Follow-up Assessments.........80
13.6.
Appendix 6: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................83
13.7.
Appendix 7: Country-specific requirements.................................................85
13.7.1.
Additional Adverse Event (AE) Reporting: Country-specific 
requirements for Canadian investigators:.....................................85
13.8.
Appendix 8: Protocol Amendment History...................................................87


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1.
SYNOPSIS
Protocol Title: An open label, randomised, parallel group clinical study to evaluate the 
effect of the Connected Inhaler System (CIS) on adherence to Relvar/Breo ELLIPTA 
therapy, in asthmatic subjects with poor control
Short Title: A clinical study to evaluate the effect of the Connected Inhaler System (CIS) 
on adherence to maintenance therapy in poorly controlled asthmatic patients
Rationale: This study will be the first to evaluate the effect of the CIS on adherence to 
maintenance therapy (Relvar/Breo ELLIPTA) in uncontrolled asthmatic patients (Asthma 
Control Test [ACT] <20 at the screening visit and ACT <20 at a subsequent 
randomisation visit following run in)
The study has been designed to assess how the CIS impacts adherence, of asthmatic 
patients, to maintenance therapy, when both the subject and the healthcare professional 
(HCP) receive data from the sensor on the patient’s Relvar/Breo ELLIPTA maintenance 
therapy. 
In addition, the five treatment arms of the study will allow evaluation of different 
elements of the CIS including, having additional data provided from a sensor on rescue 
medication and also the effect of the patient alone seeing any data with no data shared to 
the HCP, or  both the patient and HCP, seeing the data from the sensors Furthermore, this 
study will provide preliminary data evaluating the effect of the CIS on patient outcomes, 
including rescue medication use, patient reported outcomes and change in asthma control 
as assessed by the Asthma Control Test (ACT).
Objectives and Endpoints:
Objectives
Endpoints
Primary
To compare the effect of 6 months use of the 
CIS on adherence to ELLIPTA maintenance 
therapy when both the subject and the HCP are 
supplied with data from the maintenance 
sensor versus no data supplied to the subject 
and HCP (Arm 1 vs Arm 5)
Percentage of ELLIPTA doses taken (daily 
adherence1.) between the beginning of month 4 
and the end of month 6 as determined by the 
maintenance sensor
Secondary
To compare the effect of 6 months use of the 
CIS on adherence to ELLIPTA maintenance 
therapy for the following aspects of the CIS:
Percentage of ELLIPTA doses taken (daily 
adherence1.) between the beginning of month 4


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Objectives
Endpoints

Maintenance data only supplied to subjects 
versus no data supplied to the subject (Arm 
2 vs Arm 5)

Rescue and Maintenance data supplied to 
subject and HCP versus no data supplied 
to the subject and HCP (Arm 3 vs Arm 5)

Rescue and Maintenance data only 
supplied to subject versus no data supplied 
to the subject (Arm 4 vs Arm 5)
and the end of month 6 as determined by the 
maintenance sensor
To compare the effect of the CIS on adherence 
to ELLIPTA maintenance therapy of the 
individual CIS treatment arms versus no data 
supplied to the subject and HCP.

Percentage of ELLIPTA doses taken (daily 
adherence1.) between the beginning of 
month 1 and the end of month 3.

Percentage of ELLIPTA doses taken (daily 
adherence) between the beginning of 
month 1 and the end of month 6
To evaluate the effect of 6 months use of the 
CIS on a subject’s rescue medicine usage

Percentage of rescue free days measured 
between the beginning of month 4 and the 
end of month 6 as determined by the 
rescue sensor records of date, time, and 
number of inhaler actuations. 

Total rescue use measured between the 
beginning of month 4 and the end of month 
6 as determined by the rescue sensor 
records of date, time, and number of inhaler 
actuations.
To evaluate the effect of 6 months use with the 
CIS on a subject’s asthma control

Change from baseline in ACT total score at 
Month 6, measured at baseline (Visit 2, 3 or 
4) and Month 6 (Visit10)

Percentage of patients becoming controlled 
as defined as an Asthma Control Test score 
≥20 at Month 6 (Visit 10)

Percentage of patients with an increase 
from baseline ≥ 3 in ACT total score at 
Month 6 (Visit 10)

Composite endpoint - Percentage of 
patients who have either an ACT total score 
of ≥ 20 or an increase from baseline of ≥ 3 
in ACT total score at Month 6 (Visit 10)
1.
Daily adherence is defined as the subject taking one dose of Relvar/Breo ELLIPTA, within a 24 hour period, 
starting at 12.00am each day of treatment period.


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Overall Design:
This is an open-label, randomised, multi-centre, parallel group study consisting of 5 treatment arms, in asthmatic patients currently on a 
fixed dose Inhaled Corticosteroids (ICS)/ Long-Acting Beta2-Agonist (LABA) maintenance therapy.


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Number of Subjects:
Approximately 600 subjects will be screened to achieve 432 randomised and a total of 
380 subjects are anticipated to have data available for the primary analysis; an estimated 
total of 76 subjects per treatment group.
Treatment Groups and Duration:
All randomised subjects will receive Relvar/Breo ELLIPTA, at the dose allocated at the 
run in.
All subjects will have sensors attached to both their Relvar/Breo ELLIPTA and 
salbutamol Metered Dose Inhaler (MDI). It is the type of data provided by the CIS (either 
Relvar/Breo ELLIPTA alone or Relvar/Breo ELLIPTA and salbutamol MDI), as well as 
who sees that data, (subject alone or subject and HCP), that defines the treatment arms.
The 5 treatments arms are as follow:
1.
Data on Maintenance use supplied to Subject (app) and HCP (dashboard)
2.
Data on Maintenance use supplied to Subject (app)
3.
Data on Maintenance and Rescue use supplied to Subject (app) and HCP (dashboard)
4.
Data on Maintenance and Rescue use supplied to Subject (app)
5.
No data supplied to Subject or HCP
The treatment period for the study is 6 months. However, due to the flexible run in period 
a subject could be on the study for approximately 7, 8 or 9 months in total


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2.
SCHEDULE OF ACTIVITIES (SOA)
Procedures
Screen
Run-In
Treatment Period
EW
Follow
-up
Notes
Visit/Contact
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
Conditional Visits: V3 & V4 are only required if a 
subject is not included at prior run in visit. 
V6, V7, V8 & V9 are only required for Treatment 
arms 1 & 3. Randomisation to treatment arms will 
occur at Visit 2,3 or 4 when randomisation criteria 
have been met
Month of Study
-1
0
0
0
1
2
3
4
5
6
Day of Study
-28
0
0
0
28
56
84
112
140
168
175
Visit Window (days)
2
2
2
2
7
7
7
7
7
2
Conditional Visits
X
X
X
X
X
X
SCREENING ASSESSMENTS
Written Informed Consent
X
Signed by the subject and HCP/ designee prior to 
any other study assessments. May be completed 
at a separate visit to screening if required.
Subject Demography
X
Medical History
X
Asthma History 
X
Including exacerbation history for previous 12 
months and those involving hospitalisation 
Therapy History
X
Maintenance therapy over previous 12 months, 
including number of prescriptions requested or 
provided
Physical Exam
X
Full physical including height, weight and vital 
signs
Inclusion/Exclusion 
Criteria
X
X
X
X
ACT assessment for inclusion required at run-in
visits
Randomisation
X
X
X
Subject randomised to treatment at only one of 
V2, V3 or V4 once ACT criteria is met


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Procedures
Screen
Run-In
Treatment Period
EW
Follow
-up
Notes
Visit/Contact
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
Conditional Visits: V3 & V4 are only required if a 
subject is not included at prior run in visit. 
V6, V7, V8 & V9 are only required for Treatment 
arms 1 & 3. Randomisation to treatment arms will 
occur at Visit 2,3 or 4 when randomisation criteria 
have been met
Month of Study
-1
0
0
0
1
2
3
4
5
6
Day of Study
-28
0
0
0
28
56
84
112
140
168
175
Visit Window (days)
2
2
2
2
7
7
7
7
7
2
Conditional Visits
X
X
X
X
X
X
SAFETY ASSESSMENTS
Concomitant Medication
X
Urine Pregnancy Test
X
X
X
X
X
X
X
SAEs
X
X
Non-Serious Adverse 
Events that leads to 
withdrawal 
X
X
Non-serious adverse events that leads to dose 
modification, drug discontinuation, or withdrawal 
from the trial. Collected from start of run in
Non-serious Adverse
Drug Reactions
X
X
Collected from start of run in
Exacerbations
X
X
Severe Exacerbation are to be reviewed and 
recorded. Collected from start of run in
Unscheduled HCP visits
X
All secondary care contacts and all primary care 
contacts related to Asthma 
QUESTIONNAIRES & Patient Reported Outcomes (PROs) (Performed in the order given here)
ACT
X
X
X
X
X
X
X
ACT performed at V2, V3 or V4 to confirm 
inclusion for randomisation
ASUI
X1
X2
X2
X2
X
X
X
1. PRO’s only performed at screening once a 
subject is included.
2. The PRO’s are only performed at the run-in
visit (V2, V3 or V4) if a subject is randomised
to treatment
SGRQ
X2
X2
X2
X
X
X
PAM
X1
X2
X2
X2
X
X
X
MARS-A
X1
X2
X2
X2
X
X
X
BMQ
X1
X2
X2
X2
X
X
X
EXIT Questionnaire 
X
X


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Procedures
Screen
Run-In
Treatment Period
EW
Follow
-up
Notes
Visit/Contact
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
Conditional Visits: V3 & V4 are only required if a 
subject is not included at prior run in visit. 
V6, V7, V8 & V9 are only required for Treatment 
arms 1 & 3. Randomisation to treatment arms will 
occur at Visit 2,3 or 4 when randomisation criteria 
have been met
Month of Study
-1
0
0
0
1
2
3
4
5
6
Day of Study
-28
0
0
0
28
56
84
112
140
168
175
Visit Window (days)
2
2
2
2
7
7
7
7
7
2
Conditional Visits
X
X
X
X
X
X
Exit Interview
X
X
X
Interview is for sub-set of subjects who agree to 
take part and can be performed at V10 or V11 for 
logistical reason. There is a 14 day window for 
vendor to schedule and conduct exit interviews.
ASSESSMENTS
Fractional exhaled Nitric 
Oxide (FeNO)
X1
X2
X2
X2
X
X
X
1.PEF & FeNO only performed once a subject is 
included.  
2.PEF and FeNO is only performed at the Run-in
visit if a subject is randomised
FeNO performed prior to PEF
Peak Expiratory Flow 
(PEF)
X1
X2
X2
X2
X
X
X
HCP dashboard review
X
X
X
X
X
X
Subjects in treatment arms 1 and 3 only.  HCP 
will record action and outcome of review.
INVESTIGATIONAL PRODUCT
Dispense Sensors
X
Sensors must be attached and switched on in 
clinic.
Dispense Relvar/Breo 
ELLIPTA
X
X
All subjects will attend independent dispensing 
visits to collect their next Relvar/Breo ELLIPTA 
and/or salbutamol MDI as required.  Patients are 
required to bring the sensor to the dispensing 
visits.  The sensor will be attached to the new 
device and switched on at the dispensing visit.
Dispense Salbutamol MDI
X
X
Training in CIS
X
X
X
X
X
Subjects are trained in fitting the sensors at 
screening. Following randomisation, subjects will 
be trained in CIS as relevant for their treatment 
arm. Retraining can be provided at V5.


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Procedures
Screen
Run-In
Treatment Period
EW
Follow
-up
Notes
Visit/Contact
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
Conditional Visits: V3 & V4 are only required if a 
subject is not included at prior run in visit. 
V6, V7, V8 & V9 are only required for Treatment 
arms 1 & 3. Randomisation to treatment arms will 
occur at Visit 2,3 or 4 when randomisation criteria 
have been met
Month of Study
-1
0
0
0
1
2
3
4
5
6
Day of Study
-28
0
0
0
28
56
84
112
140
168
175
Visit Window (days)
2
2
2
2
7
7
7
7
7
2
Conditional Visits
X
X
X
X
X
X
Training in ELLIPTA & 
MDI correct use
X
X
Once included a subject should be trained in 
correct use of ELLIPTA and MDI devices
Correct Use Assessment 
for ELLIPTA and MDI
X
X
Inhaler use technique will be assessed for correct 
use. This need only be recorded in source.
Return Sensors
X
X
Return Relvar/Breo 
ELLIPTA
X
X
Patients are required to return their devices at the 
independent dispensing visits. Doses remaining 
on each returned ELLIPTA inhaler will be 
recorded.  
Return Salbutamol MDI
X
X
Patients to return used MDI at dispensing visits.


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3.
INTRODUCTION
GSK has, in collaboration with Propeller Health, developed a sensor which clips on to the 
ELLIPTA dry powder inhaler (DPI), herein referred to as ELLIPTA. The sensor will 
measure when the ELLIPTA mouth piece cover is fully opened and closed and this data 
can be fed back, via an application (app) on a smart phone to the patient. This will inform 
a patient if/when a dose of Relvar/Breo has been actuated from the ELLIPTA. Other 
information, including: asthma management strategies, tracking of symptoms, asthma 
triggers, medication reminders and daily asthma forecasts involving weather and air 
quality data, will also be provided via the app. Information from a second sensor on a 
patient’s rescue medication metered dose inhaler (MDI) could also provide feedback, via 
the app, to the patient on their salbutamol (albuterol) MDI use. The data from both 
Relvar/Breo ELLIPTA and salbutamol MDI can also be shared, via an online dashboard, 
with the patient’s Health Care Professional (HCP), see Figure 1 and Propeller System 
Site Manual (PSSM). The sensors, app, dashboard and systems to provide data are
subsequently described as the Connected Inhaler System (CIS).
Figure 1
Connected Inhaler System
3.1.
Study Rationale
This study will be the first to evaluate the effect of the CIS on adherence to maintenance 
therapy (Relvar/Breo ELLIPTA) in uncontrolled asthmatic patients (Asthma Control Test 
[ACT] <20 at the screening visit and ACT <20 at a subsequent randomisation visit after 
run-in). The run-in exists to ensure a stable level of control prior to entry into the study, 
given the possible change in treatment and is described in detail in Section 5.1.
The study has been designed to assess how the CIS impacts adherence of asthmatic 
patients to maintenance therapy, when both the subject and the HCP receive data on 
adherence from the sensor on the patient’s Relvar/Breo ELLIPTA maintenance therapy. 
In addition, the five treatment arms of the study will allow evaluation of different 
elements of the CIS. These include; having additional data provided from a sensor on


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rescue medication and the effect of the patient alone seeing any data with no data shared 
to the HCP, or both the patient and HCP seeing the data from the sensors. See Section 5,
Section 7 and Table 1 for details on the 5 arms. Furthermore, this study will provide 
preliminary data evaluating the effect of the CIS on patient outcomes, including rescue 
medication use, change in ACT and patient reported outcomes (PROs).
3.2.
Background
Asthma is a chronic inflammatory disease of the airways that results in hyperreactivity 
and clinically relevant episodes of wheezing, chest tightness and coughing. Although 
asthmatic symptoms can normally be controlled, by treatment, it remains a serious 
condition that is associated with a number of different impacts and co-morbidities such 
as; fatigue, activity impairment, psychological problems (anxiety, depression and stress), 
lung infections and delays in growth (paediatrics). 
The underlying pathophysiology of asthma includes epithelial sloughing, smooth muscle 
contraction, bronchial hyperreactivity and airway inflammation [Koterba, 2012]. 
Depending on the asthmatic patient, these symptoms can become worse during the 
evening and/or with exercise [Martinez, 2007]. Asthma is believed to affect the lives of 
approximately 300 million people worldwide and this number is expected to rise to 400 
million by 2025. 
There are many reasons for poor adherence including, but not limited to, difficulties 
using inhalers, forgetfulness, misunderstanding of instructions, perceptions of the 
medicine and cost [GINA, 2017]. Also, as asthma is an inflammatory condition that is 
episodic in nature, patients can exhibit symptomatic adherence to maintenance therapies
[Anarella, 2004]. 
Inadequate control of asthma symptoms continues to be a serious problem, and despite 
advancements in therapeutics for the treatment of asthma, adherence rates remain less 
than optimum [Anarella, 2004, Foster, 2014]. The significance of adherence to treatment 
regimens in the management of asthma is becoming ever more evident. A variety of 
studies have indicated that poor adherence to maintenance therapy is intimately 
associated with reduced quality of life and, increased; asthma symptoms, oral steroid 
usage, hospitalisation and mortality [Patel, 2013; Williams, 2011, Normansell, 2017]. 
Furthermore, reduced adherence to maintenance therapy can lead to an overuse of rescue 
medication, which has been linked to poorer health status [Patel, 2013]. 
Due to the chronic nature of the disease, low adherence rates are recognised as one of the 
main contributing factors to reduced control amongst asthmatic patients. Therefore, the 
requirement for routine and habitual use of maintenance therapy is paramount. 
Currently, determination of inherent adherence rates are questionable due to their largely
subjective (patient diaries), unreliable (prescription refills) and imprecise (dosage 
counters) data acquisition methodologies. Each of these methods can misrepresent what 
is occurring in the real world. Furthermore, clinicians’ estimations of adherence rates can
be inaccurate, patient self-reported adherence rates are notoriously overestimated and 
some electronic dose counters can also be problematic due to dose dumping [Bae, 2009; 


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Zeller, 2008]. Because of these uncertainties, there is an abundance of research being 
undertaken in the area of inhaler sensors for adherence. Novel solutions to some of the 
aforementioned problems are currently in development, such as; actuation switches (e.g.
Smartinhaler and Propeller Health MDI sensor) for time stamping, heated thermistors 
(MDI log) for inhalation detection, microphones (INCA Device) for detecting peak 
inspiratory flow rates and actuations, accelerometers (Amiko and MDI Log) for time 
stamping and technique feedback, and light transmitters (SmartTrack and SmartTouch) 
for detection of canister depression and time stamping. 
Dosing regimens (once daily vs. twice daily) have also unsurprisingly been found to have 
an effect on adherence to maintenance therapy.  Fewer doses required on a daily basis as 
part of maintenance therapy, has been shown to increase adherence rates as well as 
creating a more routine and habitual dosing times [Coleman, 2012]. 
It has been shown that the addition of a sensor which has the ability to feedback 
information is associated with increased adherence rates in paediatric patients of between 
30 and 50% [Chan, 2016; Foster, 2014]. Unfortunately, the population (paediatrics) and 
the inherent variability of the data make interpretation and extrapolation to other 
populations problematic. However, a 20-30% increase in adherence rates when using 
inhaled corticosteroids has been shown to lead to clinically relevant effects, such as, a 
reduction in exacerbations [Williams, 2011]. Whilst many studies have used sensors to 
measure adherence, relatively few studies have assessed the influence of sensors on 
adherence rates and even less information exists to demonstrate the link between 
adherence and clinically relevant outcomes or patient reported quality of life.
Adherence rate measurements should be unobtrusive, objective and accurate, in order to 
correctly identify innate patient adherence rates [Chan, 2015]. Accordingly, Propeller 
Health, in collaboration with GSK, has developed a sensor, which can clip onto any 
ELLIPTA DPI and can monitor the time and date that the ELLIPTA DPI cover is opened 
and closed. The sensor can be detached and transferred to subsequent inhalers by 
prescription. Propeller Health already produces a sensor that clips on to the top of a 
rescue MDI and records time and date of actuation. The data, from both of these sensors
can then be fed back to the patient or patient and their HealthCare Professional (HCP)
through the use of an app or dashboard. Patient/HCP interaction with the data through the 
app/dashboard may enable greater engagement between the patient and their HCP 
regarding their asthma. The app associated with the Propeller Health sensor also provides 
information on asthma management strategies, tracking of symptoms, asthma triggers, 
medication reminders and daily asthma forecasts involving weather and air quality data, 
in order to improve a patients’ understanding of, and relationship with, their asthma.
It is believed that engaging a patient’s interest in their asthma could improve their 
adherence to their maintenance therapy and ultimately improves their asthma outcomes 
as much of the research supports the importance of adherence rates to asthma control
[Sapir, 2017]. Therefore, if through the use of the CIS, a patient can engage with their 
asthma, this may improve adherence and ultimately improve their level of asthma control. 
Furthermore, from an HCP perspective, having accurate adherence data would make 
discussions with their patients more objective and informed when considering appropriate 
asthma management strategies. 


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3.3.
Benefit/Risk Assessment
3.3.1.
Risk assessment for Relvar/Breo 100/25mcg and 200/25mcg
For Relvar/Breo ELLIPTA, the following risks and the corresponding mitigation 
strategies, as applicable to asthma patients, were taken from the summary of safety 
concerns in the European Union – Risk Management Plan (EU-RMP Version 10). For 
Relvar/Breo the rationale for the risk assessment was derived from the 2014-2016 
Investigator Brochures, from an integrated analysis of key Relvar/Breo studies.


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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Investigational Product (IP) (fluticasone furoate [FF]/vilanterol [VI]])
Pneumonia in patients 
with asthma
In an integrated analysis of 11 
studies in asthma (7034 patients), 
the incidence of pneumonia 
(adjusted for exposure, due to low 
numbers and limited number of 
patients on placebo) seen with 
FF/VI 100/25 microgram strength 
(9.6/1000 patient years) was similar 
to placebo (8.0/1000 patient years). 
The incidence was slightly higher
for FF/VI 200/25 microgram 
(18.4/1000 patient years). No risk 
factors were identified.
In HZA115150 (SLS Asthma) the 
number of subjects who 
experienced a Pneumonia SAESI 
was low. In total, 23 subjects (1%)
randomised to initiate treatment 
with FF/VI arm experienced 
24 Pneumonia SAESIs, and 
16 subjects (<1%) randomised to
continue usual care experienced 
18 Pneumonia SAESIs.
The incidence rate of subjects 
experiencing a Pneumonia SAESI 
per 1000 subject-years at risk by 
randomised treatment arm, was 
10.36 in the FF/VI arm and 7.14 in 
the usual care arm. The number of 
Pneumonia SAESIs per 
1000 subject-years at risk by 
randomised treatment arm was 
10.81 in the FF/VI arm and 8.03 in 
the usual care arm.
The incidence ratio for Pneumonia 
SAESIs for subjects randomised to 
initiate treatment with FF/VI versus 
those randomised to continue usual 
care was 1.4 (95% CI: 0.8, 2.7). 
The upper limit of the 95% CI was 
The risk of pneumonia in asthma 
patients is consistent with the risk 
of other ICS. Subjects are not at 
an increased risk in this study, 
since they enter the study on an 
existing ICS treatment. Subjects 
are alerted to the potential risk of 
pneumonia in the informed 
consent. 
Subjects with a concurrent 
respiratory disease are excluded 
from the study.


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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
higher than the pre-specified 
non-inferiority margin of 2; 
therefore, being randomised to 
initiate treatment with FF/VI was 
not shown to be non-inferior to 
being randomised to continue usual 
care with regards to the incidence 
of Pneumonia SAESIs.
Serious cardiovascular 
events
In an analysis performed on the 18 
key studies in subjects with 
asthma, eight serious 
cardiovascular events have been 
reported in patients exposed to 
FF/VI. Seven events in FF/VI 
100/25 and one event in FF/VI 
200/25. This represents an 
incidence less than 1% in the 
asthmatic patients exposed to 
FF/VI. a
The events reported include atrial 
fibrillation, acute coronary 
syndrome, coronary artery disease, 
hypertension, myocardial ischemia, 
tachyarrhythmia and tachycardia.
Therefore, fluticasone 
furoate/vilanterol should be used 
with caution in patients with severe 
cardiovascular disease or heart 
rhythm abnormalities, 
thyrotoxicosis, uncorrected 
hypokalaemia or patients 
predisposed to low levels of serum 
potassium.
Subjects with existing serious 
cardiovascular disease, 
thyrotoxicosis, uncorrected 
hypokalaemia or patients 
predisposed to low levels of 
serum potassium are excluded 
from the study.
Investigators are made aware of 
the potential class effects of 
LABAs and are advised to 
exercise caution for subjects with 
existing serious cardiovascular 
disease (Section 6.3 [Warnings 
and Precautions] of the IB).
Decreased bone mineral 
density and associated 
fractures
Risk of fracture has been 
associated with oral corticosteroids. 
It is unclear if inhaled 
corticosteroids carry the same risk. 
Currently the risk of reduced bone 
mineral density has not been 
observed in the asthma population 
[Jones, 2002]. In addition specific
assessments in adolescents with 
asthma have not demonstrated an 
Subjects will be informed about 
the risk of decreased bone 
mineral density and bone 
fractures in the informed consent. 
Investigators are made aware of 
the potential for this ICS class 
effect. Subjects will be advised to 
seek medical treatment if any 
signs of decreased bone mineral 
density or fractures occur.


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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
effect on bone mineral density, 
when controlled for growth [König, 
1993; Turpeinen, 2010].
In an analysis performed on the 11 
key studies in subjects with asthma 
bone fractures were reported by 
<1% (7034 patients) of subjects 
who received FF/VI 100/25 and 
was usually associated with trauma
All subjects will already be 
prescribed ICS/LABA treatments 
for their asthma. Therefore, it is 
unlikely that such an effect will 
occur.
Corticosteroid 
associated eye 
disorders
This is considered a class effect of 
ICS. Preclinical studies showed FF 
at high dose comparable to other 
high dose corticosteroids. In study 
HZA106839 (FF/VI, FF and FP in 
subjects with asthma), formal 
ophthalmic assessments were 
conducted (including lens opacities 
classification system [LOCS] III 
evaluations for ocular opacities) 
throughout the study. This study 
showed no apparent effects on lens 
opacification, compared to 
baseline. During studies in both 
subjects with asthma and COPD, 
no associated affect on ocular 
disorders was observed.
Subjects will be informed about 
the risk of corticosteroid 
associated eye disorders in the 
informed consent. They will be 
advised to seek medical 
treatment if any signs of eye 
disorder occur. Investigators are 
made aware of the potential for 
this class effect in Section 5.3.3.7 
(Ophthalmic Effects) of the IB.
All subjects will already be 
prescribed ICS/LABA treatments 
for their asthma. Therefore, it is 
unlikely that such an effect will be 
experienced.
Paradoxical 
bronchospasm may 
occur with an immediate 
increase in wheezing 
after dosing. 
First dose of Relvar/Breo will be 
administered at the clinical site 
under supervision Paradoxical 
bronchospasm should be treated 
immediately with a short-acting 
inhaled bronchodilator. 
Relvar/Breo ELLIPTA should be 
discontinued
Immediately. The subject would 
be withdrawn from study.
a.
RELVAR studies summarized include FFA109684, FFA109685, FFA109687, B2C109575, HZA106827,
HZA106829, HZA113091, HZA113714, HZA113719, HZA116863, HZA106837, HZA106839, HZA106851, 
FFA112059, FFA114496, FFA115283, FFA115285, B2C112060.
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of Relvar/Breo may be found in the Investigator’s 


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Brochure, Development Safety Update Report or Summary of Product Characteristics
Benefit Assessment.
As a result of switching from other prescribed ICS/LABA combination products and 
being randomised to a treatment arm in the study, subjects may switch from an inhaled 
therapy that is taken twice daily, to a once daily therapy (Relvar/Breo) the patients in this 
study may have better adherence and so possibly better asthma control. There is also a 
potential benefit from use of the CIS. This has the potential to increase their adherence
through interaction with the data outputs and engagement with their asthma. Data with 
marketed products suggests that adherence improves with less frequent 
administration/simplification of therapy and therefore it is expected that a once-daily 
treatment could improve adherence, which may lead to improvements in disease control 
and reductions in healthcare resource utilisation costs [Foster, 2014, Price, 2010, Toy,
2011].
3.3.2.
Overall Benefit: Risk Conclusion
GlaxoSmithKline (GSK) has assessed this study for any potential risks that a subject may 
experience. The investigational product (IP) FF/VI will be used as is detailed in the 
prescribing information and has an acceptable safety profile for clinical use and there are 
no significant associated risks. This conclusion is supported by the results of previously 
performed clinical studies with the products in healthy volunteers and subjects with 
Asthma and COPD and post-marketing experience (see local label).
There is a small risk of destabilising asthma when switching to Relvar/Breo. Patients will 
be provided with rescue medication and will be educated to recognise symptoms of 
asthma worsening and instructed to contact the HCP in this event.
Taking into account the measures taken to minimize risk to subjects participating in this
study, the potential risks identified, associated with FF/VI are justified by the anticipated 
benefits that may be afforded to patients with asthma.
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of Relvar/Breo ICS/LABA may be found in the IB, 
Summary of Product Characteristics and Subject Information Leaflet.
4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
To compare the effect of 6 months use of the 
CIS on adherence to ELLIPTA maintenance 
therapy when both the subject and the HCP are 
supplied with data from the maintenance 
sensor versus no data supplied to the subject 
and HCP (Arm 1 vs Arm 5)
Percentage of ELLIPTA doses taken (daily 
adherence1.) between the beginning of month 4 
and the end of month 6 as determined by the 
maintenance sensor


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Objectives
Endpoints
Secondary
To compare the effect of 6 months use of the 
CIS on adherence to ELLIPTA maintenance 
therapy for the following aspects of the CIS:

Maintenance data only supplied to subjects 
versus no data supplied to the subject (Arm 
2 vs Arm 5)

Rescue and Maintenance data supplied to 
subject and HCP versus no data supplied 
to the subject and HCP (Arm 3 vs Arm 5)

Rescue and Maintenance data only 
supplied to subject versus no data supplied 
to the subject (Arm 4 vs Arm 5)

Percentage of ELLIPTA doses taken (daily 
adherence1.) between the beginning of 
month 4 and the end of month 6 as 
determined by the maintenance sensor
To compare the effect of the CIS on adherence 
to ELLIPTA maintenance therapy of the 
individual CIS treatment arms versus no data 
supplied to the subject and HCP.

Percentage of ELLIPTA doses taken (daily 
adherence1.) between the beginning of 
month 1 and the end of month 3

Percentage of ELLIPTA doses taken (daily 
adherence) between the beginning of 
month 1 and the end of month 6
To evaluate the effect of 6 months use of the 
CIS on a subject’s rescue medicine usage

Percentage of rescue free days measured 
between the beginning of month 4 and the 
end of month 6 as determined by the 
rescue sensor records of date, time, and 
number of inhaler actuations. 

Total rescue use measured between the 
beginning of month 4 and the end of month 
6 as determined by the rescue sensor 
records of date, time, and number of inhaler 
actuations.
To evaluate the effect of 6 months use with the 
CIS on a subject’s asthma control

Change from baseline (Randomisation) in 
ACT total score at Month 6, measured at 
baseline (Visit 2, 3 or 4) and Month 6 
(Visit10)

Percentage of patients becoming controlled 
as defined as an Asthma Control Test score 
≥20 at Month 6 (Visit 10)

Percentage of patients with an increase 
from baseline ≥ 3 in ACT total score at 
Month 6 (Visit 10)

Composite endpoint - Percentage of 
patients who have either an ACT total score 
of ≥ 20 or an increase from baseline of ≥ 3 
in ACT total score at Month 6 (Visit 10)


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Objectives
Endpoints
Exploratory and Other Objectives
To evaluate the effect of 6 months use of the 
CIS on adherence to ELLIPTA maintenance 
therapy on the following aspects of the CIS:

HCP having access to sensor data

Rescue Medication data being available

Percentage of ELLIPTA doses taken (daily 
adherence) between the beginning of 
month 4 and the end of month 6 as 
determined by the maintenance sensor
To evaluate the effect of 6 months use with CIS 
on health care utilisation 
Health care utilisation endpoints will include the 
following and will be collected from a subject’s 
medical records. 

Number of outpatient visits relating to 
asthma

Number of primary care visits relating to 
study HCP dashboard review (for 
relevant study arms)

Number of and duration of 
hospitalisations, and ER visits due to 
asthma

Annualised rate of severe 
exacerbations

Number of unscheduled visits to 
primary care related to Asthma 
To evaluate the effect of 6 months use with CIS 
on the following patient reported outcomes
(PROs):

Asthma Symptom Utility Index (ASUI)

St Georges Respiratory Questionnaire 
(SGRQ)

Patient Activation Measure (PAM)

Medication Adherence Report Scale for 
Asthma (MARS-A)

Beliefs in Medicine Questionnaire 
(BMQ).

Percentage of patients meeting a 
responder threshold of ≥ 0.09 points 
improvement (increase) from baseline
(Randomisation) for the ASUI total 
score at Month 6

Percentage of patients meeting a 
responder threshold of ≥ 4 points 
improvement from baseline 
(Randomisation) for the SGRQ total 
score at Month 6

Mean change from baseline
(Screening) in PAM total score at 
Month 6 

Mean change from baseline
(Screening) in MARS-A total score at 
Month 6 

Mean change from baseline 
(Screening) at Month 6 in BMQ:
o
General Benefit score 
o
General Harm score 


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Objectives
Endpoints
o
General Overuse score
o
Specific Necessity score
o
Specific Concern score 
To assess the reliability and usability of the CIS

Incidence of Medical Device Incidents 
between the beginning of Month 1 and 
the end of Month 6.
To explore impact of adherence on the 
biomarker Fractional exhaled Nitric Oxide 
(FeNO)
FeNO at Screening (Visit 1), Randomisation
(Visit 2,3 or 4), Month 1 (Visit 5) and Month 6
(Visit 10).
To explore impact of adherence on the 
physiological marker Peak Expiratory Flow 
(PEF) 

PEF at Screening (Visit 1), 
Randomisation (Visit 2,3 or 4), Month 1
(Visit 5) and Month 6 (Visit 10).

Change from baseline (Visit 2, 3 or 4) in 
PEF measured at Month 1 (Visit 5) and 
Month 6 (Visit 10)
To characterize patient experience of the CIS 
for subjects

Exit Questionnaires at Month 6 (Visit 
10) 

Exit Interviews for a sub set of subjects 
at Month 6 (Visit 10)
Safety Objectives
Safety Endpoints
To evaluate the incidence of SAEs, Non-
Serious Adverse Events that lead to withdrawal 
from study and Non-serious Adverse Drug 
Reactions in asthmatic subjects using the CIS

SAEs, Non-Serious Adverse Events that 
lead to withdrawal and Non-serious 
Adverse Drug Reactions 
1.
Daily adherence is defined as the subject taking one dose of Relvar/Breo ELLIPTA, within a 24 hour period, 
starting at 12.00am each day.


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5.
STUDY DESIGN
5.1.
Overall Design
Figure 2
: Study Schematic


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This is an open-label, randomised, multi-centre, parallel group study consisting of 5 
treatment arms, in asthmatic patients currently on a fixed dose ICS/LABA maintenance 
therapy.
The procedures to be performed at each visit are shown in Section 2. The study and visits 
are described here.
At all visits will require subjects to withhold a daily dose of maintenance therapy and 
rescue medication for 6 hours; as some assessments will require this restriction for 
validity of the assessment (PEF and FeNO) and also so correct use can be demonstrated 
with that days Relvar/Breo ELLIPTA dose at any required visit.
The treatment period for the study is 6 months. However, due to the flexible run in period 
a subject could be on the study for approximately 7, 8 or 9 months in total
Screening Visit (V1)
Subjects who have provided their informed consent will be screened at Visit 1 (V1) for 
inclusion on the study. Subjects who meet all the inclusion criteria, including an ACT of 
<20, will enter the flexible run-in period. Screening and starting the flexible run-in can 
occur at the same visit, however for logistical reasons the flexible run-in can start at a 
separate visit, which must be within 7 days of the screening visit and the subject’s 
inclusion on the study. Should a subject not meet the inclusion/exclusion criteria, they 
will be registered as a screen failure.
Flexible Run-in
Following inclusion at screening all subjects will receive Relvar/Breo ELLIPTA DPI 
maintenance therapy and salbutamol MDI rescue medication and be instructed to take 
these as prescribed. 
Instruction on correct use of the Relvar/Breo ELLIPTA DPI and salbutamol MDI will be 
provided, particularly in the case of subjects previously using other devices, and/or using 
medication requiring twice-daily dosing.
Both the Relvar/Breo ELLIPTA and salbutamol MDI medication used by all subjects 
included on the study will have a sensor fitted and switched on at the clinic visit. 
However, during this run-in period, there will be no information provided to the subjects 
or HCPs on their adherence to Relvar/Breo ELLIPTA or on their use of salbutamol MDI. 
Subjects will also be instructed in fitting the sensors onto both the ELLIPTA and MDI.
The run-in period can last for 1, 2 or 3 months, dependent on a subjects ACT at end of 
each month of the run-in period.
Conditional Visits 2, 3 and 4 (V2, V3 and V4)
At the end of each month of the flexible run-in period, ACT will be re-assessed at the 
clinical centre. If at the first monthly visit of the flexible run-in the subject’s ACT is <20
(uncontrolled) then the subject will be randomised to study treatment and subsequent run-


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in visits are not required. Subjects with an ACT of ≥20 at V2 or V3 repeat the month run-
in period. However, subjects who have an ACT ≥20 at all 3 visits, during the flexible run-
in, will not be randomised and will be registered as a run-in failure.
Randomization/treatment: Conditional Visits 2, 3 and 4 (V2, V3 and V4)
Subjects who meet the randomisation inclusion criteria will be randomised to one of five 
CIS treatment arms at this visit (V2, V3 or V4). All treatment arms continue with
Relvar/Breo ELLIPTA (ICS/LABA) maintenance therapy and Salbutamol MDI rescue 
therapy as in the run-in period and both inhalers continue having a sensor fitted. The 
treatment arms are defined by whether the data, from Relvar/Breo ELLIPTA 
(maintenance) or Relvar/Breo ELLIPTA (maintenance) and salbutamol MDI (rescue), is
fed back to the subject or subject and HCP, or not at all. The 5 treatments arms are as 
follows:
1.
Data on Maintenance use supplied to Subject (app) and HCP (dashboard)
2.
Data on Maintenance use supplied to Subject (app)
3.
Data on Maintenance and Rescue use supplied to Subject (app) and HCP (dashboard)
4.
Data on Maintenance and Rescue use supplied to Subject (app)
5.
No data supplied to Subject or HCP
Following randomisation, subjects in arms 1, 2, 3 and 4, will receive training on how to 
download and use the smart phone app, including how to connect and register the sensors 
via Bluetooth to their smart phone and to the app. Subjects in arm 5 who receive no data 
will be provided with a home hub so that their data will be uploaded during study, though 
they and their HCP will not see that data. Technical and operational details around 
registering sensors, connecting sensors to smart phone or a home hub and other details of 
app connectivity and function will be provided/referenced in the Study Reference Manual
(SRM).
Visit 5 (V5)
Following randomisation, subjects will be asked to return to the site, after one month, at 
V5. At this visit the HCP will ensure that all subjects are able to use the provided inhalers
correctly (correct use). For Arms 1, 2, 3 and 4 the site should ensure the sensors are 
attached correctly to the inhalers, are connected to the smart-phone via bluetooth and the 
HCP should ensure that subjects have been able to use the app. For subjects on Arm 5, 
the HCP will need to ensure that sensors are correctly attached to the inhalers.
At this visit, for subjects on Arms 1 and 3 the HCP will also, be able to review the 
subject’s adherence to treatment from month 1, and for Arm 3 also review the subject’s
rescue medication use. The HCP can as needed use the data (Arms 1 and 3) to discuss 
with these subjects their adherence and if needed the importance of taking their 
medication as it is prescribed. In reviewing the data the HCP should consider how they 
would respond if this data was available as part of normal standard of care. For Arm 3 the 
HCP can also review the subject’s rescue medication use and again should consider how 
they would respond if this data was available as part of normal standard care. The 


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outcome of the HCP data review will be recorded in the electronic Case Report Form 
(eCRF).
Conditional Visits 6, 7, 8 and 9 (V6, V7, V8, V9)
For subjects included on treatment arms 1 and 3, the HCP will review a subject’s sensor 
data via the dashboard, as a minimum every 4 weeks. However, the data can be assessed 
more often as needed. After assessment of the data, the HCP will be able to, at their own 
discretion, act on this data by calling/emailing or inviting the subject to the clinic to 
discuss their asthma further, or they can decide to take no action. When reviewing the 
data the HCP should consider how they would respond if this data was available as part 
of normal standard of care. The action(s) and any outcomes taken in response to these 
conditional visits, initiated by the HCP, will be recorded in the eCRF and in the subject’s 
medical record, including if no action was taken. If the HCP reviews the data at a time 
other than for the conditional visit and schedules a visit for the subject, this will be 
recorded in the eCRF as an unscheduled visit. Furthermore, subjects in all arms will be 
educated to recognise symptoms of asthma worsening and instructed to contact the HCP 
in this event. These events will also be recorded in the eCRF as unscheduled visits.
Visit 10 (V10)
All Subjects will return to site for final study assessments at the end of the 6 month 
treatment period.
Visit 11 (V11 Follow Up)
A follow-up visit will take place one week (2 days) after V10 and may be conducted as 
either a clinical visit or a phone call for final safety check.  
A subject will be considered to have completed the study when they have completed all 
phases of the study including screening, flexible run-in, the randomized treatment phase, 
and safety follow-up.
Dispensing Visits
All Subjects will be asked to return to the pharmacy or an independent nurse/designee at 
the study centre if a pharmacy is not available for these dispensing visits. They will need 
to bring their used Relvar/Breo ELLIPTA and/or salbutamol MDI and clip-on sensors in 
order to pick up their next Relvar/Breo ELLIPTA and/or salbutamol MDI as required
during the course of the study. During these dispensing visits, the sensor will be attached 
to the new devices and switched on at the site. There will be no assessments performed, 
these visits are only for dispensing of study drug, as well as to ensure that subjects are 
able to transfer and pair the sensors. Subjects should return the previous Relvar/Breo 
ELLIPTA and any salbutamol MDI that need replacing at these visits.
As a minimum, the following will need to be captured: the date of visit, medication
dispensed to the subject and also medication returned by the subject, including remaining 
doses on the ELLIPTA dose counter. This data should be recorded for entry into the 
eCRF.


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Early Withdrawal Visit (EW)
Subjects who have permanently discontinued from the CIS, but continue Relvar/Breo
study treatment and have not withdrawn consent are encouraged to continue in the study 
and complete all remaining protocol specified clinic visits.  If a subject is withdrawn then
they should complete the assessments as per Section 2. Reasons for withdrawal are 
provided in Section 8.2.
5.2.
Number of Subjects
Approximately 600 subjects will be screened to achieve 432 randomised and 380 subjects 
are anticipated to have data available for the primary analysis for an estimated total of 76 
subjects per treatment group.
5.3.
Subject and Study Completion
A subject is considered to have completed the study if he/she has completed the last 
scheduled procedure shown in Section 2, including the follow up visit.
The end of the study is defined as the date that the last subject completes the last 
scheduled procedure shown in the Section 2.
5.4.
Scientific Rationale for Study Design
This study will be an open label study, as it is not possible to blind the treatment arms to 
which sensors (maintenance or rescue) are providing feedback to the patient via the app, 
and also, whether or not the patients’ HCP has access to this data via the dashboard.
A true control arm (no sensors on ELLIPTA or MDI) cannot be incorporated into the 
design.  All subjects need to have a sensor on their maintenance and rescue medication in 
order to consistently measure their adherence to maintenance and level of rescue 
medication use; as other methods of measuring adherence and rescue medication use
(paper or electronic diaries and prescription refills) have inherent problems. Therefore, 
arm 5 is considered the best attempt at a control arm as neither subjects nor HCP will 
receive any data from either the ELLIPTA or rescue medication sensors and so could be 
considered the closest possible match to normal current practise.
Any asthmatic patient who is currently uncontrolled (ACT<20) on their current
ICS/LABA medication may be recruited and will, as needed, switch to Relvar/Breo 
ELLIPTA, if not already prescribed that. Due to this possible change in maintenance 
medication, a flexible run-in period has been incorporated into the study design, to enable 
assessment of any impact associated with the change of drug/dosing frequency, or simply 
being on the study, before being randomised to treatment on the study.
The 5 treatment arms of the study will allow future development of the CIS and provide 
directional data on which aspects of the CIS have an impact on adherence, in particular,


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the impact of HCP being able to review adherence data and the impact of data being 
provided from both maintenance and rescue medications on adherence.
5.5.
Dose Justification
Relvar/Breo ELLIPTA and Salbutamol MDI will be prescribed as per label. The dosage 
of Relvar/Breo prescribed to a subject at the beginning of the study will depend on the 
dosage of their current ICS/LABA treatment and therefore, whether they will receive 
either 100/25 mcg or 200/25 mcg Relvar/Breo ELLIPTA. Changing between doses is 
permitted during the study treatment period if deemed necessary by the investigator.
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
AGE
1.
Subjects aged 18 years or older, at the time of signing the informed consent.
TYPE OF SUBJECT AND DIAGNOSIS 
2.
Subjects with documented physician diagnosis of asthma as their primary respiratory 
disease.
3.
Asthma Control Test (ACT) score <20 at screening visit
4.
Non-smokers (never smoked or not smoking for >6 months with <10 pack years 
history (Pack years = [cigarettes per day smoked/20] x number of years smoked)
SEX
5.
Male or Female subjects: 
A female subject is eligible to participate if she is not pregnant (see Appendix 4), not 
breastfeeding, and at least one of the following conditions applies:
(i)
Not a woman of childbearing potential (WOCBP) as defined in Appendix 4.
OR
(ii)
A WOCBP who agrees to follow the contraceptive guidance in Appendix 4
during the treatment period and for at least 5 days] after the last dose of study 
treatment.


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INFORMED CONSENT
6.
Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the consent form and in this protocol.
7.
Subject understands and is willing, able, and likely to comply with study procedures 
and restrictions.
8.
Subject must be able to read in a language supported by the smart phone app in their 
region
CURRENT ASTHMA THERAPY
9.
Subject must have been on maintenance therapy (Fixed dose combination 
ICS/LABA) for 3 months, cannot have changed dose in the month prior to screening
and be able to change to an equivalent dose of Relvar/Breo for the duration of the 
study. Other background asthma medication such as anti-leukotrienes and oral 
corticosteroids are permitted provided the dose has been stable for 1 month prior to 
screening.
10. Subject must be able to change to Salbutamol/Albuterol MDI rescue for the duration 
of the study and judged capable of withholding albuterol/salbutamol for at least 6 
hours prior to study visits.
DIGITAL CRITERIA
11. Subject must have their own Android or IOS smart phone and a data package 
suitable for the installation and running of the app and sending and receiving data. 
Data used by the CIS is approximately 1MB per month as a maximum; this is less 
data than a 1 minute video streamed from YouTube (2MB)).
12. Subjects must be willing and able to download the app on their personal smart phone 
and keep it turned on for the duration of the study. This will also require Bluetooth to 
be turned on for duration of the study. Subjects will also have to turn on mobile data 
for the app for the duration of study; unless travelling and when extra data roaming 
costs could be incurred.


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6.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
RELEVANT HABITS
1. Subjects with a known or suspected alcohol or drug abuse which in the opinion of the 
investigator could interfere with the subject’s proper completion of the protocol 
requirement
CONTRAINDICATIONS
2. History of life threatening asthma: Defined for this protocol as an asthma episode that 
required intubation and/or was associated with hypercapnea, respiratory arrest or 
hypoxic seizures within the last 6 months
3. A lower respiratory tract infection within 7 days of the screening visit.
4. 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.
5. History of hypersensitivity/intolerance to any components of the study inhalers (e.g., 
lactose, magnesium stearate). In addition, subjects with a history of severe milk 
protein allergy that, in the opinion of the study physician, contraindicates 
participation will also be excluded.
6. Historical or current evidence of clinically significant or rapidly progressing or 
unstable cardiovascular, neurological, cardiovascular, neurological, renal, hepatic, 
immunological, endocrine (including uncontrolled diabetes or thyroid disease) or 
hematological abnormalities that are uncontrolled. Significant is defined as any 
disease that, in the opinion of the investigator, would put the safety of the subject at 
risk through participation, or which would affect the analysis if the disease/condition 
exacerbated during the study.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
7. Patient who have ever received treatment with biological based therapy e.g. 
omalizumab, mepolizumab, for asthma
8. Subjects who have received an investigational drug and/or medical device within 30 
days of entry into this study (Screening), or within five drug half-lives of the 
investigational drug, whichever is longer
9. A subject will not be eligible for this study if he/she is an immediate family member 
of the participating investigator, sub-investigator, study coordinator, employee of the 
participating investigator, or any family member of a Propeller Health employee


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Inclusion Criteria for Randomisation
ACT Control at V2, or V3 or V4 of run-in period
1. Asthma Control Test (ACT) score <20 at randomisation visit (V2)
6.3.
Lifestyle Restrictions
There are no lifestyle restrictions.
6.4.
Screen, Run-in and Randomisation Failures
Screen failures are defined as subjects who consent to participate in the clinical study but 
are not subsequently entered the run-in period.
A subject who completes V1 assessments and is dispensed the study medication for the 
run-in period is considered to have entered the run-in period.
A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure subjects to meet the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, and any serious adverse events (SAEs) will be collected in the eCRF.
Run-in failures are defined as subjects who consent to participate in the clinical study, 
enter the run-in period but are not subsequently randomised and do not have any 
randomisation visit (V2, V3, or V4) procedures other than ACT assessment. Information 
including demography, run-in failure details, eligibility criteria, and any serious adverse 
events (SAEs) will be collected in the eCRF.
Randomisation failures are those subjects that complete at least one Randomization 
procedure other than ACT but are not subsequently randomised and do not enter the 
study treatment period.
Any subject who completes the run-in period and then meets the randomization criteria 
and is dispensed the study treatment at V2 is considered to have entered the treatment 
period.
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened, at the discretion of the investigator and should be assigned with a new 
subject number.
7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study subject according to 
the study protocol.


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7.1.
Treatments Administered
All subjects will receive Relvar/Breo ELLIPTA, either at the dose they are already 
prescribed or at the equivalent dose to their current ICS/LABA maintenance therapy if 
switched onto Relvar/Breo ELLIPTA. Guidance on which Relvar/Breo dose is 
appropriate, dependent on current therapy is included in Section 7.2.
Salbutamol MDI rescue medication will be prescribed to subjects to use as needed 
throughout the study for relief of asthma symptoms as per usual practice.
Study Treatment 
Name:
RELVAR/BREO ELLIPTA
Salbutamol MDI
Dosage 
formulation:
ELLIPTA DPI – 30 doses per 
device
Metered Dose Inhaler – 200 doses 
per device
Unit dose 
strength(s)/Dosage 
level(s):
100/25 mcg per actuation and 
200/25 mcg per actuation
100 mcg salbutamol per actuation 
Route of 
Administration
Inhaled
Inhaled
Dosing 
instructions:
One inhalation once daily
PRN
Packaging and 
Labelling
Study Treatment will be provided in 
a container. Each container will be 
labelled as required per country 
requirement.
Treatment will be provided locally. 
and will be labelled as per country 
requirements.
Manufacturer
GlaxoSmithKline (GSK)
All subjects will have sensors attached to both their Relvar/Breo ELLIPTA and 
Salbutamol MDI. It is the type of data provided by the CIS (either Relvar/Breo ELLIPTA 
alone or Relvar/Breo ELLIPTA and salbutamol MDI), as well as who sees that data
(subject alone or subject and HCP) that defines the treatment arms. See Table 1 for a 
description of what data is fed back to who for each treatment arm. Further information 
/reference material for the CIS is provided in the SRM.


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Table 1
Treatment Arms
Relvar/Breo Sensor Data 
Available to
Salbutamol MDI Sensor Data
Available to
Treatment Arm
Subject
HCP
Subject
HCP
1
X
X
2
X
3
X
X
X
X
4
X
X
5
7.2.
Relvar/Breo Dose Guidance:
FF/VI 100mcg/25mcg dose is comparable to fluticasone propionate/salmeterol low and 
medium doses. See SRM for further guidance for dose conversion for other 
corticosteroids.
Further information detailing equivalence of Relvar/Breo to other ICS/LABA 
combination treatment, for subjects who are switched, will be included in the SRM.
7.3.
Medical Devices
The clip on sensors and associated app for subjects’ Smartphone are produced by 
Propeller Health and are being provided by GSK for use in this study. These devices, 
which are fitted on to the Relvar/Breo ELLIPTA DPI and albuterol/salbutamol MDI to 
electronically record actuation data and associated app and HCP dashboard to provides
that data, both have US FDA 510(K) clearance to market (Class II device) and European 
Union (EU) European Conformity (CE) marking (Class I device).
Instructions for medical device use are provided in the SRM, PSSM and in the pack insert 
for each device.
7.4.
Dose Modification
During the treatment period, investigators may modify the dose of a given subject during 
the study. Subjects in turn may change their dose from 100/25mcg FF/VI to 200/25mcg 
FF/VI and vice-versa if deemed absolutely necessary by the investigator.


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7.5.
Method of Treatment Assignment
Assignment of Subject Number
A unique Subject Number will be assigned to any subject who has signed the informed 
consent at V1. The unique Subject Number will be used to identify individual subjects 
during the course of the study.
Assignment of Randomisation Number
At V2, V3 or V4 (Run-in visits), subjects meeting the eligibility criteria will be assigned 
to study treatment using an interactive web response system (IWRS) that will be used by 
HCP or designee to register the subject, randomise the subject and provide treatment 
assignment information. Details on how to use RAMOS NG, the IWRS, to register and 
randomise subjects is provided in the RAMOS NG IWRS manual and SRM.
Once a randomisation number has been assigned to a subject, it cannot be reassigned to 
any other subject in the study.
Subjects will be assigned to study treatment in accordance with the randomisation 
schedule. The randomisation code will be generated by GSK using a validated 
computerised system. A subject will be randomised using RAMOS NG. The study will 
use central-based randomisation system to allocate treatments.
Subjects will be randomized 1:1:1:1:1 to one of the five treatments arms for the duration 
of the treatment period. See Section 5 for description and numbering of arms.
Each investigator will be provided with sufficient study supplies to respond directly to 
subject requests for study treatment as required. Additional supplies will be supplied as 
needed to the sites. Details of how to use the IWRS system (RAMOS NG) to randomise 
subjects and manage study treatment supplies (including dispensing) is provided in the 
RAMOS NG IWRS manual and SRM.
7.6.
Blinding
The study is open label, neither the subject, HCP, site staff, or sponsor is blinded to 
treatment assignment.
7.7.
Preparation/Handling/Storage/Accountability
1.
The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment.
2.
Only subjects enrolled in the study may receive study treatment and only authorised 
site staff may supply or administer study treatment. All study treatments must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) 
area in accordance with the labeled storage conditions with access limited to the 
investigator and authorised site staff.


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3.
The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e. receipt, reconciliation, and final disposition records).
4.
Further guidance and information for the final disposition of unused study treatment 
are provided in the SRM.
Under normal conditions of handling and administration, study treatment 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.
7.8.
Treatment Compliance
The primary measure of treatment compliance for both Relvar/Breo ELLIPTA and 
Salbutamol MDI will be captured by the respective sensor for those treatments. However, 
the date of prescription and date of return of the inhaler, as well as start and finished dose 
count on each Relvar/Breo ELLIPTA, will be recorded in source documents at the 
dispensing visit and also transferred to the eCRF.
7.9.
Concomitant Therapy
All medications for asthma, excluding biological therapy and for other disorders that are 
not contra indicated in asthma, or prohibited in this study, may be continued throughout 
the study.
Please consult the prescribing information for the full list of medications which need to 
be used with caution: 
Beta-blockers: Use with caution. May block bronchodilatory effects of beta-agonists and 
produce severe bronchospasm. 
Diuretics: Use with caution. Electrocardiographic changes and/or hypokalemia associated 
with non-potassium-sparing diuretics may worsen with concomitant beta-agonists. 
Non-study asthma medications: A detailed history of previous 3 months and up to 12 
months prior to inclusion, as available, for prescriptions for maintenance medications
(ICS/LABA combination) will be captured in the subjects eCRF and also any other 
ongoing asthma medications at inclusion.
Any medication or vaccine of relevance to the study or prescribed for safety events, 
including exacerbations experienced during the study, that the subject is receiving at the 
time of enrolment or receives during the study must be recorded in the eCRF in addition 
to medical records. As minimum the following will be needed:

reason for use

dates of administration including start and end dates


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
dosage information including dose and frequency
Over-the-counter medicines, vitamins, and/or herbal supplements are not required to be 
captured.
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
7.10.
Prohibited Concomitant Medication
Subjects must abstain from taking the following medications from 5 days prior to the first 
dose of study medication until completion of the follow-up visit.

Strong cytochrome P450 3A4 inhibitors (e.g., ketoconazole)

Monoamine oxidase inhibitors and tricyclic antidepressants: 

Subjects must never have been treated with a biological therapy for asthma e.g. 
omalizumab, mepolizumab.
Patients using Relvar/Breo ELLIPTA should not use another medicine containing a 
LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for 
any reason.
Do not use in combination with an additional medicine containing a LABA because of 
risk of overdose.
For full list of cautions for use and medicine interactions please consult the prescribing 
information and/or consult the study Medical Monitor if in doubt.
7.11.
Treatment after the End of the Study
There is no plan to continue to provide treatment following the end of the study.  The 
investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific 
post-study treatment.
Medications initiated after completion of the assessments at V10 or the EW visit will not 
be recorded in the eCRF unless taken to treat an AE or asthma exacerbation. subjects who 
have completed the EW visit are allowed to use any medications prescribed by the 
Investigator or primary care physician.
8.
DISCONTINUATION CRITERIA
Subjects that permanently stop study treatment (any aspect of the CIS) are encouraged to 
remain in the study. Subjects have the right to discontinue study treatment before the end 
of the study. A subject may also be asked to discontinue study treatment at the 
investigator’s discretion.


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Subjects who withdraw from study treatment prematurely (for any reason) should, where 
possible, continue to be followed-up as per protocol until the completion of the Safety 
Follow-up assessments. If patients want to discontinue use of the CIS but will continue 
taking the Relvar/Breo ELLIPTA DPI then they will be given the option to continue to 
remain in study if they continue using the clip-on sensor for ELLIPTA. If this is not 
possible, the Investigator must encourage the subject to participate in as much of the 
study as they are willing (or able) to. For those subjects who do not want to use the 
sensor during the study, their health outcome information will be collected along with 
any additional adherence data. Likewise, subjects who change their dose of Relvar/Breo 
(FF/VI) at the discretion of the investigator during the study will be given the option to 
remain on the study, all information will continue to be collected for the duration of the 
study. However, subjects who permanently discontinue from Relvar/Breo ELLIPTA 
should be withdrawn from the study.
A subject may be withdrawn from study treatment at any time. A reason for premature 
discontinuation of study treatment must be captured in the eCRF.
8.1.
Discontinuation of Study Treatment
8.1.1.
Liver Chemistry Stopping Criteria
There are no scheduled blood tests in this study.  If however, the subject has a routine 
blood test during the study and the results suggest abnormal liver function, then the liver 
stopping criteria will apply.
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). These protocol guidelines are in alignment 
with FDA premarketing clinical liver safety guidance:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Discontinuation of study treatment for abnormal liver tests should be considered by the 
investigator when a subject meets one of the conditions outlined in the algorithm, see 
Appendix 5, or if the investigator believes that it is in the best interest of the subject.


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8.1.2.
QTc Stopping Criteria
ECGs are not planned at Screening or during this study. However, if during the study a
subject has an ECG performed the following stopping criteria apply and treatment should 
be withdrawn:
A subject who meets the bulleted criteria below will be withdrawn from the study:
QTcF>500 msec or uncorrected QT>600 msec
Change from V1 baseline: QTcF> 60msec
For patients with underlying bundle branch block, follow the discontinuation criteria 
listed below:
Discontinuation QTc with Bundle Branch Block
< 450 msec
> 500 msec
450 – 480 msec
≥ 530 msec [Note: QTc(F)>500 
msec for Korean subjects]
8.2.
Withdrawal from the Study

A subject may withdraw from the study at any time at his/her own request, or 
may be withdrawn at any time at the discretion of the investigator for safety, 
behavioural, compliance to protocol or administrative reasons.


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
Subjects should be reminded at each visit that if they do choose to withdraw 
themselves then, they should contact the Investigator or Study staff as soon as 
possible and arrange an EW visit.

Female subject will be withdrawn if they produce a positive pregnancy test 
whilst on the study.

If the subject withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent.
Refer to the Section 2 for data to be collected at the time of EW from the study
8.3.
Lost to Follow Up
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit:

The site must attempt to contact the subject and reschedule the missed visit as 
soon as possible and counsel the subject on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the subject wishes to and/or 
should continue in the study.

Before a subject is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the subject (where possible, 3 telephone 
calls and, if necessary, a certified letter to the subject’s last known mailing 
address or local equivalent methods). These contact attempts should be 
documented in the subject’s medical record.

Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
9.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarised in Section 2. 
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 subject should continue or discontinue study 
treatment.
Adherence to the study design requirements, including those specified in the Section 2, is 
essential and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 


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Procedures conducted as part of the subject’s routine clinical management (e.g., blood 
count) and obtained before signing of the informed consent form (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 Section 2.
9.1.
Efficacy Assessments
9.1.1.
Primary, Secondary and Other Adherence Measures
The Primary, Secondary and Other adherence endpoint (adherence to maintenance 
medication) data is collected by the Clip-on Sensor for ELLIPTA and records the time 
and date when the ELLIPTA cover is opened and closed. 
The sensor will be attached to subjects ELLIPTA Relvar/Breo treatment from start of 
run-in until V10. References and material for fitting the sensors, downloading the app 
and other aspects of using the CIS are included in the SRM.
9.1.2.
Secondary Efficacy Endpoints
9.1.2.1.
Asthma Control Test
This assessment is described in Section 9.1.3.1 and will be collected electronically at the 
site at the timepoints detailed in Section 2. This will be carried out via use of the 
electronic Patient Reported Outcome (ePRO) device.
9.1.2.2.
Rescue Medication Use
Rescue Medication use endpoint data is collected by the Clip on Sensor for salbutamol
MDI and records time and date when the MDI is actuated. 
The sensor will be attached to the subject’s salbutamol MDI treatment from start of run-
in until V10. Details for fitting the sensor and other aspects of using the CIS are included 
in the SRM.
9.1.3.
Questionnaires and Interviews
It is preferred that the questionnaires are administered at the same time of day at each 
visit and that this time of day is the same as when they were originally administered (as is 
feasible/appropriate), in order to avoid potential bias due to the time of day when 
responding. The subjects should not be told the results of any diagnostic tests prior to 
completing the questionnaires and the questionnaires should be completed before any 
procedures are performed on the subject to avoid influencing the subject’s response. 
Adequate time in a quiet, comfortable location must be allowed to complete all items on 
the questionnaires and if necessary, the subject must be encouraged to complete any
questionnaires or missing items fully. Full guidance for obtaining good quality data from 
patient-completed questionnaires is included in the SRM.


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All the questionnaires will be completed on an ePRO device at the clinical study site and 
at the time detailed in the Section 2. Further instructions for completing the 
questionnaires can be found in the SRM.
9.1.3.1.
Asthma Control Test (ACT)
The ACT is a validated self-administered questionnaire utilising 5 questions to assess 
asthma control during the past 4 weeks on a 5-point categorical scale (1 to 5) with a range
of 5 to 25. By answering all 5 questions a subject with asthma can obtain a score that may 
range between 5 and 25, with higher scores indicating better control. An ACT score of 5 
to 19 suggests that the subject’s asthma is unlikely to be well controlled. A score of 20 to 
25 suggests that the subject’s asthma is likely to be well controlled. The total score is 
calculated as the sum of the scores from all 5 questions [Nathan, 2004]. The minimally 
important difference (MID) for ACT is 3 [Schatz, 2009].
Subjects will complete the ACT at times shown in the Section 2 using the electronic 
version on the ePRO device at the clinical site.
The ACT has been developed as a measure of subjects’ asthma control that can be 
quickly and easily completed in clinical practice and by telephone. The questions are 
designed to be self-completed by the subject. 
Please refer to the SRM for further details.
9.1.3.2.
Asthma Symptom Utility Index (ASUI)
The ASUI is a 10-item self-administered questionnaire with 4 questions on asthma 
symptoms (Cough, wheeze, shortness of breath, awakening at night) and 1 question about 
the side effects of asthma medications [Revicki, 1998].  For each symptom, there are 2 
dimensions; frequency and severity.  The questionnaire is based on a 2-week patient 
recall of symptoms with response options of 0 to 4 for frequency (not at all, 1 to 3 days, 4 
to 7 days, and 8 to 14 days) and severity (not applicable, mild, moderate and severe).
ASUI will be completed on an ePRO device at the clinical study site and at the times 
detailed in the Section 2.
Please refer to the SRM for further details.
9.1.3.3.
St Georges Respiratory Questionnaire (SGRQ)
The St. George’s Respiratory Questionnaire is a well established instrument, comprising 
50 questions designed to measure Quality of Life in patients with diseases of airway 
obstruction, measuring symptoms, impact, and activity. The questions are designed to be 
self-completed by the subject with a recall over the past 4 weeks [Jones, 1992]
SGRQ will be completed on an ePRO device at the clinical study site and at the times 
detailed in the Section 2.
Please refer to the SRM for further details.


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9.1.3.4.
Patient Activation Measure (PAM)
Patient Activation Measure will be used to assess the knowledge, skills and confidence a 
person has in managing their own health and health care. The questionnaire will be 
completed at the times shown in the Section 2.
The PAM contains a series of 13 statements designed to assess the extent of a patient’s 
activation. These statements are about beliefs, confidence in the management of health-
related tasks and self-assessed knowledge. Patients are asked to rate the degree to which 
they agree or disagree with each statement. These answers are combined to provide a 
single score of between 0 and 100, which represents the patients’ concept of themselves 
as an active manager of their health and health care. There is no specified timeframe on 
which responses should be based, the questionnaire is suitable to be used to measure 
changes in activation over time and can be performed before and after an intervention
[Hibbard, 2004].
PAM will be completed by subjects on an ePRO device at the clinical study site and at 
the times detailed in the Section 2.
Please refer to the SRM for further details.
9.1.3.5.
Medication Adherence Report Scale for Asthma (MARS-A), 10-item 
questionnaire
Reported adherence to medication will be assessed with the Medication Adherence 
Report Scale for Asthma (MARS-A) questionnaire at times shown in the Schedule of 
Activities (SoA).
The MARS-A is a 10-item questionnaire where medication use is rated on a 5-point 
Likert scale (1 indicating ‘always’ to 5 indicating ‘never’). It has been validated as a self-
reported measure of adherence with ICS for patients with asthma, and includes generic 
(“I use it regularly every day”) and lung condition-specific questions about medication 
use (“I only use it when I feel breathless”) [Cohen, 2009]. The MARS-A has no specified 
timeframe on which responses should be based but generally refer to the present moment.
MARS-A will be completed on an ePRO device at the clinical study site and at the times 
detailed in the Section 2.
Please refer to the SRM for further details.
9.1.3.6.
Beliefs in Medicine Questionnaire (BMQ).
The BMQ questionnaire consists of the BMQ Specific, which measures perceptions of 
specific medicines, and the BMQ General, which measures more general beliefs about 
medicines. All items are rated on a 5-point Likert scale [Horne, 2002].
The BMQ General comprises a General Benefit scale, General Harm scale and a General 
Overuse scale assessing beliefs about pharmaceuticals as a class of treatment. The 
General Harm scale assesses beliefs about the intrinsic nature of medicines and the 
degree to which they are perceived as harmful and should be avoided if possible. The 
General Overuse scale represents beliefs about the use of medicines and whether they are 


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overprescribed by clinicians.  The BMQ Specific (Asthma) comprises two scales: one 
assessing patients' beliefs about the necessity of preventer medication for maintaining 
present and future health (Necessity scale), and the other assessing their concerns about 
the potential adverse consequences of using it (Concerns scale). Four items were added 
for use in patients with asthma.
BMQ will be completed on an ePRO device at the clinical study site and at the times 
detailed in the Section 2.
Please refer to the SRM for further details.
9.1.3.7.
Exit Questionnaire
All subjects will complete a questionnaire at the end of the final study visit (V10) to 
assess the CIS.  This questionnaire is designed to understand the subject’s perceptions of 
the CIS. It is self-completed on the ePRO device by subjects. It includes questions 
relating to the concepts below:   

Overall satisfaction with CIS

Parts of the CIS that were most /least helpful

Level of engagement with the CIS

Challenges/difficulties with using CIS 

Subject perception of the impact of the CIS on asthma  

Subject perception of future use of a similar system

Impact of CIS on physician interaction
9.1.3.8.
Exit Interviews
Exit interviews will be conducted for subjects at selected sites at the visit after they have
completed their course of study medication (V11). Exit interviews are qualitative 
interviews conducted with study subjects to capture a subject’s experience on changes in 
asthma and perceptions of the CIS.
Interview questions are designed to fully assess a subject’s experience in a structured 
format by a trained interviewer. Subject feedback will audio-taped for subsequent 
transcription and qualitative analysis. 
These exit interviews will be conducted by external vendors after subjects have 
completed V11. For logistical reasons, this phone call need not occur at the clinical site 
and can be completed within 14 days of V11. The analysis and report of the exit 
interview will be managed by a separate RAP.


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9.2.
Serious Adverse Events (SAE), Non-Serious Adverse Events 
that leads to withdrawal and Non Serious Adverse Drug 
Reactions (ADR)
The Investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of a, non-serious adverse events that leads to withdrawal, 
non-serious adverse drug reaction (ADR) or SAE. The definition of an ADR is any 
untoward medical occurrence in a patient or clinical investigation subject, temporally 
associated with the use of a medicinal product, for which there is a reasonable possibility 
that the untoward occurrence is causally related to the medicinal product. ADRs are a 
subset of AEs for a given medicinal product.
Potential SAEs and associated non serious ADRs may be identified from a subject’s 
primary HCP report or a subject’s health records. The HCP will have the ultimate 
responsibility for determining causality and seriousness.
In some countries extra safety information may be requested as required by local 
Regulatory Agencies and information providing detail of these extra safety events and 
how these should be reported are included in Appendix 7.
In this study, only information regarding non- serious adverse drug reactions (ADRs), 
AEs leading to withdrawal and serious adverse events (SAEs) will be detected, 
documented and reported. However, the definition of an AE is critical for the definition 
of non-serious ADRs and SAEs.
The definitions of an AE or SAE can be found in Appendix 3
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious or that caused the subject to discontinue the study (see 
Section 8.1).
9.2.1.
Time Period and Frequency for Collecting AE, ADR and SAE 
Information

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
product will be recorded from the time a subject consents to participate in the 
study up to and including any follow-up contact. 

AEs leading to withdrawals and ADRs will be collected from the start of Study 
Treatment until the follow-up contact at the timepoints specified in SoA Section 2

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the eCRF.

All SAEs will be recorded and reported to the sponsor or designee within 24 
hours, as indicated in Appendix 3 The investigator will submit any updated SAE 
data to the sponsor within 24 hours of it being available.


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
Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event to be reasonably related to the study treatment or study participation, the 
investigator must promptly notify the sponsor.

The method of recording, evaluating, and assessing causality of AEs and SAEs 
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 3.
9.2.2.
Method of Detecting AEs, ADRs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about AE
occurrence.
The Investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of a non-serious adverse drug reaction (ADR), AE 
(leading to withdrawal) or SAE.
Potential SAEs, AE (leading to withdrawal) and associated non serious ADRs may be 
identified from patient’s medical records.  The Investigator will have the ultimate 
responsibility for determining causality and seriousness.
In this study, only information regarding non- serious adverse drug reactions (ADRs), AE 
leading to withdrawal and serious adverse events (SAEs) will be detected, documented 
and reported. 
9.2.3.
Follow-up of AEs, ADRs and SAEs
After the initial AE that led to withdrawal/non-serious ADR/SAE report, the investigator 
is required to proactively follow each subject at subsequent visits/contacts. All SAEs, will 
be followed until the event is resolved, stabilized, otherwise explained, or the subject is 
lost to follow-up (as defined in Section 8.3). Further information on follow-up procedures 
is given in Appendix 3.
9.2.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of subjects 
and the safety of a study treatment under clinical investigation are met. 

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study treatment 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators.


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
Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or 
other specific safety information e.g., summary or listing of SAE) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.
In some countries extra safety information may be requested as required by local 
Regulatory Agencies and information for this and how these should be reported are 
included in Appendix 7.
9.2.5.
Cardiovascular and Death Events
For any cardiovascular events as detailed in Appendix 3 and all deaths, whether or not 
they are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF 
will be required to be completed. These sections include questions regarding 
cardiovascular (including sudden cardiac death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV Medical 
Dictionary of Regulatory Activities (MedDRA) terms. The CV information should be 
recorded in the specific cardiovascular section of the CRF within one week of receipt of a 
CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
9.2.6.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
The following disease related events (DREs) are common in subjects with asthma and 
can be serious/life threatening:
9.2.6.1.
Asthma Exacerbations
For the purposes of this study, severe asthma exacerbations will be collected and 
recorded on the asthma exacerbation eCRF page from the start of treatment until follow 
up/or the EW visit for those subjects that withdraw from participation in the study.
A severe asthma exacerbation is defined as deterioration of asthma requiring the 
use/additional use of systemic corticosteroids (tablets, suspension, or injection), or 
antibiotics and inpatient hospitalisation, or emergency department visit due to asthma that 
required systemic corticosteroids or antibiotics. Further clarification will be present in the 
SRM.
Asthma exacerbations should not be recorded as an AE unless they meet the definition of 
an SAE.


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These events will be recorded on the DRE page in the subject’s eCRF within 24 hours of 
the physician becoming aware. The time period for collection of exacerbation 
information in the eCRF will be from the time that the ICF is signed until the Exit visit or 
EW.
For consistency, exacerbations separated by less than 7 days will be treated as a 
continuation of the same exacerbation.
9.2.7.
Pregnancy
Details of all pregnancies in female subjects will be collected after the start of study 
treatment and until at least 5 terminal half-lives after the last dose.
If a pregnancy is reported, the investigator should inform GSK within 2 weeks of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4.
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
9.2.8.
Medical Device Incidents (Including Malfunctions)
Procedures for Documenting Medical Device Incidents are provided in Appendix 6.
9.3.
Treatment of Overdose
For this study, any dose of Relvar/Breo ELLIPTA greater than the prescribed dose within 
a 24-hour time period will be considered an overdose.
GSK is not recommending specific treatment guidelines for overdose and toxicity 
management. The investigator is advised to refer to the relevant document(s) for detailed 
information regarding warnings, precautions, contraindications, adverse events, and other 
significant data pertaining to the study drug being used in this study. Such documents 
may include, but not be limited to, the IB or equivalent document provided by GSK.
In the event of an overdose, the HCP/treating physician should:
1.
Contact the Medical Monitor immediately.
2.
Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the subject.
9.4.
Screening and Safety Assessments
Planned time points for all screening and safety assessments are provided in Section 2.


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9.4.1.
Physical Examinations

A complete physical examination will include, at a minimum, assessments of the 
Skin, Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. 
Height and weight will also be measured and recorded.

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
The physical exam is to inform on inclusion and only needs to be recorded in the 
subject’s source/medical notes.  Physical exams will be performed at the time points 
specified in the Section 2.
9.4.2.
Vital Signs
Vital signs (systolic and diastolic blood pressure and pulse rate) will be performed at the 
screening visit only as part of physical exam.  The measurement will be taken after 5 
minutes rest in a semi-supine position.  One reading of blood pressure and pulse will be 
taken.
The vital signs are to inform on inclusion and only needs to be recorded in the subject’s 
source/medical notes.
9.4.3.
Clinical Safety Laboratory Assessments
Urine pregnancy tests are performed at timelines detailed in Section 2. The tests will be 
provided locally. The results of the tests should be recorded in the subject’s medical 
records only.
If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in subject management or are considered 
clinically significant by the investigator (e.g., SAE or AE), then the results must be 
recorded in the eCRF.
9.5.
Biomarkers
Subjects should not use their rescue medication for at least 6 hours before each FeNO and 
PEF assessment, unless essential for clinical need. Subjects should also withhold 
ICS/LABA for (1 dosing interval ) approximately 12-24 hours  prior to FeNO and PEF 
assessment.
9.5.1.
FeNO in breath
FeNO will be measured using a handheld electronic device. Measurements will be 
obtained in accordance with the American Thoracic Society (ATS)/European Respiratory 
Society (ERS) Recommendations for Standardized Procedures for the Online and Offline 
Measurement of Exhaled Lower Respiratory Nitric Oxide and Nasal Nitric Oxide 
[Silkoff, 2005]. All sites will use standardized equipment provided by a central vendor. 
For each observation, at least 2 measurements will be obtained to establish 
reproducibility (up to 8 measurements can be performed). FeNO measurements will be 


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interpreted in accordance with the Official ATS Clinical Practice Guideline: 
Interpretation of Exhaled Nitric Oxide Levels (FeNO) for Clinical Applications [Dweik, 
2011]. FeNO observations must be completed before PEF assessments. Peak Expiratory 
Flow (PEF)
PEF will be performed using a Mini Wright Peak Flow Meter provided by GSK. Details 
of how this procedure is performed is detailed in the SRM. 
PEF will be taken in triplicate at timelines detailed in the Section 2. All 3 measures 
should be recorded in the subject’s record and transferred to the eCRF.
9.5.2.
Peak Expiratory Flow (PEF)
PEF will be performed using a Mini Wright Peak Flow Meter provided by GSK. Details 
of how this procedure is performed is detailed in the SRM. 
PEF will be taken in triplicate at timelines detailed in the Section 2. All 3 measures 
should be recorded in the subjects record and transferred to the eCRF.
9.6.
Prescription Record for Asthma Maintenance Medication
The following will be collected in the eCRF and confirmed by a subject’s medical 
records, or the prescribing physician. Prescriptions for a subject’s asthma maintenance 
therapy (ICS/LABA combinations) for a minimum of 3 months and up to 12 months prior 
to inclusion, as available.
9.7.
Medical Resource Utilisation and Health Economics
Medical resource utilisation associated with medical encounters, will be collected in the 
eCRF by the investigator and study-site personnel for all subjects throughout the study. 
These events should be recorded and reviewed by the HCP or designee with the subject at 
all study visits and where available confirmed with a subject’s medical records.
Protocol-mandated procedures, tests, and encounters are excluded, though visits relating 
to HCP review of the CIS dashboard will be captured. 
The data collected may be used to conduct exploratory health care resource utilization 
(HCRU) and economic analyses and will include:

Number of outpatient visits relating to asthma

Number of primary care visits relating to study HCP dashboard review (for 
relevant study arms)

Number of and duration of hospitalisations, and ER visits due to asthma

Number of prescriptions filled/requested for maintenance medication in the 12 
months prior to inclusion. 

Annualised rate of severe exacerbations


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
Number of unscheduled visits to primary care related to Asthma 
10.
DATA MANAGEMENT

For this study, subject data will be entered into a GSK defined eCRF, 
transmitted electronically to GSK or designee and combined with data provided 
from other sources in a validated data system.

Management of clinical data will be performed in accordance with applicable 
GSK standards and data cleaning procedures to ensure the integrity of the data, 
e.g., removing errors and inconsistencies in the data.

Adverse events and concomitant medication terms will be coded using 
MedDRA (Medical Dictionary for Regulatory Activities) and an internal 
validated medication dictionary, GSKDrug.

eCRFs (including queries and audit trails) will be retained by GSK, and copies 
will be sent to the investigator to maintain as the investigator copy. Subject 
initials will not be collected or transmitted to GSK according to GSK policy.
11.
STATISTICAL CONSIDERATIONS
11.1.
Hypothesis
The main purpose of the study is to compare the effect of 6 months use with the CIS on 
adherence to ELLIPTA maintenance therapy with adherence to ELLIPTA maintenance 
therapy without CIS use (sensor alone), in subjects with poorly controlled asthma.  This 
study aims to demonstrate the superiority of the CIS on adherence to Relvar/Breo
ELLIPTA with an app compared to Relvar/Breo ELLIPTA (with sensor alone).  The 
primary endpoint is mean percentage of ELLIPTA doses taken (daily adherence) between 
Months 4 and 6 as determined by the maintenance sensor daily adherence over the last 
three months of the study period (between months 4 to 6).  
The test for the primary treatment comparison will be a test between Arm 1 versus Arm 
5.  This will be based on a two-sided hypothesis testing approach: the null hypothesis is 
the difference between Arm 1 and Arm 5 is equal to zero. The alternative hypothesis is 
that the difference is not equal to zero.  The hypotheses associated with the statistical test 
of the primary endpoint are written below:
H0: Ti – Tj = 0
(where i = Arm 1 and j = Arm 5) The null hypothesis: that the difference in response 
between Arm 1 and Arm 5 is zero.
Ha: Ti – Tj 0
The alternative hypothesis: that the difference is not zero.


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Other comparisons of interest for the primary endpoint are the individual comparisons of
Arms 2, 3 and 4 with Arm 5 in order to obtain estimated mean treatment differences and 
95% confidence intervals. This will be a descriptive comparison to inform on the relative 
benefits of the individual aspects of the CIS and no formal inference is planned.
The effect on adherence to maintenance therapy between arms with HCP and no HCP 
interaction, and arms with rescue medication use feedback versus none, will be also 
assessed.
The comparisons of interest for the other secondary and safety endpoints are as stated 
above for the primary endpoint. Arms 1, 2, 3 and 4 will be individually compared to Arm 
5, as relevant to the endpoint, in order to obtain estimated mean treatment differences and 
95% confidence intervals. This will be a descriptive comparison and no formal inference 
is planned.
11.2.
Sample Size Determination
11.2.1.
Sample Size Assumptions
The fixed sample size calculation is based on the primary endpoint, percentage of 
ELLIPTA doses taken (daily adherence) between Months 4 and 6 as determined by the 
maintenance sensor and has approximately 90% power to detect an absolute difference of 
15% in the primary comparison.  The treatment difference is based on the limited 
published data [Charles, 2007, van Boven, 2016].  This assumes a conservative standard 
deviation of 28% (based on a previous study [Charles, 2007]) and significance declared at 
the two-sided 5% level. 
Approximately 432 patients will be randomised in order to obtain at least 380 subjects 
(i.e. 76 subjects per arm) with available data over the last three months of the treatment 
period, in anticipation of a 12% drop-out within the first three months.  Subjects will be 
randomised to one of five treatment arms with a ratio of 1:1:1:1:1.
Using the above assumptions the smallest observed effect predicted to result in a 
statistically significant difference between treatment groups is 9% (minimum detectable 
difference).
11.2.2.
Sample Size Sensitivity
Due to limited historical data within GSK, an external party was hired to conduct a 
literature review. Based on results from the literature review only one paper in an 
asthmatic adult population provided adherence rates and variability estimates that could 
be used as assumptions for power calculations [Charles, 2007]. 
The study presented sample size assumptions for the treatment difference in mean daily 
% adherence of 10% and a standard deviation of the data of 18% [s1]. The reported raw 
means (standard deviation) of mean daily % adherence were 88% (16%) and 66% (27%) 
in the intervention and control groups, respectively. Due to uncertainty in data variability 
a wide range of values were explored. Table 2 below presents the power achieved with 


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the proposed sample size of 76 completers per arm should the assumptions of standard 
deviation of the data change.
Table 2
Standard Deviation Affect on Power from the Fixed Sample Size
Standard Deviation (%)
Power for Primary Comparison
22
99
24
97
26
94
28
90
30
86
32
81
34
77
11.3.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled 
All subjects who sign the ICF
Total Population
The Total Population will comprise all subjects screened and for 
whom a record exists on the study database and will be used for the 
tabulation and listing of reasons for withdrawal before 
randomisation.
Intent-to-treat
The Intent–to–Treat (ITT) population is defined as all subjects who 
have been randomised and exposed to at least one dose of 
treatment. The ITT population will be used for all endpoint analyses 
and Outcomes will be reported according to the randomised 
treatment allocation. 
11.4.
Statistical Analyses
Where possible, data from subjects who withdraw prematurely from the study treatment 
or the study will be included in any relevant analyses. Specific details for inclusion will 
be detailed in the Reporting and Analysis Plan (RAP).
The covariates to be considered in the efficacy analyses include age, sex, region and the 
baseline values, if relevant. Other covariates, if appropriate, may be considered. Specific 
details will be provided in the RAP.


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11.4.1.
Adherence Analyses
Endpoint
Statistical Analysis Methods
Primary
The primary analysis will estimate the treatment effect of 6 months use of the 
ELLIPTA maintenance therapy with CIS when both the subject and the HCP are 
supplied with data from the maintenance sensor versus no data supplied to the 
subject and HCP (Arm 1 vs Arm 5) for the primary endpoint percentage of ELLIPTA 
doses taken (daily adherence) between the beginning of Month 4 and the end of 
Month 6 as determined by the maintenance sensor.  The analysis will be performed 
on the ITT population.
The analysis will be performed on the percentage adherence between Months 4 
and 6 measured using an Analysis of Covariance (ANCOVA) model allowing for 
effects due to randomised treatment, baseline adherence, duration (days) in run-in, 
region, sex, and age (years).  Baseline adherence will be the percentage ELLIPTA 
doses taken (daily adherence) during the last 28 days of the run-in period prior to 
randomisation. Any subjects with missing intermittent adherence data will be 
imputed to as non-adherent i.e. assumed to have not taken their treatment within 
the 24 hour time period/window, where there is no evidence of a medical device 
incident having occurred.
Subjects who prematurely discontinue from study will have their post-withdrawal 
daily adherence data imputed using data from the control arm using an appropriate 
method of imputation, such as the jump to reference method.  This method of 
assessing the primary endpoint corresponds to a de-facto treatment policy 
estimand which reflects the anticipated behaviour that subjects will continue to take 
an asthma combination therapy without the CIS intervention.  
Missing data due to a medical device incident such as device failure, technical 
failure of the e-sensor, or data transmission failure will be assumed to be missing 
at random (MAR). For each subject the percentage adherence measure will be 
calculated under the assumption that any missing data is MAR, from the proportion 
of the number of days a subject is adherent divided by the number of days data 
provided for the last 3 months treatment period.
The adjusted means for each treatment and the estimated treatment difference for 
the primary treatment comparison of Arm 1 versus Arm 5 will be presented 
together with a 95% confidence interval for the difference and corresponding p-
value.
Summary statistics (mean, standard deviation, median, minimum, maximum) of the 
primary endpoint will be provided.
Where possible, adherence data collected from subjects who withdraw prematurely 
from study treatment will be included in the analysis.
Sensitivity analyses of the primary adherence endpoint will be performed on the 
ITT population and an assessment of the impact of the missing data will be carried 
out using multiple imputation methods under different assumptions for missing data
for withdrawn subjects.  Details will be provided in the RAP.


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Endpoint
Statistical Analysis Methods
Secondary
The following secondary analyses will estimate the treatment effect of 6 months 
use of the ELLIPTA maintenance therapy with CIS for the following aspects of the 
CIS:

Maintenance data only supplied to subjects versus no data supplied to the 
subject (Arm 2 vs Arm 5)

Rescue and Maintenance data supplied to subject and HCP versus no data 
supplied to the subject and HCP (Arm 3 vs Arm 5)

Rescue and Maintenance data only supplied to subject versus no data 
supplied to the subject (Arm 4 vs Arm 5)
for the following secondary endpoints:

Percentage of ELLIPTA doses taken (daily adherence) between the 
beginning of Month 4 and the end of Month 6 as determined by the 
maintenance sensor, 

Percentage of ELLIPTA doses taken (daily adherence) between the 
beginning of Month 1 and the end of Month 3

Percentage of ELLIPTA doses taken (daily adherence) between the 
beginning of Month 1 and the end of Month 6
The analysis will be performed using an ANCOVA model allowing for effects due to 
randomised treatment effect, baseline adherence, duration (days) in run-in, region, 
sex, and age (years).  Baseline adherence will be the percentage ELLIPTA doses 
taken (daily adherence) during the last 28 days of the run-in period prior to 
randomisation.  Any subjects with missing intermittent adherence data will be 
imputed to as non-adherent i.e. assumed to have not taken their treatment within 
the 24 hour time period/window, where there is no evidence of device or 
technical/transmission failure.  
Where possible, adherence data collected from subjects who withdraw prematurely 
from study treatment will be included in the analysis.  Subjects who prematurely 
discontinue from study will be handled as per the primary endpoint analysis.  
The adjusted means for each treatment and the estimated treatment difference for 
the treatment comparisons of Arm 2 versus Arm 5, Arm 3 versus Arm 5 and Arm 4 
versus Arm 5 will be presented together with the 95% confidence interval for the 
differences and corresponding p-values.
Summary statistics (mean, standard deviation, median, minimum, maximum) of the 
secondary endpoint will be provided.
If a subject has changed dose during the study, sensitivity analyses on the 
secondary endpoint(s) regarding ACT will be performed where these subjects are 
removed from the analysed population. Further details will be provided in the RAP.
Exploratory
Will be described in the RAP.


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11.4.2.
Safety Analyses
All safety analyses will be performed on the ITT Population. 
Endpoint
Statistical Analysis Methods
Safety 
SAEs, AEs leading to withdrawal and non-serious ADRs will be collected.
Safety endpoints will include:

Incidence and type of serious adverse events

Incidence and type of adverse drug reactions

Incidence and type of non-serious adverse events leading to study 
withdrawal

Incidence of subjects experiencing a severe exacerbation
The incidence of any given adverse event (SAE or ADR) for each treatment 
group is defined as the proportion of subjects in that group who have experienced 
at least one such adverse event during the study period.
The number and percentage of subjects with SAEs, non-serious ADRs and AEs 
leading to study withdrawal will be summarised by preferred term. 
The number and percentage of subjects experiencing severe exacerbations over 
treatment period and the follow-up period will be summarised for each treatment 
group alongside the primary causes of the exacerbation.
11.4.3.
Other Analyses
All other exploratory endpoints, except for qualitative data from exit interviews and 
questionnaires, will be detailed in the RAP.
Analysis of the qualitative data from exit interviews will be analyzed following a separate
qualitative analysis plan and presented in a separate Clinical Study Report (CSR).


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13.
APPENDICES
13.1.
Appendix 1: Abbreviations and Trademarks
ACT
Asthma Control Test
ADR
Adverse Drug Reaction
AE
Adverse Event
ALT
Alanine amino transferase
ANCOVA
Analysis of Covariance
ASE
All Subjects Enrolled
ASUI
Asthma  Symptom Utility Index
ATS
American Thoracic Society
BMQ
Beliefs in Medicine Questionnaire
CE
Europen Conformity
CFR
Code of Federal Regulations
CI
Confidence Interval
CIOMS
Council for International Organizations of Medical Sciences
CIS
Connected Inhaler System
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic Obstructive Pulmonary Disease
CP
Conditional Power
CRF
Case Report Form
CSR
Clinical Study Report
CV
Cardiovascular
DPI
Dry Powder Inhaler
DRE
Disease Related Event
ER
Emergency Room
ERS
European Respiratory Society
EW
Early Withdrawal
EU-RMP
European Union – Risk Management Plan
FDA
Food And Drug Administration
FeNO
Fractional exhaled Nitric Oxide
FF
Fluticasone Furoate
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GSK
GlaxoSmithKline
HCP
Healthcare Professional
HCRU
Health Care Resource Utilization
HIPAA
Health Insurance Portability and Accountability Act
HPA
Hypothalamic-pituitary adrenal axis
HRT
Hormonal Replacement Therapy
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference On Harmonisation
ICS
Inhaled Corticosteroids
IEC
Independent Ethics Committees


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IP
Investigational Product
IRB
Institutional Review Boards
ITT
Intent-to-Treat
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IWRS
Interactive Web Response System
LABA
Long-Acting Beta2-Agonist
LOCS
Lens Opacities Classification System
MAR
Missing At Random
MARS-A
Medication Adherence Report Scale for Asthma
MDI
Metered Dose Inhaler
MedRA
Medical Dictionary of Regulatory Activities
MHPD
Marketed Health Products Directorate
MID
Minimally Important Difference
MSDS
Material Safety Data Sheet
PAM
Patient Activation Measure
PEF
Peak Expiratory Flow  
PIL
Patient Instruction Leaflet
PRO
Patient Reported Outcomes
RAP
Reporting Analysis Plan
SAE
Serious Adverse Event
SGRQ
St Georges Respiratory Questionnaire
SoA
Schedule of Activities
SRM
Study Reference Manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
UFIE
Unusual Failure in Efficacy
VI
Vilantrol
WOCP
Woman Of Childbearing Potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
BREO
Amiko and MDI Log
ELLIPTA
INCA Device
GSKDrug
MedDRA
RELVAR
Propeller
RAMOS NG
SmartTrack and SmartTouch


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13.2.
Appendix 2: Study Governance Considerations
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (e.g., advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study subjects. 

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 Code of Federal Regulations (CFR), ICH guidelines, 
the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the subject or his/her legally authorized representative and answer all questions 
regarding the study. 


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
Subjects must be informed that their participation is voluntary. Subjects or their 
legally authorized representative will be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH 
guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was 
obtained before the subject 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.

Subjects 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 subject or the subject’s legally 
authorized representative. 

Subjects who are rescreened are required to sign a new ICF.
Data Protection

Subjects will be assigned a unique identifier by the sponsor. Any subject records 
or datasets that are transferred to the sponsor will contain the identifier only; 
subject names or any information which would make the participant identifiable 
will not be transferred. 

The subject 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 subject. 

The subject 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.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments. 

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with
International Committee of Medical Journal Editors authorship requirements.


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Dissemination of Clinical Study Data
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.
Data Quality Assurance

All subject data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (eg, laboratory 
data). The investigator is responsible for verifying that data entries are accurate 
and correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF.

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of subjects are 
being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
Clinical Study Report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without 
written notification to the sponsor. 
Source Documents

Source documents provide evidence for the existence of the subject and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.


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
Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available.
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines
Inadequate recruitment of subjects by the investigator
Discontinuation of further study treatment development


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13.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
AE Definition
An AE is any untoward medical occurrence in a clinical study subject, temporally 
associated with the use of a study treatment, whether or not considered related to the 
study treatment.
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
Events Meeting the AE Definition 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator (ie, not related to progression of underlying 
disease).
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
New conditions detected or diagnosed after study treatment administration even though it 
may have been present before the start of the study.
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae.
"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfil the definition of an AE 
or SAE. 
The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfil the definition of an AE or SAE. Also, "lack of 
efficacy" or "failure of expected pharmacological action" constitutes an AE or SAE.
Events NOT Meeting the AE Definition 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition.


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The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s 
condition.
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads 
to the procedure is the AE.
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject 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 subject has been detained (usually involving 
at least an overnight stay) at the hospital or emergency ward for observation and/or 
treatment that would not have been appropriate in the physician’s office or outpatient 
setting. Complications that occur during hospitalization are AE. If a complication 
prolongs hospitalization or 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 disability/incapacity
The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions.
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (e.g., sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption.


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e.
Is a congenital anomaly/birth defect
f.
Other situations:
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:
Myocardial infarction/unstable angina
Congestive heart failure
Arrhythmias
Valvulopathy
Pulmonary hypertension
Cerebrovascular events/stroke and transient ischemic attack
Peripheral arterial thromboembolism
Deep venous thrombosis/pulmonary embolism

Revascularization
Recording AE and SAE
AE and SAE Recording
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) related 
to the event.
The investigator will then record all relevant AE/SAE information in the CRF.
It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK /AE/SAE CRF page.
There may be instances when copies of medical records for certain cases are requested by 


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GSK. In this case, all subject identifiers, with the exception of the subject number, will be 
redacted on the copies of the medical records before submission to GSK.
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 
Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not 
interfering with everyday activities.
Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities.
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating the 
intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality
The investigator is obligated to assess the relationship between study treatment and each 
occurrence of each AE/SAE.
A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.
The investigator will use clinical judgment to determine the relationship.
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study treatment administration 
will be considered and investigated.
The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK. However, it is very important that 
the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to GSK.
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.


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The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
If a subject dies during participation in the study or during a recognized follow-up period, 
the investigator will provide GSK with a copy of any post-mortem findings including 
histopathology
New or updated information will be recorded in the originally completed CRF.
The investigator will submit any updated SAE data to GSK within 24 hours of receipt of 
the information.
Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool
The primary mechanism for reporting SAE to GSK will be the electronic data collection 
tool.
If the electronic system is unavailable for more than 24 hours, then the site will use the 
paper SAE data collection tool (see next section).
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
The investigator or medically-qualified sub-investigator must show evidence within the 
eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hours of SAE 
entry into the eCRF.
After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.
If a site receives a report of a new SAE from a study subject 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 SRM.
SAE Reporting to GSK via Paper CRF
Scanned transmission of the SAE paper, by email of CRF is the preferred method to 
transmit this information to the medical monitor or the SAE coordinator.


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In rare circumstances and in the absence of email, notification by telephone is acceptable 
with a copy of the SAE data collection tool sent by overnight mail or courier service.
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
Contacts for SAE reporting can be found in the SRM


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13.4.
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s: review of subject’s
medical records, medical examination, or medical history interview.
3. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment.
Contraception Guidance
Female subjects
Female subjects of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 
3. 


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Table 3
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing ) hormonal contraception associated with 
inhibition of ovulationb

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulationb

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.)
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the subject.)
NOTES: 
a.
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for subjects in clinical studies. 
b.
Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of 
the contraceptive method. In this case two highly effective methods of contraception should be utilized during the 
treatment period and for at least 5 days after the last dose of study treatment 
Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine test
Additional pregnancy testing should be performed during the treatment period as 
decribed in the SOA  and a time (>5 days) corresponding to time needed to eliminate 
study treatment after the last dose of study treatment and as required locally 


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Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected 
Pregnancy testing, with a sensitivity of [5, 10, 25] mIU/mL will be performed using the 
test kit provided locally or by the sponsor and in accordance with instructions provided in 
its package insert  
Collection of Pregnancy Information
Female Subjects who become pregnant
Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study. 
Information will be recorded on the appropriate form and submitted to GSK within 2 
weeks of learning of a subject's pregnancy. 
Subject will be followed to determine the outcome of the pregnancy. The investigator 
will collect follow up information on subject and neonate, which will be forwarded to 
GSK Generally, follow-up will not be required for longer than 6 to 8 weeks beyond the 
estimated delivery date.  
Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or SAE. 
A spontaneous abortion is always considered to be an SAE and will be reported as such.  
Any SAE occurring as a result of a post-study pregnancy which is considered reasonably 
related to the study treatment by the investigator, will be reported to GSK as described in 
Appendix 3. While the investigator is not obligated to actively seek this information in 
former study subjects, he or she may learn of an SAE through spontaneous reporting. 
Any female subject who becomes pregnant while participating  
will discontinue study treatment or be withdrawn from the study


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13.5.
Appendix 5: Liver Safety: Required Actions, Follow-up 
Assessments
Phase III-IV liver chemistry stopping criteria and required follow up assessments 


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Liver Chemistry Stopping Criteria 
ALT-absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN  persists for 2 weeks
ALT 3xULN but <5xULN  persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot 
Monitor
ALT 5xULN but <8xULN and cannot be monitored weekly for 2 weeks
ALT 3xULN but <5xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to  liver injury or hypersensitivity
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Immediately discontinue  study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries 
resolve, stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge subject with 
study treatment 

Permanently discontinue study treatment and 
continue subject in the study for any protocol 
specified follow up assessments
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 
hrs

Viral hepatitis serology4

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Only in those with underlying chronic 
Hepatitis B at study entry (identified by 
positive Hepatitis B surface antigen) 
quantitative Hepatitis B DNA and Hepatitis 
delta antibody5.

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on
the concomitant medications report form
including acetaminophen, herbal 


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
Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 
recommended
For All other criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24-
72 hrs 

Monitor subjects weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form (CRF) 
page
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins.

Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver injury 
in subjects with definite or likely 
acetaminophen use in the preceding week
[James, 2009]). 

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if alanine aminotransferase (ALT) 3xULN 
and bilirubin 2xULN. Additionally, if serum bilirubin fractionation testing is unavailable, record presence of 
detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)   
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen (HbsAg) and Hepatitis B Core Antibody (IgM); 
Hepatitis C RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, 
obtain heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
5.
If Hepatitis delta antibody assay cannot be performed,, it can be replaced with a PCR of Hepatitis D RNA virus 
(where needed) [Le Gal, 2005] .


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13.6.
Appendix 6: Medical Device Incidents: Definition and 
Procedures for Recording, Evaluating, Follow-up, and 
Reporting
Definition and Documentation of Medical Device Incidents
Definitions of a Medical Device Incident
The detection and documentation procedures described in this protocol apply to all GSK 
medical devices provided for use in the study (see Section 7.3 for the list of GSK medical 
devices). 
Medical Device Incident Definition
A medical device incident is any malfunction or deterioration in the characteristics and/or 
performance of a device as well as any inadequacy in the labeling or the instructions for 
use which, directly or indirectly, might lead to or might have led to the death of a 
subject/user/other person or to a serious deterioration in his/her state of health.
Not all incidents lead to death or serious deterioration in health. The nonoccurrence of 
such a result might have been due to other fortunate circumstances or to the intervention 
of health care personnel.
It is sufficient that:

An incident associated with a device happened and

The incident was such that, if it occurred again, might lead to death or a serious 
deterioration in health.
A serious deterioration in state of health can include any of the following:

Life-threatening illness

Permanent impairment of body function or permanent damage to body structure

Condition necessitating medical or surgical intervention to prevent one of the 
above 

Fetal distress, fetal death, or any congenital abnormality or birth defects
Examples of incidents
A subject, user, caregiver, or healthcare professional is injured as a result of a medical 
device failure or its misuse.
A subject’s study treatment is interrupted or compromised by a medical device failure.
A misdiagnosis due to medical device failure leads to inappropriate treatment.
A subject’s health deteriorates due to medical device failure.


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Documenting Medical Device Incidents
Medical Device Incident Documenting
Any medical device incident occurring during the study will be documented in the 
subject’s medical records, in accordance with the investigator’s normal clinical practice, 
and on the appropriate form.
For incidents fulfilling the definition of an AE or an SAE, the appropriate AE/SAE CRF 
page will be completed as described in Appendix 3
The form will be completed as thoroughly as possible and signed by the investigator 
before transmittal to the GSK.
It is very important that the investigator provides his/her assessment of causality 
(relationship to the medical device provided by GSK) at the time of the initial report and 
describes any corrective or remedial actions taken to prevent recurrence of the incident.
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 an incident. This includes 
any amendment to the device design to prevent recurrence.


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13.7.
Appendix 7: Country-specific requirements
13.7.1.
Additional Adverse Event (AE) Reporting: Country-specific 
requirements for Canadian investigators:
The purpose of this information is  to comply with Health Canada guidelines. They state 
that all events associated with lack of efficacy of marketed investigational products must 
be documented and reported.
Health Canada requires pharmaceutical manufacturers to expeditiously report domestic 
cases of unusual failure in efficacy (UFIE) for new drugs to the Marketed Health 
Products Directorate (MHPD) within 15 days of first notification. This regulation applies 
to marketed drugs, and used as directed per the Canadian prescribing information, 
including those drugs used in Phase IV (non CTA filed) clinical trials.  
Adverse event (AE): Any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment. An AE can therefore be 
any unfavourable and unintended sign (including an abnormal laboratory finding) 
symptom or disease (new or exacerbated) temporally associated with the use of a 
Medicinal Product. For a marketed Medicinal Product, this can also include failure to 
produce expected benefits (i.e. lack of efficacy, with or without an adverse event), 
In order for GSK to comply this Canadian regulatory requirement, Canadian investigators 
are required to collect, record and report lack of efficacy events as per Table 4.
Table 4
Collection and Reporting of Adverse Events and Lack of Efficacy
Adverse 
Event 
criteria
Electronic case record 
form (eCRF) only
Paper form only
Electronic case 
record form 
(eCRF) + Paper 
form
Non serious 
Non drug related lack of 
efficacy reports with 
associated signs or 
symptoms or clinical 
sequelae 
Drug related lack of 
efficacy reports 
without associated 
signs or symptoms or 
clinical sequelae.
Drug related lack 
of efficacy with 
associated signs or 
symptoms or 
clinical sequelae  
Serious
Non drug related lack of 
efficacy reports with 
associated signs or 
symptoms or clinical 
sequelae 
Drug related lack of 
efficacy reports 
without associated 
signs or symptoms or 
clinical sequelae. 
Drug related lack 
of efficacy reports 
with associated 
signs or symptoms 
or clinical sequelae 


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The investigator will then record all relevant information regarding an AE/SAE in the 
electronic CRF “and/or paper form as applicable
For lack of efficacy reports the paper form will be used to submit to GSK as per Table 4.
All paper forms are required to be faxed to GSK Canada’s Drug Safety department 
at 
 within 24 hrs of first awareness.
PPD


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13.8.
Appendix 8: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).


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TITLE PAGE
Protocol Title: An open label, randomised, parallel group clinical study to evaluate the 
effect of the Connected Inhaler System (CIS) on adherence to Relvar/Breo ELLIPTA 
therapy, in asthmatic subjects with poor control.
Protocol Number: 207040
Short Title: A clinical study to evaluate the effect of the Connected Inhaler System (CIS) 
on adherence to maintenance therapy in poorly controlled asthmatic patients.
Compound Number:
GW685698+GW642444 (GSK2285997)
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information can be found in the Study Reference 
Manual
Regulatory Agency Identifying Number(s): EUDRACT: 2017-002266-45, IND 
077855
Approval Date: 22-JUN-2017
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.


PPD
PPD


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TABLE OF CONTENTS
PAGE
1.
SYNOPSIS...............................................................................................................6
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................10
3.
INTRODUCTION....................................................................................................14
3.1.
Study Rationale ..........................................................................................14
3.2.
Background ................................................................................................15
3.3.
Benefit/Risk Assessment ............................................................................17
3.3.1.
Risk assessment for Relvar/Breo 100/25mcg and 
200/25mcg...................................................................................17
3.3.2.
Overall Benefit:Risk Conclusion...................................................21
4.
OBJECTIVES AND ENDPOINTS...........................................................................21
5.
STUDY DESIGN ....................................................................................................25
5.1.
Overall Design ............................................................................................25
5.2.
Number of Subjects ....................................................................................29
5.3.
Subject and Study Completion....................................................................29
5.4.
Scientific Rationale for Study Design ..........................................................29
5.5.
Dose Justification........................................................................................30
6.
STUDY POPULATION...........................................................................................30
6.1.
Inclusion Criteria.........................................................................................30
6.2.
Exclusion Criteria........................................................................................32
6.3.
Lifestyle Restrictions...................................................................................33
6.4.
Screen, Run-in and Randomisation Failures...............................................33
7.
TREATMENTS.......................................................................................................33
7.1.
Treatments Administered............................................................................34
7.2.
Relvar/Breo Dose Guidance: ......................................................................35
7.3.
Medical Devices..........................................................................................35
7.4.
Dose Modification .......................................................................................35
7.5.
Method of Treatment Assignment ...............................................................36
7.6.
Blinding.......................................................................................................36
7.7.
Preparation/Handling/Storage/Accountability..............................................36
7.8.
Treatment Compliance................................................................................37
7.9.
Concomitant Therapy..................................................................................37
7.10.
Prohibited Concomitant Medication.............................................................38
7.11.
Treatment after the End of the Study ..........................................................38
8.
DISCONTINUATION CRITERIA.............................................................................38
8.1.
Discontinuation of Study Treatment ............................................................39
8.1.1.
Liver Chemistry Stopping Criteria ................................................39
8.1.2.
QTc Stopping Criteria ..................................................................40
8.2.
Withdrawal from the Study..........................................................................40
8.3.
Lost to Follow Up........................................................................................41
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................41
9.1.
Efficacy Assessments.................................................................................42


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9.1.1.
Primary, Secondary and Other Adherence Measures ..................42
9.1.2.
Secondary Efficacy Endpoints .....................................................42
9.1.2.1.
Asthma Control Test...................................................42
9.1.2.2.
Rescue Medication Use..............................................42
9.1.3.
Questionnaires and Interviews.....................................................42
9.1.3.1.
Asthma Control Test (ACT) ........................................43
9.1.3.2.
Asthma Symptom Utility Index (ASUI) ........................43
9.1.3.3.
St Georges Respiratory Questionnaire (SGRQ) .........43
9.1.3.4.
Patient Activation Measure (PAM)..............................44
9.1.3.5.
Medication Adherence Report Scale for 
Asthma (MARS-A), 10-item questionnaire..................44
9.1.3.6.
Beliefs in Medicine Questionnaire (BMQ). ..................44
9.1.3.7.
Exit Questionnaire ......................................................45
9.1.3.8.
Exit Interviews ............................................................45
9.2.
Serious Adverse Events (SAE), Non-Serious Adverse Events that 
leads to withdrawal and Non Serious Adverse Drug Reactions 
(ADR) .........................................................................................................46
9.2.1.
Time Period and Frequency for Collecting AE, ADR and 
SAE Information...........................................................................46
9.2.2.
Method of Detecting Aes, ADRs and SAEs..................................47
9.2.3.
Follow-up of AEs, ADRs and SAEs..............................................47
9.2.4.
Regulatory Reporting Requirements for SAEs .............................47
9.2.5.
Cardiovascular and Death Events................................................48
9.2.6.
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as SAEs...............................................48
9.2.6.1.
Asthma Exacerbations................................................48
9.2.7.
Pregnancy ...................................................................................49
9.2.8.
Medical Device Incidents (Including Malfunctions).......................49
9.3.
Treatment of Overdose...............................................................................49
9.4.
Screening and Safety Assessments............................................................49
9.4.1.
Physical Examinations.................................................................50
9.4.2.
Vital Signs....................................................................................50
9.4.3.
Clinical Safety Laboratory Assessments ......................................50
9.5.
Biomarkers .................................................................................................50
9.5.1.
FeNO in breath ............................................................................50
9.6.
Peak Expiratory Flow (PEF)........................................................................51
9.7.
Prescription Record for Asthma Maintenance Medication...........................51
9.8.
Medical Resource Utilisation and Health Economics ..................................51
10. DATA MANAGEMENT ...........................................................................................52
11. STATISTICAL CONSIDERATIONS........................................................................52
11.1.
Hypothesis..................................................................................................52
11.2.
Sample Size Determination ........................................................................53
11.2.1.
Sample Size Assumptions ...........................................................53
11.2.2.
Sample Size Sensitivity................................................................53
11.2.3.
Sample Size Re-estimation..........................................................54
11.3.
Populations for Analyses ............................................................................55
11.4.
Statistical Analyses.....................................................................................55
11.4.1.
Adherence Analyses....................................................................55
11.4.2.
Safety Analyses...........................................................................57
11.4.3.
Other Analyses ............................................................................58


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11.4.4.
Interim Analyses ..........................................................................58
12. REFERENCES.......................................................................................................59
13. APPENDICES........................................................................................................63
13.1.
Appendix 1: Abbreviations ..........................................................................63
13.2.
Appendix 2: Trademarks.............................................................................64
13.3.
Appendix 3: Study Governance Considerations..........................................65
13.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................69
13.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................75
13.6.
Appendix 6: Liver Safety: Required Actions, Follow-up Assessments.........78
13.7.
Appendix 7: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................81
13.8.
Appendix 8: Country-specific requirements.................................................83
13.8.1.
Additional Adverse Event (AE) Reporting: Country-specific 
requirements for Canadian investigators:.....................................83


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1.
SYNOPSIS
Protocol Title: An open label, randomised, parallel group clinical study to evaluate the 
effect of the Connected Inhaler System (CIS) on adherence to Relvar/Breo ELLIPTA 
therapy, in asthmatic subjects with poor control
Short Title: A clinical study to evaluate the effect of the Connected Inhaler System (CIS) 
on adherence to maintenance therapy in poorly controlled asthmatic patients
Rationale: This study will be the first to evaluate the effect of the CIS on adherence to 
maintenance therapy (Relvar/Breo ELLIPTA) in uncontrolled asthmatic patients (Asthma 
Control Test [ACT] <20 at the screening visit and ACT <20 at a subsequent 
randomisation visit following run in)
The study has been designed to assess how the CIS impacts adherence, of asthmatic 
patients, to maintenance therapy, when both the subject and the healthcare professional 
(HCP) receive data from the sensor on the patient’s Relvar/Breo ELLIPTA maintenance 
therapy. 
In addition, the five treatment arms of the study will allow evaluation of different 
elements of the CIS including, having additional data provided from a sensor on rescue 
medication and also the effect of the patient alone seeing any data with no data shared to 
the HCP, or  both the patient and HCP, seeing the data from the sensors Furthermore, this 
study will provide preliminary data evaluating the effect of the CIS on patient outcomes, 
including rescue medication use, patient reported outcomes and change in asthma control 
as as assessed by the Asthma Control Test (ACT).
Objectives and Endpoints:
Objectives
Endpoints
Primary
To compare the effect of 6 months use of the 
CIS on adherence to ELLIPTA maintenance 
therapy when both the subject and the HCP are 
supplied with data from the maintenance 
sensor versus no data supplied to the subject 
and HCP (Arm 1 vs Arm 5)
Percentage of ELLIPTA doses taken (daily 
adherence1.) between the beginning of month 4 
and the end of month 6 as determined by the 
maintenance sensor


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Secondary
To compare the effect of 6 months use of the 
CIS on adherence to ELLIPTA maintenance 
therapy for the following aspects of the CIS:

Maintenance data only supplied to subjects 
versus no data supplied to the subject (Arm 
2 vs Arm 5)

Rescue and Maintenance data supplied  to 
subject and HCP versus no data supplied 
to the subject and HCP (Arm 3 vs Arm 5)

Rescue and Maintenance data only 
supplied  to subject versus no data 
supplied to the subject (Arm 4 vs Arm 5)
Percentage of ELLIPTA doses taken (daily 
adherence1.) between the beginning of month 4 
and the end of month 6 as determined by the 
maintenance sensor
To compare the effect of the CIS on adherence 
to ELLIPTA maintenance therapy of the 
individual CIS treatment arms versus no data 
supplied to the subject and HCP.

Percentage of ELLIPTA doses taken (daily 
adherence1.) between the beginning of 
month 1 and the end of month 3.

Percentage of ELLIPTA doses taken (daily 
adherence) between the beginning of 
month 1 and the end of month 6
To evaluate the effect of 6 months use of the 
CIS on a subject’s rescue medicine usage

Percentage of rescue free days measured 
between the beginning of month 4 and the 
end of month 6 as determined by the 
rescue sensor records of date, time, and 
number of inhaler actuations. 

Total rescue use measured between the 
beginning of month 4 and the end of month 
6 as determined by the rescue sensor 
records of date, time, and number of inhaler 
actuations.
To evaluate the effect of 6 months use with the 
CIS on a subject’s asthma control

Change from baseline in ACT total score at 
Month 6, measured at baseline (Visit 2, 3 or 
4) and Month 6 (Visit10)

Percentage of patients becoming controlled 
as defined as an Asthma Control Test score 
≥20 at Month 6 (Visit 10)

Percentage of patients with an increase 
from baseline ≥ 3 in ACT total score at 
Month 6 (Visit 10)
1.
Daily adherence is defined as the subject taking one dose of Relvar/Breo ELLIPTA, within a 24 hour period, 
starting at 12.00am each day of treatment period.


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Overall Design:
This is an open-label, randomised, multi-centre, parallel group study consisting of 5 treatment arms, in asthmatic patients currently on a 
fixed dose Inhaled Corticosteroids (ICS)/ Long-Acting Beta2-Agonist (LABA) maintenance therapy.


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Number of Subjects:
Approximately 600  subjects will be screened to achieve 432 randomised and a total of 
380 subjects are anticipated to have data available for the primary analysis; an estimated 
total of 76 subjects per treatment group.
An unblinded sample size re-estimation will take place, once 50% of the planned number 
of subjects have completed Visit 10. An adjustment of the sample size, for arms 1 and 5, 
is conditional on the primary endpoint analysis results observed.   However, no more than 
a further 42 subjects will be randomised in to each of arms 1 and 5 to provide an 
anticipated maximum of approximately 114 (76+38) subjects in each of those 2 arms and 
so an estimated total number of 456 subjects in all arms.
Treatment Groups and Duration:
All randomised subjects will receive Relvar/Breo ELLIPTA, at the dose allocated at the 
run in.
All subjects will have sensors attached to both their Relvar/Breo ELLIPTA and 
salbutamol Metered Dose Inhaler (MDI). It is the type of data provided by the CIS  
(either Relvar/Breo ELLIPTA alone or Relvar/Breo ELLIPTAand salbutamol MDI) , as 
well as who sees that data, (subject alone or subject and HCP), that defines the treatment 
arms.
The 5 treatments arms are as follow:
1.
Data on Maintenance use supplied to Subject (app) and HCP (dashboard)
2.
Data on Maintenance use supplied to Subject (app)
3.
Data on Maintenance and Rescue use supplied to Subject (app) and HCP (dashboard)
4.
Data on Maintenance and Rescue use supplied to Subject (app)
5.
No data supplied to Subject or HCP
The treatment period for the study is 6 months. However, due to the flexible run in period 
a subject could be on the study for approximately 7, 8 or 9 months in total


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2.
SCHEDULE OF ACTIVITIES (SOA)
Procedures
Screen
Run-In
Treatment Period
EW
Follow
-up
Notes
Visit/Contact
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
Conditional Visits::V3& V4 are only required if a 
subject is not included at prior run in visit. 
V6, V7, V8  & V9 are only  required for Treatment 
arms 1 & 3. Randomisation to treatment arms will 
occur at Visit 2,3 or 4 when randomisation criteria 
have been met
Month of Study
-1
0
0
0
1
2
3
4
5
6
Day of Study
-28
0
0
0
28
56
84
112
140
168
175
Visit Window (days)
2
2
2
2
7
7
7
7
7
2
Conditional Visits
X
X
X
X
X
X
SCREENING ASSESSMENTS
Written Informed Consent
X
Signed by the subject and HCP/ designee prior to 
any other study assessments. May be completed 
at a separate visit to screening  if required.
Subject Demography
X
Medical History
X
Asthma History 
X
Including exacerbation history for previous 12 
months and those involving hospitalisation 
Therapy History
X
Maintenance therapy over previous 12 months, 
including number of prescriptions requested or 
provided
Physical Exam
X
Full physical including height, weight and vital 
signs
Inclusion/Exclusion 
Criteria
X
X
X
X
ACT assessment for inclusion required at run-in
visits
Randomisation
X
X
X
Subject  randomised to treatment at only one of 
V2, V3 or V4 once ACT criteria is met


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Procedures
Screen
Run-In
Treatment Period
EW
Follow
-up
Notes
Visit/Contact
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
Conditional Visits::V3& V4 are only required if a 
subject is not included at prior run in visit. 
V6, V7, V8  & V9 are only  required for Treatment 
arms 1 & 3. Randomisation to treatment arms will 
occur at Visit 2,3 or 4 when randomisation criteria 
have been met
Month of Study
-1
0
0
0
1
2
3
4
5
6
Day of Study
-28
0
0
0
28
56
84
112
140
168
175
Visit Window (days)
2
2
2
2
7
7
7
7
7
2
Conditional Visits
X
X
X
X
X
X
SAFETY ASSESSMENTS
Concomitant Medication
X
Urine Pregnancy Test
X
X
X
X
X
X
X
SAEs
X
X
Non-Serious Adverse 
Events that leads to 
withdrawal 
X
Non-serious adverse events that leads to dose 
modification, drug discontinuation, or withdrawal 
from the trial
Non-serious Adverse
Drug Reactions
X
Exacerbations
X
Severe Exacerbation are to be reviewed and 
recorded
Unscheduled HCP visits
X
All secondary care contacts and all primary care 
contacts related to Asthma 
QUESTIONNAIRES & Patient Reported Outcomes (PROs) (Performed in  the order given here)
ACT
X
X
X
X
X
X
X
ACT performed at V2, V3 or V4 to confirm 
inclusion for  randomisation
ASUI
X1
X2
X2
X2
X
X
X
1. PRO’s only performed at screening once a 
subject is included.
2. The PRO’s are only performed at the run-in
visit (V2, V3 or V4) if a subject is randomised
to treatment
SGRQ
X2
X2
X2
X
X
X
PAM
X1
X2
X2
X2
X
X
X
MARS-A
X1
X2
X2
X2
X
X
X
BMQ
X1
X2
X2
X2
X
X
X
EXIT Questionnaire 
X
X


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Procedures
Screen
Run-In
Treatment Period
EW
Follow
-up
Notes
Visit/Contact
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
Conditional Visits::V3& V4 are only required if a 
subject is not included at prior run in visit. 
V6, V7, V8  & V9 are only  required for Treatment 
arms 1 & 3. Randomisation to treatment arms will 
occur at Visit 2,3 or 4 when randomisation criteria 
have been met
Month of Study
-1
0
0
0
1
2
3
4
5
6
Day of Study
-28
0
0
0
28
56
84
112
140
168
175
Visit Window (days)
2
2
2
2
7
7
7
7
7
2
Conditional Visits
X
X
X
X
X
X
Exit Interview
X
X
X
Interview is for sub-set of subjects who agree to 
take part and can be performed at V10 or V11 for 
logistical reason. There is a 14 day window for 
vendor to schedule and conduct exit interviews.
ASSESSMENTS
Fractional exhaled Nitric 
Oxide (FeNO)
X1
X2
X2
X2
X
X
X
1.PEF &  FeNO only performed once a subject is 
included.  
2.PEF and FeNO  is only performed at the Run in 
visit if a subject is randomised
FeNO performed prior to PEF
Peak Expiratory Flow  
(PEF)
X1
X2
X2
X2
X
X
X
HCP dashboard review
X
X
X
X
X
X
Subjects in treatment arms 1 and 3 only.  HCP 
will record action and outcome of review.
INVESTIGATIONAL PRODUCT
Dispense Sensors
X
Sensors must be attached and switched on in 
clinic.
Dispense Relvar/Breo 
ELLIPTA
X
X
All subjects will attend independent dispensing 
visits to collect their next Relvar/Breo ELLIPTA 
and/or salbutamol MDI as required.  Patients are 
required to bring the sensor to the dispensing 
visits.  The sensor will be attached to the new 
device and switched on at the dispensing visit.
Dispense Salbutamol MDI
X
X
Training in CIS
X
X
X
X
X
Subjects are trained in fitting the sensors at 
screening. Following randomisation, subjects will 
be trained in CIS as relevant for their treatment 
arm. Retraining can be provided at V5


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Procedures
Screen
Run-In
Treatment Period
EW
Follow
-up
Notes
Visit/Contact
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
Conditional Visits::V3& V4 are only required if a 
subject is not included at prior run in visit. 
V6, V7, V8  & V9 are only  required for Treatment 
arms 1 & 3. Randomisation to treatment arms will 
occur at Visit 2,3 or 4 when randomisation criteria 
have been met
Month of Study
-1
0
0
0
1
2
3
4
5
6
Day of Study
-28
0
0
0
28
56
84
112
140
168
175
Visit Window (days)
2
2
2
2
7
7
7
7
7
2
Conditional Visits
X
X
X
X
X
X
Training in ELLIPTA & 
MDI correct use
X
X
Once included a subject should be trained in 
correct use of ELLIPTA and MDI devices
Correct Use Assessment 
for ELLIPTA and MDI
X
X
Inhaler use technique will be assessed for correct 
use. This need only be recorded in source.
Return Sensors
X
X
Return  Relvar/Breo 
ELLIPTA
X
X
Patients are required to return their devices at the 
independent dispensing visits. Doses remaining 
on each returned ELLIPTA inhaler will be 
recorded.  
Return  Salbutamol MDI
X
X
Patients to return used MDI at dispensing visits.


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3.
INTRODUCTION
GSK has, in collaboration with Propeller Health, developed a sensor which clips on to the 
ELLIPTA dry powder inhaler (DPI), herein referred to as ELLIPTA. The sensor will 
measure when the ELLIPTA mouth piece cover is fully opened and closed and this data 
can be fed back, via an application (app) on a smart phone to the patient. This will inform 
a patient if/when a dose of Relvar/Breo has been actuated from the ELLIPTA. Other 
information, including: asthma management strategies, tracking of symptoms, asthma 
triggers, medication reminders and daily asthma forecasts involving weather and air 
quality data, will also be provided via the app. Information from a second sensor on a  
patient’s rescue medication metered dose inhaler (MDI) could also provide feedback, via 
the app, to the patient on their salbutamol (albuterol) MDI use. The data from both 
Relvar/Breo ELLIPTA and salbutamol MDI can also be shared, via an online dashboard, 
with the patient’s Health Care Professional (HCP), see Figure 1 and Propeller System 
Site Manual (PSSM). The sensors, app, dashboard and systems to provide data are
subsequently described as the Connected Inhaler System (CIS).
Figure 1
Connected Inhaler System
3.1.
Study Rationale
This study will be the first to evaluate the effect of the CIS on adherence to maintenance 
therapy (Relvar/Breo ELLIPTA) in uncontrolled asthmatic patients (Asthma Control Test 
[ACT] <20 at the screening visit and ACT <20 at a subsequent randomisation visit after 
run-in). The run-in exists to ensure a stable level of control prior to entry into the study, 
given the possible change in treatment and is described in detail in Section 5.1.
The study has been designed to assess how the CIS impacts adherence of asthmatic 
patients to maintenance therapy, when both the subject and the HCP receive data on 
adherence from the sensor on the patient’s Relvar/Breo ELLIPTA maintenance therapy. 
In addition, the five treatment arms of the study will allow evaluation of different 
elements of the CIS. These include; having additional data provided from a sensor on


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rescue medication and the effect of the patient alone seeing any data with no data shared 
to the HCP, or both the patient and HCP seeing the data from the sensors. See Section 5,
Section 7 and Table 1 for details on the 5 arms. Furthermore, this study will provide 
preliminary data evaluating the effect of the CIS on patient outcomes, including rescue 
medication use, change in ACT and patient reported outcomes (PROs).
3.2.
Background
Asthma is a chronic inflammatory disease of the airways that results in hyperreactivity 
and clinically relevant episodes of wheezing, chest tightness and coughing. Although 
asthmatic symptoms can normally be controlled, by treatment, it remains a serious 
condition that is associated with a number of different impacts and co-morbidities such 
as; fatigue, activity impairment, psychological problems (anxiety, depression and stress), 
lung infections and delays in growth (paediatrics). 
The underlying pathophysiology of asthma includes epithelial sloughing, smooth muscle 
contraction, bronchial hyperreactivity and airway inflammation [Koterba, 2012]. 
Depending on the asthmatic patient, these symptoms can become worse during the 
evening and/or with exercise [Martinez, 2007]. Asthma is believed to affect the lives of 
approximately 300 million people worldwide and this number is expected to rise to 400 
million by 2025. 
There are many reasons for poor adherence including, but not limited to, difficulties 
using inhalers, forgetfulness, misunderstanding of instructions, perceptions of the 
medicine and cost [GINA, 2017]. Also, as asthma is an inflammatory condition that is 
episodic in nature, patients can exhibit symptomatic adherence to maintenance therapies
[Anarella, 2004]. 
Inadequate control of asthma symptoms continues to be a serious problem, and despite 
advancements in therapeutics for the treatment of asthma, adherence rates remain less 
than optimum [Anarella, 2004, Foster, 2014]. The significance of adherence to treatment 
regimens in the management of asthma is becoming ever more evident. A variety of 
studies have indicated that poor adherence to maintenance therapy is intimately 
associated with reduced quality of life and, increased; asthma symptoms, oral steroid 
usage, hospitalisation and mortality [Patel, 2013; Williams, 2011, Normansell, 2017]. 
Furthermore, reduced adherence to maintenance therapy can lead to an overuse of rescue 
medication, which has been linked to poorer health status [Patel,2013]. 
Due to the chronic nature of the disease, low adherence rates are recognised as one of the 
main contributing factors to reduced control amongst asthmatic patients. Therefore, the 
requirement for routine and habitual use of maintenance therapy is paramount. 
Currently, determination of inherent adherence rates are questionable due to their largely 
subjective (patient diaries), unreliable (prescription refills) and imprecise (dosage 
counters) data acquisition methodologies. Each of these methods can misrepresent what 
is occurring in the real world. Furthermore, clinicians’ estimations of adherence rates can
be inaccurate, patient self-reported adherence rates are notoriously overestimated and 
some electronic dose counters can also be problematic due to dose dumping [Bae, 2009; 


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Zeller, 2008]. Because of these uncertainties, there is an abundance of research being 
undertaken in the area of inhaler sensors for adherence. Novel solutions to some of the 
aforementioned problems are currently in development, such as; actuation switches (e.g.
Smartinhaler and Propeller Health MDI sensor) for time stamping, heated thermistors 
(MDI log) for inhalation detection, microphones (INCA Device) for detecting peak 
inspiratory flow rates and actuations, accelerometers (Amiko and MDI Log) for time 
stamping and technique feedback, and light transmitters (SmartTrack and SmartTouch) 
for detection of canister depression and time stamping. 
Dosing regimens (once daily vs. twice daily) have also unsurprisingly been found to have 
an effect on adherence to maintenance therapy.  Fewer doses required on a daily basis as 
part of maintenance therapy, has been shown to increase adherence rates as well as 
creating a more routine and habitual dosing times [Coleman, 2012]. 
It has been shown that the addition of a sensor which has the ability to feedback 
information is associated with increased adherence rates in paediatric patients of between 
30 and 50% [Chan, 2016; Foster, 2014]. Unfortunately, the population (paediatrics) and 
the inherent variability of the data make interpretation and extrapolation to other 
populations problematic. However, a 20-30% increase in adherence rates when using 
inhaled corticosteroids has been shown to lead to clinically relevant effects, such as, a 
reduction in exacerbations [Williams, 2011]. Whilst many studies have used sensors to 
measure adherence, relatively few studies have assessed the influence of sensors on 
adherence rates and even less information exists to demonstrate the link between 
adherence and clinically relevant outcomes or patient reported quality of life.
Adherence rate measurements should be unobtrusive, objective and accurate, in order to 
correctly identify innate patient adherence rates [Chan, 2015]. Accordingly, Propeller 
Health, in collaboration with GSK, has developed a sensor, which can clip onto any 
ELLIPTA DPI and can monitor the time and date that the ELLIPTA DPI cover is opened 
and closed. The sensor can be detached and transferred to subsequent inhalers by 
prescription. Propeller Health already produces a sensor that clips on to the top of a 
rescue MDI and records time and date of actuation. The data, from both of these sensors
can then be fed back to the patient or patient and their HealthCare Professional (HCP)
through the use of an app or dashboard. Patient/HCP interaction with the data through the 
app/dashboard may enable greater engagement between the patient and their HCP 
regarding their asthma. The app associated with the Propellor Health sensor also provides 
information on asthma management strategies, tracking of symptoms, asthma triggers, 
medication reminders and daily asthma forecasts involving weather and air quality data, 
in order to improve a patients’ understanding of, and relationship with, their asthma.
It is believed that engaging a patient’s interest in their asthma could improve their 
adherence to their maintenance therapy and ultimately improves their asthma outcomes 
as much of the research supports the importance of adherence rates to asthma control
[Sapir, 2017]. Therefore, if through the use of the CIS, a patient can engage with their 
asthma, this may improve adherence and ultimately improve their level of asthma control. 
Furthermore, from an HCP perspective, having accurate adherence data would make 
discussions with their patients more objective and informed when considering appropriate 
asthma management strategies. 


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3.3.
Benefit/Risk Assessment
3.3.1.
Risk assessment for Relvar/Breo 100/25mcg and 200/25mcg
For Relvar/Breo ELLIPTA, the following risks and the corresponding mitigation 
strategies, as applicable to asthma patients, were taken from the summary of safety 
concerns in the European Union – Risk Management Plan (EU-RMP). For Relvar/Breo 
the rationale for the risk assessment was derived from the 2014-2016 Investigator 
Brochures, from an integrated analysis of key Relvar/Breo studies.
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Investigational Product (IP) (fluticasone furoate [FF]/vilanterol [VI]])
Pneumonia in patients 
with asthma
The incidence (adjusted for 
exposure) seen with FF/VI 100/25 
microgram strength (9.6/1000 
patient years) was similar to 
placebo (8.0/1000 patient years). 
The incidence was slightly higher 
for FF/VI 200/25 microgram 
(18.4/1000 patient years). No risk 
factors were identified.
The risk of pneumonia in asthma 
patients is consistent with the risk 
of other ICS. Subjects are not at 
an increased risk in this study, 
since they enter the study on an 
existing ICS treatment. Subjects 
are alerted to the potential risk of 
pneumonia in the informed 
consent. 
Subjects with a concurrent 
respiratory disease are excluded 
from the study.
Asthma related 
intubations and deaths
This is a class effect of Long-Acting 
Beta2-Agonist (LABA) in asthma. 
This has not been observed for 
FF/VI.
A Food And Drug Administration 
(FDA) meta-analysis of LABA vs. 
no LABA (60,954 patients in 110 
trials) by age group on a composite 
endpoint of asthma-related deaths, 
intubations, and hospitalizations 
(asthma composite index) showed 
a statistically significant difference 
among age groups.  The composite 
event incidence difference for all 
ages was 6.3 events per 1000 
patient-years (95% CI: 2.2-10.3) 
with LABAs compared with no 
LABA use. Among the 15,192 
patients with concurrent ICS use, 
the incidence difference was 0.4 
events per 1000 patient-years (95% 
Subjects with a history of life-
threatening asthma are excluded 
from the study.


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CI: -3.8 to 4.6).  The authors noted 
a trend of greater excess risk with 
LABA among the younger age 
groups [McMahon, 2011].
Three large studies (two in adults, 
one in children) with ICS/LABA 
compounds  have shown no 
increased risk of serious asthma 
related events compared with ICS 
alone (Stempel, 2016a; Stempel et 
al, 2016b, Peters et al, 2016 ).
Serious cardiovascular 
events
In an analysis performed on the 18 
key studies in subjects with 
asthma, eight serious 
cardiovascular events have been 
reported in patients exposed to 
FF/VI. Seven events in FF/VI 
100/25 and one event in FF/VI 
200/25. This represents an 
incidence less than 1% in the 
asthmatic patients exposed to 
FF/VI. a
The events reported include atrial 
fibrillation, acute coronary 
syndrome, coronary artery disease, 
hypertension, myocardial ischemia, 
tachyarrhythmia and tachycardia.
Therefore fluticasone 
furoate/vilanterol should be used 
with caution in patients with severe 
cardiovascular disease or heart 
rhythm abnormalities, 
thyrotoxicosis, uncorrected 
hypokalaemia or patients 
predisposed to low levels of serum 
potassium.
Subjects with existing serious 
cardiovascular disease, 
thyrotoxicosis, uncorrected 
hypokalaemia or patients 
predisposed to low levels of 
serum potassium are excluded 
from the study.
Investigators are made aware of 
the potential class effects of 
LABAs and are advised to 
exercise caution for subjects with 
existing serious cardiovascular 
disease (Section 6.3 [Warnings 
and Precautions] of the IB).
Hypersensitivity
No FF/VI drug related 
hypersensitivity was noted in 
clinical trials.
Spontaneous reports of 
hypersensitivity reactions have 
been reported in post-marketing 
data for FF/VI. A possible causal 
association cannot be ruled out 
Subjects will be informed about 
the risk of hypersensitivity in the 
informed consent. They will be 
advised to seek medical 
treatment if any signs of 
hypersensitivity occur.
Subjects with milk protein allergy 
or known hypersensitivity to FF, 
VI, the classes ICS or beta-


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based on the temporal association 
between drug administration and 
hypersensitivity events including 
anaphylactic reaction, angioedema, 
urticaria, pruritis and rash.
agonist or any ingredient of the 
Investigational Product (IP)
preparation will be excluded from 
participating in the study.
Decreased bone mineral 
density and associated 
fractures
Risk of fracture has been 
associated with oral corticosteroids. 
It is unclear if inhaled 
corticosteroids carry the same risk. 
Currently the risk of reduced bone 
mineral density has not been 
observed in the asthma population 
[Jones, 2002]. In addition specific 
assessments in adolescents with 
asthma have not demonstrated an 
effect on bone mineral density, 
when controlled for growth [König, 
1993; Turpeinen, 2010].
In an analysis performed on the 11 
key studies in subjects with asthma 
bone fractures were reported by 
<1% (7034 patients) of subjects 
who received FF/VI 100/25 and 
was usually associated with trauma
Subjects will be informed about 
the risk of decreased bone 
mineral density and bone 
fractures in the informed consent. 
Investigators are made aware of 
the potential for this ICS class 
effect. Subjects will be advised to 
seek medical treatment if any 
signs of decreased bone mineral 
density or fractures occur.
All subjects will already be 
prescribed ICS/LABA treatments 
for their asthma. Therefore, it is 
unlikely that such an effect will 
occur.
Adrenal Suppression
This is considered a class effect of 
ICS. Preclinical studies showed 
that FF effects are comparable with 
other corticosteroids. No studies 
have shown a clinically relevant 
effect of FF/VI on the hypothalamic-
pituitary adrenal axis (HPA) at the 
100/25 strength. This includes a 
formal HPA study (HZA106851), 
using 24-hour serum cortisol 
measurements, and multiple 
studies with chronic obstructive 
pulmonary disease (COPD) and 
asthma subjects which monitored 
urinary cortisol.
Subjects will be informed about 
the risk of adrenal suppression in 
the informed consent. 
Investigators are made aware of 
the potential for this class effect 
in Section 6.3 (Warnings and 
Precautions) of the Investigators 
Brochure (IB). If systematic 
symptoms appear, investigators 
should implement an appropriate 
treatment while observing the 
subject’s’ asthma symptoms.
All subjects will already be 
prescribed ICS/LABA treatments 
for their asthma. Therefore, it is 
unlikely that such an effect will be 
experienced.
Corticosteroid 
associated eye 
This is considered a class effect of 
ICS. Preclinical studies showed FF 
Subjects will be informed about 
the risk of corticosteroid 


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disorders
at high dose comparable to other 
high dose corticosteroids. In study 
HZA106839 (FF/VI, FF and FP in 
subjects with asthma), formal 
ophthalmic assessments were 
conducted (including lens opacities 
classification system [LOCS] III 
evaluations for ocular opacities) 
throughout the study. This study 
showed no apparent effects on lens 
opacification, compared to 
baseline. During studies in both 
subjects with asthma and COPD, 
no associated affect on ocular 
disorders was observed.
associated eye disorders in the 
informed consent. They will be 
advised to seek medical 
treatment if any signs of eye 
disorder occur. Investigators are 
made aware of the potential for 
this class effect in Section 5.3.3.7 
(Ophthalmic Effects) of the IB.
All subjects will already be 
prescribed ICS/LABA treatments 
for their asthma. Therefore, it is 
unlikely that such an effect will be 
experienced.
Paradoxical 
bronchospasm may 
occur with an immediate 
increase in wheezing 
after dosing. 
First dose of Relvar/Breo will be 
administered at the clinical site 
under supervision Paradoxical 
bronchospasm should be treated 
immediately with a short-acting 
inhaled bronchodilator. 
Relvar/Breo ELLIPTA should be 
discontinued
Immediately. The subject would 
be withdrawn from study.
a.
RELVAR studies summarized include FFA109684, FFA109685, FFA109687, B2C109575, HZA106827,
HZA106829, HZA113091, HZA113714, HZA113719, HZA116863, HZA106837, HZA106839, HZA106851, 
FFA112059, FFA114496, FFA115283, FFA115285, B2C112060.
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of Relvar/Breo may be found in the Investigator’s 
Brochure, Development Safety Update Report or Summary of Product 
Characteristics.Benefit Assessment.
As a result of switching from other prescribed ICS/LABA combination products and 
being randomised to a treatment arm in the study, subjects may switch from an inhaled 
therapy that is taken twice daily, to a once daily therapy (Relvar/Breo) the patients in this 
study may have better adherence and so possibly better asthma control. There is also a 
potential benefit from use of the CIS. This has the potential to increase their adherence
through interaction with the data ouputs and engagement with their asthma. Data with 
marketed products suggests that adherence improves with less frequent 
administration/simplification of therapy and therefore it is expected that a once-daily 
treatment could improve adherence, which may lead to improvements in disease control 
and reductions in healthcare resource utilisation costs [Foster, 2014, Price, 2010, Toy,
2011].


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3.3.2.
Overall Benefit:Risk Conclusion
GlaxoSmithKline (GSK) has assessed this study for any potential risks that a subject may 
experience. The investigational product (IP) FF/VI will be used as is detailed in the 
prescribing information and has an acceptable safety profile for clinical use and there are 
no significant associated risks. This conclusion is supported by the results of previously 
performed clinical studies with the products in healthy volunteers and subjects with 
Asthma and COPD and post-marketing experience (see local label).
There is a small risk of destabilising asthma when switching to Relvar/Breo. Patients will 
be provided with rescue medication and will be educated to recognise symptoms of 
asthma worsening and instructed to contact the HCP in this event.
Taking into account the measures taken to minimize risk to subjects participating in this
study, the potential risks identified, associated with FF/VI are justified by the anticipated 
benefits that may be afforded to patients with asthma.
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of Relvar/Breo ICS/LABA may be found in the IB, 
Summary of Product Characteristics and Subject Information Leaflet.
4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
To compare the effect of 6 months use of the 
CIS on adherence to ELLIPTA maintenance 
therapy when both the subject and the HCP are 
supplied with data from the maintenance 
sensor versus no data supplied to the subject 
and HCP (Arm 1 vs Arm 5)
Percentage of ELLIPTA doses taken (daily 
adherence1.) between the beginning of month 4 
and the end of month 6 as determined by the 
maintenance sensor
Secondary
To compare the effect of 6 months use of the 
CIS on adherence to ELLIPTA maintenance 
therapy for the following aspects of the CIS:

Maintenance data only supplied to subjects 
versus no data supplied to the subject (Arm 
2 vs Arm 5)

Rescue and Maintenance data supplied  to 
subject and HCP versus no data supplied 
to the subject and HCP (Arm 3 vs Arm 5)

Rescue and Maintenance data only 
supplied  to subject versus no data 
supplied to the subject (Arm 4 vs Arm 5)

Percentage of ELLIPTA doses taken (daily 
adherence1.) between the beginning of 
month 4 and the end of month 6 as 
determined by the maintenance sensor
To compare the effect of the CIS on adherence 
to ELLIPTA maintenance therapy of the 
individual CIS treatment arms versus no data 
supplied to the subject and HCP.

Percentage of ELLIPTA doses taken (daily 
adherence1.) between the beginning of 
month 1 and the end of month 3

Percentage of ELLIPTA doses taken (daily 


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adherence) between the beginning of 
month 1 and the end of month 6
To evaluate the effect of 6 months use of the 
CIS on a subject’s rescue medicine usage

Percentage of rescue free days measured 
between the beginning of month 4 and the 
end of month 6 as determined by the 
rescue sensor records of date, time, and 
number of inhaler actuations. 

Total rescue use measured between the 
beginning of month 4 and the end of month 
6 as determined by the rescue sensor 
records of date, time, and number of inhaler 
actuations.
To evaluate the effect of 6 months use with the 
CIS on a subject’s asthma control

Change from baseline (Randomisation) in 
ACT total score at Month 6, measured at 
baseline (Visit 2, 3 or 4) and Month 6 
(Visit10)

Percentage of patients becoming controlled 
as defined as an Asthma Control Test score 
≥20 at Month 6 (Visit 10)

Percentage of patients with an increase 
from baseline ≥ 3 in ACT total score at 
Month 6 (Visit 10)


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Exploratory and Other Objectives
To evaluate the effect of 6 months use of the 
CIS on adherence to ELLIPTA maintenance 
therapy on the following aspects of the CIS:

HCP having access to sensor data

Rescue Medication data being available

Percentage of ELLIPTA doses taken (daily 
adherence) between the beginning of 
month 4 and the end of month 6 as 
determined by the maintenance sensor
To evaluate the effect of 6 months use with CIS 
on health care utilisation 
Health care utilisation endpoints will include the 
following and will be collected from a subject’s 
medical records. 

Number of outpatient visits relating to 
asthma

Number of primary care visits relating to 
study HCP dashboard review (for 
relevant study arms)

Number of and duration of 
hospitalisations, and ER visits due to 
asthma

Number of prescriptions filled/requested 
for maintenance medication in the 12 
months prior to inclusion. 

Annualised rate of severe 
exacerbations

Number of unscheduled visits to 
primary care related to Asthma 
To evaluate the effect of 6 months use with CIS 
on the following patient reported outcomes
(PROs):

Asthma  Symptom Utility Index (ASUI)

St Georges Respiratory Questionnaire 
(SGRQ)

Patient Activation Measure (PAM)

Medication Adherence Report Scale for 
Asthma (MARS-A)

Beliefs in Medicine Questionnaire 
(BMQ).

Percentage of patients meeting a 
responder threshold of ≥ 0.9 points 
improvement (decrease) from baseline
(Randomisation) for the ASUI total 
score at Month 6

Percentage of patients meeting a 
responder threshold of ≥ 4 points 
improvement from baseline ( 
Randomisation) for the SGRQ total 
score at Month 6

Mean change from baseline
(Screening) in PAM total score at 
Month 6 

Mean change from baseline
(Screening) in MARS-A total score at 
Month 6 

Mean change from baseline
(Screening) in BMQ total score at 


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Month 6
To assess the reliability and usability of the CIS

Incidence of Medical Device Incidents 
between the beginning of Month 1 and 
the end of Month 6.
To explore impact of adherence on the 
biomarker Fractionated exhaled Nitric Oxide 
(FeNO)
FeNo at Screening (Visit 1), Randomisation
(Visit 2,3 or 4), Month 1 (Visit 5) and Month 6
(Visit 10).
To explore impact of adherence on the 
physiological marker Peak Expiratory Flow 
(PEF) 

PEF at Screening (Visit 1), 
Randomisation (Visit 2,3 or 4), Month 1
(Visit 5) and Month 6 (Visit 10).

Change from baseline (Visit 2, 3 or 4) in 
PEF measured at Month 1 (Visit 5) and 
Month 6 (Visit 10)
To characterize patient experience of the CIS 
for subjects

Exit Questionnaires at Month 6 (Visit 
10) 

Exit Interviews for a sub set of subjects 
at Month 6 (Visit 10)
Safety Objectives
Safety Endpoints
To evaluate the incidence of SAEs, Non-
Serious Adverse Events that lead to withdrawal 
from study and Non-serious Adverse Drug 
Reactions in asthmatic subjects using the CIS

SAEs, Non-Serious Adverse Events that 
lead to withdrawal and Non-serious 
Adverse Drug Reactions 
1.
Daily adherence is defined as the subject taking one dose of Relvar/Breo ELLIPTA, within a 24 hour period, 
starting at 12.00am each day.


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5.
STUDY DESIGN
5.1.
Overall Design
Figure 2
: Study Schematic


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This is an open-label, randomised, multi-centre, parallel group study consisting of 5 
treatment arms, in asthmatic patients currently on a fixed dose ICS/LABA maintenance 
therapy.
The procedures to be performed at each visit are shown in Section 2.The study and visits 
are described here.
At all visits will require subjects to withhold a daily dose of maintenance therapy and 
rescue medication for 6 hours; as some assessments will require ths restriction for 
validity of the assessment (PEF and FeNO) and also so correct use can be demonstrated 
with that days Relvar/Breo ELLIPTA dose at any required visit.
The treatment period for the study is 6 months. However, due to the flexible run in period 
a subject could be on the study for approximately 7, 8 or 9 months in total
Screening Visit (V1)
Subjects who have provided their informed consent will be screened at Visit 1 (V1) for 
inclusion on the study. Subjects who meet all the inclusion criteria, including an ACT of 
<20, will enter the flexible run-in period. Screening and starting the flexible run-in can 
occur at the same visit, however for logistical reasons the flexible run-in can start at a 
separate visit, which must be within 7 days of the screening visit and the subject’s 
inclusion on the study. Should a subject not meet the the inclusion/exclusion criteria, they 
will be registered as a screen failure.
Flexible Run-in
Following inclusion at screening all subjects will receive Relvar/Breo ELLIPTA DPI 
maintenance therapy and salbutamol MDI rescue medication and be instructed to take 
these as prescribed. 
Instruction on correct use of the Relvar/Breo ELLIPTA DPI and salbutamol MDI will be 
provided, particularly in the case of subjects previously using other devices, and/or using 
medication requiring twice-daily dosing.
Both the Relvar/Breo ELLIPTA and salbutamol MDI medication used by all subjects 
included on the study will have a sensor fitted and switched on at the clinic visit. 
However, during this run-in period, there will be no information provided to the subjects 
or HCPs on their adherence to Relvar/Breo ELLIPTA or on their use of salbutamol MDI. 
Subjects will also be instructed in fitting the sensors onto both the ELLIPTA and MDI.
The run-in period can last for 1, 2 or 3 months, dependent on a subjects ACT at end of 
each month of the run-in period.
Conditional Visits 2, 3 and 4 (V2, V3 and V4)
At the end of each month of the flexible run-in period, ACT will be re-assessed at the 
clinical centre. If at the first monthly visit of the flexible run-in the subject’s ACT is <20
(uncontrolled) then the subject will be randomised to study treatment and subsequent run-


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in visits are not required. Subjects with an ACT of ≥20 at V2 or V3 repeat the month run-
in period. However, subjects who have an ACT ≥20 at all 3 visits, during the flexible run-
in, will not be randomised and will be registered as a run-in failure.
Randomization/treatment: Conditional Visits 2, 3 and 4 (V2, V3 and V4)
Subjects who meet the randomisation inclusion criteria will be randomised to one of five 
CIS treatment arms at this visit (V2, V3 or V4). All treatment arms continue with
Relvar/Breo ELLIPTA (ICS/LABA) maintenance therapy and Salbutamol MDI rescue 
therapy as in the run-in period and both inhalers continue having a sensor fitted. The 
treatment arms are defined by whether the data, from Relvar/Breo ELLIPTA 
(maintenance) or Relvar/Breo ELLIPTA (maintenance)  and salbutamol MDI (rescue), is 
fed back to the subject or subject and HCP, or not at all. The 5 treatments arms are as 
follows:
1.
Data on Maintenance use supplied to Subject (app) and HCP (dashboard)
2.
Data on Maintenance use supplied to Subject (app)
3.
Data on Maintenance and Rescue use supplied to Subject (app) and HCP (dashboard)
4.
Data on Maintenance and Rescue use supplied to Subject (app)
5.
No data supplied to Subject or HCP
Following randomisation, subjects in arms 1, 2, 3 and 4, will receive training on how to 
download and use the smart phone app, including how to connect and register the sensors 
via Bluetooth to their smart phone and to the app. Subjects in arm 5 who receive no data 
will be provided with a home hub so that their data will be uploaded during study, though 
they and their HCP will not see that data. Technical and operational details around 
registering sensors, connecting sensors to smart phone or a home hub and other details of 
app connectivity and function will be provided/referenced in the Study Reference Manual
(SRM).
Visit 5 (V5)
Following randomisation, subjects will be asked to return to the site, after one month, at 
V5. At this visit the HCP will ensure that all subjects are able to use the provided inhalers
correctly (correct use). For Arms 1, 2, 3 and 4 the site should ensure the sensors are 
attached correctly to the inhalers, are connected to the smart-phone via bluetooth and the 
HCP should ensure that subjects have been able to use the app. For subjects on Arm 5, 
the HCP will need to ensure that sensors are correctly attached to the inhalers.
At this visit, for subjects on Arms 1 and 3 the HCP will also, be able to review the 
subject’s adherence to treatment from month 1, and for Arm 3 also review the subject’s
rescue medication use. The HCP can as needed use the data (Arms 1 and 3) to discuss 
with these subjects their adherence and if needed the importance of taking their 
medication as it is prescribed. In reviewing the data the HCP should consider how they 
would respond if this data was available as part of normal standard of care. For Arm 3 the 
HCP can also review the subject’s rescue medication use and again should consider how 
they would respond if this data was available as part of normal standard care. The 


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outcome of the HCP data review will be recorded in the electronic Case Report Form 
(eCRF).
Conditional Visits 6, 7, 8 and 9 (V6, V7, V8, V9)
For subjects included on treatment arms 1 and 3, the HCP will review a subject’s sensor 
data via the dashboard,as a minimum every 4 weeks. However, the data can be assessed 
more often as needed. After assessment of the data, the HCP will be able to, at their own 
discretion, act on this data by calling/emailing or inviting the subject to the clinic to 
discuss their asthma further, or they can decide to take no action. When reviewing the 
data the HCP should consider how they would respond if this data was available as part 
of normal standard of care. The action(s) and any outcomes taken in response to these 
conditional visits, initiated by the HCP, will be recorded in the eCRF and in the subject’s 
medical record, including if no action was taken. If the HCP reviews the data at a time 
other than for the conditional visit and schedules a visit for the subject, this will be 
recorded in the eCRF as an unscheduled visit. Furthermore,subjects in all arms will be 
educated to recognise symptoms of asthma worsening and instructed to contact the HCP 
in this event. These events will also be recorded in the eCRF as unscheduled visits.
Visit 10 (V10)
All Subjects will return to site for final study assessments at the end of the 6 month 
treatment period.
Visit 11 (V11 Follow Up)
A follow-up visit will take place one week (2 days) after V10 and may be conducted as 
either a clinical visit or a phone call for final safety check.  
A subject will be considered to have completed the study when they have completed all 
phases of the study including screening, flexible run-in, the randomized treatment phase, 
and safety follow-up.
Dispensing Visits
All Subjects will be asked to return to the pharmacy or an independent nurse/designee at 
the study centre if a pharmacy is not available for these dispensing visits. They will need 
to bring their used Relvar/Breo ELLIPTA and/or salbutamol MDI and clip-on sensors in 
order to pick up their next Relvar/Breo ELLIPTA and/or salbutamol MDI as required
during the course of the study. During these dispensing visits, the sensor will be attached 
to the new devices and switched on at the site. There will be no assessments performed, 
these visits are only for dispensing of study drug, as well as to ensure that subjects are 
able to transfer and pair the sensors. Subjects should return the previous Relvar/Breo 
ELLIPTA and any salbutamol MDI that need replacing at these visits.
As a minimum, the following will need to be captured: the date of visit, medication
dispensed to the subject and also medication returned by the subject, including remaining 
doses on the ELLIPTA dose counter. This data should be recorded for entry into the 
eCRF.


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Early Withdrawal Visit (EW)
Subjects who have permanently discontinued study treatment and have not withdrawn 
consent are encouraged to continue in the study and complete all remaining protocol 
specified clinic visits  If a subject is withdrawn then they should complete the 
assessments as per Section 2. Reasons for withdrawal are provided in Section 8.2.
5.2.
Number of Subjects
Approximately 600 subjects will be screened to achieve 432 randomised and 380 
subjects are anticipated to have data available for the primary analysis for an estimated 
total of 76 subjects per treatment group.
An unblinded sample size re-estimation will take place, once 50% of the planned number 
of subjects have completed V10. An adjustment of the sample size, for arms 1 and 5, is 
conditional on the primary endpoint analysis results observed. However, no more than a 
further 42 subjects will be randomised in to each of arms 1 and 5 to provide a maximum 
of approximately 114 (76+38) subjects with data available for the primary analysis in
each of those 2 arms and so a total number of 456 subjects in all arms are expected.
5.3.
Subject and Study Completion
A subject is considered to have completed the study if he/she has completed the last 
scheduled procedure shown in Section 2, including the follow up visit.
The end of the study is defined as the date that the last subject completes the last 
scheduled procedure shown in the Section 2.
5.4.
Scientific Rationale for Study Design
This study will be an open label study, as it is not possible to blind the treatment arms to 
which sensors (maintenance or rescue) are providing feedback to the patient via the app, 
and also, whether or not the patients’ HCP has access to this data via the dashboard.
A true control arm (no sensors on ELLIPTA or MDI) cannot be incorporated into the 
design.  All subjects need to have a sensor on their maintenance and rescue medication in 
order to consistently measure their adherence to maintenance and level of rescue 
medication use; as other methods of measuring adherence and rescue medication use
(paper or electronic diaries and prescription refills) have inherent problems. Therefore, 
arm 5 is considered the best attempt at a control arm as neither subjects nor HCP will 
receive any data from either the ELLIPTA or rescue medication sensors and so could be 
considered the closest possible match to normal current practise.
Any asthmatic patient who is currently uncontrolled (ACT<20) on their current
ICS/LABA medication may be recruited and will, as needed, switch to Relvar/Breo 
ELLIPTA, if not already prescribed that. Due to this possible change in maintenance 
medication, a flexible run-in period has been incorporated into the study design, to enable 
assessment of any impact associated with the change of drug/dosing frequency, or simply 
being on the study, before being randomised to treatment on the study.


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The 5 treatment arms of the study will allow future development of the CIS and provide 
directional data on which aspects of the CIS have an impact on adherence, in particular,
the impact of HCP being able to review adherence data and the impact of data being 
provided from both maintenance and rescue medications on adherence.
Due to the novelty of CIS and the limited literature to guide this study in terms of 
statistical assumptions, an unblinded sample size re-estimation will take place once 50% 
of the planned number of evaluable subjects have completed. Further information on this 
process is provided in Section 11.
5.5.
Dose Justification
Relvar/Breo ELLIPTA and Salbutamol MDI will be prescribed as per label. The dosage 
of Relvar/Breo prescribed to a subject at the beginning of the study will depend on the 
dosage of their current ICS/LABA treatment and therefore,whether they will receive 
either 100/25 mcg or 200/25 mcg Relvar/Breo ELLIPTA. Changing between doses is 
permitted during the study treatment period if deemed necessary by the investigator.
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
AGE
1.
Subjects aged 18 years or older, at the time of signing the informed consent.
TYPE OF SUBJECT AND DIAGNOSIS 
2.
Subjects with documented physician diagnosis of asthma as their primary respiratory 
disease.
3.
Asthma Control Test (ACT) score <20 at screening visit
4.
Non-smokers (never smoked or not smoking for >6 months with <10 pack years 
history (Pack years = [cigarettes per day smoked/20] x number of years smoked)
SEX
5.
Male or Female subjects: 
A female subject is eligible to participate if she is not pregnant (see Appendix 5), not 
breastfeeding, and at least one of the following conditions applies:
(i)
Not a woman of childbearing potential (WOCBP) as defined in Appendix 5.
OR
(ii)
A WOCBP who agrees to follow the contraceptive guidance in Appendix 5
during the treatment period and for at least 5 days] after the last dose of study 
treatment.


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INFORMED CONSENT
6.
Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the consent form and in this protocol.
7.
Subject understands and is willing, able, and likely to comply with study procedures 
and restrictions.
8.
Subject must be able to read in a language supported by the smart phone app in their 
region
CURRENT ASTHMA THERAPY
9.
Subject must have been on maintenance therapy (Fixed dose combination 
ICS/LABA) for 3 months, cannot have changed dose in the month prior to screening
and be able to change to an equivalent dose of Relvar/Breo for the duration of the 
study. Other background asthma medication such as anti-leukotrienes and oral 
corticosteroids are permitted provided the dose has been stable for 1 month prior to 
screening.
10. Subject must be able to change to Salbutamol/Albuterol MDI rescue for the duration 
of the study and judged capable of withholding albuterol/salbutamol for at least 6 
hours prior to study visits.
DIGITAL CRITERIA
11. Subject must have their own Android or IOS smart phone and a data package 
suitable for the installation and running of the app and sending and receiving data. 
Data used by the CIS is approximately 1MB per month as a maximum; this is less 
data than a 1 minute video streamed from YouTube (2MB)).
12. Subjects must be willing and able to download the app on their personal smart 
phone and keep it turned on for the duration of the study. This will also require 
Bluetooth to be turned on for duration of the study. Subjects will also have to turn on
mobile data for the app for the duration of study; unless travelling and when extra 
data roaming costs could be incurred.


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6.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
RELEVANT HABITS
1. Subjects with a known or suspected alcohol or drug abuse which in the opinion of the 
investigator could interfere with the subject’s proper completion of the protocol 
requirement
CONTRAINDICATIONS
2. History of life threatening asthma: Defined for this protocol as an asthma episode that 
required intubation and/or was associated with hypercapnea, respiratory arrest or 
hypoxic seizures within the last 6 months
3. A lower respiratory tract infection within 7 days of the screening visit.
4. 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.
5. History of hypersensitivity/intolerance to any components of the study inhalers (e.g., 
lactose, magnesium stearate). In addition, subjects with a history of severe milk 
protein allergy that, in the opinion of the study physician, contraindicates 
participation will also be excluded.
6. Historical or current evidence of clinically significant or rapidly progressing or 
unstable cardiovascular, neurological, cardiovascular, neurological, renal, hepatic, 
immunological, endocrine (including uncontrolled diabetes or thyroid disease) or 
hematological abnormalities that are uncontrolled. Significant is defined as any 
disease that, in the opinion of the investigator, would put the safety of the subject at 
risk through participation, or which would affect the analysis if the disease/condition 
exacerbated during the study.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
7. Patient who have ever received treatment with biological based therapy e.g. 
omalizumab, mepolizumab, for asthma
8. Subjects who have received an investigational drug and/or medical device within 30 
days of entry into this study (Screening), or within five drug half-lives of the 
investigational drug, whichever is longer
9. A subject will not be eligible for this study if he/she is an immediate family member 
of the participating investigator, sub-investigator, study coordinator, employee of the 
participating investigator, or any family member of a Propeller Health employee


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Inclusion Criteria for Randomisation
ACT Control at V2, or V3 or V4 of run-in period
1. Asthma Control Test (ACT) score <20 at randomisation visit (V2)
6.3.
Lifestyle Restrictions
There are no lifestyle restrictions.
6.4.
Screen, Run-in and Randomisation Failures
Screen failures are defined as subjects who consent to participate in the clinical study but 
are not subsequently entered into the run-in period.
A subject who completes V1 assessments and is dispensed the study medication for the 
run-in period is considered to have entered the run-in period.
A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure subjects to meet the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, and any serious adverse events (SAEs) will be collected in the eCRF.
Run-in failuresare defined as subjects who consent to participate in the clinical study, 
enter the run-in period but are not subsequently randomised and do not have any 
randomisation visit (V2, V3, or V4) procedures other than ACT assessment. Information 
including demography, run-in failure details, eligibility criteria, and any serious adverse 
events (SAEs) will be collected in the eCRF.
Randomisation failures are those subjects that complete at least one Randomization 
procedure other than ACT but are not subsequently randomised and  do not enter the 
study treatment period.
Any subject who completes the run-in period and then meets the randomization criteria 
and is dispensed the study treatment at V2 is considered to have entered the treatment 
period.
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened, at the discretion of the investigator and should be assigned with a new 
subject number.
7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study subject according to 
the study protocol.


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7.1.
Treatments Administered
All subjects will receive Relvar/Breo ELLIPTA, either at the dose they are already 
prescribed or at the equivalent dose to their current ICS/LABA maintenance therapy if 
switched onto Relvar/Breo ELLIPTA. Guidance on which Relvar/Breo dose is 
appropriate, dependent on current therapy is included in Section 7.2.
Salbutamol MDI rescue medication will be prescribed to subjects to use as needed 
throughout the study for relief of asthma symptoms as per usual practice.
Study Treatment 
Name:
RELVAR/BREO ELLIPTA
Salbutamol MDI
Dosage 
formulation:
ELLIPTA DPI – 30 doses per 
device
Metered Dose Inhaler – 200 doses 
per device
Unit dose 
strength(s)/Dosage 
level(s):
100/25 mcg per actuation and 
200/25 mcg per actuation
100 mcg salbutamol per actuation 
Route of 
Administration
Inhaled
Inhaled
Dosing 
instructions:
One inhalation once daily
PRN
Packaging and 
Labelling
Study Treatment will be provided in 
a container. Each container will be 
labelled as required per country 
requirement.
Treatment will be provided locally. 
and will be labelled as per country 
requirements.
Manufacturer
GlaxoSmithKline (GSK)
All subjects will have sensors attached to both their Relvar/Breo ELLIPTA and 
Salbutamol MDI. It is the type of data provided by the CIS  (either Relvar/Breo 
ELLIPTA alone or Relvar/Breo ELLIPTAand salbutamol MDI) , as well as who sees that 
data (subject alone or subject and HCP) that defines the treatment arms. See Table 1 for a 
description of what data is fed back to who for each treatment arm. Further information 
/reference material for the CIS is provided in the SRM.


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Table 1
Treatment Arms
Relvar/Breo Sensor Data 
Available to
Salbutamol MDI Sensor 
DataAvailable to
Treatment 
Arm
Subject
HCP
Subject
HCP
1
X
X
2
X
3
X
X
X
X
4
X
X
5
7.2.
Relvar/Breo Dose Guidance:
FF/VI 100mcg/25mcg dose is comparable to fluticasone propionate/salmeterol low and 
medium doses. See SRM for further guidance for dose conversion for other 
corticosteroids.
Further information detailing equivalence of Relvar/Breo to other ICS/LABA 
combination treatment, for subjects who are switched, will be included in the SRM.
7.3.
Medical Devices
The clip on sensors and associated app for subjects’ Smartphone are produced by 
Propeller Health and are being provided by GSK for use in this study. These devices, 
which are fitted on to the Relvar/Breo ELLIPTA DPI and albuterol/salbutamol MDI to 
electronically record actuation data and associated app and HCP dashboard to provides
that data, both have US FDA 510(K) clearance to market (Class II device) and European 
Union (EU) European Confiormity (CE) marking (Class I device).
Instructions for medical device use are provided in the SRM, PSSM and in the pack insert 
for each device.
7.4.
Dose Modification
During the treatment period, investigators may modify the dose of a given subject during 
the study. Subjects in turn may change their dose from 100/25mcg FF/VI to 200/25mcg 
FF/VI and vice-versa if deemed absolutely necessary by the investigator.


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7.5.
Method of Treatment Assignment
Assignment of Subject Number
A unique Subject Number will be assigned to any subject who has signed the informed 
consent at V1. The unique Subject Number will be used to identify individual subjects 
during the course of the study.
Assignment of Randomisation Number
At V2, V3 or V4 (Run-in visits), subjects meeting the eligibility criteria will be assigned 
to study treatment using an interactive web response system (IWRS) that will be used by 
HCP or designee to register the subject, randomise the subject and provide treatment 
assignment information. Details on how to use RAMOS NG, the IWRS, to register and 
randomise subjects is provided in the RAMOS NG IWRS manual and SRM.
Once a randomisation number has been assigned to a subject, it cannot be reassigned to 
any other subject in the study.
Subjects will be assigned to study treatment in accordance with the randomisation 
schedule. The randomisation code will be generated by GSK using a validated 
computerised system. A subject will be randomised using RAMOS NG. The study will 
use central-based randomisation system to allocate treatments.
Subjects will be randomized 1:1:1:1:1 to one of the five treatments arms for the duration 
of the treatment period. Following the interim analysis and if extra subjects are required 
in arms 1 and 5, then those subjects will be randomised 1:1 in those arms. See Section 5
for description and numbering of arms.
Each investigator will be provided with sufficient study supplies to respond directly to 
subject requests for study treatment as required. Additional supplies will be supplied as 
needed to the sites. Details of how to use the IWRS system (RAMOS NG) to randomise 
subjects and manage study treatment supplies (including dispensing) is provided in the 
RAMOS NG IWRS manual and SRM.
7.6.
Blinding
The study is open label, neither the subject, HCP, site staff, or sponsor is blinded to 
treatment assignment.
7.7.
Preparation/Handling/Storage/Accountability
1.
The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment.
2.
Only subjects enrolled in the study may receive study treatment and only authorised 
site staff may supply or administer study treatment. All study treatments must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) 


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area in accordance with the labeled storage conditions with access limited to the 
investigator and authorised site staff.
3.
The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records).
4.
Further guidance and information for the final disposition of unused study treatment 
are provided in the SRM.
Under normal conditions of handling and administration, study treatment 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.
7.8.
Treatment Compliance
The primary measure of treatment compliance for both Relvar/Breo ELLIPTA and 
Salbutamol MDI will be captured by the respective sensor for those treatments. However, 
the date of prescription and date of  return of the inhaler, as well as start and finished 
dose count on each Relvar/Breo ELLIPTA, will be recorded in source documents at the 
dispensing visit and also transferred to the eCRF.
7.9.
Concomitant Therapy
All medications for asthma, excluding biological therapy and for other disorders that are 
not contra indicated in asthma, or prohibited in this study, may be continued throughout 
the study.
Please consult the prescribing information for the full list of medications which need to 
be used with caution: 
Beta-blockers: Use with caution. May block bronchodilatory effects of beta-agonists and 
produce severe bronchospasm. 
Diuretics: Use with caution. Electrocardiographic changes and/or hypokalemia associated 
with non-potassium-sparing diuretics may worsen with concomitant beta-agonists. 
Non-study asthma medications: A detailed history of previous 1 year, for prescriptions
for maintenance medications will be captured in the subjects eCRF and also any other 
ongoing asthma medications at inclusion.
Any medication or vaccine of relevance to the study or prescribed for safety events, 
including exacerbations experienced during the study, that the subject is receiving at the 
time of enrolment or receives during the study must be recorded in the eCRF in addition 
to medical records. As minimum the following will be needed:

reason for use


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
dates of administration including start and end dates

dosage information including dose and frequency
Over-the-counter medicines, vitamins, and/or herbal supplements are not required to be 
captured.
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
7.10.
Prohibited Concomitant Medication
Subjects must abstain from taking the following medications from 5 days prior to the first 
dose of study medication until completion of the follow-up visit.

Strong cytochrome P450 3A4 inhibitors (e.g., ketoconazole)

Monoamine oxidase inhibitors and tricyclic antidepressants: 

Subjects must never have been treated with a biological therapy for asthma e.g. 
omalizumab, mepolizumab.
Patients using Relvar/Breo ELLIPTA should not use another medicine containing a 
LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for 
any reason.
Do not use in combination with an additional medicine containing a LABA because of 
risk of overdose.
For full list of cautions for use and medicine interactions please consult the prescribing 
information and/or consult the study Medical Monitor if in doubt.
7.11.
Treatment after the End of the Study
There is no plan to continue to provide treatment following the end of the study.  The 
investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific 
post-study treatment.
Medications initiated after completion of the assessments at V10 or the EW visit will not 
be recorded in the eCRF unless taken to treat an AE or asthma exacerbation. subjects who 
have completed the EW visit are allowed to use any medications prescribed by the 
Investigator or primary care physician.
8.
DISCONTINUATION CRITERIA
Subjects that permanently stop study treatment are encouraged to remain in the study. 
Subjects have the right to discontinue study treatment before the end of the study. A 
subject may also be asked to discontinue study treatment at the investigator’s discretion.


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Subjects who withdraw from study treatment prematurely (for any reason) should, where 
possible, continue to be followed-up as per protocol until the completion of the Safety 
Follow-up assessments. If patients want to discontinue use of the CIS but will continue 
taking the Relvar/Breo ELLIPTA DPI then they will be given the option to continue to 
remain in study if they continue using the clip-on sensor for ELLIPTA. If this is not 
possible, the Investigator must encourage the subject to participate in as much of the 
study as they are willing (or able) to. Likewise, subjects who change their dose of 
Relvar/Breo (FF/VI) at the discretion of the investigator during the study will be given 
the option to remain on the study. For those subjects who do not want to use the sensor
during the study, their health outcome information will be collected along with any 
additional adherence data. For those subjects who change dose, all information will 
continue to be collected for the duration of the study.
A subject may be withdrawn from study treatment at any time. A reason for premature 
discontinuation of study treatment must be captured in the eCRF.
8.1.
Discontinuation of Study Treatment
8.1.1.
Liver Chemistry Stopping Criteria
There are no scheduled blood tests in this study.  If however the subject has a routine 
blood test during the study and the results suggest abnormal liver function, then the liver 
stopping criteria will apply.
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). These protocol guidelines are in alignment 
with FDA premarketing clinical liver safety guidance:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Discontinuation of study treatment for abnormal liver tests should be considered by the 
investigator when a subject meets one of the conditions outlined in the algorithm , see 
Appendix 6,or if the investigator believes that it is in the best interest of the subject.


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8.1.2.
QTc Stopping Criteria
ECGs are not planned at Screening or during this study. However, if during the study a
subject has an ECG performed the following stopping criteria apply and treatment should 
be withdrawn:
A subject who meets the bulleted criteria below will be withdrawn from the study:
QTcF>500 msec or uncorrected QT>600 msec
Change from V1 baseline: QTcF> 60msec
For patients with underlying bundle branch block, follow the discontinuation criteria 
listed below:
Discontinuation QTc with 
Bundle Branch Block
< 450 msec
> 500 msec
450 – 480 msec
≥ 530 msec [Note: QTc(F)>500 
msec for Korean subjects]
8.2.
Withdrawal from the Study

A subject may withdraw from the study at any time at his/her own request, or 
may be withdrawn at any time at the discretion of the investigator for safety, 
behavioural, compliance to protocol or administrative reasons.


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
Subjects should be reminded at each visit  that if  they do choose to withdraw 
themselves then, they should contact the Investigator or Study staff  as soon as 
possible and arrange an EW visit.

Female subject will be withdrawn if they produce a positive pregnancy test 
whilst on the study.

If the subject withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent.
Refer to the Section 2 for data to be collected at the time of EW from the study
8.3.
Lost to Follow Up
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit:

The site must attempt to contact the subject and reschedule the missed visit as 
soon as possible and counsel the subject on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the subject wishes to and/or 
should continue in the study.

Before a subject is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the subject (where possible, 3 telephone 
calls and, if necessary, a certified letter to the subject’s last known mailing 
address or local equivalent methods). These contact attempts should be 
documented in the subject’s medical record.

Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
9.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarised in the Section 2. 
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 subject should continue or discontinue study 
treatment.
Adherence to the study design requirements, including those specified in the Section 2, is 
essential and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 


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Procedures conducted as part of the subject’s routine clinical management (e.g., blood 
count) and obtained before signing of the informed consent form (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 Section 2.
9.1.
Efficacy Assessments
9.1.1.
Primary, Secondary and Other Adherence Measures
The Primary, Secondary and Other adherence endpoint (adherence to maintenance 
medication) data is collected by the Clip-on Sensor for ELLIPTA and records the time 
and date when the ELLIPTA cover is opened and closed. 
The sensor will be attached to subjects ELLIPTA Relvar/Breo treatment from start of 
run-in until V10. References and material for fitting the sensors, downloading the app 
and other aspects of using the CIS are included in the SRM.
9.1.2.
Secondary Efficacy Endpoints
9.1.2.1.
Asthma Control Test
This assessment is described in Section 9.1.3.1 and will be collected electronically at the 
site at the timepoints detailed in Section 2. This will be carried out via use of the 
electronic Patient Reported Outcome (ePRO) device.
9.1.2.2.
Rescue Medication Use
Rescue Medication use endpoint data is collected by the Clip on Sensor for salbutamol
MDI and records time and date when the MDI is actuated. 
The sensor will be attached to the subject’s salbutamol MDI treatment from start of run-
in until V10. Details for fitting the sensor and other aspects of using the CIS are included 
in the SRM.
9.1.3.
Questionnaires and Interviews
It is preferred that the questionnaires are administered at the same time of day at each 
visit and that this time of day is the same as when they were originally administered (as is 
feasible/appropriate), in order to avoid potential bias due to the time of day when 
responding. The subjects should not be told the results of any diagnostic tests prior to 
completing the questionnaires and the questionnaires should be completed before any 
procedures are performed on the subject to avoid influencing the subject’s response. 
Adequate time in a quiet, comfortable location must be allowed to complete all items on 
the questionnaires and if necessary, the subject must be encouraged to complete any
questionnaires or missing items fully.Full guidance for obtaining good quality data from 
patient-completed questionnaires is included in the SRM.
All the questionnaires will be completed on an ePRO device at the clinical study site and 
at the time detailed in the Section 2.


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Further instructions for completing the questionnaires can be found in the SRM.
9.1.3.1.
Asthma Control Test (ACT)
The ACT is a validated self-administered questionnaire utilising 5 questions to assess 
asthma control during the past 4 weeks on a 5-point categorical scale (1 to 5) with a range 
of 5 to 25. By answering all 5 questions a subject with asthma can obtain a score that may 
range between 5 and 25, with higher scores indicating better control. An ACT score of 5 
to 19 suggests that the subject’s asthma is unlikely to be well controlled. A score of 20 to 
25 suggests that the subject’s asthma is likely to be well controlled. The total score is 
calculated as the sum of the scores from all 5 questions[Nathan, 2004]. The minimally 
important difference (MID) for ACT is 3 [Schatz, 2009].
Subjects will complete the ACT at times shown in the Section 2 using the electronic 
version on the ePRO device at the clinical site.
The ACT has been developed as a measure of subjects’ asthma control that can be 
quickly and easily completed in clinical practice and by telephone. The questions are 
designed to be self-completed by the subject. 
Please refer to the SRM for further details.
9.1.3.2.
Asthma Symptom Utility Index (ASUI)
The ASUI is a 10-item self-administered questionnaire with 4 questions on asthma 
symptoms (Cough, wheeze, shortness of breath, awakening at night) and 1 question about 
the side effects of asthma medications [Revicki, 1998].  For each symptom, there are 2 
dimensions; frequency and severity.  The questionnaire is based on a 2-week patient 
recall of symptoms with response options of 0 to 4 for frequency (not at all, 1 to 3 days, 4 
to 7 days, and 8 to 14 days) and severity (not applicable, mild, moderate and severe).
ASUI will be completed on an ePRO device at the clinical study site and at the times 
detailed in the Section 2.
Please refer to the SRM for further details.
9.1.3.3.
St Georges Respiratory Questionnaire (SGRQ)
The St. George’s Respiratory Questionnaire is a well established instrument, comprising 
50 questions designed to measure Quality of Life in patients with diseases of airway 
obstruction, measuring symptoms, impact, and activity. The questions are designed to be 
self-completed by the subject with a recall over the past 4 weeks [Jones, 1992]
SGRQ will be completed on an ePRO device at the clinical study site and at the times 
detailed in the Section 2.
Please refer to the SRM for further details.


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9.1.3.4.
Patient Activation Measure (PAM)
Patient Activation Measure will be used to assess the knowledge, skills and confidence a 
person has in managing their own health and health care. The questionnaire will be 
completed at the times shown in the Section 2.
The PAM contains a series of 13 statements designed to assess the extent of a patient’s 
activation. These statements are about beliefs, confidence in the management of health-
related tasks and self-assessed knowledge. Patients are asked to rate the degree to which 
they agree or disagree with each statement. These answers are combined to provide a 
single score of between 0 and 100, which represents the patients’ concept of themselves 
as an active manager of their health and health care. There is no specified timeframe on 
which responses should be based, the questionnaire is suitable to be used to measure 
changes in activation over time and can be performed before and after an intervention
[Hibbard, 2004].
PAM will be completed by subjects on an ePRO device at the clinical study site and at 
the times detailed in the Section 2.
Please refer to the SRM for further details.
9.1.3.5.
Medication Adherence Report Scale for Asthma (MARS-A), 10-item 
questionnaire
Reported adherence to medication will be assessed with the Medication Adherence 
Report Scale for Asthma (MARS-A) questionnaire at times shown in the Schedule of 
Activities (SoA).
The MARS-A is a 10-item questionnaire where medication use is rated on a 5-point 
Likert scale (1 indicating ‘always’ to 5 indicating ‘never’). It has been validated as a self-
reported measure of adherence with ICS for patients with asthma, and includes generic 
(“I use it regularly every day”) and lung condition-specific questions about medication 
use (“I only use it when I feel breathless”) [Cohen, 2009]. The MARS-A has no 
specified timeframe on which responses should be based but generally refer to the present 
moment. MARS-A will be completed on an ePRO device at the clinical study site and at 
the times detailed in the Section 2.
Please refer to the SRM for further details.
9.1.3.6.
Beliefs in Medicine Questionnaire (BMQ).
The BMQ questionnaire consists of the BMQ Specific, which measures perceptions of 
specific medicines, and the BMQ General, which measures more general beliefs about 
medicines. All items are rated on a 5-point Likert scale [Horne, 2002].
The BMQ General comprises a General Harm scale and a General Overuse scale 
assessing beliefs about pharmaceuticals as a class of treatment. The General Harm scale 
assesses beliefs about the intrinsic nature of medicines and the degree to which they are 
perceived as harmful and should be avoided if possible. The General Overuse scale 
represents beliefs about the use of medicines and whether they are overprescribed by 


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clinicians.  The BMQ Specific (Asthma) comprises two scales: one assessing patients' 
beliefs about the necessity of preventer medication for maintaining present and future 
health (Necessity scale), and the other assessing their concerns about the potential 
adverse consequences of using it (Concerns scale). Four items were added for use in 
patients with asthma.
BMQ will be completed on an ePRO device at the clinical study site and at the times 
detailed in the Section 2.
Please refer to the SRM for further details.
9.1.3.7.
Exit Questionnaire
All subjects will complete a questionnaire at the end of the final study visit (V10) to 
assess the CIS.  This questionnaire is designed to understand the subject’s perceptions of 
the CIS. It is self-completed on the ePRO device by subjects. It includes questions 
relating to the concepts below:   

Overall satisfaction with CIS

Parts of the CIS that were most /least helpful

Level of engagement with the CIS

Challenges/difficulties with using CIS 

Subject perception of the impact of the CIS on asthma  

Subject perception of future use of a similar system

Impact of CIS on physician interaction
9.1.3.8.
Exit Interviews
Exit interviews will be conducted for subjects at selected sites at the visit after they have
completed their course of study medication (V11). Exit interviews are qualitative 
interviews conducted with study subjects to capture a subjects experience on changes in 
asthma and perceptions of the CIS.
Interview questions are designed to fully assess a subject’s experience in a structured 
format by a trained interviewer. Subject feedback will audio-taped for subsequent 
transcription and qualitative analysis. 
These exit interviews will be conducted by external vendors after subjects have 
completed V11. The analysis and report of the exit interview will be managed by a 
separate RAP. 


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9.2.
Serious Adverse Events (SAE), Non-Serious Adverse Events 
that leads to withdrawal and Non Serious Adverse Drug 
Reactions (ADR)
The  Investigator or site staff will be responsible for detecting, documenting and 
reporting events that meet the definition of a, non-serious adverse events that leads to 
withdrawal, non-serious adverse drug reaction (ADR) or SAE.The definition of an ADR 
is any untoward medical occurrence in a patient or clinical investigation subject, 
temporally associated with the use of a medicinal product, for which there is a reasonable 
possibility that the untoward occurrence is causally related to the medicinal product. 
ADRs are a subset of AEs for a given medicinal product.
Potential SAEs and associated non serious ADRs may be identified from a subject’s 
primary HCP report or a subjects health records. The HCP will have the ultimate 
responsibility for determining causality and seriousness.
In some countries extra safety information may be requested as required by local 
Regulatory Agencies and information providing detail of these extra safety events and 
how these should be reported are included in Appendix 8.
In this study, only information regarding non- serious adverse drug reactions (ADRs), 
AEs leading to withdrawal and serious adverse events (SAEs) will be detected, 
documented and reported. However, the definition of an AE is critical for the definition 
of non-serious ADRs and SAEs.
The definitions of an AE or SAE can be found in Appendix 4
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious or that caused the subject to discontinue the study (see 
Section 8.1).
9.2.1.
Time Period and Frequency for Collecting AE, ADR and SAE 
Information

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
product will be recorded from the time a subject consents to participate in the 
study up to and including any follow-up contact. 

AEs leading to withdrawals and ADRs will be collected from the start of Study 
Treatment until the follow-up contact at the timepoints specified in SoA Section 2

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the eCRF.

All SAEs will be recorded and reported to the sponsor or designee within 24 
hours, as indicated in Appendix 4 The investigator will submit any updated SAE 
data to the sponsor within 24 hours of it being available.


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
Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event to be reasonably related to the study treatment or study participation, the 
investigator must promptly notify the sponsor.

The method of recording, evaluating, and assessing causality of AEs and SAEs 
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 4.
9.2.2.
Method of Detecting Aes, ADRs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about AE
occurrence.
The Investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of a non-serious adverse drug reaction (ADR), AE 
(leading to withdrawal) or SAE.
Potential SAEs, AE (leading to withdrawal) and associated non serious ADRs may be 
identified from patients medical records.  The Investigator will have the ultimate 
responsibility for determining causality and seriousness.  .
In this study, only information regarding non- serious adverse drug reactions (ADRs), AE 
leading to withdrawal and serious adverse events (SAEs) will be detected, documented 
and reported. 
9.2.3.
Follow-up of AEs, ADRs and SAEs
After the initial AE that led to withdrawal/non-serious ADR/SAE report, the investigator 
is required to proactively follow each subject at subsequent visits/contacts. All SAEs, will 
be followed until the event is resolved, stabilized, otherwise explained, or the subject is 
lost to follow-up (as defined in Section 8.3). Further information on follow-up procedures 
is given in Appendix 4.
9.2.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of subjects 
and the safety of a study treatment under clinical investigation are met. 

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study treatment 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators.


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
Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or 
other specific safety information e.g., summary or listing of SAE) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.
In some countries extra safety information may be requested as required by local 
Regulatory Agencies and information for this and how these should be reported are 
included in Appendix 8.
9.2.5.
Cardiovascular and Death Events
For any cardiovascular events as detailed in Appendix 4 and all deaths, whether or not 
they are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF 
will be required to be completed. These sections include questions regarding 
cardiovascular (including sudden cardiac death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV Medical 
Dictionary of Regulatory Activities (MedDRA) terms. The CV information should be 
recorded in the specific cardiovascular section of the CRF within one week of receipt of a 
CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
9.2.6.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
The following disease related events (DREs) are common in subjects with asthma and 
can be serious/life threatening:
9.2.6.1.
Asthma Exacerbations
For the purposes of this study, severe asthma exacerbations will be collected and
recorded on the asthma exacerbation eCRF page from the start of treatment until follow 
up/or the EW visit for those subjects that withdraw from participation in the study.
A severe asthma exacerbation is defined as deterioration of asthma requiring the 
use/additional use of systemic corticosteroids (tablets, suspension, or injection), or 
antibiotics, an inpatient hospitalisation, or emergency department visit due to asthma that 
required systemic corticosteroids or antibiotics. Further clarification will be present in the 
SRM.
Asthma exacerbations should not be recorded as an AE unless they meet the definition of 
an SAE.


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These events will be recorded on the DRE page in the subject’s eCRF within 24 hours of 
the physician becoming aware. The time period for collection of exacerbation 
information in the eCRF will be from the time that the ICF is signed until the Exit visit or 
EW.
For consistency, exacerbations separated by less than 7 days will be treated as a 
continuation of the same exacerbation.
9.2.7.
Pregnancy
Details of all pregnancies in female subjects will be collected after the start of study 
treatment and until at least 5 terminal half-lives after the last dose.
If a pregnancy is reported, the investigator should inform GSK within 2 weeks of 
learning of the pregnancy and should follow the procedures outlined in Appendix 5.
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
9.2.8.
Medical Device Incidents (Including Malfunctions)
Procedures for Documenting Medical Device Incidents are provided in Appendix 7.
9.3.
Treatment of Overdose
For this study, any dose of Relvar/Breo ELLIPTA greater than the prescribed dose within 
a 24-hour time period will be considered an overdose.
GSK is not recommending specific treatment guidelines for overdose and toxicity 
management. The investigator is advised to refer to the relevant document(s) for detailed 
information regarding warnings, precautions, contraindications, adverse events, and other 
significant data pertaining to the study drug being used in this study. Such documents 
may include, but not be limited to, the IB or equivalent document provided by GSK.
In the event of an overdose, the HCP/treating physician should:
1.
Contact the Medical Monitor immediately.
2.
Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the subject.
9.4.
Screening and Safety Assessments
Planned time points for all screening and safety assessments are provided in Section 2.


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9.4.1.
Physical Examinations

A complete physical examination will include, at a minimum, assessments of the 
Skin, Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. 
Height and weight will also be measured and recorded.

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
The physical exam is to inform on inclusion and only needs to be recorded in the subjects 
source/medical notes.  Physical exams will be performed at the time points specified in 
the Section 2.
9.4.2.
Vital Signs
Vital signs (systolic and diastolic blood pressure and pulse rate) will be performed at the 
screening visit only as part of physical exam  The measurement will be taken after 5 
minutes rest in a semi-supine position.  One reading of blood pressure and pulse will be 
taken.
The vital signs are to  inform on inclusion and only needs to be recorded in the subjects 
source/medical notes.
9.4.3.
Clinical Safety Laboratory Assessments
Urine pregnancy tests are performed at timelines detailed in Section 2. The tests will be 
provided locally. The results of the tests should be recorded in the subject’s medical 
records only.
If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in subject management or are considered 
clinically significant by the investigator (e.g., SAE or AE), then the results must be 
recorded in the eCRF.
9.5.
Biomarkers
9.5.1.
FeNO in breath
FeNO will be measured using a handheld electronic device. Measurements will be 
obtained in accordance with the American Thoracic Society (ATS)/European Respiratory 
Society (ERS) Recommendations for Standardized Procedures for the Online and Offline 
Measurement of Exhaled Lower Respiratory Nitric Oxide and Nasal Nitric Oxide 
[Silkoff, 2005]. All sites will use standardized equipment provided by a central vendor. 
For each observation, at least 2 measurements will be obtained to establish 
reproducibility (up to 8 measurements can be performed). FeNO measurements will be 
interpreted in accordance with the Official ATS Clinical Practice Guideline: 
Interpretation of Exhaled Nitric Oxide Levels (FeNO) for Clinical Applications [Dweik, 
2011]. FeNO observations must be completed before PEF assessments. Subjects should 
not use their rescue medication for at least 6 hours before each FeNO assessment, unless 


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essential for clinical need. Subjects should also withhold Breo/Relvar ELLIPTA for (1 
dosing interval ) approximately 24 hours  prior to FeNO assessment.
9.6.
Peak Expiratory Flow (PEF)
At visits where PEF is to be taken the subjects should withhold Salbutamol for 6 hrs 
before the visit and Relvar/Breo ELLIPTA for approximately 24 hours prior to 
assessment. 
PEF will be performed using a Mini Wright Peak Flow Meter provided by GSK. Details 
of how this procedure is performed is detailed in the SRM. 
PEF will be taken in triplicate at timelines detailed in the Section 2. All 3 measures 
should be recorded in the subjects record and transferred to the eCRF.
9.7.
Prescription Record for Asthma Maintenance Medication
The following will be collected in the eCRF and confirmed by a subjects medical 
record’s, or the prescribing physician. Prescriptions for a subjects asthma maintenance 
therapy (ICS or ICS/LABA combinations) for the 12 months prior to inclusion.
9.8.
Medical Resource Utilisation and Health Economics
Medical resource utilisation associated with medical encounters, will be collected in the 
eCRF by the investigator and study-site personnel for all subjects throughout the study. 
These events should be recorded and  reviewed by the HCP or designee with the subject
at all study visits and where available confirmed with a subjects medical records.
Protocol-mandated procedures, tests, and encounters are excluded, though visits relating 
to HCP review of the CIS dashboard will be captured. 
The data collected may be used to conduct exploratory health care resource utilization 
(HCRU) and economic analyses and will include:

Number of outpatient visits relating to asthma

Number of primary care visits relating to study HCP dashboard review (for 
relevant study arms)

Number of and duration of hospitalisations, and ER visits due to asthma

Number of prescriptions filled/requested for maintenance medication in the 12 
months prior to inclusion. 

Annualised rate of severe exacerbations

Number of unscheduled visits to primary care related to Asthma 


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10.
DATA MANAGEMENT

For this study, subject data will be entered into a GSK defined eCRF, 
transmitted electronically to GSK or designee and combined with data provided 
from other sources in a validated data system.

Management of clinical data will be performed in accordance with applicable 
GSK standards and data cleaning procedures to ensure the integrity of the data, 
e.g., removing errors and inconsistencies in the data.

Adverse events and concomitant medication terms will be coded using 
MedDRA (Medical Dictionary for Regulatory Activities) and an internal 
validated medication dictionary, GSKDrug.

eCRFs (including queries and audit trails) will be retained by GSK, and copies 
will be sent to the investigator to maintain as the investigator copy. Subject 
initials will not be collected or transmitted to GSK according to GSK policy.
11.
STATISTICAL CONSIDERATIONS
11.1.
Hypothesis
The main purpose of the study is to compare the effect of 6 months use with the CIS on 
adherence to ELLIPTA maintenance therapy with adherence to ELLIPTA maintenance 
therapy without CIS use (sensor alone), in subjects with poorly controlled asthma.  This 
study aims to demonstrate the superiority of the CIS on adherence to Relvar/Breo
ELLIPTA with an app compared to Relvar/Breo ELLIPTA (with sensor alone).  The 
primary endpoint is mean percentage of ELLIPTA doses taken (daily adherence) between 
Months 4 and 6 as determined by the maintenance sensor daily adherence over the last 
three months of the study period (between months 4 to 6).  
The test for the primary treatment comparison will be a test between Arm 1 versus Arm 
5.  This will be based on a two-sided hypothesis testing approach: the null hypothesis is 
the difference between Arm 1 and Arm 5 is equal to zero. The alternative hypothesis is 
that the difference is not equal to zero.  The hypotheses associated with the statistical test 
of the primary endpoint are written below:
H0: Ti – Tj = 0
(where i = Arm 1 and j = Arm 5) The null hypothesis: that the difference in response 
between Arm 1 and Arm 5 is zero.
Ha: Ti – Tj 0
The alternative hypothesis: that the difference is not zero.
Other comparisons of interest for the primary endpoint are the individual comparisons of
Arms 2, 3 and 4 with Arm 5 in order to obtain estimated mean treatment differences and 


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95% confidence intervals. This will be a descriptive comparison to inform on the relative 
benefits of the individual aspects of the CIS and no formal inference is planned.
The effect on adherence to maintenance therapy between arms with HCP and no HCP 
interaction, and arms with rescue medication use feedback versus none, will be also 
assessed.
The comparisons of interest for the other secondary and safety endpoints are as stated 
above for the primary endpoint. Arms 1, 2, 3 and 4 will be individually compared to Arm 
5, as relevant to the endpoint, in order to obtain  estimated mean treatment differences 
and 95% confidence intervals. This will be a descriptive comparison and no formal 
inference is planned.
11.2.
Sample Size Determination
11.2.1.
Sample Size Assumptions
The fixed sample size calculation is based on the primary endpoint, percentage of 
ELLIPTA doses taken (daily adherence) between Months 4 and 6 as determined by the 
maintenance sensor and has approximately 90% power to detect an absolute difference 
of 15% in the primary comparison.  The treatment difference is based on the limited 
published data [Charles, 2007, van Boven, 2016].  This assumes a conservative standard 
deviation of 28% (based on a previous study [Charles, 2007]) and significance declared at 
the two-sided 5% level. 
Approximately 432 patients will be randomised in order to obtain at least 380 subjects 
(i.e. 76 subjects per arm) with available data over the last three months of the treatment 
period, in anticipation of a 12% drop-out within the first three months.  Subjects will be 
randomised to one of five treatment arms with a ratio of 1:1:1:1:1.
Using the above assumptions the smallest observed effect predicted to result in a 
statistically significant difference between treatment groups is 9% (minimum detectable 
difference).
11.2.2.
Sample Size Sensitivity
Due to limited historical data within GSK, an external party was hired to conduct a 
literature review. Based on results from the literature review only one paper in an 
asthmatic adult population provided adherence rates and variability estimates that could 
be used as assumptions for power calculations [Charles, 2007]. 
The study presented sample size assumptions for the treatment difference in mean daily 
% adherence of 10% and a standard deviation of the data of 18% [s1]. The reported raw 
means (standard deviation) of mean daily % adherence were 88% (16%) and 66% (27%) 
in the intervention and control groups, respectively. Due to uncertainty in data variability 
a wide range of values were explored. Table 2 belowpresents the power achieved with the 
proposed sample size of 76 completers per arm should the assumptions of standard 
deviation of the data change.


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Table 2
Standard Deviation Affect on Power from the Fixed Sample Size
Standard Deviation (%)
Power for Primary 
Comparison
22
99
24
97
26
94
28
90
30
86
32
81
34
77
11.2.3.
Sample Size Re-estimation
Due to the uncertainty on the true treatment effect and data variability, and to reduce the 
risk of running an underpowered study, it is considered appropriate to adopt an adaptive 
approach to the sample size for this study. This will offer a mechanism to adjust the 
sample size in response to updated treatment effect and variability estimates seen at a 
planned interim analysis [Mehta, 2011] . The proposal is as follows:

Start with a fixed sample size calculation based on the primary endpoint.

Independent statistician performs a planned unblinded interim analysis to 
examine data based on 50% of subjects on each arm having completed the 6 
months treatment period.

Based on the interim results (i.e.: treatment effect, data variability and 
conditional power) maintain or increase the sample size in order to obtain the 
desired power of 90%.
The conditional power based on the interim results will assess as to where it falls within 
certain regions established prior to the trial starting.  Should the conditional power be in 
the favourable or unfavourable range the sample size will not be adjusted and will remain 
at the fixed size for all treatment arms. Conditional power falling into the promising zone 
will have a sample size increase applied to treatment arm 1 and 5 only. However, no 
more than a further 42 subjects will be randomised in to each of the treatment arms 1 and 
5 to provide a maximum of approximately 114 (76+38) subjects with data available for 
the primary analysis in each of those 2 arms such that a total number of 456 subjects in 
all arms are expected.
The regions and their implications on sample size are detailed below:
Favourable
conditional power at interim (CPinterim) ≥ 90%
Promising
CP min ≤ CPinterim < 90%
Unfavourable
CPinterim < CP min
Full details of the adaptive method for sample size specified above will be given in the 
reporting and analysis plan (RAP).


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11.3.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled 
All subjects who sign the ICF
Total Population
The Total Population will comprise all subjects screened and for 
whom a record exists on the study database and will be used for the 
tabulation and listing of reasons for withdrawal before 
randomisation.
Intent-to-treat
The Intent–to–Treat (ITT) population is defined as all subjects who 
have been randomised and exposed to at least one dose of 
treatment. The ITT population will be used for all endpoint analyses  
and Outcomes will be reported according to the randomised 
treatment allocation. 
11.4.
Statistical Analyses
Where possible, data from subjects who withdraw prematurely from the study treatment 
or the study will be included in any relevant analyses. Specific details for inclusion will 
be detailed in the Reporting and Analysis  Plan (RAP).
The covariates to be considered in the efficacy analyses include age, sex, region and the 
baseline values, if relevant. Other covariates, if appropriate, may be considered. Specific 
details will be provided in the RAP.
11.4.1.
Adherence Analyses
Endpoint
Statistical Analysis Methods
Primary
The primary analysis will estimate the treatment effect of 6 months use of the  
ELLIPTA maintenance therapy with CIS when both the subject and the HCP are 
supplied with data from the maintenance sensor versus no data supplied to the 
subject and HCP (Arm 1 vs Arm 5) for the primary endpoint percentage of ELLIPTA 
doses taken (daily adherence) between the beginning of Month 4 and the end of 
Month 6 as determined by the maintenance sensor.  The analysis will be performed 
on the ITT population.
The analysis will be performed on the percentage adherence between Months 4 
and 6 measure using an Analysis of Covariance (ANCOVA) model allowing for 
effects due to randomised treatment, baseline adherence, duration (days) in run-in, 
region, sex, and age (years).  Baseline adherence will be the percentage ELLIPTA 
doses taken (daily adherence) during the last 28 days of the run-in period prior to 
randomisation. Any subjects with missing intermittent adherence data will be 


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imputed to as non-adherent i.e. assumed to have not taken their treatment within 
the 24 hour time period/window, where there is no evidence of a medical device 
incident having occurred.
Subjects who prematurely discontinue from study will have their post-withdrawal 
daily adherence data imputed using data from the control arm using an appropriate 
method of imputation, such as the jump to reference method.  This method of 
assessing the primary endpoint corresponds to a de-facto treatment policy 
estimand which reflects the anticipated behaviour that subjects will continue to take 
an asthma combination therapy without the CIS intervention.  
Missing data due to a medical device incident such as device failure, technical 
failure of the e-sensor, or data transmission failure will be assumed to be missing 
at random (MAR). For each subject the percentage adherence measure will be 
calculated under the assumption that any missing data is MAR, from the proportion 
of the number of days a subject is adherent divided by the number of days data 
provided for the last 3 months treatment period.
The adjusted means for each treatment and the estimated treatment difference for 
the primary treatment comparison of Arm 1 versus Arm 5 will be presented 
together with a 95% confidence interval for the difference and corresponding p-
value.
Summary statistics (mean, standard deviation, median, minimum, maximum) of the 
primary endpoint will be provided.
Where possible, adherence data collected from subjects who withdraw prematurely 
from study treatment will be included in the analysis.
Sensitivity analyses of the primary adherence endpoint will be performed on the 
ITT population and an assessment of the impact of the missing data will be carried 
out using multiple imputation methods under different assumptions for missing data
for withdrawn subjects.  Details will be provided in the RAP.
Secondary
The following secondary analyses will estimate the treatment effect of 6 months 
use of the  ELLIPTA maintenance therapy with CIS for the following aspects of the 
CIS:

Maintenance data only supplied to subjects versus no data supplied to the 
subject (Arm 2 vs Arm 5)

Rescue and Maintenance data supplied to subject and HCP versus no data 
supplied to the subject and HCP (Arm 3 vs Arm 5)

Rescue and Maintenance data only supplied to subject versus no data 
supplied to the subject (Arm 4 vs Arm 5)
for the following secondary endpoints:

Percentage of ELLIPTA doses taken (daily adherence) between the 
beginning of Month 4 and the end of Month 6 as determined by the 
maintenance sensor, 

Percentage of ELLIPTA doses taken (daily adherence) between the 
beginning of Month 1 and the end of Month 3


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
Percentage of ELLIPTA doses taken (daily adherence) between the 
beginning of Month 1 and the end of Month 6
The analysis will be performed using an ANCOVA model allowing for effects due to 
randomised treatment effect, baseline adherence, duration (days) in run-in, region, 
sex, and age (years).  Baseline adherence will be the percentage ELLIPTA doses 
taken (daily adherence) during the last 28 days of the run-in period prior to 
randomisation.  Any subjects with missing intermittent adherence data will be 
imputed to as non-adherent i.e. assumed to have not taken their treatment within 
the 24 hour time period/window, where there is no evidence of device or 
technical/transmission failure.  
Where possible, adherence data collected from subjects who withdraw prematurely 
from study treatment will be included in the analysis.  Subjects who prematurely 
discontinue from study will be handled as per the primary endpoint analysis.  
The adjusted means for each treatment and the estimated treatment difference for 
the treatment comparisons of Arm 2 versus Arm 5, Arm 3 versus Arm 5 and Arm 4 
versus Arm 5 will be presented together with the 95% confidence interval for the 
differences and corresponding p-values.
Summary statistics (mean, standard deviation, median, minimum, maximum) of the 
secondary endpoint will be provided.
If a subject has changed dose during the study, sensitivity analyses on the 
secondary endpoint(s) regarding ACT will be performed where these subjects are 
removed from the analysed population. Further details will be provided in the RAP.
Exploratory
Will be described in the RAP.
11.4.2.
Safety Analyses
All safety analyses will be performed on the ITT Population. 
Endpoint
Statistical Analysis Methods
Safety 
SAEs, AEs leading to withdrawal and non-serious ADRs will be collected.
Safety endpoints will include:

Incidence and type of serious adverse events

Incidence and type of adverse drug reactions

Incidence and type of non-serious adverse events leading to study 
withdrawal

Incidence of subjects experiencing a severe exacerbation
The incidence of any given adverse event (SAE or ADR) for each treatment 
group is defined as the proportion of subjects in that group who have experienced 
at least one such adverse event during the study period.


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The number and percentage of subjects with SAEs, non-serious ADRs and AEs 
leading to study withdrawal will be summarised by preferred term. 
The number and percentage of subjects experiencing  severe exacerbations over 
treatment period and the follow-up period will be summarised for each treatment 
group alongside the primary causes of the exacerbation.
11.4.3.
Other Analyses
All other exploratory endpoints, except for qualitative data from exit interviews and 
questionnaires, will be detailed in the RAP.
Analysis of the qualitative data from exit interviews will be analyzed following a separate
qualitative analysis plan and presented in a separate Clinical Study Report (CSR).
11.4.4.
Interim Analyses
An interim analysis will be conducted when 50% of subjects complete 6 months of 
treatment to conduct a sample size re-estimation (refer to Section 11.2.3 for details). 
At this interim analysis the adherence data will be reviewed by an independent statistics 
and programming group independent of the study team. In order to minimise the 
introduction of any operational bias, good operating procedures will be built into an 
interim analysis charter which will detail who will access the data, rules for altering the 
sample size and the procedure to be followed when recommending the sample size 
alteration.  The unblinded interim analysis will be conducted by an internal statistics and 
programming group independent of the study team and reviewed by an independent 
interim analysis review committee who will notify of the sample size outcome after 50%
of subjects have completed the 6 month treatment period. 
This independent statistics and programming group will have access to unblinded data 
within a restricted and firewalled area to ensure the study team remain blind. 
Only the primary endpoint will be analysed at this stage to determine the conditional 
power of having success at the end of the trial given the interim results.
Further details of the internal statistics and programmer group role, data to be reviewed, 
committee membership, criteria, decisions and communication plan will be outlined 
clearly in the charter.
Recruitment will continue while the interim analysis is being conducted.


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12.
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Bone Metabolism in Asthma and Mild Chronic Obstructve Pulmonary Disease. Cochrane 
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13.
APPENDICES
13.1.
Appendix 1: Abbreviations
ACT
Asthma Control Test
ADR
Adverse Drug Reaction
AE
Adverse Event
ALT
Alanine amino transferase
ANCOVA
Analysis of Covariance
ASE
All Subjects Enrolled
ASUI
Asthma  Symptom Utility Index
ATS
American Thoracic Society
BMQ
Beliefs in Medicine Questionnaire
CE
Europen Conformity
CFR
Code of Federal Regulations
CI
Confidence Interval
CIOMS
Council for International Organizations of Medical Sciences
CIS
Connected Inhaler System
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic Obstructive Pulmonary Disease
CP
Conditional Power
CRF
Case Report Form
CSR
Clinical Study Report
CV
Cardiovascular
DPI
Dry Powder Inhaler
DRE
Disease Related Event
ER
Emergency Room
ERS
European Respiratory Society
EW
Early Withdrawal
EU-RMP
European Union – Risk Management Plan
FDA
Food And Drug Administration
FeNO
Fractional exhaled Nitric Oxide
FF
Fluticasone Furoate
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GSK
GlaxoSmithKline
HCP
Healthcare Professional
HCRU
Health Care Resource Utilization
HIPAA
Health Insurance Portability and Accountability Act
HPA
Hypothalamic-pituitary adrenal axis
HRT
Hormonal Replacement Therapy
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference On Harmonisation
ICS
Inhaled Corticosteroids
IEC
Independent Ethics Committees


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IP
Investigational Product
IRB
Institutional Review Boards
ITT
Intent-to-Treat
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IWRS
Interactive Web Response System
LABA
Long-Acting Beta2-Agonist
LOCS
Lens Opacities Classification System
MAR
Missing At Random
MARS-A
Medication Adherence Report Scale for Asthma
MDI
Metered Dose Inhaler
MedRA
Medical Dictionary of Regulatory Activities
MHPD
Marketed Health Products Directorate
MID
Minimally Important Difference
MSDS
Material Safety Data Sheet
PAM
Patient Activation Measure
PEF
Peak Expiratory Flow  
PIL
Patient Instruction Leaflet
PRO
Patient Reported Outcomes
RAP
Reporting Analysis Plan
SAE
Serious Adverse Event
SGRQ
St Georges Respiratory Questionnaire
SoA
Schedule of Activities
SRM
Study Reference Manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
UFIE
Unusual Failure in Efficacy
VI
Vilantrol
WOCP
Woman Of Childbearing Potential
13.2.
Appendix 2: Trademarks
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
BREO
Amiko and MDI Log
ELLIPTA
INCA Device
GSKDrug
MedDRA
RELVAR
RAMOS NG
Propeller
SmartTrack and SmartTouch


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13.3.
Appendix 3: Study Governance Considerations
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (e.g., advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study subjects. 

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 Code of Federal Regulations (CFR),, ICH guidelines, 
the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the subject or his/her legally authorized representative and answer all questions 
regarding the study. 


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
Subjects must be informed that their participation is voluntary. Subjects or their 
legally authorized representative will be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH 
guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was 
obtained before the subject 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.

Subjects 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 subject or the subject’s legally 
authorized representative. 

Subjects who are rescreened are required to sign a new ICF.
Data Protection

Subjects will be assigned a unique identifier by the sponsor. Any subject records 
or datasets that are transferred to the sponsor will contain the identifier only; 
subject names or any information which would make the participant identifiable 
will not be transferred. 

The subject 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 subject. 

The subject 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.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.


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Dissemination of Clinical Study Data
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.
Data Quality Assurance

All subject data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (eg, laboratory 
data). The investigator is responsible for verifying that data entries are accurate 
and correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of subjects are 
being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
Clinical Study Report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without 
written notification to the sponsor. 
Source Documents

Source documents provide evidence for the existence of the subject and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.


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
Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous
medical records or transfer records, depending on the study. Also, current 
medical records must be available.
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines
Inadequate recruitment of subjects by the investigator
Discontinuation of further study treatment development


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13.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
AE Definition
An AE is any untoward medical occurrence in a clinical study subject, temporally 
associated with the use of a study treatment, whether or not considered related to the 
study treatment.
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
Events Meeting the AE Definition 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator (ie, not related to progression of underlying 
disease).
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
New conditions detected or diagnosed after study treatment administration even though it 
may have been present before the start of the study.
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae.
"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfil the definition of an AE 
or SAE. 
The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfil the definition of an AE or SAE. Also, "lack of 
efficacy" or "failure of expected pharmacological action" constitutes an AE or SAE.
Events NOT Meeting the AE Definition 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition.


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The disease/disorder being studied or expected progression, signs, or symptoms of the
disease/disorder being studied, unless more severe than expected for the subject’s 
condition.
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads 
to the procedure is the AE.
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject 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 subject has been detained (usually involving 
at least an overnight stay) at the hospital or emergency ward for observation and/or 
treatment that would not have been appropriate in the physician’s office or outpatient 
setting. Complications that occur during hospitalization are AE. If a complication 
prolongs hospitalization or 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 disability/incapacity
The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions.
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (e.g., sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption.


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e.
Is a congenital anomaly/birth defect
f.
Other situations:
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:
Myocardial infarction/unstable angina
Congestive heart failure
Arrhythmias
Valvulopathy
Pulmonary hypertension
Cerebrovascular events/stroke and transient ischemic attack
Peripheral arterial thromboembolism
Deep venous thrombosis/pulmonary embolism

Revascularization
Recording AE and SAE
AE and SAE Recording
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) related 
to the event.
The investigator will then record all relevant AE/SAE information in the CRF.
It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK /AE/SAE CRF page.
There may be instances when copies of medical records for certain cases are requested by 


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GSK. In this case, all subject identifiers, with the exception of the subject number, will be 
redacted on the copies of the medical records before submission to GSK.
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 
Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not 
interfering with everyday activities.
Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities.
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating the 
intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality
The investigator is obligated to assess the relationship between study treatment and each
occurrence of each AE/SAE.
A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.
The investigator will use clinical judgment to determine the relationship.
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study treatment administration 
will be considered and investigated.
The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK. However, it is very important that 
the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to GSK.
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.


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The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
If a subject dies during participation in the study or during a recognized follow-up period, 
the investigator will provide GSK with a copy of any post-mortem findings including 
histopathology
New or updated information will be recorded in the originally completed CRF.
The investigator will submit any updated SAE data to GSK within 24 hours of receipt of 
the information.
Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool
The primary mechanism for reporting SAE to GSK will be the electronic data collection 
tool.
If the electronic system is unavailable for more than 24 hours, then the site will use the 
paper SAE data collection tool (see next section).
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
The investigator or medically-qualified sub-investigator must show evidence within the 
eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hours of SAE 
entry into the eCRF.
After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.
If a site receives a report of a new SAE from a study subject 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 SRM.


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SAE Reporting to GSK via Paper CRF
Scanned transmission of the SAE paper, by email of CRF is the preferred method to 
transmit this information to the medical monitor or the SAE coordinator.
In rare circumstances and in the absence of email, notification by telephone is acceptable 
with a copy of the SAE data collection tool sent by overnight mail or courier service.
Initial notification via telephone does not replace the need for the investigator to
complete and sign the SAE CRF pages within the designated reporting time frames.
Contacts for SAE reporting can be found in the SRM


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13.5.
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s: review of subject’s 
medical records, medical examination, or medical history interview.
3. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment.
Contraception Guidance
Female subjects
Female subjects of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 
3. 


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Table 3
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing ) hormonal contraception associated with 
inhibition of ovulationb

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulationb

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.)
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the subject.)
NOTES: 
a.
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for subjects in clinical studies. 
b.
Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of 
the contraceptive method. In this case two highly effective methods of contraception should be utilized during the 
treatment period and for at least 5 days after the last dose of study treatment 
Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine test
Additional pregnancy testing should be performed during the treatment period as 
decribed in the SOA  and a time (>5 days) corresponding to time needed to eliminate 
study treatment after the last dose of study treatment and as required locally 


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Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected 
Pregnancy testing, with a sensitivity of [5, 10, 25] mIU/mL will be performed using the 
test kit provided locally or by the sponsor and in accordance with instructions provided in 
its package insert  
Collection of Pregnancy Information
Female Subjects who become pregnant
Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study. 
Information will be recorded on the appropriate form and submitted to GSK within 2 
weeks of learning of a subject's pregnancy. 
Subject will be followed to determine the outcome of the pregnancy. The investigator 
will collect follow up information on subject and neonate, which will be forwarded to 
GSK Generally, follow-up will not be required for longer than 6 to 8 weeks beyond the 
estimated delivery date.  
Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or SAE. 
A spontaneous abortion is always considered to be an SAE and will be reported as such.  
Any SAE occurring as a result of a post-study pregnancy which is considered reasonably 
related to the study treatment by the investigator, will be reported to GSK as described in 
Appendix 4. While the investigator is not obligated to actively seek this information in 
former study subjects, he or she may learn of an SAE through spontaneous reporting. 
Any female subject who becomes pregnant while participating  
will discontinue study treatment or be withdrawn from the study


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13.6.
Appendix 6: Liver Safety: Required Actions, Follow-up 
Assessments
Phase III-IV liver chemistry stopping criteria and required follow up assessments 


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Liver Chemistry Stopping Criteria 
ALT-absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN  persists for 2 weeks
ALT 3xULN but <5xULN  persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot 
Monitor
ALT 5xULN but <8xULN and cannot be monitored weekly for 2 weeks
ALT 3xULN but <5xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to  liver injury or hypersensitivity
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Immediately discontinue  study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries 
resolve, stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge subject with 
study treatment 

Permanently discontinue study treatment and 
continue subject in the study for any protocol 
specified follow up assessments
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 
hrs

Viral hepatitis serology4

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Only in those with underlying chronic 
Hepatitis B at study entry (identified by 
positive Hepatitis B surface antigen) 
quantitative Hepatitis B DNA and Hepatitis 
delta antibody5.

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form
including acetaminophen, herbal 


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
Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 
recommended
For All other criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24-
72 hrs 

Monitor subjects weekly until liver 
chemistries resolve, stabilize or return to
within baseline
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form (CRF) 
page
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins.

Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver injury 
in subjects with definite or likely 
acetaminophen use in the preceding week
[James, 2009]). 

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if alanine aminotransferase (ALT) 3xULN 
and bilirubin 2xULN. Additionally, if serum bilirubin fractionation testing is unavailable, record presence of 
detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)   
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen (HbsAg) and Hepatitis B Core Antibody (IgM); 
Hepatitis C RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, 
obtain heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
5.
If Hepatitis delta antibody assay cannot be performed,, it can be replaced with a PCR of Hepatitis D RNA virus 
(where needed) [Le Gal, 2005] .


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13.7.
Appendix 7: Medical Device Incidents: Definition and 
Procedures for Recording, Evaluating, Follow-up, and 
Reporting
Definition and Documentation of Medical Device Incidents
Definitions of a Medical Device Incident
The detection and documentation procedures described in this protocol apply to all GSK 
medical devices provided for use in the study (see Section 7.3 for the list of GSK medical 
devices). 
Medical Device Incident Definition
A medical device incident is any malfunction or deterioration in the characteristics and/or 
performance of a device as well as any inadequacy in the labeling or the instructions for 
use which, directly or indirectly, might lead to or might have led to the death of a 
subject/user/other person or to a serious deterioration in his/her state of health.
Not all incidents lead to death or serious deterioration in health. The nonoccurrence of 
such a result might have been due to other fortunate circumstances or to the intervention 
of health care personnel.
It is sufficient that:

An incident associated with a device happened and

The incident was such that, if it occurred again, might lead to death or a serious 
deterioration in health.
A serious deterioration in state of health can include any of the following:

Life-threatening illness

Permanent impairment of body function or permanent damage to body structure

Condition necessitating medical or surgical intervention to prevent one of the 
above 

Fetal distress, fetal death, or any congenital abnormality or birth defects
Examples of incidents
A subject, user, caregiver, or healthcare professional is injured as a result of a medical 
device failure or its misuse.
A subject’s study treatment is interrupted or compromised by a medical device failure.
A misdiagnosis due to medical device failure leads to inappropriate treatment.
A subject’s health deteriorates due to medical device failure.


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Documenting Medical Device Incidents
Medical Device Incident Documenting
Any medical device incident occurring during the study will be documented in the 
subject’s medical records, in accordance with the investigator’s normal clinical practice, 
and on the appropriate form.
For incidents fulfilling the definition of an AE or an SAE, the appropriate AE/SAE CRF 
page will be completed as described in Appendix 4
The form will be completed as thoroughly as possible and signed by the investigator 
before transmittal to the GSK.
It is very important that the investigator provides his/her assessment of causality 
(relationship to the medical device provided by GSK) at the time of the initial report and 
describes any corrective or remedial actions taken to prevent recurrence of the incident.
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 an incident. This includes 
any amendment to the device design to prevent recurrence.


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13.8.
Appendix 8: Country-specific requirements
13.8.1.
Additional Adverse Event (AE) Reporting: Country-specific 
requirements for Canadian investigators:
The purpose of this information is  to comply with Health Canada guidelines. They state 
that all events associated with lack of efficacy of marketed investigational products must 
be documented and reported.
Health Canada requires pharmaceutical manufacturers to expeditiously report domestic 
cases of unusual failure in efficacy (UFIE) for new drugs to the Marketed Health 
Products Directorate (MHPD) within 15 days of first notification. This regulation applies 
to marketed drugs, and used as directed per the Canadian prescribing information, 
including those drugs used in Phase IV (non CTA filed) clinical trials.  
Adverse event (AE): Any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment. An AE can therefore be 
any unfavourable and unintended sign (including an abnormal laboratory finding) 
symptom or disease (new or exacerbated) temporally associated with the use of a 
Medicinal Product. For a marketed Medicinal Product, this can also include failure to 
produce expected benefits (i.e. lack of efficacy, with or without an adverse event), 
In order for GSK to comply this Canadian regulatory requirement, Canadian investigators 
are required to collect, record and report lack of efficacy events as per Table 4.
Table 4
Collection and Reporting of Adverse Events and Lack of Efficacy
Adverse 
Event 
criteria
Electronic case record 
form (eCRF) only
Paper form only
Electronic case 
record form 
(eCRF) + Paper 
form
Non serious 
Non drug related lack of 
efficacy reports with 
associated signs or 
symptoms or clinical 
sequelae 
Drug related lack of 
efficacy reports 
without associated 
signs or symptoms or 
clinical sequelae.
Drug related lack 
of efficacy with 
associated signs or 
symptoms or 
clinical sequelae  
Serious
Non drug related lack of 
efficacy reports with 
associated signs or 
symptoms or clinical 
sequelae 
Drug related lack of 
efficacy reports 
without associated 
signs or symptoms or 
clinical sequelae. 
Drug related lack 
of efficacy reports 
with associated 
signs or symptoms 
or clinical sequelae 


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The investigator will then record all relevant information regarding an AE/SAE in the 
electronic CRF “and/or paper form as applicable
For lack of efficacy reports the paper form will be used to submit to GSK as per Table 4.
All paper forms are required to be faxed to GSK Canada’s Drug Safety department 
at 
 within 24 hrs of first awareness.
PPD

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
207040
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan 207040 for an open label, 
randomised, parallel group clinical study to evaluate the
effect of the Connected Inhaler System (CIS) on adherence to 
Relvar/Breo ELLIPTA therapy, in asthmatic subjects with 
poor control.
Compound Number 
:
GW685698+GW642444 (GSK2285997)
Effective Date 
:
21-FEB-2019
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report (CSR) for Protocol 207040.

This RAP is intended to describe the study population, efficacy and safety analyses 
required for the study.

This RAP will be provided to the study team members to convey the content of the 
final Statistical Analysis Complete (SAC) deliverable.
RAP Author(s):
Author
Date
Lead
Principal Statistician (Respiratory, Biostatistics UK)
14 FEB 2019
Co-Authors
Associate Statistician, (Respiratory, Biostatistics India)
15 FEB 2019
Study Statistician (Respiratory, Biostatistics UK)
14 FEB 2019
Copyright 2019 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD
PPD


CONFIDENTIAL
The GlaxoSmithKline group of companies
207040
2
RAP Team Review Confirmations (Method E-mail):
Reviewer
Date
15 FEB 2019
Clinical Investigation Leader (Respiratory, Head Unit 
Physician, Clinical Development)
Clinical Development Director (Respiratory, Head Unit 
Physician, Clinical Pharmacology and Discovery Medicine)
15 FEB 2019
Project Statistician (Respiratory, Biostatistics UK)
15 FEB 2019
Lead Programmer (Respiratory, Biostatistics UK)
18 FEB 2019
Clinical Statistics and Clinical Programming Line Approvals
(Method: Pharma TMF eSignature):
Approver
Date
21 FEB 2019
Senior Statistics Director (Respiratory, Clinical Statistics)
21 FEB 2019
Programming Manager (Respiratory, Clinical Programming)
PPD
PPD
PPD
PPD
PPD
PPD


CONFIDENTIAL
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TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................8
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................8
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................8
2.2.
Study Objectives and Endpoints ...................................................................9
2.3.
Study Design ..............................................................................................12
2.4.
Statistical Hypothesis..................................................................................14
3.
PLANNED ANALYSES ..........................................................................................16
3.1.
Interim Analyses .........................................................................................16
3.2.
Final Analyses ............................................................................................16
4.
ANALYSIS POPULATIONS ...................................................................................17
4.1.
Protocol Deviations.....................................................................................17
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................18
5.1.
Study Treatment & Sub-group Display Descriptors.....................................18
5.2.
Baseline Definitions ....................................................................................19
5.3.
Multicentre Studies .....................................................................................20
5.4.
Examination of Covariates, Other Strata and Subgroups............................21
5.4.1.
Covariates and Other Strata ........................................................21
5.4.2.
Examination of Subgroups...........................................................21
5.5.
Multiple Comparisons and Multiplicity .........................................................21
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................22
6.
STUDY POPULATION ANALYSES .......................................................................23
6.1.
Overview of Planned Study Population Analyses........................................23
6.2.
Supplementary Information for Study Population Displays..........................23
6.2.1.
Disease and Baseline Characteristics..........................................23
6.2.2.
Preferred Time of Dosing.............................................................24
6.2.3.
Study Medication Exposure and Compliance...............................24
6.2.4.
HCP dashboard review................................................................24
7.
EFFICACY ANALYSES..........................................................................................25
7.1.
Primary Efficacy Analysis............................................................................25
7.1.1.
Endpoint ......................................................................................25
7.1.2.
Summary Measure ......................................................................25
7.1.3.
Population of Interest...................................................................25
7.1.4.
Strategy for Intercurrent (Post-Randomisation) Events ................26
7.1.4.1.
Events prior to premature discontinuation of 
the ELLIPTA maintenance sensor ..............................28
7.1.4.2.
Events following premature discontinuation of 
the ELLIPTA maintenance sensor ..............................28
7.1.5.
Statistical Analyses / Methods .....................................................28
7.1.5.1.
Statistical Methodology Specification..........................29
7.2.
Secondary Efficacy Analyses......................................................................31


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7.2.1.
ELLIPTA Adherence Measure Endpoints.....................................31
7.2.1.1.
Summary Measure .....................................................31
7.2.1.2.
Population of Interest..................................................32
7.2.1.3.
Strategy for Intercurrent (Post-Randomisation) 
Events ........................................................................32
7.2.1.3.1.
Events prior to premature 
discontinuation of the ELLIPTA 
maintenance sensor ...............................32
7.2.1.3.2.
Events following premature 
discontinuation of the ELLIPTA 
maintenance sensor ...............................32
7.2.1.4.
Statistical Analyses / Methods ....................................32
7.2.1.5.
Statistical Analyses / Methodology 
Specification...............................................................33
7.2.1.5.1.
The percentage of ELLIPTA doses 
taken (daily adherence) between 
the beginning of Month 4 and the 
end of Month 6........................................33
7.2.1.5.2.
The percentage of ELLIPTA doses 
taken (daily adherence) between 
the beginning of Month 1 and the 
end of Month 6........................................35
7.2.1.5.3.
The percentage of ELLIPTA doses 
taken (daily adherence) between 
the beginning of Month 1 and the 
end of Month 3........................................37
7.2.2.
MDI Rescue Medication Use Endpoints.......................................39
7.2.2.1.
Summary Measure .....................................................39
7.2.2.2.
Population of Interest..................................................39
7.2.2.3.
Strategy for Intercurrent (Post-Randomisation) 
Events ........................................................................40
7.2.2.3.1.
Events following premature 
discontinuation of the MDI sensor...........42
7.2.2.4.
Statistical Analyses / Methods ....................................42
7.2.2.5.
Statistical Analyses / Methodology 
Specification...............................................................42
7.2.3.
Asthma Control Endpoints ...........................................................44
7.2.3.1.
Summary Measure .....................................................44
7.2.3.2.
Population of Interest..................................................45
7.2.3.3.
Strategy for Intercurrent (Post-Randomisation) 
Events ........................................................................45
7.2.3.3.1.
Change from baseline 
(Randomisation) in ACT total 
score at Month 6 (Visit 10)......................45
7.2.3.3.2.
Percentage of patients becoming 
controlled as defined as an 
Asthma Control Test score ≥20 at 
Month 6 (Visit 10) ...................................45
7.2.3.3.3.
Percentage of patients with an 
increase from baseline ≥ 3 in ACT 
total score at Month 6 (Visit 10) ..............46


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7.2.3.3.4.
Percentage of patients who have 
either an ACT total score of ≥ 20 
and/or an increase from baseline 
of ≥ 3 in ACT total score at Month 
6 (Visit 10) ..............................................46
7.2.3.4.
Statistical Analyses / Methodology 
Specification...............................................................46
7.2.3.4.1.
Change from baseline in ACT total 
score at month 6.....................................47
7.2.3.4.2.
ACT total score ≥20 at month 6 ..............47
7.2.3.4.3.
Increase from Baseline of ≥ 3 in 
ACT total score at month 6 .....................48
7.2.3.4.4.
ACT total score of ≥ 20 and/or an 
increase from baseline of ≥ 3 in 
ACT total score at Month 6 (Visit 
10)..........................................................49
7.3.
Exploratory and Other Analyses .................................................................49
7.3.1.
Exploratory ELLIPTA Adherence Measure Analyses ...................50
7.3.1.1.
Endpoint.....................................................................50
7.3.1.2.
Summary Measure .....................................................50
7.3.1.3.
Population of Interest..................................................50
7.3.1.4.
Strategy for Intercurrent (Post-Randomisation) 
Events ........................................................................50
7.3.1.4.1.
Events prior to premature 
discontinuation of the ELLIPTA 
maintenance sensor ...............................51
7.3.1.4.2.
Events following premature 
discontinuation of the ELLIPTA 
maintenance sensor ...............................51
7.3.1.5.
Statistical Analyses / Methods ....................................51
7.3.1.6.
Statistical Analyses / Methodology 
Specification...............................................................52
7.3.1.6.1.
The percentage of ELLIPTA doses 
taken (daily adherence) between 
the beginning of Month 4 and the 
end of Month 6........................................52
7.3.2.
Exploratory Health Care Utilization Analyses ...............................54
7.3.2.1.
Endpoints ...................................................................54
7.3.2.2.
Population of Interest..................................................54
7.3.3.
Exploratory Patient Reported Outcomes (PROs) Analyses..........55
7.3.3.1.
Endpoints ...................................................................55
7.3.3.2.
Summary Measure .....................................................56
7.3.3.3.
Population of Interest..................................................56
7.3.3.4.
Strategy for Intercurrent (Post-Randomisation) 
Events ........................................................................56
7.3.3.4.1.
Percentage of patients meeting a 
responder threshold of ≥ 0.09 
points improvement from baseline 
(randomisation) for the ASUI total 
score at Month 6 (Visit 10)......................57


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7.3.3.4.2.
Change from baseline 
(randomisation) in ASUI total 
score at month 6 (Visit 10)......................57
7.3.3.4.3.
Percentage of patients meeting a 
responder threshold of ≥ 4 points 
improvement (decrease) from 
baseline (randomisation) for the 
SGRQ total score at month 6 (Visit 
10)..........................................................57
7.3.3.4.4.
Change from baseline 
(Randomisation) in SGRQ total 
score at Month 6 (Visit 10)......................58
7.3.3.4.5.
Change from baseline (Screening) 
in PAM-13, MARS-A, and BMQ 
total score at Month 6 (Visit 10) ..............58
7.3.3.5.
Statistical Analyses / Methodology 
Specification...............................................................58
7.3.3.5.1.
Increase from Baseline of ≥ 0.09
in ASUI total score at Month 6 
(Visit 10) .................................................58
7.3.3.5.2.
Change from baseline 
(Randomisation) in ASUI total 
score at Month 6 (Visit 10)......................59
7.3.3.5.3.
Increase from Baseline of ≥ 4 in
SGRQ total score at Month 6 (Visit 
10)..........................................................60
7.3.3.5.4.
Change from baseline 
(Randomisation) in SGRQ total 
score at Month 6 (Visit 10)......................60
7.3.4.
Exploratory Fractionated Exhaled Nitric Oxide (FeNO) and 
Peak Expiratory Flow (PEF) Analyses .........................................61
7.3.4.1.
Endpoints ...................................................................61
7.3.4.2.
Summary Measures ...................................................61
7.3.4.3.
Population of Interest..................................................62
7.3.4.4.
Strategy for Intercurrent (Post-Randomisation) 
Events ........................................................................62
7.3.4.5.
Statistical Analyses / Methodology 
Specification...............................................................62
7.3.5.
Qualitative data from exit interviews.............................................63
8.
SAFETY ANALYSES .............................................................................................64
8.1.
Adverse Events Analyses ...........................................................................64
8.2.
Adverse Events of Special Interest .............................................................64
8.3.
Pregnancy ..................................................................................................65
8.4.
Other Safety Measures...............................................................................65
9.
REFERENCES.......................................................................................................66
10. APPENDICES........................................................................................................67
10.1.
Appendix 1: Schedule of Activities ..............................................................67
10.1.1.
Protocol Defined Schedule of Events...........................................67
10.2.
Appendix 2: Assessment Windows .............................................................71


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10.2.1.
General........................................................................................71
10.2.2.
Definitions of Assessment Windows for Adherence and 
Rescue Medication Use Analyses................................................71
10.3.
Appendix 3: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................73
10.3.1.
Study Phases ..............................................................................73
10.3.1.1.
Study Phases for Concomitant Medication .................73
10.3.1.2.
Study Phases for Asthma Exacerbations....................73
10.3.1.3.
Treatment Emergent Flag for Adverse Events............74
10.4.
Appendix 4: Data Display Standards & Handling Conventions....................75
10.4.1.
Reporting Process .......................................................................75
10.4.2.
Reporting Standards....................................................................75
10.5.
Appendix 5: Derived and Transformed Data ...............................................77
10.5.1.
General........................................................................................77
10.5.2.
Study Population..........................................................................77
10.5.3.
Efficacy........................................................................................79
10.5.3.1.
ELLIPTA Device Sensor Assessments.......................79
10.5.3.2.
MDI Device Sensor Assessments...............................88
10.5.3.3.
Patient Reported Outcomes .......................................96
10.5.4.
Safety ........................................................................................100
10.6.
Appendix 6: Reporting Standards for Missing Data...................................101
10.6.1.
Premature Withdrawals..............................................................101
10.6.2.
Handling of Missing Data...........................................................101
10.6.3.
Handling of Partial Dates ...........................................................101
10.7.
Appendix 7: Abbreviations & Trade Marks ................................................103
10.7.1.
Abbreviations.............................................................................103
10.7.2.
Trademarks ...............................................................................104
10.8.
Appendix 8: List of Data Displays .............................................................105
10.8.1.
Data Display Numbering............................................................105
10.8.2.
Mock Example Shell Referencing ..............................................105
10.8.3.
Deliverables...............................................................................105
10.8.4.
Study Population Tables............................................................106
10.8.5.
Study Population Figures...........................................................112
10.8.6.
Efficacy Tables ..........................................................................112
10.8.7.
Efficacy Figures .........................................................................119
10.8.8.
Safety Tables.............................................................................126
10.8.9.
ICH Listings ...............................................................................133
10.8.10. Non-ICH Listings........................................................................135
10.9.
Appendix 9: Example Mock Shells for Data Displays ................................138


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1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report (CSR) for Protocol 207040 [GlaxoSmithKline 
Document Number: 2016N307903_01 (Dated: 10SEP2018)].
Revision Chronology:
2016N307903_00
22-JUN-2017
Original
2016N307903_01
10-SEP-2018
Amendment 1
All data displays (Tables, Figures & Listings) will use the term “Subject” which reflects 
CDISC and GSK Data Display Standards terminology.
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Changes from the planned statistical analysis specified in protocol amendment 1 are 
outlined in Table 1.
Table 1
Changes to Protocol Defined Analysis Plan
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes
Duration of run-in included in 
analysis models as a continuous 
covariate, measured in days.
Duration of run-in included in 
analysis models as a categorical 
covariate of number of visits.
Participants can complete the 
run-in period in 1, 2 or 3 visits, 
use of a categorical covariate is 
more flexible than the 
assumption of a linear 
relationship.
Missing data due to a medical device 
incident will be assumed to be 
missing at random within the last 3 
months treatment period.
Missing data due to a medical 
device incident will be assumed 
to be missing at random within 
each month of the treatment 
period.
Monthly adherence rates are 
used within the imputation
model to allow for variation in 
adherence over time. 
Participants who prematurely 
discontinue from study will have their 
post-withdrawal daily adherence data 
imputed using data from the control 
arm
Participants who prematurely 
discontinue from use of the 
ELLIPTA maintenance sensor
will have subsequent adherence 
data imputed using data from 
the control arm
The ELLIPTA maintenance 
sensor may be discontinued 
without withdrawal from the 
study
Protocol Section 11.3 Populations for 
Analyses
RAP Section 4 Analysis 
Populations
The analysis populations have 
been updated to follow the study 
populations standard definitions 
and statistical displays


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Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes
Mean change from baseline 
(Randomisation) in ASUI and 
SGRQ total score at Month 6 
included in the RAP as an 
additional endpoint
To support the exploratory 
summaries and analyses for 
ASUI and SGRQ continuous 
endpoint
Composite endpoint - Percentage of 
patients who have either an ACT 
total score of ≥ 20 or an increase 
from baseline of ≥ 3 in ACT total 
score at Month 6 (Visit 10).
Composite endpoint -
Percentage of patients who 
have either an ACT total score 
of ≥ 20 and/or an increase from 
baseline of ≥ 3 in ACT total 
score at Month 6 (Visit 10).
The condition ‘and/or’ will be 
applied to the composite ACT 
endpoint to replace ‘or’ to clarify 
that participants who achieve 
both an ACT total score of ≥ 20 
and an increase from baseline 
of ≥ 3 in ACT total score at 
Month 6, in addition to those 
who only achieve one, will be 
considered a responder.
Change from baseline (Visit 2, 3 
or 4) in FeNO measured at 
Month 1 (Visit 5) and Month 6 
(Visit 10)
To support the exploratory 
summary of impact of 
adherence on the biomarker 
Fractionated Exhaled Nitric 
Oxide (FeNO)
2.2.
Study Objectives and Endpoints
Objectives
Endpoints
Primary Objectives
Primary Endpoints
To compare the effect of 6 months use of 
the CIS on adherence to ELLIPTA 
maintenance therapy when both the 
participant and the HCP are supplied with 
data from the maintenance sensor versus 
no data supplied to the participant and 
HCP (Arm 1 vs Arm 5)
Percentage of ELLIPTA doses taken (daily adherence1.) 
between the beginning of month 4 and the end of month 6 as 
determined by the maintenance sensor 
Secondary Objectives
Secondary Endpoints
To compare the effect of 6 months use of 
the CIS on adherence to ELLIPTA 
maintenance therapy for the following 
aspects of the CIS:

Maintenance data only supplied to 
participants versus no data supplied 
to the participant (Arm 2 vs Arm 5)

Rescue and Maintenance data 
supplied to participant and HCP 
versus no data supplied to the 
participant and HCP (Arm 3 vs Arm 5)

Rescue and Maintenance data only 
supplied to participant versus no data 
supplied to the participant (Arm 4 vs 

Percentage of ELLIPTA doses taken (daily adherence1.) 
between the beginning of month 4 and the end of month 6 
as determined by the maintenance sensor 


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Objectives
Endpoints
Arm 5)
To compare the effect of the CIS on 
adherence to ELLIPTA maintenance 
therapy of the individual CIS treatment 
arms versus no data supplied to the 
participant and HCP.

Percentage of ELLIPTA doses taken (daily adherence1.) 
between the beginning of month 1 and the end of month 3 

Percentage of ELLIPTA doses taken (daily adherence) 
between the beginning of month 1 and the end of month 6
To evaluate the effect of 6 months use of 
the CIS on a participant’s rescue medicine 
usage 

Percentage of rescue free days measured between the 
beginning of month 4 and the end of month 6 as 
determined by the rescue sensor records of date, time, 
and number of inhaler actuations. 

Total rescue use measured between the beginning of 
month 4 and the end of month 6 as determined by the 
rescue sensor records of date, time, and number of 
inhaler actuations.
To evaluate the effect of 6 months use 
with the CIS on a participant’s asthma 
control 

Change from baseline (Randomisation) in ACT total score 
at Month 6, measured at baseline (Visit 2, 3 or 4) and 
Month 6 (Visit 10)

Percentage of patients becoming controlled as defined as 
an Asthma Control Test score ≥20 at Month 6 (Visit 10)

Percentage of patients with an increase from baseline ≥ 3 
in ACT total score at Month 6 (Visit 10)

Composite endpoint - Percentage of patients who have 
either an ACT total score of ≥ 20 and/or an increase from 
baseline of ≥ 3 in ACT total score at Month 6 (Visit 10).
Exploratory and Other Objectives
Exploratory Endpoints
To evaluate the effect of 6 months use of 
the CIS on adherence to ELLIPTA 
maintenance therapy on the following 
aspects of the CIS:

HCP having access to sensor data

Rescue Medication data being 
available

Percentage of ELLIPTA doses taken (daily adherence) 
between the beginning of month 4 and the end of month 6 
as determined by the maintenance sensor 

To evaluate the effect of 6 months use 
with CIS on health care utilisation 

Health care utilisation endpoints will include the following 
and will be collected from a participant’s medical 
records. 

Number of outpatient visits relating to asthma

Number of primary care visits relating to study HCP 
dashboard review (for relevant study arms)

Number of and duration of hospitalisations, and ER 
visits due to asthma

Annualised rate of severe exacerbations

Number of unscheduled visits to primary care related 
to Asthma
To evaluate the effect of 6 months use 
with CIS on the following patient reported 

Percentage of patients meeting a responder threshold of 
≥ 0.09 points improvement from baseline 


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Objectives
Endpoints
outcomes (PROs):

Asthma Symptom Utility Index 
(ASUI)

St Georges Respiratory 
Questionnaire (SGRQ)

Patient Activation Measure (PAM)

Medication Adherence Report 
Scale for Asthma (MARS-A)

Beliefs in Medicine Questionnaire 
(BMQ).
(Randomisation) for the ASUI total score at Month 6

Mean change from baseline (Randomisation) in ASUI
total score at Month 6 

Percentage of patients meeting a responder threshold of 
≥ 4 points improvement from baseline (Randomisation) 
for the SGRQ total score at Month 6

Mean change from baseline (Randomisation) in SGRQ
total score at Month 6 

Mean change from baseline (Screening) in PAM total 
score at Month 6 

Mean change from baseline (Screening) in MARS-A total 
score at Month 6 

Mean change from baseline (Screening) at Month 6 in 
BMQ:
o
General Benefit score
o
General Harm score
o
General Overuse score
o
Specific Necessity score
o
Specific Concern score

To assess the reliability and usability 
of the CIS

Incidence of Medical Device Incidents between the 
beginning of Month 1 and the end of Month 6.

To explore impact of adherence on 
the biomarker Fractionated Exhaled
Nitric Oxide (FeNO)

FeNO at Screening (Visit 1), Randomisation (Visit 2,3 or 
4), Month 1 (Visit 5) and Month 6 (Visit 10).

Change from baseline (Visit 2, 3 or 4) in FeNO measured 
at Month 1 (Visit 5) and Month 6 (Visit 10)

To explore impact of adherence on 
the physiological marker Peak 
Expiratory Flow (PEF) 

PEF at Screening (Visit 1), Randomisation (Visit 2,3 or 4), 
Month 1 (Visit 5) and Month 6 (Visit 10).

Change from baseline (Visit 2, 3 or 4) in PEF measured 
at Month 1 (Visit 5) and Month 6 (Visit 10)

To characterize patient experience of 
the CIS for participants

Exit Questionnaires at Month 6 (Visit 10) 

Exit Interviews for a sub set of participants at Month 6 
(Visit 10)
Safety Objectives
Safety Endpoints
To evaluate the incidence of SAEs, Non-
Serious Adverse Events that lead to 
withdrawal from study and Non-Serious
Adverse Drug Reactions in asthmatic 
participants using the CIS

SAEs, Non-Serious Adverse Events that lead to 
withdrawal and Non-Serious Adverse Drug Reactions 
1.
Daily adherence is defined as the participant taking one dose of Relvar/Breo ELLIPTA, within a 24-hour
period, starting at 12.00am each day


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2.3.
Study Design
Overview of Study Design and Key Features
Design Features
This is an open-label, randomised, multi-centre, parallel group study consisting of 5 treatment arms, in asthmatic patients currently on a 
fixed dose Inhaled Corticosteroids (ICS)/ Long-Acting Beta2-Agonist (LABA) maintenance therapy.
Further details of the study design can be found in Section 5 (Study Design) of the 207040 protocol 


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Overview of Study Design and Key Features
[GlaxoSmithKline Document Number 2016N307903_01].
Time & Events
Refer to Appendix 1: Schedule of Activities
Treatment 
Assignment
All randomised participants will receive Relvar/Breo ELLIPTA, at the dose allocated at the run in. Salbutamol Metered Dose Inhaler (MDI)
rescue medication will be prescribed to participants to use as needed throughout the study for relief of asthma symptoms as per usual 
practice
All participants will have sensors attached to both their Relvar/Breo ELLIPTA and salbutamol MDI. It is the type of data provided by the CIS
(either Relvar/Breo ELLIPTA alone or Relvar/Breo ELLIPTA and salbutamol MDI), as well as who sees that data, (participant alone or 
participant and HCP), that defines the treatment arms.
Participants will be randomized 1:1:1:1:1 to one of the five treatments arms for the duration of the treatment period:

Arm 1: Data on Maintenance use supplied to Participant (app) and HCP (dashboard)

Arm 2: Data on Maintenance use supplied to Participant (app)

Arm 3: Data on Maintenance and Rescue use supplied to Participant (app) and HCP (dashboard)

Arm 4: Data on Maintenance and Rescue use supplied to Participant (app)

Arm 5: No data supplied to Participant or HCP
The treatment period for the study is 6 months. However, due to the flexible run in period a participant could be on the study for 
approximately 7, 8 or 9 months in total.  
GSK RandAll NG will be used to generate the randomisation schedule. Centralized randomisation will be used. GSK RAMOS NG will be 
used for treatment allocation.


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2.4.
Statistical Hypothesis
The main purpose of the study is to compare the effect of 6 months use with the 
Connected Inhaler System (CIS) on adherence to Relvar/Breo ELLIPTA maintenance 
therapy with adherence to Relvar/Breo ELLIPTA maintenance therapy without CIS use 
(sensor alone), in participants with poorly controlled asthma. 
All participants receive Relvar/Breo ELLIPTA, either at the dose they are already 
prescribed or at the equivalent dose to their current ICS/LABA maintenance therapy if 
switched onto Relvar/Breo ELLIPTA at enrolment.  All participants will have sensors 
attached to both their Relvar/Breo ELLIPTA and Salbutamol MDI. It is the type of data 
provided by the CIS (either Relvar/Breo ELLIPTA alone or Relvar/Breo ELLIPTA and 
salbutamol MDI), as well as who sees that data (participant alone or participant and HCP) 
that defines the treatment arms.
This study aims to demonstrate the superiority of the CIS on adherence to Relvar/Breo 
ELLIPTA with an app compared to Relvar/Breo ELLIPTA (with sensor alone).  
The primary endpoint is mean percentage of ELLIPTA doses taken (daily adherence) 
between Months 4 and 6 as determined by the maintenance sensor daily adherence over 
the last three months of the study period (between months 4 to 6).  
The test for the primary treatment comparison will be a test between Arm 1 versus Arm 
5.  This will be based on a two-sided hypothesis testing approach: the null hypothesis is 
the difference between Arm 1 and Arm 5 is equal to zero. The alternative hypothesis is 
that the difference is not equal to zero.  The hypotheses associated with the statistical test 
of the primary endpoint are written below:
H0: Ti – Tj = 0
(where i = Arm 1 and j = Arm 5) The null hypothesis: that the difference in response 
between Arm 1 and Arm 5 is zero.
Ha: Ti – Tj 0
The alternative hypothesis: that the difference is not zero.
Other comparisons of interest for the primary endpoint are the individual comparisons of 
Arms 2, 3 and 4 with Arm 5 in order to obtain estimated mean treatment differences, 95% 
confidence intervals (CIs) and p-values. This will be a descriptive comparison to inform 
on the relative benefits of the individual aspects of the CIS and no formal inference is 
planned.
The effect on adherence to maintenance therapy between arms with HCP and no HCP 
interaction i.e. Arm 1 v Arm 2 and Arm 3 v Arm 4, and arms with rescue medication use 
feedback versus none i.e. Arm 1 v Arm 3 and Arm 2 v Arm 4, will be also assessed.
The comparisons of interest for the other secondary and safety endpoints are as stated 
above for the primary endpoint.  Arms 1, 2, 3 and 4 will be individually compared to Arm 


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5, as relevant to the endpoint, to obtain estimated mean treatment differences, 95% 
confidence intervals and p-values. This will be a descriptive comparison and no formal 
inference is planned.


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3.
PLANNED ANALYSES
To minimize the risk of breaking the study blind during the pre-programming of analysis 
datasets and displays for the final analyses, an unblinded team of programmers will 
scramble the data in a secure area according to a pre-defined blinding strategy, before 
releasing to Clinical Statistics and Programming (S&P).
3.1.
Interim Analyses
An interim analysis was originally planned to be conducted when 50% of subjects 
complete 6 months of study treatment in order to conduct a sample size re-estimation. 
However the requirement for the interim analysis and sample size-re-estimation was 
decided no longer necessary and removed from the study protocol.
3.2.
Final Analyses
The final planned analyses will be performed after the completion of the following 
sequential steps:
1.
All participants have completed the study or have been withdrawn as defined in the 
protocol. 
2.
All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data Management
(DM).
3.
System Independent (SI) data to Study Data Tabulation Model (SDTM) data 
conversion has completed by Conversion Service Provider at Source Data Lock 
(SDL).
4.
All criteria for unblinding the randomisation codes have been met. 
5.
Randomisation codes have been distributed according to RandAll NG procedures.
Release of randomisation code, unblinding of study treatment and participant level 
treatment of SDTM data, and related quality control activities have been completed 
by S&P.
6.
DBF on SDTM datasets has been declared by DM upon receipt of the final, 
treatment unblinded SDTM data from S&P. 


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4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
All participants

All participants who signed the ICF
Study Population
Screened 

All participants who were screened for eligibility.
Study Population
Enrolled

All participants who passed screening and entered the 
study. Included are: Run-in Failures; Randomized 
Participants
Note screening failures are excluded from the Enrolled 
population as they did not enter the study.
Study Population
Safety
Randomized 

All participants who were randomly assigned to a
treatment arm in the study.

This population will be based on the treatment arm the 
participant was randomised to.
Study Population
Intent-To-Treat 
(ITT)

The ITT population comprises all randomised 
participants, excluding those who were randomised in 
error.  A participant who is recorded as a screen or run-
in failure but is randomised, and does not receive a 
dose of study treatment, is considered to have been 
randomised in error.  Any other participant who received 
a randomisation number will be considered to have 
been randomised.

This population will be based on the treatment arm the 
participant was randomised to.
Study Population
Efficacy (ELLIPTA 
Adherence, Rescue
Medications Use, PRO, 
PEF and FeNO)
Safety
Refer to Section 10.8 Appendix 8: List of Data Displays which will detail the population used for each display.
4.1.
Protocol Deviations
This dataset will be the basis for the summaries and listings of protocol deviations.  A 
separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion 
page of the eCRF.


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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
Relvar/Breo ELLIPTA 
Sensor Data 
Available to
Salbutamol/Rescue
MDI Sensor Data 
Available to
RandAll NG Randomisation System
Data Displays for Reporting
Arm
Participant
HCP
Participant
HCP
Code
Description
Full Description
Short 
Description
Order
in 
Table, 
List, 
Figure 
(TLF)
1
X
X
1
Data on Maintenance use supplied to Participant
(app) and HCP (dashboard)
Arm 1: Maintenance use data supplied to 
Participant and HCP
Arm 1
1
2
X
2
Data on Maintenance use supplied to Participant
(app)
Arm 2: Maintenance use data supplied to 
Participant
Arm 2
2
3
X
X
X
X
3
Data on Maintenance and Rescue use supplied 
to Participant (app) and HCP (dashboard)
Arm 3: Maintenance and Rescue use data 
supplied to Participant and HCP
Arm 3
3
4
X
X
4
Data on Maintenance and Rescue use supplied 
to Participant (app)
Arm 4: Maintenance and Rescue use data 
supplied to Participant
Arm 4
4
5
5
No data supplied to Participant or HCP
Arm 5: No data supplied to Participant or 
HCP
Arm 5
5
Arm 1: Maintenance use data supplied to Participant and HCP, Arm 2: Maintenance use data supplied to Participant, Arm 3: Maintenance 
and Rescue use data supplied to Participant and HCP, Arm 4: Maintenance and Rescue use data supplied to Participant, Arm 5: No data 
supplied to Participant or HCP.


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All participants will have sensors attached to both their Relvar/Breo ELLIPTA and 
Salbutamol (albuterol) MDI. It is the type of data provided by the CIS (either 
Relvar/Breo ELLIPTA alone or Relvar/Breo ELLIPTA and salbutamol MDI), as well as 
who sees that data (participant alone or participant and HCP) that defines the treatment 
arms. See Section 5.1 Study Treatment & Sub-group Display Descriptors for a 
description of what data is fed back to whom for each treatment arm, and the treatment 
group descriptors. 
Where possible the full description will be used in data displays. If it is necessary to use 
the short description, for example in figure legends, the footnote shown under the table in 
Section 5.1 Study Treatment & Sub-group Display Descriptors will be included. Where 
treatment comparisons are included in a data display and the full treatment descriptions 
do not also appear within the display, the same footnote will be included.
5.2.
Baseline Definitions
Baseline adherence will be the percentage of ELLIPTA doses taken (daily adherence) 
during the last 28 days of the run-in period prior to randomisation. This will be 
determined using the randomisation date.  A minimum of 14 run-in days prior to 
randomisation will be required to determine baseline adherence otherwise it will be set to 
missing.  Any missing intermittent daily adherence data will be imputed as non-adherent 
i.e. the participant will be assumed to have not taken their treatment within the 24-hour
time period/window, where there is no evidence of a medical device incident having 
occurred. Missing data due to a medical device incident such as,

device failure

technical failure of the ELLIPTA maintenance sensor

data transmission failure,
will be assumed to be missing at random (MAR). For each participant the baseline 
percentage adherence measure will be calculated as the number of days a participant is 
adherent divided by the number of days without medical device incident within the 
baseline assessment period * 100. See Section 10.2.2 Definitions of Assessment 
Windows for Adherence and Rescue Medication Use Analyses, for the definition of the 
baseline assessment period.
Baseline rescue free days will be the percentage rescue free days (RFDs) during the last 
28 days of the run-in period prior to randomisation.  This baseline will be determined in 
the same manner as the adherence baseline.
Where baseline assessments are determined from the randomisation visit, no unscheduled 
assessments will be considered as the baseline value.
Where baseline assessments are determined from the screening visit, Visit 1 will be used 
and no unscheduled screening visits will be considered as the baseline value.
If time is not collected, Day 1 assessments are assumed to be taken prior to first dose and 
used as baseline.


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Parameter
Study Assessments Considered as Baseline
Baseline Used in Data 
Display
Visit 1 
Screening
Study Days
-28 to -1
Randomisation 
Visit, Study Day 
1 (Pre-Dose)
Efficacy
ELLIPTA Adherence
Endpoints (%)
x
% adherence from Day -28 
to Day -1 
Rescue Free Days
(RFDs) (%)
x
% RFDs from Day -28 to 
Day -1 
Total Rescue Use
(TRU) (puffs)
x
Total use from Day -28 to 
Day -1
ACT Total score
x
Randomisation
SGRQ Total score
x
Randomisation
ASUI Total score
x
Randomisation
PAM-13 Total score
x
Screening
BMQ Total score
x
Screening
MARS-A Total score
x
Screening
PEF (litres/minute)
x
Randomisation - use 
maximum value at visit
FeNO (parts per billion)
x
Randomisation -  use 
maximum value at visit
Notes:

Day 1 is referenced as Day 0 (Randomisation visit at either Visit 2 or 3 or 4) in Section 2.3 and Section 10.1
Appendix 1: Schedule of Activities but will be reported as Day 1 per Clinical Data Interchange Standards 
Consortium (CDISC) reporting guidelines. 

Unless otherwise stated, if the baseline for an endpoint is missing it will not be imputed using a different timepoint 
or derivation but will remain missing.
5.3.
Multicentre Studies
It is likely that many centres will enrol very small number of participants. Consequently, 
all centres within the same country will be pooled. In addition, if there are any countries 
enrolling very small numbers in total (<12 in the Intent to Treat population), these 
countries will be pooled with another country within a similar geographical region. All 
amalgamations will be finalised and documented prior to unblinding the treatment arm
codes. These amalgamations will be used wherever region is incorporated into an
analysis or summary.
In this multicentre global study, enrolment will be presented by centre, country and 
region (if required).


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5.4.
Examination of Covariates, Other Strata and Subgroups
5.4.1.
Covariates and Other Strata
Unless otherwise stated, all models used for adherence and rescue free days will allow for 
fixed effects due to randomised treatment arm, baseline (of the analysis variable), 
duration of run-in (visits), country, gender, and age (years - determined from screening 
date).  Randomised treatment arm, duration of run-in, country, and gender will be 
included as categorical covariates; baseline and age will be included as continuous 
covariates.
The covariates to be considered in the patient reported outcomes (PRO) analyses include
randomised treatment arm, age (years - determined from screening date), gender, country 
and baseline (of the analysis variable), if relevant.
The covariate region will replace country should amalgamation of countries, as described 
in Section 5.3 Multicentre Studies, be required.
The list of covariates and other strata may be used in descriptive summaries and 
statistical analyses, some of which may also be used for subgroup analyses. 
5.4.2.
Examination of Subgroups
The following outcomes will be summarized by randomised treatment arm within 
subgroups defined by country.

Enrollment

Demographic characteristics

Ellipta adherence
For these summaries, subgroups will be defined as in Table 2.
Table 2
Category
Subgroups
Country

US, Canada, Germany, Italy, Netherlands, 
Spain, UK
Baseline ACT total score

<=15, 16 - 19
Age (years – as determine from screening date)

18-35, 36-48, 49-58, >58 years
Notes: Details of the planned summaries are presented in Section 10.8 Appendix 8: List of Data Displays
5.5.
Multiple Comparisons and Multiplicity
No adjustments for multiplicity will be applied. 


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5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
10.1
Appendix 1: Schedule of Activities
10.2
Appendix 2: Assessment Windows
10.3
Appendix 3: Study Phases and Treatment Emergent Adverse Events
10.4
Appendix 4: Data Display Standards & Handling Conventions
10.5
Appendix 5: Derived and Transformed Data
10.6
Appendix 6: Reporting Standards for Missing Data
10.7
Appendix 7: Abbreviations & Trade Marks
10.8
Appendix 8: List of Data Displays


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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
Study population summaries will be based on the ITT population, unless otherwise 
specified.
Study population displays including summaries and lists of study populations, screening
and run-in status, participant study and study drug disposition, participant enrolment, 
inclusion and exclusion and important protocol deviations, demographic, age, race and 
baseline characteristics (including height, weight and BMI), medical conditions, family 
and smoking history and prior and concomitant medications will be based on GSK Core 
Data Standards.  Details of the planned displays are presented in Section 10.8 Appendix 
8: List of Data Displays.
Concomitant medications will be coded using the GSK Drug coding dictionary. 
Summaries of the number and percentage of participants taking concomitant medications 
will be displayed by ingredient without regard to Anatomical Therapeutical Chemical 
(ATC) classifications. These summaries will include single-ingredient medications and 
will present multi-ingredient medications according to the combination of the component 
ingredients. Summaries will be split into asthma and non-asthma concomitant 
medications, as well as into those taken pre-screening, during run-in, whilst on-treatment
and post-treatment (as described in Section 10.3.1 Study Phases).
Asthma maintenance concomitant medications taken by participants in the 12 months 
prior to screening (pre-screening) will also be summarised as well as those used to treat 
severe exacerbations experienced whilst on study.
6.2.
Supplementary Information for Study Population Displays
6.2.1.
Disease and Baseline Characteristics
Summary of attendance at each scheduled clinic visit will be presented.
Summaries and lists of the Relvar/Breo ELLIPTA and Salbutamol MDI sensor statuses as 
well as the App status during the study will be presented.  
Asthma exacerbation history (12-month history) at screening will be summarised with 
frequency distributions of the number of exacerbations treated with oral/systemic 
corticosteroids not involving hospitalization; the number of exacerbations treated without 
oral/systemic corticosteroids not involving hospitalization; the number of exacerbations 
requiring hospitalization; and the total number of exacerbations (i.e., those not involving 
hospitalization and those involving hospitalization). 
Asthma duration will also be summarised.
The screening and baseline lung function test and exhaled nitric oxide summaries will 
include screening (Visit 1) pre-bronchodilator and pre-ICS/LABA, PEF (in litres per 
minute (L/min)) and FeNO (millilitres per second (mL/sec)).  Baseline PEF (L/min) and 


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FeNO (mL/sec) measured at Randomisation (Visit 2/3/4) will also be summarised.
Additionally, screening and baseline PEF will be summarised by country.
Prescription details (12-month history) at screening will be summarised with frequency 
distributions of the number of asthma maintenance therapy prescriptions requested or 
prescribed; the number of asthma maintenance therapy requested or prescribed that 
would need to be 100% compliant.  Compliance in the previous 12 months will be 
calculated as 100 * (Actual number of prescriptions) / (Number of prescriptions needed 
to be 100% compliant) and summarised.  These data will also be listed.
6.2.2.
Preferred Time of Dosing
Summary statistics to summarise percentage of total ELLIPTA doses taken at preferred 
time of dosing for each participant will be presented. A participant is considered as 
having taken their dose at their preferred time if the actual time of the ELLIPTA dose is 
recorded 1 hour of their preferred time as captured on the eCRF at screening.  A 
histogram of individual dose deviations (in minutes) from preferred time will also be 
presented per treatment group.  These data will also be listed.
6.2.3.
Study Medication Exposure and Compliance
Duration (days) of exposure to study medication will be calculated based on 
randomisation date and latest (stop) of all dates recorded for the participant. Duration will 
be summarised categorically and with descriptive statistics. Total years exposed to 
Relvar/Breo after randomisation will also be presented.  Further details are presented in 
Section 10.5 Appendix 5: Derived and Transformed Data
Calculation of Relvar/Breo study medication compliance after randomisation, will be 
based on the ELLIPTA device dose counter (which displays the number of doses 
remaining) as described in Section 10.5 Appendix 5: Derived and Transformed Data. 
Treatment compliance (calculated as a percentage) will be summarised categorically and 
with descriptive statistics.
All exposure and compliance data will be listed.
A summary of the number of puffs per day as recorded by the ELLIPTA Relvar/Breo and 
MDI sensors will be summarised and graphically presented.
6.2.4.
HCP dashboard review
The actions taken by the HCP post the dashboard data review will be summarized and 
listed by visit for Arms 1 and 3.


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7.
EFFICACY ANALYSES
7.1.
Primary Efficacy Analysis 
The primary analysis will estimate the treatment arm effect of 6 months use of the 
Relvar/Breo ELLIPTA maintenance therapy with CIS when both the participant and the 
HCP are supplied with data from the ELLITPA sensor versus no data supplied to the 
participant and HCP (Arm 1 vs Arm 5).
7.1.1.
Endpoint
The primary endpoint is the percentage of ELLIPTA doses taken (daily adherence) 
between the beginning of Month 4 and the end of Month 6 as determined by the 
maintenance sensor.  Daily adherence is defined as the participant taking one dose of 
Relvar/Breo ELLIPTA, within a 24-hour period, starting at 12.00am each day of the run-
in and treatment period.
7.1.2.
Summary Measure
The mean difference in daily adherence between Arm 1 and Arm 5 will be estimated 
from an Analysis of Covariance (ANCOVA) model allowing for effects due to 
randomised treatment arm, baseline adherence, duration of run-in (visits), country, 
gender, and age (years).
7.1.3.
Population of Interest 
The primary efficacy analysis will be based on the Intent-To-Treat population.


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7.1.4.
Strategy for Intercurrent (Post-Randomisation) Events
The following steps in Table 3 will be applied sequentially when deriving the primary endpoint. See Section 10.5.3.1 ELLIPTA Device 
Sensor Assessments for full details of the missing data imputations process.
Table 3
Intercurrent 
Event Estimation 
Rules
(to be applied 
sequentially)
Intercurrent Event (IE)
Strategy with Rationale
Estimation Method following IE
1
None (completed as randomised) 
Without discontinuation of CIS 
feedback or ELLIPTA maintenance 
sensor

Premature discontinuation from 
rescue/salbutamol MDI sensor

Change of dose of ELLIPTA
Discontinuation of CIS feedback, but 
not ELLIPTA maintenance sensor

Premature discontinuation from 
App and/or HCP interaction
Treatment policy: 
Directly assessed using observed adherence 
data while ELLIPTA maintenance sensor is in 
use, regardless of whether the CIS feedback is 
discontinued.
Data are available; no imputation 
required
2
Discontinuation of ELLIPTA 
maintenance sensor only
Treatment policy:
Without the ELLIPTA maintenance sensor, no 
CIS feedback is possible, assume

participants continue to take ELLIPTA as 
Jump to Reference (J2R)
Imputation


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Intercurrent 
Event Estimation 
Rules
(to be applied 
sequentially)
Intercurrent Event (IE)
Strategy with Rationale
Estimation Method following IE
they would have without the CIS 
intervention

adherence will be like that in the control 
(no CIS feedback) group
3
Discontinuation of ELLIPTA
Whilst on treatment:
ELLIPTA adherence is only a relevant measure 
while ELLIPTA treatment is appropriate.  It is 
assumed that ELLIPTA treatment is no longer 
appropriate if the participant discontinues 
ELLIPTA but remains in the study or withdraws 
for a reason related to ELLIPTA. 
Follow-up after ELLIPTA 
discontinuation is excluded, i.e. no 
data; adherence is weighted by 
proportion of months 4 to 6 for 
which data is included*
4
Premature withdrawal from the study, 
not related to ELLIPTA discontinuation 
or CIS, and concurrent with
discontinuation of the ELLIPTA 
maintenance sensor
Hypothetical: 
When study withdrawal is unrelated to ELLIPTA 
or the CIS then reasonable to assume that 
participant would have continued with ELLIPTA 
and their CIS intervention, had the unrelated 
event not occurred
Missing at Random (MAR)
Imputation
* Discontinuation of ELLIPTA prior to the start of month 4 will lead to a participant being excluded from the primary analysis


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7.1.4.1.
Events prior to premature discontinuation of the ELLIPTA maintenance 
sensor
The treatment policy estimand is directly assessed using the observed adherence data 
while the ELLIPTA maintenance sensor is in use, regardless of whether the CIS feedback 
is discontinued.
Any missing intermittent adherence data will be imputed as non-adherent i.e. the 
participant will be assumed to have not taken their treatment within the 24-hour time 
period/window, where there is no evidence of device or technical/transmission failure.
Missing intermittent adherence data due to a medical device incident such as device 
failure, technical failure of the sensor, or data transmission failure will be assumed to be 
missing at random (MAR).  For each participant, the percentage adherence measure will 
be calculated from the proportion of the number of days a participant is adherent divided 
by the number of days data provided in that month.
7.1.4.2.
Events following premature discontinuation of the ELLIPTA 
maintenance sensor
It is assumed that participants would continue to take ELLIPTA as they would have 
without the CIS intervention (J2R imputation) following discontinuation of the ELLIPTA 
maintenance sensor.
It is assumed that ELLIPTA treatment is no longer appropriate if the participant
discontinues ELLIPTA but remains in the study or withdraws for a reason related to 
ELLIPTA. The ELLIPTA adherence endpoint is no longer considered relevant and 
subsequent follow-up is excluded from the analysis, with participants weighted in the 
analysis by the proportion of months 4 to 6 for which data is included.
It is assumed that participants would continue to take ELLIPTA as they would have with 
their allocated CIS intervention (MAR imputation) following concurrent discontinuation 
of the ELLIPTA maintenance sensor and withdrawal unrelated to ELLIPTA or CIS.
See Section 10.5.3.1 ELLIPTA Device Sensor Assessments for further derivation details.
7.1.5.
Statistical Analyses / Methods
Details of the planned displays will be provided in Section 10.8, Appendix 8: List of Data 
Displays and will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints /variables defined in Section 7.1.1, Endpoint will 
be summarised using descriptive statistics, graphically presented (where appropriate) and
listed.


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7.1.5.1.
Statistical Methodology Specification
Endpoint / Variables
The primary endpoint is the percentage of ELLIPTA doses taken (daily adherence) between the beginning 
of Month 4 and the end of Month 6 as determined by the maintenance sensor.  Daily adherence is defined 
as the participant taking one dose of Relvar/Breo ELLIPTA within a 24 hour period, starting at 12.00am each 
day of treatment period.
Multiple Imputation Specification
Imputation will be carried out using monthly adherence rates for months 1 to 6. 1000 draws will be used. For 
each draw, four intermediate imputation datasets will be created to allow for the handling of fully unobserved 
months (using set A imputations) and partially unobserved months (using set B imputations).  

Set A where the partially observed month is directly estimated under the MAR assumption as the 
proportion of the number of days a participant is adherent divided by the number of days data 
provided in that month.

J2R imputations

MAR imputations

Set B where the partially observed month is set to missing.

J2R imputations

MAR imputations
The timing of the intercurrent events of discontinuation of the ELLIPTA maintenance sensor, discontinuation 
of ELLIPTA and withdrawal from study will be used to identify the proportion of each month to be assigned 
as observed data, J2R imputed data, MAR imputed data, or no data. The strategy for handling intercurrent 
events is described in Section 7.1.4 Strategy for Intercurrent (Post-Randomisation) Events. 
Within each imputation draw, for each month, the observed and any imputed data will be combined to 
provide a percentage adherence value. The values for months 4 to 6 will be combined to create the value 
for the primary analysis and the weight to be assigned to each participant.
Multiple imputation using Rubin’s rules will be used to estimate the treatment effect and associated standard 
error, by performing the ANCOVA analysis described below on the primary endpoint within each dataset.
The multiple imputation will be implemented using the methods described in Carpenter, 2013, using the 
macros available from https://missingdata.lshtm.ac.uk/2017/04/06/gsk-five-macros/..
Model Specification
The analysis will be performed on the percentage adherence between Months 4 and 6 using an Analysis of 
Covariance (ANCOVA) model allowing for effects due to randomised treatment arm, baseline adherence, 
duration of run-in (visits), country, gender, and age (years).  
Baseline adherence will be the percentage ELLIPTA doses taken (daily adherence) during the last 28 days 
of the run-in period prior to randomisation. Randomised treatment arm, duration of run-in (visits), country, 
and gender will be included as categorical covariates; baseline adherence and age (years) will be included 
as continuous covariates.


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Each participant will be weighted by the proportion of months 4 to 6 for which data is included in the 
percentage adherence endpoint (both observed and imputed data are accounted for in the weighting).
Data from all 5 treatment arms will be included in the model and used to estimate the difference between 
Arm 1 and Arm 5 for the primary objective.
Model Checking & Diagnostics
Normality assumptions underlying the ANCOVA model used for analysis will be examined in a limited 
number of imputed datasets by obtaining a normal probability plot of the residuals and a plot of the residuals 
versus the fitted values (i.e. checking the normality assumption and constant variance assumption of the 
model respectively) to gain confidence that the model assumptions are reasonable.
If there are any departures from the distributional assumptions, alternative models may be explored using 
appropriately transformed data.
Interactions with treatment will be explored for other model covariates and tests for interactions will be at the 
2-sided 10% significance level. Any significant interactions that are found will be thoroughly investigated and 
where necessary, extra outputs will be produced.
Model Results Presentation
Summary statistics (n, mean, standard deviation, median, minimum, maximum) of the primary endpoint will 
be provided, based on the observed percentages.
The adjusted means for each treatment and the estimated treatment difference for the primary treatment 
comparison of Arm 1 versus Arm 5 will be presented together with a 95% confidence interval for the 
difference and corresponding Wald test statistic and p-value from the multiple imputation procedure.
Subgroup Analyses
For the analysis by baseline total ACT score (<=15, 16-19), the model will additionally include the baseline 
ACT total score category and randomised treatment arm-by-baseline ACT total score category interaction 
as covariates.
For the analysis by age group (18-35, 36-48, 49-58, >58 years), the model will additionally include age 
group and randomised treatment arm-by-age group interaction as covariates.
The adjusted means for each treatment and the estimated treatment difference for the treatment 
comparisons of Arm 2 versus Arm 5, Arm 3 versus Arm 5 and Arm 4 versus Arm 5 will be presented 
together with the 95% confidence interval for the differences and corresponding p-values from the multiple 
imputation procedure.
Sensitivity Analysis

A sensitivity analysis will be performed estimating the treatment effect by utilizing a generalized linear 
model (GLM) and not running the multiple imputation process. The model will follow a binomial 
distribution with the logit link function. The covariates included in the GLM will be the same as those
included in the primary analysis. Model assumptions will be checked using standardised residual plots, 
and model results presentation will be the same as described for the primary analysis. Missing data will 
be assumed to be MAR.


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7.2.
Secondary Efficacy Analyses
The secondary analysis of daily adherence during month 4 to 6 will estimate the 
treatment effect of 6 months use of the ELLIPTA maintenance therapy with CIS for the 
following aspects of the CIS:

Maintenance data only supplied to participants versus no data supplied to the 
participant (Arm 2 vs Arm 5)

Rescue and Maintenance data supplied to participant and HCP versus no data 
supplied to the participant and HCP (Arm 3 vs Arm 5)

Rescue and Maintenance data only supplied to participant versus no data supplied to 
the participant (Arm 4 vs Arm 5)
In addition, secondary analyses of daily adherence during month 1 to 6 and month 1 to 3 
will estimate the treatment effect of 6 months use of the ELLIPTA maintenance therapy 
with CIS when the participant and the HCP are supplied with data from maintenance and 
rescue sensors versus no data supplied to participant and HCP (Arm 1, 2, 3, 4 vs Arm 5).
Secondary analysis to evaluate the effect of 6 months use of the CIS on a participant’s 
rescue medication usage will be conducted, as well as an evaluation of the effect of 6 
months use with the CIS on participant’s asthma control.
7.2.1.
ELLIPTA Adherence Measure Endpoints
The adherence secondary endpoints are:

The percentage of ELLIPTA doses taken (daily adherence) between the beginning of 
Month 4 and the end of Month 6 as determined by the maintenance sensor.  Daily 
adherence is defined as the participant taking one dose of Relvar/Breo ELLIPTA, 
within a 24-hour period, starting at 12.00am each day of the run-in and treatment 
period.

The percentage of ELLIPTA doses taken (daily adherence) between the beginning of 
Month 1 and the end of Month 6 as determined by the maintenance sensor.  Daily 
adherence is defined as the participant taking one dose of Relvar/Breo ELLIPTA, 
within a 24-hour period, starting at 12.00am each day of the run-in and treatment 
period.

The percentage of ELLIPTA doses taken (daily adherence) between the beginning of 
Month 1 and the end of Month 3 as determined by the maintenance sensor.  Daily 
adherence is defined as the participant taking one dose of Relvar/Breo ELLIPTA, 
within a 24-hour period, starting at 12.00am each day of the run-in and treatment 
period.
7.2.1.1.
Summary Measure
The mean difference in daily adherence between the comparisons of interest will be 
estimated from an Analysis of Covariance (ANCOVA) model allowing for effects due to 
randomised treatment, baseline adherence, duration of run-in (visits), country, gender, 
and age (years).


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7.2.1.2.
Population of Interest 
The secondary efficacy analyses will be based on the Intent-To-Treat population.
7.2.1.3.
Strategy for Intercurrent (Post-Randomisation) Events
The steps detailed in Section 7.1.4 Strategy for Intercurrent (Post-Randomisation) Events
will be applied sequentially when deriving the secondary adherence endpoints. 
7.2.1.3.1.
Events prior to premature discontinuation of the ELLIPTA maintenance 
sensor
The treatment policy estimand is directly assessed using the observed adherence data 
while the ELLIPTA maintenance sensor is in use, regardless of whether the CIS feedback 
is discontinued.
Any missing intermittent adherence data will be imputed as non-adherent i.e. the 
participant will be assumed to have not taken their treatment within the 24-hour time 
period/window, where there is no evidence of device or technical/transmission failure.
Missing intermittent adherence data due to a medical device incident such as device 
failure, technical failure of the sensor, or data transmission failure will be assumed to be 
missing at random (MAR).  For each participant, the percentage adherence measure will 
be calculated from the proportion of the number of days a participant is adherent divided 
by the number of days data provided in that month.
7.2.1.3.2.
Events following premature discontinuation of the ELLIPTA 
maintenance sensor
It is assumed that participants would continue to take ELLIPTA as they would have 
without the CIS intervention (J2R imputation) following discontinuation of the ELLIPTA 
maintenance sensor.
It is assumed that ELLIPTA treatment is no longer appropriate if the participant
discontinues ELLIPTA but remains in the study or withdraws for a reason related to 
ELLIPTA. The ELLIPTA adherence endpoint is no longer considered relevant and 
subsequent follow-up is excluded from the analysis, with participants weighted in the 
analysis by the proportion of months 4 to 6 for which data is included.
It is assumed that participants would continue to take ELLIPTA as they would have with 
their allocated CIS intervention (MAR imputation) following concurrent discontinuation 
of the ELLIPTA maintenance sensor and withdrawal unrelated to ELLIPTA or CIS.
See Section 10.5.3.1 ELLIPTA Device Sensor Assessments further derivation details.
7.2.1.4.
Statistical Analyses / Methods
Details of the planned displays will be provided in Section 10.8, Appendix 8: List of Data 
Displays and will be based on GSK data standards and statistical principles.


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Unless otherwise specified, endpoints /variables defined in Section 7.1.1, Endpoint will 
be summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
7.2.1.5.
Statistical Analyses / Methodology Specification
7.2.1.5.1.
The percentage of ELLIPTA doses taken (daily adherence) between the 
beginning of Month 4 and the end of Month 6
Endpoint / Variables
Percentage of ELLIPTA doses taken (daily adherence) between the beginning of Month 4 and the end of 
Month 6 as determined by the maintenance sensor for the following treatment arm comparisons:

Arm 2 vs Arm 5

Arm 3 vs Arm 5

Arm 4 vs Arm 5
Daily adherence is defined as the participant taking one dose of Relvar/Breo ELLIPTA within a 24-hour
period, starting at 12.00am each day of treatment period.
Multiple Imputation Specification
Imputation will be carried out using monthly adherence rates for months 1 to 6. 1000 draws will be used. For 
each draw, four intermediate imputation datasets will be created to allow for the handling of fully unobserved 
months (using set A imputations) and partially unobserved months (using set B imputations).  

Set A where the partially observed month is directly estimated under the MAR assumption as the 
proportion of the number of days a participant is adherent divided by the number of days data 
provided in that month.

J2R imputations

MAR imputations

Set B where the partially observed month is set to missing.

J2R imputations

MAR imputations 
The timing of the intercurrent events of discontinuation of the ELLIPTA maintenance sensor, discontinuation 
of ELLIPTA and withdrawal from study will be used to identify the proportion of each month to be assigned 
as observed data, J2R imputed data, MAR imputed data, or no data. The strategy for handling intercurrent 
events is described in Section 7.1.4 Strategy for Intercurrent (Post-Randomisation) Events. 
Within each imputation draw, for each month, the observed and any imputed data will be combined to 
provide a percentage adherence value. The values for months 4 to 6 will be combined to create the value 
for the secondary analysis and the weight to be assigned to each participant.
Multiple imputation using Rubin’s rules will be used to estimate the treatment effect and associated standard 
error, by performing the ANCOVA analysis described below on the secondary endpoint within each dataset.
The multiple imputation will be implemented using the methods described in Carpenter, 2013, using the 
macros available from https://missingdata.lshtm.ac.uk/2017/04/06/gsk-five-macros/..


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Model Specification
The analysis will be performed on the percentage adherence between Months 4 and 6 using an Analysis of 
Covariance (ANCOVA) model allowing for effects due to randomised treatment arm, baseline adherence, 
duration of run-in (visits), country, gender, and age (years).  
Baseline adherence will be the percentage ELLIPTA doses taken (daily adherence) during the last 28 days 
of the run-in period prior to randomisation. Randomised treatment, duration of run-in (visits), country, and 
gender will be included as categorical covariates; baseline adherence and age (years) will be included as 
continuous covariates.
Each participant will be weighted by the proportion of months 4 to 6 for which data is included in the 
percentage adherence endpoint (both observed and imputed data are accounted for in the weighting).
Data from all 5 treatment arms will be included in the model, and used to estimate the difference between:

Arm 2 and Arm 5

Arm 3 and Arm 5

Arm 4 and Arm 5
Model Checking & Diagnostics
Normality assumptions underlying the ANCOVA model used for analysis will be examined in a limited 
number of imputed datasets by obtaining a normal probability plot of the residuals and a plot of the residuals 
versus the fitted values (i.e. checking the normality assumption and constant variance assumption of the 
model respectively) to gain confidence that the model assumptions are reasonable.
If there are any departures from the distributional assumptions, alternative models may be explored using 
appropriately transformed data.
Interactions with treatment will be explored for other model covariates and tests for interactions will be at the 
2-sided 10% significance level. Any significant interactions that are found will be thoroughly investigated and 
where necessary, extra outputs will be produced.
Model Results Presentation
Summary statistics (mean, standard deviation, median, minimum, maximum) of the primary endpoint will be 
provided, based on the observed percentages.
The adjusted means for each treatment and the estimated treatment difference for the treatment 
comparisons of Arm 2 versus Arm 5, Arm 3 versus Arm 5 and Arm 4 versus Arm 5 will be presented 
together with the 95% confidence interval for the differences and corresponding p-values from the multiple 
imputation procedure.
Subgroup Analyses
For the analysis by baseline total ACT score (<=15, 16-19), the model will additionally include the baseline 
ACT total score category and randomised treatment arm-by-baseline ACT total score category interaction 
as covariates.
For the analysis by age group (18-35, 36-48, 49-58, >58 years), the model will additionally include age 
group and randomised treatment arm-by-age group interaction as covariates.


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The adjusted means for each treatment and the estimated treatment difference for the treatment 
comparisons of Arm 2 versus Arm 5, Arm 3 versus Arm 5 and Arm 4 versus Arm 5 will be presented 
together with the 95% confidence interval for the differences and corresponding p-values from the multiple 
imputation procedure.
Sensitivity Analysis

A sensitivity analysis will be performed estimating the treatment effect by utilizing a generalized linear 
model (GLM) and not running the multiple imputation process. The model will follow a binomial 
distribution with the logit link function. The covariates included in the GLM will be the same as those 
included in the primary analysis. Model assumptions will be checked using standardised residual plots, 
and model results presentation will be the same as described for the primary analysis. Missing data will 
be assumed to be MAR.
7.2.1.5.2.
The percentage of ELLIPTA doses taken (daily adherence) between the 
beginning of Month 1 and the end of Month 6
Endpoint / Variables
Percentage of ELLIPTA doses taken (daily adherence) between the beginning of Month 1 and the end of 
Month 6 as determined by the maintenance sensor for the following treatment arm comparisons:

Arm 1 vs Arm 5

Arm 2 vs Arm 5

Arm 3 vs Arm 5

Arm 4 vs Arm 5
Daily adherence is defined as the participant taking one dose of Relvar/Breo ELLIPTA within a 24-hour
period, starting at 12.00am each day of treatment period.
Multiple Imputation Specification
Imputation will be carried out using monthly adherence rates for months 1 to 6. 1000 draws will be used. For 
each draw, four intermediate imputation datasets will be created to allow for the handling of fully unobserved 
months (using set A imputations) and partially unobserved months (using set B imputations).  

Set A where the partially observed month is directly estimated under the MAR assumption as the 
proportion of the number of days a participant is adherent divided by the number of days data 
provided in that month.

J2R imputations

MAR imputations

Set B where the partially observed month is set to missing.

J2R imputations

MAR imputations 
The timing of the intercurrent events of discontinuation of the ELLIPTA maintenance sensor, discontinuation 
of ELLIPTA and withdrawal from study will be used to identify the proportion of each month to be assigned 
as observed data, J2R imputed data, MAR imputed data, or no data. The strategy for handling intercurrent 


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events is described in Section 7.1.4 Strategy for Intercurrent (Post-Randomisation) Events. 
Within each imputation draw, for each month, the observed and any imputed data will be combined to 
provide a percentage adherence value. The values for months 4 to 6 will be combined to create the value 
for the primary analysis and the weight to be assigned to each participant.
Multiple imputation using Rubin’s rules will be used to estimate the treatment effect and associated standard 
error, by performing the ANCOVA analysis described below on the primary endpoint within each dataset.
The multiple imputation will be implemented using the methods described in Carpenter, 2013, using the 
macros available from https://missingdata.lshtm.ac.uk/2017/04/06/gsk-five-macros/.  
Model Specification
The analysis will be performed on the percentage adherence between Months 1 and 6 using an Analysis of 
Covariance (ANCOVA) model allowing for effects due to randomised treatment arm, baseline adherence, 
duration of run-in (visits), country, gender, and age (years).  
Baseline adherence will be the percentage ELLIPTA doses taken (daily adherence) during the last 28 days 
of the run-in period prior to randomisation. Randomised treatment, duration of run-in (visits), country, and 
gender will be included as categorical covariates; baseline adherence and age (years) will be included as 
continuous covariates.
Each participant will be weighted by the proportion of months 1 to 6 for which data is included in the 
percentage adherence endpoint (both observed and imputed data are accounted for in the weighting).
Data from all 5 treatment arms will be included in the model, and used to estimate the difference between:

Arm 1 and Arm 5

Arm 2 and Arm 5

Arm 3 and Arm 5

Arm 4 and Arm 5
Model Checking & Diagnostics
Normality assumptions underlying the ANCOVA model used for analysis will be examined in a limited 
number of imputed datasets by obtaining a normal probability plot of the residuals and a plot of the residuals 
versus the fitted values (i.e. checking the normality assumption and constant variance assumption of the 
model respectively) to gain confidence that the model assumptions are reasonable.
If there are any departures from the distributional assumptions, alternative models may be explored using 
appropriately transformed data.
Interactions with treatment will be explored for other model covariates and tests for interactions will be at the 
2-sided 10% significance level. Any significant interactions that are found will be thoroughly investigated and 
where necessary, extra outputs will be produced.
Model Results Presentation
Summary statistics (n, mean, standard deviation, median, minimum, maximum) of the primary endpoint will 
be provided, based on the observed percentages.


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The adjusted means for each treatment arm and the estimated treatment arm difference for the treatment 
comparisons of Arm 1 versus Arm 5, Arm 2 versus Arm 5, Arm 3 versus Arm 5 and Arm 4 versus Arm 5 will 
be presented together with the 95% confidence interval for the differences and corresponding p-values from 
the multiple imputation procedure.
Sensitivity Analysis

A sensitivity analysis will be performed estimating the treatment effect by utilizing a generalized linear 
model (GLM) and not running the multiple imputation process. The model will follow a binomial 
distribution with the logit link function. The covariates included in the GLM will be the same as those 
included in the primary analysis. Model assumptions will be checked by using standardised residual 
plots, and the model results presentation will be the same as described for the primary analysis. 
Missing data will be assumed to be MAR.
7.2.1.5.3.
The percentage of ELLIPTA doses taken (daily adherence) between the 
beginning of Month 1 and the end of Month 3
Endpoint / Variables
Percentage of ELLIPTA doses taken (daily adherence) between the beginning of Month 1 and the end of 
Month 3 as determined by the maintenance sensor for the following treatment arm comparisons:

Arm 1 vs Arm 5

Arm 2 vs Arm 5

Arm 3 vs Arm 5

Arm 4 vs Arm 5
Daily adherence is defined as the participant taking one dose of Relvar/Breo ELLIPTA within a 24-hour
period, starting at 12.00am each day of treatment period.
Multiple Imputation Specification
Imputation will be carried out using monthly adherence rates for months 1 to 6. 1000 draws will be used. For 
each draw, four intermediate imputation datasets will be created to allow for the handling of fully unobserved 
months (using set A imputations) and partially unobserved months (using set B imputations).  

Set A where the partially observed month is directly estimated under the MAR assumption as the 
proportion of the number of days a participant is adherent divided by the number of days data 
provided in that month.

J2R imputations

MAR imputations

Set B where the partially observed month is set to missing.

J2R imputations

MAR imputations 
The timing of the intercurrent events of discontinuation of the ELLIPTA maintenance sensor, discontinuation 
of ELLIPTA and withdrawal from study will be used to identify the proportion of each month to be assigned 
as observed data, J2R imputed data, MAR imputed data, or no data. The strategy for handling intercurrent 


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events is described in Section 7.1.4 Strategy for Intercurrent (Post-Randomisation) Events. 
Within each imputation draw, for each month, the observed and any imputed data will be combined to 
provide a percentage adherence value. The values for months 4 to 6 will be combined to create the value 
for the primary analysis and the weight to be assigned to each participant.
Multiple imputation using Rubin’s rules will be used to estimate the treatment effect and associated standard 
error, by performing the ANCOVA analysis described below on the primary endpoint within each dataset.
The multiple imputation will be implemented using the methods described in Carpenter, 2013, using the 
macros available from https://missingdata.lshtm.ac.uk/2017/04/06/gsk-five-macros/.
Model Specification
The analysis will be performed on the percentage adherence between Months 1 and 3 using an Analysis of 
Covariance (ANCOVA) model allowing for effects due to randomised treatment arm, baseline adherence, 
duration of run-in (visits), country, gender, and age (years).  
Baseline adherence will be the percentage ELLIPTA doses taken (daily adherence) during the last 28 days 
of the run-in period prior to randomisation. Randomised treatment arm, duration of run-in (visits), country, 
and gender will be included as categorical covariates; baseline adherence and age (years) will be included 
as continuous covariates.
Each participant will be weighted by the proportion of months 1 to 3 for which data is included in the 
percentage adherence endpoint (both observed and imputed data are accounted for in the weighting).
Data from all 5 treatment arms will be included in the model, and used to estimate the difference between:

Arm 1 and Arm 5

Arm 2 and Arm 5

Arm 3 and Arm 5

Arm 4 and Arm 5
Model Checking & Diagnostics
Normality assumptions underlying the ANCOVA model used for analysis will be examined in a limited 
number of imputed datasets by obtaining a normal probability plot of the residuals and a plot of the residuals 
versus the fitted values (i.e. checking the normality assumption and constant variance assumption of the 
model respectively) to gain confidence that the model assumptions are reasonable.
If there are any departures from the distributional assumptions, alternative models may be explored using 
appropriately transformed data.
Interactions with treatment will be explored for other model covariates and tests for interactions will be at the
2-sided 10% significance level. Any significant interactions that are found will be thoroughly investigated and 
where necessary, extra outputs will be produced.
Model Results Presentation
Summary statistics (n, mean, standard deviation, median, minimum, maximum) of the primary endpoint will 
be provided, based on the observed percentages.


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The adjusted means for each treatment and the estimated treatment difference for the treatment 
comparisons of Arm 1 versus Arm 5, Arm 2 versus Arm 5, Arm 3 versus Arm 5 and Arm 4 versus Arm 5 will 
be presented together with the 95% confidence interval for the differences and corresponding p-values from 
the multiple imputation procedure.
Sensitivity Analysis

A sensitivity analysis will be performed estimating the treatment effect by utilizing a generalized linear 
model (GLM) and not running the multiple imputation process. The model will follow a binomial 
distribution with the logit link function. The covariates included in the GLM will be the same as those 
included in the primary analysis. Model assumptions will be checked by using standardised residual 
plots, and the model results presentation will be the same as described for the primary analysis. 
Missing data will be assumed to be MAR.
7.2.2.
MDI Rescue Medication Use Endpoints

Percentage of rescue free days measured between the beginning of month 4 and 
the end of month 6 as determined by the MDI rescue sensor records of date, time, 
and number of inhaler actuations.

Total rescue use measured between the beginning of month 4 and the end of 
month 6 as determined by the MDI rescue sensor records of date, time, and 
number of inhaler actuations.
7.2.2.1.
Summary Measure
The rescue medicine summary measures are:

The mean difference in percentage of rescue free days between the treatment arms 
will be estimated from an Analysis of Covariance (ANCOVA) model allowing for 
effects due to randomised treatment, baseline rescue-free, duration of run-in 
(visits), country, gender, and age (years).

The mean total rescue use for the treatment arms will be summarised using 
summary statistics (n, mean, SD, median, min, max) for each treatment arm for 
each Month separately, and totalled Month 4 – 6.
7.2.2.2.
Population of Interest 
These secondary efficacy analyses will be based on the Intent-To-Treat population.


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7.2.2.3.
Strategy for Intercurrent (Post-Randomisation) Events
It is assumed that salbutamol MDI rescue medication use does not permanently discontinue for asthmatic participants, regardless of 
whether they are used in addition to maintenance therapy or not.
The following steps in Table 4 will be applied sequentially when deriving the rescue free days endpoint. See Section 10.5.3.2 MDI 
Device Sensor Assessments for full details of the missing data imputations process.
Table 4
Intercurrent 
Event Estimation 
Rules
(to be applied 
sequentially)
Intercurrent Event (IE)
Strategy with Rationale
Estimation Method following IE
1
None (completed as randomised) 
Without discontinuation of CIS 
feedback or MDI eSensor

Premature discontinuation from 
ELLIPTA eSensor

Premature discontinuation from 
ELLIPTA

Change of dose of ELLIPTA
Discontinuation of CIS feedback, but 
not MDI eSensor
•
Premature discontinuation from 
App and/or HCP interaction
Treatment policy: 
Directly assessed using observed rescue data 
while MDI sensor is in use, regardless of 
whether the CIS feedback is discontinued.
Data are available; no imputation 
required 


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Intercurrent 
Event Estimation 
Rules
(to be applied 
sequentially)
Intercurrent Event (IE)
Strategy with Rationale
Estimation Method following IE
2
Discontinuation from MDI eSensor but
not the study
Hypothetical:
Without the sensor, no CIS feedback is possible 
and so it is assumed that rescue use will be like 
that in the control group for those randomised to 
Arm 3 and 4.  Since Arms 1 and 2 never have 
CIS feedback, without the sensor it is assumed 
that rescue use will continue as before.
MAR imputation (Arms 1&2)
J2R imputation (Arms 3&4)
3
Premature withdrawal from the study 
Hypothetical:
Without the sensor, no CIS feedback is possible 
and so it is assumed that rescue use will be like 
that in the control group for those randomised to 
Arm 3 and 4.  Since Arms 1 and 2 never have 
CIS feedback, without the sensor it is assumed 
that rescue use will continue as before.
MAR imputation (Arms 1&2)
J2R imputation (Arms 3&4)
4
Premature withdrawal from the study 
not related to CIS, and concurrent with 
discontinuation of the MDI sensor
Hypothetical: 
When study withdrawal is unrelated to the CIS 
then it is reasonable to assume that the 
participant would have continued with MDI and 
the Sensor, had the unrelated event not 
occurred.
Missing at Random (MAR) 
Imputation


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7.2.2.3.1.
Events following premature discontinuation of the MDI sensor
It is assumed that participants would continue to take MDI as they would have without 
the CIS intervention (jump to reference imputation) following discontinuation of the MDI 
sensor if receiving treatment Arms 3 and 4, otherwise continue to take MDI as they 
would have with their allocated CIS interventions (MAR).
It is assumed that participants would continue to take MDI as they would have with their 
allocated CIS interventions (MAR) following concurrent discontinuation of MDI sensor 
and withdrawal from study if unrelated to CIS.
7.2.2.4.
Statistical Analyses / Methods
Details of the planned displays will be provided in Section 10.8, Appendix 8: List of Data 
Displays and will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints /variables defined in Section 7.2.2 MDI Rescue 
Medication Use Endpoints, Section 7.1.1 Endpoint will be summarised using descriptive 
statistics, graphically presented (where appropriate) and listed.
7.2.2.5.
Statistical Analyses / Methodology Specification
Endpoint / Variables
The percentage of rescue free days measured between the beginning of month 4 and the end of month 6 as 
determined by the MDI rescue sensor for the following treatment arm comparisons
Multiple Imputation Specification
Imputation will be carried out using monthly rescue free rates for months 1 to 6. 1000 draws will be used. 
For each draw, four intermediate imputation datasets will be created to allow for the handling of fully 
unobserved months (using set A imputations) and partially unobserved months (using set B imputations).  

Set A where the partially observed month is directly estimated under the MAR assumption as the 
proportion of the number of days a participant is adherent divided by the number of days data 
provided in that month.

J2R imputations

MAR imputations

Set B where the partially observed month is set to missing.

J2R imputations

MAR imputations 
The timing of the intercurrent events of discontinuation of the MDI sensor and withdrawal from study will be 
used to identify the proportion of each month to be assigned as observed data, J2R imputed data or MAR 
imputed data. The strategy for handling intercurrent events is described in Section 7.2.2.3 Strategy for 
Intercurrent (Post-Randomisation) Events. 


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Within each imputation draw, for each month, the observed and any imputed data will be combined to 
provide a percentage rescue free day value. The values for months 4 to 6 will be combined to create the 
value for the secondary analysis and the weight to be assigned to each participant.
Multiple imputation using Rubin’s rules will be used to estimate the treatment effect and associated standard 
error, by performing the ANCOVA analysis described below on the secondary endpoint within each dataset.
The multiple imputation will be implemented using the methods described in Carpenter, 2013, using the 
macros available from https://missingdata.lshtm.ac.uk/2017/04/06/gsk-five-macros/.  
Model Specification
The analysis will be performed on the percentage of rescue free days between Months 4 and 6 using an 
Analysis of Covariance (ANCOVA) model allowing for effects due to randomised treatment arm, baseline 
rescue free days percentage, duration of run-in (visits), country, gender, and age (years).  
Baseline rescue free days will be the percentage rescue free days during the last 28 days of the run-in 
period prior to randomisation. Randomised treatment, duration of run-in (visits), country, and gender will be 
included as categorical covariates; baseline rescue free days percentage and age (years) will be included 
as continuous covariates.
Each participant will be weighted by the proportion of months 4 to 6 for which data is included in the 
percentage rescue free days endpoint (both observed and imputed data are accounted for in the weighting).
Data from all 5 treatment arms will be included in the model, and used to estimate the difference between:

Arm 1 and Arm 5

Arm 2 and Arm 5

Arm 3 and Arm 5

Arm 4 and Arm 5
Model Checking & Diagnostics
Normality assumptions underlying the ANCOVA model used for analysis will be examined in a limited 
number of imputed datasets by obtaining a normal probability plot of the residuals and a plot of the residuals 
versus the fitted values (i.e. checking the normality assumption and constant variance assumption of the 
model respectively) to gain confidence that the model assumptions are reasonable.
If there are any departures from the distributional assumptions, alternative models may be explored using 
appropriately transformed data.
Interactions with treatment will be explored for other model covariates and tests for interactions will be at the 
2-sided 10% significance level. Any significant interactions that are found will be thoroughly investigated and 
where necessary, extra outputs will be produced.
Model Results Presentation
Summary statistics (mean, standard deviation, median, minimum, maximum) of the primary endpoint will be 
provided, based on the observed percentages.
The adjusted means for each treatment and the estimated treatment difference for the treatment 
comparisons of Arm 1 versus Arm 5, Arm 2 versus Arm 5, Arm 3 versus Arm 5 and Arm 4 versus Arm 5 will 
be presented together with the 95% confidence interval for the differences and corresponding p-values from 


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the multiple imputation procedure.
Endpoint / Variables
Total rescue use measured between the beginning of month 4 and the end of month 6 as determined by the 
MDI rescue sensor
Summary
The endpoint will be summarised using descriptive statistics (n, mean, SD, median, min, max) for 
each treatment arm.
To explore the effect of 6 months use of the CIS on a participant’s rescue medicine usage, the following 
displays will be presented,

Summary statistics (n, mean, SD, median, min, max) of Total rescue use measured between the 
beginning of month 4 and the end of month 6 as determined by the MDI rescue sensor

Total rescue use will be summarized by each individual month (Month 1 – Month 6) and then 
displayed as a total between month 4 – 6.
7.2.3.
Asthma Control Endpoints
The asthma control secondary endpoints are:

Change from baseline (Randomisation) in ACT total score at Month 6 (Visit 10), 
measured at baseline (Visit 2, 3 or 4) and Month 6 (Visit 10)

Percentage of patients becoming controlled as defined as an Asthma Control Test 
score ≥20 at Month 6 (Visit 10)

Percentage of patients with an increase from baseline ≥ 3 in ACT total score at 
Month 6 (Visit 10)

Percentage of patients who have either an ACT total score of ≥ 20 and/or an 
increase from baseline of ≥ 3 in ACT total score at Month 6 (Visit 10)
7.2.3.1.
Summary Measure
The asthma control summary measures are:

The difference in LS means of the change from baseline in ACT total score at 
month 6, along with a 95% confidence interval and p-value for the difference, 
analysed using an MMRM model. 

An adjusted odds ratio on percentage of patients becoming controlled as defined 
as an ACT total score ≥ 20 at Month 6, along with a 95% confidence interval and 
p-value for the percentage, analysed using a logistic regression model.

An adjusted odds ratio on percentage of patients with an increase from baseline ≥ 
3 in ACT total score at Month 6, along with a 95% confidence interval and p-
value for the percentage, analysed using a logistic regression model.

An adjusted odds ratio on percentage of patients who have either an ACT total 
score of ≥ 20 and/or an increase from baseline of ≥ 3 in ACT total score at Month 
6, along with a 95% confidence interval and p-value for the percentage, analysed 
using a logistic regression model.


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7.2.3.2.
Population of Interest
The asthma control analyses will be based on the Intent-to-Treat population.
7.2.3.3.
Strategy for Intercurrent (Post-Randomisation) Events
Intercurrent events for the asthma control outcomes were identified as:

Early discontinuation of ELLIPTA

Early discontinuation of the APP

Early discontinuation of ELLIPTA sensor

Early discontinuation of MDI sensor

Early withdrawal from study

Use of MDI rescue medication

Use of prohibited medications 

Change of dose of ELLIPTA
The “Treatment policy” strategy will be applied to handle the “Early discontinuation of 
ELLIPTA sensor”, “Early discontinuation of the APP”, “Early discontinuation of MDI 
sensor”, “Use of MDI rescue medication”, “Use of prohibited medications” and “change 
of dose of ELLIPTA” for all asthma control exploratory endpoints. The strategy implies 
direct use of ACT data irrespective of the occurrence of these intercurrent events. 
7.2.3.3.1.
Change from baseline (Randomisation) in ACT total score at Month 6
(Visit 10)
The “treatment policy” strategy will be applied to all handle all the intercurrent events 
listed in Section 7.2.3.3 Strategy for Intercurrent (Post-Randomisation) Events. In other 
words, all observed data before early discontinuation of the study respective of treatment 
arm status (on-treatment) or CIS discontinuation status will be included in the analysis. 
No missing data will be imputed, missing data will be considered MAR. Therefore, the 
primary treatment arm effect to be estimated will be the mean change from baseline in 
ACT total score at month 6 and remaining on study.
7.2.3.3.2.
Percentage of patients becoming controlled as defined as an Asthma 
Control Test score ≥20 at Month 6 (Visit 10)
The “Composite” strategy will be used for the “Early discontinuation of ELLIPTA” and 
‘Early discontinuation of study” intercurrent events. In the occurrence of these
intercurrent events, the effect to be estimated will be the effect on the outcome of 
achieving an ACT total score of ≥ 20 at month 6 and remaining on ELLIPTA (off-
ELLIPTA treatment data is not collected). Participants who do not meet the 
improvement threshold, have missing values for their ACT total score at month 6, or 
prematurely discontinue using ELLIPTA or the study will be classified as non-responders 
in all planned analyses for this endpoint.
The “Treatment policy” strategy will be used to handle discontinuation of the 
APP/sensor. This means direct assessment of ACT total score at month 6 against the 
responder criteria, irrespective of CIS discontinuation status.


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7.2.3.3.3.
Percentage of patients with an increase from baseline ≥ 3 in ACT total 
score at Month 6 (Visit 10)
The “Composite” strategy will be used for the “Early discontinuation of ELLIPTA” and 
‘Early discontinuation of study” intercurrent events. In the occurrence of these 
intercurrent events, the effect to be estimated will be the effect on the outcome of 
achieving an increase from baseline of ≥ 3 in ACT total score at month 6 and remaining 
on ELLIPTA (off-ELLIPTA treatment data is not collected). Participants who do not 
meet the improvement threshold, have missing values for their ACT total score at month 
6, or discontinue using ELLIPTA or the study will be classified as non-responders in all 
planned analyses for this endpoint.
The “Treatment policy” strategy will be used to handle discontinuation of the 
APP/sensor. This means direct assessment of ACT total score at month 6 against the 
responder criteria, irrespective of CIS discontinuation status.
7.2.3.3.4.
Percentage of patients who have either an ACT total score of ≥ 20 
and/or an increase from baseline of ≥ 3 in ACT total score at Month 6 
(Visit 10)
The “Composite” strategy will be used for the “Early discontinuation of ELLIPTA” and 
‘Early discontinuation of study” intercurrent events. In the occurrence of these 
intercurrent events, the effect to be estimated will be the effect on the composite outcome 
of achieving an ACT total score of ≥ 20 and/or an increase from baseline of ≥ 3 in ACT 
total score at month 6 and remaining on ELLIPTA (off-ELLIPTA treatment data is not 
collected). Participants who do not meet the improvement threshold, have missing values 
for their ACT total score at month 6, or discontinue using ELLIPTA during or the study 
will be classified as non-responders in all planned analyses for this endpoint.
The “Treatment policy” strategy will be used to handle discontinuation of the 
APP/sensor. This means direct assessment of ACT total score at month 6 against the 
responder criteria, irrespective of CIS discontinuation status.
7.2.3.4.
Statistical Analyses / Methodology Specification
Details of the planned displays will be provided in 10.8 Appendix 8: List of Data 
Displays and will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints/variables defined in Section 7.2.3.1 Summary 
Measure will be summarised using descriptive statistics, graphically presented (where 
appropriate) and listed.


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7.2.3.4.1.
Change from baseline in ACT total score at month 6
Endpoint / Variables
Change from baseline in ACT total score Month 6 (visit 10)
Model Specification
This endpoint will be analysed using a mixed model repeated measures (MMRM) model utilising the REML 
estimation approach and the default unstructured covariance matrix structure. Whilst missing data are not 
implicitly imputed in this analysis, there is an underlying assumption that the data are MAR. All non-missing 
data for a participant will be used within the analysis and, via modelling of the within-participant correlation 
structure, the derived treatment differences will be adjusted to take into account missing data.
Terms fitted in the model will include: 

Dependent Variable: change from baseline in ACT total score 

Covariates:
o
Fixed categorical:  randomised treatment arm, visit (month 1 and 6), gender and country.
o
Fixed continuous:  baseline ACT total score and age
o
Interaction terms: randomised treatment arm-by-visit, baseline ACT total score-by-visit
o
Random effect: participant
Model Checking & Diagnostics

If this model fails to converge, alternative correlation structures may be considered

Appropriate graphs will be reviewed as part of the model checking process to ensure that distributional 
assumptions hold. These will include a normal probability plot of the residuals and a plot of the 
residuals versus the fitted values (checking the normality assumption and constant variance 
assumption of the model, respectively).

Interactions with treatment will be explored for other model covariates and tests for interactions will be 
at the 2-sided 10% significance level. Any significant interactions that are found will be thoroughly 
investigated and where necessary, extra outputs will be produced.
Model Results Presentation
Adjusted mean change from baseline values for each treatment arm will be presented with their associated 
standard errors. The estimated treatment difference along with corresponding standard error, 95% 
confidence interval (CI) and p-value will be presented for the treatment comparisons at month 6 (Visit 10).
7.2.3.4.2.
ACT total score ≥20 at month 6
Endpoint / Variables
Percentage of patients becoming controlled as defined as an Asthma Control Test score ≥20 at Month 6 (Visit 
10)
Model Specification
This endpoint will be analysed using a logistic regression model. Only the month 6 (visit 10) data will be 
included in the model. Month 1 (visit 5) data will not be implemented since by this timepoint participants may 
not have reverted to steady medicating behaviour.
Will not be included since participants may not have reverted to normally medicating practise within one 
month’s use of the CIS/
Terms in the model:

Dependent variable: ACT total score ≥20 responder/non-responder at month 6 (binary score) 


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
Covariates:  
o
Categorical: randomised treatment arm, gender and country
o
Continuous: baseline ACT total score and age. 
Patients who have a missing ACT total score at month 6 (visit 10) (i.e. no ACT data on-treatment) will be 
classified as non-responders at that visit.
Computation of confidence intervals for the odds ratios is based in the individual Wald tests.
Model Checking & Diagnostics
If the likelihood maximisation algorithm fails to converge due to complete or quasi-complete separation of the 
data then Firth’s penalized likelihood (Firth, 1993) will be implemented by use of the FIRTH option on the 
MODEL statement in PROC LOGISTIC. 
The fit of the logistic regression model will be assessed by examining the ROC curve and other diagnostic plots
Model Results Presentation
The number and percentage of participants with a response within each randomised treatment arm will be 
presented by visit, together with the adjusted odds ratio comparing CIS Arms 1, 2, 3, 4 with Arm 5, associated 
95% CIs and p-values.
7.2.3.4.3.
Increase from Baseline of ≥ 3 in ACT total score at month 6
Endpoint
Percentage of patients with an increase from baseline ≥ 3 in ACT total score at Month 6 (Visit 10)
Model Specification
This endpoint will be analysed using a logistic regression model. Only the month 6 (visit 10) data will be 
included in the model. Month 1 (visit 5) data will not be implemented since by this timepoint participants may 
not have reverted to steady medicating behaviour.
Terms in the model:

Dependent variable: Increase from baseline of ≥ 3 in ACT total score at month 6 responder/non-
responder (binary score) 

Covariates:  
o
Categorical: randomised treatment arm, gender and country
o
Continuous: baseline ACT total score and age. 
Patients who have a missing ACT total score at month 6 (visit 10) (i.e. no ACT data on-treatment) will be 
classified as non-responders at that visit. 
Computation of confidence intervals for the odds rations is based in the individual Wald tests.
Model Checking & Diagnostics
If the likelihood maximisation algorithm fails to converge due to complete or quasi-complete separation of the 
data then Firth’s penalized likelihood (Firth, 1993) will be implemented by use of the FIRTH option on the 
MODEL statement in PROC LOGISTIC. 
The fit of the logistic regression model will be assessed by examining the ROC curve and other diagnostic plots


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Model Results Presentation
The number and percentage of participants with a response within each randomised treatment arm will be 
presented by visit, together with the adjusted odds ratio comparing CIS Arms 1, 2, 3, 4 with Arm 5, associated 
95% CIs and p-values.
7.2.3.4.4.
ACT total score of ≥ 20 and/or an increase from baseline of ≥ 3 in ACT 
total score at Month 6 (Visit 10).
Endpoint 
Percentage of patients who have either an ACT total score of ≥ 20 and/or an increase from baseline of ≥ 3 in 
ACT total score at Month 6 (Visit 10).
Model Specification
This endpoint will be analysed using a logistic regression model. Only the month 6 (visit 10) data will be 
included in the model.  Month 1 (visit 5) data will not be implemented since by this timepoint participants may 
not have reverted to steady medicating behaviour.
Terms in the model:

Dependent variable: Composite ACT total score ≥ 20 and/or increase from baseline of ≥ 3 in ACT 
total score at month 6 responder/non-responder (binary score) 

Covariates:  
o
Categorical: randomised treatment arm, gender and country
o
Continuous: baseline ACT total score and age. 
Patients who have a missing ACT total score at month 6 (visit 10) (i.e. no ACT data on-treatment) will be 
classified as non-responders at that visit. 
Computation of confidence intervals for the odds rations is based in the individual Wald tests.
Model Checking & Diagnostics
If the likelihood maximisation algorithm fails to converge due to complete or quasi-complete separation of the 
data then Firth’s penalized likelihood (Firth, 1993) will be implemented by use of the FIRTH option on the 
MODEL statement in PROC LOGISTIC. 
The fit of the logistic regression model will be assessed by examining the ROC curve and other diagnostic 
plots. 
Model Results Presentation
The number and percentage of participants with a response within each randomised treatment arm will be 
presented by visit, together with the adjusted odds ratio comparing CIS Arms 1, 2, 3, 4 with Arm 5, associated 
95% CIs and p-values.
7.3.
Exploratory and Other Analyses
The impact of the HCP having access to sensor data on percentage of ELLIPTA doses 
taken (daily adherence) between the beginning of month 4 and the end of month 6 as 
determined by the maintenance sensor will be assessed by the following comparisons:

Arm 1 vs Arm 2


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
Arm 3 vs Arm 4
The impact of having Rescue Medication data being available on the percentage of 
ELLIPTA doses taken (daily adherence) between the beginning of month 4 and the end 
of month 6 as determined by the maintenance sensor will be assessed by the following 
comparisons:

Arm 1 vs Arm 3

Arm 2 vs Arm 4
These estimates will be generated from the multiple imputation analysis used to assess 
the primary endpoint. 
The effect of 6 months use with CIS on health care utilisation will be explored as well as 
its effect on the following patient reported outcomes (PROs); asthma system utility index 
(ASUI). St. Georges Respiratory Questionnaire (SGRQ), Patient Activation Measure 
(PAM), Medication Adherence Report Scale for Asthma (MARS-A), Beliefs in Medicine 
Questionnaire (BMQ).
The reliability and usability of the CIS, as well as the impact of the adherence on
Fractional exhaled nitric oxide (FeNO) and Peak Expiratory Flow (PEF) will be assessed.
7.3.1.
Exploratory ELLIPTA Adherence Measure Analyses
7.3.1.1.
Endpoint
The percentage of ELLIPTA doses taken (daily adherence) between the beginning of 
Month 4 and the end of Month 6 as determined by the maintenance sensor.  Daily 
adherence is defined as the participant taking one dose of Relvar/Breo ELLIPTA, within 
a 24-hour period, starting at 12.00am each day of the run-in and treatment period
7.3.1.2.
Summary Measure
The mean difference in daily adherence between the comparisons of interest will be 
estimated from an Analysis of Covariance (ANCOVA) model allowing for effects due to 
randomised treatment, baseline adherence, duration of run-in (visits), country, gender, 
and age (years).
7.3.1.3.
Population of Interest 
The exploratory adherence analyses will be based on the Intent-To-Treat population.
7.3.1.4.
Strategy for Intercurrent (Post-Randomisation) Events
The steps detailed in Section 7.1.4 Strategy for Intercurrent (Post-Randomisation) Events
will be applied sequentially when deriving the secondary adherence endpoints. See 
Section 10.5.3.1 ELLIPTA Device Sensor Assessments for further derivation details.


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7.3.1.4.1.
Events prior to premature discontinuation of the ELLIPTA maintenance 
sensor
The treatment policy estimand is directly assessed using the observed adherence data 
while the ELLIPTA maintenance sensor is in use, regardless of whether the CIS feedback 
is discontinued.
Any missing intermittent adherence data will be imputed as non-adherent i.e. the 
participant will be assumed to have not taken their treatment within the 24-hour time 
period/window, where there is no evidence of device or technical/transmission failure.
Missing intermittent adherence data due to a medical device incident such as device 
failure, technical failure of the sensor, or data transmission failure will be assumed to be 
missing at random (MAR).  For each participant, the percentage adherence measure will 
be calculated from the proportion of the number of days a participant is adherent divided 
by the number of days data provided in that month.
7.3.1.4.2.
Events following premature discontinuation of the ELLIPTA 
maintenance sensor
It is assumed that participants would continue to take ELLIPTA as they would have 
without the CIS intervention (J2R imputation) following discontinuation of the ELLIPTA 
maintenance sensor.
It is assumed that ELLIPTA treatment is no longer appropriate if the participant
discontinues ELLIPTA but remains in the study or withdraws for a reason related to 
ELLIPTA. The ELLIPTA adherence endpoint is no longer considered relevant and 
subsequent follow-up is excluded from the analysis, with participants weighted in the 
analysis by the proportion of months 4 to 6 for which data is included.
It is assumed that participants would continue to take ELLIPTA as they would have with 
their allocated CIS intervention (MAR imputation) following concurrent discontinuation 
of the ELLIPTA maintenance sensor and withdrawal unrelated to ELLIPTA or CIS.
7.3.1.5.
Statistical Analyses / Methods
Details of the planned displays will be provided in Section 10.8, Appendix 8: List of Data 
Displays and will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints /variables defined in Section 7.3.1.1 Endpoint will 
be summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.


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7.3.1.6.
Statistical Analyses / Methodology Specification
7.3.1.6.1.
The percentage of ELLIPTA doses taken (daily adherence) between the 
beginning of Month 4 and the end of Month 6
Endpoint / Variables
The percentage of ELLIPTA doses taken (daily adherence) between the beginning of Month 4 and the end 
of Month 6 as determined by the maintenance sensor for the following treatment arm comparisons:

HCP having access to sensor data

Arm 1 vs Arm 2

Arm 3 vs Arm 4

Rescue medication data being available

Arm 1 vs Arm 3

Arm 2 vs Arm 4
Daily adherence is defined as the participant taking one dose of Relvar/Breo ELLIPTA within a 24-hour
period, starting at 12.00am each day of treatment period.
Multiple Imputation Specification
Imputation will be carried out using monthly adherence rates for months 1 to 6. 1000 draws will be used. For 
each draw, four intermediate imputation datasets will be created to allow for the handling of fully unobserved 
months (using set A imputations) and partially unobserved months (using set B imputations).  

Set A where the partially observed month is directly estimated under the MAR assumption as the 
proportion of the number of days a participant is adherent divided by the number of days data 
provided in that month.

J2R imputations

MAR imputations

Set B where the partially observed month is set to missing.

J2R imputations

MAR imputations 
The timing of the intercurrent events of discontinuation of the ELLIPTA maintenance sensor, discontinuation 
of ELLIPTA and withdrawal from study will be used to identify the proportion of each month to be assigned 
as observed data, J2R imputed data, MAR imputed data, or no data. The strategy for handling intercurrent 
events is described in Section 7.1.4 Strategy for Intercurrent (Post-Randomisation) Events.
Within each imputation draw, for each month, the observed and any imputed data will be combined to 
provide a percentage adherence value. The values for months 1 to 6 will be combined to create the value 


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for the secondary analysis and the weight to be assigned to each participant.
Multiple imputation using Rubin’s rules will be used to estimate the treatment effect and associated standard 
error, by performing the ANCOVA analysis described below on the secondary endpoint within each dataset.
The multiple imputation will be implemented using the methods described in Carpenter, 2013, using the 
macros available from https://missingdata.lshtm.ac.uk/2017/04/06/gsk-five-macros/.
Model Specification
The analysis will be performed on the percentage adherence between Months 4 and 6 using an Analysis of 
Covariance (ANCOVA) model allowing for effects due to randomised treatment arm, baseline adherence, 
duration of run-in (visits), country, gender, and age (years).  
Baseline adherence will be the percentage ELLIPTA doses taken (daily adherence) during the last 28 days 
of the run-in period prior to randomisation. Randomised treatment, duration of run-in (visits), country, and 
gender will be included as categorical covariates; baseline adherence and age (years) will be included as 
continuous covariates.
Each participant will be weighted by the proportion of months 4 to 6 for which data is included in the 
percentage adherence endpoint (both observed and imputed data are accounted for in the weighting).
Data from five individual CIS treatment arms will be included in the model, and used to estimate the 
difference between:

Arm 1 and Arm 2

Arm 3 and Arm 4

Arm 1 and Arm 3

Arm 2 and Arm 4
Model Checking & Diagnostics
Normality assumptions underlying the ANCOVA model used for analysis will be examined in a limited 
number of imputed datasets by obtaining a normal probability plot of the residuals and a plot of the residuals 
versus the fitted values (i.e. checking the normality assumption and constant variance assumption of the 
model respectively) to gain confidence that the model assumptions are reasonable.
If there are any departures from the distributional assumptions, alternative models may be explored using 
appropriately transformed data.
Interactions with treatment will be explored for other model covariates and tests for interactions will be at the 
2-sided 10% significance level. Any significant interactions that are found will be thoroughly investigated and 
where necessary, extra outputs will be produced.
Model Results Presentation
Summary statistics (mean, standard deviation, median, minimum, maximum) of the primary endpoint will be 
provided, based on the observed percentages.
The adjusted means for each treatment arm and the estimated treatment arm difference for the treatment 
arm comparisons of interest will be presented together with the 95% confidence interval for the differences 


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and corresponding p-values from the multiple imputation procedure.
7.3.2.
Exploratory Health Care Utilization Analyses
7.3.2.1.
Endpoints

Number of outpatient visits relating to asthma

Number of primary care visits relating to study HCP dashboard review (for relevant 
study arms)

Number of and duration of hospitalisations, and ER visits due to asthma

Annualised rate of severe exacerbations

Number of unscheduled visits to primary care related to Asthma
7.3.2.2.
Population of Interest 
The exploratory analyses will be based on the Intent-To-Treat population.
Endpoint
Healthcare Utilisation -

Number of outpatient visits relating to asthma

Number of and duration of hospitalisations, and ER visits due to asthma

Number of unscheduled visits to primary care related to Asthma 
Summary

The number and percentage of participants by frequency of unscheduled healthcare resource contacts 
(0, 1, 2, 3, 4, >4) will be summarized by contact type and treatment arm to characterize the level of 
healthcare associated with an asthma exacerbation. The frequency counts for each participant will be 
the total sum of contacts (or days in hospital) by type.

The following types of healthcare contact for an exacerbation are recorded in the eCRF:

Number of telephone calls

Number of home/day visits

Number of home/night visits

Number of physician office/practice visits

Number of urgent care/outpatient visits

Number of emergency room visits

Number of inpatient hospitalisation days

Number of contacts due to an exacerbation


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Endpoint
Healthcare Utilisation -

Number of primary care visits relating to study HCP dashboard review (for relevant study arms) 
Summary

The number and percentage of participants by frequency of unscheduled healthcare resource contacts 
(0, 1, 2, 3, 4, >4) will be summarized by contact type and treatment arm to characterize the level of 
healthcare associated with an asthma exacerbation. The frequency counts for each participant will be 
the total sum of contacts (or days in hospital) by type.
Endpoint
Healthcare Utilisation -

Annual rate of severe asthma exacerbations
Summary 

The number and percentage of participants reporting an asthma exacerbation (on-treatment and post-
treatment) will be summarised by treatment arm.

The number and percentage of participants with each number of exacerbations (0, 1, 2, 3, 4, >4) and 
the total number of exacerbations per treatment arm will also be summarised.

For the purposes of summarizing these data, the annualized rate of severe asthma exacerbations for 
the ITT population will be calculated for each participant as 
o
the number of exacerbations / time on Relvar/Breo (in years) from randomisation. 

The summaries will include on-treatment exacerbations, from randomisation date to min(stop date of 
exposure + 1 day, date of study discontinuation).

The number and percentage of participants with an exacerbation that led to withdrawal of study, 
hospitalization, systemic/oral corticosteroids/antibiotics/medication being taken, or emergency room 
visit will be summarised by treatment arm.

A listing of severe exacerbations will be provided.
7.3.3.
Exploratory Patient Reported Outcomes (PROs) Analyses
7.3.3.1.
Endpoints

Percentage of patients meeting a responder threshold of ≥ 0.09 points improvement 
from baseline (randomisation) for the ASUI total score at month 6

Change from baseline (randomisation) in ASUI total score at month 6

Percentage of patients meeting a responder threshold of ≥ 4 points improvement
(decrease) from baseline (randomisation) for the SGRQ total score at month 6

Change from baseline (randomisation) in SRGQ total score at month 6

Change from baseline (screening) in PAM total score at month 6

Change from baseline (screening) in MARS-A total score at month 6

Change from baseline (screening) in BMQ – General Benefit score at month 6

Change from baseline (screening) in BMQ – General Harm score at month 6

Change from baseline (screening) in BMQ – General Overuse score at month 6

Change from baseline (screening) in BMQ – Specific Necessity score at month 6

Change from baseline (screening) in BMQ – Specific Concern score at month 6


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7.3.3.2.
Summary Measure
The PRO summary measures to determine treatment arm effect are:

An adjusted odds ratio on percentage of patients meeting a responder threshold of 
≥ 0.09 points improvement from baseline for the ASUI total score at Month 6, 
along with a 95% confidence interval and p-value for the percentage, analysed 
using a logistic regression model.

The difference in LS means of the change from baseline in ASUI total score at 
month 6, along with a 95% confidence interval and p-value for the difference, 
analysed using an MMRM model. 

An adjusted odds ratio on percentage of patients meeting a responder threshold of 
≥ 4 points improvement (decrease) from baseline for the SGRQ total score at 
Month 6, along with a 95% confidence interval and p-value for the percentage, 
analysed using a logistic regression model.

The difference in LS means of the change from baseline in SGRQ total score at 
month 6, along with a 95% confidence interval and p-value for the difference, 
analysed using an MMRM model. 

Mean change from baseline (screening) in PAM-13 total score at month 6.

Mean change from baseline (screening) in MARS-A total score at month 6

Mean change from baseline (screening) in BMQ – General Benefit score at month 
6

Mean change from baseline (screening) in BMQ – General Harm score at month 6

Mean change from baseline (screening) in BMQ – General Overuse score at 
month 6

Mean change from baseline (screening) in BMQ – Specific Necessity score at 
month 6

Mean change from baseline (screening) in BMQ – Specific Concern score at 
month 6
7.3.3.3.
Population of Interest
The PRO exploratory summaries and analysis will be based on the “Intent-to-Treat” 
population.
7.3.3.4.
Strategy for Intercurrent (Post-Randomisation) Events
Intercurrent events for the ASUI and SGRQ outcomes were identified as:

Early discontinuation of ELLIPTA

Early discontinuation of the APP

Early discontinuation of ELLIPTA sensor

Early discontinuation of MDI sensor

Early withdrawal from study

Use of MDI rescue medication

Use of prohibited medications 

Change of dose of ELLIPTA


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The “Treatment policy” strategy will be applied to handle the “Early discontinuation of 
ELLIPTA sensor”, “Early discontinuation of the APP”, “Early discontinuation of MDI 
sensor”, “Use of MDI rescue medication”, “Use of prohibited medications” and “change 
of dose of ELLIPTA” for all PRO exploratory endpoints. The strategy implies direct use 
of PRO data irrespective of the occurrence of these intercurrent events. 
7.3.3.4.1.
Percentage of patients meeting a responder threshold of ≥ 0.09 points 
improvement from baseline (randomisation) for the ASUI total score at 
Month 6 (Visit 10)
The “Composite” strategy will be used for the “Early discontinuation of ELLIPTA” and 
‘Early discontinuation of study” intercurrent events. In the occurrence of these 
intercurrent events, the effect to be estimated will be the effect on the outcome of 
achieving an improvement from baseline of ≥ 0.09 in ASUI total score at month 6 and 
remaining on ELLIPTA (off-ELLIPTA treatment data is not collected). Participants who 
do not meet the improvement threshold, have missing values for their ASUI total score at 
month 6, or discontinue using ELLIPTA or the study will be classified as non-responders 
in all planned analyses for this endpoint.
The “Treatment policy” strategy will be used to handle discontinuation of the
APP/sensor. This means direct assessment of ASUI total score at month 6 against the
responder criteria, irrespective of CIS discontinuation status. 
7.3.3.4.2.
Change from baseline (randomisation) in ASUI total score at month 6
(Visit 10)
The “treatment policy” strategy will be applied to all handle all the intercurrent events 
listed in 7.4.3.4. In other words, all observed data before early discontinuation of the 
study respective of treatment status (on-treatment) or CIS discontinuation status will be 
included in the analysis. No missing data will be imputed, missing data will be 
considered MAR. Therefore, the primary treatment effect to be estimated will be the 
mean change from baseline in ASUI total score at month 6 and remaining on the study. 
7.3.3.4.3.
Percentage of patients meeting a responder threshold of ≥ 4 points 
improvement (decrease) from baseline (randomisation) for the SGRQ 
total score at month 6 (Visit 10)
The “Composite” strategy will be used for the “Early discontinuation of ELLIPTA” and 
‘Early discontinuation of study” intercurrent events. In the occurrence of these 
intercurrent events, the effect to be estimated will be the effect on the outcome of 
achieving an improvement from baseline of ≥ 4 in SGRQ total score at month 6 and 
remaining on ELLIPTA (off-ELLIPTA treatment data is not collected). Participants who 
do not meet the improvement threshold, have missing values for their SGRQ total score 
at month 6, or discontinue using ELLIPTA or the study will be classified as non-
responders in all planned analyses for this endpoint.
The “Treatment policy” strategy will be used to handle discontinuation of the
APP/sensor. This means direct assessment of SGRQ total score at month 6 against the
responder criteria, irrespective of CIS discontinuation status. 


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7.3.3.4.4.
Change from baseline (Randomisation) in SGRQ total score at Month 6
(Visit 10)
The “treatment policy” strategy will be applied to all handle all the intercurrent events 
listed in 7.4.3.4. In other words, all observed data before early discontinuation of the 
study respective of treatment status (on-treatment) or CIS discontinuation status will be 
included in the analysis. No missing data will be imputed, missing data will be 
considered MAR. Therefore, the primary treatment effect to be estimated will be the 
mean change from baseline in SGRQ total score at month 6 and remaining on the study. 
7.3.3.4.5.
Change from baseline (Screening) in PAM-13, MARS-A, and BMQ total 
score at Month 6 (Visit 10)
The mean change from baseline in PAM-13, MARS-A and all scales for the BMQ 
questionnaires at month 6 will be summarised using descriptive statistics (n, mean, SD, 
median, min, max) for each treatment arm. The “treatment policy” strategy will be 
applied to all handle all the intercurrent events listed in 7.4.3.4. In other words, all 
observed data before early discontinuation of the study respective of treatment status (on-
treatment) or CIS discontinuation status will be included in the analysis. No missing data 
will be imputed, missing data will be considered MAR. Therefore, the primary treatment 
arm effect to be estimated will be the mean change from baseline in total score at month 
6 and remaining on the study. 
No formal statistical analyses will be performed for these endpoints.
7.3.3.5.
Statistical Analyses / Methodology Specification
Details of the planned displays will be provided in Section 10.8, Appendix 8: List of Data 
Displays and will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 7.3.3.1, Endpoints, 
will be summarised using descriptive statistics, graphically presented (where appropriate) 
and listed.
7.3.3.5.1.
Increase from Baseline of ≥ 0.09 in ASUI total score at Month 6 (Visit 
10)
Endpoint / Variables
Percentage of patients meeting a responder threshold of ≥ 0.09 points improvement from baseline for the ASUI 
total score at Month 6 (Visit 10)
Model Specification
This endpoint will be analysed using a logistic regression model. Only the month 6 (visit 10) data will be 
included in the model. Month 1 (visit 5) data will not be implemented since by this timepoint participants may 
not have reverted to steady medicating behaviour
Terms in the model:

Dependent variable: ASUI responder/non-responder score (binary score) 

Covariates:  
o
Categorical: randomised treatment arm, gender and country
o
Continuous: baseline ASUI total score and age. 


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Patients who have a missing ASUI total score at month 6 (visit 10) (i.e. no ASUI data on-treatment) will be 
classified as non-responders at that visit. This rule will apply to all above analyses.
Computation of confidence intervals for the odds ratios is based in the individual Wald tests.
Model Checking & Diagnostics
If the likelihood maximisation algorithm fails to converge due to complete or quasi-complete separation of the 
data then Firth’s penalized likelihood (Firth, 1993) will be implemented by use of the FIRTH option on the 
MODEL statement in PROC LOGISTIC. 
The fit off the logistic regression model will be assessed by examining the ROC curve and other diagnostic 
plots.
Model Results Presentation
The number and percentage of participants with a response within each randomised treatment arm will be 
presented by visit, together with the adjusted odds ratio comparing CIS Arms 1, 2, 3, 4 with Arm 5, associated 
95% CIs and p-values. 
7.3.3.5.2.
Change from baseline (Randomisation) in ASUI total score at Month 6
(Visit 10)
Endpoint / Variables
Mean change from baseline in ASUI total score at Month 6 (Visit 10)
Model Specification
This endpoint will be analysed using a mixed model repeated measures (MMRM) model utilising the REML 
estimation approach and the default unstructured covariance matrix structure. Whilst missing data are not 
implicitly imputed in this analysis, there is an underlying assumption that the data are MAR. All non-missing 
data for a participant will be used within the analysis and, via modelling of the within-participant correlation 
structure, the derived treatment differences will be adjusted to take into account missing data.
Terms fitted in the model will include: 

Dependent Variable: change from baseline in ASUI total score at month 6

Covariates:
o
Fixed categorical:  randomised treatment arm, visit (month 1 and 6), gender and country.
o
Fixed continuous:  baseline ASUI total score and age
o
Interaction terms: randomised treatment arm-by-visit, baseline ASUI total score-by-visit
o
Random effect: participant
Model Checking & Diagnostics

If this model fails to converge, alternative correlation structures may be considered

Appropriate graphs will be reviewed as part of the model checking process to ensure that distributional 
assumptions hold. These will include a normal probability plot of the residuals and a plot of the residuals 
versus the fitted values (checking the normality assumption and constant variance assumption of the 
model, respectively).

Interactions with treatment will be explored for other model covariates and tests for interactions will be at 
the 2-sided 10% significance level. Any significant interactions that are found will be thoroughly 
investigated and where necessary, extra outputs will be produced.


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Model Results Presentation
Adjusted mean change from baseline values for each treatment arm will be presented with their associated 
standard errors. The estimated treatment difference along with corresponding standard error, 95% confidence 
interval (CI) and p-value will be presented for the treatment comparisons at month 6 (Visit 10).
7.3.3.5.3.
Increase from Baseline of ≥ 4 in SGRQ total score at Month 6 (Visit 10)
Endpoint / Variables
Percentage of patients meeting a responder threshold of ≥ 4 points improvement from baseline for the SGRQ
total score at month 6
Model Specification
This endpoint will be analysed using a logistic regression model. Only the month 6 (visit 10) data will be 
included in the model. Month 1 (visit 5) data will not be implemented since by this timepoint participants may 
not have reverted to steady medicating behaviour
Terms in the model:

Dependent variable: SGRQ responder/non-responder score (binary score) 

Covariates:  
o
Categorical: randomised treatment arm, gender and country
o
Continuous: baseline SGRQ total score and age. 
Patients who have a missing SGRQ total score at month 6 (visit 10) (i.e. no SGRQ data on-treatment) will be 
classified as non-responders at that visit. This rule will apply to all above analyses.
Computation of confidence intervals for the odds ratios is based in the individual Wald tests.
Model Checking & Diagnostics
If the likelihood maximisation algorithm fails to converge due to complete or quasi-complete separation of the 
data then Firth’s penalized likelihood (Firth, 1993) will be implemented by use of the FIRTH option on the 
MODEL statement in PROC LOGISTIC. 
The fit of the logistic regression model will be assessed by examining the ROC curve and other diagnostic 
plots.
Model Results Presentation
The number and percentage of participants with a response within each randomised treatment arm will be 
presented by visit, together with the adjusted odds ratio comparing CIS Arms 1, 2, 3, 4 with Arm 5, associated 
95% CIs and p-values.
7.3.3.5.4.
Change from baseline (Randomisation) in SGRQ total score at Month 6
(Visit 10)
Endpoint / Variables
Mean change from baseline in SGRQ total score at Month 6 (Visit 10)
Model Specification
This endpoint will be analysed using a mixed model repeated measures (MMRM) model utilising the REML 
estimation approach and the default unstructured covariance matrix structure. Whilst missing data are not 
implicitly imputed in this analysis, there is an underlying assumption that the data are MAR. All non-missing 
data for a participant will be used within the analysis and, via modelling of the within-participant correlation 


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structure, the derived treatment differences will be adjusted to take into account missing data.
Terms fitted in the model will include: 

Dependent Variable: change from baseline in SGRQ total score at month 6

Covariates:
o
Fixed categorical:  randomised treatment arm, visit (month 1 and 6), gender and country.
o
Fixed continuous:  baseline SGRQ total score and age
o
Interaction terms: randomised treatment arm-by-visit, baseline SGRQ total score-by-visit
o
Random effect: participant
Model Checking & Diagnostics

If this model fails to converge, alternative correlation structures may be considered

Appropriate graphs will be reviewed as part of the model checking process to ensure that 
distributional assumptions hold. These will include a normal probability plot of the residuals and a 
plot of the residuals versus the fitted values (checking the normality assumption and constant 
variance assumption of the model, respectively).

Interactions with treatment will be explored for other model covariates and tests for interactions will 
be at the 2-sided 10% significance level. Any significant interactions that are found will be thoroughly 
investigated and where necessary, extra outputs will be produced.
Model Results Presentation
Adjusted mean change from baseline values for each treatment arm will be presented with their associated 
standard errors. The estimated treatment difference along with corresponding standard error, 95% confidence 
interval (CI) and p-value will be presented for the treatment comparisons at month 6 (Visit 10).
7.3.4.
Exploratory Fractionated Exhaled Nitric Oxide (FeNO) and Peak 
Expiratory Flow (PEF) Analyses
7.3.4.1.
Endpoints

FeNO at Screening (Visit 1), Randomisation (Visit 2,3 or 4), Month 1 (Visit 5) 
and Month 6 (Visit 10).

Change from baseline (randomisation) in FeNO measured at Month 1 (Visit 5) 
and Month 6 (Visit 10)

PEF at Screening (Visit 1), Randomisation (Visit 2,3 or 4), Month 1 (Visit 5) and 
Month 6 (Visit 10).

Change from baseline (randomisation) in PEF measured at Month 1 (Visit 5) and 
Month 6 (Visit 10)
7.3.4.2.
Summary Measures
The FeNO and PEF summary measures are:

Summary statistics (n, mean, SD, median, min, max) for each treatment arm of 
screening (Visit 1), Randomisation (Visit 2,3 or 4), Month 1 (Visit 5) and Month 
6 (Visit 10) and changes from baseline (screening) at month 1 (visit 5) and month 
6 (visit 10)


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7.3.4.3.
Population of Interest
The FeNO and PEF exploratory summaries will be based on the Intent-to-Treat 
population.
7.3.4.4.
Strategy for Intercurrent (Post-Randomisation) Events
Intercurrent events for the FeNO and PEF outcomes were identified as:

Early discontinuation of ELLIPTA

Early discontinuation of the APP

Early discontinuation of ELLIPTA sensor

Early discontinuation of MDI sensor

Early withdrawal from study

Use of MDI rescue medication

Use of prohibited medications 

Change of dose of ELLIPTA
The “Treatment policy” strategy will be applied to handle all intercurrent event for the 
FeNO and PEF exploratory endpoints. The strategy implies direct use of FeNO and PEF
data irrespective of the occurrence of these intercurrent events. 
7.3.4.5.
Statistical Analyses / Methodology Specification
Details of the planned displays will be provided in Section 10.8, Appendix 8: List of Data 
Displays and will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 7.3.4.1 Endpoints
will be summarised using descriptive statistics, graphically presented (where appropriate) 
and listed.  No formal statistical analyses will be performed for these endpoints.
Endpoint

FeNO at Screening (Visit 1), Randomisation (Visit 2,3 or 4), Month 1 (Visit 5) and Month 6 (Visit 10)

Change from baseline (randomisation) in FeNO measured at Month 1 (Visit 5) and Month 6 (Visit 10)

PEF at Screening (Visit 1), Randomisation (Visit 2,3 or 4), Month 1 (Visit 5) and Month 6 (Visit 10)

Change from baseline (randomisation) in PEF measured at Month 1 (Visit 5) and Month 6 (Visit 10)
Summary
All endpoints to be summarised using descriptive statistics (n, mean, SD, median, min, max) for each 
randomised treatment arm.
To explore the impact of maintenance adherence levels on FeNO and PEF, the following displays will be 
presented,

Summary statistics (n, mean, SD, median, min, max) of change from baseline at Month 6 (Visit 10) in 
FeNO per quartile of the observed primary endpoint measure, percentage of ELLIPTA doses taken 
(daily adherence) between the beginning of Month 4 and the end of Month 6 as determined by the 


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maintenance sensor

Summary statistics (n, mean, SD, median, min, max) of change from baseline at Month 6 (Visit 10) in 
PEF per quartile of the observed primary endpoint measure, percentage of ELLIPTA doses taken (daily 
adherence) between the beginning of Month 4 and the end of Month 6 as determined by the 
maintenance sensor

Note: the quartiles of a ranked adherence data values are four subsets whose boundaries are the three 
quartile points (25th, 50th and 75thpercentiles)

A scatter plot of the change from baseline at Month 6 (Visit 10) in FeNO by observed primary endpoint 
measure will be presented.  This will be repeated for change from baseline at Month 6 (Visit 10) in PEF.
7.3.5.
Qualitative data from exit interviews
Analysis of the qualitative data from exit interviews will be analyzed following a separate 
qualitative analysis plan and presented in a separate Clinical Study Report (CSR).


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8.
SAFETY ANALYSES
Safety analyses will be based on the ITT Population and will include all study data (run-
in, on and post-treatment), unless otherwise specified.
Safety endpoints will include:

Incidence and type of serious adverse events

Incidence and type of adverse drug reactions (ADR)

Incidence and type of non-serious adverse events leading to study withdrawal
8.1.
Adverse Events Analyses
SAEs, AEs leading to withdrawal and non-serious ADRs will be collected.
The incidence of any given adverse event (SAE, ADR or non-serious AEs leading to 
withdrawal) for each treatment group is defined as the proportion of participants in that 
group who have experienced at least one such adverse event during the study period.
Adverse event (SAE or ADR) summaries including the summary of adverse drug 
reactions (ADRs), Serious (SAEs) and non-serious adverse events leading to withdrawal
of study will be based on GSK Core Data Standards. The details of the planned displays 
are provided in Section 10.8 Appendix 8: List of Data Displays.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) coding dictionary. The version of MedDRA used in reporting will be noted in 
a footnote of the AE overview table.
For the standard on-treatment and post-treatment AE tables, the number and percentage 
of participants with all AEs (regardless of causality) will be summarized for each 
treatment group by system organ class (SOC) and preferred term (PT). The ordering of 
the SOCs and the PTs within the SOCs will both be in descending order of total 
incidence. A SOC will not be presented when the overall incidence for any AE within the 
particular system is zero. If the total incidence for any two or more AEs is equal, the 
events will be presented in alphabetical order.
8.2.
Adverse Events of Special Interest
A comprehensive list of MedDRA terms based on clinical and safety review will be used 
to identify AEs of special interest to FF and Relvar/Breo. Changes to the MedDRA 
dictionary may occur between the start of the study and the time of reporting and/or 
emerging data from on-going studies may highlight additional AEs of special interest; 
therefore, the list of terms to be used for each event of interest and the specific events of 
interest will be based on the clinical and safety review agreements documented and in 
place at time of reporting and prior to unblinding the study. The details of the planned 
displays are provided in Section 10.8 Appendix 8: List of Data Displays.


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The number and percentage of participants with on-treatment AEs of special interest will 
be summarized for each treatment group by special interest term, subgroup and PT. The 
ordering of the special interest terms, the subgroups and the PTs within them will all be 
in descending order of total incidence. If the total incidence for any two or more AEs is 
equal, the events will be presented in alphabetical order. This summary will be produced 
for non-serious ADRs, and repeated for serious ADRs, all ADRs and SAEs.  The list of 
MedDRA terms used to identify AEs of special interest will be displayed.
8.3.
Pregnancy
Any pregnancies reported during the study will be summarized in CSR case narratives. 
Any pregnancy complication or elective termination of a pregnancy for medical reasons 
will be recorded as an AE or SAE and included in summaries and listings of AEs/SAEs.
8.4.
Other Safety Measures
All Relvar/Breo ELLIPTA inhaler device malfunction data for participants reporting at 
least one inhaler malfunction will be listed. 


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9.
REFERENCES
Bime, C., Wei, C., Holbrook, J., Sockrider, M., Revicki, D. and Wise, R. Asthma 
Symptom Utility Index: Reliability, validity, responsiveness, and the minimal important 
difference in adult asthmatic patients. Journal of Allergy and Clinical Immunology. 2012; 
130(5):1078-1084.
Carpenter, JR, Roger, J, and Kenward, MG. Analysis of longitudinal trials with missing 
data: A framework for relevant, accessible assumptions, and inference via multiple 
imputation. Journal of Biopharmaceutical Statistics 2013;23:1352–71.
Cohen J, Mann D, Wisnivesky J. Assessing the validity of self-reported medication 
adherence among inner-city asthmatic adults: The Medication Adherence Report Scale 
for Asthma. Annals of Allergy Asthma Immunology. 2009 Oct;103(4):325-31.
Firth D. Bias Reduction of Maximum Likelihood Estimates. Biometrika. 1993;80:27–38.
GlaxoSmithKline Document Number 2016N307903_01: Study 207040; An open label, 
randomised, parallel group clinical study to evaluate the effect of the Connected Inhaler 
System (CIS) on adherence to Relvar/Breo ELLIPTA therapy, in asthmatic participants 
with poor control.
Hibbard J, Stockard J, Mahoney R, and Tusler M. Development of the Patient Activation 
Measure (PAM): Conceptualizing and Measuring Activation in Patients and Consumers. 
HSR: Health Services Research 2004; 39:4, Part I
Jones P, Francis H, Quirk H et al. A Self-Complete Measure of Health Status for Chronic 
Airflow Limitation;The St. George's Respiratory Questionnaire. American Review of 
Respiratory Disease 1992; 145:1321-1327
Nathan R, Sorkness C, Kosinski M et al. Development of the asthma control test: A 
survey for assessing asthma control. Journal of Allergy and Clinical Immunology. 
Volume 113, Issue 1, January 2004, Pages 59–65
Revicki D A, Leidy N K, Et al. Integrating patient preferences into health outcomes 
assessment: The multivariable Asthma Symptoim Utility Index. Chest. 1998;114:998-
1007.
Schatz M, Kosinski M, Yarlas AS, Hanlon J, Watson ME, Jhingran P. The minimally 
important difference of the Asthma Control Test, The Journal of allergy and clinical 
immunology (2009)


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10.
APPENDICES
10.1.
Appendix 1: Schedule of Activities
10.1.1.
Protocol Defined Schedule of Events
Procedures
Screen
Run-In
Treatment Period
EW
Follow
-up
Notes
Visit/Contact
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
Conditional Visits: V3 & V4 are only required if a 
participant is not included at prior run in visit. 
V6, V7, V8 & V9 are only required for Treatment 
arms 1 & 3. Randomisation to treatment arms will 
occur at Visit 2,3 or 4 when randomisation criteria 
have been met
Month of Study
-1
0
0
0
1
2
3
4
5
6
Day of Study
-28
0
0
0
28
56
84
112
140
168
175
Visit Window (days)
2
2
2
2
7
7
7
7
7
2
Conditional Visits
X
X
X
X
X
X
SCREENING ASSESSMENTS
Written Informed Consent
X
Signed by the participant and HCP/ designee 
prior to any other study assessments. May be 
completed at a separate visit to screening if 
required.
Participant Demography
X
Medical History
X
Asthma History 
X
Including exacerbation history for previous 12 
months and those involving hospitalisation 
Therapy History
X
Maintenance therapy over previous 12 months, 
including number of prescriptions requested or 
provided
Physical Exam
X
Full physical including height, weight and vital 
signs
Inclusion/Exclusion 
Criteria
X
X
X
X
ACT assessment for inclusion required at run-in 
visits
Randomisation
X
X
X
Participant randomised to treatment at only one of 
V2, V3 or V4 once ACT criteria is met


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Procedures
Screen
Run-In
Treatment Period
EW
Follow
-up
Notes
Visit/Contact
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
Conditional Visits: V3 & V4 are only required if a 
participant is not included at prior run in visit. 
V6, V7, V8 & V9 are only required for Treatment 
arms 1 & 3. Randomisation to treatment arms will 
occur at Visit 2,3 or 4 when randomisation criteria 
have been met
Month of Study
-1
0
0
0
1
2
3
4
5
6
Day of Study
-28
0
0
0
28
56
84
112
140
168
175
Visit Window (days)
2
2
2
2
7
7
7
7
7
2
Conditional Visits
X
X
X
X
X
X
SAFETY ASSESSMENTS
Concomitant Medication
X
Urine Pregnancy Test
X
X
X
X
X
X
X
SAEs
X
X
Non-Serious Adverse 
Events that leads to 
withdrawal 
X
X
Non-serious adverse events that leads to dose 
modification, drug discontinuation, or withdrawal 
from the trial. Collected from start of run in
Non-serious Adverse
Drug Reactions
X
X
Collected from start of run in
Exacerbations
X
X
Severe Exacerbation are to be reviewed and 
recorded. Collected from start of run in
Unscheduled HCP visits
X
All secondary care contacts and all primary care 
contacts related to Asthma 
QUESTIONNAIRES & Patient Reported Outcomes (PROs) (Performed in the order given here)
ACT
X
X
X
X
X
X
X
ACT performed at V2, V3 or V4 to confirm 
inclusion for randomisation
ASUI
X1
X2
X2
X2
X
X
X
1. PRO’s only performed at screening once a 
participant is included.
2. The PRO’s are only performed at the run-in 
visit (V2, V3 or V4) if a participant is 
randomised to treatment
SGRQ
X2
X2
X2
X
X
X
PAM
X1
X2
X2
X2
X
X
X
MARS-A
X1
X2
X2
X2
X
X
X
BMQ
X1
X2
X2
X2
X
X
X
EXIT Questionnaire 
X
X


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Procedures
Screen
Run-In
Treatment Period
EW
Follow
-up
Notes
Visit/Contact
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
Conditional Visits: V3 & V4 are only required if a 
participant is not included at prior run in visit. 
V6, V7, V8 & V9 are only required for Treatment 
arms 1 & 3. Randomisation to treatment arms will 
occur at Visit 2,3 or 4 when randomisation criteria 
have been met
Month of Study
-1
0
0
0
1
2
3
4
5
6
Day of Study
-28
0
0
0
28
56
84
112
140
168
175
Visit Window (days)
2
2
2
2
7
7
7
7
7
2
Conditional Visits
X
X
X
X
X
X
Exit Interview
X
X
X
Interview is for sub-set of participants who agree 
to take part and can be performed at V10 or V11 
for logistical reason. There is a 14 day window for 
vendor to schedule and conduct exit interviews. 
ASSESSMENTS
Fractional exhaled Nitric 
Oxide (FeNO)
X1
X2
X2
X2
X
X
X
1.PEF & FeNO only performed once a participant
is included.  
2.PEF and FeNO is only performed at the Run-in 
visit if a participant is randomised
FeNO performed prior to PEF
Peak Expiratory Flow 
(PEF)
X1
X2
X2
X2
X
X
X
HCP dashboard review
X
X
X
X
X
X
Participants in treatment arms 1 and 3 only.  HCP 
will record action and outcome of review.
INVESTIGATIONAL PRODUCT
Dispense Sensors
X
Sensors must be attached and switched on in 
clinic.
Dispense Relvar/Breo 
ELLIPTA
X
X
All participants will attend independent dispensing 
visits to collect their next Relvar/Breo ELLIPTA 
and/or salbutamol MDI as required.  Patients are 
required to bring the sensor to the dispensing 
visits.  The sensor will be attached to the new 
device and switched on at the dispensing visit.
Dispense Salbutamol MDI
X
X
Training in CIS
X
X
X
X
X
Participants are trained in fitting the sensors at 
screening. Following randomisation, participants 
will be trained in CIS as relevant for their 
treatment arm. Retraining can be provided at V5.


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Procedures
Screen
Run-In
Treatment Period
EW
Follow
-up
Notes
Visit/Contact
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
Conditional Visits: V3 & V4 are only required if a 
participant is not included at prior run in visit. 
V6, V7, V8 & V9 are only required for Treatment 
arms 1 & 3. Randomisation to treatment arms will 
occur at Visit 2,3 or 4 when randomisation criteria 
have been met
Month of Study
-1
0
0
0
1
2
3
4
5
6
Day of Study
-28
0
0
0
28
56
84
112
140
168
175
Visit Window (days)
2
2
2
2
7
7
7
7
7
2
Conditional Visits
X
X
X
X
X
X
Training in ELLIPTA & 
MDI correct use
X
X
Once included a participant should be trained in 
correct use of ELLIPTA and MDI devices
Correct Use Assessment 
for ELLIPTA and MDI
X
X
Inhaler use technique will be assessed for correct 
use. This need only be recorded in source.
Return Sensors
X
X
Return Relvar/Breo 
ELLIPTA
X
X
Patients are required to return their devices at the 
independent dispensing visits. Doses remaining 
on each returned ELLIPTA inhaler will be 
recorded.  
Return Salbutamol MDI
X
X
Patients to return used MDI at dispensing visits.


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10.2.
Appendix 2: Assessment Windows
10.2.1.
General
Clinic visits are scheduled to take place as specified in Appendix 1: Schedule of 
Activities. Individual measurements will be reported based on the visits they are assigned 
to in the study database without adjustment. Measurements outside visit windows will not 
be excluded from analyses.
If a circumstance should arise where multiple measurements have been collected and 
recorded against the same timepoint, then the first valid value will be used for that 
timepoint.
The maximum value obtained from the multiple PEF and FeNO assessments at a visit 
will be used in summaries and analyses.  Participants who withhold a daily dose of 
maintenance therapy and rescue medication for 6 hours prior to the assessment will have 
value included in the summaries.
10.2.2.
Definitions of Assessment Windows for Adherence and Rescue
Medication Use Analyses
All participants have a sensor on their maintenance and rescue medication to consistently 
measure their adherence to maintenance and level of rescue medication use in the study.  
The sensors are attached to participants ELLIPTA Relvar/Breo maintenance treatment 
and MDI rescue medication from start of Visit 1 until Visit 10.  The sensors record the 
time and date when the Relvar/Breo ELLIPTA cover is opened and closed and the 
salbutamol MDI rescue medication is actuated.
Study day 1 is defined as the day of randomisation. This could be the day of Visit 2, 3 or 
4, dependent on the length of the run-in period. Study day for all other visits, assessments
and events are calculated relative to this.
The following information in Table 5 displays which sensor records are summarised for 
each analysis time period (Analysis Month).  Any sensor data recorded post the Month 6 
(day 168) time period will not be included in the analysis of ELLIPTA adherence or 
salbutamol MDI rescue medication use of sensor data.  


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Table 5
Sensor Data Assessment Windows
Sensor Data Assessment Windows
Analysis 
Month
Analysis Period
Beginning Timepoint
Ending Timepoint
Baseline
Latest of either Day -28 or day after Visit 1
(minimum of 14 days must be present to create 
a baseline)
Day -1
(Day prior to randomisation)
1
Day 1
(Day of randomisation)
Day 28 or discontinuation from 
adherence/rescue assessment if within 
month 1
2
Day 29
Day 56 or discontinuation from 
adherence/rescue assessment if within 
month 2
3
Day 57
Day 84 or discontinuation from 
adherence/rescue assessment if within 
month 3
4
Day 85
Day 112 or discontinuation from 
adherence/rescue assessment if within 
month 4
5
Day 113
Day 140 or discontinuation from 
adherence/rescue assessment if within 
month 5
6
Day 141
Earliest of either day of visit 10, Day 168 
or discontinuation from adherence/rescue 
assessment if within month 6 if 
participant is a completer 
OTHERWISE
Day 168 or discontinuation from 
adherence/rescue assessment if within 
month 6
Note: ‘Discontinuation from adherence/rescue assessment’ occurs at the earliest of premature 
discontinuation from use of the ELLIPTA /MDI sensor, premature discontinuation of ELLIPTA (for 
adherence measures), or premature withdrawal from the study.


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10.3.
Appendix 3: Study Phases and Treatment Emergent 
Adverse Events
10.3.1.
Study Phases
Since participants are on Relvar/Breo study treatment from the time they enter run-in, 
assessments and events will be classified according to time of occurrence relative to the 
randomisation date and last stop date of Relvar/Breo treatment. The randomisation and 
latest exposure treatment stop dates will be used to determine whether an assessment or 
event was during pre-screening treatment, run-in treatment, on-treatment or post-
treatment. If it is not possible to tell whether an assessment or event was on-treatment or 
not, it will be considered as on-treatment.
10.3.1.1.
Study Phases for Concomitant Medication
A medication will be summarised in every study phase (pre-screening, run-in, on- or 
post-treatment) in which it was taken, so a medication that was started during the run-in 
period and stopped during the post-randomisation treatment period will appear in both the 
run-in-treatment and the on-treatment summaries.
On-treatment will be considered to be from the day of randomisation to treatment arm
until the last (Relvar/Breo) treatment stop date. Post-treatment will be considered to be 
from the day after the last treatment stop date and onward. Run-in-treatment will be 
considered from the screening visit until prior to randomisation to treatment arm date.If a 
participant’s last treatment stop date is missing, this will be assumed to the date of the 
last recorded on-treatment visit up to Visit 10 (not including the Follow-up visit) or the 
return of the last Relvar/Breo container, whichever is later.
Study Phase
Definition
Pre-Screening 
Treatment
Date of Medication < Screening Visit Date
Run-in Treatment
(Date of Medication  ≥ Screening Visit date) and (Date of Medication < Randomisation 
Date)
On-Treatment
(Date of Medication ≥ Randomisation Date) and (Date of Medication ≤Last Treatment 
Stop Date)
Post-Treatment
Date of Medication > Last Treatment Stop Date 
10.3.1.2.
Study Phases for Asthma Exacerbations
Study Phase
Definition
Run-in-Treatment
(Exacerbation Onset Date ≥ Screening Visit date) and (Exacerbation Onset Date < 
Randomisation Date)
On-Treatment 
(Exacerbation Onset Date ≥ Randomisation Date) and (Exacerbation Onset Date ≤ 
Last Treatment Stop Date)+1
Post-Treatment
Exacerbation Onset Date > Last Treatment Stop Date+1


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10.3.1.3.
Treatment Emergent Flag for Adverse Events
Study Phase
Definition
Run-in-
Treatment*
(AE Start Date ≥ Screening Visit date) and (AE Start Date < Randomisation Date)
On-Treatment 
(AE Start Date ≥ Randomisation Date) and (AE Start Date ≤ Last Treatment Stop 
Date)+1
Post-Treatment
AE Start Date > Treatment Stop Date + 1
Onset Time Since 
First Dose (days)*
Time Since First Dose will be derived as followed:

If Randomisation Date or AE Onset Date are missing => missing

If Randomisation Date > AE Onset Date then => AE Onset Date – Randomisation
Date

If Randomisation Date ≤ AE Onset Date then => AE Onset Date – Randomisation
Date + 1
*For participants who enter the run-in treatment phase but do not get randomised, use the 
last run-in date instead of randomisation date for the “Run-in-Treatment” phase and 
“Onset Time Since First Dose (days)” as the participants would not have a randomisation 
date.


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10.4.
Appendix 4: Data Display Standards & Handling 
Conventions
10.4.1.
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
uksal1x00175
HARP Compound
arenv/arprod/gw685698_gw642444/mid207040/final_01
Analysis Datasets 

Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.2 & ADaM IG 
Version 1.0). If the Study Data Standardization Plan (SDSP) exists for a study, ensure the CDISC 
versions are consistent.
Generation of RTF Files

Rich Text Format (RTF) files will be generated for final reporting effort.
10.4.2.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 
All data displays (Tables, Figures & Listings) will use the term “Subject” which reflects CDISC and GSK 
Data Display Standards terminology
Formats

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected, unless otherwise stated.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but may be 
adjusted to a clinically interpretable number of DP’s.

All data will be reported according to the treatment the participant was randomised to unless otherwise 
stated.

Numeric data will be reported (in listings) at the precision collected in the eCRF or recorded in the raw 
dataset if from non-eCRF sources.
Specification of Number of Decimal Places for Descriptive Statistics
Label 
Description
Number of decimal places (dp) 
more than raw data
N 
Number of participants in the 
treatment group
Always present to 0 dp 
n 
Number of participants with non-
missing values
Always present to 0 dp 
Mean
Arithmetic Mean
1 dp 


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SD
Standard Deviation
2 dp 
Median
Median
1 dp 
Min.
Minimum
0 dp 
Max.
Maximum
0 dp 
Specification of Number of Decimal Places for Statistical Analysis
Label 
Description
Number of decimal places (dp) 
more than raw data
LS Mean
Adjusted mean for the treatment 
group
1 dp
LS Mean Change
Adjusted mean change from 
baseline for the treatment group
1 dp
Std Err
Standard error
2 dp
Difference
Treatment difference
1 dp
Odds Ratio
Treatment odds ratio
Always present to 2 dp
Relative Risk
Treatment relative risk
Always present to 2 dp
95% CI 
95% Confidence interval around 
difference/ratio/relative risk
Same number of dp as the 
difference/ratio/relative risk
p-value 
p-value
Always present to 3 dp 
(or <0.001 or >0.999)
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to treatment dosing will be used in figures, summaries, statistical analyses 
and calculation of any derived parameters, unless otherwise stated.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the participant’s listings. 
Unscheduled Visits

Unscheduled visits will not be included in summary tables and/or figures.

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.

The programs for statistical analysis tables will create SAS datasets with the unrounded numbers from 
the statistical models to be used in any graphs. This will include all LS means, standard errors, 
treatment differences or ratios and confidence intervals. This will be done for all analysis tables 
regardless of whether or not a figure is planned as part of statistical analysis complete (SAC).

The programs for all graphical displays will additionally create a CSV file with the final data that is used 
in the graph in order to allow the graph to be redrawn for any potential future publication requirement


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10.5.
Appendix 5: Derived and Transformed Data
10.5.1.
General
Study Day

Calculated as the number of days from first randomisation:

Ref Date = Missing → Study Day = Missing 

Ref Date < Randomisation Date → Study Day = Ref Date – Randomisation Date

Ref Date ≥ Randomisation Date → Study Day = Ref Date – (Randomisation Date) + 1    
Change from Baseline

Calculated as the difference between the value of the endpoint at the timepoint of interest and the 
baseline value as defined in Section 5.2 Baseline Definitions
Time Since First Dose

Calculated as the number of days from first dose date of post randomisation treatment:

Ref Date = Missing → Time Since First Dose = Missing 

Ref Date < Randomisation Date → Time Since First Dose = Ref Date – Randomisation Date

Ref Date ≥ Randomisation Date → Time Since First Dose = Ref Date – (Randomisation Date) +1    
Study Treatment Start and Stop Dates

In this study, participants who permanently discontinue Relvar/Breo study treatment, any sensors or the 
App may continue in the study attending the remaining visits and completing the scheduled 
assessments.

Data displays will state if pre-screening, run-in treatment, on-treatment, post-treatment, or both on-
treatment and post-treatment data are included in the summary or analysis, when applicable.  On-
treatment is defined as Relvar/Breo study treatment from the date of randomisation to treatment arm.

Relvar/Breo on-treatment start date will be defined as the randomisation date and Relvar/Breo 
Treatment Stop Date will be defined as the latest treatment stop date (from the study treatment 
compliance eCRF log and treatment discontinuation eCRF page). These dates will be used to 
determine whether a measurement is run-in, on or post-treatment. (See Section 10.3.1 Study Phases).
Multiple Measurements at One Analysis Time Point

PEF and FeNO assessments are performed multiple times per visit.  The maximum value obtained at 
the visit will be included in summaries of these data.
10.5.2.
Study Population
Demographics
Age

GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed as 
follows:
o
Any participant with a missing day will have this imputed as day ‘15’. 
o
Any participant with a missing date and month will have this imputed as PPD


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Demographics

Birth date will be presented in listings as ‘YYYY’.

Completely missing dates of birth will remain as missing, with no imputation applied. Consequently, the 
age of the participant will not be calculated and will remain missing.

Age, in whole years, will be calculated with respect to the date of screening (Visit 1).
Body Mass Index

Calculated as Weight (kg) / [Height (m)]2
Race 

The five high level Food and Drug Administration (FDA) race categories and designated Asian 
subcategories are:
1.
African American/African Heritage
2.
American Indian or Alaska Native
3.
Asian
a.
Central/South Asian Heritage
b.
Japanese/East Asian Heritage/South East Asian Heritage
c.
Mixed Asian Heritage (only required if data exists)
4.
Native Hawaiian or other Pacific Islander
5.
White

These categories and subcategories will be summarized along with all combinations of high level 
categories which exist in the data. All five of the high level race categories and the two Asian 
subcategories must appear on the display even if there are no participants in a particular category, but 
combinations that do not exist in the data do not need to be represented. Combinations will be 
represented as the concatenation of the high level category terms, e.g., “White & Asian.” The 
designated Asian subcategories will not be summarized as combinations with other categories.

In addition, the standard race categories collected per IDSL will be summarized along with categories 
for mixed race. The categories are: 
1.
African American/African Heritage
2.
American Indian or Alaska Native
3.
Asian - Central/South Asian Heritage
4.
Asian – East Asian Heritage
5.
Asian – Japanese Heritage
6.
Asian – South East Asian Heritage
7.
Asian – Mixed Race
8.
Native Hawaiian or other Pacific Islander
9.
White – Arabic/North African Heritage
10. White – White/Caucasian/European Heritage
11. White – Mixed Race
12. Mixed Race

“Asian – Mixed Race” is only used if more than one Asian category is selected, but no non-Asian 
races. Similarly, “White – Mixed Race” is only used if both of the White categories are selected, and no 
non-White races. If multiple races of different types are selected, then the overall “Mixed Race” 
category is used.

A participant will only be represented in a single category. A participant who selects a combination of 
races will be counted as “Asian – Mixed Race,” “White – Mixed Race,” or “Mixed Race,” but not in 
each of the constituent terms. Therefore, the counts will add up to the total number of participants with 
a response, and the percentages will add to 100%.


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Treatment Compliance

Relvar/Breo treatment compliance, calculated as a percentage, will be based on the total number of 
inhalations taken from the study drug inhaler(s) and the expected number of inhalations to be taken.

The expected number of inhalations will be derived as the expected number of inhalations per day (1 for 
OD dosing) multiplied by the number of days on study drug based on treatment start date and treatment 
stop date.

The total number of inhalations taken will be based on the dose counters of the inhalers, which are re-
supplied during the study. If there is no dose counter information at all then the compliance will be 
missing, however, as long as the information from one dose counter is present, treatment compliance will 
be calculated. If a dose counter start count is missing then it will be assumed to be 30. All inhalers 
dispensed will be used, provided the dose counter stop counts are non-missing.

Treatment compliance will be calculated based on the formula:
where Total_Number_of_Inhalations_Taken is the total number of doses taken from all inhalers, 
Expected_Inhalations is equal to 1 and Start_Date and Stop_Date are the earliest treatment start date on 
or post randomisation and the latest treatment stop date recorded for all the inhalers used in the 
calculation.
Extent of Exposure and Study Duration

Relvar/Breo on-treatment start date will be defined as the randomisation date and Relvar/Breo Treatment 
Stop Date will be defined as the latest treatment stop date (from the study treatment compliance eCRF 
log and treatment discontinuation eCRF page) for the participant. These dates will be used to determine 
whether a measurement is run-in, on or post-treatment. (See Section 10.3.1 Study Phases). Study 
conclusion is defined as completion or withdrawal, as applicable.

Duration of exposure to study drug will be calculated as:
o
Duration of Exposure (days) = Treatment Stop Date – Randomisation Date + 1

Duration of post-treatment time spent in the study will be calculated as:
o
Duration of Post-Treatment Study Time (days) = Study Conclusion Date – Treatment Stop Date

Duration of total time spent in the study will be calculated as:
o Duration of Study Time (days) = Study Conclusion Date – Randomisation Date + 1

Years exposed will be calculated as: 
o Last treatment stop date - Randomisation Date +1 / 365.25.
o Total Years Exposed will be the sum of the year exposed per treatment arm. 
10.5.3.
Efficacy
10.5.3.1.
ELLIPTA Device Sensor Assessments
Percentage of ELLIPTA doses taken (daily adherence) Endpoint
Overview of Calculation 
1.
Create a dataset (Observed Data A) to calculate the monthly observed percentage of ELLIPTA 
adherence values (from month 1 to month 6) accounting for the following, 
a.
number of days adherent to ELLIPTA (as prescribed)
b.
number of days post ELLLIPTA maintenance sensor permanent discontinuation
c.
the intermittent missing daily adherence data due to device incident.  
d.
Non-adherent days (i.e. none of the above and those days with more than one dose in 24-
hour period).


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Percentage of ELLIPTA doses taken (daily adherence) Endpoint
2.
Duplicate the observed monthly adherence values dataset (Observed Dataset A).  Using the 
values in the duplicate dataset (Dataset B), impute the month where the sensor was permanently 
discontinued before the end of that month (and therefore presents a monthly adherence rate based 
on partly observed sensor data for that month) as missing unless the participant is a study 
completer. 
3.
Using each of the two observed datasets (Observed Dataset A and Observed Dataset B), create 
four separate imputed datasets (J2R-Dataset A, J2R-Dataset B, MAR-Dataset A, MAR-Dataset B) 
that account for the two imputation methods (J2R or MAR) that may be applied to participants’ data 
after discontinuation of the maintenance sensor, ELLIPTA or withdrawal from study.  Imputation will 
be carried out using observed monthly adherence rates for months 1 to 6. 1000 draws will be used. 
Completely missing intermediate monthly values will be assumed MAR. The multiple imputation will 
be implemented using the methods described in Carpenter, 2013, using the macros (Part1A, 
Part1B, Part2A and Part2B) available from https://missingdata.lshtm.ac.uk/2017/04/06/gsk-five-
macros/ using seeds documented in the RAP for the respective endpoint.
4.
The Observed Datasets (A and B), imputed datasets (J2R-Dataset A, J2R-Dataset B, MAR-
Dataset A, MAR-Dataset B) and the timing of the intercurrent events; permanent discontinuation of 
the ELLIPTA maintenance sensor; permanent discontinuation of ELLIPTA treatment and 
withdrawal from study; will be used to create an analysis dataset (Dataset C) that identifies the 
proportion of each month to be assigned as observed data, J2R imputed data, MAR imputed data, 
or no data. The strategy for handling intercurrent events is described in Section 7.1.4 Strategy for 
Intercurrent (Post-Randomisation) Events.  
Within each imputation draw, for each missing month, the observed and any imputed data will be 
combined to provide a percentage adherence value. The values for months 4 to 6, months 1-3 and 
months 1-6, will be combined to create the value for the respective primary and secondary 
endpoint analyses and the weight to be assigned to each participant.
5.
Analyse using Multiple Imputation macro Part3
a.
Perform ANCOVA on the endpoint for each imputed dataset to obtain treatment effect 
estimate and standard error
b.
Combine estimates across imputations using Rubin’s rules


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Percentage of ELLIPTA doses taken (daily adherence) Endpoint
The intercurrent events identified as part of the primary endpoint estimand and derivation are detailed in 
full in Section 7.2.1.3 Strategy for Intercurrent (Post-Randomisation) Events.  Below are two schematics 
of the intercurrent event patterns and their estimation rules.
Intercurrent Event Patterns
Intercurrent Event ‘Estimation Rules’ 1-4


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Percentage of ELLIPTA doses taken (daily adherence) Endpoint
Intercurrent Events related to Relvar/Breo or CIS
In order to implement the intercurrent event strategy detailed in Section 7.1.4 Strategy for Intercurrent 
(Post-Randomisation) Events, it is necessary to determine if and when the reasons for permanent 
discontinuations related to CIS or ELLIPTA Relvar/Breo treatment occur.
The date and reason for permanently withdrawing from ELLIPTA treatment will be determined from the 
study treatment (Relvar/Breo ELLIPTA) discontinuation page of the eCRF.  
ELLIPTA discontinuation reasons classified as not related to ELLIPTA are as follows: 

AE - not treatment related (determine from the AE that lead to withdrawal to treatment if study 
treatment related, on the AE eCRF page)

Protocol deviation - not related to study treatment

Participant reached protocol defined stopping criteria - not related to study treatment

Study closed/terminated

Lost to follow-up

Investigator discretion - not related to study treatment

Decision by participant or proxy - not related to study treatment
ELLIPTA discontinuation reasons classified as related to ELLIPTA are as follows: 

AE - treatment related (determine from the AE that lead to withdrawal to treatment if study 
treatment related, on the AE eCRF page)

Lack of efficacy

Protocol deviation - related to study treatment

Participant reached protocol defined stopping criteria (except pregnancy) - related to study 
treatment 

Investigator discretion - related to study treatment

Decision by participant or proxy - related to study treatment
The date and reason for withdrawing from the study will be determined from the study conclusion page of 
the eCRF.  
Study discontinuation reasons classified as related to CIS are as follows:

Withdrew consent – dissatisfaction with the connected inhaler system (CIS)


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Percentage of ELLIPTA doses taken (daily adherence) Endpoint
Monthly Percentage of ELLIPTA doses taken (daily adherence) - Calculation
STEP 1: Creating the observed adherence dataset (Observed Dataset A)
To determine the monthly observed percentage of ELLIPTA adherence values (Observed Dataset A) the 
following should be applied for each month:
For Baseline Analysis Month, for each participant create a count of each of the following types of Days 
D1 = Adherence recorded
D2 = Device incident
D3 = Post discontinuation of maintenance Sensor
D4 = Non-adherent (including those imputed as non-adherent)

D5=D1 + D2 + D3 + D4, i.e. The total number of days within the Baseline Analysis Month; the 
total number of days between Beginning Timepoint and Ending Timepoint as defined in Table 5
in Section 10.2 Appendix 2: Assessment Windows.
For Analysis Month 1, 2, 3, 4 and 5, for each participant create a count of each of the following types of 
days:
D1 = Adherence recorded
D2 = Device incident
D3 = Post discontinuation of maintenance Sensor
D4 = Non-adherent (including those imputed as non-adherent)
D5 = D1 + D2 + D3 + D4, i.e. The total number of days within the Analysis Month; the total number of 
days between Beginning Timepoint and Ending Timepoint as defined in Table 5 in Section 10.2 Appendix 
2: Assessment Windows.
For Analysis Month 6, for each participant create a count of each of the following types of days:
D1 = Adherence recorded
D2 = Device incident
D3 = Post discontinuation of maintenance sensor
D4 = Non-adherent (including those imputed as non-adherent)
D5 = D1 + D2 + D3 + D4, i.e. the total number of days within Analysis Month 6; the total number of days 
between Beginning Timepoint and Ending Timepoint as defined in Table 5 in Section 10.2 Appendix 2: 
Assessment Windows.
The following observations from the sensor and eCRF will be required to determine the above Days and 
the differences between missing at random due to device/sensor incident and non-adherent days.

Device malfunction date

Sensor malfunction date

Permanent discontinuation of maintenance sensor

First and last individual sensor synchronisation dates
The first and last individual sensor synchronisation dates will be provided in the sensor dataset.   These 
dates will be used to assess whether missing observations are due to non-adherent days or data being 
missing at random due to device/sensor malfunction.
For each Analysis Month, the Observed adherence for that month will be calculated as follows: 


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Percentage of ELLIPTA doses taken (daily adherence) Endpoint
STEP 2:  Creating the modified observed adherence dataset (Observed Dataset B)
The Observed Dataset A will be duplicated.  Using the values in the duplicate dataset (Observed Dataset 
B) the Analysis Month where the maintenance sensor was permanently discontinued before the end of 
that month (and therefore presents a monthly adherence rate based on partly observed sensor data for 
that month) will be imputed as missing; i.e.in Dataset B, if within an Analysis Month (D3>0 and D3<D5) 
then set monthly value for that Analysis Month to missing. (Note: unless the participant is a completer in 
which case do not set the value to missing for that Analysis Month)
STEP 3: Creating the reference imputed datasets under MAR and J2R method
Using each of the two observed datasets (Observed Dataset A and Observed Dataset B) monthly values, 
create four separate reference imputed datasets (J2R-Dataset A, J2R-Dataset B, MAR-Dataset A, MAR-
Dataset B) that account for the two imputation methods (J2R or MAR).  Completely missing intermediate 
monthly values will be assumed MAR.
The multiple imputation will be implemented using the methods described in Carpenter, 2013 using 
macros, Part1A, Part1B, Part2A and Part2B (available from 
https://missingdata.lshtm.ac.uk/2017/04/06/gsk-five-macros/).  The seeds are documented at the end of 
Section 10.5.3.1. and 1000 draws will be used in the relevant macros parameters.
Due to the range of the monthly adherence percentages being limited between 0 and 100, the multiple 
imputation process can generate percentages outside the possible range of values (< 0% or > 100%). A 
cap will be put in place where values imputed < 0 will be set as 0 and values imputed as > 100 set as 
100.
STEP 4:  Creating the Monthly Analysis values dataset
For each month within each participant create a count of each of the following durations based on 
intercurrent events: Let,
m1 = maintenance sensor still in use
m2 = maintenance sensor discontinued, but ELLIPTA Relvar/Breo not discontinued
m3 = ELLIPTA Relvar/Breo discontinued (includes days post withdrawal from the study). Note, if 
participant is a completer then for Analysis Month 6, m3=0.
m4 = m1 + m2 + m3
Calculate the proportion of days the sensor was still in use from the total number of days ELLIPTA was in 
use within a month, m1/(m1+m2)
Calculate the proportion of days the sensor was discontinued from the total number of days ELLIPTA 
was in use within a month, m2/(m1+m2)
Set participants monthly values to observed, MARA, MARB, J2RA, J2RB imputation, no data each with 
an m1, m2, m3 and m4 duration. 


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Percentage of ELLIPTA doses taken (daily adherence) Endpoint
Examples include to following;

A participant who prematurely discontinues sensor after 15 days of Analysis Month 5 and 
concurrently discontinues ELLIPTA maintenance therapy and study withdrawal after 10 days of 
Analysis Month 6
Subject 
Id
Draw
Month
A
B
J2RA
J2RB
MARA
MARB
m1
m2
m3
m4
X
1
1
77
77
77
77
77
77
28
0
0
28
X
1
2
82
82
82
82
82
82
28
0
0
28
X
1
3
87
87
87
87
87
87
28
0
0
28
X
1
4
77
77
77
77
77
77
28
0
0
28
X
1
5
71
.
71
77
71
78
15
13
0
28
X
1
6
.
.
80
79
77
76
0
10
18
28

A participant who concurrently prematurely discontinues sensor, ELLIPTA maintenance therapy and 
study withdrawal after 15 days of Analysis Month 5
Subject 
Id
Draw
Month
A
B
J2RA
J2RB
MARA
MARB
m1
m2
m3
m4
X
1
1
77
77
77
77
77
77
28
0
0
28
X
1
2
80
80
80
80
80
80
28
0
0
28
X
1
3
79
79
79
79
79
79
28
0
0
28
X
1
4
75
75
75
75
75
75
28
0
0
28
X
1
5
83
.
83
77
83
79
15
0
13
28
X
1
6
.
.
77
77
75
80
0
0
28
28

A participant who completes the study after 26 days in Analysis Month 6
Subject 
Id
Draw
Month
A
B
J2RA
J2RB
MARA
MARB
m1
m2
m3
m4
X
1
1
77
77
77
77
77
77
28
0
0
28
X
1
2
82
82
82
82
82
82
28
0
0
28
X
1
3
87
87
87
87
87
87
28
0
0
28
X
1
4
77
77
77
77
77
77
28
0
0
28
X
1
5
80
80
80
80
80
80
28
0
0
28
X
1
6
82
82
82
82
82
82
15
11
0
26

If the sensor is in use for at least a day within a month, m1>0 then let the analysis value be a 
combined value (weighted average) of the J2RA observed and J2RB imputed values, by taking a 
proportion of each value based on the proportion of days sensor was still in use and discontinued 
whilst on ELLIPTA respectively;
      Analysis value = m1/m1+m2  x (value from J2RA) + m2/m1+m2  x (value from J2RB)
Note the weight is, m1 + m2

Else if the sensor was not used in the month, m1=0 then let the analysis value be the  imputed value,
      Analysis value = value from J2RA dataset (which is the imputed value)
Implement special cases of J2R post-discontinuation of ELLIPTA by identifying participants where 
ELLIPTA is prematurely discontinued and the participant concurrently withdraws from the study, and 
ELLIPTA discontinuation reason is not related to ELLIPTA:


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Percentage of ELLIPTA doses taken (daily adherence) Endpoint

If the sensor is in use for at least a day within a month, m1>0 then let the analysis value be a 
combined value (weighted average) of the J2RA observed and J2RB imputed values, by taking a 
proportion of each value based on the proportion of days the sensor is in use and not in use in that 
month
      Analysis value = m1/m4 x (value from J2RA) + (m2+m3)/m4 x (value from J2RB)
Note the weight is, m4

Else if the sensor was not used in the month, m1=0 then let the analysis value be the imputed value,
      Analysis value = value from J2RA dataset (which is the imputed value)
Implement special case of MAR post-discontinuation of ELLIPTA by identify participants where ELLIPTA 
is prematurely discontinued and the participant concurrently discontinues the maintenance eSensor and 
concurrently withdraws from the study, and ELLIPTA discontinuation reason is not related to ELLIPTA 
and study withdrawal is not related to CIS.
Where ELLIPTA  has not been discontinued after the sensor but on the same day, m2=0.

If the sensor is in use for at least a day within a month, m1>0 then let the analysis value be a 
combined value (weighted average) of the J2RA observed and MARB imputed values, by taking a 
proportion of each value based on the proportion of days the ELLIPTA was in use and not in use in 
that month 
      Analysis Value = m1/m4 x (value from J2RA) + m3/m4 x (value from MARB)

Else 
      Analysis Value = m1/m4 x (value from J2RA) + m3/m4 x (value from MARA)
Note the weights are m4
STEP 5: Primary and Secondary Percentage of ELLIPTA doses taken Endpoints calculation 
The calculations presented in the previous steps support the final derivation of the following primary and 
secondary endpoints, the percentage of ELLIPTA doses taken between 
o
the beginning of Month 4 and the end of Month 6
o
the beginning of Month 1 and the end of Month 6
o
the beginning of Month 1 and the end of Month 3
For participants who complete the study treatment (i.e. no premature discontinuation of ELLIPTA 
Relvar/Breo) during the endpoint period of interest:
Analysis Endpoint is the average of monthly Analysis Values over the number of months in the 
endpoint period of interest, i.e.
o
Month 4 to Month 6 
o
Month 1 to Month 6 
o
Month 1 to Month 3 
For participants who prematurely discontinue ELLIPTA during the endpoint period of interest for reasons 
related to ELLIPTA, then the weight is the total duration on ELLIPTA within the endpoint period of interest 
and applied to each analysis month based on the duration within that month.  This weight should be 
applied to each monthly Analysis value within the period of interest and results summed together to 
produce the final endpoint/response variable for modelling within macro Part 3.


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Percentage of ELLIPTA doses taken (daily adherence) Endpoint
Note the weight is, total duration of ELLIPTA use within the period of interest .  The proportion of weight 
to apply per monthly Analysis value is m1+m2/total duration of ELLIPTA use within the period of interest
For participants who prematurely discontinue ELLIPTA during the endpoint period of interest for reasons 
not related to ELLIPTA or CIS, or just related to CIS, the MAR or J2R imputation assumes participants 
would have continued taking ELLIPTA until the end of the period of interest. The weight is the total 
duration within the endpoint period of interest. This weight will be applied to each monthly Analysis value 
within the period of interest and results summed together to produce the final endpoint/response variable 
for modelling within macro Part 3.
Note the weight is, total expected ELLIPTA duration within the period of interest.  The proportion of 
weight to apply per monthly Analysis value is m1+m2+m3/ Total expected ELLIPTA duration within the 
period of interest.
Percentage of ELLIPTA doses taken (daily adherence) – Sensitivity Analysis
Sensitivity analyses will be performed estimating the treatment effect by utilizing a generalized linear 
model (GLM) and not running the multiple imputation process. The model will follow a binomial 
distribution with the logit link function. 
The sensitivity analyses will be performed for the following primary and secondary endpoints relating to 
the percentage of ELLIPTA doses taken between 
o
the beginning of Month 4 and the end of Month 6
o
the beginning of Month 1 and the end of Month 6
o
the beginning of Month 1 and the end of Month 3
Model assumptions will be checked by using standardised residual plots. Missing data will be assumed to 
be MAR.
The weighting strategy is to be applied as detailed above.
Percentage of ELLIPTA doses taken (daily adherence) Endpoint
Seeds for Multiple Imputations Macros
Seeds for all planned MI analyses were determined in advance using the following SAS code and 
documented within this RAP prior to unblinding:
data temp;
  do i = 1 to 6;
    number=round(10000*ranuni(0),1);
   output;
  end;
run;
proc print;
run;
Part 1B Macro Seed for Parameter Estimation Using Bayesian MCMC Procedure 
Endpoint
Input Dataset
Macro Seed
Percentage of Daily Adherence
Observed Dataset A
2124
Observed Dataset B
5071


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Part 2B Macro Seeds for Multiple Imputation of Datasets
Endpoint
Multiple Imputation 
Method
Macro Seed Output Dataset
Percentage of Daily Adherence
MAR 
8517
MAR Dataset A
J2R
6888
J2R Dataset A
MAR
6388
MAR Dataset B
J2R
8674
J2R Dataset B
10.5.3.2.
MDI Device Sensor Assessments
Percentage of Rescue Free Days Endpoint 
Overview of Calculation 
1.
Create a dataset (Observed Data A) to calculate the monthly observed percentage of MDI 
rescue free days values (from month 1 to month 6) accounting for the following, 
a.
number of days MDI rescue medication was used (at least once per day)
b.
number of days post MDI rescue use sensor permanent discontinuation
c.
the intermittent missing daily MDI rescue use data due to device incident  
d.
MDI Rescue free days (i.e. none of the above).
2.
Duplicate the observed monthly MDI rescue free values dataset (Observed Dataset A).  Using 
the values in the duplicate dataset (Dataset B), impute the month where the sensor was 
permanently discontinued before the end of that month (and therefore presents a monthly 
adherence rate based on partly observed sensor data for that month) as missing unless the 
participant is a study completer. 
3.
Using each of the two observed datasets (Observed Dataset A and Observed Dataset B), create 
four separate imputed datasets (J2R-Dataset A, J2R-Dataset B, MAR-Dataset A, MAR-Dataset 
B) that account for the two imputation methods (J2R or MAR) that may be applied to participants 
data after discontinuation of the MDI rescue sensor or withdrawal from study. Imputation will be 
carried out using observed monthly MDI rescue free rates for months 1 to 6. 1000 draws will be 
used. Completely missing intermediate monthly values will be assumed MAR. The multiple 
imputation will be implemented using the methods described in Carpenter, 2013, using the 
macros (Part1A, Part1B, Part2A and Part2B) available from 
https://missingdata.lshtm.ac.uk/2017/04/06/gsk-five-macros/ using seeds documented in the 
RAP for the respective endpoint.
4.
The Observed Datasets (A and B), imputed datasets (J2R-Dataset A, J2R-Dataset B, MAR-
Dataset A, MAR-Dataset B) and the timing of the intercurrent events; permanent discontinuation 
of the MDI rescue sensor and withdrawal from study; will be used to create an analysis dataset 
(Dataset C) that identifies the proportion of each month to be assigned as observed data, J2R 
imputed data or MAR imputed data. The strategy for handling intercurrent events is described in 
Section 7.2.2.3 Strategy for Intercurrent (Post-Randomisation) Events.  
Within each imputation draw, for each missing month, the observed and any imputed data will 
be combined to provide a percentage of rescue free days value. The values for months 4 to 6 
will be combined to create the value for the respective secondary endpoint analysis and the 
weight to be assigned to each participant.
5.
Analyse using Multiple Imputation macro Part3


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a.
Perform ANCOVA on the endpoint for each imputed dataset to obtain treatment effect 
estimate and standard error
b.
Combine estimates across imputations using Rubin’s rules
Percentage of Rescue Free Days Endpoint 
The intercurrent events identified as part of this secondary endpoint estimand and derivation are detailed in 
full in Section 7.2.2.3 Strategy for Intercurrent (Post-Randomisation) Events.  Below are two schematics of 
the intercurrent event patterns and their estimation rules.
Intercurrent Event Patterns
Intercurrent Event ‘Estimation Rules’ 1-4


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Percentage of Rescue Free Days Endpoint 
Intercurrent Events related to CIS
In order to implement the intercurrent event strategy detailed in Section 7.2.2.3 Strategy for Intercurrent 
(Post-Randomisation) Events, it is necessary to determine if and when the reasons for permanent 
discontinuations related to CIS occur.
The date and reason for withdrawing from the study will be determined from the study conclusion page of 
the eCRF.  
Study discontinuation reasons classified as related to CIS are as follows:

Withdrew consent – dissatisfaction with the connected inhaler system (CIS)
Percentage of Rescue Free Days Endpoint 
Monthly Percentage of Rescue Free Days - Calculation
STEP 1: Creating the observed adherence dataset (Observed Dataset A)
To determine the monthly observed percentage of rescue free days values (Observed Dataset A) the 
following should be applied for each month:
For Baseline Analysis Month, for each participant create a count of each of the following types of Days 
D1 = Rescue use recorded
D2 = Device incident
D3 = Post discontinuation of MDI rescue sensor
D4 = MDI rescue free
D5=D1 + D2 + D3 + D4, i.e. The total number of days within the Baseline Analysis Month; the total 
number of days between Beginning Timepoint and Ending Timepoint as defined in Table 5 in Section 
10.2 Appendix 2: Assessment Windows.
For Analysis Month 1, 2, 3, 4 and 5, for each participant create a count of each of the following types of 
days:
D1 = Rescue use recorded
D2 = Device incident
D3 = Post discontinuation of MDI rescue sensor
D4 = MDI rescue free
D5 = D1 + D2 + D3 + D4, i.e. The total number of days within the Analysis Month; the total number of 
days between Beginning Timepoint and Ending Timepoint as defined in Table 5 in Section 10.2 Appendix 
2: Assessment Windows.
For Analysis Month 6, for each participant create a count of each of the following types of days:
D1 = Rescue use recorded
D2 = Device incident
D3 = Post discontinuation of MDI rescue sensor
D4 = MDI rescue free
D5 = D1 + D2 + D3 + D4, i.e. the total number of days within Analysis Month 6; the total number of days 
between Beginning Timepoint and Ending Timepoint as defined in Table 5 in Section 10.2 Appendix 2: 
Assessment Windows.


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Percentage of Rescue Free Days Endpoint 
The following observations from the sensor and eCRF will be required to determine the above Days and 
the differences between missing at random due to device/sensor incident and non-adherent days.

Device malfunction date

Sensor malfunction date

Permanent discontinuation of MDI rescue sensor

First and last individual sensor synchronisation dates
The first and last individual sensor synchronisation dates will be provided in the sensor dataset.   These 
dates will be used to assess whether missing observations are due to rescue free days or data being 
missing at random due to device/sensor malfunction.
For each Analysis Month, the Observed MDI rescue free days (%) for that month will be calculated as 
follows: 
STEP 2:  Creating the modified observed MDI rescue free dataset (Observed Dataset B)
The Observed Dataset A will be duplicated.  Using the values in the duplicate dataset (Observed Dataset 
B) the Analysis Month where the MDI rescue sensor was permanently discontinued before the end of that 
month (and therefore presents a monthly rescue free rate based on partly observed sensor data for that 
month) will be imputed as missing; i.e.in Dataset B, if within an Analysis Month (D3>0 and D3<D5) then 
set monthly value for that Analysis Month to missing.  (Note: unless the participant is a completer in 
which case do not set the value to missing for that Analysis Month).
STEP 3: Creating the reference imputed datasets under MAR and J2R method
Using each of the two observed datasets (Observed Dataset A and Observed Dataset B) monthly values, 
create four separate reference imputed datasets (J2R-Dataset A, J2R-Dataset B, MAR-Dataset A, MAR-
Dataset B) that account for the two imputation methods (J2R or MAR).  Completely missing intermediate 
monthly values will be assumed MAR.
The multiple imputation will be implemented using the methods described in Carpenter, 2013 using 
macros, Part1A, Part1B, Part2A and Part2B (available from 
https://missingdata.lshtm.ac.uk/2017/04/06/gsk-five-macros/).  The seeds are documented at the end of 
Section 10.5.3.2 and 1000 draws will be used in the relevant macros parameters.
Due to the range of the rescue free days percentages being limited between 0 and 100, the multiple 
imputation process can generate percentages outside the possible range of values (< 0% or > 100%). A 
cap will be put in place where values imputed < 0 will be set as 0 and values imputed as > 100 set as 
100.
STEP 4:  Creating the Monthly Analysis values dataset
For each month within each participant create a count of each of the following durations based on 
intercurrent events: Let,
r1 = MDI rescue sensor still in use


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Percentage of Rescue Free Days Endpoint 
r2 = MDI rescue sensor discontinued but MDI rescue use ongoing until study withdrawal
r3 = MDI rescue discontinued at study withdrawal (includes days post withdrawal from the study). Note, if 
participant is a completer then for Analysis Month 6, r3=0.
r4 = r1 + r2 + r3
Note: it is assumed that MDI rescue use is not discontinued until permanent discontinuation of the study.  
Therefore, discontinuation date of MDI rescue use is the same date as permanent discontinuation of 
study
Set participants monthly values to observed, MARA, MARB, J2RA, J2RB imputation, no data each with a 
r1, r2, r3 duration.  
Examples include to following;

A participant who prematurely discontinues sensor after 20 days of Analysis Month 5 and withdraws 
from study after 5 days of Analysis Month 6
Subject 
Id
Draw
Month
A
B
J2RA
J2RB
MARA
MARB
r1
r2
r3
r4
X
1
1
77
77
77
77
77
77
28
0
0
28
X
1
2
82
82
82
82
82
82
28
0
0
28
X
1
3
87
87
87
87
87
87
28
0
0
28
X
1
4
77
77
77
77
77
77
28
0
0
28
X
1
5
71
.
71
77
71
78
20
8
0
28
X
1
6
.
.
80
79
77
76
0
5
23
28

A participant who concurrently prematurely discontinues sensor and withdraws from study after 20 
days of Analysis Month 5
Subject 
Id
Draw
Month
A
B
J2RA
J2RB
MARA
MARB
r1
r2
r3
r4
X
1
1
77
77
77
77
77
77
28
0
0
28
X
1
2
80
80
80
80
80
80
28
0
0
28
X
1
3
79
79
79
79
79
79
28
0
0
28
X
1
4
75
75
75
75
75
75
28
0
0
28
X
1
5
83
.
83
77
83
79
20
0
8
28
X
1
6
.
.
77
77
75
80
0
0
28
28

A participant who completes the study after 27 days in Analysis Month 6
Subject 
Id
Draw
Month
A
B
J2RA
J2RB
MARA
MARB
r1
r2
r3
r4
X
1
1
77
77
77
77
77
77
28
0
0
28
X
1
2
82
82
82
82
82
82
28
0
0
28
X
1
3
87
87
87
87
87
87
28
0
0
28
X
1
4
77
77
77
77
77
77
28
0
0
28
X
1
5
80
80
80
80
80
80
28
0
0
28
X
1
6
82
82
82
82
82
82
15
12
0
27
For Arms 1 and 2,

If the sensor is in use for at least a day within a month, r1>0 then let the analysis value be a 
combined value (weighted average) of the J2RA observed and MARB imputed values, by taking a 
proportion of each value based on the proportion of days the sensor is in use and not in use in that 
month


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Percentage of Rescue Free Days Endpoint 
     Analysis value = r1/r4 x (value from J2RA) + (r2+r3)/r4 x (value from MARB)
Note the weight is, r4

Else if the sensor was not used in the month, r1=0 then let the analysis value be the imputed value,
      Analysis value = value from J2RA dataset (which is the imputed value)
Implement special case of MAR post-early discontinuation of study by identifying participants where the 
MDI rescue sensor is prematurely discontinued and the participant concurrently withdraws from the 
study.  Where study withdrawal has not been discontinued after the sensor but on the same day, r2=0.

If the sensor is in use for at least a day within a month, r1>0 then let the analysis value be a 
combined value (weighted average) of the J2RA observed and MARB imputed values, by taking a 
proportion of each value based on the proportion of days the MDI rescue was in use and not in use 
in that month 
      Analysis Value = r1/r4 x (value from J2RA) + r3/r4 x (value from MARB)
Note the weights are r4

Else if the sensor was not used in the month, r1=0 then let the analysis value be the imputed value,
      Analysis value = value from MARA dataset (which is the imputed value)
For Arm 3 and 4,

If the sensor is in use for at least a day within a month, r1>0 then let the analysis value be a 
combined value (weighted average) of the J2RA observed and J2RB imputed values, by taking a 
proportion of each value based on the proportion of days the MDI sensor is in use and not in use in 
that month
      Analysis value = r1/r4 x (value from J2RA) + (r2+r3)/r4 x (value from J2RB)
Note the weight is, r4

Else if the sensor was not used in the month, r1=0 then let the analysis value be the imputed value,
      Analysis value = value from J2RA dataset (which is the imputed value)
Implement special case of MAR post-early discontinuation of study by identifying participants where the 
MDI rescue sensor is prematurely discontinued and the participant concurrently withdraws from the study 
and study withdrawal reason is not related to CIS.  Where study withdrawal has not been discontinued 
after the sensor but on the same day, r2=0.

If the sensor is in use for at least a day within a month, r1>0 then let the analysis value be a 
combined value (weighted average) of the J2RA observed and MARB imputed values, by taking a 
proportion of each value based on the proportion of days the MDI rescue was in use and not in use 
in that month 
      Analysis Value = r1/r4 x (value from J2RA) + r3/r4 x (value from MARB)
Note the weights are r4

Else if the sensor was not used in the month, r1=0 then let the analysis value be the imputed value,
      Analysis value = value from MARA dataset (which is the imputed value)
Implement special case of J2R post-early discontinuation of study by identifying participants where the 
MDI rescue sensor is prematurely discontinued and the participant concurrently withdraws from the study 
and study withdrawal reason is related to CIS.  Where study withdrawal has not been discontinued after 
the sensor but on the same day, r2=0.


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Percentage of Rescue Free Days Endpoint 

If the sensor is in use for at least a day within a month, r1>0 then let the analysis value be a 
combined value (weighted average) of the J2RA observed and J2RB imputed values, by taking a 
proportion of each value based on the proportion of days the MDI rescue was in use and not in use 
in that month 
      Analysis Value = r1/r4 x (value from J2RA) + r3/r4 x (value from J2RB)
Note the weights are r4

Else if the sensor was not used in the month, r1=0 then let the analysis value be the imputed value,
      Analysis value = value from J2RA dataset (which is the imputed value
STEP 5: Secondary Endpoint Percentage of Rescue Free Days Endpoint calculation 
The calculations presented in the previous steps support the final derivation of the following secondary 
endpoint, the percentage of rescue free days between 
o
the beginning of Month 4 and the end of Month 6
For participants who complete the study during the endpoint period of interest:
Analysis Endpoint is the average of monthly Analysis Values over the number of months in the 
endpoint period of interest, i.e.
o
Month 4 to Month 6 
For participants who prematurely discontinue the study during the endpoint period of interest for reasons 
related or not related to CIS, the MAR or J2R imputation assumes participants would have continued in 
the study until the end of the period of interest. The weight is the total duration within the endpoint period 
of interest. This weight will be applied to each month within the period of interest and results summed 
together to produce the final endpoint/response variable for modelling within macro Part 3.
Note the weight is, total expected study duration within the period of interest.  The proportion of weight to 
apply per monthly Analysis value is r1+r2+r3/ Total expected study duration within the period of interest.


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Percentage of Rescue Free Days Endpoint 
Seeds for Multiple Imputations Macros
Seeds for all planned MI analyses were determined in advance using the following SAS code and 
documented within this RAP prior to unblinding:
data temp;
  do i = 1 to 6;
    number=round(10000*ranuni(0),1);
   output;
  end;
run;
proc print;
run;
Part 1B Macro Seed for Parameter Estimation Using Bayesian MCMC Procedure 
Endpoint
Input Dataset
Macro Seed
Percentage of Rescue Free Days
Observed Dataset A
9170
Observed Dataset B
5337
Part 2B Macro Seeds for Multiple Imputation of Datasets
Endpoint
Multiple Imputation 
Method
Macro Seed Output Dataset
Percentage of Rescue Free Days
MAR 
2553
MAR Dataset A
J2R
8350
J2R Dataset A
MAR
4380
MAR Dataset B
J2R
2045
J2R Dataset B


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10.5.3.3.
Patient Reported Outcomes
Asthma Control Test (ACT)
The ACT is a validated self-administered questionnaire utilising 5 questions to assess asthma control during 
the past 4 weeks on a 5-point categorical scale (1 to 5). 
By answering all 5 questions, a participant with asthma can obtain a score that may range between 5 and 
25, with higher scores indicating better control. An ACT total score of 5 to 19 suggests that the participant’s 
asthma is unlikely to be well controlled. A score of 20 to 25 suggests that the participant’s asthma is likely to 
be well controlled. The minimally important difference (MID) for ACT is 3 [Schatz, 2009].
The total score is calculated as the sum of the scores from all 5 questions [Nathan,2004], provided all 
scores are non-missing; if any individual scores are missing then the overall score will be set to missing.
The ACT total scores calculated using the electronic version on the ePRO device will be used; i.e. total 
scores will not be rederived from the individual question responses.
ACT will be completed on an ePRO device at the clinical study site and at the times detailed in Appendix 1: 
Schedule of Activities.
Asthma Symptom Utility Index (ASUI)
The ASUI is a 10-item self-administered questionnaire with 4 questions on asthma symptoms (Cough, 
wheeze, shortness of breath, awakening at night) and 1 question about the side effects of asthma 
medications [Revicki, 1998].  
For each symptom, there are 2 dimensions; frequency and severity.  The questionnaire is based on a 2-
week patient recall of symptoms with response options of 0 to 4 for frequency (not at all, 1 to 3 days, 4 to 7 
days, and 8 to 14 days) and severity (not applicable, mild, moderate and severe).
ASUI score ranges from 0 (worst possible symptoms) to 1 (no symptoms) and the MID of the ASUI is 
considered to be 0.09 [Bime, 2012]. If the response to any question is missing then the ASUI is also set to 
missing.
A multi-attributable utility theory was used to construct a model for calculating ASUI utilities from individual 
patient responses [Revicki, 1998]. The multi-attributable utility function is:
where ASUI is the utility of the symptom state on a scale where the best state (no symptoms) has a score of 
1 and worst possible symptoms (severe symptoms for 8 to 14 days) has a score of 0; and is is the score for 
the level on symptom i. The table below shows the coefficients for calculating the ASUI scores:
Symptom (Attribute)
Level, d
Cough, S1
Wheeze, S2
Dyspnoea, 
S3
Awaken at 
Night, S4
Medication Side 
Effects, S5
1 None
1.0
1.0
1.0
1.0
1.0
2 Mild, 1-3
0.985
0.962
0.946
0.955
0.970
3 Mild, 4-7
0.963
0.940
0.920
0.931
0.954
4 Mild, 8-14
0.935
0.913
0.885
0.899
0.930
5 Moderate, 1-3
0.955
0.913
0.892
0.909
0.924
6 Moderate, 4-7
0.920
0.886
0.860
0.880
0.900
7 Moderate, 8-
14
0.875
0.851
0.818
0.845
0.862
8 Severe, 1-3
0.863
0.810
0.771
0.821
0.824
9 Severe, 4-7
0.813
0.772
0.729
0.781
0.789
10 Severe, 8-14
0.751
0.729
0.681
0.734
0.730


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ASUI will be completed on an ePRO device at the clinical study site and at the times detailed in Appendix 1: 
Schedule of Activities.
St. George’s Respiratory Questionnaire (SGRQ)
The St. George’s Respiratory Questionnaire is a well-established instrument, comprising a 50-item 
questionnaire designed to measure Quality of Life in patients with diseases of airway obstruction, measuring 
symptoms, impact, and activity. 
The questions are designed to be self-completed by the participant with a recall over the past 4 weeks 
[Jones, 1992]. 
Scores are expressed as the percentage of overall impairment with 100 equalling to the worst possible 
health status and 0 indicating the best possible health status.
Scoring in each domain of the SGRQ (Symptoms, Activity, Impacts) and the Total score are described in the 
St George’s Respiratory Questionnaire Manuel (Version 2.3, 2009).  
SGRQ will be completed on an ePRO device at the clinical study site and at the times detailed in Appendix 
1: Schedule of Activities.
Patient Activation Measure (PAM-13)
Patient Activation Measure will be used to assess the knowledge, skills and confidence a
person has in managing their own health and health care.
The PAM contains a series of 13 statements designed to assess the extent of a patient’s activation. These 
statements are about beliefs, confidence in the management of health-related tasks and self-assessed 
knowledge. Patients are asked to rate the degree to which they agree or disagree with each statement. 
These answers are combined to provide a single score of between 0 and 100, which represents the 
patients’ concept of themselves as an active manager of their health and health care. There is no specified 
timeframe on which responses should be based, the questionnaire is suitable to be used to measure
changes in activation over time and can be performed before and after an intervention [Hibbard, 2004].
The 13 items have four possible response options: (1) disagree strongly, (2) disagree, (3) agree and (4)
agree strongly, and an additional “Not applicable” option. The total PAM score is then calculated by dividing 
the raw score over the number of items answered (not including the non-applicable items) and multiplied by 
13. This score is then transformed to a scale with a range of 0-100 based on calibration tables and 
proprietary PAM algorithm (http://www.insigniahealth.com/). The score will be provided for analysis.
Medication Adherence Report Scale for Asthma (MARS-A)
The MARS-A is a 10-item questionnaire where medication use is rated on a 5-point
Likert scale (1 indicating ‘always’ to 5 indicating ‘never’). It has been validated as a self-reported
measure of adherence with ICS for patients with asthma, and includes generic
(“I use it regularly every day”) and lung condition-specific questions about medication
use (“I only use it when I feel breathless”) [Cohen, 2009].
The MARS-A 10-Score will be calculated for each participant as the sum of scores for each of the ten 
questions divided by the number of non-missing responses to the ten questions.
If some responses are missing the MARS-A 10-score is calculated as follows for each participant:

If eight or more of the questions have been answered, the missing responses for that participant
will be imputed to the average score


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
If less than eight of the questions have been answered, the overall MARS-A 10-score for that 
participant will be set to missing
MARS-A will be completed on an ePRO device at the clinical study site and at the times detailed in 
Appendix 1: Schedule of Activities.
Beliefs in Medicine Questionnaire (BMQ)
The BMQ questionnaire consists of the BMQ Specific, which measures perceptions of specific medicines, 
and the BMQ General, which measures more general beliefs about medicines. All items are scored on a 5-
point Likert scale ranging from Strongly Disagree (1) to Strongly Agree (5). 
The BMQ Specific questionnaire  is formed of the 6 item Necessity and 12 item Concern scales, and the 
General questionnaire is formed of the 4 item Benefit, 5 item Harm and 3 item Overuse scales. 
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by
third party copyright laws and therefore have been excluded.


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Scores obtained for individual items within scales are summed together to provide a total score. The BMQ 
Specific and General will be completed on an ePRO device at the clinical study site and at the times 
detailed in Appendix 1: Schedule of Activities.
Biomarkers
PEF and FeNO

Participants should not use their rescue medication for at least 6 hours before each FeNO and PEF 
assessment, unless essential for clinical need. Participants should also withhold ICS/LABA for (1 
dosing interval ) approximately 12-24 hours prior to FeNO and PEF assessment.

PEF and FeNO will be taken in triplicate at the times detailed in Appendix 1: Schedule of Activities. All 3 
measures will be recorded in the eCRF.

The maximum value from the 3 measures taken at each visit will be used in the calculation of the FeNO
and PEF endpoints.
Severe Asthma Exacerbations
General
Missing onset or resolution dates will be handled as follows:

Single event with missing onset and/or resolution dates:
(a)
Missing onset date: set onset date = study treatment start date
(b)
Missing resolution date: set resolution date = study treatment stop date
(c)
Both missing: imputed per both (a) and (b)

Multiple events, one event with some missing onset/resolution dates; on the assumption any partial 
date information does not occur during the other events:
(a)
Missing onset date: set onset date = max[(resolution date of the nearest previous event) + 1 
day, study treatment start date]
(b)
Missing resolution date: set resolution date = min[(onset date of the nearest subsequent event) 
- 1 day, study treatment stop date] 
(c)
Both missing: determine the largest gap between study treatment start date and first event 
onset date, between first event resolution date and next event(s) onset dates (if any), between 
last event resolution date and study treatment stop date. If there is more than one gap which is 
the largest, then take the first occurrence. Then impute as follows:
onset date = (onset date of largest gap) + 1 day
resolution date = (resolution date of largest gap) + 1 day


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10.5.4.
Safety
Adverse Events

Adverse events will be coded using the current MedDRA coding dictionary at the time of reporting 
providing a Preferred Term (PT) and a System Organ Class (SOC) for analysis and reporting.
ADRs and SAEs of Special Interest
ADR and SAE groups of special interest have been defined as SAEs which are included in specified areas 
of interest for Relvar/Breo.  They are identified by groupings of preferred terms based on the Medical 
Dictionary for Regulatory Activities (MedDRA) dictionary version used in each reporting effort.  Groupings or 
subgroups may be defined, based on relevant combination of preferred terms, or on Standardised MedDRA 
queries (SMQs).
SAEs of special interest will be confirmed prior to final data, based on the MedDRA version in use at the 
time


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10.6.
Appendix 6: Reporting Standards for Missing Data
10.6.1.
Premature Withdrawals
Element
Reporting Detail
General

Participant study completion (as specified in the protocol) is defined as completing all 
visits of the study including the follow-up phone contact.

Withdrawn participants will not be replaced in the study.

All available data from participants who are withdrawn from the study will be included in 
listings and where possible any available data from withdrawn participants will be 
included in summaries or analyses, unless otherwise specified.
10.6.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank fields on 
the collection instrument:
o
These data will be indicated by the use of a “blank” in participant listing displays. If 
all data for a specific visit are missing, the visit will be excluded from the display.
o
Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and will be displayed as such.
MMRM
Analysis

All the available assessments taken at scheduled visits will be included in the repeated 
measures models in which missing data are not explicitly imputed but the correlation 
between visits for all participants is used to adjust the estimate of treatment effect 
considering any missing data.
Rescue Free 
Days 
Endpoint

Handling of missing sensor data is detailed in Section 7.2.2.3 Strategy for Intercurrent 
(Post-Randomisation) Events, as well Section 10.5.3.2 MDI Device Sensor 
Assessments.
ACT

Handling of missing ACT data is detailed in Section 7.2.3.3 Strategy for Intercurrent 
(Post-Randomisation) Events.
Other PROs

Handling of missing PRO data is detailed in Section 7.3.3.4 Strategy for Intercurrent 
(Post-Randomisation) Events, as well in Section 10.5.3.3 Patient Reported Outcomes.
10.6.3.
Handling of Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in participant listing displays.
Adverse 
Events

The eCRF does not allow partial dates to be captured for AEs. All dates will either be 
complete or missing.

Completely missing start or end dates will remain missing, with no imputation applied.

Where AE onset dates are missing then the AE will be considered on-treatment.
Concomitant 
Medications

The eCRF allows partial dates to be captured for concomitant medications.

Partial dates for any concomitant medications recorded in the eCRF will be imputed 
using the following convention:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will be 
used for the month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month.


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Element
Reporting Detail

The answers to the questions “Taken Prior to Study?” and “Ongoing?” which are 
recorded in the eCRF will also be taken into consideration to determine if the 
medication was started pre-treatment or continued post-treatment. In each case, 
should the answers suggest a different classification than the dates, the medication 
will be summarized in all possible classifications (pre-/during/post-treatment) in which 
it could conceivably have been taken.
Exacerbations

Exacerbations are treated in the same way as AEs. 


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10.7.
Appendix 7: Abbreviations & Trade Marks
10.7.1.
Abbreviations
Abbreviation
Description
ACT
Asthma Control Test
ADaM
Analysis Data Model
ADR
Adverse Drug Reaction
AE
Adverse Event
ANCOVA
Analysis of Covariance
A&R
Analysis and Reporting 
ASUI
Asthma Symptom Utility Index
ATC
Anatomical Therapeutical Chemical
BMQ
Beliefs in Medicine Questionnaire
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CIS
Connected Inhaler System
CS
Clinical Statistics
CSR
Clinical Study Report
DBF
Database Freeze
DBR
Database Release
DOB
Date of Birth
DP
Decimal Places
DM
Data Management
DPI
Dry powder inhaler
eCRF
Electronic Case Record Form
ER
Emergency Room
EW
Early Withdrawal
FeNO
Fractional exhaled Nitric Oxide
GLM
Generalized Linear Model
GSK
GlaxoSmithKline
HCP
Healthcare Professional
HCRU
Health Care Resource Utilization
IA
Interim Analysis
ICH
International Conference on Harmonization
ICF
Informed Consent Form
ICS
Inhaled Corticosteroid
IDSL
Integrated Data Standards Library
ITT
Intent-To-Treat
J2R
Jump to reference
LABA
Long-Acting Beta2-Agonist
MAR
Missing At Random
MARS-A
Medication Adherence Report Scale for Asthma
MDI
Metered dose inhaler
MMRM
Mixed Model Repeated Measures
PAM
Patient Activation Measure
PDMP
Protocol Deviation Management Plan
PEF
Peak Expiratory Flow
PRO
Patient Reported Outcomes
PT
Preferred Term


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Abbreviation
Description
QC
Quality Control
RAP
Reporting & Analysis Plan
RFD
Rescue Free Day
RAMOS
Randomisation & Medication Ordering System 
SAC
Statistical Analysis Complete
SAE
Serious Adverse Event
S&P
Statistics and Programming
SD
Standard Deviation
SDL
Source Data Lock
SDTM
Study Data Tabulation Model
SGRQ
St. Georges Respiratory Questionnaire
SI
System Independent
SMQ
Standardised MedDRA Queries
SOC
System Organ Class
TRU
Total Rescue Use
SOP
Standard Operation Procedure
TA
Therapeutic Area
TFL
Tables, Figures & Listings
10.7.2.
Trademarks
Trademarks of the GlaxoSmithKline Group 
of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
BREO
ACT
ELLIPTA
ASUI
RELVAR
BMQ
MARS-A
MedDRA
PAM-13
RAMOS NG
SAS
SGRQ


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10.8.
Appendix 8: List of Data Displays
10.8.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.01 to 1.44
1.01 to 1.02
Efficacy
2.01 to 2.41
2.01 to 2.22
Safety
3.01 to 3.29
None
Section
Listings
ICH Listings
1 to 19
Other Listings
20 to 44
10.8.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 9: Example Mock Shells for Data Displays: Example 
Mock Shells for Data Displays.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Efficacy
EFF_Fn
EFF_Tn
EFF_Ln
Safety
Not applicable
SAFE_Tn
SAFE_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL /  Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’
10.8.3.
Deliverables
Delivery [Priority] [1]
Description
SAC [2]
Final Statistical Analysis Complete
DRY RUN [1]
Dry Run
NOTES: 
1.
Indicates priority (i.e. order) in which displays will be generated for the reporting effort


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10.8.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
Screened
IDSL_SP1
Summary of Subject Populations 
See Section 4 for population details
SAC [2]
DRY RUN [1]
1.2.
Enrolled
IDSL_ES6
Summary of Screening Status and Reasons for Screen Failure
SAC [2]
DRY RUN [1]
1.3.
Enrolled
IDSL_ES6
Summary of Run-in Status and Reasons for Run-In Failure
SAC [2]
DRY RUN [1]
1.4.
ITT
POP_T1
Summary of Attendance at Each Visit
Note: Visit 2/3/4 subjects may be 
randomised or re-entered into run-in 
up 3 times if ACT ≥ 20.
Note: Visits 6/7/8/9 are Healthcare 
Professional Dashboard reviews for 
Arm 1 and Arm 3 .
SAC [2]
DRY RUN [1]
1.5.
ITT
IDSL_ES1
Summary of Subject Disposition for the Subject Conclusion 
Record
SAC [2]
DRY RUN [1]
1.6.
ITT
IDSL_ES4
Summary of Subject Disposition at Each Study Epoch
SAC [2]
DRY RUN [1]
1.7.
ITT
IDSL_SD1
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment
SAC [2]
DRY RUN [1]
1.8.
ITT
POP_T2
Summary of Relvar/Breo ELLIPTA Sensor Status
SAC [2]
DRY RUN [1]


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Study Population Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
1.9.
ITT
POP_T2
Summary of Salbutamol MDI Sensor Status
SAC [2]
DRY RUN [1]
1.10.
ITT
POP_T3
Summary of App Status
SAC [2]
DRY RUN [1]
1.11.
Enrolled
IDSL_NS1
Summary of Number of Subjects Enrolled by Country and Site 
ID
Disclosure display
Add “No Treatment” column
Do by page by country to help fit all 
columns in one width.
SAC [2]
DRY RUN [1]
1.12.
ITT
IDSL_NS1
Summary of Number of Subjects Enrolled by Country and Site 
ID
Do by page by country for 
consistency with above display
SAC [2]
DRY RUN [1]
1.13.
ITT
IDSL_IE1
Summary of Inclusion/Exclusion Criteria Deviations
SAC [2]
DRY RUN [1]
1.14.
ITT
IDSL_DV1
Summary of Important Protocol Deviations
SAC [2]
DRY RUN [1]
Demographic and Baseline Characteristics
1.15.
ITT
IDSL_DM1
Summary of Demographic Characteristics
Include, Gender, Age (years), Age 
group categories: 18-64, 65-84 and 
>=85, Ethnicity, Height, Weight, BMI
SAC [2]
DRY RUN [1]
1.16.
ITT
IDSL_DM1
Summary of Demographic Characteristics by Country
SAC [2]
DRY RUN [1]
1.17.
Enrolled
IDSL_DM11
Summary of Age ranges
Disclosure displays / Categories: 
18-64, 65-84 and >=85.
Include “No Treatment” column
SAC [2]
DRY RUN [1]


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Study Population Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
1.18.
ITT
IDSL_DM5
Summary of Race and Racial Combinations
SAC [2]
DRY RUN [1]
1.19.
ITT
IDSL_DM6
Summary of Race and Racial Combination Details
SAC [2]
DRY RUN [1]
Medical Conditions
1.20.
ITT
IDSL_MH4
Summary of Current Medical Conditions
SAC [2]
DRY RUN [1]
1.21.
ITT
IDSL_MH4
Summary of Past Medical Conditions
SAC [2]
DRY RUN [1]
1.22.
ITT
IDSL_FH1
Summary of Family History of Cardiovascular Risk Factors
SAC [2]
DRY RUN [1]
1.23.
ITT
IDSL_SU1
Summary of Substance Use at Screening
Include Smoking History, for the 
Current and Former Smokers 
include Years smoked, 
Cigarettes/Day, Smoking Pack 
Years
SAC [2]
DRY RUN [1]
Disease Characteristics
1.24.
ITT
POP_T4
Summary of Asthma Duration at Screening
SAC [2]
DRY RUN [1]
1.25.
ITT
POP_T5
Summary of Exacerbation History at Screening
SAC [2]
DRY RUN [1]
1.26.
ITT
POP_T6
Summary of Screening and Randomisation Peak Expiratory 
Flow (PEF)
Summarize using the maximum 
value at visit
SAC [2]
DRY RUN [1]


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Study Population Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
1.27.
ITT
POP_T6
Summary of Screening and Randomisation Peak Expiratory 
Flow (PEF) by Country
Summarize using the maximum 
value at visit
SAC [2]
DRY RUN [1]
1.28.
ITT
POP_T6
Summary of Screening and Randomisation Fractional Exhaled 
Nitric Oxide (FeNO)
Summarize using the maximum 
value at visit
SAC [2]
DRY RUN [1]
Concomitant Medications
1.29.
ITT
IDSL_CM1
Summary of Concomitant Medications Taken in the Run-in, 
Medications Given for Severe Exacerbation
SAC [2]
DRY RUN [1]
1.30.
ITT
IDSL_CM1
Summary of On-Treatment Asthma Concomitant Medications, 
Medications Given for Severe Exacerbation
SAC [2]
DRY RUN [1]
1.31.
ITT
IDSL_CM1
Summary of On-Treatment Asthma Concomitant Medications
SAC [2]
DRY RUN [1]
1.32.
ITT
IDSL_CM1
Summary of Post-Treatment Asthma Concomitant Medications
SAC [2]
DRY RUN [1]
1.33.
ITT
IDSL_CM1
Summary of Run-in Treatment Asthma Concomitant Medications
SAC [2]
DRY RUN [1]
1.34.
ITT
IDSL_CM1
Summary of On-Treatment Non-Asthma Concomitant 
Medications
SAC [2]
DRY RUN [1]
1.35.
ITT
IDSL_CM1
Summary of Post-Treatment Non-Asthma Concomitant 
Medications
SAC [2]
DRY RUN [1]
1.36.
ITT
IDSL_CM1
Summary of Run-in Treatment Non-Asthma Concomitant 
Medications
SAC [2]
DRY RUN [1]


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Study Population Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
1.37.
ITT
IDSL_CM1
Summary of Asthma Concomitant Medications Taken Prior to 
Screening
Ensure the observations dates are 
pre-screening visit 1 (there is a 
specific prior conmeds page in 
eCRF
SAC [2]
DRY RUN [1]
Exposure and Treatment Compliance
1.38.
ITT
POP_T7
Summary of Exposure to Study Medication
Post-randomisation treatment 
exposure
SAC [2]
DRY RUN [1]
1.39.
ITT
POP_T8
Summary of the Frequency of Puffs Per Day – ELLIPTA Sensor
Programming Note: Repeat for 
Months 2, 3, 4, 5, 6, Months 4-6, 
Months 1-6 and Months 1-
3.Frequency of puffs per day over 
the baseline and on-treatment 
period as defined in the 
Assessment Windows of RAP
SAC [2]
DRY RUN [1]
1.40.
ITT
POP_T8
Summary of the Frequency of Puffs Per Day – MDI Sensor
Programming Note: Repeat for 
Months 2, 3, 4, 5, 6, Months 4-6, 
Months 1-6 and Months 1-
3.Frequency of puffs per day over 
the baseline and on-treatment 
period as defined in the 
Assessment Windows of RAP
SAC [2]
DRY RUN [1]


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Study Population Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
1.41.
ITT
POP_T9
Summary of Treatment Compliance 
Post-randomisation compliance
Note: Treatment compliance = 
(Total number of inhalation taken / 
Expected Inhalation x (Stop date -
Start date + 1)) x 100 where Total 
Number of Inhalations Taken is the 
total number of doses taken from all 
inhalers, Expected Inhalations is 
equal to 1 and Start Date and Stop 
Date are the earliest treatment start 
date on or post randomisation and 
the latest treatment stop date 
recorded for all the inhalers.
SAC [2]
DRY RUN [1]
Others
1.42.
ITT
POP_T10
Summary of Incidence of Preferred Time of Dosing over the 
Treatment Period
SAC [2]
DRY RUN [1]
1.43.
ITT
POP_T11
Summary of HCP Dashboard Review by Visit
Note: Visits 6/7/8/9 are Healthcare 
Professional Dashboard reviews for 
Arm 1 and Arm 3
[1] Action taken – Email/Text/Phone 
Contact 
SAC [2]
DRY RUN [1]
1.44.
ITT
POP_T12
Summary of Prior Prescription Details 
SAC [2]
DRY RUN [1]


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10.8.5.
Study Population Figures
Study Population Figures
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Relvar/Breo ELLIPTA Adherence
1.1.
ITT
POP_F1
Frequency of ELLIPTA Puffs Per Day– ELLIPTA Sensor
Programming Note: Repeat for 
Period: Month 1, 2, 3, 4, 5, 6, Month 
4-6, Month 1-3, Month 1-6.
SAC [2]
DRY RUN [1]
1.2.
ITT
POP_F1
Frequency of MDI Puffs Per Day – MDI Sensor
Programming Note: Repeat for 
Period: Month 1, 2, 3, 4, 5, 6, Month 
4-6, Month 1-3, Month 1-6.
SAC [2]
DRY RUN [1]
10.8.6.
Efficacy Tables
Efficacy Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Relvar/Breo ELLIPTA Adherence
2.1.
ITT
EFF_T1
Summary of Monthly Percentage of ELLIPTA doses taken (daily 
adherence) between the beginning of month 1 and the end of 
month 6 as determined by the maintenance sensor – Observed 
Data
Use the observed monthly values 
(month 1, 2, 3, 4, 5, 6)
[1] Baseline adherence is calculated 
using up to the last 28 days of daily 
adherence data during the run-in 
period.
SAC [2]
DRY RUN [1]


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Efficacy Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.2.
ITT
EFF_T2
Summary of Statistical Analysis of Percentage of ELLIPTA 
doses taken (daily adherence) between the beginning of month 
4 and the end of month 6 as determined by the maintenance 
sensor
Present comparisons Arm 1,2,3,4 v 
Arm 5
SAC [2]
DRY RUN [1]
2.3.
ITT
EFF_T2
Summary of Statistical Analysis of Percentage of ELLIPTA 
doses taken (daily adherence) between the beginning of month 
4 and the end of month 6 as determined by the maintenance 
sensor – Generalised Linear Model (Sensitivity Analysis)
Present comparisons Arm 1,2,3,4 v 
Arm 5
SAC [2]
2.4.
ITT
EFF_T3
Summary of Statistical Analysis of Percentage of ELLIPTA 
doses taken (daily adherence) between the beginning of month 
4 and the end of month 6 as determined by the maintenance 
sensor by Baseline ACT Total Score Group
Subgroup analysis output
Update footer with interaction 
between treatment group arm and 
baseline ACT Total Score Group
SAC [2]
DRY RUN [1]
2.5.
ITT
EFF_T3
Summary of Statistical Analysis of Percentage of ELLIPTA 
doses taken (daily adherence) between the beginning of month 
4 and the end of month 6 as determined by the maintenance 
sensor by Age Group
Subgroup analysis output
Update footer with interaction 
between treatment group arm and 
baseline ACT Total Score Group
SAC [2]
DRY RUN [1]
2.6.
ITT
EFF_T4
Summary of Statistical Analysis of Percentage of ELLIPTA 
doses taken (daily adherence) between the beginning of month 
1 and the end of month 3 as determined by the maintenance 
sensor
Present comparisons Arms 1,2,3,4 
v Arm 5
SAC [2]
DRY RUN [1]
2.7.
ITT
EFF_T4
Summary of Statistical Analysis of Percentage of ELLIPTA 
doses taken (daily adherence) between the beginning of month 
1 and the end of month 3 as determined by the maintenance 
sensor – Generalised Linear Model (Sensitivity Analysis)
Present comparisons Arm 1,2,3,4 v 
Arm 5
SAC [2]


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Efficacy Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.8.
ITT
EFF_T4
Summary of Statistical Analysis of Percentage of ELLIPTA 
doses taken (daily adherence) between the beginning of month 
1 and the end of month 6 as determined by the maintenance 
sensor
Present comparisons Arms 1,2,3,4 
v Arm 5
SAC [2]
DRY RUN [1]
2.9.
ITT
EFF_T4
Summary of Statistical Analysis of Percentage of ELLIPTA 
doses taken (daily adherence) between the beginning of month 
1 and the end of month 6 as determined by the maintenance 
sensor – Generalised Linear Model (Sensitivity Analysis)
Present comparisons Arm 1,2,3,4 v 
Arm 5
SAC [2]
2.10.
ITT
EFF_T5
Summary of Statistical Analysis of Percentage of ELLIPTA 
doses taken (daily adherence) between the beginning of month 
4 and the end of month 6 as determined by the maintenance 
sensor – Impact of Feedback of Sensor Data to HCP
Present comparisons Arm 1 v 2, 
Arm 3 v 4
SAC [2]
DRY RUN [1]
2.11.
ITT
EFF_T6
Summary of Statistical Analysis of Percentage of ELLIPTA 
doses taken (daily adherence) between the beginning of month 
4 and the end of month 6 as determined by the maintenance 
sensor – Impact of Feedback on Rescue Medication Use
Present comparisons Arm 1 v 3, 
Arm 2 v 4
SAC [2]
DRY RUN [1]
Salbutamol MDI Rescue Medication Use
2.12.
ITT
EFF_T1
Summary of Monthly Percentage of Rescue Free Days between 
the beginning of month 1 and then end of month 6 as 
determined by the rescue medication sensor – Observed Data
Use the observed monthly values 
(month 1, 2, 3, 4, 5, 6)
[1] Baseline rescue free use is 
calculated using up to the last 28 
days of daily rescue use data during 
the run-in period.
SAC [2]
DRY RUN [1]
2.13.
ITT
EFF_T4
Summary of Statistical Analysis of Percentage of Rescue Free 
Days between the beginning of month 4 and the end of month 6 
as determined by the maintenance sensor
Present comparisons Arms 1,2,3,4 
v Arm 5
SAC [2]
DRY RUN [1]


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Efficacy Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.14.
ITT
EFF_T1
Summary of Total Rescue Medication Use as determined by the 
maintenance sensor 
SAC [2]
DRY RUN [1]
Asthma Control Test (ACT)
2.15.
ITT
EFF_T1
Summary of Asthma Control Test (ACT) Total Score
Programming Note: Add screening
visit score.
[1] Baseline ACT total score is
taken at Randomisation visit.
SAC [2]
DRY RUN [1]
2.16.
ITT
EFF_T4
Summary of the Statistical Analysis of Change from Baseline 
(Randomisation) in ACT Total Score at Month 6
SAC [2]
DRY RUN [1]
2.17.
ITT
EFF_T12
Summary of Percentage of Subjects Who Have Either an ACT 
Total Score >= 20 and/ or >= 3 Point Increase from Baseline in 
ACT Total Score
See SLS T2.1
SAC [2]
DRY RUN [1]
2.18.
ITT
EFF_T13
Summary of the Statistical Analysis of Percentage of Patients 
Who Have an ACT Total Score of >=20 at Month 6
SAC [2]
DRY RUN [1]
2.19.
ITT
EFF_T13
Summary of the Statistical Analysis of Percentage of Patients 
with an Increase from Baseline ≥3 in ACT Total Score at Month 
6
SAC [2]
DRY RUN [1]
2.20.
ITT
EFF_T13
Summary of the Statistical Analysis of Percentage of Patients 
Who Have Either an ACT Total Score of ≥ 20 and/or an 
Increase from Baseline of ≥ 3 in ACT Total Score at Month 6
SAC [2]
DRY RUN [1]
Unscheduled Health Care Utilisation
2.21.
ITT
EFF_T14
Summary of Unscheduled Asthma Related Healthcare Utilisation
During the Study
SAC [2]
DRY RUN [1]
2.22.
ITT
EFF_T22
Summary of Primary Care Visits relating to HCP Dashboard 
Review
SAC [2]
DRY RUN [1]


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Efficacy Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Severe On-treatment Exacerbations
2.23.
ITT
EFF_T15
Summary of Severe On-Treatment and Post-Treatment Asthma 
Exacerbations
Exacerbation duration and rates will 
only be determined from those 
events that have dates of onset and 
resolution
Include a total column
SAC [2]
DRY RUN [1]
Asthma Symptom Utility Index (ASUI)
2.24.
ITT
EFF_T1
Summary of Asthma Symptom Utility Index (ASUI) Score
Programming Note: Add screening
visit score. Decimal places need to 
be increased by 2 dp for all values.
[1] Baseline ASUI total score is
taken at Randomisation visit.Note: 
SAC [2]
DRY RUN [1]
2.25.
ITT
EFF_T16
Summary of Statistical Analysis of Percentage of Patients 
Meeting a Responder Threshold of ≥ 0.09 Points Improvement
(Increase) from Baseline (Randomisation) for the ASUI Total 
Score at Visit 10 (Month 6)
SAC [2]
DRY RUN [1]
2.26.
ITT
EFF_T4
Summary of Statistical Analysis of Change from Baseline
(Randomisation) in Asthma Symptom Utility Index (ASUI) Score 
at Visit 10 (Month 6)
SAC [2]
DRY RUN [1]
St. George’s Respiratory Questionnaire (SGRQ)
2.27.
ITT
EFF_T1
Summary of St. George’s Respiratory Questionnaire (SGRQ) 
Total Score
Programming Note: Add screening
visit score.
[1] Baseline SGRQ total score is 
taken at Randomisation visit.
SAC [2]
DRY RUN [1]


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Efficacy Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.28.
ITT
EFF_T13
Statistical Analysis of Percentage of Patients Meeting a 
Responder Threshold of ≥ 4 Points Improvement (Decrease)
from Baseline (Randomisation) for the SGRQ Total Score at 
Visit 10 (Month 6)
SAC [2]
DRY RUN [1]
2.29.
ITT
EFF_T4
Summary of Statistical Analysis of Change from Baseline 
(Randomisation) in St. George’s Respiratory Questionnaire 
(SGRQ) at Visit 10 (Month 6)
SAC [2]
DRY RUN [1]
Patient Activation Measure (PAM-13)
2.30.
ITT
EFF_T1
Summary of Patient Activation Measure (PAM) 13 Total Score
Programming Note: Add 
randomisation visit score.
[1] Baseline PAM-13 total score is
taken at Screening visit.
SAC [2]
DRY RUN [1]
Medication Adherence Rating Scale Asthma (MARS-A)
2.31.
ITT
EFF_T1
Summary of Medication Adherence Report Scale-Asthma 
(MARS-A) Total Score
Programming Note: Add 
randomisation visit score.
[1] Baseline MARS-A total score is
taken at Screening visit.
SAC [2]
DRY RUN [1]
Beliefs about Medicines (BMQ)
2.32.
ITT
EFF_T1
Summary of BMQ General Benefit Total Score
Programming Note: Add 
randomisation visit score.
[1] Baseline BMQ total score is 
taken at Screening visit.
SAC [2]
DRY RUN [1]
2.33.
ITT
EFF_T1
Summary of BMQ General Harm Total Score
Programming Note: Add 
randomisation visit score.
[1] Baseline BMQ total score is 
taken at Screening visit.
SAC [2]
DRY RUN [1]


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Efficacy Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.34.
ITT
EFF_T1
Summary of BMQ General Overuse Total Score
Programming Note: Add 
randomisation visit score.
[1] Baseline BMQ total score is 
taken at Screening visit.
SAC [2]
DRY RUN [1]
2.35.
ITT
EFF_T1
Summary of BMQ Specific Necessity Total Score
Programming Note: Add 
randomisation visit score.
[1] Baseline BMQ total score is 
taken at Screening visit.
SAC [2]
DRY RUN [1]
2.36.
ITT
EFF_T1
Summary of BMQ Specific Concern Total Score
Programming Note: Add 
randomisation visit score.
[1] Baseline BMQ total score is 
taken at Screening visit.
SAC [2]
DRY RUN [1]
Medical Device Incidents
2.37.
ITT
EFF_T21
Summary of Medical Device Incidents (Sensors)
SAC [2]
DRY RUN [1]
Fractional Exhaled Nitric Oxide (FeNO) and Peak Expiratory Flow (PEF)
2.38.
ITT
EFF_T1
Summary of Fractional Exhaled Nitric Oxide (FeNO)
Programming Note: Add screening
visit reading.
[1] Baseline FeNO readings are
taken at Randomisation visit.
SAC [2]
DRY RUN [1]
2.39.
ITT
EFF_T23
Summary of Change from Baseline (Randomisation) in
Fractional Exhaled Nitric Oxide (FeNO) at Month 6 (Visit 10) by 
Percentage of ELLIPTA doses taken (daily adherence) between 
the beginning of Month 4 and the end of Month 6 Group
The adherence observations should 
be those taken from the analysis 
dataset holding the observed % 
values.  These should be grouped 
in quantiles using the 25th, 50th and 
75th percentiles as the data group 
boundaries.
SAC [2]
DRY RUN [1]


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Efficacy Tables
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.40.
ITT
EFF_T1
Summary of Peak Expiratory Flow (PEF)
Programming Note: Add screening
visit reading.
[1] Baseline FeNO readings are 
taken at Randomisation visit.
SAC [2]
DRY RUN [1]
2.41.
ITT
EFF_T23
Summary of Change from Baseline (Randomisation) in Peak 
Expiratory Flow (PEF) at Month 6 (Visit 10) by Percentage of 
ELLIPTA doses taken (daily adherence) between the beginning 
of Month 4 and the end of Month 6 Group
The adherence observations should 
be those taken from the analysis 
dataset holding the observed % 
values.  These should be grouped 
in quantiles using the 25th, 50th and 
75th percentiles as the data group 
boundaries
SAC [2]
DRY RUN [1]
10.8.7.
Efficacy Figures
Efficacy: Figures
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Relvar/Breo ELLIPTA Adherence
2.1.
ITT
EFF_F5
Box plot of Monthly Percentage of ELLIPTA doses taken (daily 
adherence) as determined by the maintenance sensor –
Observed Data
Month 1, 2, 3, 4, 5, and 6, ave 
month 1-3, ave month 4-6, ave 
month 1-6 across the x-axis.  
Monthly observed % value on the y-
axis.  Present each treatment over 
each month, off-set from one 
another
SAC [2]
DRY RUN [1]


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Efficacy: Figures
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.2.
ITT
EFF_F3
Adjusted Treatment Differences for Percentage of ELLIPTA 
doses taken (daily adherence) between the beginning of month 
4 and the end of month 6 as determined by the maintenance 
sensor – Comparisons Arm 1,2,3,4 v Arm 5
ANCOVA Primary endpoint analysis
Present “Treatment Arm Difference 
(95% CI) versus Arm 5” on y-axis 
and “Treatment Arms” Arm 1, Arm 
2, Arm 3 and Arm 4 on the x-axis.  
SAC [2]
DRY RUN [1]
2.3.
ITT
EFF_F4
Summary of Interaction Tests for Percentage of ELLIPTA doses 
taken (daily adherence) between the beginning of month 4 and 
the end of month 6 as determined by the maintenance sensor -
– Comparisons Arm 1,2,3,4 v Arm 5
Footer: the results displays are from 
an ANCOVA adjusted for 
randomised treatment arm, baseline 
adherence, duration of run-in 
(visits), country, gender
[1] age (years), covariate, and two-
way interaction between 
randomised treatment arm and 
covariate
[2] covariate, two-way interaction 
between randomised treatment 
group and covariate.
SAC [2]
DRY RUN [1]
2.4.
ITT
EFF_F2
Scatter Plot of Percentage of ELLIPTA doses taken (daily 
adherence) between the beginning of month 4 and the end of 
month 6 as determined by the maintenance sensor (Observed 
values) by Age
Requires the primary endpoint 
observed value, each treatment arm
presented with a unique 
symbol/pattern
SAC [2]
DRY RUN [1]
2.5.
ITT
EFF_F2
Scatter Plot of Percentage of ELLIPTA doses taken (daily 
adherence) between the beginning of month 4 and the end of 
month 6 as determined by the maintenance sensor (Observed 
values) by Baseline ACT Total Score
Requires the primary endpoint 
observed value, each treatment arm 
presented with a unique 
symbol/pattern
SAC [2]
DRY RUN [1]


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Efficacy: Figures
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.6.
ITT
EFF_F3
Adjusted Treatment Differences for Percentage of ELLIPTA 
doses taken (daily adherence) between the beginning of month 
4 and the end of month 6 as determined by the maintenance 
sensor – Impact of Feedback of Sensor Data to HCP
ANCOVA Present comparisons Arm 
1 v 2, Arm 3 v 4
Present “Treatment Arm Difference 
(95% CI)” on y-axis and “Treatment 
Arms” “Arm 1 vs Arm 2” and “Arm 3 
vs Arm 4” on the x-axis
SAC [2]
DRY RUN [1]
2.7.
ITT
EFF_F3
Adjusted Treatment Differences for Percentage of ELLIPTA 
doses taken (daily adherence) between the beginning of month 
4 and the end of month 6 as determined by the maintenance 
sensor – Impact of Feedback on Rescue Medication Use
ANCOVA Present comparisons Arm 
1 v 3, Arm 2 v 4
Present “Treatment Arm Difference 
(95% CI)” on y-axis and “Treatment 
Arms” “Arm 1 vs Arm 3” and “Arm 2 
vs Arm 4” on the x-axis
SAC [2]
DRY RUN [1]
2.8.
ITT
EFF_F3
Adjusted Treatment Differences for Percentage of ELLIPTA 
doses taken (daily adherence) between the beginning of month 
1 and the end of month 3 as determined by the maintenance 
sensor – Comparisons Arm 1,2,3,4 v Arm 5
ANCOVA Present comparisons 
Arms 1,2,3,4 v Arm 5
Present “Treatment Arm Difference 
(95% CI) versus Arm 5” on y-axis 
and “Treatment Arms” Arm 1, Arm 
2, Arm 3 and Arm 4 on the x-axis.  
SAC [2]
DRY RUN [1]
2.9.
ITT
EFF_F3
Adjusted Treatment Differences for Percentage of ELLIPTA 
doses taken (daily adherence) between the beginning of month 
1 and the end of month 6 as determined by the maintenance 
sensor – Comparisons Arm 1,2,3,4 v Arm 5
ANCOVA Present comparisons 
Arms 1,2,3,4 v Arm 5
Present “Treatment Arm Difference 
(95% CI) versus Arm 5” on y-axis 
and “Treatment Arms” Arm 1, Arm 
2, Arm 3 and Arm 4 on the x-axis.  
SAC [2]
DRY RUN [1]


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Efficacy: Figures
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Salbutamol MDI Rescue Medication Use
2.10.
ITT
EFF_F5
Box plot of Monthly Percentage of Rescue Free Days as 
determined by the rescue medication MDI sensor
Month 1, 2, 3, 4, 5, and 6, ave month 4-
6 across the x-axis.  Monthly observed 
% value on the y-axis.  Present each 
treatment over each month, off-set from 
one another
SAC [2]
DRY RUN [1]
2.11.
ITT
EFF_F3
Adjusted Treatment Differences for Percentage of Rescue Free 
Days between the beginning of month 4 and the end of month 6 
as determined by the rescue medication MDI sensor –
Comparisons Arm 1,2,3,4 v Arm 5
ANCOVA
Present “Treatment Arm Difference 
(95% CI) versus Arm 5” on y-axis 
and “Treatment Arms” Arm 1, Arm 
2, Arm 3 and Arm 4 on the x-axis.  
SAC [2]
DRY RUN [1]
Asthma Control Test (ACT)
2.12.
ITT
EFF_F3
Summary of ACT Total Score
Present “ACT Total Score (MeanSD)” 
on y-axis and “Visit” on x-axis Baseline, 
Visit 5 (Month 1), Visit 10 (Month 6). 
Present mean ACT Total Score SD 
separately for treatment group at each 
visit, connecting the means with a solid 
line. Distinguish the treatment groups 
by different line types.
[1] Baseline FeNO readings are taken 
at Randomisation visit.
SAC [2]
DRY RUN [1]


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Efficacy: Figures
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.13.
ITT
EFF_F3
Summary of Statistical Analysis for Change from Baseline 
(Randomisation) in ACT Total Score at Month 6
(MMRM) Present “Treatment Arm 
Difference (95% CI) versus Arm 5” on 
y-axis and “Visit” on x-axis Visit 5 
(Month 1), Visit 10 (Month 6).  Present 
Difference and 95% CI change from 
baseline in treatment arm difference 
and CI separately for treatment group 
at each visit. Distinguish the treatment 
groups by different line types.
SAC [2]
DRY RUN [1]
2.14.
ITT
EFF_F1
Forest Plot for Odds Ratio of Percentage of Subjects Who Have 
Either an ACT Total Score >= 20 and/or Increase from Baseline 
of >= 3 in ACT Total Score at Visit 10 (Month 6)
See example display for full visual.  
Present each treatment comparison per 
page. Within the plot Favours Arm 5 
should on the left and Favour Arm x on 
the right per page.  Three odds ratios 
should be presented, one for each of 
the ACT responder models –

ACT Total Score of 
>=20

ACT Total Score 
Increase from Baseline ≥3

ACT Total Score of ≥ 
20 and/or an Increase from 
Baseline of ≥ 3 
SAC [2]
DRY RUN [1]


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Efficacy: Figures
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Asthma Symptom Utility Index (ASUI)
2.15.
ITT
EFF_F3
Summary of ASUI Total Score
Present “ASUI Total Score (Mean 
SD)” on y-axis and “Visit” on x-axis 
Baseline, Visit 5 (Month 1), Visit 10 
(Month 6). Present mean ASUI Total 
Score SD separately for treatment 
group at each visit, connecting the 
means with a solid line. Distinguish the 
treatment groups by different line types.
Note: Baseline ASUI total score is
taken at Randomisation visit.
SAC [2]
DRY RUN [1]
2.16.
ITT
EFF_F3
Summary of Statistical Analysis for Change from Baseline 
(Randomisation) in ASUI Total Score at Visit 10 (Month 6)
(MMRM) Present “Treatment Arm 
Difference (95% CI) versus Arm 5” on 
y-axis and “Visit” on x-axis Visit 5 
(Month 1), Visit 10 (Month 6).  Present 
Difference and 95% CI change from 
baseline in treatment arm difference 
and CI separately for treatment group 
at each visit. Distinguish the treatment 
groups by different line types.
SAC [2]
DRY RUN [1]
2.17.
ITT
EFF_F1
Forest Plot for Odds Ratio of Percentage of Patients Meeting a 
Responder Threshold of ≥ 0.09 Points Improvement from 
Baseline (Randomisation) for the ASUI Total Score at Visit 10 
(Month 6)
See example display for full visual.  
Present each treatment comparison per 
page. Within the plot Favours Arm 5 
should on the left and Favour Arm x on 
the right per page.  Odds ratio should 
be presented for logistic reg. analysis  

ASUI
SAC [2]
DRY RUN [1]


CONFIDENTIAL
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125
Efficacy: Figures
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
St. George’s Respiratory Questionnaire (SGRQ)
2.18.
ITT
EFF_F3
Summary of SGRQ Total Score
Present “SGRQ Total Score (Mean 
SD)” on y-axis and “Visit” on x-axis 
Baseline, Visit 5 (Month 1), Visit 10 
(Month 6). Present mean SGRQ Total 
Score SD separately for treatment 
group at each visit, connecting the 
means with a solid line. Distinguish the 
treatment groups by different line types.
Note: Baseline SGRQ total score is 
taken at Randomisation visit.
SAC [2]
DRY RUN [1]
2.19.
ITT
EFF_F3
Summary of Statistical Analysis for Change from Baseline 
(Randomisation) in SGRQ Total Score at Visit 10 (Month 6)
(MMRM) Present “Treatment Arm 
Difference (95% CI) versus Arm 5” on 
y-axis and “Visit” on x-axis Visit 5 
(Month 1), Visit 10 (Month 6).  Present 
Difference and 95% CI change from 
baseline in treatment arm difference 
and CI separately for treatment group 
at each visit. Distinguish the treatment 
groups by different line types.
SAC [2]
DRY RUN [1]
2.20.
ITT
EFF_F1
Forest Plot for Odds Ratio of Percentage of Patients Meeting a 
Responder Threshold of ≥ 4 Points Improvement from Baseline 
(Randomisation) for the SGRQ Total Score at Visit 10 (Month 6)
See example display for full visual.  
Present each treatment comparison per 
page. Within the plot Favours Arm 5 
should on the left and Favour Arm x on 
the right per page.  Odds ratio should 
be presented, for logistic reg. analysis  

SGRQ
SAC [2]
DRY RUN [1]


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Efficacy: Figures
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Fractional Exhaled Nitric Oxide (FeNO) and Peak Expiratory Flow (PEF)
2.21.
ITT
EFF_F2
Scatter Plot of Percentage of ELLIPTA doses taken (daily 
adherence) between the beginning of month 4 and the end of 
month 6 as determined by the maintenance sensor (observed 
values) by Change from Baseline (Randomisation) in FeNO at 
Month 6 (Visit 10)
Requires the primary endpoint 
observed value, each treatment arm 
presented with a unique 
symbol/pattern
SAC [2]
DRY RUN [1]
2.22.
ITT
EFF_F2
Scatter Plot of Percentage of ELLIPTA doses taken (daily 
adherence) between the beginning of month 4 and the end of 
month 6 as determined by the maintenance sensor (observed 
values) by Change from Baseline (Randomisation) in PEF at 
Month 6 (Visit 10)
Requires the primary endpoint 
observed value, each treatment arm 
presented with a unique 
symbol/pattern
SAC [2]
DRY RUN [1]
10.8.8.
Safety Tables
Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
3.1.
ITT
SAFE_T1
Overview of On-Treatment and Post-Treatment Non-
Serious AEs leading to Withdrawal, Non-Serious ADRs and 
SAEs
Include total column
SAC [2]
DRY RUN [1]
3.2.
ITT
SAFE_T1
Overview of Run-In Treatment Non-Serious AEs leading to 
Withdrawal, Non-Serious ADRs and SAEs
Include total column
SAC [2]
DRY RUN [1]


CONFIDENTIAL
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Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.3.
Not in ITT
SAFE_T1
Overview of Run-In Treatment Non-Serious AEs leading to 
Withdrawal, Non-Serious ADRs and SAEs for Subjects not 
in ITT
Total column only
SAC [2]
DRY RUN [1]
3.4.
ITT
IDSL_AE15
Summary of Common (>=1%) Non-serious Adverse Events 
by System Organ Class and Preferred Term (Number of 
Subjects and Occurrences) 
Include total column.  Do not 
apply rounding. 
Footnote: Non-serious 
Adverse Events includes non-
serious ADRs and non-serious 
AEs leading to withdrawal
Disclosure table.
SAC [2]
DRY RUN [1]
3.5.
ITT
IDSL_AE15
Summary of Common (>=1%) Run-In Treatment Non-
Serious Adverse Events by System Organ Class and 
Preferred Term (Number of Subjects and Occurrences) 
Include total column only. Do 
not apply rounding.
Footnote: Non-serious 
Adverse Events includes non-
serious ADRs and non-serious 
AEs leading to withdrawal
Disclosure table.
SAC [2]
DRY RUN [1]
3.6.
Not in ITT
IDSL_AE15
Summary of Common (>=1%) Run-In Treatment Non-
Serious Adverse Events by System Organ Class and 
Preferred Term (Number of Subjects and Occurrences) for 
Subjects not in ITT
Include total column only. Do 
not apply rounding.
Footnote: Non-serious 
Adverse Events includes non-
serious ADRs and non-serious 
SAC [2]
DRY RUN [1]


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128
Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
AEs leading to withdrawal
Disclosure table.
Adverse Drug Reactions (ADRs)
3.7.
ITT
IDSL_AE1
Summary of On-Treatment Adverse Drug Reactions
Include total column.  All ADRs 
(Non-serious and Serious)
SAC [2]
DRY RUN [1]
3.8.
ITT
IDSL_AE1
Summary of Post-Treatment Adverse Drug Reactions
Include total column.  All ADRs 
(Non-serious and Serious)
SAC [2]
DRY RUN [1]
3.9.
ITT
IDSL_AE1
Summary of On-Treatment Serious Adverse Drug Reactions
Include total column
SAC [2]
DRY RUN [1]
3.10.
ITT
IDSL_AE1
Summary of Post-Treatment Serious Adverse Drug 
Reactions
Include total column
SAC [2]
DRY RUN [1]
3.11.
ITT
IDSL_AE1
Summary of On-Treatment Non-Serious Adverse Drug 
Reactions
Include total column
SAC [2]
DRY RUN [1]
3.12.
ITT
IDSL_AE1
Summary of Post-Treatment Non-Serious Adverse Drug 
Reactions
Include total column
SAC [2]
DRY RUN [1]


CONFIDENTIAL
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129
Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Serious Adverse Events (SAEs)
3.13.
ITT
IDSL_AE16
Summary of Serious Adverse Events by System Organ 
Class and Preferred Term (Number of Subjects and 
Occurrences)
Include total column
SAC [2]
DRY RUN [1]
3.14.
ITT
IDSL_AE16
Summary of Run-In Treatment Serious Adverse Events by 
System Organ Class and Preferred Term (Number of 
Subjects and Occurrences)
Include total column
SAC [2]
DRY RUN [1]
3.15.
Not in ITT
IDSL_AE16
Summary of Run-In Treatment Serious Adverse Events by 
System Organ Class and Preferred Term (Number of 
Subjects and Occurrences) for Subjects not in ITT
Include total column
SAC [2]
DRY RUN [1]
3.16.
ITT
IDSL_AE1
Summary of On-Treatment Serious Adverse Events
Include total column
SAC [2]
DRY RUN [1]
3.17.
ITT
IDSL_AE1
Summary of Post-Treatment Serious Adverse Events
Include total column
SAC [2]
DRY RUN [1]
Adverse Events leading to Withdrawal
3.18.
ITT
IDSL_AE1
Summary of All On-treatment or Post-Treatment Adverse 
Events Leading to Permanent Discontinuation of Study Drug 
or Withdrawal from Study
Footnote: All Adverse Events 
includes ADRs, SAEs and 
Non-serious AEs leading to 
withdrawal
Include total column
SAC [2]
DRY RUN [1]


CONFIDENTIAL
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130
Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.19.
ITT
IDSL_AE1
Summary of All On-treatment or Post-Treatment Serious 
Adverse Events Leading to Permanent Discontinuation of 
Study Drug or Withdrawal from Study
Include total column
SAC [2]
DRY RUN [1]
3.20.
ITT
IDSL_AE1
Summary of On-treatment or Post-Treatment Non-Serious 
Adverse Events Leading to Permanent Discontinuation of 
Study Drug or Withdrawal from Study
Include total column
SAC [2]
DRY RUN [1]
3.21.
ITT
IDSL_AE1
Summary of  On-treatment or Post-Treatment Adverse Drug 
Reactions Leading to Permanent Discontinuation of Study 
Drug or Withdrawal from Study
Include total column
SAC [2]
DRY RUN [1]
Adverse Events of Special Interest
3.22.
ITT
IDSL_AE1
Summary of On-Treatment Non-Serious Adverse Drug 
Reactions of Special Interest
Footnote: [1] This special 
interest group/subgroup was 
defined using Special 
MedDRA Queries
Include total column
SAC [2]
DRY RUN [1]
3.23.
ITT
IDSL_AE1
Summary of On-Treatment Serious Adverse Drug Reactions 
of Special Interest
Footnote: [1] This special 
interest group/subgroup was 
defined using Special 
MedDRA Queries
Include total column
SAC [2]
DRY RUN [1]


CONFIDENTIAL
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Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.24.
ITT
IDSL_AE1
Summary of On-Treatment Adverse Drug Reactions of 
Special Interest
Footnote: [1] This special 
interest group/subgroup was 
defined using Special 
MedDRA Queries
Include total column
SAC [2]
DRY RUN [1]
3.25.
ITT
IDSL_AE1
Summary of On-Treatment Serious Adverse Events of 
Special Interest
Footnote: [1] This special 
interest group/subgroup was 
defined using Special 
MedDRA Queries
Include total column
SAC [2]
DRY RUN [1]
Most Commonly Reported Events/Reactions
3.26.
ITT
SAFE_T2
Top Ten Most Commonly Reported On-Treatment Adverse 
Events Per Treatment Group
Footnote: All Adverse Events 
includes ADRs, SAEs and 
Non-serious AEs leading to 
withdrawal
Include total column
SAC [2]
DRY RUN [1]
3.27.
ITT
SAFE_T2
Top Ten Most Commonly Reported On-Treatment Adverse 
Drug Reactions Per Treatment Group
ADRs only
Include total column
SAC [2]
DRY RUN [1]


CONFIDENTIAL
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Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Plain Language Summary Displays
3.28.
ITT
IDSL_AE15
Summary of Common (>=1%) Serious Drug-Related 
Adverse Events by System Organ Class and Preferred 
Term (Number of Subjects and Occurrences)
Include total column
SAC [2]
DRY RUN [1]
3.29.
ITT
IDSL_AE15
Summary of Common (>=1%) Non-Serious Drug-Related 
Adverse Events by System Organ Class and Preferred 
Term (Number of Subjects and Occurrences)
Footnote: Non-serious 
Adverse Events includes non-
serious ADRs and non-serious 
AEs leading to withdrawal
Include total column
SAC [2]
DRY RUN [1]


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10.8.9.
ICH Listings
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.
Screened
IDSL_ES7
Listing of Reasons for Screen Failure
SAC [2]
2.
Enrolled
IDSL_ES7
Listing of Reasons for Run-in Failure
SAC [2]
3.
Screened
IDSL_ES9
Listing of Subjects Who Were Rescreened
SAC [2]
4.
ITT
IDSL_ES2
Listing of Reasons for Study Withdrawal
SAC [2]
5.
ITT
IDSL_SD2
Listing of Reasons for Study Treatment Discontinuation
SAC [2]
6.
ITT
IDSL_TA1
Listing of Planned and Actual Treatments
Planned arm is determine from the 
RANDALL dataset and Actual 
treatment arm received determine 
from the eCRF data
SAC [2]
Exposure
7.
ITT
IDSL_EX3
Listing of Exposure 
SAC [2]
Protocol Deviations
8.
ITT
IDSL_DV2
Listing of Important Protocol Deviations 
SAC [2]
9.
ITT
IDSL_IE3
Listing of Subjects with Inclusion/Exclusion Criteria Deviations
SAC [2]
Demographic and Baseline Characteristics
10.
ITT
IDSL_DM2 
Listing of Demographic Characteristics
Include Height, Weight, BMI in the 
listing
SAC [2]
11.
ITT
IDSL_DM9 
Listing of Race
SAC [2]


CONFIDENTIAL
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134
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events
12.
ITT
IDSL_AE8
Listing of All Adverse Events
Footnote: All Adverse Events 
includes ADRs, SAEs and Non-
serious AEs leading to withdrawal
SAC [2]
13.
ITT
IDSL_AE7
Listing of Subject Numbers for Individual Adverse Events
SAC [2]
14.
ITT
IDSL_AE2
Listing of Relationship Between Adverse Event System Organ 
Class, Preferred Term and Verbatim Text
SAC [2]
15.
Not in ITT
IDSL_AE8
Listing of All Adverse Events for Subjects not in Intent-to-Treat 
Population 
Footnote: All Adverse Events 
includes ADRs, SAEs and Non-
serious AEs leading to withdrawal
SAC [2]
Serious and Other Significant Adverse Events
16.
ITT
IDSL_AE8
Listing of Fatal Serious Adverse Events
Fatal and Non-Fatal SAEs are 
combined into a single listing for 
ClinPharm studies (i.e., “Listing of 
Serious Adverse Events”).
SAC [2]
17.
ITT
IDSL_AE8
Listing of Non-Fatal Serious Adverse Events
Fatal and Non-Fatal SAEs are 
combined into a single listing for 
ClinPharm studies (i.e., “Listing of 
Serious Adverse Events”).
SAC [2]
18.
ITT
IDSL_AE14
Listing of Reasons for Considering as a Serious Adverse Event
SAC [2]
19.
ITT
IDSL_AE8
Listing of All Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment
Footnote: All Adverse Events 
includes ADRs, SAEs and Non-
serious AEs leading to withdrawal
SAC []


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10.8.10.
Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Study Population
20.
Enrolled
POP_L1
Listing of Subjects Screened but Not in the Intent-to-Treat 
Population
SAC [2]
21.
ITT
POP_L2
Listing of Subjects by Country 
SAC [2]
22.
ITT
POP_L3
Listing of Family History of Cardiovascular Risk Factors 
SAC [2]
23.
ITT
IDSL_SU2
Listing of Substance Use
SAC [2]
24.
ITT
POP_L4
Listing of Asthma History
SAC [2]
25.
ITT
POP_L5
Listing of Prescription Details
SAC [2]
26.
ITT
POP_L6
Listing of Preferred time of dosing
SAC [2]
27.
ITT
POP_L7
Listing of HCP Dashboard Review
SAC [2]
28.
ITT
POP_L8
Listing of Treatment Compliance
SAC [2]
Medical Conditions
29.
ITT
IDSL_MH2
Listing of Medical Conditions 
SAC [2]


CONFIDENTIAL
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136
Non-ICH: Listings
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Concomitant Medications
30.
ITT
IDSL_CM3 
Listing of Concomitant Medications
Note: IDSL shell in development. 
Required for ClinPharm studies 
instead of a corresponding table. 
Not required for studies where a 
table is produced.
SAC [2]
31.
ITT
IDSL_CM6
Relationship between ATC Level 1, Ingredient and Verbatim 
Text
SAC [2]
Adverse Events of Special Interest
32.
ITT
SAFE_L1
Listing of Adverse Event of Special Interest Group, 
Subgroup, Sub-SMQ and Preferred Term
SAC [2]
Device Malfunction
33.
Enrolled
SAFE_L2
Listing of Relvar/Breo Ellipta Sensor Status
SAC [2]
34.
Enrolled
SAFE_L3
Listing of Salbutamol MDI Sensor Status
SAC [2]
35.
ITT
SAFE_L4
Listing of Sensor App Status
SAC [2]
36.
ITT
SAFE_L5
Listing of Device Malfunction
SAC [2]


CONFIDENTIAL
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137
Non-ICH: Listings
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Efficacy
37.
ITT
EFF_L1
Listing of Relvar/Breo ELLIPTA Adherence 
SAC [2]
38.
ITT
EFF_L2
Listing of Salbutamol MDI Rescue Free Days and Total 
Rescue Use
SAC [2]
39.
ITT
EFF_L3
Listing of Patient Reported Outcome Questionnaire Total 
Scores – ACT, ASUI, MARS-A, PAM-13 and SGRQ
SAC [2]
40.
ITT
EFF_L3
Listing of Patient Reported Outcome Questionnaire Total 
Scores – BMQ
Replace the different 
questionnaire headings with the 
separate scales of the BMQ 
general and specific
SAC [2]
41.
ITT
EFF_L4
Listing of Severe Asthma Exacerbations
SAC [2]
42.
ITT
EFF_L5
Listing of Unscheduled Asthma Related Healthcare 
Utilisation  
SAC [2]
43.
ITT
EFF_L11
Listing of Peak Expiratory Flow (PEF) and Fractional 
Exhaled Nitric Oxide (FeNO) Results
SAC [2]
Cardiovascular Events (Patient profiles)
44.
Enrolled
IDSL_DEATH
Listing of All Cause Deaths
SAC [2]


CONFIDENTIAL
207040
138
10.9.
Appendix 9: Example Mock Shells for Data Displays
STUDY POPULATION TABLES
POP_T1
Protocol: 207040 
Page 1 of x
Population: Intent-to-Treat
Table 1.4
Summary of Attendance at Each Visit
Visit
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Total
(N=XXX)
(N=XXX)
(N=XXX)
(N=XXX)
(N=XXX)
(N=XXX)
-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Visit 1 (Screening)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
Visit 2 (Run-In)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
Visit 3 (Run-In)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
Visit 4 (Run-In)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
Visit 5 (Month 1)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
Visit 6 (Month 2)
xxx (xxx%)
N/A
xxx (xxx%)
N/A
N/A
xxx (xxx%)
Visit 7 (Month 3)
xxx (xxx%)
N/A
xxx (xxx%)
N/A
N/A
xxx (xxx%)
Visit 8 (Month 4)
xxx (xxx%)
N/A
xxx (xxx%)
N/A
N/A
xxx (xxx%)
Visit 9 (Month 5)
xxx (xxx%)
N/A
xxx (xxx%)
N/A
N/A
xxx (xxx%)
Visit 10 (Month 6)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
Visit 11 (Follow-Up)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
Early Withdrawal
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
Note: Visit 2/3/4 subjects may be randomised or re-entered into run-in up 3 times if ACT ≥ 20.  
Note: Visits 6/7/8/9 are Healthcare Professional Dashboard reviews for Arm 1 and Arm 3.


CONFIDENTIAL
207040
139
POP_T2
Protocol: 207040 
Page 1 of x
Population: Intent-to-Treat
Table 1.8
Summary of Relvar/Breo ELLIPTA Sensor Status
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Total
(N=XXX)
(N=XXX)
(N=XXX)
(N=XXX)
(N=XXX)
(N=XXX)
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Number of Subjects who Activated a Sensor
xxx
xxx
xxx
xxx
xxx
xxx
Number of Sensors Activated
xxx
xxx
xxx
xxx
xxx
xxx
Was the Sensor Returned?
    Yes
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
       No
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
                Reason sensor was not returned
                           Lost
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
                         Subject Lost to Follow-up
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
                          Other
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
Did the sensor malfunction?
      Yes
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
       No
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
Did the subject permanently stop using their 
activated sensor during the Study
       Yes
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
      No
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)


CONFIDENTIAL
207040
140
POP_T2
Protocol: 207040 
Page 2 of x
Population: Intent-to-Treat
Table 1.8
Summary of Relvar/Breo ELLIPTA Sensor Status
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Total
(N=XXX)
(N=XXX)
(N=XXX)
(N=XXX)
(N=XXX)
(N=XXX)
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Did the subject permanently stop using sensors 
from the study
       Yes
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
      No
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
Note: Did the subject permanently stop using their activated sensor during the Study – How many activated sensors the subject permanently stopped using during the 
study.
Note: Did the subject permanently stop using sensors from the study - These the number of subjects who did not activate a new sensor after permanently stopping 
their previous sensor while still on the study.


CONFIDENTIAL
207040
141
POP_T2
Protocol: 207040 
Page 1 of x
Population: Intent-to-Treat
Table 1.9
Summary of Salbutamol MDI Sensor Status
Programming note: Repeat as per Table 1.xxx


CONFIDENTIAL
207040
142
POP_T3
Protocol: 207040 
Page 1 of x
Population: Intent-to-Treat
Table 1.10
Summary of App Status
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Total
(N=XXX)
(N=XXX)
(N=XXX)
(N=XXX)
(N=XXX)
(N=XXX)
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Did subject permanently discontinue form 
the Sensor App during the study?
n
xxx
xxx
xxx
xxx
xxx
xxx
No
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
Yes
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
Note: As reported by data collected  in the eCRF.


CONFIDENTIAL
207040
143
POP_T4
Protocol: 207040 
Page 1 of x
Population: Intent-to-Treat
Table 1.24
Summary of Asthma Duration at Screening
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Total
(N=XXX)
(N=XXX)
(N=XXX)
(N=XXX)
(N=XXX)
(N=XXX)
-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Duration of Asthma
   n
xxx
xxx
xxx
xxx
xxx
xxx
   < 6 months
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
   >= 6 month to < 1 year
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
   >= 1 year to < 5 years
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
   >= 5 years to < 10 years
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
  >= 10 years
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)


CONFIDENTIAL
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144
Example 
: POP_T5
Protocol
: 207040
Page 1 of 2
Population
: Intent-to-Treat
Table 1.25
Summary of Asthma Exacerbation History at Screening
Arm 1
(N=xxx)
Arm 2
(N=xxx)
Arm 3
(N=xxx)
Arm 4
(N=xxx)
Arm 5
(N=xxx)
Total
(N=xxx)
Total number of exacerbations during the 12 months prior to screening
 n                      
xx 
xx 
xx 
xx 
xx 
xx 
 0
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
 1
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
>1
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
Number of exacerbations during the 12 months prior to screening
 n
xx
xx
xx
xx
xx
xx
 Mean
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
 SD
 x.xx
 x.xx
 x.xx
 x.xx
x.xx
 x.xx
 Median
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
 Min.
xx
xx
xx
xx
xx
xx
 Max.
xx
xx
xx
xx
xx
xx
Note: Number of severe asthma exacerbations reported in the 12 months prior to Screening (Visit 1)


CONFIDENTIAL
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145
POP_T5
Protocol: 207040 
Population: Intent-to-Treat
Page 2 of 2
Table 1.25
Summary of Asthma Exacerbation History at Screening
Arm 1
(N=xxx)
Arm 2
(N=xxx)
Arm 3
(N=xxx)
Arm 4
(N=xxx)
Arm 5
(N=xxx)
Total
(N=xxx)
Did not require oral/systemic corticosteroids (not involving hospitalisation)
 n                      
xx 
xx 
xx 
xx 
xx 
xx 
 0
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
 1
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
 > 1
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
Required oral/systemic corticosteroids (not involving hospitalisation)
 n                      
xx 
xx 
xx 
xx 
xx 
xx 
 0
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
 1
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
 > 1
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
Required hospitalisation                  
 n                      
xx 
xx 
xx 
xx 
xx 
xx 
 0
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
 1
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
 > 1
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
Note: Number of severe asthma exacerbations reported in the 12 months prior to Screening (Visit 1).


CONFIDENTIAL
207040
146
Example: POP_T6
Protocol: 207040 
Page 1 of 1
Population: Intent-to-Treat
Table 1.26
Summary of Screening and Baseline (Randomisation) Peak Expiratory Flow (PEF)
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Total
(N=XXX)
(N=XXX)
(N=XXX)
(N=XXX)
(N=XXX)
(N=XXX)
-----------------
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
---
Screening Pre-
bronchodilator PEF 
(L/min)  
n
xxx
xxx
xxx
xxx
xxx
xxx
Mean
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
SD
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Median
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
Min.
xx
 xx
 xx
 xx
 xx
  xx
Max.
xxx
xxx
xxx
xxx
xxx
xxx
Baseline Pre-
bronchodilator PEF 
(L/min)  
n
xxx
xxx
xxx
xxx
xxx
xxx
Mean
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
SD
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Median
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
Min.
xx
xx
xx
xx
xx
xx
Max.
xxx
xxx
xxx
xxx
xxx
xxx


CONFIDENTIAL
207040
147
Example: POP_T6
Protocol: 207040 
Page 1 of x
Population: Intent-to-Treat
Table 1.27
Summary of Screening and Baseline (Randomisation) Peak Expiratory Flow (PEF) by Country
Country: xxxxxx
Programming note:  Repeat on subsequent pages by Country in alphabetical order.


CONFIDENTIAL
207040
148
Example: POP_T6
Protocol:207040                                                           
Page 1 of 1
Population: Intent-to-Treat
Table 1.28
Summary of Screening and Baseline (Randomisation) Exhaled Nitric Oxide (FeNO)
Arm 1
(N=xx)
Arm 2
(N=xx)
Arm 3
(N=xx)
Arm 4
(N=xx)
Arm 5
(N=xx)
Total
(N=xx)
Screening FeNO (ppb) 
n
xxx
xxx
xxx
xxx
xxx
xxx
Mean
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
SD
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Median
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
Min.
xx
xx
xx
xx
xx
xx
Max.
xxx
xxx
xxx
xxx
xxx
xxx
Baseline FeNO (ppb)
n
xxx
xxx
xxx
xxx
xxx
xxx
Mean
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
SD
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Median
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
Min.
xx
xx
xx
xx
xx
xx
Max.
xxx
xxx
xxx
xxx
xxx
xxx


CONFIDENTIAL
207040
149
Example: POP_T7:
Protocol: 207040 
         
   Page 1 of 1
Population: Intent-to-Treat 
Table 1.38
Summary of Exposure to Study Medication
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Total
Overall
(N=xx)
(N=xx)
(N=xx)
(N=xx)
(N=xx)
(N=xx)
---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Exposure (days) [1]
N
xxx
xxx
xxx
xxx
xxx
xxx
Mean
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
SD
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Median
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
Min.
xx
xx
xx
xx
xx
xx
Max.
xxx
xxx
xxx
xxx
xxx
xxx
Total Subject Years (years)
xxx
    xxx
xxx
xxx
xxx
xxx
Range of Exposure
<= 6 weeks
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
<= 12 weeks
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
<= 18 weeks
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
<= 24 weeks
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
> 24 weeks
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
[1] Exposure to study medication = treatment stop date – randomisation date + 1, regardless of dosage modification.


CONFIDENTIAL
207040
150
Example POP_T8
Protocol: 207040                                                                                                                                                                                                                           Page 1 of 1
Population: Intent-to-Treat
Table 1.39
Summary of the Frequency of Puffs Per Day – ELLIPTA Relvar/Breo Sensor
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Total
Period
(N=xx)
(N=xx)
(N=xx)
(N=xx)
(N=xx)
(N=xx)
Baseline
Number of subjects
xx 
xx 
xx 
xx 
xx 
xx 
Number of subject days
xx 
xx 
xx 
xx 
xx 
xx 
 0 per day [1]
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
 1 per day
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
 2 per day
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
 3 per day
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
 4 per day
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
 >=5 per day
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
Month 1
Number of subjects
xx 
xx 
xx 
xx 
xx 
xx 
Number of subject days
xx 
xx 
xx 
xx 
xx 
xx 
 0 per day [1]
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
 1 per day
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
 2 per day
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
 3 per day
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
 4 per day
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
 >=5 per day
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
.........
Note: Number of subject days are number of days a subject has contributed to in that time period
[1]: 0 per day can constitute of: No puffs recorded, Device Incidents, or Post discontinuation of ELLIPTA maintenance sensor
Programming Note: Repeat for Months 2, 3, 4, 5, 6, Months 4-6, Months 1-6 and Months 1-3.


CONFIDENTIAL
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151
Example POP_T8
Protocol: 207040                                                                                                                                                                                                                           Page 1 of 1
Population: Intent-to-Treat
Table 1.40
Summary of the Frequency of Puffs Per Day – MDI Sensor 
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Total
Period
(N=xx)
(N=xx)
(N=xx)
(N=xx)
(N=xx)
(N=xx)
Baseline
Number of subjects
xx 
xx 
xx 
xx 
xx 
xx 
Number of subject days
xx 
xx 
xx 
xx 
xx
xx 
 0 per day [1]
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
 1 per day
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
 2 per day
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
 3 per day
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
 4 per day
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
 5 per day
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
 6 per day
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
 7 per day
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
 8 per day
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
 >=9 per day
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
Month 1
Number of subjects
xx 
xx 
xx 
xx 
xx 
xx 
Number of subject days
xx 
xx 
xx 
xx 
xx 
xx 
 0 per day [1]
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
 1 per day
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
 2 per day
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
 3 per day
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
 4 per day
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
 5 per day
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
xx (%)
......
......
....
Note: Number of subject days are number of days a subject has contributed to in that time period
[1]: 0 per day can constitute of: No puffs recorded, Device Incidents, or Post discontinuation of MDI maintenance sensor
Programming Note: Repeat for Months 2, 3, 4, 5, 6 and Months 4-6.


CONFIDENTIAL
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152
Example POP_T9
Protocol:207040
Page 1 of 1
Population: Intent-to-Treat
Table 1.41
Summary of Treatment Compliance
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Total
Overall Compliance (%)
(N=xx)
(N=xx)
(N=xx)
(N=xx)
(N=xx)
(N=xx)
n
xxx
xxx
xxx
xxx
xxx
xxx
Mean
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
SD
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Median
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
Min.
xx
xx
xx
xx
xx
xx
Max.
xxx
xxx
xxx
xxx
xxx
xxx
< 80%
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
80% - < 100%
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
100% - < 120%
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
>=120%
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)


CONFIDENTIAL
207040
153
Example POP_T10
Protocol:207040
Page 1 of 1
Population: Intent-to-Treat
Table 1.42
Summary of Incidence of Preferred Time of Dosing Over the Treatment Period
%
Arm 1
(N=xxx)
Arm 2
(N=xxx)
Arm 3
(N=xxx)
Arm 4
(N=xxx)
Arm 5
(N=xxx)
n
xxx
xxx
xxx
xxx
xxx
Mean
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
SD
xx.xx
xx.xx
xx.xx
xx.xx
xx.xx
Median
xxx.x
xxx.x
xxx.x
xxx.x
xxx.x
Min.
xx
xx
xx
xx
xx
Max.
xxx
xxx
xxx
xxx
xxx
Note: A subject is considered as having taken their dose at their preferred time if the actuation time from the Relvar/Breo ELLIPTA sensor is recorded 1 hour of their 
preferred time as captured on the eCRF at screening


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Example POP_T11
Protocol:207040
Page 1 of X
Population: Intent-to-Treat
Table 1.43
Summary of HCP Dashboard Review by Visit
Visit: Visit 5
Actions taken post review
Arm 1
(N=xxx)
Arm 3
(N=xxx)
n
xxx
xxx
No action taken
xxx (xx%)
xxx (xx%)
Action Taken
xxx (xx%)
xxx (xx%)
Discuss adherence
xxx (xx%)
xxx (xx%)
Discuss rescue medication
xxx (xx%)
xxx (xx%)
Subject was called in for an unscheduled clinic visit
xxx (xx%)
xxx (xx%)
Other
xxx (xx%)
xxx (xx%)
Programming note:  Repeat subsequent pages by visits 6,7,8, 9 and 10 and Unscheduled


CONFIDENTIAL
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Example: POP_T12
Protocol: 207040  
Page 1 of 1
Population: Intent-to-Treat
Table 1.44
Summary of Asthma Maintenance Therapy Prescription Details in the Previous 12 Months
Arm 1
(N=xxx)
Arm 2
(N=xxx)
Arm 3
(N=xxx)
Arm 4
(N=xxx)
Arm 5
(N=xxx)
Actual number of prescriptions requested in previous 12 months
 n
xx
xx
xx
xx
xx
 Mean
xx.x
xx.x
xx.x
xx.x
xx.x
 SD
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
 Median
xx.x
xx.x
xx.x
xx.x
xx.x
 Min.
xx
xx
xx
xx
xx
 Max.
xx
xx
xx
xx
xx
Number of prescriptions requested/prescribed to be 100% compliant in previous 12 months
 n
xx
xx
xx
xx
xx
 Mean
xx.x
xx.x
xx.x
xx.x
xx.x
 SD
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
 Median
xx.x
xx.x
xx.x
xx.x
xx.x
 Min.
xx
xx
xx
xx
xx
 Max.
xx
xx
xx
xx
xx
Prescription Compliance in previous 12 months (%)
 n
xx
xx
xx
xx
xx
 Mean
xx.x
xx.x
xx.x
xx.x
xx.x
 SD
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
 Median
xx.x
xx.x
xx.x
xx.x
xx.x
 Min.
xx
xx
xx
xx
xx
 Max.
xx
xx
xx
xx
xx
Note: Prescription compliance is calculated as 100*(Actual number of prescriptions)/(Number of prescriptions requested/prescribed to be 100% compliant)


CONFIDENTIAL
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156
STUDY POPULATION FIGURES
Example 
: POP_F1
Protocol
: 207040
Page 1 of x
Population : Intent-to-Treat
Figure 1.02
Frequency of ELLIPTA Puffs Per Day
Period: Baseline
Note: 0 Puffs per day can constitute of: No puffs recorded, Device Incidents, or Post discontinuation of ELLIPTA maintenance sensor
Programming Note: Repeat for Period: Month 1, 2, 3, 4, 5, 6, Month 4-6, Month 1-3, Month 1-6.


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157
EFFICACY TABLES
Example : EFF_T1
Protocol
: 207040
Page 1 of x
Population : Intent-to-Treat
Table 2.01
Summary of Monthly Percentage of ELLIPTA doses taken (daily adherence) between the beginning of month 1 and end of month 6 as determined by the maintenance
sensor – Observed Monthly Data
Month 
Arm 1
(N=xxx)
Arm 2
(N=xxx)
Arm 3
(N=xxx)
Arm 4
(N=xxx)
Arm 5
(N=xxx)
Baseline (%)
 n
xx
xx
xx
xx
xx
 Mean
xx.x
xx.x
xx.x
xx.x
xx.x
 SD
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
 Median
xx.x
xx.x
xx.x
xx.x
xx.x
 Min.
xx
xx
xx
xx
xx
 Max.
xx
xx
xx
xx
xx
Month 1 (%)
 n
xx
xx
xx
xx
xx
 Mean
xx.x
xx.x
xx.x
xx.x
xx.x
 SD
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
 Median
xx.x
xx.x
xx.x
xx.x
xx.x
 Min.
xx
xx
xx
xx
xx
 Max.
xx
xx
xx
xx
xx
Average Month 1 to 6 (%)
 n
xx
xx
xx
xx
xx
 Mean
xx.x
xx.x
xx.x
xx.x
xx.x
 SD
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
 Median
xx.x
xx.x
xx.x
xx.x
xx.x
 Min.
xx
xx
xx
xx
xx
 Max.
xx
xx
xx
xx
xx
Programming note: Continue table to include all monthly timelines (month2, month 3, month 4, month 5, month 6, average month 4-6, average month 1-3, average 
month 1-6)


CONFIDENTIAL
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Example : EFF_T2
Protocol
: 207040
Page 1 of 1
Population : Intent-to-Treat
Table 2.02
Summary of Statistical Analysis of Percentage of ELLIPTA doses taken (daily adherence) between the beginning of month 4 and the end of month 6 as determined by 
the maintenance sensor
Month 4 to 6 (%)
Arm 1
(N=xxx)
Arm 2
(N=xxx)
Arm 3
(N=xxx)
Arm 4
(N=xxx)
Arm 5
(N=xxx)
 n
xx
xx
xx
xx
xx
LS Mean (Std Error)
xx.x
xx.x
xx.x
xx.x
xx.x
CIS Arm vs Arm 5
 Difference
xx.x
xx.x
xx.x
xx.x
95% C.I.
(x.xx, x.xx)
(x.xx, x.xx)
(x.xx, x.xx)
(x.xx, x.xx)
 p-value
xx.xxx
xx.xxx
xx.xxx
xx.xxx
[1] Monthly adherence values were weighted by amount of observed data available and time on ELLIPTA between month 4 and 6


CONFIDENTIAL
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Example : EFF_T3 
Protocol
: 207040
Page 1 of 1
Population : Intent-to-Treat
Table 2.xx
Summary of Statistical Analysis of Percentage of ELLIPTA doses taken (daily adherence) between the beginning of month 4 and the end of month 6 as determined by 
the maintenance sensor by Baseline ACT Total Score Group
Table 2.xx
Summary of Statistical Analysis of Percentage of ELLIPTA doses taken (daily adherence) between the beginning of month 4 and the end of month 6 as determined by 
the maintenance sensor by Age Group


CONFIDENTIAL
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160
Example : EFF_T4
Protocol
: 207040
Page 1 of 1
Population : Intent-to-Treat
Table 2.xx
Summary of Statistical Analysis of Percentage of ELLIPTA doses taken (daily adherence) between the beginning of month 1 and the end of month 3 as determined by 
the maintenance sensor
Month 1 to 3 (%)
Arm 1
(N=xxx)
Arm 2
(N=xxx)
Arm 3
(N=xxx)
Arm 4
(N=xxx)
Arm 5
(N=xxx)
 n
xx
xx
xx
xx
xx
LS Mean (Std Error)
xx.x
xx.x
xx.x
xx.x
xx.x
CIS Arm vs Arm 5
 Difference
xx.x
xx.x
xx.x
xx.x
 95% C.I.
(x.xx, x.xx)
(x.xx, x.xx)
(x.xx, x.xx)
(x.xx, x.xx)
 p-value
xx.xxx
xx.xxx
xx.xxx
xx.xxx


CONFIDENTIAL
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161
Example : EFF_T4
Protocol
: 207040
Page 1 of 1
Population : Intent-to-Treat
Table 2.xx
Summary of Statistical Analysis of Percentage of ELLIPTA doses taken (daily adherence) between the beginning of month 1 and the end of month 6 as determined by 
the maintenance sensor
Month 1 to 6 (%)
Arm 1
(N=xxx)
Arm 2
(N=xxx)
Arm 3
(N=xxx)
Arm 4
(N=xxx)
Arm 5
(N=xxx)
 n
xx
xx
xx
xx
xx
LS Mean (Std Error)
xx.x
xx.x
xx.x
xx.x
xx.x
CIS Arm vs Arm 5
 Difference
xx.x
xx.x
xx.x
xx.x
 95% C.I.
(x.xx, x.xx)
(x.xx, x.xx)
(x.xx, x.xx)
(x.xx, x.xx)
 p-value
xx.xxx
xx.xxx
xx.xxx
xx.xxx


CONFIDENTIAL
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162
Example : EFF_T5
Protocol
: 207040
Page 1 of 1
Population : Intent-to-Treat
Table 2.xx
Summary of Statistical Analysis of Percentage of ELLIPTA doses taken (daily adherence) between the beginning of month 4 and the end of month 6 as determined by 
the maintenance sensor – Impact of Feedback of Sensor Data to HCP
Month 4 to 6 (%)
Arm 1
(N=xxx)
Arm 2
(N=xxx)
Arm 3
(N=xxx)
Arm 4
(N=xxx)
Arm 5
(N=xxx)
n
xx
xx
xx
xx
xx
LS Mean (Std Error)
xx.x
xx.x
xx.x
xx.x
xx.x
CIS Arm 1 vs Arm 2
 Difference
xx.x
 95% C.I.
(x.xx, x.xx)
 p-value
xx.xxx
CIS Arm 3 vs Arm 4
 Difference
xx.x
 95% C.I.
(x.xx, x.xx)
 p-value
xx.xxx


CONFIDENTIAL
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163
Example : EFF_T6
Protocol
: 207040
Page 1 of 1
Population : Intent-to-Treat
Table 2.xx
Summary of Statistical Analysis of Percentage of ELLIPTA doses taken (daily adherence) between the beginning of month 4 and the end of month 6 as determined by 
the maintenance sensor – Impact of Feedback on Rescue Medication Use
Month 4 to 6 (%)
Arm 1
(N=xxx)
Arm 2
(N=xxx)
Arm 3
(N=xxx)
Arm 4
(N=xxx)
Arm 5
(N=xxx)
n
xx
xx
xx
xx
xx
LS Mean (Std Error)
xx.x
xx.x
xx.x
xx.x
xx.x
CIS Arm 1 vs Arm 3
 Difference
xx.x
 95% C.I.
(x.xx, x.xx)
 p-value
xx.xxx
CIS Arm 2 vs Arm 4
xx.x
 Difference
(x.xx, x.xx)
 95% C.I.
xx.xxx
 p-value


CONFIDENTIAL
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164
Example : EFF_T1
Protocol
: 207040
Page 1 of 1
Population : Intent-to-Treat
Table 2.xx
Summary of Monthly Percentage of Rescue Free Days between the beginning of month 1 and then end of month 6 as determine by the MDI rescue medication sensor 
– Observed Data
Month 
Arm 1
(N=xxx)
Arm 2
(N=xxx)
Arm 3
(N=xxx)
Arm 4
(N=xxx)
Arm 5
(N=xxx)
Baseline (%)
 n
xx
xx
xx
xx
xx
 Mean
xx.x
xx.x
xx.x
xx.x
xx.x
 SD
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
 Median
xx.x
xx.x
xx.x
xx.x
xx.x
 Min.
xx
xx
xx
xx
xx
 Max.
xx
xx
xx
xx
xx
Month 1 (%)
 n
xx
xx
xx
xx
xx
 Mean
xx.x
xx.x
xx.x
xx.x
xx.x
 SD
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
 Median
xx.x
xx.x
xx.x
xx.x
xx.x
 Min.
xx
xx
xx
xx
xx
 Max.
xx
xx
xx
xx
xx
Average Month 1 to 6 (%)
 n
xx
xx
xx
xx
xx
 Mean
xx.x
xx.x
xx.x
xx.x
xx.x
 SD
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
 Median
xx.x
xx.x
xx.x
xx.x
xx.x
 Min.
xx
xx
xx
xx
xx
 Max.
xx
xx
xx
xx
xx
Programming note: Continue table to include all monthly timelines (month 2, month 3, month 4, month 5, month 6, average month 4-6)


CONFIDENTIAL
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165
Example : EFF_T4
Protocol
: 207040
Page 1 of 1
Population : Intent-to-Treat
Table 2.xx
Summary of Statistical Analysis of Percentage of Rescue Free Days between the beginning of month 4 and then end of month 6 as determine by the MDI rescue 
medication sensor
Month 4 to 6 (%)
Arm 1
(N=xxx)
Arm 2
(N=xxx)
Arm 3
(N=xxx)
Arm 4
(N=xxx)
Arm 5
(N=xxx)
 n
xx
xx
xx
xx
xx
LS Mean (Std Error)
xx.x
xx.x
xx.x
xx.x
xx.x
CIS Arm vs Arm 5
 Difference
xx.x
xx.x
xx.x
xx.x
 95% C.I.
(x.xx, x.xx)
(x.xx, x.xx)
(x.xx, x.xx)
(x.xx, x.xx)
 p-value
xx.xxx
xx.xxx
xx.xxx
xx.xxx
[1] Monthly adherence values were weighted by amount of observed data available and time on ELLIPTA between month 4 and 6


CONFIDENTIAL
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166
Example : EFF_T1
Protocol
: 207040
Page 1 of 1
Population : Intent-to-Treat
Table 2.xx
Summary of Total Rescue Use as Determined by the Maintenance Sensor
Month 
Arm 1
(N=xxx)
Arm 2
(N=xxx)
Arm 3
(N=xxx)
Arm 4
(N=xxx)
Arm 5
(N=xxx)
Baseline
 n
xx
xx
xx
xx
xx
 Mean
xx.x
xx.x
xx.x
xx.x
xx.x
 SD
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
 Median
xx.x
xx.x
xx.x
xx.x
xx.x
 Min.
xx
xx
xx
xx
xx
 Max.
xx
xx
xx
xx
xx
Month 1
 n
xx
xx
xx
xx
xx
 Mean
xx.x
xx.x
xx.x
xx.x
xx.x
 SD
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
 Median
xx.x
xx.x
xx.x
xx.x
xx.x
 Min.
xx
xx
xx
xx
xx
 Max.
xx
xx
xx
xx
xx
Average Month 1 to 6
 n
xx
xx
xx
xx
xx
 Mean
xx.x
xx.x
xx.x
xx.x
xx.x
 SD
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
 Median
xx.x
xx.x
xx.x
xx.x
xx.x
 Min.
xx
xx
xx
xx
xx
 Max.
xx
xx
xx
xx
xx
Programming note: Continue table to include all monthly timelines (month 2, month 3, month 4, month 5, month 6, average month 4-6)


CONFIDENTIAL
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167
Example
: EFF_T1
Protocol
: 207040
Page 1 of x
Population : Intent-to-Treat
Table 2.xx
Summary of Asthma Control Test (ACT) Total Score
Visit
Arm 1
(N=xxx)
Arm 2
(N=xxx)
Arm 3
(N=xxx)
Arm 4
(N=xxx)
Arm 5
(N=xxx)
Baseline [1]
n
xx
xx
xx
xx
xx
Mean
xx.x
xx.x
xx.x
xx.x
xx.x
SD
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
Median
xx.x
xx.x
xx.x
xx.x
xx.x
Min.
xx
xx
xx
xx
xx
Max.
xx
xx
xx
xx
xx
Visit 5 (Month 1)
n
xx
xx
xx
xx
xx
Mean
xx.x
xx.x
xx.x
xx.x
xx.x
SD
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
Median
xx.x
xx.x
xx.x
xx.x
xx.x
Min.
xx
xx
xx
xx
xx
Max.
xx
xx
xx
xx
xx
Change from Baseline at Visit 5
n
xx
xx
xx
xx
xx
(Month 1)
Mean
xx.x
xx.x
xx.x
xx.x
xx.x
SD
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
Median
xx.x
xx.x
xx.x
xx.x
xx.x
[1] Baseline ACT total score is taken at randomisation visit.
Programming note: repeat for Visit 10 (Month 6), Change from Baseline at Visit 10 (Month 6), Early Withdrawal, Change from Baseline at Early withdrawal


CONFIDENTIAL
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168
Example
: EFF_T4
Protocol
: 207040
Page 1 of 1
Population: Intent-to-Treat
Table 2.xx
Summary of the Statistical Analysis of Change from Baseline (Randomisation) in ACT Total Score at Visit 10 (Month 6)
Arm 1
(N=xxx)
Arm 2
(N=xxx)
Arm 3
N=xxx)
Arm 4
(N=xxx)
Arm 5
(N=xxx)
n
xx 
xx 
xx 
xx 
xx
LS Mean Change (SE)
xx.xx (x.xxx)
xx.xx (x.xxx)
xx.xx (x.xxx)
xx.xx (x.xxx)
xx.xx (x.xxx)
CIS Arm vs. Arm 5
 Difference 
xx.x 
xx.x 
xx.x 
xx.x 
 95% CI
(xx.x, xx.x)
(xx.x, xx.x)
(xx.x, xx.x)
(xx.x, xx.x)
 p-value
x.xxx
x.xxx
x.xxx
x.xxx
Note: The analysis method was an MMRM adjusted for randomised treatment arm, (visit), baseline ACT total score, randomised treatment arm-by-visit interaction, 
baseline ACT total score-by-visit interaction, gender, age, country and subject fitted as a random factor.
Note: The Restricted Maximum Likelihood (REML) estimation approach was used with a default covariance structure of unstructured.
Programming note: Should computational issues be encountered when using an unstructured covariance structure, other structures 
including AR1 and CS should be considered and the second footnote updated as appropriate.


CONFIDENTIAL
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169
Example
: EFF_T12
Protocol
: 207040                                                                            
  Page 1 of 1
Population
: Intent-to-Treat
Table 2.xx
Summary of Percentage of Subjects Who Have Either an ACT Total Score of >= 20 and/or >= 3 Point Increase from Baseline (Randomisation) in ACT Total Score
Visit
Arm 1
(N=xxx)
Arm 2
(N=xxx)
Arm 3
(N=xxx)
Arm 4
(N=xxx)
Arm 5
(N=xxx)
Visit 5 (Month 
1)
n
xxx
xxx
xxx
xxx
xxx
ACT Total Score >= 20 and/or >= 3 Point Increase from 
Baseline
xxx (xx%)
xxx (xx%)
xxx (xx%)
xxx 
(xx%)
xxx (xx%)
ACT Total Score >= 20
xxx (xx%)
xxx (xx%)
xxx (xx%)
xxx 
(xx%)
xxx (xx%)
>= 3 Point Increase from Baseline
xxx (xx%)
xxx (xx%)
xxx (xx%)
xxx 
(xx%)
xxx (xx%)
 
Visit 10 (Month 
6)
n
xxx
xxx
xxx
xxx
xxx
ACT Total Score >= 20 and/or >= 3 Point Increase from 
Baseline
xxx (xx%)
xxx (xx%)
xxx (xx%)
xxx 
(xx%)
xxx (xx%)
ACT Total Score >= 20
xxx (xx%)
xxx (xx%)
xxx (xx%)
xxx 
(xx%)
xxx (xx%)
>= 3 Point Increase from Baseline
xxx (xx%)
xxx (xx%)
xxx (xx%)
xxx 
(xx%)
xxx (xx%)


CONFIDENTIAL
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170
Example
: EFF_T13
Protocol
: 207040
  Page 1 of 1
Population
: Intent-to-Treat
Table 2.xx
Summary of the Statistical Analysis of Percentage of Subjects Who Have an ACT Total Score of ≥ 20 at Visit 10 (Month 6)
[1] Responder is defined as an ACT total score >= 20.
Note: The analysis method was logistic regression adjusted for randomised treatment arm, baseline ACT total score, country, gender and age
Arm 1
(N=xxx)
Arm 2
(N=xxx)
Arm 3
(N=xxx)
Arm 4
(N=xxx)
Arm 5
(N=xxx)
n
xxx
xxx
xxx
xxx
xxx
Responder [1]
xxx (xx%)
xxx (xx%)
xxx (xx%)
xxx (xx%)
xxx (xx%)
Non-Responder 
xxx (xx%)
xxx (xx%)
xxx (xx%)
xxx (xx%)
xxx (xx%)
 
CIS Arm v Arm 5
Adjusted Odds Ratio
x.xx
x.xx
x.xx
x.xx
95% C.I.
(x.xx, x.xx)
(x.xx, x.xx)
(x.xx, x.xx)
(x.xx, x.xx)
p-value
x.xx 
x.xx 
x.xx 
x.xx 


CONFIDENTIAL
207040
171
Example
: EFF_T13
Protocol
: 207040
  Page 1 of 1
Population
: Intent-to-Treat
Table 2.xx
Summary of the Statistical Analysis of Percentage of Subjects with an Increase from Baseline (Randomisation) ≥3 in ACT Total Score at Visit 10 (Month 6)
[1] Responder is defined as an increase from baseline of >= 3 in ACT total score.
Note: The analysis method was logistic regression adjusted for randomised treatment arm, baseline ACT total score, country, gender and age
Arm 1
(N=xxx)
Arm 2
(N=xxx)
Arm 3
(N=xxx)
Arm 4
(N=xxx)
Arm 5
(N=xxx)
n
xxx
xxx
xxx
xxx
xxx
Responder [1]
xxx (xx%)
xxx (xx%)
xxx (xx%)
xxx (xx%)
xxx (xx%)
Non-Responder 
xxx (xx%)
xxx (xx%)
xxx (xx%)
xxx (xx%)
xxx (xx%)
 
CIS Arm v Arm 5
Adjusted Odds Ratio
x.xx
x.xx
x.xx
x.xx
95% C.I.
(x.xx, x.xx)
(x.xx, x.xx)
(x.xx, x.xx)
(x.xx, x.xx)
p-value
x.xx 
x.xx 
x.xx 
x.xx 


CONFIDENTIAL
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172
Example
: EFF_T13
Protocol
: 207040
  Page 1 of 1
Population
: Intent-to-Treat
Table 2.xx
Summary of the Statistical Analysis of Percentage of Subjects Who Have Either an ACT Total Score of >=20 and/or an Increase from Baseline (Randomisation) of >=3
in ACT Total Score at Visit 10 (Month 6)
[1] Responder is defined as an ACT total score >= 20 and/or an increase from baseline of >= 3.
Note: The analysis method was logistic regression adjusted for randomised treatment arm, baseline ACT total score, country, gender and age
Arm 1
(N=xxx)
Arm 2
(N=xxx)
Arm 3
(N=xxx)
Arm 4
(N=xxx)
Arm 5
(N=xxx)
n
xxx
xxx
xxx
xxx
xxx
Responder [1]
xxx (xx%)
xxx (xx%)
xxx (xx%)
xxx (xx%)
xxx (xx%)
Non-Responder 
xxx (xx%)
xxx (xx%)
xxx (xx%)
xxx (xx%)
xxx (xx%)
 
CIS Arm v Arm 5
Adjusted Odds Ratio
x.xx
x.xx
x.xx
x.xx
95% C.I.
(x.xx, x.xx)
(x.xx, x.xx)
(x.xx, x.xx)
(x.xx, x.xx)
p-value
x.xx 
x.xx 
x.xx 
x.xx 


CONFIDENTIAL
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173
Example
: EFF_T14
Protocol
: 207040
  Page 1 of x
Population
: Intent-to-Treat
Table 2.xx
Summary of Unscheduled Asthma Related Healthcare Resource Utilisation During the Study
Arm 1
(N=XXX)
Arm 2
(N=XXX)
Arm 3
(N=XXX)
Arm 4
(N=XXX)
Arm 5
(N=XXX)
Had unscheduled healthcare 
utilisation
n (%)
xxx (xx%)
xxx (xx%)
xxx (xx%)
xxx (xx%)
xxx (xx%)
Number of telephone calls
n
xxx
xxx
xxx
xxx
xxx
0
xxx (%)
xxx (%)
xxx (%)
xxx (%)
xxx (%)
1
xxx (%)
xxx (%)
xxx (%)
xxx (%)
xxx (%)
2
xxx (%)
xxx (%)
xxx (%)
xxx (%)
xxx (%)
3
xxx (%)
xxx (%)
xxx (%)
xxx (%)
xxx (%)
>3
xxx (%)
xxx (%)
xxx (%)
xxx (%)
xxx (%)
Total [1]
xxx 
xxx 
xxx
xxx
xxx 
Number of home visits (Day)
n
xxx
xxx
xxx
xxx
xxx
0
xxx (%)
xxx (%)
xxx (%)
xxx (%)
xxx (%)
1
xxx (%)
xxx (%)
xxx (%)
xxx (%)
xxx (%)
2
xxx (%)
xxx (%)
xxx (%)
xxx (%)
xxx (%)
3
xxx (%)
xxx (%)
xxx (%)
xxx (%)
xxx (%)
>3
xxx (%)
xxx (%)
xxx (%)
xxx (%)
xxx (%)
Total [1]
xxx 
xxx 
xxx 
xxx 
xxx
[1] Total number of days/contacts across all subjects.


CONFIDENTIAL
207040
174
Example
: EFF_T14
Protocol
: 207040
  Page 2 of x
Population
: Intent-to-Treat
Table 2.xx
Summary of Unscheduled Asthma Related Healthcare Resource Utilisation During the Study
Arm 1
(N=XXX)
Arm 2
(N=XXX)
Arm 3
(N=XXX)
Arm 4
(N=XXX)
Arm 5
(N=XXX)
Number of home visits (Night)
n
xxx
xxx
xxx
xxx
xxx
0
xxx (%)
xxx (%)
xxx (%)
xxx (%)
xxx (%)
1
xxx (%)
xxx (%)
xxx (%)
xxx (%)
xxx (%)
2
xxx (%)
xxx (%)
xxx (%)
xxx (%)
xxx (%)
3
xxx (%)
xxx (%)
xxx (%)
xxx (%)
xxx (%)
>3
xxx (%)
xxx (%)
xxx (%)
xxx (%)
xxx (%)
Total [1]
xxx
xxx
xxx
xxx
xxx
Number of office/practice visits
n
xxx
xxx
xxx
xxx
xxx
0
xxx (%)
xxx (%)
xxx (%)
xxx (%)
xxx (%)
1
xxx (%)
xxx (%)
xxx (%)
xxx (%)
xxx (%)
2
xxx (%)
xxx (%)
xxx (%)
xxx (%)
xxx (%)
3
xxx (%)
xxx (%)
xxx (%)
xxx (%)
xxx (%)
>3
xxx (%)
xxx (%)
xxx (%)
xxx (%)
xxx (%)
Total [1]
xxx
xxx
xxx
xxx
xxx
Number of urgent care/outpatient visits
n
Xxx
xxx
xxx
xxx
xxx
0
xxx (%)
xxx (%)
xxx (%)
xxx (%)
xxx (%)
1
xxx (%)
xxx (%)
xxx (%)
xxx (%)
xxx (%)
2
xxx (%)
xxx (%)
xxx (%)
xxx (%)
xxx (%)
3
xxx (%)
xxx (%)
xxx (%)
xxx (%)
xxx (%)
>3
xxx (%)
xxx (%)
xxx (%)
xxx (%)
xxx (%)
Total [1]
xxx
xxx
xxx
xxx
xxx
[1] Total number of days/ contacts across all subjects.


CONFIDENTIAL
207040
175
Example
: EFF_T14
Protocol
: 207040
  Page 3 of x
Population
: Intent-to-Treat
Table 2.xx
Summary of Unscheduled Asthma Related Healthcare Resource Utilisation During the Study
Arm 1
(N=XXX)
Arm 2
(N=XXX)
Arm 3
(N=XXX)
Arm 4
(N=XXX)
Arm 5
(N=XXX)
Number of emergency room visits
n
xxx
xxx
xxx
xxx
xxx
0
xxx (%)
xxx (%)
xxx (%)
xxx (%)
xxx (%)
1
xxx (%)
xxx (%)
xxx (%)
xxx (%)
xxx (%)
2
xxx (%)
xxx (%)
xxx (%)
xxx (%)
xxx (%)
3
xxx (%)
xxx (%)
xxx (%)
xxx (%)
xxx (%)
>3
xxx (%)
xxx (%)
xxx (%)
xxx (%)
xxx (%)
Total [1]
xxx
xxx
xxx
xxx
xxx
Number of days inpatient hospitalisation days
n
xxx
xxx
xxx
xxx
xxx
0
xxx (%)
xxx (%)
xxx (%)
xxx (%)
xxx (%)
1
xxx (%)
xxx (%)
xxx (%)
xxx (%)
xxx (%)
2
xxx (%)
xxx (%)
xxx (%)
xxx (%)
xxx (%)
3
xxx (%)
xxx (%)
xxx (%)
xxx (%)
xxx (%)
>3
xxx (%)
xxx (%)
xxx (%)
xxx (%)
xxx (%)
Total [1]
xxx
xxx
xxx
xxx
xxx
[1] Total number of days/ contacts across all subjects.


CONFIDENTIAL
207040
176
Example
: EFF_T22
Protocol
: 207040
  Page 1 of x
Population
: Intent-to-Treat
Table 2.xx
Summary of Primary Care Visits relating to HCP Dashboard Review
Arm 1
(N=XXX)
Arm 2
(N=XXX)
Arm 3
(N=XXX)
Arm 4
(N=XXX)
Arm 5
(N=XXX)
Number of Subjects called in for an unscheduled clinic visit
   xx
xx
         xx
xx
xx 
Number of unscheduled clinic visits
    xx
xx
         xx
xx
xx


CONFIDENTIAL
207040
177
Example : EFF_T15
Protocol
: 207040
Page 1 of 2
Population : Intent-to-Treat
Table 2.xx
Summary of Severe On-Treatment and Post-Treatment Asthma Exacerbations
Time: On-Treatment
Arm 1
(N=xxx)
Arm 2
(N=xxx)
Arm 3
(N=xxx)
Arm 4
(N=xxx)
Arm 5
(N=xxx)
Total
(N=xxx)
No. of subjects with one or more severe asthma exacerbation
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
                     
Total no. of severe asthma exacerbations
xx 
xx 
xx 
xx 
xx 
xx 
Number of severe asthma exacerbations per subject
 0
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
 1
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
 > 1
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
Duration of severe asthma exacerbation (days) [1]
 n 
xx
xx
xx
xx
xx
xx
 Mean
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
 SD
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
 Median
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
 Min.
xx
xx
xx
xx
xx
xx
 Max.
xx
xx
xx
xx
xx
xx
[1] Summary only includes exacerbations for which a date of onset and resolution were provided in the eCRF.  
Programming Note: Repeat for Post-Treatment


CONFIDENTIAL
207040
178
Example : EFF_T15
Protocol
: 207040
Page 2 of 2
Population : Intent-to-Treat
Table 2.xx
Summary of Severe On-Treatment and Post-Treatment Asthma Exacerbations
Time: On-Treatment
Arm 1
(N=xxx)
Arm 2 
(N=xxx)
Arm 3 
(N=xxx)
Arm 4 
(N=xxx)
Arm 5 
(N=xxx)
Total 
(N=xxx)
No. of subjects with an exacerbation outcome
 Resolved
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
 Fatal
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
 Not resolved
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
No. of subjects with exacerbations: 
 Requiring use of systemic/oral corticosteroids
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
 Leading to hospitalisation
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
 Requiring emergency room visit
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
No. of subjects with exacerbations requiring intubation
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
No. of subjects with exacerbations leading to withdrawal from study
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
Annual severe asthma exacerbation rate [1]
 n
xx
xx
xx
xx
xx
xx
 Mean
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
 SD
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
 Median
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
 Min.
xx
xx
xx
xx
xx
xx
 Max.
xx
xx
xx
xx
xx
xx
[1] Summary only includes exacerbations for which a date of onset and resolution were provided in the eCRF..


CONFIDENTIAL
207040
179
Example
EFF_T1
Protocol 
: 207040
Page 1 of 1
Population : Intent-to-Treat
Table 2.xx
Summary of Asthma Symptom Utility Index (ASUI) Score
Visit
Arm 1
(N=xxx)
Arm 2
(N=xxx)
Arm 3
(N=xxx)
Arm 4
(N=xxx)
Arm 5
(N=xxx)
Baseline [1]
n
xx
xx
xx
xx
xx
Mean
xx.x
xx.x
xx.x
xx.x
xx.x
SD
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
Median
xx.x
xx.x
xx.x
xx.x
xx.x
Min.
xx
xx
xx
xx
xx
Max.
xx
xx
xx
xx
xx
Visit 5 (Month 1)
n
xx
xx
xx
xx
xx
Mean
xx.x
xx.x
xx.x
xx.x
xx.x
SD
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
Median
xx.x
xx.x
xx.x
xx.x
xx.x
Min.
xx
xx
xx
xx
xx
Max.
xx
xx
xx
xx
xx
Change from Baseline at Visit 5
n
xx
xx
xx
xx
xx
(Month 1)
Mean
xx.x
xx.x
xx.x
xx.x
xx.x
SD
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
Median
xx.x
xx.x
xx.x
xx.x
xx.x
Min.
xx
xx
xx
xx
xx
Max.
xx
xx
xx
xx
xx
[1] Baseline ASUI total score is taken at randomisation visit.
Programming note: repeat, Visit 10 (Month 6), Change from Baseline at Visit 10 (Month 6), Early Withdrawal


CONFIDENTIAL
207040
180
Example EFF_T16
Protocol 
: 207040
Page 1 of 1
Population : Intent-to-Treat
Table 2.xx
Summary of Statistical Analysis of Percentage of Subjects Meeting a Responder Threshold of 0.09 Points Improvement (Increase) from Baseline (Randomisation) for 
the ASUI Total Score at Visit 10 (Month 6)
[1] Responder is defined as an ASUI total score >= 0.09 points increase from baseline.
Note: The analysis method was logistic regression adjusted for randomised treatment arm, baseline ASUI total score, country, gender and age
Arm 1
(N=xxx)
Arm 2
(N=xxx)
Arm 3
(N=xxx)
Arm 4
(N=xxx)
Arm 5
(N=xxx)
n
xxx
xxx
xxx
xxx
xxx
Responder [1]
xxx (xx%)
xxx (xx%)
xxx (xx%)
xxx (xx%)
xxx (xx%)
Non-Responder 
xxx (xx%)
xxx (xx%)
xxx (xx%)
xxx (xx%)
xxx (xx%)
 
CIS Arm v Arm 5
Adjusted Odds Ratio
x.xx
x.xx
x.xx
x.xx
95% C.I.
(x.xx, x.xx)
(x.xx, x.xx)
(x.xx, x.xx)
(x.xx, x.xx)
p-value
x.xx 
x.xx 
x.xx 
x.xx 


CONFIDENTIAL
207040
181
Example
: EFF_T4
Protocol
: 207040
Page 1 of 1
Population: Intent-to-Treat
Table 2.xx
Summary of the Statistical Analysis of Change from Baseline (Randomisation) in Asthma Symptom Utility Index (ASUI) Total Score at Visit 10 (Month 6)
Arm 1
(N=xxx)
Arm 2
(N=xxx)
Arm 3
N=xxx)
Arm 4
(N=xxx)
Arm 5
(N=xxx)
n
xx 
xx 
xx 
xx 
xx 
LS Mean Change (SE)
xx.xx (x.xxx)
xx.xx (x.xxx)
xx.xx (x.xxx)
xx.xx (x.xxx)
xx.xx (x.xxx)
CIS Arm vs. Arm 5
 Difference 
xx.x 
xx.x 
xx.x 
xx.x 
 95% CI
(xx.x, xx.x)
(xx.x, xx.x)
(xx.x, xx.x)
(xx.x, xx.x)
 p-value
x.xxx
x.xxx
x.xxx
x.xxx
Note: The analysis method was an MMRM adjusted for randomised treatment arm, visit, baseline ASUI total score, randomised treatment arm-by-visit interaction, 
baseline ASUI total score-by-visit interaction, gender, age, country and subject fitted as a random factor.
Note: The Restricted Maximum Likelihood (REML) estimation approach was used with a default covariance structure of unstructured.
Programming note: Should computational issues be encountered when using an unstructured covariance structure, other structures including AR1 and 
CS should be considered and the second footnote updated as appropriate.


CONFIDENTIAL
207040
182
Example
: EFF_T1
Protocol
: 207040
  Page 1 of 1
Population
: Intent-to-Treat
Table 2.xx
Summary of St. George’s Respiratory Questionnaire (SGRQ) Total Score
Visit
Arm 1
(N=xxx)
Arm 2
(N=xxx)
Arm 3
(N=xxx)
Arm 4
(N=xxx)
Arm 5
(N=xxx)
Baseline [1]
n
xx
xx
xx
xx
xx
Mean
xx.x
xx.x
xx.x
xx.x
xx.x
SD
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
Median
xx.x
xx.x
xx.x
xx.x
xx.x
Min.
xx
xx
xx
xx
xx
Max.
xx
xx
xx
xx
xx
Visit 5 (Month 1)
n
xx
xx
xx
xx
xx
Mean
xx.x
xx.x
xx.x
xx.x
xx.x
SD
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
Median
xx.x
xx.x
xx.x
xx.x
xx.x
Min.
xx
xx
xx
xx
xx
Max.
xx
xx
xx
xx
xx
Change from Baseline at Visit 5
n
xx
xx
xx
xx
xx
(Month 1)
Mean
xx.x
xx.x
xx.x
xx.x
xx.x
SD
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
Median
xx.x
xx.x
xx.x
xx.x
xx.x
Min.
xx
xx
xx
xx
xx
Max.
xx
xx
xx
xx
xx
[1] Baseline SGRQ total score is taken at randomisation visit
Programming note: repeat for Visit 10 (Month 6), Change from Baseline at Visit 10 (Month 6), Early Withdrawal


CONFIDENTIAL
207040
183
Example
: EFF_T13
Protocol
: 207040
  Page 1 of 1
Population
: Intent-to-Treat
Table 2.xx
Summary of the Statistical Analysis of Percentage of Subjects Meeting a Responder Threshold of ≥4 Points Improvement (Decrease) from Baseline (Randomisation) 
for the SGRQ Total Score at Visit 10 (Month 6)
[1] Responder is defined as SGRQ total score >= 4 points decrease from baseline.
Note: The analysis method was logistic regression adjusted for randomised treatment arm, baseline SGRQ total score, country, gender and age
Arm 1
(N=xxx)
Arm 2
(N=xxx)
Arm 3
(N=xxx)
Arm 4
(N=xxx)
Arm 5
(N=xxx)
n
xxx
xxx
xxx
xxx
xxx
Responder [1]
xxx (xx%)
xxx (xx%)
xxx (xx%)
xxx (xx%)
xxx (xx%)
Non-Responder 
xxx (xx%)
xxx (xx%)
xxx (xx%)
xxx (xx%)
xxx (xx%)
 
CIS Arm v Arm 5
Adjusted Odds Ratio
x.xx
x.xx
x.xx
x.xx
95% C.I.
(x.xx, x.xx)
(x.xx, x.xx)
(x.xx, x.xx)
(x.xx, x.xx)
p-value
x.xx 
x.xx 
x.xx 
x.xx 


CONFIDENTIAL
207040
184
Example
: EFF_T
Protocol
: 207040
  Page 1 of 1
Population
: Intent-to-Treat
Table 2.xx
Summary of the Statistical Analysis of Change from Baseline (Randomisation) in SGRQ at Visit 10 (Month 6)
Arm 1
(N=xxx)
Arm 2
(N=xxx)
Arm 3
N=xxx)
Arm 4
(N=xxx)
Arm 5
(N=xxx)
n
xx 
xx 
xx 
xx 
xx 
LS Mean Change (SE)
xx.xx (x.xxx)
xx.xx (x.xxx)
xx.xx (x.xxx)
xx.xx (x.xxx)
xx.xx (x.xxx)
CIS Arm vs. Arm 5
 Difference 
xx.x 
xx.x 
xx.x 
xx.x 
 95% CI
(xx.x, xx.x)
(xx.x, xx.x)
(xx.x, xx.x)
(xx.x, xx.x)
 p-value
x.xxx
x.xxx
x.xxx
x.xxx
Note: The analysis method was an MMRM adjusted for randomised treatment arm, visit, baseline SGRQ total score, randomised treatment arm-by-visit interaction, 
baseline SGRQ total score-by-visit interaction, gender, age, country and subject fitted as a random factor.
Note: The Restricted Maximum Likelihood (REML) estimation approach was used with a default covariance structure of unstructured.
Programming note: Should computational issues be encountered when using an unstructured covariance structure, other structures including AR1 and 
CS should be considered and the second footnote updated as appropriate.


CONFIDENTIAL
207040
185
Example
: EFF_T1
Protocol
: 207040
  Page 1 of 1
Population
: Intent-to-Treat
Table 2.xx
Summary of Patient Activation Measure (PAM) 13 Total Score
Visit
Arm 1
(N=xxx)
Arm 2
(N=xxx)
Arm 3
(N=xxx)
Arm 4
(N=xxx)
Arm 5 (N=xxx)
Baseline [1]
n
xx
xx
xx
xx
xx
Mean
xx.x
xx.x
xx.x
xx.x
xx.x
SD
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
Median
xx.x
xx.x
xx.x
xx.x
xx.x
Min.
xx
xx
xx
xx
xx
Max.
xx
xx
xx
xx
xx
Visit 5 (month 1)
n
xx
xx
xx
xx
xx
Mean
xx.x
xx.x
xx.x
xx.x
xx.x
SD
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
Median
xx.x
xx.x
xx.x
xx.x
xx.x
Min.
xx
xx
xx
xx
xx
Max.
xx
xx
xx
xx
xx
[1] Baseline PAM-13 total score is taken from Screening Visit
Programming note: repeat for Randomisation Visit, Change from Baseline at Visit 5 (Month 1), Visit 10 (Month 6), Change from Baseline at Visit 10 (Month 6), Early 
Withdrawal
Note: The total PAM score is calculated by dividing the raw score over the number of items answered and multiplied by 13. This score is then transformed to a scale 
within a range of 0-100 based on calibration tables and proprietary PAM algorithm.


CONFIDENTIAL
207040
186
Example 
: EFF_T28
Protocol
: 207040
Page 1 of x
Population
: Intent-to-Treat
Table 2.xx
Summary of Medication Adherence Report Scale - Asthma (MARS-A) Total Score
Visit
Arm 1
(N=xxx)
Arm 2
(N=xxx)
Arm 3
(N=xxx)
Arm 4
(N=xxx)
Arm 5
(N=xxx)
Baseline [1]
n
xx
xx
xx
xx
xx
Mean
xx.x
xx.x
xx.x
xx.x
xx.x
SD
 x.xx
 x.xx
 x.xx
 x.xx
x.xx
Median
xx.x
xx.x
xx.x
xx.x
xx.x
Min.
xx
xx
xx
xx
xx
Max.
xx
xx
xx
xx
xx
Visit 5 (Month 1)
n
xx
xx
xx
xx
xx
Mean
xx.x
xx.x
xx.x
xx.x
xx.x
SD
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
Median
xx.x
xx.x
xx.x
xx.x
xx.x
Min.
xx
xx
xx
xx
xx
Max.
xx
xx
xx
xx
xx
[1] Baseline MARS-A 10 total score is taken from screening visit.
Note: MARS-A 10 Total Score is based on the mean score across all ten questions per visit.
Programming note: repeat for Randomisation visit, Change from Baseline at Visit 5 (Month 1), Visit 10 (Month 6), Change from Baseline at Visit 10 (Month 6), Early 
Withdrawal


CONFIDENTIAL
207040
187
EFF_T19
Protocol:207040
Page 1 of x
Population: Intent-to-Treat
Table 2.xx
Summary of Beliefs in Medicine Questionnaire (BMQ) General Benefit Total Score
Visit
Arm 1
(N=xxx)
Arm 2
(N=xxx)
Arm 3
(N=xxx)
Arm 4
(N=xxx)
Arm 5
(N=xxx)
Baseline [1]
n
xx
xx
xx
xx
xx
Mean
xx.x
xx.x
xx.x
xx.x
xx.x
SD
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
Median
xx.x
xx.x
xx.x
xx.x
xx.x
Min.
xx
xx
xx
xx
xx
Max.
xx
xx
xx
xx
xx
Visit 5 (Month 1)
n
xx
xx
xx
xx
xx
Mean
xx.x
xx.x
xx.x
xx.x
xx.x
SD
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
Median
xx.x
xx.x
xx.x
xx.x
xx.x
Min.
xx
xx
xx
xx
xx
Max.
xx
xx
xx
xx
xx
[1] Baseline BMQ total score is taken from screening visit.
Note: BMQ Score is based on the total score across all items within the BMQ measure
Programming note: repeat for Randomisation visit, Change from Baseline at Visit 5 (Month 1), Visit 10 (Month 6), Change from Baseline at Visit 10 (Month 6), Early 
Withdrawal


CONFIDENTIAL
207040
188
Repeat for:
Table 2.28 Summary of Beliefs in Medicine Questionnaire (BMQ) General Harm Total Score
Programming note: Use the items as presented in RAP
Table:2.29 Summary of Beliefs in Medicine Questionnaire (BMQ) General Overuse Total Score 
Programming note: Use the items as presented in RAP
Table:2.30 Summary of Beliefs in Medicine Questionnaire (BMQ) Specific Necessity Total Score
Programming note: Use the items as presented in RAP
Table:2.31 Summary of Beliefs in Medicine Questionnaire (BMQ) Specific Concern Total Score 
Programming note: Use the items as presented in RAP


CONFIDENTIAL
207040
189
EFF_T21
Protocol:207040
Page 1 of 1
Population: Intent-to-Treat
Table 2.xx
Summary of Medical Device Incidents (Sensors)
Arm 1
(N=xxx)
Arm 2
(N=xxx)
Arm 3
(N=xxx)
Arm 4
(N=xxx)
Arm 5
(N=xxx)
Total
(N=xxx)
Relvar/Breo ELLIPTA Sensor
Number of incidents
xxx
xxx
xxx
xxx
xxx
xxx
Subjects with at least one 
incident
xxx (xx%)
xxx (xx%)
xxx (xx%)
xxx (xx%)
xxx (xx%)
xxx (xx%)
SABA MDI Sensor
Number of incidents
xxx
xxx
xxx
xxx
xxx
xxx
Subjects with at least one 
incident
xxx (xx%)
xxx (xx%)
xxx (xx%)
xxx (xx%)
xxx (xx%)
xxx (xx%)
Note: Devices incidents are classed as sensor malfunctions as noted in the eCRF.


CONFIDENTIAL
207040
190
EFF_T1
Protocol:207040
Page 1 of 1
Population: Intent-to-Treat
Table 2.xx
Summary of Fractional Exhaled Nitric Oxide (FeNO)
Visit
Arm 1
(N=xxx)
Arm 2
(N=xxx)
Arm 3
(N=xxx)
Arm 4
(N=xxx)
Arm 5
(N=xxx)
Baseline [1]
n
xx
xx
xx
xx
xx
Mean
xx.x
xx.x
xx.x
xx.x
xx.x
SD
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
Median
xx.x
xx.x
xx.x
xx.x
xx.x
Min.
xx
xx
xx
xx
xx
Max.
xx
xx
xx
xx
xx
Visit 5 (Month 1)
n
xx
xx
xx
xx
xx
Mean
xx.x
xx.x
xx.x
xx.x
xx.x
SD
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
Median
xx.x
xx.x
xx.x
xx.x
xx.x
Min.
xx
xx
xx
xx
xx
Max.
xx
xx
xx
xx
xx
Change from Baseline at Visit 5
n
xx
xx
xx
xx
xx
Mean
xx.x
xx.x
xx.x
xx.x
xx.x
SD
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
Median
xx.x
xx.x
xx.x
xx.x
xx.x
Min.
xx
xx
xx
xx
xx
Max.
xx
xx
xx
xx
xx
[1] Baseline FeNO reading is taken from the Randomisation visit.
Programming note: repeat for Screening visit, Visit 10 (Month 6), Change from Baseline at Visit 10 (Month 6), 4, Early Withdrawal, 


CONFIDENTIAL
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EFF_T23
Protocol:207040
Page 1 of 1
Population: Intent-to-Treat
Table 2.xx
Summary of Change from Baseline (Randomisation) in Fractional Exhaled Nitric Oxide (FeNO) at Month 6 (Visit 10) by Percentage of ELLIPTA doses taken (daily 
adherence) between the beginning of Month 4 and the end of Month 6 Group
Adherence: <range of quartile %>
Visit
Arm 1
(N=xxx)
Arm 2
(N=xxx)
Arm 3
(N=xxx)
Arm 4
(N=xxx)
Arm 5
(N=xxx)
Total
(N=xxx)
Baseline
n
xx
xx
xx
xx
xx
xx
Mean
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
SD
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
Median
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
Min.
xx
xx
xx
xx
xx
xx
Max.
xx
xx
xx
xx
xx
xx
Visit 10 (Month 6)
n
xx
xx
xx
xx
xx
xx
Mean
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
SD
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
Median
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
Min.
xx
xx
xx
xx
xx
xx
Max.
xx
xx
xx
xx
xx
xx
Change from Baseline at Visit 10
n
xx
xx
xx
xx
xx
xx
Mean
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
SD
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
Median
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
Min.
xx
xx
xx
xx
xx
xx
Max.
xx
xx
xx
xx
xx
xx
EFF_T23


CONFIDENTIAL
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Protocol:207040
Page 1 of 1
Population: Intent-to-Treat
Table 2.xx
Summary of Change from Baseline (Randomisation) in Peak Expiratory Flow (PEF) at Month 6 (Visit 10) by Percentage of ELLIPTA doses taken (daily adherence) 
between the beginning of Month 4 and the end of Month 6 Group
Adherence: <range of quartile %>
Visit
Arm 1
(N=xxx)
Arm 2
(N=xxx)
Arm 3
(N=xxx)
Arm 4
(N=xxx)
Arm 5
(N=xxx)
Total
(N=xxx)
Baseline
n
xx
xx
xx
xx
xx
xx
Mean
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
SD
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
Median
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
Min.
xx
xx
xx
xx
xx
xx
Max.
xx
xx
xx
xx
xx
xx
Visit 10 (Month 6)
n
xx
xx
xx
xx
xx
xx
Mean
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
SD
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
Median
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
Min.
xx
xx
xx
xx
xx
xx
Max.
xx
xx
xx
xx
xx
xx
Change from Baseline at Visit 10
n
xx
xx
xx
xx
xx
xx
Mean
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
SD
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
Median
xx.x
xx.x
xx.x
xx.x
xx.x
xx.x
Min.
xx
xx
xx
xx
xx
xx
Max.
xx
xx
xx
xx
xx
xx
EFF_T1
Protocol:207040
Page 1 of 1


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193
Population: Intent-to-Treat
Table 2.xx
Summary of Peak Expiratory Flow (PEF) (Litres/min) 
Visit
Arm 1
(N=xxx)
Arm 2
(N=xxx)
Arm 3
(N=xxx)
Arm 4
(N=xxx)
Arm 5
(N=xxx)
Baseline [1]
n
xx
xx
xx
xx
xx
Mean
xx.x
xx.x
xx.x
xx.x
xx.x
SD
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
Median
xx.x
xx.x
xx.x
xx.x
xx.x
Min.
xx
xx
xx
xx
xx
Max.
xx
xx
xx
xx
xx
Visit 5 (Month 1)
n
xx
xx
xx
xx
xx
Mean
xx.x
xx.x
xx.x
xx.x
xx.x
SD
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
Median
xx.x
xx.x
xx.x
xx.x
xx.x
Min.
xx
xx
xx
xx
xx
Max.
xx
xx
xx
xx
xx
Change from Baseline at Visit 5
n
xx
xx
xx
xx
xx
Mean
xx.x
xx.x
xx.x
xx.x
xx.x
SD
 x.xx
 x.xx
 x.xx
 x.xx
 x.xx
Median
xx.x
xx.x
xx.x
xx.x
xx.x
Min.
xx
xx
xx
xx
xx
Max.
xx
xx
xx
xx
xx
[1] Baseline PEF reading is taken from the randomisation visit.
Programming note: repeat for Visit 10 (Month 6), Change from Baseline at Visit 10 (Month 6), 4, Early Withdrawal


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EFFICACY FIGURES
Example: EFF_F1
Protocol: 207040
Page 1 of 1
Population: Intent-to-Treat
Figure 2.xx
Forest Plot for Odds Ratio of Either an ACT Total Score >= 20 and/ or Increase from Baseline of >= 3 in ACT Total Score at Visit 10 (Month 6)
Treatment Group: Arm 1


CONFIDENTIAL
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195
*=Proportion of responders, defined as ACT Total Score >= 20 and/ or Increase from Baseline of >= 3 in ACT Total Score at Visit 10 (Month 6)
Note: The analysis method was logistic regression adjusted for randomised treatment arm, baseline ACT total score, country, gender and age
Programming note: page 1 comparison between Arm 5 and Arm 1, following pages present the remaining Arm 5 v 2,3,4 treatment arm comparison
Example: EFF_F2
Protocol: 207040
Page 1 of 1
Population: Intent-to-Treat
Figure 2.xx
Scatter Plot of Percentage of ELLIPTA doses taken (daily adherence) between the beginning of month 4 and the end of month 6 
as determined by the maintenance sensor (Observed values) by Age


CONFIDENTIAL
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196
Programming Note: Requires the primary endpoint observed value, each treatment arm presented with a unique symbol/pattern. Be consistent with symbols/colours 
across all figures.


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197
Example: EFF_F3
Protocol: 207040
Page 1 of 1
Population: Intent-to-Treat
Figure 2.xx
Summary of Statistical Analysis for Change from Baseline (Randomisation) in ACT Total Score at Month 6
Programming Note: Present “Change from Baseline ACT Total Score” on y-axis and “Visit” on x-axis Baseline, Visit 5 (Month 1), Visit 10 (Month 6).  Present mean 
ACT Total Score +- SD separately for treatment group at each visit, connecting the means with a solid line. Distinguish the treatment groups by different line types.


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198
Example: EFF_F4
Protocol: 207040
Page 1 of 1
Population: Intent-to-Treat
Figure 2.xx
Summary of Interaction Tests for Percentage of ELLIPTA doses taken (daily adherence) between the beginning of month 4 and the end of month 6 as determined by 
the maintenance sensor - – Comparisons Arm 1,2,3,4 v Arm 5
Note: The results displays are from an ANCOVA adjusted for randomised treatment arm, baseline adherence, duration of run-in (visits), country, gender
[1] age (years), covariate, and two-way interaction between randomised treatment arm and covariate
[2] covariate, two-way interaction between randomised treatment group and covariate.


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199
Example: EFF_F5
Protocol: 207040
Page 1 of 1
Population: Intent-to-Treat
Figure 2.xx
Box plot of Monthly Percentage of ELLIPTA doses taken (daily adherence) as determined by the maintenance sensor
Note: Baseline adherence is calculated using up to the last 28 days of daily adherence data during the run-in period.


CONFIDENTIAL
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200
SAFETY TABLES
Example: SAFE_T1
Page 1 of X
Protocol: 207040
Population: Intent-to-Treat
Table 3.1
Overview of On-Treatment and Post-Treatment Non-Serious AEs leading to Withdrawal, Non-Serious ADRs and SAEs
Arm 1
(N=XXX)
Arm 2
(N=XXX)
Arm 3
(N=XXX)
Arm 4
(N=XXX))
Arm 5
(N=XXX)
Total
(N=XXX)
Any Non-Serious AE
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
Any Non-Serious ADR’s
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx (xx%)
xxx  (xx%)
Any On-Treatment Non-Serious ADRs
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
Any Post-Treatment Non-Serious ADRs
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
Any AEs leading to permanent discontinuation of study drug or 
withdrawal from study [1]
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
Any SAE
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
Any On-Treatment SAEs
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
Any Post-Treatment SAEs
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
Any On-Treatment Serious ADRs
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
Any Post-Treatment Serious ADRs 
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
Any On-Treatment Fatal SAEs
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
Any Post-Treatment Fatal SAEs
xxx  (xx%)
xxx  (xx%)
xxx  (xx%)
xxx (xx%)
xxx  (xx%)
xxx  (xx%)
Footnote: [1] Includes both on-treatment and post-treatment Non-Serious Adverse events leading to withdrawal, Non-serious ADRs and SAEs


CONFIDENTIAL
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201
SAFE_T2:
Page 1 of X
Protocol: 207040
Population: Intent-to-Treat  
Table 3.xx
Top Ten Most Commonly Reported On-Treatment Adverse Events Per Treatment Group
Dictionary-Derived Term
Arm 1
(N=XXX)
Arm 2
(N=XXX)
Arm 3
(N=XXX)
Arm 4
(N=XXX)
Arm 5
(N=XXX)
Total
(N=XXX)
    
Viral upper respiratory tract infection
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
Headache
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
Chronic obstructive pulmonary disease
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
Upper respiratory tract infection
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
Influenza
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
Pneumonia
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
Pharyngitis
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
Back pain
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
Hypertension
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
Bronchitis
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
Cough
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
Note: The 10 most frequent preferred terms in Arm 1, Arm 2, Arm 3, Arm 4 and Arm 5.


CONFIDENTIAL
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202
SAFE_T2:
Page 1 of X
Protocol: 207040
Population: Intent-to-Treat  
Table 3.xx
Top Ten Most Commonly Reported On-Treatment Adverse Drug Reactions Per Treatment Group
Dictionary-Derived Term
Arm 1
(N=XXX)
Arm 2
(N=XXX)
Arm 3
(N=XXX)
Arm 4
(N=XXX)
Arm 5
(N=XXX)
Total
(N=XXX)
    
Viral upper respiratory tract infection
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
Headache
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
Chronic obstructive pulmonary disease
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
Upper respiratory tract infection
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
Influenza
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
Pneumonia
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
Pharyngitis
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
Back pain
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
Hypertension
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
Bronchitis
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
Note: The 10 most frequent preferred terms in Arm 1, Arm 2, Arm 3, Arm 4 and Arm 4, and the 10 most frequent in Arm 5 are presented.


CONFIDENTIAL
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203
LISTINGS
POP_L1
Protocol: 207040                               
                                            Page 1 of x
Population: Enrolled
Listing xx
Listing of Subjects Screened but Not in the Intent-to-Treat Population
Treatment
Site Id./
Unique Subject Id.
Disposition Status
Reason for Screen Failure/Run-in/Withdrawal
Arm 1
xxxxxx/
xxxxxx.xxxxxx.xxxxx
Early Withdrawal
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
xxxxxx/
xxxxxx.xxxxxx.xxxxx
Early Withdraw
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
Arm 3
xxxxxx/
xxxxxx.xxxxxx.xxxxx
Early Withdrawal
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
xxxxxx/
xxxxxx.xxxxxx.xxxxx
Early Withdraw
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
Non Treatment
xxxxxx/
xxxxxx.xxxxxx.xxxxx
Screen Failure
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
xxxxxx/
xxxxxx.xxxxxx.xxxxx
Rin-in Failure
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx


CONFIDENTIAL
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204
POP_L2
Protocol: 207040                               
                                            Page 1 of x
Population: Intent-to-Treat
Listing xx
Listing of Subjects by Country
Country
Investigator
Name
Subject 
Treatment Arm
Netherlands
ARM1
ARM3
ARM4
United Kingdom
ARM2
PPD


CONFIDENTIAL
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205
POP_L3
Protocol: 207040                                                                            
Page 1 of x
Population: Intent-to-Treat
Listing xx
Listing of Family History of Cardiovascular Risk Factors
Site Id./
Unique Subject Id.
ARM
Family History [1]
ARM1
Yes
Unknown
ARM3
Unknown
Yes
ARM4
Unknown
Footnote: [1] Family history of premature coronary artery disease in women < 65 years or men < 55 years in first degree relatives only (e.g., biological mother or father, 
biological brother or sister, biological son or daughter).
PPD


CONFIDENTIAL
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206
POP_L4
Protocol: 207040                                                                            
Page 1 of x
Population: Intent-to-Treat
Listing xx
Listing of Asthma  History
                                                                                  Number of Asthma
                                                 Duration of Asthma        Exacerbations in Last 12 Months_
     Treatment        Inv.      Subj.       Years       Months          Type 1^          Type 2#
     -------------------------------------------------------------------------------------------------------
     Arm 1            xxxxx      xxxx        xx          xx            xx                 xx
                                 xxxx        xx          xx            xx                 xx
                                 xxxx        xx          xx            xx                 xx
                                 xxxx        xx          xx            xx                 xx
                      xxxxx      xxxx        xx          xx            xx                 xx
                                 xxxx        xx          xx            xx                 xx
                                 xxxx        xx          xx            xx                 xx
                                 xxxx        xx          xx            xx                 xx
                             
     Arm 2            xxxxx      xxxx        xx          xx            xx                 xx
                                 xxxx        xx          xx            xx                 xx
                                 xxxx        xx          xx            xx                 xx
                                 xxxx        xx          xx            xx                 xx
                      xxxxx      xxxx        xx          xx            xx                 xx
                                 xxxx        xx          xx            xx                 xx
                                 xxxx        xx          xx            xx                 xx
                                 xxxx        xx          xx            xx                 xx
^Type 1: Required oral/systemic corticosteroids (not involving hospitalization)
#Type 2: Required hospitalization


CONFIDENTIAL
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207
POP_L5
Protocol:207040                                                           
Page 1 of x
Population: All Subjects Enrolled
Listing xx
Listing of Prescription Details
Site Id./
Unique Subject Id.
Actual number of prescriptions
[1]
Number of prescriptions needing 100% compliance
[2]
4
11
8
5
[1] Actual number of asthma maintenance therapy prescriptions requested by subject or prescribed for subject.
[2] Number of asthma maintenance therapy prescriptions requested or prescribed that would be needed to be 100% compliant.
PPD


CONFIDENTIAL
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208
POP_L6
Protocol: 207040                                                                     
        Page 1 of x
Population: Intent-to-Treat
Listing xx
Listing of Preferred time of dosing
Site Id./
Unique Subject Id.
Treatment Arm
Preferred time
Incidence of 
Preferred time (%)
1
15:30
57.34%
2
9:00
89.23%
Note: A subject is considered as having taken their dose at their preferred time if the actuation time from the Relvar/Breo ELLIPTA sensor is recorded 1 hour of their 
preferred time as captured on the eCRF at screening
PPD


CONFIDENTIAL
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209
POP_L7
Protocol:207040                                                           
Page 1 of x
Population: Intent-to-Treat
Listing xx
Listing of HCP Dashboard Review
Site Id./
Unique Subject Id.
Treatment
Visit
Date of Dashboard data review
Was action taken
Action(s) Taken
Arm 4
Xxxxxxx
12DEC2008
N
Discuss adherence
Arm 2
xxxxxxx
03FEB2009
Y
Discuss rescue medication
PPD


CONFIDENTIAL
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210
SAFE_L8
Protocol: 207040                                                                            
Page 1 of x
Population: Intent-to-Treat
Listing xx
Listing of Treatment Compliance
Site Id./
Unique Subject Id.
Protocol
prescribed dose
Start Date/ 
Study Day
Stop Date/
Study Day
Overall Compliance
200/25 mcg QD
1
1
71
200/25 mcg QD
1
1
107
PPD
PPD
PPD
PPD
PPD


CONFIDENTIAL
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211
SAFE_L1
Protocol: 207040                          
                                                
  Page 1 of x
Population: Intent-to-Treat
Listing xx
Listing of Adverse Event of Special Interest Group, Subgroup, Sub-SMQ and Preferred Term
AESI Group
AESI Subgroup
Sub-SMQ
  Preferred Term
Adrenal suppression
ACTH stimulation test abnormal
Addison's disease
Adrenal androgen deficiency
Adrenal atrophy
Adrenal insufficiency


CONFIDENTIAL
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212
SAFE_L2
Protocol: 207040
Page 1 of x
Population: ITT
Listing xx
Listing of Relvar/Breo ELLIPTA Sensor Status
Site id/
Subj.
Treatment
Date of Sensor 
activation
Serial 
Number
Sensor 
return 
status
Sensor 
return date
Reasons for not 
returning the 
Sensor
Date of Sensor 
malfunction
Date of 
permanently 
stopping the use of 
Sensor
PPD


CONFIDENTIAL
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213
SAFE_L3
Protocol: 207040                                                                            
Page 1 of x
Population: Enrolled
Listing xx
Listing of Salbutamol MDI Sensor Status
Site id/
Subj.
Treatment
Date of Sensor 
activation
Serial 
Number
Sensor 
return 
status
Sensor 
return date
Reasons for not 
returning the 
Sensor
Date of Sensor 
malfunction
Date of 
permanently 
stopping the use of 
Sensor
PPD


CONFIDENTIAL
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214
SAFE_L4
Protocol: 207040                                                                         
   Page 1 of x
Population: Intent-to-Treat
Listing xx
Listing of Sensor App Status
Site id./
Subj.
Arm
Date of permanent 
discontinuation/study day
Arm 1
 23
Arm 5
 43
PPD
PPD
PPD


CONFIDENTIAL
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215
SAFE_L5
Protocol: 207040                                                                           
Page 1 of x
Population: ITT
Listing xx
Listing of Device Malfunction
Site id./
Subj.
Arm
Date of malfunction
Malfunctioning device type
Reasons for device 
malfunction
Arm 2
07FEB2008
ELLIPTA
Dose counter is 
ambiguous
Arm 4
12FEB2008
Rescue Medication
Inhaler is cracked or 
broken apart
PPD


CONFIDENTIAL
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216
EFF_L1
Protocol: 207040                                                                           
Page 1 of x
Population: Intent-to-Treat
Listing xx
Listing of Relvar/Breo ELLIPTA Adherence – Observed Data
Site id./
Subj.
Arm
Month
Day
Number of Days
Adherence (%)
Arm 2
Baseline
Month 1
....
Adherence recorded
Device incident
Post discontinuation of maintenance Sensor
Non-adherent
Adherence recorded
Device incident
Post discontinuation of maintenance Sensor
Non-adherent
28
0
0
0
20
0
0
8
100%
71.42%
Arm 4
Baseline
Month 1
.....
Adherence recorded
Device incident
Post discontinuation of maintenance Sensor
Non-adherent
Adherence recorded
Device incident
Post discontinuation of maintenance Sensor
Non-adherent
28
0
0
0
18
1
0
9
100%
.......
Programming Note: Repeat for Month 2, 3, 4, 5 and 6
PPD


CONFIDENTIAL
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217
EFF_L2
Protocol: 207040                                                                           
Page 1 of x
Population: Intent-to-Treat
Listing xx
Listing of Salbutamol MDI Rescue Free Days and Total Rescue Use – Observed Data
Site id./
Subj.
Arm
Month
Day
Number of Days
Rescue Free (%)
Total Rescue Use 
(Puffs)
Arm 1
Baseline
Month 1
....
Rescue use recorded
Device incident
Post discontinuation of MDI rescue sensor
MDI rescue free
Rescue use recorded
Device incident
Post discontinuation of MDI rescue sensor
MDI rescue free
9
0
0
19
20
0
0
8
67.86%
28.58%
15
42
Arm 3
Baseline
Month 1
.....
Rescue use recorded
Device incident
Post discontinuation of MDI rescue sensor
MDI rescue free
Rescue use recorded
Device incident
Post discontinuation of MDI rescue sensor
MDI rescue free
0
0
0
28
18
1
0
9
100%
.......
0
29
Programming Note: Repeat for Month 2, 3, 4, 5 and 6
PPD


CONFIDENTIAL
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218
EFF_L3
Protocol: 207040                                                                           
Page 1 of x
Population: ITT
Listing xx
Listing of Patient Reported Outcome Questionnaire Total Scores
Treatment: Arm 1
Inv./
Subj.
Visit/
Study Date/
Study Day
ACT
ASUI
Total Score
MARS-A
PAM-13
SGRQ
BMQ
xxxxxx/
xxxxx
xxxxx
DDMMMYYYY/
xx


CONFIDENTIAL
207040
219
EFF_L4
Protocol: 207040                                                                            
Page 1 of x
Population: Intent-to-Treat
Listing xx
Listing of Severe Asthma Exacerbations
Treatment/ Inv./
Subj.
Days Since 
1st Dose of 
Onset
Date of 
Onset/
Resolution
Outcome
Withdrawn
from
Study
Treatment?
Systemic/
Oral Corti-
costeroids
Taken?
Antibiotics
Taken?
A medication
Taken?
Hospitalized/
ER Visit/
Intubated?
xxxxxxx/
xx
DDMMMYYYY/
xxxxxx
xxx
xxx
xxx
xxx
xxx/xxx/xxx
xxx/
DDMMMYYYY
xxxxx
xxxxxxx/
xx
DDMMMYYYY/
xxxxxx
xxx
xxx
xxx
xxx
xxx/xxx/xxx
xxx/
DDMMMYYYY
xxxxx
xxxxxxx/
xx
DDMMMYYYY/
xxxxxx
xxx
xxx
xxx
xxx
xxx/xxx/xxx
xxx/
DDMMMYYYY
xxxxx
xxxxxxx/
xx
DDMMMYYYY/
xxxxxx
xxx
xxx
xxx
xxx
xxx/xxx/xxx
xxx/
DDMMMYYYY
xxxxx
xx
DDMMMYYYY/
xxxxxx
xxx
xxx
xxx
xxx
xxx/xxx/xxx
DDMMMYYYY


CONFIDENTIAL
207040
220
EFF_L5
Protocol: 207040                                                                            
Page 1 of x
Population: Intent-to-Treat
Listing xx
Listing of Unscheduled Asthma Related Healthcare Utilisation
Treatment: Placebo
                                                                                       Number of
                                                                                       Inpatient
                                            Number of    Number of                  Hospitalisation
                              Number of     physician       urgent                        Days
                 Number of   Home Visits      office/        care/    Number of  ______________________
    Inv./        Telephone  ______________   practice   outpatient    emergency                 General
    Subj.            Calls   Day    Night      visits       visits  room visits         ICU        Ward
    ---------------------------------------------------------------------------------------------------
    xxxxxx/            x      x       x            x          x            x            x           x
    xxxxxxx.
    xxxxxx


CONFIDENTIAL
207040
221
EFF_L11
Protocol: 207040                                                                            
Page 1 of x
Population: Intent-to-Treat
Listing xx
Listing of Peak Expiratory Flow (PEF) and Fractional Exhaled Nitric Oxide (FeNO) Results
Site 
I.D/ 
Subj.
Treatment 
Arm
Visit
Date
PEF (unit)
FeNO (ppb)
FeNO Flow 
rate 
(mL/sec)
xxxx
xxxx
xxxxxxxxx
DDMMMYYYY
xxxxxxxxx
xxxxxxxxx
xxxxxxxxx
DDMMMYYYY
xxxxxxxxx
xxxxxxxxx
...
....
....
Programming Note: Include the FeNO flow rate (mL/sec)