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
Phase: PHASE4
Conditions: Asthma
Sponsor: GlaxoSmithKline

2016N307903_01
CONFIDENTIAL
GlaxoSmithKline group of companies
207040
1
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

2016N307903_01
CONFIDENTIAL
207040
3
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.

2016N307903_01
CONFIDENTIAL
207040
4
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.

2016N307903_01
CONFIDENTIAL
207040
5
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.

2016N307903_01
CONFIDENTIAL
207040
6
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

2016N307903_01
CONFIDENTIAL
207040
7
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

2016N307903_01
CONFIDENTIAL
207040
8
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

2016N307903_01
CONFIDENTIAL
207040
9
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

2016N307903_01
CONFIDENTIAL
207040
10
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.

2016N307903_01
CONFIDENTIAL
207040
11
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.

2016N307903_01
CONFIDENTIAL
207040
12
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

2016N307903_01
CONFIDENTIAL
207040
13
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

2016N307903_01
CONFIDENTIAL
207040
14
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

2016N307903_01
CONFIDENTIAL
207040
15
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.

2016N307903_01
CONFIDENTIAL
207040
16
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.

2016N307903_01
CONFIDENTIAL
207040
17
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

2016N307903_01
CONFIDENTIAL
207040
18
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; 

2016N307903_01
CONFIDENTIAL
207040
19
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. 

2016N307903_01
CONFIDENTIAL
207040
20
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.

2016N307903_01
CONFIDENTIAL
207040
21
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.

2016N307903_01
CONFIDENTIAL
207040
22
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.

2016N307903_01
CONFIDENTIAL
207040
23
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 

2016N307903_01
CONFIDENTIAL
207040
24
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

2016N307903_01
CONFIDENTIAL
207040
25
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)

2016N307903_01
CONFIDENTIAL
207040
26
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 

2016N307903_01
CONFIDENTIAL
207040
27
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.

2016N307903_01
CONFIDENTIAL
207040
28
5.
STUDY DESIGN
5.1.
Overall Design
Figure 2
: Study Schematic

2016N307903_01
CONFIDENTIAL
207040
29
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-

2016N307903_01
CONFIDENTIAL
207040
30
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 

2016N307903_01
CONFIDENTIAL
207040
31
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.

2016N307903_01
CONFIDENTIAL
207040
32
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,

2016N307903_01
CONFIDENTIAL
207040
33
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.

2016N307903_01
CONFIDENTIAL
207040
34
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.

2016N307903_01
CONFIDENTIAL
207040
35
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

2016N307903_01
CONFIDENTIAL
207040
36
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.

2016N307903_01
CONFIDENTIAL
207040
37
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.

2016N307903_01
CONFIDENTIAL
207040
38
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.

2016N307903_01
CONFIDENTIAL
207040
39
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.

2016N307903_01
CONFIDENTIAL
207040
40
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

2016N307903_01
CONFIDENTIAL
207040
41

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.

2016N307903_01
CONFIDENTIAL
207040
42
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.

2016N307903_01
CONFIDENTIAL
207040
43
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.

2016N307903_01
CONFIDENTIAL
207040
44

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. 

2016N307903_01
CONFIDENTIAL
207040
45
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.

2016N307903_01
CONFIDENTIAL
207040
46
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.

2016N307903_01
CONFIDENTIAL
207040
47
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 

2016N307903_01
CONFIDENTIAL
207040
48
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.

2016N307903_01
CONFIDENTIAL
207040
49
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.

2016N307903_01
CONFIDENTIAL
207040
50

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.

2016N307903_01
CONFIDENTIAL
207040
51

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.

2016N307903_01
CONFIDENTIAL
207040
52
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.

2016N307903_01
CONFIDENTIAL
207040
53
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 

2016N307903_01
CONFIDENTIAL
207040
54
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

2016N307903_01
CONFIDENTIAL
207040
55

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.

2016N307903_01
CONFIDENTIAL
207040
56
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 

2016N307903_01
CONFIDENTIAL
207040
57
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.

2016N307903_01
CONFIDENTIAL
207040
58
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.

2016N307903_01
CONFIDENTIAL
207040
59
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.

2016N307903_01
CONFIDENTIAL
207040
60
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).

2016N307903_01
CONFIDENTIAL
207040
61
12.
REFERENCES
Anarella J, Roohan P, Balistreri E, Gesten F. A Survey of Medicaid Recipients with 
Asthma: Perceptions of Self Management, Access and Care. CHEST. 2004;125:1359-67.
Bae Y-J, Kim T-B, Jee Y-K, Park H-W, Chang Y-S, Cho S-H, Cho Y S, Moon H-B. 
Severe Asthma Patients in Korea Overestimate Their Adherence to Inhaled 
Corticosteroids. Journal of Asthma. 2009;46:591-595. 
Chan A, Harrison J, Black P, Mitchell E, Foster J. Using Electronic Monitoring Devices 
to Measure Inhaler Adherence: A Practical Guide for Clinicians. Journal of Allergy and 
Clinical Immunology. 2015;3:335-49. 
Chan A, Stewart A, Foster J, Mitchell E, Camargo C, Harrison J. Factors associated with 
medication adherence in school-aged children with asthma. European Respiratory 
Journal Open Research. 2016;2:1-9. 
Charles T, Quinn D, Weatherall M, Aldington S, Beasley R, Holt S. An audiovisual 
reminder improves adherence with inhaled corticosteroids therapy in asthma. Journal of 
Allergy and Clinical Immunology. 2007;4:811-16. 
Cochrane M, Bala M, Downs K, Mauskopf J, Ben-Joseph R. Inhaled corticosteroids for 
asthma therapy: patient compliance, devices, and inhalation technique. CHEST. 
2000;117:542-550. 
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.
Coleman C, Limone B, Sobieraj D, Lee S, Roberts M, Kaur R, Alam T. Dosing 
frequency and medication adherence in chronic disease. Journal of Managed Care 
Pharmacy. 2012;18:527-539. 
Dweik R, Boggs PB, Erzurum SC, Irvin CG, Leigh MW, Lundberg JO, Olin AC, 
Plummer AL, Taylor DR. An official ATS clinical practice guideline: interpretation of 
exhaled nitric oxide levels (FENO) for clinical applications. American Journal 
Respiratory Critical Care Medicine. 2011;184:602-15. 
Foster J, Usherwood T, Smith L, Sawyer S, Xuan W, Rand C, Reddel H. Inhaler 
reminders improve adherence with controller treatment in primary care patients with 
asthma. Journal of Allergy and Clinical Immunology. 2014;134:6.
Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and 
Prevention, 2017. Available from: ginasthma.org
Hee Hong S, Sanders B, West D. Inappropriate use of inhaled beta agonists and its 
association with patient health status. Current Medical Respiratory Opinions. 
2006;22:33-40.

2016N307903_01
CONFIDENTIAL
207040
62
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 39:4, Part I (August 2004)
Horne R, Weinman J. Self-Regulation and self management in asthma: Exploring the role 
of illness prerceptions and treatment beliefs in explaining non-adherence to preventer 
medication. Psychology and Health, 2002, VoL 17, No 1, pp, 17-32
James L, Letzig L, Simpson P, Capparelli E, Roberts D, Hinson J, Davern T, Lee W. 
Pharmacokinetics of acetaminophen-protein adducts in adults with acetaminophen 
overdose and acute liver failure. Drug Metabolism and Disposition. 2009;37:1779-84.
Jones A, Fay J, Burr M, Stone M, Hood K, Roberts G. Inhaled Corticosteroids Effects on 
Bone Metabolism in Asthma and Mild Chronic Obstructve Pulmonary Disease. Cochrane 
Database of Systematic Reviews. 2002;1:1-21.
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
König P, Hillmana L, Cervantesa C, Levinea C et al. Bone Metabolism in Children with 
Asthma Treated with Inhaled Beclomethasone Dipropionate. Journal of Pediatrics. 
1993;122:219-226. 
Koterba A, Saltoun C. Asthma Classification. Allergy and Asthma Proceedings. 
2012;33:S28-S31. 
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Deny P, Gault E. Quantification of 
Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates Different 
Patterns of Virological Response to Interferon Therapy in Chronically Infected Patients. 
Journal of Clinical Microbiology. 2005;43:2363-69. 
Martinez F. Genes, environments, development and asthma: A reappraisal. European 
Respiratory Journal. 2007;29:179-84. 
Milgrom H, Bender B, Ackerson L, Bowry P, Smith B, Rand C. Non-compliance and 
treatment failure in children with asthma. Journal of Allergy and Clinical Immunology. 
1996;98:1051-7. 
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
Normansell R, Kew KM, Stovold E. Interventions to improve adherence to inhaled 
steroids for asthma (Review). Cochrane Database of Systematic Reviews 2017, Issue 4. 
Art. No.: CD012226. DOI: 10.1002/14651858.CD012226.pub2.

2016N307903_01
CONFIDENTIAL
207040
63
Patel M, Pilcher J, Reddel H, Pritchard A, Corin A, Helm C. Metrics of salbutamol use as 
predictors of future adverse outcomes in asthma. Clinical and Experimental Allery. 
2013;43:1144-51. 
Price D, Robertson A, Bullen K, Rand C, Horne R, Staudinger H. Improved adherence 
with once-daily versus twice-daily dosing of mometasone furoate administered via a dry 
powder inhaler: a randomized open-label study. BMC Pulmonary Medicine 2010; 10:1-9
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. 
Sapir T, Moreo K, Greene L, Simone L, Carter J, Mateka J, Hanania N. Assessing patient 
and provider perceptions of factors associated with patient engagement in asthma care. 
Annals of the American Thoracic Society. 2017;14:659-66. 
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) 
Silkoff P. ATS/ARS Recommendations for Standardized Procedures for the Online and 
Offline Measurement of Exhaled Lower Respiratory Nitric Oxide and Nasal Nitric Oxide. 
American Thoracic Society Documents. 2005;171:912-30. 
Toy EL, Beaulieu NU, McHale JM, Welland TR, Plauschinat CA, Swensen A, Duh MS. 
Treatment of COPD: relationships between daily dosing frequency, adherence, resource 
use, and costs. Respir Med 2011; 105:435-44
Turpeinen M, Pelkonen A, Nikander K, Sorva R, Selroos O, Juntunen-Backman K, 
Haahtela T. Bone mineral density in children treated with daily or periodical inhaled 
budesonide: the Helsinki Early Intervention Childhood Asthma study. Pediatric 
Research. 2010;68:169-173. 
van Boven et. al. Enhancing Respiratory Medication Adherence: The Role of Health Care 
Professionals and Cost-Effectiveness Considerations. Journal of Allergy and Clinical 
Immunology Practice 2016; 4: 835-846
Wells KE, Peterson EL, Ahmedani BK, et al. Real-world effects of once vs greater daily 
inhaled corticosteroid dosing on medication adherence. Annals of Allergy and Asthma 
Immunology. 2013 Sep;111(3):216-20.
Willams L, Pladevall M, Xi H, Peterson E, Joseph C, Lafata J. Relationship between 
adherence to inhaled corticosteroids and poor outcomes among adults with asthma. 
Journal of Allergy and Clinical Immunology. 2004;114:1288-93. 
Williams L, Peterson E, Wells K, Ahmedani B, Kumar R, Burchard E, Chowdry V, 
Favro D, Lanfear D, Pladevall M. Quantifying the proportion of severe asthma 
exacerbations attributable to inhaled corticosteroid nonadherence. Journal of Allergy and 
Clinical Immunology. 2011;128:1185-1191. 

2016N307903_01
CONFIDENTIAL
207040
64
Zeller A, Taegtmeyer A, Martina B, Battegay E, Tschudi P. Physicians' ability to predict 
patients' adherence to antihypertensive medication in primary care. Hypertension 
Research. 2008;31:1765-71. 

2016N307903_01
CONFIDENTIAL
207040
65
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

2016N307903_01
CONFIDENTIAL
207040
66
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

2016N307903_01
CONFIDENTIAL
207040
67
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. 

2016N307903_01
CONFIDENTIAL
207040
68

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.

2016N307903_01
CONFIDENTIAL
207040
69
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.

2016N307903_01
CONFIDENTIAL
207040
70

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

2016N307903_01
CONFIDENTIAL
207040
71
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.

2016N307903_01
CONFIDENTIAL
207040
72
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.

2016N307903_01
CONFIDENTIAL
207040
73
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 

2016N307903_01
CONFIDENTIAL
207040
74
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.

2016N307903_01
CONFIDENTIAL
207040
75
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.

2016N307903_01
CONFIDENTIAL
207040
76
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

2016N307903_01
CONFIDENTIAL
207040
77
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. 

2016N307903_01
CONFIDENTIAL
207040
78
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 

2016N307903_01
CONFIDENTIAL
207040
79
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

2016N307903_01
CONFIDENTIAL
207040
80
13.5.
Appendix 5: Liver Safety: Required Actions, Follow-up 
Assessments
Phase III-IV liver chemistry stopping criteria and required follow up assessments 

2016N307903_01
CONFIDENTIAL
207040
81
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 

2016N307903_01
CONFIDENTIAL
207040
82

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] .

2016N307903_01
CONFIDENTIAL
207040
83
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.

2016N307903_01
CONFIDENTIAL
207040
84
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.

2016N307903_01
CONFIDENTIAL
207040
85
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 

2016N307903_01
CONFIDENTIAL
207040
86
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

2016N307903_01
CONFIDENTIAL
207040
87
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).

2016N307903_00
CONFIDENTIAL
GlaxoSmithKline group of companies
207040
1
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

2016N307903_00
CONFIDENTIAL
207040
3
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

2016N307903_00
CONFIDENTIAL
207040
4
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

2016N307903_00
CONFIDENTIAL
207040
5
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

2016N307903_00
CONFIDENTIAL
207040
6
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

2016N307903_00
CONFIDENTIAL
207040
7
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.

2016N307903_00
CONFIDENTIAL
207040
8
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.

2016N307903_00
CONFIDENTIAL
207040
9
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

2016N307903_00
CONFIDENTIAL
207040
10
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

2016N307903_00
CONFIDENTIAL
207040
11
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

2016N307903_00
CONFIDENTIAL
207040
12
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

2016N307903_00
CONFIDENTIAL
207040
13
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.

2016N307903_00
CONFIDENTIAL
207040
14
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

2016N307903_00
CONFIDENTIAL
207040
15
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; 

2016N307903_00
CONFIDENTIAL
207040
16
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. 

2016N307903_00
CONFIDENTIAL
207040
17
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.

2016N307903_00
CONFIDENTIAL
207040
18
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-

2016N307903_00
CONFIDENTIAL
207040
19
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 

2016N307903_00
CONFIDENTIAL
207040
20
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].

2016N307903_00
CONFIDENTIAL
207040
21
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 

2016N307903_00
CONFIDENTIAL
207040
22
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)

2016N307903_00
CONFIDENTIAL
207040
23
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 

2016N307903_00
CONFIDENTIAL
207040
24
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.

2016N307903_00
CONFIDENTIAL
207040
25
5.
STUDY DESIGN
5.1.
Overall Design
Figure 2
: Study Schematic

2016N307903_00
CONFIDENTIAL
207040
26
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-

2016N307903_00
CONFIDENTIAL
207040
27
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 

2016N307903_00
CONFIDENTIAL
207040
28
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.

2016N307903_00
CONFIDENTIAL
207040
29
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.

2016N307903_00
CONFIDENTIAL
207040
30
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.

2016N307903_00
CONFIDENTIAL
207040
31
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.

2016N307903_00
CONFIDENTIAL
207040
32
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

2016N307903_00
CONFIDENTIAL
207040
33
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.

2016N307903_00
CONFIDENTIAL
207040
34
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.

2016N307903_00
CONFIDENTIAL
207040
35
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.

2016N307903_00
CONFIDENTIAL
207040
36
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) 

2016N307903_00
CONFIDENTIAL
207040
37
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

2016N307903_00
CONFIDENTIAL
207040
38

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.

2016N307903_00
CONFIDENTIAL
207040
39
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.

2016N307903_00
CONFIDENTIAL
207040
40
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.

2016N307903_00
CONFIDENTIAL
207040
41

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. 

2016N307903_00
CONFIDENTIAL
207040
42
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.

2016N307903_00
CONFIDENTIAL
207040
43
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.

2016N307903_00
CONFIDENTIAL
207040
44
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 

2016N307903_00
CONFIDENTIAL
207040
45
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. 

2016N307903_00
CONFIDENTIAL
207040
46
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.

2016N307903_00
CONFIDENTIAL
207040
47

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.

2016N307903_00
CONFIDENTIAL
207040
48

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.

2016N307903_00
CONFIDENTIAL
207040
49
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.

2016N307903_00
CONFIDENTIAL
207040
50
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 

2016N307903_00
CONFIDENTIAL
207040
51
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 

2016N307903_00
CONFIDENTIAL
207040
52
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 

2016N307903_00
CONFIDENTIAL
207040
53
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.

2016N307903_00
CONFIDENTIAL
207040
54
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).

2016N307903_00
CONFIDENTIAL
207040
55
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 

2016N307903_00
CONFIDENTIAL
207040
56
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

2016N307903_00
CONFIDENTIAL
207040
57

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.

2016N307903_00
CONFIDENTIAL
207040
58
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.

2016N307903_00
CONFIDENTIAL
207040
59
12.
REFERENCES
Anarella J, Roohan P, Balistreri E, Gesten F. A Survey of Medicaid Recipients with 
Asthma: Perceptions of Self Management, Access and Care. CHEST. 2004;125:1359-67.
Bae Y-J, Kim T-B, Jee Y-K, Park H-W, Chang Y-S, Cho S-H, Cho Y S, Moon H-B. 
Severe Asthma Patients in Korea Overestimate Their Adherence to Inhaled 
Corticosteroids. Journal of Asthma. 2009;46:591-595. 
Chan A, Harrison J, Black P, Mitchell E, Foster J. Using Electronic Monitoring Devices 
to Measure Inhaler Adherence: A Practical Guide for Clinicians. Journal of Allergy and 
Clinical Immunology. 2015;3:335-49. 
Chan A, Stewart A, Foster J, Mitchell E, Camargo C, Harrison J. Factors associated with 
medication adherence in school-aged children with asthma. European Respiratory 
Journal Open Research. 2016;2:1-9. 
Charles T, Quinn D, Weatherall M, Aldington S, Beasley R, Holt S. An audiovisual 
reminder improves adherence with inhaled corticosteroids therapy in asthma. Journal of 
Allergy and Clinical Immunology. 2007;4:811-16. 
Cochrane M, Bala M, Downs K, Mauskopf J, Ben-Joseph R. Inhaled corticosteroids for 
asthma therapy: patient compliance, devices, and inhalation technique. CHEST. 
2000;117:542-550. 
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.
Coleman C, Limone B, Sobieraj D, Lee S, Roberts M, Kaur R, Alam T. Dosing 
frequency and medication adherence in chronic disease. Journal of Managed Care 
Pharmacy. 2012;18:527-539. 
Dweik R, Boggs PB, Erzurum SC, Irvin CG, Leigh MW, Lundberg JO, Olin AC, 
Plummer AL, Taylor DR. An official ATS clinical practice guideline: interpretation of 
exhaled nitric oxide levels (FENO) for clinical applications. American Journal 
Respiratory Critical Care Medicine. 2011;184:602-15. 
Foster J, Usherwood T, Smith L, Sawyer S, Xuan W, Rand C, Reddel H. Inhaler remiders 
improve adherence with controller treatment in primary care patients with asthma. 
Journal of Allergy and Clinical Immunology. 2014;134:6.
Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and 
Prevention, 2017. Available from: ginasthma.org
Hee Hong S, Sanders B, West D. Inappropriate use of inhaled beta agonists and its 
association with patient health status. Current Medical Respiratory Opinions. 
2006;22:33-40.

2016N307903_00
CONFIDENTIAL
207040
60
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 39:4, Part I (August 2004)
Horne R, Weinman J. Self-Regulation and self management in asthma: Exploring the role 
of illness prerceptions and treatment beliefs in explaining non-adherence to preventer 
medication. Psychology and Health, 2002, VoL 17, No 1, pp, 17-32
James L, Letzig L, Simpson P, Capparelli E, Roberts D, Hinson J, Davern T, Lee W. 
Pharmacokinetics of acetaminophen-protein adducts in adults with acetaminophen 
overdose and acute liver failure. Drug Metabolism and Disposition. 2009;37:1779-84.
Jones A, Fay J, Burr M, Stone M, Hood K, Roberts G. Inhaled Corticosteroids Effects on 
Bone Metabolism in Asthma and Mild Chronic Obstructve Pulmonary Disease. Cochrane 
Database of Systematic Reviews. 2002;1:1-21.
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
König P, Hillmana L, Cervantesa C, Levinea C et al. Bone Metabolism in Children with 
Asthma Treated with Inhaled Beclomethasone Dipropionate. Journal of Pediatrics. 
1993;122:219-226. 
Koterba A, Saltoun C. Asthma Classification. Allergy and Asthma Proceedings. 
2012;33:S28-S31. 
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Deny P, Gault E. Quantification of 
Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates Different 
Patterns of Virological Response to Interferon Therapy in Chronically Infected Patients. 
Journal of Clinical Microbiology. 2005;43:2363-69. 
Martinez F. Genes, environments, development and asthma: A reappraisal. European 
Respiratory Journal. 2007;29:179-84. 
McMahon A, Levenson M, McEvoy B, Mosholder A, Murphy D. Age and risks of FDA-
approved long acting beta adrenergic receptor agonists. Pediatrics. 2011;128:1147-54. 
Mehta C, Pocock S. Adaptive increase in sample size when interim results are promising: 
A practical guide with examples. Statistics in Medicine. 2011;30:3267-84. 
Milgrom H, Bender B, Ackerson L, Bowry P, Smith B, Rand C. Non-compliance and 
treatment failure in children with asthma. Journal of Allergy and Clinical Immunology. 
1996;98:1051-7. 
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

2016N307903_00
CONFIDENTIAL
207040
61
Normansell R, Kew KM, Stovold E. Interventions to improve adherence to inhaled 
steroids for asthma (Review). Cochrane Database of Systematic Reviews 2017, Issue 4. 
Art. No.: CD012226. DOI: 10.1002/14651858.CD012226.pub2.
Patel M, Pilcher J, Reddel H, Pritchard A, Corin A, Helm C. Metrics of salbutamol use as 
predictors of future adverse outcomes in asthma. Clinical and Experimental Allery. 
2013;43:1144-51. 
Peters et al (2016) N Engl J Med 2016;375:850-60. DOI: 10.1056/NEJMoa1511190 
Price D, Robertson A, Bullen K, Rand C, Horne R, Staudinger H. Improved adherence 
with once-daily versus twice-daily dosing of mometasone furoate administered via a dry 
powder inhaler: a randomized open-label study. BMC Pulmonary Medicine 2010; 10:1-9
Revicki D A, Leidy N K et al.  Integrating patient preferencesinto health outcomes 
assessment:  The mulvivariable Asthma Symptoms Utility Index.  Chest 1998;114:998-
1007.
Sapir T, Moreo K, Greene L, Simone L, Carter J, Mateka J, Hanania N. Assessing patient 
and provider perceptions of factors associated with patient engagement in asthma care. 
Annals of the American Thoracic Society. 2017;14:659-66. 
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) 
Silkoff P. ATS/ARS Recommendations for Standardized Procedures for the Online and 
Offline Measurement of Exhaled Lower Respiratory Nitric Oxide and Nasal Nitric Oxide. 
American Thoracic Society Documents. 2005;171:912-30. 
Stempel et al (2016a) N Engl J Med 2016; 374:1822-1830May 12, 2016DOI: 
10.1056/NEJMoa1511049
Stempel et al (2016b) N Engl J Med 2016; 375:840-849September 1, 2016DOI: 
10.1056/NEJMoa1606356  
Toy EL, Beaulieu NU, McHale JM, Welland TR, Plauschinat CA, Swensen A, Duh MS. 
Treatment of COPD: relationships between daily dosing frequency, adherence, resource 
use, and costs. Respir Med 2011; 105:435-44
Turpeinen M, Pelkonen A, Nikander K, Sorva R, Selroos O, Juntunen-Backman K, 
Haahtela T. Bone mineral density in children treated with daily or periodical inhaled 
budesonide: the Helsinki Early Intervention Childhood Asthma study. Pediatric 
Research. 2010;68:169-173. 
van Boven et. al. Enhancing Respiratory Medication Adherence: The Role of Health Care 
Professionals and Cost-Effectiveness Considerations. Journal of Allergy and Clinical 
Immunology Practice 2016; 4: 835-846

2016N307903_00
CONFIDENTIAL
207040
62
Wells KE, Peterson EL, Ahmedani BK, et al. Real-world effects of once vs greater daily 
inhaled corticosteroid dosing on medication adherence. Annals of Allergy and Asthma 
Immunology. 2013 Sep;111(3):216-20.
Willams L, Pladevall M, Xi H, Peterson E, Joseph C, Lafata J. Relationship between 
adherence to inhaled corticosteroids and poor outcomes among adults with asthma. 
Journal of Allergy and Clinical Immunology. 2004;114:1288-93. 
Williams L, Peterson E, Wells K, Ahmedani B, Kumar R, Burchard E, Chowdry V, 
Favro D, Lanfear D, Pladevall M. Quantifying the proportion of severe asthma 
exacerbations attributable to inhaled corticosteroid nonadherence. Journal of Allergy and 
Clinical Immunology. 2011;128:1185-1191. 
Zeller A, Taegtmeyer A, Martina B, Battegay E, Tschudi P. Physicians' ability to predict 
patients' adherence to antihypertensive medication in primary care. Hypertension 
Research. 2008;31:1765-71. 

2016N307903_00
CONFIDENTIAL
207040
63
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

2016N307903_00
CONFIDENTIAL
207040
64
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

2016N307903_00
CONFIDENTIAL
207040
65
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. 

2016N307903_00
CONFIDENTIAL
207040
66

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.

2016N307903_00
CONFIDENTIAL
207040
67
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.

2016N307903_00
CONFIDENTIAL
207040
68

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

2016N307903_00
CONFIDENTIAL
207040
69
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.

2016N307903_00
CONFIDENTIAL
207040
70
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.

2016N307903_00
CONFIDENTIAL
207040
71
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 

2016N307903_00
CONFIDENTIAL
207040
72
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.

2016N307903_00
CONFIDENTIAL
207040
73
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.

2016N307903_00
CONFIDENTIAL
207040
74
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

2016N307903_00
CONFIDENTIAL
207040
75
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. 

2016N307903_00
CONFIDENTIAL
207040
76
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 

2016N307903_00
CONFIDENTIAL
207040
77
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

2016N307903_00
CONFIDENTIAL
207040
78
13.6.
Appendix 6: Liver Safety: Required Actions, Follow-up 
Assessments
Phase III-IV liver chemistry stopping criteria and required follow up assessments 

2016N307903_00
CONFIDENTIAL
207040
79
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 

2016N307903_00
CONFIDENTIAL
207040
80

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] .

2016N307903_00
CONFIDENTIAL
207040
81
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.

2016N307903_00
CONFIDENTIAL
207040
82
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.

2016N307903_00
CONFIDENTIAL
207040
83
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 

2016N307903_00
CONFIDENTIAL
207040
84
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