Conditions: Asthma
Keywords: umeclidinium bromide fluticasone furoate vilanterol fixed dose combination lung function albuterol/salbutamol asthma closed triple therapy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2436
Healthy volunteers: no

Brief summary:
A once-daily 'closed' triple FDC therapy of FF/UMEC/VI via a single ELLIPTA® dry powder inhaler (DPI) is being developed by GlaxoSmithKline (GSK) with the aim of providing a new treatment option for the management of asthma by improving lung function, health-related quality of life (HRQoL) and symptom control over established combination therapies. This is a phase III, multi-center, active-controlled, double-blind, parallel-group study to compare the efficacy, safety and tolerability of the FDC of FF/UMEC/VI with the FDC of FF/VI. This study has 5 phases: Pre-Screening (Visit 0), Screening/Run-in, Enrolment/Stabilization, Randomization/Treatment, and Follow up. At Visit 1 (Screening), subjects meeting all protocol defined inclusion/exclusion criteria will enter a 3-week run-in period and will receive fixed dose inhaled corticosteroid/long-acting beta agonist (ICS/LABA) (fluticasone/salmeterol, 250/50 micrograms (mcg), via the DISKUS® DPI) one inhalation twice a day. At Visit 2 (Enrolment), eligible subjects will be enrolled into the 2-week stabilization period to receive FF/VI (100/25 mcg via the ELLIPTA DPI once a day, in the morning). At the conclusion of the stabilization period (Visit 3), all subjects who meet the pre-defined randomization criteria will be randomized 1:1:1:1:1:1 during the treatment period to receive either FF/UMEC/VI (100/62.5/25 mcg; 200/62.5/25 mcg; 100/31.25/25 mcg; 200/31.25/25 mcg) or FF/VI (100/25 mcg; 200/25 mcg) via the ELLIPTA DPI once daily in the morning. The duration of the treatment period is variable but will be a minimum of 24 weeks and a maximum of 52 weeks. Subjects will have up to 6 on-treatment clinic visits scheduled at Visits 3, 4, 5, 6, 7 and 8/End of Study (EOS) (Weeks 0, 4, 12, 24, 36 and 52, respectively). A follow-up visit will be conducted approximately 7 days after the end of treatment period or, if applicable, after the early withdrawal visit. Subjects will be provided with short acting albuterol/salbutamol to be used on an as-needed basis (rescue medication) throughout the study. Approximately 2250 subjects will be randomized, with approximately 375 subjects randomized to each of the 6 double-blind treatment arms to ensure approximately 337 evaluable subjects per treatment arm. DISKUS and ELLIPTA are registered trademarks of GSK groups of companies.

Detailed description:

Arms:
arm 1: Subjects will receive FF/UMEC/VI (100/31.25/25) mcg inhalation powder via DPI, once daily in the morning. Subjects may receive albuterol/salbutamol as a rescue medication when needed during the treatment period. arm 2: Subjects will receive FF/UMEC/VI (100/62.5/25) mcg inhalation powder via DPI, once daily in the morning. Subjects will also receive albuterol/salbutamol as a rescue medication when needed during the treatment period. arm 3: Subjects will receive FF/UMEC/VI (200/31.25/25) mcg inhalation powder via DPI, once daily in the morning. Subjects may receive albuterol/salbutamol as a rescue medication when needed during the treatment period. arm 4: Subjects may receive FF/UMEC/VI (200/62.5/25) mcg inhalation powder via DPI, once daily in the morning. Subjects may receive albuterol/salbutamol as a rescue medication when needed during the treatment period. arm 5: Subjects will receive FF/VI (100/25) mcg inhalation powder via DPI, once daily in the morning. Subjects may receive albuterol/salbutamol as a rescue medication when needed during the treatment period. arm 6: Subjects will receive FF/VI (200/25) mcg inhalation powder via DPI, once daily in the morning. Subjects may receive albuterol/salbutamol as a rescue medication when needed during the treatment period.

Interventions: intervention 1: FF/UMEC/VI (100/31.25/25) mcg intervention 2: FF/UMEC/VI (100/62.5/25) mcg intervention 3: FF/UMEC/VI (200/31.25/25) mcg intervention 4: FF/UMEC/VI (200/62.5/25) mcg intervention 5: FF/VI (100/25) mcg intervention 6: FF/VI (200/25) mcg intervention 7: Fluticasone/salmeterol (FSC) intervention 8: Albuterol/salbutamol intervention 9: ELLIPTA DPI intervention 10: DISKUS DPI intervention 11: METERED-DOSE INHALER (MDI)
Intervention descriptions: intervention 1: Dry white powder delivered via the ELLIPTA DPI (one inhalation once-daily \[QD\] in the morning). The ELLIPTA DPI holds 2 individual blister strips with 30 blisters on each strip: the first strip contains FF 100 mcg in each blister and the second strip contains UMEC 31.25 mcg and VI 25 mcg in each blister. intervention 2: Dry white powder delivered via the ELLIPTA DPI (one inhalation, QD in the morning). The ELLIPTA DPI holds 2 individual blister strips with 30 blisters on each strip: the first strip contains FF 100 mcg in each blister and the second strip contains UMEC 62.5 mcg and VI 25 mcg in each blister. intervention 3: Dry white powder delivered via the ELLIPTA DPI (one inhalation, QD in the morning). The ELLIPTA DPI holds 2 individual blister strips with 30 blisters on each strip: the first strip contains FF 200 mcg in each blister and the second strip contains UMEC 31.25 mcg and VI 25 mcg in each blister. intervention 4: Dry white powder delivered via the ELLIPTA DPI (one inhalation, QD in the morning). The ELLIPTA DPI holds 2 individual blister strips with 30 blisters on each strip: the first strip contains FF 200 mcg in each blister and the second strip contains UMEC 62.5 mcg and VI 25 mcg in each blister. intervention 5: Dry white powder delivered via the ELLIPTA DPI (one inhalation, QD in the morning). The ELLIPTA DPI holds 2 individual blister strips with 30 blisters on each strip: the first strip contains FF 100 mcg in each blister and the second strip contains VI 25 mcg in each blister. intervention 6: Dry white powder delivered via the ELLIPTA DPI (one inhalation, QD in the morning). The ELLIPTA DPI holds 2 individual blister strips with 30 blisters on each strip: the first strip contains FF 200 mcg in each blister and the second strip contains VI 25 mcg in each blister. intervention 7: Dry white powder delivered via the DISKUS DPI (one inhalation twice daily: one in the morning and one in the evening). The DISKUS DPI holds a strip of 60 blisters; each blister contains FP 250 mcg and 50 mcg of salmeterol. intervention 8: This is a rescue medication administered via metered-dose inhaler (MDI) which will be used when needed during the study. intervention 9: The ELLIPTA device will be used during the stabilization period and the treatment period. The ELLIPTA DPI is a moulded plastic two-sided device that can hold two individual blister strips which contain powder formulation for oral inhalation. intervention 10: The DISKUS device will be used during the run-in period. The DISKUS DPI is a plastic inhalation delivery system containing a single-foil blister strip of a powder formulation of FSC for oral inhalation. intervention 11: Albuterol/salbutamol (rescue medication) will be delivered via metered-dose inhaler (MDI) will be used for reversibility testing.

Protocol document:
Prot_000.pdf: 
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TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A Phase III, randomized, double-blind, active controlled, parallel 
group study, comparing the efficacy, safety and tolerability of 
the fixed dose combination FF/UMEC/VI with the fixed dose 
dual combination of FF/VI, administered once-daily via a dry 
powder inhaler in subjects with inadequately controlled asthma
Compound Number:
GSK573719+GW642444+GW685698
Development Phase:
III A
Effective Date:
05-DEC-2017
Protocol Amendment Number:  04
Author (s):
 
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
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Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2016N271022_00
2016-JUN-06
Original
2016N271022_01
2016-JUN-09
Re-Publishing
Following publication of the original protocol but prior to distribution of the document, 
an exploratory analysis of the psychometric properties of the Evaluating Respiratory 
Symptoms (E-RS) and Supplemental asthma items was included in the protocol 
(Section 9.4.6). This necessitated a re-publishing of the protocol.
2016N271022_02
2016-DEC-13
Amendment No. 1

The Medical Monitor details have been updated.

In Section 1, the protocol synopsis has been updated to mirror the information 
presented in the main body of the protocol.

In Section 2.1, the text has been updated to clarify that the Global Initiative for 
Asthma guidelines (GINA, 2016) recommends a long-acting muscarinic 
antagonist (LAMA) as an add-on treatment option.

In Section 3 and Section 7.3.1.3:
o
The Other Secondary endpoint “Mean change from baseline in 
Evaluating Respiratory Symptoms (E-RS) total score” will be assessed 
over Weeks 21 to 24 (rather than over the first 24 weeks) of the 
treatment period.

In Section 3 and Section 7.3.1.4:
o
The Asthma Control Questionnaire (ACQ) total score that denotes 
controlled asthma has been corrected to align with Section 7.3.3.2 
(Asthma Control Questionnaire).
o
The Other endpoints “Mean change from baseline in E-RS domain 
scores” and “Percent of patients meeting a responder threshold of ≥ 2 
points improvement from baseline for the E-RS total score” will be 
assessed over Weeks 21 to 24 of the treatment period (rather than ‘over 
the first 24 weeks of the treatment period’ and ‘at Week 24’, 
respectively).

Section 4.2 and Section 6.9.2 have been updated to clarify that the last dose of 
ICS/LABA asthma medication has to be taken 24 hours prior to the Screening 
visit (Visit 1).

In Section 4.6.1, the Summary of Data/Rationale for Risk associated with 
Systemic ICS Effects has been updated to clarify that study HZA106851
assessed the effect of Investigational Product on 24 hour urinary (rather than 
serum) cortisol excretion.

In Section 5.1:
o
Inclusion Criteria number 4 (Asthma Control) has been amended.
o
The wording regarding acceptable doses of commonly prescribed ICS 
medication in Inclusion Criteria number 5 (Current Asthma 
Maintenance Therapy) has been amended.


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
In Section 5.2:
o
The Note related to Exclusion Criteria number 2 (Asthma Exacerbation) 
has been clarified.
o
Exclusion criteria number 3 (Chronic Obstructive Pulmonary Disease) 
has been clarified.
o
Exclusion criteria number 14 (Tobacco Use) has been clarified.

In Section 5.6.1 and Section 6.3, the requirement to withdraw a subject from 
study treatment/the study following the unblinding of the study treatment 
assigned to a subject has been removed.

In Section 5.6.4, the text has been amended to clarify that the QT interval 
corrected for heart rate by Fredericia’s formula (i.e. QTcF), rather than Bazett’s 
formula (i.e. QTcB), will be used throughout the study.

In Section 6.1, use of the study-provided fluticasone propionate (FP) has been 
clarified.

In Section 6.6, the instruction to contact the study sponsor/site monitor to 
discuss subject eligibility for continued participation in the study has been 
deleted.

In Section 6.9, the time-period for recording asthma medication in the eCRF 
has been amended to align with the associated inclusion criterion for the study.

In Section 6.9.1.1:
o
The permitted dose of systemic corticosteroids has been clarified.
o
The temporary use of medications for the treatment of moderate asthma 
exacerbations has been clarified.

Continuous Positive Airway Pressure (CPAP) for the treatment of obstructive 
sleep apnea has been included as a permitted non-drug therapy in Section 
6.9.1.3.

In Section 6.9.2:
o
The temporary use of inhaled long-acting anticholinergics and inhaled 
long-acting beta2-agonists (other than study treatment) has been 
prohibited.
o
Medical marijuana has been included as a prohibited medication.

In Section 7.1:
o
The Time and Events Table has been updated to clarify the time-
windows associated with Visit 1, Visit 2 and Visit 3.
o
Footnote 5 has been updated to clarify that the Informed Consent Form 
must be signed prior to ‘protocol-specified’ medication cessation.
o
Footnote 15 has been updated to clarify when the 3-week run-in period 
may commence should the airway reversibility assessment need to be 
repeated.
o
Footnote 18 has been updated to clarify the timing of the ECG 
assessments.
o
In Footnote 27, the timing of Early Withdrawal visit assessments has 
been clarified.
o
In Footnote 30, the pre-randomization use of the study-provided 
fluticasone propionate has been clarified.

In Section 7.3.4.1, the washout period for short-acting β2- agonists has been 


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clarified

In Section 7.3.5, Section 7.3.6, Section 7.5.1.2 and Section 7.5.8, the 
description of the data collected on the Medical Problems/Medications Taken 
worksheet has been revised to allow for the collection of data related to study 
treatment (as well as non-study treatment).

In Section 7.3.6, instructions for collecting the occurrence of asthma 
exacerbations in the electronic Case Report Form (eCRF) have been included.

In Section 7.5.2, a blank row in the provided table has been deleted.

In Section 7.5.6, the timing of the ECG assessments has been clarified.

In Section 7.6, the order of assessments has been amended.

In Section 9.2.2, the power for the key secondary endpoint (and associated 
graphs) has been re-calculated and updated.

In Section 9.3.4, Level 3b and Level 5 of the Multiplicity Adjustment Plan have 
been updated to amend the wording of the ‘mean change from baseline in E-RS 
score’ endpoint (in order to align with the associated amendments made in 
Section 3 and Section 7.3.1.3).

In Section 9.4, a typographical error has been corrected.
2016N271022_03
2017-JUN-23
Amendment No. 2

In Section 3.0:
o
(Other Objectives) has been amended to remove the word ‘morning’. 
Mean change from baseline in morning evening (PM) PEF over the first 
24 weeks of the treatment period.
o
The responder threshold language has been amended for ACQ-7, ACQ-
6 and ACQ-5 to state “0.5 points improvement (decrease) from 
baseline”. Originally stated “0.5 in change from baseline”.
o
Percent of patients meeting a responder threshold of ≥ 2 points 
improvement (decrease) from baseline for the E-RS total score over 
Weeks 21 to 24 (inclusive) of the treatment period. Added the word 
“decrease).
o
Percent of patients meeting a responder threshold of ≥ 0.5 points 
improvement (increase) from baseline for the AQLQ total score at 
Week 24. Added the word “increase”).

In Section 5.1 Inclusion Criteria
o
Current Asthma Maintenance Therapy; added BTS/SIGN and Japanese 
guidance for adult asthma as additional supported guidance.
o
Spirometry; Has been expanded to <85%. A best pre-bronchodilator 
morning (AM) FEV1 ≥30% and <85% (was 80%) of the predicted
normal value at Visit 1.

In Section 5.3.1 Inclusion Criteria for Enrolment
o
Spirometry; Has been expanded to <90%. A best pre-bronchodilator 
morning (AM) FEV1 ≥30% and <90% (was 80%) of the predicted
normal value at Visit 1.

In Section 7.1:
o
In the Time and Events Table for the Screening Visit box, Serum 
pregnancy test, to include foot note #21; Assessments to be conducted 
in females of reproductive potential.


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
In Section 7.3.1.4:
o
The responder threshold language has been amended for ACQ-7, ACQ-
6 and ACQ-5 to state “0.5 points improvement (decrease) from 
baseline”. Originally stated “0.5 in change from baseline”.
o
Percent of patients meeting a responder threshold of ≥ 2 points 
improvement (decrease) from baseline for the E-RS total score over 
Weeks 21 to 24 (inclusive) of the treatment period. Added the word 
“decrease).
o
Percent of patients meeting a responder threshold of ≥ 0.5 points 
improvement (increase) from baseline for the AQLQ total score at 
Week 24. Added the word “increase”).

In Section 7.3.5.1.6:
o
Clearly defined baseline value for alerts as 7 days prior to 
randomization.

In Section 9.3.1, typographical error was corrected.

In Section 9.3.4, Multiple Comparisons and Multiplicity:
o
Multiplicity adjustment plan has been updated to ensure the strong 
control on the family-wise Type I Error across multiple endpoints and 
multiple treatment comparisons.

In Section 11.0, References:
o
An additional reference (Japanese guideline for adult asthma 2017) has 
been added for guidance. 
2016N271022_04
2017-SEP-29
Amendment No. 3

In Section 1: Protocol Synopsis for Study 205715; Treatment Arms and 
Duration
o
Update and define the variable treatment period and transition date to
determine the planned end of study visit (Week 24, 36, or 52) for each 
randomized subject.

In Section 4.2: Treatment Arms and Duration
o
Update and define the variable treatment period and transition date to 
determine the planned end of study visit (Week 24, 36, or 52) for each 
randomized subject.

In Section 5.7: Subject and Study Completion
o
Update and define the variable treatment period and transition date to 
determine the planned end of study visit (Week 24, 36, or 52) for each 
randomized subject.

In the Appendix; Section 12.7.1 Country Specific Requirements, was updated 
to remove minimum requirement for Japanese subjects. 

The following sections all had the statement referring to “country specific 
requirements” removed, see Section 4.3, Section 7.1 (foot note #22) and 
Section 7.6.1.1. 
2016N271022_05
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Amendment No. 4


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
Section 6.1: amended to reflect the fact that study-specific FP (provided to 
subjects at the Investigator’s discretion for the treatment of symptoms of a 
moderate asthma exacerbation) does not need to be administered at a specific 
dose or via the DISKUS dry powder inhaler (DPI).

Section 7.2: amended to clarify that dispensing FP to subjects at Visit 1 is at the 
Investigator’s discretion.


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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information: 
Role
Name
Day Time Phone Number and email 
address
After-hours 
Phone/Cell/
Pager 
Number
Site 
Address
Primary 
Medical 
Monitor
Please refer to the Study Reference 
Manual (SRM) for phone number 
details.
Please refer to the SRM.
Secondary 
Medical 
Monitor
Please refer to the SRM for phone 
number details.
Please refer to the SRM.
SAE contact 
information 
Medical 
monitor as 
above
Sponsor Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
Iron Bridge Road 
Stockley Park West, Uxbridge, Middlesex, UB11 1BU, UK
Telephone: 
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.   
Regulatory Agency Identifying Number(s):  IND No. 114873; EudraCT No. 2016-
001304-37
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 205715
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date


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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 205715......................................................14
2.
INTRODUCTION....................................................................................................18
2.1.
Study Rationale ..........................................................................................18
2.2.
Brief Background ........................................................................................19
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................20
4.
STUDY DESIGN ....................................................................................................23
4.1.
Overall Design ............................................................................................23
4.2.
Treatment Arms and Duration.....................................................................24
4.3.
Type and Number of Subjects.....................................................................29
4.4.
Design Justification.....................................................................................29
4.5.
Dose Justification........................................................................................30
4.6.
Benefit: Risk Assessment ...........................................................................30
4.6.1.
Risk Assessment .........................................................................31
4.6.2.
Benefit Assessment.....................................................................37
4.6.3.
Overall Benefit: Risk Conclusion..................................................37
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............37
5.1.
Inclusion Criteria.........................................................................................38
5.2.
Exclusion Criteria........................................................................................40
5.3.
Enrolment Criteria.......................................................................................43
5.3.1.
Inclusion Criteria for Enrolment....................................................43
5.3.2.
Exclusion Criteria for Enrolment...................................................43
5.4.
Randomization Criteria ...............................................................................44
5.4.1.
Inclusion Criteria for Randomization ............................................44
5.4.2.
Exclusion Criteria for Randomization ...........................................44
5.5.
Pre-Screening/Screening/Run-in Failures...................................................45
5.6.
Withdrawal/Stopping Criteria.......................................................................46
5.6.1.
Withdrawal from Study Treatment................................................46
5.6.2.
Withdrawal from the Study...........................................................46
5.6.3.
Liver Chemistry Stopping Criteria ................................................47
5.6.3.1.
Study Treatment Restart or Rechallenge....................47
5.6.4.
QTc Stopping Criteria ..................................................................47
5.7.
Subject and Study Completion....................................................................48
6.
STUDY TREATMENT ............................................................................................49
6.1.
Investigational Product and Other Study Treatment....................................49
6.1.1.
Study Treatment, albuterol/salbutamol, ipratropium and 
FP Return ....................................................................................52
6.2.
Treatment Assignment................................................................................52
6.3.
Blinding.......................................................................................................53
6.4.
Packaging and Labeling..............................................................................53
6.5.
Preparation/Handling/Storage/Accountability..............................................53
6.6.
Compliance with Study Treatment Administration.......................................54
6.7.
Treatment of Study Treatment Overdose....................................................54
6.8.
Treatment after the End of the Study ..........................................................55
6.9.
Concomitant Medications and Non-Drug Therapies....................................55


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6.9.1.
Permitted Medications and Non-Drug Therapies..........................55
6.9.1.1.
Permitted Asthma Medications ...................................55
6.9.1.2.
Permitted Non-Asthma Medications ...........................56
6.9.1.3.
Permitted Non-Drug Therapies...................................57
6.9.2.
Prohibited Medications and Non-Drug Therapies.........................57
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................59
7.1.
Time and Events Table...............................................................................60
7.2.
Screening and Critical Baseline Assessments ............................................68
7.3.
Efficacy.......................................................................................................69
7.3.1.
Efficacy Endpoints .......................................................................69
7.3.1.1.
Primary Efficacy Endpoint...........................................69
7.3.1.2.
Key Secondary Efficacy Endpoint...............................69
7.3.1.3.
Other Secondary Efficacy Endpoints ..........................69
7.3.1.4.
Other Efficacy Endpoints ............................................69
7.3.2.
Efficacy Assessments..................................................................71
7.3.3.
Questionnaires ............................................................................71
7.3.3.1.
Global Assessment of Severity and Response 
to Treatment...............................................................71
7.3.3.2.
Asthma Control Questionnaire (ACQ).........................71
7.3.3.3.
St. George’s Respiratory Questionnaire 
(SGRQ) ......................................................................72
7.3.3.4.
Asthma Quality of Life Questionnaire (AQLQ) ............72
7.3.3.5.
Healthcare Resource Utilization..................................72
7.3.4.
Pulmonary Function Tests ...........................................................72
7.3.4.1.
Reversibility................................................................73
7.3.4.1.1.
Albuterol/Salbutamol...............................73
7.3.4.1.2.
Ipratropium .............................................74
7.3.5.
Daily Diaries ................................................................................74
7.3.5.1.
eDiary Questionnaires, Assessments and 
Alerts..........................................................................75
7.3.5.1.1.
E-RS.......................................................75
7.3.5.1.2.
Supplemental Asthma Items...................75
7.3.5.1.3.
Night-time Awakening, Asthma 
Symptom and Physical Activity 
Questions ...............................................76
7.3.5.1.4.
Rescue Albuterol/Salbutamol Use ..........76
7.3.5.1.5.
Morning and Evening Home 
Spirometry..............................................76
7.3.5.1.6.
Alerts......................................................77
7.3.6.
Asthma Exacerbations.................................................................77
7.3.6.1.
Moderate Asthma Exacerbation..................................78
7.3.6.2.
Severe Asthma Exacerbation .....................................79
7.4.
Health Outcomes........................................................................................79
7.4.1.
Work Productivity and Activity Impairment-Specific Health 
Problem (WPAI-SHP) ..................................................................79
7.5.
Safety .........................................................................................................80
7.5.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........80
7.5.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................80
7.5.1.2.
Method of Detecting AEs and SAEs ...........................80
7.5.1.3.
Follow-up of AEs and SAEs........................................81


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7.5.1.4.
Cardiovascular and Death Events ..............................81
7.5.1.4.1.
Cardiovascular Events............................81
7.5.1.4.2.
Death Events..........................................81
7.5.1.5.
Pneumonia .................................................................81
7.5.1.6.
Radiography (Chest X-Rays)......................................82
7.5.1.7.
Regulatory Reporting Requirements for SAEs............82
7.5.2.
Adverse Events of Special Interest (AESIs) .................................83
7.5.3.
Pregnancy ...................................................................................84
7.5.4.
Physical Exams ...........................................................................84
7.5.5.
Vital Signs....................................................................................84
7.5.6.
Electrocardiogram (ECG).............................................................84
7.5.7.
Clinical Safety Laboratory Assessments ......................................85
7.5.8.
Paper Medical Problems/Medications Taken Worksheet .............86
7.6.
Pharmacokinetics (PK) ...............................................................................87
7.6.1.
Blood Sample Collection..............................................................87
7.6.1.1.
Pharmacokinetic Sub-study........................................87
7.6.2.
Sample Analysis ..........................................................................88
7.7.
Genetics .....................................................................................................88
8.
DATA MANAGEMENT ...........................................................................................88
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................89
9.1.
Hypotheses.................................................................................................89
9.2.
Sample Size Considerations.......................................................................90
9.2.1.
Sample Size Assumptions ...........................................................90
9.2.2.
Sample Size Sensitivity................................................................91
9.2.3.
Sample Size Re-estimation or Adjustment...................................94
9.3.
Data Analysis Considerations .....................................................................95
9.3.1.
Analysis Populations....................................................................95
9.3.2.
Interim Analysis ...........................................................................95
9.3.3.
Treatment Comparisons ..............................................................95
9.3.4.
Multiple Comparisons and Multiplicity ..........................................96
9.4.
Key Elements of Analysis Plan .................................................................100
9.4.1.
Primary Analyses.......................................................................100
9.4.2.
Secondary Analyses ..................................................................101
9.4.3.
Other Analyses ..........................................................................101
9.4.4.
Examination of Subgroups and Phenotypic Characteristics .......102
9.4.5.
Pharmacokinetic Analyses.........................................................102
9.4.6.
Exploratory Analysis ..................................................................102
10. STUDY GOVERNANCE CONSIDERATIONS......................................................102
10.1.
Posting of Information on Publicly Available Clinical Trial Registers..........102
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ......................................................................................102
10.3.
Quality Control (Study Monitoring) ............................................................103
10.4.
Quality Assurance.....................................................................................103
10.5.
Study and Site Closure .............................................................................104
10.6.
Records Retention....................................................................................104
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication ...............105
11. REFERENCES.....................................................................................................106


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12. APPENDICES......................................................................................................109
12.1.
Appendix 1 – Abbreviations and Trademarks............................................109
12.2.
Appendix 2 Liver Safety Required Actions and Follow up 
Assessments ............................................................................................112
12.3.
Appendix 3 Genetic Research ..................................................................116
12.4.
Appendix 4 Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events.............................................119
12.4.1.
Definition of Adverse Events......................................................119
12.4.2.
Definition of Serious Adverse Events.........................................120
12.4.3.
Definition of Cardiovascular Events ...........................................121
12.4.4.
Recording of AEs and SAEs ......................................................122
12.4.5.
Evaluating AEs and SAEs..........................................................122
12.4.6.
Reporting of SAEs to GSK.........................................................124
12.5.
Appendix 5 Reproduction..........................................................................125
12.5.1.
Females of Non-Reproductive Potential and Females of 
Reproductive Potential...............................................................125
12.5.2.
List of Highly Effective Methods for Avoiding Pregnancy in 
Females of Reproductive Potential (FRP)..................................125
12.5.3.
Collection of Pregnancy Information ..........................................126
12.5.4.
References ................................................................................127
12.6.
Appendix 6 Daily eDiary Questions...........................................................129
12.6.1.
Morning Questions.....................................................................129
12.6.2.
Evening Questions.....................................................................129
12.7.
Appendix 7 Country Specific Requirements..............................................132
12.7.1.
Country Specific Requirement for the Randomization of 
Subjects.....................................................................................132
12.8.
Appendix 8 Protocol Changes...................................................................133
12.8.1.
Protocol Amendment 01 ............................................................133
12.8.2.
Protocol Amendment 02 ............................................................163
12.8.3.
Protocol Amendment 03 ............................................................174
12.8.4.
Protocol Amendment 04 ............................................................181


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1.
PROTOCOL SYNOPSIS FOR STUDY 205715
Rationale
Despite availability of treatments and published guidelines, patients may have asthma 
that is inadequately controlled.  The prevalence of inadequately controlled asthma varies 
based on the definition used for control. In a sample of asthmatics visiting their 
healthcare provider for any reason, 58% of adult asthmatics were estimated to have 
uncontrolled asthma based on the Asthma Control Test (ACT, defined as an ACT score 
≤19).
The GINA guidelines recommend a long-acting muscarinic antagonist (LAMA) as an 
add-on treatment option for adults with asthma that are currently taking medium to high 
dose inhaled corticosteroid/long-acting beta2 agonist (ICS/ LABA) treatment and have a 
history of exacerbations. Exacerbations are an important endpoint in asthma therapy; 
however, symptom control is also important in determining what patients could benefit 
from step-up therapy. Data from the GlaxoSmithKline (GSK) PhIIb study 200699 
demonstrated that the LAMA Umeclidinium (UMEC), when added to the ICS fluticasone 
furoate (FF), reduced albuterol/salbutamol use and improved symptoms in a sub-group of 
subjects with the primary diagnosis of asthma. 
GSK is currently developing a once-daily ‘closed’ triple therapy of an
ICS/LAMA/LABA combination [FF/UMEC/Vilanterol (VI)] in a single device, with the 
aim of providing a new treatment option for the management of asthma by improving
lung function, health-related quality of life (HRQoL) and symptom control over 
established combination therapies. Through the comparison of a closed triple therapy to a 
standard of care ICS/LABA combination therapy this study will provide important 
information to prescribers regarding the benefit of step-up to closed triple therapy to 
patients uncontrolled on ICS/LABA.
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary
To evaluate the effects of FF/UMEC/VI  on 
lung function compared with FF/VI after 
24 weeks of treatment
Mean change from baseline in trough 
Forced Expiratory Volume in 1 second
(FEV1) at Week 24
Key Secondary
To evaluate the efficacy of FF/UMEC/VI 
compared with FF/VI
Annualized rate of moderate/severe asthma 
exacerbations
Other Secondary 
To evaluate the efficacy of FF/UMEC/VI 
compared with FF/VI

Mean change from baseline in clinic 
FEV1 at 3 hours post study 
treatment at Week 24

Mean change from baseline in 
Asthma Control Questionnaire-7 


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Objectives
Endpoints
(ACQ-7) total score at Week 24

Mean change from baseline in St. 
George's Respiratory Questionnaire 
(SGRQ) total score at Week 24

Mean change from baseline in 
Evaluating Respiratory Symptoms 
(E-RS) total score over Weeks 21 to 
24 (inclusive) of the treatment 
period
To evaluate the safety of FF/UMEC/VI 
compared with FF/VI

Incidence and type of adverse 
events

Electrocardiogram (ECG)
measurements

Vital signs

Clinical hematological and 
chemistry parameters
Overall Design
This is a phase III, randomized, double-blind, active controlled, 6-arm parallel group, 
global multicenter study evaluating FF/UMEC/VI (100/31.25/25, 100/62.5/25, 
200/31.25/25 and 200/62.5/25 micrograms [mcg]) versus FF/VI (100/25 and 200/25 
mcg), given once daily in the morning.


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Treatment Arms and Duration
As the duration of the treatment period is variable (see below for details), eligible 
subjects will be requested to participate in the study for a minimum of approximately 32 
weeks and a maximum of approximately 60 weeks (Visit 0 to the Follow-up contact, 
inclusive) during which time, subjects will complete the following 5 phases of the study:

Pre-screening: Details about the study and procedures will be explained 
through the informed consent process. The Pre-screening Visit (Visit 0) must be 
completed prior to initiating any Visit 1 procedures.

Screening / run-in: Subjects who meet all the eligibility criteria at Visit 1 
(Screening), will enter the run-in period for approximately 3 weeks in order to 
continue to assess the subject’s eligibility for the study. Subjects will take the 
last dose of their usual (i.e. pre-study) ICS/LABA asthma medication 24 hours 
prior to the Screening Visit. Subjects satisfying all inclusion/exclusion criteria 
and who have successfully completed all protocol procedures at screening will
be provided with fixed dose ICS/LABA (fluticasone/salmeterol [FSC], 250/50
mcg, via the DISKUS™ dry powder inhaler [DPI]) to take 1 inhalation twice a 
day during the 3-week run-in period, and rescue medication 
(albuterol/salbutamol) to use on an as-needed basis throughout the study.

Enrolment / stabilization: Subjects will self-administer their last dose of run-in 
FSC treatment on the morning prior to Visit 2 (i.e. 24 hours prior to the 
Enrolment Visit). At Visit 2 (the Enrolment Visit), subjects who meet all the 
eligibility criteria will be provided with fixed dose ICS/LABA 
(fluticasone/vilanterol [FF/VI], 100/25 mcg, via the ELLIPTA™ DPI) to take 
once a day during the 2-week stabilization period. The 2-week stabilization 
period is necessary in order to allow subjects to become accustomed to using the 
ELLIPTA DPI (having used the DISKUS DPI during the run-in period) as well 
as to continue to assess the subject’s eligibility for the study and collect baseline 
eDiary data.

Treatment: Subjects will self-administer their last dose of stabilization FF/VI 
treatment on the morning prior to Visit 3 (i.e. 24 hours prior to the
Randomization Visit). At Visit 3 (the Randomization Visit), subjects who meet 
all of the randomization criteria will be randomised 1:1:1:1:1:1 to one of the 
following six double-blind study treatments:

FF/UMEC/VI 100/62.5/25 mcg once daily (QD)

FF/UMEC/VI 200/62.5/25 mcg QD

FF/UMEC/VI 100/31.25/25 mcg QD

FF/UMEC/VI 200/31.25/25 mcg QD

FF/VI 100/25 mcg QD

FF/VI 200/25 mcg QD
Study treatment will be administered via the ELLIPTA DPI in the morning.


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The duration of the treatment period is variable but will be a minimum of 24 
weeks and a maximum of 52 weeks. In accordance with the protocol-defined 
visit schedule, subjects will have up to 6 on-treatment clinic visits scheduled at 
Visits 3, 4, 5, 6, 7 and 8/End of Study (EOS) (Weeks 0, 4, 12, 24, 36 and 52, 
respectively).
The date that the whole study will complete (henceforth referred to as the study 
completion date) will be determined based on the randomization date of the final 
subject in the study; the study completion date will be set at 181 days (i.e. 25 
weeks and 6 days) post the final subject’s randomization date.
To determine when the final treatment/EOS visit will occur for each randomized 
subject in this variable duration study (i.e. at Week 24, Week 36 or Week 52 of 
the treatment period), a date henceforth referred to as the transition date will be 
communicated to the study sites by GSK. GSK will communicate a provisional 
transition date to all study sites on an ongoing basis during the study, until a 
fixed actual transition date is communicated at least 20 weeks in advance of the 
selected date (unless extenuating circumstances dictate otherwise). The date 
selected by GSK as the actual transition date will always be more than 12 days 
prior to the study completion date. At the Investigator’s discretion, subjects 
should be informed of the transition date (provisional and actual) on an ongoing 
basis during the study so that their expected final treatment/EOS visit can be 
planned using the provisional transition date and then confirmed once the actual 
transition date is known.
Subjects who complete 52 weeks of study treatment prior to the actual transition 
date being communicated will have their final treatment/EOS visit at their Week 
52 clinic assessment visit.
After the actual transition date is communicated, subjects must adhere to their
study visit schedule and complete a minimum of 24 weeks of study treatment. A 
subject’s final treatment/EOS visit will be defined as follows:
–
Subjects whose Week 24 clinic assessment visit is scheduled to occur 
on or after the actual transition date (without consideration of available 
visit time-windows) will have their final treatment/EOS visit at their 
Week 24 clinic assessment visit. 
–
Subjects who have their Week 24, Week 36 or Week 52 clinic 
assessment visit scheduled to occur before the actual transition date 
(without consideration of available visit time-windows) will have their 
final treatment/EOS visit at the clinic assessment visit that is scheduled 
to occur before but closest to the actual transition date (without 
consideration of available visit time-windows).
The subject’s final treatment/EOS visit must include all assessments specified 
for Visit 8/EOS.


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
Safety follow-up: A safety follow-up telephone contact or clinic visit will be 
conducted approximately 7 days after the subject completes all of the protocol-
defined procedures for Visit 8/EOS or, if applicable, the Early Withdrawal Visit. 
A subject will be considered to have completed the study upon completion of all 
assessments and procedures for Visit 8/EOS and including a successful follow-
up contact/visit.
Type and Number of Subjects
Patients with inadequately controlled asthma (i.e. patients with an ACQ-6 score ≥1.5) 
despite treatment with maintenance asthma medication (>250 mcg/day FP or equivalent 
plus LABA).
The total number of randomized subjects required is approximately 2250, with 375 
subjects randomized to each of the 6 double-blind treatment arms.  Randomization will 
be stratified by pre-study ICS treatment strength (mid, high) at screening to ensure 
treatment balance within each stratum.
Analysis
This is a superiority study to demonstrate the add-on benefit of UMEC at two dosage 
strengths 62.5 mcg and 31.25 mcg in a single inhaler when compared to FF/VI. For each 
test on each efficacy endpoint, the null hypothesis is that there is no difference between
treatment groups. The alternative hypothesis is that there is a difference between 
treatment groups. The primary efficacy analysis for the primary endpoint of change from 
baseline in trough FEV1 will evaluate the “de facto” type estimand in the Intent-to-Treat 
population, using a mixed-model repeated measures (MMRM) analysis, including all 
trough FEV1 recorded post randomization.
2.
INTRODUCTION
2.1.
Study Rationale
The Global Initiative for Asthma guidelines [GINA 2016] recommend a long-acting 
muscarinic antagonist (LAMA) as an add-on treatment option for adults (≥18 years) with 
asthma that are currently taking medium-to-high dose inhaled corticosteroid and long-
acting beta2 agonist (ICS/LABA) maintenance therapy and have a history of 
exacerbations. Exacerbations are an important endpoint in asthma therapy; however, 
symptom control is also important in determining what patients could benefit from step-
up therapy.
GlaxoSmithKline (GSK) is currently developing a once-daily ‘closed’ triple therapy of a 
ICS/LAMA/LABA combination [fluticasone furoate (FF)/umeclidinium 
(UMEC)/vilanterol (VI)] in a single device, with the aim of providing a new treatment 
option for the management of asthma, by improving lung function, symptom control and 
health-related quality of life (HRQoL) over established combination therapies. Through
the comparison of a closed triple therapy to a standard of care ICS/LABA combination 


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therapy this study will provide important information to prescribers regarding the benefit 
of step-up to closed triple therapy to patients uncontrolled on ICS/LABA.
2.2.
Brief Background
Despite the availability of treatments and published guidelines, patients may have asthma 
that is inadequately controlled.  The prevalence of inadequately controlled asthma varies 
based on the definition used for control. In a sample of asthmatics visiting their 
healthcare provider for any reason, 58% of adult asthmatics were estimated to have 
uncontrolled asthma based on the Asthma Control Test (ACT, defined as an ACT score 
≤19) [Stanford 2010].
Consistent with these observations, an analysis of asthma patients in the United States 
(US) found that 29%-31% of asthma patients treated with high dose ICS/LABA therapy 
experienced exacerbations [Schatz 2014].  In a Dutch survey of 929 patients treated with 
high dose ICS/LABA or medium/high dose ICS/LABA and maintenance oral 
corticosteroid (OCS), who self-reported asthma or chronic obstructive pulmonary disease 
(COPD) with <10 smoking pack years, 74% of patients were classified as difficult to 
control (Asthma Control Questionnaire (ACQ) score >1.5, or experienced 
≥3 exacerbations in a year, or ≥1 hospitalization in a year).  Half (50.6%) of these 
patients had an ACQ score >1.5, 21.7% had ≥3 exacerbations in a year, and 21.7% had 
≥1 hospitalization in a year.  Based on this sample, an estimated 17.4% of the Dutch 
asthma population was estimated to be on high dose ICS/LABA or medium/high dose 
ICS/LABA and maintenance OCS and have difficult to control asthma [Hekking 2015].  
Although patients with asthma can be effectively treated with available controller 
medications, a subset of patients do not adequately respond to current standard therapy, 
as measured by symptom questionnaires (ACT, ACQ) and exacerbations.
The goal of asthma treatment is to achieve and maintain asthma control and to reduce the 
future risk of exacerbations.  ICSs are considered the most effective anti-inflammatory 
treatments for all severities of persistent asthma [National Institutes of Health (NIH)
2007; GINA 2016].  Treatment with ICS controls asthma symptoms, improves quality of 
life and lung function, decreases airway hyper-responsiveness, controls airway 
inflammation, and reduces the frequency and severity of asthma exacerbations, thereby 
reducing asthma morbidity.  The dose of ICS is selected based on the severity of the 
patient’s asthma.  In patients who are symptomatic on ICS alone, add-on therapy with 
another controller, in particular a LABA is preferred to increasing the dose of ICS to 
achieve asthma control.  The addition of a LABA to an ICS improves symptom scores, 
decreases nocturnal asthma symptoms, improves lung function and reduces the number of 
asthma exacerbations [Ducharme 2010].  Combination ICS/LABA inhalation products 
have been developed as a result of this need.  In difficult to treat persistent asthma, some 
patients continue to be symptomatic despite treatment with ICS and LABA combination 
medications and the current guidelines [GINA 2016; NIH 2007; British Thoracic Society 
/ Scottish Intercollegiate Guidelines Network (BTS/SIGN) 2016] recommend treatment 
with high-dose inhaled or oral glucocorticosteroids in combination with LABAs and/or 
additional controller medications.


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In the European Union (EU), tiotropium bromide (LAMA) is licensed as an add-on 
maintenance bronchodilator treatment in adult patients with asthma who are currently 
treated with the maintenance combination of ICS (≥800 micrograms (mcg)
budesonide/day or equivalent) and LABA and who experienced one or more severe 
exacerbations in the previous year [Spiriva Respimat Summary of Product Characteristics 
(SPC) 2016].  In the US, tiotropium bromide was recently approved for the maintenance 
treatment of asthma, in patients 12 years of age and older [Spiriva Respimat United 
States Product Insert (USPI), 2016].  The benefit of adding a LAMA to both ICS 
monotherapy and ICS/LABA fixed combination therapy was demonstrated in four Phase 
III confirmatory studies (416, 417 [Kerstjens 2012]; 418 and 419 [Kerstjens 2015]), in 
symptomatic asthma patients (ACQ score ≥1.5).  The Phase III studies supporting the 
tiotropium application showed that addition of tiotropium bromide to ICS/LABA 
maintenance therapy significantly improved lung function and reduced the risk of severe 
asthma exacerbation.
3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary
To evaluate the effects of FF/UMEC/VI  on 
lung function compared with FF/VI after 
24 weeks of treatment
Mean change from baseline in trough 
Forced Expiratory Volume in 1 second 
(FEV1) at Week 24
Key Secondary
To evaluate the efficacy of FF/UMEC/VI 
compared with FF/VI
Annualized rate of moderate/severe asthma 
exacerbations


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Objectives
Endpoints
Other Secondary 
To evaluate the efficacy of FF/UMEC/VI 
compared with FF/VI

Mean change from baseline in clinic 
FEV1 at 3 hours post study treatment at 
Week 24

Mean change from baseline in 
ACQ-7 total score at Week 24

Mean change from baseline in St. 
George's Respiratory Questionnaire 
(SGRQ) total score at Week 24

Mean change from baseline in 
Evaluating Respiratory Symptoms (E-
RS) total score over Weeks 21 to 24 
(inclusive) of the treatment period.
To evaluate the safety of FF/UMEC/VI 
compared with FF/VI

Incidence and type of adverse events
(AEs)

Electrocardiogram (ECG)
measurements

Vital signs

Clinical hematological and chemistry 
parameters
Other Objectives
To evaluate other efficacy assessments of 
FF/UMEC/VI compared with FF/VI

Mean change from baseline in clinic 
trough FEV1 over the first 24 weeks of 
the treatment period

Mean change from baseline in home 
daily trough FEV1 over the first 24 
weeks of the treatment period

Annualized rate of severe asthma 
exacerbations

Time to first severe asthma 
exacerbation

Time to first moderate/severe asthma 
exacerbation

Percent of patients meeting a 
responder threshold of 0.5 points 
improvement (decrease) from baseline 
for the ACQ-7 at Week 24

Percent of patients meeting a 


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Objectives
Endpoints
responder threshold of 0.5 points 
improvement (decrease) from baseline 
for the ACQ-6 at Week 24

Percent of patients meeting a 
responder threshold of 0.5 points 
improvement (decrease) from baseline 
for the ACQ-5 at Week 24

Percentage of patients that have 
achieved asthma control based on 
ACQ-7 (i.e. a total score 0.75) at both 
Week 12 and Week 24

Percentage of patients that have 
achieved asthma control based on 
ACQ-6 (i.e. a total score 0.75) at both 
Week 12 and Week 24

Percentage of patients that have 
achieved asthma control based on 
ACQ-5 (i.e. a total score 0.75) at both 
Week 12 and Week 24

Mean change from baseline in SGRQ
domain scores at Week 24

Percent of patients meeting a
responder threshold of ≥ 4 points 
improvement (decrease) from baseline 
for the SGRQ total score at Week 24

Mean change from baseline in E-RS 
domain scores over Weeks 21 to 24 
(inclusive) of the treatment period

Percent of patients meeting a 
responder threshold of ≥ 2 points 
improvement (decrease) from baseline 
for the E-RS total score over Weeks 21 
to 24 (inclusive) of the treatment 
period

Mean change from baseline in 
the Asthma Quality of Life 
Questionnaire (AQLQ) total score at 
Week 24

Percent of patients meeting a 
responder threshold of ≥ 0.5 points 
improvement (increase) from baseline 


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Objectives
Endpoints
for the AQLQ total score at Week 24

Mean change from baseline in morning 
(AM) pre-dose Peak Expiratory Flow 
(PEF) over the first 24 weeks of the 
treatment period

Mean change from baseline in evening 
(PM) PEF over the first 24 weeks of 
the treatment period

Mean change from baseline in the 
percentage of symptom-free days over 
the first 24 weeks of the treatment 
period 1

Mean change from baseline in the 
percentage of rescue medication-free 
days over the first 24 weeks of the 
treatment period

Mean change from baseline in daily 
rescue medication use over the first 24 
weeks of the treatment period

Unscheduled asthma-related healthcare 
resource utilization over the first 24 
weeks of the treatment period
To evaluate the systemic exposure of FF, 
UMEC and VI following FF/UMEC/VI
Area Under the Curve (AUC(0-) [=24h]), 
Cmax
To collect blood samples for a genetics 
research study
To be described in a separate document
1 Assessed using eDiary data (excluding E-RS total/domain scores and supplemental asthma questions).
4.
STUDY DESIGN
4.1.
Overall Design
This study employs a multi-centre, active-controlled, double-blind, parallel-group design.
At the conclusion of the 3-week run-in period (Visit 2), all subjects who meet the pre-
defined criteria will be enrolled to receive FF/VI (100/25 mcg via the ELLIPTA dry 
powder inhaler [DPI]) once a day, in the morning, during the 2-week stabilization period. 
At the conclusion of the stabilization period (Visit 3), all subjects who meet the pre-
defined criteria will be randomised 1:1:1:1:1:1 to receive either FF/UMEC/VI 
(100/31.25/25; 100/62.5/25; 200/31.25/25; 200/62.5/25 mcg) or FF/VI (100/25; 200/25 
mcg) via the ELLIPTA DPI once daily in the morning for the duration of the treatment 
period (see Section 4.2 for further details on study treatment assignment and duration).


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Subjects who permanently discontinue study treatment are not required to withdraw from 
the study. 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 (see Section 5.6).
4.2.
Treatment Arms and Duration
As the duration of the treatment period is variable (see Table 1 for details), eligible 
subjects will be requested to participate in the study for a minimum of approximately 32 
weeks and a maximum of approximately 60 weeks (Visit 0 to the Follow-up contact, 
inclusive) during which time, subjects will complete the 5 phases of the study described 
in Table 1:
Table 1
Study Phases
Phase
Phase Title
Duration
Description
1
Pre-screening
Between 1 
and 14 
days
Details about the study and procedures
will be explained through the informed 
consent process. The Pre-screening Visit 
(Visit 0) must be completed prior to 
initiating any Screening Visit (Visit 1)
procedures. Subjects will continue 
treatment with their regular (i.e. pre-
study) asthma medication(s) during the 
pre-screening period; however, 
medications that are prohibited within a 
specified time interval prior to Visit 1 are 


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Phase
Phase Title
Duration
Description
defined in Section 6.9.2.
2
Screening / Run-in
3 weeks
Subjects who meet all the eligibility 
criteria at Visit 1 (Screening), will enter 
the run-in period for approximately 3 
weeks to continue assessing the subject’s 
eligibility for the study. Subjects will take 
the last dose of their regular (i.e. pre-
study) ICS/LABA asthma medication 
24 hours prior to Visit 1 (i.e. 24 hours 
prior to the Screening Visit). Subjects 
satisfying all inclusion/exclusion criteria 
and who have successfully completed all 
protocol procedures at screening will be 
provided with fixed dose ICS/LABA 
(fluticasone/salmeterol [FSC], 250/50 
mcg, via the DISKUS DPI) to take twice 
a day during the 3-week run-in period, 
and rescue medication 
(albuterol/salbutamol) to use on an as-
needed basis throughout the study. Those
subjects that are not eligible to continue 
in the study at the end of the 3-week run-
in period (Visit 2) will be deemed run-in 
failures (see Section 5.5).
3
Enrolment/Stabilizati
on
2 weeks
Subjects will self-administer their last 
dose of run-in FSC treatment on the 
morning prior to Visit 2 (i.e. 24 hours 
prior to the Enrolment Visit). At Visit 2 
(Enrolment), subjects who meet all the 
eligibility criteria will be provided with 
fixed dose ICS/LABA 
(fluticasone/vilanterol [FF/VI], 100/25 
mcg, via the ELLIPTA DPI) to take once 
a day, in the morning, during the 2-week 
stabilization period. Those subjects that 
are not eligible to continue in the study at 
the end of the 2-week stabilization period
(Visit 3) will be deemed stabilization
failures (see Section 5.5).
4
Treatment
A 
minimum 
of 24 
weeks; a 
Subjects will self-administer their last 
dose of stabilization FF/VI treatment on 
the morning prior to Visit 3 (i.e. 24 
hours prior to the Randomization Visit). 


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Phase
Phase Title
Duration
Description
maximum 
of 52 
weeks
At Visit 3 (Randomization), subjects who 
meet all of the randomization criteria will 
be randomized 1:1:1:1:1:1 to one of the 
following six double-blind study 
treatments during the treatment period
(stratified by pre-study ICS treatment 
strength [mid, high]):
FF/UMEC/VI 100/62.5/25 mcg once 
daily (QD)
FF/UMEC/VI 200/62.5/25 mcg QD
FF/UMEC/VI 100/31.25/25 mcg QD
FF/UMEC/VI 200/31.25/25 mcg QD
FF/VI 100/25 mcg QD
FF/VI 200/25 mcg QD
Study treatment will be administered via 
the ELLIPTA DPI in the morning. 
The duration of the treatment period is 
variable but will be a minimum of 24 
weeks and a maximum of 52 weeks. In 
accordance with the protocol-defined 
visit schedule, subjects will have up to 6 
on-treatment clinic visits scheduled at 
Visits 3, 4, 5, 6, 7 and 8/End of Study 
(EOS) (Weeks 0, 4, 12, 24, 36 and 52, 
respectively).
The date that the whole study will 
complete (henceforth referred to as the 
study completion date) will be 
determined based on the randomization 
date of the final subject in the study; the 
study completion date will be set at 
181 days (i.e. 25 weeks and 6 days) post 
the final subject’s randomization date. 
To determine when the final 
treatment/EOS visit will occur for each 
randomized subject in this variable 
duration study (i.e. at Week 24, Week 36 
or Week 52 of the treatment period), a 
date henceforth referred to as the 
transition date will be communicated to 


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Phase
Phase Title
Duration
Description
the study sites by GSK. GSK will 
communicate a provisional transition 
date to all study sites on an ongoing basis 
during the study, until a fixed actual
transition date is communicated at least 
20 weeks in advance of the selected date
(unless extenuating circumstances dictate 
otherwise). The date selected by GSK as 
the actual transition date will always be 
more than 12 days prior to the study 
completion date. At the Investigator’s 
discretion, subjects should be informed of 
the transition date (provisional and 
actual) on an ongoing basis during the 
study so that their expected final 
treatment/EOS visit can be planned using 
the provisional transition date and then 
confirmed once the actual transition date 
is known.
Subjects who complete 52 weeks of study 
treatment prior to the actual transition 
date being communicated will have their 
final treatment/EOS visit at their Week 
52 clinic assessment visit.
After the actual transition date is 
communicated, subjects must adhere to 
their study visit schedule and complete a 
minimum of 24 weeks of study treatment. 
A subject’s final treatment/EOS visit will 
be defined as follows:
–
Subjects whose Week 
24 clinic assessment 
visit is scheduled to 
occur on or after the 
actual transition date 
(without consideration 
of available visit time-
windows) will have 
their final 
treatment/EOS visit at 
their Week 24 clinic 


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Phase
Phase Title
Duration
Description
assessment visit. 
–
Subjects who have 
their Week 24, Week 
36 or Week 52 clinic 
assessment visit 
scheduled to occur 
before the actual 
transition date 
(without consideration 
of available visit time-
windows) will have 
their final 
treatment/EOS visit at 
the clinic assessment 
visit that is scheduled 
to occur before but 
closest to the actual 
transition date 
(without consideration 
of available visit time-
windows).
The subject’s final treatment/EOS visit 
must include all assessments specified for 
Visit 8/EOS.
5
Safety Follow-up
See 
Descriptio
n column 
for details
A safety follow-up telephone contact or 
clinic visit will be conducted 
approximately 7 days after the subject 
completes all of the protocol-defined 
procedures for Visit 8/EOS or, if 
applicable, the Early Withdrawal visit. A 
subject will be considered to have 
completed the study upon completion of 
all assessments and procedures for Visit 
8/EOS and including a successful follow-
up contact/visit.


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4.3.
Type and Number of Subjects
Patients with inadequately controlled asthma (i.e. patients with an ACQ-6 score ≥1.5 
prior to enrolment at Visit 2) despite treatment with maintenance asthma medication.
The total number of randomized subjects required is approximately 2250, with 375
subjects randomized to each of the 6 double-blind treatment arms (to ensure 
approximately 337 evaluable subjects per treatment arm; see Section 9.2.1 ).  
Randomization will be stratified by pre-study ICS treatment strength (mid, high) at 
screening to ensure treatment balance within each stratum.
4.4.
Design Justification
This study will use a multicenter, randomized, double-blind, active-controlled, parallel-
group design. This is a well-established design to evaluate the efficacy and safety of an 
investigational drug.  A placebo arm is not included as it is not considered appropriate for 
patients with inadequately controlled asthma despite maintenance therapy. In addition, 
the comparison of interest is FF/UMEC/VI versus FF/VI for each UMEC dose. 
FF/UMEC and UMEC/VI treatment arms are not included as these are not fixed dose 
combinations that are currently available for asthma patients.
The aim of the study is to evaluate if patients with inadequately controlled asthma, 
despite treatment with ICS/LABA, can benefit from a once-daily fixed dose combination 
of FF/UMEC/VI.  Eligible subjects must have the clinical need for daily asthma 
maintenance therapy, namely ICS/LABA, for at least 12 weeks prior to Screening.  
Subjects are required to wash-out their current asthma maintenance therapy and switch to 
FSC (250/50 mcg twice daily) treatment, administered via the DISKUS DPI, during the 
3-week run-in period.  The 3-week run-in period is necessary to standardize asthma 
maintenance therapy in all patients prior to the baseline collection period (i.e. the 
stabilization period). Subjects will take their last dose of FSC the morning prior to the 
Enrolment Visit (i.e. 24 hours prior to Visit 2). At Visit 2, all eligible subjects will be 
enrolled into the study to receive FF/VI (100/25 mcg QD) for 2 weeks during the 
stabilization period; at Visit 3 eligible subjects will be randomised to receive one of the 
possible six double-blind study treatments during the treatment period. The 2-week 
stabilization period is necessary in order to establish baseline symptoms for all subjects, 
on the same once-daily maintenance therapy, as well as to allow subjects to become 
accustomed to using the ELLIPTA DPI (having previously used the DISKUS DPI during 
the run-in period). Subjects will take their last dose of stabilization period FF/VI
treatment the morning prior to commencing double-blind study treatment at Visit 3 (i.e. 
24 hours prior to the Randomization Visit).
As this is not primarily a severe asthma exacerbation study, up to 52 weeks of data will 
be sufficient to demonstrate a robust and persistent treatment effect for a bronchodilator. 
A minimum treatment period of 24 weeks is considered to be of adequate duration in 
order to assess the efficacy of FF/UMEC/VI, compared to FF/VI, in terms of lung 
function and other efficacy endpoints.  To allow evaluation of the effect of FF/UMEC/VI 
on non-lung function endpoints, including moderate/severe exacerbations, the data from 
the two FF/UMEC/VI arms for each fixed UMEC dose will be pooled and compared to 


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pooled data from the two FF/VI arms. The integrated analyses will provide a more 
precise overall estimate for the treatment effect size of the addition of UMEC to FF/VI 
and also allows us to determine the effect of adding UMEC to the current standard of care 
(which could be FF100/VI or FF200/VI). In this instance, pooling is considered similar to 
respiratory studies evaluating the effect of one medication in a separate inhaler added to 
the patient’s existing therapy approach which isn’t standardized.
A treatment period of up to 52 weeks is considered to be of suitable duration to collect 
asthma exacerbation data as well as to assess the safety of FF/UMEC/VI (given the 
extensive studies conducted in the mono- and dual-therapy programs for FF, UMEC, 
FF/VI, and UMEC/VI).
4.5.
Dose Justification
The FF/UMEC/VI (100/31.25/25, 100/62.5/25, 200/31.25/25 and 200/62.5/25 mcg) doses 
were selected based on the doses licensed by the Food and Drug Administration (FDA)
and the European Medicines Agency (EMA) for FF/VI for the treatment of asthma, and 
data from GSK Phase IIb study 200699, a dose-ranging study that evaluated four doses of 
umeclidinium in combination with fluticasone furoate (100 mcg) over a 4-week treatment 
period, in reversible subjects with fixed airway obstruction.  The primary endpoint was 
the change from baseline in trough FEV1. 
The 200699 data showed UMEC 62.5 mcg to be an effective dose; after 4 weeks of 
treatment in patients with a primary diagnosis of asthma, an increase in trough FEV1 of 
136ml (milliliters) was observed in those subjects treated with FF/UMEC (100/62.5 mcg) 
compared to those subjects treated with FF (100 mcg) alone. However, study 200699 did 
not assess the UMEC 31.25 mcg dose, therefore, the efficacy and safety profile of this 
dose will be assessed in this study. No safety signal was identified with any of the UMEC 
doses (15.6, 62.5, 125 and 250 mcg) evaluated in the 200699 study.
4.6.
Benefit: Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with GSK 
GW685698+GW642444+GSK573719 (FF/UMEC/VI) can be found in the Investigator’s 
Brochure (IB).  Marketed ICS/LABA products will be used for run-in (FSC), stabilization 
(FF/VI) and comparator (FF/VI) treatments.  These products will be used in accordance 
with the product labels and further details on the experience with these products can be 
found in the Investigator Brochures and/or product labelling.  The following section 
outlines the risk assessment and mitigation strategy for this protocol:


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4.6.1.
Risk Assessment
Potential Risk of Clinical
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [e.g., GSK685698+GSK573719+GW642444] 
Cardiovascular effects of 
UMEC and VI
UMEC
Cardiovascular effects are a potential class effect associated with anti-
muscarinic therapies.
In the UMEC/VI clinical development program in Chronic Obstructive 
Pulmonary Disease (COPD) patients, UMEC/VI was generally well tolerated. 
Overall, a low number of atrial arrhythmias were reported based on 12-lead 
ECGs, Holter ECGs, or AEs, of which some occurred with a higher incidence 
in active treatment groups compared to placebo.  There was no additive 
effect with the combination over individual components.  Few of these 
findings were reported as Serious Adverse Events (SAEs) and none were 
fatal. In a narrow* Major Adverse Cardiac Event (MACE) analysis, the 
incidence of non-fatal myocardial infarction (Medical Dictionary for 
Regulatory Activities (MedDRA) Preferred Terms (PTs) of myocardial 
infarction and acute myocardial infarction) was low (<1%) across all 
treatment groups, although small imbalances in exposure adjusted frequency 
were observed between UMEC- and VI containing treatment groups when 
compared with placebo and tiotropium.  There was no obvious dose 
relationship or additive effect from the combination.  Whether this represents 
a true effect is difficult to determine due to the small numbers. During clinical 
studies in COPD (62.5 and 125mcg daily dose of UMEC) and in Healthy 
Volunteers (in the Thorough QT study, UMEC 500mcg daily dose), no effect 
was observed on heart rate, blood pressure or QT.
Mitigation strategy for UMEC and VI:
- Exclusion criteria as specified in Section 
5.2 of the protocol
- Collection of cardiovascular risk factors 
and medical history at baseline
- ECGs as per schedule in Section 7.1 .
- Vital sign assessments (heart rate and 
blood pressure) as per schedule in 
Section 7.1 .
- Cardiovascular AEs and Serious AEs 
(SAEs) will be captured on the electronic 
Case Report Form (eCRF) (see Section 
12.4.3)
- Protocol defined stopping criteria as per 
Section 5.6.  
-MACE analysis
-Instream review of blinded data


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Potential Risk of Clinical
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
VI
In the FF/VI clinical development program in patients with COPD, the 
cardiovascular safety profile of VI and FF/VI was broadly consistent with the 
known pharmacology of LABAs in patients with COPD. VI at doses up to 
100mcg in healthy subjects and subjects with asthma or COPD was not 
consistently associated with clinically relevant or statistically significant 
effects on blood pressure after either single or repeat dose administration. 
Data from Thorough QT (TQT) studies with FF, FF/VI and UMEC/VI suggest 
that, at the doses to be used in phase III studies, the closed triple 
(FF/UMEC/VI) is unlikely to cause clinically relevant effects on QTc1. No 
difference in QTcF2 was observed between UMEC/VI 125/25mcg or UMEC 
500mcg and placebo. UMEC/VI 500/100mcg increased QTcF on average by 
8.2msec (milliseconds) (90% Confidence Intervals (CI): 6.2, 10.2) at 30 
minutes (min) only. A lack of effect was demonstrated for QTcF with FF/VI 
200/25mcg (for 7 days). At a supratherapeutic dose of FF/VI (800/100mcg 
for 7 days), the largest mean time-matched difference from placebo was 9.6 
msec (90% CI: 7.2, 12.0) at 30 min only.
1 QT interval corrected for heart rate
2 QT interval corrected for heart rate by Fridericia’s formula
Anticholinergic effects 
(including constipation 
nausea, dry mouth, 
glaucoma, raised intraocular 
pressure and blurred vision, 
urinary retention) 
In clinical studies in COPD, few anticholinergic effects were associated with 
UMEC; those observed included dry mouth, constipation and cough.  Based 
on post-marketing experience dysgeusia has been added as an Adverse 
Drug Reaction (ADR) for inhaled UMEC and UMEC/VI.  
ICS has a similar class risk of glaucoma and elevated intraocular pressure 
(IOP); however, these effects occur by a different mechanism that is not 
- Patients with known narrow-angle 
glaucoma, prostatic hyperplasia or 
bladder outflow obstruction that, in the 
opinion of the Investigator, 
contraindicates study participation or use 
of an inhaled anticholinergic, will be 
excluded from participating in the study.


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Potential Risk of Clinical
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
expected to be synergistic or additive when FF is used in combination with 
UMEC.
- Review AEs/SAEs
Systemic ICS effects
-Adrenal suppression
-Cataracts & glaucoma
-Reduced bone mineral 
density and associated 
fractures
No studies have shown a clinically relevant effect of FF/VI or FF on the 
hypothalamic pituitary axis (HPA). This includes a formal HPA study 
(HZA106851), which assessed the effects of FF/VI 100/25 and 200/25 on 
serum cortisol and 24 hour urinary cortisol excretion, and multiple studies 
with COPD and asthma subjects which monitored urinary cortisol.  
During clinical development of FF & FF/VI no events of Adrenal Suppression 
were reported.  There has been no evidence for adrenal suppression based 
on post-marketing experience to date.  
In study HZA106839 (FF/VI, FF and fluticasone propionate (FP) in subjects 
with asthma), formal Ophthalmic assessments were conducted (including 
Lens Opacities Classification System III (LOCS III) evaluations for ocular 
opacities) throughout the study. This study showed no apparent effects on 
lens opacification, compared to baseline assessment.  
During studies in both subjects with asthma and COPD, no associated affect 
on ocular disorders was observed.  Spontaneous data received to date does 
not alter the understanding of this risk.  
A decrease in bone mineral density and the risk of fractures is a class 
concern for any ICS-containing product for the treatment of COPD.
In two replicate 12 month studies in the FF/VI clinical program, in a total of 
3,255 patients with COPD, the incidence of bone fractures overall was low in 
all treatment groups, with a higher incidence in all FF/VI groups (2%) 
compared with the VI 25 mcg group (<1%).  Although there were more 
- Review AEs/SAEs
- The occurrence of bone fractures will be 
recorded in the eCRF.


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Potential Risk of Clinical
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
fractures in the FF/VI groups compared with the VI 25 mcg group, fractures 
typically associated with corticosteroid use (e.g., spinal 
compression/thoracolumbar vertebral fractures, hip and acetabular fractures) 
occurred in <1% of the FF/VI and VI treatment arms.  In an integrated 
analysis of 11 studies in asthma with FF/VI (7,034 patients) and 10 studies in 
asthma with FF (6,219), the incidence of fractures with FF/VI and FF was 
1%, and usually associated with trauma.  
Pneumonia
While ICS use is a recognised risk for pneumonia in patients with COPD.  A 
clear causal relationship between inhaled corticosteroid use and pneumonia 
in subjects with asthma has not been established.  
In an 18 study integration in the FF/VI asthma program, the incidence of 
pneumonia (adjusted for exposure) observed with FF/VI 100/25 and FF 100 
(8.5/1000 patient years and 9.6/1000 patient years, respectively) was similar 
to that seen with placebo (9.3/1000 patient years). A higher incidence in the 
FF/VI 200/25 and FF 200 arms were observed (18.3/1000 patient years and 
23.6/1000 patient years, respectively). However, the 95% CIs were wide and 
overlapped across all treatment groups, including placebo. Few of the 
pneumonia events led to hospitalisation with either strength, and there were 
no observed differences in the incidence of serious events between the two 
treatment strengths.  The risk of pneumonia in asthma patients is very low 
and is consistent with the risk of other ICS.  
Pneumonia experience with UMEC
In the All Clinical Studies grouping, the incidence of on-treatment AEs in the 
Pneumonia and lower respiratory tract infection (LRTI) adverse events of 
special interest (AESI) category with UMEC 62.5 mcg (1%; 34.6/1000SY) 
Exclusion criteria:
- Immune suppression (e.g., Human 
Immunodeficiency Virus [HIV], Lupus) or 
other risk factors for pneumonia 
(e.g.,neurological disorders affecting 
control of the upper airway, such as 
Parkinson’s Disease, Myasthenia Gravis).
-Subjects at potentially high risk (e.g., 
very low body mass index [BMI] or 
severely malnourished) will only be 
included at the discretion of the 
Investigator.
Medical history will also be taken for 
pneumonia in previous 12 months, 
including recording of any episodes 
resulting in hospitalisation.  
The occurrence of pneumonia will be 
recorded in the eCRF.


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Potential Risk of Clinical
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
was similar to placebo (1%; 34.8/1000SY) and lower than the incidence 
reported in the UMEC 125 mcg (3%; 72.6/1000SY). A higher incidence of 
AEs in the Pneumonia AESI category was reported for UMEC 125 mcg (2%; 
37.4/1000SY) compared with UMEC 62.5 mcg (<1%; 19.8/1000SY) and 
placebo (<1%; 10.7/1000SY). The proportion of subjects with SAEs in the 
Pneumonia AESI category was similar between both UMEC treatment 
groups, UMEC 62.5 mcg (<1%; 4.9/1000SY) and UMEC 125 mcg (<1%; 
17.6/1000SY) and placebo (<1%; 10.7/1000SY).
Where possible a chest X-ray should be 
performed to confirm a diagnosis, 
whenever a subject has a suspected 
pneumonia.
All reports of pneumonia (radiographically 
confirmed and unconfirmed) must be 
reported as an AE or SAE, if applicable 
Instream review of blinded data.
Review of AESI relevant for pneumonia 
using pre-specified MedDRA preferred 
terms. AE terms relating to other Lower 
Respiratory Tract Infections (excluding 
pneumonia) will also be reviewed.  
Hypersensitivity
There have been post-marketing reports of hypersensitivity reactions with 
FF/VI and UMEC/VI, including anaphylaxis, angioedema, rash, and urticaria.  
The formulation also contains lactose.
Subjects with a history of allergy or 
hypersensitivity to any corticosteroid, 
anticholinergic/muscarinic receptor 
antagonist, beta2-agonist, lactose/milk 
protein or magnesium stearate are 
excluded from participation in this study
(Section 5.2). 
-Review AEs/SAEs
Paradoxical bronchospasm
Rare reports of paradoxical bronchospasm (which may be life threatening) 
with other inhalational products have been reported.  There have been rare 
post-marketing reports of paradoxical bronchospasm with FF/VI and 
UMEC/VI.
Patients will undergo regular medical 
assessments during clinical studies.  
-Review AEs/SAEs
Pregnancy and lactation
There are no data from the use of FF/UMEC/VI in pregnant women.  
Females who are pregnant or breast-


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Potential Risk of Clinical
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
There has been limited pregnancy exposure to FF and FF/VI in humans. 
Animal studies have shown reproductive toxicity after administration of 
corticosteroids and beta2-agonists. 
There is a limited amount of data from the use of umeclidinium in pregnant 
women. Animal studies do not indicate direct or indirect harmful effects with 
respect to reproductive toxicity. 
There is limited information on the excretion of FF or VI or their metabolites 
in human milk. However, other corticosteroids and beta2-agonists are 
detected in human milk.
It is unknown whether umeclidinium is excreted in human milk. The excretion 
of FF/UMEC/VI in breast milk has not been evaluated. A risk to breastfed 
newborns/infants cannot be excluded. 
feeding are not eligible for participating in 
the study.
Females of child-bearing potential will 
need to follow the contraceptive 
requirements that are specified in 
Appendix 5.


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The risks for FF/VI and FSC are recognised pharmacological class effects associated with 
ICS and LABA therapy.  The experience with these individual products is provided in the 
respective Investigator Brochures and/or product labelling.  Some of the experience with 
FF/VI is described in the table above, as this provides relevant background information 
for FF/UMEC/VI.
4.6.2.
Benefit Assessment
The addition of UMEC to FF/VI in asthma has the potential to improve lung function, 
reduce moderate/severe exacerbations and improve quality of life in patients whose 
asthma is inadequately controlled on ICS/LABA alone.  Current asthma treatment 
guidelines recommend the addition of a LAMA (tiotropium) for patients that are 
uncontrolled on ICS/LABA (GINA 2016 Steps 4 and 5); the availability of the 
FF/UMEC/VI combination would therefore be consistent with this approach.  The 
combination in a closed triple combination would provide the convenience of once daily 
dosing and reduce the need for multiple inhalers.  Furthermore, the availability of two 
doses of FF would allow the prescriber to select an appropriate inhaled corticosteroid 
dose based on the severity of asthma.
4.6.3.
Overall Benefit: Risk Conclusion
Taking into account the measures taken to minimize risk to subjects participating in the 
study, the potential risks identified in association with FF/UMEC/VI are justified by the 
anticipated benefits that may be afforded to subjects with asthma.  
The current experience with FF, UMEC and VI and the lack of significant safety 
concerns relevant to the asthma population provides reassurance that the potential risks 
associated with the known pharmacology of these compounds is offset by the potential 
significant benefits that are afforded to patients inadequately controlled on ICS/LABA 
therapy.  
The ICS/LABAs used as run-in (FSC) and stabilization/comparator arms (FF/VI) are 
both marketed for the treatment of asthma and have favourable benefit-risk profiles.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the IB.
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
In order to confirm eligibility, a review of each subject’s medical records must be 
performed prior to a subject entering the run-in period. To be enrolled into the study, 
subjects will be required to meet the additional enrolment criteria (see Section 5.3); to be 


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randomised into the study, subjects will be required to meet the additional randomization
criteria (see Section 5.4).
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE
1. 18 years of age or older at the time of signing the informed consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Diagnosis: Subjects with a diagnosis of asthma as defined by the National Institutes 
of Health [NIH 2007] at least one year prior to Visit 0.
3. Symptomatic: Subjects with inadequately controlled asthma (ACQ-6 score ≥1.5) 
despite ICS/LABA maintenance therapy at Visit 1.
4. Asthma Control: Note: please refer to the SRM for guidance on the following:
In the 1 year prior to Visit 1:

A documented healthcare contact for acute asthma symptoms
OR

A documented temporary change in asthma therapy for acute asthma 
symptoms, according to a pre-specified asthma action plan (or equivalent)
5. Current Asthma Maintenance Therapy: Subjects are eligible if they have required 
daily ICS/LABA for at least 12 weeks prior to Visit 0 with no changes to 
maintenance asthma medications during the 6 weeks immediately prior to Visit 0
(including no changes to a stable total dose of ICS of >250 mcg/day fluticasone 
proprionate [FP, or equivalent]).
Examples of acceptable doses of commonly prescribed ICS medication are provided 
in the GINA guidelines [GINA 2016], [BTS/SIGN 2016], [Japanese guidelines for 
adult asthma 2017].  Dosing regimen (once or twice daily to equal the total daily 
dose) should be restricted to the current local product labels/treatment guidelines.
6. Spirometry:
A best pre-bronchodilator morning (AM) FEV1 ≥30% and <85% of the predicted 
normal value at Visit 1.  Predicted values will be based upon the European 
Respiratory Society (ERS) Global Lung Function Initiative [Quanjer 2012].
7. Reversibility of Disease: airway reversibility defined as ≥12% and ≥200 mL increase 
in FEV1 between 20 and 60 minutes following 4 inhalations of albuterol/salbutamol 
aerosol at Visit 1.
Note: If the subject does not meet the above reversibility criteria at Visit 1 then the 
reversibility assessment may be repeated once within 7 days of Visit 1 if either 
criteria a) or b) are met:


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a) ≥9% increase in FEV1 between 20 and 60 minutes following 4 inhalations of 
albuterol/salbutamol aerosol at Visit 1.
b) Documented evidence of a reversibility assessment within 1 year prior to 
Visit 1 which demonstrated a post-bronchodilator increase in FEV1 of ≥12% 
and ≥200 mL.
Should the subject successfully demonstrate airway reversibility (defined as ≥12% 
and ≥200 mL increase in FEV1 between 20 and 60 minutes following 4 inhalations of 
albuterol/salbutamol aerosol) at the second attempt then, provided that all other 
eligibility criteria assessed at Visit 1 are met, the subject may enter the 3-week run-
in period (see Section 7.3.4.1).
8. Short-Acting β2 Agonists (SABAs): All subjects must be able to replace their current 
SABA inhaler with albuterol/salbutamol aerosol inhaler at Visit 1 as needed for the 
duration of the study. Subjects must be judged capable of withholding 
albuterol/salbutamol for at least 6 hours prior to study visits.
SEX
9. Male or Eligible Female, defined as having documentation of non-reproductive 
potential or reproductive potential as follows:
A female subject is eligible to participate if she is not pregnant (as confirmed by a 
negative serum human chorionic gonadotrophin (hCG) test), not lactating, is not 
planning on becoming pregnant during the study and at least one of the following 
conditions applies:
a. Non-reproductive potential defined as:
Pre-menopausal females with one of the following:
Documented tubal ligation
Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion 
Hysterectomy
Documented Bilateral Oophorectomy
Postmenopausal defined as 12 months of spontaneous amenorrhea with an 
appropriate clinical profile (e.g., age appropriate, >45 years, in the absence of 
hormone replacement therapy). In questionable cases for women <60 years of 
age, a blood sample with simultaneous follicle stimulating hormone and 
estradiol falling into the central laboratory’s postmenopausal reference range is 
confirmatory.  Females under 60 years of age, who are on hormone replacement 
therapy (HRT) and whose menopausal status is in doubt, are required to use a 
highly effective method to avoid pregnancy if they wish to continue their HRT 
during the study.  Otherwise, they must discontinue HRT to allow confirmation 
of post-menopausal status prior to study enrolment. For most forms of HRT, at 
least 2 to 4 weeks will elapse between the cessation of therapy and the blood 
draw; this interval depends on the type and dosage of HRT.  Following 


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confirmation of their post-menopausal status, subjects can resume use of HRT 
during the study without use of a highly effective method to avoid pregnancy.
b. Reproductive potential and agrees to follow one of the options listed in the 
Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of 
Reproductive Potential (FRP) (see Appendix 5) from the screening visit until after 
the last dose of study medication and completion of the follow-up visit.
c. The Investigator is responsible for ensuring that subjects understand how to 
properly use these methods of contraception.
INFORMED CONSENT
10. Informed Consent: Able to give written informed consent prior to participation in 
the study, which will include the ability to comply with the requirements and 
restrictions listed in the consent form and in this protocol.  Subjects must be able to 
read, comprehend, and write at a level sufficient to complete study related materials.
5.2.
Exclusion Criteria
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardise the scientific integrity of the study, regulatory acceptability or subject safety.  
Therefore, adherence to the criteria as specified in the protocol is essential.
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
1. Pneumonia: Chest X-ray documented pneumonia in the 6 weeks prior to Visit 1.
2. Asthma Exacerbation: Any asthma exacerbation requiring a change in maintenance 
asthma therapy in the 6 weeks prior to Visit 1.
Note: Subjects requiring a temporary change in asthma therapy (e.g., oral 
corticosteroids or increased dose of ICS) to treat an exacerbation in the 6 weeks 
prior to Visit 1 are not explicitly excluded at Visit 1 provided that, at the 
Investigator’s discretion, the subject’s condition is stable after they have resumed
their pre-exacerbation maintenance asthma therapy (without modification) and they 
are considered appropriate for enrolment into this study of up to 12 months’ 
duration.
3. Chronic Obstructive Pulmonary Disease: Subjects with the diagnosis of chronic 
obstructive pulmonary disease, as per Global Initiative for Chronic Obstructive Lung 
Disease (GOLD 2016) guidelines, including all of the following:

History of exposure to risk factors (i.e., especially tobacco smoke, 
occupational dusts and chemicals, smoke from home cooking and heating 
fuels). For personal tobacco use, see exclusion criterion number 14: Tobacco 
Use;


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AND

A post-albuterol/salbutamol FEV1/Forced Vital Capacity (FVC) ratio of <0.70 
and a post-albuterol/salbutamol FEV1 of ≤70% of predicted normal values;
AND

Onset of disease ≥40 years of age
4. Concurrent respiratory disorders: Subjects with current evidence of pneumonia, 
active tuberculosis, lung cancer, significant bronchiectasis, sarcoidosis, lung fibrosis, 
pulmonary hypertension, interstitial lung diseases or other active pulmonary diseases 
or abnormalities other than asthma.
5. Risk Factors for Pneumonia: immune suppression (e.g., HIV, Lupus) or other risk 
factors for pneumonia (e.g., neurological disorders affecting control of the upper 
airway, such as Parkinson’s Disease, Myasthenia Gravis).
Patients at potentially high risk (e.g., very low BMI, severely malnourished, or very 
low FEV1) will only be included at the discretion of the Investigator.
6. Other diseases/abnormalities: Subjects with historical or current evidence of 
clinically significant cardiovascular, neurological, psychiatric, renal, hepatic, 
immunological, gastrointestinal, urogenital, nervous system, musculoskeletal, skin, 
sensory, 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 efficacy or safety analysis if the 
disease/condition exacerbated during the study.
7. Unstable liver disease as defined by the presence of ascites, encephalopathy, 
coagulopathy, hypoalbuminaemia, esophageal or gastric varices or persistent 
jaundice, cirrhosis, known biliary abnormalities (with the exception of Gilbert’s 
syndrome or asymptomatic gallstones).  Note: Chronic stable hepatitis B and C are 
acceptable if the subject otherwise meets entry criteria
8. Clinically significant ECG abnormality: Evidence of a clinically significant 
abnormality in the 12-lead ECG performed during screening. The Investigator will 
determine the clinical significance of each abnormal ECG finding in relation to the 
subject’s medical history and exclude subjects who would be at undue risk by 
participating in the trial. An abnormal and clinically significant finding is defined as a 
12-lead tracing that is interpreted as, but not limited to, any of the following:

Atrial Fibrillation (AF) with rapid ventricular rate >120 beats per minute 
(BPM);

Sustained or nonsustained ventricular tachycardia (VT);

Second degree heart block Mobitz type II and third degree heart block (unless 
pacemaker or defibrillator had been inserted);

QTcF ≥500 msec in patients with QRS <120 msec and QTcF ≥530 msec in 
patients with QRS ≥120 msec
9. Unstable or life threatening cardiac disease: subjects with any of the following at 
Screening (Visit 1) would be excluded:

Myocardial infarction or unstable angina in the last 6 months

Unstable or life threatening cardiac arrhythmia requiring intervention in the 


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last 3 months

New York Heart Association (NYHA) Class IV Heart failure [American Heart 
Association 2016]
10. Antimuscarinic effects: Subjects with a medical condition such as narrow-angle 
glaucoma, urinary retention, prostatic hypertrophy or bladder neck obstruction should 
only be included if in the opinion of the Investigator the benefit outweighs the risk 
and that the condition would not contraindicate study participation.
11. Cancer: Subjects with carcinoma that has not been in complete remission for at least 
5 years. Subjects who have had carcinoma in situ of the cervix, squamous cell 
carcinoma and basal cell carcinoma of the skin would not be excluded based on the 
5 year waiting period if the subject has been considered cured by treatment.
12. Questionable validity of consent: Subjects with a history of psychiatric disease, 
intellectual deficiency, poor motivation or other conditions that will limit the validity 
of informed consent to participate in the study.
CONCOMITANT MEDICATIONS/TREATMENTS
13. Medication prior to spirometry: Subjects who are medically unable to withhold 
their albuterol/salbutamol for the 6-hour period required prior to spirometry testing at 
each study visit.
RELEVANT HABITS
14. Tobacco Use: Subjects who are:

Current smokers (defined as subjects who have used inhaled tobacco products 
within the 12 months prior to Visit 1 [i.e., cigarettes, e-cigarettes/vaping, cigars or 
pipe tobacco]).

Former smokers with a smoking history of 10 pack years (e.g., 
20 cigarettes/day for 10 years).
Note: Refer to the SRM for the formula for calculating pack years.
15. Drug/alcohol abuse: Subjects with a known or suspected history of alcohol or drug 
abuse within the last 2 years.
CONTRAINDICATIONS 
16. Allergy or Hypersensitivity: A history of allergy or hypersensitivity to any 
corticosteroid, anticholinergic/muscarinic receptor antagonist, beta2-agonist, 
lactose/milk protein or magnesium stearate.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
17. Non-compliance: Subjects at risk of non-compliance, or unable to comply with the 
study procedures.  Any infirmity, disability, or geographic location that would limit 
compliance for scheduled visits.
18. Affiliation with Investigator site: Study Investigators, sub-Investigators, study 
coordinators, employees of a participating Investigator or study site, or immediate 
family members of the aforementioned that is involved with this study.


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19. Inability to read: In the opinion of the Investigator, any subject who is unable to read 
and/or would not be able to complete study related materials.
5.3.
Enrolment Criteria
Those subjects who meet the enrolment criteria will be enrolled into the study until the 
target of approximately 2250 randomised subjects is reached.  
At the end of the run-in period, study subjects must fulfil the following additional criteria 
in order to be enrolled in the study and enter the 2-week stabilization period:
5.3.1.
Inclusion Criteria for Enrolment
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
1. Inadequately controlled asthma: Subjects with inadequately controlled asthma 
(ACQ-6 score ≥1.5) at Visit 2.
2. Percent-predicted FEV1: A best pre-bronchodilator morning (AM) FEV1 ≥30% and 
<90% of the predicted normal value at Visit 2. Predicted values will be based upon 
the ERS Global Lung Function Initiative [Quanjer 2012].
CONCURRENT CONDITIONS/MEDICAL HISTORY
3. Liver function tests at Visit 1:

alanine aminotransferase (ALT) <2 x upper limit of normal (ULN)

alkaline phosphatase  ≤1.5 x ULN

bilirubin ≤1.5 x ULN (isolated bilirubin >1.5 x ULN is acceptable if bilirubin 
is fractionated and direct bilirubin <35%)
eDIARY
4. Compliance with completion of the Daily eDiary reporting defined as completion of 
all questions/assessments on 4 of the last 7 days during the run-in period.
5.3.2.
Exclusion Criteria for Enrolment
CONCURRENT CONDITIONS/MEDICAL HISTORY
1. Respiratory Infection: Occurrence of a culture-documented or suspected bacterial or 
viral infection of the upper or lower respiratory tract, sinus or middle ear during the 
run-in period that led to a change in asthma management or, in the opinion of the 
Investigator, is expected to affect the subject’s asthma status or the subject’s ability to 
participate in the study.
2. Severe asthma exacerbation: Evidence of a severe exacerbation during screening or 
the run-in period, defined as deterioration of asthma requiring the use of systemic 
corticosteroids (tablets, suspension, or injection) for at least 3 days1 or an in-patient 
hospitalization or emergency department visit due to asthma that required systemic 
corticosteroids.


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1 For subjects on maintenance systemic corticosteroids, at least double the existing 
maintenance dose for at least 3 days is required.
CONCOMITANT MEDICATIONS/TREATMENTS
3. Asthma medication: Changes in asthma medication (excluding run-in medication 
and albuterol/salbutamol inhalation aerosol provided at Visit 1).
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
4. Laboratory test abnormalities: Evidence of clinically significant abnormal 
laboratory tests during screening or run-in which are still abnormal upon repeat 
analysis and are not believed to be due to disease(s) present.  Each Investigator will 
use his/her own discretion in determining the clinical significance of the abnormality.
5.4.
Randomization Criteria
Those subjects who meet the randomization criteria will be randomised into the study 
until the target of approximately 2250 randomised subjects is reached.  
At the end of the stabilization period, study subjects must fulfil the following additional 
criteria in order to be randomized into the study and enter the treatment period:
5.4.1.
Inclusion Criteria for Randomization
eDIARY
1. Compliance with completion of the Daily eDiary reporting defined as completion of 
all questions/assessments on 4 of the last 7 days during the stabilization period.
5.4.2.
Exclusion Criteria for Randomization
CONCURRENT CONDITIONS/MEDICAL HISTORY
1. Respiratory Infection: Occurrence of a culture-documented or suspected bacterial or 
viral infection of the upper or lower respiratory tract, sinus or middle ear during the 
stabilization period that led to a change in asthma management or, in the opinion of 
the Investigator, is expected to affect the subject’s asthma status or the subject’s 
ability to participate in the study.
2. Severe asthma exacerbation: Evidence of a severe exacerbation during enrolment or 
the stabilization period, defined as deterioration of asthma requiring the use of 
systemic corticosteroids (tablets, suspension, or injection) for at least 3 days1 or an in-
patient hospitalization or emergency department visit due to asthma that required 
systemic corticosteroids.
1 For subjects on maintenance systemic corticosteroids, at least double the existing 
maintenance dose for at least 3 days is required.
CONCOMITANT MEDICATIONS/TREATMENTS
3. Asthma medication: Changes in asthma medication (excluding stabilization period
medication provided at Visit 2 and albuterol/salbutamol inhalation aerosol provided at 


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Visit 1).
5.5.
Pre-Screening/Screening/Run-in Failures
A subject will be assigned a subject number at the time the informed consent is signed.
The study interactive response technology (IRT) system (RAMOS NG) will be contacted 
to report pre-screen failures. The following information will be collected in the eCRF for 
subjects who are pre-screen failures:

Date of informed consent form (ICF) signature

Demographic information including race, age and gender

Subject number

Serious Adverse Event information only for any SAE considered as related to 
study participation

Investigator signature page
For the purposes of this study pre-screen failures, screening failures, run-in failures and 
stabilization failures will be defined as follows:

Pre-screening failures: those subjects that sign the informed consent document 
but do not have a Visit 1 (Screening) procedure.

Screening failures: those subjects that complete at least one Visit 1 (Screening) 
procedure but do not enter the run-in period. 
A subject who completes Visit 1 assessments and is dispensed the study 
medication for the run-in period is considered to have entered the run-in period.

Run-in failures: those subjects that enter the run-in period but do not 
subsequently enter the stabilization period.
Any subject who completes the run-in period and then meets the eligibility 
criteria and is dispensed the stabilization period study medication at Visit 2 is 
considered to have entered the stabilization period.

Stabilization failures: those enrolled subjects that enter the stabilization period 
but are not subsequently randomised at Visit 3.
RAMOS NG will be contacted to report pre-screening, screening, run-in and stabilization 
failures.
In order to ensure transparent reporting of screen/run-in failure subjects, meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements, and 
respond to queries from Regulatory authorities, a minimal set of screen/run-
in/stabilization failure information is required including demography, screen/run-
in/stabilization failure details, eligibility criteria, and any SAEs (see Section 7.5.1.7 and 
Appendix 4). Further details are provided in the study-specific eCRF completion 
guidelines document.


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Re-screening of subjects will be permitted; however, advance written approval to proceed 
with re-screening a subject must be obtained from the Medical Monitor (for contact 
details, see the medical monitor/Sponsor Information Page at the beginning of this 
protocol).
5.6.
Withdrawal/Stopping Criteria
5.6.1.
Withdrawal from Study Treatment
Subjects who withdraw from double-blind 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 (Section 7.1; refer to the SRM for further details). 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.
A subject may be withdrawn from study treatment at any time. A reason for premature 
discontinuation of study treatment (e.g., AE, lack of efficacy [including acute moderate 
or severe asthma exacerbation], protocol deviation, Investigator discretion, consent 
withdrawn etc.) must be captured in the eCRF.
A subject must be withdrawn from study treatment if any of the following stopping 
criteria are met: 

Liver Chemistry: Meets any of the protocol-defined liver chemistry stopping criteria 
(see Section 5.6.3 and Appendix 2)

QTc: Meets any of the protocol-defined stopping criteria (see Section 5.6.4)

Pregnancy: Positive pregnancy test (see Section 7.5.3 and Appendix 5)
5.6.2.
Withdrawal from the Study
A subject may withdraw from the study at any time at his/her own request; if a subject 
withdraws from the study, he/she may request destruction of any samples taken, and the 
Investigator must document this in the site study records.
A reason for the withdrawal from the study must be captured in the eCRF.
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as 
soon as possible. 

The site must 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. 

In cases where the 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 


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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, only then will he/she be considered 
to have withdrawn from the study with a primary reason of “Lost to Follow-up”.
In the event of early withdrawal from the study, every effort should be made to have the 
subject to return to the clinic for an Early Withdrawal Visit and Safety Follow-up, and to 
return all study related materials. Assessments to be performed during the Early 
Withdrawal Visit and the Safety Follow-up contact are described in the Time and Events 
table (Section 7.1).
5.6.3.
Liver Chemistry Stopping Criteria
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). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Liver chemistry stopping criteria 1-5 are defined in Appendix 2.
5.6.3.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed.
5.6.4.
QTc Stopping Criteria
Details on performing ECG assessments can be found in Section 7.5.6.

The QT interval corrected for heart rate by Fredericia’s formula (QTcF) must be 
used for each individual subject to determine eligibility for and discontinuation 
from the study.  This formula may not be changed or substituted for the duration 
of the study.

QTcF must continue to be used for all subjects for all QTc data being collected 
for data analysis.  Safety ECGs and other non-protocol specified ECGs are an 
exception.  

The QTcF should be based on single or averaged QTcF values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording period.

For this study, the following QTc stopping criteria will apply:

QTcF>500 msec or uncorrected QT>600 msec

Bundle branch block: QTcF530 msec

Change from baseline: QTcF> 60msec


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5.7.
Subject and Study Completion
The date that the whole study will complete (henceforth referred to as the study 
completion date) will be determined based on the randomization date of the final subject 
in the study; the study completion date will be set at 181 days (i.e. 25 weeks and 6 days) 
post the final subject’s randomization date. 
To determine when the final treatment/EOS visit will occur for each randomized subject 
in this variable duration study (i.e. at Week 24, Week 36 or Week 52 of the treatment 
period), a date henceforth referred to as the transition date will be communicated to the 
study sites by GSK. GSK will communicate a provisional transition date to all study sites 
on an ongoing basis during the study, until a fixed actual transition date is communicated 
at least 20 weeks in advance of the selected date (unless extenuating circumstances 
dictate otherwise). The date selected by GSK as the actual transition date will always be 
more than 12 days prior to the study completion date. At the Investigator’s discretion, 
subjects should be informed of the transition date (provisional and actual) on an ongoing 
basis during the study so that their expected final treatment/EOS visit can be planned 
using the provisional transition date and then confirmed once the actual transition date is 
known.
Subjects who complete 52 weeks of study treatment prior to the actual transition date 
being communicated will have their final treatment/EOS visit at their Week 52 clinic 
assessment visit.
After the actual transition date is communicated, subjects must adhere to their study visit 
schedule and complete a minimum of 24 weeks of study treatment. A subject’s final 
treatment/EOS visit will be defined as follows:
–
Subjects whose Week 24 clinic assessment visit is scheduled to occur 
on or after the actual transition date (without consideration of available 
visit time-windows) will have their final treatment/EOS visit at their 
Week 24 clinic assessment visit. 
–
Subjects who have their Week 24, Week 36 or Week 52 clinic 
assessment visit scheduled to occur before the actual transition date 
(without consideration of available visit time-windows) will have their 
final treatment/EOS visit at the clinic assessment visit that is scheduled 
to occur before but closest to the actual transition date (without 
consideration of available visit time-windows).
The subject’s final treatment/EOS visit must include all assessments specified for 
Visit 8/EOS.
A safety follow-up telephone contact or clinic visit will be conducted approximately 
7 days after the subject completes all of the protocol-defined procedures for Visit 8/EOS 
or, if applicable, the Early Withdrawal Visit. A subject will be considered to have 
completed the study upon completion of all assessments and procedures for Visit 8/EOS
and including a successful follow-up contact/visit.


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6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.
The DISKUS device will be used during the 3-week run-in period of the study.  The 
DISKUS is a plastic inhalation delivery system containing a single-foil blister strip of a 
powder formulation of FSC intended for oral inhalation only.  Each blister on the single-
foil strip within the device contains 250 mcg of microfine FP and 72.5 mcg of microfine 
salmeterol xinafoate salt, equivalent to 50 mcg of salmeterol base, in 12.5 mg of 
formulation containing lactose (see Table 2).  Each blister contains 1 complete dose of 
both medications. FSC will be sourced from local commercial stock.  If not available 
locally, GSK will source centrally. The contents of the label will be in accordance with 
all applicable regulatory requirements.


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Table 2
Description of FSC Inhalation Powder in DISKUS
Formulation
Single strip
FP and salmeterol blended with lactose
Dosage Form
DPI with 60 doses (1 strip with 60 blisters)
Unit Dose Strengths
250 mcg FP and 50 mcg salmeterol per blister
Physical description
Dry white powder
Route of Administration
Inhaled
The ELLIPTA device will be used during the stabilization period and the treatment 
period.  The ELLIPTA DPI is a moulded plastic two-sided device that can hold two 
individual blister strips.  Descriptions of the study treatments administered via the 
ELLIPTA are provided in Table 3.
Table 3
Description of Study Treatment Inhalation Powder in ELLIPTA
FF/UMEC/VI 
First strip 
Second strip 
FF blended with lactose
UMEC and VI blended with lactose 
and magnesium stearate
Dosage Form 
ELLIPTA with 30 doses (2 strips with 30 blisters per strip)
Unit Dose 
Strengths 
100 or 200 mcg per blister
UMEC 31.25 or 62.5 mcg per 
blister, VI 25 mcg per blister
Physical 
description 
Dry white powder
Dry white powder
Route of 
Administration 
Inhaled
FF/VI
First strip
Second strip
FF blended with lactose
VI blended with lactose and 
magnesium stearate
Dosage Form 
ELLIPTA with 30 doses (2 strips with 30 blisters per strip)
Unit Dose 
Strengths 
100 or 200 mcg per blister
25 mcg per blister
Physical 
description 
Dry white powder
Dry white powder
Route of 
Administration 
Inhaled
Each subject will be instructed on the proper use of the ELLIPTA and will inhale once 
from the ELLIPTA each morning for the duration of the 2-week stabilization period and 
the subsequent treatment period.
Subjects will self-administer their first dose of stabilization-period study treatment 
(FF/VI 100/25 mcg) in the clinic during the enrolment visit (Visit 2) and will continue to 
administer FF/VI at approximately the same time each morning for the duration of the 
stabilization period.


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At Visit 3, the stabilization period ELLIPTA device will be collected from all subjects 
and an ELLIPTA device containing one of the double-blind study treatments (see Section 
6.2) will be provided; subjects will self-administer their first dose of double-blind study 
treatment in the clinic during Visit 3 and will continue to administer double-blind study 
treatment at approximately the same time each morning for the duration of the treatment 
period. Subjects will take their last dose of study treatment in the clinic during Visit 
8/EOS (or at the Early Withdrawal Visit, if applicable) and a safety follow-up will be 
conducted approximately one week later.
On the morning of all study clinic visits after Visit 1 (i.e. the day of Visit 2 onwards), 
subjects will refrain from taking their morning dose of study treatment until instructed to 
do so by clinic personnel.
Albuterol/salbutamol via metered-dose inhaler (MDI) will be issued for reversibility 
testing at Visit 1.  An albuterol/salbutamol MDI for as needed (prn) use throughout the 
study will be provided starting at Visit 1; at the Investigator’s discretion, more than one 
MDI may be provided at any one time. Albuterol/salbutamol will be sourced from local 
commercial stock.  If not available locally, GSK will source centrally. The contents of the 
label will be in accordance with all applicable regulatory requirements.
Ipratropium via MDI will be issued for reversibility testing at Visit 2. Ipratropium will be 
sourced from local commercial stock. The contents of the label will be in accordance 
with all applicable regulatory requirements.
At the Investigator’s discretion, provision will be made from Visit 11 onwards for 
subjects to temporarily receive inhaled fluticasone propionate (FP) to treat the symptoms 
of a moderate asthma exacerbation (see Section 6.9.1.1 and Section 7.3.6.1). Treatment 
start and stop dates will be recorded in the eCRF.
1Note: Should the subject use the provided FP prior to randomization at Visit 3, the 
enrolment or randomization concomitant medication exclusion criteria would be met (see 
Section 5.3.2 and Section 5.4.2).
FP will be sourced from local commercial stock; if not available locally, GSK will source 
centrally. The contents of the label will be in accordance with all applicable regulatory 
requirements. A record of the number of FP-containing inhalers dispensed to each subject 
must be maintained and reconciled with study treatment records.
Under normal conditions of handling and administration, study treatment is not expected 
to pose significant safety risks to site staff.  Take adequate precautions to avoid direct eye 
or skin contact and the generation of aerosols or mists. Notify the monitor of any 
unintentional occupational exposure.  A Material Safety Data Sheet (MSDS) describing 
the occupational hazards and recommended handling precautions will be provided to site 
staff if required by local laws or will otherwise be available from GSK upon request.
Study treatment must be stored in a secure area under the appropriate physical conditions 
for the product.  Access to the investigational product will be limited to the Investigator
and authorized site staff.  Investigational product must be dispensed to or administered by 
only those subjects enrolled in the study and in accordance with the protocol.


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6.1.1.
Study Treatment, albuterol/salbutamol, ipratropium and FP 
Return
All used and unused study treatment, albuterol/salbutamol, ipratropium and FP will be 
returned to GSK at the end of the study to be available for disposal.  In some instances 
for sites outside the US, study supplies will be disposed of locally either by the site, the 
country medical department or third-party vendor.  Detailed instructions for the return of 
the study drug can be found in the SRM.
If any DISKUS or ELLIPTA fails to function properly, the subject should return to the 
clinic as soon as possible to obtain a new inhaler.  The site will use the IRT system 
(RAMOS NG) to obtain a new treatment pack number for the subject and dispense a new 
study treatment kit from the site’s study treatment supply as instructed by the IRT 
system.
In addition, any DPI or MDI that fails to function properly must be identified and 
returned to GSK for testing.  Details of the failure will be documented in the eCRF.
6.2.
Treatment Assignment
Subjects will be assigned to study treatment in accordance with the randomization 
schedule. The randomization code will be generated by GSK using a validated 
computerized system. Subjects will be randomized using an IRT system (RAMOS NG). 
The study will use central-based randomization to allocate treatments(see Appendix 7 for 
country-specific requirements). Once a randomization number is assigned to a subject it 
cannot be reassigned to any other subject in the study.
Following the 2-week stabilization period and subject to satisfying all eligibility criteria, 
subjects will be stratified by pre-study ICS treatment dosage strength (mid, high) at 
screening and randomized 1:1:1:1:1:1 to one of the following six double-blind treatments 
for the duration of the treatment period: 

FF/UMEC/VI 100/62.5/25 mcg QD

FF/UMEC/VI 200/62.5/25 mcg QD

FF/UMEC/VI 100/31.25/25 mcg QD

FF/UMEC/VI 200/31.25/25 mcg QD

FF/VI 100/25 mcg QD

FF/VI 200/25 mcg QD
The duration of double-blind treatment for each subject is a minimum of 24 weeks and a 
maximum of 52 weeks (see Section 4.2); on the morning of each scheduled clinic study
visit, subjects will refrain from taking their morning dose of study treatment until 
instructed to do so by clinic personnel. Study treatment will be taken at the clinic at 
approximately the same time of day as taken at the Enrolment Visit (Visit 2). On the 
other days during the treatment period (i.e. “non-clinic days”), subjects will be instructed 
to take their study treatment each morning at approximately the same time. Each 
Investigator will be provided with sufficient supplies to conduct the trial. Additional 


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treatment packs will be supplied as needed to the sites. Details of how to use the IRT 
system (RAMOS NG) to randomize subjects and manage study treatment supplies 
(including dispensing) is provided in the RAMOS NG IRT manual and SRM.
6.3.
Blinding
This will be a double-blind study and the following will apply. 

The Investigator or treating physician may unblind a subject’s treatment 
assignment only in the case of an emergency OR in the event of a serious 
medical condition when knowledge of the study treatment is essential for the 
appropriate clinical management or welfare of the subject as judged by the 
Investigator. 

Investigators have direct access to the subject’s individual study treatment. 

It is preferred (but not required) that the Investigator first contacts the Medical 
Monitor or appropriate GSK study personnel to discuss options before unblinding 
the subject’s treatment assignment. 

If GSK personnel are not contacted before the unblinding, the Investigator must 
notify GSK as soon as possible after unblinding, but without revealing the 
treatment assignment of the unblinded subject, unless that information is 
important for the safety of subjects currently in the study. 

The date and reason for the unblinding must be fully documented in the eCRF 
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any subject with an SAE. If the SAE requires that an expedited 
regulatory report be sent to one or more regulatory agencies, a copy of the report, 
identifying the subject’s treatment assignment, may be sent to Investigators in accordance 
with local regulations and/or GSK policy. Subjects will not be withdrawn from the study.
6.4.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.5.
Preparation/Handling/Storage/Accountability

Only subjects enrolled in the study may receive study treatment and only 
authorized site staff may supply study treatment.  All study treatments must be 
stored in a secure environmentally controlled and monitored (manual or 
automated) area in accordance with the labelled storage conditions with access 
limited to the Investigator and authorized site staff. 

The Investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e. receipt, reconciliation and final disposition records).  


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
Further guidance and information for 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.  Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. In the case 
of unintentional occupational exposure notify the monitor, Medical Monitor 
and/or GSK study contact.

A 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.
6.6.
Compliance with Study Treatment Administration
When subjects are dosed at the study site, they will receive study treatment under medical 
supervision.  The date and time of each dose administered in the clinic will be recorded in 
the eCRF.  The dose of study treatment and study subject identification will be confirmed 
at the time of dosing by a member of the study site staff. 
At scheduled clinic visits, subject compliance with study treatment administration since 
the previous scheduled clinic visit will be assessed by recording the number of doses 
remaining in the DISKUS or ELLIPTA, as applicable, in the eCRF (see the SRM for 
details), by reviewing the eDiary (see Section 7.3.5) and by querying the subject, as 
necessary. Subjects should be 80% to 120% compliant on taking study treatment
between each pair of scheduled and consecutive on-treatment clinic visits. Subjects who 
fall outside this range should be re-educated on treatment compliance by their site. This 
re-education should be documented in the subject’s source document. 
When subjects self-administer study treatment(s) at home (i.e. not at the study site), 
compliance with study treatment administration should be monitored by the Investigator 
(or designee) by reviewing the transmitted eDiary data via the vendor-provided portal 
(see Section 7.3.5); subjects should be immediately contacted for re-education on 
treatment compliance if non-compliance (as assessed by the Investigator or designee) is 
observed. This re-education should be documented in the subject’s source document.
A record of the number of DISKUSs and ELLIPTAs dispensed to each subject must be 
maintained and reconciled with study treatment and compliance records.  Study treatment 
start and stop dates will be recorded in the eCRF.
6.7.
Treatment of Study Treatment Overdose
An overdose is defined as a dose greater than the total doses described above which 
results in clinical signs and symptoms.  These should be recorded by the Investigator on 
the AE/SAE pages.  In the event of an overdose of study treatment, the Investigator
should use clinical judgment in treating the overdose and contact the GSK medical 
monitor.
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 


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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.
6.8.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because other treatment options are available.
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.
6.9.
Concomitant Medications and Non-Drug Therapies
All asthma medications used within approximately 6 weeks prior to pre-screening (Visit 
0) and during the study (including the post-treatment period) should be recorded in the 
eCRF.
All non-asthma medications taken during the study (after randomization including post-
treatment) and any changes to concomitant medications will be recorded in the eCRF. 
Note: Study provided albuterol/salbutamol and ipratropium should not be recorded in the 
eCRF; however non-study supplied albuterol/salbutamol or ipratropium will be recorded 
in the eCRF. The use of study provided and non-study provided FP and additional 
asthma medications added temporarily for moderate asthma exacerbations will be 
recorded in the eCRF.
The minimum requirement is that the drug name, dose, route and the dates of 
administration are to be recorded.
Medications initiated after completion of the assessments at Visit 8/EOS or the Early 
Withdrawal Visit will not be recorded in the eCRF unless taken to treat an AE or asthma 
exacerbation. Detailed information of permitted and prohibited medications is included in 
the SRM for your reference. Subjects who have completed the Early Withdrawal Visit
are allowed to use any medications prescribed by the Investigator or primary care 
physician.
6.9.1.
Permitted Medications and Non-Drug Therapies
6.9.1.1.
Permitted Asthma Medications
In addition to study treatment, the following medications are permitted during this study:

Study-provided albuterol/salbutamol will be dispensed at Visit 1 for use as relief 
medication throughout the duration of the study. Subjects must be judged capable 
of withholding albuterol/salbutamol for at least 6 hours prior to study visits.

Systemic corticosteroids (≤5 milligrams (mg)/day of prednisone [or an equivalent 
dose of an alternative systemic corticosteroid]) will be permitted provided that 
treatment was initiated at least 12 weeks prior to Visit 1, remains stable for the 8 


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weeks prior to Visit 1 and the subject remains in the maintenance phase (i.e., it is 
not weaned) throughout the study (the only exception being the treatment of 
moderate/severe asthma exacerbations [see below]).

Anti-immunoglobulin E (IgE) (e.g. omalizumab) treatment will be permitted 
provided that treatment was initiated at least 16 weeks prior to Visit 1 and the 
subject remains in the maintenance phase throughout the study.

Anti-interleukin (IL)-5 (e.g. mepolizumab) treatment will be permitted provided 
that treatment was initiated at least 16 weeks prior to Visit 1 and the subject 
remains in the maintenance phase throughout the study.
Temporary additions in medications are permitted for the treatment of moderate 
asthma exacerbations (see Section 7.3.6.1) at the Investigator’s/treating physician’s 
discretion. Asthma exacerbations should be treated in line with national and 
international recommendations and local medical standards. Asthma medications 
permitted on a temporary basis to treat a moderate asthma exacerbation include but are 
not limited to the following (the Medical Monitor may be contacted for additional 
guidance, see the medical monitor/Sponsor Information Page):

An increase in ICS dose (including but not limited to the use of study-
provided FP which may be used by the subject at a total daily dose deemed 
appropriate by the Investigator/treating physician).

Systemic corticosteroids (tablets, suspension or injection) for no more than 2 
days (or an increase in systemic corticosteroid dose for those subjects 
receiving maintenance systemic corticosteroids for no more than 2 days).

An Investigator-advised change in SABA use (i.e., routinely scheduled versus 
as needed use).

Leukotriene receptor antagonists (LTRAs) and leukotriene modifiers.

Oral theophylline.

By definition, a severe asthma exacerbation will be treated with systemic 
corticosteroid (tablets, suspension or injection) for at least 3 consecutive days 
(or at least double the existing maintenance dose of systemic corticosteroid, if 
applicable, for at least 3 consecutive days). See Section 7.3.6.2.
6.9.1.2.
Permitted Non-Asthma Medications
The following medications are permitted during this study:

Medications for rhinitis (e.g., intranasal corticosteroids, antihistamines [including 
ocular and intranasal], cromolyn, nedocromil, nasal decongestants)
Note: Use of these medications should be captured on the concomitant medication 
pages of the eCRF prior to ECG measurements.

Antibiotics for short term treatment of acute infections. Long term treatment with 
topical or ophthalmic antibiotics are permitted.


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
Decongestants: Subjects may take decongestants during the study, but these are 
disallowed for 24 hours prior to ECG measurements.

Immunotherapy: Immunotherapy for the treatment of allergies is allowed during 
the study provided it was initiated 4 weeks prior to Visit 1 and subjects remain in 
the maintenance phase for the duration of the study.

Topical and ophthalmic corticosteroids.

Systemic and ophthalmic beta-blockers: Administer with caution as systemic 
beta-blockers block the pulmonary effect of beta-agonists and may produce severe 
bronchospasm in patients with reversible obstructive airways disease. 
Cardioselective beta-blockers should be considered, although they also should be 
administered with caution.

Localized corticosteroid injections (e.g. intra-articular and epidural).

Tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs). 
(Administer with extreme caution as they may potentiate the effects of beta-
agonists on the cardiovascular system, including QTc prolongation)

Diuretics.  (Caution is advised in the co-administration of beta-agonists with non-
potassium sparing diuretics as this may result in ECG changes and/or 
hypokalemia)

Cytochrome P450 3A4 (CYP3A4) inhibitors (Caution should be exercised when 
considering the coadministration of long-term ketoconazole and other known 
strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, 
itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, 
troleandomycin, voriconazole) because increased systemic corticosteroid and 
increased cardiovascular adverse effects may occur)

Vaccinations (Influenza vaccine, Pneumonia vaccine, Shingles vaccine, etc.) 
(Administration of influenza and pneumonia vaccines should be considered based 
on clinical discretion of the Investigator and local/national guidelines. Current 
influenza vaccines and pneumonia vaccines will be captured on the concomitant 
medication pages of the eCRF)
All medications for other disorders may be continued throughout the study provided their
use would not be expected to affect the subjects’ lung function or safety assessments
(e.g., cardiac measurements). However, no systemic corticosteroids for other conditions 
will be permitted.
6.9.1.3.
Permitted Non-Drug Therapies
Continuous Positive Airway Pressure (CPAP) for the treatment of obstructive sleep apnea 
is permitted if initiated at least 6 weeks prior to the Screening Visit (Visit 1) and the 
subject continues CPAP treatment throughout the study.  This treatment must be captured 
in the eCRF.
6.9.2.
Prohibited Medications and Non-Drug Therapies
Use of the medications listed in Table 4 is not permitted during the study.


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Table 4
Concomitant Medications
Medication
No use during the study and/or within the 
following time interval before Visit 1
Inhaled short-acting anticholinergics
6 hours
Inhaled short-acting anticholinergics+ Short-
acting beta agonist combination
6 hours
Inhaled long-acting anticholinergics other than 
study treatment
2 days. Temporary use during the study is also 
prohibited.
Immunosuppressive medications
including immunomodulators
12 weeks
Inhaled long-acting beta2-agonists (e.g., 
salmeterol, formoterol) or combination products 
containing inhaled long-acting beta2-agonists 
(e.g., Seretide, Symbicort)
Inhaled very long-acting beta2-agonists, 
(Indacaterol, Olodaterol)
Oral long-acting beta2-agonists (e.g., 
bambuterol) 
These must be withheld at least 24h prior to 
Visit 1; other than the study treatment, they will 
not be permitted during the study (including for 
temporary use).
10 days prior to Visit 1 for Indacaterol and 
Olodaterol component. Temporary use during 
the study is also prohibited.
Inhaled short-acting beta2-agonist (rescue 
albuterol/salbutamol will be provided and is 
permitted during the study)
6 hours (including all study visits)
Theophyllines, slow-release
bronchodilators, ketotifen, nedocromil sodium,
sodium cromoglycate, roflumilast
48 hours. Temporary use will be permitted 
during the study to treat moderate asthma 
exacerbations
Anti-leukotrienes
48 hours. Temporary use will be permitted 
during the study to treat moderate asthma 
exacerbations
Medical marijuana
6 months. Medical marijuana administered via 
the inhaled route is strictly prohibited. Other 
routes of administration of medical marijuana 
are also prohibited UNLESS written permission
is obtained from the Medical Monitor prior to 
Visit 1.
Any other investigational drug
30 days or within 5 drug half-lives of the 
investigational drug (whichever is longer)


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7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table Section 7.1.


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7.1.
Time and Events Table
Protocol Activity
Pre-
Screen1
Screen
Run-in
Enrolment
Stabilization
Treatment Period
Follow-up
Fixed Treatment Period
Variable Treatment 
Period
Visit
0
11
22
33
Random-
ization
4
5
6
7
8
End of Study 
(EOS)
Early 
Withdrawal 
(EW)4
Safety
Follow-up Contact
Study Day
-49 to -36
-35
-14
1
29
85
169
253
365
Week
-6 to -7
-5
-2
0
4
12
24
36
52
1 week after Visit 
8/EOS or EW Visit
Window
-5/+2d
-5/+2d
-5/+2d
-5/+2d
-5/+2d
-1/+4d
Written Informed 
Consent5
x
Genetic Informed 
Consent6
x
Demography
x
Medical history
x
Asthma History7
x
Exacerbation History
x
Concomitant 
Medication 
Assessment
x
x
x
x
x
x
x
x
x
x
x
Inclusion/Exclusion 
criteria
x
x
Smoking History and 
status
x
Randomization8
x
Register visit in IRT 
(RAMOS NG)9
x
x
x
x
x
x
x
x
x
x
x
Efficacy 
Assessments
Global Assessment of 
Severity10
x
x
x
x
x
x
x


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Protocol Activity
Pre-
Screen1
Screen
Run-in
Enrolment
Stabilization
Treatment Period
Follow-up
Fixed Treatment Period
Variable Treatment 
Period
Visit
0
11
22
33
Random-
ization
4
5
6
7
8
End of Study 
(EOS)
Early 
Withdrawal 
(EW)4
Safety
Follow-up Contact
Study Day
-49 to -36
-35
-14
1
29
85
169
253
365
Week
-6 to -7
-5
-2
0
4
12
24
36
52
1 week after Visit 
8/EOS or EW Visit
Window
-5/+2d
-5/+2d
-5/+2d
-5/+2d
-5/+2d
-1/+4d
Global Assessment of 
Response to 
Treatment10
x
x
x
x
x
x
ACQ10
x
x
x
x
x
x
x
x
x
SGRQ10
x
x
x
x
x
x
AQLQ10
x
x
x
x
x
x
x
Healthcare Resource 
Utilization10
x
x
x
x
x
x
x
E-RS + asthma 
symptoms + PEF + 
home FEV110, 11
x
eDiary/device training 
and registration
x
Dispense eDiary
x
Collect eDiary
x
x
eDiary review
x
x
x
x
x
x
x
x
Dispense paper 
Medical 
Problems/Medications 
Taken worksheet
x
x
x
x
x
x
x
x
x
x


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Protocol Activity
Pre-
Screen1
Screen
Run-in
Enrolment
Stabilization
Treatment Period
Follow-up
Fixed Treatment Period
Variable Treatment 
Period
Visit
0
11
22
33
Random-
ization
4
5
6
7
8
End of Study 
(EOS)
Early 
Withdrawal 
(EW)4
Safety
Follow-up Contact
Study Day
-49 to -36
-35
-14
1
29
85
169
253
365
Week
-6 to -7
-5
-2
0
4
12
24
36
52
1 week after Visit 
8/EOS or EW Visit
Window
-5/+2d
-5/+2d
-5/+2d
-5/+2d
-5/+2d
-1/+4d
Review paper Medical 
Problems/Medications 
Taken worksheet
x
x
x
x
x
x
x
x
x
x
Pre-dose spirometry 
(clinic)
x12
x12
x13
x12
x12
x13
x12
x13
x13, 14
Post-dose spirometry 
(clinic)
x13
x13
x13
x13, 14
Reversibility test
x15
x16
Exacerbation 
assessment
x
x
x
x
x
x
x
x
x
Health Outcomes
WPAI-SHP10
x
x
x
x
x
Safety Assessments
Physical Examination
x
x
x
x
Vital Signs
x17
x
x
x
x
x
x
x
x
ECG18
x
x
x
x
x
Adverse Events
x
x
x
x
x
x
x
x
x
x


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Protocol Activity
Pre-
Screen1
Screen
Run-in
Enrolment
Stabilization
Treatment Period
Follow-up
Fixed Treatment Period
Variable Treatment 
Period
Visit
0
11
22
33
Random-
ization
4
5
6
7
8
End of Study 
(EOS)
Early 
Withdrawal 
(EW)4
Safety
Follow-up Contact
Study Day
-49 to -36
-35
-14
1
29
85
169
253
365
Week
-6 to -7
-5
-2
0
4
12
24
36
52
1 week after Visit 
8/EOS or EW Visit
Window
-5/+2d
-5/+2d
-5/+2d
-5/+2d
-5/+2d
-1/+4d
Serious Adverse 
Events
x
x
x
x
x
x
x
x
x
x
x
FeNO19
x
Laboratory 
Assessments
Hematology and 
clinical chemistry
x
x
x
x
x
Total Serum IgE
x
Urinalysis
x
x
x
x
x
Pharmacogenetic 
sample20
x
Serum pregnancy test
X21
x21
x21
x21
Urine pregnancy 
test21
x
x
x
x
x
PK samples
x22
x23
x23, 24
x23
Study Treatment
Dispense ICS/LABA 
run-in medication
x25


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Protocol Activity
Pre-
Screen1
Screen
Run-in
Enrolment
Stabilization
Treatment Period
Follow-up
Fixed Treatment Period
Variable Treatment 
Period
Visit
0
11
22
33
Random-
ization
4
5
6
7
8
End of Study 
(EOS)
Early 
Withdrawal 
(EW)4
Safety
Follow-up Contact
Study Day
-49 to -36
-35
-14
1
29
85
169
253
365
Week
-6 to -7
-5
-2
0
4
12
24
36
52
1 week after Visit 
8/EOS or EW Visit
Window
-5/+2d
-5/+2d
-5/+2d
-5/+2d
-5/+2d
-1/+4d
Assess run-in 
medication 
compliance
x
Collect ICS/LABA 
run-in medication
x
Dispense ICS/LABA 
stabilization 
medication
x
Assess stabilization 
medication 
compliance
x
Collect ICS/LABA 
stabilization 
medication
x
Administer double-
blind study 
treatment26
x
x
x
x
x
x
x27
Dispense double-
blind study treatment 
(Scheduled)
x
x
x
x
x
Dispense double-
blind study treatment 
(Unscheduled)
x28
Assess double-blind 
study treatment 
compliance
x
x
x
x
x
x


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Protocol Activity
Pre-
Screen1
Screen
Run-in
Enrolment
Stabilization
Treatment Period
Follow-up
Fixed Treatment Period
Variable Treatment 
Period
Visit
0
11
22
33
Random-
ization
4
5
6
7
8
End of Study 
(EOS)
Early 
Withdrawal 
(EW)4
Safety
Follow-up Contact
Study Day
-49 to -36
-35
-14
1
29
85
169
253
365
Week
-6 to -7
-5
-2
0
4
12
24
36
52
1 week after Visit 
8/EOS or EW Visit
Window
-5/+2d
-5/+2d
-5/+2d
-5/+2d
-5/+2d
-1/+4d
Collect double-blind 
study treatment
(Scheduled)
x
x
x
x
x
x
Collect double-blind 
study treatment
(Unscheduled)
x29
Dispense 
albuterol/salbutamol, 
as required
x
x
x
x
x
x
x
Collect 
albuterol/salbutamol, 
as required
x
x
x
x
x
x
x
x
Dispense FP, as 
required30
x
x
x
x
x
x
x
Collect FP, as 
required
x
x
x
x
x
x
x
x
Notes:
1.
Visit 1 should be completed 1 day but 14 days after Visit 0; however, if it is local and routine medical practice to request that a subject withhold their ICS/LABA medication for at 
least 24 hours prior to a clinic visit then, provided that the subject has complied with the request, Visit 0 and Visit 1 can occur on the same day.
2.
Visit 2 may be conducted up to 3 days before the scheduled date of Visit 2. The duration of the run-in period (i.e. the time period between Visits 1 and 2) must be 18 days but 
26 days.
3.
Visit 3 must always be conducted 14 days but 17 days after Visit 2.
4.
EW Visit should be conducted if double-blind study treatment is discontinued AND the subject discontinues from participating in the study.
5.
The ICF must be signed before any study procedures, including protocol-specified medication cessation.
6.
Genetics research consent may be obtained at the same time as the study IC and must be obtained prior to obtaining a genetic blood sample.


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7.
The assessment of asthma history will include: the age of the subject when they were first provided with an inhaler for asthma; completion of an asthma medical history 
questionnaire (a copy of this questionnaire and instructions for its use can be found in the SRM).
8.
Subjects must not be randomised prior to confirming their eligibility to participate in the study.
9.
The IRT will be used for randomization, emergency unblinding and study treatment supply management (Please refer to the RAMOS NG IRT manual and SRM for more 
information).
10. Assessment(s) to be completed prior to the administration of study treatment.
11. To be completed using the provided combined spirometer/eDiary device. Assessments should be completed in the morning upon wakening and in the evening immediately prior to 
going to bed.
12. Spirometry to be performed between 6am and 11am after withholding rescue medication for at least 6 hours and prior to taking the morning dose of study treatment. Pre-dose 
spirometry assessments should be performed at the same time of day at each applicable visit.
13. Pre-dose spirometry to be performed between 6am and 11am, prior to taking the morning dose of study treatment. Post-dose spirometry is to be performed 3 hours (15 minutes) 
after taking the morning dose of study treatment. Rescue medication should be withheld for at least 6 hours prior to the pre-dose spirometry assessments until after completion of 
the 3-hour post-dose spirometry assessments. Pre- and post-dose spirometry assessments should be performed at the same time of day at each applicable visit.
14. In the event that double-blind study treatment is not administered at this visit, spirometry assessments should be performed at the same time of day as the pre- and post-dose 
spirometry assessments at the preceding on-treatment clinic visits.
15. Following completion of the pre-dose spirometry assessments, the reversibility test will be conducted between 20 and 60 minutes following 4 inhalations of albuterol/salbutamol 
aerosol. If airway reversibility is not demonstrated at Visit 1 then the assessment may be repeated within 7 days of Visit 1 (see Section 7.3.4.1.1 for details of the criteria to be met 
before a repeat of the reversibility assessment is permitted). If airway reversibility is successfully demonstrated at the second attempt and all other eligibility criteria assessed at 
Visit 1 are met then the subject may commence the 3-week run-in period (starting on the date that airway reversibility was successfully demonstrated at the second attempt).
16. Following completion of the pre-dose spirometry assessments, the reversibility test will be conducted between 60 and 90 minutes following 4 inhalations of ipratropium aerosol 
(see Section 7.3.4.1)
17. The vital signs assessment will include the measurement of height and weight at this visit only.
18. At the Screening Visit (Visit 1), the ECG is to be obtained after the vital signs assessment but prior to performing the pre-bronchodilator spirometry assessment (see Section 
7.5.6). At all post-randomization visits the ECG is to be obtained 15 minutes to 45 minutes after the administration of study treatment.
19. Exhaled Nitric Oxide is widely accepted as a non-invasive marker for airway inflammation and will be assessed to characterise the study subject population. Details on performing 
the FeNO assessment, including information on the equipment provided and its use, are documented in the SRM and the third-party vendor manual.
20. Pharmacogenetic sample may be drawn any time from Visit 3 onwards.
21. Assessments only to be conducted in females of reproductive potential.
22. Pharmacokinetic (PK) subset: In a subset of approximately 20% of all randomized subjects, PK samples will be obtained at pre-dose on the visit day, and 1 sample in each of the 
following three time windows: 5min-30min, 45min-90min, and 2-3h post dose on the visit day. NOTE: the date and time of study treatment administration on the day prior to the 
visit must be recorded in the eCRF. 
23. PK sample to be obtained at pre-dose on the visit day (This PK sample is to be obtained from ALL study subjects). NOTE: the date and time of study treatment administration on 
the day prior to the visit must be recorded in the eCRF.
24. PK sample to be obtained at this visit ONLY in the event that Visit 8/EOS assessments are conducted at Week 24.
25. In the event that the reversibility assessment needs to be repeated within 7 days of Visit 1 (see Section 7.3.4.1.1) then the medication for the 3-week run-in period must not be 
dispensed until airway reversibility is successfully demonstrated at the second attempt and all other eligibility criteria assessed at Visit 1 are confirmed as met.
26. Study treatment should be administered at the same time of day at each applicable clinic visit.


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27. The administration of study treatment at this visit is optional. If study treatment is not administered at this visit then those assessments which are scheduled based on the time of 
study treatment administration should be performed at approximately the same time of day as performed at the preceding post-randomization visits.
28. Between scheduled visits, unscheduled visits to the study clinic to re-supply the subject with double-blind study treatment is permitted after Visit 3 but before Visit 8/EOS. The IRT 
will be used for study treatment supply management (Please refer to the RAMOS NG IRT manual and SRM for more information).
29. In the event that the subject attends the study clinic for the unscheduled dispensing of double-blind study treatment, previously dispensed study treatment should be collected for 
drug accountability purposes.
30. FP may be used temporarily to treat the symptoms of a moderate asthma exacerbation, at the Investigator’s discretion. However, please note that a subject’s use of the provided 
FP prior to randomization at Visit 3 would meet the enrolment or randomization concomitant medication exclusion criteria (see Section 5.3.2 and Section 5.4.2)
.


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7.2.
Screening and Critical Baseline Assessments
No study related procedures may be performed until the informed consent form has 
been signed by the subject.  A Pre-Screening visit (Visit 0) is required in order to 
administer the informed consent before any changes are made to the subject’s current 
medical regimen.  Selection and modification of the subject’s medications prior to study 
participation is based on the physician’s judgment according to sound medical practice, 
principles, and each subject’s needs.  A subject’s treatment must not be changed merely 
for the purpose of enabling the subject’s participation in the study.
During the Pre-Screening visit (Visit 0) the following information will be captured in the 
eCRF for each subject: 

Date of ICF signature

Demographic information including race, age and gender

Subject number

Serious Adverse Event information only for any SAE considered as related to 
study participation

Investigator signature page
The additional following critical baseline assessments will be conducted at Screening 
(Visit 1):

Weight and height

Asthma diagnosis history including:

The age of the subject when they were first provided with an inhaler for 
asthma

Completion of an asthma medical history questionnaire: a copy of this 
questionnaire and instructions for its use can be found in the SRM

Smoking history and status

Exacerbation history

Asthma and other concurrent medications

Medical History including previous and/or concurrent medical conditions, 
detailed cardiovascular risk factor history, pneumonia, and pneumonia vaccine 
status

Reason for screen failure (if applicable)

Vital signs

ACQ

Pre-and post-albuterol/salbutamol lung function

Inclusion/Exclusion criteria assessment


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
Physical examination

12-lead ECG

Child bearing status assessment for all potential female subjects

Clinical laboratory tests (including hematology, chemistry, urinalysis and serum 
pregnancy test)

SAE assessment
In addition, the following procedures must be completed at Screening (Visit 1):
Electronic device training / dispense eDiary
Review/dispense Medical Problems/Medication Taken worksheet
Dispense albuterol/salbutamol
Dispense FSC run-in medication
Dispense FP (as applicable, per Investigator discretion)
7.3.
Efficacy
For a definition of baseline for each of the endpoints listed below, please refer to Section 
9.4.
7.3.1.
Efficacy Endpoints
7.3.1.1.
Primary Efficacy Endpoint
Mean change from baseline in clinic trough FEV1 at Week 24
7.3.1.2.
Key Secondary Efficacy Endpoint
Annualized rate of moderate/severe asthma exacerbations.
7.3.1.3.
Other Secondary Efficacy Endpoints

Mean change from baseline in clinic FEV1 at 3 hours post study treatment at 
Week 24

Mean change from baseline in ACQ-7 total score at Week 24

Mean change from baseline in SGRQ total score at Week 24

Mean change from baseline in E-RS total score over Weeks 21 to 24 (inclusive) 
of the treatment period
7.3.1.4.
Other Efficacy Endpoints

Mean change from baseline in clinic trough FEV1 over the first 24 weeks of the
treatment period

Mean change from baseline in daily home trough FEV1 over the first 24 weeks of 
the treatment period


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
Annualized rate of severe asthma exacerbations

Time to first severe asthma exacerbation

Time to first moderate/severe asthma exacerbation

Percent of patients meeting a responder threshold of 0.5 points improvement 
(decrease) from baseline for the ACQ-7 at Week 24

Percent of patients meeting a responder threshold of 0.5 points improvement 
(decrease) from baseline for the ACQ-6 at Week 24

Percent of patients meeting a responder threshold of 0.5 points improvement 
(decrease) from baseline for the ACQ-5 at Week 24

Percentage of patients that have achieved asthma control based on ACQ-7 (i.e. a 
total score 0.75) at both Week 12 and Week 24

Percentage of patients that have achieved asthma control based on ACQ-6 (i.e. a 
total score 0.75) at both Week 12 and Week 24

Percentage of patients that have achieved asthma control based on ACQ-5 (i.e. a 
total score 0.75) at both Week 12 and Week 24

Mean change from baseline in SGRQ domain scores at Week 24

Percent of patients meeting a responder threshold of ≥ 4 points improvement 
(decrease) from baseline for the SGRQ total score at Week 24

Mean change from baseline in E-RS domain scores over Weeks 21 to 24 
(inclusive) of the treatment period

Percent of patients meeting a responder threshold of ≥ 2 points improvement 
(decrease) from baseline for the E-RS total score over Weeks 21 to 24 (inclusive) 
of the treatment period

Mean change from baseline in AQLQ total score at Week 24

Percent of patients meeting a responder threshold of ≥ 0.5 points improvement 
(increase) from baseline for the AQLQ total score at Week 24

Mean change from baseline in morning (AM) pre-dose PEF over the first 24 
weeks of the treatment period

Mean change from baseline in evening (PM) PEF over the first 24 weeks of the
treatment period

Mean change from baseline in the percentage of symptom-free days over the first 
24 weeks of the treatment period
Note: this endpoint will be assessed using eDiary data (excluding E-RS 
total/domain scores and supplemental asthma questions); see Section 7.3.5.1.3
and Appendix 6. A symptom-free day is defined as subjects having on that day: a 
daytime asthma symptom score of 0 (i.e. no asthma symptoms) AND a physical 
limitation score of 0 (i.e. not at all limited) AND no nocturnal awakenings due to 
asthma symptoms.


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
Mean change from baseline in the percentage of rescue medication-free days over 
the first 24 weeks of the treatment period

Mean change from baseline in daily rescue medication use over the first 24 weeks 
of the treatment period

Unscheduled asthma-related healthcare resource utilization over the first 24 
weeks of the treatment period
7.3.2.
Efficacy Assessments
The timings of all efficacy assessments are documented in the Time and Events table (see 
Section 7.1).
7.3.3.
Questionnaires
The questionnaires should be completed before any procedures are performed on the 
subject to avoid influencing the subject’s response. To avoid biasing responses, the 
subjects should not be told the results of diagnostic tests prior to completing the 
questionnaires and it is recommended that the questionnaires be administered at the same 
time of day during each visit (as applicable) using the provided electronic device (unless 
otherwise specified).  Adequate time must be allowed to complete all items on the 
questionnaires; the questionnaires must be reviewed for completeness and, if necessary, 
the subject must be encouraged to complete any missing assessments or items.
Instructions for completing the questionnaires can be found in the SRM.
7.3.3.1.
Global Assessment of Severity and Response to Treatment
The subject will be asked to complete the Global Assessment of Severity and Response to 
Treatment at the visits specified in the Time and Events table (Section 7.1). The Global 
Assessment of Severity is a single item questionnaire; subjects are asked to rate their 
asthma symptoms at the study visit using a five-point scale (none, mild, moderate, severe, 
very severe).  The Response to Treatment is a single question of the patient’s overall 
evaluation of response to treatment, using a seven-point rating scale with the following 
definitions: 1 = significantly improved; 2 = moderately improved; 3 = mildly improved; 
4 = no change; 5 = mildly worse; 6 = moderately worse; and 7 = significantly worse. 
7.3.3.2.
Asthma Control Questionnaire (ACQ)
The ACQ measures seven attributes of asthma control [Juniper 1999].  Six attributes are 
measured with a patient-completed questionnaire, and the questions are designed to be 
self-completed by the subject.  Subjects will complete the ACQ at specified study visits.  
The six questions (concerning nocturnal awakening, waking in the morning, activity 
limitation, shortness of breath, wheeze and rescue medication use) enquire about the 
frequency and/or severity of symptoms over the previous week.  The response options for 
all these questions consist of a zero (no impairment/limitation) to six (total impairment/ 
limitation) scale.  The recall period is the past week.  The seventh attribute of the ACQ-7 
is lung function (FEV1%-predicted) which will be included via study visit spirometry.   


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Two shortened versions of the ACQ exist.  The two shortened versions include the ACQ-
5 (a five-item measure using only the symptoms items) and the ACQ-6 (six-item 
measures and rescue bronchodilator use). The measurement properties were very similar 
for all versions of the ACQ (original 7-item ACQ and shortened versions) [Juniper 2005; 
Wyrwich 2011].  For all versions, a score of 0.75 indicates well-controlled asthma and a 
score 1.5 indicates poorly controlled asthma [Juniper 2006].  A change of 0.5 in score 
suggests a clinically important change in score [Juniper 2005].
7.3.3.3.
St. George’s 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 [Jones 1992] with a recall over the past 3 months. Higher 
scores indicate worse health status, and a change of 4 points is considered a clinically 
relevant change [Jones 2005].
7.3.3.4.
Asthma Quality of Life Questionnaire (AQLQ)
The Asthma Quality of Life Questionnaire (AQLQ) was developed to measure the 
functional impairments related to asthma experienced by adults 17+ years old.  The 
AQLQ (+12), is a modified version of the original AQLQ and validated for use in asthma 
patients between the ages of 12 and 70 [Juniper 2005]. The response scale ranges from 1 
(totally impaired) to 7 (not at all impaired).  The questions are designed to be self-
completed by the subject with a recall over the past 2 weeks.  Higher scores indicate 
better asthma-related HR-QoL, and a change of 0.5 is considered clinically important 
[Juniper 1994].
7.3.3.5.
Healthcare Resource Utilization
All unscheduled asthma-related healthcare utilization will be recorded in the eCRF at the 
time points specified in the Time and Events table (Section 7.1). Unscheduled asthma-
related healthcare utilization includes telephone contacts, specialist nurse visits, visits to a 
physician’s office, home visits (day and night time), outpatient visits, visits to urgent 
care, visits to the emergency department, and hospitalizations associated with the 
subject’s worsening of symptoms.  The Medical Problems/Medication Taken worksheet
(see Section 7.5.8) used by the subject to record all healthcare contacts experienced since 
the last visit will be presented to the Investigator (or designee) at the clinic visits.  
Subjects will be asked to bring their worksheet to every study site visit as it will be used 
to assist subject recall in discussions with the Investigator, for site staff to then enter as 
appropriate in the eCRF.  The Investigator (or designee) should ask the subject if any of 
the healthcare contacts that are recorded on the worksheet were due to a worsening of 
asthma symptoms.  The Investigator can refer to his/her records to verify or supplement 
information given by the subject, if necessary.
7.3.4.
Pulmonary Function Tests
Spirometry will be performed at the study site to assess FEV1 and FVC. At least 3 
acceptable spirometry manoeuvres (from a maximum of 8 attempts) should be achieved 


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on each occasion that spirometry assessments are performed, in accordance with the 
ATS/ERS standards [Miller 2005]. The highest of 3 technically acceptable measurements 
will be recorded at each visit:

Pre-dose Spirometry: At Visits 3 through 8/EOS (and the Early Withdrawal 
Visit, if applicable), subjects should withhold short-acting beta-2-agonists 
(SABAs) for 6 hours prior to the clinic visit, if possible. Spirometry 
assessments must be performed:
o
Between 6am and 11am on the day of the visit.
o
At the same time of day (1 hour) as the assessment performed at Visit 3 
(the baseline assessment).
o
At least 24 hours after the subject’s last morning dose of study treatment 
on the day prior to the visit.
o
Before the subject’s morning dose of study treatment on the day of the 
visit.

Post-dose Spirometry: At Visits 3, 6 and 8/EOS (and the Early Withdrawal 
Visit, if applicable), spirometry assessments must be performed 3 hours after the 
subject’s morning dose of study treatment; the assessment performed at Visits 6 
and 8/EOS should be performed at the same time of day (1 hour) as the 
assessment performed at Visit 3 (the baseline assessment). At each visit, subjects 
should withhold short-acting beta-2-agonists (SABAs) between receiving their 
morning dose of study treatment and completing the spirometry assessments, if 
possible.
Spirometry equipment will be provided to all sites by a third-party vendor; the same 
third-party vendor will also centrally analyse the spirometry data from this study. Details 
on performing the spirometry assessments, including information on the equipment 
provided and its use as well as specific instructions on performing the spirometry 
manoeuvres, are documented in the SRM and the third-party vendor manual.
7.3.4.1.
Reversibility
All reversibility evaluations should follow the recommendations of the ATS/ERS Task 
force: Standardization of Lung Function Testing [Miller 2005]. A pre-bronchodilator
spirometry assessment should be performed after a washout period of at least 6 hours for 
short-acting β2- agonists.
Percent reversibility will be calculated as follows:
(Post-bronchodilator FEV1 – Pre-bronchodilator FEV1)
x 100
Pre-bronchodilator FEV1
7.3.4.1.1.
Albuterol/Salbutamol
The reversibility requirement for eligibility must be assessed at Visit 1. Subjects must 
demonstrate a 12% and 200 mL increase in FEV1 to be eligible for the study. If these 
reversibility criteria are not met at Visit 1 then the subject may not enter the 3-week run-
in period; however, the reversibility assessment may be repeated once within 7 days of 
Visit 1 if either criteria a) or b) are met:


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a) ≥9% increase in FEV1 between 20 and 60 minutes following 4 inhalations of 
albuterol/salbutamol aerosol at Visit 1.
b) Documented evidence of a reversibility assessment within 1 year prior to Visit 1 
which demonstrated a post-bronchodilator increase in FEV1 of ≥12% and ≥200 
mL.
Should the subject successfully demonstrate airway reversibility (defined as ≥12% and 
≥200 mL increase in FEV1 between 20 and 60 minutes following 4 inhalations of 
albuterol/salbutamol aerosol) at the second attempt then, provided that all other eligibility 
criteria assessed at Visit 1 are met, the subject may enter the 3-week run-in period.
To perform the reversibility assessment, 4 puffs of the provided salbutamol/albuterol is 
administered (a spacer device may be used, if required). Following completion of the pre-
bronchodilator assessment, a second spirometry assessment is performed within 20 to 60
minutes after administration of the salbutamol/albuterol.
7.3.4.1.2.
Ipratropium
At Visit 2, subjects will perform a reversibility assessment using ipratropium as the 
bronchodilator. As the aim of this assessment is to aid the characterisation of the study 
population, subjects are not required to demonstrate a 12% and 200 mL increase in 
FEV1 to ipratropium to be eligible for the study.
To perform the reversibility assessment, 4 puffs (approximately 80 mcg total) of the 
provided ipratropium is administered (a spacer device may be used, if required).
Following completion of the pre-bronchodilator assessment at Visit 2, a second 
spirometry assessment is performed within 60 to 90 minutes after administration of the 
ipratropium.
For a list of countries whose study subjects may not perform this assessment, please refer 
to the SRM.
7.3.5.
Daily Diaries
Subjects will be issued with a combination spirometer and eDiary device at Visit 1 for 
twice daily use (in the morning upon waking and in the evening just before going to bed)
throughout the study. The eDiary device will be provided by a third-party vendor. 
Information on the device and its use are documented in the SRM and the third-party 
vendor manual. Subjects will be instructed on how to use the device in order to record 
results for the following in the eDiary each day from Visit 1 onwards:

Daily symptom assessment (E-RS and supplemental asthma items; night-time 
awakening, asthma symptom and physical activity questions)

The number of inhalations of rescue albuterol/salbutamol used during the day and 
night.

Morning and evening FEV1

Morning and Evening Peak Expiratory Flow (PEF)


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
Morning and evening FSC medication use (during the run-in period only)

Morning FF/VI medication use (during the stabilization period only)

Morning double-blind study medication use (during the treatment period only)
Section 7.3.5.1 describes the assessments and questionnaires recorded on the eDiary 
device, as well as the alerts that can be triggered based on recorded results. The data from 
the eDiary device will be automatically transmitted to a centralised server on a daily 
basis. The Investigator and designee(s) will be provided with access to the transmitted 
eDiary data via a vendor-provided portal and should review the data on an ongoing basis 
to check for the incidence of alerts (see Section 7.3.5.1.6) as well as subject compliance 
with eDiary use and study treatment administration.
Subjects will also be issued with a paper Medical Problems/Medications Taken
worksheet to record medical problems experienced and medications used during the 
study (please refer to the SRM for further details). Subjects must also use this paper 
worksheet to record all healthcare contacts that occur during their participation in the 
study. This paper worksheet will be used to assist subject recall in discussions with the 
Investigator, for site staff to then enter as appropriate in the eCRF.
7.3.5.1.
eDiary Questionnaires, Assessments and Alerts
For information on the eDiary questions, please refer to Appendix 6.
7.3.5.1.1.
E-RS
The Evaluating Respiratory Symptoms (E-RS) in COPD consists of 11 items from the 14 
item Exacerbations of COPD (EXACT-PRO) instrument.  E-RS is intended to capture 
information related to respiratory symptoms, i.e. breathlessness, cough, sputum 
production, chest congestion and chest tightness. The E-RS was developed for use in 
patients with COPD but symptom experience of patients with asthma may be 
appropriately measured with the E-RS. The daily recording of information allows an 
assessment of the underlying day to day variability of a patient's symptoms. The 
instrument is to be completed daily each night prior to going to bed.  The 11-items are 
scored on a 5-point scale of “not at all” to “extreme”.  The E-RS has a scoring range of 0-
40.
7.3.5.1.2.
Supplemental Asthma Items
To ensure that asthma symptoms are completely evaluated, two additional questions will 
be asked.  A question on wheeze, a symptom of importance in asthma will also be asked 
within the context of the daily diary. An item on breathlessness activities will evaluate 
shortness of breath associated with strenuous activities.  Subjects will be asked to respond 
to the question ‘Did you wheeze today?’ with response options of: Not at all, Rarely, 
Occasionally, Frequently, Almost constantly.  Subjects will be asked to respond to the 
question “Were you short of breath today when performing strenuous activities such 
climbing stairs, running, or participating in sports activity with a response scale of not at 
all, slightly, moderately, severely, extremely or too breathless to do these.  


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7.3.5.1.3.
Night-time Awakening, Asthma Symptom and Physical Activity 
Questions
Every morning upon waking (from the morning after Visit 1 onwards), subjects will 
answer a question on the occurrence of night-time awakenings due to asthma symptoms. 
The subject’s response to the question on the occurrence of night-time awakenings will 
be either ‘Yes’ (i.e. Did you wake up due to asthma symptoms (i.e. wheezing, coughing, 
shortness of breath, or chest tightness) or ‘No’ (i.e. they did not experience at least one 
night-time awakening due to asthma symptoms). If ‘Yes’, subjects will be asked to 
respond either ‘Yes’ or ‘No’ to the question on rescue medication (i.e. when you woke up 
due to your asthma symptoms did you use any rescue bronchodilator?).
On the evening of Visit 1 (just before going to bed) and every evening there-after, 
subjects will answer a question on daytime asthma symptoms and daytime physical 
activity limitation. These questions will be answered on a 5-point scale (0 to 4) with ‘0’ 
representing no daytime asthma symptoms/physical activity limitations and ‘4’ 
representing very severe daytime asthma symptoms or total daytime activity limitation.
(Please describe the severity of your asthma symptoms today (i.e. cough, wheeze, chest 
tightness, shortness of breath) today [0=no asthma symptoms, 1=mild asthma symptoms, 
2= moderate asthma symptoms, 3=severe asthma symptoms, 4= very severe asthma 
symptoms. How limited were you in your activities today because of your asthma (0=not 
at all limited, 1=a little limited, 2=moderately limited, 3=severely limited, 4=totally 
limited).
7.3.5.1.4.
Rescue Albuterol/Salbutamol Use
The number of puffs of albuterol/salbutamol self-administered by the subject each day for
the relief of asthma symptoms will be recorded morning and evening in the eDiary. Upon 
awakening in the morning, subjects should record the number of puffs of 
albuterol/salbutamol taken since completing the eDiary assessments on the evening of the 
previous day. Each evening, before going to bed, subjects should record the number of 
puffs of albuterol/salbutamol taken since completing the eDiary that morning (except on 
the day of Visit 1 when the number of puffs of albuterol/salbutamol taken since being 
provided with the albuterol/salbutamol MDI should be recorded). Subjects should be
instructed that study-provided albuterol/salbutamol should be used on an “as needed”
basis only.
Any use of non-study-provided rescue medication should be recorded as a concomitant 
medication in the eCRF. Use of study-provided rescue albuterol/salbutamol should not be 
recorded as a concomitant medication in the eCRF; however, the use of study-provided 
albuterol/salbutamol prior to exercise as a preventative measure should be recorded as a 
concomitant medication in the eCRF.
7.3.5.1.5.
Morning and Evening Home Spirometry
An electronic home spirometer/eDiary device will be issued to subjects at Visit 1 for 
daily monitoring of their lung function (i.e. FEV1 and PEF). The home Spirometer/eDiary 
device will be provided by a third-party vendor. Information on the device and its use are 
documented in the SRM and the third-party vendor manual. Subjects will conduct 


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spirometry maneuvers each morning, prior to study medication dosing, and each evening. 
Three measurements for each session will be performed by the subjects using the 
spirometer/eDiary device; the highest value from the three FEV1 and PEF measurements 
will be recorded. Assessments will be performed:

After completing all other eDiary assessments

Prior to albuterol/salbutamol use

Prior to study medication dosing
Data from the home FEV1 assessments will be used to determine the time to maximal 
effect of the assigned double-blind study treatment.
7.3.5.1.6.
Alerts
The following alerts for a change from baseline in asthma symptoms, lung function, 
and/or rescue medication use that may indicate the onset of a moderate/severe asthma 
exacerbation, will be programmed into the eDiary:

Nocturnal awakening(s) due to asthma requiring albuterol/salbutamol use for 2 
consecutive nights.

An increase of ≥1.0 (on a 5-point scale) from baseline in daytime asthma 
symptom score on 2 consecutive days.

An increase from baseline of ≥ 4 puffs /day of albuterol/salbutamol use on 2 
consecutive days.

A ≥20% decrease in AM PEF from baseline on 2 consecutive mornings.

A ≥20% decrease in PM PEF from baseline on 2 consecutive evenings

A ≥20% decrease in AM FEV1 from baseline on 2 consecutive mornings.

A ≥20% decrease in PM FEV1 from baseline on 2 consecutive evenings.
The baseline value, for the purpose of alerts, is defined as the average value over the last 
7 days prior to randomization. Subjects will be instructed to contact the Investigator if 
any of the above alert criteria are met (either by telephone and/or by visiting the study 
clinic).
The data from the home spirometer/eDiary device will be automatically transmitted to a 
centralised server on a daily basis. The Investigator and designee(s) will be provided with 
access to the transmitted eDiary data via a vendor-provided portal and should review the 
data on an ongoing basis to check for the incidence of alerts as well as subject 
compliance with eDiary use. The Investigator or designee(s) is instructed to evaluate 
subjects who meet eDiary alert criteria for signs or symptoms of an asthma exacerbation 
and to provide appropriate medical care (see Section 7.3.6).
7.3.6.
Asthma Exacerbations
For the purposes of this study, moderate/severe asthma exacerbations will be collected 
and recorded on the asthma exacerbation eCRF page from the start of randomized double 
blinded treatment until Visit 8/EOS Visit or the Early Withdrawal Visit for those subjects 


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that withdraw from participation in the study (see Section 5.6). Moderate/severe asthma 
exacerbations should not be recorded as an adverse event unless:

They meet the definition of an Adverse Event (see Appendix 4) and occur: 
o
After the start of study treatment until the start of double blinded study 
treatment or;
o
After completion of the Visit 8/EOS Visit (or Early Withdrawal Visit) 
assessments until the follow-up contact.
OR

They meet the definition of a Serious Adverse Event (see Appendix 4).
Note: The SAE page of the eCRF should be completed in addition to the asthma 
exacerbation eCRF page if the exacerbation occurs after the start of double 
blinded treatment but before completion of the Visit 8/EOS Visit or Early 
Withdrawal Visit assessments.
For consistency, exacerbations separated by less than 7 days will be treated as a 
continuation of the same exacerbation.
Alerts will be programmed into the eDiary to instruct the subject to contact the 
Investigator immediately for a medical assessment (see Section 7.3.5.1.6 ). The 
notification of decreasing asthma control from the eDiary will assist the Investigator in 
the identification of new asthma exacerbations.
Subjects will also complete a paper Medical Problems/Medications Taken worksheet to 
record medical problems experienced and medications used during the study, as well as 
all emergency department visits and/or hospitalizations that occur during their 
participation in the study. This paper worksheet must be reviewed by the Investigator (or 
designee) at each visit to the study site to assist the Investigator in the identification of 
new asthma exacerbations.
All moderate/severe asthma exacerbations will be recorded in the eCRF by the 
Investigator (or designee).
7.3.6.1.
Moderate Asthma Exacerbation
All eDiary alerts will be evaluated by the Investigator (or appropriately trained designee). 
The Investigator will utilize clinical discretion and available objective evidence 
(including eDiary data) to determine if the patient is experiencing a moderate asthma 
exacerbation.  Examples of key considerations include subject’s past medical history, 
severity and duration of current symptoms, and known asthma triggers. Guidance for 
identifying moderate exacerbations includes the following [Reddel 2009, Virchow 2015]:

A moderate asthma exacerbation is considered to be a deterioration in asthma 
symptoms, deterioration in lung function, or increased rescue bronchodilator use 
lasting for at least 2 days or more, but will not be severe enough to warrant 
systemic corticosteroid use (or a doubling or more of the maintenance systemic 
corticosteroid dose, if applicable) for 3 days or more and/or hospitalisation.


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
A moderate asthma exacerbation is an event that, when recognized, should result 
in a temporary change in treatment, in an effort to prevent the exacerbation from 
becoming severe.
As eDiary alerts are triggered on the second day of a change from baseline in asthma 
symptoms, lung function, and/or rescue medication, subjects and Investigators are asked 
to investigate eDiary alerts at the time they are received. Subjects are also instructed to 
contact the Investigator for signs of worsening asthma that may not be triggered by 
eDiary data. The paper Medical Problems/Medications Taken worksheet must also be 
reviewed by the Investigator (or appropriately trained designee) at each visit to the study 
site to assist the Investigator in the identification of new asthma exacerbations.  At the 
Investigator’s discretion, a temporary change in background asthma medication will be 
permitted in order to treat the symptoms of a moderate asthma exacerbation (see Section 
6.9.1.1 for details). If a subject experiences a second moderate asthma exacerbation 
requiring a change in therapy, the Investigator may choose to continue the additional 
therapy for as long as medically appropriate.
7.3.6.2.
Severe Asthma Exacerbation
A severe asthma exacerbation is defined as:
The deterioration of asthma requiring the use of systemic corticosteroids (tablets, 
suspension or injection), or an increase from a stable maintenance dose1, for at least 3 
days.
1 For subjects receiving maintenance systemic corticosteroids, at least double the 
maintenance systemic corticosteroid dose for at least 3 days is required.
OR
An inpatient hospitalization or emergency department visit because of asthma, requiring 
systemic corticosteroids.
7.4.
Health Outcomes
7.4.1.
Work Productivity and Activity Impairment-Specific Health 
Problem (WPAI-SHP)
The WPAI-SHP (version 2) is a self administered tool comprised of 6 questions which 
address absenteeism, presenteeism (reduced effectiveness while working), overall work 
productivity loss (absenteeism plus presenteeism), and activity impairment.  This 
validated tool captures data from the past 7 days.  WPAI-SHP (asthma) outcomes are 
scored as impairment percentages, with a higher percentage indicating greater 
impairment and less productivity [Reilly 1993].
The WPAI-SHP will be completed at specific study visits as defined in the Time and 
Events table (see Section 7.1).


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7.5.
Safety
Planned time points for all safety assessments are listed in the Time and Events table 
(Section 7.1).
7.5.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 4.
The Investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
7.5.1.1.
Time period and Frequency for collecting AE 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 will be collected from the start of Study Treatment until the follow-up 
contact (see Section 7.5.1.3), at the timepoints specified in the Time and Events 
table (Section 7.1).

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 GSK within 24 hours, as indicated in 
Appendix 4.

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 reasonably related to the study treatment or study participation, the 
Investigator must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 4
7.5.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact?” 

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?” 


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Subjects will be issued with a paper Medical Problems/Medications Taken worksheet to 
record medical problems experienced and medications used during the study (please refer 
to the SRM for further details). This paper worksheet will be used to assist subject recall 
in discussions with the Investigator (or designee), for site staff to then enter as 
appropriate in the eCRF.
7.5.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the Investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs, and non-serious AEs of special interest 
(as defined in Section 7.5.2) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.6.2). Further information on follow-up procedures is given in 
Appendix 4.
7.5.1.4.
Cardiovascular and Death Events
7.5.1.4.1.
Cardiovascular Events
Cardiovascular-related AEs and SAEs that will require the Investigator to complete event
specific pages in the eCRF are listed in Appendix 4.
Cardiovascular events information should be recorded on the corresponding eCRF pages 
within one week of when the AE/SAE(s) are first reported. Please refer to Appendix 4 for
timelines for reporting AE/SAEs.
7.5.1.4.2.
Death Events
In addition, all deaths will require completion of a specific death data collection page in 
the eCRF. The death data collection page in the eCRF includes questions regarding 
cardiovascular (including sudden cardiac death) and non-cardiovascular death.
Death information should be recorded on the death eCRF page within one week of when 
the death is first reported.
Please refer to Appendix 4 for timelines for reporting SAEs.
7.5.1.5.
Pneumonia
Medical history will also be taken for pneumonia in previous 12 months, including 
recording of any episodes resulting in hospitalisation. Where possible a chest X-ray 
should be performed to confirm a diagnosis, whenever a subject has a suspected 
pneumonia.  Suspected pneumonias will require confirmation as defined by the presence 
of new infiltrate(s) on chest x-ray AND at least 2 of the following signs and symptoms: 

Increased cough 

Increased sputum purulence (color) or production 

Auscultatory findings of adventitious sounds (e.g., egophony, bronchial breath 
sounds, rales, etc.)


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
Dyspnea or tachypnea

Fever (oral temperature > 37.5 degrees centigrade [°C])

Elevated white blood cells (WBC) (>10,000/millimetres cubed [mm3] or >15% 
immature forms)

Hypoxemia (Oxyhemoglobin (HbO2) saturation <88% or at least 2% lower than 
baseline value)
All pneumonias must be captured on the AE/SAE page of the eCRF and on the 
pneumonia page of the eCRF. 
For all suspected cases of pneumonia, investigators are strongly encouraged to confirm 
the diagnosis (this includes obtaining a chest x-ray) and to initiate appropriate therapy as 
promptly as possible. All diagnoses of pneumonia (radiographically confirmed or 
unconfirmed) must be reported as an AE or SAE (if applicable).
7.5.1.6.
Radiography (Chest X-Rays)
Confirmation by chest x-ray (posteroanterior and lateral) should be performed as soon as 
possible and preferably within 48 hours of suspected pneumonia.  In all cases, the signs 
and symptoms that were used to identify the pneumonia must be documented in the 
source documents and eCRF. Diagnoses of pneumonia must be recorded as adverse 
events in the eCRF.
7.5.1.7.
Regulatory Reporting Requirements for SAEs
Prompt notification by the Investigator to GSK of SAEs related to study treatment (even 
for non- interventional post-marketing studies) is essential so that legal obligations and 
ethical responsibilities towards the safety of subjects and the safety of a product under 
clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and Investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to Investigators as necessary.
An Investigator who receives an Investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.


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7.5.2.
Adverse Events of Special Interest (AESIs)
AE groups of special interest have been defined as AEs which have specified areas of
interest for one or more of class of drugs (ICS, LAMA, LABA). Some AE groups may 
have subgroups defined.
The following table presents the current special interest AE groups and subgroups. These
may be updated prior to conclusion of the study reporting. The final list, including the
preferred terms which contribute to each of the groups will be documented a priori in the 
study Reporting and Analysis Plan (RAP).
Special interest AE group
Special interest AE subgroup
Cardiovascular effects
Cardiac arrhythmia
Cardiac failure
Cardiac ischemia
Stroke
Anticholinergic syndrome
-
Urinary retention
-
Dry mouth / drying of 
airway secretions
-
Gastrointestinal obstruction
-
Antimuscarinic ocular 
effects / Corticosteroids 
associated eye disorders
Glaucoma (antimuscarinic/corticosteroid)
Cataracts (corticosteroid)
Pneumonia and LRTI
Pneumonia 
LRTI excluding pneumonia
Adrenal suppression
-
Decreased bone mineral 
density and associated 
fractures
-
Effects on glucose
-
Effects on potassium
-


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Special interest AE group
Special interest AE subgroup
Tremor
-
Asthma intubations, and 
deaths
-
Hypersensitivity
-
Local steroid effects
-
7.5.3.
Pregnancy

Details of all pregnancies in female subjects will be collected after the start of 
dosing and until the safety follow-up contact/visit.

If a pregnancy is reported then the Investigator should inform GSK within 2 
weeks of learning of the pregnancy and should follow the procedures outlined in 
Appendix 5.
7.5.4.
Physical Exams
Physical exams will be performed at the time points specified in the Time and Events 
table (Section 7.1).

A complete physical examination will include, at a minimum, assessment of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems.

Height and weight will be measured at Visit 1.
7.5.5.
Vital Signs
Vital signs will be performed at the time points specified in the Time and Events table 
(Section 7.1) prior to conducting spirometry and prior to taking the morning dose of 
study treatment. Blood pressure (systolic and diastolic) and pulse rate will be measured in 
the sitting position after approximately 5 minutes rest. A single set of values will be 
collected and recorded in the source documentation and eCRF.
7.5.6.
Electrocardiogram (ECG)
All sites will use standardised ECG equipment provided by a centralized external vendor. 
At the Screening Visit (Visit 1), a single 12-lead ECG and rhythm strip will be recorded 
after the measurement of vital signs but before performing the pre-bronchodilator 
spirometry assessment. At the post-randomization visits, a single 12-lead ECG and 
rhythm strip will be recorded 15 to 45 minutes after the administration of study treatment. 
Recordings will be made at the time-points defined in the Time and Events table (Section 
7.1). All ECG measurements will be made with the subject in a supine position having 
rested in this position for approximately 5 minutes before each reading.


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For subjects who meet the QTc, protocol defined stopping criteria, triplicate ECGs (over 
a brief period of time) should be performed (Section 5.6.4).
The Investigator, a designated sub-Investigator or other appropriately trained site 
personnel will be responsible for performing each 12-lead ECG. The Investigator must 
provide his/her dated signature on the original paper tracing, attesting to the authenticity 
of the ECG machine interpretation.
All ECGs will be electronically transmitted to an independent cardiologist and evaluated. 
The independent cardiologist, blinded to treatment assignment, will be responsible for 
providing measurements of heart rate, QT intervals and an interpretation of all ECGs 
collected in this study. A hard copy of these results will be sent to the Investigator. The 
Investigator must provide his/her dated signature on the confirmed report, attesting to 
his/her review of the independent cardiologist’s assessment.
Details of the cardiac monitoring procedures will be provided by the centralized 
cardiology service provider.
7.5.7.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments (haematology, clinical chemistry and 
urinalysis) must be conducted in accordance with the Laboratory Manual, and Protocol 
Time and Events table (Section 7.1). Laboratory requisition forms must be completed 
and samples must be clearly labelled with the subject number, protocol number, 
site/centre number, and visit date. Details for the preparation and shipment of samples 
will be provided by the laboratory and are detailed in the Laboratory Manual. Reference 
ranges for all safety parameters will be provided to the site by the laboratory responsible 
for the assessments.
All blood samples which will be taken pre-dose, will be sent to a central laboratory for 
analysis (details provided in the Laboratory Manual). Standard reference ranges will be 
used.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the Investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the eCRF.
Refer to the Laboratory Manual for appropriate processing and handling of samples to 
avoid duplicate and/or additional blood draws.
Haematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 5.


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Table 5
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
WBC count with Differential:
Red Blood Cell (RBC)
Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry 1
Blood Urea 
Nitrogen 
(BUN)
Potassium
AST (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose 
Calcium
Alkaline phosphatise
Albumin
Total Serum 
IgE2
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood and ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

FSH and estradiol (as needed in females of non-reproductive
potential only)

Serum/urine hCG Pregnancy test (as specified in the Time and 
Events table [Section 7.1])
NOTES:
1.
Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up 
Assessments after liver stopping or monitoring event are given in Section 5.6.3 and 
Appendix 2.
2.
Total Serum IgE is required at Visit 1 only.
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study should be repeated until the values return to normal or 
baseline.  If such values do not return to normal within a period judged reasonable by the 
Investigator, the etiology should be identified and the sponsor notified. 
7.5.8.
Paper Medical Problems/Medications Taken Worksheet
Subjects will be issued with a paper Medical Problems/Medications Taken worksheet to 
record medical problems experienced and medications used during the study (please refer 
to the SRM for further details). Subjects must also use this paper worksheet to record all 
emergency department visits and/or hospitalizations that occur during their participation 
in the study. Subjects will be asked to bring their paper worksheet to every study site visit 


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as it will be used to assist subject recall in discussions with the Investigator (or designee), 
for site staff to then enter as appropriate in the eCRF.
7.6.
Pharmacokinetics (PK)
Concentrations of FF, UMEC and VI in plasma will be determined using currently
approved assay methodology under the control of GSK. A population PK approach will 
be employed in this study; the PK samples will be collected at the time points specified in 
Section 7.1.
The actual date and time of each blood sample collection will be recorded in the eCRF. 
The date and time of study treatment administration on the day prior to the clinic visit 
will be recorded in the eCRF. This is to ensure appropriate usage of the pre-dose PK data.
Details of PK blood sample collection (including volume to be collected), processing, 
storage and shipping procedures are provided in the SRM.
The following points must be noted: 

If assessments are scheduled for the same nominal time, THEN the assessments 
should occur in the following order (as applicable):
1. Vital signs
2. 12-lead ECG
3. blood draws.  
Note: The timing of the assessments should allow the blood draw to occur at the 
exact nominal time.

The change in timing or addition of time points for any planned study 
assessments must be documented in a Note to File which is approved by the
relevant GSK study team member and then archived in the study sponsor and 
site study files, but this will not constitute a protocol amendment. 

The IRB/IEC will be informed of any safety issues that require alteration of the 
safety monitoring scheme or amendment of the Informed Consent Form. 

No more than 500 mL of blood will be collected over the duration of the study, 
including any extra assessments that may be required.
7.6.1.
Blood Sample Collection
Blood samples for PK analysis of FF, UMEC and VI will be collected pre-dose from 
ALL subjects at Visit 6 (or Visit 8/EOS [if this visit occurs at Week 24] or, if applicable, 
the Early Withdrawal Visit [see Section 7.1]).
7.6.1.1.
Pharmacokinetic Sub-study
At Visit 3, consenting subjects who are randomised to participate in the main study will 
be entered into the PK sub-study.


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In a subset of approximately 20% of the subjects randomised to participate in the main 
study, PK samples will be obtained at pre-dose on the day of Visit 5, and 1 sample in 
each of the following three time windows: 5min-30min, 45min-90min, and 2-3h post 
dose on the day of Visit 5. 
The methodology for inclusion of consenting subjects into the PK sub-study is provided 
in the SRM.
7.6.2.
Sample Analysis
Plasma analysis will be performed under the management of Bioanalytical Science and
Toxicokinetics (BST), Drug Metabolism and Pharmacokinetics (DMPK), GSK. 
Concentrations of UMEC, VI and FF will be determined in plasma samples using the 
currently approved analytical methodology.
Personnel involved in the bioanalysis of PK samples will be unblinded as per GSK
policy. Samples will be analyzed only for relevant analyte, e.g. (FF/VI) treatment
samples will not be analyzed for UMEC concentrations. 
Raw data will be stored in the Good Laboratory Practice (GLP) Archives, GSK or at a 
designated contract laboratory. Once the plasma has been analyzed for UMEC, VI and FF 
any remaining plasma may be analyzed qualitatively for other circulating metabolites and 
the results reported under a separate DMPK protocol.
7.7.
Genetics
Information regarding genetic/ pharmacogenetic (PGx) research is included in Appendix 
3.  The IEC/IRB and, where required, the applicable regulatory agency must approve the 
PGx and genetic assessments before these can be conducted at the site.  The approval(s) 
must be in writing and will clearly specify approval of the PGx and genetic assessments 
(i.e., approval of Appendix 3).  In some cases, approval of the PGx and genetic 
assessments can occur after approval is obtained for the rest of the study.  If so, then the 
written approval will clearly indicate approval of the PGx and genetic assessments is 
being deferred and the study, except for PGx and genetic assessments, can be initiated.  
When PGx and genetic assessments will not be approved, then the approval for the rest of 
the study will clearly indicate this and therefore, PGx and genetic assessments will not be 
conducted.
8.
DATA MANAGEMENT

For this study subject data will be entered into GSK defined eCRFs, 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.


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
Adverse events and concomitant medications 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.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
The primary objective of this study is to evaluate the efficacy and safety of UMEC in 
combination with FF/VI in subjects with asthma over a 24 week treatment period.  This is 
a superiority study to demonstrate the add-on benefit of UMEC at two dosage strengths
62.5 mcg and 31.25 mcg in a single inhaler when compare to FF/VI. The primary 
efficacy endpoint is the mean change from baseline in trough FEV1 at the end of the 24-
week treatment period.
For each test on each efficacy endpoint, the null hypothesis is that there is no difference 
between treatment groups. 
H0: T1 – T2 = 0
The alternative hypothesis is that there is a difference between treatment groups.
H1: T1 – T2 ≠ 0
For the primary endpoint and other lung function related efficacy endpoints, the primary 
treatment comparisons of interest are the comparisons for each triple therapy and the 
respective dual therapy FF/VI without the UMEC component as follows:  
UMEC 62.5 mcg: 

FF/UMEC/VI 100/62.5/25 mcg vs. FF/VI 100/25 mcg

FF/UMEC/VI 200/62.5/25 mcg vs. FF/ VI 200/25 mcg
UMEC 31.25 mcg: 

FF/UMEC/VI 100/31.25/25 mcg vs. FF/VI 100/25 mcg

FF/UMEC/VI 200/31.25/25 mcg vs. FF/ VI 200/25 mcg
Therefore T1 and T2 for these endpoints are the mean changes from baseline for the 
individual triple therapy and dual therapy, respectively, as listed above. 
For the key secondary endpoint and all other non-lung function efficacy endpoints, the 
primary treatment comparisons of interest are the comparisons between triple therapy and 
dual therapy for a fixed dose of UMEC:


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
(FF/UMEC/VI 100/62.5/25, 200/62.5/25) vs. (FF/VI 100/25,  200/25)

(FF/UMEC/VI 100/31.25/25, 200/31.25/25) vs. (FF/VI 100/25,  200/25)
For example, T1 and T2 in the hypothesis associated with the key secondary efficacy 
endpoint are the averages of the mean annualized rate of moderate/severe exacerbations 
for the triple therapies over two FF doses at a given UMEC dose, and for the dual 
therapies over two FF doses, respectively.
Details on all pairwise treatment comparisons of interest are provided in Section 9.3.3.
9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
Sample size calculation is based on the primary efficacy endpoint of mean change from 
baseline in trough FEV1 at the end of the 24-week treatment period.
A total of 2250 randomized subjects are required for this study, with 375 subjects in each 
of the six double-blind treatment groups: 

FF/VI 100/25 mcg

FF/VI 200/25 mcg

FF/UMEC/VI 100/31.25/25 mcg

FF/UMEC/VI 200/31.25/25 mcg

FF/UMEC/VI 100/62.5/25 mcg

FF/UMEC/VI 200/62.5/25 mcg
Assuming 10% missing data on spirometry at the end of the 24-week treatment period,
due to early withdrawal from study, approximately 337 subjects per treatment group 
should have trough FEV1 data available for the analysis. 
The standard deviation for the mean change from baseline in trough FEV1 at the end of 
the 24-week treatment period is estimated to be 400 mL based on previous asthma 
studies.  The proposed sample size of n=337 per treatment group should provide 90% 
power, assuming a difference of 100 mL, based on a two sample t-test with a two sided 
significance level of 0.05 for each of the two primary comparisons of interest for each 
UMEC dose.
For the target population, it is assumed that the mean exacerbation rate is 2 per year for 
the control group FF/VI; this was based on a review of previous FF/VI asthma 
exacerbation study conducted by GSK and Tio asthma studies conducted by Boehringer 
Ingelheim.  The proposed sample size of 750 randomzed subject per arm (based on the 
treatment comparison of combined triple therapies and combined dual therapies with both 
FF doses) should have  approximately 95% power if the true reduction in exacerbation 


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rate for triple therapy vs. dual therapy is 20%. The calculation assumes the number of 
exacerbations per year follows a negative binomial distribution [Keene 2007], with a 
dispersion parameter k=0.7 based on a previous FF/VI asthma exacerbation study, and 
assumes the following accelerative recruitment rate per week over a period of 39 weeks:

3.5 weeks at 15 patients/week

4.5 weeks at 25 patients/week

4.5 weeks at 35 patients/week

4.5 weeks at 45 patients/week

4.5 weeks at 55 patients/week

4.5 weeks at 70 patients/week

13 weeks at 90 patients/week 
The duration of the treatment period is variable but will be at least 24 weeks and up to a
maximum of 52 weeks, with the end of study date being established once the last subject 
has been randomized.
9.2.2.
Sample Size Sensitivity
To demonstrate the sensitivity of the sample size calculation for this study, the following 
table and graph show the power function for a fixed sample size of n=337 per arm in the 
ITT population for the primary efficacy analysis, varying the observed treatment 
difference and estimated standard deviation on the change from baseline in trough FEV1
at the end of the 24-week treatment period.


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Treatment difference (mL)
Standard Deviation
80
90
100
110
120
350
0.84
0.92
0.96
0.98
0.99
375
0.79
0.88
0.93
0.97
0.99
400
0.74
0.83
0.90
0.95
0.97
425
0.69
0.78
0.86
0.92
0.96
450
0.64
0.74
0.82
0.89
0.93
Power vs Treatment Difference (mL) by SD
Alpha=0.05 N1=337 N2=N1 2-Sided T-Test
Treatment Difference (mL)
Power
80
90
100
110
120
0.50
0.60
0.70
0.80
0.90
1.00
SD
350
375
400
425
450
For the key secondary endpoint, the following table shows the power function for a fixed 
sample size of n=750 per arm (combining two FF containing triple arms or dual arms for 
a fixed UMEC dose) or for a fixed sample size of n=375 per arm (individual treatment 
group) in the ITT population, varying the mean annualized rate of exacerbations in the 
control group, the true treatment effect (relative reduction in moderate/severe 
exacerbations) and the dispersion assumption in a variable duration study, assuming an 


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accelerative recruitment rate per week over a period of 39 weeks as given in Section 
9.2.1.
dispersion
FF/VI 
rate
FF/UMEC/VI 
rate
Relative 
Reduction
power
n=750/arm
n=375/arm
0.7
1.50
1.275
15%
0.62
0.37
1.50
1.200
20%
0.87
0.59
1.50
1.125
25%
0.98
0.81
2.00
1.700
15%
0.70
0.41
2.00
1.600
20%
0.92
0.67
2.00
1.500
25%
0.99
0.87
2.50
2.125
15%
0.75
0.49
2.50
2.000
20%
0.95
0.72
2.50
1.875
25%
>0.99
0.90
0.8
1.50
1.275
15%
0.61
0.36
1.50
1.200
20%
0.86
0.56
1.50
1.125
25%
0.97
0.77
2.00
1.700
15%
0.65
0.41
2.00
1.600
20%
0.91
0.66
2.00
1.500
25%
0.99
0.85
2.50
2.125
15%
0.73
0.44
2.50
2.000
20%
0.94
0.69
2.50
1.875
25%
>0.99
0.88
The power for the statistical test on the key secondary efficacy endpoint was further 
evaluated for a fixed UMEC dose, assuming a constant rate of recruitment at 40, 50, or 
75 subjects per week throughout the enrolment period.  The power functions were 
illustrated below for n=750/arm and n=375/arm, respecitvely, assuming dispersion=0.7 
and a mean annualized rate of moderate/severe exacerbations of 2 for FF/VI group.


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9.2.3.
Sample Size Re-estimation or Adjustment
No sample size re-estimation is planned.


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9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
The following subject populations will be identified:
All Subjects Enrolled Population: This population will comprise all subjects for whom a 
record exists on the study database, including pre-screened subjects that sign the 
informed consent document but do not complete a Visit 1 (screening) procedure (i.e., pre-
screening failures), or subjects that complete at least one Visit 1 procedure but do not 
enter the run-in period (i.e., screening failures). This population will be used for the 
summary of subject disposition. 
All Subjects Screened Population: This population contains all subjects that complete at 
least one Visit 1 (Screening) procedure. This population will be used for the summary of 
subject disposition (including reasons for screening failures, run-in failures, and 
stabilization failures) and for the listing of AEs and SAEs for non-randomized subjects. 
Intent-to-Treat (ITT) Population: This population will comprise all randomized subjects, 
excluding those who were randomized in error. A subject who is recorded as a screen 
failure, run-in failure, or stabilization failure, but is randomized and does not receive a 
dose of study treatment, is considered to be randomized in error. Any other subject who 
receives a randomization number will be considered to have been randomized. This will 
constitute the primary population for all efficacy and safety analyses. 
Pharmacokinetic (PK) population: This population will comprise all subjects in the ITT 
Population for whom a PK sample was obtained and analyzed.
9.3.2.
Interim Analysis
No interim analysis is planned for this study.
9.3.3.
Treatment Comparisons
To demonstrate the benefit of UMEC when added to FF/VI treatment arms with the same 
FF dose, the primary comparisons of interest for the primary efficacy endpoint are:

The replicate efficacy for UMEC 62.5 mcg dosage:
o
FF/UMEC/VI 100/62.5/25 mcg vs. FF/VI 100/25 mcg
o
FF/UMEC/VI 200/62.5/25 mcg vs. FF/ VI 200/25 mcg

The replicate efficacy for UMEC 31.25 mcg dosage:
o
FF/UMEC/VI 100/31.25/25 mcg vs. FF/VI 100/25 mcg
o
FF/UMEC/VI 200/31.25/25 mcg vs. FF/ VI 200/25 mcg
For the multiple comparisons and multiplicity adjustment, see Section 9.3.4 .
To allow evaluation of the effect of FF/UMEC/VI on non-lung function efficacy 
endpoints, including the key secondary efficacy endpoint on moderate/severe 


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exacerbations, for each fixed UMEC dose, the data from the two FF/UMEC/VI arms will 
be pooled and compared to the pooled data from the two FF/VI arms.

FF/UMEC/VI (100/62.5/25 and 200/62.5/25) vs. FF/VI (100/25 and 200/25) 

FF/UMEC/VI (100/31.25/25 and 200/31.25/25) vs. FF/VI (100/25 and 200/25).
The integrated analyses will provide a more precise overall estimate for the treatment 
effect size of the addition of UMEC to FF/VI.
Other pairwise treatment comparisons of interest consist of the following assessments for 
all efficacy endpoints:
1)
Triple therapy with low dose FF vs. dual therapy with high dose FF:

FF/UMEC/VI 100/62.5/25 vs. FF/VI 200/25

FF/UMEC/VI 100/31.25/25 vs. FF/VI 200/25
2) The benefit of increase FF dose in triple therapy:

FF/UMEC/VI 200/62.5/25 vs.  FF/UMEC/VI 100/62.5/25

FF/UMEC/VI 200/31.25/25 vs.  FF/UMEC/VI 100/31.25/25
3) The benefit of increasing UMEC dose in triple therapy:

FF/UMEC/VI 100/62.5/25 vs. FF/UMEC/VI 100/31.25/25

FF/UMEC/VI 200/62.5/25 vs. FF/UMEC/VI 200/31.25/25
9.3.4.
Multiple Comparisons and Multiplicity
In order to account for multiple tests involving two UMEC doses and across multiple 
efficacy endpoints, a step-down testing procedure will be applied whereby inference for a 
test in the pre-defined hierarchy is dependent upon statistical significance having been 
achieved for the previous tests in the hierarchy. 
A step-down closed testing approach will be applied for the primary efficacy endpoint, 
the key secondary efficacy endpoint, and the secondary efficacy endpoints SGRQ, ACQ-
7, and E-RS. Specifically, if the defined treatment comparisons for the primary efficacy 
endpoint between triple therapy and dual therapy at the high dose of UMEC 62.5 mcg are 
statistically significant at the 0.05 level for both fixed FF doses (100 and 200mcg), then 
the replicate efficacy of UMEC 62.5mcg is demonstrated, and the defined treatment
comparison between triple therapy and dual therapy will be tested for the key secondary 
efficacy endpoint of moderate/severe asthma exacerbations based on the combined data 
of both FF doses for UMEC 62.5mcg. If the test for the key secondary efficacy endpoint 
is statistically significant at the 0.05 level, then the secondary efficacy endpoints for 
SGRQ (Mean change from baseline in SGRQ at Week 24) and ACQ-7 (Mean change 
from baseline in ACQ-7 at Week 24) will be tested sequentially based on the combined 
data of both FF doses for UMEC 62.5mcg at significance level 0.05.


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If all tests mentioned above for UMEC 62.5 mcg are statistically significant at the 0.05 
level, the above testing hierarchy for the primary efficacy endpoint, the key secondary 
efficacy endpoint, and the secondary efficacy endpoints SGRQ and ACQ-7 will be 
repeated for the low dose of UMEC 31.25 mcg.
If all tests for the primary, the key secondary, and the secondary efficacy endpoints for 
SGRQ and ACQ-7 are statistically significant at the 0.05 level for both UMEC 62.5mcg 
and 31.25mcg, the secondary endpoint for E-RS (Mean change from baseline in E-RS 
score over the Weeks 21-24 (inclusive) of the treatment period) will be tested at the 
significance level 0.05 for UMEC 62.5 and UMEC 31.25 in sequence.
The family-wise Type I Error is strongly controlled at 0.05 level for both UMEC 
62.5mcg and UMEC 31.25mcg on the primary endpoint (trough FEV1),  the key 
secondary endpoint (moderate/severe asthma exacerbations), and the secondary endpoints 
on SGRQ, ACQ-7, and E-RS.  
All secondary non-lung function efficacy endpoints will be tested for triple vs. dual using 
the combined data of both FF doses, at a given UMEC dose. The full testing hierarchy is 
provided below:


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Multiplicity Adjustment Plan
Level 2: Key secondary endpoint, UMEC 62.5 mcg: Annualized rate of moderate/severe asthma 
exacerbations, 
One comparison based on pooled data:
(FF/UMEC/VI 100/62.5/25, 200/62.5/25) vs. (FF/VI 100/25, 200/25)
Test needs to be significant at 0.05 level in order to move to Level 3 test.  
Level 3: Secondary endpoint, UMEC 62.5 mcg: Mean change from baseline in SGRQ at Week 24, 
One comparison based on pooled data:
(FF/UMEC/VI 100/62.5/25, 200/62.5/25) vs. (FF/VI 100/25, 200/25)
Test needs to be significant at 0.05 level in order to move to Level 4 test.  
Level 5: Primary endpoint, UMEC 31.25mcg:  Mean change from baseline in trough FEV1 at Week 
24,
Two comparisons:
FF/UMEC/VI 100/31.25/25 vs. FF/VI 100/25 
FF/UMEC/VI 200/31.25/25 vs. FF/VI 200/25
Both tests need to be significant at 0.05 level in order to demonstrate replicate efficacy for UMEC 
31.25mcg and move to Level 6 test. 
Level 4: Secondary endpoint, UMEC 62.5 mcg: Mean change from baseline in ACQ-7 at Week 24, 
One comparison based on pooled data:
(FF/UMEC/VI 100/62.5/25, 200/62.5/25) vs. (FF/VI 100/25, 200/25)
Test needs to be significant at 0.05 level in order to move to Level 5 tests.  
Level 1: Primary endpoint, UMEC 62.5 mcg:  Mean change from baseline in trough FEV1 at Week 
24, 
Two comparisons:
FF/UMEC/VI 100/62.5/25 vs. FF/VI 100/25 
FF/UMEC/VI 200/62.5/25 vs. FF/VI 200/25
Both tests need to be significant at 0.05 level in order to demonstrate replicate efficacy for UMEC 
62.5 mcg in order to move to Level 2 test. 


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For all non-lung function secondary efficacy endpoints and all other efficacy endpoints, 
the following treatment comparisons of triple therapy vs. dual therapy at a fixed FF dose, 
for each given UMEC dose, will also be made without adjusting for multiplicity:
Level 6: Key secondary endpoint, UMEC 31.25 mcg: Annualized rate of moderate/severe asthma 
exacerbations, 
One comparison based on pooled data:
(FF/UMEC/VI 100/31.25/25, 200/31.25/25) vs. (FF/VI 100/25, 200/25)
Test needs to be significant at 0.05 level in order to move to Level 7 test.  
Level 7: Secondary endpoints, UMEC 31.25 mcg: Mean change from baseline in SGRQ at Week 
24.
One comparison based on pooled data:
(FF/UMEC/VI 100/31.25/25, 200/ 31.25/25) vs. (FF/VI 100/25, 200/25)
Test needs to be significant at 0.05 level in order to move to Level 8 test. 
Level 8: Secondary endpoint, UMEC 31.25 mcg: Mean change from baseline in ACQ-7 at Week 
24.
One comparison based on pooled data:
(FF/UMEC/VI 100/31.25/25, 200/ 31.25/25) vs. (FF/VI 100/25, 200/25)
Test needs to be significant at 0.05 level in order to move to Level 9 test.  
Level 9: Secondary endpoint, UMEC 62.5 mcg: Mean change from baseline in E-RS score over 
Weeks 21-24 (inclusive) of the treatment period.
One comparison based on pooled data:
(FF/UMEC/VI 100/62.5/25, 200/62.5/25) vs. (FF/VI 100/25, 200/25)
Test needs to be significant at 0.05 level in order to move to Level 10 test.  
Level 10: Secondary endpoint, UMEC 31.25 mcg: Mean change from baseline in E-RS score over 
Weeks 21-24 (inclusive) of the treatment period.
One comparison based on pooled data:
(FF/UMEC/VI 100/31.25/25, 200/31.25/25) vs. (FF/VI 100/25, 200/25)


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
FF/UMEC/VI 100/31.25/25 mcg vs. FF/VI 100/25 mcg

FF/UMEC/VI 200/31.25/25 mcg vs. FF/ VI 200/25 mcg

FF/UMEC/VI 100/62.5/25 mcg vs. FF/VI 100/25 mcg

FF/UMEC/VI 200/62.5/25 mcg vs. FF/ VI 200/25 mcg
For all efficacy endpoints (primary, secondary, and other), treatment comparisons 
between triple therapy at low dose FF vs. dual therapy with high dose FF, or the benefit 
of increasing FF dose in a triple therapy, or the benefit of increasing UMEC dose in a
triple therapy as outlined in 1) to 3) of Section 9.3.3 , respectively, will also be made 
without adjusting for multiplicity. 
9.4.
Key Elements of Analysis Plan
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). 
In general, the baseline value is the last assessment value prior to randomization at Visit 3
for the efficacy endpoints based on assessments at clinic visits, and the average value 
over the last 14 days prior to randomization during the stabilization period for the 
efficacy endpoints based on subjects’ diary data.  The covariates to be considered in the 
efficacy analyses include age, sex, the randomization stratification variable, and the 
baseline value, if relevant. For the pooled analyses of triple therapy vs. dual on non-lung 
function efficacy endpoints using combined data from both FF doses, the FF dosage will 
also be included in the analysis model as a categorical covariate to account for possible 
heterogeneity and/or data variability resulted from different ICS doses. Other covariates, 
if appropriate, may be considered. Specific details will be provided in the RAP.
9.4.1.
Primary Analyses
The primary efficacy endpoint is the mean change from baseline in trough FEV1 at the 
end of the 24-week treatment period. For each subject, the baseline value of clinic FEV1 
is the last acceptable/borderline acceptable (pre-dose) FEV1 value obtained prior to 
randomization (either from Visit 3 pre-dose or from Visit 2 pre-bronchodilator).
The primary efficacy analysis will evaluate the “de facto” type estimand in the Intent-to-
Treat population, using a mixed-model repeated measures (MMRM) analysis, including 
all trough FEV1 recorded post randomization.  Analyses will include the fixed, 
categorical effects of treatment, visit, treatment by visit interaction, sex, randomization 
stratification by pre-study ICS treatment dosage strength (mid, high) at screening, as well 
as the continuous, fixed covariates of age, baseline value, and baseline value by visit 
interaction.  Point estimates and 95% confidence intervals will be calculated for the 
following primary comparisons of interest. 
There are two treatment comparisons to demonstrate the replicate efficacy for the UMEC 
62.5 mcg dose:


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
FF/UMEC/VI 100/62.5/25 mcg vs. FF/VI 100/25 mcg

FF/UMEC/VI 200/62.5/25 mcg vs. FF/ VI 200/25 mcg
Additionally, there will be two treatment comparisons for the UMEC 31.25 mcg dose to 
demonstrate the replicate efficacy for the UMEC 31.25 mcg dose:

FF/UMEC/VI 100/31.25/25 mcg vs. FF/VI 100/25 mcg

FF/UMEC/VI 200/31.25/25 mcg vs. FF/ VI 200/25 mcg
In addition, a de jure estimand, including data collected over the randomized double-
blind treatment period, will be analyzed using a MMRM model. Sensitivity analyses to 
assess the impact of missing data will be detailed in the RAP.
Other pairwise treatment comparisons of interest as outlined in Section 9.3.3 will also be 
provided for the primary efficacy endpoint.
9.4.2.
Secondary Analyses
The key secondary efficacy endpoint is the annualized rate of moderate/severe asthma 
exacerbations.  Moderate/severe asthma exacerbations from the start to the end of double-
blinded study period will be used in the analysis, regardless of subject’s IP completion 
status. Exacerbations separated by less than 7 days will be treated as a continuation of the 
same exacerbation.
The exacerbation rate will be analysed using a generalised linear model, assuming the 
number of exacerbations has a negative binomial probability distribution and that its 
mean is related to covariate factors with a ‘log link’ function. The logarithm of time 
(year) on study will be used as an offset variable. The model will include covariates for 
age, sex, treatment group, randomization stratification by pre-study ICS treatment dosage 
strength (mid, high) at screening, and the FF dosage (categorical). 
For each given UMEC dose, there is one treatment comparison of interest to demonstrate 
the efficacy of UMEC for the key secondary endpoint, based on the pooled data from 
both FF doses for triple therapy and dual therapy, respectively:

FF/UMEC/VI (100/62.5/25 and 200/62.5/25) vs. FF/VI (100/25 and 200/25) 

FF/UMEC/VI (100/31.25/25 and 200/31.25/25) vs. FF/VI (100/25 and 200/25).
All pairwise treatment comparisons of interest as outlined in Section 9.3.3 will also be 
provided for the key secondary efficacy endpoint.
9.4.3.
Other Analyses
Full details of the analyses to be performed on all efficacy endpoints, as well as details of 
time points to be analyzed, will be given in the RAP.


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9.4.4.
Examination of Subgroups and Phenotypic Characteristics
To explore differential responses and the phenotypic characteristics, subgroup and 
exploratory analyses may be considered. Of particular interest are the following 
phenotypic variables: age, sex, baseline lung function, reversibility to albuterol and 
ipratropium, asthma disease history, atopic status, exacerbation history, and biomarkers 
(blood and FeNO). The details of these exploratory analyses will be provided in the RAP.
9.4.5.
Pharmacokinetic Analyses
The purpose of PK sampling in this study is for characterisation of PK of FF, UMEC and 
VI in the target asthma patients following FF/UMEC/VI administration. Plasma 
concentration-time data for FF, UMEC and VI will be subjected separately to nonlinear 
mixed effects modelling using NONMEM or other programs to develop the population 
PK models. Full details of the analyses for PK endpoints will be provided in the RAP.
9.4.6.
Exploratory Analysis
The psychometric properties of the E-RS (see Section 7.3.5.1.1) and Supplemental 
asthma items (see Section 7.3.5.1.2) will be evaluated to support qualification of the E-
RS as an endpoint for asthma.  These exploratory analyses may be provided in a separate 
RAP.
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with International 
Conference on Harmonisation (ICH) Good Clinical Practice (GCP) and applicable 
country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable


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
Obtaining signed informed consent

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol 
deviations to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, 
or both.

Signed informed consent must be obtained for each subject prior to participation 
in the study

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, 
written approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the eCRF
will serve as the source document.
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements.
The Investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents.
10.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and 
the regulatory agencies may conduct a regulatory inspection at any time during or 
after completion of the study. 


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
In the event of an assessment, audit or inspection, the Investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss 
the conduct of the study, any findings/relevant issues and to implement any 
corrective and/or preventative actions to address any findings/issues identified.
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the Investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard 
Operating Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this 
study at any time for reasons including, but not limited to, safety or ethical issues 
or severe non-compliance. For multicenter studies, this can occur at one or more 
or at all sites.  

If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the Investigator or the head of the medical institution (where 
applicable).  When feasible, GSK will provide advance notification to the 
Investigator or the head of the medical institution, where applicable, of the 
impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all Investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.  

If required by applicable regulations, the Investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the Investigator or the head of the medical 
institution (where applicable) must maintain all site study records (except for 
those required by local regulations to be maintained elsewhere), in a safe and 
secure location.  

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review 
in conjunction with assessment of the facility, supporting systems, and relevant 
site staff.  

Where permitted by local laws/regulations or institutional policy, some or all of 
these records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.  


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
The Investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, 
including re-generating a hard copy, if required.  Furthermore, the Investigator
must ensure there is an acceptable back-up of these reproductions and that an 
acceptable quality control process exists for making these reproductions.

GSK will inform the Investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by 
any institutional requirements or local laws or regulations, GSK 
standards/procedures, and/or institutional requirements.  

The Investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of 
ownership of the records in the event the Investigator is no longer associated with 
the site.
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
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. GSK will provide the Investigator with the randomization codes for their site 
only after completion of the full statistical analysis.
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.


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11.
REFERENCES
American Heart Association.  Classes of Heart Failure.  Available at: 
http://www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classes-
of-Heart-Failure_UCM_306328_Article.jsp (4 May 2016).
British Guideline on the Management of Asthma. British Thoracic Society / Scottish 
Intercollegiate Guidelines Network (BTS/SIGN) 2016. Available from: https://www.brit-
thoracic.org.uk/guidelines-and-quality-standards/asthma-guideline/
Ducharme FM, Ni Chroinin M, Greenstone I, Lasseson TJ. Addition of long-acting 
beta2-agonists to inhaled steroids versus higher dose inhaled steroids in adults and 
children with persistent asthma. Cochrane Database Syst Rev 2010; 14 4):CD005533.
Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. 
National Asthma Education and Prevention Programme, National Heart, Lung and Blood 
Institute, National Institutes of Health (NIH) 2007. Available from: 
http://www.nhlbi.nih.gov/health-pro/guidelines/current/asthma-guidelines
Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma 
(GINA) 2016. Available from: http://www.ginasthma.org/
Global Strategy for the Diagnosis, Management and Prevention of COPD, Global
Initiative for Chronic Obstructive Lung Disease (GOLD) 2016. Available from: 
http://www.goldcopd.org/
Hekking PP, Wener RR, Amelink M, Zwinderman AH, Bouvy ML, Bel EH. The 
prevalence of severe refractory asthma. J Allergy Clin Immunol 2015;135(4):896-902.
Ichinose M, Sugiura H, Nagase H, Yamaguchi M, Inoue H, Sagara H, et al. Japanese 
guidelines for adult asthma 2017. Allergol Int. 2017;66(2):163-189
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA,et al. 
Pharmacokinetics of acetaminophen-protein adducts in adults with acetaminophen 
overdose and acute liver failure. Drug Metab Dispos 2009;37:1779-1784.
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status for chronic airflow limitation. The St. George's Respiratory Questionnaire. Am Rev 
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Jones PW. St. George’s Respiratory Questionnaire: MCID. Journal of Chronic 
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Juniper EF, Bousquet J, Abetz L, Bateman ED; GOAL Committee. Identifying 'well-
controlled' and 'not well-controlled' asthma using the Asthma Control Questionnaire. 
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a questionnaire to measure asthma control. Eur Respir J 1999;14:902-907.
Juniper EF, Svensson K, Mörk AC, Ståhl E. Measurement properties and interpretation of 
three shortened versions of the asthma control questionnaire. Respir Med 2005;99:553-
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Juniper EF, Svensson K, Mörk AC, Ståhl E. Modification of the Asthma Quality of Life 
Questionnaire (standardised) in patients 12 years and older. Health and Quality of Life 
Outcomes 2005;3:58.
Keene ON, Jones MRK, Lane PW, Anderson J. Analysis of exacerbation rates in asthma 
and chronic obstructive pulmonary disease: example from the TRISTAN study. 
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active-comparator, randomised trials. Lancet Respir Med 2015;3:367-76.
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asthma poorly controlled with standard combination therapy. N Engl J Med
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12.
APPENDICES
12.1.
Appendix 1 – Abbreviations and Trademarks
Abbreviations
ACQ
Asthma Control Questionnaire
ACT
Asthma Control Test
ADR
Adverse Drug Reaction
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine Transaminase
AM
Morning
AQLQ
Asthma Quality of Life Questionnaire
AST
Aspartate Transaminase
ATS
American Thoracic Society
AUC
Area Under the Curve
BID
Twice daily
BMI
Body Mass Index
BPM
Beats Per Minute
BST
Bioanalytical Science and Toxicokinetics
BTS/SIGN
British Thoracic Society / Scottish Intercollegiate 
Guidelines Network
BUN
Blood Urea Nitrogen
CI
Confidence Interval
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic Obstructive Pulmonary Disease
DNA
Deoxyribonucleic acid
DMPK
Drug Metabolism and Pharmacokinetics
DPI
Dry Powder Inhaler
ECG
Electrocardiogram
(e)CRF
(Electronic) Case Report Form
eDiary
Electronic Diary
EMA
European Medicines Agency
EOS
End of study
E-RS
Evaluating Respiratory Symptoms
ERS
European Respiratory Society
EU
European Union
EW
Early Withdrawal
FDA
Food and Drug Administration
FeNO
Fractional Exhaled Nitric Oxide
FEV1
Forced expiratory volume in 1 second
FF
Fluticasone Furoate
FP
Fluticasone Propionate
FRP
Female of Reproductive Potential
FSC
Fluticasone Salmeterol Combination


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FSH
Follicle Stimulating Hormone
FVC
Forced Vital Capacity
GCP
Good clinical practice
GCSP
Global Clinical Safety and Pharmacovigilance
GINA
Global Initiative for Asthma
GLP
Good Laboratory Practice
GOLD
Global Initiative for Chronic Obstructive Lung Disease
GSK
GlaxoSmithKline
hCG
Human Chorionic Gonadotropin
HIV
Human Immunodeficiency Virus
HPA
Hypothalamic Pituitary Axis
HR-QoL
Health-Related Quality of Life
HRT
Hormone Replacement Therapy
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
ICS
Inhaled Corticosteroids
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IL
Interleukin
IOP
Intraocular Pressure
IP
Investigational Product
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
Intent to Treat
kg
Kilogram
L/min
Liters per minute
LABA
Long-Acting Beta-2-Agonists
LAMA
Long-Acting Muscarinic Antagonist
LOCS III
Lens Opacities Classification System III
LRTI
Lower Respiratory Tract Infection
LTRA
Leukotriene Receptor Antagonist
MACE
Major Adverse Cardiac Event
MAOI
Monoamine Oxidase Inhibitors
MedDRA
Medicinal Dictionary for Regulatory Activities
mcg (g)
Microgram
MDI
Metered Dose Inhaler
mg
Milligram
min
Minute
mL
Milliliter
MMRM
Mixed-Model Repeated Measures
MSDS
Material Safety Data Sheet
msec
Millisecond
NIH
National Institutes of Health
NYHA
New York Heart Association
OCS
Oral Corticosteroids


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PEF
Peak Expiratory Flow
PK
Pharmacokinetic
PM
Afternoon
prn
As needed
QD
Once daily
QTc
QT interval corrected for heart rate
QTcB
QT interval corrected for heart rate by Bazett’s formula
QTcF
QT interval corrected for heart rate by Fridericia’s formula
RAP
Reporting and Analysis Plan
RBC
Red Blood Cell
RNA
Ribonucleic acid
SABA
Short-Acting Beta-2-Agonists
SAE
Serious Adverse Event
SGRQ
St. George’s Respiratory Questionnaire
SPC
Summary of Product Characteristics
SRM
Study Reference Manual
TQT
Thorough QT
ULN
Upper Limit of Normal
UMEC
Umeclidinium
US
United States
VI
Vilanterol
VT
Ventricular Tachycardia
WBC
White Blood Cell
WPAI-SHP
Work Productivity and Activity Impairment-Specific Health 
Problem
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
DISKUS
NONMEM
ELLIPTA


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12.2.
Appendix 2 Liver Safety Required Actions and Follow up 
Assessments
Liver chemistry stopping and follow up criteria have been designed to assure subject 
safety and evaluate liver event etiology (in alignment with the FDA premarketing clinical 
liver safety guidance [Food and Drug Administration 2009]).
Liver chemistry stopping criteria 1-5 are defined below:
1.
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) (or ALT 3xULN 
and INR>1.5, if INR measured)
NOTE: If serum bilirubin fractionation is not immediately available, withdraw study drug 
if ALT 3xULN and bilirubin 2xULN. Serum bilirubin fractionation should be 
performed if testing is available. If testing is unavailable, record presence of detectable 
urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver 
injury.
2.
ALT 8xULN.
3.
ALT 5xULN but <8 xULN persists for 2 weeks
4.
ALT  3xULN if associated with symptoms (new or worsening) believed to be 
related to  hepatitis (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).
5.
ALT 5xULN but <8 xULN and cannot be monitored weekly for 2 weeks
When any of the liver chemistry stopping criteria 1-5 is met, do the following:

Immediately withdraw investigational product

Report the event to GSK within 24 hours of learning its occurrence

Complete the liver event CRF and SAE data collection tool if the event also meets 
the criteria for an SAE. All events of ALT 3xULN and bilirubin 2xULN (>35% 
direct) (or ALT 3xULN and INR>1.5, if INR measured); INR measurement is not 
required and the threshold value stated will not apply to patients receiving 
anticoagulants), termed ‘Hy’s Law’, must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis). 
NOTE: if serum bilirubin fractionation is not immediately available, withdraw study drug 
if ALT 3xULN and bilirubin 2xULN. Serum bilirubin fractionation should be 
performed if testing is available. If testing is unavailable, record presence of detectable 
urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver 
injury.

Complete the liver imaging and/or liver biopsy CRFs if these tests are performed

Perform liver event follow up assessments, and monitor the subject until liver 
chemistries resolve, stabilize, or return to baseline values as described below. 


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
Withdraw the subject from the study (unless further safety follow up is required) 
after completion of the liver chemistry monitoring as described below.

Do not re-challenge with investigational product.
In addition, for criterion 1: 

Make every reasonable attempt to have subjects return to clinic within 24 hours for 
repeat liver chemistries, liver event follow up assessments (see below), and close 
monitoring

A specialist or hepatology consultation is recommended

Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values
For criteria 2, 3, 4 and 5:

Make every reasonable attempt to have subjects return to clinic within 24-72 hrs for 
repeat liver chemistries and liver event follow up assessments (see below)

Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values; criterion 5 subjects 
should be monitored as frequently as possible.
Subjects with ALT 5xULN and <8xULN which exhibit a decrease to ALT x3xULN, 
but <5xULN and bilirubin <2xULN without hepatitis symptoms or rash, and who can be 
monitored weekly for 4 weeks:

Notify the GSK medical monitor within 24 hours of learning of the abnormality to 
discuss subject safety

Can continue investigational product 

Must return weekly for repeat liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilize or return to within baseline 

If at any time these subjects meet the liver chemistry stopping criteria, proceed as 
described above

If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, monitor 
subjects twice monthly until liver chemistries normalize or return to within baseline 
values. 
For criteria 1-5, make every attempt to carry out the liver event follow up assessments
described below:

Viral hepatitis serology including:

Hepatitis A IgM antibody;

Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); 

Hepatitis C RNA; 

Cytomegalovirus IgM antibody;  


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
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  

Hepatitis E IgM antibody 

Blood sample for PK analysis, obtained within 72 hours of last dose.  Record the 
date/time of the PK blood sample draw and the date/time of the last dose of 
investigational product prior to blood sample draw on the CRF. If the date or time of 
the last dose is unclear, provide the subject’s best approximation. If the date/time of 
the last dose cannot be approximated OR a PK sample cannot be collected in the 
time period indicated above, do not obtain a PK sample. Instructions for sample 
handling and shipping are in the SRM.

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 hepatitis or 
hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever rash or eosinophilia as relevant on the AE report form

Record use of concomitant medications, acetaminophen, herbal remedies, other over 
the counter medications, or putative hepatotoxins, on the concomitant medications 
report form.

Record alcohol use on the liver event alcohol intake case report form
The following are required for subjects with ALT 3xULN and bilirubin 2xULN (>35% 
direct) but are optional for other abnormal liver chemistries:

Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney 
microsomal antibodies.

Serum acetaminophen adduct assay (quantifies potential acetaminophen contribution 
to liver injury, detectable by HPLC assay more than 1 week following 
acetaminophen use) [James 2009].  

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 antibody.

Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to 
evaluate liver disease.


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Figure 1
Phase III-IV Liver Safety Algorithms
Phase III-IV Liver Safety Algorithms
ALT>3xULN
plus 
bilirubin >2x 
ULN (or
plus INR >1.5, 
if measured)*
No
Yes
Yes
•Instruct subject to stop investigational product (IP)
•Notify GSK + arrange clinical followup within 24-72h
•Perform liver chemistries and liver event follow up 
assessments (serology, PK sample etc as in protocol) 
•Complete liver event CRF, SAE data collection tool if 
appropriate, + liver imaging +/or biopsy CRFs if  tests 
performed.
•Obtain weekly liver chemistries [**as far as possible] 
until resolved, stabilised or returned to baseline 
•Withdraw subject from study after liver chemistry 
monitoring complete + do not re-challenge with IP
•Instruct subject to stop investigational product (IP)
•Notify GSK + arrange clinical followup within 24h
•Perform liver chemistries and liver event follow up 
assessments (serology, PK sample etc as in protocol) 
•Report as SAE (excl. hepatic impairment or cirrhosis 
studies)+ complete liver event CRF, SAE data collection 
tool, + liver imaging +/or biopsy CRFs if tests performed.
•Obtain twice weekly liver chemistries until resolved, 
stabilised or returned to baseline values
•Consultation with hepatologist/specialist recommended
•Withdraw subject from study after liver chemistry 
monitoring complete + do not re-challenge with IP
Hepatitis 
symptoms
or rash?
No
Able to 
monitor 
weekly for 
4 weeks?
Yes
No**
Yes
Continue IP
Obtain twice 
monthly liver 
chemistries until 
normalised or 
back to baseline 
values
Yes
Yes
ALT<3xULN 
+ bilirubin
<2xULN 
after ? 4 
wks?
Yes
ALT 
>5xULN 
but 
<8xULN
No
ALT 
>8xULN
Yes
ALT >5 
and 
<8xULN 
for > 2 
wks
Yes
No
ALT>3xULN 
but <5xULN 
+ bilirubin
<2xULN+no 
symptoms
No
Able to 
monitor 
weekly for 
> 2 wks?
No
No
Notify GSK within 24h 
to discuss subject 
safety
Continue IP
Check liver chemistry 
weekly for 4 weeks
Yes
No
*INR value not applicable to patients on anticoagulants


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12.3.
Appendix 3 Genetic Research
Genetics – Background
Naturally occurring genetic variation may contribute to inter-individual variability in 
response to medicines, as well as an individual's risk of developing specific diseases. 
Genetic factors associated with disease characteristics may also be associated with 
response to therapy, and could help to explain some clinical study outcomes. For 
example, genetic variants associated with age-related macular degeneration (AMD) are 
reported to account for much of the risk for the condition [Gorin 2012] with certain 
variants reported to influence treatment response [Chen 2012]. Thus, knowledge of the 
genetic etiology of disease may better inform understanding of disease and the 
development of medicines. Additionally, genetic variability may impact the 
pharmacokinetics (absorption, distribution, metabolism, and elimination), or 
pharmacodynamics (relationship between concentration and pharmacologic effects or the 
time course of pharmacologic effects) of a specific medicine and/or clinical outcomes 
(efficacy and/or safety) observed in a clinical study.
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and: 

Response to medicine or any concomitant medicines;

Asthma susceptibility, severity, and progression and related conditions
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic 
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the study can participate in genetic research.  Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research.
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 


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identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.  

A 6ml blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. A 
blood sample is collected at the baseline visit, after the subject has been randomized 
and provided informed consent for genetic research. Instructions for collection and 
shipping of the genetic sample are described in the laboratory manual. The DNA 
from the blood sample may undergo quality control analyses to confirm the integrity 
of the sample. If there are concerns regarding the quality of the sample, then the 
sample may be destroyed. The blood sample is taken on a single occasion unless a 
duplicate sample is required due to an inability to utilize the original sample.  
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study.   This number can be traced or linked back to 
the subject by the Investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number). 
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study, or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 
for the purpose stated in this protocol and in the informed consent form.  Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study.  Genetic informed consent must be obtained prior to any blood being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA 
sample is retained

Discontinue participation in the genetic research and destroy the genetic DNA 
sample 
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the Investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. 


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Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis. 

If a subject withdraws consent for genetic research and genotype data has not been 
analyzed, it will not be analyzed or used for future research.  

Genetic data that has been analyzed at the time of withdrawn consent will 
continue to be stored and used, as appropriate.
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the Investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to 
complete this process as it will be completed as part of the consent and sample 
reconciliation process.  In this instance a sample destruction form will not be available to
include in the site files.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic 
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined.  Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care.
References
Chen H, Yu KD, Xu GZ. Association between Variant Y402H in Age-Related Macular 
Degeneration (AMD) Susceptibility Gene CFH and Treatment Response of AMD: A 
Meta-Analysis. PloS ONE 2012; 7: e42464
Gorin MB. Genetic insights into age-related macular degeneration: Controversies 
addressing risk, causality, and therapeutics. Mol. Asp. Med. 2012; 33: 467-486.


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12.4.
Appendix 4 Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.4.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

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 medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the Investigator.

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 prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected 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 this is an intentional overdose taken with possible suicidal/self-
harming intent.  This 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.  However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition 
of an AE or SAE.
Events NOT meeting definition of an AE include:

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.

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 


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leads to the procedure is an AE.

Situations where 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.
12.4.2.
Definition of Serious Adverse Events
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, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a. Results in death
b. Is life-threatening
NOTE:
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 hospitalization or prolongation of existing hospitalization
NOTE:

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 out-patient setting.  Complications that occur during hospitalization are 
AEs.  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 disability/incapacity
NOTE:

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 or prevent everyday 
life functions but do not constitute a substantial disruption


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e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether 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 should also be considered 
serious.

Examples of such events are 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
g. Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.
12.4.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following 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


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12.4.4.
Recording of AEs and SAEs
AEs 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) 
relative to the event.

The Investigator will then record all relevant information regarding an AE/SAE 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 GSK.  In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.

Subject-completed Value Evidence and Outcomes questionnaires and the collection 
of AE data are independent components of the study.

Responses to each question in the Value Evidence and Outcomes questionnaire will 
be treated in accordance with standard scoring and statistical procedures detailed by 
the scale’s developer.

The use of a single question from a multidimensional health survey to designate a 
cause-effect relationship to an AE is inappropriate.
12.4.5.
Evaluating AEs and SAEs
Assessment of Intensity
The Investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one 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 is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.


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Assessment of Causality

The Investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence 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 natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The Investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of 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 when 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 
prior to the initial transmission of the SAE data to GSK.

The Investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The Investigator is obligated to assist.  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 the designated 
reporting time frames.


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12.4.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the assigned SAE contact (see the 
Medical Monitor/Sponsor Information page at the beginning of this protocol)

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The Investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) 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, the site can report this information on a paper SAE form or to the assigned 
SAE contact by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.


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12.5.
Appendix 5 Reproduction
12.5.1.
Females of Non-Reproductive Potential and Females of 
Reproductive Potential
A female subject is eligible to participate if she is not pregnant (as confirmed by a 
negative serum human chorionic gonadotrophin (hCG) test), not lactating, is not planning 
on becoming pregnant during the study and at least one of the following conditions 
applies:

Non-reproductive potential defined as:
Pre-menopausal females with one of the following:
Documented tubal ligation
Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion 
Hysterectomy
Documented Bilateral Oophorectomy
Postmenopausal defined as 12 months of spontaneous amenorrhea with an 
appropriate clinical profile (e.g., age appropriate, >45 years, in the absence of 
hormone replacement therapy). In questionable cases for women <60 years of 
age, a blood sample with simultaneous follicle stimulating hormone and 
estradiol falling into the central laboratory’s postmenopausal reference range is 
confirmatory.  Females under 60 years of age, who are on HRT and whose 
menopausal status is in doubt, are required to use a highly effective method to 
avoid pregnancy if they wish to continue their HRT during the study.  
Otherwise, they must discontinue HRT to allow confirmation of post-
menopausal status prior to study enrolment. For most forms of HRT, at least 2 
to 4 weeks will elapse between the cessation of therapy and the blood draw; this 
interval depends on the type and dosage of HRT.  Following confirmation of 
their post-menopausal status, subjects can resume use of HRT during the study 
without use of a highly effective method to avoid pregnancy.

Reproductive potential and agrees to follow one of the options listed in the Modified 
List of Highly Effective Methods for Avoiding Pregnancy in Females of 
Reproductive Potential (FRP) (see Section 12.5.2) from the screening visit until after 
the last dose of study medication and completion of the follow-up visit.
12.5.2.
List of Highly Effective Methods for Avoiding Pregnancy in 
Females of Reproductive Potential (FRP)
The list does not apply to FRP with same sex partners or for subjects who are and will 
continue to be abstinent from penile-vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyle. Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.


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1.
Contraceptive subdermal implant
2.
Intrauterine device or intrauterine system
3.
Combined estrogen and progestogen oral contraceptive [Hatcher 2011])
4.
Injectable progestogen [Hatcher 2011]
5.
Contraceptive vaginal ring [Hatcher 2011]
6.
Percutaneous contraceptive patches [Hatcher 2011]
7.
Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher 2011]. The documentation on male sterility can come from the site 
personnel’s: review of subject’s medical records, medical examination and/or semen 
analysis, or medical history interview provided by her or her partner.
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The Investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
12.5.3.
Collection of Pregnancy Information

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 mother and infant, 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 participants, he or she may learn of an SAE through 
spontaneous reporting.
Any female subject who becomes pregnant while participating in the study will 
immediately discontinue study medication.


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12.5.4.
References
CHMP, 2005 - EMA - Guideline on Adjuvants in Vaccines for Human Use, 
(CHMP/VEG/134716/2004), January 2005.
Cole LA, Khanlian SA, Sutton JM, Davies S, Rayburn WF. Accuracy of home pregnancy 
tests at the time of missed menses. Am J Ob Gyn 2004(190):100-5.
EMA/CHMP/ICH/449035/2009: General principles to address virus and vector shedding. 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/
WC500002680.pdf Accessed 28 Nov 2014.
EMEA/CHMP/GTWP/125459/2006: Guideline on the Nonclinical Studies Required 
Before First Clinical Use of Gene Therapy Medicinal Products [2008]
FDA CBER Guidance for industry, “Considerations for Developmental Toxicity Studies 
for Preventive and Therapeutic Vaccines for Infectious Disease Indications. U.S. FDA; 
Feb. 2006. 
FDA Medical Devices Safety Alerts and Notices, “Blood human chorionic gonadotropin 
(hCG) assays: What laboratorians should know about false-positive results”, 
http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/TipsandArticlesonDeviceS
afety/ucm109390.htm, accessed 17 Nov 2014.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, Policar MS, 
editors. Contraceptive Technology. 20th edition. Atlanta, Georgia: Ardent Media, Inc., 
2011: 50. Table 3-2.
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use. ICH Harmonized Tripartite Guideline. Detection of 
Toxicity to Reproduction for Medicinal Products & Toxicity to Male Fertility. Parent 
Guideline dated 24 June 1993 (Addendum dated 9 November 2000 incorporated in 
November 2005. ICH S5 (R2)
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use.  ICH Harmonized Tripartite Guideline. Nonclinical 
Evaluation for Anticancer Pharmaceuticals. ICH S9. 2009.
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use. ICH Harmonized Tripartite Guideline. Nonclinical 
Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for 
Pharmaceuticals. ICH M3 (R2). 2009.
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use. ICH Harmonized Tripartite Guideline. Preclinical 
Safety Evaluation of Biotechnology-Derived Pharmaceuticals. ICH S6 and Addendum 
ICH S6 (R1). 2011.


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Machaud G, ErnstKronenberg HM, Melmed S, Polonsky KS, Larsen PR, editors.
Williams Textbook of Endocrinology, 11th edition. Philadelphia: Saunders, 2008.
Strauss JF, Barbieri RL, editors. Yen and Jaffe’s Reproductive Endocrinology. 5th 
edition, Philadelphia, Elsevier/Saunders, 2004.
U.S. Dept of Health and Human Services, FDA, Center For Biologics Evaluation and 
Research: Guidance for Human Somatic Cell Therapy and Gene Therapy [1998]
WHO, 2013 - WHO - Guidelines on the Nonclinical Evaluation of Vaccine Adjuvants 
and Adjuvanted Vaccines, 2013
World Health Organization. WHO/CONRAD Technical Consultation on Nonoxynol-9.
World Health Organization; Department of Reproductive Health and Research; Geneva; 
9-10 October 2001. Summary Report. 2001. WHO/RHR/03.8.


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12.6.
Appendix 6 Daily eDiary Questions
12.6.1.
Morning Questions
The subject should complete the morning eDiary questions upon wakening and prior to 
the administration of study treatment.
Night-time Awakening
1.
Did you wake up due to asthma 
symptoms (i.e. wheezing, 
coughing, shortness of breath, or 
chest tightness).
No
Yes
2.
If Yes; when you woke up due to 
your asthma symptoms did you 
use any rescue inhaler?
No
Yes
12.6.2.
Evening Questions
The subject should complete the evening eDiary questions just before going to bed.
E-RS
1.
Did your chest feel 
congested today?
Not at all
Slightly
Moderately
Severely
Extremely
2.
How often did you cough 
today?
Not at all 
Rarely 
Occasionally 
Frequently 
Almost constantly 
3.
How much mucus (phlegm) 
did you bring up when 
coughing today?
None at all 
A little 
Some 
A great deal 
A very great deal 
4.
How difficult was it to 
bring up mucus (phlegm) 
today?
Not at all 
Slightly 
Moderately 


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Quite a bit 
Extremely 
5.
Did you have chest 
discomfort today?
Not at all 
Slight 
Moderate 
Severe 
Extreme 
6. 
Did your chest feel tight 
today?
Not at all
Slightly
Moderately
Severely
Extremely
7. 
Were you breathless today?
Not at all
Slightly
Moderately
Severely
Extremely
8. 
Describe how breathless 
you were today:
Unaware of breathlessness
Breathless during strenuous activity
Breathless during light activity
Breathless when washing or dressing
Present when resting 
9. 
Were you short of breath 
today when performing 
your usual personal care
activities like washing or 
dressing?
Not at all 
Slightly 
Moderately 
Severely 
Extremely 
Too breathless to do these
10.
Were you short of breath 
today when performing 
your usual indoor activities 
like cleaning or household 
work?
Not at all 
Slightly 
Moderately 
Severely 
Extremely 
Too breathless to do these
11. 
Were you short of breath 
today when performing 
your usual activities outside 
the home such as yard work 
or errands?
Not at all 
Slightly 
Moderately 
Severely 
Extremely 
Too breathless to do these


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Supplemental Asthma Items
1. Did you wheeze today?’ 
Not at all 
Rarely 
Occasionally 
Frequently 
Almost constantly
2. Were you short of breath today 
when performing strenuous 
activities such climbing stairs, 
running, or participating in 
sports activity.  
Not at all 
Slightly 
Moderately 
Severely 
Extremely
Asthma Symptom and Physical Activity Questions
1. Please describe the severity of 
your asthma symptoms today 
(i.e. cough, wheeze, chest 
tightness, shortness of breath
No asthma symptoms
Mild asthma symptoms
Moderate asthma symptoms
Severe asthma symptoms
Very severe asthma symptoms
2. How limited were you in your 
activities today because of your 
asthma
Not at all limited
A little limited
Moderately limited
Severely limited
Totally limited


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12.7.
Appendix 7 Country Specific Requirements
12.7.1.
Country Specific Requirement for the Randomization of Subjects
Japan Only: Subjects will be stratified by pre-study ICS treatment dosage strength (mid, 
high) at screening and will be assigned to study treatment in accordance with a country-
specific randomization schedule (to ensure treatment balance within each stratum (mid-
or high-dose pre-study ICS treatment dosage strength). The randomization code will be 
generated by GSK using a validated computerized system. Subjects will be randomized 
using an IRT system (RAMOS NG). Once a randomization number is assigned to a 
subject it cannot be reassigned to any other subject in the study.


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12.8.
Appendix 8 Protocol Changes
12.8.1.
Protocol Amendment 01
This amendment applies to all sites.
List of protocol changes:
Text which has been added to the protocol is highlighted in bold, italic typeface. Text 
which has been deleted from the protocol is indicated by strike-through format.
Change Section, Text affected, and Rationale
1.
Medical Monitor/SAE Contact Information:
Changed from:
Role
Name
Day Time Phone Number 
and email address
After-hours 
Phone/Cell/
Pager 
Number
Site Address
Primary 
Medical 
Monitor
709 
Swedeland
Road, 
UW2531, King 
of Prussia, PA 
19406
Secondary 
Medical 
Monitor
 
Gunnels 
Wood Rd, 
Stevenage 
SG1 2NY
SAE 
contact  
information 
Medical 
monitor 
as above
PPD
PPD
PPD
PPD
PPD
PPD


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Change Section, Text affected, and Rationale
Changed to:
Role
Name
Day Time Phone Number and 
email address
After-hours 
Phone/Cell/
Pager 
Number
Site 
Addres
s
Primary 
Medical 
Monitor
Please refer to the Study 
Reference Manual (SRM) for 
phone number details.
709 
Swedel
and 
Road, 
UW253
1, King 
of 
Prussia
, PA 
19406
Please refer to the 
SRM.
Secondary 
Medical 
Monitor
Please refer to the SRM for 
phone number details.
Gunnel
s Wood 
Rd, 
Steven
age 
SG1 
2NY
Please refer to the 
SRM.
SAE contact  
information 
Medical 
monitor 
as above
Rationale: To capture a change in the assigned Medical Monitors as well as to 
provide a means to readily update the Medical Monitor contact details.
2.
Section 1 Protocol Synopsis: Rationale, second paragraph, first sentence:
Changed from:
The GINA guidelines recommend a long-acting muscarinic antagonist (LAMA)
as add-on treatment for adults with asthma that are currently taking medium to 
high dose inhaled corticosteroid/long-acting beta2 agonist (ICS/ LABA) 
treatment and have a history of exacerbations.
PPD
PPD
PPD
PPD
PPD
PPD


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Change Section, Text affected, and Rationale
Changed to:
The GINA guidelines recommend a long-acting muscarinic antagonist (LAMA)
as an add-on treatment option for adults with asthma that are currently taking 
medium to high dose inhaled corticosteroid/long-acting beta2 agonist (ICS/
LABA) treatment and have a history of exacerbations.
Rationale: To clarify the recommendation in the GINA guidelines.
3.
Section 1 Protocol Synopsis: Objective(s)/Endpoint(s) table, other secondary, 
endpoints column, fourth bullet-point
AND
Section 3 Objective(s) and Endpoint(s) table: other secondary, endpoints 
column, fourth bullet-point
AND
Section 7.3.1.3 Other Secondary Efficacy Endpoints: fourth bullet-point:
Changed from:

Mean change from baseline in Evaluating Respiratory Symptoms (E-
RS) total score over the first 24 weeks of the treatment period
Changed to:

Mean change from baseline in Evaluating Respiratory Symptoms (E-
RS) total score over Weeks 21 to 24 (inclusive) the first 24 weeks of the 
treatment period
Rationale: To align with the primary endpoint and Patient Reported 
Outcome/Quality of Life related secondary endpoints on the assessment time 
period and the statistical analysis methodology.
4.
Section 1 Protocol Synopsis: Treatment Arms and Duration, first paragraph, 
second bullet-point (Screening / run-in), second sentence:
Changed from:
Subjects will take the last dose of their usual (i.e. pre-study) ICS/LABA asthma 
medication the morning prior to Visit 1 (i.e. 24 hours prior to the Screening 
Visit).
Changed to:
Subjects will take the last dose of their usual (i.e. pre-study) ICS/LABA asthma 


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Change Section, Text affected, and Rationale
medication the morning prior to Visit 1 (i.e. 24 hours prior to the Screening 
Visit).
Rationale: To clarify that an Investigator is able to request that a subject 
withhold their ICS/LABA asthma medication for longer than the morning prior 
to Visit 1.
5.
Section 2.1 Study Rationale: first paragraph, first sentence:
Changed from:
The Global Initiative for Asthma guidelines [GINA 2016] recommend a long-
acting muscarinic antagonist (LAMA) as add-on treatment for adults (≥18 
years) with asthma that are currently taking medium-to-high dose inhaled 
corticosteroid and long-acting beta2 agonist (ICS/LABA) maintenance therapy 
and have a history of exacerbations.
Changed to:
The Global Initiative for Asthma guidelines [GINA 2016] recommend a long-
acting muscarinic antagonist (LAMA) as an add-on treatment option for adults 
(≥18 years) with asthma that are currently taking medium-to-high dose inhaled 
corticosteroid and long-acting beta2 agonist (ICS/LABA) maintenance therapy 
and have a history of exacerbations.
Rationale: To clarify the recommendation in the GINA guidelines.
6.
Section 3 Objective(s) and Endpoint(s): other objectives, endpoints column, 
ninth, tenth, eleventh, fourteenth and fifteenth bullet-points
AND
Section 7.3.1.4 Other Efficacy Endpoints: ninth, tenth, eleventh, fourteenth and 
fifteenth bullet-points:
Changed from:

Percentage of patients that have achieved asthma control based on 
ACQ-7 (i.e. a total score <0.75) at both Week 12 and Week 24

Percentage of patients that have achieved asthma control based on 
ACQ-6 (i.e. a total score <0.75) at both Week 12 and Week 24

Percentage of patients that have achieved asthma control based on 
ACQ-5 (i.e. a total score <0.75) at both Week 12 and Week 24

Mean change from baseline in E-RS domain scores over the first 24 
weeks of the treatment period


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Change Section, Text affected, and Rationale

Percent of patients meeting a responder threshold of ≥ 2 points 
improvement from baseline for the E-RS total score at Week 24
Changed to:

Percentage of patients that have achieved asthma control based on 
ACQ-7 (i.e. a total score <0.75) at both Week 12 and Week 24

Percentage of patients that have achieved asthma control based on 
ACQ-6 (i.e. a total score <0.75) at both Week 12 and Week 24

Percentage of patients that have achieved asthma control based on 
ACQ-5 (i.e. a total score <0.75) at both Week 12 and Week 24

Mean change from baseline in E-RS domain scores over Weeks 21 to 24 
(inclusive) the first 24 weeks of the treatment period

Percent of patients meeting a responder threshold of ≥ 2 points 
improvement from baseline for the E-RS total score over Weeks 21 to 
24 (inclusive) of the treatment period at Week 24
Rationale: To clarify:

The Asthma Control Questionnaire (ACQ) total score that denotes 
controlled asthma.

The endpoints “Mean change from baseline in E-RS domain scores” 
and “Percent of patients meeting a responder threshold of ≥ 2 points 
improvement from baseline for the E-RS total score” will be assessed 
over Weeks 21 to 24 (inclusive) of the treatment period (rather than 
‘over the first 24 weeks of the treatment period’ and ‘at Week 24’, 
respectively) to align with the secondary E-RS endpoint (i.e. mean 
change from baseline in E-RS total score).
7.
Section 4.2 Treatment Arms and Duration: Table 1, Phase 2 (Screening / Run-
in), description column, second sentence:
Changed from:
Subjects will take the last dose of their regular (i.e. pre-study) ICS/LABA 
asthma medication the morning prior to Visit 1 (i.e. 24 hours prior to the 
Screening Visit).
Changed to:
Subjects will take the last dose of their regular (i.e. pre-study) ICS/LABA 
asthma medication 24 hours the morning prior to Visit 1 (i.e. 24 hours 
prior to the Screening Visit).


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Rationale: To clarify that an Investigator is able to request that a subject 
withhold their ICS/LABA asthma medication for longer than the morning prior 
to Visit 1.
8.
Section 4.6.1 Risk Assessment (table): Systemic ICS effects row, Summary of 
Data/Rationale for Risk column, first paragraph:
Changed from:

No studies have shown a clinically relevant effect of FF/VI or FF on the 
hypothalamic pituitary axis (HPA). This includes a formal HPA study 
(HZA106851), which assessed the effects of FF/VI 100/25 and 200/25 on 
serum cortisol and 24 hour serum cortisol excretion, and multiple studies 
with COPD and asthma subjects which monitored urinary cortisol.
Changed to:

No studies have shown a clinically relevant effect of FF/VI or FF on the 
hypothalamic pituitary axis (HPA). This includes a formal HPA study 
(HZA106851), which assessed the effects of FF/VI 100/25 and 200/25 on 
serum cortisol and 24 hour serum urinary cortisol excretion, and multiple 
studies with COPD and asthma subjects which monitored urinary cortisol.
Rationale: To clarify that study HZA106851 assessed the effect of 
Investigational Product on 24 hour urinary (rather than serum) cortisol 
excretion.
9.
Section 5.1 Inclusion Criteria: inclusion criterion number 4:
Changed from:
Asthma Control: A documented non-routine healthcare visit due to acute 
asthma symptoms in the 1 year prior to Visit 1.
Changed to:
Asthma Control: A documented non-routine healthcare visit due to acute 
asthma symptoms in the 1 year prior to Visit 1. Note: please refer to the SRM 
for guidance on the following:
In the 1 year prior to Visit 1:
A documented healthcare contact for acute asthma symptoms
OR
A documented temporary change in asthma therapy for acute asthma 
symptoms, according to a pre-specified asthma action plan (or 
equivalent)


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Rationale: To align the criteria with the ‘real-world’ reporting/treatment of 
acute asthma symptoms.
10.
Section 5.1 Inclusion Criteria: inclusion criterion number 5:
Changed from:
Current Asthma Maintenance Therapy: Subjects are eligible if they have 
required daily ICS/LABA for at least 12 weeks prior to Visit 0 with no changes 
to maintenance asthma medications during the 6 weeks immediately prior to 
Visit 0 (including no changes to a stable total dose of ICS of >250 mcg/day 
fluticasone proprionate [FP, or equivalent]).
Examples of acceptable doses of commonly prescribed ICS and LABA or 
ICS/LABA combination medication is provided in the Study Reference Manual 
(SRM).  Dosing regimen (once or twice daily to equal the total daily dose) 
should be restricted to the current local product labels.
Changed to:
Current Asthma Maintenance Therapy: Subjects are eligible if they have 
required daily ICS/LABA for at least 12 weeks prior to Visit 0 with no changes 
to maintenance asthma medications during the 6 weeks immediately prior to 
Visit 0 (including no changes to a stable total dose of ICS of >250 mcg/day 
fluticasone proprionate [FP, or equivalent]).
Examples of acceptable doses of commonly prescribed ICS and LABA or 
ICS/LABA combination medication is are provided in the GINA guidelines 
[GINA 2016] Study Reference Manual (SRM).  Dosing regimen (once or twice 
daily to equal the total daily dose) should be restricted to the current local 
product labels/treatment guidelines.
Rationale: The criteria requires that, in the 6 weeks immediately prior to Visit 
0, there be no change to a stable total dose of ICS of >250 mcg/day FP (or 
equivalent) but there is no minimum total daily dose of LABA specified; 
therefore, only acceptable doses of commonly prescribed ICS (not LABA) need 
to be provided. The SRM references the GINA 2016 guidelines for acceptable 
doses of commonly prescribed ICS medication so a direct reference to the 
GINA 2016 guidelines has been provided in the protocol.
11.
Section 5.2 Exclusion Criteria: exclusion criterion number 2:
Changed from:
Asthma Exacerbation: Any asthma exacerbation requiring a change in 
maintenance asthma therapy in the 6 weeks prior to Visit 1.
Note: Subjects who experience an asthma exacerbation in the 6 weeks prior to 
Visit 1 are not explicitly excluded at Visit 1 provided that, at the Investigator’s 


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discretion, the subject’s condition is stable and they are considered 
appropriate for enrolment into this study of up to 12 months’ duration.
Changed to:
Asthma Exacerbation: Any asthma exacerbation requiring a change in 
maintenance asthma therapy in the 6 weeks prior to Visit 1.
Note: Subjects who experience an asthma exacerbation in the 6 weeks prior to 
Visit 1 are not explicitly excluded at Visit 1 provided that, at the Investigator’s 
discretion, the subject’s condition is stable and they are considered 
appropriate for enrolment into this study of up to 12 months’ duration.
Subjects requiring a temporary change in asthma therapy (e.g., oral 
corticosteroids or increased dose of ICS) to treat an exacerbation in the 6 
weeks prior to Visit 1 are not explicitly excluded at Visit 1 provided that, at 
the Investigator’s discretion, the subject’s condition is stable after they have 
resumed their pre-exacerbation maintenance asthma therapy (without 
modification) and they are considered appropriate for enrolment into this 
study of up to 12 months’ duration.
Rationale: To clarify which subjects may not be excluded from the study in the 
event that they experience an asthma exacerbation in the 6 weeks prior to Visit 
1.
12.
Section 5.2 Exclusion Criteria: exclusion criterion number 3:
Changed from:
Chronic Obstructive Pulmonary Disease: Subjects with the diagnosis of 
chronic obstructive pulmonary disease, as per Global Initiative for Chronic 
Obstructive Lung Disease (GOLD 2016) guidelines, including all of the 
following:
History of exposure to risk factors (i.e., especially tobacco smoke, 
occupational dusts and chemicals, smoke from home cooking and 
heating fuels);
AND
A post-albuterol/salbutamol FEV1/Forced Vital Capacity (FVC) ratio of 
<0.70 and a post-albuterol/salbutamol FEV1 of ≤70% of predicted 
normal values;
AND
Onset of disease ≥40 years of age
Changed to:
Chronic Obstructive Pulmonary Disease: Subjects with the diagnosis of 
chronic obstructive pulmonary disease, as per Global Initiative for Chronic 


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Obstructive Lung Disease (GOLD 2016) guidelines, including all of the 
following:
History of exposure to risk factors (i.e., especially tobacco smoke, 
occupational dusts and chemicals, smoke from home cooking and 
heating fuels). For personal tobacco use, see exclusion criterion 
number 14: Tobacco Use;
AND
A post-albuterol/salbutamol FEV1/Forced Vital Capacity (FVC) ratio of 
<0.70 and a post-albuterol/salbutamol FEV1 of ≤70% of predicted 
normal values;
AND
Onset of disease ≥40 years of age
Rationale: To clarify that although the Investigator should consider exposure 
to tobacco smoke as a risk factor, the exclusion criteria concerning personal 
tobacco use are documented in exclusion criterion number 14. 
13.
Section 5.2 Exclusion Criteria: exclusion criterion number 14:
Changed from:
Tobacco Use: Current smoker or a smoking history of 10 pack years (e.g., 
20 cigarettes/day for 10 years).  A subject may not have used inhaled tobacco 
products within the past 12 months (i.e., cigarettes, e-cigarettes/vaping, cigars or 
pipe tobacco).
Note: Refer to the SRM for the formula for calculating pack years.
Changed to:
Tobacco Use: Current smoker or a smoking history of 10 pack years (e.g., 
20 cigarettes/day for 10 years).  A subject may not have used inhaled tobacco 
products within the past 12 months (i.e., cigarettes, e-cigarettes/vaping, cigars or 
pipe tobacco).Subjects who are:

Current smokers (defined as subjects who have used inhaled tobacco 
products within the 12 months prior to Visit 1 [i.e., cigarettes, e-
cigarettes/vaping, cigars or pipe tobacco]).

Former smokers with a smoking history of 10 pack years (e.g., 
20 cigarettes/day for 10 years).
Note: Refer to the SRM for the formula for calculating pack years.
Rationale: To clarify the definition of a ‘current smoker’ and, therefore, the 
definition of a ‘former smoker’.
14.
Section 5.6.1 Withdrawal from Study Treatment: third paragraph, fourth bullet-


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point:
Changed from:

Study treatment unblinded: Unblinding of the study treatment assigned to a 
subject (see Section 6.3).
Changed to:

Study treatment unblinded: Unblinding of the study treatment assigned to a 
subject (see Section 6.3).
Rationale: It is not necessary to mandate that a subject must be withdrawn from 
study treatment for the sole reason that the treatment assigned to a subject is 
unblinded; however, the reason for the unblinding must still be captured in the 
eCRF.
15.
Section 5.6.4 QTc Stopping Criteria:
Changed from:
Details on performing ECG assessments can be found in Section 7.5.6.

The same QT correction formula must be used for each individual subject
to determine eligibility for and discontinuation from the study.  This 
formula may not be changed or substituted once the subject has been 
enrolled.

For example, if a subject is eligible for the protocol based on QTcB (QT 
interval corrected for heart rate by Bazett’s formula), then QTcB must be 
used for discontinuation of this individual subject as well.

Once the QT correction formula has been chosen for a subject’s 
eligibility, the same formula must continue to be used for that subject for 
all QTc data being collected for data analysis.  Safety ECGs and other 
non-protocol specified ECGs are an exception.  

The QTc should be based on single or averaged QTc values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording 
period.

For this study, the following QTc stopping criteria will apply:

QTcF>500 msec or uncorrected QT>600 msec

Bundle branch block: QTcF530 msec

Change from baseline: QTcF> 60msec


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Changed to:
Details on performing ECG assessments can be found in Section 7.5.6.

The QT interval corrected for heart rate by Fredericia’s formula (QTcF)
same QT correction formula must be used for each individual subject to 
determine eligibility for and discontinuation from the study.  This formula 
may not be changed or substituted for the duration of the studyonce the 
subject has been enrolled.

For example, if a subject is eligible for the protocol based on QTcB (QT 
interval corrected for heart rate by Bazett’s formula), then QTcB must be 
used for discontinuation of this individual subject as well.

Once the QT correction formula has been chosen for a subject’s 
eligibility, the same formulaQTcF must continue to be used for all that
subjects for all QTc data being collected for data analysis.  Safety ECGs 
and other non-protocol specified ECGs are an exception.  

The QTcF should be based on single or averaged QTcF values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording 
period.

For this study, the following QT c stopping criteria will apply:

QTcF>500 msec or uncorrected QT>600 msec

Bundle branch block: QTcF530 msec

Change from baseline: QTcF> 60msec
Rationale: The QT interval corrected for heart rate by Fredericia’s formula 
(QTcF) will be used throughout the study. The QT interval corrected for heart rate 
by Bazett’s formula (QTcB) will not be used (safety ECGs and other non-protocol 
specified ECGs are an exception).
16.
Section 6.1 Investigational Product and Other Study Treatment: tenth paragraph:
Changed from:
At the Investigator’s discretion, provision will be made from Visit 1 onwards for 
subjects to temporarily receive fluticasone propionate (FP; 100 mcg BID or 
equivalent) via the DISKUS DPI to treat the symptoms of a moderate asthma
exacerbation (see Section 7.3.6.1); treatment start and stop dates will be recorded 
in the eCRF. FP will be sourced from local commercial stock; if not available 
locally, GSK will source centrally. The contents of the label will be in accordance 
with all applicable regulatory requirements. A record of the number of FP-
containing DISKUS DPIs dispensed to each subject must be maintained and 
reconciled with study treatment records.


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Changed to:
At the Investigator’s discretion, provision will be made from Visit 11 onwards for 
subjects to temporarily receive fluticasone propionate (FP; 100 mcg BID [or 
equivalent]) via the DISKUS DPI to treat the symptoms of a moderate asthma
exacerbation (see Section 6.9.1.1 and Section 7.3.6.1).; Ttreatment start and stop 
dates will be recorded in the eCRF.
1Note: Should the subject use the provided FP prior to randomization at Visit 3, 
the enrolment or randomization concomitant medication exclusion criteria 
would be met (see Section 5.3.2 and Section 5.4.2).
FP will be sourced from local commercial stock; if not available locally, GSK will 
source centrally. The contents of the label will be in accordance with all applicable 
regulatory requirements. A record of the number of FP-containing DISKUS DPIs 
dispensed to each subject must be maintained and reconciled with study treatment 
records.
Rationale: The total daily dose of the study-provided FP (to be used temporarily 
to treat the symptoms of a moderate asthma exacerbation) is at the Investigator’s 
discretion; therefore it is not appropriate to specify that FP should be administered 
twice daily (i.e. BID). In addition, a statement has been included to indicate that 
although FP will be provided to the subject at Visit 1, its use by the subject prior 
to randomization at Visit 3 will meet the study exclusion criteria.
17.
Section 6.3 Blinding: second paragraph:
Changed from:
A subject will be withdrawn from the study if the subject’s treatment code is 
unblinded by the Investigator or treating physician. The primary reason for 
discontinuation (the event or condition which led to the unblinding) will be 
recorded in the eCRF.
Changed to:
A subject will be withdrawn from the study if the subject’s treatment code is 
unblinded by the Investigator or treating physician. The primary reason for 
discontinuation (the event or condition which led to the unblinding) will be 
recorded in the eCRF.
Rationale: It is not necessary to mandate that a subject must be withdrawn from 
the study for the sole reason that the treatment assigned to a subject is unblinded.
18.
Section 6.6 Compliance with Study Treatment Administration: fourth paragraph, 
first sentence:


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Changed from:
If the double-blind study treatment is prematurely discontinued during the course 
of the study or treatment compliance repeatedly falls outside of acceptable ranges, 
the study sponsor/site monitor must be contacted to discuss subject eligibility for 
continued participation in the study.
Changed to:
If the double-blind study treatment is prematurely discontinued during the course 
of the study or treatment compliance repeatedly falls outside of acceptable ranges, 
the study sponsor/site monitor must be contacted to discuss subject eligibility for 
continued participation in the study.
Rationale: Subjects should continue to be followed-up as per protocol until the 
completion of the Safety Follow-up assessments.
19.
Section 6.9 Concomitant Medications and Non-Drug Therapies: first paragraph, 
first sentence:
Changed from:
All asthma medications used within approximately 6 weeks prior to screening and 
during the study (including the post-treatment period) should be recorded in the 
eCRF.
Changed to:
All asthma medications used within approximately 6 weeks prior to pre-screening
(Visit 0) and during the study (including the post-treatment period) should be 
recorded in the eCRF.
Rationale: To align with Inclusion Criterion number 5 which requires no changes 
to maintenance asthma medications during the 6 weeks immediately prior to Visit 
0.
20.
Section 6.9.1.1 Permitted Asthma Medications: first paragraph, second bullet-
point:
Changed from:

Systemic corticosteroids (≤5 milligrams (mg)/day) will be permitted 
provided that treatment was initiated at least 12 weeks prior to Visit 1, 
remains stable for the 8 weeks prior to Visit 1 and the subject remains in 
the maintenance phase (i.e., it is not weaned) throughout the study (the 
only exception being the treatment of moderate/severe asthma 
exacerbations [see below]).


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Changed to:

Systemic corticosteroids (≤5 milligrams (mg)/day of prednisone [or an 
equivalent dose of an alternative systemic corticosteroid]) will be 
permitted provided that treatment was initiated at least 12 weeks prior to 
Visit 1, remains stable for the 8 weeks prior to Visit 1 and the subject 
remains in the maintenance phase (i.e., it is not weaned) throughout the 
study (the only exception being the treatment of moderate/severe asthma 
exacerbations [see below]).
Rationale: To clarify the permitted daily dose of systemic corticosteroids.
21.
Section 6.9.1.1 Permitted Asthma Medications: second paragraph (including first 
bullet-point):
Changed from:
Temporary changes in medications are permitted for the treatment of moderate 
asthma exacerbations (see Section 7.3.6.1) at the Investigator’s/treating 
physician’s discretion. Asthma exacerbations should be treated in line with 
national and international recommendations and local medical standards. Asthma 
medications permitted on a temporary basis to treat a moderate asthma 
exacerbation include but are not limited to the following (the Medical Monitor 
may be contacted for additional guidance, see the medical monitor/Sponsor 
Information Page):
An increase in ICS dose (including but not limited to fluticasone 
propionate [FP; 100 mcg BID or equivalent] which will be provided for 
this purpose).
Changed to:
Temporary additions changes in medications are permitted for the treatment of 
moderate asthma exacerbations (see Section 7.3.6.1) at the Investigator’s/treating 
physician’s discretion. Asthma exacerbations should be treated in line with 
national and international recommendations and local medical standards. Asthma 
medications permitted on a temporary basis to treat a moderate asthma 
exacerbation include but are not limited to the following (the Medical Monitor 
may be contacted for additional guidance, see the medical monitor/Sponsor 
Information Page):
An increase in ICS dose (including but not limited to the use of study-
provided fluticasone propionate [FP; 100 mcg BID or equivalent] which 
may be used by the subject at a total daily dose deemed appropriate by 
the Investigator/treating physician will be provided for this purpose).
Rationale: To clarify that:
Medications used temporarily for the treatment of moderate asthma 


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exacerbations are in addition to the protocol-defined study treatment 
(rather than a change in study treatment).
The total daily dose of study-provided FP used to treat a moderate asthma 
exacerbation is at the discretion of the Investigator/treating physician.
22.
Section 6.9.1 Permitted Medications and Non-Drug Therapies
Added as Section 6.9.1.3 Permitted Non-Drug Therapies:
Continuous Positive Airway Pressure (CPAP) for the treatment of obstructive 
sleep apnea is permitted if initiated at least 6 weeks prior to the Screening Visit 
(Visit 1) and the subject continues CPAP treatment throughout the study.  This 
treatment must be captured in the eCRF.
Rationale: To allow subjects to continue pre-study initiated CPAP for the 
treatment of obstructive sleep apnea.
23.
Section 6.9.2 Prohibited Medications and Non-Drug Therapies; Table 4 
Concomitant Medications
Changed from:
Medication
No use during the study and/or within the 
following time interval before Visit 1
Inhaled short-acting anticholinergics
6 hours
Inhaled short-acting anticholinergics+ 
Short-acting beta agonist combination
6 hours
Inhaled long-acting anticholinergics other 
than study treatment
2 days
Immunosuppressive medications
including immunomodulators
12 weeks
Inhaled long-acting beta2-agonists (e.g., 
salmeterol, formoterol) or combination 
products containing inhaled long-acting 
beta2-agonists (e.g., Seretide, Symbicort)
Inhaled very long-acting beta2-agonists, 
(Indacaterol, Olodaterol)
Oral long-acting beta2-agonists (e.g., 
bambuterol) 
These must be withheld after the regular 
dose on the morning of the day before 
Visit 1 (at least 24h prior to Visit 1); other 
than the study treatment, they will not be 
permitted during the study.
10 days prior to Visit 1 for Indacaterol and 
Olodaterol component.
Inhaled short-acting beta2-agonist (rescue 
albuterol/salbutamol will be provided and is 
permitted during the study)
6 hours (including all study visits)
Theophyllines, slow-release
bronchodilators, ketotifen, nedocromil 
sodium,
48 hours. Temporary use will be permitted 
during the study to treat moderate asthma 
exacerbations


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sodium cromoglycate, roflumilast
Anti-leukotrienes
48 hours. Temporary use will be permitted 
during the study to treat moderate asthma 
exacerbations
Any other investigational drug
30 days or within 5 drug half-lives of the 
investigational drug (whichever is longer)
Changed to:
Medication
No use during the study and/or within the following 
time interval before Visit 1
Inhaled short-acting 
anticholinergics
6 hours
Inhaled short-acting 
anticholinergics+ Short-acting beta 
agonist combination
6 hours
Inhaled long-acting anticholinergics
other than study treatment
2 days. Temporary use during the study is also 
prohibited.
Immunosuppressive medications
including immunomodulators
12 weeks
Inhaled long-acting beta2-agonists 
(e.g., salmeterol, formoterol) or 
combination products containing 
inhaled long-acting beta2-agonists 
(e.g., Seretide, Symbicort)
Inhaled very long-acting beta2-
agonists, (Indacaterol, Olodaterol)
Oral long-acting beta2-agonists 
(e.g., bambuterol) 
These must be withheld after the regular dose on 
the morning of the day before Visit 1 (at least 24h 
prior to Visit 1); other than the study treatment, 
they will not be permitted during the study 
(including for temporary use).
10 days prior to Visit 1 for Indacaterol and 
Olodaterol component. Temporary use during 
the study is also prohibited.
Inhaled short-acting beta2-agonist 
(rescue albuterol/salbutamol will be 
provided and is permitted during 
the study)
6 hours (including all study visits)
Theophyllines, slow-release
bronchodilators, ketotifen, 
nedocromil sodium,
sodium cromoglycate, roflumilast
48 hours. Temporary use will be permitted during 
the study to treat moderate asthma exacerbations
Anti-leukotrienes
48 hours. Temporary use will be permitted during 
the study to treat moderate asthma exacerbations
Medical marijuana
6 months. Medical marijuana administered via 
the inhaled route is strictly prohibited. Other 
routes of administration of medical marijuana 
are also prohibited UNLESS written 
permission is obtained from the Medical 


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Monitor prior to Visit 1.
Any other investigational drug
30 days or within 5 drug half-lives of the 
investigational drug (whichever is longer)
Rationale: 

To clarify that the temporary use of LABAs and LAMAs during the study 
is prohibited.

To clarify the time-period prior to Visit 1 that LABA medication must be 
withheld.

To address the possible use of medical marijuana during the study.


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24.
Section 7.1 Time and Events Table
Changed from:
Notes:
1.
Visit 1 must be completed 1 day but 14 days after Visit 0.
2.
Visit 3 must always be conducted 14 days after Visit 2.
3.
EW Visit should be conducted if double-blind study treatment is discontinued AND the subject discontinues from participating in the study.
4.
The time window for this visit means that Visit 2 may be conducted up to 3 days before or up to 5 days after the scheduled date of Visit 2.
5.
The ICF must be signed before any study procedures, including medication cessation.
15. Following completion of the pre-dose spirometry assessments, the reversibility test will be conducted between 20 and 60 minutes following 4 inhalations of 
albuterol/salbutamol aerosol. If airway reversibility is not demonstrated at Visit 1 then the assessment may be repeated within 7 days of Visit 1 (see Section 7.3.4.1.1
for details of the criteria to be met before a repeat of the reversibility assessment is permitted). If airway reversibility is successfully demonstrated at the second 
attempt and all other eligibility criteria assessed at Visit 1 are met then the subject may enter the 3-week run-in period.
18. ECG to be obtained 15 minutes to 45 minutes after the administration of study treatment.
27. The administration of study treatment at this visit is optional.
30. FP 100 mcg BID (or equivalent) may be used temporarily to treat the symptoms of a moderate asthma exacerbation, at the Investigator’s discretion.


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Changed to:
Notes:
1.
Visit 1 should must be completed 1 day but 14 days after Visit 0; however, if it is local and routine medical practice to request that a subject withhold their 
ICS/LABA medication for at least 24 hours prior to a clinic visit then, provided that the subject has complied with the request, Visit 0 and Visit 1 can occur 
on the same day.
2.
Visit 3 must always be conducted 14 days after Visit 2. Visit 2 may be conducted up to 3 days before the scheduled date of Visit 2. The duration of the run-in 
period (i.e. the time period between Visits 1 and 2) must be 18 days but 26 days.
3.
EW Visit should be conducted if double-blind study treatment is discontinued AND the subject discontinues from participating in the study. Visit 3 must always be 
conducted 14 days but 17 days after Visit 2.
4.
The time window for this visit means that Visit 2 may be conducted up to 3 days before or up to 5 days after the scheduled date of Visit 2. EW Visit should be 
conducted if double-blind study treatment is discontinued AND the subject discontinues from participating in the study.
5.
The ICF must be signed before any study procedures, including protocol-specified medication cessation.
15. Following completion of the pre-dose spirometry assessments, the reversibility test will be conducted between 20 and 60 minutes following 4 inhalations of 
albuterol/salbutamol aerosol. If airway reversibility is not demonstrated at Visit 1 then the assessment may be repeated within 7 days of Visit 1 (see Section 7.3.4.1.1
for details of the criteria to be met before a repeat of the reversibility assessment is permitted). If airway reversibility is successfully demonstrated at the second 
attempt and all other eligibility criteria assessed at Visit 1 are met then the subject may commence enter the 3-week run-in period (starting on the date that airway 
reversibility was successfully demonstrated at the second attempt).
18. At the Screening Visit (Visit 1), the ECG is to be obtained after the vital signs assessment but prior to performing the pre-bronchodilator spirometry
assessment (see Section 7.5.6). At all post-randomization visits the ECG is to be obtained 15 minutes to 45 minutes after the administration of study treatment.
27. The administration of study treatment at this visit is optional. If study treatment is not administered at this visit then those assessments which are scheduled 
based on the time of study treatment administration should be performed at approximately the same time of day as performed at the preceding post-


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randomization visits.
30. FP 100 mcg BID (or equivalent) may be used temporarily to treat the symptoms of a moderate asthma exacerbation, at the Investigator’s discretion. However, 
please note that a subject’s use of the provided FP prior to randomization at Visit 3 would meet the enrolment or randomization concomitant medication 
exclusion criteria (see Section 5.3.2 and Section 5.4.2).
Rationale:

In the table header, the footnote numbers have been amended to align with the order of the amended footnotes.

The Visit 2 time window has been deleted (along with the associated footnote); the explanation of the time window is 
now captured in footnote 2 in order to clarify the possible length of the run-in period when the time windows are 
applied.

The maximum duration of the stabilization period (i.e. the time period between Visits 2 and 3) has been included to 
clarify the possible length of the stabilization period.

Footnote number 5 has been amended to align with the amended wording of footnote number 1.

In the event that it is necessary to repeat the airway reversibility assessment, footnote number 15 has been amended to 
clarify that if airway reversibility is successfully demonstrated at the second attempt then the run-in period will 
commence on the date that the this repeat reversibility assessment was conducted.

Footnote number 18 has been amended to clarify that the ECG assessment conducted at the Screening Visit should be 
done prior to the pre-bronchodilator spirometry assessment in order to mitigate any effect that albuterol/salbutamol 
administration may have on the ECG assessment.

Footnote 27 has been amended to clarify when the Early Withdrawal Visit assessments should be conducted in the event 
that study treatment is not administered at this visit (the administration of study treatment at this visit is optional).


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
Footnote 30 has been amended to clarify that a subject’s pre-randomization use of the study-provided FP will meet the 
exclusion criteria for the study.


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25.
Section 7.3.4.1 Reversibility: first paragraph, second sentence:
Changed from:
A pre-bronchodilator spirometry assessment should be performed after a 
washout period of at least 4 hours for short-acting β2- agonists.
Changed to:
A pre-bronchodilator spirometry assessment should be performed after a 
washout period of at least 4 6 hours for short-acting β2- agonists.
Rationale: Correction of a typographical error.
26.
Section 7.3.5 Daily Diaries: third paragraph, first sentence
Changed from:
Subjects will also be issued with a paper Medical Problems/Medications Taken
worksheet to record any medical problems and non-study specific medications 
used during the study.
Changed to:
Subjects will also be issued with a paper Medical Problems/Medications 
Taken worksheet to record medical problems experienced and medications 
used during the study (please refer to the SRM for further details).Subjects
will also be issued with a paper Medical Problems/Medications Taken 
worksheet to record any medical problems and non-study specific medications 
used during the study.
Rationale: The paper Medical Problems/Medications Taken worksheet will be 
used to record study specific and non-study specific medications used during 
the study.
27.
Section 7.3.6 Asthma Exacerbations:
Changed from:
Moderate/severe asthma exacerbation data will be collected from the start of
randomized double blinded treatment until Visit 8/EOS Visit or the Early 
Withdrawal Visit for those subjects that withdraw from participation in the 
study (see Section 5.6). For consistency, exacerbations separated by less than 7 
days will be treated as a continuation of the same exacerbation.
Alerts will be programmed into the eDiary to instruct the subject to contact the 
Investigator immediately for a medical assessment (see Section 7.3.5.1.6). The 
notification of decreasing asthma control from the eDiary will assist the 


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Investigator in the identification of new asthma exacerbations.
Subjects will also complete a paper Medical Problems/Medications Taken
worksheet to record any medical problems and non-study specific medications 
used during the study, as well as all emergency department visits and/or 
hospitalizations that occur during their participation in the study. This paper 
worksheet must be reviewed by the Investigator (or designee) at each visit to 
the study site to assist the Investigator in the identification of new asthma 
exacerbations.
All moderate/severe asthma exacerbations will be recorded in the eCRF by the 
Investigator (or designee).
Changed to:
Moderate/severe asthma exacerbation data will be collected For the purposes 
of this study, moderate/severe asthma exacerbations will be collected and 
recorded on the asthma exacerbation eCRF page from the start of randomized 
double blinded treatment until Visit 8/EOS Visit or the Early Withdrawal Visit 
for those subjects that withdraw from participation in the study (see Section 
5.6). Moderate/severe asthma exacerbations should not be recorded as an 
adverse event unless:

They meet the definition of an Adverse Event (see Appendix 4) and 
occur: 
o
After the start of study treatment until the start of double 
blinded study treatment or;
o
After completion of the Visit 8/EOS Visit (or Early Withdrawal 
Visit) assessments until the follow-up contact.
OR

They meet the definition of a Serious Adverse Event (see Appendix 4).
Note: The SAE page of the eCRF should be completed in addition to 
the asthma exacerbation eCRF page if the exacerbation occurs after 
the start of double blinded treatment but before completion of the Visit 
8/EOS Visit or Early Withdrawal Visit assessments.
For consistency, exacerbations separated by less than 7 days will be treated as a 
continuation of the same exacerbation.
Alerts will be programmed into the eDiary to instruct the subject to contact the 
Investigator immediately for a medical assessment (see Section 7.3.5.1.6). The 
notification of decreasing asthma control from the eDiary will assist the 


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Investigator in the identification of new asthma exacerbations.
Subjects will also complete a paper Medical Problems/Medications Taken 
worksheet to record medical problems experienced and medications used 
during the studySubjects will also complete a paper Medical 
Problems/Medications Taken worksheet to record any medical problems and 
non-study specific medications used during the study, as well as all emergency 
department visits and/or hospitalizations that occur during their participation in 
the study. This paper worksheet must be reviewed by the Investigator (or 
designee) at each visit to the study site to assist the Investigator in the 
identification of new asthma exacerbations.
All moderate/severe asthma exacerbations will be recorded in the eCRF by the 
Investigator (or designee).
Rationale:

To clarify how asthma exacerbations should be recorded in the eCRF.

The paper Medical Problems/Medications Taken worksheet will be used 
to record study specific and non-study specific medications used during 
the study.
28.
Section 7.5.1.2 Method of Detecting AEs and SAEs: second paragraph, first 
sentence:
AND
Section 7.5.8 Paper Medical Problems/Medications Taken Worksheet: first 
paragraph, first sentence:
Changed from:
Subjects will be issued with a paper Medical Problems/Medications Taken
worksheet to record any medical problems and non-study specific medications 
used during the study.
Changed to:
Subjects will be issued with a paper Medical Problems/Medications Taken 
worksheet to record medical problems experienced and medications used 
during the study (please refer to the SRM for further details).Subjects will be 
issued with a paper Medical Problems/Medications Taken worksheet to record 
any medical problems and non-study specific medications used during the 
study.
Rationale: The paper Medical Problems/Medications Taken worksheet will be 
used to record study specific and non-study specific medications used during 
the study.


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29.
Section 7.5.6 Electrocardiogram (ECG): first paragraph:
Changed from:
All sites will use standardised ECG equipment provided by a centralized external 
vendor. A single 12-lead ECG and rhythm strip will be recorded after 
measurement of vital signs and spirometry. Recordings will be made at the time-
points defined in the Time and Events table (Section 7.1). All ECG measurements 
will be made with the subject in a supine position having rested in this position 
for approximately 5 minutes before each reading.
Changed to:
All sites will use standardised ECG equipment provided by a centralized external 
vendor. At the Screening Visit (Visit 1), a single 12-lead ECG and rhythm strip 
will be recorded after the measurement of vital signs but before and performing 
the pre-bronchodilator spirometry assessment. At the post-randomization visits, 
a single 12-lead ECG and rhythm strip will be recorded 15 to 45 minutes after 
the administration of study treatment. Recordings will be made at the time-
points defined in the Time and Events table (Section 7.1). All ECG measurements 
will be made with the subject in a supine position having rested in this position 
for approximately 5 minutes before each reading.
Rationale: To clarify the timing of the pre- and post-randomization ECG 
assessments.
30.
Section 7.6 Pharmacokinetics (PK): fourth paragraph, first bullet-point:
Changed from:
The following points must be noted: 

If assessments are scheduled for the same nominal time, THEN the 
assessments should occur in the following order:
1. 12-lead ECG
2. vital signs
3. blood draws.  
Note: The timing of the assessments should allow the blood draw to occur at the 
exact nominal time.
Changed to:
The following points must be noted: 

If assessments are scheduled for the same nominal time, THEN the 


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assessments should occur in the following order (as applicable):
1. Vital signs12-lead ECG
2. 12-lead ECGvital signs
3. blood draws.  
Note: The timing of the assessments should allow the blood draw to occur at the 
exact nominal time.
Rationale: To clarify the order of assessments.
31.
Section 9.2.2 Sample Size Sensitivity: power function table AND power of triple
vs. dual for a fixed UMEC dose graphs:
Changed from:
dispersion
FF/VI 
rate
FF/UMEC/VI 
rate
Relative 
Reduction
power
n=750/arm
n=375/arm
0.7
1.50
1.275
15%
0.66
0.40
1.50
1.200
20%
0.90
0.63
1.50
1.125
25%
0.98
0.84
2.00
1.700
15%
0.73
0.45
2.00
1.600
20%
0.94
0.72
2.00
1.500
25%
>0.99
0.89
2.50
2.125
15%
0.77
0.50
2.50
2.000
20%
0.97
0.76
2.50
1.875
25%
>0.99
0.93
0.8
1.50
1.275
15%
0.62
0.40
1.50
1.200
20%
0.88
0.64
1.50
1.125
25%
0.99
0.82
2.00
1.700
15%
0.70
0.45
2.00
1.600
20%
0.93
0.65
2.00
1.500
25%
>0.99
0.87
2.50
2.125
15%
0.76
0.47
2.50
2.000
20%
0.95
0.73
2.50
1.875
25%
>0.99
0.91


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Changed to:
dispersion
FF/VI 
rate
FF/UMEC/VI 
rate
Relative 
Reduction
power
n=750/arm
n=375/arm
0.7
1.50
1.275
15%
0.6662
0.4037
1.50
1.200
20%
0.9087
0.6359
1.50
1.125
25%
0.98
0.8481
2.00
1.700
15%
0.7370
0.4541
2.00
1.600
20%
0.9492
0.7267
2.00
1.500
25%
>0.99
0.8987
2.50
2.125
15%
0.7775
0.5049
2.50
2.000
20%
0.9795
0.7672
2.50
1.875
25%
>0.99
0.9390
0.8
1.50
1.275
15%
0.6261
0.4036


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1.50
1.200
20%
0.8886
0.6456
1.50
1.125
25%
0.9997
0.8277
2.00
1.700
15%
0.7065
0.4541
2.00
1.600
20%
0.9391
0.6566
2.00
1.500
25%
>0.99
0.8785
2.50
2.125
15%
0.7673
0.4744
2.50
2.000
20%
0.9594
0.7369
2.50
1.875
25%
>0.99
0.9188


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Rationale: To capture the change to the power calculation based on the proposed 
study duration that is truncated to the scheduled visits at Weeks 24, 36 and 52. 
The original power calculation was based on the variable duration up to Week 52.
32.
Section 9.3.4 Multiple Comparisons and Multiplicity: Multiplicity Adjustment 
Plan, level 3b AND level 5, mean change from baseline in E-RS total score 
endpoint:
Changed from:
Mean change from baseline in E-RS score over the 24 week treatment period
a.
(FF/UMEC/VI 100/62.5/25, 200/62.5/25) vs. (FF/VI 100/25,  200/25)
Changed to:
Mean change from baseline in E-RS score over Weeks 21 to 24 (inclusive) of
the 24 week treatment period
a.
(FF/UMEC/VI 100/62.5/25, 200/62.5/25) vs. (FF/VI 100/25,  200/25)
Rationale: To align the Multiplicity Adjustment Plan with the Other Secondary 
endpoints.
33.
Section 9.4 Key Elements of Analysis Plan: second paragraph, third sentence:
Changed from:


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For the pooled analyses of triple therapy vs. dual on non-lung function efficacy 
endpoints using combined data from both FF doses, the FF dosage will also be 
included in the analysis model as a categorical covariate to account for possible 
heterogeneity and/or data variability resulted in different ICS doses.
Changed to:
For the pooled analyses of triple therapy vs. dual on non-lung function efficacy 
endpoints using combined data from both FF doses, the FF dosage will also be 
included in the analysis model as a categorical covariate to account for possible 
heterogeneity and/or data variability resulted from in different ICS doses.
Rationale: To correct a typographical error.
12.8.2.
Protocol Amendment 02
Protocol changes for Amendment 02 (23-JUN-2017), from amendment 01 (13-DEC-
2016)
This amendment applies to all sites.
Amendment 02 Summary and Rationale
List of Specific changes:
Text which has been added to the protocol is highlighted in bold, italic typeface. Text 
which has been deleted from the protocol is indicated by strike-through format.
Change Section, Text affected, and Rationale
34.
Section 3 Other Objectives: clarify morning or evening.
Changed from:
Mean change from baseline in morning evening (PM) PEF over the first 24 
weeks of the treatment period
Changed to:
Mean change from baseline in morning evening (PM) PEF over the first 24 
weeks of the treatment period
Rationale: To clearly define “evening” (PM) PEF over the first 24 weeks of 
the treatment period. 
35.
Section 3 Other Objectives: amend responder threshold language for ACQ-7, 


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ACQ-6, ACQ-5, E-RS & AQLQ to clearly define and be consistent with 
protocol
Changed from:

Percent of patients meeting a responder threshold of 0.5 in change

from baseline for the ACQ-7 at Week 24

Percent of patients meeting a responder threshold of 0.5 in change

from baseline for the ACQ-6 at Week 24

Percent of patients meeting a responder threshold of 0.5 in change

from baseline for the ACQ-5 at Week 24

Percent of patients meeting a responder threshold of 2 points 
improvement from baseline for the E-RS total score over Weeks 21 to 
24 (inclusive) of the treatment period. 

Percent of patients meeting a responder threshold of ≥ 0.5 points 
improvement from baseline for the AQLQ total score at Week 24. 
Changed to:

Percent of patients meeting a responder threshold of 0.5 in change
points improvment (decrease) from baseline for the ACQ-7 at Week 24

Percent of patients meeting a responder threshold of 0.5 in change
points improvement (decrease) from baseline for the ACQ-6 at Week 
24

Percent of patients meeting a responder threshold of 0.5 in change
points improvement (decrease) from baseline for the ACQ-5 at Week 
24

Percent of patients meeting a responder threshold of ≥ 2 points 
improvement (decrease) from baseline for the E-RS total score over 
Weeks 21 to 24 (inclusive) of the treatment period. 

Percent of patients meeting a responder threshold of ≥ 0.5 points 
improvement (increase) from baseline for the AQLQ total score at 
Week 24. 
Rationale: To clearly define the ACQ-7, ACQ-6, ACQ-5, E-RS & AQLQ 
responder threshold and be consistent with protocol language, as well as “Other 
Efficacy Endpoints”
36.
Section 5.1 Inclusion Criteria
Changed from:
Current Asthma Maintenance Therapy:


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
Examples of acceptable doses of commonly prescribed ICS medication 
are provided in the GINA guidelines [GINA 2016].  
Changed to:
Current Asthma Maintenance Therapy:

Examples of acceptable doses of commonly prescribed ICS medication 
are provided in the GINA guidelines [GINA 2016, BTS/SIGN 2016, 
Japanese guidelines for adult asthma 2017].  
Rationale: To include additional supported guidance in the following 
documents; BTS/SIGN Guideline (2016) and Japanese guidelines adult asthma 
(2017).
37.
Section 5.1 Inclusion Criteria
Changed from:
Spirometry:

A best pre-bronchodilator morning (AM) FEV1 ≥30% and 
<80% of the predicted normal value at Visit 1. Predicted values 
will be based upon the European Respiratory Society (ERS) 
Global Lung Function Initiative [Quanjer 2012].
Changed to:
Spirometry:

A best pre-bronchodilator morning (AM) FEV1 ≥30% and 
<85% of the predicted normal value at Visit 1. Predicted values 
will be based upon the European Respiratory Society (ERS) 
Global Lung Function Initiative [Quanjer 2012].
Rationale: To broaden the eligibility criteria to include patients with less 
pulmonary impairment who remain uncontrolled on ICS/LABA.
38.
Section 5.3.1 Inclusion Criteria for Enrolment
Changed from:
Percent-predicted FEV1:

A best pre-bronchodilator morning (AM) FEV1 ≥30% and 
<80% of the predicted normal value at Visit 1. Predicted values 
will be based upon the European Respiratory Society (ERS) 
Global Lung Function Initiative [Quanjer 2012].


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Changed to:
Percent-predicted FEV1:

A best pre-bronchodilator morning (AM) FEV1 ≥30% and 
<90% of the predicted normal value at Visit 1. Predicted values 
will be based upon the European Respiratory Society (ERS) 
Global Lung Function Initiative [Quanjer 2012].
Rationale: To broaden the eligibility criteria to include patients with less 
pulmonary impairment who remain uncontrolled on ICS/LABA.
39.
Section 7.1 Time and Events Table; Screening visit box for Serum pregnancy 
test
Changed from:

Screening visit box for Serum pregnancy test with no footnote
Changed to:

Screening visit box for Serum pregnancy test includes footnote 
#21; Assessments to be conducted in females of reproductive 
potential
Rationale: clearly define that only assessments of Serum pregnancy to be 


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conducted in females of reproductive potential
40.
Section 7.3.1.4 Other Efficacy Endpoints: amend responder threshold language 
for ACQ-7, ACQ-6, ACQ-5, E-RS & AQLQ to clearly define and be consistent 
with protocol language
Changed from:

Percent of patients meeting a responder threshold of 0.5 in change from 
baseline for the ACQ-7 at Week 24

Percent of patients meeting a responder threshold of 0.5 in change from 
baseline for the ACQ-6 at Week 24

Percent of patients meeting a responder threshold of 0.5 in change from 
baseline for the ACQ-5 at Week 24

Percent of patients meeting a responder threshold of ≥ 2 points 
improvement from baseline for the E-RS total score over Weeks 21 to 24 
(inclusive) of the treatment period. 

Percent of patients meeting a responder threshold of ≥ 0.5 points 
improvement from baseline for the AQLQ total score at Week 24. 
Changed to:

Percent of patients meeting a responder threshold of 0.5 in change points 
improvement (decrease) from baseline for the ACQ-7 at Week 24

Percent of patients meeting a responder threshold of 0.5 in change points 
improvement (decrease) from baseline for the ACQ-6 at Week 24

Percent of patients meeting a responder threshold of 0.5 in change points 
improvement (decrease) from baseline for the ACQ-5 at Week 24

Percent of patients meeting a responder threshold of ≥ 2 points 
improvement (decrease) from baseline for the E-RS total score over Weeks 
21 to 24 (inclusive) of the treatment period. 

Percent of patients meeting a responder threshold of ≥ 0.5 points 
improvement (increase) from baseline for the AQLQ total score at Week 
24. 
Rationale: To clearly define the ACQ-7, ACQ-6, ACQ-5, E-RS & AQLQ 
responder threshold and be consistent with the protocol language, as well as 
consistent with “Other Objectives”.
41.
Section 7.3.5.1.6 Alerts
Changed from:
Subjects will be instructed to contact the Investigator if any of the above alert 


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criteria are met (either by telephone and/or by visiting the study clinic).
Changed to:
The baseline value, for the purpose of alerts, is defined as the average value 
over the last 7 days prior to randomization. Subjects will be instructed to 
contact the Investigator if any of the above alert criteria are met (either by 
telephone and/or by visiting the study clinic).
Rationale: To clearly define the baseline value alerts.
42.
Section 9.3.1 Analysis Population: Corrected typographical error.
Changed from:
Pharmacokinetic (PK) population: This population will comprise all subject in 
the ITT Population for whom a PK sample was obtained and analyzed.
Changed to:
Pharmacokinetic (PK) population: This population will comprise all subjects in 
the ITT Population for whom a PK sample was obtained and analyzed.
Rationale: Corrected typographical error. Added ‘s’ to end of subject.
43.
Section 9.3.4 Multiple Comparisons and Multiplicity
Changed from:
A step-down closed testing approach will be applied for the primary and the 
key secondary efficacy endpoints. Specifically, if the defined treatment 
comparisons for the primary efficacy endpoint between triple therapy and dual 
therapy at high dose of UMEC 62.5 mcg are significant at 0.05 level for both 
fixed FF doses, then the replicate efficacy of UMEC 62.5mcg is demonstrated, 
and the defined treatment comparison between triple therapy and dual therapy 
will be test for the key secondary efficacy endpoint on moderate/severe asthma 
exacerbation based on the combined data of both FF doses. If the test for the 
key secondary efficacy endpoint is significant at 0.05 level, then the above 
testing hierarchy for the primary and the key secondary efficacy endpoints will 
be repeated for the low dose of UMEC 31.25 mcg. 
The family-wise Type I Error is strongly controlled at 0.05 level for the 
primary endpoint (trough FEV1) and the key secondary endpoint 
(moderate/severe asthma exacerbations) for the UMEC 62.5 mcg dose.  
In addition, for a given UMEC dose, the secondary endpoints (Mean change 
from baseline in FEV1 at 3 hour post-dose at Week 24, Mean change from 
baseline in ACQ-7 at Week 24, Mean change from baseline in SGRQ at Week 


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24, Mean change from baseline in E-RS score over the 24 week treatment 
period) are nested under the primary and the key secondary endpoints. If the 
defined treatment comparisons for the high dose of UMEC 62.5 mcg 
demonstrate statistical significance at the 5% level on the primary efficacy 
endpoint and the key secondary endpoint, then inferences relating to the 
secondary endpoints for the high dose of UMEC 62.5 mcg will be made; the 
same strategy will be applied for the low dose of UMEC 31.25 mcg. 
Changed to:
A step-down closed testing approach will be applied for the primary efficacy 
endpoint and the key secondary efficacy endpoints, and the secondary efficacy 
endpoints SGRQ, ACQ-7, and E-RS. Specifically, if the defined treatment 
comparisons for the primary efficacy endpoint between triple therapy and dual 
therapy at the high dose of UMEC 62.5 mcg are statistically significant at the
0.05 level for both fixed FF doses (100 and 200mcg), then the replicate 
efficacy of UMEC 62.5mcg is demonstrated, and the defined treatment 
comparison between triple therapy and dual therapy will be tested for the key 
secondary efficacy endpoint on of moderate/severe asthma exacerbations based 
on the combined data of both FF doses for UMEC 62.5mcg. If the test for the 
key secondary efficacy endpoint is statistically significant at the 0.05 level, 
then the secondary efficacy endpoints for SGRQ (Mean change from baseline 
in SGRQ at Week 24) and ACQ-7 (Mean change from baseline in ACQ-7 at
Week 24) will be tested sequentially based on the combined data of both FF 
doses for UMEC 62.5mcg at significance level 0.05.the above testing 
hierarchy for the primary and the key secondary efficacy endpoints will be 
repeated for the low dose of UMEC 31.25 mcg.
If all tests mentioned above for UMEC 62.5 mcg are statistically significant 
at the 0.05 level, the above testing hierarchy for the primary efficacy 
endpoint,  the key secondary efficacy endpoint, and the secondary efficacy 
endpoints SGRQ and ACQ-7 will be repeated for the low dose of UMEC 
31.25 mcg.
If all tests for the primary, the key secondary, and the secondary efficacy 
endpoints for SGRQ and ACQ-7 are statistically significant at the 0.05 level 
for both UMEC 62.5mcg and 31.25mcg, the secondary endpoint for E-RS 
(Mean change from baseline in E-RS score over the Weeks 21-24 (inclusive) 
of the treatment period) will be tested at the significance level 0.05 for UMEC 
62.5 and UMEC 31.25 in sequence.
The family-wise Type I Error is strongly controlled at 0.05 level for both 
UMEC 62.5mcg and UMEC 31.25mcg on the primary endpoint (trough FEV1) 
and the key secondary endpoint (moderate/severe asthma exacerbations), and 
the secondary endpoints on SGRQ, ACQ-7, and E-RS for the UMEC 62.5 
mcg dose.  


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Change Section, Text affected, and Rationale
In addition, for a given UMEC dose, the secondary endpoints (Mean change 
from baseline in FEV1 at 3 hour post-dose at Week 24, Mean change from 
baseline in ACQ-7 at Week 24, Mean change from baseline in SGRQ at Week 
24, Mean change from baseline in E-RS score over the 24 week treatment 
period) are nested under the primary and the key secondary endpoints. If the 
defined treatment comparisons for the high dose of UMEC 62.5 mcg 
demonstrate statistical significance at the 5% level on the primary efficacy 
endpoint and the key secondary endpoint, then inferences relating to the 
secondary endpoints for the high dose of UMEC 62.5 mcg will be made; the 
same strategy will be applied for the low dose of UMEC 31.25 mcg. 
Rationale: Miltiplicity adjustment plan has been updated to ensure the strong 
control on the family-wise Type I Error across multiple endpoints and multiple 
treatment comparisons.
44.
Section 9.3.4 Multiple Comparisons and Multiplicity, Multiplicity Adjustment 
Plan: update the order and hierarchy within the multiplicity plan.
Changed from:
Level 1: Primary endpoint, UMEC 62.5 mcg: Mean change from baseline in 
trough FEV1 at Week 24, Two comparisons: FF/UMEC/VI 100/62.5/25 vs. 
FF/VI 100/25 FF/UMEC/VI 200/62.5/25 vs. FF/VI 200/25. Both tests need to 
be significant at 0.05 level in order to demonstrate replicate efficacy for UMEC 
62.5 mcg in order to move to Level 2 test.
Level 2: Key secondary endpoint, UMEC 62.5 mcg: annualized rate of 
moderate/severe asthma exacerbations, One comparison based on pooled data:
(FF/UMEC/VI 100/62.5/25, 200/62.5/25) vs. (FF/VI 100/25, 200/25). Test 
needs to be significant at 0.05 level in order to move to Level 3 tests.
Level 3a: Primary endpoint, UMEC 31.25mcg: Mean change from baseline in 
trough FEV1 at Week 24, Two comparisons: FF/UMEC/VI 100/31.25/25 vs. 
FF/VI 100/25 FF/UMEC/VI 200/31.25/25 vs. FF/VI 200/25. Both tests need to 
be significant at 0.05 level in order to demonstrate replicate efficacy for UMEC 
31.25mcg and move to Level 4 tests.
Level 3b: Secondary endpoints, UMEC 62.5 mcg, four endpoints test 
sequentially at the level 0.05.

1) Mean change from baseline in FEV1 at 3 hour post-dose at Week 24. 
Two comparisons adjust by Hochberg procedure) a) FF/UMEC/VI 
100/62.5/25 vs. FF/VI 100/25 b) FF/UMEC/VI 200/62.5/25 vs. FF/VI
200/25

2) Mean change from baseline in ACQ-7 at Week 24 a) (FF/UMEC/VI 
100/62.5/25, 200/62.5/25) vs. (FF/VI 100/25, 200/25)


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Change Section, Text affected, and Rationale

3) Mean change from baseline in SGRQ at Week 24 a) (FF/UMEC/VI 
100/62.5/25, 200/62.5/25) vs. (FF/VI 100/25, 200/25)

4) Mean change from baseline in E-RS score over Weeks 21 to 24 
(inclusive) of the treatment period a) (FF/UMEC/VI 100/62.5/25,
200/62.5/25) vs. (FF/VI 100/25, 200/25)
Level 4: Key secondary endpoint, UMEC 31.25 mcg: annualized rate of 
moderate/severe asthma exacerbations, One comparison based on pooled data:
(FF/UMEC/VI 100/31.25/25, 200/31.25/25) vs. (FF/VI 100/25, 200/25). Test 
needs to be significant at 0.05 level in order to move to Level 5 tests.
Level 5: Secondary endpoints, UMEC 31.25 mcg, four endpoints test 
sequentially at the level 0.05.

1) Mean change from baseline in FEV1 at 3 hour post-dose at Week 24. 
Two comparisons adjust by Hochberg procedure) a) FF/UMEC/VI 
100/31.25/25 vs. FF/VI 100/25 b) FF/UMEC/VI 200/31.25/25 vs. FF/VI
200/25

2) Mean change from baseline in ACQ-7 at Week 24 a) (FF/UMEC/VI 
100/31.25/25, 200/31.25/25) vs. (FF/VI 100/25, 200/25)

3) Mean change from baseline in SGRQ at Week 24 a) (FF/UMEC/VI 
100/62.5/25, 200/31.25/25) vs. (FF/VI 100/25, 200/25)

4) Mean change from baseline in E-RS score over Weeks 21 to 24 
(inclusive) of the treatment period a) (FF/UMEC/VI 100/31.25/25,
200/31.25/25) vs. (FF/VI 100/25, 200/25)
Changed to:
Level 1: Primary endpoint, UMEC 62.5 mcg: Mean change from baseline in 
trough FEV1 at Week 24, Two comparisons: FF/UMEC/VI 100/62.5/25 vs. 
FF/VI 100/25 FF/UMEC/VI 200/62.5/25 vs. FF/VI 200/25. Both tests need to 
be significant at 0.05 level in order to demonstrate replicate efficacy for UMEC 
62.5 mcg in order to move to Level 2 test.
Level 2: Key secondary endpoint, UMEC 62.5 mcg: annualized rate of 
moderate/severe asthma exacerbations, One comparison based on pooled data:
(FF/UMEC/VI 100/62.5/25, 200/62.5/25) vs. (FF/VI 100/25, 200/25). Test 
needs to be significant at 0.05 level in order to move to Level 3 tests.
Level 3: Secondary endpoint, UMEC 62.5 mcg: Mean change from baseline in 
SGRQ at Week 24, One comparison based on pooled data: (FF/UMEC/VI 
100/62.5/25, 200/62.5/25) vs. (FF/VI 100/25, 200/25). Test needs to be 
significant at 0.05 level in order to move to Level 4 test.
Level 4: Secondary endpoint, UMEC 62.5 mcg: Mean change from baseline in 


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Change Section, Text affected, and Rationale
ACQ-7 at Week 24, One comparison based on pooled data: (FF/UMEC/VI 
100/62.5/25, 200/62.5/25) vs. (FF/VI 100/25, 200/25). Test needs to be 
significant at 0.05 level in order to move to Level 5 tests.
Level 5: Primary endpoint, UMEC 31.25mcg: Mean change from baseline in 
trough FEV1 at Week 24, Two comparisons: FF/UMEC/VI 100/31.25/25 vs. 
FF/VI 100/25 FF/UMEC/VI 200/31.25/25 vs. FF/VI 200/25. Both tests need to 
be significant at 0.05 level in order to demonstrate replicate efficacy for UMEC 
31.25mcg and move to Level 6 tests.
Level 6: Key secondary endpoint, UMEC 31.25 mcg: annualized rate of 
moderate/severe asthma exacerbations, One comparison based on pooled data:
(FF/UMEC/VI 100/31.25/25, 200/31.25/25) vs. (FF/VI 100/25, 200/25). Test 
needs to be significant at 0.05 level in order to move to Level 7 tests.
Level 7: Secondary endpoint, UMEC 31.25 mcg: Mean change from baseline 
in SGRQ at Week 24, One comparison based on pooled data: (FF/UMEC/VI 
100/31.25/25, 200/31.25/25) vs. (FF/VI 100/25, 200/25). Test needs to be 
significant at 0.05 level in order to move to Level 8 test.
Level 8: Secondary endpoint, UMEC 31.25 mcg: Mean change from baseline 
in ACQ-7 at Week 24, One comparison based on pooled data: (FF/UMEC/VI 
100/31.25/25, 200/31.25/25) vs. (FF/VI 100/25, 200/25). Test needs to be 
significant at 0.05 level in order to move to Level 9 tests.
Level 9: Secondary endpoint, UMEC 62.5 mcg: Mean change from baseline in 
E-RS score over Weeks 21-24 (inclusive) of the treatment period. One 
comparison based on pooled data: (FF/UMEC/VI 100/62.5/25, 200/62.5/25) vs. 
(FF/VI 100/25, 200/25). Test needs to be significant at 0.05 level in order to 
move to Level 10 test.
Level 10: Secondary endpoint, UMEC 31.25 mcg: Mean change from baseline 
in E-RS score over Weeks 21-24 (inclusive) of the treatment period. One 
comparison based on pooled data: (FF/UMEC/VI 100/31.25/25, 200/31.25/25) 
vs. (FF/VI 100/25, 200/25)
Rationale: Miltiplicity adjustment plan has been updated to ensure the strong 
control on the family-wise Type I Error across multiple endpoints and multiple 
treatment comparisons.
45.
Section 9.3.4: Multiple Comparisons and Multiplicity, Multiplicity Adjustment 
Plan 
Changed from:
For all efficacy endpoints (primary, secondary, and other), treatment 
comparisons between triple therapy at low dose FF vs. dual therapy with high 
dose FF, or the benefit of increasing FF dose in a triple therapy, or the benefit 
of increasing UMEC dose in a triple therapy as outlined in 1) to 3) of Section 
9.3.3 , respectively, will also be made without adjusting for multiplicity. Any p-


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Change Section, Text affected, and Rationale
values 0.05 will be identified as nominally significant.
Changed to:
For all efficacy endpoints (primary, secondary, and other), treatment 
comparisons between triple therapy at low dose FF vs. dual therapy with high 
dose FF, or the benefit of increasing FF dose in a triple therapy, or the benefit 
of increasing UMEC dose in a triple therapy as outlined in 1) to 3) of Section 
9.3.3   respectively, will also be made without adjusting for multiplicity. Any p-
values 0.05 will be identified as nominally significant.
Rationale: To align the Multiplicity Adjustment Plan with the Reporting and 
Analysis Plan (RAP).
46.
Section 11.0 References
Changed from:
Hekking PP, Wener RR, Amelink M, Zwinderman AH, Bouvy ML, Bel EH. 
The prevalence of severe refractory asthma. J Allergy Clin Immunol
2015;135(4):896-902.
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA,et al. 
Pharmacokinetics of acetaminophen-protein adducts in adults with 
acetaminophen overdose and acute liver failure. Drug Metab Dispos
2009;37:1779-1784.
Changed to:
Hekking PP, Wener RR, Amelink M, Zwinderman AH, Bouvy ML, Bel EH. 
The prevalence of severe refractory asthma. J Allergy Clin Immunol
2015;135(4):896-902.
Ichinose M, Sugiura H, Nagase H, Yamaguchi M, Inoue H, Sagara H, et al. 
Japanese guidelines for adult asthma 2017. Allergol Int. 2017;66(2):163-189
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA,et al. 
Pharmacokinetics of acetaminophen-protein adducts in adults with 
acetaminophen overdose and acute liver failure. Drug Metab Dispos
2009;37:1779-1784.
Rationale: Added the reference to Japanese Guidelines for Adult Asthma


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12.8.3.
Protocol Amendment 03
Protocol changes for Amendment 03 (29-SEP-2017), from amendment 02 (23 JUN-
2017)
This amendment applies to all sites.
Amendment 03 Summary and Rationale
List of Specific changes:
Text which has been added to the protocol is highlighted in bold, italic typeface. Text 
which has been deleted from the protocol is indicated by strike-through format.
47.
Section 1: Protocol Synopsis for Study 205715; Treatment Arms and Duration  
Changed from:
The date that the whole study will complete (henceforth referred to as the study 
completion date) will be determined based on the randomization date of the 
final subject in the study; the study completion date will be set at 181 days (i.e. 
25 weeks and 6 days) post the final subject’s randomization date. The study 
treatment cut-off date for all ongoing subjects will then be set at 11 days (i.e. 1 
week and 4 days) prior to the study completion date. The study sites will be 
notified in advance to inform all ongoing subjects of the study treatment cut-off 
date and the study completion date.
Once the study treatment cut-off and study completion dates are determined, 
ongoing subjects must continue to adhere to their pre-planned study visit 
schedule; however, the on-treatment clinic assessment visit that is scheduled to 
occur before but closest to the study treatment cut-off date (without 
consideration of available visit time-windows) will be defined as the subject’s 
final treatment/EOS visit.  The subject’s final treatment/EOS visit must include 
all assessments specified for Visit 8/EOS. 
Changed to:
The date that the whole study will complete (henceforth referred to as the study 
completion date) will be determined based on the randomization date of the 
final subject in the study; the study completion date will be set at 181 days (i.e. 
25 weeks and 6 days) post the final subject’s randomization date. The study 
treatment cut-off date for all ongoing subjects will then be set at 11 days (i.e. 1 
week and 4 days) prior to the study completion date. The study sites will be 
notified in advance to inform all ongoing subjects of the study treatment cut-off 
date and the study completion date.
To determine when the final treatment/EOS visit will occur for each 
randomized subject in this variable duration study (i.e. at Week 24, Week 36 
or Week 52 of the treatment period), a date henceforth referred to as the 
transition date will be communicated to the study sites by GSK. GSK will 


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communicate a provisional transition date to all study sites on an ongoing 
basis during the study, until a fixed actual transition date is communicated at 
least 20 weeks in advance of the selected date (unless extenuating
circumstances dictate otherwise). The date selected by GSK as the actual 
transition date will always be more than 12 days prior to the study completion 
date. At the Investigator’s discretion, subjects should be informed of the 
transition date (provisional and actual) on an ongoing basis during the study 
so that their expected final treatment/EOS visit can be planned using the 
provisional transition date and then confirmed once the actual transition date 
is known.
Subjects who complete 52 weeks of study treatment prior to the actual 
transition date being communicated will have their final treatment/EOS visit 
at their Week 52 clinic assessment visit.
Once the study treatment cut-off and study completion dates are determined, 
ongoing subjects must continue to adhere to their pre-planned study visit 
schedule; however, the on-treatment clinic assessment visit that is scheduled to 
occur before but closest to the study treatment cut-off date (without 
consideration of available visit time-windows) will be defined as the subject’s 
final treatment/EOS visit.  The subject’s final treatment/EOS visit must include 
all assessments specified for Visit 8/EOS. 
After the actual transition date is communicated, subjects must adhere to 
their study visit schedule and complete a minimum of 24 weeks of study 
treatment. A subject’s final treatment/EOS visit will be defined as follows:
–
Subjects whose Week 24 clinic assessment visit is scheduled to 
occur on or after the actual transition date (without 
consideration of available visit time-windows) will have their 
final treatment/EOS visit at their Week 24 clinic assessment 
visit. 
–
Subjects who have their Week 24, Week 36 or Week 52 clinic 
assessment visit scheduled to occur before the actual transition 
date (without consideration of available visit time-windows) 
will have their final treatment/EOS visit at the clinic 
assessment visit that is scheduled to occur before but closest to 
the actual transition date (without consideration of available 
visit time-windows).
The subject’s final treatment/EOS visit must include all assessments specified 
for Visit 8/EOS.
Rationale: The protocol is being amended to base the variable treatment 
period on the planned recruitment rather than the date of the last subject 
randomized. This aligns planned exposure more closely with actual exposure 


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and enables sites and participants to plan according to the variable treatment 
period. The term ‘study treatment cut-off date’ will be replaced with ‘transition 
date’ to avoid confusion. 
48.
Section 4.2: Treatment Arms and Duration; Phase 4, Treatment  
Changed from:
The date that the whole study will complete (henceforth referred to as the study 
completion date) will be determined based on the randomization date of the 
final subject in the study; the study completion date will be set at 181 days (i.e. 
25 weeks and 6 days) post the final subject’s randomization date. The study 
treatment cut-off date for all ongoing subjects will then be set at 11 days (i.e. 1 
week and 4 days) prior to the study completion date. The study sites will be 
notified in advance to inform all ongoing subjects of the study treatment cut-off 
date and the study completion date.
Once the study treatment cut-off and study completion dates are determined, 
ongoing subjects must continue to adhere to their pre-planned study visit 
schedule; however, the on-treatment clinic assessment visit that is scheduled to 
occur before but closest to the study treatment cut-off date (without 
consideration of available visit time-windows) will be defined as the subject’s 
final treatment/EOS visit.  The subject’s final treatment/EOS visit must include 
all assessments specified for Visit 8/EOS. 
Changed to:
The date that the whole study will complete (henceforth referred to as the study 
completion date) will be determined based on the randomization date of the 
final subject in the study; the study completion date will be set at 181 days (i.e. 
25 weeks and 6 days) post the final subject’s randomization date. The study 
treatment cut-off date for all ongoing subjects will then be set at 11 days (i.e. 1 
week and 4 days) prior to the study completion date. The study sites will be 
notified in advance to inform all ongoing subjects of the study treatment cut-off 
date and the study completion date.
To determine when the final treatment/EOS visit will occur for each 
randomized subject in this variable duration study (i.e. at Week 24, Week 36 
or Week 52 of the treatment period), a date henceforth referred to as the 
transition date will be communicated to the study sites by GSK. GSK will 
communicate a provisional transition date to all study sites on an ongoing 
basis during the study, until a fixed actual transition date is communicated at 
least 20 weeks in advance of the selected date (unless extenuating
circumstances dictate otherwise). The date selected by GSK as the actual 
transition date will always be more than 12 days prior to the study completion 
date. At the Investigator’s discretion, subjects should be informed of the 
transition date (provisional and actual) on an ongoing basis during the study 
so that their expected final treatment/EOS visit can be planned using the 
provisional transition date and then confirmed once the actual transition date 


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is known.
Subjects who complete 52 weeks of study treatment prior to the actual 
transition date being communicated will have their final treatment/EOS visit 
at their Week 52 clinic assessment visit.
Once the study treatment cut-off and study completion dates are determined, 
ongoing subjects must continue to adhere to their pre-planned study visit 
schedule; however, the on-treatment clinic assessment visit that is scheduled to 
occur before but closest to the study treatment cut-off date (without 
consideration of available visit time-windows) will be defined as the subject’s 
final treatment/EOS visit.  The subject’s final treatment/EOS visit must include 
all assessments specified for Visit 8/EOS. 
After the actual transition date is communicated, subjects must adhere to 
their study visit schedule and complete a minimum of 24 weeks of study 
treatment. A subject’s final treatment/EOS visit will be defined as follows:
–
Subjects whose Week 24 clinic assessment visit is scheduled to 
occur on or after the actual transition date (without 
consideration of available visit time-windows) will have their 
final treatment/EOS visit at their Week 24 clinic assessment 
visit. 
–
Subjects who have their Week 24, Week 36 or Week 52 clinic 
assessment visit scheduled to occur before the actual transition 
date (without consideration of available visit time-windows) 
will have their final treatment/EOS visit at the clinic 
assessment visit that is scheduled to occur before but closest to 
the actual transition date (without consideration of available 
visit time-windows).
The subject’s final treatment/EOS visit must include all assessments specified 
for Visit 8/EOS.
Rationale: The protocol is being amended to base the variable treatment period 
on the planned recruitment rather than the date of the last subject randomized. 
This aligns planned exposure more closely with actual exposure and enables 
sites and participants to plan according to the variable treatment period. The 
term ‘study treatment cut-off date’ will be replaced with ‘transition date’ to 
avoid confusion.
49.
Section 4.3: Type and Number of Subjects (last sentence)    
Changed from:
For country-specific requirements on the number of randomized subjects see 


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Appendix 7.
Changed to:
For country-specific requirements on the number of randomized subjects see 
Appendix 7.
Rationale: The minimum requirement for Japanese subjects is no longer 
dependent on study 205715. 
50.
Section 5.7: Subject and Study Completion  
Changed from:
The date that the whole study will complete (henceforth referred to as the study 
completion date) will be determined based on the randomization date of the 
final subject in the study; the study completion date will be set at 181 days (i.e. 
25 weeks and 6 days) post the final subject’s randomization date. The study 
treatment cut-off date for all ongoing subjects will then be set at 11 days (i.e. 1 
week and 4 days) prior to the study completion date. The study sites will be 
notified in advance to inform all ongoing subjects of the study treatment cut-off 
date and the study completion date.
Once the study treatment cut-off and study completion dates are determined, 
ongoing subjects must continue to adhere to their pre-planned study visit 
schedule; however, the on-treatment clinic assessment visit that is scheduled to 
occur before but closest to the study treatment cut-off date (without 
consideration of available visit time-windows) will be defined as the subject’s 
final treatment/EOS visit.  The subject’s final treatment/EOS visit must include 
all assessments specified for Visit 8/EOS. 
Changed to:
The date that the whole study will complete (henceforth referred to as the study 
completion date) will be determined based on the randomization date of the 
final subject in the study; the study completion date will be set at 181 days (i.e. 
25 weeks and 6 days) post the final subject’s randomization date. The study 
treatment cut-off date for all ongoing subjects will then be set at 11 days (i.e. 1 
week and 4 days) prior to the study completion date. The study sites will be 
notified in advance to inform all ongoing subjects of the study treatment cut-off 
date and the study completion date.
To determine when the final treatment/EOS visit will occur for each 
randomized subject in this variable duration study (i.e. at Week 24, Week 36 
or Week 52 of the treatment period), a date henceforth referred to as the 
transition date will be communicated to the study sites by GSK. GSK will 
communicate a provisional transition date to all study sites on an ongoing 
basis during the study, until a fixed actual transition date is communicated at 
least 20 weeks in advance of the selected date (unless extenuating
circumstances dictate otherwise). The date selected by GSK as the actual 


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transition date will always be more than 12 days prior to the study completion 
date. At the Investigator’s discretion, subjects should be informed of the 
transition date (provisional and actual) on an ongoing basis during the study 
so that their expected final treatment/EOS visit can be planned using the 
provisional transition date and then confirmed once the actual transition date 
is known.
Subjects who complete 52 weeks of study treatment prior to the actual 
transition date being communicated will have their final treatment/EOS visit 
at their Week 52 clinic assessment visit.
Once the study treatment cut-off and study completion dates are determined, 
ongoing subjects must continue to adhere to their pre-planned study visit 
schedule; however, the on-treatment clinic assessment visit that is scheduled to 
occur before but closest to the study treatment cut-off date (without 
consideration of available visit time-windows) will be defined as the subject’s 
final treatment/EOS visit.  The subject’s final treatment/EOS visit must include 
all assessments specified for Visit 8/EOS (See Section 7.1). 
After the actual transition date is communicated, subjects must adhere to 
their study visit schedule and complete a minimum of 24 weeks of study 
treatment. A subject’s final treatment/EOS visit will be defined as follows:
–
Subjects whose Week 24 clinic assessment visit is scheduled to 
occur on or after the actual transition date (without 
consideration of available visit time-windows) will have their 
final treatment/EOS visit at their Week 24 clinic assessment 
visit. 
–
Subjects who have their Week 24, Week 36 or Week 52 clinic 
assessment visit scheduled to occur before the actual transition 
date (without consideration of available visit time-windows) 
will have their final treatment/EOS visit at the clinic 
assessment visit that is scheduled to occur before but closest to 
the actual transition date (without consideration of available 
visit time-windows).
The subject’s final treatment/EOS visit must include all assessments specified 
for Visit 8/EOS.
Rationale: The protocol is being amended to base the variable treatment period 
on the planned recruitment rather than the date of the last subject randomized. 
This aligns planned exposure more closely with actual exposure and enables 
sites and participants to plan according to the variable treatment period. The 
term ‘study treatment cut-off date’ will be replaced with ‘transition date’ to 
avoid confusion.


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51.  
Section 7.1: Time and Events Table; Footnote #22 (last sentence)   
Changed from: 
(see Appendix 7 for country-specific requirements)  
Changed to: 
(see Appendix 7 for country-specific requirements)  
Rationale: The minimum requirement for Japanese subjects is no longer 
dependent on study 205715.  
52.  
Section 7.6.1.1: Pharmacokinetic Substudy (2nd Paragraph, last sentence)     
Changed from: 
See Appendix 7 or country-specific requirements related to the PK sub-study 
Changed to: 
See Appendix 7 for country-specific requirements related to the PK sub-study. 
Rationale: The minimum requirement for Japanese subjects is no longer 
dependent on study 205715.   
53.  
Section 12.7.1: Country Specific Requirement for the Randomization of 
Subjects   
Changed from: 
Japan Only: The total number of randomized subjects required in Japan is 
approximately 300 of the 2250 randomized subjects required for the study, with 
approximately 50 Japanese subjects randomized to each of the 6 double-blind 
treatment arms. At Visit 3, approximately 20% of consenting Japanese subjects 
who are randomised to participate in the main study will be entered into the PK 
sub-study (see Section 7.6) 
Subjects will be stratified by pre-study ICS treatment dosage strength (mid, 
high) at screening and will be assigned to study treatment in accordance with a 
country-specific randomization schedule (to ensure treatment balance within 
each stratum (mid- or high-dose pre-study ICS treatment dosage strength). The 
randomization code will be generated by GSK using a validated computerized 
system. Subjects will be randomized using an IRT system (RAMOS NG). Once 
a randomization number is assigned to a subject it cannot be reassigned to any 
other subject in the study. 
Changed to: 
Japan Only: The total number of randomized subjects required in Japan is 


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approximately 300 of the 2250 randomized subjects required for the study, with 
approximately 50 Japanese subjects randomized to each of the 6 double-blind 
treatment arms. At Visit 3, approximately 20% of consenting Japanese subjects 
who are randomised to participate in the main study will be entered into the PK 
sub-study (see Section 7.6) 
Japan Only: Subjects will be stratified by pre-study ICS treatment dosage 
strength (mid, high) at screening and will be assigned to study treatment in 
accordance with a country-specific randomization schedule (to ensure treatment 
balance within each stratum (mid- or high-dose pre-study ICS treatment dosage 
strength). The randomization code will be generated by GSK using a validated 
computerized system. Subjects will be randomized using an IRT system 
(RAMOS NG). Once a randomization number is assigned to a subject it cannot 
be reassigned to any other subject in the study. 
Rationale: The minimum requirement for Japanese subjects is no longer 
dependent on study 205715.  
 
12.8.4. 
Protocol Amendment 04 
Protocol changes for Amendment 04 (05-DEC-2017), from amendment 03 (29-SEP-
2017) 
This amendment applies to all sites. 
Amendment 04 Summary and Rationale 
List of Specific changes: 
Text which has been added to the protocol is highlighted in bold, italic typeface. Text 
which has been deleted from the protocol is indicated by strike-through format. 
54.  
Section 6.1: Investigational Product and Other Study Treatment, paragraphs 10 
and 11 
Changed from: 
At the Investigator’s discretion, provision will be made from Visit 11 onwards 
for subjects to temporarily receive fluticasone propionate (FP 100 mcg [or 
equivalent]) via DISKUS DPI to treat the symptoms of a moderate asthma 
exacerbation (see Section 6.9.1.1 and Section 7.3.6.1). Treatment start and stop 
dates will be recorded in the eCRF.  
1Note: Should the subject use the provided FP prior to randomization at Visit 3, 
the enrolment or randomization concomitant medication exclusion criteria 
would be met (see Section 5.3.2 and Section 5.4.2). 
FP will be sourced from local commercial stock; if not available locally, GSK 


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will source centrally. The contents of the label will be in accordance with all 
applicable regulatory requirements. A record of the number of FP-containing 
DISKUS DPIs dispensed to each subject must be maintained and reconciled 
with study treatment records. 
Changed to: 
At the Investigator’s discretion, provision will be made from Visit 11 onwards 
for subjects to temporarily receive inhaled fluticasone propionate (FP)  100 
mcg [or equivalent]) via DISKUS DPI to treat the symptoms of a moderate 
asthma exacerbation (see Section 6.9.1.1 and Section 7.3.6.1). Treatment start 
and stop dates will be recorded in the eCRF.  
1Note: Should the subject use the provided FP prior to randomization at Visit 3, 
the enrolment or randomization concomitant medication exclusion criteria 
would be met (see Section 5.3.2 and Section 5.4.2). 
FP will be sourced from local commercial stock; if not available locally, GSK 
will source centrally. The contents of the label will be in accordance with all 
applicable regulatory requirements. A record of the number of FP-containing 
DISKUS DPIs inhalers dispensed to each subject must be maintained and 
reconciled with study treatment records. 
Rationale: FP is being provided (at the Investigator’s discretion) for the 
treatment of symptoms of a moderate asthma exacerbation; it is not necessary 
for the administration of FP to be via the DISKUS DPI. 
55.  
Section 7.2: Screening and Critical Baseline Assessments; final bullet-point 
Changed from: 
• Dispense FP 
Changed to: 
• Dispense FP (as applicable, per Investigator discretion) 
Rationale: To clarify that dispensing FP to subjects at Visit 1 is at the 
Investigator’s discretion. 
 

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
205715
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for Study 205715, a Phase III, 
randomized, double-blind, active controlled, parallel group 
study, comparing the efficacy, safety and tolerability of the 
fixed dose combination FF/UMEC/VI with the fixed dose 
dual combination of FF/VI, administered once-daily via a dry 
powder inhaler in subjects with inadequately controlled 
asthma
Compound Number 
:
GSK573719 + GW642444 + GW685698 (GSK2834425)
Effective Date 
:
28-FEB-2019
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 205715.

This RAP is intended to describe the efficacy, safety, and health outcomes analyses 
required for the study. 

This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable.
RAP Authors
Author
Date
Lead statistician role handed 
over: 18-May-2018
Associated Director, Biostatistics, Parexel International, 
on behalf of GSK
Lead statistician role handed 
over: 01-Nov-2018
Statistical Leader
25-FEB-2019
Statistical Leader
Copyright 2019 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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Clinical Statistics and Clinical Programming Line Approvals
(Method: Pharma TMF eSignature):
Approver
Date
27-FEB-2019
Director (Respiratory, Clinical Statistics)
28-FEB2019
Manager (Respiratory, Clinical Programming)
RAP Team Reviewer Confirmations (Method: E-mail):
Reviewer
Date
25-FEB-2019
Manager (Respiratory, Clinical Development)
25-FEB-2019
Manager (Respiratory, Clinical Programming)
25-FEB-2019
Physician Project Lead (Respiratory, Clinical 
Development)
26-FEB-2019
Director (Patient Centred Outcomes, Value Evidence and 
Outcomes)
25-FEB-2019
Director (Respiratory, Clinical Pharmacology Modelling & 
Simulations)
 
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TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................6
1.1.
Reporting & analysis plan synopsis...............................................................6
2.
SUMMARY OF KEY PROTOCOL INFORMATION ................................................11
2.1.
Changes to the Protocol Defined Statistical Analysis Plan..........................11
2.2.
Study Objectives and Endpoints .................................................................12
2.3.
Study Design ..............................................................................................15
2.4.
Statistical Hypotheses / Statistical Analyses ...............................................17
3.
PLANNED ANALYSES ..........................................................................................18
3.1.
Interim Analyses .........................................................................................18
3.2.
Final Analyses ............................................................................................18
4.
ANALYSIS POPULATIONS ...................................................................................18
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................20
5.1.
Study Treatment & Sub-group Display Descriptors.....................................20
5.2.
Baseline Definition & Derivations ................................................................21
5.3.
Change from Baseline Definitions and Derivations .....................................22
5.3.1.
Clinic Assessments......................................................................22
5.3.2.
Diary Assessments......................................................................23
5.4.
Multi-Centre Studies ...................................................................................24
5.5.
Examination of Covariates, Other Strata and Subgroups............................24
5.5.1.
Covariates and Other Strata ........................................................24
5.5.2.
Examination of Subgroups...........................................................25
5.6.
Multiple Comparisons and Multiplicity .........................................................26
5.7.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................29
6.
STUDY POPULATION ANALYSES .......................................................................30
6.1.
Disposition of Participants...........................................................................31
6.2.
Demographic and Baseline Characteristics.................................................32
6.3.
Concomitant Medications............................................................................33
6.4.
Treatment Compliance................................................................................34
7.
EFFICACY ANALYSES..........................................................................................35
7.1.
Primary Efficacy Analyses ..........................................................................38
7.1.1.
Endpoint / Variables.....................................................................38
7.1.2.
Summary Measure ......................................................................38
7.1.3.
Population of Interest...................................................................38
7.1.4.
Strategy for Intercurrent (Post-Randomization) Events ................39
7.1.5.
Statistical Analyses / Methods .....................................................39
7.1.6.
Statistical Methodology Specification...........................................41
7.2.
Key Secondary Analyses ............................................................................45
7.2.1.
Endpoint / Variables.....................................................................45
7.2.2.
Summary Measure ......................................................................46
7.2.3.
Population of Interest...................................................................46
 
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7.2.4.
Strategy for Intercurrent (Post-Randomization) Events ................46
7.2.5.
Statistical Analyses / Methods .....................................................46
7.2.6.
Statistical Methodology Specification...........................................49
7.3.
Other Secondary Analyses .........................................................................52
7.3.1.
Endpoint / Variables.....................................................................52
7.3.2.
Summary Measure ......................................................................53
7.3.3.
Population of Interest...................................................................53
7.3.4.
Strategy for Intercurrent (Post-Randomization) Events ................53
7.3.5.
Statistical Analyses / Methods .....................................................53
7.3.5.1.
Statistical Methodology Specification..........................53
7.4.
Other Efficacy Analyses..............................................................................56
7.4.1.
Endpoint / Variables.....................................................................57
7.4.2.
Summary Measure ......................................................................59
7.4.3.
Population of Interest...................................................................60
7.4.4.
Strategy for Intercurrent (Post-Randomization) Events ................60
7.4.4.1.
Statistical Methodology Specification..........................60
8.
SAFETY ANALYSES .............................................................................................67
8.1.
Extent of Exposure .....................................................................................70
8.2.
Adverse Events Analyses ...........................................................................71
8.3.
Adverse Events of Special Interest Analyses..............................................71
8.4.
Major Adverse Cardiac Events....................................................................73
8.5.
Clinical Laboratory Analyses.......................................................................74
8.6.
Other Safety Analyses ................................................................................74
8.6.1.
Vital Signs....................................................................................74
8.6.2.
ECG.............................................................................................74
8.6.3.
Pregnancy ...................................................................................75
8.6.4.
Planned Statistical Analyses of Safety Endpoints ........................75
8.6.4.1.
Vital Signs and ECGs.................................................75
9.
POP PK DATA SPECIFICATION ...........................................................................75
9.1.
Pop PK Dataset Specification .....................................................................75
10. REFERENCES.......................................................................................................81
11. APPENDICES........................................................................................................83
11.1.
Appendix 1: Protocol Deviation Management .............................................83
11.2.
Appendix 2: Protocol Defined Schedule of Events ......................................84
11.2.1.
Time and Events Table................................................................84
11.3.
Appendix 3: Assessment Windows .............................................................92
11.3.1.
General........................................................................................92
11.3.2.
Variable Duration.........................................................................93
11.4.
Appendix 4: Study Phases..........................................................................94
11.5.
Appendix 5: Data Display Standards & Handling Conventions....................95
11.5.1.
Reporting Process .......................................................................95
11.5.2.
Reporting Standards....................................................................95
11.6.
Appendix 6: Derived and Transformed Data ...............................................97
11.6.1.
General........................................................................................97
11.6.2.
Study Population..........................................................................99
11.6.3.
Efficacy......................................................................................101
11.6.4.
Safety ........................................................................................108
11.7.
Appendix 7: Reporting Standards for Missing Data...................................112
 
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11.7.1.
Premature Withdrawals..............................................................112
11.7.2.
Handling of Missing Data...........................................................112
11.7.2.1.
Handling of Missing and Partial Dates ......................113
11.7.2.2.
Handling of Missing Data for Statistical 
Analysis....................................................................114
11.8.
Appendix 8: Model Checking and Diagnostics for Statistical Analyses......................115
11.9.
Appendix 9: Abbreviations & Trade Marks ................................................118
11.9.1.
Abbreviations.............................................................................118
11.9.2.
Trademarks ...............................................................................120
11.10. Appendix 10: List of Data Displays............................................................121
11.10.1. Data Display Numbering............................................................121
11.10.2. Mock Example Shell Referencing ..............................................121
11.10.3. Deliverables...............................................................................121
11.10.4. Study Population Tables............................................................122
11.10.5. Study Population Figures...........................................................126
11.10.6. Efficacy Tables ..........................................................................127
11.10.7. Efficacy Figures .........................................................................142
11.10.8. Safety Tables.............................................................................156
11.10.9. Safety Figures ...........................................................................164
11.10.10.ICH Listings ...............................................................................166
11.10.11.Non-ICH Listings........................................................................171
 
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1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol for study 205715.
1.1.
Reporting & analysis plan synopsis
Overview
Key Elements of the RAP
Purpose

This Reporting and Analysis Plan (RAP) details planned analyses and 
outputs required for the final Clinical Study Report (CSR) of study 205715. 
Protocol
This RAP is based on the following protocol and protocol amendments: 

Original protocol (Dated: 09Jun2016, GSK Document No.: 
2016N271022_01).

Protocol amendment #1 (Dated: 13Dec2016, GSK Document No.: 
2016N271022_02).

Protocol amendment #2 (Dated: 23Jun2017, GSK Document No.: 
2016N271022_03).

Protocol amendment #3 (Dated: 29Sep2017, GSK Document No.: 
2016N271022_04).

Protocol amendment #4 (Dated: 05Dec2017, GSK Document No.: 
2016N271022_05).
Primary 
Objective 

To evaluate the effects of FF/UMEC/VI on lung function compared with FF/VI 
after 24 weeks of treatment
Key 
Secondary 
Objective

To evaluate the efficacy of FF/UMEC/VI compared with FF/VI
Other
Secondary 
Objective

To evaluate other efficacy assessments of FF/UMEC/VI compared with FF/VI
Primary 
Endpoint

Mean change from baseline in trough Forced Expiratory Volume in 1 second 
(FEV1) at Week 24
Key 
Secondary 
Endpoint

Annualized rate of moderate/severe asthma exacerbations
Other 
Secondary 
Endpoints

Mean change from baseline in clinic FEV1 at 3 hours post-study treatment at 
Week 24

Mean change from baseline in Asthma Control Questionnaire-7 (ACQ-7) total 
score at Week 24

Mean change from baseline in St. George's Respiratory Questionnaire 
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Overview
Key Elements of the RAP

Mean change from baseline in Evaluating Respiratory Symptoms (E-RS) 
total score over the Weeks 21-24 (inclusive) of the treatment period
Other 
Endpoints

Mean change from baseline in clinic trough FEV1 over the first 24 weeks 
of the treatment period

Mean change from baseline in home daily trough FEV1 over the first 24 
weeks of the treatment period

Annualized rate of severe asthma exacerbations

Time to first severe asthma exacerbation

Time to first moderate/severe asthma exacerbation

Percent of patients meeting a responder threshold of 0.5 points 
improvement (decrease) from baseline for the ACQ-7 at Week 24

Percent of patients meeting a responder threshold of 0.5 points 
improvement (decrease) from baseline for the ACQ-6 at Week 24

Percent of patients meeting a responder threshold of 0.5 points 
improvement (decrease) from baseline for the ACQ-5 at Week 24

Percentage of patients that have achieved asthma control based on ACQ-
7 (i.e. a total score ≤0.75) at both Week 12 and Week 24

Percentage of patients that have achieved asthma control based on ACQ-
6 (i.e. a total score ≤0.75) at both Week 12 and Week 24

Percentage of patients that have achieved asthma control based on ACQ-
5 (i.e. a total score ≤0.75) at both Week 12 and Week 24

Mean change from baseline in SGRQ domain scores at Week 24

Percent of patients meeting a responder threshold of ≥ 4 points 
improvement (decrease) from baseline for the SGRQ total score at Week 24

Mean change from baseline in E-RS domain scores over the Weeks 21-
24 (inclusive) of the treatment period

Percent of patients meeting a responder threshold of ≥ 2 points 
improvement (decrease) from baseline for the E-RS total score over the 
Weeks 21-24 (inclusive) of the treatment period

Mean change from baseline in the Asthma Quality of Life Questionnaire 
(AQLQ) total score at Week 24

Percent of patients meeting a responder threshold of ≥ 0.5 points 
improvement (increase) from baseline for the AQLQ total score at Week 24

Mean change from baseline in morning (AM) pre-dose Peak Expiratory 
Flow (PEF) over the first 24 weeks of the treatment period

Mean change from baseline in evening (PM) PEF over the first 24 weeks 
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Overview
Key Elements of the RAP

Mean change from baseline in the percentage of symptom-free days over 
the first 24 weeks of the treatment period

Mean change from baseline in the percentage of rescue medication-free 
days over the first 24 weeks of the treatment period

Mean change from baseline in daily rescue medication use over the first 
24 weeks of the treatment period

Unscheduled asthma-related healthcare resource utilization over the first 24 
weeks of the treatment period
Study 
Design

This is a phase IIIa, randomized, double-blind, active controlled, 6-arm 
parallel group, global multi-center study evaluating FF/UMEC/VI 
(100/31.25/25, 100/62.5/25, 200/31.25/25 and 200/62.5/25 micrograms [mcg]) 
versus FF/VI (100/25 and 200/25 mcg), given once daily (OD) in the morning
(AM) via ELLIPTA.

The target total number of randomized participants is approximately 2250, 
with 375 participants randomized to each of the 6 double-blind treatment 
arms.

Participants who permanently discontinue study treatment are not required to 
withdraw from the study. Participants 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.
Planned 
Analyses

No interim analysis is planned for this study. 

The final analysis will be conducted after Data Base Freeze (DBF) of the 
study data. All decisions regarding the final analysis, as defined in this RAP 
document, will be made by Source Data Lock (SDL) based on the treatment-
blinded study data.
Analysis
Populations

Intent-to-treat (ITT) population, which comprises all randomized participants, 
excluding those who were randomized in error. A participant who is recorded 
as a screen failure, run-in failure, or stabilisation failure, but is randomized
and does not receive a dose of study treatment, is considered to be 
randomized in error. Any other participant who receives a randomization
number will be considered to have been randomized. All efficacy and safety 
analyses will be based on the ITT population.

All Subjects Enrolled population, which comprises all participants for whom a 
record exists on the study database, including pre-screened participants that 
sign the informed consent document but do not complete a Visit 1 (screening) 
procedure (i.e., pre-screening failures), or participants that complete at least 
one Visit 1 procedure but do not enter the run-in period (i.e., screening 
failures). This population will be used for the summary of participant
disposition.

All Subjects Screened population, which comprises all participants that 
complete at least one Visit 1 (Screening) procedure.
 
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Overview
Key Elements of the RAP

PK population: This population will comprise all participants in the ITT 
Population for whom a PK sample was obtained and analysed.
Hypothesis
The primary objective of this study is to evaluate the efficacy and safety of UMEC 
in combination with FF/VI in participants with asthma over a 24-week treatment 
period.  This is a superiority study to demonstrate the add-on benefit of UMEC at 
two dosage strengths 62.5 mcg and 31.25 mcg in a single inhaler when compared 
to FF/VI. The primary efficacy endpoint is the mean change from baseline in 
trough FEV1 at the end of the 24-week treatment period.
For each test on each efficacy endpoint, the null hypothesis is that there is no 
difference between treatment groups. 
H0: T1 – T2 = 0
The alternative hypothesis is that there is a difference between treatment groups.
H1: T1 – T2 ≠ 0
For the primary endpoint and other lung function related efficacy endpoints, the 
primary treatment comparisons of interest are the comparisons for each triple 
therapy and the respective dual therapy FF/VI without the UMEC component as 
follows:  
UMEC 62.5 mcg: 

FF/UMEC/VI 100/62.5/25 mcg vs. FF/VI 100/25 mcg

FF/UMEC/VI 200/62.5/25 mcg vs. FF/VI 200/25 mcg
UMEC 31.25 mcg: 

FF/UMEC/VI 100/31.25/25 mcg vs. FF/VI 100/25 mcg

FF/UMEC/VI 200/31.25/25 mcg vs. FF/VI 200/25 mcg
Therefore, T1 and T2 for these endpoints are the mean changes from baseline for 
the individual triple therapy and dual therapy, respectively, as listed above. 
For the key secondary endpoint and all other non-lung function efficacy endpoints, 
the primary treatment comparisons of interest are the comparisons between triple 
therapy and dual therapy for a fixed dose of UMEC:

(FF/UMEC/VI 100/62.5/25, 200/62.5/25) vs. (FF/VI 100/25, 200/25)

(FF/UMEC/VI 100/31.25/25, 200/31.25/25) vs. (FF/VI 100/25, 200/25)
For example, T1 and T2 in the hypothesis associated with the key secondary 
efficacy endpoint are the averages of the mean annualized rate of 
moderate/severe exacerbations for the triple therapies over two FF doses at a 
given UMEC dose, and for the dual therapies over two FF doses, respectively.
Primary 

The primary efficacy analysis will evaluate the “de facto” type estimand in the 
 
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Overview
Key Elements of the RAP
Analyses
Intent-to-Treat population, using a mixed-model repeated measures (MMRM) 
analysis, including all trough FEV1 recorded post-randomization prior to and at 
Week 24, both on- and post-treatment, and without imputation. Analyses will 
include age, sex, region, baseline value, stratification by pre-study ICS 
dosage at screening, treatment, visit, treatment by visit interaction, and 
baseline value by visit interaction.
Secondary 
Analyses

The analysis for the key secondary endpoint on the annualized rate of 
moderate/severe asthma exacerbations will be analyzed using a generalized 
linear model, assuming the number of exacerbations has a negative binomial 
probability distribution and that its mean is related to covariate factors with a 
‘log link’ function. The logarithm of time (year) on study will be used as an 
offset variable. The model will include covariates for age, sex, region, 
treatment group, stratification by pre-study ICS dosage at screening, and 
severe asthma exacerbations in the previous year (0, 1, >=2). For the pooled 
analysis, all 6-arm data will be included in the analysis model, and treatment 
comparisons will be performed using LSMESTIMATE statement in SAS 
PROC GENMOD, appropriately for the treatments and treatment comparisons 
of interest. Moderate/severe asthma exacerbations from the start to the end of 
treatment period will be used in the analysis, regardless of participant’s IP 
completion status. 
Multiplicity

A step-down closed testing approach will be applied for the primary efficacy 
endpoint, the key secondary efficacy endpoint, and the secondary efficacy 
endpoints SGRQ, ACQ-7, and E-RS. 

Specifically, if the defined treatment comparisons for the primary efficacy 
endpoint between triple therapy and dual therapy at the high dose of UMEC 
62.5 mcg are statistically significant at the 0.05 level for both fixed FF doses 
(100 and 200mcg), then the replicate efficacy of UMEC 62.5mcg is 
demonstrated, and the defined treatment comparison between triple therapy 
and dual therapy will be tested for the key secondary efficacy endpoint of 
moderate/severe asthma exacerbations based on the combined data of both 
FF doses for UMEC 62.5mcg. If the test for the key secondary efficacy 
endpoint is significant at the 0.05 level, then the secondary efficacy endpoints 
for SGRQ and ACQ-7 will be tested sequentially based on the combined data 
of both FF doses for UMEC 62.5mcg at significance level 0.05. 

If all tests mentioned above for UMEC 62.5 mcg are statistically significant at 
the 0.05 level, the above testing hierarchy will be repeated for the low dose of 
UMEC 31.25 mcg.  

If all tests for the primary, the key secondary, and the secondary efficacy 
endpoints for SGRQ and ACQ-7 are statistically significant at the 0.05 level 
for both UMEC 62.5mcg and 31.25mcg, the secondary endpoint for E-RS will 
be tested at the significance level 0.05 for UMEC 62.5 and UMEC 31.25 in 
sequence. 

The family-wise Type I Error is strongly controlled at 0.05 level for both UMEC 
62.5mcg and UMEC 31.25mcg on the primary endpoint (trough FEV1), the 
 
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Overview
Key Elements of the RAP
key secondary endpoint (moderate/severe asthma exacerbations), and the 
secondary endpoints on SGRQ, ACQ-7, and E-RS.
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Changes from the planned statistical analysis specified in the protocol are outlined in the 
table below.  In addition, in order to comply with regulatory guidance where the protocol 
referred to “Subjects” the analysis plan refers to “Participants”, with the exception of 
displays and study populations.  
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes
Key secondary endpoint: 
The pooled analysis was to 
include the pooled (FF doses) 3-
arm data and the FF dosage as a 
(categorical) covariate in the 
analysis model.
Key secondary endpoint: 
The pooled analysis will 
include all 6-arm data in the 
model. The treatment effect 
(pooled over FF doses) will 
be estimated using 
LSMESTIMATE statement in 
SAS PROC GENMOD.
This change is to ensure a 
consistent analysis method 
for pooled analyses (FF 
doses) in the CSR and the 
pooled analyses (FF 
doses, UMEC doses, FF 
and UMEC doses) planned 
for the submission (SDAP). 
The method proposed in 
the protocol for pooled (FF 
doses) analysis cannot be 
applied for the pooled 
(UMEC doses, FF and 
UMEC doses) analyses in 
SDAP due to study design. 
Region was not included as a 
covariate for the proposed 
primary and key secondary 
analysis.
Region is added as a 
covariate for all statistical 
analysis models. 
The study is a global study
with 15 participating 
countries across multiple 
regions. The change is to 
ensure that the statistical 
analysis adjusts for 
possible region effect due 
to differences in local 
medical practices in the 
treatment of asthma.
Exacerbation history was not 
included as a covariate in the 
proposed statistical analysis for 
the key secondary endpoint.
The severe asthma 
exacerbations in the previous 
year (0, 1, >=2) is added as a 
covariate for all asthma 
exacerbation related 
analyses. 
This change is to ensure 
that the exacerbation 
analysis is adjusted for 
asthma severity based on 
exacerbation history.  
No mention of a randomized
Defines a randomized
In order for the randomized
 
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Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes
population
population
population to be included 
in the summary of analysis 
populations and so clearly 
show the flow of 
participants through the 
study, see Section 4.
Refers to randomization
stratification variable
Analyses and subgroup 
analyses will use the actual 
pre-study ICS dosage at 
screening as collected in the 
eCRF.
Interest is in the impact of 
actual pre-study ICS 
dosage at screening rather 
than randomized strata, 
and so due to participants 
being mis-stratified at 
randomization, the RAP 
has been updated to clarify 
the actual strata a 
participant belongs to will 
be used (i.e. their actual 
pre-study ICS dosage at 
screening), rather than the 
strata under which they 
were randomized. 
NA
Addition of endpoint for home 
daily PM FEV1 and analysis.
To give complete picture of 
the home daily FEV1 data.
For all efficacy endpoints primary, 
secondary, and other), treatment 
comparisons between triple 
therapy at low dose FF vs. dual 
therapy with high dose FF, or the 
benefit of increasing FF dose in a 
triple therapy, or the benefit of 
increasing UMEC dose in a triple 
therapy will be made without 
adjusting for multiplicity.
All comparisons will be 
carried out for the primary 
and secondary endpoints. For 
the other endpoints, only the 
primary comparisons will be 
presented, unless the 
endpoint is supportive of a 
secondary endpoint.
Simplify the analyses to 
focus on only the data 
needed to achieve the 
objectives of the study. 
See Section 7 for the 
comparisons to be 
presented.
2.2.
Study Objectives and Endpoints
Objectives
Endpoints
Primary Objective
Primary Endpoint

To evaluate the effects of 
FF/UMEC/VI on lung function 
compared with FF/VI after 24 
weeks of treatment

Mean change from baseline in trough Forced 
Expiratory Volume in 1 second (FEV1) at Week 24
Key Secondary Objective
Key Secondary Endpoint
To evaluate the efficacy of 
FF/UMEC/VI compared with FF/VI

Annualized rate of moderate/severe asthma 
exacerbations
 
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Objectives
Endpoints
Other Secondary Objectives
Other Secondary Endpoints

To evaluate the efficacy of 
FF/UMEC/VI compared with FF/VI

Mean change from baseline in clinic FEV1 at 3 
hours post study treatment at Week 24

Mean change from baseline in Asthma Control 
Questionnaire-7 (ACQ-7) total score at Week 24

Mean change from baseline in St. George's 
Respiratory Questionnaire (SGRQ) total score at 
Week 24

Mean change from baseline in Evaluating 
Respiratory Symptoms (E-RS) total score over 
Weeks 21-24 (inclusive) of the treatment period

To evaluate the safety of 
FF/UMEC/VI compared with FF/VI

Incidence and type of adverse events (AEs)

Electrocardiogram (ECG) measurements

Vital signs

Clinical hematological and chemistry parameters
Other Objectives
Other Efficacy Endpoints

To evaluate other efficacy 
assessments of FF/UMEC/VI 
compared with FF/VI

Mean change from baseline in clinic trough FEV1
over the first 24 weeks of the treatment period

Mean change from baseline in home daily trough 
FEV1 over the first 24 weeks of the treatment 
period

Annualized rate of severe asthma exacerbations

Time to first severe asthma exacerbation

Time to first moderate/severe asthma 
exacerbation

Percent of patients meeting a responder 
threshold of 0.5 points improvement (decrease) 
from baseline for the ACQ-7 at Week 24

Percent of patients meeting a responder 
threshold of 0.5 points improvement (decrease) 
from baseline for the ACQ-6 at Week 24

Percent of patients meeting a responder 
threshold of 0.5 points improvement (decrease) 
from baseline for the ACQ-5 at Week 24

Percentage of patients that have achieved 
asthma control based on ACQ-7 (i.e. a total score 
≤0.75) at both Week 12 and Week 24

Percentage of patients that have achieved 
asthma control based on ACQ-6 (i.e. a total score 
 
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Objectives
Endpoints
≤0.75) at both Week 12 and Week 24

Percentage of patients that have achieved 
asthma control based on ACQ-5 (i.e. a total score 
≤0.75) at both Week 12 and Week 24

Mean change from baseline in SGRQ domain 
scores at Week 24

Percent of patients meeting a responder 
threshold of ≥ 4 points improvement (decrease) 
from baseline for the SGRQ total score at Week 
24

Mean change from baseline in E-RS domain 
scores over Weeks 21-24 (inclusive) of the 
treatment period

Percent of patients meeting a responder 
threshold of ≥ 2 points improvement (decrease) 
from baseline for the E-RS total score over 
Weeks 21-24 (inclusive) of the treatment period

Mean change from baseline in the Asthma 
Quality of Life Questionnaire (AQLQ) total score 
at Week 24

Percent of patients meeting a responder 
threshold of ≥ 0.5 points improvement (increase) 
from baseline for the AQLQ total score at Week 
24

Mean change from baseline in morning (AM) pre-
dose Peak Expiratory Flow (PEF) over the first 24 
weeks of the treatment period

Mean change from baseline in evening (PM) PEF 
over the first 24 weeks of the treatment period

Mean change from baseline in the percentage of 
symptom-free days over the first 24 weeks of the 
treatment period

Mean change from baseline in the percentage of 
rescue medication-free days over the first 24 
weeks of the treatment period

Mean change from baseline in daily rescue 
medication use over the first 24 weeks of the 
treatment period

Unscheduled asthma-related healthcare resource 
utilization over the first 24 weeks of the treatment 
 
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Objectives
Endpoints
period

To evaluate the systemic 
exposure of FF, UMEC and VI 
following FF/UMEC/VI
Area Under the Curve (AUC(0-τ) [τ=24h]), Cmax

To collect blood samples for a 
genetics research study
To be described in a separate document
2.3.
Study Design
Overview of Study Design and Key Features
Design
Features

This is a phase IIIa, randomized, double-blind, active controlled, 6-arm parallel 
group, global multi-centre study evaluating FF/UMEC/VI (100/31.25/25, 
100/62.5/25, 200/31.25/25 and 200/62.5/25 mcg) versus FF/VI (100/25 and 
200/25 mcg), given OD AM.

The target total number of randomized participants is approximately 2250, with 
375 participants randomized to each of the 6 double-blind treatment arms. 

Participants who permanently discontinue study treatment are not required to 
withdraw from the study. Participants 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.
Dosing

The double-blind treatment will be delivered via an ELLIPTA dry powder 
inhaler [DPI] OD AM during the treatment period.

The duration of the treatment period is variable but will be a minimum of 24 
weeks and a maximum of 52 weeks. The study completion date will be 
determined based on the date of last participant randomized in the study, who 
will be on the double-blind study treatment for 24 weeks with a follow up visit 1-
 
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Overview of Study Design and Key Features
week post-treatment.  To determine when the final treatment/End of Study 
(EOS) visit will occur for each randomized participant in this variable duration 
study (i.e. at Week 24, Week 36 or Week 52 of the treatment period), a 
transition date will be determined and communicated to the study sites by 
GSK. A participant’s final treatment/EOS visit will be defined as follows:
-
Participants who complete 52 weeks of study treatment prior to the actual 
transition date being communicated will have their final treatment/EOS visit 
at their Week 52 clinic assessment visit.
-
Participants whose Week 24 clinic assessment visit is scheduled to occur 
on or after the actual transition date (without consideration of available visit 
time windows) will have their final treatment/EOS visit at their Week 24 
clinic assessment visit.
-
Participants who have their Week 24, Week 36 or Week 52 clinic 
assessment visit scheduled to occur before the actual transition date 
(without consideration of available visit time windows) will have their final 
treatment/EOS visit at the clinic assessment visit that is scheduled to occur 
before but closest to the actual transition date (without consideration of 
available visit time windows).
Time & 
Events

Refer to Appendix 2: Protocol Defined Schedule of Events
Treatment 
Assignment

Eligible participants will enter a 3-week run-in period on fluticasone/salmeterol 
[FSC], 250/50 mcg twice a day via the DISKUS DPI, followed by a 2-week 
stabilization period on FF/VI 100/25 mcg via the ELLIPTA DPI once a day in 
the morning.

At the conclusion of the stabilisation period, eligible participants are to be 
randomized 1:1:1:1:1:1 to receive one of the following six double-blind study
treatments:
o
FF/UMEC/VI 100/62.5/25 mcg 
o
FF/UMEC/VI 200/62.5/25 mcg 
o
FF/UMEC/VI 100/31.25/25 mcg 
o
FF/UMEC/VI 200/31.25/25 mcg 
o
FF/VI 100/25 mcg 
o
FF/VI 200/25 mcg

The randomization code will be generated using GlaxoSmithKline (GSK) 
software (RANDALL NG) and stratified by pre-study ICS dosage at screening. 
The study will use one central randomization schedule to allocate treatments 
for all randomized participants except those from Japan. A separate 
randomization schedule will be generated for Japan to ensure the treatment 
balance in a total number of approximately 300 randomized participants for the 
country specific requirement. 

Participants will be randomized using an IRT system (RAMOS NG).
Interim 
Analysis

No interim analysis is planned for this study.
 
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2.4.
Statistical Hypotheses / Statistical Analyses
The primary objective of this study is to evaluate the efficacy and safety of UMEC in 
combination with FF/VI in participants with asthma over a 24-week treatment period.  
This is a superiority study to demonstrate the add-on benefit of UMEC at two dosage 
strengths 62.5 mcg and 31.25 mcg in a single inhaler when compare to FF/VI. The 
primary efficacy endpoint is the mean change from baseline in trough FEV1 at the end of 
the 24-week treatment period.
For each test on each efficacy endpoint, the null hypothesis is that there is no difference 
between treatment groups. 
H0: T1 – T2 = 0
The alternative hypothesis is that there is a difference between treatment groups.
H1: T1 – T2 ≠ 0
For the primary endpoint and other lung function related efficacy endpoints, the primary 
treatment comparisons of interest are the comparisons for each triple therapy and the 
respective dual therapy FF/VI without the UMEC component as follows:  
UMEC 62.5 mcg: 

FF/UMEC/VI 100/62.5/25 mcg vs. FF/VI 100/25 mcg

FF/UMEC/VI 200/62.5/25 mcg vs. FF/VI 200/25 mcg
UMEC 31.25 mcg: 

FF/UMEC/VI 100/31.25/25 mcg vs. FF/VI 100/25 mcg

FF/UMEC/VI 200/31.25/25 mcg vs. FF/VI 200/25 mcg
Therefore, T1 and T2 for these endpoints are the mean changes from baseline for the 
individual triple therapy and dual therapy, respectively, as listed above. 
For the key secondary endpoint and all other non-lung function efficacy endpoints, the 
primary treatment comparisons of interest are the comparisons between triple therapy and
dual therapy for a fixed dose of UMEC:

(FF/UMEC/VI 100/62.5/25, 200/62.5/25) vs. (FF/VI 100/25, 200/25)

(FF/UMEC/VI 100/31.25/25, 200/31.25/25) vs. (FF/VI 100/25, 200/25)
For example, T1 and T2 in the hypothesis associated with the key secondary efficacy 
endpoint are the averages of the mean annualized rate of moderate/severe exacerbations 
for the triple therapies over two FF doses at a given UMEC dose, and for the dual 
therapies over two FF doses, respectively.
 
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3.
PLANNED ANALYSES
3.1.
Interim Analyses
No interim analysis is planned for this study.
3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All participants have completed the study as defined in the protocol.
2.
All required database cleaning activities have been completed and final database 
release (DBR) has been declared by Data Management (DM).
3.
System Independent (SI) data to Study Data Tabulation Model (SDTM) data 
conversion has completed by Conversion Service Provider at Source Data Lock 
(SDL).
4.
All criteria for unblinding the randomization codes have been met. Randomization
codes have been distributed according to RandAll NG procedures. Release of 
randomization code and treatment container list, unblinding of study treatment and 
participant level treatment of SDTM data, and related quality control activities have 
been completed by Statistics and Programming (S&P).
5.
Database freeze on SDTM datasets has been declared by DM upon receipt of the 
final, treatment unblinded SDTM data from S&P. 
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
All Subjects 
Enrolled 

This population will comprise all participants for 
whom a record exists on the study database, 
including pre-screened participants that sign the 
informed consent document but do not complete 
a Visit 1 (screening) procedure (i.e., pre-
screening failures), or participants that complete 
at least one Visit 1 procedure but do not enter 
the run-in period (i.e., screening failures). 

Study Population
All Subjects 
Screened 

This population contains all participants that 
complete at least one Visit 1 (Screening) 
procedure

Study Population

Adverse events 
for non-ITT 
participants
Randomized

This population will comprise of all participants 
who were randomized (i.e. received a 
randomization number)

Study population
Intent-to-Treat 
(ITT)

This population will comprise all randomized
participants, excluding those who were 
randomized in error. A participant who is 

Study population

Efficacy

Safety
 
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Population
Definition / Criteria
Analyses Evaluated
recorded as a screen failure, run-in failure, or 
stabilisation failure, but is randomized and does 
not receive a dose of study treatment, is 
considered to be randomized in error.

Health outcomes
Pharmacokinetic

This population will comprise all participants in 
the ITT Population for whom a PK sample was 
obtained and analysed.

PK
Refer to Appendix 10: List of Data Displays which details the population used for each display.
 
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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting 
Code
Description
Description
Displays
Order in TFL
1
FF/VI 100/25 QD
FF/VI 100/25
FF/VI 100/25
1
2
FF/VI 200/25 QD
FF/VI 200/25
FF/VI 200/25
4
3
FF/UMEC/VI 
100/31.25/25 QD
FF/UMEC/VI 
100/31.25/25
FF/UMEC/VI 
100/31.25/25
2
4
FF/UMEC/VI 
200/31.25/25 QD
FF/UMEC/VI 
200/31.25/25
FF/UMEC/VI 
200/31.25/25
5
5
FF/UMEC/VI 
100/62.5/25 QD
FF/UMEC/VI 
100/62.5/25
FF/UMEC/VI 
100/62.5/25
3
6
FF/UMEC/VI 
200/62.5/25 QD
FF/UMEC/VI 
200/62.5/25
FF/UMEC/VI 
200/62.5/25
6
7*
N/A
FF/VI 100/25 or 
200/25
FF/VI
7
8*
N/A
FF/UMEC/VI 
100/31.25/25 or 
200/31.25/25
FF/UMEC/VI 
UMEC 31.25
8
9*
N/A
FF/UMEC/VI 
100/62/5/25 or 
200/62.5/25
FF/UMEC/VI 
UMEC 62.5
9
NOTES:
*:     applicable only to the displays based on the pooled analysis. 
The details on the treatment comparisons of interest are provided in Section 7. 
 
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5.2.
Baseline Definition & Derivations
For clinic FEV1, the Baseline value is the last acceptable/borderline acceptable pre-dose 
FEV1 prior to randomized treatment start date (either from pre-dose at Day 1 or pre-
bronchodilator at Enrolment Visit or at an unscheduled visit which occurs between the 
Enrolment Visit and Day 1).
For ACQ, SGRQ, and AQLQ, baseline value for each endpoint is the derived value based 
on the questionnaire administered at the randomization visit. 
For the safety assessments of clinical laboratory, vital signs, and ECGs, the baseline 
value is the latest value recorded prior to first dose, including pre-dose unscheduled 
visits.
For diary data the baseline is the average value over the last 14 days prior to randomized
treatment start (for more details see Section 5.3.2). If fewer than 7 days of data over the 
baseline period are available, the baseline value will be set as missing.
If time is not collected, Day 1 clinic assessments (or Day 1 AM diary assessments) are 
assumed to be taken prior to first dose and used in the derivation for baseline.
All baselines will be referred to as ‘Baseline’ in the summary outputs.
Parameter
Study Assessments Considered as Baseline
Clinic Assessments
Screening
Day 1 (Pre-Dose)
Efficacy
Trough FEV1, FEV1 3h post study 
treatment
X*
ACQ-5, ACQ-6, ACQ-7, SGRQ, 
AQLQ, Global Assessment of 
Severity
X
Safety
Clinical Laboratory (incl. total 
serum IgE and FeNO) †
X
ECGs†
X
Vital signs†
X
Diary Assessments
Baseline Period
Efficacy
Home Daily Trough FEV1, 
Home Daily AM PEF
Last 14 AM assessments during the stabilisation period, 
including AM assessment on the day of first treatment, prior 
 
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Parameter
Study Assessments Considered as Baseline
to first dose (i.e., treatment start date per protocol)
Home Daily PM FEV1, Home 
Daily PM PEF
Last 14 PM assessments immediately preceding first 
treatment during the stabilisation period
%Symptom free days, % rescue 
medication free days, daily 
rescue medication use 
Last 14 days during the stabilisation period, including AM 
assessments on the day of treatment i.e., treatment start date 
per protocol).
E-RS total score and domain 
scores
Last 14 PM assessments immediately preceding first 
treatment date during the stabilisation period
*: last acceptable/borderline acceptable (pre-dose) FEV1 value obtained prior to treatment (either from pre-dose at Visit 
3 (Randomization) or from pre-bronchodilator at Visit 2 or unscheduled assessments between Visit 2 and Visit 3).  
† latest value taken prior to first dose including pre-randomized treatment unscheduled visits.
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing.
For participants that did not receive any randomized study treatment, baseline is defined 
as the value from the protocol schedule baseline visit. Unscheduled visits will not be 
considered.
5.3.
Change from Baseline Definitions and Derivations
5.3.1.
Clinic Assessments
For any efficacy and safety endpoint based on clinic assessment, the change from 
baseline value at a given clinic visit is the value at the clinic visit minus the baseline 
value. 
Maximum increase from baseline is the maximum on-treatment value over all timepoints 
– baseline value. 
Maximum decrease from baseline is the minimum on-treatment value over all timepoints 
– baseline value.
 
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5.3.2.
Diary Assessments
Day 1 of post-randomization diary data consist of PM assessment on Day 1 (the day of 
Randomization Visit) and AM assessment on the day after Randomization Visit. 
Similarly, for any given day, daily assessments consist of the PM assessment on that day 
and the AM assessment the day after.   
The periods over the 52 weeks with 4-week time intervals are defined as follows:
Weeks
AM assessment 
Days
PM 
assessment / 
E-RS Days
Rescue medication use/ 
Symptoms free days
Weeks -2 and -1
(Baseline)
-13 to 1
-14 to -1
PM day -14 to AM day 1
1-4
2-29
1-28
PM day 1 to AM day 29
5-8
30-57
29-56
PM day 29 to AM day 57
9-12
58-85
57-84
PM day 57 to AM day 85
13-16
86-113
85-112
PM day 85 to AM day 113
17-20
114-141
113-140
PM day 113 to AM day 141
21-24
142-169
141-168
PM day 141 to AM day 169
25-28
170-197
169-196
PM day 169 to AM day 197
29-32
198-225
197-224
PM day 197 to AM day 225
33-36
226-253
225-252
PM day 225 to AM day 253
37-40
254-281
251-280
PM day 251 to AM day 281
41-44
282-309
281-308
PM day 281 to AM day 309
45-48
310-337
309-336
PM day 309 to AM day 337
49-52
328-365
327-364
PM day 327 to AM day 365
1-24
2-169
1-168
PM day 1 to AM day 169
For any given period (e.g., over a 4-week period), the value for a given diary endpoint is 
calculated using all available data as the average of the non-missing daily values over that 
period. If fewer than 14 days of data are available over a 4-week period, the period value 
will be set as missing. In general, if the data are available for fewer than 50% of the days 
 
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in the period, the period value will be set as missing. The change from baseline over that 
period will be calculated as the participant's period value minus the baseline value. 
For the purpose of efficacy analyses and summaries based on diary data, data collected 
outside of the defined periods will be excluded. 
5.4.
Multi-Centre Studies
Due to the large number of centers participating in this study, a geographical region will 
be used rather than adjusting for center in the statistical analyses.  The center grouping 
will be created based on geographical region and number of randomized participants in a 
country, in order to define groups of roughly similar size.
Geographic 
Region
Countries
Total # Randomized /
Planned 
Europe
Germany, Italy, Netherlands, Poland, 
Romania, Spain, United Kingdom, 
766 / 575
Russia
Russian Federation
643 / 500
United States
United States
399 / 400
Rest of World
Argentina, Australia, Canada, Japan, 
Republic of Korea, South Africa
631 / 735
5.5.
Examination of Covariates, Other Strata and Subgroups
5.5.1.
Covariates and Other Strata
Covariates will be included in statistical analyses as detailed in the statistical model 
specifications in Section 7.
The covariates to be included in the primary analysis model are sex, age, region, pre-
study ICS dosage at screening and baseline FEV1.  A summary of significance levels for 
the main effects from the primary analysis model and their interactions with treatment 
will be provided, see Section 7.1.5 for details.
The rationale for including each of these covariates are as follows:

Sex and age are known to be strongly associated with lung function (Quanjer 2012).

Region will account for any differences in background standard of care between 
regions. In particular, due to a high proportion of participants from Russia, the 
inclusion of region will help ensure the results are applicable across all regions.

Inclusion of Baseline as a covariate is standard statistical practice, and recommended 
by the EMA guidance, Points to Consider on Adjustment for Baseline Covariates.

Inclusion of the stratification variable pre-study ICS dosage at screening as a 
covariate is recommended by ICH-E9 (Statistical Principles for Clinical Trials).  The 
actual strata a participant belongs to, as indicated in the eCRF will be used for this 
covariate, regardless of mis-stratification. 
 
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5.5.2.
Examination of Subgroups
The following subgroups will be used in descriptive summaries for the primary and the 
key secondary efficacy endpoints, and the on-treatment adverse events. 
Subgroup
Categories 
Derivation
Gender
Male
Female
N/A
Age (years)
5 categories:
<18
18 to <65
65 to <75
75 to <85
≥85
Calculated as age at Pre-screening Visit. Only 
year of birth is collected, therefore age will be 
imputed.
2 categories:
<65
≥65
Race
Black
Asian
White
Other

Black includes African American/African 
Heritage.

‘Other’ includes:

American Indian or Alaskan Native

Native Hawaiian or Other Pacific 
Islander

Multiple race
Region
Europe
Russia
United States (USA)
Rest of World (RoW)
See Section 5.4
Pre-study ICS 
dosage at 
screening
Mid
High
Per stratification collected in the eCRF.
Body Mass Index 
(BMI)
<25 kg/m2
≥25 kg/m2
Defined at baseline (last measurement prior to 
randomized treatment start date, including 
unscheduled visits)
CV History/Risk 
Factor at Screening
Yes
No
‘Yes’ is defined as having had at least one of 
the following past or current medical 
conditions at screening:
- Arrhythmia
- Congestive Heart Failure
- Coronary Artery Disease
- Myocardial Infarction
- Cerebrovascular Accident
- Hypertension 
- Diabetes
- Hypercholesterolemia
 
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NOTES: details on the derivations are provided in Section 11.6.
Subgroups will be summarized in a descriptive manner only. The following will be 
presented for each subgroup:

Summary of FEV1 and change from baseline in FEV1 over time

Summary of moderate and severe exacerbations (Pooled FF doses)

Summary of On-treatment AEs
5.6.
Multiple Comparisons and Multiplicity
In order to account for multiple tests involving two UMEC doses and across multiple 
efficacy endpoints, a step-down testing procedure will be applied whereby inference for a
test in the pre-defined hierarchy is dependent upon statistical significance having been 
achieved for the previous tests in the hierarchy. 
A step-down closed testing approach will be applied for the primary efficacy endpoint, 
the key secondary efficacy endpoint, and the secondary efficacy endpoints SGRQ, ACQ-
7, and E-RS. Specifically, if the defined treatment comparisons for the primary efficacy 
endpoint between triple therapy and dual therapy at the high dose of UMEC 62.5 mcg are 
statistically significant at the 0.05 level for both fixed FF doses (100 and 200mcg), then 
the replicate efficacy of UMEC 62.5mcg is demonstrated, and the defined treatment 
comparison between triple therapy and dual therapy will be tested for the key secondary 
efficacy endpoint of moderate/severe asthma exacerbations based on the combined data 
of both FF doses for UMEC 62.5mcg. If the test for the key secondary efficacy endpoint 
is statistically significant at the 0.05 level, then the secondary efficacy endpoints for 
SGRQ (Mean change from baseline in SGRQ at Week 24) and ACQ-7 (Mean change 
from baseline in ACQ-7 at Week 24) will be tested sequentially based on the combined 
data of both FF doses foe UMEC 62.5mcg at significance level 0.05. 
If all tests mentioned above for UMEC 62.5 mcg are statistically significant at the 0.05 
level, the above testing hierarchy for the primary efficacy endpoint, the key secondary 
efficacy endpoint, and the secondary efficacy endpoints SGRQ and ACQ-7 will be 
repeated for the low dose of UMEC 31.25 mcg. 
If all tests for the primary, the key secondary, and the secondary efficacy endpoints for 
SGRQ and ACQ-7 are statistically significant at the 0.05 level for both UMEC 62.5mcg 
and 31.25mcg, the secondary endpoint for E-RS (Mean change from baseline in E-RS 
score over the Weeks 21-24 [inclusive] of the treatment period) will be tested at the 
significance level 0.05 for UMEC 62.5 and UMEC 31.25 in sequence. 
The family-wise Type I Error is strongly controlled at 0.05 level for both UMEC 
62.5mcg and UMEC 31.25mcg on the primary endpoint (trough FEV1), the key 
secondary endpoint (moderate/severe asthma exacerbations), and the secondary endpoints 
on SGRQ, ACQ-7, and E-RS.  
All secondary non-lung function efficacy endpoints will be tested for triple vs. dual using 
the combined data of both FF doses, at a given UMEC dose. The full testing hierarchy is 
provided below: 
 
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Multiplicity Adjustment Plan
Level 1: Primary endpoint, UMEC 62.5 mcg:  Mean change from baseline in trough FEV1 at Week 24, 
Two comparisons:
FF/UMEC/VI 100/62.5/25 vs. FF/VI 100/25 
FF/UMEC/VI 200/62.5/25 vs. FF/VI 200/25
Both tests need to be significant at 0.05 level in order to demonstrate replicate efficacy for UMEC 62.5 
mcg in order to move to Level 2 test. 
Level 2: Key secondary endpoint, UMEC 62.5 mcg: Annualized rate of moderate/severe asthma 
exacerbations, 
One comparison based on pooled data:
(FF/UMEC/VI 100/62.5/25, 200/62.5/25) vs. (FF/VI 100/25, 200/25)
Test needs to be significant at 0.05 level in order to move to Level 3 test.  
Level 3: Secondary endpoint, UMEC 62.5 mcg: Mean change from baseline in SGRQ at Week 24, 
One comparison based on pooled data:
(FF/UMEC/VI 100/62.5/25, 200/62.5/25) vs. (FF/VI 100/25, 200/25)
Test needs to be significant at 0.05 level in order to move to Level 4 test.  
Level 4: Secondary endpoint, UMEC 62.5 mcg: Mean change from baseline in ACQ-7 at Week 24, 
One comparison based on pooled data:
(FF/UMEC/VI 100/62.5/25, 200/62.5/25) vs. (FF/VI 100/25, 200/25)
Test needs to be significant at 0.05 level in order to move to Level 5 tests.  
Level 5: Primary endpoint, UMEC 31.25mcg:  Mean change from baseline in trough FEV1 at Week 24,
Two comparisons:
FF/UMEC/VI 100/31.25/25 vs. FF/VI 100/25 
FF/UMEC/VI 200/31.25/25 vs. FF/VI 200/25
Both tests need to be significant at 0.05 level in order to demonstrate replicate efficacy for UMEC 
31.25mcg and move to Level 6 test. 
 
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Level 6: Key secondary endpoint, UMEC 31.25 mcg: Annualized rate of moderate/severe asthma 
exacerbations, 
One comparison based on pooled data:
(FF/UMEC/VI 100/31.25/25, 200/31.25/25) vs. (FF/VI 100/25, 200/25)
Test needs to be significant at 0.05 level in order to move to Level 7 test.  
Level 7: Secondary endpoints, UMEC 31.25 mcg: Mean change from baseline in SGRQ at Week 24.
One comparison based on pooled data:
(FF/UMEC/VI 100/31.25/25, 200/ 31.25/25) vs. (FF/VI 100/25, 200/25)
Test needs to be significant at 0.05 level in order to move to Level 8 test. 
Level 8: Secondary endpoint, UMEC 31.25 mcg: Mean change from baseline in ACQ-7 at Week 24.
One comparison based on pooled data:
(FF/UMEC/VI 100/31.25/25, 200/ 31.25/25) vs. (FF/VI 100/25, 200/25)
Test needs to be significant at 0.05 level in order to move to Level 9 test.  
Level 9: Secondary endpoint, UMEC 62.5 mcg: Mean change from baseline in E-RS score over Weeks 
21-24 (inclusive) of the treatment period.
One comparison based on pooled data:
(FF/UMEC/VI 100/62.5/25, 200/62.5/25) vs. (FF/VI 100/25, 200/25)
Test needs to be significant at 0.05 level in order to move to Level 10 test.  
Level 10: Secondary endpoint, UMEC 31.25 mcg: Mean change from baseline in E-RS score over 
Weeks 21-24 (inclusive) of the treatment period.
One comparison based on pooled data:
(FF/UMEC/VI 100/31.25/25, 200/31.25/25) vs. (FF/VI 100/25, 200/25)
 
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For any endpoints and/or treatment comparisons not mentioned in the multiplicity 
adjustment plan, treatment comparisons will be made without adjusting for multiplicity. 
5.7.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
11.3
Appendix 3: Assessment Windows
11.4
Appendix 4: Study Phases
11.5
Appendix 5: Data Display Standards & Handling Conventions
11.6
Appendix 6: Derived and Transformed Data
11.7
Appendix 7: Reporting Standards for Missing Data
11.8
Appendix 8: Model Checking and Diagnostics for Statistical Analyses
 
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6.
STUDY POPULATION ANALYSES
The study population analyses include the summaries of participant’s disposition, 
protocol deviations, demographic and baseline characteristics, prior and concomitant 
medications, and exposure and treatment compliance will be based on GSK Core Data 
Standards. All summaries will be based on the ITT population, unless otherwise 
specified. Displays which use the All Subject Enrolled population are identified below.
An overview of the planned study population analyses is provided below, with the 
detailed list of data displays being presented in Appendix 10: List of Data Displays
Display Type
Data Displays Generated
Table
Figure
Listing
Subject Disposition
Study Populations
Y1
Reasons for Screen Failures, Run-in Failures, and 
Stabilization Failure
Y1
Y2
Rescreen Subjects
Y1
Y1
Number of Subjects by Country and Investigator
Y, Y1
Study Treatment Status
Y
Y
Y
Study Disposition
Y
Y
Y
Inclusion and Exclusion Criteria Deviations
Y
Y
Important Protocol Deviations 
Y
Y1
Clinic Visits (Attendance/Phone Contact)
Y
Planned and Actual EOS Visit
Y
Demography and Baseline Characteristics
Demographic Characteristics
Y
Y
Age Ranges
Y
Race
Y
Y
Medical Conditions (Current/ Past)
Y
Y
Pneumonia history
Y
Y
Cardiovascular Risk Factors
Y
Y
Smoking Status
Y
Y
Disease Duration
Y
Y
Asthma Medical History Questionnaire
Y
Asthma Exacerbation History
Y
Y
Lung Function Based on Clinic Spirometry
Y
Y
Lung Function Based on Home Spirometry
Y
Y
Fractional Exhaled Nitric Oxide (FeNO)
Y
Serum IgE
Y
ACQ Score 
Y
Concomitant Medications
Asthma Medications 
Y
Y
Non-Asthma Medications
Y
Y
Asthma Maintenance Therapy 
Y
Relationship between ATC Level 1/Ingredient/Verbatim 
Text for Non-Asthma Medications
Y
Treatment Compliance
Treatment Compliance
Y
Y
 
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Display Type
Data Displays Generated
Table
Figure
Listing
Randomized and Actual Treatments
Y
Treatment Blind Broken During Study
Y
Treatment Misallocations
Y
NOTES:
Y = Yes display generated.
1.
All Subjects Enrolled population
2.
All Subjects Screened population
6.1.
Disposition of Participants
The overall subject disposition will be summarized for the All Subjects Enrolled 
population, including the number and percentage of participants in each treatment group 
and overall, who were pre-screened (All Subject Enrolled population), screened (All 
Subjects Screened), randomized, ITT population, and have a PK sample obtained and 
analysed (PK population).  Additionally, the reasons for Screen Failure, Run-in Failure, 
or Stabilisation Failure will be summarized for the All Subjects Enrolled Population. 
Listings of failures prior to randomization will be generated. A listing will also be 
generated for the rescreened participants (All Subjects Enrolled population) to include 
information on unique subject id, all subject ids, all visit dates, and final status (screen 
failure, run-in failure, enrolment failure, randomized) under each subject ID.
The number and percentage of participants at each centre and within each country will be 
summarized.  This will be repeated using the ITT population. 
The number and percentage of participants who completed the double-blind study 
treatment as well as the number who stopped the study treatment prior to the end of the 
study will be summarized, along with the reasons for discontinuation of the study 
treatment, and these will also be listed.  A Kaplan-Meier curve will be generated for time 
to early discontinuation from study treatment. Time to early withdrawal from study 
treatment is measured from the date of treatment initiation to the date of treatment stop. 
For participants who are lost to follow up prior to their EOS visit, these participants will 
be considered as discontinuing from treatment early and the last study treatment date will 
be used, see Section 11.7.2 for details of handling missing dates.  Participants who 
complete the study treatment per protocol are censored at the date of end of study visit.
The number and percentage of participants who completed the study as well as the 
number who withdrew early from the study will be summarized, along with reasons for 
early withdrawal from the study, and these will also be listed. A Kaplan-Meier curve will 
be generated for time to early withdrawal from study. Time to early withdrawal from 
study is measured from the date of treatment initiation the date of early withdrawal from 
the study for participants who have early withdrawal (EW) visit. Participants who 
complete the study per protocol are censored at the date of end of study visit. For 
participants who lost to follow-up without EW visit, the study conclusion date will be 
used or date of last contact if no study conclusion record is available.
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, participant management or participant assessment) will be 
summarized and listed.
 
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A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion 
page of the eCRF.
The number and percentage of participant’s study treatment status (on-treatment/post-
treatment) at each clinic visit will be summarized. The number and percentage of 
participants attending the safety follow-up contact will also be summarized. 
The number and percentage of participants for the planned End of Study (EOS) visit at 
Week 24, 36, 52, as well as the number and percentage of participants for the actual EOS 
visit and EW prior to the planned EOS visit will be summarized
6.2.
Demographic and Baseline Characteristics
Each of the following types of data will be summarized:

Demographic data (age, sex, ethnicity, weight, height, body mass index (BMI))

Pre-study ICS Dosage at Screening)

Age ranges (12-17, 18-64, >=65-84, >=85)

Race and racial combinations, race and racial combination details

Disease Duration (duration of asthma, onset age (year) of asthma)

Asthma medical history questionnaire

History of exacerbations over the previous year (Number of exacerbations in 
previous year (0,1, ≥2) treated without oral/systemic corticosteroids, treated with 
oral/systemic corticosteroids, requiring hospitalization, treated with oral/systemic 
corticosteroids or requiring hospitalization, and total number of exacerbations)

Smoking history (smoking status of non-smoker or former smoker, and pack years 
for former smokers)

Cardiovascular history/risk factors and family history of cardiovascular risk 
factors.

Spirometry at Visit 1 and Visit 2: pre- and post-bronchodilator for FEV1, FVC, 
and FEV1/FVC, reversibility by albuterol/salbutamol at Visit 1 and by 
ipratropium at Visit 2, and associated percent predicted values. Note: Predicted 
values will be based upon the European Respiratory Society (ERS) Global Lung 
Function Initiative [Quanjer, 2012].

Spirometry at Visit 3: pre-dose FEV1, FVC, FEV1/FVC, and associated percent 
predicted values.
 
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
Change in pre-bronchodilator / pre-dose FEV1 from Visit 1 to Visit 2 during 
run-in period, from Visit 2 to Visit 3 during the stabilisation period, and from 
Visit 1 to Visit 3 during the run-in/stabilisation periods.

Home spirometry during the three weeks of the run-in period and the two weeks 
of the stabilisation period.

FeNO at Visit 3.

Total serum IgE at Visit 1.

ACQ-5, ACQ-6, and ACQ-7 scores at Visit 1, Visit 2, and Visit 3.

Change in ACQ-5, ACQ-6, and ACQ-7 scores from Visit 1 to Visit 2 during 
run-in period, from Visit 2 to Visit 3 during the stabilisation period, and from 
Visit 1 to Visit 3 during the run-in/stabilisation periods.

Summary of past and current medical histories.

Summary of pneumonia history.
In addition to the tables listed above; demography, race and racial combination details, 
disease history and history of exacerbations will also be summarized by pooled FF 
treatment groups. 
6.3.
Concomitant Medications
Summaries will be provided for the asthma medications at 
-
Study entry
-
During the screening/run-in period
-
During the stabilisation period
-
On-treatment period
-
Post-treatment period
-
Post-study period
-
Asthma medication tables will report by respiratory medication class (RMC) and 
ingredient
Non-asthma medications will be summarized for the:
-
On-treatment period
-
Post-treatment period
-
Post-study period
Non-Asthma medication tables will report by Anatomical Therapeutic Chemical (ATC) 
level 1 and ingredient. Multi-ingredient medications will be presented according to their 
combination ATC classification rather than the classification of the ingredients.
Listings will be provided for the asthma and non-asthma concomitant medications.
 
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At study entry, asthma maintenance therapy containing inhaled corticosteroid (ICS),
long-acting beta-2-agonist (LABA) long-acting muscarinic antagonist (LAMA), oral 
corticosteroid (OCS), leukotriene receptor antagonist (LTRA), xanthines (oral 
prescription only) or biologic will also be summarized and combinations presented. An 
“other” category will also be presented including nedocromil or cromolyn sodium. 
Combination therapies may be in a single inhaler or separate inhalers. A similar table will 
be produced to display maintenance therapy following IP discontinuation.
In addition, the asthma maintenance therapy at study entry will be presented by pooled 
FF treatment groups
The concomitant medications used for the treatment of moderate and severe asthma
exacerbations during the study will also be summarized. These include, but not limited to, 
the protocol permitted concomitant medications of inhaled corticosteroids (including but 
not limited to the use of study provided FP), the systemic corticosteroids (tablets, 
suspension or injection), an investigator-advised change in SABA use (i.e., routinely 
scheduled versus as needed use), leukotriene receptor antagonists (LTRAs) and 
leukotriene modifiers, and oral xanthines.
6.4.
Treatment Compliance
Treatment compliance will be assessed for the entire treatment period as well as the first 
24 weeks of the treatment period for each individual treatment arm. Additional details on 
the derivations, are provided in Section 11.6.2. 
Compliance will also be presented by pooled FF doses. 
 
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7.
EFFICACY ANALYSES
All efficacy analyses will evaluate the “de facto” type estimand (see Section 7.1.4 for 
details) based on the ITT population, including data collected during the study, both on-
and post-treatment without imputation, unless otherwise specified. 
To demonstrate the benefit of UMEC when added to FF/VI treatment arms with the same 
FF dose, the primary comparisons of interest for the primary efficacy endpoint are:
1) The replicate efficacy for UMEC 62.5 mcg dosage:
o
FF/UMEC/VI 100/62.5/25 mcg vs. FF/VI 100/25 mcg
o
FF/UMEC/VI 200/62.5/25 mcg vs. FF/ VI 200/25 mcg
2) The replicate efficacy for UMEC 31.25 mcg dosage:
o
FF/UMEC/VI 100/31.25/25 mcg vs. FF/VI 100/25 mcg
o
FF/UMEC/VI 200/31.25/25 mcg vs. FF/ VI 200/25 mcg
Other pairwise treatment comparisons of interest consist of the following assessments for 
the primary efficacy endpoint:
3) Triple therapy with low dose FF vs. dual therapy with high dose FF:
o
FF/UMEC/VI 100/62.5/25 vs. FF/VI 200/25
o
FF/UMEC/VI 100/31.25/25 vs. FF/VI 200/25
4) The impact of increasing FF dose in triple therapy:
o
FF/UMEC/VI 200/62.5/25 vs.  FF/UMEC/VI 100/62.5/25
o
FF/UMEC/VI 200/31.25/25 vs.  FF/UMEC/VI 100/31.25/25
5) The impact of increasing UMEC dose in triple therapy:
o
FF/UMEC/VI 100/62.5/25 vs. FF/UMEC/VI 100/31.25/25
o
FF/UMEC/VI 200/62.5/25 vs.  FF/UMEC/VI 200/31.25/25
6) The benefit of FF 200 containing therapies over FF/VI 100/25, the asthma 
medication used prior to randomization, during the stabilization phase:
o
FF/VI 200/25 vs. FF/VI 100/25
o
FF/UMEC/VI 200/31.25/25 vs. FF/VI 100/25
o
FF/UMEC/VI 200/62.5/25 vs.  FF/VI 100/25
To allow evaluation of the effect of FF/UMEC/VI on non-lung function efficacy 
endpoints, including the key secondary efficacy endpoint on moderate/severe 
exacerbations, for each fixed UMEC dose, the data from the two FF/UMEC/VI arms will 
be pooled and compared to the pooled data from the two FF/VI arms.
 
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7) Benefit of UMEC added on to FF/VI: UMEC 62.5 mcg dosage:
o
FF/UMEC/VI (100/62.5/25 and 200/62.5/25) vs. FF/VI (100/25 and 200/25) 
8) Benefit of UMEC added on to FF/VI: UMEC 31.25 mcg dosage:
o
FF/UMEC/VI (100/31.25/25 and 200/31.25/25) vs. FF/VI (100/25 and 200/25)
The pooled analyses will provide a more precise overall estimate for the treatment effect 
size of the addition of UMEC to FF/VI. 
The benefit of increasing UMEC dose in triple therapy will also be assessed by 
comparing triple therapies containing UMEC 62.5mcg vs triple therapies containing 
UMEC 31.25mcg for all non-lung function endpoints: 
9) UMEC 62.5 vs. UMEC 31.25
oFF/UMEC/VI (100/62.5/25 & 200/62.5/25) vs. FF/UMEC/VI (100/31.25/25 & 
200/31.25/25)
All comparisons will be carried out for the primary and secondary endpoints.  For the 
other endpoints, only the primary comparisons will be presented, unless the endpoint is 
supportive of a secondary endpoint. Details on the comparisons presented for each 
endpoint are given in the table below.
Endpoint
Treatment comparisons
(as specified above)
1)
2)
3)
4)
5)
6)
7)
8)
9)
Primary endpoint
Trough FEV1
P1
P5
O
O
O
O
O
O
O
Secondary endpoints
Moderate/ Severe exacerbations
O
O
O
O
O
O
P2
P6
O
FEV1 at 3 hours post study treatment
P
P
O
O
O
O
O
O
O
SGRQ total score
O
O
O
O
O
O
P3
P7
O
ACQ-7
O
O
O
O
O
O
P4
P8
O
E-RS total score
O
O
O
O
O
O
P9
P10
O
Other endpoints
Clinic trough FEV1 over the first 24 weeks of the treatment 
period
P
P
Home daily trough FEV1
P
P
Home daily PM FEV1
P
P
Annualized rate of severe asthma exacerbations
O
O
P
P
Time to first severe asthma exacerbation
O
O
P
P
Time to first moderate/severe asthma exacerbation
O
O
O
O
O
O
P
P
O
ACQ-7 responder
O
O
O
O
O
O
P
P
O
ACQ-6 and ACQ-5 responder
P
P
ACQ-7 Asthma Control
O
O
O
O
O
O
P
P
O
ACQ-6 and ACQ-5 Asthma Control
P
P
SGRQ domain scores 
P
P
SGRQ responder
O
O
O
O
O
O
P
P
O
 
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Endpoint
Treatment comparisons
(as specified above)
1)
2)
3)
4)
5)
6)
7)
8)
9)
E-RS domain scores
P
P
E-RS responder
O
O
O
O
O
O
P
P
O
Asthma Quality of Life Questionnaire (AQLQ) total 
P
P
AQLQ responder
P
P
AM PEF
P
P
PM PEF
P
P
Symptom-free days 
P
P
Rescue medication-free days 
P
P
Daily rescue medication use 
P
P
P=primary comparison of interest for given endpoint, O=Other comparison of interest for given endpoint
Superscripts denote where analysis comes into the multiplicity hierarchy.
The pooled (FF doses) statistical analyses will be performed using all 6-arm data and 
LSMESTIMATE statement in SAS PROC MIXED for the secondary endpoints with 
repeated measurements during the study (e.g., SGRQ, ACQ-7, and E-RS), PROC 
GENMOD for the key secondary endpoint and other endpoints related to the rate of 
asthma exacerbations), or PROC PHREG for time to event endpoints, with the 
corresponding specification of treatment codes with order, see illustrative examples in the 
table below, for a given linear function of the least square means. 
LSMESTIMATE Statement for Pooled Analyses
Analysis 
Type 
Display 
Type
Description for treatments and 
treatment comparisons of Interest
LSMESTIMATE Statement: 
specification of linear 
function of 6-arm 
treatments by data display 
order* 
Pooled FF 
doses
LS mean
FF/VI
0.5, 0, 0, 0.5, 0, 0
FF/UMEC/VI at UMEC 31.25 
0, 0.5, 0, 0, 0.5, 0
FF/UMEC/VI at UMEC 62.5 
0, 0, 0.5, 0, 0, 0.5
LS mean 
difference 
FF/UMEC/VI at UMEC 31.25 vs FF/VI
-0.5, 0.5, 0, -0.5, 0.5, 0
FF/UMEC/VI at UMEC 62.5 vs FF/VI
-0.5, 0, 0.5, -0.5, 0, 0.5
FF/UMEC/VI at UMEC 62.5 vs 
FF/UMEC/VI at UMEC 31.25 
0, -0.5, 0.5, 0, -0.5, 0.5
*: as defined in Section 5.1.
This pooled analysis method for the key secondary endpoint is deviated from the 
proposed analysis method in the protocol. The rationale for this deviation is provided in 
Section 2.1.
The multiplicity adjustment for the multiple comparisons in the efficacy analyses across 
multiple endpoints and multiple doses are provided in Section 5.6.
 
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7.1.
Primary Efficacy Analyses
The overview of the planned efficacy analyses for the primary endpoint is provided 
below. The full details of primary efficacy analysis data displays are presented in 
Appendix 10: List of Data Displays
Primary Efficacy 
Endpoint 
Absolute
Change from Baseline
Stats 
Analysis
Summary
Individual
Stats 
Analysis
Summary
Individual
T
T
L
T
F
T
F
L
Clinic Trough FEV1
Trough FEV1 (de facto 
type estimand, primary 
analysis)
Y
Y
Y
Y
Y
Y
Y
Y
Trough FEV1 (de jure 
type estimand, 
supportive analysis)
Y
Y
Y
Y
Y
Y
Y
Trough FEV1 (de facto 
type estimand excluding 
sites with data concerns, 
supportive analysis)
Y
Y
Y
Y
Y
Y
Y
Trough FEV1 (Missing 
data imputations 
Sensitivity Analyses)
Y
Y
Y
Trough FEV1 (Pooled FF 
dose, de facto estimand, 
of other interest)
Y
Y
Y
Y
Y
Trough FEV1 by 
subgroup
Y
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TF related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual participant observed raw data.
7.1.1.
Endpoint / Variables
The primary efficacy endpoint is change from baseline in clinic trough FEV1 at Week 24. 
7.1.2.
Summary Measure
The mean change from baseline in trough FEV1 at Week 24 will be compared between 
treatment groups.
7.1.3.
Population of Interest 
The primary efficacy analyses will be based on the ITT population.
 
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7.1.4.
Strategy for Intercurrent (Post-Randomization) Events
A “treatment policy” strategy will be used to handle all intercurrent events, including 
treatment discontinuation, use of rescue medication provided for the study or for asthma 
exacerbations, temporary treatment interruption, or treatment switches. 
Participants who discontinue study treatment prematurely are encouraged to stay in the 
study and return for all clinic visits as planned. Data collected on- or post-treatment 
discontinuation will be included in the primary analysis, regardless of the use of rescue 
medications or treatment switches. This analysis corresponds to the “de facto” analysis 
pre-specified in the protocol and thus referenced throughout this document. 
For the primary analysis, no imputation of missing data are planned. Missing data are
assumed Missing at Random (MAR) handled via Mixed Model Repeated Measures 
(MMRM) analysis.  To examine the sensitivity of the results of the primary analysis to 
departures from this assumption, further sensitivity analyses will be performed using 
alternative assumptions on the missing data.
7.1.5.
Statistical Analyses / Methods
The primary efficacy analysis will evaluate the “de facto” type estimand in the Intent-to-
Treat population, using a mixed-model repeated measures (MMRM) analysis (see details 
in Section 7.1.6).
Supportive analysis based on the ‘de jure’ type estimand will be performed, including 
only on-treatment FEV1 data collected prior to and at Week 24, using MMRM with the 
same covariates as in the ‘de facto’ primary analysis. Post-treatment data will not be 
utilized in the analysis, nor will imputation be made for any missing data. 
A supportive analysis will be performed for the primary efficacy endpoint based on the 
“de facto” type estimand, excluding all randomized participants enrolled at Site No. 
 and Site No. 
 as a result of study non-compliance based on the GSK issue-
investigation report, and the standard GSK monitoring and auditing practices.
Additionally, subjects randomized at sites 
 and 
 will be excluded due to a 
lack of confidence in the data received.
The primary ‘de facto’ analysis includes all FEV1 data collected following 
discontinuation of randomized treatment for participants who remain in the study and
assumes that any remaining missing data due to early withdrawal from the study prior to 
Week 24 is missing at random (MAR).  To examine the sensitivity of the results of the 
primary analysis to departures from this assumption, further sensitivity analyses will be 
performed using alternative assumptions. For each proposed imputation method, the 
sensitivity analysis will be performed, including both observed and imputed FEV1 data.
The following different algorithms are proposed to impute the post-treatment missing 
data for the primary efficacy endpoint (change from baseline in trough FEV1 at Week 
24).  Intermediate missing data will be imputed as MAR. All approaches will utilize all 
on and post-treatment data available. 
 
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1. Tipping Point:
This method will explore the potential effect of missing data on the reliability of the 
results by using different assumptions regarding the primary endpoint outcome in 
participants who withdraw from study early. Participants who withdraw from study 
earlier than Week 24 will have missing data imputed first assuming a missing at 
random mechanism and then adding on a “marginal delta” prior to analyzing the 
imputed datasets and combining the results. The marginal deltas are to vary 
independently for FF/UMEC/VI and FF/VI.  
The deltas to be investigated are pre-selected multiples of the observed treatment 
effect. If the observed treatment effect from the primary analysis is x, the deltas to be 
investigated will range from -3x to +x mL for both active and placebo arms, in 
increments of 0.5x mL. The increment or range may be refined based on the analysis 
results and the location of the tipping point. 
For each of the four primary comparisons of triple vs. dual (a fixed dose of FF and a 
fixed dose of UMEC): the delta for these two relevant FF/UMEC/VI and FF/VI arms 
will be allowed to vary independently, while assuming MAR (delta=0mL) for the 
other four treatment arms. The imputation model will contain the same terms as in the 
primary analysis MMRM model.
For a given pair of ‘delta comparison’ as in the table below, complete sets of Week 
24 data for all 6 treatment arms will be produced with multiple imputation based on 
missing at random (MAR) assumption. For each of the multiple imputations, the 
relevant deltas (+ and/or -) will be added to the imputed FEV1 under MAR for each 
respective treatment arm. 
For example, the grid for the comparison between FF/UMEC/VI 100/62.5/25 and 
FF/VI 100/25 is as follows: The mean change from baseline post-withdrawal from 
study is calculated as mean of delta + change under the MAR assumptions 
(FF/UMEC/VI 100/62/5/25 = z (mL), and FF/VI 100/25 = y (mL)) for each 
respective treatment group. Of the less interest for the sensitivity analysis are the 
greyed-out grid points for the deltas where FF/UMEC/VI performs relatively better 
than FF/VI. 
FF/UMEC/VI 100/62.5/25
Delta (mL)
-3x
-2.5x
-2x
-1.5x
-x
-0.5x
0
0.5x
x
FF/VI 100/25
Delta 
(mL)
Mean 
change 
post-
withdrawal
-3x+z
-2.5x+z
-2x+z-
-1.5x+z
-x+z
-0.5x+z
z
0.5x+z
x+z
-3x
-3x+y
-2.5x
-2.5x+y
-2x
-2x+y
-1.5x
-1.5x+y
 
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-x
-x+y
-0.5x
-0.5x+y
0
y
0.5x
0.5x+y
x
x+y
The analysis results will be used to evaluate the plausibility of the assumed difference 
from MAR for missing outcomes on each treatment arm under which (Tipping Point) 
the conclusions change, i.e., under which there is no longer evidence of a treatment 
effect, and clinical judgment will be applied as to the plausibility of the associated 
assumptions.
Repeat this process for each of the four primary treatment comparisons of interest as 
outlined in Section 7.
2. Jump to Reference:
This method assumes that participants with post-treatment missing data in the test 
groups (FF/UMEC/VI) would have provided data similar to those in the reference 
group [Carpenter et al, 2013]. This approach represents the situation where the 
participant’s expected mean change from baseline in Trough FEV1 is shifted to that of 
the reference arm (FF/VI with the same FF dose), regardless of the UMEC dose in 
their randomized treatment. Post-treatment missing data in the reference groups 
(FF/VI 100/25 or 200/25 mcg) are imputed under MAR. 
The analysis will include data from all treatment arms and the primary treatment 
comparisons as outlined in Section 7 will be presented. For FF/UMEC/VI 
100/62.5/25 & 100/31.25/25 the reference arm will be FF/VI 100/25. For 
FF/UMEC/VI 200/62.5/25 & 200/31.25/25 the reference arm will be FF/VI 200/25.
Missing data prior to treatment discontinuation will be imputed assuming the 
participants are on their randomized treatment for that time point (MAR). The 
imputation model will contain the same terms as in the primary analysis MMRM
model.
7.1.6.
Statistical Methodology Specification
Primary Statistical Analyses
Endpoint

Mean change from baseline in trough FEV1at Week 24
Primary Model Specification

Mixed Models Repeated Measures (MMRM) model.

The analysis is based on ‘de facto’ type estimand, based on the ITT population.

Clinic trough FEV1 (both on- and post-treatment) data collected prior to and at Week 24 will 
be included in the analysis. 

No imputation is made on missing data. 
 
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Primary Statistical Analyses

While missing data are not explicitly imputed in the MMRM analyses, there is an underlying 
assumption that the data are missing at random. All available data will be utilized via 
modeling of the within-participant correlation structure, the derived treatment differences will 
be adjusted to take into account the missing data.

Terms in the model: 
o Dependent Variable: change from baseline in trough FEV1 at each visit
o Covariates:

Categorical:  treatment group, sex, region, visit, pre-study ICS dosage at screening, 

Continuous:  age, baseline value for clinic FEV1
o Interaction: baseline*Visit, treatment*Visit
o Repeated: Visit

The model will be fit with an unstructured variance-covariance matrix.

The LS mean trough FEV1 and LS mean change from baseline in trough FEV1 will be 
estimated using the observed marginal distributions of the study population covariates by 
inclusion of the OM (observed margins) dataset in SAS. 
Model Checking & Diagnostics

Refer to Appendix 8: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

Baseline summaries will be presented for all participants, those who are on-treatment at 
week 24 and those who are off-treatment at week 24 and for those who are missing data at 
week 24. 

Data collected at all scheduled clinic visits, both on- and post-treatment, will be summarized 
by visit (absolute value and change from baseline).

Boxplots of the change from baseline at each clinic visit will be presented.

Empirical distribution function plots of the change from baseline at each clinic visit will be 
presented.

Least-square (LS) means and LS mean change from baseline values for each treatment 
group will be presented with their associated standard errors. The estimated treatment 
difference along with corresponding standard error, 95% CI and unadjusted p-value will be 
presented for all treatment comparisons specified in Section 7 at Weeks 4, 12, and 24.

LS mean change from baseline values and LS mean treatment differences (and associated 
95% CIs) for the comparisons of the two FF/UMEC/VI vs. a FF/VI at a given FF dose will be 
will also be presented graphically at Weeks 4, 12, and 24, for each of the FF doses in two 
separate panels.
Exploring interaction terms

Interaction by treatment terms will added to the main model one at a time for the following 
main effect covariates: age, baseline value for clinic FEV1, region, sex and pre-study ICS 
dosage at screening.

Summary of test results for main effect covariates in main model will be presented along 
with the test results for the interaction terms mentioned above.
 
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Primary Statistical Analyses
Supportive Statistical Analyses

An ‘on-treatment’ analysis will be performed, corresponding to the ‘de jure’ type estimand
analysis specified in the protocol. 
o
The endpoint/variable, summary measure and population of interest will be the 
same as for the primary analysis, as outlined above.
o
The MMRM model fitted will be the same as stated above. 
o
Strategy for Intercurrent (Post-Randomization) Events:

An “on-treatment” strategy will be used to handle the intercurrent event of 
treatment discontinuation. Data collected after treatment discontinuation 
will be excluded from the analysis and only on-treatment data will be used.

No imputation of missing data is planned. Missing data is assumed Missing 
at Random (MAR) and handled via Mixed Model Repeated Measures 
(MMRM) analysis.
The same outputs as for the on- and post-treatment (de facto) estimate will be produced
Supportive Statistical analysis - removing sites
The primary model will be repeated excluding participants from sites 
 
and 
The results of the fitted model will be presented. Summaries and figures will not be produced.
 
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Primary Statistical Analyses
Sensitivity analyses – imputation of missing data

Imputation Model: Mixed Models Repeated Measures (MMRM) model
o
Dependent Variable: change from baseline in trough FEV1 at each visit
o
Covariates:

Categorical:  treatment group, sex, region, visit, pre-study ICS dosage at screening,

Continuous:  age, baseline value for clinic FEV1
o
Interaction: baseline*Visit, treatment*Visit, age*Visit, sex*Visit, region*visit, pre-study ICS 
treatment dosage*visit
o
Repeated: Visit

Imputation methods:
o
Tipping Point
o
Jump to Reference

For each of the multiple imputations, complete datasets of clinic trough FEV1 at Week 24 
(both observed and imputed) will be analysed using an ANCOVA model (on each 
imputation). 

Analysis model: 
o
Dependent Variable: change from baseline in trough FEV1 at each visit
o
Covariates:

Categorical:  treatment group, sex, region, pre-study ICS dosage at screening 

Continuous:  age, baseline value for clinic FEV1. 
o
All 6-arm data are included in the model.

Multiple imputation methods will be used with results from the ANCOVA combined across 
imputations using Rubin’s method [Rubin 1987] as implemented in SAS PROC
MIANALYZE.

Details for the sensitivity analysis under each imputation method for post-study missing data 
are provided in Section 7.1.5.

The LS mean and LS mean change (and 95% confidence intervals) will be presented as well 
as the primary comparison of interest detailed in Section 7.  

A forest plot of the LS mean treatment difference at week 24 will be presented for the 
primary de facto analysis, the supportive and sensitivity analyses and J2R analysis. 

For the tipping point analysis, a heat map of the p-values will be produced for each of the 
primary comparisons of interest for the different deltas applied.  

Model checking and diagnostics will not be performed for the imputed datasets. 
Pooled FF doses
The primary ‘de facto’ analysis will be repeated for the pooled FF doses.  The analysis model will
be the same as specified above. Note:

All 6-arm data are included in the model.

LSMESTIMATE statement will be used with the treatment code as specified Section 7.

The boxplots and empirical plots will not be produced for these analyses.
Subgroups
Summaries of the baseline and change from baseline will be presented for each of the 
subgroups listed in Section 5.5.2.
 
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7.2.
Key Secondary Analyses
An overview of the planned key secondary is provided below. The full details of data 
displays are presented in Appendix 10: List of Data Displays.
Key Secondary Endpoint
Absolute
Stats Analysis
Summary
Individual
T
F
T
L
Annualized rate of 
moderate/severe asthma 
exacerbations using pooled FF 
doses (Negative Binomial, de 
facto type estimand, of primary 
interest)
Y
Y
Y
Annualized rate of 
moderate/severe asthma 
exacerbations using pooled FF 
doses (de jure type estimand, 
supportive)
Y
Y
Y
Annualized rate of 
moderate/severe asthma 
exacerbations using pooled FF 
doses (de facto type estimand 
excluding sites with data 
concerns, supportive analysis)
Y
Annualized rate of 
moderate/severe asthma 
exacerbations (Sensitivity 
analyses, missing data 
imputations)
Y
Y
Annualized rate of 
moderate/severe asthma 
exacerbations using unpooled 
doses (de facto type estimand, of 
other interest)
Y
Y
Y
Y
Annualized rate of 
moderate/severe asthma 
exacerbations by subgroup
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TF related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual participant observed raw data.
7.2.1.
Endpoint / Variables
The key secondary endpoint is the annualized rate of moderate/severe asthma 
exacerbations.  
 
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7.2.2.
Summary Measure
The ratio of annualized moderate/severe exacerbation rates will be used to compare the 
treatments.
7.2.3.
Population of Interest 
Analyses will be based on the ITT population.
7.2.4.
Strategy for Intercurrent (Post-Randomization) Events
The “treatment policy” strategy for the key secondary is the same as for the primary 
efficacy analysis outlined in Section 7.1.4. 
To examine the sensitivity of the results of the key secondary endpoint analysis to 
departures from this assumption, further sensitivity analyses will be performed using 
alternative assumptions on the missing data, see details in Section 7.2.5.
7.2.5.
Statistical Analyses / Methods
Asthma exacerbations will be summarized for the periods: Weeks 1-52, Weeks 1-24, and 
Weeks 25-52 (see Section 11.6.3), including the following details of the event: 
-
Number of participants contributing to the reporting period
-
Duration of time in reporting period (days) 
-
Number and percent of participants with moderate / severe exacerbations (0, 1, 2,
>2)
-
Number of moderate / severe exacerbations
-
Number and percent of exacerbations that required hospitalization, emergency 
room visit, or the use of systemic corticosteroids.
-
Outcome and duration (days) of moderate/severe exacerbations
-
Number and percent of participants with severe exacerbations
-
Require hospitalization
-
Require visit to emergency room
-
Require the use of systemic corticosteroid
-
Number and percent of participants with moderate exacerbations
-
Number with deterioration in asthma symptoms, deterioration in lung 
function, increased rescue bronchodilator use (and all possible 
combinations of the three).
-
Number who took medication
Summaries for weeks 1-52 will also be provided by gender, age, race, region, pre-study 
ICS dosage at screening, BMI and CV History/Risk Factor at Screening.
 
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The exacerbation rate will be analyzed using a generalized linear model, assuming the 
number of exacerbations has a negative binomial probability distribution and that its 
mean is related to covariate factors with a ‘log link’ function. The logarithm of time 
(year) on study will be used as an offset variable. Missing data due to early withdrawal 
from the study will not be imputed. 
The exacerbation rate over the first 24 weeks of the study will also be analyzed in the 
same manner. 
Supportive analysis for the pooled FF doses, based on ‘de jure’ type estimand will be 
performed, including all on-treatment moderate/severe exacerbation data collected during 
double-blind treatment period.
Sensitivity analysis will be performed for the key secondary efficacy endpoint based on 
the ‘de facto’ type estimand, excluding all randomized participants enrolled at Site No. 
 and Site No. 
 as a result of study non-compliance based on the GSK 
issue-investigation report, and the standard GSK monitoring and auditing practices.
Additionally, subjects randomized at sites 
 and 
 will be excluded due to a 
lack of confidence in the data received.
The ‘de facto’ type estimand analysis for the key secondary endpoint includes all 
moderate/severe asthma exacerbations following discontinuation of randomized
treatment for participants who remain in the study and assumes that any remaining 
missing data due to early withdrawal from study prior to the planned end of study visit is 
Missing at Random (MAR). To examine the sensitivity of the analysis result to 
departures from this assumption, further sensitivity analyses will be performed using 
alternative assumptions analogous to those used for the primary endpoint.  For each 
proposed imputation method, the sensitivity analysis will include both observed (on and 
post-treatment) and imputed asthma exacerbation events.  The following different 
algorithms are proposed to impute the post-treatment missing data.  
These analyses will be performed for weeks 1-52 only. 
For each approach, exacerbations in the unobserved period will be imputed only up to the 
participant’s planned end of study visit date determined by participant’s randomization
date (see Section 11.3.2).

Tipping Point:
This method will explore the potential effect of missing data on the reliability of the 
results by using different assumptions regarding the moderate/severe asthma 
exacerbation rate in participants who withdraw from study early. Participants who 
withdrew from the study earlier than their planned end of study will have missing 
data imputed for the period of time between withdrawal from the study to the planned 
end of study visit first assuming missing at random (MAR) and then multiplying the 
estimated exacerbation rate under MAR by different deltas.  The imputed 
exacerbation rates will vary independently for FF/UMEC/VI arms and FF/VI arms. 
 
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The deltas to be investigated are pre-selected multiples of the observed rate reduction. 
If the observed rate reduction from the key secondary analysis is x, the deltas to be 
investigated will range from 1-x to 1+3x for both active and placebo arms, in 
increments of 0.5x (For example, if the observed rate reduction is 20% (x=0.2) the 
imputed rates will be multiplied by deltas of 0.8 to 1.6 in increments of 0.1).  The 
increment or range may be refined based on the analysis results and the location of 
tipping point.
For the comparison of FF/UMEC/VI UMEC 62.5 vs. FF/VI: a delta is applied to the 
two triple arms involving UMEC 62.5, and separately a delta is applied to the two 
FF/VI arms, and both deltas will be allowed to vary independently; the delta will be 
equal to 1 (i.e., under MAR assumption) for the triples involving UMEC 31.25. The 
same approach will be taken for the comparison of FF/UMEC/VI UMEC 31.25 vs 
FF/VI, this time varying the delta applied to the triple arms involving UMEC 31.25 
and setting the delta for the triples involving UMEC 62.5 equal to 1. The imputation 
model will contain the same covariates as in the key secondary endpoint analysis (de 
facto) model (with MAR rates being delta-adjusted). 
For a given pair of ‘delta comparison’ as in the table below, complete sets of 
exacerbation data (observed and imputed exacerbations) for all 6 treatment arms will 
be produced with multiple imputation based on missing at random (MAR) 
assumption. For each of the multiple imputations, the relevant deltas will be 
multiplied to the imputed exacerbation rates under MAR for the respective treatment 
arms. 
For example, the grid for the comparison between triples at UMEC 62.5 and duals is 
as follows: The post-withdrawal mean rate is calculated as the delta *mean rate under 
the MAR assumption (triples at UMEC 62.5 = z, and duals = y). The greyed-out grid 
points for the deltas are of less interest in the sensitivity analysis where Triples 
FF/UMEC/VI at UMEC 62.5 performs relatively better than duals FF/VI when the 
imputed exacerbations for the post-withdrawal missing data are deviated from the 
estimates under MAR in the pooled (FF doses) analysis for the respective treatment 
arms. The cell with delta = 1 for both FF/UMEC/VI and FF/VI represents the key 
secondary analysis result under MAR.
Triples at UMEC 62.5
Delta
0.8
1
1.2
1.4
1.6
Duals
Delta
Mean rate
post-withdrawal
(1-x)*z
1*z
(1+x)*z
(1+2x)*z
(1+3x)*z
1.6
(1+3x)*y
1.4
(1+2x)*y
1.2
(1+x)*y
1
1*y
0.8
(1-x)*y
 
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The analysis results will be used to evaluate the plausibility of the assumed difference 
from MAR for missing outcomes on each treatment arm under which (Tipping Point) 
the conclusions change, i.e., under which there is no longer evidence of a treatment 
effect, and clinical judgment will be applied as to the plausibility of the associated 
assumptions.
This process will be repeated for each of the primary treatment comparisons of 
FF/UMEC/VI vs. FF/VI as outlined in Section 7.

Jump to Reference:
This method assumes that participants in the test groups (FF/UMEC/VI) with missing 
data after study withdrawal would have provided post-treatment data similar to those 
in the respective reference group. This approach represents the situation where the 
participant’s expected rate of exacerbations is shifted to that of the reference arm. The 
FF/VI 100/25 will be the reference arm for the FF/UMEC/VI 100/62.5/25 and 
FF/UMEC/VI 100/31.25/25 arms, and FF/VI 200/25 will be the reference arm for the 
FF/UMEC/VI 200/62.5/25 and FF/UMEC/VI 200/31.25/25 arms. Post-study missing 
data in the reference groups (FF/VI 100/25 or FF/VI 200/25) are imputed under 
MAR. 
This approach uses multiple imputation methods based on pattern mixture models 
[Keene, 2014]. The imputation model will contain the same covariates as in the key 
secondary efficacy analysis (de facto) model (exacerbation rates being constructed as 
though patients “jump to reference” in the unobserved period).
The primary treatment comparisons as outlined in Section 7, based on pooled FF 
doses, will be presented.
A listing of exacerbations where the onset occurs within 14 days of study withdrawal or 
withdrawal from treatment will also be produced.
Further analysis details for asthma exacerbation related endpoints are provided in Section 
7.2.6.
7.2.6.
Statistical Methodology Specification
Secondary Statistical Analyses
Endpoint

Annualized rate of moderate/severe asthma exacerbations
Model Specification

Generalized linear model assuming a negative binomial distribution

The analysis is based on ‘de facto’ type estimand, including all moderate/severe 
exacerbations observed during the study (both on- and post-treatment).

Terms in the model:

Dependent variable: number of recorded moderate/severe asthma exacerbations 
experienced per participant during the study (both on- and post-treatment). 

Covariates: 
 
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Secondary Statistical Analyses
o
Categorical: treatment group, sex, region, pre-study ICS dosage at screening, 
severe asthma exacerbations in the previous year (0, 1, >=2).  
o
Continuous: age. 

Offset: logarithm of time (year) on study 

For the pooled analysis:
o All 6-arm data are included in the model.
o LSMESTIMATE statement will be used with the treatment code as specified Section 7.

Mean annualized rate of moderate/severe asthma exacerbations will be estimated using the 
observed marginal distributions of the study population covariates by inclusion of the OM 
(obsmargins) option. 
Model Checking & Diagnostics

Refer to Appendix 8: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

Summary table of the number of events, and details of the events will be produced for the 
periods Weeks 1-24, 1-52 and 25-52 (See Section 11.6.3 for more details)

Treatment group mean annualized moderate/severe exacerbation rates, treatment rate 
ratios and associated 95% confidence intervals (CI) and p-values will be presented for all 
treatment comparisons specified in Section 7. The treatment rate ratios and associated 95% 
CIs will also be presented graphically.

Percentage reduction in annualized moderate/severe exacerbation rates and associated 
95% CIs will also be presented.
Exploring Interaction Terms

Interaction by treatment terms will added to the main model one at a time for the following 
main effect covariates: age, region, sex and pre-study ICS dosage at screening, severe 
exacerbations in the previous year.

Summary of test results for main effect covariates in main model will be presented along 
with the test results for the interaction terms mentioned above.
Supportive Statistical Analyses

An ‘on-treatment’ analysis will be performed, corresponding to the ‘de jure’ type estimand 
analysis specified in the protocol. 
o
The endpoint/variable, summary measure and population of interest will be the 
same as for the primary analysis, as outlined in Section 7.2.1, Section 7.2.2 and 
Section 7.2.3 respectively.
o
The covariates will be included in the model as stated above.
o
Offset: logarithm of time (year) on treatment. 
o
Strategy for Intercurrent (Post-Randomization) Events:

An “on-treatment” strategy will be used to handle the intercurrent event of 
treatment discontinuation. Data collected after treatment discontinuation will 
be excluded from the analysis and only on-treatment data will be used.

No imputation of missing data is planned. Missing data is assumed 
Missing at Random (MAR).
Sensitivity analysis - removing sites
The primary model will be repeated excluding participants from sites 
 
and 
using data from weeks 1-52.  
The results of the fitted model will be presented. Summaries and figures will not be produced.
 
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Secondary Statistical Analyses
Sensitivity Statistical Analyses – missing data imputation

Generalized linear model assuming a negative binomial distribution

Imputation methods:

Tipping Point

Jump to Reference

For each of the multiple imputations, the complete datasets of moderate/severe asthma 
exacerbations (both recorded and imputed) will then be analysed using a negative binomial 
model (on each imputation). 

Imputation and analysis model:

Dependent variable:
o
Imputation model: Number of recorded moderate/severe asthma exacerbations 
experienced per participant. 
o
Analysis model: Number of recorded and imputed moderate/severe asthma 
exacerbations experienced per participant.

Covariates: 
o
Categorical: treatment group, sex, region, pre-study ICS dosage at screening, 
severe asthma exacerbations in the previous year (0, 1, >=2).  
o
Continuous: age. 

Offset: logarithm of time (year) on study (imputation: on- and post-treatment data, 
analysis: including imputed time on study up to EOS or planned EOS).

All 6-arm data are included in the model.

LSMESTIMATE statement will be used with the treatment code as specified Section 7.

Multiple imputation methods will be used with results from the negative binomial model 
combined across imputations on the log-scale, using Rubin’s method [Rubin 1987] as 
implemented in SAS PROC MIANALYZE before exponentiating to obtain the estimates for 
the rates and rate ratios

Details for the sensitivity analysis under each imputation method for post-study missing data 
are provided in Section 7.2.1.

The mean annualized exacerbation rate, rate ratio (and 95% CIs) for the primary comparison 
of interest detailed in Section 7 will be presented. For the J2R imputation, the percentage 
reductions (and 95% Cis) will also be presented. 

A forest plot of the rate ratios (and 95% CI) will be presented for the de facto, de jure, 
sensitivity and J2R analyses. 

For the tipping point analysis, a heat map of the p-values will be produced for each of the 
primary comparisons of interest for the different deltas applied.  A line plot of the rate ratio 
and 95% CI will also be produced across the deltas applied to the UMEC/FF/VI arms, with 
the delta for the FF/VI arm set to 0 (MAR). The tipping point where the two-sided p-value 
rises above 0.05 will be included in the plot if possible.

Model checking and diagnostics will not be performed for the imputed datasets.
Unpooled data
The ‘de facto’ summary outputs, analysis and figures will be repeated on the unpooled data.
Subgroups
Summaries will be presented for weeks 1-52 for each of the subgroups listed in Section 5.5.2.
 
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7.3.
Other Secondary Analyses
An overview of the planned secondary analyses is provided below. The full details of 
secondary efficacy analyses data displays are presented in Appendix 10: List of Data 
Displays.
Endpoint 
Absolute
Change from Baseline
Stats 
Analysis
Summary
Individual
Stats 
Analysis
Summary
Individual
T
T
L
T
F
T
F
L
Clinic FEV1 at 3 hours post 
study treatment (de jure 
type estimand)
Y
Y
Y
Y
Y
Y
Y
Y
Clinic FEV1 at 3 hours post 
study treatment (de jure 
type estimand, pooled FF 
doses)
Y
Y
Y
Y
Y
Y
SGRQ total score using 
pooled FF doses (de facto 
type estimand)
Y
Y
Y
Y
Y
Y
SGRQ total score
(de facto type estimand)
Y
Y
Y
Y
Y
Y
ACQ-7 total score using 
pooled FF doses (de facto 
type estimand)
Y
Y
Y
Y
Y
Y
ACQ-7 total score 
(de facto type estimand)
Y
Y
Y
Y
Y
Y
E-RS total score using 
pooled FF doses (de facto 
type estimand)
Y
Y
Y
Y
Y
Y
E-RS total score
(de facto type estimand)
Y
Y
Y
Y
Y
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TF related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual participant observed raw data.
7.3.1.
Endpoint / Variables
As specified in the protocol, other secondary endpoints are:

Change from baseline in clinic FEV1 at 3 hours post study treatment at Week 24

Change from baseline in St. George's Respiratory Questionnaire (SGRQ) total score 
at Week 24

Change from baseline in Asthma Control Questionnaire-7 (ACQ-7) total score at 
Week 24

Change from baseline in Evaluating Respiratory Symptoms (E-RS) total score over 
Weeks 21-24 (inclusive)
 
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7.3.2.
Summary Measure

Mean treatment difference on change from baseline in clinic FEV1 at 3 hours post 
study treatment at Week 24

Mean treatment difference on change from baseline in SGRQ total score at Week 24

Mean treatment difference on change from baseline in ACQ-7 total score at Week 24

Mean treatment difference on change from baseline in E-RS total score over Weeks 
21-24 (inclusive).
7.3.3.
Population of Interest 
The secondary efficacy analyses will be based on the ITT population.
7.3.4.
Strategy for Intercurrent (Post-Randomization) Events
No imputation will be made for missing data. 
7.3.5.
Statistical Analyses / Methods
7.3.5.1.
Statistical Methodology Specification
Endpoint 

Mean change from baseline in clinic FEV1 at 3 hours post study treatment at Week 24
Model Specification

Baseline value is defined in Section 5.2. 

The analysis is based on the on-treatment (de jure) type estimand, including on-treatment 
data collected at Week 24.  This is because those participants who withdraw from study 
treatment will not be able to provide the 3 hours post study treatment assessment in the 
remainder of the study and so a de facto analysis is not possible.

Change from baseline in clinic FEV1 at 3 hours post study treatment at Week 24 will be 
analyzed using an Analysis of Covariance (ANCOVA) model

Terms in the model:
o
Dependent Variable: change from baseline in clinic FEV1 at 3 hours post study treatment
at Week 24. 
o
Covariates:

Categorical:  treatment group, sex, region, pre-study ICS dosage at screening.

Continuous:  age, baseline value for clinic FEV1

The LS mean FEV1 at 3 hours post study treatment and LS mean change from baseline in FEV1 at 3 
hours post study treatment will be estimated using the observed marginal distributions of the 
study population covariates by inclusion of the OM (observed margins) option in SAS.

The analysis will be repeated for the pooled FF doses, LSMESTIMATE statement will be used 
with the treatment code as specified Section 7.
Model Checking & Diagnostics

Refer to Appendix 8: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

Absolute values, change from pre-dose FEV1 and change from baseline in clinic FEV1 at 3 
hours post study treatment at Day 1, Weeks 24, 36 and 52 will be summarized.

For the unpooled data, box plots and empirical distribution function plots for the change from 
baseline in clinic FEV1 at 3 hours post study treatment at Week 24 will be presented.
 
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
Least-Squares (LS) means and LS mean change from baseline values for each treatment 
group will be presented with their associated standard errors. The estimated treatment 
difference along with corresponding standard error, 95% CI and unadjusted p-value will be 
presented for all treatment comparisons specified in Section 7. 

The LS mean change from baseline and LS mean treatment differences (and associated 95% 
CIs) for the comparisons of the two FF/UMEC/VI vs. a FF/VI at a given FF dose will be will also 
be presented graphically at Week 24, for each of the FF doses in two separate panels.
Endpoints

Change from baseline in SGRQ total score at Week 24

Change from baseline in ACQ-7 total score at Week 24

Change from baseline in E-RS total score at Week 24
Model Specification

Analyses are based on the treatment policy (de facto) type estimand using the pooled FF 
doses.

Baseline definitions are provided in Section 5.2.

The change from baseline for each endpoint will be analyzed using a Mixed Models Repeated 
Measures (MMRM) model.

Terms in the MMRM model 
o
Period: 

SGRQ: Clinic visits Week 12 and 24

ACQ-7: Clinic visits at Week 4, 12 and 24

E-RS: Weeks 1-4, Weeks 5-8, Weeks 9-12, Weeks 13-16, Weeks 17-20, Weeks 21-
24. 
o
Covariates:

Categorical: treatment group, sex, region, pre-study ICS dosage at screening and 
period.

Continuous: age, baseline value  
o
Interaction: baseline*period, treatment*period

Repeated: period
o
All 6-arm data are included in the model.
o
LSMESTIMATE statement will be used with the treatment code as specified Section 7.
o
For the E-RS endpoint, the average treatment effect over the 24-week treatment period 
will also be obtained from the model and presented in the analysis output.

The model will be fitted with an unstructured variance-covariance matrix.

The OM option in SAS will be used to derive the LS means based on the distribution of the 
covariates observed in the data 
Analyses of other interest:

The summaries and analyses will be repeated for the ‘de facto’ type estimates using the 
unpooled data.  
Model Checking & Diagnostics
Refer to Appendix 8: Model Checking and Diagnostics for Statistical Analyses.
 
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Model Results Presentation

Absolute values and change from baseline will be summarized by period.

For the ACQ endpoint, the number and percentage of participants in each control category 
(see Section 11.6.3) and the change in control category will be presented.  A shift table of the 
number and percentages of participants in each control category relative to baseline will also 
be presented. 

Boxplots of the change from baseline at each clinic visit will be presented.

Empirical distribution function plots of the change from baseline at each clinical visit will be 
presented.

Least-Squares (LS) means and LS mean change from baseline values for each treatment 
group will be presented with their associated standard errors for the relevant periods. The 
estimated treatment difference along with corresponding standard error, 95% CI and 
unadjusted p-value will be presented for all treatment comparisons specified in Section 2.4 at 
each timepoint.

The LS mean change from baseline and treatment differences (and associated 95% CIs) at 
each timepoint will also be presented graphically.  
o
Where unpooled FF is presented the figures will present the comparisons of the two 
FF/UMEC/VI vs. FF/VI at a given FF dose at each timepoint, with the FF doses in two 
separate panels.
o
Where pooled FF is presented the figures will present the comparisons of the pooled 
FF/UMEC/VI vs.  FF/VI at a given UMEC dose will be presented graphically at each time 
point. 
 
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7.4.
Other Efficacy Analyses
An overview of the planned other efficacy analyses is provided below. The full details of 
data displays are presented in Appendix 10: List of Data Displays.
All analyses will use the de-facto type estimand, unless otherwise stated.
For all non-lung function endpoints, analyses will focus on pooled FF doses. In addition, 
analyses of exacerbation endpoints and responder rates for ACQ-7, SGRQ and E-RS will 
present unpooled treatment comparisons. 
For the lung function related endpoints only the unpooled analyses will be performed. 
The treatment comparisons that will be presented for each endpoint are detailed in 
Section 7.
Other Endpoint 
Absolute
Change from Baseline
Stats 
Analysis
Summary
Individual
Stats 
Analysis
Summary
Individual
T
F
T
F
L
T
F
T
F
L
Clinic trough FEV1
over the first 24 weeks 
of the treatment period
Y
Y
Y
Y
Y
Y
Y
Home daily trough 
FEV1
Y
Y
Y
Y
Y
Y
Y
Y
Home daily PM FEV1
Y
Y
Y
Y
Y
Y
Y
Y
Annualized rate of 
severe asthma 
exacerbations
Y
Y
Y
Time to first severe 
asthma exacerbation
Y
Y
Y
Time to first 
moderate/severe 
asthma exacerbation
Y
Y
Y
ACQ-7, ACQ-6 and 
ACQ-5 responder
Y
Y
Y
ACQ-7, ACQ-6 and 
ACQ-5 Asthma Control
Y
Y
Y
SGRQ domain scores 
Y
Y
Y
Y
Y
Y
Y
SGRQ responder
Y
Y
Y
E-RS domain scores
Y
Y
Y
Y
Y
Y
Y
E-RS responder
Y
Y
Y
Asthma Quality of Life 
Y
Y
Y
Y
Y
Y
Y
 
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Other Endpoint 
Absolute
Change from Baseline
Stats 
Analysis
Summary
Individual
Stats 
Analysis
Summary
Individual
T
F
T
F
L
T
F
T
F
L
Questionnaire (AQLQ) 
total 
AQLQ responder
Y
Y
Y
Home daily AM PEF
Y
Y
Y
Y
Y
Y
Y
Y
Home daily PM PEF
Y
Y
Y
Y
Y
Y
Y
Y
Symptom-free days 
Y
Y
Y
Y
Y
Y
Y
Rescue medication-
free days 
Y
Y
Y
Y
Y
Y
Y
Daily rescue 
medication use 
Y
Y
Y
Y
Y
Y
Y
Healthcare Outcomes
Global assessment of 
severity and response 
to treatment 
Y
Work Productivity and 
Activity Impairment-
Specific Health
Problem
Y
Unscheduled asthma 
related healthcare 
resource utilization 
Y
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TF related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual participant observed raw data.
7.4.1.
Endpoint / Variables
As specified in the protocol, other efficacy endpoints are:

Change from baseline in clinic trough FEV1 over the first 24 weeks of the 
treatment period (weighted mean)

Change from baseline in home daily trough FEV1 over the first 24 weeks of the 
treatment period

Change from baseline in home daily PM FEV1 over the first 24 weeks of the 
treatment period

Annualized rate of severe asthma exacerbations

Time to first severe asthma exacerbation

Time to first moderate/severe asthma exacerbation
 
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
Percent of patients meeting a responder threshold of 0.5 points improvement 
(decrease) from baseline for the ACQ-7 at Week 24

Percent of patients meeting a responder threshold of 0.5 points improvement 
(decrease) from baseline for the ACQ-6 at Week 24

Percentage of patients meeting a responder threshold of 0.5 points improvement 
(decrease) from baseline for the ACQ-5 at Week 24

Percentage of patients that have achieved asthma control based on ACQ-7 (i.e. a 
total score ≤0.75) at both Week 12 and Week 24

Percentage of patients that have achieved asthma control based on ACQ-6 (i.e. a 
total score ≤0.75) at both Week 12 and Week 24

Percentage of patients that have achieved asthma control based on ACQ-5 (i.e. a 
total score ≤0.75) at both Week 12 and Week 24

Change from baseline in SGRQ domain scores (symptoms, activity, impact) at 
Week 24

Percent of patients meeting a responder threshold of ≥ 4 points improvement 
(decrease) from baseline for the SGRQ total score at Week 24

Change from baseline in E-RS domain scores (breathlessness, cough and sputum, 
chest) over Weeks 21-24 (inclusive) of the treatment period

Percent of patients meeting a responder threshold of ≥ 2 points improvement 
(decrease) from baseline for the E-RS total score over Weeks 21-24 (inclusive) of 
the treatment period

Change from baseline in the Asthma Quality of Life Questionnaire (AQLQ) total 
score at Week 24

Percent of patients meeting a responder threshold of ≥ 0.5 points improvement 
(increase) from baseline for the AQLQ total score at Week 24

Change from baseline in morning (AM) pre-dose Peak Expiratory Flow (PEF) 
over the first 24 weeks of the treatment period

Change from baseline in evening (PM) PEF over the first 24 weeks of the 
treatment period

Change from baseline in the percentage of symptom-free days over the first 24 
weeks of the treatment period 

Change from baseline in the percentage of rescue medication-free days over the 
first 24 weeks of the treatment period

Change from baseline in daily rescue medication use over the first 24 weeks of 
the treatment period.

Unscheduled asthma-related healthcare resource utilization over the first 24 
weeks of the treatment period.
 
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7.4.2.
Summary Measure

Mean treatment difference on change from baseline in clinic trough FEV1 over the 
first 24 weeks of the treatment period (weighted mean)

Mean treatment difference on change from baseline in home daily trough FEV1
over the first 24 weeks of the treatment period

Mean treatment difference on change from baseline in home daily PM FEV1 over 
the first 24 weeks of the treatment period

Rate ratio on annualized rate of severe asthma exacerbations

Hazard Ratio on time to first severe asthma exacerbation

Hazard Ratio on time to first moderate/severe asthma exacerbation

Odds ratio on percent of patients meeting a responder threshold of 0.5 points 
improvement (decrease) from baseline for the ACQ-7 at Week 24

Odds ratio on percent of patients meeting a responder threshold of 0.5 points 
improvement (decrease) from baseline for the ACQ-6 at Week 24

Odds ratio on percentage of patients meeting a responder threshold of 0.5 points 
improvement (decrease) from baseline for the ACQ-5 at Week 24

Odds ratio on percentage of patients that have achieved asthma control based on 
ACQ-7 (i.e. a total score ≤0.75) at both Week 12 and Week 24

Odds ratio on percentage of patients that have achieved asthma control based on 
ACQ-6 (i.e. a total score ≤0.75) at both Week 12 and Week 24

Odds ratio on percentage of patients that have achieved asthma control based on 
ACQ-5 (i.e. a total score ≤0.75) at both Week 12 and Week 24

Mean treatment difference on change from baseline in SGRQ domain scores 
(symptoms, activity, impact) at Week 24

Odds ratio on percent of patients meeting a responder threshold of ≥ 4 points 
improvement (decrease) from baseline for the SGRQ total score at Week 24

Mean treatment difference on change from baseline in E-RS domain scores 
(breathlessness, cough and sputum, chest) over Weeks 21-24 (inclusive) of the 
treatment period

Odds ratio on percent of patients meeting a responder threshold of ≥ 2 points 
improvement (decrease) from baseline for the E-RS total score over Weeks 21-24 
(inclusive) of the treatment period

Mean treatment difference on change from baseline in the Asthma Quality of Life 
Questionnaire (AQLQ) total score at Week 24

Odds ratio on percent of patients meeting a responder threshold of ≥ 0.5 points 
improvement (increase) from baseline for the AQLQ total score at Week 24

Mean treatment difference on change from baseline in morning (AM) pre-dose 
Peak Expiratory Flow (PEF) over the first 24 weeks of the treatment period
 
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
Mean treatment difference on change from baseline in evening (PM) PEF over the 
first 24 weeks of the treatment period

Mean treatment difference on change from baseline in the percentage of 
symptom-free days over the first 24 weeks of the treatment period 

Mean treatment difference on change from baseline in the percentage of rescue 
medication-free days over the first 24 weeks of the treatment period

Mean treatment difference on change from baseline in daily rescue medication 
use over the first 24 weeks of the treatment period.

Unscheduled asthma-related healthcare resource utilization over the first 24 
weeks of the treatment period.
7.4.3.
Population of Interest 
The Other efficacy analyses will be based on the Intent-To-Treat population
7.4.4.
Strategy for Intercurrent (Post-Randomization) Events
No imputation will be made for missing data.
In general, a “treatment policy” strategy will be used to handle all intercurrent events, as 
described in Section 7.1.4, with the exception of the analyses of responders and asthma 
control. 
For these analyses, a “treatment policy” strategy will be used to handle the intercurrent 
event of early discontinuation from study treatment, and a “composite” strategy will be 
used to handle the intercurrent event of premature withdrawal from study, where subjects 
who withdraw from the study prior to the timepoint of interest are considered non-
responders at that timepoint. Participants with missing data at the timepoint of interest, 
regardless of treatment status, will be considered as non-responders. The endpoint 
analyzed will therefore essentially be the percent of participants who do not prematurely 
discontinue from the study, have data available at the timepoint and meet the responder 
threshold.
7.4.4.1.
Statistical Methodology Specification
Endpoint
Mean change from baseline in clinic trough FEV1 over the first 24 weeks of the treatment period
Model Specification

Clinic trough FEV1 over the first 24 weeks of the treatment period and the change from 
baseline will be summarized.

Baseline value is defined in Section 5.2. 

The analysis is based the on- and post-treatment (de facto) type estimand, including all clinic 
trough FEV1 data collected at all scheduled clinic visits prior to and on Week 24 (both on- and 
 
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post-treatment). The derivation of clinic trough FEV1 AUC0-24w will use all data collected at 
Baseline, Weeks 4, 12, and 24.

Change from baseline in clinic trough FEV1 over the first 24 Weeks will be analyzed using an 
ANCOVA model.

Terms in the model:
o
Covariates:

Categorical:  treatment group, sex, region, pre-study ICS dosage at screening, 

Continuous:  age, baseline value for clinic FEV1

The LS mean FEV1 over the first 24 weeks and LS mean change from baseline over the first 
24 weeks will be estimated using the observed marginal distributions of the study population 
covariates by inclusion of the OM (observed margins) option in SAS.
Model Checking & Diagnostics

Refer to Appendix 8: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

Summary statistics of the absolute and change from baseline in FEV1 over the first 24 weeks 
will be presented.

Least-Squares (LS) means and LS mean change from baseline values for each treatment 
group will be presented with their associated standard errors. The estimated treatment 
difference along with corresponding standard error, 95% CI and unadjusted p-value will be 
presented for all treatment comparisons specified in Section 7. 

The LS mean change from baseline and LS mean treatment differences (and associated 95% 
CIs) for the comparisons of the two FF/UMEC/VI vs. a FF/VI at a given FF dose will also be 
presented graphically at Week 24, for each of the FF doses in two separate panels.
Endpoints

Mean change from baseline in home daily trough FEV1 over the first 24 weeks of the treatment 
period

Mean change from baseline in home daily PM FEV1 over the first 24 weeks of the treatment 
period

Mean change from baseline in home daily morning (AM) pre-dose PEF over the first 24 weeks 
of the treatment period

Mean change from baseline in home daily evening (PM) PEF over the first 24 weeks of the 
treatment period

Mean change from baseline in E-RS Breathlessness scores over Weeks 21-24 (inclusive) of 
the treatment period

Mean change from baseline in E-RS Cough & Sputum scores over Weeks 21-24 (inclusive) of 
the treatment period

Mean change from baseline in E-RS Chest Symptoms scores over Weeks 21-24 (inclusive) of 
the treatment period

Mean change from baseline in the percentage of symptom-free days over the first 24 weeks of 
the treatment period

Mean change from baseline in the percentage of rescue medication-free days over the first 24 
weeks of the treatment period

Mean change from baseline in daily rescue medication use over the first 24 weeks of the 
 
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treatment period.
Model Specification

These analyses will be performed using an MMRM model as for the E-RS data detailed in 
Section 7.3.5.1, using the on- and post-treatment (de facto) type estimand.

The home daily trough FEV1, PM FEV1, AM PEF and PM PEF endpoints will be analyzed and 
presented using unpooled doses. 

The E-RS domains, percentage of symptom free days, percentage of rescue medication free 
days and daily rescue medication use will be analyzed and presented using the pooled FF 
doses. 

The home daily trough FEV1, PM FEV1, AM PEF and PM PEF endpoints will also be 
summarized in 1 weekly periods up to week 52. 

To assess for time to maximal effect of UMEC when comparing FF/UMEC/VI to FF/VI, weekly 
changes from baseline in Home Daily Trough FEV1 over the first 8 weeks of the treatment 
period will also be analyzed using the same MMRM detailed in Section 7.3.5.1. Here the period 
term is:
oWeek 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8 
The LS mean change from baseline and LS mean treatment difference in percentage of symptom-
free days and percentage of rescue medication-free days will also be presented as the 
equivalent number of additional symptom-free/rescue medication-free days per week.
Model Checking & Diagnostics

Refer to Appendix 8: Model Checking and Diagnostics for Statistical Analyses
Model Results Presentation

These analyses will be presented as for the E-RS data detailed in Section 7.3.5.1.  Box plots 
and empirical distribution plots will not be presented. 

A plot of the LS mean change and LS mean treatment difference will be produced for the 
Home Daily Trough FEV1 data for the 1-weekly intervals up to week 8 (in a similar manner to 
the 4-weekly data up to week 24). 

A line plot of the unadjusted weekly mean change from baseline in home daily trough FEV1, 
PM FEV1, AM and PM PEF will be presented up to 24 weeks. 

For the E-RS domain (Breathlessness, cough & sputum and chest symptom) scores, these will 
be included in the same summaries and presented by domain. A forest plot will display the 
treatment estimate and 95% CI for the E-RS total score and domain scores at Weeks 21- 24.
Endpoint

Annualized rate of severe asthma exacerbations
Model Specification

Data for weeks 1-52 will be analyzed using a generalized mixed model as specified in Section 
7.2.6 based on the on- and post-treatment (de facto) type estimand, presenting both unpooled 
and pooled FF dose treatment comparisons.
Model Checking & Diagnostics

Refer to Appendix 8: Model Checking and Diagnostics for Statistical Analyses
Model Results Presentation

See Section 7.2.6
 
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Endpoints

Time to first severe asthma exacerbation

Time to first moderate/severe asthma exacerbation
Model Specification

Cox’s proportional hazards model

All asthma exacerbations observed during the study (on- or post-treatment) will be used in the 
analyses

Terms in the model:

Response: time to first severe (or moderate/severe) asthma exacerbation during the study 
(both on- and post-treatment) 

Covariates:
o
Categorical: treatment group, sex, region, pre-study ICS dosage at screening, severe 
asthma exacerbations in the previous year (0, 1, >=2).  
o
Continuous: age

The ‘exact’ method will be used for handling ties. If the analysis will not run using the ‘exact’ 
method, then the ‘Efron’ method for handling ties will be used instead.

For the pooled analysis:

All 6-arm data are included in the model.

LSMESTIMATE statement will be used with the treatment code as specified Section 7.

The analyses will be repeated using unpooled data.
Model Checking & Diagnostics

Refer to Appendix 8: Model Checking and Diagnostics for Statistical Analyses
Model Results Presentation

Hazard ratios for pairwise treatment comparisons with associated 95% CIs and p-values will be 
presented.

Kaplan-Meier survivor functions will be obtained for each treatment group using PROC 
LIFETEST with a TIME statement. 
Endpoints

Percent of patients meeting a responder threshold of 0.5 points improvement (decrease) from 
baseline for the ACQ-7 at Week 24

Percent of patients meeting a responder threshold of 0.5 points improvement (decrease) from 
baseline for the ACQ-6 at Week 24

Percentage of patients meeting a responder threshold of 0.5 points improvement (decrease) 
from baseline for the ACQ-5 at Week 24

Percent of patients meeting a responder threshold of ≥ 4 points improvement (decrease) from 
baseline for the SGRQ total score at Week 24

Percent of patients meeting a responder threshold of ≥2 points improvement (decrease) from 
baseline for the E-RS total score over Weeks 21-24 (inclusive) of the treatment period

Percent of patients meeting a responder threshold of ≥ 0.5 points improvement (increase) from 
baseline for the AQLQ total score at Week 24
Model Specification

The analysis includes on-and post-treatment data and is based on the ITT population.
 
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
For details of handling missing data, see Section 11.7.2.

Analyses for the ACQ-7, SGRQ and E-RS total score will present unpooled and pooled FF 
doses treatment comparisons.

Analyses for the ACQ-5, ACQ-6 and AQLQ will be carried out for the pooled FF doses.

Percent of participants meeting the responder threshold will be summarized by period, and 
analyzed using a generalized linear model (logistic regression), including all data up to week 
24.

Computation of confidence intervals for the odds ratios is based on the individual Wald tests 
calculated on the log scale and then back transformed. 

Period: 

ACQ-5, ACQ-6, ACQ-7, AQLQ: Clinic visits at Week 4, 12 and 24

SGRQ: Clinic visits Week 12 and 24

E-RS: Weeks 1-4, Weeks 5-8, Weeks 9-12, Weeks 13-16, Weeks 17-20, Weeks 21-
24. 

Terms in the model:

Dependent Variable: Responder (Yes/No)

Covariates:

Categorical: treatment group, sex, region, pre-study ICS dosage at screening
and period. 

Continuous: age, Baseline value

Interaction:   Baseline*period, treatment*period

Link function: Logit

All 6-arm data are included in the model.

Where the output presents the pooled FF doses, LSMESTIMATE statement will be used with 
the treatment code as specified Section 7.

The model will be fitted with an unstructured variance-covariance matrix.

The OM option in SAS will be used.
Model Checking & Diagnostics

Refer to Appendix 8: Model Checking and Diagnostics for Statistical Analyses
Model Results Presentation

Number and percentage of responders and non-responders for each treatment at each Week 
will be presented. The number of non-responders due to missing data will also be presented.

The odds ratio for all treatment comparisons as specified in Section 7, with associated 95% 
CI and p-value will be presented by visit.

A forest plot displaying the odds ratios (and 95% CI) for the primary treatment comparisons 
as specified in Section 7 at week 24 (weeks 21-24 for the E-RS endpoint) will be presented.
Endpoints

Percentage of patients that have achieved asthma control based on ACQ-7 (i.e. a total score 
≤0.75) at both Week 12 and Week 24

Percentage of patients that have achieved asthma control based on ACQ-6 (i.e. a total score 
≤0.75) at both Week 12 and Week 24

Percentage of patients that have achieved asthma control based on ACQ-5 (i.e. a total score 
≤0.75) at both Week 12 and Week 24 
Model Specification

The analysis includes on-and post-treatment data and is based on the ITT population.

For details of handling missing data, see Section 11.7.2.

Analysis for the ACQ-7 will present unpooled and pooled FF dose treatment comparisons.
 
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
Analyses for the ACQ-5 and ACQ-6 will be carried out for the pooled FF doses.

Percent of participants meeting the asthma control criterial will be summarized and analyzed 
using a generalized linear model (logistic regression).

Computation of confidence intervals for the odds ratios is based on the individual Wald tests 
calculated on the log scale and then back transformed.

Terms in the model:
o Dependent Variable: Asthma control (Yes/No)
o Covariates:

Categorical: treatment group, sex, region and pre-study ICS dosage at 
screening

Continuous: age, Baseline value

Link function: Logit

All 6-arm data are included in the model.

Where the output presents the pooled FF doses, LSMESTIMATE statement will be used 
with the treatment code as specified Section 7.

The model will be fitted with an unstructured variance-covariance matrix.

The OM option in SAS will be used.
Model Checking & Diagnostics

Refer to Appendix 8: Model Checking and Diagnostics for Statistical Analyses
Model Results Presentation

Number and percentage of participants with and without asthma control for each treatment.
The number of participants without asthma control due to missing data will also be 
presented.

Odds ratio for treatment comparison with associated 95% CI and p-value as specified 
Section 7.

A forest plot displaying the odds ratios (and 95% CI) for the primary treatment comparisons 
as specified in Section 7 at week 24 will be presented.
Endpoint

Mean change from baseline in SGRQ domain scores at Week 24
Model Specification

Change from baseline in SGRQ domain scores will be summarized and analyzed as for the 
SGRQ total score as specified in Section 7.3.5.1, for each domain separately.

Summaries and analyses will use the on- and post-treatment (de facto) type estimand and
be presented for pooled FF doses. 
Model Checking & Diagnostics

Refer to Appendix 8: Model Checking and Diagnostics for Statistical Analyses
Model Results Presentation

As for the SGRQ specified in Section 7.3.5.1.  Summaries and analyses will be presented by 
domain. A forest plot will display the treatment estimate and 95% CI for the SGRQ total 
score and domain scores at Week 24.
 
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Endpoint

Mean change from baseline in AQLQ total score at Week 24
Model Specification

Change from baseline in AQLQ total score will be summarized and analyzed as for the 
SGRQ endpoint as specified in Section 7.3.5.1.

Summaries and analyses will use the on- and post-treatment (de facto) type estimand and 
be presented for pooled FF. 
Model Checking & Diagnostics

Refer to Appendix 8: Model Checking and Diagnostics for Statistical Analyses
Model Results Presentation

As for the SGRQ specified in Section 7.3.5.1.  
Other Statistical Analyses
Endpoints

Unscheduled asthma-related healthcare resource utilization over the first 24 weeks.

WPAI-SHP

Global assessment of severity

Global assessment of response to treatment
Model Specification

Summaries will use the on- and post-treatment (de facto) type estimand and be presented 
for unpooled data.

No formal statistical analyses will be carried out.

Unscheduled asthma-related healthcare resource utilization will also be summarized by contact type 
(related to an exacerbation/not related to an exacerbation) and up to 52 weeks for subjects with ≥36 
Weeks of planned treatment exposure.
Model Checking & Diagnostics
Not applicable
Model Results Presentation

Summary statistics appropriate for the data collected at visits where data was collected.
 
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8.
SAFETY ANALYSES
All safety analyses will be based on the ITT population. On-treatment safety data 
collected at scheduled clinic visits will be summarized and analyzed by treatment and by 
visit, unless otherwise specified. On-treatment adverse events and post-treatment adverse 
events will be summarized separately.  All data will be listed, unless otherwise specified. 
An overview of the planned analyses is provided below. The full details of safety analysis 
data displays are presented in Appendix 10: List of Data Displays
Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
L
T
F
L
Exposure
Extent of Treatment Exposure 
(unpooled and pooled FF doses)
Y
Post-Treatment Duration on 
Study
Y
Adverse Events (AEs)
Relationship of AE System Organ 
Class, Preferred Term and 
Verbatim Text
Y1
AEs during screening/ run-in 
period
Y
Y1
AEs during stabilization period
Y
Y1
Overview of On-Treatment AEs 
Y
On-Treatment AEs 
Y
Y
On-Treatment AEs adjusted for 
exposure (per thousand person-
years)
Y
On-Treatment AEs in the 
respiratory, thoracic and 
mediastinal disorders SOC
Y
On-Treatment AEs in the 
respiratory, thoracic and 
mediastinal disorders SOC (per 
thousand person-years)
Y
Post-Treatment AEs during the 
study
Y
Y
Post-Study AEs
Y
Y
On Treatment AEs during Weeks 
1-24 
Y
On Treatment AEs during Weeks 
1-36 for participants with ≥ 36 
weeks of planned treatment 
exposure 
Y
On Treatment AEs during Weeks 
1-52 for participants with 52 
weeks of planned treatment 
Y
 
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Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
L
T
F
L
exposure 
On-Treatment Drug-Related AEs 
Y
On-Treatment Drug-Related AEs 
during the study adjusted for 
exposure (per thousand person-
years)
Y
Post-Treatment Drug-Related AEs 
Y
On-Treatment SAEs
Y
On-Treatment SAEs adjusted for 
exposure (per thousand person-
years)
Y
Post-Treatment SAEs
Y
Non-fatal SAEs
Y
Fatal SAEs
Y
On-Treatment Drug-Related SAEs
Y
On-Treatment Drug-Related SAEs 
adjusted for exposure (per 
thousand person-years)
Y
On-Treatment SAEs during 
Weeks 1-24
Y
On-Treatment SAEs during 
Weeks 1-36 for participants with ≥ 
36 weeks of planned treatment 
exposure
Y
On-Treatment SAEs during 
Weeks 1-52 for participants with 
52 weeks of planned treatment 
exposure
Y
On-Treatment AEs Leading to 
Permanent Discontinuation of 
Study Drug or Withdrawal from 
Study
Y
Y
Post-Treatment AEs Leading to 
Withdrawal from Study
Y
Y
On-Treatment AESIs
Y
Y
On-Treatment AESIs adjusted for 
exposure (per thousand person-
years)
Y
Post-treatment AESIs 
Y
On-Treatment AESIs during 
Weeks 1-24
Y
On-Treatment AESIs during 
Weeks 1-36 for participants with ≥ 
36 weeks of planned treatment 
exposure
Y
On-Treatment AESIs during 
Weeks 1-52 for participants with 
52 weeks of planned treatment 
Y
 
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Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
L
T
F
L
exposure
On-Treatment SAEs of Special 
Interest
Y
Y
On-Treatment SAEs of Special 
Interest adjusted for exposure 
(per thousand person-years)
Y
Post-treatment SAEs of special 
interest
Y
On-treatment AEs (3% or More of 
Participants in Any Treatment 
Group) 
Y
The 10 Most Frequent On-
treatment Adverse Events in Each 
Treatment Group
Y
On-Treatment AEs during Study 
by Subgroups
Y
Subject Numbers for Individual 
AEs
Y
Subject Numbers for On-
Treatment AEs of Special Interest
Y
MACE 
On-Treatment Major Adverse 
Cardiac Events (Narrow 
Definition)
Y
On-Treatment Major Adverse 
Cardiac Events (Broad Definition)
Y
On-Treatment Major Adverse 
Cardiac Events (Narrow 
Definition) adjusted for exposure 
(per thousand person-years)
Y
On-Treatment Major Adverse 
Cardiac Events (Broad Definition) 
adjusted for exposure (per 
thousand person-years)
Y
Pneumonia and radiography (Chest X-rays)
On-Treatment Pneumonia and 
radiography (Chest X-rays)
Y
Y
Liver Events
Medical conditions for 
participants with liver stopping 
events
Y
Liver Event Results and Time of 
Event Relative to Treatment
Y
Liver Event Substance Use
Y
Liver Event Information for 
RUCAM Score
Y
Liver Biopsy Details
Y
Liver Imaging Details
Y
 
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Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
L
T
F
L
Laboratory Parameters
Chemistry Values for Participants 
with at Least One Value Outside 
the Normal Range
Y
Chemistry Data
Y
Y
Y
Y
Chemistry Data Outside the 
Normal Range
Y
Chemistry Changes from Baseline 
Relative to the Normal Range
Y
Hematology Values for 
Participants with at Least One 
Value Outside the Normal Range
Y
Hematology Data
Y
Y
Y
Y
Hematology Data Outside the 
Normal Range
Y
Hematology Changes from 
Baseline Relative to the Normal 
Range
Y
Worst Case Urinalysis Results 
Post-Baseline Relative to 
Baseline
Y
Y
Vital Signs
Vital Sign Data (Pulse Rate, Sys 
BP, Dia BP)2
Y
Y
Y
Y2
12-Lead ECGs
ECG Values2
Y
Y
Y2
Y
ECG Findings
Y
Y
ECG Findings Shifts from 
Baseline
Y
QTcF Categories
Y
Y
ECG Abnormalities
Y
Y
Y
Maximum Post-Baseline QTcF
Y
Y
Y
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Summary = Represents TF related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual participant observed raw data.     
1 – All Subjects Enrolled population
2 – Statistical analysis also performed for change from baseline in vital signs (pulse rate, SBP, DBP) and ECG 
parameters (PR interval, QTc(F) interval and heart rate)
8.1.
Extent of Exposure 
The extent of exposure to fluticasone/salmeterol [FSC], 250/50 mcg, via the DISKUS 
DPI during the run-in period, to FF/VI 100/25mcg, via the ELLIPTA DPI during the 
stabilization period, to randomised study treatment and post-treatment data will be 
summarized by the categories in Section 11.6.4. The number of days of post-treatment 
 
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data will also be summarized for all participants with at least one day of post-treatment 
data. 
8.2.
Adverse Events Analyses
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs) 
and other significant AEs will be based on GSK Core Data Standards. 
The CRF texts for adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) and will be reported using the primary System Organ 
Class (SOC) and the Preferred Term.    
Adverse events will be summarized and grouped by primary SOC and by adverse event 
(i.e., Preferred Term) within primary SOC.  Results will be displayed in the order of 
decreasing frequency, both across primary SOC and within primary SOC.  The number of 
participants with one or more events of any type will also be calculated.  The relationship 
of primary SOC, Preferred Terms, and verbatim text will be listed.
The following summaries will be provided:
-
AEs during screening/run-in.
-
AEs during stabilization period.
-
On-treatment AEs: All AEs, drug-related AEs, all SAEs, drug-related SAEs
-
Outputs will be repeated adjusted for exposure (per thousand persons years) to 
account for variable treatment duration
-
Post-treatment AEs: All AEs, drug related AEs, all SAEs
-
Post-study AEs.
Adverse events will also be summarized by gender, age, race, region, pre-study ICS 
dosage at screening, BMI and CV History/Risk Factor at Screening.
In addition, the on-treatment AEs and on-treatment SAEs will be presented (see Section 
11.6.4 for more details on participants and reporting period included in each table):
-
Up to week 24
-
Up to week 36 for all participants whose EOS visit or planned EOS visit is after 
week 24
-
Up to week 52 for all participants whose EOS visit or planned EOS visit is after 
week 36
In addition, common (3% or more participants in any treatment arm) on-treatment 
adverse will be presented. To support this, the 10 most frequent AEs in each treatment 
group will be presented.
8.3.
Adverse Events of Special Interest Analyses
Adverse events of special interest have been defined as AEs which have specified areas 
of interest for one or more of the compounds (FF, VI and/or UMEC) or combination 
therapies (FF/UMEC/VI and/or FF/VI).  These consist of groupings of preferred terms 
 
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based on the MedDRA dictionary version used in each reporting effort.  Subgroups may 
be defined, based on relevant combination of preferred terms, or on Standardized 
MedDRA queries (SMQ).
The table below presents the special interest AE groups for FF, UMEC and VI, defined 
upon the release of version 21.1 of the MedDRA dictionary.   
Special Interest AE 
Group
Special Interest AE 
Subgroup
PTs/SMQs for Inclusion
Cardiovascular effects*
Cardiac arrhythmia
Cardiac arrhythmia 
(SMQ), excluding 
congenital and neonatal 
arrhythmias
Cardiac failure 
Cardiac Failure (SMQ)
Cardiac ischaemia
Ischaemic Heart Disease 
(SMQ)
Stroke
Central nervous system 
haemorrhages and 
cerebrovascular 
conditions (SMQ)
Hypertension
Hypertension (SMQ)
Pneumonia
Infective pneumonia (SMQ)
LRTI excluding infective 
pneumonia SMQ
Selected PTs
Decreased bone mineral 
density and associated 
fractures
Osteoporosis/Osteopenia 
(SMQ)
Selected PTs
Hypersensitivity
Hypersensitivity (SMQ)
Angioedema (SMQ)
Anaphylactic reaction 
(SMQ)
Anticholinergic 
Syndrome*
Anticholinergic Syndrome 
SMQ
Gastrointestinal 
obstruction*
Gastrointestinal 
obstruction SMQ
Adrenal Suppression
Selected PTs
Antimuscarinic ocular 
effects / Corticosteroid 
Associated Eye Disorders
Glaucoma (antimuscarinic 
/ corticosteroid)
Glaucoma (SMQ), 
Cataracts 
(corticosteroids)
Lens disorder (SMQ)
Effects on Glucose 
Hyperglycaemia/new 
onset diabetes mellitus 
(SMQ)
Local steroid effects 
Selected PTs
Urinary retention*
Selected PTs
Effects on potassium 
Selected PTs
Tremor 
Selected PTs
Asthma/Bronchospasm 
for Asthma-related 
intubations and deaths 
Asthma/bronchospasm 
SMQ
 
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Special Interest AE 
Group
Special Interest AE 
Subgroup
PTs/SMQs for Inclusion
Dry mouth / Drying of
airway secretions*
Selected PTs (narrow and 
broad focus)
*: of interest for UMEC 
Adverse events of special interest will be summarized in the same manner outlined in 
Section 8.2 for overall AEs, and by the study population subgroups identified in Section 
5.5.2.
In addition, the on-treatment AESIs will be summarized (see Section 11.6.4 for more 
details on participants and reporting period included in each table):
-
Up to week 24
-
Up to week 36 for all participants whose EOS visit or planned EOS visit is after 
week 24
-
Up to week 52 for all participants whose EOS visit or planned EOS visit is after 
week 36
8.4.
Major Adverse Cardiac Events 
Major Adverse Cardiac Events (MACE) endpoint will be analyzed using broad and 
narrow definitions. 
The broad MACE will be defined as:
-
Cardiac Ischaemia Special Interest AE Subgroup (Ischaemic Heart Disease SMQ) 
excluding fatalities, 
-
Stroke Special Interest AE Subgroup (Central Nervous System Haemorrhages and 
Cerebrovascular Conditions SMQ) excluding fatalities
The narrow MACE will be defined as:
-
PTs of “myocardial infarction” and “acute myocardial infarction” excluding 
fatalities, 
-
Stroke Special Interest AE Subgroup (Central Nervous System Haemorrhages and 
Cerebrovascular Conditions SMQ) excluding fatalities
The broad and narrow MACE tables will also be provided adjusted for exposure (per 
thousand persons years) to account for variable treatment duration.
CV deaths will be considered in the CSR, alongside the broad and narrow MACE defined 
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8.5.
Clinical Laboratory Analyses
On-treatment laboratory evaluations including the analyses of Chemistry laboratory tests, 
Hematology laboratory tests, Urinalysis, and liver function tests will be based on GSK 
Core Data Standards. The details of the planned displays are in Appendix 10: List of Data 
Displays
Laboratory values will be classified as ‘Low’, ’Normal’, or ‘High’ based on the provided 
normal ranges. 
Change from baseline values will be classified relative to the normal range as ‘To Low’, 
‘To Normal or No Change’, or ‘To High’.  Participants who do not change categories or 
move from out-of-range to normal will be classified as ‘To Normal or No Change’.
An ‘any time post-baseline’ change classification will be derived for each treatment in 
which participants will be counted in the ‘To Low’ or ‘To High’ categories if they 
reported a change from a ‘Normal’ baseline to a value below or above the normal range, 
respectively, at any on-treatment scheduled, unscheduled, or EW visit during the 
associated treatment.  Participants who did not report a change to a value outside the 
normal range at any visit while taking the associated treatment will be counted in the ‘To 
Normal or No Change’ category.
8.6.
Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. 
8.6.1.
Vital Signs
Vital signs (pulse rate, diastolic blood pressure, and systolic blood pressure) are measured 
at every clinic visit, starting at Visit 1, and prior to conducting spirometry. 
The ‘minimum post-baseline’ and ‘maximum post-baseline’ value will be derived as the 
minimum and maximum on-treatment value recorded at any scheduled, unscheduled, or 
Early Withdrawal (EW) visit after the start of study treatment. See Section 8.6.4 for 
details on the statistical analysis of vital signs data.
8.6.2.
ECG
The on-treatment ECG measurements of interest are QTc (F), QTc(B), heart rate, and PR 
interval.  All ECG data present in the database will be considered valid and will be 
reported (even if the ECG had a technical error).
A ‘maximum post-baseline’ and ‘minimum post-baseline’ QTc (F), QTc(B), PR interval, 
and heart rate value will be derived as the maximum (or minimum) on-treatment value 
recorded at any scheduled, unscheduled, or EW visit after the start of study treatment.
Absolute and change from baseline QTc (F) values (including ‘maximum post-baseline’) 
will be categorized as detailed in Section 11.6.4.
 
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See Section 8.6.4 for details on the statistical analysis of QTc (F), PR interval and heart 
rate data.
An ‘any time post-baseline’ ECG interpretation will be derived as the worst on-treatment 
interpretation recorded at a scheduled, unscheduled, or EW visit after the start of study 
treatment.  The order of severity from worst to best for ECG interpretation is: abnormal, 
normal, unable to evaluate.
8.6.3.
Pregnancy
Any pregnancies reported during the study will be summarized in case narratives. Any 
pregnancy complication or elective termination of a pregnancy for medical reasons will 
be recorded as an AE or SAE and included in summaries and listings of AEs/SAEs.
8.6.4.
Planned Statistical Analyses of Safety Endpoints
8.6.4.1.
Vital Signs and ECGs
Statistical Analysis of Safety Endpoints
Endpoints

Change from baseline in Pulse rate

Change from baseline in Systolic BP

Change from baseline in Diastolic BP

Change from baseline in QTc (F)

Change from baseline in PR Interval

Change from baseline in Heart Rate (ECG)
Model Specification, Checking, Results Presentation and SAS code

Data up to Week 24 for these endpoints will be analyzed using the same methodology as 
trough FEV1 in Section 7.1.6 using the on-treatment (de jure) type estimand and unpooled 
data. 

Treatment comparisons 1) and 2) only as defined in Section 7 will be presented.
9.
POP PK DATA SPECIFICATION
Population PK analysis will be the subject of a separate RAP and reported separately.  
Pop PK dataset preparation will be performed by Contract Research Organisation.
9.1.
Pop PK Dataset Specification
General Description:

Missing or unknown values in covariates, if not to be imputed, will be assigned -99;

The dataset is sorted by STUDYID, SUBJID, DATETIME, EVID descending unless 
specify otherwise

The data items (columns) in the analysis-ready data file will be provided the same 
order as follows.

Non-numerical concentration values (such as missing samples, not assayed samples, 
or non-reportable samples) will not be included. 
 
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
Participants with no quantifiable concentration values will be included.

Dosing events occurring prior to the subsequent PK sample(s) will be included (i.e., 
dosing events on the preceding day for pre-dose PK samples, and dosing events at the 
specified visit for post-dose samples)

Liver event data will be retained in the dataset.
The dataset will be a comma delimited ASCII text file and will be named: 
NM.205715.PK.v1.csv.
Table 1 provides a list of variables required for the Pop PK dataset and format for the 
variables. 
Table 1
Variables required in the Pop PK (*Mandatory variable name, 
included for traceability)
Variable
Label (Variable 
description)
Type
Units
Missing 
value
Codes/Derivation/Notes
ID
NONMEM subject 
identifier
Intege
r
None
Never
Sequential subject identifier to 
start at 
STUDYID*
Unique identifier for 
a study
Char
None
Never
205715
USUBJID*
Unique subject 
identifier
Char
None
Never
Identifier used to uniquely identify 
a subject across all studies for all 
applications or submissions 
involving the product. As in the 
SAS dataset.
SUBJID*
Subject identifier 
for study
Char
None
Never
Subject identifier, which must be 
unique within the study. As in the 
SAS dataset.
COUNTRY*
Country
Char
None
Never
Country of the investigational site 
in which the subject participated in 
the trial.
e.g. USA
CNC
NONMEM Country 
code
Intege
r
None
Never
As in SAS dataset if available, 
otherwise generate a numerical 
code for each country, e.g. 1, 2,…
SITEID*
Unique identifier for 
a study site
Num
None
Never
e.g. 
 any lead zero should 
not be included.
DGRP
Actual Treatment 
group
Char
None
Never
As in SAS dataset
e.g. FF/UMEC/VI 100/62.5/25
DOSEFF
Dose amount of FF
Num
ug
Never
Actual dose amount to be entered 
in all rows for each subject.
e.g. DOSEFF=100 for 
FF/UMEC/VI 100/62.5/25
DOSEUMEC
Dose amount of 
UMEC
Num
ug
Never
Actual dose amount to be entered 
in all rows for each subject.
e.g. DOSEUMEC=62.5 for 
FF/UMEC/VI 100/62.5/25;
DOSEUMEC=0 for FF/VI 100/25
 
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Variable
Label (Variable 
description)
Type
Units
Missing 
value
Codes/Derivation/Notes
DOSEVI
Dose amount of VI
Num
ug
Never
Actual dose amount to be entered 
in all rows for each subject.
e.g. DOSEVI=25 for FF/UMEC/VI 
100/62.5/25
VISIT
Planned Study visit
Char
none
Never
Scheduled visit, as in SAS dataset
VISITNUM
Planned study visit
Num
none
Never
Scheduled visit, as in SAS 
dataset, in numeric format
DAY
Study day number 
of record
Num
day
Never
Day of study relative to first IP 
dose
PTM
Planned Time 
Char
None
Only for 
dosing 
records
Planned Time As in SAS dataset
Blank for dosing records.
DATETIME
Date and time of 
dose and PK 
sample 
MM/D
D/YYY
Y 
HH:M
M:SS
None
Never
Date and time of dose and PK 
measurement record
TIME
Relative time from 
LAST dose to 
sample
Num
h
Never
Actual time from last dose of IP 
prior to sample.
For pre-dose sample on a visit, 
TIME=relative time from the 
dose taken at the previous day.
For dosing records, set TIME = 0.
AMTFF
NONMEM Amount 
of FF administered
Num
ug
Never
AMTFF=DOSEFF for rows of 
dosing event
AMT=’0’ for observation rows
AMTUMEC
NONMEM Amount 
of UMEC 
administered
Num
ug
Never
AMTFF=DOSEUMEC for rows of 
dosing event
AMT=’0’ for observation rows
AMTVI
NONMEM Amount 
of VI administered
Num
ug
Never
AMTFF=DOSEVI for rows of 
dosing event
AMT=’0’ for observation rows
ANALYTE
Analyte measured
char
None
Never
As in the SMS2000
e.g. FF, UMEC, VI
RESC
Conc for 
corresponding 
ANALYTE (char)
char
pg/mL
blank
As in the SMS2000. If 
measurement is below LLQ, it is 
populated as NQ, otherwise, it is 
populated as the actual 
measurement. No sample (NS), 
insufficient sample (IS) and no 
result (NR) records will be 
excluded from dataset.
CONC
Conc for 
corresponding 
ANALYTE (num)
Num
pg/mL
“.”
Dosing row CONC=0.
NQ will be included in the dataset 
but set as “.”
 
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Variable
Label (Variable 
description)
Type
Units
Missing 
value
Codes/Derivation/Notes
LNCONC
Natural log of 
CONC column 
Num
None
Never
If CONC=0 or CONC=”.”, then 
LNCONC=’.’
LLQ
Lower Limit of 
quantification 
Num
pg/mL
Never
Lower limit of quantification of 
assay. 
LLQ=0 for dosing rows.
LNLLQ
Natural log of LLQ 
Num
None
Never
If LLQ=0, then LNLLQ=’.’
LABL
Label describing 
the record
Char
None
Never
LABL explains the type of 
measurement for CONC for the 
current record
LABL=DOSE for dosing row,
LABL=CONC for observation 
rows.
TYPE
For handling NQ 
values in NONMEM
Intege
r
If LABL=DOSE then TYPE = 0,
If CONC value present TYPE = 1 
If LABL=CONC and CONC value 
missing TYPE = 2
MDV1
Missing data 
variable
Intege
r
0 if LABL contains CONC;
1 if LABL contains DOSE
EVID
NONMEM Event ID
Intege
r
None
Never
EVID=1 for LABL=DOSE, 
EVID=0 for LABL=CONC
II
NONMEM Inter-
dose interval
Intege
r
Specif
y
Never
II=24 for dosing rows,
II=0 for PK observation rows.
SS
Steady-state data 
item
Intege
r
None
Never
SS=1 for dosing records 
SS=0 for  PK observation rows
RATE
NONMEM Rate of 
drug infusion
Intege
r
None
Never
Rate = 0 For PK observation rows,
Rate = -2 for dosing records
MDV
NONMEM Missing 
data value
Intege
r
None
Never
MDV=1 for dosing records
MDV=0 for CONC >0
MDV=1 for CONC=”.”
OCC
Occasion
Intege
r
None
Never
e.g. OCC=1 for Week 12
OCC=2 for Week 24
OCC=3 for Week 52
OCC=4 for Early Withdrawal
POPTEXT
Subject population 
text
Char
None
Never
POPTEXT=“ASTHMA”
AGE
Subject Age
Num
Specif
y
-99
From source data.
SEX
Subject gender 
Intege
r
None
Never
0=Male, 1=Female
SEXTEXT
Subject gender text
Char
None
Never
Text corresponding to code for 
SEX
BMI
Baseline Body 
Mass Index
Num
Specif
y
-99
From source data.
Formula: 
Weight(kg)/(height(m)**2)
WT
Baseline Subject 
weight
Num
Specif
y
-99
From source data.
HT
Baseline Subject 
height
Num
Specif
y
-99
From source data.
 
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Variable
Label (Variable 
description)
Type
Units
Missing 
value
Codes/Derivation/Notes
RACE
Subject race code1
Intege
r
None
-99
From source data e.g.
1=African American / African 
Heritage
2=American Indian or Alaska 
Native
3=Asian – Central / South Asian 
Heritage
4=Asian – East Asian Heritage
5=Asian – Japanese Heritage
6=Asian – South East Asian 
Heritage
7=Asian – Mixed Race
8=Native Hawaiian or other Pacific 
Islander
9=White – Arabic / North African 
Heritage
10=White – White / Caucasian / 
European Heritage
11=White – Mixed Race
12=Mixed Race
RACETXT
Subject race text
Char
None
Never
Text corresponding to code for 
RACE
ETHN
Subject ethnicity
Num
None
-99
From source data definition. 
E.g. 1=Hispanic or Latino, 2=Non-
Hispanic
ETHNTEXT
Subject ethnicity 
text
Char
None
Never
Text corresponding to code for 
ETHN.
REGN
Region for subject
Num
None
-99
1 = Japan (All subjects recruited 
from study centres in Japan)
2 = Korea (All subjects recruited 
from study centres in South 
Korea)
3 = Rest of the World (to include 
all other countries)
SMOK
Subject smoking 
status
Intege
r
None
Never
0=Non-smoker, 1=Smoker, 
2=Former smoker
SMOKTEXT
Subject smoking 
status text
Char
None
Never
Text corresponding to code for 
SMOK
FEV1
FEV1 at baseline
Num
None
Never
As in the source dataset
FVC
FVC at baseline
Num
None
Never
As in the source dataset
FEV1FVC
Ratio of FEV1 and 
FVC at baseline
Num
None
Never
As in the source dataset
0=>=0.7 (70%); 1=<0.7 (70%)
CRCL
Baseline Creatinine 
Clearance 
Num
mL/mi
n
-99
From source data.
formula e.g.
Creatinine Clearance will be 
calculated based on the Cockcroft-
Gault equation.

CrCL (ml/min) = [140 –
AGE (in 
 
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Variable
Label (Variable 
description)
Type
Units
Missing 
value
Codes/Derivation/Notes
years)]*Weight(kg)*0.85 
(for female patients) / 
[72* Serum Creatinine 
(micromol/L) * 0.0113]
ALT
Alanine 
aminotransferase 
Num
-99
Baseline defined in the source 
dataset
AST
Aspartate 
aminotransferase
Num
-99
Baseline defined in the source 
dataset
ALB
Albumin
Num
-99
Baseline defined in the source 
dataset
TBIL
Total bilirubin
Num
-99
Baseline defined in the source 
dataset
SCR
Serum Creatinine
Num
micro
mol/L
-99
Baseline defined in the source 
dataset
PKSUB
PK substudy 
indicator
Intege
r
1 – if subject is in PK subset 
(same for all rows for the subject)
0 – if subject is not in PK subset
ERRCONT
Incorrect container 
indicator
Intege
r
1 – if subject received an incorrect 
container and any of the PK 
sampling or dosing dates/times 
are between the treatment start 
and end date (inclusive) of the 
incorrect container (flag only those 
specific PK records)
0 – otherwise
EXCREC
Exception record
Char
None
Blank
Flag for records for which the 
date/time and other information 
was obtained from the PK 
Exceptions Document, via data 
management. 
These records were not entered 
into the CRF database and 
correspond to samples that may 
have been taken in error or at an 
incorrect visit.
 
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10.
REFERENCES
Asthma Control Questionnaire, Background, Administration and Analysis, May, 2012.  
Asthma Quality of Life Questionnaires (AQLQ, AQLQ(S), MiniAQLQ and Acute 
AQLQ), Background, Administration and Analysis, May, 2012.
Atkinson, AC. (1985) Plots, Transformations and Regression. Clarendon Press.
Carpenter JR, Roger JH, Kenward MG. Analysis of longitudinal trials with protocol 
deviation: a framework for relevant, accessible assumptions, and inference via multiple 
Imputation. Journal of Biopharmaceutical Statistics 2013,23:1352-1371
E-RS (Evaluating Respiratory Symptoms (E-RSTM) in COPD (E-RSTM: COPD) User 
Manual, Version 5.0. March, 2016.
GlaxoSmithKline Document Number 2016N271022_01 Study 205715, a Phase III, 
randomized, double-blind, active controlled, parallel group study, comparing the efficacy, 
safety and tolerability of the fixed dose combination FF/UMEC/VI with the fixed dose 
dual combination of FF/VI, administered once-daily via a dry powder inhaler in subjects 
with inadequately controlled asthma. Effective Date: 09-Jun-2016
GlaxoSmithKline Document Number 2016N271022_02 Study 205715, a Phase III, 
randomized, double-blind, active controlled, parallel group study, comparing the efficacy, 
safety and tolerability of the fixed dose combination FF/UMEC/VI with the fixed dose 
dual combination of FF/VI, administered once-daily via a dry powder inhaler in subjects 
with inadequately controlled asthma. Effective Date: 13-Dec-2016
GlaxoSmithKline Document Number 2016N271022_03 Study 205715, a Phase III, 
randomized, double-blind, active controlled, parallel group study, comparing the efficacy, 
safety and tolerability of the fixed dose combination FF/UMEC/VI with the fixed dose 
dual combination of FF/VI, administered once-daily via a dry powder inhaler in subjects 
with inadequately controlled asthma. Effective Date: 23-Jun-2017
GlaxoSmithKline Document Number 2016N271022_04 Study 205715, a Phase III, 
randomized, double-blind, active controlled, parallel group study, comparing the efficacy, 
safety and tolerability of the fixed dose combination FF/UMEC/VI with the fixed dose 
dual combination of FF/VI, administered once-daily via a dry powder inhaler in subjects 
with inadequately controlled asthma. Effective Date: 29-Sep-2017
GlaxoSmithKline Document Number 2016N271022_05 Study 205715, a Phase III, 
randomized, double-blind, active controlled, parallel group study, comparing the efficacy, 
safety and tolerability of the fixed dose combination FF/UMEC/VI with the fixed dose 
dual combination of FF/VI, administered once-daily via a dry powder inhaler in subjects 
with inadequately controlled asthma. Effective Date: 05-Dec-2017
Keene ON, Roger JH, Hartley BF, Kenward MG. Missing data sensitivity analysis for 
recurrent event data using controlled imputation. Pharmaceutical Statistics. 2014;13:258-
264. 
 
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Mallinckrodt, CH, Lin Q, Lipkovich I, and Molenberghsb G. A structured approach to 
choosing estimands and estimators in longitudinal clinical trial, Pharmaceut. Statist. 
2012, 11 456–461
Quanjer PH, Stanojevic S, Cole TJ, Baur X, L Hall GL, Culver B, Enright PL, Hankinson 
JL, Zheng J, Stocks J and the ERS Global Lung Function Initiative. Multi-ethnic 
reference values for spirometry for the 3-95 year age range: the global lung function 2012 
equations. Report of the Global Lung Function Initiatives, ERS Task Force to establish 
improved Lung Function Reference Values, Supplement Eur Repir J vol 39, 2012.
Rubin DB. Multiple Imputation for Nonresponse in Surveys. Wiley: New York, 1987.
St George’s Respiratory Questionnaire Manual, Version 2.3, June, 2009
 
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11.
APPENDICES
11.1.
Appendix 1: Protocol Deviation Management 
Protocol deviations (PDs) will be tracked by the study team throughout the conduct of the 
study in accordance with the Protocol Deviation Management Plan.
-
Data will be reviewed by source data lock to ensure all important deviations are 
captured and categorised on the protocol deviations dataset (except for the PD of 
taking incorrect treatment). 
-
Participants who received an incorrect container will be captured as an important 
protocol deviation. The actual treatment in the incorrect container will be 
identified and quality controlled by S&P either as incorrect treatment or 
unplanned treatment per randomization schedule prior to DBF.
-
This dataset will be the basis for the summaries and listings of protocol 
deviations.
No per-protocol analysis is planned for this study.
 
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11.2.
Appendix 2: Protocol Defined Schedule of Events
11.2.1.
Time and Events Table
Protocol Activity
Pre-
Screen1
Screen
Run-in
Enrolment
Stabilization
Treatment Period
Follow-up
Fixed Treatment Period
Variable Treatment Period
Visit
0
11
22
33
Random-
ization
4
5
6
7
8
End of Study 
(EOS)
Early 
Withdrawal 
(EW)4
Safety
Follow-up 
Contact
Study Day
-49 to -36
-35
-14
1
29
85
169
253
365
Week
-6 to -7
-5
-2
0
4
12
24
36
52
1 week after Visit 
8/EOS or EW 
Visit
Window
-3/+5d4
-5/+2d
-5/+2d
-5/+2d
-5/+2d
-5/+2d
-1/+4d
Written Informed 
Consent5
x
Genetic Informed 
Consent6
x
Demography
x
Medical history
x
Asthma History7
x
Exacerbation History
x
Concomitant 
Medication 
Assessment
x
x
x
x
x
X
x
x
x
x
x
Inclusion/Exclusion 
criteria
x
x
Smoking History and 
status
x
Randomization8
x
Register visit in IRT 
(RAMOS NG)9
x
x
x
x
x
X
x
x
x
x
x
Efficacy 
Assessments
Global Assessment of 
Severity10
x
x
X
x
x
x
x
 
 
 
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Protocol Activity
Pre-
Screen1
Screen
Run-in
Enrolment
Stabilization
Treatment Period
Follow-up
Fixed Treatment Period
Variable Treatment Period
Visit
0
11
22
33
Random-
ization
4
5
6
7
8
End of Study 
(EOS)
Early 
Withdrawal 
(EW)4
Safety
Follow-up 
Contact
Study Day
-49 to -36
-35
-14
1
29
85
169
253
365
Week
-6 to -7
-5
-2
0
4
12
24
36
52
1 week after Visit 
8/EOS or EW 
Visit
Window
-3/+5d4
-5/+2d
-5/+2d
-5/+2d
-5/+2d
-5/+2d
-1/+4d
Global Assessment of 
Response to 
Treatment10
x
X
x
x
x
x
ACQ10
x
x
x
x
X
x
x
x
x
SGRQ10
x
X
x
x
x
x
AQLQ10
x
x
X
x
x
x
x
Healthcare Resource 
Utilization10
x
x
X
x
x
x
x
E-RS + asthma 
symptoms + PEF + 
home FEV110, 11
X
eDiary/device training 
and registration
x
Dispense eDiary
x
Collect eDiary
x
x
eDiary review
x
x
x
X
x
x
x
x
Dispense paper 
Medical 
Problems/Medications 
Taken worksheet
x
x
x
x
x
X
x
x
x
x
 
 
 
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Protocol Activity
Pre-
Screen1
Screen
Run-in
Enrolment
Stabilization
Treatment Period
Follow-up
Fixed Treatment Period
Variable Treatment Period
Visit
0
11
22
33
Random-
ization
4
5
6
7
8
End of Study 
(EOS)
Early 
Withdrawal 
(EW)4
Safety
Follow-up 
Contact
Study Day
-49 to -36
-35
-14
1
29
85
169
253
365
Week
-6 to -7
-5
-2
0
4
12
24
36
52
1 week after Visit 
8/EOS or EW 
Visit
Window
-3/+5d4
-5/+2d
-5/+2d
-5/+2d
-5/+2d
-5/+2d
-1/+4d
Review paper Medical 
Problems/Medications 
Taken worksheet
x
x
x
x
X
x
x
x
x
x
Pre-dose spirometry 
(clinic)
x12
x12
x13
x12
x12
x13
x12
x13
x13, 14
Post-dose spirometry 
(clinic)
x13
x13
x13
x13, 14
Reversibility test
x15
x16
Exacerbation 
assessment
x
x
x
X
x
x
x
x
x
Health Outcomes
WPAI-SHP10
x
X
x
x
x
Safety Assessments
Physical Examination
x
x
x
x
Vital Signs
x17
x
x
x
X
x
x
x
x
ECG18
x
x
x
x
x
Adverse Events
x
x
x
x
x
x
x
x
x
 
 
 
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Protocol Activity
Pre-
Screen1
Screen
Run-in
Enrolment
Stabilization
Treatment Period
Follow-up
Fixed Treatment Period
Variable Treatment Period
Visit
0
11
22
33
Random-
ization
4
5
6
7
8
End of Study 
(EOS)
Early 
Withdrawal 
(EW)4
Safety
Follow-up 
Contact
Study Day
-49 to -36
-35
-14
1
29
85
169
253
365
Week
-6 to -7
-5
-2
0
4
12
24
36
52
1 week after Visit 
8/EOS or EW 
Visit
Window
-3/+5d4
-5/+2d
-5/+2d
-5/+2d
-5/+2d
-5/+2d
-1/+4d
Serious Adverse 
Events
X
x
x
x
x
x
x
x
x
x
x
FeNO19
x
Laboratory 
Assessments
Hematology and 
clinical chemistry
x
x
x
x
x
Total Serum IgE
x
Urinalysis
x
x
x
x
x
Pharmacogenetic 
sample20
x
Serum pregnancy test
x21
x21
x21
x21
Urine pregnancy 
test21
x
x
x
x
x
PK samples
x22
x23
x23, 24
x23
Study Treatment
Dispense ICS/LABA 
run-in medication
x25
 
 
 
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Protocol Activity
Pre-
Screen1
Screen
Run-in
Enrolment
Stabilization
Treatment Period
Follow-up
Fixed Treatment Period
Variable Treatment Period
Visit
0
11
22
33
Random-
ization
4
5
6
7
8
End of Study 
(EOS)
Early 
Withdrawal 
(EW)4
Safety
Follow-up 
Contact
Study Day
-49 to -36
-35
-14
1
29
85
169
253
365
Week
-6 to -7
-5
-2
0
4
12
24
36
52
1 week after Visit 
8/EOS or EW 
Visit
Window
-3/+5d4
-5/+2d
-5/+2d
-5/+2d
-5/+2d
-5/+2d
-1/+4d
Assess run-in 
medication 
compliance
x
Collect ICS/LABA 
run-in medication
x
Dispense ICS/LABA 
stabilization 
medication
x
Assess stabilization 
medication 
compliance
x
Collect ICS/LABA 
stabilization 
medication
x
Administer double-
blind study 
treatment26
x
x
x
x
x
x
x27
Dispense double-
blind study treatment 
(Scheduled)
x
x
x
x
x
Dispense double-
blind study treatment 
(Unscheduled)
x28
Assess double-blind 
study treatment 
compliance
x
x
x
x
x
x
 
 
 
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Protocol Activity
Pre-
Screen1
Screen
Run-in
Enrolment
Stabilization
Treatment Period
Follow-up
Fixed Treatment Period
Variable Treatment Period
Visit
0
11
22
33
Random-
ization
4
5
6
7
8
End of Study 
(EOS)
Early 
Withdrawal 
(EW)4
Safety
Follow-up 
Contact
Study Day
-49 to -36
-35
-14
1
29
85
169
253
365
Week
-6 to -7
-5
-2
0
4
12
24
36
52
1 week after Visit 
8/EOS or EW 
Visit
Window
-3/+5d4
-5/+2d
-5/+2d
-5/+2d
-5/+2d
-5/+2d
-1/+4d
Collect double-blind 
study treatment
(Scheduled)
x
x
x
x
x
x
Collect double-blind 
study treatment
(Unscheduled)
x29
Dispense 
albuterol/salbutamol, 
as required
x
x
x
x
x
x
x
Collect 
albuterol/salbutamol, 
as required
x
x
x
x
x
x
x
x
Dispense FP, as 
required30
x
x
x
x
x
x
x
Collect FP, as 
required
x
x
x
x
x
x
x
x
Notes:
1.
Visit 1 must be completed 1 day but 14 days after Visit 0; however, if it is local and routine medical practice to request that a participant withhold their ICS at least 24 hours prior 
to a clinic visit then, provided that the participant has complied with the request, Visit 0 and Visit 1 can occur on the same day.
2.
Visit 2 may be conducted up to 3 days before the scheduled date of Visit 2. The duration of the run-in period (i.e. the time period between Visits 1 and 2) must be 18 days but 
≤26 days.
3.
Visit 3 must always be conducted 14 days but 17 days after Visit 2.
4.
EW Visit should be conducted if double-blind study treatment is discontinued AND the participant discontinues from participating in the study.
5.
The ICF must be signed before any study procedures, including medication cessation.
 
 
 
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6.
Genetics research consent may be obtained at the same time as the study IC and must be obtained prior to obtaining a genetic blood sample.
7.
The assessment of asthma history will include: the age of the participant when they were first provided with an inhaler for asthma; completion of an asthma medical history 
questionnaire (a copy of this questionnaire and instructions for its use can be found in the SRM).
8.
Participants must not be randomized prior to confirming their eligibility to participate in the study.
9.
The IRT will be used for randomization, emergency unblinding and study treatment supply management (Please refer to the RAMOS NG IRT manual and SRM for more 
information).
10. Assessment(s) to be completed prior to the administration of study treatment.
11. To be completed using the provided combined spirometer/eDiary device. Assessments should be completed in the morning upon wakening and in the evening immediately prior to 
going to bed.
12. Spirometry to be performed between 6am and 11am after withholding rescue medication for at least 6 hours and prior to taking the morning dose of study treatment. Pre-dose 
spirometry assessments should be performed at the same time of day at each applicable visit.
13. Pre-dose spirometry to be performed between 6am and 11am, prior to taking the morning dose of study treatment. Post-dose spirometry is to be performed 3 hours (± 15 minutes) 
after taking the morning dose of study treatment. Rescue medication should be withheld for at least 6 hours prior to the pre-dose spirometry assessments until after completion of 
the 3-hour post-dose spirometry assessments. Pre- and post-dose spirometry assessments should be performed at the same time of day at each applicable visit.
14. In the event that double-blind study treatment is not administered at this visit, spirometry assessments should be performed at the same time of day as the pre- and post-dose 
spirometry assessments at the preceding on-treatment clinic visits.
15. Following completion of the pre-dose spirometry assessments, the reversibility test will be conducted between 20 and 60 minutes following 4 inhalations of albuterol/salbutamol 
aerosol. If airway reversibility is not demonstrated at Visit 1 then the assessment may be repeated within 7 days of Visit 1 (see Section 7.3.4.1.1. of the protocol for details of the 
criteria to be met before a repeat of the reversibility assessment is permitted). If airway reversibility is successfully demonstrated at the second attempt and all other eligibility 
criteria assessed at Visit 1 are met then the participant may enter the 3-week run-in period (starting on the date that airway reversibility was successfully demonstrated at the 
second attempt).
16. Following completion of the pre-dose spirometry assessments, the reversibility test will be conducted between 60 and 90 minutes following 4 inhalations of ipratropium aerosol 
(see Section 7.3.4.1 of the protocol)
17. The vital signs assessment will include the measurement of height and weight at this visit only.
18. At the Screening Visit (Visit 1), the ECG is to be obtained after the vital signs assessment but prior to performing the pre-bronchodilator spirometry assessment (see Section 7.5.6 
of the protocol). At all post-randomization visits the ECG is to be obtained 15 minutes to 45 minutes after the administration of study treatment.
19. Exhaled Nitric Oxide is widely accepted as a non-invasive marker for airway inflammation and will be assessed to characterise the study participant population. Details on 
performing the FeNO assessment, including information on the equipment provided and its use, are documented in the SRM and the third-party vendor manual.
20. Pharmacogenetic sample may be drawn any time from Visit 3 onwards.
21. Assessments only to be conducted in females of reproductive potential.
22. Pharmacokinetic (PK) subset: In a subset of approximately 20% of all randomized participants, PK samples will be obtained at pre-dose on the visit day, and 1 sample in each of 
the following three time windows: 5min-30min, 45min-90min, and 2-3h post-dose on the visit day. NOTE: the date and time of study treatment administration on the day prior to 
the visit must be recorded in the eCRF. See Appendix 7 of the protocol for country-specific requirements.
23. PK sample to be obtained at pre-dose on the visit day (This PK sample is to be obtained from ALL study participants). NOTE: the date and time of study treatment administration 
on the day prior to the visit must be recorded in the eCRF.
24. PK sample to be obtained at this visit ONLY in the event that Visit 8/EOS assessments are conducted at Week 24.
 
 
 
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25. In the event that the reversibility assessment needs to be repeated within 7 days of Visit 1 (see Section 7.3.4.1.1 of the protocol) then the medication for the 3-week run-in period 
must not be dispensed until airway reversibility is successfully demonstrated at the second attempt and all other eligibility criteria assessed at Visit 1 are confirmed as met.
26. Study treatment should be administered at the same time of day at each applicable clinic visit.
27. The administration of study treatment at this visit is optional. If study treatment is not administered at this visit then those assessments which are scheduled based on the time of 
study treatment administration should be performed at approximately the same time of day as performed at the preceding post-randomization visits
28. Between scheduled visits, unscheduled visits to the study clinic to re-supply the participant with double-blind study treatment is permitted after Visit 3 but before Visit 8/EOS. The 
IRT will be used for study treatment supply management (Please refer to the RAMOS NG IRT manual and SRM for more information).
29. In the event that the participant attends the study clinic for the unscheduled dispensing of double-blind study treatment, previously dispensed study treatment should be collected 
for drug accountability purposes.
30. FP may be used temporarily to treat the symptoms of a moderate asthma exacerbation, at the Investigator’s discretion. However, please note that a participant’s use of the 
provided FP prior to randomization at Visit 3 would meet the enrolment or randomization concomitant medication exclusion criteria (see Section 5.3.2 and Section 5.4.2 of the 
protocol)
 
 
 
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11.3.
Appendix 3: Assessment Windows
11.3.1.
General
In general, data will be reported according to the nominal time of clinic visits and 
assessments as specified in the protocol. For example, if a participant had recorded values 
for the Week 4 visit on the 22nd day of treatment, the data will be presented as Week 4 
values in the summary tables.
The post-randomization clinic data collected at EW/ End of Study (EOS) visits in the 
eCRF and SDTM data will be mapped based on study day as follows:
Study days
Target date 
for visit
Visit/Week
15 to 56
29
Visit 4/ Week 4
57 to 126
85
Visit5/ Week 12
127 to 210
169
Visit 6/Week 24
211 to 308
253
Visit 7/Week 36
>=309
365
Visit 8/ Week 52
If a participant has an EW visit on or before day 14 then the data collected at this study 
visit will be listed but excluded from visit-based summaries, figures and analyses. 
Note: 
- For SGRQ, WPAI-SHP, laboratory and PK endpoints there is no planned assessment at 
week 4 and so data that slots to week 4 will be excluded from summaries and analyses.
- For ECG there is no planned assessment at week 12, and so data that slots to week 12 
will be excluded from summaries and analyses.
- For FEV1 3 hrs post study treatment there are no planned assessments at weeks 4 and 
12, and so data that slots to weeks 4 and 12 will be excluded from summaries and 
analyses.
Multiple assessments slotting to the same visit
If there is more than one non-missing value within an assessment window for a given 
analysis or summary, the measure from the scheduled visit will take priority.
All data will be listed.  
 
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11.3.2.
Variable Duration
The duration of the treatment period is variable but will be a minimum of 24 weeks and a 
maximum of 52 weeks. 
For participants with an EOS visit, the visit will be mapped to the windows as specified 
in Section 11.3.1.  
For participants who are lost to follow up or withdraw from the study early, then their 
planned EOS visit will be:
-
if randomized date is on or after the 27th August 2017 then a participant’s
planned EOS visit is week 24. 
-
if randomized date is on or between the 7th May 2017 and the 26th August 
2017 then a participant’s planned EOS visit is week 36
-
if randomization date is on or prior to the 6th May 2017 then a participant’s 
planned EOS is week 52
If a participant has a EW visit past their planned EOS visit as defined above, then their 
planned EOS date become the next scheduled clinic visit (i.e. if a participant has a 
planned EOS visit of week 24 with an EW visit at week 28, then their planned EOS visit 
will become week 36). Similarly, if a participant is reported as lost to follow up after 
attending their planned EOS visit, then their planned EOS visit will become the next 
scheduled clinic visit. Thus,

If a participant has a planned EOS visit of week 24, attends this visit and then is 
subsequently lost to follow up (for example, at week 28 based on study 
conclusion date), then their planned EOS visit will become week 36).

If a participant has a planned EOS visit of week 24, does not attend this visit, and 
is lost to follow up at a later time point (for example, week 25 based on study 
conclusion date), then their planned EOS visit will remain as week 24.
The study completion date will be set at 181 days (i.e. 25 weeks and 6 days) post the final 
participant’s randomization date. 
 
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11.4.
Appendix 4: Study Phases 
Study phases for assessments scheduled at a set time will be defined in accordance with 
the planned relative time of the assessment. 
Any events/assessments for participants not in the ITT population will be assigned a Pre-
treatment phase.
For all events and assessments, the study phases will be defined as follows:
Study Phase
Definition
Screening/Run-
In period
Visit 1 date ≤ Event Onset Date or Assessment Date/Time < Visit 2 date or date of 
first dose of Stabilization treatment, whichever is later
Stabilization 
period
Date of first dose of Stabilization treatment ≤ Event Onset Date or Assessment 
Date/Time < Randomized treatment start date.
Note: if baseline assessment and done on treatment start date then assumed to be 
done prior to treatment start. 
On-Treatment 
Randomized treatment start date ≤ Event Onset Date or Assessment Date/Time ≤ 
Study Treatment Stop Date +1 or any assessment with a missing or partial 
date unless there is evidence it was not on-treatment
Post-Treatment 
1
Randomized Treatment Stop Date +1 < Event Onset Date or Assessment 
Date/Time ≤ Last Scheduled Clinic Visit (i.e., Visit 8 [EOS Visit] or Early 
Withdrawal Visit [EW])2
Note: if any participant does not receive a dose of randomized treatment then all 
post-baseline data prior to EW or EOS visit is considered as post-treatment.
Post-Study
Event Onset Date > Last Scheduled Clinic Visit (i.e., Visit 8 (EOS Visit) or Early 
Withdrawal Visit)2 +1 day
Note, for participants who continue in the study after IP discontinuation (i.e. where 
treatment discontinuation date < Visit 8 (EOS visit) date or EW visit date), the rule 
will be:
Event Onset Date > Last Scheduled Clinic Visit (i.e. Visit 8 (EOS Visit) or EW 
Visit)2
1: Applicable only for participants who continue in the study after IP discontinuation. 
2 If a subject is lost to follow up and does not have an EoS or EW visit, their study conclusion date will 
be used if available. If no study conclusion date is available, the last contact date will be used.
Classification of a concomitant medication into study phase (at study entry, 
screening/run-in period, stabilization period, on-treatment, post-treatment, or post-study) 
will be made with reference to the study phase as defined above.  A medication will be 
classified into every period in which it was taken.  For medications with partial start and 
stop dates, the medication will be classified into every period in which it could have been 
taken.
 
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11.5.
Appendix 5: Data Display Standards & Handling 
Conventions
11.5.1.
Reporting Process
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
: UK1SALX00175
HARP Area
: /arenv/arprod/gsk2834425/mid205715/final
QC Spreadsheet
: /arenv/arwork/gsk2834425/mid205715/final/documents
Analysis Datasets 

Analysis datasets will be created according to CDISC standards (SDTM Implementation Guide 
Version 3.1.3 or higher & ADaM Implementation Guide Version 1.0 or higher.

For creation of ADaM datasets (ADCM/ADAE), the same version of dictionary datasets will be 
implemented for conversion from SI to SDTM.
Generation of RTF Files

Rich Text Format (RTF) files will be generated for the final reporting efforts to be used for the 
CSR writing.
11.5.2.
Reporting Standards
Reporting Standards
General

Displays will use the term “Subjects” to refer to “Participants”.

The current GSK Pooled Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated:

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 
Formats

All data (including data collected following study treatment discontinuation [post-treatment]) will 
be reported according to the treatment to which the participant was randomized unless 
otherwise stated.  However, there may be additional adhoc displays for individual participants 
using the actual treatment received.

The reported precision of data will follow IDSL statistical principles but may be adjusted to a 
clinically interpretable number of decimal places.

In most cases, percentages between 1% and 99%, inclusive, will be rounded to integers. 
Percentages greater than 0%, but less than 1%, will be reported as <1%, and percentages 
greater than 99%, but less than 100%, will be reported as >99%. For some rare events, 
percentages may be reported in 1 decimal point. In this case, percentages greater than 0%, 
 
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Reporting Standards
but less than 0.1%, will be reported as <0.1%.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but 
may be adjusted to a clinically interpretable number of decimal places.
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

If an assessment is reported for a scheduled visit regardless of assessment date/time 
relative to protocol T&E, the data will be used for that visit.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to 
IDSL Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the participant’s listings. 
Unscheduled Visits

Unscheduled visits will not be included in summary tables except as part of a ‘worst case post-
baseline’ assessment.

All unscheduled visits will be included in listings.

Unscheduled visits may be used for baseline where specified in Section 5.2.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.
 
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11.6.
Appendix 6: Derived and Transformed Data
11.6.1.
General
Study Day

Calculated as the number of days from randomization date:

Reference Date = Missing → Study Day = Missing 

Reference Date < Treatment Start Date →Study Day = Reference Date – Treatment 
Start Date    

Reference Date ≥ Treatment Start Date →Study Day = Reference Date – Treatment 
Start + 1    
Treatment Period Completion/Withdrawal and Study Completion/Withdrawal

A participant is considered to have completed the treatment period if the answer to the 
question “Was the study treatment stopped permanently before the scheduled end of the 
treatment period?” on the Study Treatment Discontinuation eCRF page is “No”.  Date of 
completion of treatment period will be the treatment stop date.

A participant is considered to have completed the study if the answer to the question “Was 
the participant withdrawn from the study?” on the Study Conclusion eCRF page is “No”.   
Otherwise, if the answer is “Yes” then the participant is considered to have withdrawn early 
from study.  The date of study completion/withdrawal as entered on the eCRF will be used 
as the study completion/withdrawal date.

If a participant prematurely discontinues IP, according to the CRF instructions participants 
should be reported as continuing in the study if they attend either normal visits, or the safety 
follow-up visit after the early withdrawal visit (DSCONT=’Y’). To identify participants who are 
continuing in the study per the normal visit schedule and providing post-treatment data, the 
following will be implemented:
o
If a participant prematurely discontinues IP and study at the same time, they are not 
considered to be continuing in the study (i.e. DSCONT will be “N”).
o
If a participant prematurely discontinues IP and only has an EW visit and a safety 
follow up visit on or after the date of IP discontinuation they are not considered to be 
continuing in the study (DSCONT will be “Y”). Note, if a participant initially continues in 
the study following IP discontinuation but then discontinues study prior to the next 
scheduled clinic visit they will be considered as not continuing in the study as they will 
not be providing post-treatment data.
o
If a participant prematurely discontinues IP and has a scheduled visit (not EW or safety 
follow-up visit) on or after the date of IP discontinuation then the participant is 
continuing in the study (DSCONT will be “Y”).
 
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Planned and Actual Randomized Treatment
For participants who received the correct treatment throughout the study, the actual treatment 
will be the same as the planned treatment. For participants who received an incorrect treatment, 
the actual treatment will be derived as follows:

If the number of doses on an incorrect treatment is less than the number of doses on 
the planned treatment, then the actual treatment is assigned as planned treatment.

If the number of doses on an incorrect treatment is greater than the number of doses 
on the planned treatment, then the actual treatment is assigned as the incorrect 
treatment.

If the number of doses on an incorrect treatment and planned treatment are the same, 
the actual treatment is assigned as the treatment with the highest UMEC and/or FF 
dose.

If an incorrect container was dispensed and not returned, such that it is not possible to 
ascertain whether or not any doses were taken from the incorrect container, it will be 
assumed that the participant took all possible doses from this container (i.e., 30 doses 
in total).
Participants excluded from ITT population

A participant who is recorded as a screen failure, run-in failure, or stabilization failure, 
but is randomized and does not receive a dose of study treatment, is considered to be 
randomized in error and will be excluded from the ITT population

These participants will be identified using the deviations dataset where the term 
“Randomized in Error:” is reported.
 
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11.6.2.
Study Population
Demographics
Age

Age will be calculated based on the Pre-Screening Visit date (or Screening, if pre-screening 
not performed).

Only year of birth is collected on eCRF. Day and Month of birth are imputed as 30 June. Age 
is derived using the date of the pre-screening visit. 

All participants with imputed age of 17 or 18 years will be source data verified, and presence 
/ absence of protocol deviation on the inclusion criteria #1 will be taken into consideration in 
the derivation for the analysis variable age. 

Birth date will be presented in listings as ‘YYYY’.
Age at onset

This will be derived as age at pre-screening visit (or screening, if pre-screening not 
performed)-disease duration.

If a participant has age of onset of <0 this will be queried by data management.

As we do not collect date of birth to the exact date negative values could occur. In these 
cases, the age of onset will be set to 0.
Body Mass Index (BMI)

Calculated as weight (kg) / [height (m)]2

BMI will be presented as for summary statistics with 1 decimal place. 
Clinic Spirometry Assessment

At Visit 1, if the spirometry assessment is repeated for a given participant to meet the 
eligibility criteria on the reversibility, the repeated spirometry data will be used for that visit.
Cardiovascular History and Risk Factor
Cardiovascular history and risk factors will be assessed at Visit 1. Participants with one or more 
of the following terms recorded as either current or past medical conditions at Visit 1 is 
considered to have cardiovascular history/risk factors: 

Cardiovascular history 
o
arrhythmia, 
o
congestive heart failure, 
o
coronary artery disease, 
o
myocardial infarction, 
o
cerebrovascular accidents, 

Cardiovascular risk factors 
o
hypertension, 
o
diabetes mellitus, 
o
hypercholesterolemia.  
Treatment Compliance  

If a dose counter start count is missing, then it will be assumed to be 30 for the ELLIPTA 
DPI. If any dose counter stop is missing, then the number of doses taken will be set to 
missing for that inhaler.

Number of doses of study drug taken by each participant from each inhaler = Dose 
 
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Demographics
counter start value – dose counter stop value.

The derivation for treatment compliance during the double-blind treatment period is 
defined as the sum of (dose counter start value – dose counter stop value) over all 
inhalers dispensed to the participant and returned during the double-blind treatment 
period (i.e. from randomization to EOS/EW visit) and percentage compliance will be 
calculated as follows:
Treatment compliance
=
Total number of doses received
X 100
Treatment stop date – treatment start date +1
If a participant is lost to follow up (without EOS/EW visit) then their treatment stop date 
will be handled in accordance to Section 11.7.2 and doses received will be calculated for 
inhalers dispensed and returned from randomization to treatment stop date. 

The derivation of the treatment compliance during the first 24 weeks is as follows:

For participants who withdraw from IP prior to week 24 or with End of Study visit 
at Week 24 is the same as the treatment compliance during the double-blind 
treatment period. 

For participants who continue the double-blind study treatment beyond Week 24 
is defined as the sum of (dose counter start value – dose counter stop value) 
over all inhalers dispensed to the participant prior to Visit 6 (Week 24) and 
returned by the participant on or before Visit 6 (Week 24) during the double-blind 
treatment period divided by the treatment duration covered by these inhalers, 
i.e., Week 24 clinic visit date – treatment start date Note: participants received 
first dose of the newly dispensed inhaler in clinic per protocol. 

Overall compliance will be categorized as follows:

< 50 %

≥50 % to < 80%

≥80 % to < 95 %

≥95 % to ≤105 %

>105 % to ≤120 %

>120 %.

If a participant receives a treatment other than the randomized treatment during the 
study, the compliance will still be calculated using data from all containers received and 
overall exposure start and stop dates.
Severe exacerbation in the previous year
The number of severe exacerbations in the previous year is defined as:
Number of exacerbations in the last 12 months that required oral/systemic corticosteroids (not involving 
hospitalisation) + Number of exacerbations in the last 12 months that required hospitalisation
 
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11.6.3.
Efficacy
Spirometry
Trough FEV1 and FVC

The trough value for FEV1 at Weeks 4, 12, 24, 36 and 52 visits is the value of the pre-dose 
(prior to taking the morning dose of study treatment) assessment. 
Post study treatment FEV1

The post study treatment value for FEV1 at Week 24 and at the End of Study visit is the 
assessment value approximately 3 hours after administering the study medication. 
Trough FEV1 over time
To evaluate the effect of UMEC over the first 24 weeks of the treatment period, the (weighted) 
mean trough FEV1 over the first 24 weeks of the treatment period will be calculated as the FEV1 
area under the curve (AUC0-24w) normalized for time. Specifically, FEV1 weighted mean AUC0-24w
will be calculated based on all non-missing data as area under the curve from day 1 to week 24 
using the linear trapezoidal rule divided by the observation time (24 weeks) to report in liter (L) 
units. If one or more observations are missing between two non-missing observations, the value(s) 
will be linearly interpolated between the two non-missing values. 
The weighted mean AUC0-24w will be calculated over the nominal assessment time per protocol as 
follows:
WM FEV1 AUC0-24w =  
w
t
t
t
FEV
t
FEV
i
i
i
i
i
24
)
(
*
))
(
)
(
(
2
1
3
0
1
1
1
1






Where, t0 = 0 (week), t1= 4 (week), t2=12 (week), and t3=24 (week); FEV1 (t0) = baseline trough 
FEV1, and for i>0, FEV1 (ti) = trough FEV1 reading at planned week ti.
If baseline, week 24 or any two timepoints are missing the AUC will not be calculated.
Asthma Exacerbations
General

Exacerbations will be presented based on onset date relative to the period being 
summarized. i.e. if the onset date occurs within the study period then it will be reported within 
that study period)
The following data will be included in the exacerbation analyses and summaries
Analysis
Time 
point
Data to be included (i.e. from participants first dose up to date/study 
day specified)
On- and post-
1-52 
-
Up to EOS/ EW/study conclusion date*/date of death
 
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Asthma Exacerbations
treatment
1-24 
-
If participants planned EOS visit is week 24: EOS/EW
visit/study conclusion date*/date of death
-
If participants planned EOS visit is later than week 24 use 
data up to the minimum of study day 169, EW, lost to follow 
up*, date of death.
25-
52
-
If participants planned EOS visit is later than week 24 and 
they have not withdrawn from the study before study day 
170, then data from day 170 to EW/EOS /study conclusion
date*/date of death will be included in the analysis.
-
Data from participants who have withdrawn from study 
before study day 170 or whose planned EOS visit was week 
24 will be excluded from these summaries. 
On- and post-
treatment 
sensitivity 
analysis
1-52
-
For participants with an EOS visit, all data up to the EOS visit 
will be included
-
For participants without an EOS visit, all data available plus 
imputed data up to the participants planned EOS visit will be 
included.
On-treatment
1-52 
-
If a participant does not withdraw from treatment prior to 
withdrawing from/completing the study (or being lost to follow 
up or dying) then up to last treatment date.
-
If a participant withdraws from treatment prior to 
withdrawing/completing the study (or being lost to follow up 
or dying) then up to last treatment date+1
1-24
-
If a participant’s planned EOS visit is week 24 and the 
participant does not withdraw from treatment prior to 
withdrawing from/completing the study (or being lost to follow 
up or dying): Last date of treatment
-
If a participant’s planned EOS visit is week 24 and the 
participant withdraws from treatment prior to withdrawing 
from/completing the study (or being lost to follow up or 
dying)): Last date of treatment +1
-
If a participant’s planned EOS is later than week 24 and 
participant does not withdraw from treatment prior to 
withdrawing from/completing the study (or being lost to follow 
up or dying): use the minimum of (169, Last treatment date)
-
If a participant’s planned EOS is later than week 24 and 
participant withdraws from treatment prior to withdrawing 
from/completing the study (or being lost to follow up or 
dying): use the minimum of (169, Last treatment date+1)
25-
52
-
If participants planned EOS visit is later than week 24 and 
they have not withdrawn from the treatment before study day 
170 then data from day 170 up to the following timepoint will 
be used:
o
If the participant does not withdraw from treatment 
 
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Asthma Exacerbations
prior to withdrawing from/completing the study (or 
being lost to follow up or dying): Last date of 
treatment
o
If the participant withdraws from treatment prior to 
withdrawing from/completing the study (or being lost 
to follow up or dying): Last date of treatment+1
-
Data from participants who have withdrawn from treatment 
before study day 170 or whose planned EOS visit was week 
24 will be excluded from these summaries.
*if no study conclusion date, then use last contact date.

Denominators will be based on the number of participants with data available for the period 
being summarized.

Exacerbations separated by less than 7 days will be treated as a continuation of the same 
exacerbation

The duration of an exacerbation will be calculated as exacerbation resolution date or date of 
death - exacerbation onset date + 1.
Time to First Exacerbation

On- and Post-Treatment Exacerbations: The time to first exacerbation will be calculated as 
exacerbation onset date of first exacerbation – date of start of treatment+1. Participants will 
be represented from their Day 1 date to the start date of their first exacerbation up to and 
including the end of study date/early withdrawal date day. Participants that have not 
experienced an exacerbation on or before the end of study date/early withdrawal/ lost to 
follow up study/ date of death day are censored at the end of study date/early withdrawal 
date /study conclusion date (or date of last contact if no study conclusion date)/ date of 
death.
Asthma Control Questionnaire (ACQ)
General
Scoring instructions can be found Asthma Control Questionnaire: Background, Administration and 
Analysis, May, 2012.
The ACQ consists of seven attributes of asthma control (denoted as ACQ-7), and is to be 
administrated on all scheduled clinic visits.  Six attributes (ACQ-6), to be self-completed by the 
participant in a 6-item questionnaire, enquire about the frequency and/or severity of symptoms over 
the previous week in the following sequential order on: nocturnal awakening, symptoms on waking 
in the morning, activity limitation, shortness of breath, wheeze, and rescue medication use. ACQ-5 
consists of the first five questions of ACQ, measuring asthma symptoms. The seventh attribute 
measures the lung function, which will be included via study visit spirometry assessment on pre-
bronchodilator FEV1 % predicted value using Quanjer equation [Quanjer 2012]. The score for 
ACQ-5, ACQ-6, or ACQ-7 is the mean of the 5, 6 or 7 items, respectively.  

All 7 items of ACQ have response on 0-6 ordinal scale (0=no impairment/limitation, 6=total 
impairment/ limitation). For each version of ACQ (5, 6, 7), the total score is calculated as the 
 
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Asthma Control Questionnaire (ACQ)
average of all non-missing item responses [Asthma Control Questionnaire, Background, 
Administration and Analysis, May, 2012]. 

Only one of the first five item responses are allowed to be missing in calculating the total 
scores for all versions of ACQ.

If the language of the ACQ conducted at a post-baseline visit is different to the language used 
at Day 1 baseline, all ACQ scores at that visit and all subsequent visits will be set to missing.

If the language of the ACQ changes during the run-in phase, stabilization phase and 
randomization, the change in these periods will only be calculated where the language 
remained consistent.

If the language of the ACQ is missing at any visit (including Baseline) and is the same at all 
remaining non-missing visits, the language at the missing visit will be assumed to be 
unchanged
ACQ control categories
ACQ total scores at each visit will be summarized by the following asthma control categories: 
a) well controlled, i.e., ACQ total score ≤ 0.75, 
b) partially controlled   i.e., 0.75 < ACQ total score <1.5, 
c)
inadequately controlled, i.e., ACQ total score ≥1.5. 
Shift from baseline at each visit in ACQ total score will also be summarized by the following 
categories: 
a) Improved (defined as from inadequately controlled at baseline to partially or well controlled 
at visit, or from partially controlled at baseline to well controlled at visit)
b) Unchanged (defined as same asthma control category at visit and baseline)
c)
Worsening (defined as from well controlled at baseline to partially or inadequately 
controlled at visit, or from partially controlled at baseline to inadequately controlled at visit)
Responder Status according to ACQ Total Score

A participant will be considered a responder according to ACQ total score if their ACQ total 
score has decreased at least 0.5 units from the baseline ACQ total score.

A participant will be considered a non-responder if their ACQ total score has decreased by 
less than 0.5 units, has not changed, or has increased compared to baseline.

Missing data will be handled as detailed in Section 11.7.2.
St. George’s Respiratory Questionnaire (SGRQ)
General

Details for how to score the SGRQ, including handling of missing data, are outlined in the 
 
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St. George’s Respiratory Questionnaire (SGRQ)
SGRQ manual (June, 2009).

Changes from baseline in domain and total score will be calculated.

If the language of the SGRQ conducted at a post-treatment visit is different to the language 
used at Day 1 baseline, all SGRQ scores at that visit and all subsequent visits will be set to 
missing.

If the language of the SGRQ is missing at any visit (including Baseline) and is the same at 
all remaining non-missing visits, the language at the missing visit will be assumed to be 
unchanged
Responder Status according to SGRQ Total Score

A participant will be considered a responder according to SGRQ total score if their SGRQ 
total score has decreased at least 4 units from the baseline SGRQ total score.

A participant will be considered a non-responder if their SGRQ total score has decreased by 
less than 4 units, has not changed, or has increased compared to baseline.

Missing data will be handled as detailed in Section 11.7.2.
Asthma Quality of Life Questionnaire (AQLQ)
General

Details for how to score the AQLQ, including handling of missing data, are outlined in the 
AQLQ manual (May, 2012).  

Changes from baseline in total score will be calculated.

If the language of the AQLQ conducted at a post-treatment visit is different to the language 
used at Day 1 baseline, all AQLQ scores at that visit and all subsequent visits will be set to 
missing.

If the language of the AQLQ is missing at any visit (including Baseline) and is the same at all 
remaining non-missing visits, the language at the missing visit will be assumed to be 
unchanged
Responder Status according to AQLQ Total Score

A participant will be considered a responder according to AQLQ total score if their AQLQ total 
score has increased at least 0.5 from the baseline AQLQ total score.

A participant will be considered a non-responder if their AQLQ total score has increased by 
less than 0.5 units, has not changed, or has decreased compared to baseline.

Missing data will be handled as detailed in Section 11.7.2.
 
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Calculation of Daily eDiary Endpoints
General

Efficacy endpoints based on diary assessments include E-RS total score and subscale 
scores (breathlessness, cough & sputum, chest symptoms), Home Daily AM (trough) and 
PM FEV1, AM and PM PEF, percentage of symptom-free days, percentage of rescue 
medication-free days, and daily rescue medication use. 

The detailed derivations for diary data are provide in Section 5.2 for baseline value and 
Section 5.3.2 for post-baseline values.  

If the language of the E-RS conducted post-randomization is different to the language 
used during the baseline period, all E-RS scores post-randomization will be set to 
missing.

The E-RS scoring instructions can be found in Appendix B of the User Manual [E-RS 
(Evaluating Respiratory Symptoms (E-RSTM) in COPD (E-RSTM: COPD) User Manual, 
Version 5.0. March, 2016].
Symptom-free days

For a given day, a participant has a symptom-free day if the responses to both the evening 
(measures symptoms during the day) and following morning’s (measures nocturnal symptoms 
from the previous night) assessments indicate no symptoms. 

A participant has a symptom-free day if the participant has no asthma symptoms AND the 
participant’s activities are not at all limited AND the participant has no nocturnal awakenings 
due to asthma symptoms, per diary data as in the table below:  
Assessment 
Time
Question
Outcome
Morning 
Did you wake up due to asthma symptoms 
(i.e. wheezing, coughing, shortness of 
breath, or chest tightness)?
No
Evening 
Please describe the severity of your 
asthma symptoms today (i.e. cough, 
wheeze, chest tightness, shortness of 
breath)
No 
asthma 
symptoms
How limited were you in your activities 
today because of your asthma
Not at all 
limited

If any of these outcomes is missing the symptom free day status will be set to missing

If there is more than one morning or evening assessment assigned to a study day, then all 
records need to concur that no symptoms occurred for it to be considered a symptom free day 

Percentage of symptom free days will be calculated as the (number of symptom free days/total 
 
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number of days with non-missing symptom free day status)*100 within a given reporting period.

If >50% of days within a reporting period have missing symptom free day status, the 
percentage of symptom free days will be considered missing for that period.
Rescue Medication free days

For a given day, a participant has a rescue medication-free day if the responses to both the 
evening (measures rescue medication use during the day) and following morning’s (measures 
rescue medication use during the previous night) assessments indicate no use of rescue 
medication. 

If either the evening and following morning’s assessment is missing then the days rescue 
medication use is set to missing. 

If there is more than one morning or evening assessment assigned to a study day, then all 
records need to concur that no rescue medication was taken for it to be considered a rescue 
medication free day 

Percentage of rescue medication free days will be calculated as the (number of rescue 
medication free days/total number of days with non-missing rescue medication free day 
status)*100 within a given reporting period.

If >50% of days within a reporting period have missing rescue medication free day status, the 
percentage of rescue medication free days will be considered missing for that period.
Number of puffs per day

For a given day, the number of puffs will be the sum of the evening number of puffs (measures 
rescue medication use during the day) and following morning’s number of puffs (measures 
rescue medication use during the previous night).

If a participant only has one of these assessments, then the number of puffs will be set to 
missing. 

If a participant has both an evening and a morning assessment and > 1 assessment at either of 
those timepoint, use the maximum value reported for the timepoint (i.e. number of 
puffs=max(morning) + max(evening))
Healthcare Resource Utilization
The total number of unscheduled asthma related healthcare resource utilization, including 
telephone contacts, specialist nurse visits, visits to a physician’s office, home visits (day and 
night time), outpatient visits, visits to urgent care, visits to the emergency department, and 
hospitalizations associated with the participant’s worsening of symptoms will be calculated. 
The following data will be included in the summaries
Analysis
Time point
Data to be included (i.e. from participants first dose up to 
date/study day specified)
On- and 
post-
treatment
1-24
-
If participants planned EOS visit is week 24: EOS/EW 
visit/study conclusion date*/date of death
-
If participants planned EOS visit is later than week 24 
use data up to the minimum of study day 169, EW
study conclusion date*, date of death.
1-52 
-
All health utilization data for participants with planned 
 
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with >=36 
planned 
exposure
EOS visit at Week 36 or Week 52.
*if no study conclusion date then use last contact date
11.6.4.
Safety
Extent of Exposure
Treatment Exposure During the Run-in and Stabilization Periods

Duration of exposure to FSC during the run-in period is calculated as: 

Run-in treatment stop date – Run-in treatment start date +1

Duration of exposure to FF/VI 100/25 during the stabilization period is calculated as: 

Stabilization treatment stop date – Stabilization treatment start date +1

Exposure during the run-in and stabilization phase will be summarized as continuous and 
using the following categories:
o
≥1 day, ≥1 weeks, ≥2 weeks, ≥3 weeks (Run-in period only)
In case of missing dates, no imputation will be performed. Exposure will be considered missing.
Randomized Treatment Exposure and Post-Treatment On-Study Duration 

Duration of treatment exposure to study treatment is calculated as: 

treatment stop date – treatment start date +1

Duration of Post-treatment time spent on study is calculated as: 
o
Last Scheduled Clinic Visit (i.e., Visit 8 (EOS Visit) or Early Withdrawal Visit) – (treatment stop 
date+1).
Randomized Treatment Exposure Categories

Treatment Exposure will be summarized as continuous, and using the following categories:
o
≥1 day, ≥4 weeks, ≥8 weeks, ≥12 weeks, ≥16 weeks, ≥20 weeks, ≥24 weeks, ≥28 
weeks, ≥32 weeks, ≥36 weeks, ≥40 weeks, ≥44 weeks, ≥48 weeks and ≥52 week, 24 
weeks (-5/+2 days), 36 weeks (-5/+2 days), 52 weeks (-5/+2 days)
o
24 weeks (-5/+2 days) will be based on Day 169. 36 weeks (-5/+2 days) will be based on 
Day 253. 52 weeks (-5/+2 days) will be based on Day 365.
o
Subjects whose planned End of Study visit is Week 36 or 52, are included if their 
Week 24 visit falls within the protocol permitted visit window and they are still on 
study treatment at this visit.
o
Subjects whose planned End of Study visit is Week 52, are included if their Week 36 
visit falls within the protocol permitted visit window and they are still on study 
treatment at this visit.
Post-treatment On-Study Duration

Post-treatment On-Study duration will be summarized as continuous and using the following 
categories:
o
Duration (Week): (0, 4], (4, 12], (12, 24], (24, 36], > 36 
 
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Adverse Events
Adverse Event Rate

Event rate per thousand person-years will be displayed on most On-Treatment AE data 
displays listed in Section 11.10.8. Event rate per thousand person-years will be calculated 
as the number of events x 1000 divided by the total participant exposure during the time-
period of interest. 
On-treatment adverse events by time in study
The following data/participants with data will be included in the AE summaries for specific time 
periods. Exposure for the time periods will also be calculated as defined below to allow the 
presentation of rates.
Time point
Data to be included
Up to 24 
weeks
-
If participants planned EOS visit is week 24: up to last treatment date
+1
-
If participants planned EOS visit is later than week 24 use data up to 
the minimum (169, last treatment date+1)
Up to 36 
weeks
-
If participants planned EOS visit is week 24: exclude from summary 
table
-
If participants planned EOS visit is week 36: up to last treatment date 
+1
-
If participants planned EOS visit is week 52 use data up to the 
minimum (253, last treatment date+1)
Up to 52 
weeks
-
If participants planned EOS visit is week 24: exclude from summary 
table
-
If participants planned EOS visit is week 36: exclude from summary 
table
-
If participants planned EOS visit is week 52 use data up to last 
treatment date+1
Maximum/Minimum Post-Baseline and Worst-Case Post-Baseline
Definition
Reporting Details
Maximum post-baseline
Maximum value over all on-treatment timepoints
Minimum post-baseline
(Assessments that do not have a 
lower limit = 0)
Minimum value over all on-treatment timepoints 
Worst case post-baseline
(ECG findings)
‘Abnormal’ if any on-treatment assessment is evaluated as 
‘Abnormal’
‘Unable to evaluate’ if all on-treatment assessments are 
‘Unable to evaluate’
‘Normal’ if any on-treatment assessment is evaluated as 
‘Normal’ and there are no on-treatment assessments 
evaluated as ‘Abnormal’
Note: Assessment of minimum/maximum/worst-case post-baseline will include on-treatment data from 
scheduled, unscheduled and study discontinuation visits (if applicable).
 
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Laboratory Parameters

Non-quantifiable laboratory results will be treated as missing in summary displays.  
However, the results will be listed as received (e.g. ‘<x’ or ‘>x’).

An ‘any visit post-baseline’ classification will be derived, in which participants will be counted 
in the ‘low’ and ‘high’ categories if they reported a low or high value at any scheduled or 
unscheduled on-treatment visit during the study. 

Change from baseline values will be classified relative to the normal range as ‘to low’, ‘to 
normal or no change’ or ‘to high’. Participants who do not change categories or move from 
out-of-range to normal will be classified as ‘to normal or no change’.

An ‘any visit post-baseline’ change classification will be derived, in which participants will be 
counted in the ‘to low’ and ‘to high’ categories if they reported a change from a ‘normal’ 
baseline to a value below or above the normal range (respectively) at any on-treatment 
scheduled or unscheduled visit during the study. Participants who did not report a change to 
a value outside the normal range at any visit after the start of study treatment will be counted 
in the ‘to normal or no change’ category. 
Multiple Measurements for Post-Baseline Visits for Safety

Participants having both high and low values relative to normal ranges at post-baseline on-
treatment visits for safety parameters will be counted in both the high and low categories of 
the “any visit post-baseline” row of related summary tables.
Urinanalysis
Potential Clinical Importance is defined as an increase in Protein or Occult Blood post-baseline 
relative to Baseline (Screening), or if microscopy is performed.
ECG
QTcF and QTcF change from baseline results will be reported in categories as below
ECG Parameter
Units
Ranges
Lower
Upper
Absolute
Absolute QTcF Interval
msec
0
≤ 450
> 450
≤ 480
> 480
≤ 500
> 500
≤ 530
> 530
Change from Baseline
Change from Baseline QTcF
msec
≤-60
>-60
≤-30
>-30
≤0
>0
≤ 30
> 30
≤60
> 60
 
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Pneumonia (AESI)
Pneumonia Event Rate

Pneumonia events will be events classified in the pneumonia AESI group (rather than events 
recorded on the Pneumonia Details eCRF page).

Pneumonia event rate will be calculated as the number of events x 1000 divided by the total 
participant exposure during the time period of interest.
Association of Chest X-Ray with Pneumonia Event

A chest X-ray is considered associated with pneumonia if it is performed within -7 to +14 
days of the date of onset of pneumonia. Pneumonia is considered to be supported by a 
chest X-ray if the finding of the associated X-ray is consistent with the diagnosis of 
pneumonia, as recorded on eCRF page for chest X-ray.
MACE
Broad MACE criteria
Narrow MACE criteria
Ischaemic heart disease SMQ:

Myocardial infarction SMQ 
(excluding fatalities)

Other ischemic heart disease SMQ 
(excluding fatalities)
Central nervous system haemorrhages and 
cerebrovascular conditions SMQ (excluding 
fatalities)
-Myocardial infarction PT (excluding fatalities)
-Acute myocardial infarction PT (excluding 
fatalities)
Central nervous system haemorrhages and 
cerebrovascular conditions SMQ (excluding 
fatalities)
 
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11.7.
Appendix 7: Reporting Standards for Missing Data
11.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Withdrawal from Study Prior to Randomization

Participants who are pre-screening failures, screening failures, run-in 
failures, or stabilization failures (see Protocol Section 5.5 for the definitions) 
will be reported to account for the participant disposition.

Withdrawal from Study Treatment

Randomized participants who withdraw from double-blind study treatment 
prematurely (for any reason) should, where possible, continue to be 
followed-up as per protocol until the end of the study, after returning to the 
appropriate asthma therapy per investigator’s discretion.  Post-treatment 
data will be included in the statistical analyses.

Withdrawal from Study

See Appendix 2 for details on data collected at the Early Withdrawal visit.

Participant study completion (i.e. as specified in the protocol) was defined as ‘A 
participant will be considered to have completed the study upon completion of 
all assessments and procedures for Visit 8/EOS and including a successful 
follow-up contact/visit.’ 
11.7.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to 
blank fields on the collection instrument:
o
These data will be indicated by the use of a “blank” in participant listing 
displays unless all data for a specific visit are missing in which case the 
visit is not displayed in the listing. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered 
to be missing data and should be displayed as such.
o
No imputation will be made for any missing numerical data, except in the 
sensitivity analysis of primary endpoints to assess the impact of missing 
data on study results.  Missing data will generally not be considered in 
the calculation of percentages (i.e., the denominator will not include 
participants who have missing data at a given time point).
Responder 
Analysis

Participants with a missing baseline will have responder status as missing.

Participants with missing data at scheduled clinic visit, regardless of 
treatment status, will be considered as non-responders.  

For ACQ/SGRQ/AQLQ, participants that have withdrawn from study prior to 
the visit Week 24 will be imputed as non-responders at all visits after early 
 
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Element
Reporting Detail
withdrawal visit where the assessment was expected to be performed, up to 
Week 24. 

For E-RS and subscales, participants that have withdrawn from study prior 
Week 24 in question will be imputed as non-responders at time periods post-
study withdrawal. This includes time periods up to and including Weeks 21-
24.
Asthma 
Control 
Based on 
ACQ 

Participants with missing data at Week 12 or Week 24 will be classified as not 
achieving asthma control regardless of reasons in the summaries and 
analyses.

Participants with missing data at baseline will be excluded from the analysis,
due to the inclusion of baseline as a covariate.
11.7.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in participant listing displays.

Dates which are completely missing will not be imputed, with the exception of 
the treatment stop date.  Details for imputation of the treatment stop date are 
provided below.
Study 
treatment 
start and 
stop date

If the study treatment start date is missing, the Visit 3 (Day 1) date will be 
used.

If overall treatment stop date is missing or partial, it will be imputed as 
follows:

For participants who attended an Early Withdrawal visit, use the date of 
the Early Withdrawal visit

For participants who attended the last on-treatment visit, use the End of 
Study Visit date 

For participants who died and did not attend the last on-treatment visit, 
use the date of death

For all other participants, use the last recorded exposure stop date
Adverse 
Events

Partial dates were not permitted to be entered in the eCRF for AEs, therefore 
no imputation of AE dates will be performed.

Concomitant 
Medications

Partial dates for any concomitant medications will be imputed using the 
following convention:
O
If the partial date is a start date, a '01' will be used for the day and 'Jan' 
will be used for the month
O
If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month.

The recorded partial date will be displayed in listings.
 
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11.7.2.2.
Handling of Missing Data for Statistical Analysis
The utilization of efficacy data in the statistical analyses are summarized in the table 
below:
Treatment / 
Study status 
Data 
status
Data Inclusion for Analysis
Primary analysis    
'de facto' estimand, 
without imputation
Supportive analysis
‘de Jure’ estimand, 
without imputation
Sensitivity 
Analysis 'de 
facto' estimand
with imputation
on-
treatment
have data
Yes
Yes
Yes: not imputed
post-
treatment
have data
Yes
No
Yes: not imputed
post-
treatment
missing 
data
No
No
Yes: imputed
Imputed post-treatment missing data will be imputed from early withdrawal visit date + 1 
to planned end of study visit. 
See Section 7.1.5 and Section 7.2.5 on the details for the proposed sensitivity analyses.
 
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11.8.
Appendix 8: Model Checking and Diagnostics for Statistical Analyses
Endpoints

Change from baseline in Trough FEV1

Change from baseline in ACQ total score 

Change from baseline in SGRQ total score and domain scores

Change from baseline in AQLQ total score

Change from baseline in home daily trough FEV1 over the first 24 weeks of 
the treatment period

Change from baseline in morning (AM) pre-dose PEF over the first 24 weeks 
of the treatment period

Change from baseline in evening (PM) PEF over the first 24 weeks of the 
treatment period

Change from baseline in E-RS Breathlessness scores over Weeks 21-24 
(inclusive) of the treatment period

Change from baseline in E-RS Cough & Sputum scores over Weeks 21-24 
(inclusive) of the treatment period

Change from baseline in E-RS Chest Symptoms scores over Weeks 21-24 
(inclusive) of the treatment period

Change from baseline in the percentage of symptom-free days over the first 
24 weeks of the treatment period

Change from baseline in the percentage of rescue medication-free days over 
the first 24 weeks of the treatment period

Change from baseline in daily rescue medication use over the first 24 weeks 
of the treatment period.

Change from baseline in Pulse rate

Change from baseline in Systolic BP

Change from baseline in Diastolic BP

Change from baseline in QTcF

Change from baseline in PR Interval

Change from baseline in Heart rate (ECG)
Analysis

MMRM

The Kenward and Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used.
o
In the event the model fails to run using the KR method, then the residual method 
will be used instead.

An unstructured covariance structure for the R matrix will be used by specifying ‘type=UN’ 
on the REPEATED line.
o
In the event that this model fails to converge, alternative correlation structures may 
be considered such as CSH or CS. 
o
Akaike's Information Criteria (AIC) will be used to assist with the selection of 
covariance structure.

Distributional assumptions underlying the model used for analysis will be examined by 
obtaining a normal probability plot of the residuals and a plot of the residuals versus the 
fitted values (i.e. checking the normality assumption and constant variance assumption of 
 
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the model respectively) to gain confidence that the model assumptions are reasonable]. 
Endpoints

Mean change from baseline in clinic FEV1 at 3 hours post study treatment at 
Week 24

Mean change from baseline in clinic trough FEV1 over the first 24 weeks of 
the treatment period 
Analysis

ANCOVA

Distributional assumptions underlying the model used for analysis will be examined by 
obtaining a normal probability plot of the residuals and a plot of the residuals versus the 
fitted values (i.e. checking the normality assumption and constant variance assumption of 
the model respectively) to gain confidence that the model assumptions are reasonable].
Endpoints

Annualized rate of moderate/severe asthma exacerbations 

Annualized rate of severe asthma exacerbations 
Analysis

Negative binomial regression

The fit of the regression models will be examined using “Q-Q” plots of the standardized 
residuals. Interpretation of these plots will be aided by the addition of simulated envelopes 
as proposed by Atkinson (Atkinson, 1985).

If the model fails to converge, then the number of severe exacerbations will be fitted as a 
binary (0, >=1) variable.  If the model still vails to converge removal of the covariate for 
number of severe exacerbations in the previous year will be considered. 
Endpoints

Time to first moderate/severe asthma exacerbation

Time to first severe asthma exacerbation
Analysis

Cox’s proportional hazard model

The proportional hazards assumption will be examined by obtaining the Kaplan-Meier 
estimates of the survival function S(t) over time separately for each treatment group. Under 
the assumption of proportional hazards between the treatment groups, ln{−ln[S(t)]} for two 
groups should be parallel to each other and the distance between them constant. If the 
curves are approximately parallel, then the proportional hazards assumption is not violated. 
If these curves cross each other or diverge greatly from the assumption of parallel lines, then 
the assumption is not met.

The ‘exact’ method for handling ties will be used. If the analysis will not run using the ‘exact’ 
method, the ‘Efron’ method for handling ties will be used instead.
Endpoints

Percent of patients meeting a responder threshold of 0.5 points 
improvement (decrease) from baseline for the ACQ-7 at Week 24

Percent of patients meeting a responder threshold of 0.5 points 
improvement (decrease)from baseline for the ACQ-6 at Week 4

Percent of patients meeting a responder threshold of 0.5 points 
improvement (decrease) from baseline for the ACQ-5 at Week 24

Percentage of patients that have achieved asthma control based on ACQ-7 
(i.e. a total score ≤0.75) at both Week 12 and Week 24
 
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
Percentage of patients that have achieved asthma control based on ACQ-6 
(i.e. a total score ≤0.75) at both Week 12 and Week 24

Percentage of patients that have achieved asthma control based on ACQ-5 
(i.e. a total score ≤0.75) at both Week 12 and Week 24

Percent of patients meeting a responder threshold of ≥ 4 points improvement 
(decrease) from baseline for the SGRQ total score at Week 24

Percent of patients meeting a responder threshold of ≥ 0.5 points 
improvement (increase) from baseline for the AQLQ total score at Week 24
Analysis

Generalized linear model

The Kenward and Roger method for approximating the denominator degrees of freedom 
and correcting for bias in the estimated variance-covariance of the fixed effects will be 
used.
O
In the event the model fails to run using the KR method, then the residual method 
will be used instead.

Computation of confidence intervals for the odds ratios is based on the individual Wald tests. 

Pearson residuals will be plotted by using PLOTS=PEARSONPANEL option for the model 
statement in SAS.
 
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11.9.
Appendix 9: Abbreviations & Trade Marks
11.9.1.
Abbreviations
Abbreviation
Description
ACQ
Asthma Control Questionnaire
ADaM
Analysis Data Model
AE
Adverse Event
AESI
Adverse Event of Special Interest
AIC
Akaike's Information Criteria
A&R
Analysis and Reporting 
ALT
Alanine Transaminase
AM
Morning
AQLQ
Asthma Quality of Life Questionnaire
AST
Aspartate Transaminase
AUC
Area Under the Curve
BID
Twice Daily
BMI
Body Mass Index
BPM
Beats Per Minute
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CPMS
Clinical Pharmacology Modelling & Simulation
CS
Clinical Statistics
CSR
Clinical Study Report
CTR
Clinical Trial Register
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
DM
Data Management
DOB
Date of Birth
DP
Decimal Places
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eDiary
Electronic Diary
EMA
European Medicines Agency
EOS
End of Study
E-RS1
Evaluating Respiratory Symptoms
EU
European Union
EW
Early Withdrawal
FDA
Food and Drug Administration
FeNO
Fractional Exhaled Nitric Oxide
FEV1
Forced expiratory volume in 1 second
FF
Fluticasone Furoate
FP
Fluticasone Propionate
FSC
Fluticasone Salmeterol Combination
FVC
Forced Vital Capacity
GSK
GlaxoSmithKline
ICH
International Conference on Harmonization
 
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Abbreviation
Description
ICS
Inhaled Corticosteroids
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
IMMS
International Modules Management System
IP
Investigational Product
ITT
Intent-To-Treat
kg
Kilogram
GUI
Guidance
L
Liters
L/min
Liters per minute
LABA
Long-Acting Beta-2-Agonist
LAMA
Long-Acting Muscarinic Antagonist
LRTI
Lower Respiratory Tract Infection
LTRA
Leukotriene Receptor Antagonist
m
Meter
MACE
Major Adverse Cardiac Event
MedDRA
Medicinal Dictionary for Regulatory Activities
mcg (g)
Microgram
min
Minute
MMRM
Mixed Model Repeated Measures
msec
Millisecond
OCS
Oral Corticosteroid
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PEF
Peak Expiratory Flow
PK
Pharmacokinetic
PM
Afternoon
QC
Quality Control
QD
Once daily
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RAMOS
Randomization & Medication Ordering System 
RTF
Rich Text Format
SABA
Short-Acting Beta-2-Agonists
SAC
Statistical Analysis Complete
SAE
Serious Adverse Event
S&P
Statistics and Programming
SDTM
Study Data Tabulation Model
SGRQ
Saint George’s Respiratory Questionnaire
SI
System Independent
SMQ
Standardized MedDRA Query
SOP
Standard Operation Procedure
TA
Therapeutic Area
 
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Abbreviation
Description
TFL
Tables, Figures & Listings 
UMEC
Umeclidinium
US
United States
VI
Vilanterol
1 E-RS is now renamed Evaluating Respiratory Symptoms in COPD (E-RS: COPD). The term E-RS is used 
throughout this document for consistency with the study protocol
11.9.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
DISKUS
E-RS: COPD
ELLIPTA
SAS
 
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11.10.
Appendix 10: List of Data Displays
11.10.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.54
1.1 to 1.2
Efficacy
2.1 to 2.138
2.1 to 2.118
Safety
3.1 to 3.90
3.1 to 3.18
Section
Listings
ICH Listings
1 to 37
Other Listings
38 to 74
11.10.2.
Mock Example Shell Referencing
Displays will follow IDSL standards where possible. Example mock-up displays will be 
provided in separate documents. Modifications and additional specifications for IDSL 
outputs will also be detailed in these documents, therefore where the mock displays differ 
from IDSL, the mock display should be followed.
11.10.3.
Deliverables
Delivery [Priority] 
Description
SAC [1]
Headline results
SAC 
Statistical Analysis Complete 
 
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11.10.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
All Subjects 
Enrolled
SP1
Summary of Subject Populations
SAC [1]
1.2.
All Subjects 
Enrolled
ES6
Summary of Screen Failures, Run-in Failures, and Stabilization 
Failures
SAC [1]
1.3.
All Subjects 
Enrolled
SP_T1
Summary of Rescreens in the Study and Failure Reasons
SAC
1.4.
All Subjects
Enrolled
NS1
Summary of Subject Enrolment by Country and Site ID 
SAC
1.5.
ITT
NS1
Summary of Subject Included in the ITT population by Country 
and Site ID 
SAC
1.6.
ITT
SD1
Summary of Treatment Status
SAC [1]
1.7.
ITT
ES1
Summary of Subject Disposition
SAC [1]
1.8.
ITT
IE2
Summary of Inclusion, Exclusion, Enrolment, or Randomization
Criteria Deviations
SAC
1.9.
ITT
DV1
Summary of Important Protocol Deviations
SAC
1.10.
ITT
SP_T2
Summary of Treatment Status at Each Clinic Visit
SAC
1.11.
ITT
SP_T3
Summary of Planned and Actual End of Study Visit
SAC
Demography and Baseline Characteristics
1.12.
ITT
DM1
Summary of Demographic Characteristics
SAC [1]
 
 
 
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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.13.
ITT
DM1
Summary of Demographic Characteristics – Pooled FF Doses  
SAC 
1.14.
All Subjects 
Enrolled
DM11
Summary of Age Ranges
SAC
1.15.
ITT
DM5
Summary of Race and Racial Combinations
SAC
1.16.
ITT
DM5
Summary of Race and Racial Combinations – Pooled FF
SAC
1.17.
ITT
DM6
Summary of Race and Racial Combination Details
SAC
1.18.
ITT
SP_T20
Summary of Pre-Study ICS Dosage at Screening
SAC [1]
1.19.
ITT
SP_T4
Summary of Disease Duration
SAC
1.20.
ITT
SP_T4
Summary of Disease Duration – Pooled FF Doses
SAC
1.21.
ITT
SP_T5
Summary of Asthma Medical History Questionnaire
SAC
1.22.
ITT
SP_T6
Summary of Exacerbation History
SAC [1]
1.23.
ITT
SP_T6
Summary of Exacerbation History – Pooled FF Doses
SAC 
1.24.
ITT
SU1 (subset)
Summary of Smoking Status
SAC
1.25.
ITT
SP_T7
Summary of Cardiovascular History / Risk Factors
SAC [1] 
1.26.
ITT
FH1
Summary of Family History of Cardiovascular Risk Factors
SAC
1.27.
ITT
SP_T8
Summary of Clinic Spirometry at Screening, Enrolment, and 
Randomization (Day 1)
SAC [1]
1.28.
ITT
SP_T8
Summary of Clinic Spirometry at Screening, Enrolment, and 
Randomization (Day 1) – Pooled FF Doses
SAC [1]
1.29.
ITT
SP_T9
Summary of Change in Clinic Pre-Bronchodilator / Pre-Dose 
FEV1 (L) during Run-In and Stabilization Periods
SAC [1]
1.30.
ITT
SP_T10
Summary of Home Daily Spirometry During Run-in and 
Stabilization Periods
SAC
 
 
 
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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.31.
ITT
SP_T11
Summary of Fractional Exhaled Nitric Oxide (ppb) at Baseline
SAC
1.32.
ITT
SP_t12
Summary of Total Serum IgE (KU/L)
at Baseline
SAC
1.33.
ITT
SP_T13
Summary of ACQ Scores at Screening, Enrolment, and 
Randomization (Day 1)
SAC [1]
1.34.
ITT
SP_T14
Summary of Change in Pre-Treatment ACQ Scores 
SAC [1]
1.35.
ITT
MH1
Summary of Current Medical Conditions
SAC
1.36.
ITT
MH1
Summary of Past Medical Conditions
SAC
1.37.
ITT
SP_T15
Summary of Pneumonia History
SAC
Concomitant Medications
1.38.
ITT
SP_T16
Summary of Asthma Maintenance Therapy at Study Entry
SAC
1.39.
ITT
SP_T16
Summary of Asthma Maintenance Therapy at Study Entry 
– Pooled FF Doses
SAC
1.40.
ITT
CM1
Summary of Asthma Concomitant Medications at Study 
Entry
SAC
1.41.
ITT
CM1
Summary of Asthma Concomitant Medications During the 
Screening/Run-in Period
SAC
1.42.
ITT
CM1
Summary of Asthma Concomitant Medications During the 
Stabilization Period
SAC
1.43.
ITT
CM1
Summary of On-Treatment Asthma Concomitant 
Medications 
SAC
1.44.
ITT
CM1
Summary of Post-Treatment Asthma Medications 
SAC
 
 
 
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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.45.
ITT
SP_T17
Summary of Asthma Maintenance Therapy Following 
Treatment Discontinuation 
SAC
1.46.
ITT
CM1
Summary of Post-Study Asthma Medications 
SAC
1.47.
ITT
SP_T21
Summary of Concomitant Medications Used for the 
Treatment of Moderate/Severe Asthma Exacerbations 
SAC
1.48.
ITT
CM1
Summary of On-Treatment Non-Asthma Concomitant 
Medications 
SAC
1.49.
ITT
CM1
Summary of Post-Treatment Non-Asthma Medications 
SAC
1.50.
ITT
CM1
Summary of Post-Study Non-Asthma Medications 
SAC
Treatment Compliance
1.51.
ITT
SP_T18
Summary of Treatment Compliance (%) 
SAC
1.52.
ITT
SP_T18
Summary of Treatment Compliance (%) – Pooled FF 
Doses
SAC
1.53.
ITT
SP_T19
Summary of Treatment Compliance (%) up to Week 24
SAC
1.54.
ITT
SP_T19
Summary of Treatment Compliance (%) up to Week 24 –
Pooled FF Doses
SAC
 
 
 
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11.10.5.
Study Population Figures
Study Population Figures
No.
Population
IDSL ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
ITT
SP_T1
Kaplan-Meier Plot of Time to Early Discontinuation from Study 
Treatment
SAC
1.2.
ITT
SP_T1
Kaplan-Meier Plot of Time to Early Withdrawal from Study 
SAC
 
 
 
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11.10.6.
Efficacy Tables
Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Primary Efficacy Endpoint
2.1.
ITT
EFF_T1
Summary of Baseline Clinic Trough FEV1 (L) 
SAC [1]
2.2.
ITT
EFF_T2
Summary of Clinic Trough FEV1 (L) (On- and Post-Treatment)
Weeks 4, 12, 24,36, 52 
SAC [1]
2.3.
ITT
EFF_T4
Analysis of Mean Change from Baseline in Clinic Trough FEV1
(L) up to Week 24 (On- and Post-Treatment)
Weeks 4, 12, 24
SAC [1]
2.4.
ITT
EFF_T5
Summary of Test Results for all Covariates and Interactions 
Included in the MMRM Analysis Model for Change from Baseline 
in Clinic Trough FEV1 (L)
Week 24
SAC
2.5.
ITT
EFF_T3
Summary of Clinic Trough FEV1 (L) by Treatment Status (On-
and Post-Treatment)
Weeks 4, 12, 24,36, 52 
SAC
2.6.
ITT
EFF_T4
Supportive Analysis of Mean Change from Baseline in Clinic 
Trough FEV1 (L) up to Week 24 (On-Treatment) 
Weeks 4, 12, 24
SAC
2.7.
ITT
EFF_T4
Supportive Analysis of Mean Change from Baseline in Clinic 
Trough FEV1 (L) up to Week 24 Excluding Sites with Data 
Concerns (On- and Post-Treatment) 
Weeks 4, 12, 24
SAC
2.8.
ITT
EFF_T7
Sensitivity Analysis of Mean Change from Baseline in Clinic 
Trough FEV1 (L) at Week 24 (Jump to Reference) (On- and 
Post-Treatment)
Present Week 24 only
SAC
2.9.
ITT
EFF_T9
Sensitivity Analysis of Mean Change from Baseline in Clinic 
Trough FEV1 (L) at Week 24 (Tipping Point): FF/UMEC/VI 
100/62.5/25 v FF/VI 100/25 (On- and Post-Treatment)
Present Week 24 only
SAC
2.10.
ITT
EFF_T8
Sensitivity Analysis of Mean Change from Baseline in Clinic 
Trough FEV1 (L) at Week 24 (Tipping Point p-value Grid): 
FF/UMEC/VI 100/62.5/25 v FF/VI 100/25 (On- and Post-
Present Week 24 only
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Treatment)
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.11.
ITT
EFF_T9
Sensitivity Analysis of Mean Change from Baseline in Clinic 
Trough FEV1 (L) at Week 24 (Tipping Point): FF/UMEC/VI 
200/62.5/25 v FF/VI 200/25 (On- and Post-Treatment)
Present Week 24 only
SAC
2.12.
ITT
EFF_T8
Sensitivity Analysis of Mean Change from Baseline in Clinic 
Trough FEV1 (L) at Week 24 (Tipping Point p-value Grid): 
FF/UMEC/VI 200/62.5/25 v FF/VI 200/25 (On- and Post-
Treatment)
Present Week 24 only
SAC
2.13.
ITT
EFF_T9
Sensitivity Analysis of Mean Change from Baseline in Clinic 
Trough FEV1 (L) at Week 24 (Tipping Point): FF/UMEC/VI 
100/31.25/25 v FF/VI 100/25 (On- and Post-Treatment)
Present Week 24 only
SAC
2.14.
ITT
EFF_T8
Sensitivity Analysis of Mean Change from Baseline in Clinic 
Trough FEV1 (L) at Week 24 (Tipping Point p-value Grid): 
FF/UMEC/VI 100/31.25/25 v FF/VI 100/25 (On- and Post-
Treatment)
Present Week 24 only
SAC
2.15.
ITT
EFF_T9
Sensitivity Analysis of Mean Change from Baseline in Clinic
Trough FEV1 (L) at Week 24 (Tipping Point): FF/UMEC/VI 
200/31.25/25 v FF/VI 200/25 (On- and Post-Treatment)
Present Week 24 only
SAC
2.16.
ITT
EFF_T8
Sensitivity Analysis of Mean Change from Baseline in Clinic 
Trough FEV1 (L) at Week 24 (Tipping Point p-value Grid): 
FF/UMEC/VI 200/31.25/25 v FF/VI 200/25 (On- and Post-
Treatment)
Present Week 24 only
SAC
2.17.
ITT
EFF_T1
Summary of Baseline Clinic Trough FEV1 (L) – Pooled FF Doses  
SAC
2.18.
ITT
EFF_T2
Summary of Clinic Trough FEV1 (L) (On- and Post-Treatment) –
Pooled FF Doses  
Weeks 4, 12, 24,36, 52 
SAC
2.19.
ITT
EFF_T6
Analysis of Mean Change from Baseline in Clinic Trough FEV1
(L) up to Week 24 (On- and Post-Treatment) – Pooled FF Doses  Weeks 4, 12, 24
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.20.
ITT
EFF_10
Summary of Baseline Clinic Trough FEV1 (L) by Gender
SAC
2.21.
ITT
EFF_T2
Summary of Clinic Trough FEV1 (L) by Gender (On- and Post-
Treatment)
Weeks 4, 12, 24,36, 52
SAC
2.22.
ITT
EFF_T10
Summary of Baseline Clinic Trough FEV1 (L) by Age (<18, 18 to 
<65, 65 to <75, 75 to <85, ≥85 years)
SAC
2.23.
ITT
EFF_T2
Summary of Clinic Trough FEV1 (L) by Age (<18, 18 to <65, 65 
to <75, 75 to <85, ≥85 years) (On- and Post-Treatment)
Weeks 4, 12, 24,36, 52
SAC
2.24.
ITT
EFF_T10
Summary of Baseline Clinic Trough FEV1 (L) by Age (<65, ≥65 
years)
SAC
2.25.
ITT
EFF_T2
Summary of Clinic Trough FEV1 (L) by Age (<65, ≥65 years) 
(On- and Post-Treatment)
Weeks 4, 12, 24,36, 52
SAC
2.26.
ITT
EFF_T10
Summary of Baseline Clinic Trough FEV1 (L) by Race
SAC
2.27.
ITT
EFF_T2
Summary of Clinic Trough FEV1 (L) by Race (On- and Post-
Treatment)
Weeks 4, 12, 24,36, 52
SAC
2.28.
ITT
EFF_T10
Summary of Baseline Clinic Trough FEV1 (L) by Region
2.29.
ITT
EFF_T2
Summary of Clinic Trough FEV1 (L) by Region (On- and Post-
Treatment) 
Weeks 4, 12, 24,36, 52
SAC
2.30.
ITT
EFF_T10
Summary of Baseline Clinic Trough FEV1 (L) by Pre-Study ICS 
Dosage at Screening
SAC
2.31.
ITT
EFF_T2
Summary of Clinic Trough FEV1 (L) by Pre-Study ICS Dosage at 
Screening (On- and Post-Treatment)
Weeks 4, 12, 24,36, 52
SAC
2.32.
ITT
EFF_T10
Summary of Baseline Clinic Trough FEV1 (L) by BMI
2.33.
ITT
EFF_T2
Summary of Clinic Trough FEV1 (L) by BMI (On- and Post-
Treatment)
Weeks 4, 12, 24,36, 52
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.34.
ITT
EFF_T10
Summary of Baseline Clinic Trough FEV1 (L) by CV History/Risk 
Factor at Screening
2.35.
ITT
EFF_T2
Summary of Clinic Trough FEV1 (L) by CV History/Risk Factor at 
Screening (On- and Post-Treatment)
Weeks 4, 12, 24,36, 52
SAC
Key Secondary Efficacy Endpoint
2.36.
ITT
EFF_T11
Summary of Moderate and Severe Asthma Exacerbations (On-
and Post-Treatment) – Pooled FF Doses  
Weeks 1-52, 1-24, 25-52
SAC [1]
2.37.
ITT
EFF_T12
Analysis of Moderate/Severe Asthma Exacerbations (On- and 
Post-Treatment) – Pooled FF Doses   
Weeks 1-52, 1-24
SAC [1]
2.38.
ITT
EFF_T5
Summary of Test Results for all Covariates and Interactions 
Included in the the Negative Binomial Analysis Model for 
Moderate/Severe Asthma Exacerbations (On-and Post-
Treatment) – Pooled FF Doses
Weeks 1-52, 1-24
SAC
2.39.
ITT
EFF_T11
Summary of Moderate and Severe Asthma Exacerbations (On-
Treatment) – Pooled FF Doses
Weeks 1-52, 1-24, 25-52
SAC
2.40.
ITT
EFF_T12
Supportive Analysis of Moderate/Severe Asthma Exacerbations 
(On-Treatment) – Pooled FF Doses
Weeks 1-52, 1-24
SAC
2.41.
ITT
EFF_T12
Supportive Analysis of Moderate/Severe Asthma Exacerbations 
(On- and Post-Treatment) Excluding Sites with Data Concerns –
Pooled FF Doses
Weeks 1-52
SAC
2.42.
ITT
EFF_T12
Sensitivity Analysis of Moderate/Severe Asthma Exacerbations 
(Jump to Reference) (On- and Post-Treatment) – Pooled FF 
Doses
Weeks 1-52
SAC
2.43.
ITT
EFF_T14
Sensitivity Analysis of Moderate/Severe Asthma Exacerbations 
(Tipping Point): FF/UMEC/VI UMEC 62.5 vs. FF/VI over Week 
1-52 (On- and Post-Treatment)– Pooled FF Doses
Weeks 1-52
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.44.
ITT
EFF_T15
Sensitivity Analysis of Moderate/Severe Asthma Exacerbations 
(Tipping Point p-value Grid): FF/UMEC/VI UMEC 62.5 vs. FF/VI 
over Week 1-52 (On- and Post-Treatment) – Pooled FF Doses
Weeks 1-52
SAC
2.45.
ITT
EFF_T14
Sensitivity Analysis of Moderate/Severe Asthma Exacerbations 
(Tipping Point): FF/UMEC/VI UMEC 31.25vs. FF/VI over Week 
1-52 (On- and Post-Treatment) – Pooled FF Doses
Weeks 1-52
SAC
2.46.
ITT
EFF_T15
Sensitivity Analysis of Moderate/Severe Asthma Exacerbations 
(Tipping Point p-value Grid): FF/UMEC/VIUMEC 31.25 vs. FF/VI 
over Week 1-52 (On- and Post-Treatment) – Pooled FF Doses
Weeks 1-52
SAC
2.47.
ITT
EFF_T11
Summary of Moderate and Severe Asthma Exacerbations (On-
and Post-Treatment)
Weeks 1-52, 1-24, 25-52
SAC [1]
2.48.
ITT
EFF_T13
Analysis of Moderate/Severe Asthma Exacerbations (On- and 
Post-Treatment)
Weeks 1-52, 1-24
SAC [1]
2.49.
ITT
EFF_T11
Summary of Moderate and Severe Asthma Exacerbations by 
Gender (On- and Post-Treatment) - Pooled FF Doses
Weeks 1-52
SAC
2.50.
ITT
EFF_T11
Summary of Moderate and Severe Asthma Exacerbations by 
Age (<18, 18 to <65, 65 to <75, 75 to <85, ≥85 years) (On- and 
Post-Treatment) - Pooled FF Doses
Weeks 1-52
SAC
2.51.
ITT
EFF_T11
Summary of Moderate and Severe Asthma Exacerbations by 
Age (<65, ≥65 years) (On- and Post-Treatment) - Pooled FF 
Doses
Weeks 1-52
SAC
2.52.
ITT
EFF_T11
Summary of Moderate and Severe Asthma Exacerbations by 
Race (On- and Post-Treatment) - Pooled FF Doses
Weeks 1-52
SAC
2.53.
ITT
EFF_T11
Summary of Moderate and Severe Asthma Exacerbations by 
Region (On- and Post-Treatment) - Pooled FF Doses
Weeks 1-52
SAC
2.54.
ITT
EFF_T11
Summary of Moderate and Severe Asthma Exacerbations by 
Weeks 1-52
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Pre-Study ICS Dosage at Screening (On- and Post-Treatment) -
Pooled FF Doses
2.55.
ITT
EFF_T11
Summary of Moderate and Severe Asthma Exacerbations by 
BMI (On- and Post-Treatment) - Pooled FF Doses
Weeks 1-52
SAC
2.56.
ITT
EFF_T11
Summary of Moderate and Severe Asthma Exacerbations by CV 
History/Risk Factor at Screening (On- and Post-Treatment) -
Pooled FF Doses
Weeks 1-52
SAC
Other Secondary Efficacy Endpoints
2.57.
ITT
EFF_T16
Summary of Change from Baseline in Clinic FEV1 (L) at 3 Hours 
Post Study Treatment (On-Treatment) 
Day 1, Weeks 24and 52
SAC
2.58.
ITT
EFF_T4
Analysis of Mean Change from Baseline in Clinic FEV1 (L) at 3 
Hours Post Study Treatment at Week 24 (On-Treatment) 
Week 24
SAC
2.59.
ITT
EFF_T16
Summary of Change from Baseline in Clinic FEV1 (L) at 3 Hours 
Post Study Treatment (On-Treatment) - Pooled FF Doses
Day 1, Weeks 24 and 52
SAC
2.60.
ITT
EFF_T6
Analysis of Mean Change from Baseline in Clinic FEV1 (L) at 3 
Hours Post Study Treatment at Week 24 (On-Treatment) -
Pooled FF Doses
Week 24
SAC
2.61.
ITT
EFF_T20
Summary of Baseline SGRQ Scores – Pooled FF Doses
Includes baseline total score and 
domain scores for symptoms, 
activity, and impact.
SAC [1]
2.62.
ITT
EFF_T2
Summary of SGRQ Total Score (On- and Post-Treatment) –
Pooled FF Doses
Weeks 12, 24,36, 52
SAC [1]
2.63.
ITT
EFF_T6
Analysis of Mean Change from Baseline in SGRQ Total Score 
up to Week 24 up to Week 24 (On- and Post-Treatment) –
Pooled FF Doses    
Weeks 12, 24
SAC [1]
2.64.
ITT
EFF_T20
Summary of Baseline SGRQ Scores
Includes baseline total score and 
SAC [1] 
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
domain scores
2.65.
ITT
EFF_T2
Summary of SGRQ Total Score (On- and Post-Treatment)  
Weeks 12, 24,36, 52
SAC [1]
2.66.
ITT
EFF_T4
Analysis of Mean Change from Baseline in SGRQ Total Score 
up to Week 24 (On- and Post-Treatment)
Weeks 12, 24
SAC [1]
2.67.
ITT
EFF_T17
Summary of Baseline ACQ-7 Total Score – Pooled FF Doses  
SAC [1]
2.68.
ITT
EFF_T18
Summary of ACQ-7 Total Score (On- and Post-Treatment) –
Pooled FF Doses  
Weeks 4, 12, 24,36, 52 
SAC [1]
2.69.
ITT
EFF_T19
Shift in ACQ-7 Total Score Control Category from Baseline (On-
and Post-Treatment) – Pooled FF Doses  
Baseline to Weeks 4, 12, 24,36, 52 
SAC
2.70.
ITT
EFF_T6
Analysis of Mean Change from Baseline in ACQ-7 Total Score 
up to Week 24 (On- and Post-Treatment) – Pooled FF Doses  
Weeks 4, 12, 24
SAC [1]
2.71.
ITT
EFF_T18
Summary of ACQ-7 Total Score (On- and Post-Treatment)
Weeks 4, 12, 24,36, 52 
SAC [1]
2.72.
ITT
EFF_T19
Shift in ACQ-7 Total Score Control Category from Baseline (On-
and Post-Treatment)
Baseline to Weeks 4, 12, 24,36, 52 
SAC
2.73.
ITT
EFF_T4
Analysis of Mean Change from Baseline in ACQ-7 Total Score 
up to Week 24 (On- and Post-Treatment)
Weeks 4, 12, 24
SAC [1]
2.74.
ITT
EFF_T20
Summary of Baseline E-RS Scores – Pooled FF Doses   
Includes baseline total score and 
domain scores for breathlessness, 
cough and sputum, and chest
SAC
2.75.
ITT
EFF_T21
Summary of E-RS Total Score (On- and Post-Treatment) –
Pooled FF Doses   
4 weekly up to 52 weeks and
weeks 1 to 24
SAC
2.76.
ITT
EFF_T6
Analysis of Mean Change from Baseline in E-RS Total Score up 
to Week 24 by 4-Weekly Intervals (On- and Post-Treatment) –
Pooled FF Doses
4 weekly up to 24 weeks, weeks 1 
to 24
SAC
2.77.
ITT
EFF_T20
Summary of Baseline E-RS Scores
Includes baseline total score and 
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
domain scores for breathlessness, 
cough and sputum, and chest
2.78.
ITT
EFF_T21
Summary of E-RS Total Score (On- and Post-Treatment)
4 weekly up to 52 weeks and
weeks 1 to 24
SAC
2.79.
ITT
EFF_T4
Analysis of Mean Change from Baseline in E-RS Total Score up 
to Week 24 by 4-Weekly Intervals (On- and Post-Treatment)
4 weekly up to 24 weeks, weeks 1 
to 24
SAC
2.80.
ITT
EFF_T22
Summary of Analyses in Testing Hierarchy (On- and Post-
Treatment)
SAC
Other Efficacy Endpoints
2.81.
ITT
EFF_T2
Summary of Clinic Spirometry Data (On- and Post-Treatment)
Week 4, 12, 24, 36 and 52.  Include 
FVC, FEV/FVC ratio and % 
predicted. Include pre- and post-
dose where applicable.
SAC
2.82.
ITT
EFF_T23
Summary of Clinic Trough FEV1 (L) Over the First 24 Weeks of 
the Treatment Period (On- and Post-Treatment) 
AUC0-24w
SAC
2.83.
ITT
EFF_T4
Analysis of Mean Change from Baseline in Clinic Trough FEV1
(L) Over the First 24 Weeks of the Treatment Period (On- and 
Post-Treatment)
AUC0-24w
SAC
2.84.
ITT
EFF_T21
Summary of Home Daily Trough FEV1 (L) (On- and Post-
Treatment)
4 weekly up to 52 weeks and
weeks 1 to 24
SAC
2.85.
ITT
EFF_T21
Summary of Home Daily Trough FEV1 (L) by 1-Week Intervals 
(On- and Post-Treatment)  
1-week up to 52 weeks
SAC
2.86.
ITT
EFF_T4
Analysis of Mean Change from Baseline in Home Daily Trough
FEV1 (L) up to Week 24 by 4-Weekly intervals (On- and Post-
Treatment)
4 weekly up to 24 weeks, weeks 1 
to 24
SAC
2.87.
ITT
EFF_T4
Analysis of Mean Change from Baseline in Home Daily Trough
1-week up to 8 weeks
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
FEV1 (L) up to Week 8 by 1-Week Intervals (On- and Post-
Treatment)  
2.88.
ITT
EFF_T21
Summary of Home Daily PM FEV1 (L) (On- and Post-Treatment)
4 weekly up to 52 weeks and
weeks 1 to 24
SAC
2.89.
ITT
EFF_T21
Summary of Home Daily PM FEV1 (L) by 1-Week Intervals (On-
and Post-Treatment)
1-week up to 52 weeks
SAC
2.90.
ITT
EFF_T4
Analysis of Mean Change from Baseline in Home Daily PM FEV1
(L) up to Week 24 by 4-Weekly intervals (On- and Post-
Treatment)
4 weekly up to 24 weeks, weeks 1 
to 24
SAC
2.91.
ITT
EFF_T21
Summary of Home Daily AM PEF (L/min) (On- and Post-
Treatment) 
4 weekly up to 52 weeks and
weeks 1 to 24
SAC
2.92.
ITT
EFF_T21
Summary of Home Daily AM PEF (L/min) by 1-Week Intervals 
(On- and Post-Treatment)  
1-weekly intervals to week 52
SAC
2.93.
ITT
EFF_T4
Analysis of Mean Change from Baseline in Home Daily AM PEF 
(L/min) up to Week 24 by 4-Weekly Intervals (On- and Post-
Treatment)
4 weekly up to 24 weeks, weeks 1 
to 24
SAC
2.94.
ITT
EFF_T21
Summary of Home Daily PM PEF (L/min) (On- and Post-
Treatment)
4 weekly up to 52 weeks and
weeks 1 to 24
SAC
2.95.
ITT
EFF_T21
Summary of Home Daily PM PEF (L/min) by 1-Week Intervals 
(On- and Post-Treatment)  
1 weekly intervals to week 52
SAC
2.96.
ITT
EFF_T4
Analysis of Mean Change from Baseline in Home Daily PM PEF 
(L/min) up to Week 24 by 4-Weekly Intervals (On- and Post-
Treatment)
4 weekly up to 24 weeks, weeks 1 
to 24
SAC
2.97.
ITT
EFF_T12
Analysis of Severe Asthma Exacerbations (On- and Post-
Treatment) – Pooled FF Doses  
Weeks 1-52
SAC
2.98.
ITT
EFF_T13
Analysis of Severe Asthma Exacerbations (On- and Post-
Weeks 1-52
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Treatment)
2.99.
ITT
EFF_T28
Summary and Analysis of Time to First Moderate/Severe 
Asthma Exacerbation (Days) (On- and Post-Treatment) –
Pooled FF Doses  
Weeks 1-52
SAC
2.100.
ITT
EFF_T29
Summary and Analysis of Time to First Moderate/Severe 
Asthma Exacerbation (Days) (On- and Post-Treatment)
Weeks 1-52
SAC
2.101.
ITT
EFF_T28
Summary and Analysis of Time to First Severe Asthma 
Exacerbation (Days) (On- and Post-Treatment) – Pooled FF 
Doses
Weeks 1-52
SAC
2.102.
ITT
EFF_T29
Summary and Analysis of Time to First Severe Asthma 
Exacerbation (Days) (On- and Post-Treatment)
Weeks 1-52
SAC
2.103.
ITT
EFF_T24
Summary and Analysis of Percent of Patients Meeting a 
Responder Threshold of 0.5 points improvement (decrease) 
from Baseline for ACQ-7 Total Score up to Week 24 (On- and 
Post-Treatment) – Pooled FF Doses
Weeks 4, 12, 24
SAC
2.104.
ITT
EFF_T25
Summary and Analysis of Percent of Patients Meeting a 
Responder Threshold of 0.5 points improvement (decrease) 
from Baseline for ACQ-7 Total Score up to Week 24 (On- and 
Post-Treatment)
Weeks 4, 12, 24
SAC
2.105.
ITT
EFF_T24
Summary and Analysis of Percent of Patients Meeting a 
Responder Threshold of 0.5 points improvement (decrease)
from Baseline for ACQ-6 Total Score up to Week 24 (On- and 
Post-Treatment) – Pooled FF Doses
Weeks 4, 12, 24
SAC
2.106.
ITT
EFF_T24
Summary and Analysis of Percent of Patients Meeting a 
Responder Threshold of 0.5 points improvement (decrease)
from Baseline for ACQ-5 Total Score up to Week 24 (On- and 
Post-Treatment) – Pooled FF Doses
Weeks 4, 12, 24
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.107.
ITT
EFF_T26
Summary and Analysis of Percent of Patients Who Have
Achieved Asthma Control Based on ACQ-7 (i.e. a Total Score 
≤0.75) at Both Week 12 and Week 24 (On- and Post-Treatment) 
– Pooled FF Doses
Includes data from weeks 12, 24
SAC
2.108.
ITT
EFF_T27
Summary and Analysis of Percent of Patients Who Have
Achieved Asthma Control Based on ACQ-7 (i.e. a Total Score 
≤0.75) at Both Week 12 and Week 24 (On- and Post-Treatment)
Includes data from weeks 12, 24
SAC
2.109.
ITT
EFF_T26
Summary and Analysis of Percent of Patients Who Have
Achieved Asthma Control Based on ACQ-6 (i.e. a Total Score 
≤0.75) at Both Week 12 and Week 24 (On- and Post-Treatment) 
– Pooled FF Doses
Includes data from weeks 12, 24
SAC
2.110.
ITT
EFF_T26
Summary and Analysis of Percent of Patients Who Have
Achieved Asthma Control Based on ACQ-5 (i.e. a Total Score 
≤0.75) at Both Week 12 and Week 24 (On- and Post-Treatment) 
– Pooled FF Doses
Includes data from weeks 12, 24
SAC
2.111.
ITT
EFF_T2
Summary of SGRQ Domain Scores (On- and Post-Treatment) –
Pooled FF Doses 
Includes domain scores for 
symptoms, activity, and impact.
Weeks 12, 24, 36, 52
SAC
2.112.
ITT
EFF_T6
Analysis of Mean Change from Baseline in SGRQ Domain 
Scores up to Week 24 (On- and Post-Treatment) – Pooled FF 
Doses  
Weeks 12, 24
SAC
2.113.
ITT
EFF_T24
Summary and Analysis of Percent of Patients Meeting a 
Responder Threshold of ≥ 4 Points Improvement (Decrease) 
from Baseline for the SGRQ Total Score up to Week 24 (On-
and Post-Treatment) – Pooled FF Doses
Weeks 12, 24
SAC
2.114.
ITT
EFF_T25
Summary and Analysis of Percent of Patients Meeting a 
Responder Threshold of ≥ 4 Points Improvement (Decrease) 
from Baseline for the SGRQ Total Score up to Week 24 (On-
Weeks 12, 24
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
and Post-Treatment)
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.115.
ITT
EFF_T21
Summary of E-RS Domain Scores (On- and Post-Treatment) –
Pooled FF Doses  
Includes domain scores for 
breathlessness, cough and sputum, 
and chest. 
4 weekly up to week 52 and weeks 
1-24
SAC
2.116.
ITT
EFF_T6
Analysis of Mean Change from Baseline in E-RS Domain Scores 
up to Week 24 by 4-Weekly Intervals (On- and Post-Treatment)
– Pooled FF Doses  
Includes domain scores for 
breathlessness, cough and sputum, 
and chest
4 weekly up to week 24, and weeks 
1-24
SAC
2.117.
ITT
EFF_T24
Summary and Analysis of Percent of Patients Meeting a 
Responder Threshold of ≥ 2 Points Improvement (Decrease) 
from Baseline for the E-RS Total Score up to Week 24 by 4-
Weekly Intervals (On- and Post-Treatment) – Pooled FF Doses
4 weekly up to week 24
SAC
2.118.
ITT
EFF_T25
Summary and Analysis of Percent of Patients Meeting a 
Responder Threshold of ≥ 2 Points Improvement (Decrease) 
from Baseline for the E-RS Total Score up to Week 24 by 4-
Weekly Intervals (On- and Post-Treatment)
4 weekly up to week 24
SAC
2.119.
ITT
EFF_T20
Summary of Baseline AQLQ Total Score– Pooled FF Doses  
SAC
2.120.
ITT
EFF_T2
Summary of AQLQ Total Score (On- and Post-Treatment) –
Pooled FF Doses  
Weeks 4, 12, 24, 36 and 52
SAC
2.121.
ITT
EFF_T6
Analysis of Mean Change from Baseline in AQLQ Total Score 
up to Week 24 (On- and Post-Treatment) – Pooled FF Doses  
Weeks 4, 12 and 24
SAC
2.122.
ITT
EFF_T24
Summary and Analysis of Percent of Patients Meeting a 
Responder Threshold of ≥ 0.5 Points Improvement (Increase) 
from Baseline for the AQLQ Total Score up to Week 24 (On- and 
Post-Treatment) - Pooled FF Doses
Weeks 4, 12, 24
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.123.
ITT
EFF_T20
Summary of Baseline Percentage of Symptom-Free Days –
Pooled FF Doses
SAC
2.124.
ITT
EFF_T21
Summary of Percentage of Symptom-Free Days (On- and Post-
Treatment) – Pooled FF Doses
4 weekly up to 52 weeks and
weeks 1 to 24
SAC
2.125.
ITT
EFF_T34
Analysis of Mean Change from Baseline in the Percentage of 
Symptom-Free Days up to Week 24 by 4-Weekly Intervals (On-
and Post-Treatment) – Pooled FF Doses
4 weekly up to 24 weeks, weeks 1 
to 24
SAC
2.126.
ITT
EFF_T20
Summary of Baseline Percentage of Rescue Medication-Free 
Days– Pooled FF Doses
SAC
2.127.
ITT
EFF_T21
Summary of Percentage of Rescue Medication-Free Days (On-
and Post-Treatment) – Pooled FF Doses
4 weekly up to 52 weeks and
weeks 1 to 24
SAC
2.128.
ITT
EFF_T34
Analysis of Mean Change from Baseline in the Percentage of 
Rescue Medication-Free Days up to Week 24 by 4-Weekly 
Intervals (On- and Post-Treatment) – Pooled FF Doses
4 weekly up to 24 weeks, weeks 1 
to 24
SAC
2.129.
ITT
EFF_T20
Summary of Baseline Daily Rescue Medication Use (Puffs/Day) 
– Pooled FF Doses
SAC
2.130.
ITT
EFF_T21
Summary of Daily Rescue Medication Use (Puffs/Day) (On- and 
Post-Treatment) – Pooled FF Doses
4 weekly up to 52 weeks and
weeks 1 to 24
SAC
2.131.
ITT
EFF_T6
Analysis of Mean Change from Baseline in Daily Rescue 
Medication Use (Puffs/Day) up to Week 24 by 4-Weekly 
Intervals (On- and Post-Treatment) – Pooled FF Doses
4 weekly up to 24 weeks, weeks 1 
to 24
SAC
2.132.
ITT
EFF_T31
Summary of Baseline Global Assessment of Severity
SAC
2.133.
ITT
EFF_T32
Summary of Global Assessment of Severity and Response to 
Treatment (On- and Post-Treatment)
Weeks 4, 12, 24, 36 and 52
SAC
2.134.
ITT
EFF_T33
Summary of Work Productivity and Activity Impairment-Specific 
Health Problem (On- and Post-Treatment) 
Day 1, Week 12, Week 24, and 
Week 52
SAC
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.135.
ITT
EFF_T30
Summary of Unscheduled Asthma-Related Healthcare Resource 
Utilization up to Week 24 (On- and Post-Treatment)
SAC
2.136.
ITT
EFF_T30
Summary of Unscheduled Asthma-Related Healthcare Resource 
Utilization up to Week 52 for Subjects with ≥ 36 Weeks of 
Planned Treatment Exposure (On- and Post-Treatment)
SAC
2.137.
ITT
EFF_T30
Summary of Unscheduled Asthma-Related Healthcare Resource 
Utilization up to Week 24 (On- and Post-Treatment) by Contact 
Type
SAC
2.138.
ITT
EFF_T30
Summary of Unscheduled Asthma-Related Healthcare Resource 
Utilization up to Week 52 for Subjects with ≥ 36 Weeks of 
Planned Treatment Exposure (On- and Post-Treatment) by 
Contact Type
SAC
11.10.7.
Efficacy Figures
Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Primary Efficacy Endpoint
2.1.
ITT
EFF_F1
Box Plot of Change from Baseline in Clinic Trough FEV1 (L) (On-
and Post-Treatment)
Page per time point. Weeks 4, 12, 
24, 36 and 52
SAC [1]
2.2.
ITT
EFF_F2
Empirical Distribution Function Plot of Change from Baseline in 
Clinic Trough FEV1 (L) (On- and Post-Treatment)
Weeks 4, 12, 24, 36 and 52
SAC
2.3.
ITT
EFF_F3
Least Squares Mean (95% CI) Change from Baseline in Clinic 
weeks 4, 12, 24
SAC [1]
 
 
 
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Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Trough FEV1 (L) up to Week 24 (On- and Post-Treatment)
2.4.
ITT
EFF_F4
Least Squares Mean (95% CI) Treatment Difference in Change 
from Baseline in Clinic Trough FEV1 (L) up to Week 24 (On- and 
Post-Treatment)
weeks 4, 12, 24
SAC [1]
2.5.
ITT
EFF_F1
Box Plot of Change from Baseline in Clinic Trough FEV1 (L) (On-
Treatment)
Weeks 4, 12, 24, 36 and 52
SAC
2.6.
ITT
EFF_F2
Empirical Distribution Function Plot of Change from Baseline in 
Clinic Trough FEV1 (L) (On-Treatment)
Weeks 4, 12, 24, 36 and 52
SAC
2.7.
ITT
EFF_F3
Least Squares Mean (95% CI) Change from Baseline in Clinic
Trough FEV1 (L) up to Week 24 (On-Treatment)
Weeks 4, 12, 24
SAC
2.8.
ITT
EFF_F4
Least Squares Mean (95% CI) Treatment Difference in Change 
from Baseline in Clinic Trough FEV1 (L) up to Week 24 (On-
Treatment)
Weeks 4, 12, 24
SAC
2.9.
ITT
EFF_F7
Forest Plot of Least Squares Mean (95% CI) Treatment 
Difference in Change from Baseline in Clinic Trough FEV1 (L) 
and Associated Supportive/Sensitivity Analyses at Week 24
Forest plot at Week 24
SAC
2.10.
ITT
EFF_F5
Tipping Point Heat Plot for Mean Change from Baseline in Clinic 
Trough FEV1 (L) Difference FF/UMEC/VI 100/62.5/25 v FF/VI 
100/25 at Week 24 (On- and Post-Treatment)
Week 24
SAC
2.11.
ITT
EFF_F6
Tipping Point Line Plot for Mean Change from Baseline in Clinic 
Trough FEV1 (L) Difference FF/UMEC/VI 100/62.5/25 v FF/VI 
100/25 at Week 24 (On- and Post-Treatment)
Week 24
SAC
2.12.
ITT
EFF_F5
Tipping Point Heat Plot for Mean Change from Baseline in Clinic 
Trough FEV1 (L) Difference FF/UMEC/VI 200/62.5/25 v FF/VI 
200/25 at Week 24 (On- and Post-Treatment)
Week 24
SAC
2.13.
ITT
EFF_F6
Tipping Point Line Plot for Mean Change from Baseline in Clinic 
Week 24
SAC
 
 
 
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Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Trough FEV1 (L) Difference FF/UMEC/VI 200/62.5/25 v FF/VI 
200/25 at Week 24 (On- and Post-Treatment)
2.14.
ITT
EFF_F5
Tipping Point Heat Plot for Mean Change from Baseline in Clinic 
Trough FEV1 (L) Difference FF/UMEC/VI 100/31.25/25 v FF/VI 
100/25 at Week 24 (On- and Post-Treatment)
Week 24
SAC
2.15.
ITT
EFF_F6
Tipping Point Line Plot for Mean Change from Baseline in Clinic 
Trough FEV1 (L) Difference FF/UMEC/VI 100/31.25/25 v FF/VI 
100/25 at Week 24 (On- and Post-Treatment)
Week 24
SAC
2.16.
ITT
EFF_F5
Tipping Point Heat Plot for Mean Change from Baseline in Clinic 
Trough FEV1 (L) Difference FF/UMEC/VI 200/31.25/25 v FF/VI 
200/25 at Week 24 (On- and Post-Treatment)
Week 24
SAC
2.17.
ITT
EFF_F6
Tipping Point Line Plot for Mean Change from Baseline in Clinic 
Trough FEV1 (L) Difference FF/UMEC/VI 200/31.25/25 v FF/VI 
200/25 at Week 24 (On- and Post-Treatment)
Week 24
SAC
2.18.
ITT
EFF_F3
Least Squares Mean (95% CI) Change from Baseline in Clinic 
Trough FEV1 (L) up to Week 24 (On- and Post-Treatment) -
Pooled FF Doses
Weeks 4, 12, 24
SAC
2.19.
ITT
EFF_F4
Least Squares Mean (95% CI) Treatment Difference in Change 
from Baseline in Clinic Trough FEV1 (L) up to Week 24 (On- and 
Post-Treatment) - Pooled FF Doses
Weeks 4, 12, 24
SAC
Key Secondary Efficacy Endpoint
2.20.
ITT
EFF_F8
Forest Plot of Adjusted Moderate/Severe Asthma Exacerbations 
Rate Ratio (On- and Post-Treatment) - Pooled FF Doses
Weeks 1-24 and 1-52
SAC [1]
2.21.
ITT
EFF_F8
Forest Plot of Adjusted Moderate/Severe Asthma Exacerbations 
Rate Ratio (On-Treatment) - Pooled FF Doses
Weeks 1-24 and 1-52
SAC
2.22.
ITT
EFF_F9
Forest Plot of Adjusted Moderate/Severe Asthma Exacerbations 
Weeks 1-52
SAC
 
 
 
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Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Rate Ratio and Associated Supportive/Sensitivity Analyses over 
Weeks 1-52 - Pooled FF Doses
2.23.
ITT
EFF_F5
Tipping Point Heat Plot for Adjusted Moderate/Severe Asthma 
Exacerbations Rate Ratio over Weeks 1-52 FF/UMEC/VI UMEC 
62.5 vs. FF/VI (On- and Post-Treatment) - Pooled FF Doses
Weeks 1-52
SAC
2.24.
ITT
EFF_F6
Tipping Point Line Plot Adjusted Moderate/Severe Asthma 
Exacerbations Rate Ratio over Weeks 1-52 FF/UMEC/VI UMEC 
62.5 vs. FF/VI (On- and Post-Treatment) - Pooled FF Doses
Weeks 1-52
SAC
2.25.
ITT
EFF_F5
Tipping Point Heat Plot for Adjusted Moderate/Severe Asthma 
Exacerbations Rate Ratio over Weeks 1-52 FF/UMEC/VI UMEC 
31.25 vs. FF/VI (On- and Post-Treatment) - Pooled FF Doses
Weeks 1-52
SAC
2.26.
ITT
EFF_F6
Tipping Point Line Plot Adjusted Moderate/Severe Asthma 
Exacerbations Rate Ratio over Weeks 1-52 FF/UMEC/VI UMEC 
31.25 vs. FF/VI (On- and Post-Treatment) - Pooled FF Doses
Weeks 1-52
SAC
2.27.
ITT
EFF_F9
Forest Plot of Adjusted Moderate/Severe Asthma Exacerbations 
Rate Ratio (On- and Post-Treatment)
Weeks 1-24 and 1-52
SAC [1]
Other Secondary Efficacy Endpoints
2.28.
ITT
EFF_F1
Box Plot of Change from Baseline in Clinic FEV1 (L) at 3 Hours 
Post Study Treatment at Week 24 (On-Treatment)
At week 24
SAC
2.29.
ITT
EFF_F2
Empirical Distribution Function Plot of Change from Baseline in 
Clinic FEV1 (L) at 3 Hours Post Study Treatment at Week 24 
(On-Treatment)
At week 24
SAC
2.30.
ITT
EFF_F10
Least Squares Mean (95% CI) Change from Baseline in Clinic 
FEV1 (L) at 3 Hours Post Study Treatment at Week 24 (On-
Treatment)
At week 24
SAC
2.31.
ITT
EFF_F11
Least Squares Mean (95% CI) Treatment Difference in Change 
At week 24
SAC
 
 
 
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Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
from Baseline in Clinic FEV1 (L) at 3 Hours Post Study 
Treatment at Week 24 (On-Treatment)
2.32.
ITT
EFF_F10
Least Squares Mean (95% CI) Change from Baseline in Clinic 
FEV1 (L) at 3 Hours Post Study Treatment at Week 24 (On-
Treatment) - Pooled FF Doses
At week 24
SAC
2.33.
ITT
EFF_F11
Least Squares Mean (95% CI) Treatment Difference in Change 
from Baseline in Clinic FEV1 (L) at 3 Hours Post Study 
Treatment at Week 24 (On-Treatment) - Pooled FF Doses
At week 24
SAC
2.34.
ITT
EFF_F1
Box Plot of Change from Baseline in SGRQ Total Score (On-
and Post-Treatment) - Pooled FF Doses
At weeks 12, 24, 36 and 52
SAC
2.35.
ITT
EFF_F2
Empirical Distribution Function Plot of Change from Baseline in 
SGRQ Total Score (On- and Post-Treatment) - Pooled FF 
Doses
At weeks 12, 24, 36 and 52
SAC
2.36.
ITT
EFF_F3
Least Squares Mean (95% CI) Change from Baseline in SGRQ 
Total Score up to Week 24 (On- and Post-Treatment) - Pooled 
FF Doses
At weeks 12, and 24
SAC
2.37.
ITT
EFF_F4
Least Squares Mean (95% CI) Treatment Difference in Change 
from Baseline in SGRQ Total Score up to Week 24 (On- and 
Post-Treatment) - Pooled FF Doses
At weeks 12, and 24
SAC
2.38.
ITT
EFF_F1
Box Plot of Change from Baseline in SGRQ Total Score (On-
and Post-Treatment)
At weeks 12, 24, 36 and 52
SAC
2.39.
ITT
EFF_F2
Empirical Distribution Function Plot of Change from Baseline in 
SGRQ Total Score (On- and Post-Treatment) 
At weeks 12, 24, 36 and 52
SAC
2.40.
ITT
EFF_F3
Least Squares Mean (95% CI) Change from Baseline in SGRQ 
Total Score up to Week 24 (On- and Post-Treatment)
At weeks 12, and 24
SAC
2.41.
ITT
EFF_F4
Least Squares Mean (95% CI) Treatment Difference in Change 
At weeks 12, and 24
SAC
 
 
 
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Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
from Baseline in SGRQ Total Score up to Week 24 (On- and 
Post-Treatment)
2.42.
ITT
EFF_F1
Box Plot of Change from Baseline in ACQ-7 Total Score (On-
and Post-Treatment) - Pooled FF Doses
At weeks 4, 12, 24, 36 and 52
SAC
2.43.
ITT
EFF_F2
Empirical Distribution Function Plot of Change from Baseline in 
ACQ-7 Total Score (On- and Post-Treatment) - Pooled FF 
Doses
At weeks 4, 12, 24, 36 and 52
SAC
2.44.
ITT
EFF_F3
Least Squares Mean (95% CI) Change from Baseline in ACQ-7 
Total Score up to Week 24 (On- and Post-Treatment) - Pooled 
FF Doses
At weeks 4, 12, and 24
SAC
2.45.
ITT
EFF_F4
Least Squares Mean (95% CI) Treatment Difference in Change 
from Baseline in ACQ-7 Total Score up to Week 24 (On- and 
Post-Treatment) - Pooled FF Doses
At weeks 4, 12, and 24
SAC
2.46.
ITT
EFF_F1
Box Plot of Change from Baseline in ACQ-7 Total Score (On-
and Post-Treatment)
At weeks 4, 12, 24, 36 and 52
SAC
2.47.
ITT
EFF_F2
Empirical Distribution Function Plot of Change from Baseline in 
ACQ-7 Total Score (On- and Post-Treatment)
At weeks 4, 12, 24, 36 and 52
SAC
2.48.
ITT
EFF_F3
Least Squares Mean (95% CI) Change from Baseline in ACQ-7 
Total Score up to Week 24 (On- and Post-Treatment)  
At weeks 4, 12, and 24
SAC
2.49.
ITT
EFF_F4
Least Squares Mean (95% CI) Treatment Difference in Change 
from Baseline in ACQ-7 Total Score up to Week 24 (On- and 
Post-Treatment)  
At weeks 4, 12, and 24
SAC
2.50.
ITT
EFF_F1
Box Plot of Change from Baseline in E-RS Total Score by 4-
Weekly Intervals (On- and Post-Treatment) - Pooled FF Doses
4-weekly intervals up to week 52
SAC
2.51.
ITT
EFF_F2
Empirical Distribution Function Plot of Change from Baseline in 
E-RS Total Score by 4-Weekly Intervals (On- and Post-
4-weekly intervals up to week 52
SAC
 
 
 
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Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Treatment) - Pooled FF Doses
2.52.
ITT
EFF_F12
Least Squares Mean (95% CI) Change from Baseline in E-RS 
Total Score up to Week 24 by 4-Weekly Intervals (On- and Post-
Treatment) - Pooled FF Doses
4-weekly intervals up to week 24
SAC
2.53.
ITT
EFF_F13
Least Squares Mean (95% CI) Treatment Difference in Change 
from Baseline in E-RS Total Score up to Week 24 by 4-Weekly 
Intervals (On- and Post-Treatment) - Pooled FF Doses
4-weekly intervals up to week 24
SAC
2.54.
ITT
EFF_F10
Forest Plot of Least Squares Mean (95% CI) Change from 
Baseline in E-RS Total Score over Weeks 1-24 (On- and Post-
Treatment) – Pooled FF Doses
Forest plot of week 1-24 analysis
SAC
2.55.
ITT
EFF_F11
Forest Plot of Least Squares Mean (95% CI) Treatment 
Difference in Change from Baseline in E-RS Total Score over 
Weeks 1-24 (On- and Post-Treatment) – Pooled FF Doses
Forest plot of week 1-24 analysis
SAC
2.56.
ITT
EFF_F1
Box Plot of Change from Baseline in E-RS Total Score by 4-
Weekly Intervals (On- and Post-Treatment)
4-weekly intervals up to week 52
SAC
2.57.
ITT
EFF_F2
Empirical Distribution Function Plot of Change from Baseline in 
E-RS Total Score by 4-Weekly Intervals (On- and Post-
Treatment)
4-weekly intervals up to week 52
SAC
2.58.
ITT
EFF_F12
Least Squares Mean (95% CI) Change from Baseline in E-RS 
Total Score up to Week 24 by 4-Weekly Intervals (On- and Post-
Treatment)
4-weekly intervals up to week 24
SAC
2.59.
ITT
EFF_F13
Least Squares Mean (95% CI) Treatment Difference in Change 
from Baseline in E-RS Total Score up to Week 24 by 4-Weekly 
Intervals (On- and Post-Treatment)
4-weekly intervals up to week 24
SAC
2.60.
ITT
EFF_F10
Forest Plot of Least Squares Mean (95% CI) Change from 
Baseline in E-RS Total Score over Weeks 1-24 (On- and Post-
Forest plot of week 1-24 analysis
SAC
 
 
 
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205715
149
Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Treatment)
2.61.
ITT
EFF_F11
Forest Plot of Least Squares Mean (95% CI) Treatment 
Difference in Change from Baseline in E-RS Total Score over 
Weeks 1-24 (On- and Post-Treatment)
Forest plot of week 1-24 analysis
SAC
Other Efficacy Endpoints
2.62.
ITT
EFF_F10
Least Squares Mean (95% CI) Change from Baseline in Clinic 
Trough FEV1 (L) over the First 24 Weeks (On- and Post-
Treatment)
AUC0-24w
SAC
2.63.
ITT
EFF_F11
Least Squares Mean (95% CI) Treatment Difference in Change 
from Baseline in Clinic Trough FEV1 (L) over the First 24 Weeks 
(On- and Post-Treatment)
AUC0-24w
SAC
2.64.
ITT
EFF_F12
Least Squares Mean (95% CI) Change from Baseline in Home 
Daily Trough FEV1 (L) up to Week 24 by 4-Weekly Intervals (On-
and Post-Treatment)
4-weekly intervals up to week 24
SAC
2.65.
ITT
EFF_F13
Least Squares Mean (95% CI) Treatment Difference in Change 
from Baseline in Home Daily Trough FEV1 (L) up to Week 24 by 
4-Weekly Intervals (On- and Post-Treatment)
4-weekly intervals up to week 24
SAC
2.66.
ITT
EFF_F10
Forest Plot of Least Squares Mean (95% CI) Change from 
Baseline in Home Daily Trough FEV1 (L) over Weeks 1-24 (On-
and Post-Treatment)
Forest plot of week 1-24 analysis
SAC
2.67.
ITT
EFF_F11
Forest Plot of Least Squares Mean (95% CI) Treatment 
Difference in Change from Baseline in Home Daily Trough FEV1
(L) over Weeks 1-24 (On- and Post-Treatment)
Forest plot of week 1-24 analysis
SAC
2.68.
ITT
EFF_F3
Least Squares Mean (95% CI) Change from Baseline in Home 
Daily Trough FEV1 (L) up to Week 8 by 1-Week Intervals (On-
and Post-Treatment)
weekly intervals up to week 8
SAC
 
 
 
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150
Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.69.
ITT
EFF_F4
Least Squares Mean (95% CI) Treatment Difference in Change 
from Baseline in Home Daily Trough FEV1 (L) up to Week 8 by 
1-Week Intervals (On- and Post-Treatment)
weekly intervals up to week 8
SAC
2.70.
ITT
EFF_F12
Descriptive Weekly Mean Change from Baseline in Home Daily 
Trough FEV1 (L) up to Week 24 (On- and Post-Treatment)
weekly intervals up to week 24
SAC
2.71.
ITT
EFF_F12
Least Squares Mean (95% CI) Change from Baseline in Home 
Daily PM FEV1 (L) up to Week 24 by 4-Weekly Intervals (On-
and Post-Treatment)
4-weekly intervals up to week 24
SAC
2.72.
ITT
EFF_F13
Least Squares Mean (95% CI) Treatment Difference in Change 
from Baseline in Home Daily PM FEV1 (L) up to Week 24 by 4-
Weekly Intervals (On- and Post-Treatment)
4-weekly intervals up to week 24
SAC
2.73.
ITT
EFF_F10
Forest Plot of Least Squares Mean (95% CI) Change from 
Baseline in Home Daily PM FEV1 (L) over Weeks 1-24 (On- and 
Post-Treatment)
Forest plot of week 1-24 analysis
SAC
2.74.
ITT
EFF_F11
Forest Plot of Least Squares Mean (95% CI) Treatment 
Difference in Change from Baseline in Home Daily PM FEV1 (L) 
over Weeks 1-24 (On- and Post-Treatment)
Forest plot of week 1-24 analysis
SAC
2.75.
ITT
EFF_F12
Descriptive Weekly Mean Change from Baseline in Home Daily 
PM FEV1 (L) up to Week 24 (On- and Post-Treatment)
weekly intervals up to week 24
SAC
2.76.
ITT
EFF_F12
Least Squares Mean (95% CI) Change from Baseline in Home 
Daily AM PEF (L/min) up to Week 24 by 4-Weekly Intervals (On-
and Post-Treatment)
4-weekly intervals up to week 24
SAC
2.77.
ITT
EFF_F13
Least Squares Mean (95% CI) Treatment Difference in Change 
from Baseline in Home Daily AM PEF (L/min) up to Week 24 by 
4-Weekly Intervals (On- and Post-Treatment)
4-weekly intervals up to week 24
SAC
2.78.
ITT
EFF_F10
Forest Plot of Least Squares Mean (95% CI) Change from 
Baseline in Home Daily AM PEF (L/min) over Weeks 1-24 (On-
Forest plot of week 1-24 analysis
SAC
 
 
 
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151
Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
and Post-Treatment)
2.79.
ITT
EFF_F11
Forest Plot of Least Squares Mean (95% CI) Treatment 
Difference in Change from Baseline in Home Daily AM PEF 
(L/min) over Weeks 1-24 (On- and Post-Treatment)
Forest plot of week 1-24 analysis
SAC
2.80.
ITT
EFF_F12
Descriptive Weekly Mean Change from Baseline in Home Daily 
AM PEF (L/min) up to Week 24 (On- and Post-Treatment)
Weekly up to 24 weeks
SAC
2.81.
ITT
EFF_F12
Least Squares Mean (95% CI) Change from Baseline in Home 
Daily PM PEF (L/min) up to Week 24 by 4-Weekly Intervals (On-
and Post-Treatment)
4-weekly intervals up to week 24
SAC
2.82.
ITT
EFF_F13
Least Squares Mean (95% CI) Treatment Difference in Change 
from Baseline in Home Daily PM PEF (L/min) up to Week 24 by 
4-Weekly Intervals (On- and Post-Treatment)
4-weekly intervals up to week 24
SAC
2.83.
ITT
EFF_F10
Forest Plot of Least Squares Mean (95% CI) Change from 
Baseline in Home Daily PM PEF (L/min) over Weeks 1-24 (On-
and Post-Treatment)
Forest plot of week 1-24 analysis
SAC
2.84.
ITT
EFF_F11
Forest Plot of Least Squares Mean (95% CI) Treatment 
Difference in Change from Baseline in Home Daily PM PEF 
(L/min) over Weeks 1-24 (On- and Post-Treatment)
Forest plot of week 1-24 analysis
SAC
2.85.
ITT
EFF_F12
Descriptive Weekly Mean Change from Baseline in Home Daily 
PM PEF (L/min) up to Week 24 (On- and Post-Treatment)
Weekly up to 24 weeks
SAC
2.86.
ITT
EFF_F14
Kaplan-Meier Plot of Time to First Moderate/Severe Asthma 
Exacerbation (On- and Post-Treatment) - Pooled FF Doses
Weeks 1-52
SAC
2.87.
ITT
EFF_F14
Kaplan-Meier Plot of Time to First Moderate/Severe Asthma 
Exacerbation (On- and Post-Treatment)
Weeks 1-52
SAC
2.88.
ITT
EFF_F14
Kaplan-Meier Plot of Time to First Severe Asthma Exacerbation 
(On- and Post-Treatment) - Pooled FF Doses
Weeks 1-52
SAC
2.89.
ITT
EFF_F14
Kaplan-Meier Plot of Time to First Severe Asthma Exacerbation 
(On- and Post-Treatment)
Weeks 1-52
SAC
2.90.
ITT
EFF_F8
Odds Ratio for Percent of Patients Meeting a Responder 
Week 24
SAC
 
 
 
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152
Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Threshold of 0.5 Improvement (Decrease) from Baseline for 
the ACQ-7 Total Score at Week 24 (On- and Post-Treatment) -
Pooled FF Doses
2.91.
ITT
EFF_F8
Odds Ratio for Percent of Patients Meeting a Responder 
Threshold of 0.5 Improvement (Decrease) from Baseline for 
the ACQ-6 Total Score at Week 24 (On- and Post-Treatment) -
Pooled FF Doses
Week 24
SAC
2.92.
ITT
EFF_F8
Odds Ratio for Percent of Patients Meeting a Responder 
Threshold of 0.5 Improvement (Decrease) from Baseline for 
the ACQ-5 Total Score at Week 24 (On- and Post-Treatment) -
Pooled FF Doses
Week 24
SAC
2.93.
ITT
EFF_F8
Odds Ratio for Percent of Patients Meeting a Responder 
Threshold of 0.5 Improvement (Decrease) from Baseline for 
the ACQ-7 Total Score at Week 24 (On- and Post-Treatment) 
Week 24
SAC
2.94.
ITT
EFF_F8
Odds Ratio for Percent of Patients that Have Achieved Asthma 
Control Based on ACQ-7 (i.e. a Total Score ≤0.75) at both Week 
12 and Week 24 (On- and Post-Treatment) - Pooled FF Doses
SAC
2.95.
ITT
EFF_F8
Odds Ratio for Percent of Patients that Have Achieved Asthma 
Control Based on ACQ-6 (i.e. a Total Score ≤0.75) at both Week 
12 and Week 24 (On- and Post-Treatment) - Pooled FF Doses
SAC
2.96.
ITT
EFF_F8
Odds Ratio for Percent of Patients that Have Achieved Asthma 
Control Based on ACQ-5 (i.e. a Total Score ≤0.75) at both Week 
12 and Week 24 (On- and Post-Treatment) - Pooled FF Doses
SAC
2.97.
ITT
EFF_F8
Odds Ratio for Percent of Patients that Have Achieved Asthma 
Control Based on ACQ-7 (i.e. a Total Score ≤0.75) at both Week 
12 and Week 24 (On- and Post-Treatment)
SAC
2.98.
ITT 
EFF_F15
Forest Plot of Least Squares Mean Treatment Difference in 
Forest plot at week 24
SAC
 
 
 
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Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Change from Baseline in SGRQ Total and Domain Scores at 
Week 24 (On- and Post-Treatment) – Pooled FF Doses  
2.99.
ITT
EFF_F8
Odds Ratio for Percent of Patients Meeting a Responder
Threshold of ≥ 4 Points Improvement (Decrease) from Baseline 
for the SGRQ Total Score at Week 24 (On- and Post-Treatment) 
- Pooled FF Doses
Week 24
SAC
2.100.
ITT
EFF_F8
Odds Ratio for Percent of Patients Meeting a Responder 
Threshold of ≥ 4 Points Improvement (Decrease) from Baseline 
for the SGRQ Total Score at Week 24 (On- and Post-Treatment)
Week 24
SAC
2.101.
ITT 
EFF_F15
Forest Plot of Least Squares Mean Treatment Difference in 
Change from Baseline in E-RS Total and Domain Scores over 
Weeks 21-24 (Inclusive) of the Treatment Period (On- and Post-
Treatment) – Pooled FF Doses  
Forest plot at weeks 21-24
SAC
2.102.
ITT
EFF_F8
Odds Ratio for Percent of Patients Meeting a Responder 
Threshold of ≥ 2 Points Improvement (Decrease) from Baseline 
for the E-RS Total Score Over Weeks 21-24 (Inclusive) of the 
Treatment Period (On- and Post-Treatment) - Pooled FF Doses
Weeks 21-24
SAC
2.103.
ITT
EFF_F8
Odds Ratio for Percent of Patients Meeting a Responder 
Threshold of ≥ 2 Points Improvement (Decrease) from Baseline 
for the E-RS Total Score Over Weeks 21-24 (Inclusive) of the 
Treatment Period (On- and Post-Treatment)
Weeks 21-24
SAC
2.104.
ITT
EFF_F3
Least Squares Mean (95% CI) Change from Baseline in AQLQ 
Total Score up to Week 24 (On- and Post-Treatment) - Pooled 
FF Doses
Weeks 4,12,24,26 and 52
SAC
2.105.
ITT
EFF_F4
Least Squares Mean (95% CI) Treatment Difference in Change 
from Baseline in AQLQ Total Score up to Week 24 (On- and 
Post-Treatment) - Pooled FF Doses
Weeks 4,12,24,26 and 52
SAC
2.106.
ITT
EFF_F8
Odds Ratio for Percent of Patients Meeting a Responder 
Threshold of ≥ 0.5 Points Improvement (Increase) from Baseline 
Week 24
SAC
 
 
 
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Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
for the AQLQ Total Score at Week 24 (On- and Post-Treatment) 
- Pooled FF Doses
2.107.
ITT
EFF_F12
Least Squares Mean (95% CI) Change from Baseline in 
Percentage of Symptom-Free Days up to Week 24 by 4-Weekly 
Intervals (On- and Post-Treatment) - Pooled FF Doses 
4-weekly intervals up to week 24
SAC
2.108.
ITT
EFF_F13
Least Squares Mean (95% CI) Treatment Difference in Change 
from Baseline in Percentage of Symptom-Free Days up to Week 
24 by 4-Weekly Intervals On- and Post-Treatment) - Pooled FF 
Doses
4-weekly intervals up to week 24
SAC
2.109.
ITT
EFF_F10
Forest Plot of Least Squares Mean (95% CI) Change from 
Baseline in Percentage of Symptom-Free Days over Weeks 1-
24 (On- and Post-Treatment) - Pooled FF Doses
Forest plot of week 1-24 analysis
SAC
2.110.
ITT
EFF_F11
Forest Plot of Least Squares Mean (95% CI) Treatment 
Difference in Change from Baseline in Percentage of Symptom-
Free Days over Weeks 1-24 (On- and Post-Treatment) - Pooled 
FF Doses
Forest plot of week 1-24 analysis
SAC
2.111.
ITT
EFF_F12
Least Squares Mean (95% CI) Change from Baseline in 
Percentage of Rescue Medication-Free Days up to Week 24 by 
4-Weekly Intervals (On- and Post-Treatment) - Pooled FF Doses
4-weekly intervals up to week 24
SAC
2.112.
ITT
EFF_F13
Least Squares Mean (95% CI) Treatment Difference in Change 
from Baseline in Percentage of Rescue Medication-Free Days
up to Week 24 by 4-Weekly Intervals (On- and Post-Treatment) -
Pooled FF Doses
4-weekly intervals up to week 24
SAC
2.113.
ITT
EFF_F10
Forest Plot of Least Squares Mean (95% CI) Change from 
Baseline in Percentage of Rescue Medication-Free Days over 
Weeks 1-24 (On- and Post-Treatment) - Pooled FF Doses
Forest plot of week 1-24 analysis
SAC
2.114.
ITT
EFF_F11
Forest Plot of Least Squares Mean (95% CI) Treatment 
Forest plot of week 1-24 analysis
SAC
 
 
 
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Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Difference in Change from Baseline in Percentage of Rescue 
Medication-Free Days over Weeks 1-24 (On- and Post-
Treatment) - Pooled FF Doses
2.115.
ITT
EFF_F12
Least Squares Mean (95% CI) Change from Baseline in Daily 
Rescue Medication Use (Puffs/Day) up to Week 24 by 4-Weekly 
Intervals (On- and Post-Treatment) - Pooled FF Doses
4-weekly intervals up to week 24
SAC
2.116.
ITT
EFF_F13
Least Squares Mean (95% CI) Treatment Difference in Change 
from Baseline in Daily Rescue Medication Use (Puffs/Day) up to 
Week 24 by 4-Weekly Intervals (On- and Post-Treatment) -
Pooled FF Doses
4-weekly intervals up to week 24
SAC
2.117.
ITT
EFF_F10
Forest Plot of Least Squares Mean (95% CI) Change from 
Baseline in Daily Rescue Medication Use (Puffs/Day) over 
Weeks 1-24 (On- and Post-Treatment) - Pooled FF Doses
Forest plot of week 1-24 analysis
SAC
2.118.
ITT
EFF_F11
Forest Plot of Least Squares Mean (95% CI) Treatment 
Difference in Change from Baseline in Daily Rescue Medication 
Use (Puffs/Day) over Weeks 1-24 (On- and Post-Treatment) -
Pooled FF Doses
Forest plot of week 1-24 analysis
SAC
 
 
 
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11.10.8.
Safety Tables
Safety: Tables
No.
Population
IDSL ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Exposure
3.1.
ITT
EX1
Summary of Exposure to Fluticasone/Salmeterol 250/50 
via the DISKUS DPI During the Run-in Period
SAC
3.2.
ITT
EX1
Summary of Exposure to FF/VI 100/25 via the ELLIPTA 
DPI During the Stabilization Period
SAC
3.3.
ITT
EX1
Summary of Exposure
SAC [1]
3.4.
ITT
EX1
Summary of Exposure – Pooled FF Doses
SAC 
3.5.
ITT
SAFE_T1
Summary of Post-Treatment Duration 
SAC
Adverse Events
3.6.
ITT
AE1
Summary of Adverse Events During Screening/Run-in Period
Include total column
SAC
3.7.
ITT
AE1
Summary of Adverse Events During Stabilization Period
Include total column
SAC
3.8.
ITT
AE13
Overview of On-Treatment Adverse Events 
SAC [1]
3.9.
ITT
SAFE_T2
Overview of On-Treatment Adverse Events per Thousand 
Person-Years
SAC
3.10.
ITT
AE1
Summary of On-Treatment Adverse Events 
SAC [1]
3.11.
ITT
SAFE_T3
Summary of On-Treatment Adverse Events per Thousand 
Person-Years
SAC
3.12.
ITT
AE1
Summary of On-Treatment Adverse Events in the Respiratory, 
Thoracic and Mediastinal Disorders System Organ Class 
(Primary or Secondary) 
SAC
3.13.
ITT
SAFE_T3
Summary of On-Treatment Adverse Events in the Respiratory, 
Thoracic and Mediastinal Disorders System Organ Class 
(Primary or Secondary) per Thousand Person-Years
SAC
 
 
 
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Safety: Tables
No.
Population
IDSL ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.14.
ITT
AE1
Summary of Post-Treatment Adverse Events 
SAC
3.15.
ITT
AE1
Summary of Post-Study Adverse Events 
SAC
3.16.
ITT
AE1
Summary of On-Treatment Adverse Events Up to Week 24
SAC
3.17.
ITT
SAFE-T3
Summary of On-Treatment Adverse Events Up to Week 24 per 
Thousand Person-Years
SAC
3.18.
ITT
AE1
Summary of On-Treatment Adverse Events Up to Week 36 for 
Subjects with ≥ 36 Weeks of Planned Treatment Exposure
SAC
3.19.
ITT
SAFE-T3
Summary of On-Treatment Adverse Events Up to Week 36 for 
Subjects with ≥ 36 Weeks of Planned Treatment Exposure per 
Thousand Person-Years
SAC
3.20.
ITT
AE1
Summary of On-Treatment Adverse Events for Subjects with 52 
Weeks of Planned Treatment Exposure
SAC
3.21.
ITT
SAFE-T3
Summary of On-Treatment Adverse Events for Subjects with 52 
Weeks of Planned Treatment Exposure per Thousand Person-
Years
SAC
3.22.
ITT
AE1
Summary of On-Treatment Drug-Related Adverse Events 
SAC [1]
3.23.
ITT
SAFE_T3
Summary of On-Treatment Drug-Related Adverse Events per 
Thousand Person-Years
SAC
3.24.
ITT
AE1
Summary of Post-Treatment Drug-Related Adverse Events 
SAC
3.25.
ITT
AE1
Summary of On-Treatment Serious Adverse Events 
SAC [1]
3.26.
ITT
SAFE_T3
Summary of On-Treatment Serious Adverse Events per 
Thousand Person-Years
SAC
3.27.
ITT
AE1
Summary of Post-Treatment Serious Adverse Events 
SAC
3.28.
ITT
AE1
Summary of On-Treatment Serious Adverse Events Up to Week 
24
SAC
3.29.
ITT
SAFE-T3
Summary of On-Treatment Serious Adverse Events Up to Week 
24 per Thousand Person-Years 
SAC
 
 
 
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Safety: Tables
No.
Population
IDSL ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.30.
ITT
AE1
Summary of On-Treatment Serious Adverse Events Up to Week 
36 for Subjects with ≥ 36 Weeks of Planned Treatment 
Exposure
SAC
3.31.
ITT
SAFE-T3
Summary of On-Treatment Serious Adverse Events Up to Week 
36 for Subjects with ≥ 36 Weeks of Planned Treatment 
Exposure per Thousand Person-Years
SAC
3.32.
ITT
AE1
Summary of On-Treatment Serious Adverse Events for Subjects 
with 52 Weeks of Planned Treatment Exposure
SAC
3.33.
ITT
SAFE-T3
Summary of On-Treatment Serious Adverse Events for Subjects 
with 52 Weeks of Planned Treatment Exposure per Thousand 
Person-Years
SAC
3.34.
ITT
AE1
Summary of On-Treatment Drug-Related Serious Adverse 
Events 
SAC
3.35.
ITT
SAFE_T3
Summary of On-Treatment Drug-Related Serious Adverse 
Events per Thousand Person-Years
SAC
3.36.
ITT
AE1
Summary of On-Treatment Non-Serious Drug-Related Adverse 
Events 
Required for Plain Language Summary
SAC
3.37.
ITT
SAFE_T3
Summary of On-Treatment Non-Serious Drug-Related Adverse 
Events per Thousand Person-Years
Required for Plain Language Summary
SAC
3.38.
ITT
AE1
Summary of On-Treatment Adverse Events Leading to 
Permanent Discontinuation of Study Drug or Withdrawal from 
the Study
SAC [1]
3.39.
ITT
AE1
Summary of Post-Treatment Adverse Events Leading to 
Withdrawal from the Study
SAC
3.40.
ITT
SAFE_T4
Summary of On-Treatment Adverse Events of Special Interest 
SAC [1]
3.41.
ITT
SAFE_T5
Summary of On-Treatment Adverse Events of Special Interest 
per Thousand Person-Years
SAC
 
 
 
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Safety: Tables
No.
Population
IDSL ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.42.
ITT
AE1
Summary of On-Treatment Adverse Events of Special Interest 
Up to Week 24
SAC
3.43.
ITT
SAFE-T5
Summary of On-Treatment Adverse Events of Special Interest 
Up to Week 24 per Thousand Person-Years 
SAC
3.44.
ITT
AE1
Summary of On-Treatment Adverse Events of Special Interest 
Up to Week 36 for Subjects with ≥ 36 Weeks of Planned 
Treatment Exposure
SAC
3.45.
ITT
SAFE-T5
Summary of On-Treatment Adverse Events of Special Interest 
Up to Week 36 for Subjects with ≥ 36 Weeks of Planned 
Treatment Exposure per Thousand Person-Years
SAC
3.46.
ITT
AE1
Summary of On-Treatment Adverse Events of Special Interest 
for Subjects with 52 Weeks of Planned Treatment Exposure
SAC
3.47.
ITT
SAFE-T5
Summary of On-Treatment Adverse Events of Special Interest 
for Subjects with 52 Weeks of Planned Treatment Exposure per 
Thousand Person-Years
SAC
3.48.
ITT
AE1
Summary of On-Treatment Serious Adverse Events of Special 
Interest 
SAC
3.49.
ITT
SAFE_T6
Summary of On-Treatment Serious Adverse Events of Special 
Interest per Thousand Person-Years
SAC
3.50.
ITT
AE1
Summary of Post-Treatment Adverse Events of Special Interest 
SAC
3.51.
ITT
AE1
Summary of Post-Treatment Serious Adverse Events of Special 
Interest 
SAC
3.52.
ITT
AE3
Summary of Common On-Treatment Adverse Events (3% or 
More of Subjects in Any Treatment Group) 
SAC
 
 
 
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Safety: Tables
No.
Population
IDSL ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.53.
ITT
AE3
Summary of the 10 Most Frequent On-Treatment Adverse 
Events in Each Treatment Group
SAC
3.54.
ITT
AE1
Summary of On-Treatment Adverse Events by Gender
SAC
3.55.
ITT
AE1
Summary of On-Treatment Adverse Events by Age (<18, 18 to 
<65, 65 to <75, 75 to <85, ≥85 years)
SAC
3.56.
ITT
AE1
Summary of On-Treatment Adverse Events by Age (<65, ≥65 
years)
SAC
3.57.
ITT
AE1
Summary of On-Treatment Adverse Events by Race
SAC
3.58.
ITT
AE1
Summary of On-Treatment Adverse Events by Region
SAC
3.59.
ITT
AE1
Summary of On-Treatment Adverse Events by Pre-Study ICS 
Dosage at Screening
SAC
3.60.
ITT
AE1
Summary of On-Treatment Adverse Events by BMI
SAC
3.61.
ITT
AE1
Summary of On-Treatment Adverse Events by CV History/Risk 
Factor at Screening
SAC
MACE
3.62.
ITT
SAFE_T6
Summary of On-Treatment Major Adverse Cardiac Events 
(MACE) – Narrow Definition
SAC
3.63.
ITT
SAFE_T6
Summary of On-Treatment Major Adverse Cardiac Events 
(MACE) – Broad Definition
SAC
3.64.
ITT
SAFE_T7
Summary of On-Treatment Major Adverse Cardiac Events 
(MACE) per Thousand Person-Years – Narrow Definition
SAC
3.65.
ITT
SAFE_T7
Summary of On-Treatment Major Adverse Cardiac Events 
(MACE) per Thousand Person-Years – Broad Definition
SAC
 
 
 
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Safety: Tables
No.
Population
IDSL ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Pneumonia and Radiography (Chest X-Rays)
3.66.
ITT
SAFE_T8
Summary of On-Treatment Pneumonia
Include the results of chest X-ray
SAC
Laboratory Parameters
3.67.
ITT
LB1
Summary of Chemistry Data (On-Treatment)
SAC
3.68.
ITT
LB1
Summary of Change from Baseline in Chemistry Data (On-
Treatment)
SAC
3.69.
ITT
SAFE_T9
Summary of Chemistry Data Outside the Normal Range (On-
Treatment)
SAC
3.70.
ITT
LB3
Summary of Chemistry Shifts from Baseline Relative to Normal 
Range (On-Treatment)
SAC
3.71.
ITT
LB1
Summary of Hematology Data (On-Treatment)
SAC
3.72.
ITT
LB1
Summary of Change from Baseline in Hematology Data (On-
Treatment)
SAC
3.73.
ITT
SAFE_T9
Summary of Hematology Data Outside the Normal Range (On-
Treatment)
SAC
3.74.
ITT
LB3
Summary of Hematology Shifts from Baseline Relative to 
Normal Range (On-Treatment)
SAC
3.75.
ITT
LB16
Summary of Worst Case Urinalysis Results Post-Baseline 
Relative to Baseline (On-Treatment)
SAC
Vital Signs
3.76.
ITT
VS1
Summary of Vital Signs (On-Treatment)
Present BMI as if calculated to 1 
decimal place.
SAC
3.77.
ITT
VS1
Summary of Change from Baseline in Vital Signs (On-
Treatment)
Present BMI as if calculated to 1 
decimal place.
SAC
 
 
 
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Safety: Tables
No.
Population
IDSL ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.78.
ITT
EFF_T4
Analysis of Mean Change from Baseline in Systolic Blood 
Pressure (mmHg) up to Week 24(On-Treatment)
SAC
3.79.
ITT
EFF_T4
Analysis of Mean Change from Baseline in Diastolic Blood 
Pressure (mmHg) up to Week 24 (On-Treatment)
SAC
3.80.
ITT
EFF_T4
Analysis of Mean Change from Baseline in Pulse Rate 
(beats/min) up to Week 24 (On-Treatment)
SAC
12-Led ECGs
3.81.
ITT
EG2
Summary of ECG Values (On-Treatment)
SAC
3.82.
ITT
EG2
Summary of Change from Baseline in ECG Values (On-
Treatment)
SAC
3.83.
ITT
SAFE_T10
Summary of ECG Findings (On-Treatment)
SAC
3.84.
ITT
SAFE_T11
Summary of ECG Findings Shifts from Baseline (On-Treatment)
SAC
3.85.
ITT
SAFE_T12
Summary of ECG Abnormalities (On-Treatment)
SAC
3.86.
ITT
EFF_T4
Analysis of Mean Change from Baseline in Heart Rate as 
Measured by ECG (beats/min) up to Week 24 (On-Treatment)
SAC
3.87.
ITT
EFF_T4
Analysis of Mean Change from Baseline in PR Interval (msec) 
up to Week 24 (On-Treatment)
SAC
3.88.
ITT
EFF_T4
Analysis of Mean Change from Baseline in QTc(F) (msec) up to 
Week 24 (On-Treatment)
SAC
EudraCT/FDAAA 
3.89.
ITT
AE16
Summary of On-Treatment Serious Adverse Events by System 
Organ Class and Preferred Term (Number of Subjects and 
Occurrences)
SAC
 
 
 
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Safety: Tables
No.
Population
IDSL ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.90.
ITT
AE15
Summary of Common (≥ 3%) On-Treatment Non-Serious 
Adverse Events by System Organ Class and Preferred Term 
(Number of Subjects and Occurrences)
SAC
 
 
 
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11.10.9.
Safety Figures
Safety: Figures
No.
Population
IDSL ID / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Exposure
3.1.
ITT
SAFE_F1
Exposure to Study Treatment over Time
SAC
3.2.
ITT
SAFE_F2
Trellis Display of Maximum Post-Baseline Liver Function 
Test Values, Versus Baseline Liver Function Test Values
(On-Treatment)
SAC
3.3.
ITT
SAFE_F3
Scatter Plots of Maximum Post-Baseline Versus Baseline 
for Chemistry Data (On-Treatment)
SAC
3.4.
ITT
SAFE_F4
Box Plots of Change from Baseline to Maximum Post-
Baseline Values for Chemistry Data (On-Treatment)
SAC
3.5.
ITT
SAFE_F3
Scatter Plots of Minimum Post-Baseline Versus Baseline 
for Chemistry Data (On-Treatment)
SAC
3.6.
ITT
SAFE_F4
Box Plots of Change from Baseline to Minimum Post-
Baseline Values for Chemistry Data (On-Treatment)
SAC
3.7.
ITT
SAFE_F3
Scatter Plots of Maximum Post-Baseline Versus Baseline 
for Hematology Data (On-Treatment)
SAC
3.8.
ITT
SAFE_F4
Box Plots of Change from Baseline to Maximum Post-
Baseline Values for Hematology Data (On-Treatment)
SAC
3.9.
ITT
SAFE_F3
Scatter Plots of Minimum Post-Baseline Versus Baseline 
for Hematology Data (On-Treatment)
SAC
 
 
 
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Safety: Figures
No.
Population
IDSL ID / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.10.
ITT
SAFE_F4
Box Plots of Change from Baseline to Minimum Post-
Baseline Values for Hematology Data (On-Treatment)
SAC
3.11.
ITT
SAFE_F5
Least Squares Mean (95% CI) Change from Baseline in 
Systolic Blood Pressure (mmHg) up to Week 24 (On-
Treatment)
SAC
3.12.
ITT
SAFE_F5
Least Squares Mean (95% CI) Change from Baseline in 
Diastolic Blood Pressure (mmHg) up to Week 24 (On-
Treatment)
SAC
3.13.
ITT
SAFE_F5
Least Squares Mean (95% CI) Change from Baseline in 
Pulse Rate (beats/min) up to Week 24 (On-Treatment)
SAC
3.14.
ITT
EG7
Empirical Distribution Function Plot of Maximum Post-
Baseline QTc(F) (msec) (On-Treatment)
SAC
3.15.
ITT
EG7
Empirical Distribution Function Plot of Change from 
Baseline in Maximum Post-Baseline QTc(F) (msec) (On-
Treatment)
SAC
3.16.
ITT
SAFE_F5
Least Squares Mean (95% CI) Change from Baseline in 
Heart Rate as Measured by ECG (beats/min) up to Week 
24 (On-Treatment)
SAC
3.17.
ITT
SAFE_F5
Least Squares Mean (95% CI) Change from Baseline in 
PR Interval (msec) up to Week 24 (On-Treatment)
SAC
3.18.
ITT
SAFE_F5
Least Squares Mean (95% CI) Change from Baseline in 
QTc(F) (msec) up to Week 24 (On-Treatment)
SAC
 
 
 
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11.10.10. ICH Listings
ICH: Listings
No.
Population
IDSL ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Study Population
1.
All Subjects 
Screened
ES7
Listing of Reasons for Screen Failure, Run-in Failure, or 
Stabilization Failure
SAC
2.
ITT
SD3
Listing of Reasons for Study Treatment Discontinuation 
SAC
3.
ITT
ES3
Listing of Reasons for Study Withdrawal
SAC
4.
ITT
TA1
Listing of Randomized and Actual Treatments
SAC
5.
ITT
TA1
Listing of Randomized and Actual Strata
Change ‘Randomized Treatment’ to 
‘Randomized Strata’ and ‘Actual 
Treatment’ to ‘Actual Strata;
SAC
6.
ITT
LIST1
Listing of Study Treatment Misallocations
SAC
7.
ITT
LIST2
Listing of Subjects for Whom the Treatment Blind was Broken 
SAC
Protocol Deviations
8.
All Subjects 
Enrolled
DV2
Listing of Important Protocol Deviations
SAC
9.
ITT
IE3
Listing of Subjects with Inclusion, Exclusion, Enrolment, or 
Randomization Criteria Deviations
SAC
Population Analyzed
10.
ITT
LIST3
Listing of Subjects Excluded from the Primary Efficacy Analysis
Include randomized subjects who 
had missing data either at baseline 
or post-baseline
SAC
 
 
 
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ICH: Listings
No.
Population
IDSL ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
11.
All Subjects 
Screened
LIST4
Listing of Subjects Who Were Randomized in Error and Not 
Included in the Intent-To-Treat Population
SAC
Demographic and Baseline Characteristics
12.
ITT
DM4
Listing of Demographic Characteristics
SAC
 
 
 
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ICH: Listings
No.
Population
IDSL ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
13.
ITT
DM10
Listing of Race
SAC
Treatment compliance
14.
ITT
LIST5
Listing of Study Treatment Compliance Data
SAC
Efficacy
15.
ITT
LIST6
Listing of Clinic Spirometry Data
SAC
16.
ITT
LIST7
Listing of Moderate/Severe Asthma Exacerbations
SAC
17.
ITT
LIST8
Listing of Asthma Exacerbations With Onset Within 14 Days 
Prior to Early Withdrawal From Study or Discontinuation of 
Study Treatment
SAC
Exposure
18.
ITT
EX3 (modified)
Listing of Exposure and Post-Treatment Study Duration
SAC
Adverse Events
19.
All Subjects 
Enrolled
AE8
Listing of All Adverse Events for Subjects Not Included in the 
Intent-To-Treat Population
SAC
20.
ITT
AE8
Listing of All Adverse Events 
SAC [1]
21.
ITT
AE8
Listing of Adverse Events for Subjects Who Received an 
Incorrect Treatment
22.
ITT
AE7
Listing of Subject Numbers for Individual Adverse Events
SAC
23.
ITT
AE8
Listing of Non-Fatal Serious Adverse Events
SAC
24.
ITT
AE8
Listing of Fatal Serious Adverse Events
SAC
25.
ITT
AE14
Listing of Reasons for Considering as a Serious Adverse Event
SAC
26.
ITT
AE8
Listing of Serious Adverse Events of Special Interest
SAC
 
 
 
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ICH: Listings
No.
Population
IDSL ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
27.
ITT
AE8
Listing of Adverse Events Leading to Discontinuation of Study 
Treatment or Early Withdrawal from Study
SAC
28.
ITT
AE8
Listing of Non-Serious Adverse Events Leading to 
Discontinuation of Study Treatment or Early Withdrawal from 
Study
SAC
29.
All Subjects 
Enrolled
AE2
Listing of Adverse Event System Organ Class, Preferred Term 
and Verbatim Text
SAC
Hepatobiliary (Liver)
30.
ITT
MH2
Listing of Medical Conditions for Subjects with Liver Stopping 
Events
IDSL
SAC
31.
ITT
SU2
Listing of Substance Use for Subjects with Liver Stopping 
Events
IDSL
SAC
All Laboratory
32.
ITT
LB5
Listing of Chemistry Values for Subjects with at Least One Value 
Outside the Normal Range
Include data of the form ‘<X’ or ‘>X’
SAC
33.
ITT
LB5
Listing of Hematology Values for Subjects with at Least One 
Value Outside the Normal Range
Include data of the form ‘<X’ or ‘>X’
SAC
34.
ITT
LB5
Listing of Urinalysis Data for Subjects with Any Value of 
Potential Clinical Importance 
SAC
ECG
35.
ITT
EG3
Listing of All ECG Values for Subjects with an Abnormal ECG 
Finding
IDSL
SAC
36.
ITT
EG5 
Listing of All ECG Findings for Subjects with an Abnormal 
Finding
IDSL
SAC
 
 
 
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ICH: Listings
No.
Population
IDSL ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Vital Signs
37.
ITT
VS4
Listing of Vital Signs
SAC
 
 
 
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11.10.11. Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Study Population
38.
All Subjects 
Enrolled
LIST9
Listing of Rescreened Subjects 
SAC
39.
ITT
MH2
Listing of Medical Conditions
SAC
40.
ITT
LIST10
Listing of Pneumonia History
SAC
41.
ITT
LIST11
Listing of Family History of Cardiovascular Risk Factors
SAC
42.
ITT
LIST12
Listing of Asthma Duration and Exacerbation History
SAC
43.
ITT
SU2
Listing of Smoking History and Status
SAC
44.
ITT
CM3
Listing of Asthma Concomitant Medications
SAC
45.
ITT
CM3
Listing of Non-Asthma Concomitant Medications
SAC
46.
Not 
Applicable
CM6
Relationship between ATC Level 1, Ingredient and Verbatim 
Text for Non-Asthma Medications
SAC
47.
ITT
LIST13
Listing of Inhaler Malfunctions
SAC
Efficacy
48.
ITT
LIST14
Listing of Derived Clinic FEV1 (L) Data
SAC
49.
ITT
LIST15
Listing of Derived Diary Data
SAC
50.
ITT
LIST16
Listing of ACQ Scores
SAC
51.
ITT
LIST17
Listing of SGRQ Scores
SAC
52.
ITT
LIST18
Listing of E-RS Scores
SAC
53.
ITT
LIST19
Listing of AQLQ Scores
SAC
 
 
 
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Non-ICH: Listings
No.
Population
IDSL ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
54.
ITT
LIST20
Listing of Global Assessment of Severity and Response to 
Treatment
SAC
55.
ITT
LIST21
Listing of Unscheduled Healthcare Resource Utilization
SAC
Safety
56.
ITT
AE7
Listing of Subject Numbers for Individual Adverse Events of 
Special Interest
SAC
57.
Not 
Applicable
LIST22
Listing of Adverse Event of Special Interest Group, Subgroup, 
Sub-SMQ, and Preferred Term
Include all pre-specified preferred terms 
regardless of whether they occurred
SAC
58.
ITT
AE8
Listing of MACE (Narrow and Broad Definition)
SAC
59.
ITT
LIST23
Listing of Pneumonia Data=
SAC
60.
ITT
LIST24
Listing of Bone Fracture Data
SAC
61.
ITT
LIVER5
Listing of Liver Event Results and Time of Event Relative to 
Treatment
SAC
62.
ITT
LIVER6
Listing of Liver Event Information for RUCAM Score
SAC
63.
ITT
LIVER7
Listing of Liver Biopsy Details
SAC
64.
ITT
LIVER8
Listing of Liver Imaging Details
SAC
65.
All Subjects 
Enrolled
IDSL
Patient Profile for Arrhythmias
SAC
66.
All Subjects 
Enrolled
IDSL
Patient Profile for Congestive Heart Failure
SAC
67.
All Subjects 
Enrolled
IDSL
Patient Profile for Cerebrovascular Events/Stroke
SAC
68.
All Subjects 
Enrolled
IDSL
Patient Profile for Deep Vein Thrombosis / Pulmonary Embolism
SAC
 
 
 
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Non-ICH: Listings
No.
Population
IDSL ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
69.
All Subjects 
Enrolled
IDSL
Patient Profile for Myocardial Infarction /Unstable Angina
SAC
70.
All Subjects 
Enrolled
IDSL
Patient Profile for Peripheral Arterial Thromboembolism
SAC
71.
All Subjects 
Enrolled
IDSL
Patient Profile for Pulmonary Hypertension
SAC
72.
All Subjects 
Enrolled
IDSL
Patient Profile for Revascularization
SAC
73.
All Subjects 
Enrolled
IDSL
Patient Profile for Valvulopathy
SAC
74.
All Subjects 
Enrolled
IDSL
Patient Profile for All Cause Deaths
SAC
 
 
 
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