A Phase IIb, 24 Week, Randomized, Double-blind, 3 Arm Parallel Group Study, Comparing the Efficacy, Safety and Tolerability of Two Doses of Umeclidinium Bromide Administered Once-daily Via a Dry Powder Inhaler, Versus Placebo, in Participants With Asthma
Phase: PHASE2
Conditions: Asthma
Sponsor: GlaxoSmithKline

2016N289466_02
CONFIDENTIAL
GlaxoSmithKline group of companies
205832
1
TITLE PAGE
Protocol Title: A Phase IIb, 24 week, randomized, double-blind, 3 arm parallel group
study, comparing the efficacy, safety and tolerability of two doses of umeclidinium 
bromide administered once-daily via a dry powder inhaler, versus placebo, in participants 
with asthma
Protocol Number:205832 / Amendment 2
Short Title: Short Title: A randomized, double-blind, parallel group study, comparing 
the efficacy, safety and tolerability of two doses of umeclidinium bromide administered 
once-daily via a dry powder inhaler, versus placebo, in participants with asthma
Compound Number:
GW685698+GSK573719
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information can be found in the Study 
Reference Manual.
Regulatory Agency Identifying Number(s): IND No. 104479, EudraCT number 2016-
002843-40
Approval Date: 06-JUL-2017
Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
2018N371775_00

 
2018N371775_00
PPD
PPD
PPD
PPD

2016N289466_02
CONFIDENTIAL
205832
3
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 2: 2016N289466_02
06-Jul-2017
Amendment 1: 2016N289466_01
15-Nov-2016
Original Protocol: 2016N289466_00
19-Aug-2016
Amendment 2 06-July-2017
Overall Rationale for the Amendment:
This protocol is being amended to:

broaden the eligibility criteria of pre-bronchodilator FEV1 from ≤85% to ≤90% 
reflective of patients with non-obstructed asthma  

Allow re-screening of subjects, with advance approval by the medical monitor. 

Correct minor typographical errors and inconsistencies within the Schedule of 
Activities (SOA) and the protocol text.
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
4
Section # and Name
Description of Change
Brief Rationale
Table of Contents: 
Section 7.1.3
Update Section 7.1.3 to 
include
albuterol/salbutamol 
medication for Return 
process
Update to include 
albuterol/salbutamol 
medication and be consistent 
with the body of the protocol
Section 2: Schedule of 
Activities (SOA)
Removed the Screen Run-
in “Window” day “-7d”
Removed the Screen Run-in 
Window day to avoid 
confusion. 
Section 2: Schedule of 
Activities (SOA)
Added language to clarify
when ECG is to be 
completed: ECG is to be 
obtained after the vital 
signs assessment but prior 
to performing the pre-
bronchodilator spirometry 
assessment (see Section 
9.4.3). At all post 
randomization visits the 
ECG is to be obtained 15 
minutes to 45 minutes after 
the administration of study 
treatment.
To correct the inconsistency 
between the Schedule of 
Activities (SOA) and body of 
the protocol
Section 6.1: Inclusion 
Criteria; inclusion criteria 
#5
Updating best pre-
bronchodilator morning 
(AM) FEV1 to ≤90%
To allow the inclusion of 
asthma patients with slightly 
less restricted lung function. 
Lung function does not always 
correlate with asthma severity
Section 6.2.2: Inclusion 
Criteria for 
Randomization; inclusion 
criteria #2 
Updating Spirometry: best 
pre-bronchodilator 
morning (AM) FEV1 to 
≤90%
To allow the inclusion of 
asthma patients with slightly 
less restricted lung function. 
Lung function does not always 
correlate with asthma severity.
Section 6.4 Pre-
Screening/Screening/Run-
In/Randomization 
Failures
Update to Include re-
screening language: 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
To allow the re-screening of 
subjects, with advance medical 
monitor approval  
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
5
Section # and Name
Description of Change
Brief Rationale
Section 7.1.3: Study 
Treatment, 
albuterol/salbutamol, and 
FF 100 mcg., Return
Update to include 
specifically the medication 
name, albuterol/salbutamol 
to the return process
Update to include 
albuterol/salbutamol
medication and be consistent 
with the body of the protocol
Section 9.1.4: Asthma 
Exacerbation
Added “moderate” to the 
last sentence in the 
paragraph
Added “moderate” to be 
consistent with other sections 
of the protocol and to clearly 
state that both moderate and 
severe exacerbations are to be 
captured in the eCRF
Section 9.4.3: 
Electorcardiograms
Added language (“but prior 
to performing pre-
bronchodilator spirometry
assessment”) to clarify 
when the ECG is to be 
done.
Added (“but prior to 
performing pre-bronchodilator
spirometry assessment”) to 
clearly explain that the ECG is 
to be performed after vitals but 
prior to spirometry. The 
specific time points for 
performing ECGs are clarified 
in the SOA
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
6
TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS...............................................................................................................9
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................13
3.
INTRODUCTION....................................................................................................19
3.1.
Study Rationale ..........................................................................................19
3.2.
Background ................................................................................................19
3.3.
Benefit/Risk Assessment ............................................................................19
3.3.1.
Risk Assessment .........................................................................20
3.3.2.
Benefit Assessment.....................................................................26
3.3.3.
Overall Benefit: Risk Conclusion..................................................26
4.
OBJECTIVES AND ENDPOINTS...........................................................................26
5.
STUDY DESIGN ....................................................................................................28
5.1.
Overall Design ............................................................................................28
5.2.
Number of Participants ...............................................................................30
5.3.
Participant and Study Completion...............................................................30
5.4.
Scientific Rationale for Study Design ..........................................................30
5.5.
Dose Justification........................................................................................31
6.
STUDY POPULATION...........................................................................................31
6.1.
Inclusion Criteria.........................................................................................31
6.2.
Exclusion Criteria........................................................................................33
6.2.1.
Randomization Criteria ................................................................35
6.2.2.
Inclusion Criteria for Randomization ............................................35
6.2.3.
Exclusion Criteria for Randomization ...........................................36
6.3.
Lifestyle Restrictions...................................................................................36
6.4.
Pre-Screening/Screening/Run-in/Randomization Failures ..........................36
7.
TREATMENTS.......................................................................................................37
7.1.
Treatments Administered............................................................................37
7.1.1.
Description of FF 100 mcg and Double-Blind Study 
Treatment ....................................................................................37
7.1.2.
Description of Albuterol/Salbutamol .............................................39
7.1.3.
Study Treatment, albuterol/salbutamol, and FF 100 mcg 
Return..........................................................................................39
7.2.
Dose Modification .......................................................................................39
7.3.
Method of Treatment Assignment ...............................................................39
7.4.
Blinding.......................................................................................................40
7.5.
Packaging and Labeling..............................................................................41
7.6.
Preparation/Handling/Storage/Accountability..............................................41
7.7.
Treatment Compliance................................................................................41
7.8.
Concomitant Therapy..................................................................................42
7.8.1.
Permitted Medications and Non-Drug Therapies..........................42
7.8.1.1.
Permitted Asthma Medications ...................................42
7.8.1.2.
Permitted Non-Asthma Medications ...........................43
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
7
7.9.
Prohibited Medications and Non-Drug Therapies........................................44
7.10.
Treatment after the End of the Study ..........................................................45
8.
DISCONTINUATION CRITERIA.............................................................................45
8.1.
Discontinuation of Study Treatment ............................................................45
8.1.1.
Liver Chemistry Stopping Criteria ................................................46
8.1.2.
QTc Stopping Criteria ..................................................................46
8.1.3.
Rechallenge.................................................................................47
8.1.3.1.
Study Treatment Restart or Rechallenge....................47
8.2.
Withdrawal from the Study..........................................................................47
8.3.
Lost to Follow Up........................................................................................48
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................48
9.1.
Efficacy Assessments.................................................................................49
9.1.1.
Questionnaires ............................................................................50
9.1.1.1.
Global Assessment of Severity and Response 
to Treatment...............................................................50
9.1.1.2.
Asthma Control Questionnaire (ACQ).........................50
9.1.1.3.
St. George’s Respiratory of Life Questionnaire 
(SGRQ) ......................................................................50
9.1.1.4.
Asthma Quality of Life Questionnaire (AQLQ) ............51
9.1.2.
Daily Diaries ................................................................................51
9.1.2.1.
eDiary Questionnaires, Assessments and 
Alerts..........................................................................51
9.1.2.1.1.
E-RS.......................................................51
9.1.2.1.2.
Supplemental Asthma Items...................52
9.1.2.1.3.
Night-time Awakening, Asthma 
Symptom and Physical Activity 
Questions ...............................................52
9.1.2.1.4.
Morning and Evening Home 
Spirometry..............................................52
9.1.2.1.5.
Alerts......................................................53
9.1.3.
Pulmonary Function Test.............................................................53
9.1.3.1.
Reversibility (Albuterol/Salbutamol)............................54
9.1.4.
Asthma Exacerbations.................................................................55
9.1.4.1.
Moderate Asthma Exacerbation..................................55
9.1.4.2.
Severe Asthma Exacerbation .....................................55
9.2.
Adverse Events...........................................................................................55
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................56
9.2.2.
Method of Detecting AEs and SAEs.............................................56
9.2.3.
Follow-up of AEs and SAEs.........................................................57
9.2.4.
Regulatory Reporting Requirements for SAEs .............................57
9.2.5.
Adverse Events of Special Interest (AESIs) .................................57
9.2.6.
Cardiovascular and Death Events................................................58
9.2.7.
Pneumonia ..................................................................................59
9.2.8.
Radiography (Chest X-Rays) .......................................................59
9.2.9.
Pregnancy ...................................................................................59
9.3.
Treatment of Overdose...............................................................................60
9.4.
Safety Assessments ...................................................................................60
9.4.1.
Physical Examinations.................................................................60
9.4.2.
Vital Signs....................................................................................60
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
8
9.4.3.
Electrocardiograms......................................................................60
9.4.4.
Clinical Safety Laboratory Assessments ......................................61
9.5.
Pharmacokinetics .......................................................................................61
9.6.
Pharmacodynamics ....................................................................................62
9.7.
Genetics .....................................................................................................62
9.8.
Biomarkers .................................................................................................62
9.9.
Health Economics OR Medical Resource Utilization and Health 
Economics..................................................................................................62
10. STATISTICAL CONSIDERATIONS........................................................................62
10.1.
Hypotheses.................................................................................................62
10.2.
Sample Size Determination ........................................................................63
10.3.
Sample Size Sensitivity...............................................................................64
10.4.
Sample site re-estimation or adjustment .....................................................65
10.5.
Data Analysis..............................................................................................65
10.5.1.
Analysis population......................................................................65
10.5.2.
Treatment Comparisons ..............................................................66
10.5.3.
Multiple Comparisons and Multiplicity ..........................................66
10.6.
Statistical Analysis......................................................................................67
10.6.1.
Primary Analyses.........................................................................67
10.6.2.
Secondary Analyses ....................................................................67
10.6.3.
Other Analyses ............................................................................68
10.6.4.
Interim Analyses ..........................................................................68
10.6.5.
Exploratory Analyses ...................................................................68
11. REFERENCES.......................................................................................................69
12. APPENDICES........................................................................................................71
12.1.
Appendix 1: Abbreviations and Trademarks................................................71
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................74
12.3.
Appendix 3: Study Governance Considerations..........................................76
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................80
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................85
12.6.
Appendix 6: Genetics..................................................................................88
12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................91
12.8.
Appendix 8: Daily Diary Questions..............................................................94
12.8.1.
Morning Questions.......................................................................94
12.8.2.
Evening Questions.......................................................................94
12.9.
Appendix 9: Country-specific requirements.................................................97
12.10. Appendix 10: Protocol Amendment History.................................................98
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
9
1.
SYNOPSIS
Protocol Title: A Phase IIb, 24 week, randomized, double-blind, 3 arm parallel group 
study, comparing the efficacy, safety and tolerability of two doses of umeclidinium 
bromide administered once-daily via a dry powder inhaler, versus placebo, in participants
with asthma
Short Title: A randomized, double-blind, parallel group study, comparing the efficacy, 
safety and tolerability of two doses of umeclidinium bromide administered once-daily via 
a dry powder inhaler, versus placebo, in participants with asthma
Rationale:
In the United States (US), the long-acting muscarinic antagonist (LAMA) tiotropium has 
been approved for the long-term maintenance treatment of asthma in patients 12 years of 
age and older.
GlaxoSmithKline (GSK) is currently developing a once-daily ‘closed’ triple therapy of an
inhaled corticosteroid (ICS)/LAMA/long-acting beta-2-agonist (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 in adults. 
Through the evaluation of UMEC 62.5 micrograms (mcg) and 31.25 mcg compared to 
placebo, this study will provide important information regarding the efficacy, safety and 
tolerability of UMEC when administered via a separate inhaler to participants on a 
background of FF without VI.
The primary objective of this study is to evaluate the effects of UMEC 62.5 mcg and 
UMEC 31.25 mcg on lung function compared with placebo after 24 weeks of treatment.
Objectives and Endpoints:
Objective
Endpoint
Primary

Evaluate the effects of UMEC 62.5 mcg 
and UMEC 31.25 mcg on lung function 
(trough Forced Expiratory Volume in 1 
second [FEV1]) vs placebo after 24 weeks 
of treatment.

Mean change from baseline in clinic 
trough FEV1 at Week 24
Secondary

Evaluate the effects of UMEC 62.5 mcg and 
UMEC 31.25 mcg on lung function (3hours
post dose FEV1) vs placebo after 24 weeks 
of treatment.

Mean change from baseline in clinic FEV1
at 3 hours post dose at Week 24
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
10
Objective
Endpoint
Safety
To evaluate the safety and tolerability of UMEC 
62.5 mcg and UMEC 31.25 mcg compared to 
placebo
Incidence and type of adverse events
Electrocardiogram (ECG) measurements
Vital signs
Overall Design:
This is a Phase IIb, randomized, double-blind, placebo controlled, 3-arm parallel group 
study, comparing the efficacy, safety and tolerability of UMEC (62.5 mcg and 
31.25 mcg) administered once-daily in participants with asthma that is not well controlled 
(i.e. participants with an Asthma Control Questionnaire-6 [ACQ-6] total score >0.75 at 
Visit 2 [the Randomization Visit]) despite treatment with maintenance ICS.
Number of Participants:
The total number of randomized participants required is approximately 384, with 128
participants randomized 1:1:1 to each of the 3 double-blind treatment arms.  
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
11
Treatment Groups and Duration:
Eligible participants will be requested to participate in the study for a maximum of 
approximately 31 weeks (Visit 0 to the Follow-up contact, inclusive) during which time, 
participants will complete the following 4 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), 
including the informed consent process, must be completed within 4 weeks prior
to Visit 1 as well as prior to any protocol-required changes to a participant’s 
usual asthma treatment and the initiation of any Visit 1 procedures.
Participants that receive LABA (or LAMA) as a component of their regular (i.e. 
pre-study) therapy must stop LABA (or LAMA) treatment from 48 hours prior 
to Visit 1 (Screening) until after they have completed the study; therefore, the 
investigator must use their clinical judgment to determine if the participant may 
stop LABA (or LAMA) prior to study entry without incurring undue risk.

Screening / run-in: Participants who meet all the eligibility criteria at Visit 1 
(Screening), will enter the run-in period for approximately 2 weeks to continue 
assessing the participant’s eligibility for the study. On the morning of Visit 1, 
participants will refrain from taking the morning dose of their regular (i.e. pre-
study) ICS asthma medication. Participants satisfying all inclusion/exclusion 
criteria and who have successfully completed all protocol procedures at 
screening will be provided with FF 100 mcg via the ELLIPTA dry-powder 
inhaler (DPI) to take once daily (QD), in the morning, during the 2-week run-in 
period; the first dose of FF 100 mcg will be self-administered by the participant 
before leaving the clinic. Participants will refrain from using their own ICS 
asthma medication during the 2-week run-in and treatment period. Participants 
will also be provided with rescue medication (albuterol/salbutamol) to use on an 
as-needed basis throughout the study.

Randomization / treatment: At Visit 2 (the Randomization Visit), participants 
who meet all of the randomization criteria will be randomized 1:1:1 to receive 
one of the following three double-blind study treatments via the ELLIPTA DPI 
during the 24-week treatment period:

UMEC 62.5 mcg QD

UMEC 31.25 mcg QD

Placebo QD
Participants will continue to administer FF 100 mcg once daily (QD), in the 
morning from a separate ELLIPTA DPI throughout the treatment period. On the 
morning of Visits 2, 3, 4, and 5, participants will perform their electronic Diary 
(eDiary) assessments at home but refrain from taking their morning dose of 
study treatment and FF 100 mcg (as applicable) until instructed to do so by
clinic personnel. At Visits 2, 3, 4 and 5, participants will self-administer study 
treatment immediately followed by FF 100 mcg whilst at the clinic. Participants 
will take their last dose of study treatment and FF 100 mcg in the clinic on Day 
169 (Visit 5). Participants are expected on non-clinic visit days to take their 
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
12
study treatment and FF 100 mcg at home in the morning at approximately the 
same time each day, as directed by the clinic. 

Safety follow-up: A safety follow-up telephone contact or clinic visit will be 
conducted approximately 7 days after the participant completes all of the 
protocol-defined procedures for Visit 5/End of Study (EOS) or, if applicable, the 
Early Withdrawal Visit. A participant will be considered to have completed the 
study when they have completed all phases of the study including screening, 
run-in, the randomized treatment phase, and safety follow-up.
Key Elements of Analysis Plan
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 clinic trough FEV1 recorded post randomization. Analyses will include the fixed, 
categorical effects of treatment, visit, treatment by visit interaction, sex, 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 
primary comparisons of interest:

UMEC 62.5 mcg versus Placebo

UMEC 31.25 mcg versus Placebo
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 reporting and analysis plan (RAP).
The details of the statistical analysis methods for the secondary efficacy endpoint will be 
provided in the RAP. 
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
13
2.
SCHEDULE OF ACTIVITIES (SOA)
Protocol Activity
Pre-
Screen
Screen
Run-in
Treatment Period
Follow-up
Visit
0
1
2
Randomization
3
4
5/End of Study 
(EOS)
Early Withdrawal 
(EW)
Safety
Follow-up Contact
Study Day
-42 to -
14
-14
1
29
85
169
Week
-6 to -2
-2
0
4
12
24
1 week after Visit 
5/EOS or EW Visit
Window
-5/+2d
-5/+2d
-5/+2d
-1/+4d
Informed consent
(ICF) a
X
Genetic ICF b
X
Inclusion and 
exclusion criteria
X
X
Demography c
X
X
Medical history 
X
Asthma history d
X
Exacerbation
history
X
Smoking History 
and status
X
Concomitant 
medication review
X
X
X
X
X
X
X
X
Register visit in 
Interactive Web 
Response System 
(IWRS) (RAMOS 
NG) e
X
X
X
X
X
X
X
Randomization f
X
Laboratory 
Assessments
Urinalysis
X
 
 
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
14
Protocol Activity
Pre-
Screen
Screen
Run-in
Treatment Period
Follow-up
Visit
0
1
2
Randomization
3
4
5/End of Study 
(EOS)
Early Withdrawal 
(EW)
Safety
Follow-up Contact
Study Day
-42 to -
14
-14
1
29
85
169
Week
-6 to -2
-2
0
4
12
24
1 week after Visit 
5/EOS or EW Visit
Window
-5/+2d
-5/+2d
-5/+2d
-1/+4d
Hematology and 
clinical chemistry g
X
Hepatitis B and C
X m
Genetic sample 
X n
Serum pregnancy 
test
X o
X o
X o
Urine pregnancy 
test
X o
X o
X o
Safety 
Assessments
Physical exam 
including height 
and weight h
X
X
X
12-lead 
Electrocardiogram
(ECG) i
X
X
X
X
Vital signs j
X
X
X
X
X
X
Adverse Event (AE) 
review
X
X
X
X
X
X
X
Serious Adverse 
Event (SAE) review
X
X
X
X
X
X
X
X
Study Treatment
Dispense
Albuterol/Salbutam
ol, as required
X
X
X
X
Collect 
Albuterol/Salbutam
ol, as required
X
X
X
X
X
 
 
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
15
Protocol Activity
Pre-
Screen
Screen
Run-in
Treatment Period
Follow-up
Visit
0
1
2
Randomization
3
4
5/End of Study 
(EOS)
Early Withdrawal 
(EW)
Safety
Follow-up Contact
Study Day
-42 to -
14
-14
1
29
85
169
Week
-6 to -2
-2
0
4
12
24
1 week after Visit 
5/EOS or EW Visit
Window
-5/+2d
-5/+2d
-5/+2d
-1/+4d
Dispense open 
label fluticasone 
furoate (FF) 100 
mcg medication
X
X
X
X
Administer open 
label FF 100 mcg
X
X
X
X
X
Collect open label 
FF 100 mcg
X
X
X
X
X
Dispense double-
blind study 
treatment
X
X
X
Administer double-
blind study 
treatment
X p
X p
X p
X p
Collect double-blind 
study treatment
X
X
X
X
Assess FF 
100 mcg run-in 
medication 
compliance
X
Assess FF 
100 mcg and 
double-blind study 
treatment 
compliance
X
X
X
X
Efficacy 
Assessments
Global Assessment 
of Severity k
X
X
X
X
X
 
 
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
16
Protocol Activity
Pre-
Screen
Screen
Run-in
Treatment Period
Follow-up
Visit
0
1
2
Randomization
3
4
5/End of Study 
(EOS)
Early Withdrawal 
(EW)
Safety
Follow-up Contact
Study Day
-42 to -
14
-14
1
29
85
169
Week
-6 to -2
-2
0
4
12
24
1 week after Visit 
5/EOS or EW Visit
Window
-5/+2d
-5/+2d
-5/+2d
-1/+4d
Global Assessment 
of Response to 
Treatment k
X
X
X
X
Asthma Control 
Questionnaire 
(ACQ-6) k
X
X q
Asthma Control 
Questionnaire 
(ACQ-5) k
X
X
X
X
St. George’s 
Respiratory 
Questionnaire 
(SGRQ) k
X
X
X
X
X
Asthma Quality of 
Life Questionnaire 
(AQLQ) k
X
X
X
X
X
Evaluating 
Respiratory 
Symptoms (E-RS) 
+Asthma symptoms 
+ Peak Expiratory 
Flow (PEF) + Home 
Forced Expiratory 
Volume in 1 second
(FEV)1 k, l
X
eDiary Dispense
X
eDiary Collect
X
X
eDiary Review
X
X
X
X
X
 
 
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
17
Protocol Activity
Pre-
Screen
Screen
Run-in
Treatment Period
Follow-up
Visit
0
1
2
Randomization
3
4
5/End of Study 
(EOS)
Early Withdrawal 
(EW)
Safety
Follow-up Contact
Study Day
-42 to -
14
-14
1
29
85
169
Week
-6 to -2
-2
0
4
12
24
1 week after Visit 
5/EOS or EW Visit
Window
-5/+2d
-5/+2d
-5/+2d
-1/+4d
Dispense paper 
Medical 
Problems/Medicatio
ns Taken 
worksheet
X
X
X
X
X
Review paper 
Medical 
Problems/Medicatio
ns Taken
worksheet
X
X
X
X
X
X
Reversibility
X r
Exacerbation 
assessment
X
X
X
X
X
Pre-dose 
spirometry (clinic)
X s
X s
X s
X s
X s
X s
Post-dose 
spirometry (clinic)
X t
X t
X t
 
 
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
18
a)
The ICF must be signed before any study procedures, including medication cessation.
b)
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.
c)
Demography may be captured at either the Pre-screen Visit or Screening Visit (for participants who do not have a Pre-screen Visit).
d)
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).
e)
The IWRS will be used for randomization, emergency unblinding and study treatment supply management (Please refer to the RAMOS NG IWRS manual and 
SRM for more information).
f)
Participants must not be randomized prior to confirming their eligibility to participate in the study.
g)
If test otherwise performed within 3 months prior to screening visit, testing at screening is not required.
h)
Physical Examination will include height and weight at Visit 1 only. 
i)
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 9.4.3 ). At all post randomization visits the ECG is to be obtained 15 minutes to 45 minutes after the administration of study treatment.
j)
The vital signs assessment will include the measurement of blood pressure, heart rate.
k)
Assessment(s) to be completed prior to the administration of study treatment.
l)
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.
m)
Hepatitis C RNA is optional however a confirmatory negative Hepatitis C RNA test must be obtained, to be able to enrol participants with positive Hepatitis C 
antibody due to prior resolved disease. Hep B/C: If test otherwise performed within 3 months prior to first dose of study treatment, testing at screening is not 
required.
n)
Pharmacogenetic sample may be drawn any time from Visit 2 onwards.
o)
Assessments only to be conducted in females of reproductive potential.
p)
Study treatment should be administered at approximately the same time of day at each applicable clinic visit.
q)
Baseline ACQ-5 will be derived from items 1-5 of the Randomization (Visit 2) ACQ-6.
r)
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 9.1.3.
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 2-week run-in period.
s)
Pre-dose spirometry should 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 and FF 100 mcg. After V2 pre-dose spirometry assessments should be performed within 1 hour of the V2 spirometry.
t)
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 within 1 hour of the V2 spirometry.
 
 
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
19
3.
INTRODUCTION
3.1.
Study Rationale
In the United States (US), the long-acting muscarinic antagonist (LAMA) tiotropium has 
been approved for the long-term maintenance treatment of asthma in patients 12 years of 
age and older.
GlaxoSmithKline (GSK) is currently developing a once-daily ‘closed’ triple therapy of a 
ICS/LAMA/long-acting beta-2-agonist (LABA) combination [FF/umeclidinium 
(UMEC)/vilanterol (VI)] in a single device, with the aim of providing a new treatment 
option for the management of asthma in adults. Through the evaluation of UMEC 
62.5 mcg and 31.25 mcg compared to placebo this study will provide important 
information regarding the efficacy and safety of UMEC when administered in a separate 
inhaler to participants on a background of FF.
The primary objective of this study is to evaluate the effects of UMEC 62.5 mcg and 
UMEC 31.25 mcg on lung function compared with placebo after 24 weeks of treatment.
3.2.
Background
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; Global Initiative for Asthma (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.  
Despite the availability of treatments and published guidelines, patients may have asthma 
that is not well controlled.
This trial will, primarily, evaluate trough FEV1 to characterize the efficacy of two doses 
of UMEC (62.5 mcg and 31.25 mcg) in the treatment of asthma when administered as an 
open combination with FF 100 mcg. UMEC is currently under development as a closed 
triple therapy in combination with FF and VI in a single inhaler.
3.3.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events related to FF and UMEC can be found in the 
Investigator’s Brochure(s) (IB). The table below provides a summary of the key risks in 
association with FF and UMEC. It is noted that both FF and UMEC have also been 
developed in combination with VI, therefore relevant safety experience is also provided 
by the FF/VI and UMEC/VI combinations.  
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
20
3.3.1.
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [e.g., GW685698+GSK573719] 
Cardiovascular effects of 
UMEC 
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 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 
- Exclusion criteria as specified in 
Section 6.2 of the protocol
- Collection of cardiovascular risk 
factors and medical history at 
baseline
- ECGs as per schedule in Section 2
- Vital sign assessments (heart rate
and blood pressure) as per schedule in 
Section 2
- Cardiovascular AEs and SAEs will 
be captured on the electronic Case 
Report Form (eCRF) (see Appendix 
4)
- Protocol defined stopping criteria as 
per Section 8.1
-MACE analysis
-Instream review of blinded data
 
 
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
21
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Healthy Volunteers (in the Thorough QT study, UMEC 500 mcg 
daily dose), no effect was observed on heart rate, blood pressure or 
QT.
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 500 mcg and placebo. 
UMEC/VI 500/100 mcg increased QTcF on average by 8.2 msec 
(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.  In addition, UMEC/VI has had 
urinary retention, dysuria, vision blurred, glaucoma and increased 
intraocular pressure and paradoxical bronchospasm added as ADRs.  
ICS has a similar class risk of glaucoma and elevated intraocular 
- 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.
- Review AEs/SAEs
 
 
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
22
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
pressure (IOP); however, these effects occur by a different 
mechanism that is not expected to be synergistic or additive when FF 
is used in combination with UMEC.
Systemic ICS effects 
-Aderenal 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 participants 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 
participants 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 participants 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 
- Review AEs/SAEs
- The occurrence of bone fractures 
will be recorded in the eCRF.
 
 
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
23
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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 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 participants 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 mcg (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.  
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).
-Participants 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 
 
 
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
24
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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) 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 participants 
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).
resulting in hospitalisation.  
The occurrence of pneumonia will be 
recorded in the eCRF.
Where possible a chest X-ray should 
be performed to confirm a diagnosis, 
whenever a participant 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.
Participants with a history of allergy 
or hypersensitivity to any 
corticosteroid, 
anticholinergic/muscarinic receptor 
antagonist, beta2-agonist, 
lactose/milk protein or magnesium 
 
 
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
25
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
stearate are excluded from 
participation in this study (Section 
6.2). 
-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 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 UMEC 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.
Females who are pregnant or breast-
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. 
 
 
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
26
The risks for FF 100 mcg are recognised pharmacological class effects associated with 
ICS therapy, which are included in the table above. The experience with FF is provided 
in the respective IB.  
3.3.2.
Benefit Assessment
The benefit of UMEC at two dosage strengths 62.5 and 31.25 mcg as compared to 
Placebo in patients with asthma on background therapy of FF 100 mcg is expected to 
improve lung function. The inclusion of two strengths of UMEC will allow comparison 
to placebo for the dose currently marketed in COPD, as well as a lower dose. This will 
help show the efficacy and safety of UMEC in asthma when administered as an open 
combination on a background of FF. Another LAMA, tiotropium, is currently approved 
for the maintenance treatment of asthma. 
3.3.3.
Overall Benefit: Risk Conclusion
Taking into account the measures taken to minimize the risk to the participants 
participating in the study, the potential risks identified in association with UMEC are 
justified by the anticipated benefits that may be afforded to participants with asthma.  
The current experience and safety profile with UMEC in previous Phase II asthma studies 
(alone and in combination with FF) and from clinical trial and marketing experience in 
the COPD population is supportive of evaluating this compound in asthma patients. The 
potential risks associated with the known pharmacology of UMEC is offset by the 
potential significant benefits that are afforded to patients not well controlled on ICS
therapy. Furthermore, the approval of another LAMA (tiotropium) for the treatment of
asthma demonstrates the suitability for the use of this class of drug in the asthma 
population.  
4.
OBJECTIVES AND ENDPOINTS
For a definition of baseline for each of the endpoints listed below, please refer to Section 
10.6.
Objectives
Endpoints
Primary

Evaluate the effects of UMEC 
62.5 mcg and UMEC 31.25 mcg 
on lung function (trough FEV1) 
versus placebo after 24 weeks of 
treatment.

Mean change from baseline in clinic 
trough FEV1 at Week 24
Secondary

Evaluate the effects of UMEC 
62.5 mcg and UMEC 31.25 mcg on 
lung function (3hours post dose 

Mean change from baseline in clinic 
FEV1 at 3 hours post dose at Week 24
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
27
Objectives
Endpoints
FEV1) versus placebo after 24 
weeks of treatment.
Safety  

To evaluate the safety and 
tolerability of UMEC 62.5 mcg and 
UMEC 31.25 mcg compared to 
placebo

Incidence and type of adverse events

ECG measurements

Vital signs
Other

To evaluate other efficacy assessments 
of UMEC 62.5 mcg and UMEC 
31.25 mcg compared to placebo

Mean change from baseline in morning 
(AM) pre-dose Peak Expiratory Flow 
(PEF) over the 24 week treatment 
period

Mean change from baseline in evening
(PM) PEF over the 24 week treatment 
period

Mean change from baseline in daily 
home trough FEV1 over the 24 week 
treatment period

Mean change from baseline in daily 
rescue medication use over the 24 
week treatment period

Mean change from baseline in SGRQ
total score 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 SGRQ 
domain scores at Week 24

Mean change from baseline in the 
AQLQ total score at Week 24

Percent of patients meeting a 
responder threshold of ≥ 0.5 points 
improvement from baseline for the 
AQLQ total score at Week 24

Mean change from baseline in E-RS
total score over the 24 week treatment 
period

Mean change from baseline in 
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
28
Objectives
Endpoints
ACQ-5 total score at Week 24

Percent of patients meeting a 
responder threshold of ≥0.5 in change 
from baseline for the ACQ-5 at Week 
24

Annualized rate of moderate/severe 
asthma exacerbations
5.
STUDY DESIGN
5.1.
Overall Design
This is a Phase IIb, randomized, double-blind, placebo controlled, 3-arm parallel group 
study, comparing the efficacy, safety and tolerability of UMEC (62.5 mcg and 
31.25 mcg) administered once-daily in participants with asthma that is not well controlled 
(i.e. participants with an ACQ-6 total score >0.75 at Visit 2 [the Randomization Visit]) 
despite treatment with maintenance ICS.
Eligible participants will be requested to participate in the study for a maximum of 
approximately 31 weeks (Visit 0 to the Follow-up contact, inclusive) during which time, 
participants will complete the following 4 phases of the study:
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
29

Pre-screening: Details about the study and procedures will be explained 
through the informed consent process. The Pre-screening Visit (Visit 0), 
including the informed consent process, must be completed within 4 weeks prior 
to Visit 1 as well as prior to any protocol-required changes to a participant’s 
usual asthma treatment and the initiation of any 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 defined in Section 7.9.
Participants that receive LABA (or LAMA) as a component of their regular (i.e. 
pre-study) therapy must stop LABA (or LAMA) treatment from 48 hours prior 
to Visit 1 (Screening) until they have completed the study; therefore, the 
investigator must use their clinical judgment to determine if the participant may 
stop LABA (or LAMA) prior to study entry without incurring undue risk.

Screening / run-in: Participants who meet all the eligibility criteria at Visit 1 
(Screening), will enter the run-in period for approximately 2 weeks to continue 
assessing the participant’s eligibility for the study. On the morning of Visit 1, 
participants will refrain from taking the morning dose of their regular (i.e. pre-
study) ICS asthma medication. Participants satisfying all inclusion/exclusion 
criteria and who have successfully completed all protocol procedures at 
screening will be provided with FF 100 mcg via the ELLIPTA dry-powder 
inhaler (DPI) to take once daily (QD), in the morning, during the 2-week run-in 
period; the first dose of FF 100 mcg will be self-administered by the participant 
before leaving the clinic. Participants will refrain from using their own ICS 
asthma medication during the 2-week run-in and treatment period. Participants 
will also be provided with rescue medication (albuterol/salbutamol) to use on an 
as-needed basis throughout the study.

Randomization / treatment: At Visit 2 (the Randomization Visit), participants 
who meet all of the randomization criteria will be randomized 1:1:1 to receive 
one of the following three double-blind study treatments via the ELLIPTA DPI 
during the 24-week treatment period:

UMEC 62.5 mcg QD

UMEC 31.25 mcg QD

Placebo QD
Participants will continue to administer FF 100 mcg once daily (QD), in the 
morning from a separate ELLIPTA DPI throughout the treatment period. On the 
morning of Visits 2, 3, 4, and 5, participants will perform their electronic Diary 
(eDiary) assessments at home but refrain from taking their morning dose of 
study treatment and FF 100 mcg (as applicable) until instructed to do so by
clinic personnel. At Visits 2, 3, 4 and 5, participants will self-administer study 
treatment immediately followed by FF 100 mcg whilst at the clinic (see Section 
7.2). Participants will take their last dose of study treatment and FF 100 mcg in 
the clinic on Day 169 (Visit 5). Participants are expected on non-clinic visit days 
to take their study treatment and FF 100 mcg at home in the morning at 
approximately the same time each day, as directed by the clinic.
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
30

Safety follow-up: A safety follow-up telephone contact or clinic visit will be 
conducted approximately 7 days after the participant completes all of the 
protocol-defined procedures for Visit 5/End of Study (EOS) or, if applicable, the 
Early Withdrawal Visit. A participant will be considered to have completed the 
study when they have completed all phases of the study including screening, 
run-in, the randomized treatment phase, and safety follow-up.
To demonstrate the benefit of UMEC the primary comparisons of interest for the primary 
efficacy endpoint are:

UMEC 62.5 mcg versus (vs) Placebo

UMEC 31.25 mcg vs Placebo
Other pairwise treatment comparisons of interest that aim to informally estimate any 
potential benefit of increasing the UMEC dose are given below for all efficacy endpoints. 

UMEC 62.5 mcg vs UMEC 31.25 mcg
For the multiple comparisons and multiplicity adjustment, please see Section 10.5.3. 
Participants who permanently discontinue double-blind 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 (see Section 8.1)
5.2.
Number of Participants
The total number of randomized participants required is approximately 384, with 128
participants randomized 1:1:1 to each of the 3 double-blind treatment arms (see Section 
10).  
5.3.
Participant and Study Completion
A participant will be considered to have completed the study when they have completed 
all phases of the study including pre-screening, screening, run-in, the randomized 
treatment phase, and safety follow-up.
The end of the study is defined as the date of the last scheduled procedure shown in the 
Schedule of Activities table (see Section 2) for the last participant in the trial globally.
5.4.
Scientific Rationale for Study Design
This study will use a multicenter, randomized, double-blind, 3 arm parallel-group design.  
This is a well-established design to evaluate the efficacy, safety, and tolerability of the 
UMEC drug.  A placebo arm is included. All participants will be placed on open-label FF 
100 mcg when they enter the 2 week run-in period and continue it through the 24 week 
treatment period. The primary objective of this study is to evaluate the effects of UMEC 
62.5 mcg and UMEC 31.25 mcg on lung function compared with placebo after 24 weeks 
of treatment.
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
31
GlaxoSmithKline (GSK) is currently developing a once-daily ‘closed’ triple therapy of a 
ICS/LAMA/LABA combination [FF/UMEC/VI)] in a single device, with the aim of
providing a new treatment option for the management of asthma in adults. Through the 
evaluation of UMEC 62.5 mcg and 31.25 mcg compared to placebo this study will 
provide important information regarding the efficacy, safety and tolerability of UMEC in 
asthma when administered via a separate inhaler to participants on a background of FF
without VI.
5.5.
Dose Justification
The 200699 (IB, GlaxoSmithKline Document 2011N123107_03, / IB Supplement, 
GlaxoSmithKline Document 2016N284764_00) data showed UMEC 62.5 mcg to be an 
effective dose; after 4 weeks of treatment in the subset of patients with a primary 
diagnosis of asthma, an average increase in change from baseline trough FEV1 at Day 29 
of 136 mL was observed in those participants treated with FF/UMEC (100/62.5 mcg) 
compared to those participants 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 
both 31.25 and 62.5 mcg doses will be assessed in this study when administered via a 
separate inhaler to participants treated on a background of FF 100 mcg. No safety signal 
was identified with any of the UMEC doses (15.6, 62.5, 125 and 250 mcg) evaluated in 
the 200699 study.
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
AGE
1. Age: 18 years of age or older at the time of signing the informed consent.
TYPE OF PARTICIPANT AND DISEASE CHARACTERISTICS
2. Diagnosis: Participants with a diagnosis of asthma as defined by the National 
Institutes of Health [NIH 2007] at least 6 months prior to Visit 0.
3. Asthma Control: ACQ-6 total score of >0.75 at Visit 1.
4. Current Asthma Maintenance Therapy: Participants are eligible if they have 
required daily ICS therapy 100 mcg/day fluticasone propionate (FP, or 
equivalent) with or without LABA or LAMA for at least 12 weeks prior to Visit 0
and there have been no changes in maintenance asthma medications during the 4 
weeks immediately prior to Visit 0.
Examples of acceptable doses of commonly prescribed ICS medication will be 
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 
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
32
labels.
5. Spirometry: Both of the following:
a.
A best pre-bronchodilator morning (AM) FEV1 ≤90% of the predicted 
normal value. Predicted values will be based upon the ERS Global Lung 
Function Initiative [Quanjer 2012].
b. A best post-bronchodilator FEV1/ forced vital capacity (FVC) ≥0.7 at 
Visit 1.
6. Reversibility of Disease: Airway reversibility is 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 participant 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:
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 participant 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 participant may 
enter the 2-week run-in period (see Section 9.1.3).
7.
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
8. Gender:
a. Male participants
b. Female participants: 
A female participant is eligible to participate if she is not pregnant (see Appendix 5),
not breastfeeding, and at least one of the following conditions applies:

Not a woman of childbearing potential (WOCBP) as defined in Appendix 5
OR

A WOCBP who agrees to follow the contraceptive guidance in Appendix 5
during the treatment period and for at least 5 days after the last dose of study 
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
33
treatment.
INFORMED CONSENT
9. 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.  Participants must be 
able to read, comprehend, and write at a level sufficient to complete study related 
materials.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
MEDICAL CONDITIONS
1.
Pneumonia: Chest X-ray documented pneumonia in the 12 weeks prior to Visit 1.
2.
Asthma Exacerbation: Any severe asthma exacerbation, defined as deterioration of 
asthma requiring the use of systemic corticosteroids (oral, parenteral or depot) within 
12 weeks of Visit 1, or an inpatient hospitalisation or emergency department visit 
due to asthma that required systemic corticosteroids within 12 weeks of Visit 1.
3.
Concurrent Respiratory Disease: Current evidence of pneumonia, pneumothorax, 
atelectasis, pulmonary fibrotic disease, bronchopulmonary dysplasia, chronic 
bronchitis, emphysema, chronic obstructive pulmonary disease, lung cancer, or other 
respiratory abnormalities other than asthma.
4.
Pregnancy: Women who are pregnant or lactating or are planning on becoming 
pregnant during the study.
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: Participants 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 participant
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 participant otherwise meets entry criteria
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
34
8.
Clinically significant ECG abnormality: Evidence of a clinically significant 
abnormality in the 12-lead ECG performed during screening or run-in. The PI will 
determine the clinical significance of each abnormal ECG finding in relation to the 
participant’s medical history and exclude participants 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:

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: participants 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 last 
3 months

New York Heart Association (NYHA) Class IV Heart failure
10. Antimuscarinic effects: Participants 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: Participants with carcinoma that has not been in complete remission for at 
least 5 years. Participants 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 participant has been considered cured by treatment.
12. Questionable validity of consent: Participants 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.
PRIOR/CONCOMITANT THERAPY
13. Medication prior to spirometry: Participants who are medically unable to withhold 
their albuterol/salbutamol for the 6-hour period required prior to spirometry testing at 
each study visit.
PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE/RELEVANT 
HABITS
14. Tobacco Use: Current smoker or a smoking history of ≥10 pack years (e.g., 
20 cigarettes/day for 10 years).  A participant may not have used inhaled tobacco 
products within the past 12 months (i.e., cigarettes, e-cigarettes/vaping, cigars or pipe 
tobacco).
15. Drug/alcohol abuse: Participants with a known or suspected history of alcohol or 
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
35
drug abuse within the last 2 years. This includes marijuana, which is considered an 
abused drug.
Diagnostic assessments
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.
Other Exclusions
17. Non-compliance: Participants 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.
19. Inability to read: In the opinion of the Investigator, any participant who is unable to 
read and/or would not be able to complete study related materials.
6.2.1.
Randomization Criteria
At the end of the run-in period (Visit 2), study participants must fulfil the following 
additional criteria in order to be randomized into the study and enter the treatment period:
6.2.2.
Inclusion Criteria for Randomization
TYPE OF PARTICIPANT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
1. Asthma Control: ACQ-6 total score of >0.75 at Visit 2.
2. Percent-predicted FEV1: Spirometry: A best pre-bronchodilator morning (AM) 
FEV1 ≤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.
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
36
6.2.3.
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 
run-in period that led to a change in asthma management or, in the opinion of the 
Investigator, is expected to affect the participant’s asthma status or the participant’s 
ability to participate in the study.
2. Asthma exacerbation: Evidence of a moderate asthma exacerbation leading to a 
change in therapy or severe exacerbation during screening or the run-in period, 
defined as deterioration of asthma requiring the use of systemic corticosteroids 
(tablets, suspension, or injection) or an in-patient hospitalization or emergency 
department visit due to asthma that required systemic corticosteroids.
CONCOMITANT MEDICATIONS/TREATMENTS
3. Asthma medication: Changes in asthma medication (excluding changes after Visit 0 
or 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.
6.3.
Lifestyle Restrictions
No lifestyle restrictions are required for this study.
6.4.
Pre-Screening/Screening/Run-in/Randomization Failures
A participant will be assigned a participant number at the time the informed consent is 
signed at Visit 0.
The study site will be responsible for reporting pre-screen failures. The following 
information will be collected in the eCRF for participants who are pre-screen failures:

Demographic information including race, age and gender

Participant 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-screening failures, screening failures, run-in failures
and randomization failures will be defined as follows:

Pre-screening failures: those participants that sign the informed consent 
document but do not have a Visit 1 (Screening) procedure.
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
37

Screening failures: those participants that complete at least one Visit 1 
(Screening) procedure but do not enter the run-in period. 
A participant 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 participants that enter the run-in period but do not have 
any Visit 2 (Randomization) procedures.

Randomization failures: those participants that complete at least one Visit 2 
(Randomization) procedure but do not enter the double-blind study treatment 
period.
Any participant who completes the run-in period and then meets the 
randomization criteria and is dispensed the double-blind study treatment at Visit 
2 is considered to have entered the treatment period.
RAMOS NG will be contacted to register the participant. 
In order to ensure transparent reporting of screen/run-in failure participants, meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements, and 
respond to queries from Regulatory authorities, a minimal set of screen/run-
in/randomization failure information is required including demography, screen/run-
in/randomization failure details, eligibility criteria, and any SAEs (see Section 9.2.4 and 
Appendix 4). Further details are provided in the study-specific eCRF completion 
guidelines document.
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).
7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol. The term ‘study treatment’ within this trial is used to describe the 
combination of products received by the participant as per the protocol design. Study 
treatment may also be used to only reference the randomized study treatment when 
described together with the FF 100 mcg open-label treatment.
7.1.
Treatments Administered
7.1.1.
Description of FF 100 mcg and Double-Blind Study Treatment
The ELLIPTA device will be used during the run-in period and the treatment period.  The 
ELLIPTA dry powder inhaler (DPI) is a molded plastic two-sided device with a dose 
counter that can hold two individual blister strips.  The ELLIPTA will deliver, when 
actuated, the contents of a single blister simultaneously from each of the two strips. The 
ELLIPTA is individually sealed in a foil laminate overwrap that also contains a silica gel 
desiccant packet.
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
38
A description of the FF (GW685698) 100 mcg inhalation powder administered via the 
ELLIPTA is provided in Table 1; descriptions of the double-blind study treatments 
administered via the ELLIPTA are provided in Table 2.
Table 1
Description of FF 100 mcg Inhalation Powder in ELLIPTA
FF 100
First Strip
Second Strip
GW685698 blended with 
lactose monohydrate
Lactose monohydrate with magnesium 
stearate1
Dosage Form
ELLIPTA DPI with 30 doses (2 strips with 30 blisters)
Unit Dose strengths
100 mcg per blister
Not applicable
Physical description
White powder
White powder
Route of 
Administration
Inhaled
1.
Magnesium stearate 1.0% w/w of total drug product.
Table 2
Description of Study Treatment Inhalation Powder in ELLIPTA
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
39
7.1.2.
Description of Albuterol/Salbutamol
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.
7.1.3.
Study Treatment, albuterol/salbutamol, and FF 100 mcg Return
ELLIPTAs containing FF 100 mcg, and study treatment, in addition to 
albuterol/salbutamol, will be dispensed to a participant during their visit to the study 
clinic (as applicable). The participant must return all dispensed ELLIPTAs and 
albuterol/salbutamol at the subsequent clinic visit. The schedule for dispensing and 
collecting FF 100 mcg and study treatment ELLIPTAs is provided in the Schedule of 
Activities table (Section 2).
All used and unused study treatment, FF 100 mcg and albuterol/salbutamol 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 Study Reference Manual (SRM).
If any ELLIPTA fails to function properly, the participant should return to the clinic as 
soon as possible to obtain a new inhaler.  The site will use the IWRS (RAMOS NG) to 
obtain a new treatment pack number for the participant and dispense a new study 
treatment kit from the site’s study treatment supply as instructed by the IWRS.
In addition, any metered dose inhaler (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.
7.2.
Dose Modification
There were no dose modifications planned for this protocol.
7.3.
Method of Treatment Assignment
Participants 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. Participants will be randomized using an interactive web response 
system (IWRS) RAMOS NG. The study will use central-based randomization to allocate 
treatments. Once a randomization number is assigned to a participant it cannot be 
reassigned to any other participant in the study.
Following the 2-week run-in period and participant to satisfying all eligibility criteria, 
participants will be randomized 1:1:1 to one of the following three double-blind 
treatments for the duration of the treatment period: 
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
40

UMEC 62.5 mcg QD

UMEC 31.25 mcg QD

Placebo QD
The duration of double-blind treatment for each participant is 24 weeks. On the morning 
of each scheduled clinic study visit, participants will refrain from taking their morning 
dose of study treatment and FF 100 mcg 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 Randomization Visit (Visit 2). On the other days during the treatment period (i.e. 
“non-clinic days”), participants 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 treatment packs will be supplied as 
needed to the sites. Details of how to use the IWRS system (RAMOS NG) to randomize 
participants and manage study treatment supplies (including dispensing) is provided in 
the RAMOS NG IWRS manual and SRM.
7.4.
Blinding
This will be a double-blind study and the following will apply. 

The Investigator or treating physician may unblind a participant’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 participant as judged by the 
Investigator. 

Investigators have direct access to the participant’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 participant’s treatment assignment. 

If GSK personnel are not contacted before the unblinding, the Investigator
must notify GSK within 24 hours after unblinding, but without revealing the 
treatment assignment of the unblinded participant, unless that information is 
important for the safety of participants currently in the study. 

The date and event or condition which led to the unblinding (i.e. the primary 
reason) will be recorded in source documentation and in the eCRF. 
Should a participant’s treatment assignment be unblinded then the participant may 
continue the assigned study treatment and be followed-up as per protocol until the 
completion of the Safety Follow-up assessments.
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any participant 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 participant’s treatment assignment, may be sent to Investigators in 
accordance with local regulations and/or GSK policy. Participants will not be withdrawn 
from the study.
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
41
7.5.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
7.6.
Preparation/Handling/Storage/Accountability
1.
The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment.
2.
Only participants enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment. All study treatments 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access 
limited to the investigator and authorized site staff.
3.
The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records).
4.
Further guidance and information for the final disposition of unused study treatment 
are provided in the SRM.
5.
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.
6.
A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK.
7.7.
Treatment Compliance
When participants are dosed at the site, they will receive FF 100 mcg and 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 participant identification 
will be confirmed at the time of dosing by a member of the study site staff.  
When participants self-administer study treatment(s) at home, compliance with study 
treatment will be assessed through querying the participant during the site visits and 
recording the number of doses remaining in the ELLIPTA in the eCRF (see the SRM for 
details).  A record of the number of ELLIPTAs dispensed to each participant must be 
maintained and reconciled with study treatment and compliance records. 
Participant compliance with FF 100 mcg and study treatment will be assessed at 
scheduled clinic visits by reviewing the eDiary and information from the dose counter on 
the returned inhaler(s) (see Section 7.1.3).  Participants should be 80% to 120% 
compliant on taking both FF 100 mcg and study treatment between each pair of 
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
42
compliant on taking both FF 100 mcg and study treatment between each pair of 
scheduled and consecutive on-treatment clinic visits, as applicable. Participants who fall 
outside this range should be re-educated on treatment compliance by their site. This re-
education should be documented in the participant’s source document. If FF 100 mcg 
and/or study treatment is prematurely discontinued during the course of the study or 
compliance repeatedly falls outside of acceptable ranges, the study sponsor/site monitor 
must be contacted to discuss participant eligibility for continued participation in the 
study.
7.8.
Concomitant Therapy
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.
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 FF 100 mcg and albuterol/salbutamol should not be recorded in 
the eCRF; however non-study supplied FF 100 mcg and albuterol/salbutamol will be 
recorded in the eCRF.
The minimum requirement is that the drug name, reason for use, dose (including unit e.g. 
mcg) and frequency, route and the dates of administration are to be recorded.
Medications initiated after completion of the assessments at Visit 5/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.  Participants who have completed the Early Withdrawal 
Visit are allowed to use any medications prescribed by the Investigator or primary care 
physician.
7.8.1.
Permitted Medications and Non-Drug Therapies
7.8.1.1.
Permitted Asthma Medications
In addition to FF 100 mcg and 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. Participants must be judged 
capable of withholding albuterol/salbutamol for at least 6 hours prior to study 
visits.
Temporary changes in medications are permitted for the treatment of moderate asthma 
exacerbations, 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 SRM for contact information
[refer to Section 9.1.4.1 for guidance on moderate asthma exacerbation]):
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
43

An increase in ICS dose.

Systemic corticosteroids (tablets, suspension or injection) 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.
7.8.1.2.
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.

Decongestants: Participants 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 participants 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, 
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
44
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 participants’ lung function or safety assessments
(e.g., cardiac measurements). However, no systemic corticosteroids will be permitted.
7.9.
Prohibited Medications and Non-Drug Therapies
Use of the medications listed in Table 3 is not permitted during the study.
Table 3
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
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) 
2 days
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)
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
45
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
Any other investigational drug
30 days or within 5 drug half-lives of the 
investigational drug (whichever is longer)
7.10.
Treatment after the End of the Study
Participants 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 participant’s medical condition, whether or not GSK is providing 
specific post-study treatment.
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
Participants that permanently stop study treatment are encouraged to remain in the 
study.  Participants have the right to discontinue study treatment before the end of the 
study.  A participant may also be asked to discontinue study treatment at the 
Investigator’s discretion.
Participants who withdraw from study treatment prematurely (for any reason) should, 
where possible, continue to be followed-up as per protocol until the completion of the 
Safety Follow-up assessments. If this is not possible, the Investigator must encourage the 
participant to participate in as much of the study as they are willing (or able) to.
A participant may be withdrawn from study treatment at any time. A reason for 
premature discontinuation of study treatment (e.g., AE, lack of efficacy [including 
moderate or severe asthma exacerbation], protocol deviation, Investigator discretion, 
consent withdrawn etc.) must be captured in the eCRF.
A participant 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 

QTc: Meets any of the protocol-defined stopping criteria 

Pregnancy: Positive pregnancy test
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
46
8.1.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). These protocol guidelines are in alignment 
with FDA premarketing clinical liver safety guidance: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Discontinuation of study treatment for abnormal liver tests should be considered by the 
investigator when a participant meets one of the conditions outlined in the algorithm or if 
the investigator believes that it is in the best interest of the participant.
Phase II Liver Chemistry Stopping and Increased Monitoring Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus
Bilirubin≥2x
ULN (>35% 
direct) 
or plus
INR>1.5, if 
measured*
Possible
Hy’s Law
ALT≥3xULN
ALT≥5xULN
ALT≥3xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
ALT≥3xULN
but able to 
monitor 
weekly for 
4 weeks
No
Yes
Yes
Yes
Yes
No
No
No
No
Yes
ALT≥3xULN
persist for
4 weeks or 
stopping 
criteria 
met
Yes
No
*INR value not applicable to subjects on anticoagulants
Yes
If subject to be monitored weekly must refer to Liver Safety Required  Actions and  Follow  up 
Assessments  section  in  the  Appendix
Must refer to Liver Safety Required Actions and Follow  up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments can be found in Appendix 7
8.1.2.
QTc Stopping Criteria
Details on performing ECG assessments can be found in Section 9.4.3.
The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study.  This formula may 
not be changed or substituted once the participant has been enrolled.
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
47

For example, if a participant 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 participant as well.

Once the QT correction formula has been chosen for a participant’s eligibility, 
the same formula must continue to be used for that participant 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 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, lead to withdrawal 
from study treatment:

QTc>500 msec or uncorrected QT>600 msec

Change from baseline: QTc> 60 msec

For patients with underlying bundle branch block, follow the discontinuation criteria 
listed below:

Baseline QTc with Bundle Branch Block <450 msec, Discontinuation QTc with 
Bundle Branch Block >500 msec

Baseline QTc with Bundle Branch Block <450-480 msec, Discontinuation QTc 
with Bundle Branch Block ≥530 msec
8.1.3.
Rechallenge
8.1.3.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed.
8.2.
Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, 
or may be withdrawn at any time at the discretion of the investigator for safety, 
behavioral, compliance or administrative reasons.

If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent.

If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records.

In the event of early withdrawal from the study, every effort should be made to 
have the participant 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 Schedule of Activities table (Section 2).
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
48
8.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 
9.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the Schedule of Activities (SoA) 
(Section 2). There are no protocol waivers or exemptions allowed. Immediate safety 
concerns should be discussed with the sponsor immediately upon occurrence or 
awareness to determine if the participant should continue or discontinue study treatment.
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
No study related procedures may be performed until the informed consent form has 
been signed by the participant.  A Pre-Screening visit (Visit 0) is required in order to 
administer the informed consent before any changes are made to the participant’s current 
medical regimen.  Selection and modification of the participant’s medications prior to 
study participation is based on the physician’s judgment according to sound medical 
practice, principles, and each participant’s needs.  A participant’s treatment must not be 
changed merely for the purpose of enabling the participant’s participation in the study.
During the Pre-Screening visit (Visit 0) the following information will be captured in the 
eCRF for each participant: 

Demographic information including race, age and gender

Participant number

Serious Adverse Event information only for any SAE considered as related to 
study participation

Investigator signature page
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
49
The additional following critical baseline assessments will be conducted at Screening 
(Visit 1):

Weight and height

Asthma diagnosis history including:

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

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

Questionnaires (ACQ; E-RS)

Pre-and post-albuterol/salbutamol lung function

Inclusion/Exclusion criteria assessment

Physical examination

12-lead ECG

Child bearing status assessment for all potential female participants

Clinical laboratory tests (including hematology, chemistry, urinalysis and serum 
pregnancy test)

AE / 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 FF 100 mcg run-in medication
9.1.
Efficacy Assessments
The timings of all efficacy assessments are specified in the Schedule of Activities (SoA)
(Section 2).
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
50
9.1.1.
Questionnaires
The questionnaires should be completed before any procedures are performed on the 
participant to avoid influencing the participant’s response. To avoid biasing responses, 
the participants 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 participant must be encouraged to complete any missing assessments or items.
Instructions for completing the questionnaires can be found in the SRM.
9.1.1.1.
Global Assessment of Severity and Response to Treatment
The participant will be asked to complete the Global Assessment of Severity and 
Response to Treatment at the visits specified in the Schedule of Activities table (Section 
2). The Global Assessment of Severity is a single item questionnaire; participants 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. Instructions for completing the questionnaires can be found in the 
SRM.
9.1.1.2.
Asthma Control Questionnaire (ACQ)
The ACQ measures attributes of asthma control [Juniper 1999], measured with questions 
designed to be self-completed by the participant.  Participants will complete the ACQ at 
specified study visits. The ACQ-5 includes five questions (concerning nocturnal 
awakening, waking in the morning, activity limitation, shortness of breath and wheeze) 
which enquire about the frequency and/or severity of symptoms over the previous week. 
The ACQ-6 includes an additional item asking about rescue medication use. 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. 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].
9.1.1.3.
St. George’s Respiratory of Life Questionnaire (SGRQ)
The SGRQ 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 participant
[Jones 1992] with a recall over the past 3 months.  A change of 4 points is considered a 
clinically relevant change [Jones 2005].
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
51
9.1.1.4.
Asthma Quality of Life Questionnaire (AQLQ)
The 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 participant with a 
recall over the past 2 weeks.  A change of 0.5 is considered clinically important [Juniper
1994].
9.1.2.
Daily Diaries
Participants 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. Participants 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 PEF

Morning FF 100 mcg medication use

Morning double-blind study medication use (during the treatment period only)
Section 9.1.2 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. 
Participants 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). Participants 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 participant recall in discussions with 
the Investigator, for site staff to then enter as appropriate in the eCRF.
9.1.2.1.
eDiary Questionnaires, Assessments and Alerts
For information on the eDiary questions, please refer to Appendix 8.
9.1.2.1.1.
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 
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
52
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.
9.1.2.1.2.
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.
9.1.2.1.3.
Night-time Awakening, Asthma Symptom and Physical Activity 
Questions
Every morning upon waking (from the morning after Visit 1 onwards), participants will 
answer a question on the occurrence of night-time awakenings due to asthma symptoms. 
The participant’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’, participants 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, 
participants 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 (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].
9.1.2.1.4.
Morning and Evening Home Spirometry
An electronic home spirometer/eDiary device will be issued to participants 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 
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
53
documented in the SRM and the third-party vendor manual. Participants will conduct 
spirometry maneuvers each morning, prior to study treatment and FF 100 mcg dosing,
and each evening. Three measurements for each session will be recorded by the 
participants in the eDiary. Assessments will be performed:

After completing all other eDiary assessments

Prior to albuterol/salbutamol use

Prior to study treatment and FF 100 mcg dosing
Data from the home FEV1 assessments will be used to determine the time to maximal 
effect of the assigned double-blind study treatment.
9.1.2.1.5.
Alerts
For safety the following alerts, indicative of worsening asthma, will be programmed into 
the eDiary with instructions for the participant to contact the investigator (either by 
telephone and/or by visiting the study clinic) if any of the alert criteria are met:

Nocturnal awakening(s) due to asthma requiring albuterol/salbutamol use for 2 
consecutive nights.

An increase from baseline of ≥ 4 puffs /day of albuterol/salbutamol use on 2 
consecutive days.

A ≥30% decrease in AM PEF from baseline on 2 consecutive mornings.

A ≥30% decrease in PM PEF from baseline on 2 consecutive evenings

A ≥30% decrease in AM FEV1 from baseline on 2 consecutive mornings.

A ≥30% decrease in PM FEV1 from baseline on 2 consecutive evenings.
9.1.3.
Pulmonary Function Test
The 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 
on each occasion that spirometry assessments are performed, in accordance with the 
American Thoracic Society / European Respiratory Society (ATS/ERS) standards [Miller
2005]. The highest of 3 technically acceptable measurements will be recorded at each 
visit:

Pre-dose Spirometry: At Visits 1 through 5/EOS (and the Early Withdrawal 
Visit, if applicable), participants 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 2
(the baseline assessment).
o
At least 24 hours after the participant’s last morning dose of study 
treatment on the day prior to the visit.
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
54
o
Before the participant’s morning dose of study treatment on the day of the 
visit.

Post-dose Spirometry: At Visits 2 and 5/EOS (and the Early Withdrawal Visit, if 
applicable), spirometry assessments must be performed 3 hours after the 
participant’s morning dose of study treatment; the assessment performed at Visit 
5/EOS should be performed at the same time of day (1 hour) as the assessment 
performed at Visit 2 (the baseline assessment). At each visit, participants 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.
9.1.3.1.
Reversibility (Albuterol/Salbutamol)
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.
To perform the reversibility assessment, 4 puffs of the provided albuterol/salbutamol 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 albuterol/salbutamol.
Percent reversibility will be calculated as follows:
(Post-bronchodilator FEV1 – Pre-bronchodilator FEV1)
x 100
Pre-bronchodilator FEV1
The reversibility requirement for eligibility must be assessed at Visit 1. Participants 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 participant may not enter the 2-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:
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 participant 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 participant may enter the 2-week run-in period.
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
55
9.1.4.
Asthma Exacerbations
Moderate and severe asthma exacerbation data will be collected from the start of 
randomized double blinded treatment until Visit 5/EOS Visit or the Early Withdrawal 
Visit for those participants that withdraw from participation in the study (see Section 
8.2). For consistency, exacerbations separated by less than 7 days will be treated as a 
continuation of the same exacerbation.
Participants will 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).
9.1.4.1.
Moderate Asthma Exacerbation
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 for 3 days or more and/or hospitalization. 

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.
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 
(Refer to Section 7.8.1 above)
The Medical Monitor may be contacted for additional guidance, see the medical 
monitor/Sponsor Information Page.
9.1.4.2.
Severe Asthma Exacerbation
A severe asthma exacerbation is defined as: 
The deterioration of asthma requiring the use of systemic corticosteroids (tablets,
suspension or injection) for at least 3 days.
OR
An inpatient hospitalization or emergency department visit because of asthma, requiring
systemic corticosteroids.
9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4.
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
56
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study, 
or that caused the participant to discontinue the study treatment or withdraw from the 
study (see Section 8).
9.2.1.
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 participant consents to participate in the 
study up to and including any follow-up contact. 

AEs will be collected from the start of Study Screening until the follow-up contact 
(see Section 9.2.3) at the timepoints specified in the Schedule of Activities (SoA) 
table (Section 2).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the eCRF.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in
Appendix 4. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.

Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the Investigator learns of any SAE, including a death, at 
any time after a participant has been discharged from the study, and he/she 
considers the event 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
9.2.2.
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 participant 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?” 
Participants will be issued with a paper Medical Problems/Medications Taken worksheet
to record any medical problems experienced and medications used during the study. This 
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
57
paper worksheet will be used to assist participant recall in discussions with the 
Investigator (or designee), for site staff to then enter as appropriate in the eCRF.
9.2.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts.  All SAEs, and non-serious AEs of special 
interest (as defined in Section 9.2.5), will be followed until the event is resolved, 
stabilized, otherwise explained, or the participant is lost to follow-up (as defined in 
Section 8.3). Further information on follow-up procedures is given in Appendix 4
9.2.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are 
met. 

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study treatment 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or 
other specific safety information eg, summary or listing of SAE) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.
9.2.5.
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). 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
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
58
Special interest AE group
Special interest AE subgroup
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
-
Hypersensitivity
-
Local steroid effects
-
9.2.6.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 4 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the eCRF will 
be required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 
The CV eCRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the eCRF within one week of receipt of a CV Event data query prompting its completion. 
The Death eCRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
59
9.2.7.
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 participant 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.)
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).
9.2.8.
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.
9.2.9.
Pregnancy
Details of all pregnancies in female participants 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.
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
60
9.3.
Treatment of 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 eCRF 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 
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.
9.4.
Safety Assessments
Planned time points for all safety assessments are provided in the Schedule of Activities 
(SoA).
9.4.1.
Physical Examinations
Physical exams will be performed at the time points specified in the Schedule of 
Activities (SoA) table (Section 2).

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.

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
9.4.2.
Vital Signs
Vital signs will be performed at the time points specified in the Schedule of Activities 
(SoA) table (Section 2) prior to conducting spirometry and prior to taking the morning 
dose of study treatment and FF 100 mcg. 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.
9.4.3.
Electrocardiograms
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
assessment but prior to performing the pre-bronchodilator spirometry assessment. 
Recordings will be made at the time-points defined in the Schedule of Activities (SoA) 
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
61
table (Section 2). All ECG measurements will be made with the participant in a supine 
position having rested in this position for approximately 5 minutes before each reading.
For participants who meet the QTc, protocol defined stopping criteria, triplicate ECGs 
(over a brief period of time) should be performed (Section 8.1.2).
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.
9.4.4.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory tests to be performed and 
to the Schedule of Activities (SoA) for the timing and frequency. 

The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 5 days after the last dose of study 
treatment should be repeated until the values return to normal or baseline or are 
no longer considered significantly abnormal by the investigator or medical 
monitor. 

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the Schedule of 
Activities (SoA).
9.5.
Pharmacokinetics
Pharmacokinetics is not relevant for this protocol.
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
62
9.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
9.7.
Genetics
Information regarding genetic/ pharmacogenetic (PGx) research is included in Appendix 
6. 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 6).
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.
9.8.
Biomarkers
Biomarkers are not evaluated in this study.
9.9.
Health Economics OR Medical Resource Utilization and 
Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study.
10.
STATISTICAL CONSIDERATIONS
10.1.
Hypotheses
The primary objective of this study is to evaluate the efficacy of UMEC 62.5 mcg and 
UMEC 31.25 mcg compared with placebo in participants with not well controlled asthma 
over a 24 week treatment period.  This is a superiority study to demonstrate the benefit of 
UMEC at two dosage strengths 62.5 mcg and 31.25 mcg when compared to Placebo in 
patients on background therapy of FF 100 mcg. The primary efficacy endpoint is the 
mean change from baseline in trough FEV1 at Week 24.
The test for the primary efficacy endpoint is such that 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
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
63
For the primary endpoint (and other lung function related efficacy endpoints), the 
primary treatment comparisons of interest are:  

UMEC 62.5mcg vs Placebo

UMEC 31.25mcg vs Placebo
For each comparison test on the primary endpoint, the null hypothesis is there is no 
difference between treatment groups.  The alternative hypothesis is there is a difference 
between treatment groups.
Therefore T1 and T2 for these endpoints are the mean changes from baseline for the 
UMEC therapy and placebo, respectively, as listed above. 
Details on all pairwise treatment comparisons of interest are provided in Section 10.5.2.
10.2.
Sample Size Determination
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 384 randomized participants are required for this study, with 128 participants 
in each of the three double-blind treatment groups: UMEC 62.5mcg, UMEC 31.25mcg or 
Placebo. Assuming 10% missing data on spirometry at the end of the 24-week treatment 
period, due to early withdrawal from study, approximately 115 participants per treatment 
group will have trough FEV1 available for the primary 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 350mL based on two previous Tiotropium moderate asthma 
studies.  The study design and population of this study aligns well with these two phase 
III, 24 week, randomised, double blind, placebo-controlled, parallel-group, active 
comparator studies of Tiotropium.  In patients with moderate asthma on a background 
therapy of ICS the standard deviations in change from baseline trough FEV1 at Week 24 
ranged from 325 to 354mL; from this a SD estimate of 350 mL was chosen. This was 
estimated from a wide selection of studies, critically to minimise the risk of reduced 
power for the primary endpoint. The range of observed treatment differences across the 
Tiotropium treatment groups is 133 – 185mL, which supports the expectation that the 
treatment effect seen in a moderate asthma population is larger than in the more severe 
asthma population in study 205715 treated on a background of FF/VI. This is in line with 
data from GSK study 200699 which showed UMEC 62.5 mcg to be an effective dose. An 
average increase in change from baseline trough FEV1 at Day 29 of 136 mL was 
observed in an asthma subset of patients treated with FF/UMEC (100/62.5) compared 
with FF (100 mcg) alone. The GSK phase III closed triple asthma study 205715, which 
this study supports, is in a more severe asthma population and conservatively assumes a 
SD estimate of 400mL.
Based on a true population difference of 130 mL, a sample size of 115 patients per 
treatment group has an estimated 80% power to observe statistical significance at the two 
sided 5% level, for each of the two primary comparisons of interest for each UMEC dose. 
Using the above assumptions the smallest observed effect predicted to result in a 
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
64
statistically significant difference between treatment groups is 90.5 mL (minimum 
detectable difference).
No interim analysis is planned for this study.
10.3.
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=115 per arm in the 
intent to treat (ITT) population for the primary efficacy analysis, varying the true
treatment difference and estimated standard deviation on the change from baseline in 
trough FEV1 at the end of the 24-week treatment period.
Treatment difference (mL)
Standard Deviation
100
115
130
145
160
300
0.71
0.82
0.91
0.95
0.98
350
0.58
0.70
0.80
0.88
0.93
400
0.47
0.58
0.69
0.78
0.86
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
65
10.4.
Sample site re-estimation or adjustment
No sample size re-estimation is planned.
10.5.
Data Analysis
10.5.1.
Analysis population
The following participant populations will be identified:
All Participants Enrolled Population: 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). This population will be used for the 
summary of participant disposition. 
All Participants Screened Population: This population contains all participants that 
complete at least one Visit 1 (Screening) procedure. This population will be used for the 
summary of participant disposition (including reasons for screening failures and run-in 
failures) and for the listing of AEs and SAEs for non-randomized participants. 
ITT Population: This population will comprise all randomized participants, excluding 
those who were randomized in error. A participant who is recorded as a screen failure or 
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
66
run-in 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. This will constitute 
the primary population for all efficacy and safety analyses. 
10.5.2.
Treatment Comparisons
To demonstrate the benefit of UMEC the primary comparisons of interest for the primary 
efficacy endpoint are:

UMEC 62.5 mcg vs Placebo

UMEC 31.25 mcg vs Placebo
Other pairwise treatment comparisons of interest that aim to informally estimate any 
potential benefit of increasing the UMEC dose are given below for all efficacy endpoints. 

UMEC 62.5 mcg vs UMEC 31.25 mcg
For the multiple comparisons and multiplicity adjustment, please see Section 10.5.3. 
10.5.3.
Multiple Comparisons and Multiplicity
In order to account for multiple tests involving the two UMEC doses 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 test in the 
hierarchy. 
A step-down procedure with the following hierarchy will be used for the primary 
comparisons in the primary endpoint.  

The contrast between UMEC 62.5 mcg vs Placebo 
(two-sided, alpha = 0.05.  Null hypothesis of no treatment difference)

The contrast between UMEC 31.25 mcg vs Placebo 
(two-sided, alpha = 0.05.  Null hypothesis of no treatment difference)
The second hypothesis will be formally tested only if the first hypothesis has been 
rejected, thus maintaining the overall significance level at 5%.  
Specifically, if the defined treatment comparison for the primary efficacy endpoint at the 
highest dose of UMEC 62.5 mcg is significant at 0.05 level then the efficacy of UMEC 
62.5 mcg is demonstrated, and the treatment comparison can be repeated on the UMEC 
31.25 mcg dose. 
Note that, in the event that the first hypothesis is not rejected a nominal p-value for the 
second hypothesis may be provided in the displays for descriptive purposes only and will 
not alter the conclusion of the step-down procedure.
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
67
No multiplicity adjustment will be made on these two treatment comparisons on the 
secondary endpoint.
For all efficacy endpoints (primary, secondary and other), treatment comparisons 
between UMEC 62.5 vs UMEC 31.25 mcg informally investigating the benefit of 
increasing UMEC dose will be made without adjusting for multiplicity.  Any p-values ≤ 
0.05 will be identified as nominally significant.
10.6.
Statistical Analysis
Where possible, data from participants 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 RAP. 
In general, the baseline value is the last assessment value prior to randomization at Visit 2
for the efficacy endpoints based on assessments at clinic visits.  The covariates to be 
considered in the efficacy analyses include age, sex, and the baseline value, if relevant. 
Other covariates, if appropriate, may be considered. Specific details will be provided in 
the RAP.
10.6.1.
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 participant, the baseline value of clinic 
FEV1 is the last acceptable/borderline acceptable (pre-dose) FEV1 value obtained prior to 
randomization (either from Visit 2 pre-dose or from Visit 1 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, 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. 

UMEC 62.5 mcg vs Placebo

UMEC 31.25 mcg vs Placebo
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 10.5.2 will also 
be provided for the primary efficacy endpoint.
10.6.2.
Secondary Analyses
Full details of the analyses to be performed on the secondary efficacy endpoint will be 
given in the RAP.
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
68
10.6.3.
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.
10.6.4.
Interim Analyses
No interim analysis is planned for this study.
10.6.5.
Exploratory Analyses
The psychometric properties of the E-RS and Supplemental asthma items will be 
evaluated to characterize the E-RS as an endpoint for asthma.  These exploratory analyses 
may be provided in a separate RAP.
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
69
11.
REFERENCES
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
GlaxoSmithKline Document Number: 2011N123107_03 GW685698+GSK573719 
Investigator’s Brochure, Version 03, dated 19 Jun 2014 
GlaxoSmithKline Document Number: 2016N284764_00 GW685698+GSK573719 
Investigator’s Brochure, Version 03, Supplement 01, dated 27 May 2016
Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma 
(GINA) 2016. Available from: http://www.ginasthma.org/
Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure of health 
status for chronic airflow limitation. The St. George's Respiratory Questionnaire. Am Rev 
Respir Dis 1992;145:1321-1327.
Jones PW. St. George’s Respiratory Questionnaire: MCID. Journal of Chronic 
Obstructive Pulmonary Disease 2005;2:75-79.
Juniper EF, Bousquet J, Abetz L, Bateman ED; GOAL Committee. Identifying 'well-
controlled' and 'not well-controlled' asthma using the Asthma Control Questionnaire.
Respir Med 2006;100:616-621.
Juniper EF, Guyatt GH, Willan A, Griffith LE. Determining a minimal important change 
in a disease-specific quality of life instrument. J Clin Epidemiol 1994;47:81-87.
Juniper EF, O'Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of 
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-
558.
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.
Miller MR et al. Standardization of Lung Function Testing. Eur Resp J 2005;26:153-161.
Quanjer P, Stanojevic S, Cole T, Baur X., Hall G, Enright P, et al. on behalf of 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. Eur Respir J 2012;40:1324-
1343.
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
70
Reddel HK, Taylor DR, Bateman ED, Boulet L-P, Boushey HA, Busse WW, et al. On
behalf of the American Thoracic Society/European Respiratory Society task force on 
asthma control and exacerbations. An official American Thoracic Society/European 
Respiratory Society statement: asthma control and exacerbations; standardizing endpoints 
for clinical asthma trials and clinical practice. Am J Respir Crit Care Med 2009;180:59-
99. 
US Department of Health and Human Sciences; Food and Drug Administration (FDA).
Guidance for Industry; Drug-Induced Liver Injury: Premarketing Clinical Evaluation 
(July 2009). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf (Accessed 16 July 2014).
Virchow JC, Backer V, de Blay F, Kuna P, Ljorring C, Prieto JL, et al. Defining 
moderate asthma exacerbations in clinical trials based on ATS/ERS joint statement. 
Respiratory Medicine 2015;109:547-556
Wyrwich KW, Khan SA, Navaratnam P, Nolte H, Gates Jr DF. Validation and agreement 
across four versions of the asthma control questionnaire in patients with persistent 
asthma. Resp Med 2011;105:698-712.
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
71
12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
ACQ
Asthma Control Questionnaire
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
BMI
Body Mass Index
BPM
Beats Per Minute
BST
Bioanalytical Science and Toxicokinetics
BUN
Blood Urea Nitrogen
CI
Confidence Interval
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic Obstructive Pulmonary Disease
DNA
Deoxyribonucleic acid
DPI
Dry Powder Inhaler
ECG
Electrocardiogram
(e)CRF
(Electronic) Case Report Form
eDiary
Electronic Diary
EOS
End of study
E-RS
Evaluating Respiratory Symptoms
ERS
European Respiratory Society
EW
Early Withdrawal
FDA
Food and Drug Administration
FEV1
Forced expiratory volume in 1 second
FF
Fluticasone Furoate
FP
Fluticasone Propionate
FSH
Follicle Stimulating Hormone
FVC
Forced Vital Capacity
GCP
Good clinical practice
GCSP
Global Clinical Safety and Pharmacovigilance
GINA
Global Initiative for Asthma
GSK
GlaxoSmithKline
hCG
Human Chorionic Gonadotropin
HIV
Human Immunodeficiency Virus
HPA
Hypothalamic Pituitary Axis
HRT
Hormone Replacement Therapy
IB
Investigator’s Brochure
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
72
ICF
Informed Consent Form
ICH
International Conference on Harmonization
ICS
Inhaled Corticosteroids
IEC
Independent Ethics Committee
IOP
Intraocular Pressure
IP
Investigational Product
IRB
Institutional Review Board
IRT
Interactive Response Technology
IWRS
Interactive Web Response System
ITT
Intent to Treat
LABA
Long-Acting Beta-2-Agonists
LAMA
Long-Acting Muscarinic Antagonist
LOCS III
Lens Opacities Classification System III
LRTI
Lower Respiratory Tract Infection
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
PEF
Peak Expiratory Flow
PK
Pharmacokinetic
PM
Evening
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
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
73
US
United States
VI
Vilanterol
VT
Ventricular Tachycardia
WBC
White Blood Cell
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
ELLIPTA
None
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
74
12.2.
Appendix 2: Clinical Laboratory Tests

All protocol required laboratory assessments (haematology, clinical chemistry 
and urinalysis) must be conducted in accordance with the Laboratory Manual, 
and Protocol Schedule of Activities (Section 2) Laboratory requisition forms 
must be completed and samples must be clearly labelled with the participant
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 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 participant 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.

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 6 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
75
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
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood and ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

Follicle stimulating hormone (FSH) and estradiol (as needed in females 
of non-reproductive potential only)

Serum/urine hCG Pregnancy test (as specified in the Schedule of 
Activities table [Section 2])
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 8.1.1 and 
Appendix 7
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
76
12.3.
Appendix 3: Study Governance Considerations
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (eg, advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study. 
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
77

Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative. 

Participants who are rescreened are required to sign a new ICF.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
78
Dissemination of Clinical Study Data

For this study participant 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.  
Data Quality Assurance

Management of clinical data will be performed in accordance with applicable 
GSK standards and data cleaning procedures to ensure the integrity of the data, 
e.g., removing errors and inconsistencies in the data.

Adverse events and concomitant 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.  Participant 
initials will not be collected or transmitted to GSK according to GSK policy.

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (eg, laboratory 
data). The investigator is responsible for verifying that data entries are accurate 
and correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years after study completion 
unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written 
approval of the sponsor. No records may be transferred to another location or 
party without written notification to the sponsor. 
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
79
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available.
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study treatment development
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
80
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study treatment, whether or not considered related to the 
study treatment.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfill the definition of an AE 
or SAE. 

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. Also, "lack of 
efficacy" or "failure of expected pharmacological action" constitutes an AE or SAE.
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
81
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
82
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
83
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
each occurrence of each AE/SAE.

A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology. 
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
84

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.
Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper SAE data collection tool (see next section).

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form or to the 
assigned SAE contact by telephone.

Contacts for SAE reporting can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
SAE Reporting to GSK via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the assigned SAE contact by telephone.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
85
12.5.
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)
Women in the following categories are not considered WOCBP
1.
Premenarchal
2.
Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
3.
Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment.
Contraception Guidance
Female participants
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in 
Table 4.
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
86
Table 4
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation 

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulationb

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.) 
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the participant.)
NOTES: 
a.
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants in clinical studies.
Pregnancy Testing

WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive urine or serum pregnancy test 

Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected 

Pregnancy testing, with a sensitivity of [5, 10, 25] mIU/mL will be performed [and 
assayed in a certified laboratory OR and assayed in the central laboratory OR using 
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
87
the test kit provided by the central laboratory / provided by the sponsor /approved by 
the sponsor and in accordance with instructions provided in its package insert]  
Collection of Pregnancy Information
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date.  

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. 

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK
as described in Appendix 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 participant who becomes pregnant while participating in the study will 
immediately discontinue study medication.
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
88
12.6.
Appendix 6: Genetics
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 participant who is enrolled in the study can participate in genetic research.  Any 
participant 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 
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
89
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 participant 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 participant 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 
participant 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.
Participants can request their sample to be destroyed at any time.
Informed Consent
Participants 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.
Participant Withdrawal from Study
If a participant who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the participant 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 participant 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. 
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
90
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 participant 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 
participant does not meet the entry criteria for participation in the study, then the 
Investigator should instruct the participant 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 Participant’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 
participant, family members, insurers, or employers of individual genotyping results that 
are not known to be relevant to the participant’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.
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
91
12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments
Phase II liver chemistry stopping and follow up criteria have been designed to assure 
participant safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance [Food and Drug Administration 2009]).
Phase II liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin)
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF and complete an 
SAE data collection tool if the event also meets 
the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the participant until liver chemistries
resolve, stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge participant with 
study treatment unless allowed per protocol and 
GSK Medical Governance approval is granted 
(refer to Section 8.1.3)
If restart/rechallenge not allowed per protocol or 
not granted, permanently discontinue study 
treatment and may continue participant in the study 
for any protocol specified follow up assessments 

Viral hepatitis serology4

Blood sample for pharmacokinetic (PK) 
analysis, obtained 72 hours after last 
dose5

Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications 
on the concomitant medications report 
form including acetaminophen, herbal 
remedies, other over the counter 
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
92
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24 hrs

Monitor participants twice weekly until liver 
chemistries resolve, stabilize or return to within 
baseline 

A specialist or hepatology consultation is 
recommended
For All other criteria: 

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24-72 
hrs 

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to within 
baseline
medications.

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG or gamma globulins).

Serum acetaminophen adduct HPLC 
assay (quantifies potential 
acetaminophen contribution to liver 
injury in participants with definite or 
likely acetaminophen use in the 
preceding week (James 2009) Not 
Required in China

Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF 
forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that participant if ALT 3xULN and bilirubin 2xULN.. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to participants receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing); Hepatitis E IgM antibody 
5.
PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
treatments.)  Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
treatment prior to blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the 
participant’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.  
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
93
Phase II liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 3xULN and <5xULN and bilirubin 
<2xULN, without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks

Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss participant 
safety. 

Participant can continue study treatment   

Participant must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time participant meets the liver chemistry 
stopping criteria, proceed as described above

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor participants twice monthly 
until liver chemistries normalize or return to within 
baseline.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
94
12.8.
Appendix 8: Daily Diary Questions
12.8.1.
Morning Questions
The participant 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
12.8.2.
Evening Questions
The participant 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 
Quite a bit 
Extremely 
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
95
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 
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
96
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
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
97
12.9.
Appendix 9: Country-specific requirements
There are currently no country specific requirements. 
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
98
12.10.
Appendix 10: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).
Amendment 1 15-November-2016
Overall Rationale for the Amendment:
To address typographical errors and inconsistencies between the Schedule of Activities 
(SOA) and the protocol text. In addition, language has been added to Exclusion criteria 
#14 to clearly explain examples of inhaled products (e-cigarettes/vaping) as well as 
provide an example of a drug; in Exclusion #15. (marijuana is considered an abused 
drug).
Section # and Name
Description of Change
Brief Rationale
Section 2: Schedule 
of Activities (SOA)
Included Line item “X” in the box for 
inclusion/exclusion criteria at Visit 2 
(randomization) 
To correct the 
inconsistency 
between the 
Schedule of 
Activities (SOA) 
and the protocol 
text.
Section 2: Schedule 
of Activities (SOA)
Included row for “Exacerbation history” and 
Line item “X” at “screening”
To correct the 
inconsistency 
between the 
Schedule of 
Activities (SOA) 
and the protocol 
text.
Section 2: Schedule 
of Activities (SOA)
Included row for Exacerbation assessment 
and line item “X” in the boxes from Visit 2 
(randomization) to “EOS/EW”. 
To correct the 
inconsistency 
between the 
Schedule of 
Activities (SOA) 
and the protocol 
text.
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
99
Section # and Name
Description of Change
Brief Rationale
Section 2: Schedule 
of Activities (SOA)
[Study Treatment]
Included row for dispensing 
Albuterol/Salbutamol and line item “X” at 
Visit 1 (screening) until Visit 4. 
To correct the 
inconsistency 
between the 
Schedule of 
Activities (SOA) 
and the protocol 
text.
Section 2: Schedule 
of Activities (SOA) 
[Study Treatment]
Included row for collection of 
Albuterol/Salbutamol and line item at Visit 2 
until Visit EOS/EW for collection of 
Albuterol/Salbutamol.
To correct the 
inconsistency 
between the 
Schedule of 
Activities (SOA) 
and the protocol 
text.
Section 3.3.1 Risk 
Assessments
(Potential Risk of 
Clinical Significance 
Systemic ICS effects 
Adrenal suppression)
Updated the information of HPA study 
(Mentioned 24 hour urinary cortisol 
excretion [Previously mentioned as 24 hour 
serum cortisol excretion]) 
Corrected the 
information of 
HPA study
Section 6.2 Exclusion 
Criteria
Example of tobacco products has been added 
to Exclusion criteria #14 Tobacco Use (e-
cigarettes/vaping)
To clearly 
explain examples 
of inhaled 
tobacco 
products.
Section 6.2 Exclusion 
Criteria
Example of a drug has been added to 
Exclusion criteria 15 Drug/alcohol abuse 
(marijuana is considered an abused drug).
Updated 
example of a 
drug/alcohol 
abuse.
Section 9, Study 
Assessments and 
Procedures 
Removed: Healthcare Resource Utilization 
(HRU) from the additional critical baseline 
assessments (Screening [Visit 1])
To correct the 
inconsistency 
between the 
Schedule of 
Activities (SOA) 
and the protocol 
text.
 
2018N371775_00

2016N289466_02
CONFIDENTIAL
205832
100
Section # and Name
Description of Change
Brief Rationale
Section 9, Study 
Assessments and 
Procedures 
Removed: Questionnaires (SGRQ; AQLQ) 
from the additional critical baseline 
assessments (Screening [Visit 1])
To correct the 
inconsistency 
between the 
Schedule of 
Activities (SOA) 
and the protocol 
text.
Section 9, Study 
Assessments and 
Procedures 
Added: Letters “AE” to the additional critical 
baseline assessments (Screening [Visit 1])
To correct the 
inconsistency 
between the 
Schedule of 
Activities (SOA)
and the protocol 
text.
Section 9.2.1, Time 
Period and Frequency 
for collecting AE and 
SAE Information
Updated the information in the second bullet; 
(Stated AEs will be collected from the start 
of Study Screening [Previously mentioned 
AEs will be collected from the start of Study 
Treatment])
To correct the 
inconsistency 
between the 
Schedule of 
Activities (SOA) 
and the protocol 
text.
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
GlaxoSmithKline group of companies
205832
1
TITLE PAGE
Protocol Title: A Phase IIb, 24 week, randomized, double-blind, 3 arm parallel group 
study, comparing the efficacy, safety and tolerability of two doses of umeclidinium 
bromide administered once-daily via a dry powder inhaler, versus placebo, in participants 
with asthma
Protocol Number: 205832/ Amendment 1
Short Title: A randomized, double-blind, parallel group study, comparing the efficacy, 
safety and tolerability of two doses of umeclidinium bromide administered once-daily via 
a dry powder inhaler, versus placebo, in participants with asthma
Compound Number:
GW685698+GSK573719
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information can be found in the Study 
Reference Manual
Regulatory Agency Identifying Number(s): IND No. 104479, EudraCT number 2016-
002843-40
Approval Date: 15-NOV-2016
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
2018N371775_00

 
2018N371775_00
PPD
PPD
PPD

2016N289466_01
CONFIDENTIAL
205832
3
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date of Issue
Amendment 1
15-Nov-2016
Original Protocol
19-Aug-2016
Overall Rationale for the Amendment:
To address typographical errors and inconsistencies between the Schedule of Activities 
(SOA) and the protocol text. In addition, language has been added to Exclusion criteria 
#14 to clearly explain examples of inhaled products (e-cigarettes/vaping) as well as 
provide an example of a drug ;in Exclusion #15. (marijuana is considered an abused 
drug).
Amendment 1 15-November-2016
Section # and Name
Description of Change
Brief Rationale
Section 2: Schedule 
of Activities (SOA)
Included Line item “X”  in the box for 
inclusion/exclusion criteria at Visit 2 
(randomization) 
To correct the 
inconsistency 
between the 
Schedule of 
Activities (SOA) 
and the protocol 
text.
Section 2: Schedule 
of Activities (SOA)
Included row for “Exacerbation history” and 
Line item “X” at “screening”
To correct the 
inconsistency 
between the 
Schedule of 
Activities (SOA) 
and the protocol 
text.
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
4
Section # and Name
Description of Change
Brief Rationale
Section 2: Schedule 
of Activities (SOA)
Included row for Exacerbation assessment 
and line item “X” in the boxes from Visit 2 
(randomization) to “EOS/EW”. 
To correct the 
inconsistency 
between the 
Schedule of 
Activities (SOA) 
and the protocol 
text.
Section 2: Schedule 
of Activities (SOA)
[Study Treatment]
Included row for dispensing 
Albuterol/Salbutamol and line item “X” at 
Visit 1 (screening) until Visit 4. 
To correct the 
inconsistency 
between the 
Schedule of 
Activities (SOA) 
and the protocol 
text.
Section 2: Schedule
of Activities (SOA) 
[Study Treatment]
Included row for collection of 
Albuterol/Salbutamol and line item at Visit 2 
until Visit EOS/EW for collection of 
Albuterol/Salbutamol.
To correct the 
inconsistency 
between the 
Schedule of 
Activities (SOA) 
and the protocol 
text.
Section 3.3.1 Risk 
Assessments
(Potential Risk of 
Clinical Significance 
Systemic ICS effects 
Adrenal suppression)
Updated the information of HPA study 
(Mentioned 24 hour urinary cortisol 
excretion [Previously mentioned as 24 hour 
serum cortisol excretion]) 
Corrected the 
information of 
HPA study
Section 6.2 Exclusion 
Criteria
Example of tobacco products has been added 
to Exclusion criteria #14 Tobacco Use (e-
cigarettes/vaping)
To clearly 
explain examples 
of inhaled 
tobacco 
products.
Section 6.2 Exclusion 
Criteria
Example of a drug has been added to 
Exclusion criteria 15 Drug/alcohol abuse 
(marijuana is considered an abused drug).
Updated 
example of a 
drug/alcohol 
abuse.
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
5
Section # and Name
Description of Change
Brief Rationale
Section 9, Study 
Assessments and 
Procedures 
Removed: Healthcare Resource Utilization 
(HRU) from the additional critical baseline 
assessments (Screening [Visit 1])
To correct the 
inconsistency 
between the 
Schedule of 
Activities (SOA) 
and the protocol 
text.
Section 9, Study 
Assessments and 
Procedures 
Removed: Questionnaires (SGRQ; AQLQ) 
from the additional critical baseline 
assessments (Screening [Visit 1])
To correct the 
inconsistency 
between the 
Schedule of 
Activities (SOA) 
and the protocol 
text.
Section 9, Study 
Assessments and 
Procedures 
Added: Letters “AE” to the additional critical 
baseline assessments (Screening [Visit 1])
To correct the 
inconsistency 
between the 
Schedule of 
Activities (SOA) 
and the protocol 
text.
Section 9.2.1, Time 
Period and Frequency 
for collecting AE and 
SAE Information
Updated the information in the second bullet; 
(Stated AEs will be collected from the start 
of Study Screening [Previously mentioned 
AEs will be collected from the start of Study 
Treatment])
To correct the 
inconsistency 
between the 
Schedule of 
Activities (SOA) 
and the protocol 
text.
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
6
TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS...............................................................................................................9
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................13
3.
INTRODUCTION....................................................................................................19
3.1.
Study Rationale ..........................................................................................19
3.2.
Background ................................................................................................19
3.3.
Benefit/Risk Assessment ............................................................................19
3.3.1.
Risk Assessment .........................................................................20
3.3.2.
Benefit Assessment.....................................................................26
3.3.3.
Overall Benefit: Risk Conclusion..................................................26
4.
OBJECTIVES AND ENDPOINTS...........................................................................26
5.
STUDY DESIGN ....................................................................................................28
5.1.
Overall Design ............................................................................................28
5.2.
Number of Participants ...............................................................................30
5.3.
Participant and Study Completion...............................................................30
5.4.
Scientific Rationale for Study Design ..........................................................30
5.5.
Dose Justification........................................................................................31
6.
STUDY POPULATION...........................................................................................31
6.1.
Inclusion Criteria.........................................................................................31
6.2.
Exclusion Criteria........................................................................................33
6.2.1.
Randomization Criteria ................................................................35
6.2.2.
Inclusion Criteria for Randomization ............................................35
6.2.3.
Exclusion Criteria for Randomization ...........................................36
6.3.
Lifestyle Restrictions...................................................................................36
6.4.
Pre-Screening/Screening/Run-in/Randomization Failures ..........................36
7.
TREATMENTS.......................................................................................................37
7.1.
Treatments Administered............................................................................37
7.1.1.
Description of FF 100 mcg and Double-Blind Study 
Treatment ....................................................................................37
7.1.2.
Description of Albuterol/Salbutamol .............................................38
7.1.3.
Study Treatment and FF 100 mcg Return....................................39
7.2.
Dose Modification .......................................................................................39
7.3.
Method of Treatment Assignment ...............................................................39
7.4.
Blinding.......................................................................................................40
7.5.
Packaging and Labeling..............................................................................40
7.6.
Preparation/Handling/Storage/Accountability..............................................41
7.7.
Treatment Compliance................................................................................41
7.8.
Concomitant Therapy..................................................................................42
7.8.1.
Permitted Medications and Non-Drug Therapies..........................42
7.8.1.1.
Permitted Asthma Medications ...................................42
7.8.1.2.
Permitted Non-Asthma Medications ...........................43
7.9.
Prohibited Medications and Non-Drug Therapies........................................44
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
7
7.10.
Treatment after the End of the Study ..........................................................44
8.
DISCONTINUATION CRITERIA.............................................................................45
8.1.
Discontinuation of Study Treatment ............................................................45
8.1.1.
Liver Chemistry Stopping Criteria ................................................45
8.1.2.
QTc Stopping Criteria ..................................................................46
8.1.3.
Rechallenge.................................................................................47
8.1.3.1.
Study Treatment Restart or Rechallenge....................47
8.2.
Withdrawal from the Study..........................................................................47
8.3.
Lost to Follow Up........................................................................................47
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................48
9.1.
Efficacy Assessments.................................................................................49
9.1.1.
Questionnaires ............................................................................49
9.1.1.1.
Global Assessment of Severity and Response 
to Treatment...............................................................49
9.1.1.2.
Asthma Control Questionnaire (ACQ).........................50
9.1.1.3.
St. George’s Respiratory of Life Questionnaire 
(SGRQ) ......................................................................50
9.1.1.4.
Asthma Quality of Life Questionnaire (AQLQ) ............50
9.1.2.
Daily Diaries ................................................................................50
9.1.2.1.
eDiary Questionnaires, Assessments and 
Alerts..........................................................................51
9.1.2.1.1.
E-RS.......................................................51
9.1.2.1.2.
Supplemental Asthma Items...................51
9.1.2.1.3.
Night-time Awakening, Asthma 
Symptom and Physical Activity 
Questions ...............................................52
9.1.2.1.4.
Morning and Evening Home 
Spirometry..............................................52
9.1.2.1.5.
Alerts......................................................52
9.1.3.
Pulmonary Function Test.............................................................53
9.1.3.1.
Reversibility (Albuterol/Salbutamol)............................54
9.1.4.
Asthma Exacerbations.................................................................54
9.1.4.1.
Moderate Asthma Exacerbation..................................55
9.1.4.2.
Severe Asthma Exacerbation .....................................55
9.2.
Adverse Events...........................................................................................55
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................55
9.2.2.
Method of Detecting AEs and SAEs.............................................56
9.2.3.
Follow-up of AEs and SAEs.........................................................56
9.2.4.
Regulatory Reporting Requirements for SAEs .............................56
9.2.5.
Adverse Events of Special Interest (AESIs) .................................57
9.2.6.
Cardiovascular and Death Events................................................58
9.2.7.
Pneumonia ..................................................................................58
9.2.8.
Radiography (Chest X-Rays) .......................................................59
9.2.9.
Pregnancy ...................................................................................59
9.3.
Treatment of Overdose...............................................................................59
9.4.
Safety Assessments ...................................................................................60
9.4.1.
Physical Examinations.................................................................60
9.4.2.
Vital Signs....................................................................................60
9.4.3.
Electrocardiograms......................................................................60
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
8
9.4.4.
Clinical Safety Laboratory Assessments ......................................61
9.5.
Pharmacokinetics .......................................................................................61
9.6.
Pharmacodynamics ....................................................................................61
9.7.
Genetics .....................................................................................................61
9.8.
Biomarkers .................................................................................................62
9.9.
Health Economics OR Medical Resource Utilization and Health 
Economics..................................................................................................62
10. STATISTICAL CONSIDERATIONS........................................................................62
10.1.
Hypotheses.................................................................................................62
10.2.
Sample Size Determination ........................................................................63
10.3.
Sample Size Sensitivity...............................................................................63
10.4.
Sample site re-estimation or adjustment .....................................................64
10.5.
Data Analysis..............................................................................................64
10.5.1.
Analysis population......................................................................64
10.5.2.
Treatment Comparisons ..............................................................65
10.5.3.
Multiple Comparisons and Multiplicity ..........................................65
10.6.
Statistical Analysis......................................................................................66
10.6.1.
Primary Analyses.........................................................................66
10.6.2.
Secondary Analyses ....................................................................67
10.6.3.
Other Analyses ............................................................................67
10.6.4.
Interim Analyses ..........................................................................67
10.6.5.
Exploratory Analyses ...................................................................67
11. REFERENCES.......................................................................................................68
12. APPENDICES........................................................................................................70
12.1.
Appendix 1: Abbreviations and Trademarks................................................70
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................73
12.3.
Appendix 3: Study Governance Considerations..........................................75
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................79
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................84
12.6.
Appendix 6: Genetics..................................................................................87
12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................90
12.8.
Appendix 8: Daily Diary Questions..............................................................93
12.8.1.
Morning Questions.......................................................................93
12.8.2.
Evening Questions.......................................................................93
12.9.
Appendix 9: Country-specific requirements.................................................96
12.10. Appendix 10: Protocol Amendment History.................................................97
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
9
1.
SYNOPSIS
Protocol Title: A Phase IIb, 24 week, randomized, double-blind, 3 arm parallel group 
study, comparing the efficacy, safety and tolerability of two doses of umeclidinium 
bromide administered once-daily via a dry powder inhaler, versus placebo, in participants
with asthma
Short Title: A randomized, double-blind, parallel group study, comparing the efficacy, 
safety and tolerability of two doses of umeclidinium bromide administered once-daily via 
a dry powder inhaler, versus placebo, in participants with asthma
Rationale:
In the United States (US), the long-acting muscarinic antagonist (LAMA) tiotropium has 
been approved for the long-term maintenance treatment of asthma in patients 12 years of 
age and older.
GlaxoSmithKline (GSK) is currently developing a once-daily ‘closed’ triple therapy of an
inhaled corticosteroid (ICS)/LAMA/long-acting beta-2-agonist (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 in adults. 
Through the evaluation of UMEC 62.5 micrograms (mcg) and 31.25 mcg compared to 
placebo, this study will provide important information regarding the efficacy, safety and 
tolerability of UMEC when administered via a separate inhaler to participants on a 
background of FF without VI.
The primary objective of this study is to evaluate the effects of UMEC 62.5 mcg and 
UMEC 31.25 mcg on lung function compared with placebo after 24 weeks of treatment.
Objectives and Endpoints:
Objective
Endpoint
Primary

Evaluate the effects of UMEC 62.5 mcg 
and UMEC 31.25 mcg on lung function 
(trough Forced Expiratory Volume in 1 
second [FEV1]) vs placebo after 24 
weeks of treatment.

Mean change from baseline in clinic 
trough FEV1 at Week 24
Secondary

Evaluate the effects of UMEC 62.5 mcg 
and UMEC 31.25 mcg on lung function 
(3hours post dose FEV1) vs placebo after 
24 weeks of treatment.

Mean change from baseline in clinic FEV1
at 3 hours post dose at Week 24
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
10
Objective
Endpoint
Safety

To evaluate the  safety and tolerability of 
UMEC 62.5 mcg and UMEC 31.25 mcg 
compared to placebo

Incidence and type of adverse events

Electrocardiogram (ECG) 
measurements

Vital signs
Overall Design:
This is a Phase IIb, randomized, double-blind, placebo controlled, 3-arm parallel group 
study, comparing the efficacy, safety and tolerability of UMEC (62.5 mcg and 
31.25 mcg) administered once-daily in participants with asthma that is not well controlled 
(i.e. participants with an Asthma Control Questionnaire-6 [ACQ-6] total score >0.75 at 
Visit 2 [the Randomization Visit]) despite treatment with maintenance ICS.
Number of Participants:
The total number of randomized participants required is approximately 384, with 128
participants randomized 1:1:1 to each of the 3 double-blind treatment arms.  
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
11
Treatment Groups and Duration:
Eligible participants will be requested to participate in the study for a maximum of 
approximately 31 weeks (Visit 0 to the Follow-up contact, inclusive) during which time, 
participants will complete the following 4 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), 
including the informed consent process, must be completed within 4 weeks prior 
to Visit 1 as well as prior to any protocol-required changes to a participant’s 
usual asthma treatment and the initiation of any Visit 1 procedures.
Participants that receive LABA (or LAMA) as a component of their regular (i.e. 
pre-study) therapy must stop LABA (or LAMA) treatment from 48 hours prior 
to Visit 1 (Screening) until after they have completed the study; therefore, the 
investigator must use their clinical judgment to determine if the participant may 
stop LABA (or LAMA) prior to study entry without incurring undue risk.

Screening / run-in: Participants who meet all the eligibility criteria at Visit 1 
(Screening), will enter the run-in period for approximately 2 weeks to continue 
assessing the participant’s eligibility for the study. On the morning of Visit 1, 
participants will refrain from taking the morning dose of their regular (i.e. pre-
study) ICS asthma medication. Participants satisfying all inclusion/exclusion 
criteria and who have successfully completed all protocol procedures at 
screening will be provided with FF 100 mcg via the ELLIPTA dry-powder 
inhaler (DPI) to take once daily (QD), in the morning, during the 2-week run-in 
period; the first dose of FF 100 mcg will be self-administered by the participant 
before leaving the clinic. Participants will refrain from using their own ICS 
asthma medication during the 2-week run-in and treatment period. Participants 
will also be provided with rescue medication (albuterol/salbutamol) to use on an 
as-needed basis throughout the study.

Randomization / treatment: At Visit 2 (the Randomization Visit), participants 
who meet all of the randomization criteria will be randomized 1:1:1 to receive 
one of the following three double-blind study treatments via the ELLIPTA DPI 
during the 24-week treatment period:

UMEC 62.5 mcg QD

UMEC 31.25 mcg QD

Placebo QD
Participants will continue to administer FF 100 mcg once daily (QD), in the 
morning from a separate ELLIPTA DPI throughout the treatment period. On the 
morning of Visits 2, 3, 4, and 5, participants will perform their electronic Diary 
(eDiary) assessments at home but refrain from taking their morning dose of 
study treatment and FF 100 mcg (as applicable) until instructed to do so by
clinic personnel. At Visits 2, 3, 4 and 5, participants will self-administer study 
treatment immediately followed by FF 100 mcg whilst at the clinic. Participants 
will take their last dose of study treatment and FF 100 mcg in the clinic on Day 
169 (Visit 5). Participants are expected on non-clinic visit days to take their 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
12
study treatment and FF 100 mcg at home in the morning at approximately the 
same time each day, as directed by the clinic. 

Safety follow-up: A safety follow-up telephone contact or clinic visit will be 
conducted approximately 7 days after the participant completes all of the 
protocol-defined procedures for Visit 5/End of Study (EOS) or, if applicable, the 
Early Withdrawal Visit. A participant will be considered to have completed the 
study when they have completed all phases of the study including screening, 
run-in, the randomized treatment phase, and safety follow-up.
Key Elements of Analysis Plan
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 clinic trough FEV1 recorded post randomization. Analyses will include the fixed, 
categorical effects of treatment, visit, treatment by visit interaction, sex, 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 
primary comparisons of interest:

UMEC 62.5 mcg versus Placebo

UMEC 31.25 mcg versus Placebo
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 reporting and analysis plan (RAP).
The details of the statistical analysis methods for the secondary efficacy endpoint will be 
provided in the RAP. 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
13
2.
SCHEDULE OF ACTIVITIES (SOA)
Protocol Activity
Pre-
Screen
Screen
Run-in
Treatment Period
Follow-up
Visit
0
1
2
Randomization
3
4
5/End of Study 
(EOS)
Early Withdrawal 
(EW)
Safety
Follow-up Contact
Study Day
-42 to -
14
-14
1
29
85
169
Week
-6 to -2
-2
0
4
12
24
1 week after Visit 
5/EOS or EW Visit
Window
-7d
-5/+2d
-5/+2d
-5/+2d
-1/+4d
Informed consent
(ICF) a
X
Genetic ICF b
X
Inclusion and 
exclusion criteria
X
X
Demography c
X
X
Medical history 
X
Asthma history d
X
Exacerbation
history
X
Smoking History 
and status
X
Concomitant 
medication review
X
X
X
X
X
X
X
X
Register visit in 
Interactive Web 
Response System 
(IWRS) (RAMOS 
NG) e
X
X
X
X
X
X
X
Randomization f
X
Laboratory 
Assessments
Urinalysis
X
 
 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
14
Protocol Activity
Pre-
Screen
Screen
Run-in
Treatment Period
Follow-up
Visit
0
1
2
Randomization
3
4
5/End of Study 
(EOS)
Early Withdrawal 
(EW)
Safety
Follow-up Contact
Study Day
-42 to -
14
-14
1
29
85
169
Week
-6 to -2
-2
0
4
12
24
1 week after Visit 
5/EOS or EW Visit
Window
-7d
-5/+2d
-5/+2d
-5/+2d
-1/+4d
Hematology and 
clinical chemistry g
X
Hepatitis B and C
X m
Genetic sample 
X n
1.
Serum pregnancy 
test
X o
X o
X o
Urine pregnancy 
test
X o
X o
X o
Safety 
Assessments
Physical exam 
including height 
and weight h
X
X
X
12-lead 
Electrocardiogram
(ECG) i
X
X
X
X
Vital signs j
X
X
X
X
X
X
Adverse Event (AE) 
review
X
X
X
X
X
X
X
Serious Adverse 
Event (SAE)  
review
X
X
X
X
X
X
X
X
Study Treatment
Dispense
Albuterol/Salbutam
ol, as required
X
X
X
X
Collect 
Albuterol/Salbutam
ol, as required
X
X
X
X
X
 
 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
15
Protocol Activity
Pre-
Screen
Screen
Run-in
Treatment Period
Follow-up
Visit
0
1
2
Randomization
3
4
5/End of Study 
(EOS)
Early Withdrawal 
(EW)
Safety
Follow-up Contact
Study Day
-42 to -
14
-14
1
29
85
169
Week
-6 to -2
-2
0
4
12
24
1 week after Visit 
5/EOS or EW Visit
Window
-7d
-5/+2d
-5/+2d
-5/+2d
-1/+4d
Dispense open 
label fluticasone 
furoate (FF) 100 
mcg medication
X
X
X
X
Administer open 
label FF 100 mcg
X
X
X
X
X
Collect open label 
FF 100 mcg
X
X
X
X
X
Dispense double-
blind study 
treatment
X
X
X
Administer double-
blind study 
treatment
X p
X p
X p
X p
Collect double-blind 
study treatment
X
X
X
X
Assess FF 
100 mcg run-in 
medication 
compliance
X
Assess FF 
100 mcg and 
double-blind study 
treatment 
compliance
X
X
X
X
Efficacy 
Assessments
Global Assessment 
of Severity k
X
X
X
X
X
 
 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
16
Protocol Activity
Pre-
Screen
Screen
Run-in
Treatment Period
Follow-up
Visit
0
1
2
Randomization
3
4
5/End of Study 
(EOS)
Early Withdrawal 
(EW)
Safety
Follow-up Contact
Study Day
-42 to -
14
-14
1
29
85
169
Week
-6 to -2
-2
0
4
12
24
1 week after Visit 
5/EOS or EW Visit
Window
-7d
-5/+2d
-5/+2d
-5/+2d
-1/+4d
Global Assessment 
of Response to 
Treatment k
X
X
X
X
Asthma Control 
Questionnaire 
(ACQ-6) k
X
X q
Asthma Control 
Questionnaire 
(ACQ-5) k
X
X
X
X
St. George’s 
Respiratory 
Questionnaire 
(SGRQ) k
X
X
X
X
X
Asthma Quality of 
Life Questionnaire 
(AQLQ) k
X
X
X
X
X
Evaluating 
Respiratory 
Symptoms (E-RS) 
+Asthma symptoms 
+ Peak Expiratory 
Flow (PEF) + Home 
Forced Expiratory 
Volume in 1 second
(FEV)1 k, l
X
eDiary Dispense
X
eDiary Collect
X
X
eDiary Review
X
X
X
X
X
 
 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
17
Protocol Activity
Pre-
Screen
Screen
Run-in
Treatment Period
Follow-up
Visit
0
1
2
Randomization
3
4
5/End of Study 
(EOS)
Early Withdrawal 
(EW)
Safety
Follow-up Contact
Study Day
-42 to -
14
-14
1
29
85
169
Week
-6 to -2
-2
0
4
12
24
1 week after Visit 
5/EOS or EW Visit
Window
-7d
-5/+2d
-5/+2d
-5/+2d
-1/+4d
Dispense paper 
Medical 
Problems/Medicatio
ns Taken 
worksheet
X
X
X
X
X
Review paper 
Medical 
Problems/Medicatio
ns Taken
worksheet
X
X
X
X
X
X
Reversibility
X r
Exacerbation 
assessment
X
X
X
X
X
Pre-dose 
spirometry (clinic)
X s
X s
X s
X s
X s
X s
Post-dose 
spirometry (clinic)
X t
X t
X t
 
 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
18
1.
Notes:
a)
The ICF must be signed before any study procedures, including medication cessation.
b)
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.
c)
Demography may be captured at either the Pre-screen Visit or Screening Visit (for participants who do not have a Pre-screen Visit).
d)
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).
e)
The IWRS will be used for randomization, emergency unblinding and study treatment supply management (Please refer to the RAMOS NG IWRS manual and 
SRM for more information).
f)
Participants must not be randomized prior to confirming their eligibility to participate in the study.
g)
If test otherwise performed within 3 months prior to first dose of study treatment, testing at screening is not required.
h)
Physical Examination will include height and weight at Visit 1 only. 
i)
ECG to be obtained 15 minutes to 45 minutes after the administration of study treatment.
j)
The vital signs assessment will include the measurement of blood pressure, heart rate.
k)
Assessment(s) to be completed prior to the administration of study treatment.
l)
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.
m)
Hepatitis C RNA is optional however a confirmatory negative Hepatitis C RNA test must be obtained, to be able to enrol participants with positive Hepatitis C 
antibody due to prior resolved disease. Hep B/C: If test otherwise performed within 3 months prior to first dose of study treatment, testing at screening is not 
required.
n)
Pharmacogenetic sample may be drawn any time from Visit 2 onwards.
o)
Assessments only to be conducted in females of reproductive potential.
p)
Study treatment should be administered at approximately the same time of day at each applicable clinic visit.
q)
Baseline ACQ-5 will be derived from items 1-5 of the Randomization (Visit 2) ACQ-6.
r)
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 9.1.3.
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 2-week run-in period.
s)
Pre-dose spirometry should 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 and FF 100 mcg. After V2 pre-dose spirometry assessments should be performed within 1 hour of the V2 spirometry.
t)
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 within 1 hour of the V2 spirometry.
1.
 
 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
19
3.
INTRODUCTION
3.1.
Study Rationale
In the United States (US), the long-acting muscarinic antagonist (LAMA) tiotropium has 
been approved for the long-term maintenance treatment of asthma in patients 12 years of 
age and older.
GlaxoSmithKline (GSK) is currently developing a once-daily ‘closed’ triple therapy of a 
ICS/LAMA/long-acting beta-2-agonist (LABA) combination [FF/umeclidinium 
(UMEC)/vilanterol (VI)] in a single device, with the aim of providing a new treatment 
option for the management of asthma in adults. Through the evaluation of UMEC 
62.5 mcg and 31.25 mcg compared to placebo this study will provide important
information regarding the efficacy and safety of UMEC when administered in a separate 
inhaler to participants on a background of FF.
The primary objective of this study is to evaluate the effects of UMEC 62.5 mcg and 
UMEC 31.25 mcg on lung function compared with placebo after 24 weeks of treatment.
3.2.
Background
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; Global Initiative for Asthma (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.  
Despite the availability of treatments and published guidelines, patients may have asthma 
that is not well controlled.
This trial will, primarily, evaluate trough FEV1 to characterize the efficacy of two doses 
of UMEC (62.5 mcg and 31.25 mcg) in the treatment of asthma when administered as an 
open combination with FF 100 mcg. UMEC is currently under development as a closed 
triple therapy in combination with FF and VI in a single inhaler.
3.3.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events related to FF and UMEC can be found in the 
Investigator’s Brochure(s) (IB). The table below provides a summary of the key risks in 
association with FF and UMEC. It is noted that both FF and UMEC have also been 
developed in combination with VI, therefore relevant safety experience is also provided 
by the FF/VI and UMEC/VI combinations.  
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
20
3.3.1.
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [e.g., GW685698+GSK573719] 
Cardiovascular effects of 
UMEC 
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 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 
- Exclusion criteria as specified in 
Section 6.2 of the protocol
- Collection of cardiovascular risk 
factors and medical history at 
baseline
- ECGs as per schedule in Section 2
- Vital sign assessments (heart rate
and blood pressure) as per schedule in 
Section 2
- Cardiovascular AEs and SAEs will 
be captured on the electronic Case 
Report Form (eCRF) (see Appendix 4)
- Protocol defined stopping criteria as 
per Section 8.1
-MACE analysis
-Instream review of blinded data
 
 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
21
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Healthy Volunteers (in the Thorough QT study, UMEC 500 mcg 
daily dose), no effect was observed on heart rate, blood pressure or 
QT.
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 500 mcg and placebo. 
UMEC/VI 500/100 mcg increased QTcF on average by 8.2 msec 
(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.  In addition, UMEC/VI has had 
urinary retention, dysuria, vision blurred, glaucoma and increased 
intraocular pressure and paradoxical bronchospasm added as ADRs.  
ICS has a similar class risk of glaucoma and elevated intraocular 
- 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.
- Review AEs/SAEs
 
 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
22
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
pressure (IOP); however these effects occur by a different mechanism 
that is not expected to be synergistic or additive when FF is used in
combination with UMEC.
Systemic ICS effects 
-Aderenal 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 participants 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 
participants 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 participants 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 
- Review AEs/SAEs
- The occurrence of bone fractures 
will be recorded in the eCRF.
 
 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
23
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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 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 participants 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 mcg (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.  
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).
-Participants 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 
 
 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
24
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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) 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 participants 
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).
resulting in hospitalisation.  
The occurrence of pneumonia will be 
recorded in the eCRF.
Where possible a chest X-ray should 
be performed to confirm a diagnosis, 
whenever a participant 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.
Participants with a history of allergy 
or hypersensitivity to any 
corticosteroid, 
anticholinergic/muscarinic receptor 
antagonist, beta2-agonist, 
lactose/milk protein or magnesium 
 
 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
25
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
stearate are excluded from 
participation in this study (Section 
6.2). 
-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 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 UMEC 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.
Females who are pregnant or breast-
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. 
 
 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
26
The risks for FF 100 mcg are recognised pharmacological class effects associated with 
ICS therapy, which are included in the table above. The experience with FF is provided 
in the respective IB.  
3.3.2.
Benefit Assessment
The benefit of UMEC at two dosage strengths 62.5 and 31.25 mcg as compared to 
Placebo in patients with asthma on background therapy of FF 100 mcg is expected to 
improve lung function. The inclusion of two strengths of UMEC will allow comparison 
to placebo for the dose currently marketed in COPD, as well as a lower dose. This will 
help show the efficacy and safety of UMEC in asthma when administered as an open 
combination on a background of FF. Another LAMA, tiotropium, is currently approved 
for the maintenance treatment of asthma. 
3.3.3.
Overall Benefit: Risk Conclusion
Taking into account the measures taken to minimize the risk to the participants 
participating in the study, the potential risks identified in association with UMEC are 
justified by the anticipated benefits that may be afforded to participants with asthma.  
The current experience and safety profile with UMEC in previous Phase II asthma studies 
(alone and in combination with FF) and from clinical trial and marketing experience in 
the COPD population is supportive of evaluating this compound in asthma patients. The 
potential risks associated with the known pharmacology of UMEC is offset by the 
potential significant benefits that are afforded to patients not well controlled on ICS
therapy. Furthermore, the approval of another LAMA (tiotropium) for the treatment of
asthma demonstrates the suitability for the use of this class of drug in the asthma 
population.  
4.
OBJECTIVES AND ENDPOINTS
For a definition of baseline for each of the endpoints listed below, please refer to Section 
10.6.
Objectives
Endpoints
Primary

Evaluate the effects of UMEC 
62.5 mcg and UMEC 31.25 mcg 
on lung function (trough FEV1) 
versus placebo after 24 weeks of 
treatment.

Mean change from baseline in clinic 
trough FEV1 at Week 24
Secondary

Evaluate the effects of UMEC 
62.5 mcg and UMEC 31.25 mcg on 
lung function (3hours post dose 

Mean change from baseline in clinic 
FEV1 at 3 hours post dose at Week 24
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
27
Objectives
Endpoints
FEV1) versus placebo after 24 
weeks of treatment.
Safety  

To evaluate the  safety and 
tolerability of UMEC 62.5 mcg and 
UMEC 31.25 mcg compared to 
placebo

Incidence and type of adverse events

ECG measurements

Vital signs
Other

To evaluate other efficacy assessments 
of UMEC 62.5 mcg and UMEC 
31.25 mcg compared to placebo

Mean change from baseline in morning 
(AM) pre-dose Peak Expiratory Flow 
(PEF) over the 24 week treatment 
period

Mean change from baseline in evening
(PM) PEF over the 24 week treatment 
period

Mean change from baseline in daily 
home trough FEV1 over the 24 week 
treatment period

Mean change from baseline in daily 
rescue medication use over the 24 
week treatment period

Mean change from baseline in SGRQ
total score 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 SGRQ 
domain scores at Week 24

Mean change from baseline in the 
AQLQ total score at Week 24

Percent of patients meeting a
responder threshold of ≥ 0.5 points 
improvement from baseline for the 
AQLQ total score at Week 24

Mean change from baseline in E-RS
total score over the 24 week treatment 
period

Mean change from baseline in 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
28
Objectives
Endpoints
ACQ-5 total score at Week 24

Percent of patients meeting a 
responder threshold of ≥0.5 in change 
from baseline for the ACQ-5 at Week 
24

Annualized rate of moderate/severe 
asthma exacerbations
5.
STUDY DESIGN
5.1.
Overall Design
This is a Phase IIb, randomized, double-blind, placebo controlled, 3-arm parallel group 
study, comparing the efficacy, safety and tolerability of UMEC (62.5 mcg and 
31.25 mcg) administered once-daily in participants with asthma that is not well controlled 
(i.e. participants with an ACQ-6 total score >0.75 at Visit 2 [the Randomization Visit]) 
despite treatment with maintenance ICS.
Eligible participants will be requested to participate in the study for a maximum of 
approximately 31 weeks (Visit 0 to the Follow-up contact, inclusive) during which time, 
participants will complete the following 4 phases of the study:
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
29

Pre-screening: Details about the study and procedures will be explained 
through the informed consent process. The Pre-screening Visit (Visit 0), 
including the informed consent process, must be completed within 4 weeks prior 
to Visit 1 as well as prior to any protocol-required changes to a participant’s 
usual asthma treatment and the initiation of any 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 defined in Section 7.9.
Participants that receive LABA (or LAMA) as a component of their regular (i.e. 
pre-study) therapy must stop LABA (or LAMA) treatment from 48 hours prior 
to Visit 1 (Screening) until they have completed the study; therefore, the 
investigator must use their clinical judgment to determine if the participant may 
stop LABA (or LAMA) prior to study entry without incurring undue risk.

Screening / run-in: Participants who meet all the eligibility criteria at Visit 1 
(Screening), will enter the run-in period for approximately 2 weeks to continue 
assessing the participant’s eligibility for the study. On the morning of Visit 1, 
participants will refrain from taking the morning dose of their regular (i.e. pre-
study) ICS asthma medication. Participants satisfying all inclusion/exclusion 
criteria and who have successfully completed all protocol procedures at 
screening will be provided with FF 100 mcg via the ELLIPTA dry-powder 
inhaler (DPI) to take once daily (QD), in the morning, during the 2-week run-in 
period; the first dose of FF 100 mcg will be self-administered by the participant 
before leaving the clinic. Participants will refrain from using their own ICS 
asthma medication during the 2-week run-in and treatment period. Participants 
will also be provided with rescue medication (albuterol/salbutamol) to use on an 
as-needed basis throughout the study.

Randomization / treatment: At Visit 2 (the Randomization Visit), participants 
who meet all of the randomization criteria will be randomized 1:1:1 to receive 
one of the following three double-blind study treatments via the ELLIPTA DPI 
during the 24-week treatment period:

UMEC 62.5 mcg QD

UMEC 31.25 mcg QD

Placebo QD
Participants will continue to administer FF 100 mcg once daily (QD), in the 
morning from a separate ELLIPTA DPI throughout the treatment period. On the 
morning of Visits 2, 3, 4, and 5, participants will perform their electronic Diary 
(eDiary) assessments at home but refrain from taking their morning dose of 
study treatment and FF 100 mcg (as applicable) until instructed to do so by
clinic personnel. At Visits 2, 3, 4 and 5, participants will self-administer study 
treatment immediately followed by FF 100 mcg whilst at the clinic (see Section 
7.2). Participants will take their last dose of study treatment and FF 100 mcg in 
the clinic on Day 169 (Visit 5). Participants are expected on non-clinic visit days 
to take their study treatment and FF 100 mcg at home in the morning at 
approximately the same time each day, as directed by the clinic.
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
30

Safety follow-up: A safety follow-up telephone contact or clinic visit will be 
conducted approximately 7 days after the participant completes all of the 
protocol-defined procedures for Visit 5/End of Study (EOS) or, if applicable, the 
Early Withdrawal Visit. A participant will be considered to have completed the 
study when they have completed all phases of the study including screening, 
run-in, the randomized treatment phase, and safety follow-up.
To demonstrate the benefit of UMEC the primary comparisons of interest for the primary 
efficacy endpoint are:

UMEC 62.5 mcg versus (vs) Placebo

UMEC 31.25 mcg vs Placebo
Other pairwise treatment comparisons of interest that aim to informally estimate any 
potential benefit of increasing the UMEC dose are given below for all efficacy endpoints. 

UMEC 62.5 mcg vs UMEC 31.25 mcg
For the multiple comparisons and multiplicity adjustment, please see Section 10.5.3. 
Participants who permanently discontinue double-blind 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 (see Section 8.1)
5.2.
Number of Participants
The total number of randomized participants required is approximately 384, with 128
participants randomized 1:1:1 to each of the 3 double-blind treatment arms (see Section 
10).  
5.3.
Participant and Study Completion
A participant will be considered to have completed the study when they have completed 
all phases of the study including pre-screening, screening, run-in, the randomized 
treatment phase, and safety follow-up.
The end of the study is defined as the date of the last scheduled procedure shown in the 
Schedule of Activities table (see Section 2) for the last participant in the trial globally.
5.4.
Scientific Rationale for Study Design
This study will use a multicenter, randomized, double-blind, 3 arm parallel-group design.  
This is a well-established design to evaluate the efficacy, safety, and tolerability of the 
UMEC drug.  A placebo arm is included. All participants will be placed on open-label FF 
100 mcg when they enter the 2 week run-in period and continue it through the 24 week 
treatment period. The primary objective of this study is to evaluate the effects of UMEC 
62.5 mcg and UMEC 31.25 mcg on lung function compared with placebo after 24 weeks 
of treatment.
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
31
GlaxoSmithKline (GSK) is currently developing a once-daily ‘closed’ triple therapy of a 
ICS/LAMA/LABA combination [FF/UMEC/VI)] in a single device, with the aim of 
providing a new treatment option for the management of asthma in adults. Through the 
evaluation of UMEC 62.5 mcg and 31.25 mcg compared to placebo this study will 
provide important information regarding the efficacy, safety and tolerability of UMEC in 
asthma when administered via a separate inhaler to participants on a background of FF
without VI.
5.5.
Dose Justification
The 200699 (IB Supplement, GlaxoSmithKline Document 2011N123107_03) data 
showed UMEC 62.5 mcg to be an effective dose; after 4 weeks of treatment in the 
subset of patients with a primary diagnosis of asthma, an average increase in change 
from baseline trough FEV1 at Day 29 of 136 mL was observed in those participants
treated with FF/UMEC (100/62.5 mcg) compared to those participants 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 both 31.25 and 62.5 mcg doses will 
be assessed in this study when administered via a separate inhaler to participants 
treated on a background of FF 100 mcg. No safety signal was identified with any of 
the UMEC doses (15.6, 62.5, 125 and 250 mcg) evaluated in the 200699 study.
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
AGE
1. Age: 18 years of age or older at the time of signing the informed consent.
TYPE OF PARTICIPANT AND DISEASE CHARACTERISTICS
2. Diagnosis: Participants with a diagnosis of asthma as defined by the National 
Institutes of Health [NIH, 2007] at least 6 months prior to Visit 0.
3. Asthma Control: ACQ-6 total score of >0.75 at Visit 1.
4. Current Asthma Maintenance Therapy: Participants are eligible if they have 
required daily ICS therapy 100 mcg/day fluticasone propionate (FP, or 
equivalent) with or without LABA or LAMA for at least 12 weeks prior to Visit 0
and there have been no changes in maintenance asthma medications during the 4 
weeks immediately prior to Visit 0.
Examples of acceptable doses of commonly prescribed ICS medication will be 
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 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
32
labels.
5. Spirometry: Both of the following:
a.
A best pre-bronchodilator morning (AM) FEV1 ≤85% of the predicted 
normal value. Predicted values will be based upon the ERS Global Lung 
Function Initiative [Quanjer, 2012].
b. A best post-bronchodilator FEV1/ forced vital capacity (FVC) ≥0.7 at 
Visit 1.
6. Reversibility of Disease: Airway reversibility is 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 participant 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:
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 participant 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 participant may 
enter the 2-week run-in period (see Section 9.1.3).
7.
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
8. Gender:
a. Male participants
b. Female participants: 
A female participant is eligible to participate if she is not pregnant (see Appendix 5),
not breastfeeding, and at least one of the following conditions applies:

Not a woman of childbearing potential (WOCBP) as defined in Appendix 5
OR

A WOCBP who agrees to follow the contraceptive guidance in Appendix 5
during the treatment period and for at least 5 days after the last dose of study 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
33
treatment.
INFORMED CONSENT
9. 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.  Participants must be 
able to read, comprehend, and write at a level sufficient to complete study related 
materials.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
MEDICAL CONDITIONS
1.
Pneumonia: Chest X-ray documented pneumonia in the 12 weeks prior to Visit 1.
2.
Asthma Exacerbation: Any severe asthma exacerbation, defined as deterioration of 
asthma requiring the use of systemic corticosteroids (oral, parenteral or depot) within 
12 weeks of Visit 1, or an inpatient hospitalisation or emergency department visit 
due to asthma that required systemic corticosteroids within 12 weeks of Visit 1.
3.
Concurrent Respiratory Disease: Current evidence of pneumonia, pneumothorax, 
atelectasis, pulmonary fibrotic disease, bronchopulmonary dysplasia, chronic 
bronchitis, emphysema, chronic obstructive pulmonary disease, lung cancer, or other 
respiratory abnormalities other than asthma.
4.
Pregnancy: Women who are pregnant or lactating or are planning on becoming 
pregnant during the study.
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: Participants 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 participant
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 participant otherwise meets entry criteria
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
34
8.
Clinically significant ECG abnormality: Evidence of a clinically significant 
abnormality in the 12-lead ECG performed during screening or run-in. The PI will 
determine the clinical significance of each abnormal ECG finding in relation to the 
participant’s medical history and exclude participants 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:

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: participants 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 last 
3 months

New York Heart Association (NYHA) Class IV Heart failure
10. Antimuscarinic effects: Participants 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: Participants with carcinoma that has not been in complete remission for at 
least 5 years. Participants 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 participant has been considered cured by treatment.
12. Questionable validity of consent: Participants 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.
PRIOR/CONCOMITANT THERAPY
13. Medication prior to spirometry: Participants who are medically unable to withhold 
their albuterol/salbutamol for the 6-hour period required prior to spirometry testing at 
each study visit.
PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE/RELEVANT 
HABITS
14. Tobacco Use: Current smoker or a smoking history of ≥10 pack years (e.g., 
20 cigarettes/day for 10 years).  A participant may not have used inhaled tobacco 
products within the past 12 months (i.e., cigarettes, e-cigarettes/vaping, cigars or pipe 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
35
tobacco).
15. Drug/alcohol abuse: Participants with a known or suspected history of alcohol or 
drug abuse within the last 2 years. This includes marijuana, which is considered an 
abused drug.
Diagnostic assessments
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.
Other Exclusions
17. Non-compliance: Participants 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.
19. Inability to read: In the opinion of the Investigator, any participant who is unable to 
read and/or would not be able to complete study related materials.
6.2.1.
Randomization Criteria
At the end of the run-in period (Visit 2), study participants must fulfil the following 
additional criteria in order to be randomized into the study and enter the treatment period:
6.2.2.
Inclusion Criteria for Randomization
TYPE OF PARTICIPANT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
1. Asthma Control: ACQ-6 total score of >0.75 at Visit 2.
2. Percent-predicted FEV1: Spirometry: A best pre-bronchodilator morning (AM) 
FEV1 ≤85% 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.
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
36
6.2.3.
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 
run-in period that led to a change in asthma management or, in the opinion of the 
Investigator, is expected to affect the participant’s asthma status or the participant’s 
ability to participate in the study.
2. Asthma exacerbation: Evidence of a moderate asthma exacerbation leading to a 
change in therapy or severe exacerbation during screening or the run-in period, 
defined as deterioration of asthma requiring the use of systemic corticosteroids 
(tablets, suspension, or injection) or an in-patient hospitalization or emergency 
department visit due to asthma that required systemic corticosteroids.
CONCOMITANT MEDICATIONS/TREATMENTS
3. Asthma medication: Changes in asthma medication (excluding changes after Visit 0 
or 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.
6.3.
Lifestyle Restrictions
No lifestyle restrictions are required for this study.
6.4.
Pre-Screening/Screening/Run-in/Randomization Failures
A participant will be assigned a participant number at the time the informed consent is 
signed at Visit 0.
The study site will be responsible for reporting pre-screen failures. The following 
information will be collected in the eCRF for participants who are pre-screen failures:

Demographic information including race, age and gender

Participant 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-screening failures, screening failures, run-in failures
and randomization failures will be defined as follows:

Pre-screening failures: those participants that sign the informed consent 
document but do not have a Visit 1 (Screening) procedure.
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
37

Screening failures: those participants that complete at least one Visit 1 
(Screening) procedure but do not enter the run-in period.
A participant 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 participants that enter the run-in period but do not have 
any Visit 2 (Randomization) procedures.

Randomization failures: those participants that complete at least one Visit 2 
(Randomization) procedure but do not enter the double-blind study treatment 
period.
Any participant who completes the run-in period and then meets the 
randomization criteria and is dispensed the double-blind study treatment at Visit 
2 is considered to have entered the treatment period.
RAMOS NG will be contacted to register the participant. 
In order to ensure transparent reporting of screen/run-in failure participants, meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements, and 
respond to queries from Regulatory authorities, a minimal set of screen/run-
in/randomization failure information is required including demography, screen/run-
in/randomization failure details, eligibility criteria, and any SAEs (see Section 9.2.4 and 
Appendix 4). Further details are provided in the study-specific eCRF completion 
guidelines document.
7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol. The term ‘study treatment’ within this trial is used to describe the 
combination of products received by the participant as per the protocol design. Study 
treatment may also be used to only reference the randomized study treatment when 
described together with the FF 100 mcg open-label treatment.
7.1.
Treatments Administered
7.1.1.
Description of FF 100 mcg and Double-Blind Study Treatment
The ELLIPTA device will be used during the run-in period and the treatment period.  The 
ELLIPTA dry powder inhaler (DPI) is a molded plastic two-sided device with a dose 
counter that can hold two individual blister strips.  The ELLIPTA will deliver, when 
actuated, the contents of a single blister simultaneously from each of the two strips. The 
ELLIPTA is individually sealed in a foil laminate overwrap that also contains a silica gel 
desiccant packet.
A description of the FF (GW685698) 100 mcg inhalation powder administered via the 
ELLIPTA is provided in Table 1; descriptions of the double-blind study treatments 
administered via the ELLIPTA are provided in Table 2.
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
38
Table 1
Description of FF 100 mcg Inhalation Powder in ELLIPTA
FF 100
First Strip
Second Strip
GW685698 blended with 
lactose monohydrate
Lactose monohydrate with magnesium 
stearate1
Dosage Form
ELLIPTA DPI with 30 doses (2 strips with 30 blisters)
Unit Dose strengths
100 mcg per blister
Not applicable
Physical description
White powder
White powder
Route of 
Administration
Inhaled
1.
Magnesium stearate 1.0% w/w of total drug product.
Table 2
Description of Study Treatment Inhalation Powder in ELLIPTA
7.1.2.
Description of Albuterol/Salbutamol
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 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
39
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.
7.1.3.
Study Treatment and FF 100 mcg Return
ELLIPTAs containing FF 100 mcg and study treatment will be dispensed to a participant 
during their visit to the study clinic (as applicable). The participant must return all 
dispensed ELLIPTAs at the subsequent clinic visit. The schedule for dispensing and 
collecting FF 100 mcg and study treatment ELLIPTAs is provided in the Schedule of 
Activities table (Section 2).
All used and unused study treatment, FF 100 mcg and albuterol/salbutamol 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 Study Reference Manual (SRM).
If any ELLIPTA fails to function properly, the participant should return to the clinic as 
soon as possible to obtain a new inhaler.  The site will use the IWRS (RAMOS NG) to 
obtain a new treatment pack number for the participant and dispense a new study 
treatment kit from the site’s study treatment supply as instructed by the IWRS.
In addition, any metered dose inhaler (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.
7.2.
Dose Modification
There were no dose modifications planned for this protocol.
7.3.
Method of Treatment Assignment
Participants 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. Participants will be randomized using an interactive web response 
system (IWRS) RAMOS NG. The study will use central-based randomization to allocate 
treatments. Once a randomization number is assigned to a participant it cannot be 
reassigned to any other participant in the study.
Following the 2-week run-in period and participant to satisfying all eligibility criteria, 
participants will be randomized 1:1:1 to one of the following three double-blind 
treatments for the duration of the treatment period: 

UMEC 62.5 mcg QD

UMEC 31.25 mcg QD

Placebo QD
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
40
The duration of double-blind treatment for each participant is 24 weeks. On the morning 
of each scheduled clinic study visit, participants will refrain from taking their morning 
dose of study treatment and FF 100 mcg 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 Randomization Visit (Visit 2). On the other days during the treatment period (i.e. 
“non-clinic days”), participants 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 treatment packs will be supplied as 
needed to the sites. Details of how to use the IWRS system (RAMOS NG) to randomize 
participants and manage study treatment supplies (including dispensing) is provided in 
the RAMOS NG IWRS manual and SRM.
7.4.
Blinding
This will be a double-blind study and the following will apply. 

The Investigator or treating physician may unblind a participant’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 participant as judged by the 
Investigator. 

Investigators have direct access to the participant’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 participant’s treatment assignment. 

If GSK personnel are not contacted before the unblinding, the Investigator must 
notify GSK within 24 hours after unblinding, but without revealing the treatment 
assignment of the unblinded participant, unless that information is important for 
the safety of participants currently in the study. 

The date and event or condition which led to the unblinding (i.e. the primary 
reason) will be recorded in source documentation and in the eCRF. 
Should a participant’s treatment assignment be unblinded then the participant may 
continue the assigned study treatment and be followed-up as per protocol until the 
completion of the Safety Follow-up assessments.
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any participant 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 participant’s treatment assignment, may be sent to Investigators in 
accordance with local regulations and/or GSK policy. Participants will not be withdrawn 
from the study.
7.5.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
41
7.6.
Preparation/Handling/Storage/Accountability
1.
The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment.
2.
Only participants enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment. All study treatments 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access 
limited to the investigator and authorized site staff.
3.
The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records).
4.
Further guidance and information for the final disposition of unused study treatment 
are provided in the SRM.

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  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 Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK.
7.7.
Treatment Compliance
When participants are dosed at the site, they will receive FF 100 mcg and 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 participant identification 
will be confirmed at the time of dosing by a member of the study site staff.  
When participants self-administer study treatment(s) at home, compliance with study 
treatment will be assessed through querying the participant during the site visits and 
recording the number of doses remaining in the ELLIPTA in the eCRF (see the SRM for 
details).  A record of the number of ELLIPTAs dispensed to each participant must be 
maintained and reconciled with study treatment and compliance records. 
Participant compliance with FF 100 mcg and study treatment will be assessed at 
scheduled clinic visits by reviewing the eDiary and information from the dose counter on 
the returned inhaler(s) (see Section 7.1.3).  Participants should be 80% to 120% 
compliant on taking both FF 100 mcg and study treatment between each pair of 
scheduled and consecutive on-treatment clinic visits, as applicable. Participants who fall 
outside this range should be re-educated on treatment compliance by their site. This re-
education should be documented in the participant’s source document. If FF 100 mcg 
and/or study treatment is prematurely discontinued during the course of the study or 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
42
compliance repeatedly falls outside of acceptable ranges, the study sponsor/site monitor 
must be contacted to discuss participant eligibility for continued participation in the 
study.
7.8.
Concomitant Therapy
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.
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 FF 100 mcg and albuterol/salbutamol should not be recorded in 
the eCRF; however non-study supplied FF 100 mcg and albuterol/salbutamol will be 
recorded in the eCRF.
The minimum requirement is that the drug name, reason for use, dose (including unit e.g. 
mcg) and frequency, route and the dates of administration are to be recorded.
Medications initiated after completion of the assessments at Visit 5/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.  Participants who have completed the Early Withdrawal 
Visit are allowed to use any medications prescribed by the Investigator or primary care 
physician.
7.8.1.
Permitted Medications and Non-Drug Therapies
7.8.1.1.
Permitted Asthma Medications
In addition to FF 100 mcg and 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. Participants must be judged 
capable of withholding albuterol/salbutamol for at least 6 hours prior to study 
visits.
Temporary changes in medications are permitted for the treatment of moderate asthma 
exacerbations, 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 SRM for contact information
[refer to Section 9.1.4.1 for guidance on moderate asthma exacerbation]):

An increase in ICS dose.

Systemic corticosteroids (tablets, suspension or injection) for no more than 2 
days.
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
43

An Investigator-advised change in SABA use (i.e., routinely scheduled versus 
as needed use).

Leukotriene receptor antagonists (LTRAs) and leukotriene modifiers.

Oral theophylline.
7.8.1.2.
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.

Decongestants: Participants 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 participants 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 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
44
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 participants’ lung function or safety assessments
(e.g., cardiac measurements). However, no systemic corticosteroids will be permitted.
7.9.
Prohibited Medications and Non-Drug Therapies
Use of the medications listed in Table 3 is not permitted during the study.
Table 3
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
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) 
2 days
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,
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
Any other investigational drug
30 days or within 5 drug half-lives of the 
investigational drug (whichever is longer)
7.10.
Treatment after the End of the Study
Participants will not receive any additional treatment from GSK after completion of the 
study because other treatment options are available.
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
45
The Investigator is responsible for ensuring that consideration has been given to the post-
study care of the participant’s medical condition, whether or not GSK is providing 
specific post-study treatment.
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
Participants that permanently stop study treatment are encouraged to remain in the 
study.  Participants have the right to discontinue study treatment before the end of the 
study.  A participant may also be asked to discontinue study treatment at the 
Investigator’s discretion.
Participants who withdraw from study treatment prematurely (for any reason) should, 
where possible, continue to be followed-up as per protocol until the completion of the 
Safety Follow-up assessments. If this is not possible, the Investigator must encourage the 
participant to participate in as much of the study as they are willing (or able) to.
A participant may be withdrawn from study treatment at any time. A reason for 
premature discontinuation of study treatment (e.g., AE, lack of efficacy [including 
moderate or severe asthma exacerbation], protocol deviation, Investigator discretion, 
consent withdrawn etc.) must be captured in the eCRF.
A participant 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 

QTc: Meets any of the protocol-defined stopping criteria 

Pregnancy: Positive pregnancy test
8.1.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). These protocol guidelines are in alignment 
with FDA premarketing clinical liver safety guidance: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Discontinuation of study treatment for abnormal liver tests should be considered by the 
investigator when a participant meets one of the conditions outlined in the algorithm or if 
the investigator believes that it is in the best interest of the participant.
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
46
Phase II Liver Chemistry Stopping and Increased Monitoring Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus
Bilirubin≥2x
ULN (>35% 
direct) 
or plus
INR>1.5, if 
measured*
Possible
Hy’s Law
ALT≥3xULN
ALT≥5xULN
ALT≥3xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
ALT≥3xULN
but able to 
monitor 
weekly for 
4 weeks
No
Yes
Yes
Yes
Yes
No
No
No
No
Yes
ALT≥3xULN
persist for
4 weeks or 
stopping 
criteria 
met
Yes
No
*INR value not applicable to subjects on anticoagulants
Yes
If subject to be monitored weekly must refer to Liver Safety Required  Actions and  Follow  up 
Assessments  section  in  the  Appendix
Must refer to Liver Safety Required Actions and Follow  up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments can be found in Appendix 7
8.1.2.
QTc Stopping Criteria
Details on performing ECG assessments can be found in Section 9.4.3.

The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study.  This formula may 
not be changed or substituted once the participant has been enrolled.

For example, if a participant 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 participant as well.

Once the QT correction formula has been chosen for a participant’s eligibility, 
the same formula must continue to be used for that participant 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 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, lead to withdrawal 
from study treatment:

QTc>500 msec or uncorrected QT>600 msec
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
47

Change from baseline: QTc> 60 msec

For patients with underlying bundle branch block, follow the discontinuation criteria 
listed below:

Baseline QTc with Bundle Branch Block <450 msec, Discontinuation QTc with 
Bundle Branch Block >500 msec

Baseline QTc with Bundle Branch Block <450-480  msec, Discontinuation QTc 
with Bundle Branch Block ≥530 msec
8.1.3.
Rechallenge
8.1.3.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed.
8.2.
Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, 
or may be withdrawn at any time at the discretion of the investigator for safety, 
behavioral, compliance or administrative reasons.

If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent.

If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records.

In the event of early withdrawal from the study, every effort should be made to 
have the participant 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 Schedule of Activities table (Section 2).
8.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 3 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
48
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 
9.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the Schedule of Activities (SoA) 
(Section 2). There are no protocol waivers or exemptions allowed. Immediate safety 
concerns should be discussed with the sponsor immediately upon occurrence or 
awareness to determine if the participant should continue or discontinue study treatment.
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
No study related procedures may be performed until the informed consent form has 
been signed by the participant.  A Pre-Screening visit (Visit 0) is required in order to 
administer the informed consent before any changes are made to the participant’s current 
medical regimen.  Selection and modification of the participant’s medications prior to 
study participation is based on the physician’s judgment according to sound medical 
practice, principles, and each participant’s needs.  A participant’s treatment must not be 
changed merely for the purpose of enabling the participant’s participation in the study.
During the Pre-Screening visit (Visit 0) the following information will be captured in the 
eCRF for each participant: 

Demographic information including race, age and gender

Participant 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 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

Smoking history and status

Exacerbation history

Asthma and other concurrent medications
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
49

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

Questionnaires (ACQ;; E-RS)

Pre-and post-albuterol/salbutamol lung function

Inclusion/Exclusion criteria assessment

Physical examination

12-lead ECG

Child bearing status assessment for all potential female participants

Clinical laboratory tests (including hematology, chemistry, urinalysis and serum 
pregnancy test)

AE / 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 FF 100 mcg run-in medication
9.1.
Efficacy Assessments
The timings of all efficacy assessments are specified in the Schedule of Activities (SoA)
(Section 2).
9.1.1.
Questionnaires
The questionnaires should be completed before any procedures are performed on the 
participant to avoid influencing the participant’s response. To avoid biasing responses, 
the participants 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 participant must be encouraged to complete any missing assessments or items.
Instructions for completing the questionnaires can be found in the SRM.
9.1.1.1.
Global Assessment of Severity and Response to Treatment
The participant will be asked to complete the Global Assessment of Severity and 
Response to Treatment at the visits specified in the Schedule of Activities table (Section 
2). The Global Assessment of Severity is a single item questionnaire; participants are 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
50
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. Instructions for completing the questionnaires can be found in the 
SRM.
9.1.1.2.
Asthma Control Questionnaire (ACQ)
The ACQ measures attributes of asthma control [Juniper 1999], measured with questions 
designed to be self-completed by the participant.  Participants will complete the ACQ at 
specified study visits. The ACQ-5 includes five questions (concerning nocturnal 
awakening, waking in the morning, activity limitation, shortness of breath and wheeze) 
which enquire about the frequency and/or severity of symptoms over the previous week. 
The ACQ-6 includes an additional item asking about rescue medication use. 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. 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].
9.1.1.3.
St. George’s Respiratory of Life Questionnaire (SGRQ)
The SGRQ 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 participant
[Jones 1992] with a recall over the past 3 months.  A change of 4 points is considered a 
clinically relevant change [Jones 2005].
9.1.1.4.
Asthma Quality of Life Questionnaire (AQLQ)
The 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 participant with a 
recall over the past 2 weeks.  A change of 0.5 is considered clinically important [Juniper
1994].
9.1.2.
Daily Diaries
Participants 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. Participants 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:
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
51

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 PEF

Morning FF 100 mcg medication use

Morning double-blind study medication use (during the treatment period only)
Section 9.1.2 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. 
Participants 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). Participants 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 participant recall in discussions with 
the Investigator, for site staff to then enter as appropriate in the eCRF.
9.1.2.1.
eDiary Questionnaires, Assessments and Alerts
For information on the eDiary questions, please refer to Appendix 8.
9.1.2.1.1.
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.
9.1.2.1.2.
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 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
52
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.
9.1.2.1.3.
Night-time Awakening, Asthma Symptom and Physical Activity 
Questions
Every morning upon waking (from the morning after Visit 1 onwards), participants will 
answer a question on the occurrence of night-time awakenings due to asthma symptoms. 
The participant’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’, participants 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, 
participants 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 (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]).
9.1.2.1.4.
Morning and Evening Home Spirometry
An electronic home spirometer/eDiary device will be issued to participants 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. Participants will conduct 
spirometry maneuvers each morning, prior to study treatment and FF 100 mcg dosing,
and each evening. Three measurements for each session will be recorded by the 
participants in the eDiary. Assessments will be performed:

After completing all other eDiary assessments

Prior to albuterol/salbutamol use

Prior to study treatment and FF 100 mcg dosing
Data from the home FEV1 assessments will be used to determine the time to maximal 
effect of the assigned double-blind study treatment.
9.1.2.1.5.
Alerts
For safety the following alerts, indicative of worsening asthma, will be programmed into 
the eDiary with instructions for the participant to contact the investigator (either by 
telephone and/or by visiting the study clinic) if any of the alert criteria are met:
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
53

Nocturnal awakening(s) due to asthma requiring albuterol/salbutamol use for 2 
consecutive nights.

An increase from baseline of ≥ 4 puffs /day of albuterol/salbutamol use on 2 
consecutive days.

A ≥30% decrease in AM PEF from baseline on 2 consecutive mornings.

A ≥30% decrease in PM PEF from baseline on 2 consecutive evenings

A ≥30% decrease in AM FEV1 from baseline on 2 consecutive mornings.

A ≥30% decrease in PM FEV1 from baseline on 2 consecutive evenings.
9.1.3.
Pulmonary Function Test
The 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 
on each occasion that spirometry assessments are performed, in accordance with the 
American Thoracic Society / European Respiratory Society (ATS/ERS) standards [Miller
2005]. The highest of 3 technically acceptable measurements will be recorded at each 
visit:

Pre-dose Spirometry: At Visits 1 through 5/EOS (and the Early Withdrawal 
Visit, if applicable), participants 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 2
(the baseline assessment).
o
At least 24 hours after the participant’s last morning  dose of study 
treatment on the day prior to the visit.
o
Before the participant’s morning  dose of study treatment on the day of the 
visit.

Post-dose Spirometry: At Visits 2 and 5/EOS (and the Early Withdrawal Visit, if 
applicable), spirometry assessments must be performed 3 hours after the 
participant’s morning  dose of study treatment; the assessment performed at Visit 
5/EOS should be performed at the same time of day (1 hour) as the assessment 
performed at Visit 2 (the baseline assessment). At each visit, participants 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.
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
54
9.1.3.1.
Reversibility (Albuterol/Salbutamol)
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.
To perform the reversibility assessment, 4 puffs of the provided albuterol/salbutamol 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 albuterol/salbutamol.
Percent reversibility will be calculated as follows:
(Post-bronchodilator FEV1 – Pre-bronchodilator FEV1)
x 100
Pre-bronchodilator FEV1
The reversibility requirement for eligibility must be assessed at Visit 1. Participants 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 participant may not enter the 2-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:
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 participant 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 participant may enter the 2-week run-in period.
9.1.4.
Asthma Exacerbations
Moderate and severe asthma exacerbation data will be collected from the start of 
randomized double blinded treatment until Visit 5/EOS Visit or the Early Withdrawal 
Visit for those participants that withdraw from participation in the study (see Section 
8.2). For consistency, exacerbations separated by less than 7 days will be treated as a 
continuation of the same exacerbation.
Participants will 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.
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
55
All severe asthma exacerbations will be recorded in the eCRF by the Investigator (or 
designee).
9.1.4.1.
Moderate Asthma Exacerbation
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 for 3 days or more and/or hospitalization. 

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.
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 
(Refer to Section 7.8.1 above)
The Medical Monitor may be contacted for additional guidance, see the
medical monitor/Sponsor Information Page.
9.1.4.2.
Severe Asthma Exacerbation
A severe asthma exacerbation is defined as: 
The deterioration of asthma requiring the use of systemic corticosteroids (tablets,
suspension or injection) for at least 3 days.
OR
An inpatient hospitalization or emergency department visit because of asthma, requiring
systemic corticosteroids.
9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4.
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study, 
or that caused the participant to discontinue the study treatment or withdraw from the 
study (see Section 8).
9.2.1.
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 participant consents to participate in the 
study up to and including any follow-up contact. 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
56

AEs will be collected from the start of Study Screening until the follow-up contact 
(see Section 9.2.3) at the timepoints specified in the Schedule of Activities (SoA) 
table (Section 2).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the eCRF.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in
Appendix 4. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.

Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the Investigator learns of any SAE, including a death, at 
any time after a participant has been discharged from the study, and he/she 
considers the event 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
9.2.2.
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 participant 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?” 
Participants will be issued with a paper Medical Problems/Medications Taken worksheet
to record any medical problems experienced and medications used during the study. This 
paper worksheet will be used to assist participant recall in discussions with the 
Investigator (or designee), for site staff to then enter as appropriate in the eCRF.
9.2.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts.  All SAEs, and non-serious AEs of special 
interest (as defined in Section 9.2.5), will be followed until the event is resolved, 
stabilized, otherwise explained, or the participant is lost to follow-up (as defined in 
Section 8.3). Further information on follow-up procedures is given in Appendix 4
9.2.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
57
participants and the safety of a study treatment under clinical investigation are 
met. 

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study treatment 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or 
other specific safety information eg, summary or listing of SAE) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.
9.2.5.
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). 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 
Glaucoma (antimuscarinic/corticosteroid)
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
58
Special interest AE group
Special interest AE subgroup
effects / Corticosteroids 
associated eye disorders
Cataracts (corticosteroid)
Pneumonia and LRTI
Pneumonia 
LRTI excluding pneumonia
Adrenal suppression
-
Decreased bone mineral 
density and associated 
fractures
-
Effects on glucose
-
Hypersensitivity
-
Local steroid effects
-
9.2.6.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 4 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the eCRF will 
be required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 
The CV eCRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the eCRF within one week of receipt of a CV Event data query prompting its completion. 
The Death eCRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
9.2.7.
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 participant 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.)
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
59

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).
9.2.8.
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.
9.2.9.
Pregnancy
Details of all pregnancies in female participants 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.
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
9.3.
Treatment of 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 eCRF 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 
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.
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
60
9.4.
Safety Assessments
Planned time points for all safety assessments are provided in the Schedule of Activities 
(SoA).
9.4.1.
Physical Examinations
Physical exams will be performed at the time points specified in the Schedule of 
Activities (SoA) table (Section 2).

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.

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
9.4.2.
Vital Signs
Vital signs will be performed at the time points specified in the Schedule of Activities 
(SoA) table (Section 2) prior to conducting spirometry and prior to taking the morning 
dose of study treatment and FF 100 mcg. 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.
9.4.3.
Electrocardiograms
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 Schedule of 
Activities (SoA) table (Section 2). All ECG measurements will be made with the 
participant in a supine position having rested in this position for approximately 5 minutes 
before each reading.
For participants who meet the QTc, protocol defined stopping criteria, triplicate ECGs 
(over a brief period of time) should be performed (Section 8.1.2).
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 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
61
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.
9.4.4.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory tests to be performed and 
to the Schedule of Activities (SoA) for the timing and frequency. 

The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 5 days after the last dose of study 
treatment should be repeated until the values return to normal or baseline or are 
no longer considered significantly abnormal by the investigator or medical 
monitor. 

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the Schedule of 
Activities (SoA).
9.5.
Pharmacokinetics
Pharmacokinetics is not relevant for this protocol.
9.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
9.7.
Genetics
Information regarding genetic/ pharmacogenetic (PGx) research is included in Appendix 
6. 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 6).
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 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
62
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.
9.8.
Biomarkers
Biomarkers are not evaluated in this study.
9.9.
Health Economics OR Medical Resource Utilization and 
Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study.
10.
STATISTICAL CONSIDERATIONS
10.1.
Hypotheses
The primary objective of this study is to evaluate the efficacy of UMEC 62.5 mcg and 
UMEC 31.25 mcg compared with placebo in participants with not well controlled asthma 
over a 24 week treatment period.  This is a superiority study to demonstrate the benefit of 
UMEC at two dosage strengths 62.5 mcg and 31.25 mcg when compared to Placebo in 
patients on background therapy of FF 100 mcg. The primary efficacy endpoint is the 
mean change from baseline in trough FEV1 at Week 24.
The test for the primary efficacy endpoint is such that 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:  

UMEC 62.5mcg vs Placebo

UMEC 31.25mcg vs Placebo
For each comparison test on the primary endpoint, the null hypothesis is there is no 
difference between treatment groups.  The alternative hypothesis is there is a difference 
between treatment groups.
Therefore T1 and T2 for these endpoints are the mean changes from baseline for the 
UMEC therapy and placebo, respectively, as listed above. 
Details on all pairwise treatment comparisons of interest are provided in Section 10.5.2.
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
63
10.2.
Sample Size Determination
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 384 randomized participants are required for this study, with 128 participants 
in each of the three double-blind treatment groups: UMEC 62.5mcg, UMEC 31.25mcg or 
Placebo. Assuming 10% missing data on spirometry at the end of the 24-week treatment 
period, due to early withdrawal from study, approximately 115 participants per treatment 
group will have trough FEV1 available for the primary 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 350mL based on two previous Tiotropium moderate asthma 
studies.  The study design and population of this study aligns well with these two phase 
III, 24 week, randomised, double blind, placebo-controlled, parallel-group, active 
comparator studies of Tiotropium.  In patients with moderate asthma on a background 
therapy of ICS the standard deviations in change from baseline trough FEV1 at Week 24 
ranged from 325 to 354mL; from this a SD estimate of 350 mL was chosen. This was 
estimated from a wide selection of studies, critically to minimise the risk of reduced 
power for the primary endpoint. The range of observed treatment differences across the 
Tiotropium treatment groups is 133 – 185mL, which supports the expectation that the 
treatment effect seen in a moderate asthma population is larger than in the more severe 
asthma population in study 205715 treated on a background of FF/VI. This is in line with 
data from GSK study 200699 which showed UMEC 62.5 mcg to be an effective dose. An 
average increase in change from baseline trough FEV1 at Day 29 of 136 mL was 
observed in an asthma subset of patients treated with FF/UMEC (100/62.5) compared 
with FF (100 mcg) alone. The GSK phase III closed triple asthma study 205715, which 
this study supports, is in a more severe asthma population and conservatively assumes a 
SD estimate of 400mL.
Based on a true population difference of 130 mL, a sample size of 115 patients per 
treatment group has an estimated 80% power to observe statistical significance at the two 
sided 5% level, for each of the two primary comparisons of interest for each UMEC dose. 
Using the above assumptions the smallest observed effect predicted to result in a 
statistically significant difference between treatment groups is 90.5 mL (minimum 
detectable difference).
No interim analysis is planned for this study.
10.3.
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=115 per arm in the 
intent to treat (ITT) population for the primary efficacy analysis, varying the true
treatment difference and estimated standard deviation on the change from baseline in 
trough FEV1 at the end of the 24-week treatment period.
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
64
Treatment difference (mL)
Standard Deviation
100
115
130
145
160
300
0.71
0.82
0.91
0.95
0.98
350
0.58
0.70
0.80
0.88
0.93
400
0.47
0.58
0.69
0.78
0.86
10.4.
Sample site re-estimation or adjustment
No sample size re-estimation is planned.
10.5.
Data Analysis
10.5.1.
Analysis population
The following participant populations will be identified:
All Participants Enrolled Population: This population will comprise all participants for 
whom a record exists on the study database, including pre-screened participants that sign 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
65
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 Participants Screened Population: This population contains all participants that 
complete at least one Visit 1 (Screening) procedure. This population will be used for the 
summary of participant disposition (including reasons for screening failures and run-in 
failures) and for the listing of AEs and SAEs for non-randomized participants. 
ITT Population: This population will comprise all randomized participants, excluding 
those who were randomized in error. A participant who is recorded as a screen failure or 
run-in 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. This will constitute 
the primary population for all efficacy and safety analyses. 
10.5.2.
Treatment Comparisons
To demonstrate the benefit of UMEC the primary comparisons of interest for the primary 
efficacy endpoint are:

UMEC 62.5 mcg vs Placebo

UMEC 31.25 mcg vs Placebo
Other pairwise treatment comparisons of interest that aim to informally estimate any 
potential benefit of increasing the UMEC dose are given below for all efficacy endpoints. 

UMEC 62.5 mcg vs UMEC 31.25 mcg
For the multiple comparisons and multiplicity adjustment, please see Section 10.5.3. 
10.5.3.
Multiple Comparisons and Multiplicity
In order to account for multiple tests involving the two UMEC doses 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 test in the 
hierarchy. 
A step-down procedure with the following hierarchy will be used for the primary 
comparisons in the primary endpoint.  

The contrast between UMEC 62.5 mcg vs Placebo 
(two-sided, alpha = 0.05.  Null hypothesis of no treatment difference)

The contrast between UMEC 31.25 mcg vs Placebo 
(two-sided, alpha = 0.05.  Null hypothesis of no treatment difference)
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
66
The second hypothesis will be formally tested only if the first hypothesis has been 
rejected, thus maintaining the overall significance level at 5%.  
Specifically, if the defined treatment comparison for the primary efficacy endpoint at the 
highest dose of UMEC 62.5 mcg is significant at 0.05 level then the efficacy of UMEC 
62.5 mcg is demonstrated, and the treatment comparison can be repeated on the UMEC 
31.25 mcg dose. 
Note that, in the event that the first hypothesis is not rejected a nominal p-value for the 
second hypothesis may be provided in the displays for descriptive purposes only and will 
not alter the conclusion of the step-down procedure.
No multiplicity adjustment will be made on these two treatment comparisons on the 
secondary endpoint.
For all efficacy endpoints (primary, secondary and other), treatment comparisons 
between UMEC 62.5 vs UMEC 31.25 mcg informally investigating the benefit of 
increasing UMEC dose will be made without adjusting for multiplicity.  Any p-values ≤ 
0.05 will be identified as nominally significant.
10.6.
Statistical Analysis
Where possible, data from participants 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 RAP. 
In general, the baseline value is the last assessment value prior to randomization at Visit 2
for the efficacy endpoints based on assessments at clinic visits.  The covariates to be 
considered in the efficacy analyses include age, sex, and the baseline value, if relevant. 
Other covariates, if appropriate, may be considered. Specific details will be provided in 
the RAP.
10.6.1.
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 participant, the baseline value of clinic 
FEV1 is the last acceptable/borderline acceptable (pre-dose) FEV1 value obtained prior to 
randomization (either from Visit 2 pre-dose or from Visit 1 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, 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. 

UMEC 62.5 mcg vs Placebo

UMEC 31.25 mcg vs Placebo
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
67
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 10.5.2 will also 
be provided for the primary efficacy endpoint.
10.6.2.
Secondary Analyses
Full details of the analyses to be performed on the secondary efficacy endpoint will be 
given in the RAP.
10.6.3.
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.
10.6.4.
Interim Analyses
No interim analysis is planned for this study.
10.6.5.
Exploratory Analyses
The psychometric properties of the E-RS and Supplemental asthma items will be 
evaluated to characterize the E-RS as an endpoint for asthma.  These exploratory analyses 
may be provided in a separate RAP.
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
68
11.
REFERENCES
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
GlaxoSmithKline Document Number: 2011N123107_03 GW685698+GSK573719 
Investigator’s Brochure, dated 19 Jun 2014 and 2016 Supplement
Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma 
(GINA) 2016. Available from: http://www.ginasthma.org/
Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure of health 
status for chronic airflow limitation. The St. George's Respiratory Questionnaire. Am Rev 
Respir Dis 1992;145:1321-1327.
Jones PW. St. George’s Respiratory Questionnaire: MCID. Journal of Chronic 
Obstructive Pulmonary Disease 2005;2:75-79.
Juniper EF, Bousquet J, Abetz L, Bateman ED; GOAL Committee. Identifying 'well-
controlled' and 'not well-controlled' asthma using the Asthma Control Questionnaire. 
Respir Med 2006;100:616-621.
Juniper EF, Guyatt GH, Willan A, Griffith LE. Determining a minimal important change 
in a disease-specific quality of life instrument. J Clin Epidemiol 1994;47:81-87.
Juniper EF, O'Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of 
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-
558.
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.
Miller MR et al. Standardization of Lung Function Testing. Eur Resp J 2005;26:153-161.
Quanjer P, Stanojevic S, Cole T, Baur X., Hall G, Enright P, et al. on behalf of 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. Eur Respir J 2012;40:1324-
1343.
Reddel HK, Taylor DR, Bateman ED, Boulet L-P, Boushey HA, Busse WW, et al. On
behalf of the American Thoracic Society/European Respiratory Society task force on 
asthma control and exacerbations. An official American Thoracic Society/European 
Respiratory Society statement: asthma control and exacerbations; standardizing endpoints 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
69
for clinical asthma trials and clinical practice. Am J Respir Crit Care Med 2009;180:59-
99. 
US Department of Health and Human Sciences; Food and Drug Administration (FDA).
Guidance for Industry; Drug-Induced Liver Injury: Premarketing Clinical Evaluation 
(July 2009). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf (Accessed 16 July 2014).
Virchow JC, Backer V, de Blay F, Kuna P, Ljorring C, Prieto JL, et al. Defining 
moderate asthma exacerbations in clinical trials based on ATS/ERS joint statement. 
Respiratory Medicine 2015;109:547-556
Wyrwich KW, Khan SA, Navaratnam P, Nolte H, Gates Jr DF. Validation and agreement 
across four versions of the asthma control questionnaire in patients with persistent 
asthma. Resp Med 2011;105:698-712.
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
70
12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
ACQ
Asthma Control Questionnaire
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
BMI
Body Mass Index
BPM
Beats Per Minute
BST
Bioanalytical Science and Toxicokinetics
BUN
Blood Urea Nitrogen
CI
Confidence Interval
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic Obstructive Pulmonary Disease
DNA
Deoxyribonucleic acid
DPI
Dry Powder Inhaler
ECG
Electrocardiogram
(e)CRF
(Electronic) Case Report Form
eDiary
Electronic Diary
EOS
End of study
E-RS
Evaluating Respiratory Symptoms
ERS
European Respiratory Society
EW
Early Withdrawal
FDA
Food and Drug Administration
FEV1
Forced expiratory volume in 1 second
FF
Fluticasone Furoate
FP
Fluticasone Propionate
FSH
Follicle Stimulating Hormone
FVC
Forced Vital Capacity
GCP
Good clinical practice
GCSP
Global Clinical Safety and Pharmacovigilance
GINA
Global Initiative for Asthma
GSK
GlaxoSmithKline
hCG
Human Chorionic Gonadotropin
HIV
Human Immunodeficiency Virus
HPA
Hypothalamic Pituitary Axis
HRT
Hormone Replacement Therapy
IB
Investigator’s Brochure
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
71
ICF
Informed Consent Form
ICH
International Conference on Harmonization
ICS
Inhaled Corticosteroids
IEC
Independent Ethics Committee
IOP
Intraocular Pressure
IP
Investigational Product
IRB
Institutional Review Board
IRT
Interactive Response Technology
IWRS
Interactive Web Response System
ITT
Intent to Treat
LABA
Long-Acting Beta-2-Agonists
LAMA
Long-Acting Muscarinic Antagonist
LOCS III
Lens Opacities Classification System III
LRTI
Lower Respiratory Tract Infection
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
PEF
Peak Expiratory Flow
PK
Pharmacokinetic
PM
Evening
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
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
72
US
United States
VI
Vilanterol
VT
Ventricular Tachycardia
WBC
White Blood Cell
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
ELLIPTA
None
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
73
12.2.
Appendix 2: Clinical Laboratory Tests

All protocol required laboratory assessments (haematology, clinical chemistry 
and urinalysis) must be conducted in accordance with the Laboratory Manual, 
and Protocol Schedule of Activities (Section 2) Laboratory requisition forms 
must be completed and samples must be clearly labelled with the participant
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 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 participant 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.

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 6 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
74
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
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood and ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

Follicle stimulating hormone (FSH) and estradiol (as needed in females 
of non-reproductive potential only)

Serum/urine hCG Pregnancy test (as specified in the Schedule of 
Activities table [Section 2])
NOTES :
5.
Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up 
Assessments after liver stopping or monitoring event are given in Section 8.1.1 and 
Appendix 7
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
75
12.3.
Appendix 3: Study Governance Considerations
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (eg, advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study. 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
76

Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative. 

Participants who are rescreened are required to sign a new ICF.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
77
Dissemination of Clinical Study Data

For this study participant 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.  
Data Quality Assurance

Management of clinical data will be performed in accordance with applicable 
GSK standards and data cleaning procedures to ensure the integrity of the data, 
e.g., removing errors and inconsistencies in the data.

Adverse events and concomitant 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.  Participant 
initials will not be collected or transmitted to GSK according to GSK policy.

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (eg, laboratory 
data). The investigator is responsible for verifying that data entries are accurate 
and correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years after study completion 
unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written 
approval of the sponsor. No records may be transferred to another location or
party without written notification to the sponsor. 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
78
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available.
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study treatment development
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
79
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study treatment, whether or not considered related to the 
study treatment.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfill the definition of an AE 
or SAE. 

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. Also, "lack of 
efficacy" or "failure of expected pharmacological action" constitutes an AE or SAE.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
80
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
81
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
82
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
each occurrence of each AE/SAE.

A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology. 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
83

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to  GSK within 24 hours of 
receipt of the information.
Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper SAE data collection tool (see next section).

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form or to the 
assigned SAE contact by telephone.

Contacts for SAE reporting can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
SAE Reporting to GSK via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the assigned SAE contact by telephone.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
84
12.5.
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)
Women in the following categories are not considered WOCBP
6. Premenarchal
7. Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
8. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment.
Contraception Guidance
Female participants
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in 
Table 4.
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
85
Table 4
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing ) hormonal contraception associated with 
inhibition of ovulation 

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulationb

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.)
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the participant.)
NOTES: 
a.
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants in clinical studies.
Pregnancy Testing

WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive urine or serum pregnancy test 

Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected 

Pregnancy testing, with a sensitivity of [5, 10, 25] mIU/mL will be performed [and 
assayed in a certified laboratory OR and assayed in the central laboratory OR using 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
86
the test kit provided by the central laboratory / provided by the sponsor /approved by 
the sponsor and in accordance with instructions provided in its package insert]  
Collection of Pregnancy Information
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date.  

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. 

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK
as described in Appendix 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 participant who becomes pregnant while participating in the study will 
immediately discontinue study medication.
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
87
12.6.
Appendix 6: Genetics
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 participant who is enrolled in the study can participate in genetic research.  Any 
participant 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 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
88
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 participant 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 participant 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 
participant 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.
Participants can request their sample to be destroyed at any time.
Informed Consent
Participants 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.
Participant Withdrawal from Study
If a participant who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the participant 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 participant 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. 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
89
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 participant 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 
participant does not meet the entry criteria for participation in the study, then the 
Investigator should instruct the participant 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 Participant’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 
participant, family members, insurers, or employers of individual genotyping results that 
are not known to be relevant to the participant’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.
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
90
12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments
Phase II liver chemistry stopping and follow up criteria have been designed to assure 
participant safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance [Food and Drug Administration, 2009]).
Phase II liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin)
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue  study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF and complete an
SAE data collection tool if the event also meets 
the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the participant until liver chemistries
resolve, stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge participant with 
study treatment unless allowed per protocol and 
GSK Medical Governance approval is granted 
(refer to Section 8.1.3)
If restart/rechallenge not allowed per protocol or 
not granted, permanently discontinue study 
treatment and may continue participant in the study 
for any protocol specified follow up assessments 

Viral hepatitis serology4

Blood sample for pharmacokinetic (PK) 
analysis, obtained 72 hours after last 
dose5

Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications 
on the concomitant medications report 
form including acetaminophen, herbal 
remedies, other over the counter 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
91
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 hrs

Monitor participants twice weekly until liver 
chemistries resolve, stabilize or return to within 
baseline 

A specialist or hepatology consultation is 
recommended
For All other criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24-72 
hrs 

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to within 
baseline
medications.

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG or gamma globulins).

Serum acetaminophen adduct HPLC 
assay (quantifies potential 
acetaminophen contribution to liver 
injury in participants with definite or 
likely acetaminophen use in the 
preceding week (James 2009) Not 
Required in China

Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF 
forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that participant if ALT 3xULN and bilirubin 2xULN.. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to participants receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
5.
PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
treatments.)  Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
treatment prior to blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the 
participant’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.  
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
92
Phase II liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 3xULN and <5xULN and bilirubin 
<2xULN, without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks

Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss participant
safety. 

Participant can continue study treatment   

Participant must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time participant meets the liver chemistry 
stopping criteria, proceed as described above

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor participants twice monthly 
until liver chemistries normalize or return to within 
baseline.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
93
12.8.
Appendix 8: Daily Diary Questions
12.8.1.
Morning Questions
The participant 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
12.8.2.
Evening Questions
The participant 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 
Quite a bit 
Extremely 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
94
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 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
95
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
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
96
12.9.
Appendix 9: Country-specific requirements
There are currently no country specific requirements. 
 
2018N371775_00

2016N289466_01
CONFIDENTIAL
205832
97
12.10.
Appendix 10: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
GlaxoSmithKline group of companies
205832
1
TITLE PAGE
Protocol Title: A Phase IIb, 24 week, randomized, double-blind, 3 arm parallel group 
study, comparing the efficacy, safety and tolerability of two doses of umeclidinium 
bromide administered once-daily via a dry powder inhaler, versus placebo, in participants
with asthma
Protocol Number: 205832
Short Title: A randomized, double-blind, parallel group study, comparing the efficacy, 
safety and tolerability of two doses of umeclidinium bromide administered once-daily via 
a dry powder inhaler, versus placebo, in participants with asthma
Compound Number:
GW685698+GSK573719
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information can be found in the Study 
Reference Manual
Regulatory Agency Identifying Number(s): IND No. 104479, EudraCT number 2016-
002843-40
Approval Date: 19-AUG-2016
Copyright 2016 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
2018N371775_00

 
2018N371775_00
PPD
PPD

2016N289466_00
CONFIDENTIAL
205832
3
TABLE OF CONTENTS
PAGE
1.
SYNOPSIS...............................................................................................................6
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................10
3.
INTRODUCTION....................................................................................................15
3.1.
Study Rationale ..........................................................................................15
3.2.
Background ................................................................................................15
3.3.
Benefit/Risk Assessment ............................................................................15
3.3.1.
Risk Assessment .........................................................................16
3.3.2.
Benefit Assessment.....................................................................22
3.3.3.
Overall Benefit: Risk Conclusion..................................................22
4.
OBJECTIVES AND ENDPOINTS...........................................................................22
5.
STUDY DESIGN ....................................................................................................24
5.1.
Overall Design ............................................................................................24
5.2.
Number of Participants ...............................................................................26
5.3.
Participant and Study Completion...............................................................26
5.4.
Scientific Rationale for Study Design ..........................................................26
5.5.
Dose Justification........................................................................................27
6.
STUDY POPULATION...........................................................................................27
6.1.
Inclusion Criteria.........................................................................................27
6.2.
Exclusion Criteria........................................................................................29
6.2.1.
Randomization Criteria ................................................................31
6.2.2.
Inclusion Criteria for Randomization ............................................31
6.2.3.
Exclusion Criteria for Randomization ...........................................32
6.3.
Lifestyle Restrictions...................................................................................32
6.4.
Pre-Screening/Screening/Run-in/Randomization Failures ..........................32
7.
TREATMENTS.......................................................................................................33
7.1.
Treatments Administered............................................................................33
7.1.1.
Description of FF 100 mcg and Double-Blind Study 
Treatment ....................................................................................33
7.1.2.
Description of Albuterol/Salbutamol .............................................34
7.1.3.
Study Treatment and FF 100 mcg Return....................................35
7.2.
Dose Modification .......................................................................................35
7.3.
Method of Treatment Assignment ...............................................................35
7.4.
Blinding.......................................................................................................36
7.5.
Packaging and Labeling..............................................................................36
7.6.
Preparation/Handling/Storage/Accountability..............................................37
7.7.
Treatment Compliance................................................................................37
7.8.
Concomitant Therapy..................................................................................38
7.8.1.
Permitted Medications and Non-Drug Therapies..........................38
7.8.1.1.
Permitted Asthma Medications ...................................38
7.8.1.2.
Permitted Non-Asthma Medications ...........................39
7.9.
Prohibited Medications and Non-Drug Therapies........................................40
7.10.
Treatment after the End of the Study ..........................................................40
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
4
8.
DISCONTINUATION CRITERIA.............................................................................41
8.1.
Discontinuation of Study Treatment ............................................................41
8.1.1.
Liver Chemistry Stopping Criteria ................................................41
8.1.2.
QTc Stopping Criteria ..................................................................42
8.1.3.
Rechallenge.................................................................................43
8.1.3.1.
Study Treatment Restart or Rechallenge....................43
8.2.
Withdrawal from the Study..........................................................................43
8.3.
Lost to Follow Up........................................................................................43
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................44
9.1.
Efficacy Assessments.................................................................................45
9.1.1.
Questionnaires ............................................................................45
9.1.1.1.
Global Assessment of Severity and Response 
to Treatment...............................................................45
9.1.1.2.
Asthma Control Questionnaire (ACQ).........................46
9.1.1.3.
St. George’s Respiratory of Life Questionnaire 
(SGRQ) ......................................................................46
9.1.1.4.
Asthma Quality of Life Questionnaire (AQLQ) ............46
9.1.2.
Daily Diaries ................................................................................46
9.1.2.1.
eDiary Questionnaires, Assessments and 
Alerts..........................................................................47
9.1.2.1.1.
E-RS.......................................................47
9.1.2.1.2.
Supplemental Asthma Items...................47
9.1.2.1.3.
Night-time Awakening, Asthma 
Symptom and Physical Activity 
Questions ...............................................48
9.1.2.1.4.
Morning and Evening Home 
Spirometry..............................................48
9.1.2.1.5.
Alerts......................................................48
9.1.3.
Pulmonary Function Test.............................................................49
9.1.3.1.
Reversibility (Albuterol/Salbutamol)............................50
9.1.4.
Asthma Exacerbations.................................................................50
9.1.4.1.
Moderate Asthma Exacerbation..................................51
9.1.4.2.
Severe Asthma Exacerbation .....................................51
9.2.
Adverse Events...........................................................................................51
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................51
9.2.2.
Method of Detecting AEs and SAEs.............................................52
9.2.3.
Follow-up of AEs and SAEs.........................................................52
9.2.4.
Regulatory Reporting Requirements for SAEs .............................52
9.2.5.
Adverse Events of Special Interest (AESIs) .................................53
9.2.6.
Cardiovascular and Death Events................................................54
9.2.7.
Pneumonia ..................................................................................54
9.2.8.
Radiography (Chest X-Rays) .......................................................55
9.2.9.
Pregnancy ...................................................................................55
9.3.
Treatment of Overdose...............................................................................55
9.4.
Safety Assessments ...................................................................................56
9.4.1.
Physical Examinations.................................................................56
9.4.2.
Vital Signs....................................................................................56
9.4.3.
Electrocardiograms......................................................................56
9.4.4.
Clinical Safety Laboratory Assessments ......................................57
9.5.
Pharmacokinetics .......................................................................................57
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
5
9.6.
Pharmacodynamics ....................................................................................57
9.7.
Genetics .....................................................................................................57
9.8.
Biomarkers .................................................................................................58
9.9.
Health Economics OR Medical Resource Utilization and Health 
Economics..................................................................................................58
10. STATISTICAL CONSIDERATIONS........................................................................58
10.1.
Hypotheses.................................................................................................58
10.2.
Sample Size Determination ........................................................................59
10.3.
Sample Size Sensitivity...............................................................................59
10.4.
Sample site re-estimation or adjustment .....................................................60
10.5.
Data Analysis..............................................................................................60
10.5.1.
Analysis population......................................................................60
10.5.2.
Treatment Comparisons ..............................................................61
10.5.3.
Multiple Comparisons and Multiplicity ..........................................61
10.6.
Statistical Analysis......................................................................................62
10.6.1.
Primary Analyses.........................................................................62
10.6.2.
Secondary Analyses ....................................................................63
10.6.3.
Other Analyses ............................................................................63
10.6.4.
Interim Analyses ..........................................................................63
10.6.5.
Exploratory Analyses ...................................................................63
11. REFERENCES.......................................................................................................64
12. APPENDICES........................................................................................................66
12.1.
Appendix 1: Abbreviations and Trademarks................................................66
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................69
12.3.
Appendix 3: Study Governance Considerations..........................................71
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................75
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................80
12.6.
Appendix 6: Genetics..................................................................................83
12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................86
12.8.
Appendix 8: Daily Diary Questions..............................................................89
12.8.1.
Morning Questions.......................................................................89
12.8.2.
Evening Questions.......................................................................89
12.9.
Appendix 9: Country-specific requirements.................................................92
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
6
1.
SYNOPSIS
Protocol Title: A Phase IIb, 24 week, randomized, double-blind, 3 arm parallel group 
study, comparing the efficacy, safety and tolerability of two doses of umeclidinium 
bromide administered once-daily via a dry powder inhaler, versus placebo, in participants
with asthma
Short Title: A randomized, double-blind, parallel group study, comparing the efficacy, 
safety and tolerability of two doses of umeclidinium bromide administered once-daily via 
a dry powder inhaler, versus placebo, in participants with asthma
Rationale:
In the United States (US), the long-acting muscarinic antagonist (LAMA) tiotropium has 
been approved for the long-term maintenance treatment of asthma in patients 12 years of 
age and older.
GlaxoSmithKline (GSK) is currently developing a once-daily ‘closed’ triple therapy of an
inhaled corticosteroid (ICS)/LAMA/long-acting beta-2-agonist (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 in adults. 
Through the evaluation of UMEC 62.5 micrograms (mcg) and 31.25 mcg compared to 
placebo, this study will provide important information regarding the efficacy, safety and 
tolerability of UMEC when administered via a separate inhaler to participants on a 
background of FF without VI.
The primary objective of this study is to evaluate the effects of UMEC 62.5 mcg and 
UMEC 31.25 mcg on lung function compared with placebo after 24 weeks of treatment.
Objectives and Endpoints:
Objective
Endpoint
Primary

Evaluate the effects of UMEC 62.5 mcg 
and UMEC 31.25 mcg on lung function 
(trough Forced Expiratory Volume in 1 
second [FEV1]) vs placebo after 24 
weeks of treatment.

Mean change from baseline in clinic 
trough FEV1 at Week 24
Secondary

Evaluate the effects of UMEC 62.5 mcg 
and UMEC 31.25 mcg on lung function 
(3hours post dose FEV1) vs placebo after 
24 weeks of treatment.

Mean change from baseline in clinic FEV1
at 3 hours post dose at Week 24
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
7
Objective
Endpoint
Safety

To evaluate the  safety and tolerability of 
UMEC 62.5 mcg and UMEC 31.25 mcg 
compared to placebo

Incidence and type of adverse events

Electrocardiogram (ECG) 
measurements

Vital signs
Overall Design:
This is a Phase IIb, randomized, double-blind, placebo controlled, 3-arm parallel group 
study, comparing the efficacy, safety and tolerability of UMEC (62.5 mcg and 
31.25 mcg) administered once-daily in participants with asthma that is not well controlled
(i.e. participants with an Asthma Control Questionnaire-6 [ACQ-6] total score >0.75 at 
Visit 2 [the Randomization Visit]) despite treatment with maintenance ICS.
Number of Participants:
The total number of randomized participants required is approximately 384, with 128
participants randomized 1:1:1 to each of the 3 double-blind treatment arms.  
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
8
Treatment Groups and Duration:
Eligible participants will be requested to participate in the study for a maximum of 
approximately 31 weeks (Visit 0 to the Follow-up contact, inclusive) during which time, 
participants will complete the following 4 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), 
including the informed consent process, must be completed within 4 weeks prior 
to Visit 1 as well as prior to any protocol-required changes to a participant’s 
usual asthma treatment and the initiation of any Visit 1 procedures.
Participants that receive LABA (or LAMA) as a component of their regular (i.e. 
pre-study) therapy must stop LABA (or LAMA) treatment from 48 hours prior 
to Visit 1 (Screening) until after they have completed the study; therefore, the 
investigator must use their clinical judgment to determine if the participant may 
stop LABA (or LAMA) prior to study entry without incurring undue risk.

Screening / run-in: Participants who meet all the eligibility criteria at Visit 1 
(Screening), will enter the run-in period for approximately 2 weeks to continue 
assessing the participant’s eligibility for the study. On the morning of Visit 1, 
participants will refrain from taking the morning dose of their regular (i.e. pre-
study) ICS asthma medication. Participants satisfying all inclusion/exclusion 
criteria and who have successfully completed all protocol procedures at 
screening will be provided with FF 100 mcg via the ELLIPTA dry-powder 
inhaler (DPI) to take once daily (QD), in the morning, during the 2-week run-in 
period; the first dose of FF 100 mcg will be self-administered by the participant 
before leaving the clinic. Participants will refrain from using their own ICS 
asthma medication during the 2-week run-in and treatment period. Participants 
will also be provided with rescue medication (albuterol/salbutamol) to use on an 
as-needed basis throughout the study.

Randomization / treatment: At Visit 2 (the Randomization Visit), participants 
who meet all of the randomization criteria will be randomized 1:1:1 to receive 
one of the following three double-blind study treatments via the ELLIPTA DPI 
during the 24-week treatment period:

UMEC 62.5 mcg QD

UMEC 31.25 mcg QD

Placebo QD
Participants will continue to administer FF 100 mcg once daily (QD), in the 
morning from a separate ELLIPTA DPI throughout the treatment period. On the 
morning of Visits 2, 3, 4, and 5, participants will perform their electronic Diary 
(eDiary) assessments at home but refrain from taking their morning dose of 
study treatment and FF 100 mcg (as applicable) until instructed to do so by
clinic personnel. At Visits 2, 3, 4 and 5, participants will self-administer study 
treatment immediately followed by FF 100 mcg whilst at the clinic. Participants 
will take their last dose of study treatment and FF 100 mcg in the clinic on Day 
169 (Visit 5). Participants are expected on non-clinic visit days to take their 
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
9
study treatment and FF 100 mcg at home in the morning at approximately the 
same time each day, as directed by the clinic. 

Safety follow-up: A safety follow-up telephone contact or clinic visit will be 
conducted approximately 7 days after the participant completes all of the 
protocol-defined procedures for Visit 5/End of Study (EOS) or, if applicable, the 
Early Withdrawal Visit. A participant will be considered to have completed the 
study when they have completed all phases of the study including screening, 
run-in, the randomized treatment phase, and safety follow-up.
Key Elements of Analysis Plan
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 clinic trough FEV1 recorded post randomization. Analyses will include the fixed, 
categorical effects of treatment, visit, treatment by visit interaction, sex, 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 
primary comparisons of interest:

UMEC 62.5 mcg versus Placebo

UMEC 31.25 mcg versus Placebo
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 reporting and analysis plan (RAP).
The details of the statistical analysis methods for the secondary efficacy endpoint will be 
provided in the RAP. 
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
10
2.
SCHEDULE OF ACTIVITIES (SOA)
Protocol Activity
Pre-
Screen
Screen
Run-in
Treatment Period
Follow-up
Visit
0
1
2
Randomization
3
4
5/End of Study 
(EOS)
Early Withdrawal 
(EW)
Safety
Follow-up Contact
Study Day
-42 to -
14
-14
1
29
85
169
Week
-6 to -2
-2
0
4
12
24
1 week after Visit 
5/EOS or EW Visit
Window
-7d
-5/+2d
-5/+2d
-5/+2d
-1/+4d
Informed consent
(ICF) a
X
Genetic ICF b
X
Inclusion and 
exclusion criteria
X
Demography c
X
X
Medical history 
X
Asthma history d
X
Smoking History 
and status
X
Concomitant 
medication review
X
X
X
X
X
X
X
X
Register visit in 
Interactive Web 
Response System
(IWRS) (RAMOS 
NG) e
X
X
X
X
X
X
X
Randomization f
X
Laboratory 
Assessments
Urinalysis
X
Hematology and 
clinical chemistry g
X
Hepatitis B and C
X m
Genetic sample 
X n
 
 
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
11
Protocol Activity
Pre-
Screen
Screen
Run-in
Treatment Period
Follow-up
Visit
0
1
2
Randomization
3
4
5/End of Study 
(EOS)
Early Withdrawal 
(EW)
Safety
Follow-up Contact
Study Day
-42 to -
14
-14
1
29
85
169
Week
-6 to -2
-2
0
4
12
24
1 week after Visit 
5/EOS or EW Visit
Window
-7d
-5/+2d
-5/+2d
-5/+2d
-1/+4d
Serum pregnancy 
test
X o
X o
X o
Urine pregnancy 
test
X o
X o
X o
Safety 
Assessments
Physical exam 
including height 
and weight h
X
X
X
12-lead 
Electrocardiogram
(ECG) i
X
X
X
X
Vital signs j
X
X
X
X
X
X
Adverse Event (AE)
review
X
X
X
X
X
X
X
Serious Adverse 
Event (SAE) 
review
X
X
X
X
X
X
X
X
Study Treatment
Dispense open 
label fluticasone 
furoate (FF) 100 
mcg medication
X
X
X
X
Administer open 
label FF 100 mcg
X
X
X
X
X
Collect open label 
FF 100 mcg
X
X
X
X
X
Dispense double-
blind study 
treatment
X
X
X
 
 
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
12
Protocol Activity
Pre-
Screen
Screen
Run-in
Treatment Period
Follow-up
Visit
0
1
2
Randomization
3
4
5/End of Study 
(EOS)
Early Withdrawal 
(EW)
Safety
Follow-up Contact
Study Day
-42 to -
14
-14
1
29
85
169
Week
-6 to -2
-2
0
4
12
24
1 week after Visit 
5/EOS or EW Visit
Window
-7d
-5/+2d
-5/+2d
-5/+2d
-1/+4d
Administer double-
blind study 
treatment
X p
X p
X p
X p
Collect double-blind 
study treatment
X
X
X
X
Assess FF 
100 mcg run-in 
medication 
compliance
X
Assess FF 
100 mcg and 
double-blind study 
treatment 
compliance
X
X
X
X
Efficacy 
Assessments
Global Assessment 
of Severity k
X
X
X
X
X
Global Assessment 
of Response to 
Treatment k
X
X
X
X
Asthma Control 
Questionnaire 
(ACQ-6) k
X
X q
Asthma Control 
Questionnaire 
(ACQ-5) k
X
X
X
X
St. George’s 
Respiratory 
Questionnaire 
(SGRQ) k
X
X
X
X
X
 
 
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
13
Protocol Activity
Pre-
Screen
Screen
Run-in
Treatment Period
Follow-up
Visit
0
1
2
Randomization
3
4
5/End of Study 
(EOS)
Early Withdrawal 
(EW)
Safety
Follow-up Contact
Study Day
-42 to -
14
-14
1
29
85
169
Week
-6 to -2
-2
0
4
12
24
1 week after Visit 
5/EOS or EW Visit
Window
-7d
-5/+2d
-5/+2d
-5/+2d
-1/+4d
Asthma Quality of 
Life Questionnaire 
(AQLQ) k
X
X
X
X
X
Evaluating 
Respiratory 
Symptoms (E-RS) 
+Asthma symptoms 
+ Peak Expiratory 
Flow (PEF) + Home 
Forced Expiratory 
Volume in 1 second
(FEV)1 k, l
X
eDiary Dispense
X
eDiary Collect
X
X
eDiary Review
X
X
X
X
X
Dispense paper 
Medical 
Problems/Medicatio
ns Taken 
worksheet
X
X
X
X
X
Review paper 
Medical 
Problems/Medicatio
ns Taken
worksheet
X
X
X
X
X
X
Reversibility
X r
Pre-dose 
spirometry (clinic)
X s
X s
X s
X s
X s
X s
Post-dose 
spirometry (clinic)
X t
X t
X t
 
 
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
14
Notes:
a)
The ICF must be signed before any study procedures, including medication cessation.
b)
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.
c)
Demography may be captured at either the Pre-screen Visit or Screening Visit (for participants who do not have a Pre-screen Visit).
d)
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).
e)
The IWRS will be used for randomization, emergency unblinding and study treatment supply management (Please refer to the RAMOS NG IWRS manual and 
SRM for more information).
f)
Participants must not be randomized prior to confirming their eligibility to participate in the study.
g)
If test otherwise performed within 3 months prior to first dose of study treatment, testing at screening is not required.
h)
Physical Examination will include height and weight at Visit 1 only. 
i)
ECG to be obtained 15 minutes to 45 minutes after the administration of study treatment.
j)
The vital signs assessment will include the measurement of blood pressure, heart rate,
k)
Assessment(s) to be completed prior to the administration of study treatment.
l)
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.
m)
Hepatitis C RNA is optional however a confirmatory negative Hepatitis C RNA test must be obtained, to be able to enrol participants with positive Hepatitis C 
antibody due to prior resolved disease. Hep B/C: If test otherwise performed within 3 months prior to first dose of study treatment, testing at screening is not 
required.
n)
Pharmacogenetic sample may be drawn any time from Visit 2 onwards.
o)
Assessments only to be conducted in females of reproductive potential.
p)
Study treatment should be administered at approximately the same time of day at each applicable clinic visit.
q)
Baseline ACQ-5 will be derived from items 1-5 of the Randomization (Visit 2) ACQ-6.
r)
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 9.1.3.
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 2-week run-in period.
s)
Pre-dose spirometry should 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 and FF 100 mcg. After V2 pre-dose spirometry assessments should be performed within 1 hour of the V2 spirometry.
t)
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 within 1 hour of the V2 spirometry.
 
 
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
15
3.
INTRODUCTION
3.1.
Study Rationale
In the United States (US), the long-acting muscarinic antagonist (LAMA) tiotropium has 
been approved for the long-term maintenance treatment of asthma in patients 12 years of 
age and older.
GlaxoSmithKline (GSK) is currently developing a once-daily ‘closed’ triple therapy of a 
ICS/LAMA/long-acting beta-2-agonist (LABA) combination [FF/umeclidinium 
(UMEC)/vilanterol (VI)] in a single device, with the aim of providing a new treatment 
option for the management of asthma in adults. Through the evaluation of UMEC 
62.5 mcg and 31.25 mcg compared to placebo this study will provide important 
information regarding the efficacy and safety of UMEC when administered in a separate 
inhaler to participants on a background of FF.
The primary objective of this study is to evaluate the effects of UMEC 62.5 mcg and 
UMEC 31.25 mcg on lung function compared with placebo after 24 weeks of treatment.
3.2.
Background
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; Global Initiative for Asthma (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.  
Despite the availability of treatments and published guidelines, patients may have asthma 
that is not well controlled.
This trial will, primarily, evaluate trough FEV1 to characterize the efficacy of two doses
of UMEC (62.5 mcg and 31.25 mcg) in the treatment of asthma when administered as an 
open combination with FF 100 mcg. UMEC is currently under development as a closed 
triple therapy in combination with FF and VI in a single inhaler.
3.3.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events related to FF and UMEC can be found in the 
Investigator’s Brochure(s) (IB). The table below provides a summary of the key risks in 
association with FF and UMEC. It is noted that both FF and UMEC have also been 
developed in combination with VI, therefore relevant safety experience is also provided 
by the FF/VI and UMEC/VI combinations.  
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
16
3.3.1.
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [e.g., GW685698+GSK573719] 
Cardiovascular effects of 
UMEC 
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 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 
- Exclusion criteria as specified in 
Section 6.2 of the protocol
- Collection of cardiovascular risk 
factors and medical history at 
baseline
- ECGs as per schedule in Section 2
- Vital sign assessments (heart rate
and blood pressure) as per schedule in 
Section 2
- Cardiovascular AEs and SAEs will 
be captured on the electronic Case 
Report Form (eCRF) (see Appendix 4)
- Protocol defined stopping criteria as 
per Section 8.1
-MACE analysis
-Instream review of blinded data
 
 
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
17
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Healthy Volunteers (in the Thorough QT study, UMEC 500 mcg 
daily dose), no effect was observed on heart rate, blood pressure or 
QT.
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 500 mcg and placebo. 
UMEC/VI 500/100 mcg increased QTcF on average by 8.2 msec 
(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.  In addition, UMEC/VI has had 
urinary retention, dysuria, vision blurred, glaucoma and increased 
intraocular pressure and paradoxical bronchospasm added as ADRs.  
ICS has a similar class risk of glaucoma and elevated intraocular 
- 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.
- Review AEs/SAEs
 
 
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
18
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
pressure (IOP); however these effects occur by a different mechanism 
that is not expected to be synergistic or additive when FF is used in
combination with UMEC.
Systemic ICS effects 
-Aderenal 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 serum cortisol excretion, and 
multiple studies with COPD and asthma participants 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 
participants 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 participants 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 
- Review AEs/SAEs
- The occurrence of bone fractures 
will be recorded in the eCRF.
 
 
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
19
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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 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 participants 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 mcg (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.  
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).
-Participants 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 
 
 
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
20
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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) 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 participants 
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).
resulting in hospitalisation.  
The occurrence of pneumonia will be 
recorded in the eCRF.
Where possible a chest X-ray should 
be performed to confirm a diagnosis, 
whenever a participant 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.
Participants with a history of allergy 
or hypersensitivity to any 
corticosteroid, 
anticholinergic/muscarinic receptor 
antagonist, beta2-agonist, 
lactose/milk protein or magnesium 
 
 
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
21
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
stearate are excluded from 
participation in this study (Section 
6.2). 
-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 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 UMEC 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.
Females who are pregnant or breast-
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. 
 
 
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
22
The risks for FF 100 mcg are recognised pharmacological class effects associated with 
ICS therapy, which are included in the table above. The experience with FF is provided 
in the respective IB.  
3.3.2.
Benefit Assessment
The benefit of UMEC at two dosage strengths 62.5 and 31.25 mcg as compared to 
Placebo in patients with asthma on background therapy of FF 100 mcg is expected to 
improve lung function. The inclusion of two strengths of UMEC will allow comparison 
to placebo for the dose currently marketed in COPD, as well as a lower dose. This will 
help show the efficacy and safety of UMEC in asthma when administered as an open 
combination on a background of FF. Another LAMA, tiotropium, is currently approved 
for the maintenance treatment of asthma. 
3.3.3.
Overall Benefit: Risk Conclusion
Taking into account the measures taken to minimize the risk to the participants 
participating in the study, the potential risks identified in association with UMEC are 
justified by the anticipated benefits that may be afforded to participants with asthma.  
The current experience and safety profile with UMEC in previous Phase II asthma studies 
(alone and in combination with FF) and from clinical trial and marketing experience in 
the COPD population is supportive of evaluating this compound in asthma patients. The 
potential risks associated with the known pharmacology of UMEC is offset by the 
potential significant benefits that are afforded to patients not well controlled on ICS
therapy. Furthermore, the approval of another LAMA (tiotropium) for the treatment of
asthma demonstrates the suitability for the use of this class of drug in the asthma 
population.  
4.
OBJECTIVES AND ENDPOINTS
For a definition of baseline for each of the endpoints listed below, please refer to Section 
10.6.
Objectives
Endpoints
Primary

Evaluate the effects of UMEC 
62.5 mcg and UMEC 31.25 mcg 
on lung function (trough FEV1) 
versus placebo after 24 weeks of 
treatment.

Mean change from baseline in clinic 
trough FEV1 at Week 24
Secondary

Evaluate the effects of UMEC 
62.5 mcg and UMEC 31.25 mcg on 
lung function (3hours post dose 

Mean change from baseline in clinic 
FEV1 at 3 hours post dose at Week 24
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
23
Objectives
Endpoints
FEV1) versus placebo after 24 
weeks of treatment.
Safety  

To evaluate the  safety and 
tolerability of UMEC 62.5 mcg and 
UMEC 31.25 mcg compared to 
placebo

Incidence and type of adverse events

ECG measurements

Vital signs
Other

To evaluate other efficacy assessments 
of UMEC 62.5 mcg and UMEC 
31.25 mcg compared to placebo

Mean change from baseline in morning 
(AM) pre-dose Peak Expiratory Flow 
(PEF) over the 24 week treatment 
period

Mean change from baseline in evening
(PM) PEF over the 24 week treatment 
period

Mean change from baseline in daily 
home trough FEV1 over the 24 week 
treatment period

Mean change from baseline in daily 
rescue medication use over the 24 
week treatment period

Mean change from baseline in SGRQ
total score 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 SGRQ 
domain scores at Week 24

Mean change from baseline in the 
AQLQ total score at Week 24

Percent of patients meeting a 
responder threshold of ≥ 0.5 points 
improvement from baseline for the 
AQLQ total score at Week 24

Mean change from baseline in E-RS
total score over the 24 week treatment 
period

Mean change from baseline in 
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
24
Objectives
Endpoints
ACQ-5 total score at Week 24

Percent of patients meeting a 
responder threshold of ≥0.5 in change 
from baseline for the ACQ-5 at Week 
24

Annualized rate of moderate/severe 
asthma exacerbations
5.
STUDY DESIGN
5.1.
Overall Design
This is a Phase IIb, randomized, double-blind, placebo controlled, 3-arm parallel group 
study, comparing the efficacy, safety and tolerability of UMEC (62.5 mcg and 
31.25 mcg) administered once-daily in participants with asthma that is not well controlled 
(i.e. participants with an ACQ-6 total score >0.75 at Visit 2 [the Randomization Visit]) 
despite treatment with maintenance ICS.
Eligible participants will be requested to participate in the study for a maximum of 
approximately 31 weeks (Visit 0 to the Follow-up contact, inclusive) during which time, 
participants will complete the following 4 phases of the study:
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
25

Pre-screening: Details about the study and procedures will be explained 
through the informed consent process. The Pre-screening Visit (Visit 0), 
including the informed consent process, must be completed within 4 weeks prior 
to Visit 1 as well as prior to any protocol-required changes to a participant’s 
usual asthma treatment and the initiation of any 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 defined in Section 7.9.
Participants that receive LABA (or LAMA) as a component of their regular (i.e. 
pre-study) therapy must stop LABA (or LAMA) treatment from 48 hours prior 
to Visit 1 (Screening) until they have completed the study; therefore, the 
investigator must use their clinical judgment to determine if the participant may 
stop LABA (or LAMA) prior to study entry without incurring undue risk.

Screening / run-in: Participants who meet all the eligibility criteria at Visit 1 
(Screening), will enter the run-in period for approximately 2 weeks to continue 
assessing the participant’s eligibility for the study. On the morning of Visit 1, 
participants will refrain from taking the morning dose of their regular (i.e. pre-
study) ICS asthma medication. Participants satisfying all inclusion/exclusion 
criteria and who have successfully completed all protocol procedures at 
screening will be provided with FF 100 mcg via the ELLIPTA dry-powder 
inhaler (DPI) to take once daily (QD), in the morning, during the 2-week run-in 
period; the first dose of FF 100 mcg will be self-administered by the participant 
before leaving the clinic. Participants will refrain from using their own ICS 
asthma medication during the 2-week run-in and treatment period. Participants 
will also be provided with rescue medication (albuterol/salbutamol) to use on an 
as-needed basis throughout the study.

Randomization / treatment: At Visit 2 (the Randomization Visit), participants 
who meet all of the randomization criteria will be randomized 1:1:1 to receive 
one of the following three double-blind study treatments via the ELLIPTA DPI 
during the 24-week treatment period:

UMEC 62.5 mcg QD

UMEC 31.25 mcg QD

Placebo QD
Participants will continue to administer FF 100 mcg once daily (QD), in the 
morning from a separate ELLIPTA DPI throughout the treatment period. On the 
morning of Visits 2, 3, 4, and 5, participants will perform their electronic Diary 
(eDiary) assessments at home but refrain from taking their morning dose of 
study treatment and FF 100 mcg (as applicable) until instructed to do so by
clinic personnel. At Visits 2, 3, 4 and 5, participants will self-administer study 
treatment immediately followed by FF 100 mcg whilst at the clinic (see Section 
7.2). Participants will take their last dose of study treatment and FF 100 mcg in 
the clinic on Day 169 (Visit 5). Participants are expected on non-clinic visit days
to take their study treatment and FF 100 mcg at home in the morning at 
approximately the same time each day, as directed by the clinic.
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
26

Safety follow-up: A safety follow-up telephone contact or clinic visit will be 
conducted approximately 7 days after the participant completes all of the 
protocol-defined procedures for Visit 5/End of Study (EOS) or, if applicable, the 
Early Withdrawal Visit. A participant will be considered to have completed the 
study when they have completed all phases of the study including screening, 
run-in, the randomized treatment phase, and safety follow-up.
To demonstrate the benefit of UMEC the primary comparisons of interest for the primary 
efficacy endpoint are:

UMEC 62.5 mcg versus (vs) Placebo

UMEC 31.25 mcg vs Placebo
Other pairwise treatment comparisons of interest that aim to informally estimate any 
potential benefit of increasing the UMEC dose are given below for all efficacy endpoints. 

UMEC 62.5 mcg vs UMEC 31.25 mcg
For the multiple comparisons and multiplicity adjustment, please see Section 10.5.3. 
Participants who permanently discontinue double-blind 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 (see Section 8.1)
5.2.
Number of Participants
The total number of randomized participants required is approximately 384, with 128
participants randomized 1:1:1 to each of the 3 double-blind treatment arms (see Section 
10).  
5.3.
Participant and Study Completion
A participant will be considered to have completed the study when they have completed 
all phases of the study including pre-screening, screening, run-in, the randomized 
treatment phase, and safety follow-up.
The end of the study is defined as the date of the last scheduled procedure shown in the 
Schedule of Activities table (see Section 2) for the last participant in the trial globally.
5.4.
Scientific Rationale for Study Design
This study will use a multicenter, randomized, double-blind, 3 arm parallel-group design.  
This is a well-established design to evaluate the efficacy, safety, and tolerability of the 
UMEC drug.  A placebo arm is included. All participants will be placed on open-label FF 
100 mcg when they enter the 2 week run-in period and continue it through the 24 week 
treatment period. The primary objective of this study is to evaluate the effects of UMEC 
62.5 mcg and UMEC 31.25 mcg on lung function compared with placebo after 24 weeks 
of treatment.
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
27
GlaxoSmithKline (GSK) is currently developing a once-daily ‘closed’ triple therapy of a 
ICS/LAMA/LABA combination [FF/UMEC/VI)] in a single device, with the aim of 
providing a new treatment option for the management of asthma in adults. Through the 
evaluation of UMEC 62.5 mcg and 31.25 mcg compared to placebo this study will 
provide important information regarding the efficacy, safety and tolerability of UMEC in 
asthma when administered via a separate inhaler to participants on a background of FF
without VI.
5.5.
Dose Justification
The 200699 (IB Supplement, GlaxoSmithKline Document 2011N123107_03) data 
showed UMEC 62.5 mcg to be an effective dose; after 4 weeks of treatment in the 
subset of patients with a primary diagnosis of asthma, an average increase in change 
from baseline trough FEV1 at Day 29 of 136 mL was observed in those participants
treated with FF/UMEC (100/62.5 mcg) compared to those participants 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 both 31.25 and 62.5 mcg doses will 
be assessed in this study when administered via a separate inhaler to participants 
treated on a background of FF 100 mcg. No safety signal was identified with any of 
the UMEC doses (15.6, 62.5, 125 and 250 mcg) evaluated in the 200699 study.
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
AGE
1. Age: 18 years of age or older at the time of signing the informed consent.
TYPE OF PARTICIPANT AND DISEASE CHARACTERISTICS
2. Diagnosis: Participants with a diagnosis of asthma as defined by the National 
Institutes of Health [NIH, 2007] at least 6 months prior to Visit 0.
3. Asthma Control: ACQ-6 total score of >0.75 at Visit 1.
4. Current Asthma Maintenance Therapy: Participants are eligible if they have 
required daily ICS therapy 100 mg/day fluticasone propionate (FP, or 
equivalent) with or without LABA or LAMA for at least 12 weeks prior to Visit 0
and there have been no changes in maintenance asthma medications during the 4 
weeks immediately prior to Visit 0.
Examples of acceptable doses of commonly prescribed ICS medication will be 
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 
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
28
labels.
5. Spirometry: Both of the following:
a.
A best pre-bronchodilator morning (AM) FEV1 ≤85% of the predicted 
normal value. Predicted values will be based upon the ERS Global Lung 
Function Initiative [Quanjer, 2012].
b. A best post-bronchodilator FEV1/ forced vital capacity (FVC) ≥0.7 at 
Visit 1.
6. Reversibility of Disease: Airway reversibility is 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 participant 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:
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 participant 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 participant may 
enter the 2-week run-in period (see Section 9.1.3).
7.
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
8. Gender:
a. Male participants
b. Female participants: 
A female participant is eligible to participate if she is not pregnant (see Appendix 5),
not breastfeeding, and at least one of the following conditions applies:

Not a woman of childbearing potential (WOCBP) as defined in Appendix 5
OR

A WOCBP who agrees to follow the contraceptive guidance in Appendix 5
during the treatment period and for at least 5 days after the last dose of study 
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
29
treatment.
INFORMED CONSENT
9. 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.  Participants must be 
able to read, comprehend, and write at a level sufficient to complete study related 
materials.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
MEDICAL CONDITIONS
1.
Pneumonia: Chest X-ray documented pneumonia in the 12 weeks prior to Visit 1.
2.
Asthma Exacerbation: Any severe asthma exacerbation, defined as deterioration of 
asthma requiring the use of systemic corticosteroids (oral, parenteral or depot) within 
12 weeks of Visit 1, or an inpatient hospitalisation or emergency department visit 
due to asthma that required systemic corticosteroids within 12 weeks of Visit 1.
3.
Concurrent Respiratory Disease: Current evidence of pneumonia, pneumothorax, 
atelectasis, pulmonary fibrotic disease, bronchopulmonary dysplasia, chronic 
bronchitis, emphysema, chronic obstructive pulmonary disease, lung cancer, or other 
respiratory abnormalities other than asthma.
4.
Pregnancy: Women who are pregnant or lactating or are planning on becoming 
pregnant during the study.
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: Participants 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 participant
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 participant otherwise meets entry criteria
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
30
8.
Clinically significant ECG abnormality: Evidence of a clinically significant 
abnormality in the 12-lead ECG performed during screening or run-in. The PI will 
determine the clinical significance of each abnormal ECG finding in relation to the 
participant’s medical history and exclude participants 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:

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: participants 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 last 
3 months

New York Heart Association (NYHA) Class IV Heart failure
10. Antimuscarinic effects: Participants 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: Participants with carcinoma that has not been in complete remission for at 
least 5 years. Participants 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 participant has been considered cured by treatment.
12. Questionable validity of consent: Participants 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.
PRIOR/CONCOMITANT THERAPY
13. Medication prior to spirometry: Participants who are medically unable to withhold 
their albuterol/salbutamol for the 6-hour period required prior to spirometry testing at 
each study visit.
PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE/RELEVANT 
HABITS
14. Tobacco Use: Current smoker or a smoking history of ≥10 pack years (e.g., 
20 cigarettes/day for 10 years).  A participant may not have used inhaled tobacco 
products within the past 12 months (i.e., cigarettes, cigars or pipe tobacco).
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
31
15. Drug/alcohol abuse: Participants with a known or suspected history of alcohol or 
drug abuse within the last 2 years.
Diagnostic assessments
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.
Other Exclusions
17. Non-compliance: Participants 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.
19. Inability to read: In the opinion of the Investigator, any participant who is unable to 
read and/or would not be able to complete study related materials.
6.2.1.
Randomization Criteria
At the end of the run-in period (Visit 2), study participants must fulfil the following 
additional criteria in order to be randomized into the study and enter the treatment period:
6.2.2.
Inclusion Criteria for Randomization
TYPE OF PARTICIPANT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
1. Asthma Control: ACQ-6 total score of >0.75 at Visit 2.
2. Percent-predicted FEV1: Spirometry: A best pre-bronchodilator morning (AM) 
FEV1 ≤85% 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.
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
32
6.2.3.
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 
run-in period that led to a change in asthma management or, in the opinion of the 
Investigator, is expected to affect the participant’s asthma status or the participant’s 
ability to participate in the study.
2. Asthma exacerbation: Evidence of a moderate asthma exacerbation leading to a 
change in therapy or severe exacerbation during screening or the run-in period, 
defined as deterioration of asthma requiring the use of systemic corticosteroids 
(tablets, suspension, or injection) or an in-patient hospitalization or emergency 
department visit due to asthma that required systemic corticosteroids.
CONCOMITANT MEDICATIONS/TREATMENTS
3. Asthma medication: Changes in asthma medication (excluding changes after Visit 0 
or 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.
6.3.
Lifestyle Restrictions
No lifestyle restrictions are required for this study.
6.4.
Pre-Screening/Screening/Run-in/Randomization Failures
A participant will be assigned a participant number at the time the informed consent is 
signed at Visit 0.
The study site will be responsible for reporting pre-screen failures. The following 
information will be collected in the eCRF for participants who are pre-screen failures:

Demographic information including race, age and gender

Participant 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-screening failures, screening failures, run-in failures
and randomization failures will be defined as follows:

Pre-screening failures: those participants that sign the informed consent 
document but do not have a Visit 1 (Screening) procedure.
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
33

Screening failures: those participants that complete at least one Visit 1 
(Screening) procedure but do not enter the run-in period. 
A participant 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 participants that enter the run-in period but do not have 
any Visit 2 (Randomization) procedures.

Randomization failures: those participants that complete at least one Visit 2 
(Randomization) procedure but do not enter the double-blind study treatment 
period.
Any participant who completes the run-in period and then meets the 
randomization criteria and is dispensed the double-blind study treatment at Visit 
2 is considered to have entered the treatment period.
RAMOS NG will be contacted to register the participant.
In order to ensure transparent reporting of screen/run-in failure participants, meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements, and 
respond to queries from Regulatory authorities, a minimal set of screen/run-
in/randomization failure information is required including demography, screen/run-
in/randomization failure details, eligibility criteria, and any SAEs (see Section 9.2.4 and
Appendix 4). Further details are provided in the study-specific eCRF completion 
guidelines document.
7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol. The term ‘study treatment’ within this trial is used to describe the 
combination of products received by the participant as per the protocol design. Study 
treatment may also be used to only reference the randomized study treatment when 
described together with the FF 100 mcg open-label treatment.
7.1.
Treatments Administered
7.1.1.
Description of FF 100 mcg and Double-Blind Study 
Treatment
The ELLIPTA device will be used during the run-in period and the treatment period.  The 
ELLIPTA dry powder inhaler (DPI) is a molded plastic two-sided device with a dose 
counter that can hold two individual blister strips.  The ELLIPTA will deliver, when 
actuated, the contents of a single blister simultaneously from each of the two strips. The 
ELLIPTA is individually sealed in a foil laminate overwrap that also contains a silica gel
desiccant packet.
A description of the FF (GW685698) 100 mcg inhalation powder administered via the 
ELLIPTA is provided in Table 1; descriptions of the double-blind study treatments 
administered via the ELLIPTA are provided in Table 2.
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
34
Table 1
Description of FF 100 mcg Inhalation Powder in ELLIPTA
FF 100
First Strip
Second Strip
GW685698 blended with 
lactose monohydrate
Lactose monohydrate with magnesium 
stearate1
Dosage Form
ELLIPTA DPI with 30 doses (2 strips with 30 blisters)
Unit Dose strengths
100 mcg per blister
Not applicable
Physical description
White powder
White powder
Route of 
Administration
Inhaled
1.
Magnesium stearate 1.0% w/w of total drug product.
Table 2
Description of Study Treatment Inhalation Powder in ELLIPTA
7.1.2.
Description of Albuterol/Salbutamol
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 
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
35
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.
7.1.3.
Study Treatment and FF 100 mcg Return
ELLIPTAs containing FF 100 mcg and study treatment will be dispensed to a participant 
during their visit to the study clinic (as applicable). The participant must return all 
dispensed ELLIPTAs at the subsequent clinic visit. The schedule for dispensing and 
collecting FF 100 mcg and study treatment ELLIPTAs is provided in the Schedule of 
Activities table (Section 2).
All used and unused study treatment, FF 100 mcg and albuterol/salbutamol 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 Study Reference Manual (SRM).
If any ELLIPTA fails to function properly, the participant should return to the clinic as 
soon as possible to obtain a new inhaler.  The site will use the IWRS (RAMOS NG) to 
obtain a new treatment pack number for the participant and dispense a new study 
treatment kit from the site’s study treatment supply as instructed by the IWRS.
In addition, any metered dose inhaler (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.
7.2.
Dose Modification
There were no dose modifications planned for this protocol.
7.3.
Method of Treatment Assignment
Participants 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. Participants will be randomized using an interactive web response
system (IWRS) RAMOS NG. The study will use central-based randomization to allocate 
treatments. Once a randomization number is assigned to a participant it cannot be 
reassigned to any other participant in the study.
Following the 2-week run-in period and participant to satisfying all eligibility criteria, 
participants will be randomized 1:1:1 to one of the following three double-blind 
treatments for the duration of the treatment period: 

UMEC 62.5 mcg QD

UMEC 31.25 mcg QD

Placebo QD
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
36
The duration of double-blind treatment for each participant is 24 weeks. On the morning 
of each scheduled clinic study visit, participants will refrain from taking their morning 
dose of study treatment and FF 100 mcg 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 Randomization Visit (Visit 2). On the other days during the treatment period (i.e. 
“non-clinic days”), participants 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 treatment packs will be supplied as 
needed to the sites. Details of how to use the IWRS system (RAMOS NG) to randomize 
participants and manage study treatment supplies (including dispensing) is provided in 
the RAMOS NG IWRS manual and SRM.
7.4.
Blinding
This will be a double-blind study and the following will apply. 

The Investigator or treating physician may unblind a participant’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 participant as judged by the 
Investigator. 

Investigators have direct access to the participant’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 participant’s treatment assignment. 

If GSK personnel are not contacted before the unblinding, the Investigator must 
notify GSK within 24 hours after unblinding, but without revealing the treatment 
assignment of the unblinded participant, unless that information is important for 
the safety of participants currently in the study. 

The date and event or condition which led to the unblinding (i.e. the primary 
reason) will be recorded in source documentation and in the eCRF.
Should a participant’s treatment assignment be unblinded then the participant may 
continue the assigned study treatment and be followed-up as per protocol until the 
completion of the Safety Follow-up assessments.
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any participant 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 participant’s treatment assignment, may be sent to Investigators in 
accordance with local regulations and/or GSK policy. Participants will not be withdrawn 
from the study.
7.5.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
37
7.6.
Preparation/Handling/Storage/Accountability
1.
The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment.
2.
Only participants enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment. All study treatments 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access 
limited to the investigator and authorized site staff.
3.
The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records).
4.
Further guidance and information for the final disposition of unused study treatment 
are provided in the SRM.

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  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 Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK.
7.7.
Treatment Compliance
When participants are dosed at the site, they will receive FF 100 mcg and 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 participant identification 
will be confirmed at the time of dosing by a member of the study site staff.  
When participants self-administer study treatment(s) at home, compliance with study 
treatment will be assessed through querying the participant during the site visits and 
recording the number of doses remaining in the ELLIPTA in the eCRF (see the SRM for 
details).  A record of the number of ELLIPTAs dispensed to each participant must be 
maintained and reconciled with study treatment and compliance records. 
Participant compliance with FF 100 mcg and study treatment will be assessed at 
scheduled clinic visits by reviewing the eDiary and information from the dose counter on 
the returned inhaler(s) (see Section 7.1.3).  Participants should be 80% to 120% 
compliant on taking both FF 100 mcg and study treatment between each pair of 
scheduled and consecutive on-treatment clinic visits, as applicable. Participants who fall 
outside this range should be re-educated on treatment compliance by their site. This re-
education should be documented in the participant’s source document. If FF 100 mcg 
and/or study treatment is prematurely discontinued during the course of the study or 
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
38
compliance repeatedly falls outside of acceptable ranges, the study sponsor/site monitor 
must be contacted to discuss participant eligibility for continued participation in the 
study.
7.8.
Concomitant Therapy
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.
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 FF 100 mcg and albuterol/salbutamol should not be recorded in 
the eCRF; however non-study supplied FF 100 mcg and albuterol/salbutamol will be 
recorded in the eCRF.
The minimum requirement is that the drug name, reason for use, dose (including unit e.g. 
mcg) and frequency, route and the dates of administration are to be recorded.
Medications initiated after completion of the assessments at Visit 5/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.  Participants who have completed the Early Withdrawal 
Visit are allowed to use any medications prescribed by the Investigator or primary care 
physician.
7.8.1.
Permitted Medications and Non-Drug Therapies
7.8.1.1.
Permitted Asthma Medications
In addition to FF 100 mcg and 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. Participants must be judged 
capable of withholding albuterol/salbutamol for at least 6 hours prior to study 
visits.
Temporary changes in medications are permitted for the treatment of moderate asthma 
exacerbations, 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 SRM for contact information
[refer to Section 9.1.4.1 for guidance on moderate asthma exacerbation]):

An increase in ICS dose.

Systemic corticosteroids (tablets, suspension or injection) for no more than 2 
days.
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
39

An Investigator-advised change in SABA use (i.e., routinely scheduled versus 
as needed use).

Leukotriene receptor antagonists (LTRAs) and leukotriene modifiers.

Oral theophylline.
7.8.1.2.
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.

Decongestants: Participants 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 participants 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 
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
40
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 participants’ lung function or safety assessments
(e.g., cardiac measurements). However, no systemic corticosteroids will be permitted.
7.9.
Prohibited Medications and Non-Drug Therapies
Use of the medications listed in Table 3 is not permitted during the study.
Table 3
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
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) 
2 days
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,
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
Any other investigational drug
30 days or within 5 drug half-lives of the 
investigational drug (whichever is longer)
7.10.
Treatment after the End of the Study
Participants will not receive any additional treatment from GSK after completion of the 
study because other treatment options are available.
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
41
The Investigator is responsible for ensuring that consideration has been given to the post-
study care of the participant’s medical condition, whether or not GSK is providing 
specific post-study treatment.
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
Participants that permanently stop study treatment are encouraged to remain in the 
study.  Participants have the right to discontinue study treatment before the end of the 
study.  A participant may also be asked to discontinue study treatment at the 
Investigator’s discretion.
Participants who withdraw from study treatment prematurely (for any reason) should, 
where possible, continue to be followed-up as per protocol until the completion of the 
Safety Follow-up assessments. If this is not possible, the Investigator must encourage the 
participant to participate in as much of the study as they are willing (or able) to.
A participant may be withdrawn from study treatment at any time. A reason for 
premature discontinuation of study treatment (e.g., AE, lack of efficacy [including 
moderate or severe asthma exacerbation], protocol deviation, Investigator discretion, 
consent withdrawn etc.) must be captured in the eCRF.
A participant 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 

QTc: Meets any of the protocol-defined stopping criteria 

Pregnancy: Positive pregnancy test
8.1.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). These protocol guidelines are in alignment 
with FDA premarketing clinical liver safety guidance: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Discontinuation of study treatment for abnormal liver tests should be considered by the 
investigator when a participant meets one of the conditions outlined in the algorithm or if 
the investigator believes that it is in the best interest of the participant.
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
42
Phase II Liver Chemistry Stopping and Increased Monitoring Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus
Bilirubin≥2x
ULN (>35% 
direct) 
or plus
INR>1.5, if 
measured*
Possible
Hy’s Law
ALT≥3xULN
ALT≥5xULN
ALT≥3xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
ALT≥3xULN
but able to 
monitor 
weekly for 
4 weeks
No
Yes
Yes
Yes
Yes
No
No
No
No
Yes
ALT≥3xULN
persist for
4 weeks or 
stopping 
criteria 
met
Yes
No
*INR value not applicable to subjects on anticoagulants
Yes
If subject to be monitored weekly must refer to Liver Safety Required  Actions and  Follow  up 
Assessments  section  in  the  Appendix
Must refer to Liver Safety Required Actions and Follow  up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments can be found in Appendix 7
8.1.2.
QTc Stopping Criteria
Details on performing ECG assessments can be found in Section 9.4.3.

The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study.  This formula may 
not be changed or substituted once the participant has been enrolled.

For example, if a participant 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 participant as well.

Once the QT correction formula has been chosen for a participant’s eligibility, 
the same formula must continue to be used for that participant 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 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, lead to withdrawal 
from study treatment:

QTc>500 msec or uncorrected QT>600 msec
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
43

Change from baseline: QTc> 60 msec

For patients with underlying bundle branch block, follow the discontinuation criteria 
listed below:

Baseline QTc with Bundle Branch Block <450 msec, Discontinuation QTc with 
Bundle Branch Block >500 msec

Baseline QTc with Bundle Branch Block <450-480  msec, Discontinuation QTc 
with Bundle Branch Block ≥530 msec
8.1.3.
Rechallenge
8.1.3.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed.
8.2.
Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, 
or may be withdrawn at any time at the discretion of the investigator for safety, 
behavioral, compliance or administrative reasons.

If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent.

If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records.

In the event of early withdrawal from the study, every effort should be made to 
have the participant 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 Schedule of Activities table (Section 2).
8.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 3 
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
44
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 
9.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the Schedule of Activities (SoA)
(Section 2). There are no protocol waivers or exemptions allowed. Immediate safety 
concerns should be discussed with the sponsor immediately upon occurrence or 
awareness to determine if the participant should continue or discontinue study treatment.
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
No study related procedures may be performed until the informed consent form has 
been signed by the participant.  A Pre-Screening visit (Visit 0) is required in order to 
administer the informed consent before any changes are made to the participant’s current 
medical regimen.  Selection and modification of the participant’s medications prior to 
study participation is based on the physician’s judgment according to sound medical 
practice, principles, and each participant’s needs.  A participant’s treatment must not be 
changed merely for the purpose of enabling the participant’s participation in the study.
During the Pre-Screening visit (Visit 0) the following information will be captured in the 
eCRF for each participant: 

Demographic information including race, age and gender

Participant 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 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

Smoking history and status

Exacerbation history

Asthma and other concurrent medications
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
45

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

Questionnaires (ACQ; SGRQ; AQLQ; E-RS)

Healthcare Resource Utilization

Pre-and post-albuterol/salbutamol lung function

Inclusion/Exclusion criteria assessment

Physical examination

12-lead ECG

Child bearing status assessment for all potential female participants

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 FF 100 mcg run-in medication
9.1.
Efficacy Assessments
The timings of all efficacy assessments are specified in the Schedule of Activities (SoA)
(Section 2).
9.1.1.
Questionnaires
The questionnaires should be completed before any procedures are performed on the 
participant to avoid influencing the participant’s response. To avoid biasing responses, 
the participants 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 participant must be encouraged to complete any missing assessments or items.
Instructions for completing the questionnaires can be found in the SRM.
9.1.1.1.
Global Assessment of Severity and Response to Treatment
The participant will be asked to complete the Global Assessment of Severity and 
Response to Treatment at the visits specified in the Schedule of Activities table (Section
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
46
2). The Global Assessment of Severity is a single item questionnaire; participants 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. Instructions for completing the questionnaires can be found in the 
SRM.
9.1.1.2.
Asthma Control Questionnaire (ACQ)
The ACQ measures attributes of asthma control [Juniper 1999], measured with questions 
designed to be self-completed by the participant.  Participants will complete the ACQ at 
specified study visits. The ACQ-5 includes five questions (concerning nocturnal 
awakening, waking in the morning, activity limitation, shortness of breath and wheeze)
which enquire about the frequency and/or severity of symptoms over the previous week.
The ACQ-6 includes an additional item asking about rescue medication use. 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. 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].
9.1.1.3.
St. George’s Respiratory of Life Questionnaire (SGRQ)
The SGRQ 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 participant
[Jones1992] with a recall over the past 3 months.  A change of 4 points is considered a 
clinically relevant change [Jones2005].
9.1.1.4.
Asthma Quality of Life Questionnaire (AQLQ)
The 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 participant with a 
recall over the past 2 weeks.  A change of 0.5 is considered clinically important [Juniper
1994].
9.1.2.
Daily Diaries
Participants 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. Participants 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:
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
47

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 PEF

Morning FF 100 mcg medication use

Morning double-blind study medication use (during the treatment period only)
Section 9.1.2 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. 
Participants 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). Participants 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 participant recall in discussions with 
the Investigator, for site staff to then enter as appropriate in the eCRF.
9.1.2.1.
eDiary Questionnaires, Assessments and Alerts
For information on the eDiary questions, please refer to Appendix 8.
9.1.2.1.1.
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.
9.1.2.1.2.
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 
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
48
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.
9.1.2.1.3.
Night-time Awakening, Asthma Symptom and Physical Activity 
Questions
Every morning upon waking (from the morning after Visit 1 onwards), participants will 
answer a question on the occurrence of night-time awakenings due to asthma symptoms. 
The participant’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’, participants 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, 
participants 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 (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]).
9.1.2.1.4.
Morning and Evening Home Spirometry
An electronic home spirometer/eDiary device will be issued to participants 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. Participants will conduct 
spirometry maneuvers each morning, prior to study treatment and FF 100 mcg dosing,
and each evening. Three measurements for each session will be recorded by the 
participants in the eDiary. Assessments will be performed:

After completing all other eDiary assessments

Prior to albuterol/salbutamol use

Prior to study treatment and FF 100 mcg dosing
Data from the home FEV1 assessments will be used to determine the time to maximal 
effect of the assigned double-blind study treatment.
9.1.2.1.5.
Alerts
For safety the following alerts, indicative of worsening asthma, will be programmed into 
the eDiary with instructions for the participant to contact the investigator (either by 
telephone and/or by visiting the study clinic) if any of the alert criteria are met:
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
49

Nocturnal awakening(s) due to asthma requiring albuterol/salbutamol use for 2 
consecutive nights.

An increase from baseline of ≥ 4 puffs /day of albuterol/salbutamol use on 2 
consecutive days.

A ≥30% decrease in AM PEF from baseline on 2 consecutive mornings.

A ≥30% decrease in PM PEF from baseline on 2 consecutive evenings

A ≥30% decrease in AM FEV1 from baseline on 2 consecutive mornings.

A ≥30% decrease in PM FEV1 from baseline on 2 consecutive evenings.
9.1.3.
Pulmonary Function Test
The 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 
on each occasion that spirometry assessments are performed, in accordance with the 
American Thoracic Society / European Respiratory Society (ATS/ERS) standards 
[Miller, 2005]. The highest of 3 technically acceptable measurements will be recorded at 
each visit:

Pre-dose Spirometry: At Visits 1 through 5/EOS (and the Early Withdrawal 
Visit, if applicable), participants 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 2
(the baseline assessment).
o
At least 24 hours after the participant’s last morning dose of study 
treatment on the day prior to the visit.
o
Before the participant’s morning dose of study treatment on the day of the 
visit.

Post-dose Spirometry: At Visits 2 and 5/EOS (and the Early Withdrawal Visit, if 
applicable), spirometry assessments must be performed 3 hours after the 
participant’s morning dose of study treatment; the assessment performed at Visit 
5/EOS should be performed at the same time of day (1 hour) as the assessment 
performed at Visit 2 (the baseline assessment). At each visit, participants 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.
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
50
9.1.3.1.
Reversibility (Albuterol/Salbutamol)
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.
To perform the reversibility assessment, 4 puffs of the provided albuterol/salbutamol 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 albuterol/salbutamol.
Percent reversibility will be calculated as follows:
(Post-bronchodilator FEV1 – Pre-bronchodilator FEV1)
x 100
Pre-bronchodilator FEV1
The reversibility requirement for eligibility must be assessed at Visit 1. Participants 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 participant may not enter the 2-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:
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 participant 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 participant may enter the 2-week run-in period.
9.1.4.
Asthma Exacerbations
Moderate and severe asthma exacerbation data will be collected from the start of 
randomized double blinded treatment until Visit 5/EOS Visit or the Early Withdrawal 
Visit for those participants that withdraw from participation in the study (see Section
8.2). For consistency, exacerbations separated by less than 7 days will be treated as a 
continuation of the same exacerbation.
Participants will 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.
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
51
All severe asthma exacerbations will be recorded in the eCRF by the Investigator (or 
designee).
9.1.4.1.
Moderate Asthma Exacerbation
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 for 3 days or more and/or hospitalization. 

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.
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 
(Refer to Section 7.8.1 above)
The Medical Monitor may be contacted for additional guidance, see the
medical monitor/Sponsor Information Page.
9.1.4.2.
Severe Asthma Exacerbation
A severe asthma exacerbation is defined as: 
The deterioration of asthma requiring the use of systemic corticosteroids (tablets,
suspension or injection) for at least 3 days.
OR
An inpatient hospitalization or emergency department visit because of asthma, requiring
systemic corticosteroids.
9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4.
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study, 
or that caused the participant to discontinue the study treatment or withdraw from the 
study (see Section 8).
9.2.1.
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 participant consents to participate in the 
study up to and including any follow-up contact. 
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
52

AEs will be collected from the start of Study Treatment until the follow-up 
contact (see Section 9.2.3) at the timepoints specified in the Schedule of Activities 
(SoA) table (Section 2).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the eCRF.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in
Appendix 4. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.

Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the Investigator learns of any SAE, including a death, at 
any time after a participant has been discharged from the study, and he/she 
considers the event 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
9.2.2.
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 participant 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?” 
Participants will be issued with a paper Medical Problems/Medications Taken worksheet
to record any medical problems experienced and medications used during the study. This 
paper worksheet will be used to assist participant recall in discussions with the 
Investigator (or designee), for site staff to then enter as appropriate in the eCRF.
9.2.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts.  All SAEs, and non-serious AEs of special 
interest (as defined in Section 9.2.5), will be followed until the event is resolved, 
stabilized, otherwise explained, or the participant is lost to follow-up (as defined in 
Section 8.3). Further information on follow-up procedures is given in Appendix 4
9.2.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
53
participants and the safety of a study treatment under clinical investigation are 
met. 

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study treatment 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or 
other specific safety information eg, summary or listing of SAE) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.
9.2.5.
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). 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 
Glaucoma (antimuscarinic/corticosteroid)
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
54
Special interest AE group
Special interest AE subgroup
effects / Corticosteroids 
associated eye disorders
Cataracts (corticosteroid)
Pneumonia and LRTI
Pneumonia 
LRTI excluding pneumonia
Adrenal suppression
-
Decreased bone mineral 
density and associated 
fractures
-
Effects on glucose
-
Hypersensitivity
-
Local steroid effects
-
9.2.6.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 4 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the eCRF will 
be required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 
The CV eCRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the eCRF within one week of receipt of a CV Event data query prompting its completion. 
The Death eCRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
9.2.7.
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 participant 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.)
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
55

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).
9.2.8.
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.
9.2.9.
Pregnancy
Details of all pregnancies in female participants 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.
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
9.3.
Treatment of 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 eCRF 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 
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.
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
56
9.4.
Safety Assessments
Planned time points for all safety assessments are provided in the Schedule of Activities 
(SoA).
9.4.1.
Physical Examinations
Physical exams will be performed at the time points specified in the Schedule of 
Activities (SoA) table (Section 2).

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.

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
9.4.2.
Vital Signs
Vital signs will be performed at the time points specified in the Schedule of Activities 
(SoA) table (Section 2) prior to conducting spirometry and prior to taking the morning 
dose of study treatment and FF 100 mcg. 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.
9.4.3.
Electrocardiograms
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 Schedule of 
Activities (SoA) table (Section 2). All ECG measurements will be made with the 
participant in a supine position having rested in this position for approximately 5 minutes 
before each reading.
For participants who meet the QTc, protocol defined stopping criteria, triplicate ECGs 
(over a brief period of time) should be performed (Section 8.1.2).
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 
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
57
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.
9.4.4.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory tests to be performed and 
to the Schedule of Activities (SoA) for the timing and frequency. 

The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 5 days after the last dose of study 
treatment should be repeated until the values return to normal or baseline or are 
no longer considered significantly abnormal by the investigator or medical 
monitor. 

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the Schedule of 
Activities (SoA).
9.5.
Pharmacokinetics
Pharmacokinetics is not relevant for this protocol.
9.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
9.7.
Genetics
Information regarding genetic/ pharmacogenetic (PGx) research is included in Appendix 
6. 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 6).
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 
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
58
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.
9.8.
Biomarkers
Biomarkers are not evaluated in this study.
9.9.
Health Economics OR Medical Resource Utilization and 
Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study.
10.
STATISTICAL CONSIDERATIONS
10.1.
Hypotheses
The primary objective of this study is to evaluate the efficacy of UMEC 62.5 mcg and 
UMEC 31.25 mcg compared with placebo in participants with not well controlled asthma 
over a 24 week treatment period.  This is a superiority study to demonstrate the benefit of 
UMEC at two dosage strengths 62.5 mcg and 31.25 mcg when compared to Placebo in 
patients on background therapy of FF 100 mcg. The primary efficacy endpoint is the 
mean change from baseline in trough FEV1 at Week 24.
The test for the primary efficacy endpoint is such that 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:  

UMEC 62.5mcg vs Placebo

UMEC 31.25mcg vs Placebo
For each comparison test on the primary endpoint, the null hypothesis is there is no 
difference between treatment groups.  The alternative hypothesis is there is a difference 
between treatment groups.
Therefore T1 and T2 for these endpoints are the mean changes from baseline for the 
UMEC therapy and placebo, respectively, as listed above. 
Details on all pairwise treatment comparisons of interest are provided in Section 10.5.2.
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
59
10.2.
Sample Size Determination
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 384 randomized participants are required for this study, with 128 participants 
in each of the three double-blind treatment groups: UMEC 62.5mcg, UMEC 31.25mcg or 
Placebo. Assuming 10% missing data on spirometry at the end of the 24-week treatment 
period, due to early withdrawal from study, approximately 115 participants per treatment 
group will have trough FEV1 available for the primary 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 350mL based on two previous Tiotropium moderate asthma 
studies.  The study design and population of this study aligns well with these two phase 
III, 24 week, randomised, double blind, placebo-controlled, parallel-group, active 
comparator studies of Tiotropium.  In patients with moderate asthma on a background 
therapy of ICS the standard deviations in change from baseline trough FEV1 at Week 24 
ranged from 325 to 354mL; from this a SD estimate of 350 mL was chosen. This was 
estimated from a wide selection of studies, critically to minimise the risk of reduced 
power for the primary endpoint. The range of observed treatment differences across the 
Tiotropium treatment groups is 133 – 185mL, which supports the expectation that the 
treatment effect seen in a moderate asthma population is larger than in the more severe 
asthma population in study 205715 treated on a background of FF/VI. This is in line with 
data from GSK study 200699 which showed UMEC 62.5 mcg to be an effective dose. An 
average increase in change from baseline trough FEV1 at Day 29 of 136 mL was 
observed in an asthma subset of patients treated with FF/UMEC (100/62.5) compared 
with FF (100 mcg) alone. The GSK phase III closed triple asthma study 205715, which 
this study supports, is in a more severe asthma population and conservatively assumes a 
SD estimate of 400mL.
Based on a true population difference of 130 mL, a sample size of 115 patients per 
treatment group has an estimated 80% power to observe statistical significance at the two 
sided 5% level, for each of the two primary comparisons of interest for each UMEC dose. 
Using the above assumptions the smallest observed effect predicted to result in a 
statistically significant difference between treatment groups is 90.5 mL (minimum 
detectable difference).
No interim analysis is planned for this study.
10.3.
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=115 per arm in the 
intent to treat (ITT) population for the primary efficacy analysis, varying the true
treatment difference and estimated standard deviation on the change from baseline in 
trough FEV1 at the end of the 24-week treatment period.
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
60
Treatment difference (mL)
Standard Deviation
100
115
130
145
160
300
0.71
0.82
0.91
0.95
0.98
350
0.58
0.70
0.80
0.88
0.93
400
0.47
0.58
0.69
0.78
0.86
10.4.
Sample site re-estimation or adjustment
No sample size re-estimation is planned.
10.5.
Data Analysis
10.5.1.
Analysis population
The following participant populations will be identified:
All Participants Enrolled Population: This population will comprise all participants for 
whom a record exists on the study database, including pre-screened participants that sign 
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
61
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 Participants Screened Population: This population contains all participants that 
complete at least one Visit 1 (Screening) procedure. This population will be used for the 
summary of participant disposition (including reasons for screening failures and run-in 
failures) and for the listing of AEs and SAEs for non-randomized participants. 
ITT Population: This population will comprise all randomized participants, excluding 
those who were randomized in error. A participant who is recorded as a screen failure or 
run-in 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. This will constitute 
the primary population for all efficacy and safety analyses. 
10.5.2.
Treatment Comparisons
To demonstrate the benefit of UMEC the primary comparisons of interest for the primary 
efficacy endpoint are:

UMEC 62.5 mcg vs Placebo

UMEC 31.25 mcg vs Placebo
Other pairwise treatment comparisons of interest that aim to informally estimate any 
potential benefit of increasing the UMEC dose are given below for all efficacy endpoints. 

UMEC 62.5 mcg vs UMEC 31.25 mcg
For the multiple comparisons and multiplicity adjustment, please see Section 10.5.3. 
10.5.3.
Multiple Comparisons and Multiplicity
In order to account for multiple tests involving the two UMEC doses 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 test in the 
hierarchy. 
A step-down procedure with the following hierarchy will be used for the primary 
comparisons in the primary endpoint.  

The contrast between UMEC 62.5 mcg vs Placebo 
(two-sided, alpha = 0.05.  Null hypothesis of no treatment difference)

The contrast between UMEC 31.25 mcg vs Placebo 
(two-sided, alpha = 0.05.  Null hypothesis of no treatment difference)
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
62
The second hypothesis will be formally tested only if the first hypothesis has been 
rejected, thus maintaining the overall significance level at 5%.  
Specifically, if the defined treatment comparison for the primary efficacy endpoint at the 
highest dose of UMEC 62.5 mcg is significant at 0.05 level then the efficacy of UMEC 
62.5 mcg is demonstrated, and the treatment comparison can be repeated on the UMEC 
31.25 mcg dose. 
Note that, in the event that the first hypothesis is not rejected a nominal p-value for the 
second hypothesis may be provided in the displays for descriptive purposes only and will 
not alter the conclusion of the step-down procedure.
No multiplicity adjustment will be made on these two treatment comparisons on the 
secondary endpoint.
For all efficacy endpoints (primary, secondary and other), treatment comparisons 
between UMEC 62.5 vs UMEC 31.25 mcg informally investigating the benefit of 
increasing UMEC dose will be made without adjusting for multiplicity.  Any p-values ≤ 
0.05 will be identified as nominally significant.
10.6.
Statistical Analysis
Where possible, data from participants 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 RAP. 
In general, the baseline value is the last assessment value prior to randomization at Visit 2
for the efficacy endpoints based on assessments at clinic visits.  The covariates to be 
considered in the efficacy analyses include age, sex, and the baseline value, if relevant. 
Other covariates, if appropriate, may be considered. Specific details will be provided in 
the RAP.
10.6.1.
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 participant, the baseline value of clinic 
FEV1 is the last acceptable/borderline acceptable (pre-dose) FEV1 value obtained prior to 
randomization (either from Visit 2 pre-dose or from Visit 1 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, 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. 

UMEC 62.5 mcg vs Placebo

UMEC 31.25 mcg vs Placebo
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
63
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 10.5.2 will also 
be provided for the primary efficacy endpoint.
10.6.2.
Secondary Analyses
Full details of the analyses to be performed on the secondary efficacy endpoint will be 
given in the RAP.
10.6.3.
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.
10.6.4.
Interim Analyses
No interim analysis is planned for this study.
10.6.5.
Exploratory Analyses
The psychometric properties of the E-RS and Supplemental asthma items will be 
evaluated to characterize the E-RS as an endpoint for asthma.  These exploratory analyses 
may be provided in a separate RAP.
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
64
11.
REFERENCES
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/
GlaxoSmithKline Document Number: 2011N123107_03 GW685698+GSK573719 
Investigator’s Brochure, dated 19 Jun 2014 and 2016 Supplement
Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure of health 
status for chronic airflow limitation. The St. George's Respiratory Questionnaire. Am Rev 
Respir Dis 1992;145:1321-1327.
Jones PW. St. George’s Respiratory Questionnaire: MCID. Journal of Chronic 
Obstructive Pulmonary Disease 2005;2:75-79.
Juniper EF, Bousquet J, Abetz L, Bateman ED; GOAL Committee. Identifying 'well-
controlled' and 'not well-controlled' asthma using the Asthma Control Questionnaire. 
Respir Med 2006;100:616-621.
Juniper EF, Guyatt GH, Willan A, Griffith LE. Determining a minimal important change
in a disease-specific quality of life instrument. J Clin Epidemiol 1994;47:81-87.
Juniper EF, O'Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of 
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-
558.
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.
Miller MR et al. Standardization of Lung Function Testing. Eur Resp J 2005;26:153-161.
Quanjer P, Stanojevic S, Cole T, Baur X., Hall G, Enright P, et al. on behalf of 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. Eur Respir J 2012;40:1324-
1343.
Reddel HK, Taylor DR, Bateman ED, Boulet L-P, Boushey HA, Busse WW, et al. On
behalf of the American Thoracic Society/European Respiratory Society task force on 
asthma control and exacerbations. An official American Thoracic Society/European 
Respiratory Society statement: asthma control and exacerbations; standardizing endpoints 
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
65
for clinical asthma trials and clinical practice. Am J Respir Crit Care Med 2009;180:59-
99. 
US Department of Health and Human Sciences; Food and Drug Administration (FDA).
Guidance for Industry; Drug-Induced Liver Injury: Premarketing Clinical Evaluation 
(July 2009). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf (Accessed 16 July 2014).
Virchow JC, Backer V, de Blay F, Kuna P, Ljorring C, Prieto JL, et al. Defining 
moderate asthma exacerbations in clinical trials based on ATS/ERS joint statement. 
Respiratory Medicine 2015;109:547-556
Wyrwich KW, Khan SA, Navaratnam P, Nolte H, Gates Jr DF. Validation and agreement 
across four versions of the asthma control questionnaire in patients with persistent 
asthma. Resp Med 2011;105:698-712.
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
66
12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
ACQ
Asthma Control Questionnaire
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
BMI
Body Mass Index
BPM
Beats Per Minute
BST
Bioanalytical Science and Toxicokinetics
BUN
Blood Urea Nitrogen
CI
Confidence Interval
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic Obstructive Pulmonary Disease
DNA
Deoxyribonucleic acid
DPI
Dry Powder Inhaler
ECG
Electrocardiogram
(e)CRF
(Electronic) Case Report Form
eDiary
Electronic Diary
EOS
End of study
E-RS
Evaluating Respiratory Symptoms
ERS
European Respiratory Society
EW
Early Withdrawal
FDA
Food and Drug Administration
FEV1
Forced expiratory volume in 1 second
FF
Fluticasone Furoate
FP
Fluticasone Propionate
FSH
Follicle Stimulating Hormone
FVC
Forced Vital Capacity
GCP
Good clinical practice
GCSP
Global Clinical Safety and Pharmacovigilance
GINA
Global Initiative for Asthma
GSK
GlaxoSmithKline
hCG
Human Chorionic Gonadotropin
HIV
Human Immunodeficiency Virus
HPA
Hypothalamic Pituitary Axis
HRT
Hormone Replacement Therapy
IB
Investigator’s Brochure
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
67
ICF
Informed Consent Form
ICH
International Conference on Harmonization
ICS
Inhaled Corticosteroids
IEC
Independent Ethics Committee
IOP
Intraocular Pressure
IP
Investigational Product
IRB
Institutional Review Board
IRT
Interactive Response Technology
IWRS
Interactive Web Response System
ITT
Intent to Treat
LABA
Long-Acting Beta-2-Agonists
LAMA
Long-Acting Muscarinic Antagonist
LOCS III
Lens Opacities Classification System III
LRTI
Lower Respiratory Tract Infection
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
PEF
Peak Expiratory Flow
PK
Pharmacokinetic
PM
Evening
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
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
68
US
United States
VI
Vilanterol
VT
Ventricular Tachycardia
WBC
White Blood Cell
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
ELLIPTA
None
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
69
12.2.
Appendix 2: Clinical Laboratory Tests

All protocol required laboratory assessments (haematology, clinical chemistry 
and urinalysis) must be conducted in accordance with the Laboratory Manual, 
and Protocol Schedule of Activities (Section 2) Laboratory requisition forms 
must be completed and samples must be clearly labelled with the participant
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 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 participant 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.

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 6 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
70
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
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood and ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

Follicle stimulating hormone (FSH) and estradiol (as needed in females 
of non-reproductive potential only)

Serum/urine hCG Pregnancy test (as specified in the Schedule of 
Activities table [Section 2])
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 8.1.1 and 
Appendix 7
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
71
12.3.
Appendix 3: Study Governance Considerations
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (eg, advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study. 
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
72

Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative. 

Participants who are rescreened are required to sign a new ICF.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
73
Dissemination of Clinical Study Data

For this study participant 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.  
Data Quality Assurance

Management of clinical data will be performed in accordance with applicable 
GSK standards and data cleaning procedures to ensure the integrity of the data, 
e.g., removing errors and inconsistencies in the data.

Adverse events and concomitant 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.  Participant 
initials will not be collected or transmitted to GSK according to GSK policy.

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (eg, laboratory 
data). The investigator is responsible for verifying that data entries are accurate 
and correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years after study completion 
unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written 
approval of the sponsor. No records may be transferred to another location or 
party without written notification to the sponsor. 
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
74
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available.
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study treatment development
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
75
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study treatment, whether or not considered related to the 
study treatment.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfill the definition of an AE 
or SAE. 

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. Also, "lack of 
efficacy" or "failure of expected pharmacological action" constitutes an AE or SAE.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
76
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
77
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
78
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
each occurrence of each AE/SAE.

A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology.
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
79

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to t GSK within 24 hours of 
receipt of the information.
Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper SAE data collection tool (see next section).

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form or to the 
assigned SAE contact by telephone.

Contacts for SAE reporting can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
SAE Reporting to GSK via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the assigned SAE contact by telephone.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
80
12.5.
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
3. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment.
Contraception Guidance
Female participants
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in 
Table 4.
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
81
Table 4
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing ) hormonal contraception associated with 
inhibition of ovulation 

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulationb

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.)
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the participant.)
NOTES: 
a.
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants in clinical studies.
Pregnancy Testing

WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive urine or serum pregnancy test 

Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected 

Pregnancy testing, with a sensitivity of [5, 10, 25] mIU/mL will be performed [and 
assayed in a certified laboratory OR and assayed in the central laboratory OR using 
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
82
the test kit provided by the central laboratory / provided by the sponsor /approved by 
the sponsor and in accordance with instructions provided in its package insert]  
Collection of Pregnancy Information
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date.  

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. 

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK
as described in Appendix 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 participant who becomes pregnant while participating in the study will 
immediately discontinue study medication.
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
83
12.6.
Appendix 6: Genetics
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 participant who is enrolled in the study can participate in genetic research.  Any 
participant 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 
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
84
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 participant 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 participant 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 
participant 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.
Participants can request their sample to be destroyed at any time.
Informed Consent
Participants 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.
Participant Withdrawal from Study
If a participant who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the participant 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 participant 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. 
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
85
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 participant 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 
participant does not meet the entry criteria for participation in the study, then the 
Investigator should instruct the participant 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 Participant’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 
participant, family members, insurers, or employers of individual genotyping results that 
are not known to be relevant to the participant’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.
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
86
12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments
Phase II liver chemistry stopping and follow up criteria have been designed to assure 
participant safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance [Food and Drug Administration, 2009]).
Phase II liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin)
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue  study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF and complete an
SAE data collection tool if the event also meets 
the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the participant until liver chemistries
resolve, stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge participant with 
study treatment unless allowed per protocol and 
GSK Medical Governance approval is granted 
(refer to Section 8.1.3)
If restart/rechallenge not allowed per protocol or 
not granted, permanently discontinue study 
treatment and may continue participant in the study 
for any protocol specified follow up assessments 

Viral hepatitis serology4

Blood sample for pharmacokinetic (PK) 
analysis, obtained 72 hours after last 
dose5

Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications 
on the concomitant medications report 
form including acetaminophen, herbal 
remedies, other over the counter 
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
87
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 hrs

Monitor participants twice weekly until liver 
chemistries resolve, stabilize or return to within 
baseline 

A specialist or hepatology consultation is 
recommended
For All other criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24-72 
hrs 

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to within 
baseline
medications.

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG or gamma globulins).

Serum acetaminophen adduct HPLC 
assay (quantifies potential 
acetaminophen contribution to liver 
injury in participants with definite or 
likely acetaminophen use in the 
preceding week (James 2009) Not 
Required in China

Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF 
forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that participant if ALT 3xULN and bilirubin 2xULN.. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to participants receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
5.
PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
treatments.)  Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
treatment prior to blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the 
participant’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.  
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
88
Phase II liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 3xULN and <5xULN and bilirubin 
<2xULN, without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks

Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss participant
safety. 

Participant can continue study treatment   

Participant must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time participant meets the liver chemistry 
stopping criteria, proceed as described above

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor participants twice monthly 
until liver chemistries normalize or return to within 
baseline.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
89
12.8.
Appendix 8: Daily Diary Questions
12.8.1.
Morning Questions
The participant 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
12.8.2.
Evening Questions
The participant 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 
Quite a bit 
Extremely 
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
90
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 
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
91
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
 
2018N371775_00

2016N289466_00
CONFIDENTIAL
205832
92
12.9.
Appendix 9: Country-specific requirements
There are currently no country specific requirements. 
 
2018N371775_00