Conditions: Asthma
Keywords: Asthma Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) Fluticasone Furoate/Vilanterol (FF/VI) ELLIPTA Chinese
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 359
Healthy volunteers: no

Brief summary:
The study aims to evaluate the efficacy, safety and tolerability of FF/UMEC/VI compared with FF/VI via ELLIPTA® inhaler in Chinese participants with inadequately controlled asthma. ELLIPTA is a registered trademark of GlaxoSmithKline group of companies.

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: None arm 4: None

Interventions: intervention 1: FF/VI intervention 2: FF/UMEC/VI intervention 3: ELLIPTA
Intervention descriptions: intervention 1: FF/VI will be administered. intervention 2: FF/UMEC/VI will be administered. intervention 3: FF/UMEC/VI and FF/VI will be administered via ELLIPTA inhaler.

Protocol document:
Prot_000.pdf: 
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TITLE PAGE 
Protocol Title: A Phase III, 12 week, randomized, double-blind, 4 arm parallel group 
bridging study, comparing the efficacy, safety and tolerability of the fixed dose 
combination FF/UMEC/VI once-daily via a dry powder inhaler with dual combination of 
FF/VI, administered in Chinese participants with inadequately controlled asthma. 
Protocol Number: 214263 Amendment 02 
Compound Number 
or Name: 
GSK2834425  
 
Brief Title: Efficacy and safety of FF/UMEC/VI in Chinese participants with 
inadequately controlled asthma 
 
Study Phase: Phase 3 
Sponsor Name and Legal Registered Address:  
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
Regulatory Agency Identifying Number(s): NA 
Medical Monitor Name and Contact Information [can be found in the Study 
Reference Manual] 
Sponsor Signatory: 
David Slade 
Senior Clinical Development Director 
Approval Date: 18 Jul 2022 
 
Copyright 2022 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited. 
 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
DNG Number 
Amendment 2 
18 Jul 2022. 
TMF-14804664 
Amendment 1 
28-Apr-2021. 
TMF-12874573 
Original Protocol 
17-Dec-2020. 
2020N447598_00 
 
Amendment 2. 18 Jul 2022 
The amendment is substantial. 
Overall Rationale for the Amendment 2: 
The amendment is mainly made to diminish the data missing risk due to COVID-19 
lockdown, and to facilitate the enrolment. Besides, some additional amendments are also 
made to provide more clear information. 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1  
Synopsis 
In the part of Number of 
Participants, the estimated 
screening number is updated 
from 550 to 890. 
When the study is conducting, the 
observed screening failure rate is 
higher than the original estimation. 
Current screening failure rate is 
around 55-60%, the screening 
number is updated accordingly. 
Section 1.3  
Schedule of Activities 
(SoA) 
Footnote 20 is newly added 
to add the possibility of 
home ACQ if the Visit 3 or 4 
or Early Withdraw (EW) is 
impacted by COVID-19 
lockdown. 
 
Footnote 21 is newly added: 
to allow Visit 4 time window 
be prolonged if it’s impacted 
by COVID-19 lockdown. 
As strict COVID-19 lockdown, 
some participants couldn’t finish 
on-site visits within current time 
window. To help collect more data, 
the possibility of home ACQ is 
added into footnote 20. And as 
observed in Global pivotal study 
that the efficacy of FF/UMEC/VI 
was stabilized from week 12 to 
week 24, the time window of Visit 
4 is prolonged (on treatment) to 
ensure efficacy data will be 
collected at Visit 4. 
Section 5.1 
Inclusion Criteria 
The requirement of daily 
ICS/LABA for at least 12 
weeks prior to Visit 0 is 
changed to 8 weeks in the 
part of Current Asthma 
Maintenance Therapy 
Based on GINA, if a patient has 
persisting uncontrolled symptoms 
despite 2-3 months of controller 
treatment, could consider any step 
up in treatment. To facilitate the 
enrolment, the duration of daily 
ICS/LABA before screening is 
shorten to 8 weeks from 12 weeks.  


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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.  
STUDY 
ASSESSMENTS AND 
PROCEDURES  
It is newly added that 
allowing Visit 4’s time 
window is prolonged if it’s 
impacted by COVID-19 
lockdown. 
As strict COVID-19 lockdown, 
some participants couldn’t finish 
on-site visits within current time 
window. As observed in Global 
pivotal study that the efficacy of 
FF/UMEC/VI was stabilized from 
week 12 to week 24, the time 
window of Visit 4 is prolonged (on 
treatment) to ensure efficacy data 
will be collected at Visit 4. 
Section 8.2.1.  
Pulmonary Function Test 
Under the pre-dose 
spirometry part, the Visit 1 is 
corrected to Visit 2. 
The visit number was mistakenly 
written. To avoid incorrect testing 
time of the pre-dose spirometry, 
it’s corrected. 
Section 8.2.2. 
Asthma control 
Questionnaire 
This section is newly added 
the possibility of home ACQ 
if the Visit 3 or 4 or EW is 
impacted by COVID-19 
lockdown. 
As strict COVID-19 lockdown, 
some participants couldn’t finish 
on-site visits within current time 
window. To help collect more data, 
the possibility of home ACQ is 
added. 
Section 8.3.4.  
Clinical Safety 
Laboratory Assessments 
The requirement of 
collecting pre-dose blood 
samples is removed. 
Meantime, it’s emphasized 
that collecting blood sample 
before the participant’s dose 
of asthma treatment on the 
day of the visit. 
When this trial is being conducted, 
some sites could only collect blood 
sample after the reversibility test, 
and Albuterol/Salbutamol will be 
used in this test. Considering that 
albuterol/salbutamol is inhaled, it 
will not have some significant 
influence on the haematology 
assessments and clinical chemistry 
tests, the blood samples collected 
after the reversibility test is 
considered acceptable. To avoid 
unnecessary confusion about it, the 
pre-dose is removed. But it’s 
emphasized that collecting blood 
sample before the participant’s 
dose of asthma treatment on the 
day of the visit. 
Section 8.4.5  
Pregnancy  
Withdraw from the study if 
pregnancy is removed. 
Efficacy data should be collected 
regardless treatment 
discontinuation status, and it’s 
mentioned in Section 7.1 that the 
participants who withdraw from 
double-blind study treatment 
prematurely (for any reason) 
should, where possible, continue to 
be followed-up as per protocol 


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Section # and Name 
Description of Change 
Brief Rationale 
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. So 
this part is corrected accordingly. 
Section 9.2  
Sample Size 
Determination 
The estimated screening 
number is updated from 550 
to 890. 
When the study is conducting, the 
observed screening failure rate is 
higher than the original estimation. 
Current screening failure rate is 
around 55-60%, the screening 
number is updated accordingly. 
Section 10.3.5  
Reporting of SAE to 
GSK 
The requirement of SAE 
reporting in Electronic case 
report form (eCRF) within 
72 hours is removed. 
Removal of additional step of 
eCRF check per GSK new 
protocol template. 
Section 10.3.5  
Reporting of SAE to 
GSK 
The contact for SAE 
reporting is added. 
The contact was not listed before. 
 
 


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TABLE OF CONTENTS 
PAGE 
1. 
PROTOCOL SUMMARY .......................................................................................... 9 
1.1. 
Synopsis ....................................................................................................... 9 
1.2. 
Schema ...................................................................................................... 15 
1.3. 
Schedule of Activities (SoA) ........................................................................ 16 
2. 
INTRODUCTION .................................................................................................... 21 
2.1. 
Study Rationale .......................................................................................... 21 
2.2. 
Background ................................................................................................ 22 
2.3. 
Benefit/Risk Assessment ............................................................................ 23 
2.3.1. 
Risk Assessment ......................................................................... 25 
2.3.2. 
Benefit Assessment ..................................................................... 32 
2.3.3. 
Overall Benefit: Risk Conclusion .................................................. 32 
3. 
OBJECTIVES AND ENDPOINTS ........................................................................... 33 
4. 
STUDY DESIGN .................................................................................................... 35 
4.1. 
Overall Design ............................................................................................ 35 
4.2. 
Scientific Rationale for Study Design .......................................................... 37 
4.3. 
Justification for Dose .................................................................................. 37 
4.4. 
End of Study Definition ............................................................................... 39 
5. 
STUDY POPULATION ........................................................................................... 39 
5.1. 
Inclusion Criteria ......................................................................................... 39 
5.2. 
Exclusion Criteria ........................................................................................ 41 
5.3. 
Lifestyle Considerations .............................................................................. 43 
5.4. 
Pre-Screening/Screening/Run-in Failures ................................................... 43 
5.5. 
Criteria for Randomisation .......................................................................... 44 
5.5.1. 
Inclusion Criteria for Randomization ............................................ 44 
5.5.2. 
Exclusion Criteria for Randomization ........................................... 45 
5.6. 
Criteria for Temporarily Delaying ................................................................ 46 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY .............................. 46 
6.1. 
Study Intervention(s) Administered ............................................................. 46 
6.1.1. 
Study Treatment and albuterol/salbutamol Return ....................... 49 
6.2. 
Preparation/Handling/Storage/Accountability .............................................. 49 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................... 50 
6.3.1. 
Treatment assignment ................................................................. 50 
6.3.2. 
Blinding ........................................................................................ 51 
6.4. 
Study Intervention Compliance ................................................................... 51 
6.5. 
Dose Modification ....................................................................................... 52 
6.6. 
Continued Access to Study Intervention after the End of the Study ............ 52 
6.7. 
Treatment of Overdose ............................................................................... 52 
6.8. 
Concomitant Therapy.................................................................................. 52 
6.8.1. 
Rescue Medicine ......................................................................... 53 
6.8.2. 
Permitted Medications and Non-Drug Therapies .......................... 53 
6.8.2.1. 
Permitted Asthma Medications ................................... 53 
6.8.2.2. 
Permitted Non-Asthma Medications ........................... 54 
6.8.2.3. 
Permitted Non-Drug Therapies ................................... 55 
6.8.3. 
Prohibited Medications and Non-Drug Therapies ......................... 55 


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7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 57 
7.1. 
Discontinuation of Study Intervention .......................................................... 57 
7.1.1. 
Liver Chemistry Stopping Criteria ................................................ 57 
7.1.2. 
QTc Stopping Criteria .................................................................. 57 
7.1.3. 
Temporary Discontinuation .......................................................... 58 
7.1.4. 
Rechallenge ................................................................................. 58 
7.2. 
Participant Discontinuation/Withdrawal from the Study ............................... 58 
7.3. 
Lost to Follow Up ........................................................................................ 59 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 60 
8.1. 
Screening and Critical Baseline Assessments ............................................ 60 
8.1.1. 
Pre-screening .............................................................................. 60 
8.1.2. 
Screening .................................................................................... 61 
8.1.3. 
Critical procedures performed at randomization Visit 
(Baseline Visit 2) .......................................................................... 61 
8.2. 
Efficacy Assessments ................................................................................. 61 
8.2.1. 
Pulmonary Function Test ............................................................. 61 
8.2.1.1. 
Reversibility ................................................................ 62 
8.2.2. 
Asthma Control Questionnaire (ACQ) .......................................... 63 
8.2.3. 
Daily Diaries ................................................................................ 64 
8.2.3.1. 
Daily Diary Questionnaires, Assessments .................. 64 
8.2.4. 
Alerts ........................................................................................... 65 
8.3. 
Safety Assessments ................................................................................... 65 
8.3.1. 
Physical Examinations ................................................................. 65 
8.3.2. 
Vital Signs .................................................................................... 65 
8.3.3. 
Electrocardiograms ...................................................................... 65 
8.3.4. 
Clinical Safety Laboratory Assessments ...................................... 66 
8.3.5. 
Pregnancy Testing ....................................................................... 68 
8.4. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other 
Safety Reporting ......................................................................................... 68 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE 
Information ................................................................................... 68 
8.4.2. 
Method of Detecting AEs and SAEs ............................................. 69 
8.4.3. 
Follow-up of AEs and SAEs ......................................................... 69 
8.4.4. 
Regulatory Reporting Requirements for SAEs ............................. 69 
8.4.5. 
Pregnancy ................................................................................... 70 
8.4.6. 
Cardiovascular and Death Events ................................................ 70 
8.4.7. 
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as SAEs............................................... 71 
8.4.8. 
Adverse Events of Special Interest .............................................. 72 
8.4.9. 
Medical Device ............................................................................ 73 
8.4.10. 
Pneumonia .................................................................................. 74 
8.4.11. 
Radiography (Chest X-Rays) ....................................................... 75 
8.5. 
Pharmacokinetics ....................................................................................... 75 
8.6. 
Genetics and/or Pharmacogenomics .......................................................... 75 
8.7. 
Biomarkers ................................................................................................. 75 
8.8. 
Immunogenicity Assessments ..................................................................... 75 
8.9. 
Health Economics ....................................................................................... 75 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 76 
9.1. 
Statistical Hypotheses................................................................................. 76 


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9.2. 
Sample Size Determination ........................................................................ 76 
9.3. 
Analysis Sets .............................................................................................. 79 
9.4. 
Statistical Analyses ..................................................................................... 79 
9.4.1. 
General Considerations ............................................................... 80 
9.4.2. 
Efficacy Analyses ......................................................................... 80 
9.4.2.1. 
Primary Endpoint ........................................................ 84 
9.4.2.2. 
Secondary Endpoint ................................................... 84 
9.4.3. 
Safety Analysis ............................................................................ 85 
9.4.4. 
Other Analysis ............................................................................. 85 
9.5. 
Interim Analysis .......................................................................................... 85 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 86 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ............................................................................................ 86 
10.1.1. 
Regulatory and Ethical Considerations ........................................ 86 
10.1.2. 
Financial Disclosure ..................................................................... 87 
10.1.3. 
Informed Consent Process .......................................................... 87 
10.1.4. 
Data Protection ............................................................................ 88 
10.1.5. 
Committees Structure .................................................................. 88 
10.1.6. 
Dissemination of Clinical Study Data ........................................... 88 
10.1.7. 
Data Quality Assurance ............................................................... 89 
10.1.8. 
Source Documents ...................................................................... 90 
10.1.9. 
Study and Site Start and Closure ................................................. 90 
10.1.10. Publication Policy ......................................................................... 91 
10.2. 
Appendix 2: Clinical Laboratory Tests ......................................................... 92 
10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ....................................... 93 
10.3.1. 
Definition of AE ............................................................................ 93 
10.3.2. 
Definition of SAE .......................................................................... 94 
10.3.3. 
Definition of Cardiovascular Events ............................................. 95 
10.3.4. 
Recording and Follow-Up of AE and SAE .................................... 96 
10.3.5. 
Reporting of SAE to GSK ............................................................. 98 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ....................................... 99 
10.4.1. 
Definitions: ................................................................................... 99 
10.4.2. 
Contraception Guidance: ........................................................... 100 
10.5. 
Appendix 5: Liver Safety: Required Actions and Follow-up 
Assessments ............................................................................................ 102 
10.6. 
Appendix 6: AEs, ADEs, SAEs, SADEs, USADEs and Device 
Deficiencies: Definition and Procedures for Recording, Evaluating, 
Follow-up, and Reporting in Medical Device Studies ................................ 105 
10.6.1. 
Definition of Medical Device AE and ADE .................................. 105 
10.6.2. 
Definition of Medical Device SAE, SADE and USADE ............... 105 
10.6.3. 
Definition of Device Deficiency ................................................... 106 
10.6.4. 
Recording and Follow-Up of AE and/or SAE and Device 
Deficiencies ............................................................................... 106 
10.6.5. 
Reporting of SAEs ..................................................................... 109 
10.6.6. 
Reporting of SADEs ................................................................... 109 
10.7. 
Appendix 7: Statistical Appendix ............................................................... 111 
10.7.1. 
Choice of posterior probability .................................................... 111 
10.7.2. 
Choice of Sample size ............................................................... 111 


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10.7.3. 
A range of possible observed treatment differences in 
China ......................................................................................... 111 
10.7.4. 
Overview of the proposed robust mixture prior and 
analysis strategy ........................................................................ 112 
10.7.5. 
Choice of weights ...................................................................... 116 
10.8. 
Appendix 8: Abbreviations and Definitions and Trademarks ..................... 117 
10.9. 
Appendix 9: Protocol Amendment History ................................................. 120 
11. REFERENCES ..................................................................................................... 122 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
A Phase III, 12 week, randomized, double-blind, 4 arm parallel group bridging study, 
comparing the efficacy, safety and tolerability of the fixed dose combination 
FF/UMEC/VI once-daily via a dry powder inhaler with dual combination of FF/VI, 
administered in Chinese participants with inadequately controlled asthma.  
Brief Title: Efficacy and safety of FF/UMEC/VI in Chinese participants with 
inadequately controlled asthma 
Rationale: 
Asthma is a common chronic airway disease imposing a significant burden on families, 
healthcare systems and the workplace. It is characterized by airway inflammation, 
increased airway responsiveness, and bronchoconstriction [GINA, 2020]. The goal of 
asthma treatment is to achieve and maintain asthma control enabling patients to avoid 
symptoms and flare-ups and lead productive lives with near normal lung function [GINA, 
2020]. 
The prevalence of asthma in China has been increasing in recent years. According to 
latest data, the prevalence of asthma in China adults is 4.2%, representing about 45.7 
million adult patients [Huang, 2019]. Despite availability of treatments and published 
guidelines, patients may have asthma that is inadequately controlled, and the asthma 
control is sub-optimal: 29-35% of China patients were still uncontrolled despite of 
inhaled corticosteroid/long-acting beta2 agonist (ICS/LABA) therapy [HZA113719 China 
CSR GSK Document number 2013N169446_00 Table 15; HZA113714 China CSR GSK 
Document number 2013N161713_00 Table 16]. Situations are similar in other regions. In 
a survey conducted among 8,000 patients with asthma from 11 European countries, 45% 
of respondents had uncontrolled asthma, and 44% of respondents reported having used 
oral steroids for asthma in the previous 12 months [Price, 2014]. An analysis of asthma 
patients in Europe found that 37.6% of asthma patients treated with ICS/LABA therapy 
remained uncontrolled [Roche, 2020].  
International and Chinese asthma guidelines [GINA, 2020; CAPG, 2016] recommend a 
long-acting muscarinic antagonist (LAMA) as add-on treatment for adults whose asthma 
is uncontrolled with medium to high dose ICS/ LABA treatment.  
GSK has developed a once-daily single-inhaled triple therapy of an ICS/LAMA/LABA 
combination [fluticasone furoate/ umeclidinium /vilanterol (FF/UMEC/VI)] via a single 
ELLIPTA dry-powder inhaler device, with the aim of providing a new treatment option 
for the management of asthma by improving lung function, health-related quality of life 
(HRQoL) and symptom control over established combination therapies. The results of the 
global PhIIIa 205715 study established that FF/UMEC/VI provided additional benefit 
compared with FF/VI in patients 18 years old whose asthma was inadequately 
controlled despite treatment with ICS (>250 µg per day of fluticasone propionate, or 
equivalent) plus LABA [Study 205715]. 


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• 
For the primary comparison of FF/UMEC/VI to FF/VI at Week 24 for change from 
baseline in trough FEV1, statistically significant treatment differences were observed 
for both FF/UMEC/VI 100/62.5/25 compared with FF/VI 100/25 (110 mL, 95% CI: 
66, 153; p<0.001) and FF/UMEC/VI 200/62.5/25 compared with FF/VI 200/25 (92 
mL, 95% CI: 49, 135; p<0.001). Treatment differences of a similar magnitude were 
also demonstrated for UMEC 31.25-containing FF/UMEC/VI treatments compared 
with FF/VI at the same dose of FF, though statistical significance could not be 
inferred due to the statistical hierarchy.  
• 
For the secondary analysis of annualised rate of moderate/ severe exacerbations, the 
data from the two FF/UMEC/VI arms for each UMEC dose were pooled and 
compared with pooled data from the two FF/VI arms. A 13.0% (95% CI: -5.2, 28.1) 
reduction in the annualised rate of moderate/severe asthma exacerbations was 
observed across Weeks 1-52 for the FF/UMEC/VI (100 and 200)/62.5/25 group 
compared with the FF/VI (100 and 200)/25 group; however, the reduction in rate did 
not reach statistical significance (p=0.151). No meaningful difference was observed 
in the annualised rate of moderate/severe exacerbations between the UMEC31.25-
containing FF/UMEC/VI group and FF/VI group.  
• 
In the patient-reported secondary endpoints included in the statistical hierarchy, large 
improvements from baseline were seen in all treatment groups. Numeric, dose-
ordered treatment differences were observed between FF/UMEC/VI group and FF/VI 
group with increasing UMEC dose for Asthma Control Questionnaire (ACQ)-7 
(UMEC 62.5 µg, treatment difference= -0·09, 95% CI: –0·16 to –0·02), a measure of 
asthma control, and evaluating respiratory symptoms (E-RS): Asthma, a measure of 
asthma symptoms (UMEC 62.5 µg, treatment difference= -0.42,95% CI: -0.78, -
0.06).  As with the analysis of annualised rate of moderate/ severe exacerbations, the 
data from the two FF/UMEC/VI arms for each UMEC dose were pooled and 
compared with pooled data from the two FF/VI arms.    
• 
Safety data did not identify any new findings for FF/UMEC/VI in this study 
considering the known class effects of ICS, LAMA and LABAs in a population of 
patients with asthma. 
However, this study did not include Chinese patients. Given the above results, the 
efficacy and safety data in this study supports the favourable benefit/risk profile for 
FF/UMEC/VI in this inadequately controlled asthma population. FF/UMEC/VI 
100/62.5/25 µg and 200/62.5/25 µg doses have been submitted for global regulatory 
review for an indication in asthma in several countries worldwide. On 9 Sep 2020, 
FF/UMEC/VI 100/62.5/25 µg and 200/62.5/25 µg were approved as the first once-daily 
single inhaler triple therapies for the treatment of asthma in the US. 
GSK plans to extend the body of evidence for FF/ UMEC/ VI with an evaluation in 
Chinese asthma patients. Through the comparison of FF/UMEC/VI to the dual 
combination therapy FF/VI, this study aims to provide important information to 
prescribers regarding the benefit of a once-daily, single-inhaler triple combination 
therapy in adult Chinese asthma patients who remain inadequately controlled despite 
treatment with ICS/LABA.  


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Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
 
• 
To evaluate the efficacy of 
FF/UMEC/VI 100/62.5/25 µg on lung 
function compared with FF/VI 100/25 
µg after 12 weeks of treatment 
• Change from baseline in trough 
Forced Expiratory Volume in 1 
second (FEV1) at Week 12 
Secondary 
 
• To evaluate the efficacy of 
FF/UMEC/VI 200/62.5/25 µg on 
lung function compared with FF/VI 
200/25 µg after 12 weeks of 
treatment 
• Change from baseline in trough 
FEV1 at Week 12 
Other secondary 
 
• To evaluate the effects of 
FF/UMEC/VI compared with 
FF/VI on asthma control after 12 
weeks of treatment 
• Change from baseline in ACQ-7 
total score at Week 12; 
Safety 
 
• To evaluate the safety of 
FF/UMEC/VI (100/62.5/25 and 
200/62.5/25 µg) compared with 
FF/VI (100/25 and 200/25 µg) 
throughout the 12-week treatment 
period. 
• Incidence and type of adverse 
events 
• Incidence of exacerbations 
• Change from baseline in ECG 
parameters 
• Incidence of worst vital sign 
results relative to normal range 
• Incidence of worst clinical 
hematological and chemistry 
results relative to normal range 
The primary clinical question of interest is: What is the effect of adding UMEC to FF/VI 
in a single inhaler when compared with FF/VI on change from baseline in trough FEV1 
after 12 weeks of treatment in Chinese participants with inadequately controlled asthma? 
This question is to be addressed regardless of study treatment discontinuation unrelated to 
a pandemic or due to pandemic infection and in the absence of study treatment 
discontinuation due to the indirect impact of a pandemic (e.g. participant or site related 
impact such as participant unable to collect/obtain study treatment due to restrictions in 
place, pharmacist not available to conduct the study and maintain the blind).  


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The primary estimand is described by the following attributes: 
o Population: Chinese participants with inadequately controlled asthma. 
o Treatment condition: FF/UMEC/VI (100/62.5/25 µg) or FF/VI (100/25 µg) given 
once daily in the morning (primary treatment comparison is FF/UMEC/VI 
100/62.5/25 µg vs. FF/VI 100/25 µg). In addition, rescue albuterol/salbutamol 
will be provided and is permitted during the study. 
o Variable: change from baseline in trough FEV1 at week 12. 
o Summary measure: Mean change from baseline. Comparison: difference in mean 
change from Baseline 
o Intercurrent events: 
o Study treatment discontinuation – if related to an indirect impact of a 
pandemic it will be handled with a hypothetical strategy (i.e. had the 
intercurrent event not occurred. In this situation, data collected after study 
treatment discontinuation will not be included in the statistical analysis 
and will be treated as missing data). Otherwise it will be handled with a 
treatment policy strategy and data collected after study treatment 
discontinuation will be included in the analysis. This will be the primary 
intercurrent event strategy. 
An additional estimand supporting the primary objective is defined similar to the primary 
estimand except a different intercurrent event strategy will be followed, where study 
treatment discontinuation due to an indirect impact of the pandemic will be handled with 
a treatment policy rather than a hypothetical strategy (i.e. all data collected after study 
treatment discontinuation will be included in the analysis). 
The estimand for the secondary objective assessing FEV1 is the same as the primary 
estimand except the treatment conditions are FF/UMEC/VI (200/62.5/25 µg) or 
FF/UMEC/VI (200/25 µg) given once daily in the morning.   
Overall Design: 
This is a 12-week, Phase III, randomized, double-blind, active controlled, 4-arm parallel 
group bridging study in Chinese asthma participants evaluating FF/UMEC/VI 
(100/62.5/25 µg) versus FF/VI (100/25 µg) and, FF/UMEC/VI (200/62.5/25 µg) versus 
FF/ VI (200/25 µg), given once daily in the morning.   
Brief Summary: 
The purpose of this study is to evaluate the efficacy, safety and tolerability of the fixed 
dose combination FF/UMEC/VI 100/62.5/25 and 200/62.5/25 µg once-daily compared 
with dual combination of FF/VI 100/25 and 200/25 µg once-daily, respectively, for 
improving lung function in Chinese participants with asthma. Study details include: 
• 
Study Duration: 16-18 weeks 
• 
Treatment Duration: 12 weeks 
• 
Number of Visits: 6 visits 
The objective of the study is to evaluate the efficacy and safety of FF/UMEC/VI 
administered once daily via a dry powder inhaler, vs FF/VI for 12 weeks. The primary 


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estimand is the difference in means between FF/UMEC/VI 100/62.5/25 and FF/VI 
100/25 µg in the change from baseline in Trough FEV1 at Week 12 in Chinese 
participants with inadequately controlled asthma regardless of study treatment 
discontinuations unrelated to any pandemic or due to pandemic infections, and in the 
absence of study treatment discontinuations due to the indirect impact of a pandemic. The 
secondary estimand assessing FEV1 is as above but for FF/UMEC/VI 200/62.5/25 versus 
FF/VI 200/25 µg. The study population will be consistent with the 205715 (CAPTAIN 
study) and consist of adult participants (≥18 years of age) with asthma diagnosis as 
defined by the Global Initiative for Asthma [GINA, 2020]. In addition, they must have 
inadequately controlled asthma (ACQ-6 score 1.5) despite ICS/LABA maintenance 
therapy at screening visit (Visit 1) and keep their daily ICS/LABA for at least 12 weeks 
with no changes to maintenance asthma medications during the 6 weeks immediately 
prior to Visit 0 (Pre-screening visit).  Participants must also have pre-bronchodilator 
morning (AM) FEV1 30% and <85% of the predicted normal value at Visit 1 and 
demonstrated reversibility. 
The study consists of a 3-week run-in period, a 12-week treatment period, and a 1-week 
safety follow-up period. Clinic Visits will occur at Pre-Screening (V0), Screening (V1), 
Randomisation (Day 1, V2), week 4 (V3), and week 12 (V4). A safety follow-up 
telephone contact or clinic visit will be conducted approximately 1 week after completing 
either the randomised treatment period or an Early Withdrawal Visit.  
In accordance with the protocol-defined visit schedule, participants will have two on-
treatment clinic visits conducted on an outpatient basis scheduled at Visits 3 (Week 4) 
and 4 (Week 12).  One week following the end of the study (or after the early withdrawal 
visit) a follow-up telephone call or clinic visit will be performed for safety assessments. 
A participant will be considered to have completed the study when he/she has completed 
all phases of the study including the last scheduled procedure shown in the Schedule of 
Activities (SoA). 
Number of Participants: 
Approximately 890 participants will be screened to achieve 356 randomly assigned to 
study intervention for a total of 89 participants per intervention group. Randomization 
will be stratified by pre-study ICS treatment strength (med, high) at screening to ensure 
treatment balance within each stratum. 
Intervention Groups and Duration: 
• Pre-screening: Details about the study and procedures will be explained through 
the informed consent process. The Pre-screening Visit (Visit 0) must be 
completed prior to initiating any Visit 1 procedures. 
• Screening / run-in:  Participants who meet all the eligibility criteria at screening 
(Visit 1), will enter the run-in period for 3 weeks in order to continue to assess the 
participant’s eligibility for the study. Participants satisfying all 
inclusion/exclusion criteria and who have successfully completed all protocol 
procedures at screening will be provided with FF/VI (100/25 µg via the ELLIPTA 
dry powder inhaler [DPI]), taken in the morning once daily during the 3-week 


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run-in period. Rescue medication (albuterol/salbutamol) will be provided to use 
on an as-needed basis throughout the study. The 3-week run-in period is 
necessary in order to allow participants to become accustomed to using the 
ELLIPTA DPI as well as to assess the participant’s eligibility for the study and 
collect baseline electronic diary (eDiary) data. 
• Randomization and Treatment: At the conclusion of the 3-week run-in period 
(Visit 2), all participants who meet the additional predefined criteria will be 
randomized 1:1:1:1 (stratified by pre-study ICS dosage [medium, high])to receive 
either FF/UMEC/VI (100/62.5/25; 200/62.5/25 µg) or FF/VI (100/25; 200/25 µg) 
via the ELLIPTA DPI for the duration of the 12-week treatment period. 
• FF/VI 100/25 µg once daily (QD) 
• FF/VI 200/25 µg QD 
• FF/UMEC/VI 100/62.5/25 µg QD 
• FF/UMEC/VI 200/62.5/25 µg QD 
Study treatment will be administered via the ELLIPTA DPI in the morning. 
• 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 4/end of study (EOS) or, if applicable, the 
Early Withdrawal Visit. A participant will be considered to have completed the 
study upon completion of all assessments and procedures for Visit 4/EOS and 
including a successful follow-up contact/visit. 
Data Monitoring/ Other Committee: [Not applicable] 


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1.2. 
Schema 
Figure 1 
Study design 
 
 


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1.3. 
Schedule of Activities (SoA) 
Protocol Activity 
Pre-Screen1 
Screen 
Run-in 
Intervention Period 
Early 
Withdrawal 
(EW)3 
Safety 
Follow-up Contact 
Visit 
0 
11 
22 
Randomization 
3 
421 
EW 
5 
Study Day 
-35 to -22 
-21 
1 
28 days post 
first dose 
84 days post 
first dose 
 
 
Week 
-5 to -4 
-3 
0 
4 
12 
 
1 week after Visit 
4/EOS or EW Visit 
Window 
 
 
 
-7/+7d 
-7/+7d 
 
-2/+5d 
Written Informed Consent4 
x 
 
 
 
 
 
 
Demography 
x 
 
 
 
 
 
 
Medical history 
 
x 
 
 
 
 
 
Asthma History5 
 
x 
 
 
 
 
 
Exacerbation History 
 
x 
 
 
 
 
 
Concomitant Medication 
Assessment 
x 
x 
x 
x 
x 
x 
x 
Inclusion/Exclusion criteria 
 
x 
x 
 
 
 
 
Smoking History and status 
 
x 
 
 
 
 
 
Randomization6 
 
 
x 
 
 
 
 
Register visit in Interactive 
Response Technology (IRT) 
(RAMOS NG)7 
x 
x 
x 
x 
x 
x 
x 
Efficacy Assessments 
 
Dispense paper Medical 
Problems/Medications Taken 
worksheet 
x 
x 
x 
x 
x 
x 
 
Review paper Medical 
Problems/Medications Taken 
worksheet 
 
x 
x 
x 
x 
x 
x 
ACQ8,20 
 
x 
x 
x 
x 
x 
 
Pre-dose spirometry  
 
x9 
x9 
x9 
x9 
x9,10 
 


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Protocol Activity 
Pre-Screen1 
Screen 
Run-in 
Intervention Period 
Early 
Withdrawal 
(EW)3 
Safety 
Follow-up Contact 
Visit 
0 
11 
22 
Randomization 
3 
421 
EW 
5 
Study Day 
-35 to -22 
-21 
1 
28 days post 
first dose 
84 days post 
first dose 
 
 
Week 
-5 to -4 
-3 
0 
4 
12 
 
1 week after Visit 
4/EOS or EW Visit 
Window 
 
 
 
-7/+7d 
-7/+7d 
 
-2/+5d 
Reversibility test 
 
x11 
 
 
 
 
 
eDiary/device training and 
registration 
 
x 
 
 
 
 
 
Dispense eDiary 
 
x 
 
 
 
 
 
Collect eDiary 
 
 
 
 
x 
x 
 
eDiary review 
 
 
x 
x 
x 
x 
 
Safety Assessments 
 
Physical Examination 
 
x 
 
 
x 
x 
 
Vital Signs 
 
x12 
x 
x 
x 
x 
 
ECG13 
 
x 
 
x 
x 
x 
 
Adverse Events 
 
x 
x 
x 
x 
x 
x 
Serious Adverse Events 
x 
x 
x 
x 
x 
x 
x 
Exacerbation assessment 
 
 
x 
x 
x 
x 
x 


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Protocol Activity 
Pre-Screen1 
Screen 
Run-in 
Intervention Period 
Early 
Withdrawal 
(EW)3 
Safety 
Follow-up Contact 
Visit 
0 
11 
22 
Randomization 
3 
421 
EW 
5 
Study Day 
-35 to -22 
-21 
1 
28 days post 
first dose 
84 days post 
first dose 
 
 
Week 
-5 to -4 
-3 
0 
4 
12 
 
1 week after Visit 
4/EOS or EW Visit 
Window 
 
 
 
-7/+7d 
-7/+7d 
 
-2/+5d 
Laboratory Assessments 
 
Hematology and clinical 
chemistry 
 
x 
 
 
x 
x 
 
Urinalysis 
 
x 
 
 
x 
x 
 
Serum pregnancy test 
 
x14 
 
 
x14 
x14 
 
Urine pregnancy test14 
 
 
x 
x 
 
 
 
Study Treatment 
Dispense ICS/LABA run-in 
medication 
 
x15 
 
 
 
 
 
Assess run-in medication 
compliance 
 
 
x 
 
 
 
 
Collect ICS/LABA run-in 
medication 
 
 
x 
 
 
 
 
Administer double-blind study 
treatment16 
 
 
x 
x 
x 
x17 
 
Dispense double-blind study 
treatment (Scheduled) 
 
 
x 
x 
 
 
 
Dispense double-blind study 
treatment (Unscheduled) 
 
 
x18 
 
 
Assess double-blind study 
treatment compliance 
 
 
 
x 
x 
x 
 


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Protocol Activity 
Pre-Screen1 
Screen 
Run-in 
Intervention Period 
Early 
Withdrawal 
(EW)3 
Safety 
Follow-up Contact 
Visit 
0 
11 
22 
Randomization 
3 
421 
EW 
5 
Study Day 
-35 to -22 
-21 
1 
28 days post 
first dose 
84 days post 
first dose 
 
 
Week 
-5 to -4 
-3 
0 
4 
12 
 
1 week after Visit 
4/EOS or EW Visit 
Window 
 
 
 
-7/+7d 
-7/+7d 
 
-2/+5d 
Collect double-blind study 
treatment 
(Scheduled) 
 
 
 
x 
x 
x 
 
Collect double-blind study 
treatment 
(Unscheduled) 
 
 
x19 
 
 
Dispense albuterol/salbutamol, 
as required 
 
x 
x 
x 
x 
 
 
Collect albuterol/salbutamol, as 
required 
 
 
x 
x 
x 
x 
 
Notes: 
1. Visit 1 should be completed ³1 day but ≤14 days after Visit 0; however, if it is local and routine medical practice to request that a participant withhold their 
ICS/LABA medication for at least 24 hours prior to a clinic visit then, provided that the participant has complied with the request, Visit 0 and Visit 1 can 
occur on the same day.  
2. Visit 2 must always be conducted ³21 days but £28 days after Visit 1.  
3. EW Visit should be conducted if double-blind study treatment is discontinued AND the participant discontinues from participating in the study.  
4. The ICF must be signed before any study procedures, including protocol-specified medication cessation.  
5. 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 Study Reference Manual [SRM]). 
6. Participants must not be randomized prior to confirming their eligibility to participate in the study.  
7. The IRT will be used for randomization, emergency unblinding and study treatment supply management (Please refer to the RAMOSNG IRT manual and 
SRM for more information).  
8. Assessment to be completed prior to the administration of study treatment. ACQ-6 will be evaluated at V1 and 2 for eligibility check, and ACQ-7 (ACQ-6 
& 5 will be derived from ACQ-7) will be evaluated at V2, 3, 4 and EW for efficacy assessment. 
9. Spirometry to be performed between 6am and 11am after withholding rescue medication for at least 6 hours and prior to taking the morning dose of study 
treatment. Pre-dose spirometry assessments should be performed at the same time of day at each applicable visit.  


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10. In the event that double-blind study treatment is not administered at this visit, spirometry assessments should be performed at the same time of day as the 
pre-dose spirometry assessments at the preceding on-treatment clinic visits.  
11. 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 
8.2.1.1 for details of the criteria to be met before a repeat of the reversibility assessment is permitted). If airway reversibility is successfully demonstrated at 
the second attempt and all other eligibility criteria assessed at Visit 1 are met then the participant may commence the 3-week run-in period (starting on the 
date that airway reversibility was successfully demonstrated at the second attempt).  
12. The vital signs assessment will include the measurement of height and weight at this visit only.  
13. 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 8.3.3). At all post-randomization visits the ECG is to be obtained 15 minutes to 45 minutes after the administration of study 
treatment.  
14. Assessments only to be conducted in females of reproductive potential.  
15. In the event that the reversibility assessment needs to be repeated within 7 days of Visit 1 (see Section 8.2.1.1) then the medication for the 3-week run-in 
period must not be dispensed until airway reversibility is successfully demonstrated at the second attempt and all other eligibility criteria assessed at Visit 1 
are confirmed as met. 
16. Study treatment should be administered at the same time of day at each applicable clinic visit. 
17. The administration of study treatment at this visit is optional. If study treatment is not administered at this visit then those assessments which are scheduled 
based on the time of study treatment administration should be performed at approximately the same time of day as performed at the preceding post-
randomization visits.  
18. Between scheduled visits, unscheduled visits to the study clinic to re-supply the participant with double-blind study treatment is permitted after Visit 2 but 
before Visit 4/EOS. The IRT will be used for study treatment supply management (Please refer to the RAMOS NG IRT manual and SRM for more 
information).  
19. In the event that the participant attends the study clinic for the unscheduled dispensing of double-blind study treatment, previously dispensed study 
treatment should be collected for drug accountability purposes.  
20. If on-site Visit 3 or Visit 4 or EW could not be conducted within time window due to COVID-19 lockdown, the participant could complete ACQ-6 from 
home, under the investigator mode (refer to SRM for the details).  
21. If Visit 4 couldn’t be done on site due to COVID-19 lockdown, the participant will be provided additional study drug and continue study treatment until 
they could come back to site for Visit 4; the time window of Visit 4 will be extended for 6 more weeks as the longest after 12 weeks’ treatment in these 
participants. 
 


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2. 
INTRODUCTION 
FF/UMEC/VI is a fixed-dose triple combination medication containing inhaled 
corticosteroid fluticasone (FF), inhaled long-acting muscarinic receptor antagonist 
umeclidinium (UMEC) and inhaled long-acting beta2 agonist vilanterol (VI) that is being 
developed for once-daily treatment of asthma and chronic obstructive pulmonary disease 
(COPD). 
2.1. 
Study Rationale  
The Global Initiative for Asthma guideline [GINA, 2020] recommends a long-acting 
muscarinic antagonist (LAMA) as an add-on treatment option for adults (≥18 years) with 
asthma that are currently taking medium-to-high dose inhaled corticosteroid and long-
acting beta2 agonist (ICS/LABA) maintenance therapy and have a history of 
exacerbations. Exacerbations are an important endpoint in asthma therapy; however, 
symptom control is also important in determining what patients could benefit from step-
up therapy. 
GSK has developed a once-daily fixed-dose triple therapy of an ICS/LAMA/LABA 
combination [fluticasone furoate/ umeclidinium /vilanterol (FF/UMEC/VI)] via a single 
ELLIPTA dry-powder inhaler device, with the aim of providing a new treatment option 
for the management of asthma by improving lung function, health-related quality of life 
(HRQoL) and symptom control over established combination therapies. The results of the 
global PhIIIa 205715 study has established that FF/UMEC/VI provided additional benefit 
compared with FF/VI in asthma patients 18years old who were inadequately controlled 
despite treatment with ICS (>250 µg per day of fluticasone propionate, or equivalent) 
plus LABA [Study 205715]. 
• 
For the primary comparison of FF/UMEC/VI to FF/VI at Week 24 for change from 
baseline in trough FEV1, statistically significant treatment differences were observed 
for both FF/UMEC/VI 100/62.5/25 compared with FF/VI 100/25 µg (110 mL, 95% 
CI: 66, 153; p<0.001) and FF/UMEC/VI 200/62.5/25 compared with FF/VI 200/25 
µg (92 mL, 95% CI: 49, 135; p<0.001). Treatment differences of a similar magnitude 
were also demonstrated for UMEC 31.25-containing FF/UMEC/VI treatments 
compared with FF/VI at the same dose of FF, though statistical significance could 
not be inferred due to the statistical hierarchy. 
• 
For the secondary analysis of annualised rate of moderate/ severe exacerbations, the 
data from the two FF/UMEC/VI arms for each UMEC dose were pooled and 
compared to pooled data from the two FF/VI arms.  A 13.0% (95% CI: -5.2, 28.1) 
reduction in the annualised rate of moderate/severe asthma exacerbations was 
observed across Weeks 1-52 for the FF/UMEC/VI (100 and 200)/62.5/25 group 
compared with the FF/VI (100 and 200)/25 group; however, the reduction in rate did 
not reach statistical significance (p=0.151). No meaningful difference was observed 
in the annualised rate of moderate/severe exacerbations between the UMEC31.25-
containing FF/UMEC/VI group and FF/VI group.  


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• 
In the patient reported secondary endpoints included in the statistical hierarchy, large 
improvements from baseline were seen in all treatment groups.  Numeric, dose-
ordered treatment differences were observed with increasing UMEC dose for ACQ-
7, a measure of asthma control, and E-RS: Asthma, a measure of asthma symptoms.  
• 
Safety data did not identify any new findings for FF/UMEC/VI in this study 
considering the known class effects of ICS, LAMA and LABAs in a population of 
patients with asthma. FF/UMEC/VI 100/62.5/25 µg and 200/62.5/25 µg doses have 
been submitted for global regulatory review for an indication in asthma in several 
countries worldwide. 
The efficacy and safety data above supports the favourable benefit/risk profile for 
FF/UMEC/VI in this inadequately controlled asthma population under ICS/LABA 
treatment. Both FF/UMEC/VI 100/62.5/25 µg and 200/62.5/25 µg doses have been 
submitted for global regulatory review for an indication in asthma in several countries 
worldwide. On 9 Sep 2020, both FF/UMEC/VI 100/62.5/25 µg and 200/62.5/25 µg were 
approved as the first once-daily single inhaler triple therapies for the treatment of asthma 
in the US. 
By the end of 02 July 2020, FF/UMEC/VI has been studied in 103 healthy volunteers, 
9,781 participants with COPD and 1,734 participants with asthma and the total number of 
participants exposed to FF/UMEC/VI in all clinical studies was 11,618. Cumulative post-
marketing exposure from launch to 31 March 2020 is estimated to be 685,428 patient-
years. No new safety concerns were identified that were not already known for FF/VI, 
UMEC/VI and UMEC.   
GSK plans to extend the body of evidence for FF/ UMEC/ VI with an evaluation in 
Chinese asthma patients. Through the comparison of FF/UMEC/VI to the dual 
combination therapy FF/VI, this study aims to provide important information to 
prescribers regarding the benefit of a once-daily, single-inhaler triple combination 
therapy in adult Chinese asthma patients who remain inadequately controlled despite 
treatment with ICS/LABA. 
2.2. 
Background 
Asthma is a common chronic airway disease imposing a significant burden on families, 
healthcare systems and the workplace. It is characterized by airway inflammation, 
increased airway responsiveness, and bronchoconstriction [GINA, 2020]. The prevalence 
of asthma in China has been increasing in recent years. According to latest data, the 
prevalence of asthma in China adults is 4.2%, representing about 45.7 million adult 
patients [Huang, 2019].  
The goal of asthma treatment is to achieve and maintain asthma control enabling patients 
to avoid symptoms and flare-ups and lead productive lives with near normal lung 
function [GINA, 2020]. Current medications for asthma patients mainly consist of ICS 
with/without LABA for long term asthma maintenance treatment. ICSs are considered the 
most effective anti-inflammatory treatments for all severities of persistent asthma [GINA, 
2020]. The dose of ICS is selected based on the severity of the patient’s asthma. In 
patients who are symptomatic on ICS alone, add-on therapy with another controller, in 


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particular a LABA is preferred to increasing the dose of ICS to achieve asthma control 
[GINA, 2020]. In difficult-to-treat persistent asthma, some patients continue to be 
symptomatic despite treatment with ICS and LABA combination medications and the 
current guidelines [GINA, 2020; CAPG, 2016] recommend treatment with high-dose 
inhaled or oral glucocorticosteroids in combination with LABAs and/or additional 
controller medications. 
Despite availability of treatments and published guidelines, patients may have asthma 
that is inadequately controlled, and the asthma control is sub-optimal: 29-35% of China 
patients were still uncontrolled despite of inhaled corticosteroid/long-acting beta2 agonist 
(ICS/LABA) therapy [[HZA113719 China CSR GSK Document number 
2013N169446_00 Table 15; HZA113714 China CSR GSK Document number 
2013N161713_00 Table 16]. 
International and Chinese guidelines [GINA, 2020; CAPG, 2016] guidelines both 
recommend a long-acting muscarinic antagonist (LAMA) as add-on treatment for adults 
whose asthma is uncontrolled with medium to high dose ICS/ LABA treatment.  
In the European Union (EU), tiotropium bromide (LAMA) is licensed as an add-on 
maintenance bronchodilator treatment in adult patients with asthma who are currently 
treated with the maintenance combination of ICS (800 micrograms (µg) budesonide/day 
or equivalent) and LABA and who experienced one or more severe exacerbations in the 
previous year [Spiriva, 2016 Respimat Summary of Product Characteristics (SPC) 2016]. 
In the US, tiotropium bromide was recently approved for the maintenance treatment of 
asthma, in patients 12 years of age and older [Spiriva, 2016 Respimat United States 
Product Insert (USPI), 2016]. The benefit of adding a LAMA to both ICS monotherapy 
and ICS/LABA fixed combination therapy was demonstrated in four Phase III 
confirmatory studies (416, 417 [Kerstjens, 2012]; 418 and 419 [Kerstjens, 2015]), in 
symptomatic asthma patients (ACQ score 1.5). The Phase III studies supporting the 
tiotropium application showed that addition of tiotropium bromide to ICS/LABA 
maintenance therapy significantly improved lung function and reduced the risk of severe 
asthma exacerbation. 
Recently, a Phase III study (IRIDIUM) also demonstrates that ICS–LABA–LAMA once-
daily combination therapy of medium-dose and high-dose mometasone furoate, 
indacaterol acetate, and glycopyrronium bromide (MF–IND–GLY), from a single inhaler, 
significantly improved lung function versus the respective once-daily MF–IND doses and 
twice-daily high-dose fluticasone–salmeterol (FLU–SAL), a well-established ICS–LABA 
combination (Kerstjens, 2020). 
2.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of GSK2834425 (FF/UMEC/VI) may be found in the 
Investigator’s Brochure (GSK Document number 2012N131935_10). Marketed 
ICS/LABA products will be used for run-in (FF/VI) and comparator (FF/VI) treatments.  
These products will be used in accordance with the product labels and further details on 
the experience with these products can be found in the Investigator Brochures and/or 


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product labelling.  The following section outlines the risk assessment and mitigation 
strategy for this protocol: 
 


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2.3.1. 
Risk Assessment 
Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Study Intervention(s) GSK2834425  
Cardiovascular effects  
 
Cardiovascular effects, such as cardiac arrhythmias e.g. atrial fibrillation 
and tachycardia, may be seen after the administration of muscarinic 
receptor antagonists or sympathomimetic agents, including umeclidinium 
or vilanterol, respectively. 
 
Vilanterol, like other beta2-agonists, can produce a clinically significant 
cardiovascular effect in some patients as measured by increases in pulse 
rate, systolic or diastolic blood pressure, and also cardiac arrhythmias, such 
as supraventricular tachycardia and extrasystoles. In addition, beta-agonists 
have been reported to produce electrocardiographic changes, such as 
flattening of the T wave, prolongation of the QTc interval, and ST segment 
depression, although the clinical significance of these findings is unknown. 
Fatalities have been reported in association with excessive use of inhaled 
sympathomimetic drugs.  
 
 
 
In the completed pivotal study in asthma, 205715, which included 2439 
participants which investigated the efficacy and safety of FF/UMEC/VI 
(100/31.25/25; 200/31.25/25; 100/62.5/25; 200/62.5/25) compared to FF/VI 
(100/25; 200/25) the percentage of participants with adverse events of 
special interest (AESIs) in the CV effects special interest group ranged 
from 4% to 7% across the treatment groups (highest in the FF/UMEC/VI 
100/62.5/25 group). CV effects AESI reported in ≥1% of participants in 
Mitigation strategy: 
- The risk of CV effects was 
mitigated by the exclusion of 
participants with unstable or 
life-threatening cardiac disease, 
collection of medical history at 
baseline including a detailed 
history of CV risk factors 
(Detailed in in Section 5.2 of the 
Protocol Amendment) 
- Collection of cardiovascular 
risk factors and medical history 
at baseline  
- ECGs as per schedule in 
Section 1.3. 
- Vital sign assessments (heart 
rate and blood pressure) as per 
schedule in Section 1.3. 
- Cardiovascular Adverse Event 
(AE)s and Serious AEs (SAEs) 


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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
any treatment group were hypertension (range: 1% to 2%) and blood 
pressure increased (range: <1% to 1%). Few AESIs in the CV effects 
special interest group met the criteria of an SAE (range: 0-4 participants 
(<1% in all groups). There were 2 CV deaths reported, 1 of circulatory 
collapse in the FF/VI 200/25 group and 1 of hypertrophic cardiomyopathy 
in FF/UMEC/VI 100/31.25/25. Neither CV death was considered drug-
related. 
There were few participants with >1 on-treatment MACE (broad definition) 
in each of the treatment groups (range: 2 to 5 participants [<1% to 1%]. For 
both the FF 100- and FF 200- containing treatment groups, there was a 
small difference in the number of narrow MACE in the UMEC 62.5-
containing FF/UMEC/VI groups vs FF/VI (1 in both FF/VI 100/25 and 
FF/UMEC/VI 100/31.25/25, and 3 in 100/62.5/25; 0 in both FF/VI 200/25 
and FF/UMEC/VI 200/31.25/25, and 2 in 200/62.5/25. No clinically 
meaningful differences were observed between FF/UMEC/VI and FF/VI 
for any ECG parameters, vital signs or laboratory parameters. (Seen in IB 
Section 5.3.6.1.6.) 
will be captured on the 
electronic Case Report Form 
(eCRF) (see Section 10.3.3) 
- Protocol defined stopping 
criteria as per Section 7.1. In 
general, if a significant finding 
is identified after enrolment, the 
investigator or qualified 
designee will determine if the 
participant can continue in the 
study and if any change in 
participant management is 
needed.  
  
- Review AEs/SAEs 
Anticholinergic 
effects (including 
constipation nausea, 
dry mouth, glaucoma, 
raised intraocular 
pressure and blurred 
vision, urinary 
retention) 
Umeclidinium is a long-acting muscarinic antagonist, which is often 
referred to as an anticholinergic. It has similar affinity to the subtypes of 
muscarinic receptors M1 to M5. When binding on the muscarinic receptor 
in organs or tissues other than the lung, UMEC might induce certain 
unwanted effects or disease worsening, ie. dry mouth, worsening of urinary 
retention, etc. 
In the completed pivotal asthma study, 205715, the percentage of 
participants with AESIs in the Anticholinergic syndrome (SMQ) special 
interest group ranged from 1% to 3% across the treatment groups and the 
events occurring in >1 participant in any treatment group were dizziness 
- Patients with known narrow-
angle glaucoma, prostatic 
hyperplasia or bladder outflow 
obstruction that, in the opinion 
of the Investigator, 
contraindicates study 
participation or use of an inhaled 
anticholinergic, will be excluded 
from participating in the study. 


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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
(range: 1 to 4 participants [<1% in all groups]), pyrexia (range: 0 to 5 
participants [<1% in all groups]), and tachycardia (range: 0 to 3 participants 
[<1% in all groups]). Dry mouth/drying of the airway secretions (broad 
focus) special interest group was the most frequently reported special 
interest group across all treatment groups (range: 22% to 24%), driven by 
nasopharyngitis (range: 13% to 
15%). In the Dry mouth/drying of the airway secretions (narrow focus) 
special interest group, 2 PTs were reported (dry throat and dry mouth), 
both occurring in few participants (4 participants 
and 3 participants, respectively). 
- Review AEs/SAEs 
 
Systemic ICS effects 
-Adrenal suppression  
-Cataracts & 
glaucoma 
- 
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 that monitored urinary cortisol. 
During clinical development of FF & FF/VI no events of Adrenal 
Suppression were reported. No events were reported in the adrenal 
suppression AESI group in the completed pivotal asthma study, 
205715.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. 
- Review AEs/SAEs 
-. Participants with a medical 
condition of glaucoma 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 


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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
 In the completed pivotal asthma study, 205715, 3 events of cataract were 
reported (one event in FF/VI 200/25; 1 event in FF/UMEC/VI 
100/62.5/25 and 1 event in FF/UMEC/VI 200/62.5/25). 
 
During studies in both participants with asthma and COPD, no associated 
effect on ocular disorders was observed. Spontaneous data received to date 
does not alter the understanding of this risk. 
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 the completed pivotal study in asthma, 205715, there was a similar and 
low incidence of pneumonia AESIs in the participants in the FF/UMEC/VI 
(range <1% to 2%) and FF/VI (2%) treatment groups. Thirty-six 
participants had an 
on-treatment event in the Infective pneumonia. SMQ) special interest group 
[<1% to 2%]). For 16 participants the Infective pneumonia (SMQ) AESI 
was serious. 
There was a small increase in the number of serious Pneumonia AESIs at 
FF 200 dose groups (n=10 participants) compared with FF 100 dose groups 
(n=6 participants). There were no pneumonia AESI with a fatal outcome. In 
the pneumonia eCRF, there was a similar incidence of on-treatment 
pneumonia in the 
FF/UMEC/VI (<1%-2%) and FF/VI (2%) treatment groups. There was a 
small increase in the number of pneumonia events as FF dose increased, 16 
participants at FF 100 doses vs 20 participants at FF 200 doses. 
 
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 


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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
In an 18 study integration in the FF/VI asthma program, the incidence of 
pneumonia (adjusted for exposure) observed with FF/VI 100/25 and FF 100 
(8.5/1000 patient years and 9.6/1000 patient years, respectively) was 
similar to that seen with placebo (9.3/1000 patient years). A higher 
incidence in the FF/VI 200/25 and FF 200 arms were observed (18.3/1000 
patient years and 23.6/1000 patient years, respectively). However, the 95% 
CIs were wide and overlapped across all treatment groups, including 
placebo. Few of the pneumonia events led to hospitalisation with either 
strength, and there were no observed differences in the incidence of serious 
events between the two treatment strengths. The risk of pneumonia in 
asthma patients is very low and is consistent with the risk of other ICS. 
 
of any episodes 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  
Review AEs/SAEs.  
 
Hypersensitivity 
In the completed pivotal asthma study, 205715, AESI for hypersensitivity 
were balanced across treatment groups for FF/VI and FF/UMEC/VI 
(4% to 5%) 
There have been post-marketing reports of hypersensitivity reactions with 
FF/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 stearate are 
excluded from participation in 
this study (Section 5.2). 


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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
-Review AEs/SAEs 
Paradoxical 
bronchospasm 
Rare reports of paradoxical bronchospasm (which may be life threatening) 
with other inhalational products have been reported. There have been rare 
post-marketing reports of paradoxical bronchospasm with FF/VI and 
UMEC/VI. 
 
Patients will undergo regular 
medical assessments during 
clinical studies. 
-Review AEs/SAEs 
 
Pregnancy and 
lactation 
There are no data from the use of FF/UMEC/VI in pregnant women. 
There has been limited pregnancy exposure to FF and FF/VI in humans. 
Animal studies have shown reproductive toxicity after administration of 
corticosteroids and beta2-agonists. 
There is a limited amount of data from the use of umeclidinium in pregnant 
women. Animal studies do not indicate direct or indirect harmful effects 
with respect to reproductive toxicity. 
There is limited information on the excretion of FF or VI or their 
metabolites in human milk. However, other corticosteroids and beta2-
agonists are detected in human milk. 
It is unknown whether umeclidinium is excreted in human milk. The 
excretion of FF/UMEC/VI in breast milk has not been evaluated. A risk to 
breastfed new-borns/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 Section 10.4, 
Appendix 4. 
 


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The risks for FF/VI are recognised pharmacological class effects associated with ICS and LABA therapy. The experience with this 
individual product is provided in the respective Investigator Brochures and/or product labelling. Some of the experience with FF/VI is 
described in the table above, as this provides relevant background information for FF/UMEC/VI.


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2.3.2. 
Benefit Assessment 
 dual combinations of FF/VI has been approved as maintenance therapy for both asthma 
and COPD and UMEC for COPD in China The addition of UMEC to FF/VI in asthma 
has the potential to improve lung function, reduce moderate/severe exacerbations and 
improve quality of life in patients whose asthma is inadequately controlled on ICS/LABA 
alone. The results of the global Ph IIIa 205715 study established that FF/UMEC/VI 
provided additional benefit compared with FF/VI in asthma patients 18years old who 
were inadequately controlled despite treatment with ICS plus LABA [Study 205715]. 
Current asthma treatment guidelines recommend the addition of a LAMA (tiotropium) 
for patients that are uncontrolled on ICS/LABA (GINA, 2020, Steps 4 and 5); the 
availability of the FF/UMEC/VI combination would therefore be consistent with this 
approach. The combination in a single-inhaled triple combination would provide the 
convenience of once daily dosing and reduce the need for multiple inhalers. Furthermore, 
the availability of two doses of FF (i.e. FF100/UMEC62.5/VI25 and 
FF200/UMEC62.5/VI25) would allow the prescriber to select an appropriate inhaled 
corticosteroid dose based on the severity of asthma. 
2.3.3. 
Overall Benefit: Risk Conclusion 
Taking into account the measures taken to minimize risk to participants participating in 
the study, the potential risks identified in association with FF/UMEC/VI are justified by 
the anticipated benefits that may be afforded to participants with asthma. In addition, the 
efficacy and safety data in the global Ph IIIa 205715 study has shown positive 
benefit/risk profile for FF/UMEC/VI in this inadequately controlled asthma population. 
The current experience with FF, UMEC and VI and the lack of significant safety 
concerns relevant to the asthma population provides reassurance that the potential risks 
associated with the known pharmacology of these compounds is offset by the potential 
significant benefits that are afforded to patients inadequately controlled on ICS/LABA 
therapy. 
The ICS/LABA used as run-in (FF/VI) is marketed for the treatment of asthma and has 
favourable benefit-risk profiles. 


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3. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
 
• To evaluate the effects of 
FF/UMEC/VI 100/62.5/25 µg on 
lung function compared with FF/VI 
100/25 µg after 12 weeks of 
treatment 
• Change from baseline in trough 
FEV1 at Week 12 
Secondary 
 
• To evaluate the effects of 
FF/UMEC/VI 200/62.5/25 µg on 
lung function compared with FF/VI 
200/25 µg after 12 weeks of 
treatment 
• Change from baseline in trough 
FEV1 at Week 12 
Other secondary 
 
• To evaluate the effects of 
FF/UMEC/VI compared with FF/VI 
on asthma control after 12 weeks of 
treatment 
• Change from baseline in ACQ-7 
total score at Week 12; 
Exploratory objectives 
 
Safety 
 
• To evaluate the safety of 
FF/UMEC/VI (100/62.5/25 and 
200/62.5/25 µg) compared with 
• 
Incidence and type of adverse events 
• 
Incidence of exacerbations  
CCI


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Objectives 
Endpoints 
FF/VI (100/25 and 200/25 µg) 
throughout the 12-week treatment 
period. 
• 
Change from baseline in ECG 
parameters 
• 
Incidence of worst vital sign results 
relative to normal range 
• 
Incidence of worst clinical 
hematological and chemistry results 
relative to normal range 
The primary clinical question of interest is: What is the effect of adding UMEC to FF/VI 
in a single inhaler when compared with FF/VI on change from baseline in trough FEV1 
after 12 weeks of treatment in Chinese participants with inadequately controlled asthma? 
This question will be addressed regardless of study treatment discontinuation unrelated to 
a pandemic or due to pandemic infection and in the absence of study treatment 
discontinuation due to the indirect impact of a pandemic (e.g. participant or site related 
impact such as participant unable to collect/obtain study treatment due to restrictions in 
place, pharmacist not available to conduct the study and maintain the blind).   
For this primary clinical question of interest, participant’s trough FEV1 measurements at 
Week 12 will be used regardless of whether they discontinued study treatment due to 
pandemic infection (e.g. participant got COVID-19) or for reasons not related to the 
pandemic. There could be cases of the pandemic at the time of the conduct of this China 
bridging study and beyond. Given that the disease area of interest is a respiratory disease 
it is important to estimate the treatment effect regardless of the participant being 
diagnosed with pandemic infection as this is likely to be the situation that FF/UMEC/VI 
(if approved and prescribed for asthma) would be taken in. It is unknown currently 
whether indirect consequences of the pandemic (such as the participant unable to 
collect/obtain study treatment due to local restrictions/lockdowns) will be an issue at the 
time of the study, but if participants are unable to collect medication or attend the study 
site due to concerns around the pandemic (or other operational issues) this is unlikely to 
be the situation in the future;  therefore, we want to estimate the treatment effect in the 
absence of this. 
The primary estimand is described by the following attributes: 
o Population: Chinese participants with inadequately controlled. 
o Treatment condition: FF/UMEC/VI (100/62.5/25 µg) or FF/VI (100/25 µg) given 
once daily in the morning (primary treatment comparison is FF/UMEC/VI 
100/62.5/25 vs. FF/VI 100/25). In addition, rescue albuterol/salbutamol will be 
provided and is permitted during the study. 
o Variable: change from baseline in trough FEV1 at week 12. 
o Summary measure: Mean change from baseline. Comparison: difference in mean 
change from baseline 
o Intercurrent events: 
o Study treatment discontinuation – if related to an indirect impact of a 
pandemic it will be handled with a hypothetical strategy (i.e. had the 
intercurrent event not occurred. In this situation, data collected after study 


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treatment discontinuation will not be included in the statistical analysis 
and will be treated as missing data). Otherwise it will be handled with a 
treatment policy strategy and data collected after study treatment 
discontinuation will be included in the analysis. This will be the primary 
intercurrent event strategy. 
An additional estimand supporting the primary objective is defined similar to the primary 
estimand except a different intercurrent event strategy will be followed, where study 
treatment discontinuation due to an indirect impact of the pandemic will be handled with 
a treatment policy rather than a hypothetical strategy (i.e. all data collected after study 
treatment discontinuation will be included in the analysis). 
The estimand for the secondary objective for FEV1 is the same as the primary estimand 
except the treatment conditions are FF/UMEC/VI (200/62.5/25 µg) or FF/UMEC/VI 
(200/25 µg) given once daily in the morning.  
4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a 12-week, Phase III, randomized, double-blind, active controlled, 4-arm parallel 
group, bridging study in Chinese asthma participants evaluating: 
• FF/UMEC/VI (100/62.5/25 µg) versus FF/VI (100/25 µg) and,  
• FF/UMEC/VI (200/62.5/25 µg) versus FF/ VI (200/25 µg)  
All given once daily in the morning.   
Participants who meet all the eligibility criteria at screening (Visit 1), will enter the run-in 
period for 3 weeks in order to continue to assess the participant’s eligibility for the study. 
Participants satisfying all inclusion/exclusion criteria and who have successfully 
completed all protocol procedures at screening will be provided with FF/VI (100/25 µg 
via the ELLIPTA dry powder inhaler [DPI]) once a day, taken in the morning, during the 
3-week run-in period. Rescue medication (albuterol/salbutamol) will be provided to use 
on an as-needed basis throughout the study.  
At the conclusion of the 3-week run-in period (Visit 2), all participants who meet the 
additional predefined criteria will be randomised 1:1:1:1 to receive either FF/UMEC/VI 
(100/62.5/25; 200/62.5/25 µg) or FF/VI (100/25; 200/25 µg) via the ELLIPTA DPI once 
daily in the morning for the duration of the 12-week treatment period (stratified by pre-
study ICS treatment strength [medium, high]). 
In accordance with the protocol-defined visit schedule, participants will have two on-
treatment clinic visits conducted on an outpatient basis scheduled at Visits 3 (Week 4) 
and Visits 4 (Week 12).  One week following the end of the study (or after the early 
withdrawal visit) a follow-up telephone call or clinic visit will be performed for safety 
assessments. 


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A participant will be considered to have completed the study when he/she has completed 
all phases of the study including the last scheduled procedure shown in the SoA (Section 
1.3). 
The end of the study is defined as the date of last scheduled procedure shown in the SoA 
for the last participant in the trial. 
Intervention Groups and Duration: 
• Pre-screening: Details about the study and procedures will be explained through 
the informed consent process. The Pre-screening Visit (Visit 0) must be 
completed prior to initiating any Visit 1 procedures. 
• Screening / run-in:  Participants who meet all the eligibility criteria at screening 
(Visit 1), will enter the run-in period for 3 weeks in order to continue to assess the 
participant’s eligibility for the study. Participants satisfying all 
inclusion/exclusion criteria and who have successfully completed all protocol 
procedures at screening will be provided with FF/VI (100/25 µg via the ELLIPTA 
dry powder inhaler [DPI]) once a day, taken in the morning, during the 3-week 
run-in period. Rescue medication (albuterol/salbutamol) will be provided to use 
on an as-needed basis throughout the study. The 3-week run-in period is 
necessary in order to allow participants to become accustomed to using the 
ELLIPTA DPI as well as to assess the participant’s eligibility for the study and 
collect baseline eDiary data. 
• Randomization and Treatment: At the conclusion of the 3-week run-in period 
(Visit 2), all participants who meet the additional predefined criteria will be 
randomized 1:1:1:1 to receive either FF/UMEC/VI (100/62.5/25; 200/62.5/25 µg) 
or FF/VI (100/25; 200/25 µg) via the ELLIPTA DPI for the duration of the 12-
week treatment period. 
• FF/VI 100/25 µg once daily (QD) 
• FF/VI 200/25 µg QD 
• FF/UMEC/VI 100/62.5/25 µg QD 
• FF/UMEC/VI 200/62.5/25 µg QD 
Study treatment will be administered via the ELLIPTA DPI in the morning. 
• 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 4/end of study (EOS) or, if applicable, the 
Early Withdrawal Visit. A participant will be considered to have completed the 
study upon completion of all assessments and procedures for Visit 4/EOS and 
including a successful follow-up contact/visit. 


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4.2. 
Scientific Rationale for Study Design 
This study will use a multicenter, randomized, double-blind, 4 arm parallel-group design. 
This is a well-established design to evaluate the efficacy and safety of an investigational 
drug. A placebo arm is not included as it is not considered appropriate for patients with 
inadequately controlled asthma despite maintenance therapy. 
The primary objective of this study is comparing the efficacy of FF/UMEC/VI 
administered once daily via a dry powder inhaler, vs FF/VI, in Chinese participants with 
asthma uncontrolled on ICS/LABA therefore examining the effect of adding UMEC to 
FF/VI. Trough FEV1 is a well characterised and accepted endpoint used to assess 
bronchodilator effects and has shown to be responsive to UMEC with clinically 
meaningful benefits in the 205715 study. 
Assessment of the response after 8-12 weeks is recommended in GINA and China asthma 
guidelines [GINA, 2020, CAPG, 2016]. This ensures enough time to assess a response to 
treatment. Relvar (FF/VI) asthma local trials have demonstrated significant improvement 
in FEV1 at 12w (China NDA approval in June 2018) with maintenance of effect at Week 
24. In addition, the pulmonary function response at 12 weeks is maintained at week 24 in 
studies of long-acting muscarinic treatments, including UMEC in the global pivotal Phase 
IIIa study 205715 (CAPTAIN). Thus, we consider that a 12-week study in Chinese 
asthma patients, in combination with the trough FEV1 data from study 205715 at Week 
12, will provide robust data to evaluate the response of asthma patients in China and will 
minimize the time to bring this medicine to patients. 
The study design mirrors the design of study 205715, which demonstrated benefits for a 
global population of asthma patients uncontrolled on ICS/ LABA. This study will 
evaluate the effects in Chinese patients and, assuming that effects consistent with the 
global population are observed, a more precise evaluation of the benefit in this 
subpopulation will conducted by combing data from the local China study with 205715 
using Bayesian dynamic borrowing (see Statistical Considerations in Section 9 ). The 
potential to borrow information from the global dataset is based on the premise that the 
underlying disease, its general management and the response to UMEC is similar in 
Chinse and non-Chinese patients. 
4.3. 
Justification for Dose 
The proposed dose and dosing regimen of FF/UMEC/VI in Chinese patients are 
100/62.5/25 and 200/62.5/25 µg once daily, which were included in global pivotal 
205715 CAPTAIN study. The dual combinations of FF/VI is available with two doses of 
FF (100 and 200 µg) combined with VI 25 µg (i.e. 100/25 and 200/25 µg). The global 
pivotal 205715 CAPTAIN study compared FF/UMEC/VI with the same FF dose of 
FF/VI (100/62.5/25 or 100/31.25/25 µg vs. 100/25; 200/62.5/25 or 200/31.25/25 vs. 
200/25 µg).  The objectives of this study are to assess single inhaler triple therapy 
(FF/UMEC/VI) compared with the same FF dose of FF/ VI in adult Chinese asthma 
patients (100/62.5/25 vs. 100/25 µg, 200/62.5/25 vs. 200/25 µg). 
The 62.5 µg UMEC dose for the FF/UMEC/VI combination has been selected based on 
data from the pivotal phase III CAPTAIN study. This study demonstrated a clinically 


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meaningful and statistically significant difference in clinic Trough FEV1 for UMEC 62.5 
containing FF/UMEC/VI treatment groups compared with FF/VI. The numerical 
difference in trough FEV1 between the UMEC 31.25- and UMEC 62.5-containing 
FF/UMEC/VI treatments was small (and it should be noted that the results for groups 
receiving UMEC 31.25 were not adjusted for multiplicity), but for measures of patient 
centric outcomes such as asthma control and symptoms a consistently greater effect was 
observed for UMEC 62.5 containing FF/UMEC/VI treatments compared with UMEC 
31.25 containing FF/UMEC/VI treatments. Further, a similar trend was observed for the 
reduction in annualized rate of moderate/severe exacerbations with FF/UMEC/VI 
100/62.5/25 reducing the annualised rate by 21.8% vs 12% for FF/UMEC/VI 100/31.25 
/25, both relative to FF/VI 100/25, although the difference was not statistically 
significant.  
Pharmacokinetic (PK) profiles of FF/UMEC/VI as mono- or comb- therapies have been 
well characterized in Chinese healthy participants. The PK data showed low, dose-
dependent systemic exposure and no meaningful PK interactions was observed among 
the components when combined, which is generally consistent with those in healthy 
Western participant studies (200587, CTT116415).  
In global studies for Trelegy in patients with asthma and COPD indications, systemic 
exposure of FF, UMEC and VI was low and the PK profiles for the three components 
showed no clinically relevant difference across ethnicities [205715 PopPK Report GSK 
Document Number 2018N393131_00; 208059 COPD PK Report GSK Document 
Number 2017N329683_00].  
In COPD studies (208059 COPD PK Report GSK Document 2017N329683_00), that 
included 15% Chinese patients, consistent systemic exposure of FF, UMEC and VI was 
observed between Chinese and non-Chinese patients. Some covariates, such as 
bodyweight, age, smoking etc, were identified as significant covariates on PK in asthma 
and COPD patients, however, the effects were not considered clinically relevant.  
FF/UMEC/VI has a large safety database in patients with asthma in 205715 CAPTAIN 
study with a total of 2439 patients randomized to the study. Safety data did not identify 
any new findings for FF/UMEC/VI in the study considering the known class effects of 
ICS, LAMA and LABAs in a population of patients with asthma. FF/UMEC/VI has a 
similar safety profile in Japanese asthma patients compared to non-Japanese patients 
included in the study. 
FF/UMEC/VI also has a similar safety profile in Chinese and non-Chinese COPD 
patients. The safety has been well characterized in large long-term studies across 
ethnicities and there is a large post marketing safety database globally. As of March 
2019, the total cumulative clinical trial exposure was 8,072 patients with 541,890 patient 
years cumulative marketing experience for FF/UMEC/ VI 100/62.5/25. The safety profile 
of FF/VI in Chinese and non-Chinese asthma patients is similar. 
Based on the information discussed above, the proposed dose and dosing regimen 
FF/UMEC/VI 100/62.5/25 and 200/62.5/25 µg are considered appropriate to be studied in 
Chinese participants with asthma. 


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4.4. 
End of Study Definition 
The end of the study is defined as the date of last scheduled procedure shown in the 
Schedule of Activities for the last participant in the trial. 
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the last scheduled procedure shown in the Schedule of 
Activities. 
5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrolment criteria, 
also known as protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria 
apply: 
Age 
1. Participant must be 18 years or older at the time of signing the informed consent. 
 
Type of Participant and Disease Characteristics 
2. Diagnosis: Participants with documented history asthma diagnosis as defined by the 
Global Initiative for Asthma [GINA, 2020] at least one year prior to Visit 0.  
3. Symptomatic: Participants with inadequately controlled asthma (ACQ-6 score ≥1.5) 
despite ICS/LABA maintenance therapy at Visit 1. 
4. Current Asthma Maintenance Therapy:  Participants are eligible if they have 
required daily ICS/LABA for at least 8 weeks prior to Visit 0 with no changes to 
maintenance asthma medications during the 6 weeks immediately prior to Visit 0 
(including no changes to a stable total dose of ICS of >250 µg/day fluticasone 
proprionate [FP, or equivalent]). 
Examples of acceptable doses of commonly prescribed ICS medication are provided 
in the GINA guidelines [GINA, 2020].  Dosing regimen (once or twice daily to equal 
the total daily dose) should be restricted to the current local product labels/treatment 
guidelines. 
5. Spirometry: 
A best pre-bronchodilator morning (AM) FEV1 ≥30% and <85% of the predicted 
normal value at Visit 1.  Predicted values will be based upon the European 
Respiratory Society (ERS) Global Lung Function Initiative [Quanjer, 2012]. 
6. Reversibility of Disease: airway reversibility defined as ≥12% and ≥200 mL increase 
in FEV1 between 20 and 60 minutes following 4 inhalations of albuterol/salbutamol 
aerosol at Visit 1. 


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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 3-week run-in period (see Section 8.2.1). 
7. Short-Acting β2 Agonists (SABAs): All participants 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. Participants must be judged capable of withholding 
albuterol/salbutamol for at least 6 hours prior to study visits. 
Sex 
8. Male or female  
Contraceptive/Barrier Requirements 
Contraceptive use should be consistent with local regulations regarding the methods of 
contraception for those participating in clinical studies. 
A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
one of the following conditions applies: 
o Is a woman of non-childbearing potential (WONCBP) as defined in Section 
10.4 Contraception and Barrier Guidance; 
OR 
o Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of <1% per year), preferably with low user dependency, as 
described in Appendix 4, for the duration of the study – screening to safety 
follow-up contact. The investigator should evaluate the potential for 
contraceptive method failure (e.g., noncompliance, recently initiated) in 
relationship to the first dose of study intervention. 
• A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as 
required by local regulations) within 24 hours before the first dose of study 
intervention (see Section 8.3.5: Pregnancy Testing).  
o  If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a 
serum pregnancy test is required. In such cases, the participant must be 
excluded from participation if the serum pregnancy result is positive.  


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• Additional requirements for pregnancy testing during and after study intervention are 
located in Section 8.3.5 Pregnancy Testing 
• The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy 
Informed Consent 
9. Capable of giving signed informed consent as described in Section 10.1 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. 
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Pneumonia: Chest X-ray documented pneumonia in the 6 weeks prior to Visit 1. 
2. Asthma Exacerbation: Any asthma exacerbation requiring a change in maintenance 
asthma therapy in the 6 weeks prior to Visit 1. 
i. 
Note: Participants requiring a temporary change in asthma therapy (e.g., 
oral corticosteroids or increased dose of ICS) to treat an exacerbation in 
the 6 weeks prior to Visit 1 are not explicitly excluded at Visit 1 provided 
that, at the Investigator’s discretion, the participant’s condition is stable 
after they have resumed their pre-exacerbation maintenance asthma therapy 
(without modification) and they are considered appropriate for enrolment 
into this study of up to 12 weeks’ duration. 
3. Chronic Obstructive Pulmonary Disease: Participants with the diagnosis of 
chronic obstructive pulmonary disease, as per Global Initiative for Chronic 
Obstructive Lung Disease (GOLD, 2016) guidelines, including all of the following: 
• 
History of exposure to risk factors (i.e., especially tobacco smoke, occupational 
dusts and chemicals, smoke from home cooking and heating fuels). For personal 
tobacco use, see Exclusion criterion number 14: Tobacco Use; 
AND 
• 
A post-albuterol/salbutamol FEV1/Forced Vital Capacity (FVC) ratio of <0.70 
and a post-albuterol/salbutamol FEV1 of 70% of predicted normal values; 
AND 
• 
Onset of disease 40 years of age 
4. Concurrent respiratory disorders: Participants with current evidence of 
pneumonia, active tuberculosis, lung cancer, significant bronchiectasis, sarcoidosis, 
lung fibrosis, pulmonary hypertension, interstitial lung diseases or other active 
pulmonary diseases or abnormalities other than asthma. 


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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 
8. Clinically significant ECG abnormality: Evidence of a clinically significant 
abnormality in the 12-lead ECG performed during screening. The Investigator will 
determine the clinical significance of each abnormal ECG finding in relation to the 
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: 
• Atrial Fibrillation (AF) with rapid ventricular rate >120 beats per minute 
(BPM); 
• Sustained or nonsustained ventricular tachycardia (VT); 
• Second degree heart block Mobitz type II and third degree heart block (unless 
pacemaker or defibrillator had been inserted); 
• QTcF ≥500 msec in patients with QRS <120 msec and QTcF ≥530 msec in 
patients with QRS ≥120 msec 
9. Unstable or life-threatening cardiac disease: 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 [American Heart 
Association, 2016] 
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 


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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 
14. Tobacco Use: Participants who are: 
• 
Current smokers (defined as participants who have used inhaled tobacco 
products within the 12 months prior to Visit 1 [i.e., cigarettes, e-
cigarettes/vaping, cigars or pipe tobacco]). 
• 
Former smokers with a smoking history of 10 pack years (e.g., 
20 cigarettes/day for 10 years). 
Note: Refer to the SRM for the formula for calculating pack years. 
15.  Drug/alcohol abuse: Participants with a known or suspected history of alcohol or 
drug abuse within the last 2 years.  
Other Exclusions 
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.  
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. 
5.3. Lifestyle Considerations 
Not applicable 
5.4. Pre-Screening/Screening/Run-in Failures 
A participant will be assigned a participant number at the time the informed consent is 
signed. 


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The study interactive response technology (IRT) system (RAMOS NG) will be contacted 
to report pre-screen failures. The following information will be collected in the eCRF for 
participants who are pre-screen failures: 
• Date of informed consent form (ICF) signature 
• Demographic information including race, age and gender 
• Participant number 
• Investigator signature page 
For the purposes of this study pre-screen failures, screening failures and run-in 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. 
• 
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 (Randomisation) procedures. 
Any participant who completes the run-in period and then meets the eligibility 
criteria and is dispensed the treatment period study medication at Visit 2 is 
considered to have entered the treatment period. 
RAMOS NG will be contacted to report pre-screening, screening and run-in failures. 
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 failure 
information is required including demography, screen/run-in failure details, eligibility 
criteria, and any SAEs (see Section 8.4.4 and Section 10.3 Appendix 3). Further details 
are provided in the study-specific eCRF completion guidelines document.  
5.5. 
Criteria for Randomisation 
At the end of the run-in period, a participant will be eligible to enter randomized 
treatment period of the study if he/she meets the following criteria: 
5.5.1. 
Inclusion Criteria for Randomization 
Type of Participant and Diagnosis Including Disease Severity 
1. Inadequately controlled asthma: Participants with inadequately controlled asthma 
(ACQ-6 score ≥1.5) at Visit 2. 
2. Percent-predicted FEV1: A best pre-bronchodilator morning (AM) FEV1 30% and 
<90% of the predicted normal value at Visit 2. Predicted values will be based upon 
the ERS Global Lung Function Initiative [Quanjer, 2012]. 


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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%) 
Diary 
4. Compliance with completion of the eDiary reporting defined as completion of all 
questions/assessment on 4 of the last 7 days during the run-in period. 
5.5.2. 
Exclusion Criteria for Randomization 
Concurrent Conditions/Medical History 
1. Respiratory Infection: Occurrence of a culture-documented or suspected bacterial or 
viral infection of the upper or lower respiratory tract, sinus or middle ear during the 
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. Severe asthma exacerbation: Evidence of a severe exacerbation during screening or 
the run-in period, defined as deterioration of asthma requiring the use of systemic 
corticosteroids (tablets, suspension, or injection) for at least 3 days1 or an in-patient 
hospitalization or emergency department visit due to asthma that required systemic 
corticosteroids. 
1 For participants on maintenance systemic corticosteroids, at least double the 
existing maintenance dose for at least 3 days is required. 
Concomitant Medications/Treatments 
3. Asthma medication: Changes in asthma medication (excluding run-in medication 
and albuterol/salbutamol inhalation aerosol provided at Visit 1). 


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Diagnostic Assessments And Other Criteria 
4. Laboratory test abnormalities: Evidence of clinically significant abnormal 
laboratory tests during screening or run-in which are still abnormal upon repeat 
analysis and are not believed to be due to disease(s) present.  Each Investigator will 
use his/her own discretion in determining the clinical significance of the abnormality. 
5.6. 
Criteria for Temporarily Delaying  
Temporarily delaying of study intervention administration is not allowed. 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT 
THERAPY 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol. 
6.1. Study Intervention(s) Administered 
The ELLIPTA device will be used during the run-in period and the treatment period.The 
ELLIPTA DPI is a moulded plastic two-sided device that can hold two individual blister 
strips.  Descriptions of the study treatments administered via the ELLIPTA are provided 
in Table 1 


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Table 1 
Description of Study Treatment Inhalation Powder in ELLIPTA 
 
FF/UMEC/VI  
 
First strip  
Second strip  
FF blended with lactose 
UMEC and VI blended with 
lactose and magnesium stearate 
Dosage Form  
ELLIPTA with 30 doses (2 strips with 30 blisters per strip) 
Unit Dose 
Strengths  
100 or 200 µg per blister 
UMEC 62.5 µg per blister, VI 25 
µg per blister  
Physical 
description  
Dry white powder 
Dry white powder 
Route of 
Administration  
Inhaled 
FF/VI 
First strip 
Second strip 
FF blended with lactose 
VI blended with lactose and 
magnesium stearate 
Dosage Form  
ELLIPTA with 30 doses (2 strips with 30 blisters per strip) 
Unit Dose 
Strengths  
100 or 200 µg per blister 
25 µg per blister 
Physical 
description  
Dry white powder 
Dry white powder 
Route of 
Administration  
Inhaled 
 
Each participant will be instructed on the proper use of the ELLIPTA and will inhale 
once from the ELLIPTA each morning for the duration of the 3-week run-in period and 
the subsequent treatment period. 
At Visit 2, the run-in period ELLIPTA device will be collected from all participants.   All 
356 participants will be randomized to one of the 4 double-blind treatment arms 1:1:1:1:  
• FF/VI ELLIPTA 100/25 µg QD 
• FF/UMEC/VI ELLIPTA 100/62.5/25 µg QD  
• FF/VI ELLIPTA 200/25 µg QD  
• FF/UMEC/VI ELLIPTA 200/62.5/25 µg QD 
Participants will self-administer their first dose of double-blind study treatment in the 
clinic during Visit 2 and will continue to administer double-blind study treatment at 
approximately the same time each morning for the duration of the treatment period. 
Participants will take their last dose of study treatment in the clinic during Visit 4/EOS 
(or at the Early Withdrawal Visit, if applicable) and a safety follow-up will be conducted 
approximately one week later. 
 


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ARM Name 
FF/VI 
ELLIPTA 
100/25 µg QD 
 
FF/UMEC/VI 
ELLIPTA 
100/62.5/25 µg 
QD  
FF/VI ELLIPTA 
200/25 µg QD  
FF/UMEC/VI 
ELLIPTA 
200/62.5/25 
µg QD 
 
Intervention 
Name 
FF/VI ELLIPTA 
100/25 µg  
FF/UMEC/VI 
ELLIPTA 
100/62.5/25 µg  
FF/VI ELLIPTA 
200/25 µg  
FF/UMEC/VI 
ELLIPTA 
200/62.5/25 µg 
Type  
Drug 
Drug 
Drug 
Drug 
Dose 
Formulation  
ELLIPTA with 30 
doses (2 strips 
with 30 blisters 
per strip) 
ELLIPTA with 30 
doses (2 strips 
with 30 blisters 
per strip) 
ELLIPTA with 30 
doses (2 strips 
with 30 blisters 
per strip) 
ELLIPTA with 
30 doses (2 
strips with 30 
blisters per strip) 
Unit Dose 
Strength(s)  
FF100 µg, VI 
2 5µg per blister 
FF100 µg, UMEC 
62.5 µg, VI 25 µg 
per blister 
FF200 µg, VI 
25 µg per blister 
FF200 µg, 
UMEC 62.5 µg, 
VI 25 µg per 
blister 
Dosage 
Level(s) 
one dose daily 
one dose daily 
one dose daily 
one dose daily 
Route of 
Administration 
inhaled  
inhaled  
inhaled  
inhaled  
Use 
active-
comparator,  
Experimental 
active-
comparator,  
Experimental 
IMP and NIMP 
NIMP 
IMP  
NIMP 
IMP 
Sourcing 
 
Provided centrally 
by the Sponsor 
Provided centrally 
by the Sponsor 
Provided centrally 
by the Sponsor 
Provided 
centrally by the 
Sponsor 
Packaging 
and Labeling 
 
Study 
Intervention will 
be provided in 
ELLIPTA. Each 
ELLIPTA will be 
labeled as 
required per 
country 
requirement. 
Study 
Intervention will 
be provided in 
ELLIPTA. Each 
ELLIPTA will be 
labeled as 
required per 
country 
requirement. 
Study 
Intervention will 
be provided in 
ELLIPTA. Each 
ELLIPTA will be 
labeled as 
required per 
country 
requirement. 
Study 
Intervention will 
be provided in 
ELLIPTA. Each 
ELLIPTA will be 
labeled as 
required per 
country 
requirement. 
 


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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 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. 
6.1.1. 
Study Treatment and albuterol/salbutamol Return 
All used and unused study treatment, albuterol/salbutamol will be returned to GSK at 
the end of the study to be available for disposal. Detailed instructions for the return 
of the study drug can be found in the 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 IRT system 
(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 IRT system. 
In addition, any DPI or MDI that fails to function properly must be identified and 
returned to GSK for testing. Details of the failure will be documented in the eCRF. 
6.2. Preparation/Handling/Storage/Accountability 
• The investigator or designee must confirm appropriate temperature conditions 
have been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention. 
• Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and 
monitored (manual or automated) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff. 
• The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study intervention accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation, and final disposition records). 
• Further guidance and information for the final disposition of unused study 
intervention are provided in the Study Reference Manual or other specified 
location.  
• Under normal conditions of handling and administration, study intervention 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. 


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6.3. 
Measures to Minimize Bias: Randomization and Blinding 
The design is randomized and double-blind. A participant may continue in the study if 
that participant’s intervention assignment is unblinded during the treatment period. 
Efforts should be made to ensure the data of the participant are collected when possible.  
6.3.1. 
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 IRT system (RAMOS 
NG). Once a randomization number is assigned to a participant it cannot be reassigned to 
any other participant in the study. 
Following the 3-week run-in period and participant to satisfying all eligibility criteria, 
participants will be stratified by pre-study ICS treatment dosage strength (medium, high) 
at screening and randomized 1:1:1:1 to one of the following four double-blind treatments 
for the duration of the treatment period: 
• FF/VI 100/25 µg QD 
• FF/UMEC/VI 100/62.5/25 µg QD 
• FF/VI 200/25 µg QD 
• FF/UMEC/VI 200/62.5/25 µg QD 
all given once daily in the morning. 
Randomisation of all participants will be stratified by the participant’s pre-study ICS 
dosage (medium or high). ‘Medium’ dose ICS will be defined as >250 to ≤500 µg /day 
FP (or equivalent), and ‘high’ dose ICS will be defined as >500 µg /day FP (or 
equivalent). In the analyses, the actual ICS dose taken prior to the study will be used, not 
the strata under which the participants are randomised.  
The duration of double-blind treatment for each participant is 12 weeks. In accordance 
with the protocol-defined visit schedule, participants will have two on-treatment clinic 
visits conducted on an outpatient basis scheduled at Visits 3 (Week 4) and 4 (Week 12). 
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 IRT 
system (RAMOS NG) to randomize participants and manage study treatment supplies 
(including dispensing) is provided in the RAMOS NG IRT manual and SRM. 


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6.3.2. 
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 as soon as possible 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 reason for the unblinding must be fully documented in the eCRF  
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
intervention 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 intervention assignment, may be sent to investigators 
in accordance with local regulations and/or GSK policy. 
6.4. Study Intervention Compliance 
• When the individual dose for a participant is prepared from a bulk supply, the 
preparation of the dose will be confirmed by a second member of the study site staff.  
• When participants are dosed at the site, they will receive study intervention directly 
from the investigator or designee, under medical supervision.  The date and time of 
each dose administered in the clinic will be recorded in the source documents.  The 
dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering 
the study intervention.   
• At scheduled clinic visits, participant compliance with study treatment administration 
since the previous scheduled clinic visit will be assessed by recording the number of 
doses remaining in the ELLIPTA, as applicable, in the eCRF (see the SRM for 
details), by reviewing the eDiary (see Section 8.2.2) and by querying the participant, 
as necessary. Participants should be 80% to 120% compliant on taking study 
treatment between each pair of scheduled and consecutive on-treatment clinic visits. 
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. 
• When participants self-administer study treatment(s) at home (i.e. not at the study 
site), compliance with study treatment administration should be monitored by the 
Investigator (or designee) by reviewing the transmitted eDiary data via the vendor-


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provided portal (see Section 8.2.2); participants should be immediately contacted for 
re-education on treatment compliance if non-compliance (as assessed by the 
Investigator or designee) is observed. This re-education should be documented in the 
participant’s source document. 
• A record of the quantity of ELLIPTAs dispensed to and administered by each 
participant must be maintained and reconciled with study intervention and 
compliance records. Intervention start and stop dates, including dates for intervention 
delays and/or dose reductions will also be recorded. 
6.5. 
Dose Modification 
Not Applicable. 
6.6. 
Continued Access to Study Intervention 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 
poststudy care of the participant’s medical condition, whether or not GSK is providing 
specific post-study treatment. 
6.7. 
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 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. 
6.8. 
Concomitant Therapy 
All asthma medications used within approximately 6 weeks prior to pre-screening 
(Visit 0) and during the study (including the post-treatment period) should be recorded in 
the eCRF. 
All non-asthma medications taken during the study (after randomization including 
posttreatment) and any changes to concomitant medications will be recorded in the 
eCRF. 


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Note: Study provided albuterol/salbutamol should not be recorded in the eCRF; however 
non-study supplied albuterol/salbutamol and other inhaled short-acting beta2-agonist 
will be recorded in the eCRF.  
The minimum requirement is that the drug name, dose, route and the dates of 
administration are to be recorded. 
Medications initiated after completion of the assessments at 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. Participates who have completed the Early Withdrawal Visit 
are allowed to use any medications prescribed by the Investigator or primary care 
physician. 
6.8.1. 
Rescue Medicine 
The study site will supply inhaled short-acting beta2-agonist rescue medication that will 
be provided by the sponsor. The following rescue medication may be used: 
• Albuterol/Salbutamol MDI  
 Rescue albuterol/salbutamol will be provided and is permitted during the study. The 
number of puffs of albuterol/salbutamol self-administered by the participant each day for 
the relief of asthma symptoms should be recorded morning and evening in the eDiary. 
6.8.2. 
Permitted Medications and Non-Drug Therapies 
6.8.2.1. 
Permitted Asthma Medications 
In addition to study treatment, the following medications are permitted during this study: 
• Study-provided albuterol/salbutamol will be dispensed at Visit 1 for use as relief 
medication throughout the duration of the study. Participants must be judged 
capable of withholding albuterol/salbutamol for at least 6 hours prior to study 
visits. 
Temporary additions in medications are permitted for the treatment of 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 medical monitor/Sponsor 
Information Page): 
• An increase in ICS dose (including but not limited to the use of FP which may be 
used by the participant at a total daily dose deemed appropriate by the 
Investigator/treating physician). 


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• Systemic corticosteroids (tablets, suspension or injection) for no more than 2 days 
(or an increase in systemic corticosteroid dose for those participants receiving 
maintenance systemic corticosteroids for no more than 2 days). 
• An Investigator-advised change in SABA use (i.e., routinely scheduled versus as 
needed use). 
• Leukotriene receptor antagonists (LTRAs) and leukotriene modifiers. 
• Oral theophylline. 
• By definition, a severe asthma exacerbation will be treated with systemic 
corticosteroid (tablets, suspension or injection) for at least 3 consecutive days (or 
at least double the existing maintenance dose of systemic corticosteroid, if 
applicable, for at least 3 consecutive days). See Section 8.4.7. 
6.8.2.2. 
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, 


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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 for other conditions 
will be permitted. 
6.8.2.3. 
Permitted Non-Drug Therapies 
Continuous Positive Airway Pressure (CPAP) for the treatment of obstructive sleep apnea 
is permitted if initiated at least 6 weeks prior to the Screening Visit (Visit 1) and the 
participant continues CPAP treatment throughout the study. This treatment must be 
captured in the eCRF. 
6.8.3. 
Prohibited Medications and Non-Drug Therapies 
Use of the medications listed in Table 2 is not permitted during the study. 


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


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7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will 
remain in the study, if possible, to be evaluated until the last visit per SOA. See the SOA 
(Section 1.3) for data to be collected at the time of discontinuation of study intervention 
and follow-up and for any further evaluations that need to be completed. 
Participants that permanently stop IP are encouraged to remain in the study.  
Participants have the right to discontinue IP before the end of the study.  A participant 
may also be asked to discontinue IP at the Investigator’s discretion. 
Participants who withdraw from double-blind study treatment prematurely (for any 
reason) should, where possible, continue to be followed-up as per protocol until the 
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 acute 
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  
7.1.1. 
Liver Chemistry Stopping Criteria 
Liver chemistry stopping, and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology. 
Discontinuation of study intervention for abnormal liver tests is required when: 
• a participant meets one of the conditions outlined in the algorithm or  
• in the presence of abnormal liver chemistry not meeting protocol-specified 
stopping rules, if the investigator believes that it is in the best interest of the 
participant.  
7.1.2. 
QTc Stopping Criteria 
• If a clinically significant finding is identified (including, but not limited to 
changes from baseline in QT interval corrected using Fridericia’s formula [QTcF] 
after enrollment, the investigator or qualified designee will determine if the 


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participant can continue in the study and if any change in participant management 
is needed. This review of the ECG printed at the time of collection must be 
documented. Any new clinically relevant finding should be reported as an AE. 
Details on performing ECG assessments can be found in Section 8.3.3. 
• The QT interval corrected for heart rate by Fredericia’s formula (QTcF) must be 
used for each individual participant to determine eligibility for and 
discontinuation from the study. This formula may not be changed or substituted 
for the duration of the study. 
• QTcF must continue to be used for all participants for all QTc data being 
collected for data analysis. Safety ECGs and other non-protocol specified 
ECGs are an exception. 
• The QTcF should be based on single or averaged QTcF values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording period.  
• For this study, the following QTc stopping criteria will apply: 
• QTcF>500 msec or uncorrected QT>600 msec 
• Bundle branch block: QTcF  530 msec 
• Change from baseline: QTcF> 60 msec 
7.1.3. 
Temporary Discontinuation 
Not Applicable 
7.1.4. 
Rechallenge 
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any participant participating in this study is not allowed. 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
• A participant may withdraw from the study at any time at his/her own request or 
may be withdrawn at any time at the discretion of the investigator for safety, 
behavioral, or compliance reasons. This is expected to be uncommon. 
• At the time of discontinuing from the study, if possible, an early discontinuation 
visit should be conducted, as shown in the SoA (Section 1.3) . See SoA for data to 
be collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 
• The participant will be permanently discontinued both from the study intervention 
and from the study at that time. 
• If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
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• 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. 
7.3. 
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, 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.  
Discontinuation of specific sites or of the study as a whole are handled as part of 
Appendix 1. 


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarized in the SoA (Section 1.3).  
• If Visit 4 couldn’t be done on site due to COVID-19 lockdown, the participant 
will be provided additional study drug and continue study treatment until they 
could come back to site for Visit 4; the time window of Visit 4 will be extended 
for 6 more weeks as the longest after 12 weeks’ treatment in these participants. 
• Protocol waivers or exemptions are not allowed  
• Immediate safety concerns should be discussed with the sponsor immediately 
upon occurrence or awareness to determine if the participant should continue or 
discontinue study intervention. 
• Adherence to the study design requirements, including those specified in the SoA, 
is essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that 
potential participants meet all eligibility criteria. The investigator will maintain a 
screening log to record details of all participants screened and to confirm 
eligibility or record reasons for screening failure, as applicable.  
• Procedures conducted as part of the participant’s routine clinical management 
(e.g., blood count) and obtained before signing of ICF may be utilized for 
screening or baseline purposes provided the procedure met the protocol-specified 
criteria and was performed within the time frame defined in the SoA. 
• Safety/Laboratory/analyte results that could unblind the study will not be reported 
to investigative sites or other blinded personnel until the study has been 
unblinded. 
• The maximum amount of blood collected from each participant over the duration 
of the study will not exceed 24 mL. 
• Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples. 
8.1. 
Screening and Critical Baseline Assessments 
8.1.1. 
Pre-screening 
Participants can perform the pre-screening Visit (Visit 0) up to 2 weeks prior (unless 
specifically authorised by the medical monitor) to or on the same day as the Screening 
Visit (Visit 1).  A participant number will be assigned at the time the ICF is signed.  
During the Pre-screening Visit, study designated personnel must provide informed 
consent to study participants. 
Once the informed consent document has been signed, pre-screening assessments can be 
conducted. The following demographic parameters will be captured: year of birth, sex, 
race and ethnicity. From the pre-screening visit onwards concomitant medications, 
exacerbations and SAEs (considered as related to study participation) must be reported. 


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8.1.2. 
Screening 
The following critical assessments will be conducted at Screening (Visit 1): 
• 
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 
• 
Asthma and other concurrent medications 
• 
ACQ-6 
• 
Pre-and post-albuterol/salbutamol lung function 
• 
Inclusion/Exclusion criteria assessment 
• 
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 run-in medications and albuterol/salbutamol; 
• 
Provide training of inhalation techniques to participants ensure participants can 
handle the inhalers correctly; 
8.1.3. 
Critical procedures performed at randomization Visit (Baseline 
Visit 2) 
• Review eDiary and retrain participant if required 
• Review Inclusion/Exclusion criteria 
• Check randomisation criteria 
• Dispense double blind treatment and rescue medications 
• Check the inhalation techniques of participants and retrain if needed to ensure 
participants can handle the inhalers correctly; 
8.2. 
Efficacy Assessments 
The timing of all efficacy assessments is documented in the SoA (see Section 1.3). 
8.2.1. 
Pulmonary Function Test 
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 (ATS)/ERS standards [Miller, 2005]. The highest of 3 
technically acceptable measurements will be recorded at each visit: 
 


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Pre-dose Spirometry: At Visits 2 through 4/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: 
• Between 6am and 11am on the day of the visit. 
• At the same time of day (1 hour) as the assessment performed at Visit 2 
(the baseline assessment) 
• At least 24 hours after the participant’s last dose of study treatment 
on the day prior to the visit. 
• Before the participant’s morning dose of study treatment on the day of the 
visit. 
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. 
8.2.1.1. 
Reversibility 
All reversibility evaluations should follow the recommendations of the ATS/ERS Task 
force: Standardization of Lung Function Testing [Miller, 2005]. A pre-bronchodilator 
spirometry assessment should be performed after a washout period of at least 6 hours for 
short-acting β2- agonists. 
 
Percent reversibility will be calculated as follows: 
 
(Post-bronchodilator FEV1 – Pre-bronchodilator FEV1) x 100 
                     Pre-bronchodilator FEV1 
Albuterol/Salbutamol 
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 3-week 
run-in period; however, the reversibility assessment may be repeated once within 7 days 
of Visit 1 if either criteria a) or b) are met: 
a) ³9% 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 3-week run-in period.  


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To perform the reversibility assessment, 4 puffs of the provided salbutamol/albuterol is 
administered (a spacer device may be used, if required). Following completion of the 
prebronchodilator assessment, a second spirometry assessment is performed within 20 to 
60 minutes after administration of the salbutamol/albuterol. 
8.2.2. 
Asthma Control Questionnaire (ACQ) 
At the clinic visits, 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 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. 
The original ACQ (ACQ-7) measures seven attributes of asthma control [Juniper, 1999]. 
Six attributes are measured with a patient-completed questionnaire, and the questions are 
designed to be self-completed by the participant. Participants will complete the ACQ at 
specified study visits. The six patient-reported questions (concerning nocturnal 
awakening, waking in the morning, activity limitation, shortness of breath, wheeze and 
rescue medication use) enquire about the frequency and/or severity of symptoms over the 
previous week. The response options for all these questions consist of a zero (no 
impairment/limitation) to six (total impairment/ limitation) scale. The recall period is the 
past week. The seventh attribute of the ACQ-7 is lung function (FEV1%-predicted) which 
will be included via study visit spirometry. 
Two shortened versions of the ACQ exist. The two shortened versions include the ACQ-5 
(a five-item measure using only the symptoms items) and the ACQ-6 (six-item measures 
and rescue bronchodilator use). The measurement properties were very similar for all 
versions of the ACQ (original 7-item ACQ and shortened versions) [Juniper, 2005; 
Wyrwich, 2011]. For all versions, a score of ≤0.75 indicates well-controlled asthma and a 
score ≥1.5 indicates poorly controlled asthma [Juniper, 2006]. A change of 0.5 in score 
suggests a clinically important change in score [Juniper, 2005]. The ACQ-7 (and its 
shorter versions) have been selected for assessment of asthma control due to their 
validation and acceptance by the Food and Drug Administration (FDA). 
In this study, participants will complete the ACQ-6 at the screening and randomization 
visits to determine eligibility for the study. ACQ-7 will be evaluated at V2, 3, 4 and EW 
for efficacy assessment. The ACQ-6 and ACQ-5 will be derived from ACQ-7. 
 
If on-site V3 or V4 or EW could not be conducted within time window due to COVID-19 
lockdown, the participant could complete ACQ-6 from home, under the investigator 
mode (refer to SRM for the details).  
 


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8.2.3. 
Daily Diaries 
Participants will be issued with an 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: 
• The number of inhalations of rescue albuterol/salbutamol used during the day and 
night. 
• Morning FF/VI medication use (during the run-in period only) 
• Morning double-blind study medication use (during the treatment period only) 
The data from the eDiary device will be automatically transmitted to a centralised server 
on a daily basis. The Investigator and designee(s) will be provided with access to the 
transmitted eDiary data via a vendor-provided portal and should review the data on an 
ongoing basis to check participant compliance with eDiary use and study treatment 
administration. 
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. 
8.2.3.1. 
Daily Diary Questionnaires, Assessments 
Rescue Albuterol/Salbutamol Use 
The number of puffs of albuterol/salbutamol self-administered by the participant each 
day for the relief of asthma symptoms will be recorded morning and evening in the 
eDiary. Upon awakening in the morning, participants should record the number of puffs 
of albuterol/salbutamol taken since completing the eDiary assessments on the evening of 
the previous day. Each evening, before going to bed, participants should record the 
number of puffs of albuterol/salbutamol taken since completing the eDiary that morning 
(except on the day of Visit 1 when the number of puffs of albuterol/salbutamol taken 
since being provided with the albuterol/salbutamol MDI should be recorded). Participants 
should be instructed that study-provided albuterol/salbutamol should be used on an “as 
needed” basis only. 
Any use of non-study-provided rescue medication should be recorded as a concomitant 
medication in the eCRF. Use of study-provided rescue albuterol/salbutamol should not be 
recorded as a concomitant medication in the eCRF; however, the use of study-provided 
albuterol/salbutamol prior to exercise as a preventative measure should be recorded as a 
concomitant medication in the eCRF. 


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8.2.4. 
Alerts 
For participants’ safety, the following alerts for a change from baseline in rescue 
medication use that may indicate the worsening of asthma, will be programmed into the 
eDiary: 
• 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. 
The baseline value, for the purpose of alerts, is defined as the average value over the last 
7 days prior to randomization. Participants will be instructed to contact the Investigator if 
any of the above alert criteria are met (either by telephone and/or by visiting the study 
clinic). 
8.3. Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.3.1. 
Physical Examinations 
• A complete physical examination will include, at a minimum, assessments of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. Height 
and weight will also be measured and recorded. 
• Investigators should pay special attention to clinical signs related to previous 
serious illnesses. 
8.3.2. 
Vital Signs 
Vital signs will be performed at the time points specified in the SoA (Section 1.3) prior to 
conducting spirometry and prior to taking the morning dose of study treatment. Blood 
pressure (systolic and diastolic) and pulse rate will be measured in the sitting position 
after approximately 5 minutes rest. A single set of values will be collected and recorded 
in the source documentation and eCRF.  
8.3.3. 
Electrocardiograms 
All sites will use standardised ECG equipment provided by a centralized external vendor. 
At the Screening Visit (Visit 1), a single 12-lead ECG and rhythm strip will be recorded 
after the measurement of vital signs but before performing the pre-bronchodilator 
spirometry assessment. At the post-randomization visits, a single 12-lead ECG and 
rhythm strip will be recorded 15 to 45 minutes after the administration of study treatment. 
Recordings will be made at the time-points defined in the SoA (Section 1.3). All ECG 
measurements will be made with the participant in a supine position having rested in this 
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For participants who meet the QTc, protocol defined stopping criteria, triplicate ECGs 
(over a brief period of time) should be performed (Section 7.1.2). 
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. 
8.3.4. 
Clinical Safety Laboratory Assessments 
All protocol required laboratory assessments (haematology, clinical chemistry and 
urinalysis) must be conducted in accordance with the Laboratory Manual, and 
Protocol SoA (Section 1.3). 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 ranges for all safety parameters will be provided to the site by the 
laboratory responsible for the assessments. 
All blood samples will be sent to a central laboratory for analysis (details provided in 
the Laboratory Manual). The blood sample will be collected before the participant’s 
dose of asthma treatment on the day of the visit. 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. 
Haematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 3. 


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Table 3 
Protocol Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Haematology 
Platelet Count  
RBC Indices: 
WBC count with Differential: 
Red Blood Cell (RBC) 
Count 
Mean 
Corpuscula 
Volume 
（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 
• FSH and estradiol (as needed in females of non-reproductive 
potential only) 
• Serum/urine hCG Pregnancy test (as specified in the SoA [Section 
1.3]) 
NOTES: 
• 
Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up 
Assessments after liver stopping or monitoring event are given in Section 7.1.1 
and Appendix 5. 
 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study 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 clinically significant/any 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. 


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8.3.5. 
Pregnancy Testing 
• Refer to Section 5.1 Inclusion Criteria for pregnancy testing entry criteria. 
• Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at scheduled study visits during study intervention period. 
• Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at the end of relevant systemic exposure and correspond with the time 
frame for female participant contraception in Section 5.1 Inclusion Criteria 
• Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the 
absence of pregnancy at any time during the participant’s participation in the 
study. 
8.4. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and 
Other Safety Reporting 
The definitions of adverse events (AE) or serious adverse events (SAEs) can be found in 
Section 10.3. 
The definitions of unsolicited and solicited adverse events can be found in Section 10.3. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant's legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study intervention or the 
study, or that caused the participant to discontinue the study intervention or study (see 
Section 7).  
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 
• All SAEs will be collected from the signature of consent form until the follow-up 
visit at the time points specified in the SoA (Section 1.3). However, any SAEs 
assessed as related to study participation (e.g., study intervention, 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.  
• All AEs will be collected from the start of intervention until the follow-up visit at the 
time points specified in the SoA (Section 1.3). 
• Medical occurrences that begin before the start of study intervention but after 
obtaining informed consent will be recorded as Medical History/Current Medical 
Conditions not as AEs. 


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• All SAEs will be recorded and reported to the sponsor or designee immediately and 
under no circumstance should this exceed 24 hours, as indicated in Appendix 3. The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it 
being available. 
• Investigators are not obligated to actively seek information on AEs or SAEs after the 
conclusion of the study participation. 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 to be reasonably related to the study intervention or 
study participation, the investigator must promptly notify the sponsor. 
8.4.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the 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 medical problems experienced and medications used during the study (please 
refer to the SRM for further details). This paper worksheet will be used to assist 
participant recall in discussions with the Investigator (or designee), for site staff to then 
enter as appropriate in the eCRF. 
8.4.3. 
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 8.4.8), will be followed until the event is resolved, 
stabilized, otherwise explained, or the participant is lost to follow-up (as defined in 
Section 7.3). Further information on follow-up procedures is given in Appendix 3. 
8.4.4. 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the investigator to the sponsor of an SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.  
• The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators. 
• An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will 
review and then file it along with the Investigator’s Brochure (GSK Document 


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number 2012N131935_10）/IDFU/package insert or state other documents and will 
notify the IRB/IEC, if appropriate according to local requirements. 
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 
8.4.5. 
Pregnancy 
• Details of all pregnancies in female participants will be collected after the start of 
study intervention and until the safety follow-up contact/visit. 
• If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the female 
participant pregnancy. While pregnancy itself is not considered to be an AE or SAE, 
any pregnancy complication or elective termination of a pregnancy for medical 
reasons will be reported as an AE or SAE. 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported 
as such. 
• The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and 
the information will be forwarded to the sponsor. 
• Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in Section 
8.4.4. 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 
discontinue study intervention. If possible, they could continue to be followed-up as 
per protocol until the completion of the Safety Follow-up assessments. 
8.4.6. 
Cardiovascular and Death Events 
For any cardiovascular events detailed in Section 10.3.3  and all deaths, whether or not 
they are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF 
will be required to be completed. These sections include questions regarding 
cardiovascular (including sudden cardiac death) and non-cardiovascular death.  
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion.   
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported. 


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8.4.7. 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs 
For the purposes of this study, severe asthma exacerbations will be collected and 
recorded on the asthma exacerbation eCRF page from the start of randomized double 
blinded treatment until Visit 4/EOS Visit or the Early Withdrawal Visit for those 
participants that withdraw from participation in the study (see Section 7). Severe asthma 
exacerbations should not be recorded as an adverse event unless: 
• They meet the definition of an Adverse Event (see Appendix 3) and occur: 
o After the start of study treatment until the start of double blinded study 
treatment or;  
o After completion of the Visit 4/EOS Visit (or Early Withdrawal Visit) 
assessments until the follow-up contact 
OR 
 
• They meet the definition of a Serious Adverse Event. (see Appendix 3) 
Note: The SAE page of the eCRF should be completed in addition to the asthma 
exacerbation eCRF page if the exacerbation occurs after the start of double 
blinded treatment but before completion of the Visit 4/EOS Visit or Early 
Withdrawal Visit assessments. 
For consistency, exacerbations separated by less than 7 days will be treated as a 
continuation of the same exacerbation. 
Participants will also complete a paper Medical Problems/Medications Taken worksheet 
to record medical problems experienced and medications used during the study, as well 
as all emergency department visits and/or hospitalizations that occur during their 
participation in the study. This paper worksheet must be reviewed by the Investigator (or 
designee) at each visit to the study site to assist the Investigator in the identification of 
new asthma exacerbations. 
All severe asthma exacerbations will be recorded in the eCRF by the Investigator (or 
designee). 
Severe Asthma Exacerbation 
A severe asthma exacerbation is defined as: 
The deterioration of asthma requiring the use of systemic corticosteroids (tablets, 
suspension or injection), or an increase from a stable maintenance dose*, for at least 3 
days. 
*For participants receiving maintenance systemic corticosteroids, at least double the 
maintenance systemic corticosteroid dose for at least 3 days is required. 
OR 


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An inpatient hospitalization or emergency department visit because of asthma, requiring 
systemic corticosteroids. 
8.4.8. 
Adverse Events of Special Interest  
AE groups of special interest have been defined as AEs which have specified areas of 
interest for one or more of class of drugs (ICS, LAMA, LABA). Some AE groups may 
have subgroups defined. 
The following table presents the current special interest AE groups and subgroups. These 
may be updated prior to conclusion of the study reporting. The final list, including the 
preferred terms which contribute to each of the groups will be documented a priori in the 
study Statistical Analysis Plan (SAP). 
Special interest AE group 
Special interest AE subgroup 
Cardiovascular effects 
Cardiac arrhythmia 
Cardiac failure 
Cardiac ischemia 
Stroke 
Anticholinergic syndrome 
- 
Urinary retention 
- 
Dry mouth / drying of 
airway secretions 
- 
Gastrointestinal obstruction 
- 
Antimuscarinic ocular 
effects / Corticosteroids 
associated eye disorders 
Glaucoma (antimuscarinic/corticosteroid) 
Cataracts (corticosteroid) 
Pneumonia and Lower 
Respiratory Tract Infection 
(LRTI) 
Pneumonia  
LRTI excluding pneumonia 
Adrenal suppression 
- 
Decreased bone mineral 
density and associated 
fractures 
- 
Effects on glucose 
- 


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Special interest AE group 
Special interest AE subgroup 
Effects on potassium 
- 
Tremor  
- 
Asthma intubations, and 
deaths 
- 
Hypersensitivity 
- 
Local steroid effects 
- 
8.4.9. 
Medical Device  
Medical devices are being provided by GSK for use in this study. GSK medical device 
incidents, including those resulting from malfunctions of the device, must be detected, 
documented, and reported by the investigator throughout the study. 
The definition of a Medical Device Deficiency can be found in Section 10.6. 
NOTE: Deficiencies fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Section 10.3 of the Protocol Amendment. 
Medical Device – this is any instrument, apparatus, appliance, material or other article, 
whether used alone or in combination, including the software necessary for its proper 
application intended by the manufacturer to be used for human beings for the purpose of:  
• diagnosis, prevention, monitoring, treatment or alleviation of disease; 
• diagnosis, monitoring, treatment, alleviation of or compensation for an injury or 
handicap; 
• investigation, replacement or modification of the anatomy or of a physiological 
process; 
• control of conception  
and which does not achieve its principle action in or on the human body by 
pharmacological, immunological or metabolic means, but may be assisted in its function 
by such means. 
Note: if these means fulfill the main purpose of the product, it is a Medicinal Product. 
The term medical device includes in vitro diagnostic (IVD) devices. 
The detection and documentation procedures described in this protocol apply to all GSK 
medical devices provided for use in the study. 
Incident – Any malfunction or deterioration in the characteristics and/or performance of 
a device, as well as any inadequacy in the labeling or the instructions for use which, 
directly or indirectly might lead to or might have led to the death of a patient, or user or 
of other persons or to a serious deterioration in their state of health. 


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Not all incidents lead to death or serious deterioration in health. The non-occurrence of 
such a result might have been due to other fortunate circumstances or to the intervention 
of health care personnel. 
It is sufficient that 
• An incident associated with a device happened and 
• The incident was such that, if it occurred again, it might lead to death or serious 
deterioration in health 
A serious deterioration in state of health can include: 
• A life-threatening illness (a) 
• Permanent impairment of body function or permanent damage to a body structure 
(b) 
• A condition necessitating medical or surgical intervention to prevent (a) or (b) 
• Any indirect harm as a consequence of an incorrect diagnostic or IVD test results 
when used within the manufacturer’s instructions for use 
• Fetal distress, fetal death or any congenital abnormality or birth defects  
Incidents include, for example: 
• inhalation of an object that has accidentally entered a spacer device and resulted 
in tracheal obstruction. 
Incidents do not include for example: 
• medical occurrences associated with metered-dose inhalers that do not fulfill the 
definition of a medical device (such events will be reported as medicinal product 
AEs) 
• non-serious medical occurrences which have no further safety implications for the 
participant or the device 
Malfunction – A failure of a device to perform in accordance with its intended purpose 
when used in accordance with the manufacturer’s instructions. 
Remedial Action – Any action other than routine maintenance or servicing of a device 
where such action is necessary to prevent recurrence of a reportable incident. 
8.4.10. 
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 


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• 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). 
8.4.11. 
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. 
8.5. 
Pharmacokinetics 
Based on systemic PK properties of FF/UMCE/VI as inhaled drugs, as well as abundant 
PK data for mono- or comb- therapies available from Chinese healthy and patients in 
historical studies, the current data are considered adequate for characterizing systemic PK 
profiles of FF/UMEC/VI in Chinese asthma patients. Therefore, no PK sample collection 
will be scheduled in the study. 
8.6. 
Genetics and/or Pharmacogenomics 
Genetics are not evaluated in this study. 
8.7. 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.8. 
Immunogenicity Assessments 
Immunogenicity are not evaluated in this study. 
8.9. 
Health Economics  
Health Economics parameters are not evaluated in this study. 


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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
This is a bridging study designed to evaluate the add-on benefit of UMEC in a single 
inhaler when compared to FF/VI in Chinese patients. The primary objective is to evaluate 
the effects of FF/UMEC/VI 100/62.5/25 µg on lung function, as measured by change 
from baseline in trough FEV1 regardless of study treatment discontinuation unrelated to a 
pandemic or due to any pandemic infection and in the absence of study treatment 
discontinuation due to the indirect impact of a pandemic, compared with FF/VI 100/25 
µg in Chinese participants with asthma over a 12-week treatment period. The effects of 
FF/UMEC/VI 200/62.5/25 µg on change from baseline in trough FEV1 at week 12 
compared with FF/VI 200/25 µg will also be assessed (secondary objective). The Chinese 
patient data collected in this study will be supplemented with data on the treatment 
difference for the same lung function endpoint from the global PhIIIa study 205715, 
using a Bayesian Dynamic Borrowing approach to analysis of the study (Schmidli, 2014). 
A frequentist hypothesis test will not be performed. Instead, the posterior distributions of 
the difference for both FF/UMEC/VI 100/62.5/25 µg vs. FF/VI 100/25 µg and 
FF/UMEC/VI 200/62.5/25 µg vs. FF/VI 200/25 µg in trough FEV1 at Week 12 will be 
derived, based on the Bayesian analysis including the global PhIIIa study 205715 
information and the data collected on Chinese patients in this study. The hypothesis of 
interest for each treatment comparison is that this difference is larger than zero, and the 
study will be considered to have shown evidence that supports this hypothesis if the 
posterior probability that the difference is larger than zero is at least 95% (a “positive 
result”). Please see Section 10.7.1 (Appendix 7) for further information on the choice of 
posterior probability. 
A hierarchical testing approach will be used to test each treatment comparison. If the test 
for the primary treatment comparison of FF/UMEC/VI 100/62.5/25 µg vs. FF/VI 100/25 
µg meets the definition of a positive result then the study will be deemed a success and 
then  the secondary treatment comparison of FF/UMEC/VI 200/62.5/25 µg vs. FF/VI 
200/25 µg will then be tested. 
9.2. 
Sample Size Determination 
Approximately 890 participants will be screened to achieve 356 randomly assigned to 
study intervention (89 patients per arm). This sample size denotes the number of 
participants with trough FEV1 data at Week 12, regardless of whether they are still on 
randomized treatment or have discontinued randomized treatment early (for reasons that 
are NOT an indirect impact of a pandemic). Study treatment discontinuation related to an 
indirect impact of a pandemic will be handled with a hypothetical strategy. This 
corresponds to the primary estimand strategy. 
The proposed sample size of 89 participants per arm has been determined using a pragmatic 
approach and reflects ~22% of the global Ph3a study (205715) sample size which would 
generally satisfy the requirement for a consistency evaluation within a global study. Please 
see Section 10.7.2 for further information on the selected sample size.  


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With this sample size, and using Bayesian dynamic borrowing with initial weight of 0.3 on 
the global 205715 study results (see Section 9.4.2 below), the probabilities of the study 
achieving a positive result for each treatment comparison under various assumptions about 
the true treatment difference in Chinese patients are shown in Table 4 (for further details 
on the a range of possible observed treatment differences in China see Statistical Appendix 
Section 10.7.3). These probabilities assume a between-individual SD of 350 mL for the 
primary endpoint (though probabilities are also shown for alternative SDs to assess the 
sensitivity to the assumed between participant sampling variation). This value was chosen 
based on results from the global asthma study 205715 (and the Japanese subset from the 
study) as well as global and Asian FF/VI asthma studies. It is a higher SD than observed 
in the global 205715 study (approximately 280-305 mL (Japanese subset (225-245 mL) 
based on the reported standard errors at Week 12 and Week 24), but a conservative estimate 
was chosen to take into account the higher variability that has been seen in other relevant 
asthma studies (FF/VI global and Asian studies’ SD ranged approximately 300-400 mL). 
The probability of a false positive result for the primary treatment comparison (assuming 
true treatment difference = 0 mL) is 19% (Table 4). This is higher than the typical type 1 
error usually applied in fully powered registration studies, but should be considered 
within the context of the bridging approach. A bridging approach is proposed because of 
the expected similarity of the treatment difference in Chinese patients and the global 
population (supported by similarities in the epidemiology, pathophysiology, 
pharmacology and clinical management of patients and consistency of treatment 
differences across key demographic factors including ethnicity), and hence there is low 
probability of the null effect being true. 
If the true treatment difference for the primary treatment comparison is 100 mL, the 
probability of the primary treatment comparison (FF/UMEC/VI 100/62.5/25 vs. FF/VI 
100/25) meeting the definition of a positive result is 85% (equivalent to the power of the 
study). If a positive result for the primary treatment comparison in the testing hierarchy is 
achieved, the secondary treatment comparison (FF/UMEC/VI 200/62.5/25 vs. FF/VI 
200/25) will be tested and the probability of meeting the definition of a positive result is 
83%, assuming the true treatment difference is 100 mL. 
Table 4 
Probability of Success for a range of possible true treatment 
differences and varying standard deviation 
Treatment 
comparison 
Standard 
Deviation 
Probability of Success†* 
when the 
true 
treatment 
difference is 
0 mL (false 
positive rate) 
when the 
true 
treatment 
difference is 
60 mL 
when the 
true 
treatment 
difference is 
86 mL 
when the 
true 
treatment 
difference is 
100 mL 
Primary:  
325 mL 
19% 
63% 
81% 
88% 


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Treatment 
comparison 
Standard 
Deviation 
Probability of Success†* 
when the 
true 
treatment 
difference is 
0 mL (false 
positive rate) 
when the 
true 
treatment 
difference is 
60 mL 
when the 
true 
treatment 
difference is 
86 mL 
when the 
true 
treatment 
difference is 
100 mL 
FF/UMEC/VI 
100/62.5/25 vs. FF/VI 
100/25 
350 mL 
19% 
61% 
78% 
85% 
400 mL 
21% 
58% 
74% 
81% 
Secondary: 
FF/UMEC/VI 
200/62.5/25 vs. FF/VI 
200/25 
325 mL 
16% 
60% 
78% 
86% 
350 mL 
18% 
58% 
76% 
83% 
400 mL 
19% 
55% 
72% 
79% 
†The probability of success values reported for the secondary treatment comparison (FF/UMEC/VI 
200/62.5/25 compared to FF/VI 200/25) are only relelvant after obtaining a positive outcome for the 
primary treatment comparison (FF/UMEC/VI 100/62.5/25 compared to FF/VI 100/25). 
*Results based on simulating 10,000 replicate studies and averaging the study results across replications. 


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9.3. 
Analysis Sets 
For purposes of analysis, the following populations are defined: 
Population 
Description 
Enrolled 
This population will comprise all participants for whom a 
record exists on the study database, including pre-screened 
participants that sign the informed consent document but do 
not complete a Visit 1 (screening) procedure (i.e., pre-
screening failures), or participants that complete at least one 
Visit 1 procedure but do not enter the run-in period (i.e., 
screening failures). 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 & run-in failures) 
and for the listing of AEs and SAEs for non-randomized 
participants 
Intent-to-Treat (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 
analyses. Participants will be analyzed according to the 
intervention they were randomized to.  
Safety Population 
All randomized participants who take at least 1 dose of 
study intervention. This will constitute the primary 
population for all safety analyses. Participants will be 
analyzed according to the intervention they actually 
received. 
9.4. 
Statistical Analyses 
The statistical analysis plan will be finalized prior to the lock and unblinding of the 
database and it will include a more technical and detailed description of the statistical 
analyses described in this section. This section is a summary of the planned statistical 
analyses of the most important endpoints including primary and key secondary endpoints. 


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9.4.1. 
General Considerations 
For clinic FEV1, the baseline value is the last acceptable/borderline acceptable pre-dose 
FEV1 prior to randomized treatment start date (Visit 2). 
9.4.2. 
Efficacy Analyses 
Bayesian Dynamic Borrowing Design 
Bayesian dynamic borrowing (BDB) provides a clinically and statistically-rigorous 
method to analyse this China bridging study given an explicit, pre-specified assumption 
about the relevance of the global 205715 study results to the Chinese population. It is 
expected that there is a similar benefit: risk profile in Chinese patients as compared to 
non-Chinese patients. This conclusion is based on the observations that:  
• The disease (including its risk factors and pathophysiology) and its management 
are similar in Chinese and non-Chinese patients CAPG, 2016; Huang, 2019; Lin, 
2018] 
• Clinical data from multiple studies with the active ingredients (FF/UMEC/VI) in 
varying combinations and monotherapy in COPD and asthma studies have shown 
similar risk:benefit profiles for Chinese patients from China and non-Chinese 
patients [Lin, 2019; 205715 PoPPK Report; CTT11685 GSK Document Number 
2017N329683_00; HZA113719 China CSR GSK Document Number 
2013N169446_00; HZA113714; HZA106827 CSR GSK Document Number 
2011N124014_00; HZA106829 CSR GSK Document Number 2011N128470_01] 
• No clinically relevant difference in PK of FF/UMEC/VI is expected between 
Chinese and non-Chinese asthma patients [205715 PopPK Report GSK Document 
Number 2018N393131_00, CTT11685, GSK Document Number 
2017N329683_00]. The safety profile of FF/ UMEC/ VI (Trelegy) is expected to 
be similar in Chinese and non-Chinese patients [Lin, 2019; 205715 PopPK Report 
GSK Document Number 2018N393131_00, Japan asthma ethnosensitivy report 
GSK Document Number 2019N411703_00; HZA113719 China CSR GSK 
Document Number 2013N169446_00; HZA106827 CSR GSK Document 
Number 2011N124014_00] 
 
Using the Bayesian approach, we can test the probability that the treatment difference in 
change from baseline in trough FEV1 at Week 12 is greater than 0 mL and assess the 
extent to which the data from this China bridging study supports the assumption of 
similarity with global 205715 study results, and obtain an estimate of the true treatment 
difference in Chinese patients based on a weighted combination of the China results and 
global results.  
The weight given to the global 205715 study data in this estimate is commensurate with 
the strength of evidence of similarity provided by the China data. The BDB analysis 
‘learns’ how much of the global 205715 study information to borrow based on the 
consistency between the observed treatment differences in the China and global studies 
and updates the weight on the global 205715 results accordingly.  


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• The stronger the evidence of consistency, the greater the increase in the updated 
(posterior) weight on the informative component relative to the prior weight, and 
hence the greater the borrowing from the global study results.  
• Conversely, if the China study results are very different to the global study 
results, the informative component is down-weighted and final inference is based 
mostly on the observed data in the China study alone.  
• The mechanism by which the weight is updated is entirely pre-specified and 
mathematically rigorous (Schmidli, 2014)  
By borrowing information from the global 205715 study, the data-driven weighted 
average treatment difference obtained from the BDB analysis is expected to be a more 
precise estimate of the true treatment difference in China than the observed treatment 
difference in the China study alone.  
The Informative Prior and Prior Weight 
The Bayesian dynamic borrowing approach will use the Week 12 results from the global 
205715 study as an ‘informative’ prior for each of the two treatment comparisons of 
interest in this China bridging study. In the primary analysis for the primary treatment 
comparison of FF/UMEC/VI 100/62.5/25 vs FF/VI 100/25 for change from baseline in 
trough FEV1 after 12 weeks in the planned China study, the global prior component is 
obtained from the sampling distribution of the difference in trough FEV1 at Week 12 
between the FF/UMEC/VI 100/62.5/25 vs FF/VI 100/25 arms in the global study 205715. 
The mean difference and its associated standard error are 86 mL and 20.1 mL, 
respectively, leading to a Normal distribution with mean 86 and standard deviation 20.1 
as the global prior component for the primary treatment comparison.  
Similarly, in the primary analysis for the secondary treatment comparison of 
FF/UMEC/VI 200/62.5/25 vs FF/VI 200/25 for change from baseline in trough FEV1 
after 12 weeks in the planned China study, the global prior component is obtained from 
the sampling distribution of the difference in trough FEV1 at Week 12 between the 
FF/UMEC/VI 200/62.5/25 vs FF/VI 200/25 arms in the global 205715 study. The mean 
treatment difference and its associated standard error are 100 mL and 20.0 mL, 
respectively, leading to a Normal distribution with mean 100 and standard deviation 20.0 
as the global prior component for the secondary treatment comparison. 
The Week 12 data from the global study was used for the informative prior, as it is 
expected that the true treatment difference in Chinese participants should be similar to 
what was observed in the global 205715 study. A second ‘weak’ prior distribution 
assuming no knowledge of the treatment difference in China will also be specified, to 
allow for the possibility that the global 205715 data do not provide relevant information 
about the treatment difference in Chinese patients. A weighted combination of the 
‘informative’ and ‘weak’ priors will be used to construct a robust mixture prior. These 
two components of the mixture prior will be fully pre-specified before the study starts. 
In the primary analysis, a prior weight of 30% is proposed for the informative component 
of the robust mixture prior, with the remainder of the weight (70%) placed on the weak 
prior to reflect a conservative starting position regarding the assumed relevance of the 
global 205715 results to Chinese patients. See Statistical Appendix Section 10.7.4 for 


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more details on the robust mixture prior and Section 10.7.5 for details on the choice of 
prior weight. 
 
The initial weight (0.3) assigned to the informative global component of the prior will be 
updated by the data observed in this China bridging study (as described at the start of  
Section 9.4.2).  
Effective Sample Size 
The updated weight itself is not directly interpretable as the fraction of the global study 
sample size that is borrowed. Instead, the effective sample size (ESS) borrowed from the 
global study can be quantified using the moment method implemented in the RBesT R 
software package v1.5-3 [Weber, 2019] Table 5 shows the expected value of the ESS 
borrowed from the global 205715 study for each treatment comparison when the true 
treatment difference in China is assumed to be 0 mL, 60 mL, 86 mL or 100 mL. This 
shows that, for both treatment comparisons, the ESS is comparable (in the range 91 to 
118 patients’ worth of information per arm) to the actual sample size in the China study 
(89 patients per arm) when true China treatment difference is consistent (in the range 60 
mL to 100 mL) with the global study result, providing reassurance that the China data are 
not overwhelmed by the global study information, even when the global results are highly 
relevant. The ESS borrowed from the global study is less than half the sample size of the 
China study when true effect is null (0 mL), providing reassurance that inference would 
be based mostly on the China data in a scenario where the global study information was 
not relevant.  
 


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Table 5 
Expected Effective Sample Size borrowed from the global 205715 
study for a range of possible true treatment differences 
Treatment 
comparison 
Expected value of Effective Sample Size borrowed per arm from the 
global 205715 study 
when the true 
treatment 
difference is 
0 mL (false 
positive rate) 
when the true 
treatment 
difference is 
60 mL 
when the true 
treatment 
difference is 
86 mL 
when the true 
treatment 
difference is 
100 mL 
Primary:  
FF/UMEC/VI 
100/62.5/25 vs. FF/VI 
100/25 
35 
107 
116 
113 
Secondary: 
FF/UMEC/VI 
200/62.5/25 vs. FF/VI 
200/25 
19 
91 
115 
118 
*Results based on simulating 10,000 replicate studies and averaging the study results across replications. 
Minimum Detectable Difference 
The minimum detectable difference (MDD) is the smallest treatment difference for each 
comparison that needs to be observed in this China study in order to meet the pre-
specified success criteria when combined with the global 205715 study results via the 
Bayesian dynamic borrowing analysis. For the proposed sample size of 89 patients per 
arm, assumed standard deviation of the change from baseline in trough FEV1 of 350 mL, 
chosen weight on the global component in the mixture prior of 0.3, and success rule that 
that posterior probability of the true treatment difference in China being > 0 mL is at least 
95%: 
• MDD for the FF/UMEC/VI 100/62.5/25 vs FF/VI 100/25 comparison is 45 mL 
• MDD for the FF/UMEC/VI 200/62.5/25 vs FF/VI 200/25 comparison is 49 mL 
For each treatment comparison, the MDD needed to conclude positive findings represents 
a threshold that is approximately 50% of the corresponding treatment difference observed 
in the global pivotal study 205715 (which were 86 mL and 100 mL for FF/UMEC/VI 
100/62.5/25 compared to FF/VI 100/25 and FF/UMEC/VI 200/62.5/25 compared to 
FF/VI 200/25, respectively). 
 


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9.4.2.1. 
Primary Endpoint 
The primary efficacy endpoint is the change from baseline in trough FEV1 at the end of 
the 12-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. 
The primary efficacy analysis will evaluate the primary estimand in the Intent-to-Treat 
population (see Section 3 for details of the primary estimand), by first using a mixed-
model repeated measures (MMRM) analysis of the observed China study data to get an 
estimate of the treatment difference for FF/UMEC/VI 100/62.5/25 vs. FF/VI 100/25 as 
well as an estimate of the variability. These estimates will then be combined with the 
global 205715 study using the robust mixture prior to obtain the final posterior 
distribution for the China treatment difference. The following fixed effects will be 
included in the model: interaction between treatment group and visit, interaction between 
baseline trough FEV1 and visit, pre-study ICS dosage strength (med, high), sex, baseline 
trough FEV1, visit and age at screening.  
The mean, median and 90% credible interval of this posterior distribution of the treatment 
difference will be reported, along with the probability that the true difference is greater 
than zero.   
The following informative normal 2-component robust mixture prior will be used for Δ:  
p(Δ) = 0.3*N(mean=86, SD=20.1) + 0.7*N(mean=0, SD=494.97) 
Where Δ is difference for FF/UMEC/VI 100/62.5/25 vs. FF/VI 100/25 in trough FEV1 at 
Week 12. 
Sensitivity analysis will be conducted to assess the impact of the different prior weights 
of the two normal components in the robust mixture prior, and the details will be 
specified in the SAP. 
 
Data collected on- or post-study treatment discontinuation (with the exception of data 
collected after study treatment discontinuation due to an indirect impact of a pandemic) 
will be included in the primary efficacy analysis and no imputation of missing data are 
planned. Missing data are assumed Missing at Random (MAR) handled via Mixed Model 
Repeated Measures (MMRM) analysis. If necessary, a tipping point analysis may be 
conducted to assess the impact of missing data and will be detailed in the SAP. 
9.4.2.2. 
Secondary Endpoint 
The secondary treatment comparison of FF/UMEC/VI 200/62.5/25 vs FF/VI 200/25 for 
change from baseline in trough FEV1 after 12 weeks will be conducted as for the primary 
endpoint except, for the secondary comparison the informative normal 2-component 
robust mixture prior is: 
p(Δ) = 0.3*N(mean=100, SD=20.0) + 0.7*N(mean=0, SD=494.97) 


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Where Δ is difference for FF/UMEC/VI 200/62.5/25 vs. FF/VI 200/25 in trough FEV1 at 
Week 12. 
Other Secondary EndpointThe other secondary endpoint of change from baseline in 
ACQ-7 total score at Week 12 will be analyzed in a descriptive manner with no formal 
hypothesis testing to be performed. The estimand will be the same as the estimand for the 
primary endpoint comparison except the variable is the change from baseline in ACQ-7 
total score at Week 12. The treatment difference for the change from baseline in ACQ-7 
total score at Week 12 will be assessed for each of below comparisons separately: 
• FF/UMEC/VI 100/62.5/25 vs. FF/VI 100/25 
• FF/UMEC/VI 200/62.5/25 vs. FF/VI 200/25 
Each comparison will be conducted using the Mixed Model Repeated Measures 
(MMRM) method, including covariates for treatment group, pre-study ICS dosage 
strength (med, high), baseline ACQ-7 total score, visit, sex, age at screening, interaction 
between treatment group and visit, and interaction between baseline ACQ-7 total score 
and visit. The comparisons will estimate the differences between treatment groups with 
no p-values to be presented. The LS-means and the associated standard errors of the 
change from baseline values will be summarized for each treatment group. The estimated 
treatment difference along with corresponding standard errors and 95% CI will be 
presented for each of the treatment comparisons.  
Full details of the analyses on all efficacy endpoints will be given in the SAP.  
9.4.3. 
Safety Analysis 
All safety analyses will be performed on the Safety Population.  
Adverse events (AEs) will be coded using the standard GSK dictionary MedDRA, and 
grouped by body system. The number and percentage of participants experiencing at least 
one AE of any type, AEs within each body system and AEs within each preferred term 
will be presented for each treatment group. Separate summaries will be provided for all 
AEs, drug related AEs, fatal AEs, non-fatal SAEs, adverse events of special interest 
(AESIs) and AEs leading to withdrawal. Deaths and SAEs, if applicable, will be 
documented in case narrative format. 
9.4.4. 
Other Analysis 
Full details of the analyses to be performed as well as details of time points to be 
analyzed for the China only data, will be given in the SAP.  
9.5. 
Interim Analysis 
No interim analysis is planned in this study. 


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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with: 
• 
Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines 
• 
Applicable ICH Good Clinical Practice (GCP) Guidelines 
• 
Applicable laws and regulations 
• The protocol, protocol amendments, ICF, IB, Investigational Directions for Use 
(IDFU] and other relevant documents (e.g., advertisements) must be submitted to 
an IRB/IEC by the investigator and reviewed and approved by the IRB/IEC 
before the study is initiated. 
• Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants.  
• Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants. 
• The investigator will be responsible for the following: 
• 
Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC 
• 
Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures 
• 
Providing oversight of the conduct of the study at the site and adherence 
to requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), ), European 
Medical Device Regulation 2017/745 for clinical device research (if 
applicable), and all other applicable local regulations 


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10.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 
10.1.3. 
Informed Consent Process 
• The investigator or his/her representative will explain the nature of the study to 
the participant or their legally authorized representative and answer all questions 
regarding the study.  
• 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 their legally 
authorized representative.  
• Participants who are rescreened are required to sign a new ICF. 
• GSK (alone or working with others) may use participant’s coded study data and 
samples and other information to carry out this study; understand the results of 
this study; learn more about the study intervention or about the study disease; 
publish the results of these research efforts; work with government agencies or 
insurers to have the the study intervention approved for medical use or approved 
for payment coverage.  
• The ICF contains a separate section that addresses the use of participant data and 
remaining samples for optional further research. The investigator or authorised 
designee will inform each participant of the possibility of further research not 
related to the study/disease. Participants will be told that they are free to refuse to 
participate and may withdraw their consent at any time and for any reason during 
the storage period. A separate signature will be required to document a 
participant's agreement to allow any participant data and/or remaining leftover 
samples to be used for further research not related to the study/disease. 
Participants who decline further research will tick the corresponding “No” box. 
 


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10.1.4. 
 Data Protection 
• Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred.  
• The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant who will be required to give 
consent for their data to be used as described in the informed consent.  
• The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed by 
the sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
10.1.5. 
Committees Structure 
• Participant safety will be continuously monitored by the study team, which 
includes safety signal detection at any time during the study 
• In particular, data will be reviewed by the Sponsor for identification of the 
following events that would potentially contribute to a requirement to pause the 
study.  
o Events considered significantly impact the safety of participants 
• Enrollment will be paused during the review. If a pausing rule is met, a decision 
will be made, based on the review, as to whether enrollment in the study will be 
allowed to resume. 
• Case unblinding may be performed for above reviews if necessary. 
10.1.6. 
Dissemination of Clinical Study Data 
• Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report.  The investigator 
will be provided reasonable access to statistical tables, figures, and relevant 
reports and will have the opportunity to review the complete study results at a 
GSK site or other mutually-agreeable location. 
• GSK will also provide all investigators who participated in the study with a 
summary of the study results and will tell the investigators what treatment their 
participants’’ received.  The investigator(s) is/are encouraged to share the 
summary results with the study participants, as appropriate. 
• Under the framework of the SHARE initiative, GSK intends to make anonymized 
participant-level data from this trial available to external researchers for scientific 
analyses or to conduct further research that can help advance medical science or 
improve patient care. This helps ensure the data provided by trial participants are 
used to maximum effect in the creation of knowledge and understanding. 
Requests for access may be made through www.clinicalstudydatarequest.com. 


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• GSK will provide the investigator with the randomization codes for their site only 
after completion of the full statistical analysis. 
• The procedures and timing for public disclosure of the protocol and results 
summary and for development of a manuscript for publication for this study will 
be in accordance with GSK Policy. 
• A manuscript will be progressed for publication in the scientific literature if the 
results provide important scientific or medical knowledge. 
10.1.7. 
Data Quality Assurance 
• All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g., laboratory 
data). The investigator is responsible for verifying that data entries are accurate 
and correct by physically or electronically signing the CRF.  
• Guidance on completion of CRFs will be provided in sponsor’s TMF system or 
from vendor data manager. 
• Quality tolerance limits (QTLs) will be pre-defined in the QTL plan to identify 
systematic issues that can impact participant safety and/or reliability of study 
results. These pre-defined parameters will be monitored during and at the end of 
the study and all deviations from the QTLs and remedial actions taken will be 
summarized in the clinical study report. 
• The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents.  
• Monitoring details describing strategy including definition of study critical data 
items and processes (e.g., risk-based initiatives in operations and quality such as 
Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the [Monitoring Plan] [contracts]. 
• The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.  
• The sponsor assumes accountability for actions delegated to other individuals 
(e.g., Contract Research Organizations). 
• Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
Clinical Study Report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. 
No records may be transferred to another location or party without written 
notification to the sponsor.  
 


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10.1.8. 
Source Documents 
• Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
• Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies 
must be explained. The investigator may need to request previous medical records 
or transfer records, depending on the study. Also, current medical records must be 
available. 
• Definition of what constitutes source data and its origin can be found in [Source 
Data Acknowledgment]. 
• The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 
• Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are 
being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements.  
10.1.9. 
Study and Site Start and Closure 
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first participant first visit and will be the study start 
date. 
Study/Site Termination 
GSK or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
For study termination: 
• Discontinuation of further study intervention development 


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For site termination: 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
• Inadequate or no recruitment of participants (evaluated after a reasonable amount 
of time) by the investigator 
• If the study is prematurely terminated or suspended, the sponsor shall promptly 
inform the investigators, the IECs/IRBs, the regulatory authorities, and any 
contract research organization(s) used in the study of the reason for termination or 
suspension, as specified by the applicable regulatory requirements. The 
investigator shall promptly inform the participant and should assure appropriate 
participant therapy and/or follow-up 
10.1.10. 
Publication Policy 
• The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.  
• The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as 
individual site data. In this case, a coordinating investigator will be designated by 
mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 


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10.2. 
Appendix 2: Clinical Laboratory Tests 
The tests detailed in Table 3 will be performed by the central laboratory.  
 Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the Protocol Amendment.  
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 
 


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10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1. 
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 intervention, whether or not 
considered related to the study intervention. 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a study intervention. 
 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., 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 intervention administration even 
though it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected intervention- intervention 
interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention 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. "Lack of 
efficacy" or "failure of expected pharmacological action" also constitutes an AE or 
SAE. 
 


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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 (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
 
10.3.2. 
Definition of SAE 
An SAE is defined as any serious adverse event that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the participant has been admitted 
(usually involving at least an overnight stay) at the hospital or emergency ward 
for observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AE. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered 
serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
d. Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. 
• This definition is not intended to include experiences of relatively minor 
medical significance such as uncomplicated headache, nausea, vomiting, 


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diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may 
interfere with or prevent everyday life functions but do not constitute a 
substantial disruption. 
e. Is a congenital anomaly/birth defect 
f. Is a suspected transmission of any infectious agent via an authorised medicinal 
product 
g. Other situations: 
• Possible Hy’s Law case: ALT≥3xULN AND total bilirubin ≥2xULN (>35% 
direct bilirubin) or international normalized ratio (INR) >1.5 must be reported 
as SAE 
• Medical or scientific judgment should be exercised by the investigator in 
deciding whether SAE reporting is appropriate in other situations such as 
significant medical events that may jeopardize the participant or may require 
medical or surgical intervention to prevent one of the other outcomes listed in 
the above definition. These events should usually be considered serious. 
o Examples of such events include invasive or malignant cancers, 
intensive treatment for allergic bronchospasm, blood dyscrasias, 
convulsions, or development of intervention dependency or intervention 
abuse. 
10.3.3. 
Definition of Cardiovascular Events 
Cardiovascular Events (CV) Definition: 
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs: 
• Myocardial infarction/unstable angina 
• Congestive heart failure 
• Arrhythmias 
• Valvulopathy 
• Pulmonary hypertension 
• Cerebrovascular events/stroke and transient ischemic attack 
• Peripheral arterial thromboembolism 
• Deep venous thrombosis/pulmonary embolism 
• Revascularization 
 


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10.3.4. 
Recording and Follow-Up of AE and SAE 
AE and SAE Recording 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory, and diagnostics reports) 
related to the event. 
• The investigator will then record all relevant AE/SAE information. 
• It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK required form. 
• There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK. 
• The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the 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 sufficient discomfort and interferes with normal 
everyday activities. 
• Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE. Severe is a category utilized for 
rating the intensity of an event; and both AE and SAE can be assessed as severe. 
• An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality 
The investigator is obligated to assess the relationship between study intervention 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. 


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• Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The investigator will also consult the Investigator’s Brochure (IB) 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. 
• New or updated information will be recorded in the originally submitted 
documents. 
• 
The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information. 
 


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10.3.5. 
Reporting of SAE to GSK 
SAE Reporting to GSK via Electronic Data Collection Tool 
• The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor/SAE coordinator by telephone. 
• 
Please mail to Qwy11935@gsk.com to report SAE. 
 
SAE Reporting to GSK via Paper Data Collection Tool 
• Facsimile transmission of the SAE paper data collection tool is the preferred 
method to transmit this information to the medical monitor or the SAE 
coordinator. 
• In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service. 
• Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE data collection tool within the designated reporting time 
frames. 
• 
Please mail to Qwy11935@gsk.com to report SAE. 


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10.4. 
Appendix 4: Contraceptive and Barrier Guidance  
10.4.1. 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
Women in the following categories are considered WOCBP (fertile): 
1. Following menarche 
2. From the time of menarche until becoming post-menopausal unless permanently 
sterile (see below) 
Notes: 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
o 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, confirmation with more than one FSH 
measurement [insert threshold if required (>40 IU/L or mIU/mL) or remove to 
allow for flexibility with different local thresholds for defining 
postmenopausal state] is required.  
o Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-estrogen 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. 
• Permanent sterilization methods (for the purpose of this study) include: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), investigator 
discretion should be applied to determining study entry. 
 
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study intervention, additional evaluation should 
be considered. 
 


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Woman of Nonchildbearing Potential (WONCBP) 
Women in the following categories are considered WONCBP: 
1. Premenopausal female with permanent infertility due to one of the following (for the 
purpose of this study): 
a) Documented hysterectomy 
b) Documented bilateral salpingectomy 
c) Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), investigator 
discretion should be applied to determining study entry. 
 
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
2. Postmenopausal female 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
o 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, confirmation with more than one FSH 
measurement [insert threshold if required (>40 IU/L or mIU/mL) or remove to 
allow for flexibility with different local thresholds for defining 
postmenopausal state] is required. 
o Females on HRT and whose menopausal status is in doubt must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment. 
 
10.4.2. 
Contraception Guidance: 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per year 
when used consistently and correctly. 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationc 
Intrauterine device (IUD) 
Intrauterine hormone-releasing system (IUS)c 
Bilateral tubal occlusion 
Azoospermic partner (vasectomized or due to a to medical cause) 


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CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Azoospermia is a highly effective contraceptive method provided that the partner is the 
sole sexual partner of the woman of childbearing potential and the absence of sperm has 
been confirmed. If not, an additional highly effective method of contraception should be 
used. Spermatogenesis cycle is approximately 90 days. 
Note: documentation of azoospermia for a male participant can come from the site 
personnel’s review of the participant’s medical records, medical examination, or medical 
history interview. 
Highly Effective Methods b That Are User Dependent Failure rate of <1% per year 
when used consistently and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationc 
• 
oral 
• 
intravaginal 
• 
transdermal 
• 
injectable 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
• 
oral 
• 
injectable 
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 intervention. 
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 
a. 
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b. 
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
c. 
 Male condoms must be used in addition to hormonal contraception. If locally required, in accordance with 
Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are limited to those 
which inhibit ovulation as the primary mode of action. 
 
Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception. Male 
condom and female condom should not be used together (due to risk of failure from friction) 
 


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10.5. 
Appendix 5: Liver Safety: Required Actions and Follow-up 
Assessments 
Phase III-IV 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). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf 
Phase III-IV liver chemistry stopping criteria and required follow up assessments  
Liver Chemistry Stopping Criteria  
ALT-absolute ALT  8xULN 
ALT Increase 
ALT  5xULN but <8xULN persists for 2 weeks 
ALT  3xULN but <5xULN persists for 4 weeks 
Bilirubin1, 2 
ALT  3xULN and bilirubin  2xULN (>35% direct bilirubin)  
INR2  
ALT  3xULN and INR>1.5, if INR measured 
Cannot 
Monitor 
ALT  5xULN but <8xULN and cannot be monitored weekly for 2 weeks 
ALT  3xULN but <5xULN and cannot be monitored weekly for 4 weeks 
Symptomatic3 ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity 
Required Actions and Follow up Assessments  
Actions 
Follow Up Assessments 
• Immediately discontinue study treatment 
• Report the event to GSK within 24 hours 
• Complete the liver event CRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2 
• Perform liver event follow up assessments  
• Monitor the participant until liver chemistries 
resolve, stabilize, or return to within 
baseline (see MONITORING below) 
• As restart/rechallenge is not allowed, 
permanently discontinue study treatment 
• Viral hepatitis serology4 
• Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend 
• Only in those with underlying chronic 
Hepatitis B at study entry (identified by 
positive Hepatitis B surface antigen) 
quantitative Hepatitis B Deoxyribonucleic 
acid (DNA) and Hepatitis delta antibody5. 
• Obtain blood sample for pharmacokinetic 
(PK) analysis, within 28 days after last 
dose6 


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Liver Chemistry Stopping Criteria  
and continue participant in the study for any 
protocol specified follow up assessments  
 
 
 
 
 
 
 
 
MONITORING: 
For bilirubin or INR criteria:  
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24 
hrs 
• 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 
• 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 
medications. 
• Record alcohol use on the liver event 
alcohol intake case report form (CRF) 
page 
For bilirubin or INR criteria: 
• Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins. 
• Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver injury 
in participants with definite or likely 
acetaminophen use in the preceding 
week [James, 2009]). NOTE: 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 
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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 (HbsAg) and Hepatitis B Core Antibody (IgM); 
Hepatitis C Ribonucleic acid (RNA); Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM 
antibody (or if unavailable, obtain heterophile antibody or monospot testing);  Hepatitis E IgM antibody  
5. If Hepatitis delta antibody assay cannot be performed, it can be replaced with a PCR of Hepatitis D RNA virus 
(where needed) [Le Gal, 2005]. 
6. 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 PK 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 
 
Phase III-IV liver chemistry increased monitoring criteria with continued therapy 
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event 
Criteria 
Actions 
 
ALT 5xULN and <8xULN and 
bilirubin <2xULN without symptoms 
believed to be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 2 weeks. 
OR 
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 ALT decreases from ALT 5xULN and <8xULN 
to ≥3xULN but <5xULN, continue to monitor liver 
chemistries weekly.  
• If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor participants twice 
monthly until liver chemistries normalize or return 
to within baseline. 
 
 


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10.6. 
Appendix 6: AEs, ADEs, SAEs, SADEs, USADEs and Device 
Deficiencies: Definition and Procedures for Recording, 
Evaluating, Follow-up, and Reporting in Medical Device 
Studies 
• The definitions and procedures detailed in this appendix are in accordance with 
ISO 14155 and European Medical Device Regulation (MDR) 2017/745 for 
clinical device research (if applicable).  
• Both the investigator and the sponsor will comply with all local medical device 
reporting requirements for medical devices. 
• The detection and documentation procedures described in this protocol apply to 
all GSK medical devices provided for use in the study. 
10.6.1. 
Definition of Medical Device AE and ADE 
 
10.6.2. 
Definition of Medical Device SAE, SADE and USADE 
A Medical Device SAE is any serious adverse event that: 
a. 
Led to death  
b. Led to serious deterioration in the health of the participant, that either resulted in: 
• 
A life-threatening illness or injury. The term ‘life-threatening' in the definition of 
‘serious' refers to an event in which the participant was at risk of death at the time of 
the event. It does not refer to an event, which hypothetically might have caused death, 
if it were more severe. 
• 
A permanent impairment of a body structure or a body function. 
Medical Device AE and ADE Definition  
• 
An AE is any untoward medical occurrence, in a clinical study participant, users, 
or other persons, temporally associated with the use of study intervention whether 
or not considered related to the investigational medical device. 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 an investigational medical device. This definition 
includes events related to the investigational medical device or comparator and 
events related to the procedures involved. 
• 
An adverse device effect (ADE) is an AE related to the use of an investigational 
medical device. This definition includes any AE resulting from insufficient or 
inadequate instructions for use, deployment, implantation, installation, or 
operation, or any malfunction of the investigational medical device as well as any 
event resulting from use error or from intentional misuse of the investigational 
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• 
Inpatient or prolonged hospitalization. Planned hospitalization for a pre-existing 
condition, or a procedure required by the protocol, without serious deterioration in 
health, is not considered an SAE. 
• 
Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function 
c. 
Led to fetal distress, fetal death or a congenital abnormality or birth defect 
d. Is a suspected transmission of any infectious agent via a medicinal product 
SADE definition 
• A SADE is defined as an adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event. 
• Any device deficiency that might have led to an SAE if appropriate action had not 
been taken, intervention had not occurred, or circumstances had been less fortunate. 
Unanticipated SADE (USADE) definition 
• 
An USADE (also identified as UADE in US Regulations 21 CFR 813.3), is a 
serious adverse device effect that by its nature, incidence, severity or outcome has 
not been identified in the current version of the risk analysis report (see Section 
2.3). 
 
10.6.3. 
Definition of Device Deficiency 
Device Deficiency Definition 
• 
A device deficiency is an inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safety, or performance. Device deficiencies 
include malfunctions, use errors, and information supplied by the manufacturer. 
10.6.4. 
Recording and Follow-Up of AE and/or SAE and Device 
Deficiencies 
AE, SAE and Device Deficiency Recording 
• 
When an AE/SAE/device deficiency occurs, it is the responsibility of the 
investigator to review all documentation (e.g., hospital progress notes, laboratory 
reports, and diagnostics reports) related to the event. 
• 
The investigator will then record all relevant AE/SAE/device deficiency 
information in the participant’s medical records, in accordance with the 
investigator’s normal clinical practice, and on the appropriate form. 


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• 
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the AE/SAE/device deficiency 
form. 
• 
There may be instances when copies of medical records for certain cases are 
requested by medical monitor. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to medical monitor. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE. 
• 
For device deficiencies, it is very important that the investigator describes any 
corrective or remedial actions taken to prevent recurrence of the deficiency. 
o A remedial action is any action other than routine maintenance or servicing of 
a medical device where such action is necessary to prevent recurrence of a 
device deficiency. This includes any amendment to the device design to 
prevent recurrence. 
Assessment of Intensity 
• The investigator will make an assessment of intensity for each AE/SAE/device 
deficiency reported during the study and assign it to one of the following 
categories:  
• Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities. 
• Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities. 
• Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE. Severe is a category used for rating 
the intensity of an event; both AEs and SAEs 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. 
• Other measures to evaluate AEs and SAEs may be utilized (e.g., National Cancer 
Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE]). 
 
Assessment of Causality 
• The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE/device deficiency 
• A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 


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• The investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The investigator will also consult the Investigator’s Brochure (IB) and/or IDFU or 
Product Information, for marketed products, in his/her assessment. 
• For each AE/SAE/device deficiency, the investigator must document in the 
medical notes that he/she has reviewed the AE/SAE/device deficiency 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/SAE/device deficiency 
• The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE/SAE/device deficiency as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care 
professionals. 
• If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology. 
• New or updated information will be recorded in the originally completed CRF. 
• The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information. 


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10.6.5. 
Reporting of SAEs 
SAE Reporting to GSK via an Electronic Data Collection Tool 
• The primary mechanism for reporting an SAE to GSK will be the electronic data 
collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next table) in order to report the event within 24 hours. 
• 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 offline to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the GSK medical monitor or the SAE coordinator by telephone. 
• Contacts for SAE reporting can be found in SRM and Investigator Site File. 
 
SAE Reporting to GSK via Paper Data CollectionTool 
• Facsimile transmission of the SAE data collection tool is the preferred method to 
transmit this information to the GSK medical monitor or the SAE coordinator. 
• In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE paper data collection tool sent by 
overnight mail or courier service. 
• Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE paper data collection tool within the designated 
reporting time frames. 
• Contacts for SAE reporting can be found in SRM and the Investigator Site File. 
10.6.6. 
Reporting of SADEs 
SADE Reporting to GSK  
NOTE: There are additional reporting obligations for medical device deficiencies 
that are potentially related to SAEs that must fulfill the legal responsibility to notify 
appropriate regulatory authorities and other entities about certain safety 
information relating to medical devices being used in clinical studies.  
• Any device deficiency that is associated with an SAE must be reported to GSK 
within 24 hours after the investigator determines that the event meets the definition 
of a device deficiency. 


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• GSK will review all device deficiencies and determine and document in writing 
whether they could have led to an SAE. These device deficiencies will be reported 
to the regulatory authorities and IRBs/IECs as required by national regulations. 
• Contacts for SAE reporting can be found in SRM and the Investigator Site File. 


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10.7. 
Appendix 7: Statistical Appendix 
10.7.1. 
Choice of posterior probability 
A 95% posterior probability that the true treatment difference in trough FEV1 > 0 mL 
represents a high level of confidence for declaring a positive treatment benefit in Chinese 
patients in the context of a bridging study where substantial evidence of treatment benefit 
in global (non-Chinese) patients already exists and is aligned with examples of Bayesian 
decision criteria given in the FDA draft guidance on Complex Innovative Designs 
[https://www.fda.gov/media/130897/download]. This represents a more rigorous 
evidentiary threshold than is typically provided by a ‘positive trend ‘design, which 
requires only that the observed treatment difference > 0. 
10.7.2. 
Choice of Sample size 
A total sample size of 356 participants (89 per arm) is considered an achievable sample 
size for a bridging study, taking into consideration:  i) the feasibility of enrollment and 
the regulatory guidelines for sample size that would generally be required for consistency 
evaluation in an MRCT global study; and ii) the aim of getting medicines to Chinese 
patients as quickly as possible in a setting where there is a strong expectation based on 
clinical and epidemiological data that efficacy in Chinese patients should be similar to 
that already demonstrated in non-Chinese patients.   
 
10.7.3. 
A range of possible observed treatment differences in China  
The observed treatment differences considered have been selected to represent the 
following scenarios: 
• 0 mL (no difference observed between FF/UMEC/VI and FF/VI) 
• 60 mL (this was the minimum detectable difference in the global 205715 study 
that was needed to meet the primary success rule in the global study 205715 for 
mean difference in change from baseline trough FEV1 for both the FF/UMEC/VI 
100/62.5/25 vs FF/VI 100/25 comparison and the FF/UMEC/VI 200/62.5/25 vs 
FF/VI 200/25 comparison) 
• 86 mL (this is the mean difference in change from baseline in trough FEV1 for 
FF/UMEC/VI 100/62.5/25 vs FF/VI 100/25 at week 12 that was observed in the 
global 205715 study) 
• 100 mL (this is the mean difference in change from baseline in trough FEV1 for 
FF/UMEC/VI 200/62.5/25 vs FF/VI 200/25 at week 12 that was observed in the 
global 205715 study) 


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10.7.4. 
Overview of the proposed robust mixture prior and analysis 
strategy 
In order to formally incorporate the global 205715 study data in this bridging study, 
informative robust mixture priors (Schmidli, 2014)  for the differences of FF/UMEC/VI 
100/62.5/25 µg vs. FF/VI 100/25 µg and FF/UMEC/VI 200/62.5/25 µg vs. FF/VI 200/25 
µg will be constructed. These priors will be updated with the China study data to derive 
the posterior distributions that will be used to test the primary and secondary hypotheses 
in the hierarchical testing strategy. The priors are a mixture of two normal distributions:   
• Component 1 is an informative prior based on change from baseline in trough 
FEV1 results at week 12 from the global study 205715, referred to as the “global 
prior”. 
• Component 2 is a “vague” prior added to enable the prior to down-weight the 
information from global data in case of conflict between the observed results in 
the China and global populations.  
Denoting the difference (FF/UMEC/VI - FF/VI) as Δ 
, the prior has the form: 
p(Δ) = w · p1(Δ) + (1-w) · p2(Δ) 
where p1(Δ) 
is the component containing the information from the global study 
prior, p2(Δ) 
is the vague component. There is a prior for each of the treatment 
comparisons of interest. 
The Informative (Global) Prior 
For the primary treatment comparison of FF/UMEC/VI 100/62.5/25 vs FF/VI 100/25 for 
change from baseline in trough FEV1 after 12 weeks in this study, the global prior 
component is obtained from the sampling distribution of the difference in trough FEV1 at 
Week 12 between the FF/UMEC/VI 100/62.5/25 vs FF/VI 100/25 arms in the global 
study 205715 (formally, it is the posterior distribution of this difference obtained by 
combining the sampling distribution of the observed treatment difference from 205715 
with a flat prior distribution). The mean difference and its associated standard error are 
86 mL and 20.1 mL, respectively, leading to a Normal distribution with mean 86 and 
standard deviation 20.1 as the global prior component for the primary treatment 
comparison.  
Similarly, for the secondary treatment comparison of FF/UMEC/VI 200/62.5/25 vs FF/VI 
200/25 for change from baseline in trough FEV1 after 12 weeks in this study, the global 
prior component is obtained from the sampling distribution of the difference in trough 
FEV1 at Week 12 between the FF/UMEC/VI 200/62.5/25 vs FF/VI 200/25 arms in the 
global 205715 study. The mean treatment difference and its associated standard error are 
100 mL and 20.0 mL, respectively, leading to a Normal distribution with mean 100 and 
standard deviation 20.0 as the global prior component for the secondary treatment 
comparison. 


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Figure 2 and Figure 3 show density plots of the global priors for each FF dose. The prior 
probability that the difference is larger than zero is >99% for both treatment comparisons. 
 
Figure 2 
Density Plot of Global Prior for Difference in Change from Baseline 
Trough FEV1 (FF/UMEC/VI 100/62.5/25 – FF/VI 100/25) at Week 12 
(mL) 
 
 
Figure 3 
Density Plot of Global Prior for Difference in Change from Baseline 
Trough FEV1 (FF/UMEC/VI 200/62.5/25 – FF/VI 200/25) at Week 12 
(mL) 
 
 


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The Vague Prior 
The vague prior has a mean of 0 mL (i.e. centred at the null hypothesis of no effect in 
China). The SD of this prior was chosen so that it contains a minimal amount of 
information equivalent to the sampling distribution of the mean treatment difference 
derived from a single observation per arm with the assumed SD in the China population.  
The SD of change from baseline in trough FEV1 in China is assumed to be 350 mL (see 
below), and therefore the SD of the vague prior is:  
√2 × 3502
1
= 494.97 𝑚𝐿 
For both FF/UMEC/VI 100/62.5/25 compared to FF/VI 100/25 and FF/UMEC/VI 
200/62.5/25 compared to FF/VI 200/25, the prior probability under this vague prior that 
the difference is larger than zero is 50%. Note that the assumption about the SD of 
change from baseline in trough FEV1, which determines the SD of the vague prior, will 
not be revisited once the China data is observed. In other words, the two components of 
the mixture prior will be fully pre-specified before the study starts.  
 
Initial weight on informative (global) prior component and effective sample size 
borrowed from the global 205715 study 
A initial (prior) weight of 30% is proposed (for both treatment comparisons) for the 
informative global component of the robust mixture prior, with the remainder of the weight 
(70%) placed on the weak prior to reflect a conservative starting position regarding the 
assumed relevance of the global 205715 results to Chinese. Combining the two components 
and their respective weights gives the following 2-component mixture normal:   
 
For FF/UMEC/VI 100/62.5/25 µg vs. FF/VI 100/25 µg: 
p(Δ) = 0.3*N(mean=86, SD=20.1) + 0.7*N(mean=0, SD=494.97) 
For FF/UMEC/VI 200/62.5/25 µg vs. FF/VI 200/25 µg: 
p(Δ) = 0.3*N(mean=100, SD=20.0) + 0.7*N(mean=0, SD=494.97) 
 
Figure 4 and Figure 5 show density plots of the mixture prior for each treatment 
comparison using the initial weight of 0.3, overlaid on top of the density plots of the two 
individual components (global and vague). According to these mixture priors, the prior 
probability that the true treatment difference in China is larger than zero is 65% for both 
comparisons. (Note that the x-axis in the plots has been truncated (at -50 mL and 
200 mL) to focus on the range of values for the true treatment difference that are 


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supported by the global prior component; the vague prior and the overall mixture prior 
have long ‘tails’ with small but non-zero probability of the true treatment difference 
being greater or less than the range of x-axis values shown).  
 
Figure 4 
Density Plot of Mixture Prior and Individual Components for 
FF/UMEC/VI 100/62.5/25 vs. FF/VI 100/25 in Change from Baseline 
Trough FEV1 at Week 12 (mL) 
 


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Figure 5 
Density Plot of Mixture Prior and Individual Components for 
FF/UMEC/VI 200/62.5/25 vs. FF/VI 200/25in Change from Baseline 
Trough FEV1 at Week 12 (mL) 
 
10.7.5. 
Choice of weights 
The scientific grounds for expecting similar benefit:risk profile in China and global study 
patients justifies a high initial weight on the informative component. However, based on 
an extensive review of the impact of the prior weight specified for the global 205715 
study (prior weights explored were: 0.0, 0.1, 0.2, 0.3, … , 0.9, 1.0) on the operating 
characteristics of the BDB design, a more conservative prior weight of 30% was felt to 
provide an acceptable trade-off between the risks of a false positive result and a false 
negative result, and to enable meaningful gains in precision due to borrowing information 
from the global study whilst ensuring that the prior does not dominate the posterior 
completely but allows the observed data in Chinese patients to contribute to the inference 
from the study.  
 


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10.8. 
Appendix 8: Abbreviations and Definitions and Trademarks 
Abbreviations 
ACQ 
Asthma Control Questionnaire 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine Transaminase 
AM 
Morning 
AST 
Aspartate Transaminase 
ATS 
American Thoracic Society 
BDB 
Bayesian Dynamic Borrowing 
BMI 
Body Mass Index 
BPM 
Beats Per Minute 
BUN 
Blood Urea Nitrogen 
CI 
Confidence Interval 
CIOMS 
Council for International Organizations of Medical 
Sciences 
CPAP 
Continuous Positive Airway Pressure 
CPK 
creatine phosphokinase 
CV 
Cardiovascular 
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 
EU 
European Union 
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 
GOLD 
Global Initiative for Chronic Obstructive Lung Disease 
GSK 
GlaxoSmithKline 
HbO2 
Oxyhemoglobin 
hCG 
Human Chorionic Gonadotropin 


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HIV 
Human Immunodeficiency Virus 
HPA 
Hypothalamic Pituitary Axis 
HR-QoL 
Health-Related Quality of Life 
HRT 
Hormone Replacement Therapy 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ICS 
Inhaled Corticosteroids 
IDFU 
Investigational Directions for Use 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 
INR 
international normalized ratio 
IOP 
Intraocular Pressure 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ITT 
Intent to Treat 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
IVD 
in vitro diagnostic 
kg 
Kilogram 
L/min 
Liters per minute 
LABA 
Long-Acting Beta-2-Agonists 
LAMA 
Long-Acting Muscarinic Antagonist 
LAR 
legally authorized representative 
LDH 
lactate dehydrogenase 
LOCS III 
Lens Opacities Classification System III 
LRTI 
Lower Respiratory Tract Infection 
LTRA 
Leukotriene Receptor Antagonist 
MACE 
Major Adverse Cardiac Event 
MAOI 
Monoamine Oxidase Inhibitors 
MDD 
Minimum Detectable Difference 
MedDRA 
Medicinal Dictionary for Regulatory Activities 
mcg (g) 
Microgram 
MCV 
Mean Corpuscula Volume 
MCH 
Mean Corpuscular Haemoglobin 
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 
pH 
potential of Hydrogen  


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PK 
Pharmacokinetic  
PM 
Afternoon 
prn 
As needed 
QD 
Once daily 
QTLs 
Quality tolerance limits 
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 
RAMOS NG 
Registration and Medication Ordering System Next 
Generation 
RBC 
Red Blood Cell 
RNA 
Ribonucleic acid 
SABA 
Short-Acting Beta-2-Agonists 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SGPT 
Serum Glutamic-Pyruvic Transaminase 
SGOT 
Serum Glutamic-Oxaloacetic Transaminase 
SPC 
Summary of Product Characteristics 
SoA 
Schedule of Activities 
SRM 
Study Reference Manual 
TQT 
Thorough QT 
ULN 
Upper Limit of Normal 
UMEC 
Umeclidinium 
US 
United States 
VI 
Vilanterol 
VT 
Ventricular Tachycardia 
WBC 
White Blood Cell 
WOCBP 
Woman of Childbearing Potential 
WONCBP 
Woman of Nonchildbearing Potential 
 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
ELLIPTA 
 
NONE 
 
 


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10.9. 
Appendix 9: 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. 28-Apr-2021 
The amendment is substantial. 
Overall Rationale for the Amendment: 
The amendment is made to meet the requirement from CDE that secondary endpoints 
need to be added to support the evaluation of the efficacy of treatment, and some 
additional amendments are also made to provide more clear information. 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.1  
Synopsis 
The change from baseline of 
ACQ-7 is added as other 
secondary endpoint.  
The secondary endpoint is added to 
meet the requirement of CDE to 
provide more information on efficacy 
of FF/UMEC/VI to support the 
assessment. 
Section 1.3  
Schedule of 
Activities (SoA) 
ACQ is added in the SOA in the 
“Efficacy assessment”, and will 
be evaluated at V1, 2, 3, 4 & 
EW. 
Footnote 8 is newly added to 
provide more information on 
how and when the ACQ will be 
evaluated. 
Footnote 18: the visit number is 
revised from “visit 3” to “visit 
2”. 
As ACQ-7, 6&5 are added as 
endpoints, the activities related to the 
evaluation of ACQ are added in the 
SOA. 
 
Content in the footnote 8 is added to 
provide clear instruction. 
Visit number in footnote 18 is 
corrected. 
Section 3. 
OBJECTIVES 
AND 
ENDPOINTS 
The change from baseline of 
ACQ-7 is added as other 
secondary endpoint. And other 
measurement related to ACQ 7, 
6 & 5 are also added. 
These secondary and exploratory 
endpoints are added to meet the 
requirement of CDE to provide more 
information on efficacy of 
FF/UMEC/VI to support the 
assessment. 
Section 5.5. 
Criteria for 
Randomisation 
“At the end of the run-in period 
(Visit 1)” is changed to “At the 
end of the run-in period”. 
The removal of “visit 1” is to avoid 
confusion. 
Section 8.1.4. 
Questionnaires 
This section is removed, and 
relevant content is combined in 
Section 8.2.2. 
To avoid repetition with the content in 
Section 8.2.2. 


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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 8.2.2. 
Asthma control 
Questionnaire 
This section is newly added to 
provide the introduction of 
ACQ. 
As ACQ is added as a study endpoint, 
the introduction of this questionnaire is 
added under efficacy assessment 
section. 
Section 8.2.4. 
Alerts 
Add the threshold for the alerts 
related to use of rescue 
mediations. 
This is added to specify the threshold 
for the alert in the eDiary. 
Section 8.4.9  
Medical Device 
Add some content to specify 
that the definition of a Medical 
Device Deficiency can be found 
in Section 10.6, and also the 
reporting requirement. 
To provide information on where to 
find the definition of Medical Device 
Deficiency. 
Section 9.4.2.2. 
Secondary 
Endpoint 
Add the content of the analysis 
method of ACQ-7. 
This is to describe the method to be 
applied for the analysis for ACQ-7. 
Section 10.6 
Appendix 6  
AEs, ADEs, 
SAEs, SADEs, 
USADEs and 
Device 
Deficiencies: 
Definition and 
Procedures for 
Recording, 
Evaluating, 
Follow-up, and 
Reporting in 
Medical Device 
Studies 
This section is newly added per 
GSK’s policy. 
To provide clear information on the 
medical device related AEs. 
Others 
Replace “subject” with 
“participant” in the document. 
To comply with GSK’s policy. 
 


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11. 
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and Fluticasone Propionate Alone in the Treatment of Persistent Asthma in Adults and 
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Powder Delivered Once Daily for 12 Weeks in the Treatment of Asthma in Adolescent 
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Signature Page for  214263 TMF-14804664 v1.0
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Date of signature: 18-Jul-2022 16:02:13 GMT+0000
PPD

SAP_001.pdf: 
Statistical Analysis Plan
Study ID: 214263
Study Official Title: A Phase III, 12 Week, Randomized, Double-blind, 4 Arm 
Parallel Group Bridging Study, Comparing the Efficacy, Safety and Tolerability 
of the Fixed Dose Combination FF/UMEC/VI Once-daily Via a Dry Powder 
Inhaler With Dual Combination of FF/VI, Administered in Chinese Participants 
With Inadequately Controlled Asthma
NCT ID: NCT04937387
Date of Document: 07-August-2024


CONFIDENTIAL 
The GlaxoSmithKline group of companies 
214263 
XBU Statistical Analysis Plan (SAP) Template v1.0 24 March 2021  
Page 1 of 44 
Information Type: 
Statistical Analysis Plan (SAP) 
TITLE PAGE 
Protocol Title: 
A Phase III, 12 week, randomized, double-blind, 4 arm parallel 
group bridging study, comparing the efficacy, safety and 
tolerability of the fixed dose combination FF/UMEC/VI once-
daily via a dry powder inhaler with dual combination of FF/VI, 
administered in Chinese participants with inadequately 
controlled asthma. 
Study Number: 
214263 
Compound 
Number: 
GSK2834425 
Abbreviated Title: 
Efficacy and safety of FF/UMEC/VI in Chinese participants 
with inadequately controlled asthma 
Sponsor Name: GlaxoSmithKline Research & Development Limited 
Regulatory Agency Identifier Number(s)  
Registry 
ID 
Clintrials.gov 
Chinadrugtrias.org.cn 
NCT04937387 
CTR20242323 
Copyright 2024 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited. 


CONFIDENTIAL 
214263 
XBU Statistical Analysis Plan (SAP) Template v1.0 24 March 2021  
Page 2 of 44 
TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 5 
1.1. 
Objectives, Estimands and Endpoints ........................................................... 5 
1.2. 
Study Design ................................................................................................ 8 
2. 
STATISTICAL HYPOTHESES ............................................................................... 10 
2.1. 
Multiplicity Adjustment ................................................................................ 11 
3. 
ANALYSIS SETS ................................................................................................... 11 
4. 
STATISTICAL ANALYSES ..................................................................................... 12 
4.1. 
General Considerations .............................................................................. 12 
4.1.1. 
General Methodology .................................................................. 12 
4.1.2. 
Baseline Definition ....................................................................... 12 
4.2. 
Primary Endpoint(s) Analyses ..................................................................... 12 
4.2.1. 
Definition of Endpoint ................................................................... 12 
4.2.2. 
Main Analytical Approach ............................................................ 13 
4.2.2.1. 
MMRM Modelling ....................................................... 14 
4.2.2.2. 
Bayesian Dynamic Borrowing ..................................... 14 
4.2.3. 
Sensitivity Analyses ..................................................................... 16 
4.2.3.1. 
Sensitivity Analysis 1: Tipping Point Analysis 
for All the Missing Values in Change form 
Baseline of FEV1 at Week 12 ...................................... 16 
4.2.3.2. 
Sensitivity Analysis 2: Tipping Point Analysis 
for the Treatment Discontinuation Due to 
Reasons Other Than Indirect Impact of a 
Pandemic ................................................................... 18 
4.2.3.3. 
Sensitivity Analysis 3: Impact of the Change in 
the Prior Weight .......................................................... 18 
4.2.4. 
Additional Estimands ................................................................... 19 
4.2.4.1. 
Estimand with Treatment Policy Strategy Only 
(Estimand 2) ............................................................... 19 
4.2.4.2. 
Estimand to Assess the Impact of COVID-19 
Infection (Estimand 3) ................................................. 19 
4.3. 
Secondary Endpoint Analyses .................................................................... 19 
4.3.1. 
Secondary Endpoint .................................................................... 19 
4.3.2. 
Other Secondary Endpoint ........................................................... 20 
4.4. 
Exploratory Endpoints Analyses ................................................................. 21 
4.5. 
Safety Analyses .......................................................................................... 23 
4.5.1. 
Extent of Exposure ...................................................................... 23 
4.5.2. 
Adverse Events............................................................................ 24 
4.5.2.1. 
Adverse Events of Special Interest (AESI) .................. 25 
4.5.2.2. 
Major Adverse Cardiac Events (MACE) ...................... 26 
4.5.2.3. 
COVID-19 Assessment and COVID-19 AEs ............... 27 
4.5.3. 
Additional Safety Assessments .................................................... 27 
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4.5.3.1. 
Severe Exacerbation .................................................. 27 
4.5.3.2. 
Laboratory Data .......................................................... 27 
4.5.3.3. 
Vital Signs .................................................................. 28 
4.5.3.4. 
ECG ........................................................................... 28 
4.6. 
Other Analyses ........................................................................................... 29 
4.7. 
Interim Analyses ......................................................................................... 29 
4.8. 
Changes to Protocol Defined Analyses ....................................................... 29 
5. 
SAMPLE SIZE DETERMINATION ......................................................................... 29 
6. 
SUPPORTING DOCUMENTATION ....................................................................... 31 
6.1. 
Appendix 1 Study Population Analyses ....................................................... 31 
6.1.1. 
Participant Disposition ................................................................. 31 
6.1.2. 
Demographic and Baseline Characteristics .................................. 32 
6.1.3. 
Protocol Deviations ...................................................................... 33 
6.1.4. 
Concomitant Medications ............................................................. 33 
6.1.5. 
Study Intervention Compliance .................................................... 34 
6.2. 
Appendix 2 Electronic Clinical Outcome Assessment (eCOA) 
Compliance ................................................................................................. 34 
6.2.1. 
Endpoint Level Compliance ......................................................... 35 
6.2.2. 
Study Level Compliance .............................................................. 35 
6.3. 
Appendix 3 Data Derivations Rule .............................................................. 36 
6.3.1. 
Planned and Actual Treatment ..................................................... 36 
6.3.2. 
Study Period ................................................................................ 36 
6.3.3. 
Study Day and Reference Dates .................................................. 38 
6.3.4. 
Assessment Window ................................................................... 38 
6.3.5. 
Multiple measurements at One Analysis Time Point .................... 39 
6.3.6. 
Handling of Partial Dates ............................................................. 40 
6.3.7. 
Abbreviations & Trade Marks ....................................................... 43 
6.3.7.1. 
Abbreviations .............................................................. 43 
6.3.7.2. 
Trademarks ................................................................ 44 
7. 
REFERENCES ....................................................................................................... 44 
 


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Version History  
SAP 
Version 
Approval Date 
Protocol Version 
(Date) on which 
SAP is Based 
Change 
Rationale 
SAP 
14 July 2021 
Final Amendment 
01  
28 April 2021 
Not Applicable 
Original 
version 
SAP 
Amendment 
1  
07 Aug 2024 
Final Amendment 
02 
18 July 2022 
1. Add the 
randomized 
population; 
2. Add the 3rd 
estimand to assess 
the impact of 
COVID-19 
infection; 
3. Clarify the 
AESI and MACE 
definition; 
4. Define the rule 
of multiple 
measurements of 
ACQ assessment 
selection. 
5. Clarify that the 
7th item response 
of ACQ-7 will be 
derived based on 
the percent-
predicted FEV1 
value. 
6. Add eCOA 
compliance 
definition; 
7. Administrative 
updates to add 
clarification 
and/or remove 
discrepancies. 
Updates 
related to 
protocol 
amendment 
and 2nd 
dry-run. 


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1. 
INTRODUCTION 
The purpose of this SAP is to describe the planned analyses to be included in the CSR for 
Study 214263. Details of the final analyses are provided. It describes the rules and 
conventions to be used in the analysis and presentation of data, the data to be summarised 
and analysed, including specificities of the statistical analyses to be performed. 
Any post-hoc, or unplanned, analyses not identified in this SAP performed will be clearly 
identified in the respective CSR. 
1.1. 
Objectives, Estimands and Endpoints 
Objectives 
Endpoints 
Primary 
 
• 
To evaluate the efficacy of 
FF/UMEC/VI 100/62.5/25 μg on lung 
function compared with FF/VI 100/25 
μg after 12 weeks of treatment  
• 
Change from baseline in trough 
Forced Expiratory Volume in 1 
second (FEV1) at Week 12 
Secondary 
 
• 
To evaluate the efficacy of 
FF/UMEC/VI 200/62.5/25 μg on lung 
function compared with FF/VI 200/25 
μg after 12 weeks of treatment  
• 
Change from baseline in trough 
FEV1 at Week 12  
Other secondary 
 
• 
To evaluate the effects of 
FF/UMEC/VI compared with FF/VI 
on asthma control after 12 weeks of 
treatment 
• 
Change from baseline in ACQ-7 
total score at Week 12 
Exploratory objectives 
 
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Objectives 
Endpoints 
Safety 
 
• 
To evaluate the safety of 
FF/UMEC/VI (100/62.5/25 and 
200/62.5/25 μg) compared with FF/VI 
(100/25 and 200/25 μg) throughout 
the 12-week treatment period.  
• 
Incidence and type of adverse events  
• 
Incidence of exacerbations  
• 
Change from baseline in ECG 
parameters  
• 
Incidence of worst vital sign results 
relative to normal range  
• 
Incidence of worst clinical 
hematological and chemistry results 
relative to normal range  
 
 
Primary estimand 
The primary clinical question of interest is: What is the effect of adding UMEC to FF/VI 
in a single inhaler when compared with FF/VI on change from baseline in trough FEV1 
after 12 weeks of treatment in Chinese participants with inadequately controlled asthma?  
This question will be addressed regardless of study treatment discontinuation unrelated to 
a pandemic or due to pandemic infection and in the absence of study treatment 
discontinuation due to the indirect impact of a pandemic (e.g. participant or site related 
impact such as participant unable to collect/obtain study treatment due to restrictions in 
place, pharmacist not available to conduct the study and maintain the blind). 
For this primary clinical question of interest, participant’s trough FEV1 measurements at 
Week 12 will be used regardless of whether they discontinued study treatment due to 
pandemic infection (e.g. participant got COVID-19) or for reasons not related to the 
pandemic. There could be cases of the pandemic at the time of the conduct of this China 
bridging study and beyond. Given that the disease area of interest is a respiratory disease 
it is important to estimate the treatment effect regardless of the participant being 
diagnosed with pandemic infection as this is likely to be the situation that FF/UMEC/VI 
(if approved and prescribed for asthma) would be taken in. It is unknown currently 
whether indirect consequences of the pandemic (such as the participant unable to 
collect/obtain study treatment due to local restrictions/lockdowns) will be an issue at the 
time of the study, but if participants are unable to collect medication or attend the study 
site due to concerns around the pandemic (or other operational issues) this is unlikely to 
be the situation in the future; therefore, we want to estimate the treatment effect in the 
absence of this. 
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The primary estimand is described by the following attributes: 
• 
Population: participants with inadequately controlled asthma. 
• 
Treatment condition: FF/UMEC/VI (100/62.5/25 μg) or FF/VI (100/25 μg) given 
once daily in the morning (primary treatment comparison is FF/UMEC/VI 
100/62.5/25 vs. FF/VI 100/25). In addition, rescue albuterol/salbutamol will be 
provided and is permitted during the study.  
• 
Variable: change from baseline in trough FEV1 at week 12.  
• 
Summary measure: Mean change from baseline. Comparison: difference in mean 
change from baseline  
• 
Intercurrent events:  
o 
Study treatment discontinuation – if related to an indirect impact of a pandemic 
it will be handled with a hypothetical strategy (i.e. had the intercurrent event not 
occurred. In this situation, data collected after study treatment discontinuation 
will not be included in the statistical analysis and will be treated as missing 
data). Otherwise it will be handled with a treatment policy strategy and data 
collected after study treatment discontinuation will be included in the analysis. 
This will be the primary intercurrent event strategy.  
An additional estimand supporting the primary objective is defined similar to the primary 
estimand except a different intercurrent event strategy will be followed, where study 
treatment discontinuation due to an indirect impact of the pandemic will be handled with 
a treatment policy rather than a hypothetical strategy (i.e. all data collected after study 
treatment discontinuation will be included in the analysis). 
A 3rd estimand to assess the impact of COVID-19 infection is also defined in which the 
incurrent event of COVID-19 infection is handled with the hypothetical strategy and the 
treatment discontinuation is handled with the treatment policy strategy. 
The estimand for the secondary objective assessing FEV1 is the same as the primary 
estimand except the treatment conditions are FF/UMEC/VI (200/62.5/25 μg) or FF/VI 
(200/25 μg) given once daily in the morning. 


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1.2. 
Study Design 
Overview of Study Design and Key Features 
Design 
Features 
This is a 12-week, Phase III, randomized, double-blind, active 
controlled, 4-arm parallel group, bridging study using Bayesian 
Dynamic Borrowing (BDB) in Chinese asthma participants evaluating:  
• 
FF/UMEC/VI (100/62.5/25 μg) versus FF/VI (100/25 μg) and,  
• 
FF/UMEC/VI (200/62.5/25 μg) versus FF/ VI (200/25 μg)  
All given once daily in the morning. 
Participants who meet all the eligibility criteria at screening (Visit 1), 
will enter the run-in period for 3 weeks in order to continue to assess 
the participant’s eligibility for the study. Participants satisfying all 
inclusion/exclusion criteria and who have successfully completed all 
protocol procedures at screening will be provided with FF/VI (100/25 
μg via the ELLIPTA dry powder inhaler [DPI]) once a day, taken in the 
morning, during the 3-week run-in period. Rescue medication 
(albuterol/salbutamol) will be provided to use on an as-needed basis 
throughout the study. 
At the conclusion of the 3-week run-in period (Visit 2), all participants 
who meet the additional predefined criteria will be randomised 1:1:1:1 
to receive either FF/UMEC/VI (100/62.5/25; 200/62.5/25 μg) or FF/VI 
(100/25; 200/25 μg) via the ELLIPTA DPI once daily in the morning 
for the duration of the 12-week treatment period (stratified by pre-study 
ICS treatment strength [medium, high]). 


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Overview of Study Design and Key Features 
In accordance with the protocol-defined visit schedule, participants will 
have two on-treatment clinic visits conducted on an outpatient basis 
scheduled at Visits 3 (Week 4) and Visits 4 (Week 12). One week 
following the end of the study (or after the early withdrawal visit) a 
follow-up telephone call or clinic visit will be performed for safety 
assessments.  
A participant will be considered to have completed the study when 
he/she has completed all phases of the study including the last 
scheduled procedure shown in the Schedule of Activities (SoA, 
Protocol Section 1.3). 
The end of the study is defined as the date of last scheduled procedure 
shown in the SoA for the last participant in the trial. 
Study 
intervention 
The ELLIPTA device will be used during the run-in period and the 
treatment period. The ELLIPTA DPI is a moulded plastic two-sided 
device that can hold two individual blister strips. 
Each participant will be instructed on the proper use of the ELLIPTA and 
will inhale once from the ELLIPTA each morning for the duration of the 
3-week run-in period and the subsequent treatment period. 
At Visit 2, the run-in period ELLIPTA device will be collected from all 
participants. All 356 participants will be randomized to one of the 4 
double-blind treatment arms. 
Participants will self-administer their first dose of double-blind study 
treatment in the clinic during Visit 2 and will continue to administer 
double-blind study treatment at approximately the same time each 
morning for the duration of the treatment period. Participants will take 
their last dose of study treatment in the clinic during Visit 4/EOS (or at 
the Early Withdrawal Visit, if applicable) and a safety follow-up will 
be conducted approximately one week later. 
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 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. 


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Overview of Study Design and Key Features 
Study 
intervention 
Assignment 
All participants who meet the additional predefined criteria will be 
randomized 1:1:1:1 to receive one of the following interventions:  
• 
FF/VI 100/25 μg once daily (QD)  
• 
FF/VI 200/25 μg QD  
• 
FF/UMEC/VI 100/62.5/25 μg QD  
• 
FF/UMEC/VI 200/62.5/25 μg QD  
Study treatment will be administered via the ELLIPTA DPI in the 
morning. 
Interim 
Analysis 
Not applicable  
2. 
STATISTICAL HYPOTHESES  
This is a bridging study designed to evaluate the add-on benefit of UMEC in a single 
inhaler when compared to FF/VI in Chinese patients with inadequately controlled asthma. 
The primary objective is to evaluate the effects of FF/UMEC/VI 100/62.5/25 μg on lung 
function, as measured by change from baseline in trough FEV1 regardless of study 
treatment discontinuation unrelated to a pandemic or due to any pandemic infection and 
in the absence of study treatment discontinuation due to the indirect impact of a 
pandemic, compared with FF/VI 100/25 μg in Chinese participants with asthma over a 
12-week treatment period. The effects of FF/UMEC/VI 200/62.5/25 μg on change from 
baseline in trough FEV1 at week 12 compared with FF/VI 200/25 μg will also be assessed 
(secondary objective). The Chinese patient data collected in this study will be 
supplemented with data on the treatment difference for the same lung function endpoint 
from the global PhIIIa study 205715, using a Bayesian Dynamic Borrowing approach to 
analysis of the study [Schmidli, 2014]. 
A frequentist hypothesis test will not be performed. Instead, the posterior distributions of 
the difference for both FF/UMEC/VI 100/62.5/25 μg vs. FF/VI 100/25 μg and 
FF/UMEC/VI 200/62.5/25 μg vs. FF/VI 200/25 μg in trough FEV1 at Week 12 will be 
derived, based on the Bayesian analysis including the global PhIIIa study 205715 
information and the data collected on Chinese patients in this study. The hypothesis of 
interest for each treatment comparison is that this difference is larger than zero, and the 
study will be considered to have shown evidence that supports this hypothesis if the 
posterior probability that the difference is larger than zero is at least 95% (a “positive 
result”). Please see Protocol Section 10.7.1 (Protocol Appendix 7) for further information 
on the choice of posterior probability. 


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2.1. 
Multiplicity Adjustment 
There are multiple doses being compared in this study. A hierarchical testing approach 
will be used to test each treatment comparison of the change from baseline in trough 
FEV1 at week 12. If the test for the primary treatment comparison of FF/UMEC/VI 
100/62.5/25 μg vs. FF/VI 100/25 μg meets the definition of a positive result then the 
study will be deemed a success and then the secondary treatment comparison of 
FF/UMEC/VI 200/62.5/25 μg vs. FF/VI 200/25 μg will be tested. All other efficacy 
endpoint will be analysed in a descriptive manner with no formal hypothesis testing and 
therefore no further multiplicity adjustments will be applied.  
3. 
ANALYSIS SETS 
For purposes of analysis, the following populations are defined: 
Analysis Set 
Definition / Criteria 
Analyses Evaluated 
Enrolled  
 
This population will comprise all participants for whom a record 
exists on the study database, including pre-screened participants 
that sign the informed consent document but do not complete 
any of Visit 1 (screening) procedures (i.e., pre-screening 
failures), or participants that complete at least one of Visit 1 
procedures but do not enter the run-in period (i.e., screening 
failures). This population will be used for the summary of 
participant disposition. 
• 
Disposition 
All Participants 
Screened Population  
 
This population contains all participants that complete at least 
one Visit 1 (Screening) procedure.  
• 
Disposition 
Randomized 
Population 
This population contains all participants who were randomized 
(i.e. received a randomization number). 
• 
Study population 
Intent-to-Treat (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 analyses. Participants will be analyzed according to the 
intervention they were randomized to.  
• 
All efficacy 
analyses 
• 
Demographic 
and baseline 
characteristic  
Safety Population  
 
All randomized participants who take at least 1 dose of study 
intervention. This will constitute the primary population for all 
safety analyses. Participants will be analyzed according to the 
intervention they actually received.  
• 
All Safety 
analyses 


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4. 
STATISTICAL ANALYSES 
4.1. 
General Considerations 
4.1.1. 
General Methodology 
In the case of wrong stratification assigned at the time of randomization, the analyses will 
be performed based on the actual stratum per data collected in eCRF. 
All raw and derived variables will be listed and described using summary statistics.  
For categorical variables, summary statistics will be displayed using descriptive statistics 
by frequency count and percentages by category.  
For quantitative variables, summary statistics will be displayed using descriptive statistics 
by number of observations, mean, standard deviation (SD), median, minimum and 
maximum.  
4.1.2. 
Baseline Definition 
For clinic FEV1, the baseline value is the latest acceptable assessment with non-missing 
value at the randomization visit (Visit 2). 
For ACQ, baseline value for each endpoint is the derived value based on the 
questionnaire items assessed at the randomization visit (Visit 2). 
For safety endpoints, the baseline value will be the latest pre-dose assessment with a non-
missing value, including those from unscheduled visits. If time is not collected, Day 1 
assessments are assumed to be taken prior to first dose and used as baseline except 
adverse event. 
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing. 
For participants that did not receive any randomized study treatment, baseline is defined 
as the value from the protocol schedule baseline visit. Unscheduled visits will not be 
considered. All baselines will be referred to as ‘Baseline’ in the summary outputs. 
4.2. 
Primary Endpoint(s) Analyses 
4.2.1. 
Definition of Endpoint 
The primary efficacy endpoint is the change from baseline in trough FEV1 at the end of 
the 12-week treatment period. Only acceptable/borderline acceptable FEV1 values will be 
included in the analysis, and values graded as “not acceptable” will be excluded.  


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4.2.2. 
Main Analytical Approach 
The primary efficacy analysis will evaluate the primary estimand in the Intent-to-Treat 
population, by first using a mixed-model repeated measures (MMRM) analysis of the 
observed China study data conducted across all the four treatment arms to get an estimate 
of the treatment difference for FF/UMEC/VI 100/62.5/25 vs. FF/VI 100/25 as well as an 
estimate of the variability. These estimates will then be combined with the global 205715 
study using the pre-specified robust mixture prior to obtain the posterior distribution for 
the China treatment difference. If the posterior probability of the treatment difference >0 
is greater than or equal to 95%, the hypothesis for difference of the treatment comparison 
(FF/UMEC/VI 100/62.5/25 vs. FF/VI 100/25) is larger than zero is supported. 
The primary analysis is to use a combination of multiple estimand strategies. Intercurrent 
events considered to have an impact on estimation of the treatment effect are:  
• 
Study treatment discontinuation related to an indirect impact of a pandemic 
• 
Study treatment discontinuation due to reasons other than indirect impact of a 
pandemic 
The impact of the intercurrent event of study treatment discontinuation related to an 
indirect impact of a pandemic in general is not expected in the clinical practice thus the 
event will be handled by the hypothetical strategy i.e. had the intercurrent event not 
occurred. As the event is not relevant to the subject but an administrative reason e.g. the 
lockdown of an investigational site, it is reasonable to consider a missingness mechanism 
of Missing at Random (MAR) for the missing primary endpoint values after the event. If 
the reason of the treatment discontinuation for a participant is reported due to COVID-19 
pandemic by the “COVID-19 Pandemic Study Impact” eCRF page, and the participant 
does not have positive / indeterminate COVID-19 test result or does not have any 
confirmed/ probable/ suspected case diagnosis if the COVID-19 test is not performed 
according to  the “COVID-19 Coronavirus Infection Assessment” eCRF page, the reason 
of his/her treatment discontinuation is considered an indirect impact of a pandemic. 
For the intercurrent event of study treatment discontinuation due to reasons other than 
indirect impact of a pandemic, the data collected before and after the event will be 
included into the primary analysis, that is, the event will be handled using the treatment 
policy strategy.  
Primary endpoint values which should be collected and included in the primary analysis 
but missing, including intermittent missing values, will be considered MAR. Missing 
values in the covariates will not be imputed.  
Mean FEV1 over time will be plotted by treatment and treatment completers/withdrawals 
if data permits.  


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4.2.2.1. 
MMRM Modelling 
With the MAR missingness assumption, the primary endpoint will be analysed firstly by 
a MMRM model. The model will include treatment, interaction between treatment group 
and visit, interaction between baseline trough FEV1 and visit, eCRF-reported pre-study 
ICS dosage strength (med, high), sex, baseline trough FEV1, visit and age at screening as 
fixed effects. If the model fails to converge due to imbalance in a covariate, this covariate 
may be removed. The restricted maximum likelihood (REML) approach will be 
employed to estimate the unstructured variance-covariance matrix of the within-patient 
repeated measures. The Kenward-Roger method will be used to estimate the denominator 
degrees of freedom.  If the model fails to converge, Kenward-Roger-2 method 
(DDFM=KENWARDROGER2 option in the Proc MIXED) or the residual method 
(DDFM=RESIDUAL option in the Proc MIXED) may be employed to estimate the 
denominator degrees of freedom.  
The MMRM analysis will be conducted using the following example SAS code based on 
the data from all four treatment arms, in which the italic variables need to be replaced to 
reflect the actual study data structure:  
proc mixed data=adam_dataset method=reml; 
class subject treatment ICS sex visit; 
model chg_FEV1 = treatment ICS sex age visit baselineFEV1 treatment*visit  
     baselineFEV1*visit   / ddfm=kr s cl; 
 
 
repeated visit/subject=subject type=un; 
lsmeans treatment*visit / cl diff om=om_dataset at (baselineFEV1 
age)=(&baselineFEV1 &age); 
run; 
The estimated treatment difference and the corresponding 95% CI will be presented. Due 
to the fact that the design is not frequentist the p-value for the comparison will not be 
reported.   
The LS-means of FEV1 and the LS-means of change from baseline of FEV1 with the 
corresponding standard error in each visit for each treatment arm will also be reported. In 
the derivation of these LS-means using Proc MIXED, a dataset om_dataset will be 
constructed to reflect the data structure of no missing observations, i.e. had each subject 
been reported with the same visits. &baselineFEV1 &age are the mean values of the 
baseline FEV1 and age of subjects in ITT population respectively.    
4.2.2.2. 
Bayesian Dynamic Borrowing 
The primary analysis will be conducted in the Bayesian paradigm using the pre-specified 
mixture prior distribution, which will be updated with the treatment difference between 
FF/UMEC/VI 100/62.5/25 and FF/VI 100/25 estimated in the MMRM analysis of the 
observed China study data. 


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Let 𝑦 denote the observed treatment difference FF/UMEC/VI 100/62.5/25 vs. FF/VI 
100/25 in trough FEV1 at Week 12 in Chinese participants estimated from the MMRM 
model in section 4.2.2.1, and let σ2 be the associated squared standard error. We assume 
𝑦 follows a normal distribution:  
𝑦|Δ ~ N(Δ, σ2) 
where Δ is the true treatment difference. 
The pre-specified prior for 𝛥 is a 2-component robust mixture prior constructed from 
205715 study result: 
 𝑝(𝛥) =  0.3 ∗𝑁(Mean = 86,  SD = 20.1) + 0.7 ∗𝑁(Mean = 0,  SD = 494.97) 
For this mixture prior distribution 𝑝(𝛥) = ∑
𝑤𝑗𝑝𝑗(𝛥),
2
𝑗=1
 the posterior distribution is also a 
mixture distribution:  
𝑝(𝛥|𝑦) = ∑𝑤′𝑗𝑝𝑗(𝛥|𝑦),
2
𝑗=1
 
where 
𝑤𝑗
′ =
𝑤𝑗𝐿𝑗(𝑦)
∑
𝑤𝑖𝐿𝑖(𝑦)
2
𝑖=1
 
and 𝐿𝑗(𝑦) is the marginal likelihood corresponding to the 𝑗-th component in the 
mixture prior As in this case each component of the mixture prior 𝑝𝑗(𝛥) is a normal 
distribution with mean 𝜇𝑗 and variance 𝜎𝑗
2, each posterior 𝑝𝑗(𝛥|𝑦) could be derived by the 
standard conjugate Bayesian analysis:   
Given prior  𝑝𝑗(𝛥), then   
𝑝𝑗(𝛥|𝑦) =  N (
μjσ2 + yσj
2
σj
2 + σ2
,
1
1/σj
2 + 1/σ2) 
and 𝑤𝑗
′ could be derived using:  
𝐿𝑗(𝑦) =
1
√2π(𝜎2 + 𝜎𝑗
2)
exp [−
1
2(𝜎2 + 𝜎𝑗
2) (𝑦−𝜇𝑗)
2] 


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The specific expression of the posterior distribution will be provided using the posterior 
weights, means and standard deviations of each component.  
The posterior mean, median and 90%, 95% credible intervals of this posterior distribution 
𝑝(𝛥|𝑦) will be reported, along with the probability that the true difference is greater than 
zero: Pr(𝛥> 0|𝑦). If the posterior probability is greater than or equal to 95%, the 
hypothesis for difference of the treatment comparison (FF/UMEC/VI 100/62.5/25 vs. 
FF/VI 100/25) is larger than zero is supported. 
4.2.3. 
 Sensitivity Analyses 
4.2.3.1. 
Sensitivity Analysis 1: Tipping Point Analysis for All the Missing 
Values in Change form Baseline of FEV1 at Week 12  
A tipping point analysis will be conducted to assess the robustness of MAR missingness 
assumption in the primary endpoint. 
This method will explore the potential effect of missing data on the reliability of the 
results by using different assumptions regarding the primary endpoint outcome. Missing 
values in the post-baseline change from baseline in trough FEV1 at week 12 will be 
imputed first assuming a MAR mechanism and then adding on a “delta” value prior to 
analyzing the imputed datasets and combining the results. The deltas range from some 
degree of worsening to some degree of improvement and are to vary independently for 
FF/UMEC/VI and FF/VI. 
The analysis results will be used to evaluate the plausibility of the assumed difference 
from MAR for missing outcomes on each treatment arm under which (Tipping Point) the 
conclusions change, i.e., under which there is no longer evidence of a treatment effect, 
and clinical judgment will be applied as to the plausibility of the associated assumptions. 
Missing Data Imputation 
The monotone missing values of the primary endpoint in the FF/UMEC/VI 100/62.5/25 
arm will be imputed with different delta adjustment.  
• 
Missing values in the post-baseline change from baseline in trough FEV1 will firstly 
be imputed under MAR assumption using the sequential regression method with the 
covariates of the MMRM model in section 4.2.2.1. In the imputation of the change 
from baseline in trough FEV1 at week 12 the observed or imputed change from 
baseline in trough FEV1 at week 4 will also be included as a fixed covariate. 1000 
complete datasets including both observed and imputed values will be generated.  


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The example SAS code to be conducted on the data from all four treatment arms 
follows in which the italic variables need to be replaced to reflect the actual study 
data structure: 
PROC MI DATA=adam_dataset SEED=20210603; 
CLASS treatment, ICS, sex; 
VAR treatment ICS sex age baseline_FEV1 chg_FEV1_visit3 chg_FEV1_visit4; 
 
MONOTONE REG (chg_FEV1_visit3 = treatment ICS sex age baselineFEV1); 
MONOTONE REG (chg_FEV1_visit4 = treatment ICS sex age baselineFEV1 
chg_FEV1_visit3); 
RUN; 
If the missingness pattern does not support the example SAS code (i.e. the data has a 
non-monotone pattern), these variables will be imputed using separate MI procedures 
in the same sequence as the example SAS code. 
Missingness in the model covariates may be imputed in advance when needed:  
PROC MI DATA=adam_dataset; 
BY treatment; 
VAR ICSn (i.e. 0/1) sexn (i.e. 0/1) age baseline_FEV1; 
MCMC; 
RUN; 
Delta adjustment is applied to the imputed monotone missing values at week 12 
only.  
For each complete data, with each applied with one of 9 × 9 delta adjustment 
scenarios, 81 delta-adjusted complete data will be generated. Delta-adjusted values 
are: 
Delta-adjusted value = Imputed value + Delta 
The deltas to be investigated are pre-selected multiples of the observed treatment 
effect from the MMRM model in section 4.2.2.1. If the observed treatment effect 
from the primary analysis is x, the deltas to be investigated will range from -3x to +x 
mL for each treatment arms, in increments of 0.5x mL, i.e.  
−3𝑥, −2.5𝑥, −2𝑥, −1.5𝑥, −𝑥, −0.5𝑥, 0, 0.5𝑥, 𝑥 
The increment or range may be refined based on the analysis results and the location 
of the tipping point. For the comparison of triple vs. dual, the delta for relevant 
FF/UMEC/VI and FF/VI arms will be allowed to vary independently, thus will form 
9 × 9 delta adjustment scenarios. The delta adjustment scenario when both deltas are 
zero is corresponding to the MAR assumption.  


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Substantive Model 
Each delta-adjusted complete data with observed and imputed values will be analyzed by 
a same MMRM model as the one in the section 4.2.2.1 based on the data from all four 
treatment groups.  
Combination of the Estimates 
The estimates for the treatment difference in primary endpoint at week 12 as well as the 
corresponding standard errors from each complete dataset with the same delta adjustment 
scenario will be combined using the Rubin’s rule.  
Bayesian Dynamic Borrowing 
The estimates from each delta adjustment scenario will be used in the Bayesian paradigm. 
In the 𝑦|Δ~N(Δ, σ2),  𝑦 is estimated as the delta-adjusted MI-based treatment difference, 
σ2 is estimated as the squared delta-adjusted MI-based standard error. The posterior mean, 
median and 90% credible interval of the posterior distribution 𝑝(𝛥|𝑦) will be reported for 
each delta adjustment scenario, along with the probability that the true difference is greater 
than zero: Pr(𝛥> 0|𝑦).  
4.2.3.2. 
Sensitivity Analysis 2: Tipping Point Analysis for the Treatment 
Discontinuation Due to Reasons Other Than Indirect Impact of a 
Pandemic 
As the intercurrent event of treatment discontinuation due to an indirect impact of a 
pandemic is not relevant to the subject but an administrative event e.g. the lockdown of 
an investigational site, it is reasonable to consider a missingness mechanism of Missing at 
Random (MAR) for the missing primary endpoint values after the event.  
Missing values after the intercurrent event of treatment discontinuation due to other 
reasons may have a Missing Not at Random (MNAR) missing mechanism. This will be 
assessed by applying tipping point analysis analogous to the one specified in section 
4.2.3.1 only on the missing values which occurred after the treatment discontinuation due 
to a reason other than an indirect impact of a pandemic. Other missing values in the 
change from baseline in FEV1 and in baseline FEV1 will be imputed under MAR. 
4.2.3.3. 
Sensitivity Analysis 3: Impact of the Change in the Prior Weight 
Another sensitivity analysis will be conducted to assess the impact of the different prior 
weights of the two normal components in the robust mixture prior for primary endpoint.  
The prior weights of the informative global component of the prior will be investigated 
from 0 to 1 in the increment of 0.05. When the prior weight is 0 or 1, the mixture prior 
will become a normal distribution thus the Bayesian diagram will be the standard 
conjugate analysis.  


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The posterior mean, median and 90% credible interval of the posterior distribution 
𝑝(𝛥|𝑦) will be reported for each prior weight, along with the probability that the true 
difference is greater than zero: Pr(𝛥> 0|𝑦).  
4.2.4. 
Additional Estimands 
4.2.4.1. 
Estimand with Treatment Policy Strategy Only (Estimand 2) 
An additional estimand supporting the primary objective is defined similar to the primary 
estimand except a different intercurrent event strategy will be followed, where study 
treatment discontinuation due to an indirect impact of the pandemic will be handled with 
a treatment policy rather than a hypothetical strategy (i.e. all data collected after study 
treatment discontinuation will be included in the analysis). 
The analysis using this estimand is analogous to the primary analysis: the analysis will be 
conducted first by applying a MMRM then combining the prior information using the 
Bayesian dynamic borrowing method. 
4.2.4.2. 
Estimand to Assess the Impact of COVID-19 Infection (Estimand 3) 
A 3rd estimand is defined to assess the impact of COVID-19 infection.  
If the participant got COVID-19 infection on or prior to randomization date, the 
participant will be excluded from the analysis. If the participant got COVID-19 infection 
after randomization day, the intercurrent event of COVID-19 infection will be handled 
with hypothetical strategy, data collected after COVID-19 infection will not be included 
in the statistical analysis and will be treated as missing data. Meanwhile, the intercurrent 
event of study treatment discontinuation will be handled with treatment policy strategy. 
The analysis using this estimand is analogous to the primary analysis: the analysis will be 
conducted first by applying a MMRM then combining the prior information using the 
Bayesian dynamic borrowing method. The missingness will be handled with MAR 
assumption. 
4.3. 
Secondary Endpoint Analyses 
4.3.1. 
Secondary Endpoint 
The secondary endpoint is the change from baseline in trough FEV1 for the comparison 
between FF/UMEC/VI (200/62.5/25 μg) or FF/VI (200/25 μg).   
The primary estimand analysis, the sensitivity analyses and the supplementary analysis of 
the secondary endpoint are analogous to the ones of the primary endpoint, except:  
• 
The endpoints in FF/UMEC/VI (200/62.5/25 μg) or FF/VI (200/25 μg FF/UMEC/VI 
200/62.5/25 vs FF/VI 200/25 are used.  
• 
The mixture prior is 


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Δ ~ 𝑝(𝛥) =  0.3 ∗𝑁(Mean = 100,  SD = 20.0) + 0.7 ∗𝑁(Mean = 0,  SD = 494.97) 
The delta-adjustment in the sensitivity analysis will be conducted conservatively in which 
a same multiplier (-3, -2.5, -2, -1.5, -1, -0.5, 0, 0.5, or 1) as of the primary endpoint would 
be used in each delta adjustment scenario. 
Based on the hierarchical testing approach, if the test for the primary treatment 
comparison of FF/UMEC/VI 100/62.5/25 vs. FF/VI 100/25 did not meet the definition of 
a positive result then the analysis of the secondary endpoint will be considered supportive 
only.  
4.3.2. 
Other Secondary Endpoint 
The other secondary endpoint is the change from baseline in ACQ-7 total score at Week 
12. 
The ACQ-7 consists of seven attributes of asthma control. All 7 items of ACQ have 
response on 0-6 ordinal scale (0=no impairment/limitation, 6=total impairment/ 
limitation). For each version of ACQ (5, 6, 7), the total score is calculated as the average 
of all non-missing item responses. Only one of the first five item responses are allowed to 
be missing in calculating the total score. 
The 7th item response of ACQ-7 at specific visit (i.e., visit 2, visit3, visit 4 and EW visit) 
will be derived based on the value of percent-predicted FEV1 (round down to integer 
percent first) based on below table: 
The percent-predicted FEV1 (%) 
The seventh item response score of 
ACQ 
Value > 95 
0 
90 ≤ Value ≤ 95 
1 
80 ≤ Value ≤ 89 
2 
70 ≤ Value ≤ 79 
3 
60 ≤ Value ≤ 69 
4 
50 ≤ Value ≤ 59 
5 
Value < 50 
6 
Missing 
Missing 
The endpoint will be analyzed in a descriptive manner with no formal hypothesis testing 
to be performed. The estimand will be the same as the estimand for the primary analysis 
except the variable is the change from baseline in ACQ-7 total score at Week 12. The 
treatment difference for the change from baseline in ACQ-7 total score at Week 12 will 
be assessed for each of below comparisons separately: 
• 
FF/UMEC/VI 100/62.5/25 vs. FF/VI 100/25 
• 
FF/UMEC/VI 200/62.5/25 vs. FF/VI 200/25 


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Each comparison will be conducted using a MMRM to be conducted on the data from all 
four treatment arms analogous to the one described in section 4.2.2.1, except the text of 
FEV1 changed to the text of ACQ-7 total score. 
The estimated treatment difference and the corresponding 95% CI will be presented. The 
LS-means of ACQ-7 total score and the LS-means of the change from baseline of ACQ-7 
total score with the corresponding standard error in each visit for each treatment arm will 
also be reported.  
4.4. 
Exploratory Endpoints Analyses 
CCI


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CCI


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4.5. 
Safety Analyses 
Safety data will be summarized based on the Safety Population and will be presented by 
each actual received treatment. 
4.5.1. 
Extent of Exposure 
The extent of exposure to FF/VI 100/25 μg via the ELLIPTA DPI during the run-in 
period, to randomized study treatment and post-treatment data will be summarized. The 
number of days of post-treatment data will be summarized for all participants with at 
least one day of post-treatment data. 
• 
Duration of exposure to FF/VI 100/25 during the run-in period is calculated as: 
o 
Run-in treatment stop date - Run-in treatment start date+1 
• 
Duration of treatment exposure to study treatment is calculated as:  
o 
treatment stop date – treatment start date +1 
CCI


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• 
Post-treatment study duration is calculated as: 
o 
Last Scheduled Clinic Visit (i.e., Visit 4 or Early Withdrawal Visit) date – 
(randomized treatment stop date +1). 
• 
Treatment Exposure will be summarized as continuous, and using the following 
categories: 
o 
≥1 day, ≥4 weeks, ≥8 weeks, ≥12 weeks, week 12 (-7/+7 days, inclusive) 
o 
Run-in Period: ≥1 day, ≥1 week, ≥2 weeks, ≥3 weeks 
o 
Post-treatment duration: >0 to 4 weeks, >4 to 12 weeks, >12 weeks 
In case of missing dates, no imputation will be performed. Exposure will be considered 
missing. 
If a dose counter start count is missing, then it will be assumed to be 30 for the ELLIPTA 
DPI. If any dose counter stop is missing, then it will be assumed to be 0 for the ELLIPTA 
DPI. Number of doses of study drug taken by each participant from each inhaler = Dose 
counter start value – Dose counter stop value. 
4.5.2. 
Adverse Events 
The CRF texts for adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). 
An overview summary of on-treatment AEs, including counts and percentages of 
participants with any AE, AEs leading to permanent discontinuation of study treatment or 
withdrawal from study, SAEs, drug-related AEs, drug-related SAEs, fatal AEs, and fatal 
drug-related SAEs will be produced. 
AEs during screening/run-in period, on-treatment AEs, post-treatment and post-study 
AEs will be summarised separately.  
AEs during screening/run-in period will be separately summarised by System Organ 
Class (SOC) and the Preferred Term (PT) in the order of decreasing frequency in the 
overall population.  
On-treatment AEs will be separately summarised by System Organ Class (SOC) and the 
Preferred Term (PT) in the order of decreasing frequency in the overall population for:  
• 
AEs 
• 
AEs by maximum intensity 
• 
Drug-related AEs 
• 
Drug-related AEs by maximum intensity 
• 
SAEs  
• 
Drug-related SAEs  


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• 
AEs leading to permanent discontinuation of study drug or study withdrawal 
• 
Non-SAEs 
• 
Common (3% or more participants in any treatment arm) AEs 
Where drug-related AE is defined as an AE for which the investigator classifies the 
possible relationship to study intervention as “Yes”. A worst-case scenario approach will 
be taken to handle missing relatedness data, i.e. if the relationship to study intervention is 
missing the AE will be classified as drug-related AE. Overview of on-treatment AEs and 
summary of on-treatment AEs will be repeated adjusted for exposure (per thousand 
person-years) to account for variable treatment duration. Event rate per thousand person-
years will be calculated as the total number of events across the participants x 1000 
divided by the total participant exposure during the time-period of interest. 
Post-treatment AEs will be separately summarised by System Organ Class (SOC) and the 
Preferred Term (PT) in the order of decreasing frequency in the overall population for:  
• 
AEs 
• 
Drug-related AEs 
• 
SAEs  
• 
AEs leading to permanent discontinuation of study drug or study withdrawal 
Post-study AEs will be summarised by System Organ Class (SOC) and the Preferred 
Term (PT) in the order of decreasing frequency in the overall population. 
All AEs, AEs leading to discontinuation of study treatment or withdrawal from the study 
and reasons for considering as a SAE will be listed.  
4.5.2.1. 
Adverse Events of Special Interest (AESI) 
Adverse events of special interest have been defined as AEs which have specified areas 
of interest for one or more of the compounds (FF, VI and/or UMEC) or combination 
therapies (FF/UMEC/VI and/or FF/VI). These consist of groupings of preferred terms 
based on the MedDRA dictionary version used in each reporting effort. Subgroups may 
be defined, based on relevant combination of preferred terms, or on Standardized 
MedDRA queries (SMQ). 
The table below presents the special interest AE groups for FF, UMEC and VI, defined 
upon the release of up-to-date version of the MedDRA dictionary. 


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Special Interest AE Group 
Special Interest AE 
Subgroup 
SMQ/PTs for Inclusion 
Cardiovascular effects 
Cardiac arrhythmia 
Cardiac arrhythmia (SMQ), excluding congenital 
and neonatal arrhythmias 
Cardiac failure  
Cardiac Failure (SMQ) 
Cardiac ischaemic  
Ischaemic Heart Disease (SMQ) 
Stroke 
Central nervous system haemorrhages and 
cerebrovascular conditions (SMQ) 
Hypertension 
Hypertension (SMQ) 
Pneumonia 
 
Infective pneumonia (SMQ) 
LRTI excluding infective 
pneumonia SMQ 
 
Selected PTs 
Decreased bone mineral density 
and associated fractures 
 
Osteoporosis/Osteopenia (SMQ) 
Selected PTs 
Hypersensitivity 
 
Hypersensitivity (SMQ) 
Angioedema (SMQ) 
Anaphylactic reaction (SMQ) 
Anticholinergic Syndrome 
 
Anticholinergic Syndrome SMQ 
Gastrointestinal obstruction 
 
Gastrointestinal obstruction SMQ 
Adrenal Suppression 
 
Selected PTs 
Antimuscarinic ocular effects / 
Corticosteroid Associated Eye 
Disorders 
Glaucoma 
(antimuscarinic / 
corticosteroid) 
Glaucoma (SMQ),  
Cataracts 
(corticosteroids) 
Lens disorder (SMQ) 
Effects on Glucose  
 
Hyperglycaemia/new onset diabetes mellitus (SMQ) 
Local steroid effects  
 
Selected PTs 
Urinary retention 
 
Selected PTs 
Effects on potassium  
 
Selected PTs 
Tremor  
 
Selected PTs 
Asthma/Bronchospasm for 
Asthma-related intubations and 
deaths  
 
Asthma/bronchospasm SMQ 
Dry mouth / Drying of airway 
secretions 
 
Selected PTs (narrow and broad focus) 
Adverse events of special interest will be summarized by AESI category and Preferred 
Term. Preferred Terms may contribute to more than one Special Interest Group. AESIs 
will be counted in each Special Interest Group in which they appear. 
4.5.2.2. 
Major Adverse Cardiac Events (MACE) 
Major Adverse Cardiac Events (MACE) will be analyzed using broad and narrow 
definitions.  
The broad MACE includes below, excluding those with fatality outcome: 
• 
Central Nervous System Haemorrhages and Cerebrovascular Conditions (SMQ) 
• 
Myocardial infarction (SMQ)  
• 
Other ischemic heart disease (SMQ) 


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The narrow MACE includes below, excluding those with fatality outcome: 
• 
PT of “myocardial infarction”  
• 
PT of “acute myocardial infarction” 
• 
Central Nervous System Haemorrhages and Cerebrovascular Conditions (SMQ) 
4.5.2.3. 
COVID-19 Assessment and COVID-19 AEs 
Number of participants with suspected, probable or confirmed for COVID-19 infection 
will be summarized according to the “COVID-19 Coronavirus Infection Diagnosis” and 
“COVID-19 Coronavirus Infection Assessment” eCRF page.  
Number of participants with COVID-19 as reported as an on-treatment AE are 
summarized. All COVID-19 AEs will be flagged in the AE listings. 
4.5.3. 
Additional Safety Assessments 
4.5.3.1. 
Severe Exacerbation 
The frequency and percentage of participants with severe asthma exacerbations, and the 
relevant outcome will be presented.  
4.5.3.2. 
Laboratory Data 
Change from baseline for Chemistry and Hematology will be summarized.  
Change from baseline for laboratory values will also be summarized using categories of 
‘To Low’, ‘To Normal or No Change’, or ‘To High’. The derivation rule follows:  
• 
Laboratory values will be classified as ‘Low’, ’Normal’, or ‘High’ based on the 
provided normal ranges.  
• 
Change from baseline values will be classified relative to the normal range as ‘To 
Low’, ‘To Normal or No Change’, or ‘To High’. Participants who do not change 
categories or move from out-of-range to normal will be classified as ‘To Normal or 
No Change’.  
• 
A ‘worst case post-baseline relative to baseline’ classification of urinalysis (occult 
blood and urine protein) results will be summarized by the ‘Any Increase’ category 
and ‘No Change/Decreased’ category. ‘Any Increase’ is defined as a change from 
baseline to a worse category, at any on-treatment post-baseline assessments 
including scheduled, unscheduled, or EW visits. ‘No Change/Decreased’ is defined 
as only no change or decreased post-baseline relative to baseline results. The result 
category levels from best to worst are ‘Negative (-)’, ‘+-’, ‘+’, ‘++’, and ‘+++’. 
Participants with missing baseline are assumed to have a result of NEGATIVE for 
the baseline value. 


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Liver Monitoring/Stopping Event Reporting will be summarized. The abnormality of 
urinalysis is based on its potential clinical importance which is defined as an increase in 
Protein or Occult Blood post-baseline relative to Baseline (Screening). 
4.5.3.3. 
Vital Signs 
Change from baseline for vital signs will be summarized.  
Change from baseline for vital signs values will also be summarized by visit and worst-
case post-baseline using categories of ‘To Low’, ‘To Normal or No Change’, or ‘To 
High’. The derivation rule is similar to Laboratory data’s (section 4.5.3.2) except the 
classification is based on the following potential clinical importance: 
• 
Pulse Rate (bpm): Low (<60), Normal (≥60 to ≤100), High (>100);  
• 
Systolic Blood Pressure (mmHg): Low (<90), Normal (≥90 to ≤140), High (>140) 
Diastolic Blood Pressure (mmHg): Low (<60), Normal (≥60 to ≤90), High (>90) 
4.5.3.4. 
ECG 
When triplicate/multiple ECG assessments are taken, mean of the measurement will be 
calculated first and summary statistics will be based on the calculated mean. This will 
apply to both baseline and post baseline assessments. 
A summary of the change from baseline in each ECG parameter by treatment group and 
visit will be provided. 
The worst-case post-baseline ECG findings will be summarized using the categories of: 
• 
‘Abnormal’ if any on-treatment assessment is evaluated as ‘Abnormal’ 
• 
‘Unable to evaluate’ if all on-treatment assessments are ‘Unable to evaluate’ 
• 
‘Normal’ if any on-treatment assessment is evaluated as ‘Normal’ and there are no 
on-treatment assessments evaluated as ‘Abnormal’ 
The maximum post-baseline QTc(F) values will be summarized using the categories of: 
• 
≤ 450 msec 
• 
> 450 to ≤ 480 msec 
• 
> 480 to ≤ 500 msec 
• 
> 500 to ≤ 530 msec 
• 
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The maximum increase in post-baseline QTc(F) values relative to baseline will be 
summarized using the categories of: 
• 
<-60 msec 
• 
≥ -60 to < -30 msec 
• 
≥ -30 to < 0 msec 
• 
≥ 0 to < 30 msec 
• 
≥ 30 to < 60 msec 
• 
≥ 60 msec 
4.6. 
Other Analyses 
Not applicable. 
4.7. 
Interim Analyses 
No interim analysis is planned in this study.  
4.8. 
Changes to Protocol Defined Analyses 
There were no changes or deviations to the originally planned statistical analysis 
specified in the protocol amendment 2 dated 18 Jul 2022. 
5. 
SAMPLE SIZE DETERMINATION 
Approximately 890 participants will be screened to achieve 356 randomly assigned to 
study intervention (89 patients per arm). This sample size denotes the number of 
participants with trough FEV1 data at Week 12, regardless of whether they are still on 
randomized treatment or have discontinued randomized treatment early (for reasons that 
are NOT an indirect impact of a pandemic). Study treatment discontinuation related to an 
indirect impact of a pandemic will be handled with a hypothetical strategy. This 
corresponds to the primary estimand strategy. 
The proposed sample size of 89 participants per arm has been determined using a 
pragmatic approach and reflects ~22% of the global Ph3a study (205715) sample size 
which would generally satisfy the requirement for a consistency evaluation within a 
global study. Please see Section protocol 10.7.2 for further information on the selected 
sample size. 


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With this sample size, and using Bayesian dynamic borrowing with initial weight of 0.3 
on the global 205715 study results (see protocol Section 9.4.2), the probabilities of the 
study achieving a positive result for each treatment comparison under various 
assumptions about the true treatment difference in Chinese patients are shown in Table 1 
(for further details on the a range of possible observed treatment differences in China see 
Protocol Statistical Appendix Section 10.7.3). These probabilities assume a between-
individual SD of 350mL for the primary endpoint (though probabilities are also shown 
for alternative SDs to assess the sensitivity to the assumed between participant sampling 
variation). This value was chosen based on results from the global asthma study 205715 
(and the Japanese subset from the study) as well as global and Asian FF/VI asthma 
studies. It is a higher SD than observed in the global 205715 study (approximately 280-
305mL (Japanese subset (225-245mL) based on the reported standard errors at Week 12 
and Week 24), but a conservative estimate was chosen to take into account the higher 
variability that has been seen in other relevant asthma studies (FF/VI global and Asian 
studies’ SD ranged approximately 300-400mL). 
The probability of a false positive result for the primary treatment comparison (assuming 
true treatment difference = 0 mL) is 19% (Table 1). This is higher than the typical type 1 
error usually applied in fully powered registration studies but should be considered within 
the context of the bridging approach. A bridging approach is proposed because of the 
expected similarity of the treatment difference in Chinese patients and the global 
population (supported by similarities in the epidemiology, pathophysiology, 
pharmacology and clinical management of patients and consistency of treatment 
differences across key demographic factors including ethnicity), and hence there is low 
probability of the null effect being true. 
If the true treatment difference for the primary treatment comparison is 100 ml, the 
probability of the primary treatment comparison (FF/UMEC/VI 100/62.5/25 vs. FF/VI 
100/25) meeting the definition of a positive result is 85% (equivalent to the power of the 
study). If a positive result for the primary treatment comparison in the testing hierarchy is 
achieved, the secondary treatment comparison (FF/UMEC/VI 200/62.5/25 vs. FF/VI 
200/25) will be tested and the probability of meeting the definition of a positive result is 
83%, assuming the true treatment difference is 100ml. 


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Table 1 
Probability of Success for a range of possible true treatment 
differences and varying standard deviation 
Treatment 
comparison  
 
Standard 
Deviation  
 
Probability of Success
†*
 
when the 
true 
treatment 
difference is 
0mL (false 
positive 
rate)  
when the 
true 
treatment 
difference 
is 60mL  
when the 
true 
treatment 
difference 
is 86mL  
when the 
true 
treatment 
difference 
is 100mL  
Primary: 
FF/UMEC/VI 
100/62.5/25 
vs. FF/VI 
100/25  
325mL  
19%  
63%  
81%  
88%  
350mL  
19%  
61%  
78%  
85%  
400mL  
21%  
58%  
74%  
81%  
Secondary: 
FF/UMEC/VI 
200/62.5/25 
vs. FF/VI 
200/25  
325mL  
16%  
60%  
78%  
86%  
350mL  
18%  
58%  
76%  
83%  
400mL  
19%  
55%  
72%  
79%  
†The probability of success values reported for the secondary treatment comparison (FF/UMEC/VI 200/62.5/25 
compared to FF/VI 200/25) are only relevant after obtaining a positive outcome for the primary treatment comparison 
(FF/UMEC/VI 100/62.5/25 compared to FF/VI 100/25).  
*Results based on simulating 10,000 replicate studies and averaging the study results across replications.  
 
6. 
SUPPORTING DOCUMENTATION 
6.1. 
Appendix 1 Study Population Analyses 
Unless otherwise specified, the study population analyses will be based on the enrolled 
population. A summary of the number of participants in each of the participant level 
analysis set will be provided. 
6.1.1. 
Participant Disposition 
The overall participant disposition will be summarized for the Enrolled population, 
including the number and percentage of participants in each treatment group and overall, 
screened (All Participants Screened), randomized, ITT population. Additionally, the 
reasons for Screen Failure, Run-in Failure, will be summarized for the Enrolled 
Population. 
Listings of failures prior to randomization will be generated.  
The number and percentage of participants at each centre will be summarized. This will 
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The number and percentage of participants who completed the double-blind study 
treatment as well as the number who stopped the study treatment prior to the end of the 
study will be summarized, along with the reasons for discontinuation of the study 
treatment, and these will also be listed. The reason of indirect impact of pandemic will be 
displayed separately in addition to the eCRF reported reasons.  
The number and percentage of participants who completed the study as well as the 
number who withdrew early from the study will be summarized, along with reasons for 
early withdrawal from the study, and these will also be listed.  
6.1.2. 
Demographic and Baseline Characteristics 
Each of the following types of data will be summarized: 
• 
Demographic data: age, sex, ethnicity, weight, height, body mass index (BMI) 
o 
Age will be also summarized in the categories of: <18, 18 to <65, 65 to <75, 75 
to <85, ≥85  
o 
Body Mass Index (BMI) is calculated as weight (kg) / [height (m)]2, will be 
presented as for summary statistics with 1 decimal place. 
• 
eCRF-Reported pre-study ICS dosage at screening 
• 
Disease Duration (duration of asthma, onset age of asthma (rounded down to integer 
in year unit)) 
• 
Asthma medical history questionnaire: the subject's quick relief inhaler (rescue 
inhaler) provide symptom relief (no relief, a little relief, some relief, a great deal of 
relief, complete relief) 
• 
Smoking history (smoking status of non-smoker or former smoker, and current 
smokers) 
• 
Medical conditions  
• 
Spirometry at Visit 1 and Visit 2 
o 
Pre- and post-bronchodilator for FEV1, FVC, and FEV1/FVC, reversibility by 
albuterol/salbutamol at Visit 1, and associated percent predicted values.  
o 
Pre-dose for FEV1, FVC at Visit 2, and associated percent predicted values. 
o 
Change in pre-dose FEV1 from Visit 1 to Visit 2 during run-in period. 
o 
At Visit 1, if the spirometry assessment is repeated for a given participant to 
meet the eligibility criteria on the reversibility, the repeated spirometry data will 
be used for that visit. 
o 
Reversibility will be summarized in the categories of: <15%, ≥15%, <400 mL, 
≥400 mL  


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• 
ACQ-6 total score at screening and randomization (day 1) Cardiovascular history 
and cardiovascular risk factors. 
o 
Cardiovascular history includes the following medical condition: arrhythmia, 
congestive heart failure, coronary artery disease, myocardial infarction, 
cerebrovascular accidents. 
o 
Cardiovascular risk factors include the following medical condition: 
hypertension, diabetes mellitus, hypercholesterolemia. 
6.1.3. 
Protocol Deviations 
Important protocol deviations will be summarized in ITT population. 
Protocol deviations will be tracked by the study team throughout the conduct of the 
study. These protocol deviations will be reviewed to identify those considered as 
important as follows: 
• 
Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations (where possible without knowing the study intervention details) 
are captured and categorised in the protocol deviations dataset (except for the PD of 
taking incorrect treatment). 
• 
Participants who received an incorrect container will be captured as an important 
protocol deviation. The actual treatment in the incorrect container will be identified 
and quality controlled by S&P either as incorrect treatment or unplanned treatment 
per randomization schedule. 
• 
This dataset will be the basis for the summaries and listings of protocol deviations. 
No per-protocol analysis is planned for this study. 
6.1.4. 
Concomitant Medications 
Summaries will be provided for the asthma medications by 
• 
At study entry 
• 
On-treatment period 
• 
Post-treatment period 
• 
Post-study period 
Summaries will be provided for the non-asthma medications by 
• 
On-treatment period 
• 
Post-treatment period 
• 
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Concomitant Medications will be coded using the GSKDrug dictionary. Asthma 
medication tables will be reported by Respiratory Medication Class (RMC) and 
ingredient. Non-Asthma medication tables will report by Anatomical Therapeutic 
Chemical (ATC) level 1 and ingredient. Multi-ingredient medications will be presented 
according to their combination ATC classification rather than the classification of the 
ingredients. 
6.1.5. 
Study Intervention Compliance 
Dose counter data handling refers to section 4.5.1.  
Treatment compliance of double blinded treatment period is derived as: 
Treatment compliance =  
Total number of doses taken
Treatment stop date – treatment start date +1 × 100% 
Overall compliance will be summarized and categorized as follows: 
• 
< 50 % 
• 
≥50 % to < 80% 
• 
≥80 % to < 95 % 
• 
≥95 % to ≤105 % 
• 
>105 % to ≤120 % 
• 
>120 %. 
If a participant receives a treatment other than the randomized treatment during the study, 
the compliance will still be calculated using data from all containers received and overall 
exposure start and stop dates. 
If a participant completed treatment and did not administer the study treatment at the day 
of last clinic visit (i.e., Visit 4 [EOS Visit] or Early Withdrawal Visit [EW]) and date of 
last dose not collected in eCRF page “Treatment Discontinuation/Completion”, then the 
day of last clinic visit (i.e., Visit 4 [EOS Visit] or Early Withdrawal Visit [EW]) will be 
deemed as the last dose day. 
6.2. 
Appendix 2 Electronic Clinical Outcome Assessment 
(eCOA) Compliance 
The compliance of ACQ eCOA data will be assessed at clinical visits and will be derived 
at overall study and visit level for the endpoint of ACQ and reported across all 
participants and by treatment group. 


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6.2.1. 
Endpoint Level Compliance 
The assessments of ACQ will be performed as detailed within Section 4.4.1. 
The compliance for ACQ eCOA (i.e. availability of a score) will be reported for each 
analysis timepoint using a frequency table. The denominator will be the number of 
expected completed questionnaires (i.e., the number of participants remaining in the 
study at the given timepoint). 
Endpoint-level compliance will be restricted to key eCOA endpoints within the study 
(ACQ-5, ACQ-6). eCOA compliance for key eCOA endpoints of ACQ-5 and ACQ-6 
across all participants will be calculated separately. The target compliance is >=90% for 
each key endpoint. The study eCOA compliance will be reported for each treatment 
group and overall. 
6.2.2. 
Study Level Compliance 
An eCOA (ACQ) will be considered complete according to the conditions mentioned in 
section 4.4.1.  
• 
The overall study level eCOA compliance will be assessed across all participants and 
across all visits between the date of the Screening visit through to the date of the 
participant’s study completion or study withdrawal.  
The target compliance for the study level is >=90%. The study ACQ eCOA 
compliance will be reported for each treatment group. 
Overall study level ACQ eCOA compliance for the study is calculated as: 
Total number of complete eCOAs
Expected number of complete eCOAs per participant × Total number of particpants × 100% 
• 
Overall visit level ACQ eCOA Compliance will be calculated across all ACQ 
eCOAs and across all participants for baseline (Day 1), Week 4 and Week 12. The 
target compliance is >=90%. The study ACQ eCOA compliance will be reported for 
each treatment group. 
Overall visit level ACQ eCOA compliance for the study is calculated as: 
Total number of complete eCOAs  at that visit
Expected number of complete eCOAs per participant × Total number of particpants at the visit × 100% 


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6.3. 
Appendix 3 Data Derivations Rule 
6.3.1. 
Planned and Actual Treatment 
For participants who received the correct treatment throughout the study, the actual 
treatment will be the same as the planned treatment. For participants who received an 
incorrect treatment, the actual treatment will be derived as follows: 
• 
If the number of doses on an incorrect treatment is less than the number of doses on 
the planned treatment then the actual treatment is assigned as planned treatment. 
• 
If the number of doses on an incorrect treatment is greater than the number of doses 
on the planned treatment then the actual treatment is assigned as the incorrect 
treatment. 
• 
If the number of doses on an incorrect treatment and planned treatment are the same, 
the actual treatment is assigned as the treatment with the UMEC and/or higher FF 
dose. 
• 
If an incorrect container was dispensed and not returned, such that it is not possible 
to ascertain whether or not any doses were taken from the incorrect container, it will 
be assumed that the participant took all possible doses from this container (i.e., 30 
doses in total). 
6.3.2. 
Study Period 
The study consists of a 1-week pre-screening period, a 3-week screening / run-in period, 
a 12-week treatment period, and a 1-week safety follow-up period.  
Pre-screening: Details about the study and procedures will be explained through the 
informed consent process. The Pre-screening Visit (Visit 0) must be completed prior to 
initiating any Visit 1 procedures.  
Screening / run-in: Participants who meet all the eligibility criteria at screening (Visit 1), 
will enter the run-in period for 3 weeks in order to continue to assess the participant’s 
eligibility for the study. Participants satisfying all inclusion/exclusion criteria and who 
have successfully completed all protocol procedures at screening will be provided with 
FF/VI (100/25 μg via the ELLIPTA dry powder inhaler [DPI]), taken in the morning 
once daily during the 3-week run-in period. Rescue medication (albuterol/salbutamol) 
will be provided to use on an as-needed basis throughout the study. The 3-week run-in 
period is necessary in order to allow participants to become accustomed to using the 
ELLIPTA DPI as well as to assess the participant’s eligibility for the study and collect 
baseline electronic diary (eDiary) data.  
Treatment period: At the conclusion of the 3-week run-in period (Visit 2), all 
participants who meet the additional predefined criteria will be randomized 1:1:1:1 to 
receive either FF/UMEC/VI (100/62.5/25; 200/62.5/25 μg) or FF/VI (100/25; 200/25 μg) 
via the ELLIPTA DPI for the duration of the 12-week treatment period.  Study treatment 
will be administered via the ELLIPTA DPI in the morning. 


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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 4/end of study (EOS) or, if applicable, the Early Withdrawal Visit. A 
participant will be considered to have completed the study upon completion of all 
assessments and procedures for Visit 4/EOS and including a successful follow-up 
contact/visit.  
For analyses of safety data and concomitant medications, during screening/run-in period, 
at study entry, on-treatment period, post-treatment and post-study period are defined as: 
Study Phase 
Definition 
At Study Entry 
Event Onset Date/Time < Visit 0 (Pre-screening Visit) Date 
and Event End Date/Time >= Visit 0 (Pre-screening Visit) 
Date - 2  
Note: if the end date/time is missing, deem as ongoing.  
Screening/Run-in 
Period 
Visit 1 (Screening/ Run-in Visit) Date <=Event Onset Date or 
Assessment Date/Time < Randomized Treatment Start Date. 
Note: for participants who didn’t receive any randomized 
treatment, the rule will be: 
Visit 1 Date <=Event Onset Date or Assessment Date/Time < 
Target Randomization Date. 
On-Treatment 
Randomized treatment start date <=Event Onset Date or 
Assessment Date/Time <=Randomized Treatment Stop Date 
+1 or any assessment with a missing or partial date unless 
there is evidence it was not on-treatment. 
Post-Treatment1 
Randomized Treatment Stop Date + 1 < Event Onset Date or 
Assessment Date/Time <=Last Scheduled Clinic Visit (i.e., 
Visit 4 [EOS Visit] or Early Withdrawal Visit [EW])2 
Note: if any participant does not receive a dose of 
randomized treatment then all post-baseline data prior to EW 
or EOS visit is considered as post-treatment. 
Post-Study 
Event Onset Date > Last Scheduled Clinic Visit (i.e., Visit 4 
(EOS Visit) or Early Withdrawal Visit)2 
Note: for participants who continue in the study after IP 
discontinuation (i.e., where treatment discontinuation date < 
Visit 4 (EOS visit) date or EW visit date), the rule will be: 
Event Onset Date > Last Scheduled Clinic Visit (i.e., Visit 4 
(EOS Visit) or EW Visit)2 


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1: Applicable only for participants who continue in the study after IP discontinuation. 
2: If a participant is lost to follow up and does not have an EOS or EW visit, the study 
conclusion date will be used if available. If no study conclusion date is available, the 
last contact date will be used. 
For analyses of concomitant medications at study entry, medications will be included if 
the start date prior to study entry (pre-screening visit [Visit 0]) and are either ongoing at 
Visit 0 or have a stop date within 2 days before Visit 0, on or after Visit 0. A medication 
will be classified into every period in which it was taken. For medications with partial 
start and stop dates, the medication will be classified into every period in which it could 
have been taken. 
6.3.3. 
Study Day and Reference Dates 
The safety reference date is the study intervention start date and will be used to calculate 
study day for safety measures.  
The efficacy reference date is the date of randomization and will be used to calculate 
study day for efficacy measures and baseline characteristics, as well as efficacy durations.  
The study day is calculated as below: 
• 
Assessment Date = Missing              → Study Day = Missing  
• 
Assessment Date < Reference Date → Study Day = Assessment Date – Ref Date 
• 
Assessment Data ≥ Reference Date → Study Day = Assessment Date – Ref Date + 1     
6.3.4. 
Assessment Window  
In general, data will be reported according to the nominal time of clinic visits and 
assessments as specified in the protocol. For example, if a participant had recorded values 
for the Week 4 visit on the 22nd day of treatment, the data will be presented as Week 4 
values in the summary tables. 
The post-randomization clinic data collected at EW/ End of Study (EOS) visits in the 
eCRF and SDTM data will be mapped based on study day as follows: 
Study days  
Target date 
for visit 
Visit/Week 
15 to 56 
29 
Visit 3/Week 4 
≥ 57 
85 
Visit 4/Week 12 
If a participant has an EW visit on or before day 14 then the data collected at this study 
visit will be listed but excluded from visit-based summaries, figures and analyses. 


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Note: 
• 
For laboratory there is no planned assessment at week 4 and so data that slots to 
week 4 will be excluded from summaries and analyses. 
• 
After mapping visit for EW/ End of Study (EOS) visits, when there is more than one 
non-missing value within an assessment window for a given analysis or summary, 
the measure from the scheduled visit will take priority. 
6.3.5. 
Multiple measurements at One Analysis Time Point 
For safety parameters, participants having both high and low values relative to normal 
ranges at post-baseline on treatment visits will be counted in both the high and low 
categories of the ‘worst-case post-baseline’ row of related summary tables. 
For ACQ assessment, if multiple measurements at one scheduled visit (i.e. visit 2, visit 3, 
visit 4), the non-missing record closest to the target study day will be used. If there are 
multiple records within the same distance from the target study day, the latest record will 
be used. 
Visit/Week 
Target date for visit 
Visit 2/Baseline 
1 
Visit 3/Week 4 
29 
Visit 4/Week 12 
85 


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6.3.6. 
Handling of Partial Dates 
Element 
Reporting Detail 
General 
• 
Partial dates will be displayed as captured in participant listing 
displays.   
• 
However, where necessary, display macros may impute dates as 
temporary variables for sorting data in listings only. In addition, 
partial dates may be imputed for ‘slotting’ data to study phases or 
for specific analysis purposes as outlined below. 
• 
Imputed partial dates will not be used to derive study day, time to 
onset or duration (e.g., time to onset or duration of adverse events), 
or elapsed time variables (e.g., time since diagnosis). In addition, 
imputed dates are not used for deriving the last contact date. 
Adverse 
Events 
• 
Partial dates for AE recorded in the CRF will be imputed using the 
following conventions: 
Missing start 
day 
If study intervention start date is missing (i.e. 
participant did not start study intervention), then set 
start date = 1st of month. 
Else if study intervention start date is not missing: 
o 
If month and year of start date = month and 
year of study intervention start date, then 
▪ 
If stop date contains a full date and stop 
date is earlier than study intervention start 
date, then set start date= 1st of month. 
▪ 
Else set start date = study intervention 
start date. 
Else set start date = 1st of month. 
Missing start 
day and month 
If study intervention start date is missing (i.e. 
participant did not start study intervention), then set 
start date = January 1. 
Else if study intervention start date is not missing: 
o 
If year of start date = year of study intervention 
start date, then 
▪ 
If stop date contains a full date and stop 
date is earlier than study intervention start 
date, then set start date = January 1. 
▪ 
Else set start date = study intervention 
start date.       
Else set start date = January 1. 


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Element 
Reporting Detail 
Missing end 
day  
A '28/29/30/31' will be used for the day (dependent 
on the month and year). 
Missing end 
day and month 
No Imputation 
Completely 
missing 
start/end date 
No imputation 
Concomitant 
Medications 
• 
Partial dates for any concomitant medications recorded in the CRF 
will be imputed using the following convention: 
Missing start 
day 
If study intervention start date is missing (i.e. 
participant did not start study intervention), then set 
start date = 1st of month. 
Else if study intervention start date is not missing: 
o 
If month and year of start date = month and year 
of study intervention start date, then 
▪ 
If stop date contains a full date and stop 
date is earlier than study intervention start 
date, then set start date= 1st of month. 
▪ 
Else set start date = study intervention start 
date. 
Else set start date = 1st of month. 
Missing start 
day and month 
If study intervention start date is missing (i.e. 
participant did not start study intervention), then set 
start date = January 1. 
Else if study intervention start date is not missing: 
o 
If year of start date = year of study intervention 
start date, then 
▪ 
If stop date contains a full date and stop 
date is earlier than study intervention start 
date, then set start date = January 1. 
▪ 
Else set start date = study intervention start 
date.       
Else set start date = January 1. 
Missing end 
day 
A '28/29/30/31' will be used for the day (dependent 
on the month and year).  


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Element 
Reporting Detail 
Missing end 
day and month 
A '31' will be used for the day and 'Dec' will be used 
for the month. 
Completely 
missing 
start/end date 
No imputation 
If an AE cannot be classified into any of 'during screening/run-in period 
', 'on-treatment', or 'post-treatment' based on its imputed start and end 
dates, the AE will be classified to “on treatment”.  
Age 
• 
Age will be calculated based on the Pre-Screening Visit date (or 
Screening, if pre-screening not performed). 
• 
Only year of birth is collected on eCRF. Day and Month of birth 
are imputed as 30 June. Age is derived using the date of the pre-
screening visit. 
• 
All participants with imputed age of 17 or 18 years will be source 
data verified, and presence/ absence of protocol deviation on the 
inclusion criteria #1 will be taken into consideration in the 
derivation for the analysis variable age. 
• 
Age will be rounded down to integer. 
• 
Birth date will be presented in listings as ‘YYYY’. 
Study 
treatment 
start and 
stop date 
• 
If the study treatment start date is missing, the Visit 2 (Day 1) date 
will be used. 
• 
If overall treatment stop date is missing or partial, it will be 
imputed as follows: 
• 
For participants who attended an Early Withdrawal visit, use the 
date of the Early Withdrawal visit 
• 
For participants who attended the last on-treatment visit, use the 
End of Study Visit date 
• 
For participants who died and did not attend the last on-treatment 
visit, use the date of death 
• 
For all other participants, use the last recorded exposure stop date 


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6.3.7. 
Abbreviations & Trade Marks 
6.3.7.1. 
Abbreviations 
Abbreviation  
Description 
ACQ 
Asthma Control Questionnaire 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ATC 
Anatomical Therapeutic Chemical 
BDB 
Bayesian Dynamic Borrowing 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CV 
Cardiovascular 
DBL 
Database Lock 
DPI 
Dry Powder Inhaler 
ECG 
Electrocardiogram 
(e)CRF 
(Electronic) Case Report Form 
eDiary 
Electronic Diary 
EOS 
End of study 
ERS 
European Respiratory Society 
FEV1 
Forced expiratory volume in 1 second 
FF 
Fluticasone Furoate 
FP 
Fluticasone Propionate 
FVC 
Forced Vital Capacity 
GSK 
GlaxoSmithKline 
ICH 
International Conference on Harmonization 
ICS 
Inhaled Corticosteroids 
IP 
Investigational Product 
ITT 
Intent to Treat 
kg 
Kilogram 
LAMA 
Long-Acting Muscarinic Antagonist 
LRTI 
Lower Respiratory Tract Infection 
LTRA 
Leukotriene Receptor Antagonist 
µg 
Microgram 
m 
Meter 
MAR 
Missing at Random 
MedDRA 
Medicinal Dictionary for Regulatory Activities 
mL 
Microliter 
MMRM 
Mixed-Model Repeated Measures 
MNAR 
Missing Not at Random 
prn 
As needed 
PD 
Protocol Deviation 
QD 
Once daily 
QTc 
QT interval corrected for heart rate 
QTcB 
QT interval corrected for heart rate by Bazett’s formula 


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Abbreviation  
Description 
QTcF 
QT interval corrected for heart rate by Fridericia’s 
formula 
RMC 
Respiratory Medication Class 
SABA 
Short-Acting Beta-2-Agonists 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SoA 
Schedule of Activities 
SMQ 
Standardized MedDRA Query 
UMEC 
Umeclidinium 
VI 
Vilanterol 
6.3.7.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
ELLIPTA 
 
SAS 
 
 
MedDRA 
7. 
REFERENCES 
Schmidli, H., Gsteiger , S., Roychoudhury , S., O'Hagan , O., Spiegelhalter , D. J., & 
Neuenschwander , B. (2014). Robust meta-analytic-predictive priors in clinical trials with 
historical control information. Biometrics, 70: 1023-32.