Conditions: Pulmonary Disease, Chronic Obstructive
Keywords: Chronic Obstructive Pulmonary Disease ELLIPTA Fluticasone Furoate Umeclidinium Vilanterol
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 229
Healthy volunteers: no

Brief summary:
This study will evaluate safety and efficacy of FF/UMEC/VI via ELLIPTA® inhaler. ELLIPTA is a registered trademark of GlaxoSmithKline group of companies.

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: FF/UMEC/VI intervention 2: ELLIPTA
Intervention descriptions: intervention 1: FF/UMEC/VI will be administered intervention 2: Participants will receive FF/UMEC/VI using ELLIPTA inhaler.

Protocol document:
Prot_000.pdf: 
TMF-16036460 
CONFIDENTIAL 
GSK group of companies 
 
212655 
 
1 
 
TITLE PAGE 
Protocol Title: Phase IV, 12-week, single arm, open label study evaluating the safety and 
efficacy of fixed dose triple combination FF/UMEC/VI administered once daily in the 
morning via a dry powder inhaler in participants with chronic obstructive pulmonary 
disease in India. 
Study Identifier: 212655/ Amendment 04 
Compound Number 
or Name: 
GSK2834425 
 
Brief Title: A single-arm, open-label study to evaluate the safety and efficacy of 
FF/UMEC/VI in participants with COPD.  
Study Phase: Phase 4 
Sponsor Name and Legal Registered Address:  
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
Regulatory Agency Identifying Number(s): N/A 
Medical Monitor Name and Contact Information [will be provided separately OR can 
be found in the Study Reference Manual] 
SPONSOR SIGNATORY: 
David J. Slade M.D. 
Clinical Development Lead 
Respiratory Clinical Sciences 
Approval Date: 03 May 2023 
 
 
Copyright 2023 the GSK group of companies.  All rights reserved.  Unauthorised 
copying or use of this information is prohibited. 
 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
2 
 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
DNG Number 
Amendment 4 
03 May 2023 
TMF-16036460 
Amendment 3 
29 Nov 2022 
TMF-15155358 
Amendment 2 
30-MAR-2021 
TMF-11895735 
Amendment 1 
17-Nov-2020 
2020N442016_01 
Original Protocol 
29-Jul-2020 
2020N442016_00 
 
Amendment 4 (date): 03 May 2023 
Overall Rationale for the amendment  
Protocol Amendment 03 was approved by DCGI. However, some of the intended updates 
for PA3 were inadvertently missed and are retained, in the protocol. This amendment is 
to correct these typographical errors.  
 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.2 Schema  
In the study design schema, 
Visit 3 on day 28 has been 
mentioned as week 12. This is a 
typographical error, and it has 
been corrected to week 4 which 
is in line with day 28. 
Correction of a typographical 
error  
4.1 Overall Design 
In the study design schema, 
Visit 3 on day 28 has been 
mentioned as week 12. This is a 
typographical error, and it has 
been corrected to week 4 which 
is in line with day 28. 
Correction of a typographical 
error 
8.1.1 Spirometry 
All participants will have 
spirometry performed at 
screening and each scheduled 
clinic visit during the treatment 
period. 
Corrected to, 
All participants will have 
spirometry performed at each 
Spirometry at screening is not 
required as per PA.3. This was 
inadvertently missed out from 
being deleted in this sentence. 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
3 
 
Section # and 
Name 
Description of Change 
Brief Rationale 
scheduled clinic visit during the 
treatment period. 
8.1.1 Spirometry 
Spirometry equipment will be 
provided through a centralized 
vendor and will calculate the 
percent reversibility for each 
participant. 
  
Corrected to, 
Spirometry equipment will be 
provided through a centralized 
vendor. 
Calculation of percent 
reversibility is not required as 
per PA.3. This was inadvertently 
missed out from being deleted in 
this sentence 
8. 3 
Method of Detecting AEs and 
SAEs 
Corrected to  
8.3.2 Method of Detecting AEs 
and SAEs 
Addition of number to the 
section 
8.3 
8.3.2 Follow-up of AEs and 
SAEs 
Corrected to 
8.3.3 Follow-up of AEs and 
SAEs 
Correction of numbering 
sequence 
8.3 
8.3.3 Adverse Events of Special 
interest 
Corrected to  
8.3.4 Adverse Events of Special 
interest 
Correction of numbering 
sequence 
 
8.3 
8.3.4 Regulatory reporting 
requirements for SAEs/AESI 
Corrected to 
8.3.5 Regulatory reporting 
requirements for SAEs/AESI 
Correction of numbering 
sequence 
 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
4 
 
Section # and 
Name 
Description of Change 
Brief Rationale 
 
8.3 
8.3.5 Pregnancy  
corrected to  
8.3.6 Pregnancy 
Correction of numbering 
sequence 
 
8.3 
8.3.6 Cardiovascular and Death 
events  
corrected to 
8.3.7 Cardiovascular and Death 
events 
Correction of numbering 
sequence 
 
8.3 
8.3.7 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 as per SAE 
reporting timelines Disease-
Related Events and/or Disease-
Related Outcomes Not 
Qualifying as SAEs 
Corrected to 
8.3.8 Disease-Related Events 
and/or Disease-Related 
Outcomes Not Qualifying as 
SAEs 
Correction of numbering 
sequence and typographical 
error in the title 
 
8.3 
8.3.8 Drug/Inhaler Combination 
Product Deficiencies  
corrected to  
8.3.9 Drug/Inhaler Combination 
Product Deficiencies 
Correction of numbering 
sequence 
 
8.3.7  
For all death and any 
cardiovascular events detailed 
in Appendix 6, 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 
Correction of formatting error 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
5 
 
Section # and 
Name 
Description of Change 
Brief Rationale 
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. 
Corrected to 
For all death and any 
cardiovascular events detailed 
in Appendix 6, 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 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
6 
 
Section # and 
Name 
Description of Change 
Brief Rationale 
completed as per SAE reporting 
timelines 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
7 
 
TABLE OF CONTENTS 
PAGE 
1. 
PROTOCOL SUMMARY ........................................................................................ 10 
1.1. 
Synopsis ..................................................................................................... 10 
1.2. 
Schema ...................................................................................................... 14 
1.3. 
Schedule of Activities (SoA) ........................................................................ 15 
2. 
INTRODUCTION .................................................................................................... 17 
2.1. 
Study Rationale .......................................................................................... 17 
2.2. 
Background ................................................................................................ 17 
2.3. 
Benefit/Risk Assessment ............................................................................ 18 
2.3.1. 
Risk Assessment ......................................................................... 19 
2.3.2. 
Benefit Assessment ..................................................................... 27 
2.3.3. 
Overall Benefit: Risk Conclusion .................................................. 27 
3. 
OBJECTIVES AND ENDPOINTS/ESTIMANDS ..................................................... 28 
4. 
STUDY DESIGN .................................................................................................... 31 
4.1. 
Overall Design ............................................................................................ 31 
4.2. 
Scientific Rationale for Study Design. ......................................................... 32 
4.3. 
Jsustification for Dose ................................................................................. 32 
4.4. 
End of Study Definition ............................................................................... 32 
5. 
STUDY POPULATION ........................................................................................... 33 
5.1. 
Inclusion Criteria ......................................................................................... 33 
5.2. 
Exclusion Criteria ........................................................................................ 34 
5.3. 
Treatment phase Criteria ............................................................................ 37 
5.4. 
Lifestyle Considerations .............................................................................. 37 
5.5. 
Screen Failures........................................................................................... 38 
5.6. 
Criteria for Temporarily Delaying Enrollment/Administration of Study 
Intervention ................................................................................................. 38 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY .............................. 39 
6.1. 
Study Intervention(s) Administered ............................................................. 39 
6.2. 
Preparation/Handling/Storage/Accountability .............................................. 39 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................... 40 
6.4. 
Study Intervention Compliance ................................................................... 40 
6.5. 
Dose Modification ....................................................................................... 40 
6.6. 
Continued Access to FF/UMEC/VI after the End of the Study ..................... 41 
6.7. 
Treatment of Overdose ............................................................................... 41 
6.8. 
Concomitant Therapy.................................................................................. 41 
6.8.1. 
Permitted Medications and Non-Drug Therapies .......................... 42 
6.8.2. 
Prohibited Medications and Non-Drug Therapies ......................... 44 
6.8.3. 
Rescue Medicine ......................................................................... 45 
7. 
DISCONTINUATION OF FF/UMEC/VI AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 46 
7.1. 
Discontinuation of FF/UMEC/VI .................................................................. 46 
7.1.1. 
Liver Chemistry Stopping Criteria ................................................ 46 
7.1.2. 
QTc Stopping Criteria .................................................................. 47 
7.1.3. 
Pregnancy stopping criteria ......................................................... 47 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
8 
 
7.1.4. 
COVID-19 stopping criteria .......................................................... 48 
7.2. 
Participant Withdrawal from the Study ........................................................ 48 
7.3. 
Lost to Follow Up ........................................................................................ 48 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 49 
8.1. 
Efficacy Assessments ................................................................................. 49 
8.1.1. 
Spirometry ................................................................................... 49 
8.2. 
Safety Assessments ................................................................................... 50 
8.2.1. 
Safety Endpoints .......................................................................... 51 
8.2.2. 
COPD exacerbations ................................................................... 51 
8.2.3. 
Pneumonia .................................................................................. 52 
8.2.4. 
Physical Examinations ................................................................. 52 
8.2.5. 
Vital Signs .................................................................................... 52 
8.2.6. 
Electrocardiograms ...................................................................... 53 
8.2.7. 
Pregnancy Testing ....................................................................... 53 
8.2.8. 
COVID-19 testing ......................................................................... 53 
8.3. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other 
Safety Reporting ......................................................................................... 54 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information ................................................................................... 54 
8.3.2. 
Method of Detecting AEs and SAEs ............................................. 55 
8.3.3. 
Follow-up of AEs and SAEs ......................................................... 55 
8.3.4. 
Adverse events of special interest................................................ 55 
8.3.5. 
Regulatory Reporting Requirements for SAEs/AESI .................... 56 
8.3.6. 
Pregnancy ................................................................................... 56 
8.3.7. 
Cardiovascular and Death Events ................................................ 57 
8.3.8. 
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as SAEs............................................... 57 
8.3.9. 
Drug/Inhaler Combination Product Deficiencies ........................... 57 
8.4. 
Pharmacokinetics ....................................................................................... 58 
8.5. 
Genetics ..................................................................................................... 58 
8.6. 
Biomarkers ................................................................................................. 58 
8.7. 
Immunogenicity Assessments ..................................................................... 58 
8.8. 
Medical Resource Utilization and Health Economics .................................. 58 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 59 
9.1. 
Statistical Hypotheses................................................................................. 59 
9.2. 
Sample Size Determination ........................................................................ 59 
9.3. 
Statistical Analyses ..................................................................................... 60 
9.3.1. 
Efficacy Analysis .......................................................................... 60 
9.3.2. 
Safety Analysis ............................................................................ 61 
9.3.3. 
Other Analysis ............................................................................. 62 
9.4. 
Interim Analysis .......................................................................................... 62 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 63 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ............................................................................................ 63 
10.1.1. 
Regulatory and Ethical Considerations ........................................ 63 
10.1.2. 
Financial Disclosure ..................................................................... 64 
10.1.3. 
Informed Consent Process .......................................................... 64 
10.1.4. 
Data Protection ............................................................................ 64 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
9 
 
10.1.5. 
Dissemination of Clinical Study Data ........................................... 65 
10.1.6. 
Data Quality Assurance ............................................................... 65 
10.1.7. 
Source Documents ...................................................................... 66 
10.1.8. 
Study and Site Start and Closure ................................................. 66 
10.1.9. 
Publication Policy ......................................................................... 67 
10.2. 
Appendix 2: Contraceptive and Barrier Guidance ....................................... 68 
10.3. 
Appendix 3: Liver Safety: Required Actions and Follow-up 
Assessments .............................................................................................. 71 
10.4. 
Appendix 4: Study Procedures during COVID-19 Pandemic ....................... 75 
10.5. 
Appendix 5: COPD Exacerbation Identification, Categorization and 
Treatment Guidelines.................................................................................. 78 
10.5.1. 
Guidelines for Identifying COPD Exacerbations ........................... 78 
10.5.2. 
COPD Exacerbation Severity ....................................................... 79 
10.5.3. 
Treatment of COPD Exacerbations .............................................. 79 
10.5.4. 
Guidelines for Treatment with Corticosteroids .............................. 79 
10.5.5. 
Guidelines for Treatment with Antibiotics ..................................... 80 
10.5.6. 
Onset and Resolution of COPD Exacerbations ............................ 80 
10.5.7. 
Guideline for assessing multiple mild exacerbations .................... 80 
10.5.8. 
Guideline for assessing exacerbations that increase in 
severity ........................................................................................ 80 
10.6. 
Appendix 6: AEs and SAEs, Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ....................................... 81 
10.6.1. 
Definition of AE ............................................................................ 81 
10.6.2. 
Definition of SAE .......................................................................... 82 
10.6.3. 
Definition of Cardiovascular Events ............................................. 83 
10.6.4. 
Recording and Follow-Up of AE and SAE .................................... 84 
10.6.5. 
Reporting of SAE to GSK ............................................................. 85 
10.7. 
Appendix 7: Abbreviations and Trademarks ................................................ 87 
10.8. 
Appendix 8: Protocol Amendment History ................................................... 90 
11. REFERENCES ....................................................................................................... 97 
 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
10 
 
1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title 
Phase IV, 12-week, single arm, open label study evaluating the safety and efficacy of 
fixed dose triple combination FF/UMEC/VI administered once daily in the morning via a 
dry powder inhaler in participants with chronic obstructive pulmonary disease in India. 
Brief Title: A single-arm, open-label study to evaluate the safety and efficacy of 
FF/UMEC/VI in participants with COPD. 
Rationale: 
Fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) is approved in many 
countries including the USA, EU, and India for the treatment of chronic obstructive 
pulmonary disease (COPD). Many multi-centre, multi-national studies have been 
conducted with FF/UMEC/VI, however, these studies did not include India as a 
participating country. As part of post approval commitment, Phase IV study for 
FF/UMEC/VI in India will be conducted, to provide safety and efficacy data from the 
Indian population. 
The primary purpose of this study is to evaluate the safety and efficacy of a single inhaler 
triple therapy combination of FF/UMEC/VI (100mcg/62.5mcg/25mcg) administered once 
daily via the ELLIPTA™ inhaler, following 12 weeks of treatment. 
Objectives and Endpoints/Estimands: 
Objectives 
Estimands/Endpoints 
Primary 
 
• To evaluate the safety profile of 
FF/UMEC/VI over 12 weeks in 
patients from India  
 
The primary Estimand is defined by the 
following: 
• Endpoint: incidence of adverse events 
(AE), serious adverse events (SAE) 
and adverse events of special interest 
(AESIs). 
• Summary measure: number and 
percentage of participants 
experiencing an AEs, SAEs and 
number and percentage of participants 
experiencing AESIs by system organ 
class and by preferred term. 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
11 
 
Objectives 
Estimands/Endpoints 
• Population of interest: COPD patients 
in India.  
• Key intercurrent events: 
discontinuation of treatment (for any 
reason)  
• Strategy for intercurrent events: a 
While on Treatment strategy will be 
used for treatment 
discontinuation.  This estimates the 
percentage of participants 
experiencing an AE or SAE while 
taking treatment. 
• Participants that test positive for 
COVID-19 will immediately 
discontinue study treatment. Therefore 
COVID-19 will be included as the 
intercurrent event of study treatment 
discontinuation and will be handled 
with While on Treatment strategy for 
the primary estimand 
A supplementary estimand will be defined 
using identical properties as for the 
primary estimand (summary measure, 
population of interest and key intercurrent 
events), however this supplementary 
estimand will report all AEs regardless of 
the discontinuation of study treatment. 
Endpoints: 
• Incidence of AEs, SAEs and AESIs 
Strategy for intercurrent events: 
• Treatment policy strategy will be used 
for treatment discontinuation. This 
summary will therefore be inclusive of 
all on-treatment and post-treatment 
AEs. 
Secondary 
 
• To evaluate the effect of 
FF/UMEC/VI on lung function  
 
 
The secondary Estimands are defined by 
the following:  
• Endpoints:  


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
12 
 
Objectives 
Estimands/Endpoints 
o change from baseline in trough 
FEV1 on Day 85 (trough FEV1 on 
Day 85 is defined as the mean of 
the FEV1 values obtained 24 
hours after morning dosing on Day 
84) 
o change from baseline in trough 
FEV1 on Day 28 (trough FEV1 on 
Day 28 is defined as the mean of 
the FEV1 values obtained prior to 
dosing on Day 28)  
• Summary measure:  
o mean change from baseline in 
trough FEV1 on Day 85  
o mean change from baseline in 
trough FEV1 on Day 28  
• Population of interest: COPD patients 
in India.  
• Key intercurrent events: 
discontinuation of treatment   
• Strategy for intercurrent events: a 
hypothetical strategy will be used for 
treatment discontinuation.  This 
estimates the effect under the 
hypothetical scenario that participants 
had not discontinued treatment.  
• Participants that test positive for 
COVID-19 will immediately 
discontinue study treatment. Therefore 
COVID-19 will be included as the 
intercurrent event of study treatment 
discontinuation and will be handled 
with hypothetical strategy for the 
secondary estimands. 
 
 
 
 
 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
13 
 
Overall Design: 
This is a phase IV, 12-week, single arm, multi-centre study evaluating single inhaler 
triple therapy (FF/UMEC/VI) once daily via the ELLIPTA (see Section 1.2 for study 
schematic). Approximately 306 participants will be screened in order to enroll 229 to the 
study treatment phase, to achieve 220 evaluable participants at the end of the study. At 
the start of the treatment period, participants will discontinue all existing COPD 
medications but may continue their study-supplied rescue salbutamol on an as-needed 
basis (rescue medication) throughout the study. 
Clinic Visits will occur at Pre-Screening (Visit 0), Screening (Visit 1), Start of Treatment 
(Day 1, Visit 2), Day 28 (Visit 3), and Day 85 (Visit 5).  Day 84 (Telephonic Visit 4) and 
Safety follow-up (Visit 6) conducted 1 week after completing the 12-week treatment 
period will be a telephone contact. Participants will sign an informed consent form (ICF) 
at a Pre-Screen or Screening Visit and will be assigned a participant identifier. Note: 
Visit 0 and Screening (Visit 1) may occur on the same day based on discretion of the 
study participant and discretion of Investigator  
Number of Participants: 
Approximately 306 participants will be screened in order to achieve 220 evaluable 
participants at the end of the study (assuming 4% withdrawal from study treatment).  
Intervention Groups and Duration: 
Participants who have consented meet all the eligibility criteria and who have 
successfully completed all protocol procedures at screening will receive the following 
study intervention for 12 weeks: 
FF/UMEC/VI 100mcg/62.5mcg/25mcg via the ELLIPTA inhaler once daily in the 
morning 
 
On the morning of study clinic Visit 2 (start of treatment), Day 28 (Visit 3) and 
telephonic contact Day 84 (telephonic Visit 4), participants will refrain from taking their 
morning dose of study intervention/COPD medication until instructed to do so by clinic 
personnel. Participants will take their last dose of study treatment on Day 84 and will 
return for their final clinical assessments on Day 85 (Visit 5). A safety follow-up (Visit 6) 
will be conducted by phone call approximately one week later. Participants may continue 
their study-supplied rescue salbutamol from the start of the study treatment phase until 
the end of the treatment period.  
A participant will be considered to have completed the study when they have completed 
all phases of the study including screening, the treatment phase, and safety follow-up. 
The total duration of participant participation will be approximately 13 weeks, 12-week 
treatment period and a 1-week follow-up period. 
Participants that permanently discontinue study intervention are not required to withdraw 
from the study. If for any reason a participant must permanently discontinue study 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
14 
 
treatment, every effort should be made by the investigator/staff to keep the participant in 
the study. However, a participant may voluntarily withdraw from participation in this 
study at any time. The investigator may also, at his or her discretion, withdraw a 
participant from further study participation. Participants who are withdrawn from the 
study will not be replaced. 
Data Monitoring/ Other Committee: No 
1.2. 
Schema 
 
 
 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
15 
 
1.3. 
Schedule of Activities (SoA) 
Protocol Activity 
Pre-
Screen 
Screen 
Treatment 
Follow-up 
Visit 0 
Visit 1  
Screen 
Visit 2  
Visit 3 
Visit 
4e (Telephon
ic) 
  
Visit 5 
Study 
treatment 
discontinuat
ion 
Safety 
Follow-up   
Visit 6f 
Study Day 
 
Week 
0/Day 1   
Week 4/Day 
28  
Week 
12/Day 84   
Week 
12/Day 85 
 
1-week 
Follow-
up/Day 92   
Window 
(Day -1) 
 
-4/+2d  
(Day 24 to 
30) 
-4/+2d 
(Day 80 to 
86) 
-4/+2d 
(Day 81 to 
87) 
 
-1/+4d 
(Day 91 to 
96) 
Written Informed 
Consent a 
X 
X 
 
 
 
 
 
 
Demography b 
X 
X 
 
 
 
 
 
 
Medical History, 
including 
cardiovascular history 
 
X 
 
 
 
 
 
 
COPD and Exacerbation 
History 
 
X 
 
 
 
 
 
 
Concomitant Medication 
Assessment 
X 
X 
X 
X 
  
X 
X 
X 
Inclusion/Exclusion 
Criteria 
 
X 
X 
 
 
 
 
 
COVID-19 test c 
 
X 
 
 
 
 
 
 
Smoking History 
 
X 
 
 
 
 
 
 
Smoking status 
X 
 
 
 
X 
X 
 
Smoking Cessation 
Counselling 
 
X 
 
 
 
X 
X 
 
CAT 
 
X 
 
 
 
 
 
 
Baseline/Trough 
Spirometry d 
 
 
X 
X 
 
X 
 
 
Exacerbation 
Assessment 
 
 
X 
X 
  
X 
X 
X 
Physical examination g 
X 
 
 
 
X 
X 
 
Adverse Events 
Assessment 
X 
X 
X 
  
X 
X 
X 
Vital signs h 
X 
 
 
 
X 
X 
 
ECG 
X 
 
 
 
 
 
 
Chest X-ray i 
X 
 
 
 
 
 
 
Oropharyngeal 
examination 
X 
 
 
 
X 
X 
 
Urine Pregnancy Test j 
X 
 
 
 
X 
X 
 
Dispense study 
treatment 
 
 
X 
X 
 
 
 
 
Administer study 
treatment k 
 
 
X 
X 
X 
 
 
 
Assess current COPD 
treatment compliance 
 
 
X 
 
 
 
 
 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
16 
 
Protocol Activity 
Pre-
Screen 
Screen 
Treatment 
Follow-up 
Visit 0 
Visit 1  
Screen 
Visit 2  
Visit 3 
Visit 
4e (Telephon
ic) 
  
Visit 5 
Study 
treatment 
discontinuat
ion 
Safety 
Follow-up   
Visit 6f 
Study Day 
 
Week 
0/Day 1   
Week 4/Day 
28  
Week 
12/Day 84   
Week 
12/Day 85 
 
1-week 
Follow-
up/Day 92   
Window 
(Day -1) 
 
-4/+2d  
(Day 24 to 
30) 
-4/+2d 
(Day 80 to 
86) 
-4/+2d 
(Day 81 to 
87) 
 
-1/+4d 
(Day 91 to 
96) 
Assess study treatment 
compliance 
 
 
 
X 
  
X 
X 
 
Collect study treatment 
 
 
 
 
 
X 
X 
 
Dispense salbutamol as 
required 
 
X 
X 
X 
 
X 
 
 
Collect salbutamol 
 
 
 
 
 
X 
X 
 
Dispense paper Medical 
Problems worksheet 
 
X 
X 
X 
 
X 
 
 
Review paper Medical 
Problems worksheet 
 
 
X 
X 
 
X 
X 
 
a. 
Informed consent must be conducted prior to performing any study procedures including the changing or 
withholding of medications. The informed consent may be given at Screening Visit 1 if the participant does not 
take or has not taken any protocol excluded medications. The Pre-screen and Screening Visits can occur on the 
same day. 
b. 
Demography may be captured at either the Pre-screen Visit or Screening Visit (for participants who do not have a 
Pre-screen Visit). 
c. 
The test should be done at Visit 1, using a molecular (PCR [polymerase chain reaction] or antigen test) approved 
by the country regulatory authorities. 
d. 
At Visits 2 and 3, trough FEV1 will be performed pre-dose prior to taking the morning dose of study 
treatment/COPD medication, between 8am and 11am and after withholding rescue salbutamol for > 4 hours. 
Trough FEV1 on Day 85 (Visit 5) will be performed 24 hours after morning dosing on Day 84 (Visit 4), after 
withholding rescue salbutamol for > 4 hours.  
e. 
At Day 84 (Visit 4), participant will be instructed by the investigator telephonically to take the morning dose of 
study treatment/COPD medication, between 8am and 11am and reminded to: 1) withhold rescue salbutamol for > 
4 hours prior to visit 5 and 2) withhold the Day 85 (Visit 5) dose of Investigative Product until after spirometry 
(Trough FEV ) has been completed.  
f. 
A safety follow-up at Day 92 (Visit 6) will be conducted telephonically. 
g. 
Physical examination may include height and weight. 
h. 
Vital signs, including temperature, blood pressure and pulse must be performed prior to spirometry.. 
i. 
Chest X-ray is required at Screening (or historical x-ray obtained within 3 months prior to Screening) and at any 
time there is a suspected pneumonia or a mod/severe exacerbation. 
j. 
All female participants of child-bearing potential will have a urine pregnancy test at Visits 1, 5 and Treatment 
Discontinuation Visit (if applicable). 
k. 
Participants will receive their first dose study treatment in the clinic at Visit 2. At Visits 3 and 4 participants must 
refrain from taking their morning dose of study treatment until instructed to do so by study staff. Visit 3 study 
treatment administration will be in the clinic and Visit 4 study treatment administration will be at home. 
When multiple assessments and procedures are performed suggested sequence order is CAT, vitals, ECG, 
spirometry. Study procedures to be completed during a COVID-19 pandemic are detailed in Appendix 4.  


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
17 
 
2. 
INTRODUCTION 
Chronic obstructive pulmonary disease (COPD) guidelines advocate the use of long-
acting muscarinic receptor antagonists (LAMA) added to the combination of an inhaled 
corticosteroid (ICS) plus a long-acting β2-adrenergic receptor agonists (LABA) as second 
line therapy for the most advanced patients with significant symptoms and a high risk of 
exacerbations. Regular treatment with ICS-containing regimens has been reported to 
improve respiratory symptoms, lung function, health related quality of life (HRQoL) and 
reduce the frequency of COPD exacerbations in patients with a forced expiratory flow in 
1 second (FEV1) <60 % predicted [Aaron, 2007; Cazzola, 2007; Hanania, 2012; Jung, 
2012; Siler, 2015; Welte, 2009].  
GlaxoSmithKline (GSK) has developed a once-daily ‘closed’ triple therapy of a 
ICS/LAMA/LABA combination [fluticasone furoate (FF)/umeclidinium 
(UMEC)/vilanterol (VI) (100/62.5/25 mcg)] in a single inhaler, to provide a new 
treatment option for the management of symptomatic COPD patients at risk for 
exacerbations. FF/UMEC/VI is approved in many countries including the USA, EU and 
India for the treatment of COPD. FF/UMEC/VI has been shown to reduce all-cause 
mortality, exacerbation frequency, improve lung function, HRQoL and symptom control 
over established dual/monotherapies [Lipson, 2020; Lipson, 2017; Lipson, 2018; 
Ferguson, 2020].  
2.1. 
Study Rationale  
Fluticasone furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) is approved in many 
countries including the USA, EU, and India for the treatment of chronic obstructive 
pulmonary disease (COPD). Many multi-centre, multi-national studies have been 
conducted with FF/UMEC/VI, however, these studies did not include India as a 
participating country. As part of the post approval commitment for fluticasone 
furoate/umeclidinium/vilanterol (FF/UMEC/VI) in India, a Phase IV study will be 
conducted, to provide safety and efficacy data from the Indian population. 
The purpose of this study is to evaluate the safety and efficacy of a single inhaler triple 
therapy combination of FF/UMEC/VI (100mcg/62.5mcg/25mcg) administered once daily 
via the ELLIPTA™, following 12 weeks of treatment, in COPD participants in India.  
2.2. 
Background  
The Phase III program for FF/UMEC/VI included two large studies of 6 to 12 months in 
duration. Studies CTT116853 (FULFIL) and CTT116855 (IMPACT).  
Study CTT116853 (FULFIL) was a Phase III, 23-week, randomised, double-blind, 
double-dummy, parallel-group study (with an extension to 52 weeks on blinded therapy 
in a subset of subjects) comparing the efficacy, safety, and tolerability of FF/UMEC/VI 
once-daily via Ellipta with budesonide/formoterol (400/12 mcg) twice daily via 
Turbuhaler in participants with COPD. 1810 patients were randomized and included in 
the ITT population. Co-primary endpoints were change from baseline in trough FEV1 and 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
18 
 
change from baseline in St George’s Respiratory Questionnaire (SGRQ) total score at 
Week 24.  
The study demonstrated clinically meaningful and statistically significant improvements 
in lung function and health related quality of life and reductions in moderate/severe 
COPD exacerbations for FF/UMEC/VI compared to budesonide/formoterol.   
The overall safety profile of FF/UMEC/VI in study CTT116853 was in line with the 
pharmacologic class of each component and with the previously approved dual 
combinations FF/VI and UMEC/VI, and no new safety signals emerged in the ITT 
Population to 24 weeks and an Extension Population to 52 weeks. 
Study CTT116855 (IMPACT) was a Phase III, 52-week, randomized, double-blind, 3-
arm parallel group study, comparing the efficacy, safety and tolerability of FF/UMEC/VI 
with FF/VI and UMEC/VI, all administered once daily in the morning via the Ellipta, in 
participants with COPD. The primary endpoint was the annual rate of moderate/severe 
exacerbations.  
A total of 10,355 participants were randomized and included in the ITT population. The 
primary objective of the study was met by demonstrating the superiority of FF/UMEC/VI 
over FF/VI and UMEC/VI for the co-primary treatment comparisons of the annual rate of 
on-treatment moderate/severe exacerbations in subjects with moderate to very severe 
COPD at risk of exacerbation. Treatment with FF/UMEC/VI resulted in a statistically 
significant reduction of on-treatment moderate/severe exacerbations of 15% compared 
with FF/VI (p<0.001) and 25% compared with UMEC/VI (p<0.001).  
FF/UMEC/VI also resulted in statistically significantly improvements in 
non-exacerbation-related measures of trough FEV1, SGRQ Total Score, CAT score, TDI 
focal score, rescue-medication use and night-time awakenings compared with both FF/VI 
and UMEC/VI demonstrating a wide range of benefit across objective evaluations of lung 
function, subjective evaluations of HRQoL, and patient-reported measures associated 
with disease symptoms. FF/UMEC/VI also reduced all-mortality compared to UMEC/VI. 
 
The overall safety profile of FF/UMEC/VI was in line with the pharmacologic class of 
each component and with the previously approved dual combinations FF/VI and 
UMEC/VI; no new safety signals were identified. 
 
A detailed description of the chemistry, pharmacology, efficacy and safety of 
FF/UMEC/VI is provided in the Investigator’s Brochure.  
2.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of FF/UMEC/VI may be found in the Investigator’s 
Brochure. 
 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
19 
 
2.3.1. 
Risk Assessment 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk  
Mitigation Strategy 
Investigational Product (IP) GSK2834425 (FF/UMEC/VI)  
Pneumonia in participants with COPD 
 
Pneumonia is a class concern for any 
inhaled corticosteroid (ICS)-containing 
product for the treatment of COPD. 
In a 52-week study (CTT116855), in a total 
of 10,355 randomised COPD patients with 
a history of moderate/severe exacerbations, 
there was a higher incidence of any event 
in the pneumonia AESI group in the ICS-
containing FF/UMEC/VI (317 participants 
[8%], rate of 95.8 per 1,000 participant-
years) and FF/VI (292 participants [7%], 
rate of 96.6 per 1,000 participant-years) 
groups compared with the UMEC/VI group 
(97 participants [5%], rate of 61.2 per 
1,000 participant-years). 
Known risk factors for pneumonia in 
patients with COPD include older age, 
male gender, prior pneumonia, low BMI, 
current smoking and more severe airflow 
limitation. These risk factors should be 
taken into consideration when using an ICS 
in participants with COPD.  
- Participants will be informed of the risk in 
the informed consent. 
- Investigators are informed of the risk in 
the IB. 
- Investigators will be instructed to remain 
vigilant for the possible development of 
pneumonia in participants with COPD as 
the clinical features of such infections 
overlap with the symptoms of COPD 
exacerbations. For suspected cases of 
pneumonia, Investigators will be 
encouraged to arrange a chest X-ray within 
48 hours of diagnosis and to treat 
appropriately (see Section 8.2.3).  
- Appropriate exclusion criteria as specified 
in Section 5.2 of the protocol   
- All diagnoses of pneumonia 
(radiographically confirmed or 
unconfirmed) must be reported as an AE or 
SAE (if applicable) as specified in Section 
8.2.3. 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
20 
 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk  
Mitigation Strategy 
 
- Chest X-ray read required at baseline and 
encouraged whenever a participant has 
suspected pneumonia or mod/severe 
exacerbations during the study.  
Serious cardiovascular events 
 
Cardiovascular (CV) effects are a potential 
class effect associated with anti-muscarinic 
and beta agonist therapies. 
In the COPD population, there is a high 
prevalence of concurrent CV disease and 
the prevalence of CV co morbidities 
increases with worsening severity of 
COPD. 
In study CTT116855 (also designated a 
category 3 safety study, as requested by the 
EU CHMP), for the Cardiovascular (CV) 
effects AESI, there were similar incidences 
and exposure adjusted rates across the 
FF/UMEC/VI, FF/VI and UMEC/VI 
treatment groups (10% to 11% and 157.0 to 
167.2, respectively). In the Major adverse 
cardiac events (MACE) analysis 2% in the 
FF/UMEC/VI group, 1% in the FF/VI 
group, and 2% in the UMEC/VI group 
reported any MACE). 
- Participants will be informed about the 
risk in the informed consent. 
- Investigators are informed of the risk in 
the IB. 
- Appropriate exclusion criteria as specified 
in Section 5.2 of the protocol, including  
- Electrocardiogram (ECG) inclusion 
criteria 
- Vital sign assessments (heart rate and 
blood pressure) as per protocol. 
- Protocol defined stopping criteria as per 
Section 7.1.2. 
 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
21 
 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk  
Mitigation Strategy 
There were no emerging safety signals 
based on review of the vital signs, ECGs 
and Holter data (where performed) across 
FF/UMEC/VI clinical development studies 
to date. 
The effect of FF/UMEC/VI on the QT 
interval has not been evaluated in a 
thorough QT (TQT) study. TQT studies for 
FF/VI and UMEC/VI did not show 
clinically relevant effects on QT interval at 
clinical doses of FF, UMEC and VI.  
Adrenal suppression 
Oral corticosteroids are known to influence 
the hypothalamic-pituitary-adrenal (HPA) 
axis leading to a reduction in cortisol 
production. Due to the low dose and low 
systemic exposure with ICSs, this potential 
effect is not clear, nor is the possible 
impact of any change in cortisol. 
In study CTT116855, no events were 
reported in the adrenal suppression AESI 
group for FF/UMEC/VI. 
With respect to the FF/VI clinical 
development program, a formal HPA study 
and multiple studies with COPD (and 
asthma) participants monitored urinary 
-Investigators are informed of the risk in 
the IB 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
22 
 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk  
Mitigation Strategy 
cortisol. These studies did not show a 
clinically relevant effect of FF/VI 100/25 
on the HPA axis. 
Corticosteroid Associated Eye Disorders 
(glaucoma, cataract, raised intra-ocular 
pressure) 
Systemic ocular effects (e.g. cataract and 
glaucoma) may occur with any ICS, 
particularly at high doses prescribed for 
long periods. However, these effects are 
much less likely to occur with ICSs 
compared with oral corticosteroids. 
In study CTT116855, the incidences of 
Ocular Effects AESI were low and similar 
across treatment groups (1% in each 
group).  
During studies with FF/VI and UMEC/VI 
in COPD participants, no associated effect 
on ocular disorders was observed. In 
addition, no effects on lens opacification 
were observed on formal ophthalmic 
assessments in a study with FF/VI, FF and 
FP in participants with asthma. 
- Participants will be informed about the 
risk in the informed consent. 
- Investigators are informed of the risk in 
the IB. 
- Appropriate exclusion criteria as specified 
in Section 5.2 of the protocol 
- If a risk is suspected, participants should 
receive appropriate assessment & treatment 
 
 
Anticholinergic effects (including 
constipation nausea, dry mouth, glaucoma, 
raised intraocular pressure and blurred 
vision, urinary retention)  
Pharmacologic class effects of LAMAs 
include anticholinergic effects, such as 
glaucoma and urinary retention. 
- Participants will be informed about the 
risk in the informed consent. 
- Investigators are informed of the risk in 
the IB. 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
23 
 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk  
Mitigation Strategy 
The incidence of narrow angle glaucoma in 
the COPD population associated with the 
use of inhaled bronchodilators (including 
LAMAs and LABAs) is relatively low.  
In study CTT116855, for the 
anticholinergic syndrome (SMQ) AESI, 
there were similar incidence and exposure-
adjusted rates across the FF/UMEC/VI, 
FF/VI and UMEC/VI treatment groups 
(incidence: 4%, 3% and 3%. Glaucoma 
SMQ incidence was 1%, <1% and 1% in 
FF/UMEC/VI, FF/VI and UMEC/VI 
treatment). Urinary retention AESI 
incidence was <1% in all treatment groups. 
- Appropriate exclusion criteria as specified 
in Section 5.2 of the protocol 
- If a risk is suspected, participants should 
receive appropriate assessment & treatment 
 
 
Decreased bone mineral density (BMD) 
and associated fractures 
Decreased bone mineral density (BMD) 
and associated fractures Reduction in bone 
density, and the subsequent risk of 
fractures, is a known potential risk with 
corticosteroids. There may be a modest 
increase in risk of fracture among 
participants with COPD treated with ICS; 
but, the results are not consistent across 
individual studies [Christensson, 2008; 
Lehouck, 2011; Weldon, 2009]. 
In study CTT116855, the incidences of 
Decreased BMD and associated fractures 
- Participants will be informed about the 
risk in the informed consent. 
- Investigators are informed of the risk in 
the IB 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
24 
 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk  
Mitigation Strategy 
AESI were similar between the 
FF/UMEC/VI, FF/VI and UMEC/VI 
treatment groups (2% in each group). 
A post-authorisation BMD safety study 
with FF/VI demonstrated non-inferiority of 
FF/VI 100/25 mcg to VI 25 mcg on the 
primary endpoint of the percent change 
from baseline in overall adjusted BMD per 
year at the total hip by the pre-defined 
noninferiority margin of -1% 
(HZC102972). 
Paradoxical bronchospasm 
The phenomenon of paradoxical 
bronchospasm may occur in association 
with all inhaled medication and may vary 
from mild to life threatening. 
In study CTT116855, the exposure adjusted 
rates for the Asthma/bronchospasm (SMQ) 
AESI across the FF/UMEC/VI, FF/VI and 
UMEC/VI treatment groups (<1% for all 
three groups respectively). 
- Participants will be informed about the 
risk in the informed consent. 
- Investigators are informed of the risk in 
the IB. 
 
Hypersensitivity 
Hypersensitivity may occur in response to 
various allergens, and hypersensitivity 
reactions have been previously described 
for ICS, LAMA and LABA drug classes. 
- Participants will be informed about the 
risk in the informed consent.  
- Investigators are informed of the risk in 
the IB. 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
25 
 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk  
Mitigation Strategy 
In study CTT116855, the incidences of 
Hypersensitivity AESI were similar 
between the FF/UMEC/VI, FF/VI and 
UMEC/VI treatment groups (5% in all 
groups). The vast majority of relevant 
events were considered not related 
following a detailed evaluation. 
Rare post-marketing cases of anaphylaxis, 
angioedema, urticaria and rash have been 
reported for FF/UMEC/VI. 
- Appropriate exclusion criteria as specified 
in Section 5.2 of the protocol. 
 
Study Procedure Risks 
Exposure to ionizing radiation from 
chest x-ray. 
The dose from a single chest X-ray should 
not exceed 20 microsieverts (µSv) and this 
corresponds to a lifetime risk of a fatal 
malignancy of about 1 in 1 million (ICRP 
103), which falls into the ‘trivial’ risk 
category as defined by ICRP 62. The study 
will minimize exposure by using x-rays 
acquired as part of clinical care whenever 
possible. It is expected that all subjects will 
require a single chest x-ray, but 
occasionally they may have a maximum of 
3 chest X-rays (up to maximum 60 µSv 
within this study, lifetime risk of fatal 
-Only participants at /or above 40 years of 
age will be eligible for inclusion. 
- Women of childbearing potential 
(WOCBP) will only be allowed to 
participate if they are using highly effective 
contraception. 
- Women of childbearing potential 
(WOCBP) will have pregnancy tests as 
specified in the SOA. 
-All procedures will be performed by a 
qualified technician. 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
26 
 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk  
Mitigation Strategy 
malignancy of approximately 1 in 
300,000).  
Other  
COVID-19 
The WHO has declared the outbreak of 
respiratory illness caused by the Severe 
Acute Respiratory Syndrome Coronavirus-
2 as a global pandemic. Initial 
observational data [Zhao, 2020] indicate 
that patients with COPD may be at 
significantly higher risk of developing 
severe disease manifestations. No definitive 
data is currently available on the impact of 
any medication classes taken by inhalation. 
-Exclusion criteria pertaining to current 
COVID-19 infection including close 
contact with other infected patients 
(Section 5.2). 
-Testing for COVID-19 at screening. 
-Withdrawal criteria in case of COVID-19 
infection (Section 7.1.4) 
 
 
 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
27 
 
2.3.2. 
Benefit Assessment 
COPD guidelines advocate the use of one or more long-acting bronchodilators (LAMA or 
LABA) in addition to ICS as therapy treatment option for the most advanced patients 
with significant symptoms and a high risk of exacerbations [GOLD, 2020]. 
Participants enrolled in this study will receive FF/UMEC/VI once daily. Participants are 
anticipated to derive clinical benefit from this combination of study treatments. In a 
disease where polypharmacy is common, the FF/UMEC/VI, once-daily combination has 
the potential to optimise bronchodilator therapy, improve patient adherence to therapy 
and, as a result, improve overall disease management.  
2.3.3. 
Overall Benefit: Risk Conclusion 
The clinical development programme for FF/UMEC/VI demonstrated a favourable 
benefit/risk for patients with COPD. This has led to approval and marketing of 
FF/UMEC/VI for a COPD indication in many countries worldwide. Current risks that 
have been identified for these therapeutic classes are based on the known pharmacology 
of the individual components: ICS, LAMA and LABA.  
Taking into account the measures taken to minimize risk to participants participating in 
this study, the potential risks identified in association with FF/UMEC/VI are justified by 
the anticipated benefits from active treatment that may be afforded to patients with 
COPD.  


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
28 
 
3. 
OBJECTIVES AND ENDPOINTS/ESTIMANDS 
Objectives 
Estimands/Endpoints 
Primary 
 
• To evaluate the safety profile of 
FF/UMEC/VI over 12 weeks in 
patients from India 
 
The primary Estimand is defined by the 
following: 
• Endpoint: incidence of adverse events 
(AE), serious adverse events (SAE) 
and adverse events of special interest 
(AESIs). 
• Summary number and percentage of 
participants experiencing an AEs, 
SAEs and number and percentage of 
participants experiencing AESIs by 
system organ class and by preferred 
term. 
• Population of interest: COPD patients 
in India.  
• Key intercurrent events: 
discontinuation of treatment   
• Strategy for intercurrent events: a 
While on Treatment strategy will be 
used for treatment 
discontinuation.  This estimates the 
percentage of participants 
experiencing an AE or SAE while 
taking treatment. 
• Participants that test positive for 
COVID-19 will immediately 
discontinue study treatment. Therefore 
COVID-19 will be included as the 
intercurrent event of study treatment 
discontinuation and will be handled 
with While on Treatment strategy for 
the primary estimand 
A supplementary estimand will be defined 
using identical properties as for the 
primary estimand (summary measure, 
population of interest and key intercurrent 
events), however this supplementary 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
29 
 
Objectives 
Estimands/Endpoints 
estimand will report all AEs regardless of 
the discontinuation of study treatment. 
Endpoints: 
• Incidence of AEs, SAEs and AESIs 
Strategy for intercurrent events: 
• Treatment policy strategy will be used 
for treatment discontinuation. This 
summary will therefore be inclusive of 
all on-treatment and post-treatment 
AEs. 
Secondary 
 
• To evaluate the effect of 
FF/UMEC/VI on lung function  
The secondary Estimands are defined by 
the following:  
• Endpoints:  
o change from baseline in trough 
FEV1 on Day 85 (trough FEV1 on 
Day 85 is defined as the mean of 
the FEV1 values obtained 24 
hours after morning dosing on Day 
84) 
o change from baseline in trough 
FEV1 on Day 28 (trough FEV1 on 
Day 28 is defined as the mean of 
the FEV1 values obtained prior to 
dosing on Day 28)  
• Summary measure:  
o mean change from baseline in 
trough FEV1 on Day 85 
o mean change from baseline in 
trough FEV1 on Day 28  
• Population of interest: COPD patients 
in India.  
• Key intercurrent events: 
discontinuation of treatment   
• Strategy for intercurrent events: a 
hypothetical strategy will be used for 
treatment discontinuation.  This 
estimates the effect under the 
hypothetical scenario that participants 
had not discontinued treatment.  


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
30 
 
Objectives 
Estimands/Endpoints 
• Participants that test positive for 
COVID-19 will immediately 
discontinue study treatment. Therefore 
COVID-19 will be included as the 
intercurrent event of study treatment 
discontinuation and will be handled 
with hypothetical strategy for the 
secondary estimands. 
 
 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
31 
 
4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a phase IV, 12-week, single arm, multicentre study evaluating single inhaler triple 
therapy (FF/UMEC/VI) once daily via the ELLIPTA inhaler.  
Figure 1 
Study Design Schema 
 
 
* At day 84 (telephonic visit), participant will be instructed by the investigator telephonically to 
take the morning dose of study treatment/COPD medication, between 8am and 11am   
Approximately 306 participants will be screened in order to enroll 229 (assuming 25% screen 
failure) to the study treatment phase and achieve 220 evaluable participants at the end of 
the study (assuming 4% withdrawal from study treatment).  
At the start of the treatment period, participants will discontinue all existing COPD 
medications but may continue their study-supplied rescue salbutamol on an as-needed 
basis (rescue medication) throughout the study.  
Clinic Visits will occur at Pre-Screening (Visit 0), Screening (Visit 1), Start of Treatment 
(Day 1, Visit 2), Day 28 (Visit 3), and Day 85 (Visit 5). Day 84 (telephonic Visit 4) and 
Safety follow-up (Visit 6) conducted 1 week after completing the 12-week treatment 
period will be a telephone contact. Participants will sign an informed consent form (ICF) 
at a Pre-Screen or Screening Visit and will be assigned a participant identifier. 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
32 
 
4.2. 
Scientific Rationale for Study Design. 
Though safety and efficacy of FF/UMEC/VI in patients with COPD has been established 
in various clinical studies across USA, Europe, and a number of other countries including 
Japan and China, this will be the first clinical study to assess safety and efficacy in 
patients in India.  
This study will use a multicenter, single arm design. A single arm study is considered 
sufficient, based on the wealth of data already generated for FF/UMEC/VI, in extensive 
studies conducted globally, containing multiple treatment arms and comparators. Eligible 
participants must have been on daily maintenance COPD medications for at least 3 
months.  
4.3. 
Jsustification for Dose 
FF/UMEC/VI (100/62.5/25mcg) is approved for the treatment of COPD in over 15 
countries/regions, including the United States (US), Canada, the EU, Japan, and other 
countries worldwide. 
4.4. 
End of Study Definition 
A participant is considered to have completed the study if he/she has completed all 
phases of the study including screening, treatment phase and safety follow-up. 
The end of the study is defined as the date of the last scheduled procedure shown in the 
Schedule of Activities table (SoA) (see Section 1.3) for the last participant in the study.  


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
33 
 
5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants eligible for enrolment in the study must meet all of the following criteria:  
1. Informed Consent: A signed and dated written informed consent prior to study 
participation. 
2. Type of participant: Outpatient. 
3. Age: Participants 40 years of age or older at Screening (Visit 1). 
4. Gender: Male or female participants. 
Female participants:  
A female participant is eligible to participate if she is not pregnant, not breastfeeding, and 
at least one of the following conditions applies: 
• Not a woman of childbearing potential (WOCBP)  
OR 
• A WOCBP who agrees to follow the contraceptive guidance in 
Appendix 2 during the treatment period and until the safety follow-up 
contact after the last dose of study intervention. 
 
5. COPD Diagnosis: An established clinical history of COPD in accordance with the 
definition by the American Thoracic Society/European Respiratory Society [Celli, 
2004]. 
6. Smoking History: Current or former cigarette smokers with a history of cigarette 
smoking of ≥10 pack-years at Screening (Visit 1) [number of pack years = (number of 
cigarettes per day / 20) x number of years smoked (e.g., 20 cigarettes per day for 10 
years, or 10 cigarettes per day for 20 years)]. Previous smokers are defined as those 
who have stopped smoking for at least 6 months prior to Visit 1. Note: Pipe and/or 
cigar use cannot be used to calculate pack-year history. 
7. Patient with history of ≥2 moderate exacerbations or one severe (hospitalized) 
exacerbation in the previous 12 months, and with a score of ≥10 on the CAT eligible 
for the study treatment in the opinion of the investigator and documented post 
salbutamol FEV1/FVC ratio of <0.70  
 
8. Existing COPD maintenance treatment: Participant must be receiving daily long-
acting maintenance treatment for their COPD for at least 3 months prior to Screening. 
To be eligible for the study treatment phase, participants must be compliant with their 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
34 
 
existing COPD maintenance therapy (in the opinion of the investigator) for the 
preceding two weeks prior to screening.  
Note: Participants receiving only short-acting COPD medications are not eligible. 
 
9. A negative test for active COVID-19 at Visit 1. The test should be done using a 
molecular (PCR or antigen test) approved by the country regulatory authorities.  
 
5.2. 
Exclusion Criteria 
Participants meeting any of the following criteria must not be enrolled in the study: 
1. Pregnancy: Women who are pregnant or lactating or are planning on becoming 
pregnant during the study. 
2. Asthma: Participants with a current diagnosis of asthma. (Participants with a prior 
history of asthma are eligible if they have a current diagnosis of COPD). 
3. Reversibility: Documented (medical records) evidence of reversibility.  
Reversibility is defined as an increase in FEV1 of ≥ 12% and ≥200mL following 
administration of salbutamol. Participants defined as non-reversible will have a post-
salbutamol increase in FEV1 of <200mL or a ≥200mL increase that is <12% from 
pre-salbutamol baseline. 
4. α1-antitrypsin deficiency: Participants with α1-antitrypsin deficiency as the 
underlying cause of COPD. 
5. Other respiratory disorders: Participants with active tuberculosis, lung cancer, and 
clinically significant (in the opinion of the investigator): bronchiectasis, sarcoidosis, 
lung fibrosis, pulmonary hypertension, interstitial lung diseases or other active 
pulmonary diseases. 
6. Lung resection: Participants with lung volume reduction surgery within the 12 
months prior to Screening. 
7. Risk Factors for Pneumonia: immune suppression (e.g. advanced HIV with high 
viral load and low CD4 count, Lupus on immunosuppressants that would increase 
risk of pneumonia) 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 for pneumonia (e.g. very low BMI, severely 
malnourished, or very low FEV1) will only be included at the discretion of the 
investigator. 
8. Pneumonia and/or moderate or severe COPD exacerbation that has not resolved 
at least 14 days prior to Screening and at least 30 days following the last dose of 
oral/systemic corticosteroids and/or antibiotics (if applicable). In addition, any 
participant that experiences pneumonia and/or moderate or severe COPD 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
35 
 
exacerbation within the preceding two weeks prior to screening during the will be 
excluded. 
9. Respiratory tract infection that has not resolved at least 7 days prior to Screening. 
10. Participants with known COVID-19 positive contacts within the past 14 days should 
be excluded for at least 14 days since the exposure and the subject remains symptom 
free.  
• Participants with symptoms suggestive of active COVID-19 infection e.g. fever, 
cough (new or worsened), etc. are also excluded  
11. Abnormal Chest x-ray: Chest x-ray (posteroanterior and lateral) reveals evidence of 
pneumonia or a clinically significant abnormality not believed to be due to the 
presence of COPD, or another condition that would hinder the ability to detect an 
infiltrate on CXR (e.g. significant cardiomegaly, pleural effusion or scarring). All 
participants will have a chest x-ray at Screening Visit 1 (or historical radiograph or 
CT scan obtained within 3 months prior to screening).  
12. 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 
haematological 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. 
13. 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.  
14. 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 
• NYHA Class IV Heart failure 
15. Abnormal and clinically significant 12-lead ECG finding at Visit 1  


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
36 
 
• 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 that would preclude a participant 
from entering the trial is defined as a 12-lead ECG tracing that is interpreted at, 
but not limited to, any of the following: 
i. Atrial Fibrillation (AF) with rapid ventricular rate >120 beats per 
minute (BPM) 
ii. Sustained and non-sustained Ventricular tachycardia (VT) 
iii. Second degree heart block Mobitz type II and third degree heart block 
(unless pacemaker or defibrillator had been inserted) 
iv. QT interval corrected for heart rate of ≥500 msec in participants with 
QRS <120 msec and QTcF ≥530 msec in participants with QRS ≥120 
msec 
 
16. Contraindications: A history of allergy or hypersensitivity to any corticosteroid, 
anticholinergic/muscarinic receptor antagonist, β2-agonist, lactose/milk protein or 
magnesium stearate or a medical condition such as narrow-angle glaucoma, prostatic 
hypertrophy or bladder neck obstruction that, in the opinion of the Investigator, 
contraindicates study participation. 
17. Cancer: Participants with carcinoma that has not been in complete remission for at 
least 5 years. Participants who have had carcinoma in situ of the cervix, squamous 
cell carcinoma and basal cell carcinoma of the skin would not be excluded based on 
the 5 year waiting period if the subject has been considered cured by treatment. 
18. Oxygen therapy: Use of long-term oxygen therapy (LTOT) described as resting 
oxygen therapy >3L/min at screening (Oxygen use ≤3L/min flow at rest is not 
exclusionary.) 
19. Pulmonary rehabilitation: participants must not start the acute phase of a pulmonary 
rehabilitation program within the 4 weeks prior to Visit 1. 
20. Medication prior to spirometry: Participants who are medically unable to withhold 
their salbutamol for the 4-hour period required prior to spirometry testing at each 
study visit. 
21. Drug/alcohol abuse: Participants with a known or suspected history of alcohol or 
drug abuse within the last 2 years. 
22. 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. 
23. 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. 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
37 
 
24. 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. 
25. 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. 
25. Medication prior to screening: Use of the following medications within the 
following time intervals prior to Visit 1 or during the study: 
Table 1 
Prohibited Medications Prior to Screening  
Medication 
No use within the following time intervals prior to Screening  
Antibiotic therapy 
30 days 
 
Systemic, Oral, parenteral 
corticosteroids 
30 days 
 
Intra-articular injections are allowed 
Any other investigational drug 
30 days or 5 half-lives whichever is longer.  
 
5.3. 
Treatment phase Criteria 
At Start of Treatment (Visit 2), study participants must fulfil the following additional 
criteria, to enter the treatment phase: 
1. Compliance with current COPD maintenance therapy  
• Participants who are non-compliant to their current COPD maintenance therapy 
for two weeks prior to screening (in the opinion of the investigator) will be 
excluded. 
2. Pneumonia and/or moderate or severe COPD exacerbation that has not resolved 
at least 14 days prior to Screening and at least 30 days following the last dose of 
oral/systemic corticosteroids and/or antibiotics (if applicable). In addition, any 
participant that experiences pneumonia and/or moderate or severe COPD 
exacerbation within the preceding two weeks prior to screening will be excluded. 
 
5.4. 
Lifestyle Considerations 
Participants should avoid the following activities prior to each pulmonary function test: 
• smoking and/or vaping and/or water pipe use for 1 hour 
• consumption of intoxicants for 8 hours 
• drinking beverages with high levels of caffeine such as tea and coffee for 2 hours 
• vigorous exercise for 1 hour 
 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
38 
 
5.5. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently entered in the study. A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, any protocol deviations and any 
serious adverse events (SAEs). 
Individuals who do not meet the criteria for participation in this study (screen failure) 
may not be rescreened. 
5.6. 
Criteria for Temporarily Delaying Enrollment/Administration 
of Study Intervention 
Not applicable.  


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
39 
 
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 
Participants will receive FF/UMEC/VI (see Table 2) and should inhale once from the 
ELLIPTA inhaler in the morning each day for the duration of the 12-week treatment 
period.  
 
Table 2 
Description of ELLIPTA™ 
 
FF/UMEC/VI  
 
First strip  
Second strip  
Dosage Form  
ELLIPTA with 30 doses (2 strips with 30 blisters per strip) 
Unit Dose 
Strengths  
100mcg per blister 
25 mcg per blister GW642444, 
62.5 mcg per blister GSK573719 
Physical 
description  
Dry white powder 
Dry white powder 
Route of 
Administration  
Inhaled 
Sourcing 
Provided centrally by the sponsor 
Packaging and 
labelling 
Each Ellipta inhaler will be labeled and placed in a labelled foil 
pouch with a desiccant. The foil pouch will then be placed in a 
window carton.  
 
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 FF/UMEC/VI and only 
authorized site staff may supply or administer FF/UMEC/VI. All study intervention 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labelled storage conditions with access 
limited to the investigator and authorized site staff. 
• 
The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records). 
CCI


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
40 
 
• 
Further guidance and information for the final disposition of unused study 
intervention are provided in the Study Reference Manual.  
• 
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) describing occupational hazards and 
recommended handling precautions will be provided to the investigator. 
 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
Blinding will not be used as this is an open label, single-arm study.  
6.4. 
Study Intervention Compliance 
At scheduled study visits participants will receive FF/UMEC/VI under medical 
supervision. The date and time of each dose administered in the clinic will be recorded in 
the eCRF. When participants self-administer study treatment at home, compliance will be 
assessed through querying each participant during site visits and recording the number of 
doses remaining in the ELLIPTA inhaler, in the source documents and eCRF.  
Participants who are non-compliant should be re-educated on the importance of treatment 
compliance. Every effort will be made to keep participants in the study and to re-educate 
participants that are non-compliant. Participants that continue to be non-compliant after 
multiple visits may be permanently discontinued from study treatment, following 
consultation with the GSK team.  
6.5. 
Dose Modification 
No dose modifications are planned for this study.  


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
41 
 
6.6. 
Continued Access to FF/UMEC/VI after the End of the Study 
Following participation completion of the study, the treating physician should determine 
what the most appropriate COPD maintenance medication is for each participant.  
FF/UMEC/VI is commercially available in India, and will be a possible treatment option 
for patients, following completion of the study.  
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 eCRF pages. In the event of an overdose of study treatment, the Investigator 
should use clinical judgment in treating the overdose and contact the GSK medical 
monitor. 
GSK is not recommending specific treatment guidelines for overdose and toxicity 
management. The Investigator is advised to refer to the relevant document(s) for detailed 
information regarding warnings, precautions, contraindications, adverse events, and other 
significant data pertaining to the study drug being used in this study, such as the IB.  
 
6.8. 
Concomitant Therapy 
All COPD medications used within 3 months prior to screening and study treatment 
period (including the post-treatment period) should be recorded in the eCRF.  
All non-COPD medications taken during the study (in the treatment phase and up to the 
safety follow-up contact) and any changes to concomitant medications will be recorded in 
the eCRF.   
The minimum requirement is that the drug name, reason for use, dose (including unit), 
frequency, route and the dates of administration (start and end dates) are to be recorded. 
Note: Study provided salbutamol should not be recorded in the eCRF however non-study 
supplied albuterol/salbutamol will be recorded in the eCRF.   
Medications initiated after completion of the treatment phase of the study (Visit 5) or 
started after discontinuation of study treatment must be recorded in the eCRF up to the 
safety follow-up contact.  
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
42 
 
6.8.1. 
Permitted Medications and Non-Drug Therapies 
6.8.1.1. 
Permitted COPD Medications 
The following COPD medications are permitted during the treatment period:  
• Study supplied salbutamol MDI or nebules (must be withheld for at least 4 hours 
prior to pulmonary function testing) 
• Mucolytics such as acetylcysteine 
• Long term oxygen therapy (flow rate of ≤3 litres/minute at rest). Oxygen therapy may 
be adjusted as deemed medically necessary at any time during the treatment phase of 
the study. Oxygen therapy must be captured on the concomitant medication page of 
the eCRF.  Supplemental oxygen is recommended for participants who exhibit 
oxyhemoglobin desaturation with rest or exertion (e.g. SaO2 ≤88 %) 
• Study provided COPD medications in the treatment period  
• Any COPD medication deemed medically necessary for the short-term treatment (≤14 
days) of a moderate/severe COPD exacerbation or pneumonia (such as oral or 
injectable corticosteroids and/or antibiotics). Any participant that experiences a 
moderate/severe COPD exacerbation or pneumonia within two weeks prior to 
screening (in the opinion of the investigator) should be excluded.  
6.8.1.2. 
Permitted Non-COPD Medications 
The following non-COPD medications are permitted during the treatment period: 
• Medications for rhinitis (e.g. intranasal corticosteroids, antihistamines, cromolyn, 
nedocromil, nasal decongestants) 
• Topical and ophthalmic corticosteroids 
• Localized corticosteroid injections (e.g. intra-articular and epidural) 
• 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) 
• Allergy immunotherapy 
• Antibiotics for short-term treatment (≤14 days) of acute infections. (Long term 
treatment with antibiotics is not allowed) 
• Systemic and ophthalmic beta-blockers. (Administer with caution as systemic 
beta-blockers block the pulmonary effect of beta-agonists and may produce severe 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
43 
 
bronchospasm in participants with reversible obstructive airways disease. Cardio-
selective beta-blockers should be considered, although they also should be 
administered with caution) 
• Smoking cessation treatments  
• Cough suppressants  
• 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 QT interval corrected for heart rate [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) 
• Use of positive airway pressure for sleep apnea 
• Oral muscarinic antagonists for the treatment of overactive bladder are permitted 
but should be used with caution as they may exacerbate medical conditions that are 
contraindicated for anticholinergics (e.g., narrow angle glaucoma and bladder 
outflow obstruction) 
• Cytochrome P450 (CYP)3A4 inhibitors. (Caution should be exercised when 
considering the coadministration of long-term ketoconazole and other known 
strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, 
itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, 
troleandomycin, voriconazole) because increased systemic corticosteroid and 
increased cardiovascular adverse effects may occur) 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
44 
 
6.8.2. 
Prohibited Medications and Non-Drug Therapies 
Use of the medications listed in Table 3 is not permitted during the study. 
Table 3 
Concomitant Prohibited Medications 
Medications Prohibited during the treatment period 
Inhaled short-acting anticholinergics 
Inhaled short-acting beta2 agonists1  
Inhaled short-acting anticholinergic/short-acting beta2-agonist combination products 
Inhaled corticosteroids (ICS) 
Inhaled corticosteroids (ICS)/Inhaled long-acting beta2-agonist (LABA) combinations (eg. 
fluticasone/salmeterol, mometasone furoate/formoterol fumarate, budesonide/formoterol 
fumarate; fluticasone furoate/vilanterol 
Phosphodiesterase 4 (PDE4) inhibitors (roflumilast) 
LABA (e.g., indacaterol, olodaterol, salmeterol etc.) 
Other LAMAs (aclidinium, glycopyrronium, umeclidinium etc.) 
LAMA/LABA combinations 
Theophyllines 
Sodium cromoglycate and nedocromil sodium 
Anti-leukotrienes 
Long term antibiotic therapy2 
Systemic, oral, parenteral corticosteroids3 
Any other investigational drug 
1. 
(rescue salbutamol will be provided and is permitted during the study)  
2. 
(Antibiotics are allowed for the short-term treatment (≤14 days) of an exacerbation or for short term treatment 
(≤14 days) of other acute infections during the study)  
3. 
(During the study oral/systemic corticosteroids may be used for ≤14 days to treat COPD 
exacerbations/pneumonia)  
Intra-articular injections are allowed 
Note: Topical and ophthalmic corticosteroids, and localized corticosteroid injections 
(intra-articular and epidural) are allowed. 
NOTE: All COPD medications (except for rescue salbutamol, mucolytics and oxygen) 
are prohibited during the study treatment period, except during the treatment of a 
moderate/severe COPD exacerbation or pneumonia. In the event of an exacerbation or 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
45 
 
pneumonia, sites should attempt to follow protocol treatment guidelines, however, 
treatment with any medication that the health care provider deems necessary is allowed.  
Caution is advised in using a LABA or LAMA to treat a participant currently taking study 
treatment as these additional medications may increase the risk of overdose.  If 
necessary, the Investigator or other health care personnel may stop the participant’s 
study treatment temporarily (≤ 14 days) in order to treat the COPD exacerbation.  
Participants who require more than two consecutive 14 day courses of treatment (i.e. 
antibiotics or corticosteroids) should be evaluated for their continuation on study 
treatment by the Investigator in consultation with the GSK medical monitor. 
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
6.8.3. 
Rescue Medicine 
The study site will supply salbutamol rescue medication that will be provided locally.  
Although the use of rescue medications is allowable at any time during the study, rescue 
medication should be withheld for at least 4h hour prior to all pulmonary function tests. 
Sites should not perform spirometry on subjects who have taken a SABA/salbutamol 
within 4 hours prior to pulmonary function tests. The subjects will need to wait at the site, 
or be rescheduled for the next day, whichever is feasible  


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
46 
 
7. 
DISCONTINUATION OF FF/UMEC/VI AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of FF/UMEC/VI 
Participants have the right to discontinue FF/UMEC/VI before the end of the study. A 
participant may also be asked to discontinue FF/UMEC/VI at the Investigator’s 
discretion.  
Participants that permanently stop FF/UMEC/VI should return to the clinic as soon as 
possible, in order to complete the Treatment Discontinuation visit. The evaluations and 
procedures to be completed are outlined in the SoA (Section 1.3) 
Participants that discontinue FF/UMEC/VI are encouraged to remain in the study and 
every effort should be made by the Investigator/staff to keep the participant in the study, 
to collect important efficacy and safety data. 
If possible, participants should return to the clinic to complete all scheduled visits. If 
this isn’t possible, visits should be completed by telephone. Ideally, participants 
should return to the clinic to complete Visit 5, to collect important spirometry data, 
however, if this isn’t possible, this visit could be completed by telephone. A safety 
follow-up phone call (Visit 6) should also be conducted 7 days after Visit 5. 
Following discontinuation of study intervention, if participants are unwilling to return to 
the clinic for their scheduled visits, the Investigator/site staff should contact the 
participant by telephone at the protocol designated visit time intervals to collect the 
following: 
• SAEs  
• AEs assessed as related to study participation 
• AEs resulting in discontinuation of study intervention or withdrawal from the 
study 
• COPD exacerbations  
• Concomitant medication  
• A safety follow-up phone call (Visit 6) should also be conducted 7 days after Visit 
5. 
A participant may be withdrawn from study intervention at any time. A reason for 
premature discontinuation of study intervention (e.g., AE, lack of efficacy, protocol 
deviation, Investigator discretion, consent withdrawn etc.) must be captured in the eCRF. 
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. 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
47 
 
Discontinuation of study intervention for abnormal liver tests should be considered by the 
Investigator when a participant meets one of the conditions outlined in the algorithm or if 
the Investigator believes that it is in the best interest of the participant. 
• 
Liver Safety Algorithms and Required Actions and Follow up Assessments can be 
found in Appendix 3. 
7.1.2. 
QTc Stopping Criteria 
Details on performing ECG assessments can be found in Section 8.2.6. 
• 
The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study.  This formula may not 
be changed or substituted once the participant has been enrolled. Safety ECGs and 
other non-protocol specified ECGs are an exception. 
• 
For example, if a participant is eligible for the protocol based on QT interval 
corrected for heart rate by Bazett’s formula (QTcB), then QTcB must be used for 
discontinuation of this individual participant as well. 
• 
Once the QT correction formula has been chosen for a participant’s eligibility, the 
same formula must continue to be used for that participant for all QTc data being 
collected for data analysis.  
• 
The QTc should be based on averaged QTc values of triplicate electrocardiograms 
obtained over a brief (e.g., 5-10 minute) recording period. 
• 
For this study, the following QTc stopping criteria will apply and lead to withdrawal 
from study treatment: 
• 
an increase in QTc by > 60 msec from baseline  
• 
or development of a QTc > 530 msec (based on an average of triplicate 
ECGs) 
• 
NOTE: These criteria should be based on the average QTc value of triplicate 
ECGs.  For example, if an ECG demonstrates a prolonged QT interval, two 
more ECGs will be obtained over a brief period and then the averaged QTc 
value of the three ECGs will be used to determine whether the participant should 
be discontinued from the study. 
7.1.3. 
Pregnancy stopping criteria 
• Any female participant that becomes pregnant while participating in the study will 
discontinue study intervention. Participants are encouraged to remain in the study 
and every effort should be made by the Investigator/staff to keep the participant in 
the study. Please see Section 8.3.6 for further details on reporting pregnancies and 
associated follow-up.  


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
48 
 
7.1.4. 
COVID-19 stopping criteria 
All participants suspected to have contracted COVID-19 must be tested using a molecular 
(PCR or antigen test) approved by the regulatory authorities in India.  
Participants that test positive for COVID-19 must immediately discontinue study 
intervention and complete the Study Treatment Discontinuation Visit. Participants are 
encouraged to remain in the study and every effort should be made by the 
Investigator/staff to keep the participant in the study. 
7.2. 
Participant 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, 
behavioural, or compliance reasons. This is expected to be uncommon. 
• 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 
withdrawal of consent. 
• If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records. 
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, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record. 
• Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study.  


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
49 
 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarized in the SoA.  
• 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 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. 
• No study related procedures may be performed until the informed consent 
form has been signed by the participant. Selection and modification of the 
participant’s medications prior to study participation is based on the physician’s 
judgment according to sound medical practice, principles, and each participant’s 
needs.  A participant’s treatment must not be changed merely for the purpose of 
enabling the participant’s participation in the study. 
The timings of all efficacy assessments are specified in the SoA (Section 1.3).  
Revised study assessments and detailed guidance on study conduct during future 
COVID-19 epidemic waves are detailed in Appendix 4.   
8.1. 
Efficacy Assessments 
8.1.1. 
Spirometry 
Spirometry measurements will be obtained using spirometry equipment that meets or 
exceeds the minimal performance recommendations of the American Thoracic Society 
(ATS) [Miller, 2005].  All sites will use standardised spirometry equipment provided by 
an external vendor.  All participants will have spirometry performed at - each scheduled 
clinic visit during the treatment period. For FEV1 and FVC determinations, at least 3 
acceptable spirometry efforts (with no more than 8) should be obtained.  Acceptable 
spirometry efforts should have a satisfactory start of test and end of test (e.g. a plateau in 
the volume-time curve) and be free from artifacts due to cough, early termination, poor 
effort, obstructed mouthpiece, equipment malfunction, or other reasons [Miller, 2005]. 
The largest FEV1 and FVC from the 3 acceptable efforts should be recorded, even if they 
do not come from the same effort. 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
50 
 
Spirometry must be performed as follows: 
• 
Started approximately between 6:00AM and 11:00AM. 
• 
After completing the CAT health outcomes assessment (Visit 1 only) 
• 
After withholding albuterol/salbutamol for 4 hours.  
• 
Before the morning dose of maintenance COPD medication or study treatment. 
• 
Participants should refrain from smoking and/or vaping and use of a water pipe for 1 
hour prior to each pulmonary function test. 
• 
Participants should abstain from drinking beverages with high levels of caffeine such 
as tea and coffee for 2 hours prior to each pulmonary function test. 
• 
Participants should not consume intoxicant for 8 hours prior to each pulmonary 
function test 
• 
Vigorous exercise should be avoided for at least 1 hour prior to each pulmonary 
function test. 
A full description of the timing and conduct of spirometry procedures is provided in the 
SRM. 
Spirometry equipment will be provided through a centralized vendor. 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. 
Adverse events (AEs) and Serious Adverse Events (SAEs) will be coded using the 
standard GSK dictionary, Medical Dictionary for Regulatory Activities (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. Initial SAEs to be reported to GSK, Health 
Authority and Ethics Committee, within 24 hours of occurrence. Follow up SAEs to be 
reported to GSK, Health Authority and Ethics Committee, within 24 hours of site 
awareness. 
Incidence of COVID-19 will be reported as an AE and SAE., as applicable. Additional 
safety analysis to evaluate the impact of COVID-19 on safety assessment may be 
performed. Details will be provided in the RAP.  
 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
51 
 
8.2.1. 
Safety Endpoints 
• 
Adverse Events, Serious Adverse Events, Adverse Event of Special Interests (AESIs)  
• 
Assessments include Physical examination, vital signs, Oropharyngeal examination, 
Electrocardiogram 
8.2.2. 
COPD exacerbations 
For this study, a COPD exacerbation is defined as a worsening of COPD symptoms 
requiring the use of any treatment other than study medication or rescue salbutamol. This 
includes the use of antibiotics, systemic corticosteroids and/or emergency treatment of 
hospitalisation.  
COPD exacerbation data will be collected from the start of the treatment period (Visit 2) 
until the safety follow up contact. 
Participants will complete a paper Medical Problems worksheet to record medical 
problems experienced during the study. This paper worksheet must be reviewed by the 
Investigator (or designee) at each visit to the study site to assist in the identification of 
new COPD exacerbations.   
All COPD exacerbations will be recorded on the COPD exacerbations page of the eCRF.  
A moderate COPD exacerbation is defined as requiring systemic corticosteroids and/or 
antibiotics.  A severe COPD exacerbation is defined as requiring hospitalization.   
Every effort should be made to conduct a chest x-ray within 48 hours of identification of 
a moderate or severe exacerbation.  
Subjects who experience a moderate or severe COPD exacerbation within two weeks 
prior to screening (in the opinion of the investigator) will be discontinued from the study 
and are not allowed to be re-screened. 
COPD exacerbations are associated with the disease under study and will not be recorded 
as AEs unless the exacerbation meets the definition of a “serious” AE as defined in 
Section 10.6 of this protocol.  Exacerbations that meet the definition of “serious” will be 
recorded on the appropriate eCRF section and should be reported to GSK,  Health 
Authority and the Ethics Committee within 24 hours of occurrence. 
Medications used to treat a COPD exacerbation will be recorded in the COPD 
concomitant medication section of the eCRF. 
Further details on COPD Exacerbation Identification, Categorization and Treatment 
Guidelines are provided in Appendix 5. 
Note: Pulse oximetry should be measured at any time a moderate or severe exacerbation 
is reported or is suspected and recorded in the source documents and on the COPD 
exacerbation page of the eCRF if applicable. 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
52 
 
8.2.3. 
Pneumonia 
All 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 (colour) or production  
• 
Auscultatory findings of adventitious sounds (e.g. egophony, bronchial breath 
sounds, rales, etc.) 
• 
Dyspnoea or tachypnea 
• 
Fever (oral temperature >37.5 °C) 
• 
Elevated white blood cells (WBC) (>10,000/mm3 or >15 % immature forms) 
• 
Hypoxemia (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.  
Participants who experience a pneumonia during within two weeks prior to screening (in 
the opinion of the investigator) will be discontinued from the study and are not allowed to 
be re-screened. 
The Investigators and site staff should remain vigilant for the possible development of 
pneumonia in participants with COPD as the clinical features of such infections overlap 
with the symptoms of COPD exacerbations. 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).  
Note: Pulse oximetry should be measured at any time pneumonia is reported or suspected 
and recorded in the source documents and on the pneumonia page of the eCRF if 
applicable. 
8.2.4. 
Physical Examinations 
• A complete physical examination will include, at a minimum, assessments of the 
Skin, Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. 
Height and weight will also be measured and recorded. 
• Investigators should pay special attention to clinical signs related to previous 
serious illnesses. 
8.2.5. 
Vital Signs 
• Vital signs will be measured in a sitting position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressure, and pulse. 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
53 
 
• Vital signs will be performed at the time points specified in the SoA table 
(Section 1.3) prior to conducting spirometry and prior to taking study treatment. 
• A single set of values will be collected and recorded in the source documentation 
and eCRF.  
8.2.6. 
Electrocardiograms 
• 
A single 12-lead ECG and rhythm strip will be recorded after measurement of 
vital signs and prior to spirometry. Recordings will be made at the time-points 
defined in the SoA table (Section 1.3). All ECG measurements will be made 
with the participant in a supine position having rested in this position for 
approximately 5 minutes before each reading. 
• 
For participants who meet the QTc, protocol defined stopping criteria, triplicate 
ECGs (over a brief period of time) should be performed (Section 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. 
8.2.7. 
Pregnancy Testing 
• Refer to Section 5.1 Inclusion Criteria for pregnancy testing entry criteria and the 
SoA table. 
• 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. 
8.2.8. 
COVID-19 testing 
• Refer to Section 5.1 Inclusion Criteria for COVID-19 testing entry criteria and the 
SoA table.  
• Additional COVID-19 tests may be performed, as determined by the investigator 
or local guidelines.  
• All positive COVID-19 tests should be reported on the COVID-19 eCRFs and the 
AE/SAE eCRFs, as well as the exacerbation/pneumonia eCRFs, as appropriate.   
• Participants that test positive for COVID-19 should discontinue study 
intervention, as specified in Section 7.1.4.  
• Positive tests should be reported to the appropriate government authorities, per 
local regulations.  


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
54 
 
8.3. 
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 10.6. 
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 Appendix 6. 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 
• All AEs and SAEs will be collected from the start of intervention (Visit 2) until the 
follow-up contact (Visit 6) at the time points specified in the SoA (Section 1.3). 
However, any SAEs assessed as related to study participation (e.g., protocol-
mandated procedures, invasive tests, or change in existing therapy) or related to a 
GSK product will be recorded from the time a participant consents to participate in 
the study. 
• 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. 
• All SAEs will be recorded and reported to the sponsor or designee, Health Authorities 
and EC, immediately and under no circumstance should this exceed 24 hours, as 
indicated in Appendix 3. The investigator will submit any updated SAE data (Follow 
up report) to the sponsor within 24 hours of it being available and awareness of the 
same. 
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 within the timelines mentioned above. 
 
 
 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
55 
 
8.3.2. 
 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.  
Participants will be issued with a paper Medical Problems worksheet to record any 
medical problems experienced during the study. This paper worksheet will be used to 
assist participant recall in discussions with the Investigator (or designee), for site staff to 
then enter as appropriate in the eCRF.  
8.3.3. 
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 events, 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 6. 
8.3.4. 
Adverse events of special interest 
Within the FF, UMEC, and VI clinical development programs for asthma/COPD, the 
following ICS, LAMA, and LABA class effects were considered adverse events of 
special interest (AESIs) (Table 4).   
Table 4 
Adverse Events of Special Interest (AESI) Definitions 
Special interest group 
Special interest subgroup 
PTs/SMQs for inclusion 
CV effects 
Cardiac arrhythmia 
Cardiac arrhythmia (SMQ), 
excluding congenital and 
neonatal arrhythmias 
 
Cardiac failure 
Cardiac failure (SMQ) 
 
Cardiac ischemia 
Ischemic Heart Disease (SMQ)  
 
Stroke 
CNS haemorrhages and 
cerebrovascular conditions 
(SMQ) 
 
Hypertension 
Hypertension (SMQ) 
Pneumonia 1 
Pneumonia 
Infective pneumonia (SMQ) 
LRTI (excluding infective pneumonia 
SMQ) 
 
Selected PTs 
Decreased BMD 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) 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
56 
 
Special interest group 
Special interest subgroup 
PTs/SMQs for inclusion 
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) 2 
Abbreviations: BMD, bone mineral density; CNS, central nervous system; CV, cardiovascular; LRTI, lower 
respiratory tract infection; PT, preferred term; RAP, Reporting and Analysis Plan; SMQ, standardized MedDRA 
queries. 
1. 
All diagnosed pneumonias (with or without radiographic confirmation) were to be recorded on the adverse 
event page of the eCRF and on the pneumonia page of the eCRF.  All suspected pneumonias were required to 
be confirmed by the presence of new infiltrates on a posteroanterior and lateral chest x-ray (48 h of 
suspected event) (details provided in Protocol Section 7.5.1.6). 
2. 
Includes nasopharyngitis. 
8.3.5. 
Regulatory Reporting Requirements for SAEs/AESI 
• Prompt notification by the investigator to the sponsor of an SAE/AESI  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. 
• For SAEs/AESIs, the investigator must always provide an assessment of causality at 
the time of the initial report. 
• An investigator who receives an investigator safety report describing an SAE/ AESI 
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 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. 
8.3.6. 
Pregnancy 
• Details of all pregnancies in female participants will be collected after the start of 
study intervention and until the safety follow-up visit. 
• If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate pregnancy notification form and submit it to GSK within 24 hours of 
awareness of the pregnancy. While pregnancy itself is not considered to be an AE or 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
57 
 
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, foetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported 
as such. 
• The participant will be followed up 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 
8.3.5. 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 but may remain in the study (if consent is not 
withdrawn). 
8.3.7. 
Cardiovascular and Death Events 
For all death and any cardiovascular events detailed in Appendix 6, 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 as per SAE 
reporting timelines   
8.3.8. 
 Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs 
COPD exacerbations are an expected disease-related outcome. COPD exacerbations 
should not be recorded as an adverse event, unless they meet the definition of an SAE 
(see Section 8.2.2 and Appendix 5 for further details). 
8.3.9. 
Drug/Inhaler Combination Product Deficiencies  
• 
FF/UMEC/VI administered via the ELLIPTA inhaler is a GSK drug/inhaler 
combination product. GSK must be notified if this Drug/Inhaler combination 
product fails to function properly as a result of an inhaler deficiency. Inhaler 
deficiencies should be reported as outlined in the SRM, and not as a safety 
event. Inhaler deficiencies will be reported to the sponsor within 24 hours. 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
58 
 
• 
It is possible for a reportable safety event to occur at the same time as a device 
malfunction. Safety events are reported as described in Section 8.3. 
8.4. 
Pharmacokinetics 
PK parameters are not evaluated in this study. 
8.5. 
Genetics 
Genetics are not evaluated in this study. 
8.6. 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.7. 
Immunogenicity Assessments 
Immunogenicity is not evaluated in this study.  
8.8. 
Medical Resource Utilization and Health Economics 
Medical Resource Utilization and Health Economics parameters are not evaluated in this 
study. 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
59 
 
9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
There will be no formal hypothesis testing.  
9.2. 
Sample Size Determination 
The primary objective of the study is to evaluate the safety profile of FF/UMEC/VI over 
12 weeks of treatment. The primary endpoint is incidence of AEs, SAEs and AESIs. 
Sample size is determined based on the calculation of the probability of observing an AE. 
Table 5 provides the probabilities of observing various numbers of AEs based on a series 
of theoretical risks of an event occurring in a given patient in a study of 12 weeks 
duration, given a sample size of 220. For example, for a theoretical risk of an AE of 
1/100 in this 12 week study, we would have a greater than 89% chance of observing at 
least one subject having the AE.  
Table 5 
Probabilities of observing a given number of subjects experiencing 
an adverse events or more (k) for given theoretical risks in a study 
of 12 weeks duration for a sample size of 220 patients  
 
Theoretical Risk of an Event* 
k 
0.0500 
0.0300 
0.0100 
0.0050 
0.0010 
0.0001 
1 
>0.9999 
0.9988 
0.8904 
0.6680 
0.1976 
0.0218 
2 
0.9998 
0.9904 
0.6469 
0.3011 
0.0209 
0.0002 
3 
0.9990 
0.9621 
0.3776 
0.0991 
0.0015 
<0.0001 
4 
0.9958 
0.8984 
0.1799 
0.0254 
<0.0001 
 
5 
0.9866 
0.7915 
0.0715 
0.0053 
 
 
6 
0.9658 
0.6488 
0.0242 
0.0009 
 
 
7 
0.9266 
0.4906 
0.0071 
0.0001 
 
 
8 
0.8634 
0.3410 
0.0018 
<0.0001 
 
 
9 
0.7748 
0.2178 
0.0004 
 
 
 
10 
0.6651 
0.1281 
<0.0001 
 
 
 
*Theoretical risk of an event occurring in a given subject in a study of 12 weeks duration. 
A study with 220 evaluable participants will also provide a precision of 32ml in 
estimating the treatment effect of change from baseline in trough FEV1 on Day 85. The 
precision is defined as the half width of 95% confidence interval (CI). The calculations 
assume an estimate of residual standard deviation (SD) of 240mL (based on mixed model 
repeated measures [MMRM] analyses of Trelegy Phase IIb FULFIL study).  
Total 229 participants will be enrolled in study treatment phase to achieve 220 evaluable 
participants at the end of the study assuming 4% withdrawal from the study treatment. 
Assuming 25% screen failure rate, approximately 306 participants will be screened. If a 
future COVID-19 pandemic increases the number of participants that discontinue study 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
60 
 
intervention or increases the amount of missing spirometry data the sample size may be 
increased. Please see Appendix 4 for further details.  Analysis Sets 
For purposes of analysis, the following populations are defined: 
Population 
Description 
Screened 
• All participants for whom a record exists in the study 
database, including screen failures and any participant 
who was not screened but experienced an SAE between 
the date of informed consent and the planned date of the 
Screening visit. 
Enrolled 
• All participants who signed the ICF and screen passed 
Intent-to Treat (ITT) 
• All participants who received at least one dose of study 
treatment. 
9.3. 
Statistical Analyses 
The statistical analysis plan will be finalized prior to data lock 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 secondary endpoints. 
9.3.1. 
Efficacy Analysis 
All efficacy analyses will be performed on the ITT Population. 
 
The efficacy endpoints are change from baseline in trough FEV1 on Day 85, and Day 28. 
 
The estimands for these endpoints are defined below: 
• Endpoint:  
o 
change from baseline in trough FEV1 on Day 85 (trough FEV1 on Day 85 
is defined as the mean of the FEV1 values obtained 24 hours after morning 
dosing on Day 84) 
o 
change from baseline in trough FEV1 on Day 28 (trough FEV1 on Day 28 
is defined as the mean of the FEV1 values obtained prior to dosing on Day 
28)    
• Summary measure:  
o 
mean change from baseline in trough FEV1 on Day 85 
o 
mean change from baseline in trough FEV1 on Day 28  
 
• Population of interest: COPD patients in India.  
• Key intercurrent events: discontinuation of treatment   
• Strategy for intercurrent events: a hypothetical strategy will be used for intercurrent 
event of treatment discontinuation. Trough FEV1 data collected up to the time of 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
61 
 
treatment discontinuation will be used in the analysis. This estimates effect under the 
hypothetical scenario that participants do not discontinue treatment. 
• Participants that test positive for COVID-19 will immediately discontinue study 
treatment. Therefore COVID-19 will be included as the intercurrent event of study 
treatment discontinuation and will be handled with hypothetical strategy for the 
estimand.  
The endpoint of change from baseline in trough FEV1 will be analysed using a mixed 
model repeated measures (MMRM) analysis. The analysis will include change from 
baseline in trough FEV1 at Day 28, and Day 85.  Mean change from baseline in trough 
FEV1 will be summarised and presented with 95% confidence interval by visit. Trough 
FEV1 collected after treatment discontinuation will be set to missing.  Missing data will 
be assumed to be missing at random (MAR). 
 
Taking prohibited medication during the treatment period is an important protocol 
deviation (PD) and will be included in the PD summary. However, this is not considered 
as an intercurrent event for the estimands.  
 
A supplementary estimand will be estimated using treatment policy strategy for the 
intercurrent event of treatment discontinuation unrelated to the COVID-19 pandemic and 
using hypothetical strategy for the intercurrent event of treatment discontinuation related 
to the COVID-19 pandemic. This supplementary treatment effect will only be estimated 
if >5% of the ITT subjects discontinued study treatment. 
 
9.3.2. 
Safety Analysis 
All safety analyses will be performed on the ITT Population.  
The primary Estimand is defined by the following: 
• Endpoint: AE, SAE and AESI. 
• Summary measure:  
o number and percentage of participants experiencing an AE  
o number and percentage of participants experiencing a SAE   
o number and percentage of patients experiencing an AESI 
• Population of interest: COPD patients in India.  
• Key intercurrent events: discontinuation of treatment   
• Strategy for intercurrent events: a While on Treatment strategy will be used for 
treatment discontinuation.  This estimates the percentage of participants experiencing 
an AE, SAE or AESI while taking treatment. 
• Participants that test positive for COVID-19 will immediately discontinue study 
treatment. Therefore COVID-19 will be included as the intercurrent event of study 
treatment discontinuation and will be handled with While on Treatment strategy for 
the primary estimand.  
A supplementary estimand will be defined using identical properties as for the primary 
estimand (summary measure, population of interest and key intercurrent events), however 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
62 
 
this supplementary estimand will report all AEs regardless of the discontinuation of study 
treatment. 
• Endpoints: Incidence of AEs, SAEs and AESIs 
• Strategy for intercurrent events: Treatment policy strategy will be used for treatment 
discontinuation. This summary will therefore be inclusive of all on-treatment and 
post-treatment AEs. 
 
In addition, summary statistics for vital signs and their change from baseline at Day 85: 
heart rate, systolic blood pressure and diastolic blood pressure will be produced. 
9.3.3. 
Other Analysis 
Full details of the analyses to be performed on the primary and other efficacy endpoints 
will be given in the Reporting and Analysis Plan (RAP). 
9.4. 
Interim Analysis 
Interim analysis is not planned but will be conducted if requested by the regulatory 
authority. 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
63 
 
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, 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 
 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
64 
 
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 and answer all questions regarding the study.  
• Participants must be informed that their participation is voluntary. Participants 
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 centre.  
• 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. 
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 FF/UMEC/VI or about the study disease; publish the results of these research 
efforts; work with government agencies or insurers to have FF/UMEC/VI approved for 
medical use or approved for payment coverage.  
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. 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
65 
 
10.1.5. 
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 
patients’ received.  The investigator(s) is/are encouraged to share the summary 
results with the study subjects, 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. 
• 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. 
10.1.6. 
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 a separate document. 
• Quality tolerance limits (QTLs) will be pre-defined in a separate document 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. 
• The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.  


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
66 
 
• 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.  
10.1.7. 
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.  
10.1.8. 
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. 
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. 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
67 
 
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 
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 subject and should assure appropriate 
participant therapy and/or follow-up 
10.1.9. 
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. 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
68 
 
10.2. 
Appendix 2: Contraceptive and Barrier Guidance  
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below) 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with ONE of the following: 
• 
Documented hysterectomy 
• 
Documented bilateral salpingectomy 
• 
Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
• 
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.  
• 
Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment. 
Contraception Guidance 
Female Participants 
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in 
Table 6.  


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
69 
 
Table 6 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent a 
Failure rate of <1 % per year when used consistently and correctly.  
Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulationb  
• oral 
• intravaginal  
• transdermal  
Progestogen-only hormonal contraception associated with inhibition of ovulation 
• injectable  
Highly Effective Methods That Are User Independent  
• Implantable progestogen-only hormonal contraception associated with inhibition 
of ovulationb 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• bilateral tubal occlusion 
Vasectomized partner  
(A vasectomized partner is a highly effective contraception method provided that the 
partner is the sole male sexual partner of the WOCBP and the absence of sperm has 
been confirmed. If not, an additional highly effective method of contraception should 
be used.)  
Sexual abstinence  
(Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study drug. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the study and the preferred and usual lifestyle of the 
Participants.)  
NOTES:  
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with 
local regulations regarding the use of contraceptive methods for participants in clinical studies. 
Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of the 
contraceptive method. In this case two highly effective methods of contraception should be utilized during the 
treatment period. 
 
Pregnancy Testing 
• 
WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive urine pregnancy test  


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
70 
 
• 
Additional pregnancy testing should be performed during the treatment period (see 
SoA) and whenever a menstrual cycle is missed or when pregnancy is otherwise 
suspected  
• 
Pregnancy testing will be performed using the test kit sourced locally and in 
accordance with instructions provided in its package insert   
• 
Any female participant who becomes pregnant while participating in the study 
will immediately discontinue study medication. 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
71 
 
10.3. 
Appendix 3: 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 aetiology (in alignment with 
the FDA premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf 
Table 7 
Phase III-IV liver chemistry stopping criteria and required follow up 
assessments 
Liver Chemistry Stopping Criteria - Liver Stopping Event 
Alanine 
Transaminase 
(ALT)-
absolute 
ALT ≥8x ULN 
ALT Increase ALT ≥5x ULN but <8x ULN persists for ≥2 weeks 
ALT ≥3x ULN but <5x ULN persists for ≥4 weeks 
Bilirubin1, 2 
ALT ≥3x ULN and bilirubin ≥2x ULN (>35 % direct bilirubin)  
International 
Normalized 
Ratio (INR)2 
ALT ≥3x ULN and INR >1.5, if INR measured 
Cannot 
Monitor 
ALT ≥5x ULN but <8x ULN and cannot be monitored weekly for ≥2 
weeks 
ALT ≥3x ULN but <5x ULN and cannot be monitored weekly for ≥4 
weeks 
Symptomatic3 ALT ≥3x ULN associated with symptoms (new or worsening) 
believed to be related to liver injury or hypersensitivity 
Required Actions and Follow up Assessments following ANY Liver Stopping 
Event 
Actions 
Follow Up Assessments 
• Immediately discontinue study treatment  
• Report the event to GSK within 24 
hours of occurrence of the SAE per 
process provided in the Study Reference 
Manual (SRM)  
• Viral hepatitis serology4 
• Only in those with underlying 
chronic hepatitis B at study entry 
(identified by positive hepatitis B 
surface antigen) quantitative 
hepatitis B DNA and hepatitis delta 
antibody5. 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
72 
 
Liver Chemistry Stopping Criteria - Liver Stopping Event 
• Complete the liver event eCRF and 
complete an SAE data collection tool if 
the event also meets the criteria for an 
SAE2 
• Perform liver event follow up 
assessments  
• Monitor the participant until liver 
chemistries resolve, stabilize, or return 
to within baseline (see MONITORING 
below) 
• Do not restart participant with study 
treatment unless allowed per protocol  
• If restart/rechallenge not allowed per 
protocol, permanently discontinue study 
treatment and may 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  
• Blood sample for pharmacokinetic 
analysis, obtained within 72 hours 
after last dose6 
• Serum creatine phosphokinase and 
lactate dehydrogenase. 
• 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 
 
For bilirubin or INR criteria: 
• Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG or gamma globulins). 
• Serum acetaminophen adduct HPLC 
assay (quantifies potential 
acetaminophen contribution to liver 
injury in participants with definite or 
likely acetaminophen use in the 
preceding week [James, 2009]).  
• Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and /or liver biopsy to 
evaluate liver disease; complete 
Liver Imaging and/or Liver Biopsy 
eCRF forms. 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
73 
 
Liver Chemistry Stopping Criteria - Liver Stopping Event 
• Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline 
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  3x ULN and bilirubin  2x ULN. 
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  3x ULN and bilirubin  2x ULN (>35 % direct bilirubin) or ALT  3x ULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to participants receiving anticoagulants 
3. New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)    
4. Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody  
5. 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 blood sample draw on the eCRF. 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 SPM.   
 
Table 8 
Phase III-IV liver chemistry increased monitoring criteria with 
continued therapy 
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event 
Criteria 
Actions 
 
ALT ≥5x ULN and <8x ULN and 
bilirubin <2x ULN without 
symptoms believed to be related to 
liver injury or hypersensitivity, 
and who can be monitored weekly 
for 2 weeks. 
OR 
ALT ≥3x ULN and <5x ULN and 
bilirubin <2x ULN without 
symptoms believed to be related to 
liver injury or hypersensitivity, 
• 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 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
74 
 
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event 
and who can be monitored weekly 
for 4 weeks. 
 
• If ALT decreases from ALT ≥5x ULN and 
<8x ULN to ≥3x ULN but <5x ULN, 
continue to monitor liver chemistries weekly.  
• If, after 4 weeks of monitoring, ALT 
<3x ULN and bilirubin <2x ULN, monitor 
participants twice monthly until liver 
chemistries normalize or return to within 
baseline. 
 
 
References 
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784. 
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E.  Quantification 
of Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates 
Different Patterns of Virological Response to Interferon Therapy in Chronically Infected 
Patients.  J Clin Microbiol. 2005;43(5):2363–2369.  


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
75 
 
10.4. 
Appendix 4: Study Procedures during COVID-19 Pandemic 
Overall Rationale for this Appendix  
COVID-19 pandemic may impact the conduct of clinical studies. Challenges may arise 
from quarantines, site closures, travel limitations, interruptions to the supply chain for the 
investigational product or other considerations if site personnel or study participants 
become infected with COVID-19. These challenges may lead to difficulties in meeting 
protocol-specified procedures.  
This protocol appendix outlines measures that may be applicable for any site impacted by 
the COVID-19 pandemic. The purpose of the appendix is to provide information on the 
measures to be taken to protect participants’ safety, welfare and rights, and promote data 
integrity. 
 
These measures will remain in place until the site is able to resume normal working 
activities. 
 
Study Procedures During COVID-19 Pandemic 
During the special circumstances caused by the current COVID-19 pandemic, you should 
consider specific public health guidance, the impact of any travel restrictions 
implemented by local/regional health authorities and local institutions, and individual 
benefit /risk when making enrollment and treatment decisions for trial participants. 
 
Every effort should be made to adhere to protocol-specified assessments for participants 
on study intervention, including follow up however when not possible, for the duration of 
these special circumstances, the following measures may be implemented for enrolled 
participants.  
• 
Clinical investigators should document in site files and in participant notes how 
restrictions related to COVID-19 led to the changes in study conduct and duration of 
those changes, and indicate which trial participants were impacted and how those 
trial participants were impacted (as per the current local COVID-19 related 
regulatory guidance).  
• 
Missing protocol required data/visits due to COVID-19 should be noted in 
participant notes and recorded as a COVID-19 protocol deviation. Visits that were 
conducted via the telephone will not be classified as missed visits, however missed 
assessments (e.g. spirometry) should be recorded as COVID-19 protocol deviations.  
Protocol Defined Procedures/Visits: 
• Study participants that are in screening should remain on their current COPD 
maintenance therapy until it is safe for participants to return to the clinic and enter 
the treatment phase. 
• Study participants in the treatment phase of the study (Visit 2 to Visit 5) should be 
contacted by sites at each scheduled study visit to collect the following: 
o SAEs  


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
76 
 
o AEs 
o COPD exacerbations  
o Concomitant medication  
o Compliance with study intervention 
• 
Note: The  secondary objective of the study is to evaluate the effect of 
FF/UMEC/VI on lung function, after 12 weeks of treatment. It will not be possible 
for study participants to complete spirometry assessments at home, therefore the 
sample size may need to be increased, to ensure there are a sufficient number of 
evaluable participants with completed spirometry assessments.   
• For study participants that have completed the treatment phase and have only the 
safety follow-up visit (Visit 6) to complete, this visit can be completed via the 
telephone, as specified in the SoA.  
Study Intervention(s) 
• 
If allowed by country regulation/ethics, study intervention (including rescue study 
medication) can be shipped direct-to-patient (DTP) from the investigational site to 
the participant’s home address. The process for this shipment must be agreed with 
GSK who will provide the relevant documentation and links to courier sites required 
to ensure shipments are adequately temperature controlled (if required) throughout 
transportation 
• 
The Principal Investigator assumes Good Clinical Practice (GCP) responsibilities for 
IMP handling and the medical control for dispensing to patients. Site Staff should 
document the dispensing in the Dispensing/Accountability Logs adding a comment 
that this was a DTP dispensing.  
• 
In some cases, trial participants who no longer have access to investigational product 
or the investigational site may need additional safety monitoring. 
Data Management/Monitoring: 
• 
If on-site monitoring is no longer permitted, GSK will consider remote Source Data 
Verification/Source Document Review (SDV/SDR) where permitted by the clinical 
site/institution. Remote SDV/SDR will be proposed to study sites to meet a patient 
and/or critical quality need, e.g., to assess participant safety or to ensure data 
integrity. In case of remote SDV/SDR, GSK will work with the site to ensure subject 
privacy.  
• 
eCRF/CRF Final or Interim Sign off Process: The Principal Investigator (PI) is 
responsible for ensuring that the data within the eCRF casebook and any other data 
sources utilized during the study for each study participant is complete and 
consistent with source documents throughout the study (ICH GCP 4.9.1 4.9.2). The 
PI may sign/re-sign the eCRF from any computer/location by accessing the 
applicable eDC platform) using his/her unique eCRF log-in credentials. The PI may 
delegate this activity to another medically qualified and trained sub-investigator and 
this must be documented on the Delegation of Responsibilities (DoR) Log. It is 
recommended that the PI identifies a sub-investigator as a back-up for eCRF 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
77 
 
signatures. The sub-investigator must be appropriately trained on the protocol and 
eCRF requirements (with training documented), and the DoR log updated 
accordingly.  
• 
Essential Document Sign Off Process: If an investigator is unable to print and sign 
essential documents such as Protocol /Amendment signature page then Email 
approval can be accepted by replying to the relevant email that is sent by GSK 
 
 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
78 
 
10.5. 
Appendix 5: COPD Exacerbation Identification, 
Categorization and Treatment Guidelines 
10.5.1. 
Guidelines for Identifying COPD Exacerbations 
The following are symptoms used to ascertain an exacerbation of COPD: 
Worsening of two or more of the following major symptoms for at least two consecutive 
days: 
• Dyspnoea 
• Sputum volume 
• Sputum purulence (color) 
OR 
Worsening of any one major symptom together with any one of the following minor 
symptoms for at least two consecutive days: 
• Sore throat 
• Colds (nasal discharge and/or nasal congestion) 
• Fever (oral temperature >37.5 °C) without other cause 
• Increased cough 
• Increased wheeze 
Participants who experience worsening COPD symptoms for greater than 24 hours 
should:  
• Contact their study Investigator and/or research coordinator immediately, and 
report to the study clinic as required 
• If the participant is unable to contact their study Investigator and/or research 
coordinator, they should contact their primary care physician (or other health care 
practitioner as required) and contact their study site as soon as possible 
• If the participant seeks emergency/acute care for worsening respiratory 
symptoms, he/she should request the caring Health Care Provider (HCP) to 
contact the Investigator as soon as possible. 
Participants with worsening respiratory symptoms will be classified as having: 
• A mild/moderate/severe exacerbation and/or pneumonia 
OR 
• A Lower Respiratory Tract Infection (LRTI) 
• Background variability of COPD 
• A non-respiratory related disease 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
79 
 
• Other respiratory related disease 
 
10.5.2. 
COPD Exacerbation Severity 
Each COPD exacerbation will be categorized based on severity as follows: 
Mild:  Worsening symptoms of COPD that are self-managed by the participant.  
Mild exacerbations are not associated with the use of corticosteroids or 
antibiotics. 
Moderate:  Worsening symptoms of COPD that require treatment with 
oral/systemic corticosteroids and/or antibiotics. 
Severe: Worsening symptoms of COPD that require treatment with in-patient 
hospitalization. 
Every effort should be made to conduct a chest x-ray within 48 hours of 
identification of a moderate or severe exacerbation.  
Details of an exacerbation should be recorded in the exacerbation page of the eCRF. 
However, exacerbations should not be recorded in the AE section of the eCRF unless 
they meet the definition of an SAE. (Pneumonia must be recorded in the AE or SAE 
section of the eCRF and on the Pneumonia page of the eCRF.) 
Use of antibiotics for the treatment of upper or lower respiratory tract infections will not 
be considered a COPD exacerbation unless the participant experiences worsening 
symptoms of COPD which match the definition of an exacerbation as given above. 
10.5.3. 
Treatment of COPD Exacerbations 
All medications used for the treatment of exacerbations must be recorded in the source 
documents and the exacerbation page of the eCRF.  All sites should follow the protocol 
treatment guidelines (as outlined below), but any medications deemed medically 
necessary may be used to treat a COPD exacerbation. However, caution is advised in 
using a LABA or LAMA to treat a participant currently taking IP as these additional 
medications may increase the risk of overdose.  If necessary, the PI or other health care 
personnel may stop the participant’s study treatment temporarily in order to treat the 
COPD exacerbation. 
10.5.4. 
Guidelines for Treatment with Corticosteroids 
If in the opinion of the Investigator/treating physician the exacerbation is severe enough 
to warrant the need for oral or systemic corticosteroids (with or without antibiotics) the 
following guidelines should be used. 
• The duration of treatment with oral/systemic corticosteroids should be 14 days (dose 
and type according to local practice)  
• The duration of treatment with oral/systemic corticosteroids should not exceed 14 
days unless approval is given by the sponsor or representative 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
80 
 
• Any course of oral/systemic corticosteroids started within 7 days of finishing a 
previous course will be considered as treatment for a single exacerbation 
10.5.5. 
Guidelines for Treatment with Antibiotics 
If there is evidence of respiratory infection that in the opinion of the Investigator or 
treating physician warrants the need for antibiotics the following guidelines should be 
followed: 
• 
The duration of treatment with antibiotics should be 7 to 14 days (dose and type 
according to local practice). If first line antibiotic treatment fails and additional 
antibiotics are used, the total duration of antibiotic treatment should not exceed 30 
days unless approval for participants to continue on study treatment, is given by the 
sponsor or representative 
• 
Any course of antibiotics started within 7 days of finishing a previous course will be 
considered as treatment for a single exacerbation 
Use of antibiotics for the treatment of upper or lower respiratory tract infections is not 
considered a COPD exacerbation unless the participant experiences worsening of 
symptoms of COPD  
10.5.6. 
Onset and Resolution of COPD Exacerbations 
For each mild, moderate and severe exacerbation, the date of onset and the date of 
resolution will be recorded in the study source documents and eCRF. 
The date of onset is the first day (of at least 2 consecutive days) of worsening symptoms. 
The date of resolution should be based on when the Investigator and/or participant 
determines that the COPD symptoms have returned to pre-exacerbation levels or to a new 
baseline.   
10.5.7. 
Guideline for assessing multiple mild exacerbations 
Two mild exacerbations can be combined into one, per the Investigator’s judgement, if 
two mild COPD exacerbations are separated by no more than three exacerbation free 
days. 
10.5.8. 
Guideline for assessing exacerbations that increase in severity 
If an exacerbation starts off as mild but becomes moderate or severe or starts off as 
moderate and becomes severe, the exacerbation should be captured as one exacerbation 
and classified by its highest level of severity. 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
81 
 
10.6. 
Appendix 6: AEs and SAEs, Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.6.1. 
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 
• 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.  
 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
82 
 
Events NOT Meeting the AE Definition  
• Any clinically significant 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. 
 
10.6.2. 
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, 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
83 
 
An SAE is defined as any serious adverse event that, at any dose: 
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. 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. 
 
10.6.3. 
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 
 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
84 
 
10.6.4. 
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. 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
85 
 
Assessment of Causality 
• 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. 
• 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 / awareness of the information. 
10.6.5. 
Reporting of SAE to GSK 
SAE Reporting to GSK via Email  
• The primary mechanism for reporting SAE to GSK will be Email. 
• The site will enter the SAE data into the electronic system as soon as it becomes 
available and report the event within 24 hours of SAE occurence to GSK by 
sending the PDF of the Electronic Case Report Form (eCRF) as defined in the 
Study Reference Manual for the study. 
• The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (e.g., check review box, signature, etc.) of review and verification of the 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
86 
 
SAE Reporting to GSK via Email  
relationship of each SAE to IP/study participation (causality) within 72 hours of 
SAE entry into the eCRF. 
• After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study 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. 
• Contacts for SAE reporting will be provided in the Study Reference Manual (SRM) 
for the study. 
 
SAE Reporting to GSK via email  
• Email transmission of the SAE via PDF copy of the CRO eCRF is the preferred 
method to transmit this information to the SAE contact. 
• 
Contacts for SAE reporting will be provided in the Study Reference Manual for the 
study.  
 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
87 
 
10.7. 
Appendix 7: Abbreviations and Trademarks 
AE 
Adverse Event 
AF 
Atrial Fibrillation 
ASE 
All Subjects Enrolled 
ATS 
American Thoracic Society 
BfS 
Federal Office for Radiation Protection 
BPM 
Beats per minute 
BMI 
Body Mass Index 
CAT 
COPD Assessment Test 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CONSORT 
Consolidated Standards of Reporting Trials 
COPD 
Chronic Obstructive Pulmonary Disease 
COVID-19 
Coronavirus Disease 2019 
CPRD 
Clinical Practice Research Database 
CT 
Computerized Tomography 
CV 
Cardiovascular 
CYP 
Cytochrome P450 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EOS 
End of study 
EU 
European Union 
FDA 
Food and Drug Administration 
FEV1 
Forced expiratory volume in 1 second 
FF 
Fluticasone Furoate 
FSH 
Follicle Stimulating Hormone 
FVC 
Forced Vital Capacity 
GCP 
Good clinical practice 
GCSP 
Global Clinical Safety and Pharmacovigilance 
GOLD 
Global Initiative for Chronic Obstructive Lung Disease 
GSK 
GlaxoSmithKline 
HCP 
Health Care Provider 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HPA 
Hypothalamic-Pituitary-Adrenal 
HPLC 
High-Performance Liquid Chromatography 
HRT 
Hormone Replacement Therapy 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ICS 
Inhaled Corticosteroids 
IEC 
Independent Ethics Committee 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
88 
 
IUD 
Intrauterine device 
IUS 
Intrauterine Hormone-Releasing System 
IWRS 
Interactive Web Response System 
ITT 
Intent-to-Treat 
Kg/m2 
Kilograms per meter squared 
LABA 
Long-Acting Beta-2-Agonists 
LAMA 
Long-Acting Muscarinic Antagonist 
LRTI 
Lower Respiratory Tract Infection 
LTOT 
Long-term oxygen therapy 
MACE 
Major Adverse Cardiac Event 
MAOI 
Monoamine Oxidase Inhibitors 
MAR 
Missing at random 
MedDRA 
Medicinal Dictionary for Regulatory Activities 
mcg 
Microgram 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MDI 
Metered Dose Inhaler 
min 
Minute 
mL 
Milliliter 
MMRM 
Mixed-Model Repeated Measures 
mPP 
Modified Per Protocol 
MSDS 
Material Safety Data Sheet 
msec 
Millisecond 
NA 
Not Applicable 
NYHA 
New York Heart Association 
PCR 
Polymerase chain reaction 
PDE4 
Phosphodiestrase 4 inhibitor 
PRAC 
Pharmacovigilance Risk Assessment Committee 
QTc 
QT interval corrected for heart rate 
QTcB 
QT interval corrected for heart rate by Bazett’s formula 
QTcF 
QT interval corrected for heart rate by Fridericia’s formula 
RAP 
Reporting and Analysis Plan 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SMQ 
Standardised MedDRA Queries 
SoA 
Schedule of Activities 
SRM 
Study Reference Manual 
SUSAR 
Suspected unexpected serious adverse reaction 
TQT 
Thorough QT 
UK 
United Kingdom 
UMEC 
Umeclidinium 
USA 
United States of America 
VI 
Vilanterol 
VT 
Ventricular Tachycardia 
WM 
Weighted Mean 
WOCBP 
Woman of child-bearing potential 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
89 
 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
ELLIPTA 
 
None 
 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
90 
 
10.8. 
Appendix 8: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC). 
Amendment 3 (date): 29 Nov 2022 
Overall Rationale for the amendment  
Based on feedback received from top pulmonologists, and review of similar studies 
conducted in India, the total number of at clinic visits is reduced from 4 to 3 and run-in 
period on existing COPD medication for 2 weeks has been removed. These changes are 
expected to simplify the study, reduce the patient burden participant drop-out rates 
without compromising the quality of the study.  
Approximately 306 participants will be screened in order to enroll 229 to the study treatment 
phase (assuming 25% screen failure rate) and achieve 220 evaluable participants at the end 
of the study (assuming 4% withdrawal from study treatment).  
 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
 
Secondary Endpoint: 
change from baseline and mean 
change from baseline in trough 
FEV1 on Day 84 removed 
Overall Design: 
Participants will enter run-in on their 
existing COPD medication for 2 
weeks post screening removed.  
Updated Day 84 visit from physical 
visit to telephone visit 
Number of Participants:  
number of participants screening 
changed from 336 to 306. 
Intervention:  
Groups and Duration: The total 
duration of participant participation 
will be approximately 13 weeks. 
Information on prescription data 
from India to be used to cap the 
approximate number of patients 
enrolled on the most widely 
prescribed COPD medications is 
removed 
These changes are expected to 
simplify the study, reduce the 
patient burden without 
compromising the quality of the 
study. 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
91 
 
1.2 Study Design 
Schema 
Updated Schema to reflect the 
proposed amendments 
 
These changes are expected to 
simplify the study, reduce the 
patient burden without 
compromising the quality of the 
study. 
1.3 Schedule of 
Activities (SoA) 
Updated the following: Day 84 visit 
from physical to telephonic, 
activities and related instructions in 
footnote. 
Updated Day 85 clinic visit activities. 
Run-in on their existing COPD 
medication for 2 weeks post 
screening removed. 
These changes are expected to 
simplify the study, reduce the 
patient burden without 
compromising the quality of the 
study. 
3 Objectives and 
endpoints/Estimands 
Secondary Endpoint: 
Change from baseline and mean 
change from baseline in trough 
FEV1 on Day 84 removed 
Since, Day 84 visit is replaced to 
a telephonic visit for medication 
reminder and effect of 
FF/UMEC/VI on lung function is 
evaluated on Day 85  
 
4.1 Overall Design 
Updated Day 84 visit from physical 
visit to telephone visit 
Participants will enter run-in on their 
existing COPD medication for 2 
weeks post screening removed.  
Number of participants screening 
changed from 336 to 306. 
Text pertaining to participants 
enrolled are representative of the 
population that may be eligible for 
SITT is removed 
 
These changes are expected to 
simplify the study, reduce the 
patient burden without 
compromising the quality of the 
study. 
5 Study Population,  
5.1 Inclusion criteria  
#7 Patient with history of ≥2 
moderate exacerbations or one 
severe (hospitalized) exacerbation 
in the previous 12 months, and with 
a score of ≥10 on the CAT eligible 
for the study treatment in the 
opinion of the investigator and 
To ensure right participants are 
enrolled in the study. 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
92 
 
documented post salbutamol 
FEV1/FVC ratio of <0.70  
#8 clarification Existing COPD 
maintenance treatment: To be 
eligible for the study treatment 
phase, participants must be 
compliant with their existing COPD 
maintenance therapy (in the opinion 
of the investigator) for the preceding 
two weeks prior to screening. 
Updated Section 5.2 Exclusion 
Criteria section to include  
Documented (medical records) 
evidence of reversibility. 
Participants who are non-
compliant to their current COPD 
maintenance therapy for two 
weeks prior to screening (in the 
opinion of the investigator) will 
be excluded 
Update below exclusion criteria 
– removed reference to run-in 
and updated changes   
Pneumonia and/or moderate or 
severe COPD exacerbation that 
has not resolved at least 14 days 
prior to Screening and at least 30 
days following the last dose of 
oral/systemic corticosteroids (if 
applicable). In addition, any 
participant that experiences 
pneumonia and/or moderate or 
severe COPD exacerbation 
within the preceding two weeks 
prior to screening will be 
excluded 
5.3 Treatment Phase 
Criteria 
1. 
Compliance with current 
COPD maintenance therapy  
• Participants who are non-
compliant to their current COPD 
maintenance therapy for two weeks 
To ensure right patient is 
enrolled in the study 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
93 
 
prior to screening (in the opinion of 
the investigator) will be excluded 
 
2. Pneumonia and/or moderate or 
severe COPD exacerbation that has 
not resolved at least 14 days prior to 
Screening and at least 30 days 
following the last dose of 
oral/systemic corticosteroids and/or 
antibiotics (if applicable). In addition, 
any participant that experiences 
pneumonia and/or moderate or 
severe COPD exacerbation within 
the preceding two weeks prior to 
screening will be excluded. 
5.5 Screen Failures 
Pneumonia and/or moderate or 
severe COPD exacerbation that has 
not resolved at least 14 days prior to 
Screening and at least 30 days 
following the last dose of 
oral/systemic corticosteroids and/or 
antibiotics (if applicable). In addition, 
any participant that experiences 
pneumonia and/or moderate or 
severe COPD exacerbation within 
the preceding two weeks prior to 
screening will be excluded and may 
not be rescreened. and may not be 
rescreened. 
To ensure right patient/ 
participant is enrolled in the 
study 
6.8 Concomitant 
Therapy  
Removed text pertaining to run-in 
period. 
These changes are expected to 
simplify the study, reduce the 
patient burden without 
compromising the quality of the 
study. 
8.3 Adverse Events 
(AEs), Serious Adverse 
Events (SAEs) and 
Other Safety Reporting 
Updated section to align with local 
regulatory safety reporting 
procedures inputs from Named 
Safety Contact 
Removed Sentinel events. 
To align with local reporting 
procedures 
 
Sentinel Event Management 
process is now retired for studies 
9.2 Sample Size 
Determination 
 Updated the total number of 
screened subjects in the study  
Considering removal of run-in 
period, the sample size has been 
updated 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
94 
 
 
Amendment 2 30-MAR-2021 
Overall Rationale for the Amendment:  
Based on feedback and recommendations from the Subject Expert Committee (SEC) in 
India, the sample size of the study has been increased from 115 to 229 participants, to 
increase the probability of observing adverse events that make up the well-established 
safety profile of FF/UMEC/VI. In addition, the increase in sample size improves the 
precision of the estimate of the lung function endpoint, which is a secondary objective of 
the study.  
Approximately 306  participants will be screened in order to recruit 229 to the study treatment 
phase (assuming 25% screen failure rate) and achieve 220 evaluable participants at the 
end of the study (assuming 4% withdrawal from study treatment).  
 
9.3 Analysis sets 
Updated text for Screened 
population and added Enrolled 
population definition  
 
To align with GSK standard to 
present the subjects disposition 
data  
9.4.1Efficacy analyses 
Removed the change from baseline 
in trough FEV1 on Day 84 analysis 
Since, Day 84 visit is replaced to 
a telephonic visit and effect of 
FF/UMEC/VI on lung function is 
evaluated on Day 85  
All Relevant sections 
All sections relevant to the key 
changes were updated 
To align with the proposed 
changes to the protocol around. 
“run-in period” and Day 84 
related schedule or assessments 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
95 
 
Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of 
Activities (SoA) 
Removed blood pressure and 
temperature from footnote f.  
 
 
Removed exacerbation assessment 
from V1. 
This was a duplication, blood 
pressure and temperature are 
included in the vital signs 
assessments (footnote g). 
 
This was included in error, 
exacerbation history is 
collected as V1. 
3 Objectives and 
endpoints/Estimands 
Removed below text  
change from baseline in trough 
FEV1 on Day 84 (trough FEV1 on 
Day 84 is defined as the mean of 
the FEV1 values obtained prior to 
dosing on Day 84) 
mean change from baseline in 
trough FEV1 on Day 84 
Consistent with changes i.e. 
day 84 will now be telephone 
call  
9.2 Sample Size 
Determination 
The sample size text and associated 
probabilities table has been 
updated. 
To reflect the increase in 
sample size. 
 
10.5.6 Onset and 
Resolution of COPD 
Exacerbations 
Reference to participant diaries has 
been removed. 
This text was included in error.  
 
 
Amendment 1: 17 Nov 2020 
Overall Rationale for the Amendment:  
Following review by and presentation of the protocol to the Subject Expert Committee 
(SEC) in India, the SEC confirmed that the primary reason for requesting that GSK 
conduct a study, is to provide safety data that is representative of the COPD population in 
India. For this reason, the primary objective of the study has been amended. The primary 
objective of the study is to evaluate the safety profile of FF/UMEC/VI over 12 weeks. 
Lung function objectives are now included in the secondary objectives and associated 
endpoints. 
 
 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
96 
 
 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
2.1 Study Rational 
4.2 Scientific 
Rationale for Study 
Design 
Text has been updated to reflect that 
the collection of safety data is the 
primary reason for conducting the 
study. 
To ensure provision of safety 
data representative of the 
COPD population in India in 
line with local regulations 
1.1 Synopsis 
3 Objectives and 
Endpoints/Estimands 
The primary and secondary objectives 
and associated endpoints/estimands 
have been switched, to make safety 
the primary objective and efficacy 
(lung function) the secondary objective 
of the study.  
To ensure provision of safety 
data representative of the 
COPD population in India in 
line with local regulations 
9.1 Statistical 
Hypotheses 
The primary and secondary objectives 
have been updated to reflect that the 
analysis of safety data is the primary 
objective and the analysis of lung 
function data is the secondary 
objective of the study.  
Safety is now the primary 
objective of the study, and 
efficacy (lung function) is the 
secondary objective. 
9.2 Sample Size 
Determination 
This section has been updated to 
reflect that the sample size is now 
determined based on the calculation of 
the probability of observing an AE.   
Safety is now the primary 
objective of the study, and so 
the sample size is determined 
by a safety endpoint.  
9.4 Statistical 
Analyses 
Section 9.4.1.and Section 9.4.2. have 
been updated to define the statistical 
analyses as efficacy (Section 9.4.1) 
and safety (Section 9.4.2) and to 
reflect that safety is the primary 
objective of the study.   
Safety is now the primary 
objective of the study, and 
efficacy (lung function) is the 
secondary objective.  


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
97 
 
11. 
REFERENCES 
Aaron SD, Vandemheen KL, Fergusson D, Maltais F, Bourbeau J, Goldstein R, Balter M 
et al. (2007) Tiotropium in Combination with Placebo, Salmeterol, or Fluticasone–
Salmeterol for Treatment of Chronic Obstructive Pulmonary Disease A Randomised 
Trial. Ann Intern Med. 146:545-555. 
Cazzola M, Andò F, Santus P, Ruggeri P, Di Marco F, Sanduzzi A et al. A pilot study to 
assess the effects of combining fluticasone propionate/salmeterol and tiotropium on the 
airflow obstruction of patients with severe-to-very severe COPD. Pul Pharm Ther 2007 
20:556–561. 
Celli BR, MacNee W, ATS/ERS Task Force. Standards for the diagnosis and treatment of 
patients with COPD: A summary of the ATS/ERS position paper.  Eur Respir J 2004; 23: 
932-946. 
Christensson C, Thoren A, Lindberg B. Safety of inhaled budesonide: clinical 
manifestations of systemic corticosteroid-related adverse effects. Drug Safety. 
2008;31:965-988. 
Ferguson GT, Brown N, Compton C, Corbridge TC, Dorais K, Fogarty C, et al. Once-
daily single-inhaler versus twice-daily multiple-inhaler triple therapy in patients with 
COPD: lung function and health status results from two replicate randomized controlled 
trials. Respir Res 2020; 21:131 
Global Strategy for the Diagnosis, Management and Prevention of COPD, Global 
Initiative for Chronic Obstructive Lung Disease (GOLD) 2020. Available from: 
http://www.goldcopd.org/. 
Hanania, HA, Crater GD, Morris AN, Emmett AH, O'Dell DM, Niewoehner DE. 
Benefits of adding fluticasone propionate/salmeterol to tiotropium in moderate to severe 
COPD. Resp Med 2012; 106: 91-101. 
Jung KS, Park HY, Park SY, Kim SK, Kim YK, Shim JJ et al. Comparison of tiotropium 
plus fluticasone propionate/salmeterol with tiotropium in COPD: A randomised 
controlled study. Resp. Med. (2012) 106: 382-389 doi:10.1016/j.rmed.2011.09.004. 
Lehouck A, Boonen S, Decramer M, Janssens W. COPD, bone metabolism, and 
osteoporosis. Chest. 2011;139:648-657. 
Lipson DA, Barnacle H, Birk R, Brealey N, Locantore N, Lomas DA, et al. FULFIL Trial: 
Once-Daily Triple Therapy in Patients with Chronic Obstructive Pulmonary Disease. Am 
J Respir Crit Care Med 2017;10.1164/rccm.201703-0449OC. 
Lipson DA, Barnhart F, Brealey N, Brooks J, Criner GJ, Day NC, et al. Once-Daily Single-
Inhaler Triple versus Dual Therapy in Patients with COPD. N Engl J Med 2018; 378:1671-
1680. 


TMF-16036460 
CONFIDENTIAL 
 
 
212655 
 
98 
 
Lipson DA, Crim C, Criner GJ, Day NC, Dransfield MT, et al. Reduction in All-Cause 
Mortality With Fluticasone Furoate/Umeclidinium/Vilanterol in Patients With Chronic 
Obstructive Pulmonary Disease. Am J Respir Crit Care Med 2020; 10.1164/rccm.201911-
2207OC 
Miller MR, Hankinson J, Odencrantz J, Standardisation of spirometry. Eur Respir J. 
2005;26:319-388. 
Quanjer P, Stanojevic S, Cole T, Baur X, Hall G, Culver B, et al. Multi-ethnic reference 
values for spirometry for the 3-95-yr age range: The global lung function 2012 equations. 
Eur Respir J 2012;40:1324-1343. 
Siler, TM, Kerwin, E, Sousa, AR, Donald, A, Ali, R, Church, A. (2015) Efficacy and 
safety of umeclidinium added to fluticasone furoate/vilanterol in chronic obstructive 
pulmonary disease: results of two randomized studies. Respir Med. 109(9), 1155-1163. 
Weldon D. The effects of corticosteroids on bone growth and bone density. Ann. Allergy 
Asthma Immunol 2009;103:3-11. 
Welte T, Miravitlles M, Hernandez P, Eriksson G, Peterson S, Polanowski T, et al. Efficacy 
and Tolerability of Budesonide/Formoterol Added to Tiotropium in Patients with Chronic 
Obstructive Pulmonary Disease. Am J Respir Crit Care Med 2009; 180:741–750. 
Zhao Q, Meng M, Kumar R, Wu Y, Huang J, Lian N, et al. The impact of COPD and 
smoking history on the severity of COVID-19: A systemic review and meta-analysis. J 
Med Virol 2020;10.1002/jmv.25889.  
 


Signature Page for  212655 TMF-16036460 v1.0
Signature Page for TMF-16036460 v1.0
Reason for signing: Approved
Name:
Role: Approver
Date of signature: 03-May-2023 14:15:30 GMT+0000
PPD

SAP_001.pdf: 
Statistical Analysis Plan
Study ID:  212655
Official Title of Study: Phase IV, 12-week, Single Arm, Open Label 
Study Evaluating the Safety and Efficacy of Fixed Dose Triple 
Combination FF/UMEC/VI Administered Once Daily in the Morning 
Via a Dry Powder Inhaler in Participants With Chronic Obstructive 
Pulmonary Disease in India
NCT ID: NCT04923347
Date of Document: 25-April-2024


212655 
Statistical Analysis Plan 
 25-Apr-24 
V4.0 
 
 
 
 
 
 
CONFIDENTIAL 
Page 1 of 39 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Protocol title: Phase IV, 12-week, single arm, open label study evaluating the safety and efficacy of fixed 
dose triple combination FF/UMEC/VI administered once daily in the morning via a dry powder inhaler in 
participants with chronic obstructive pulmonary disease in India. 
Protocol number:  212655 
Applicable protocol version: Amendment 04 
Author: 
 Biostatistician 
Internal reviewer(s): 
Associate Principal 
Biostatistician 
Sponsor representative(s): 
Revision history: V3.0  
Date: 29-Feb-24 
 
The layout of this document is based on the Guideline on the International Conference on Harmonization 
(ICH E9). 
 
 
 
PPD
PPD
PPD


212655 
Statistical Analysis Plan 
 25-Apr-24 
V4.0 
 
 
 
 
 
 
CONFIDENTIAL 
Page 2 of 39 
TABLE OF CONTENTS 
Signature page ............................................................................................................................................ 5 
Glossary of abbreviations .......................................................................................................................... 6 
1. 
Overview ............................................................................................................................................... 7 
1.1 
Introduction ..................................................................................................................................... 7 
2. 
Trial objectives ....................................................................................................................................... 8 
3. 
Trial design .......................................................................................................................................... 10 
3.1 
Design overview ........................................................................................................................... 10 
3.2 
Schedule of events ....................................................................................................................... 10 
4. 
Changes/deviations from the planned analysis .................................................................................... 11 
5. 
Analysis populations ............................................................................................................................ 12 
5.1 
Screened population ..................................................................................................................... 12 
5.2 
Enrolled population (ENRL) .......................................................................................................... 12 
5.3 
Intended-to-Treat population (ITT) ................................................................................................ 12 
6. 
General considerations ........................................................................................................................ 13 
6.1 
Baseline ........................................................................................................................................ 13 
6.2 
Stratification .................................................................................................................................. 13 
6.3 
Statistical tests .............................................................................................................................. 13 
6.4 
Common calculations ................................................................................................................... 13 
6.5 
Software ....................................................................................................................................... 13 
7. 
Statistical considerations ..................................................................................................................... 14 
7.1 
Multicentre studies ........................................................................................................................ 14 
7.2 
Missing data ................................................................................................................................. 14 
8. 
Output presentations ........................................................................................................................... 15 
9. 
Participant disposition and withdrawal ................................................................................................. 16 
9.1 
Variables and derivations ............................................................................................................. 16 
9.2 
Analysis ........................................................................................................................................ 17 


212655 
Statistical Analysis Plan 
 25-Apr-24 
V4.0 
 
 
 
 
 
 
CONFIDENTIAL 
Page 3 of 39 
10. 
Participant demographics and other baseline characteristics ........................................................... 18 
10.1 
Variables and derivations ............................................................................................................. 18 
10.2 
Analysis ........................................................................................................................................ 18 
11. 
Exposure and Compliance to study treatment .................................................................................. 19 
11.1 
Variables and derivations ............................................................................................................. 19 
11.2 
Analysis ........................................................................................................................................ 20 
12. 
Medical and treatment history .......................................................................................................... 21 
12.1 
Variables and derivations ............................................................................................................. 21 
12.2 
Analysis ........................................................................................................................................ 21 
13. 
Prior, concomitant, and other medications ........................................................................................ 22 
13.1 
Variables and derivations ............................................................................................................. 22 
13.2 
Analysis ........................................................................................................................................ 22 
14. 
Adverse events ................................................................................................................................ 23 
14.1 
Variables and derivations ............................................................................................................. 23 
14.2 
Analysis ........................................................................................................................................ 24 
15. 
Vital Signs ........................................................................................................................................ 25 
15.1 
Variables and derivations ............................................................................................................. 25 
15.2 
Analysis ........................................................................................................................................ 25 
16. 
Physical and Oropharyngeal Examination ........................................................................................ 26 
16.1 
Variables and derivations ............................................................................................................. 26 
16.2 
Analysis ........................................................................................................................................ 26 
17. 
Primary Estimand ............................................................................................................................. 27 
17.1 
Incidence of adverse events (AE), serious adverse events (SAE) and adverse events of special 
interest (AESIs) during 12 weeks. ........................................................................................................... 27 
17.1.1 
Variables and derivations ...................................................................................................... 27 
17.1.2 
Primary estimand analyses .................................................................................................... 28 


212655 
Statistical Analysis Plan 
 25-Apr-24 
V4.0 
 
 
 
 
 
 
CONFIDENTIAL 
Page 4 of 39 
18. 
Secondary efficacy estimands .......................................................................................................... 29 
18.1 
Change from baseline in trough FEV1 on Day 85 and Day 28 ...................................................... 29 
18.1.1 
Variables and derivations ...................................................................................................... 29 
18.1.2 
Secondary estimand analyses ............................................................................................... 29 
19. 
Other assessments .......................................................................................................................... 31 
20. 
Revision history ................................................................................................................................ 32 
21. 
Appendix 1: Programming Conventions for Tables, Data Listings and Figures (TLFs) ..................... 33 
21.1 
Paper Size, Orientation and Margins ............................................................................................ 33 
21.2 
Fonts ............................................................................................................................................ 33 
21.3 
Header Information ....................................................................................................................... 33 
21.4 
Table and Data Listing Table, Listing and Figure (TLF) Conventions ............................................ 34 
21.4.1 
General.................................................................................................................................. 34 
21.4.2 
Univariate statistics ................................................................................................................ 34 
21.4.3 
Frequencies and percentages [n, (m) and %] ........................................................................ 35 
21.4.4 
Confidence intervals (CIs)...................................................................................................... 35 
21.4.5 
P-values ................................................................................................................................ 35 
21.4.6 
Ratios .................................................................................................................................... 35 
21.4.7 
Spacing ................................................................................................................................. 35 
21.4.8 
Missing values ....................................................................................................................... 35 
21.5 
Figure output conventions............................................................................................................. 36 
21.6 
Dates and times ............................................................................................................................ 36 
21.7 
Spelling format .............................................................................................................................. 36 
21.8 
Presentation of treatment group.................................................................................................... 36 
21.9 
Presentation of visits ..................................................................................................................... 36 
22. 
Appendix 2: Partial date conventions and Concomitant medication guidelines ................................. 37 
 


212655 
Statistical Analysis Plan 
 25-Apr-24 
V4.0 
 
 
 
 
 
 
CONFIDENTIAL 
Page 5 of 39 
 
Signature page 
 
Authored by: 
Biostatistician  
 
 
 
 
                      ___________
Premier Research (Group) India Pvt. Ltd 
 
 
 
              Signature and date 
 
 
Internal reviewer(s): 
Associate Principal Biostatistician                                                   ____________
Premier Research (Group) India Pvt. Ltd 
 
 
 
            Signature and date 
                   
 
 
Sponsor representative(s): 
                                          
____________________________ 
GlaxoSmithKline Research & Development Limited  
                       Signature and date 
 
 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


212655 
Statistical Analysis Plan 
 25-Apr-24 
V4.0 
 
 
 
 
 
 
CONFIDENTIAL 
Page 6 of 39 
Glossary of abbreviations 
 
ABBREVIATION 
DESCRIPTION 
AE 
Adverse event 
ATC 
Anatomical Therapeutic Chemical 
CI 
Confidence interval 
CV 
Coefficient of variation 
COPD 
Chronic Obstructive Pulmonary Disease 
COVID-19 
Coronavirus Disease 2019 
DBL 
Database lock 
eCRF 
Electronic case report form 
ECG 
Electrocardiogram 
ENRL 
Enrolled Population Set 
FEV1 
Forced expiratory volume in 1 second 
ICH 
International Conference on Harmonisation 
ITT 
Intended-to-Treat population  
MedDRA 
Medical dictionary for regulatory activities 
MMRM 
Mixed Model Repeated Measure 
N 
Sample size 
ODS 
Output delivery system 
PT 
Preferred term 
RTF 
Rich text format 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SOC 
System organ class 
TEAEs 
Treatment-emergent adverse events 
TLFs 
Tables, data listings and figures 
WHO 
World Health Organization 
WHO-DD 
WHO Drug Dictionary 
 
 
 


212655 
Statistical Analysis Plan 
 25-Apr-24 
V4.0 
 
 
 
 
 
 
CONFIDENTIAL 
Page 7 of 39 
1. 
Overview 
1.1 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical analyses that have 
been outlined within the Protocol Amendment No. 4 for 212655 dated 03 May 2023. The scope of this plan 
includes the final analysis, which will be executed by the Biostatistics department unless otherwise specified. 
Any post-hoc or unplanned analyses performed but not described in this SAP will be clearly described in the 
CSR. 
 


212655 
Statistical Analysis Plan 
 25-Apr-24 
V4.0 
 
 
 
 
 
 
CONFIDENTIAL 
Page 8 of 39 
2. 
Trial objectives 
The following objectives are those stated in the protocol. 
Objectives 
Estimands/ Endpoints 
Primary 
 
To evaluate the safety profile of 
FF/UMEC/VI over 12 weeks in 
patients from India 
The primary Estimand is defined by the 
following: 
 
 
Endpoint: incidence of adverse events 
(AE), serious adverse events (SAE) and adverse 
events of special interest 
(AESIs). 
 
 
Summary number and percentage of participants 
experiencing an AEs, SAEs and number and 
percentage of participants experiencing AESIs by 
system organ class and by preferred term. 
 
 
Population of interest: COPD patients in India. 
 
 
Key intercurrent events: discontinuation of 
treatment 
 
 
Strategy for intercurrent events: a While on 
Treatment strategy will be used for treatment 
discontinuation. This estimates the percentage of 
participants experiencing an AE or SAE while taking 
treatment. 
 
 
Participants that test positive for COVID-19 will 
immediately discontinue study treatment. Therefore 
COVID-19 will be included as the intercurrent event 
of study treatment discontinuation and will be 
handled with While on Treatment strategy for the 
primary estimand. 
 
 
A supplementary estimand will be defined using 
identical properties as for the primary estimand 
(summary measure, population of interest and key 
intercurrent events), however this supplementary 
estimand will report all AEs regardless of the 
discontinuation of study treatment. 
 


212655 
Statistical Analysis Plan 
 25-Apr-24 
V4.0 
 
 
 
 
 
 
CONFIDENTIAL 
Page 9 of 39 
 
Endpoints: 
 
Incidence of AEs, SAEs and AESIs 
 
 
Strategy for intercurrent events: 
 
Treatment policy strategy will be used for 
treatment discontinuation. This summary will 
therefore be inclusive of all on-treatment and 
post-treatment AEs. 
Secondary 
 
To evaluate the effect of FF/UMEC/VI on lung function 
The secondary Estimands are defined by the following: 
 
Endpoints: 
 
change from baseline in trough FEV1 on Day 85 
(trough FEV1 on Day 85 is defined as the mean 
of the FEV1 values obtained 24 hours after 
morning dosing on Day 84) 
 
change from baseline in trough FEV1 on Day 28 
(trough FEV1 on Day 28 is defined as the mean 
of the FEV1 values obtained prior to dosing on 
Day 28) 
 
Summary measure: 
 
mean change from baseline in trough FEV1 on 
Day 85 
 
mean change from baseline in trough FEV1 on 
Day 28 
 
 
Population of interest: COPD patients in India. 
 
 
Key intercurrent events: 
discontinuation of treatment 
 
 
Strategy for intercurrent events: a hypothetical 
strategy will be used for treatment discontinuation. 
This estimates the effect under the hypothetical 
scenario that participants had not discontinued 
treatment. 
 
 
Participants that test positive for COVID-19 will 
immediately discontinue study treatment. Therefore 
COVID-19 will be included as the intercurrent event 
of study treatment discontinuation and will be 
handled 
with 
hypothetical 
strategy 
for 
the 
secondary estimands. 
 
 


212655 
Statistical Analysis Plan 
 25-Apr-24 
V4.0 
 
 
 
 
 
 
CONFIDENTIAL 
Page 10 of 39 
3. 
Trial design 
3.1 
Design overview 
This is a phase IV, 12-week, single arm, multi-centre study evaluating single inhaler triple therapy 
(FF/UMEC/VI) once daily via the ELLIPTA inhaler.  
Figure 4.1.1 Study Design Schema 
 
*At day 84 (telephonic visit), participant will be instructed by the investigator telephonically to take the morning dose of study treatment/COPD 
medication, between 8am and 11am. 
Approximately 306 participants will be screened to enrolled 229 (assuming 25% screen failure) to the study 
treatment phase for achieving 220 evaluable participants at the end of the study (assuming 4% withdrawal 
from study treatment).  
At the start of the treatment period, participants will discontinue all existing COPD medications but may 
continue their study-supplied rescue salbutamol on an as-needed basis (rescue medication) throughout the 
study. 
Clinic Visits will occur at Pre-Screening (Visit 0), Screening (Visit 1), Start of Treatment (Day 1, Visit 2), Day 
28 (Visit 3), and Day 85 (Visit 5). Day 84 (Telephonic Visit 4) and Safety follow-up (Visit 6) conducted 1 week 
after completing the 12-week treatment period will be a telephone contact. Participants will sign an informed 
consent form (ICF) at a Pre-Screen or Screening Visit and will be assigned a participant identifier. Note: Visit 
0 and Screening (Visit 1) may occur on the same day based on discretion of the study participant and 
discretion of Investigator. 
3.2 
Schedule of events 
Refer to section 1.3 schedule of activities of the protocol. 
 
 
 


212655 
Statistical Analysis Plan 
 25-Apr-24 
V4.0 
 
 
 
 
 
 
CONFIDENTIAL 
Page 11 of 39 
4. 
Changes/deviations from the planned analysis 
The statistical analysis/methods as described in the protocol were adopted. For secondary endpoint analysis, 
as mentioned in the protocol, treatment policy shall be used as supplementary estimand for secondary 
endpoints if >5% of the ITT participants discontinued study treatment. However as per the discussion of 
study team analysis will be done using treatment policy (as supplementary estimands) even if 5% do not 
discontinue the study treatment. That is the condition of 5% will not be applicable. 
Any deviation from original statistical analysis plan will be described and justified in the SAP or final clinical 
study report. 
 
 


212655 
Statistical Analysis Plan 
 25-Apr-24 
V4.0 
 
 
 
 
 
 
CONFIDENTIAL 
Page 12 of 39 
5. 
Analysis populations 
The following sets will be used for the statistical analyses: 
5.1 
Screened population 
This population will include all participants for whom a record exists in the study database, including screen 
failures and any participant who was not screened but experienced an SAE between the date of informed 
consent and the planned date of the screening visit. 
5.2 
Enrolled population (ENRL) 
This population will include all participants who signed the informed consent form (ICF), and screen passed 
and who received study intervention or underwent a post-screening procedure.  
 
NOTE:  Participants screened but never enrolled into the study (Met eligibility but not needed) are excluded 
from the Enrolled Analysis set as they did not enter the study. 
 
5.3 
Intended-to-Treat population (ITT) 
This analysis population will include all participants who received at least one dose of study treatment. 
 


212655 
Statistical Analysis Plan 
 25-Apr-24 
V4.0 
 
 
 
 
 
 
CONFIDENTIAL 
Page 13 of 39 
6. 
General considerations 
6.1 
Baseline 
Baseline is defined as the last non-missing observation made prior to the first administration of study 
treatment 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.  Unless otherwise stated, if baseline data is missing no 
derivation will be performed and baseline will be set to missing.  
Participants who prematurely withdrew from study will not be replaced. For ECG, if the latest, non-missing 
pre-dose values is from triplicate, the subject level baseline is defined as the mean of triplicate baseline 
assessments.  
6.2 
Stratification 
This is single arm trial; hence, stratification is not required. 
6.3 
Statistical tests 
There will be no formal hypothesis testing for this study. Mixed model repeated measure model (MMRM) will 
be used for secondary efficacy analysis. 
6.4 
Common calculations 
For quantitative measurements, change from baseline will be calculated as: (Test value at Visit Day X – 
Baseline value), where the baseline value is defined as the last non-missing observation taken prior to first 
exposure to study treatment. 
6.5 
Software 
All analyses will be conducted using SAS® Version 9.4 or higher. 
 
 


212655 
Statistical Analysis Plan 
 25-Apr-24 
V4.0 
 
 
 
 
 
 
CONFIDENTIAL 
Page 14 of 39 
7. 
Statistical considerations 
7.1 
Multicentre studies 
This study will be conducted over multiple centres.   
7.2 
Missing data 
For efficacy data, missing values will be assumed to be missing at random (MAR) & no imputation will be 
performed. 
For adverse event, prior and concomitant medication data, partial date imputations will be performed where 
at least the year is provided. 
 
 


212655 
Statistical Analysis Plan 
 25-Apr-24 
V4.0 
 
 
 
 
 
 
CONFIDENTIAL 
Page 15 of 39 
8. 
Output presentations 
The templates provided in the separate output templates document describe the format and content for 
presentation of tables, listings, and figures (TLFs). 
For continuous measures, summary statistics will include number of participants (n), mean, standard 
deviation (SD), median, minimum, and maximum for both the actual and the change from baseline 
measurements. For categorical measures, summary statistics will include number of participants (n), 
frequency, and percentages. 
All percentages (%) for a specific summary are calculated using the total number of participants included in 
the relevant analysis population as the denominator, unless otherwise specified. 
 
 


212655 
Statistical Analysis Plan 
 25-Apr-24 
V4.0 
 
 
 
 
 
 
CONFIDENTIAL 
Page 16 of 39 
9. 
Participant disposition and withdrawal 
9.1 
Variables and derivations 
End of trial classifications are defined as follows: 
 
Screening failure:  
Participants who consent to participate in the clinical study but are not subsequently entered in the 
study & do not meet the criteria for participation in the study. 
 
 
Completed trial:  
All participants who completed the trial, as indicated in the end of study: Trial Disposition page of 
eCRF form, will be assumed to have completed trial. 
 
 
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. Site personnel or designee are expected to 
make diligent attempts to contact participants who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site. 
 
The following parameters will be summarized for the Participant’s disposition table as per eCRF: 
 
Number of screened participants 
 
Screening status 
o Entered into trial 
o Failed 
 
Screen failure reasons 
 
Number of participants in screened population 
 
Number of participants in enrolled population 
 
Number of participants in Intent-to-Treat population 
 
Number of treatment completed participants 
 
Number of study ongoing participants 
 
Number of treatment discontinued participants 
 
Reason of treatment discontinued participants 
 
Number of study completed participants 
 
Number of study withdrawn participants 
 
Reason of study withdrawn 


212655 
Statistical Analysis Plan 
 25-Apr-24 
V4.0 
 
 
 
 
 
 
CONFIDENTIAL 
Page 17 of 39 
Note- Subjects may have only one primary reason.   
Participants who completed the study, as indicated on the “End of Study: Trial Disposition” form of the 
(eCRF), will be assumed to have completed the study. And participants who completed the treatment, as 
indicated on the “Study Treatment Discontinuation: Treatment Discontinuation” form of the (eCRF), will be 
assumed to have completed the treatment. (i.e., participants who completed the trial will be counted under 
both the “completed treatment” and “completed trial” category). 
The following parameters will be summarized for the study discontinuation table as per eCRF Participant’s 
primary reason for discontinuation (reasons mentioned in eCRF end of study form) which is as follows: 
 
Adverse event 
 
Death 
 
Lost to follow-up 
 
Pregnancy 
 
Protocol violation 
 
Screen failure 
 
Consent withdrawal not due to an adverse event  
 
Study terminated by sponsor 
 
Migration from the study site such that follow up visits are not possible 
 
Other  
9.2 
Analysis 
 
 
Population: 
SCREENED and ITT 
 
Statistics: 
All above mentioned participant’s disposition parameters, will be summarised (frequency 
& percentage) and participants listing for all participants in the study population by 
participant number will be provided.  Screening status table will be present on screened 
population. 
The percentage calculation of End of study/treatment classification is based on ITT 
population. Protocol deviation data will be summarized and listed for ITT population. 
 


212655 
Statistical Analysis Plan 
 25-Apr-24 
V4.0 
 
 
 
 
 
 
CONFIDENTIAL 
Page 18 of 39 
10. 
Participant demographics and other baseline characteristics 
10.1 
Variables and derivations 
The following demographic and other baseline characteristics will be summarized: 
 
Age  
o Number of subjects by age continuous  
o Number of subjects enrolled by age categories: 
 18-64 Years 
 65-84 Years 
 ≥ 85 Years 
 Missing 
 
Gender 
 
Height (cm) 
 
Weight (kg) 
 
10.2 
Analysis 
 
 
Population: 
Table: ITT 
Listing: ITT 
Statistics: 
Baseline and Demographic variables will be summarized and listed by participant number. 
Overall summaries will include descriptive statistics for continuous measures (number of 
participants, mean, SD, median, minimum & maximum) and for categorical measures 
(frequency, percentages, and number of missing values). 
 


212655 
Statistical Analysis Plan 
 25-Apr-24 
V4.0 
 
 
 
 
 
 
CONFIDENTIAL 
Page 19 of 39 
11. 
Exposure and Compliance to study treatment 
11.1 
Variables and derivations  
The date of first study treatment administration will be derived as the first date of dosing from the treatment 
administration eCRF page. The date of last study treatment administration will be derived as the date of last 
dose of study treatment from the treatment administration eCRF page. If this date is not available, then the 
date of last administration will be derived as the last date of dosing from the treatment administration eCRF 
page. 
Interruptions, compliance, and dose changes will not be considered for calculating the duration of exposure, 
which will be derived as follows: 
 
𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑒𝑥𝑝𝑜𝑠𝑢𝑟𝑒 (𝑑𝑎𝑦𝑠) =
(𝐷𝑎𝑡𝑒 𝑜𝑓 𝑙𝑎𝑠𝑡 𝑠𝑡𝑢𝑑𝑦 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑎𝑑𝑚𝑖𝑛𝑖𝑠𝑡𝑟𝑎𝑡𝑖𝑜𝑛 –  𝐷𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑠𝑡𝑢𝑑𝑦 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡  
𝑎𝑑𝑚𝑖𝑛𝑖𝑠𝑡𝑟𝑎𝑡𝑖𝑜𝑛) +  1 
 
Treatment compliance: 
Treatment compliance will be assessed for the entire treatment period, as well as at visits 3 and 5.  
If a dose counter start count is missing, then it will be assumed to be 30 for the ELLIPTA DPI. If any dose 
counter stop is missing, then the number of doses taken will be set to missing for that inhaler. 
Number of doses of study drug taken by each participant from each inhaler = Dose counter start value – 
dose counter stop value. 
The derivation for treatment compliance during the treatment period is defined as the sum of (dose counter 
start value – dose counter stop value) over all inhalers dispensed to the participant and returned during the 
treatment period (i.e., from study Treatment administration to EOS/EW visit) and percentage compliance will 
be calculated as follows: 
 
𝑇𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑐𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒 (%) = 
𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑑𝑜𝑠𝑒𝑠 𝑟𝑒𝑐𝑒𝑖𝑣𝑒𝑑
𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑒𝑥𝑝𝑜𝑠𝑢𝑟𝑒 (𝑑𝑎𝑦𝑠)  𝑋 100 
Overall compliance will be categorized as follows: 
 
< 50 % 
 
≥50 % to < 80% 
 
≥80 % to < 95 % 
 
≥95 % to ≤105 % 
 
>105 % to ≤120 % 
 
>120 % 
If a participant receives a treatment other than the scheduled treatment during the study, the compliance will 
still be calculated using data from all containers received and overall exposure start and stop dates. 


212655 
Statistical Analysis Plan 
 25-Apr-24 
V4.0 
 
 
 
 
 
 
CONFIDENTIAL 
Page 20 of 39 
11.2 
Analysis 
 
 
 
Population: 
Table: ITT 
Listing: ITT 
 
Statistics: 
Overall treatment exposure and compliance to study medication will be summarized by 
using continuous measures (number of participants, mean, SD, median, minimum & 
maximum) and Overall compliance categorized by count and percentage. 
The visit wise compliance counts will be presented for Visit 3, Visit 5 and End of 
Treatment.  
The listing will be presented by participant number. 
 
 


212655 
Statistical Analysis Plan 
 25-Apr-24 
V4.0 
 
 
 
 
 
 
CONFIDENTIAL 
Page 21 of 39 
12. 
Medical and treatment history 
12.1 
Variables and derivations 
Medical history will be coded using the MedDRA central coding dictionary Version 26.0 or higher. 
The following parameters will be summarised for the participant’s medical history: 
 
Number of participants with at least one medical history 
 
Number of participants for each medical history by SOC and PT 
12.2 
Analysis 
 
 
 
 
 
Population: 
Table: ITT 
Listing: ITT 
Statistics: 
Medical history will be summarised by SOC and PT (frequency and percentages) for table 
and listing also be presented. 


212655 
Statistical Analysis Plan 
 25-Apr-24 
V4.0 
 
 
 
 
 
 
CONFIDENTIAL 
Page 22 of 39 
13. 
Prior, concomitant, and other medications 
13.1 
Variables and derivations 
All medications will be coded using the WHO-DD, dated March, 1, 2023 or higher.  
Prior medications are defined as any medication taken prior to first administration of the study treatment. 
‘Concomitant medications’ are defined as any medication taken after or on the day of first administration of 
the study treatment.  
In section 22 Appendix 2 the algorithm is given for calculation of partial date imputation   for prior and 
concomitant medications, and it will be used for partially missing prior and concomitant medications, start 
and end date imputation. 
The following parameters will be summarised as prior and concomitant medications separately: 
 
Number of participants with at least one prior and concomitant medication 
 
Number of participants for each prior and concomitant medication by ATC and PT. 
13.2 
Analysis 
 
 
Population: 
Table: ITT 
Listing: ITT 
Statistics: 
Prior and concomitant medication will be summarised by ATC and PT (frequency and 
percentages) for table and listing also be presented. 


212655 
Statistical Analysis Plan 
 25-Apr-24 
V4.0 
 
 
 
 
 
 
CONFIDENTIAL 
Page 23 of 39 
14. 
Adverse events 
14.1 
Variables and derivations 
Adverse Events (AEs) will be coded using standard GSK dictionary, MedDRA central coding dictionary, 
version 26.0 or higher. 
For the definition of Adverse events (AE) and Serious adverse event (SAE) refer to the protocol section 10.6. 
The following parameters will be summarised for the participant’s adverse events as mentioned in eCRF: 
 
Number of participants with at least one AEs pre treatment 
 
Number of participants with at least one AE during treatment 
 
Number of participants with at least one AE post treatment 
 
Number of participants with at least one Drug related AE. 
 
Number of participants with at least one serious AEs 
 
Number of participants with at least one Drug related serious AEs 
 
Number of participants with at least one AESI 
 
All Adverse Events 
 
Ongoing AEs 
 
AEs by Severity 
 
AEs by Outcome 
 
AEs by Action Taken with Study treatment 
 
AEs leading to Death 
Derivations: 
 
The question “Adverse event related to study treatment” is answered “Yes,” then respective AEs will 
be considered as treatment related AE. 
 
The question “Is the adverse event serious” is answered as “Yes” then respective AE will be 
considered as serious AEs. 
 
The question “Is the adverse event serious” is answered as “Yes” and the question “Adverse event 
related to study treatment” is answered “Yes,” then respective AEs will be considered as treatment 
related SAEs. 
 
If seriousness criteria are “DEATH” and outcome of adverse event is “FATAL” then we will consider 
it as AE leading to death. 
 
Participant’s primary reason for discontinuation captured in the eCRF page, study treatment 
discontinuation is “ADVERSE EVENT” then we will consider it as AE leading to early withdrawal from 
study. 
 
Pre- Treatment AEs: AE Start Date < Study Treatment Start Date 
 
Post- Treatment AE’s: AE Start Date > Study Treatment Stop Date  


212655 
Statistical Analysis Plan 
 25-Apr-24 
V4.0 
 
 
 
 
 
 
CONFIDENTIAL 
Page 24 of 39 
 
During Treatment AE’s: Treatment Start Date ≤ AE Start Date ≥ Treatment Stop Date 
In section 22 Appendix 2 the algorithm is given for calculation of partial date imputation for Adverse 
Events, and it will be used for partially missing AE, start and end date imputation.  
14.2 
Analysis 
 
 
Population: 
Table: ITT 
Listing: ITT 
Statistics: 
An overall summary will be presented as the number of participants within each of the 
event type categories described in the above section, including the incidence of AEs by 
preferred term (PT) and System organ class (SOC) sorted by decreasing frequency within 
the SOC & PT. Number and proportion of participants with AEs will be presented. Both 
number of participants, number of event (One participant may be counted more than once) 
and percentage will be provided.  
The summary of drug related adverse events, serious adverse events, serious drug related 
adverse events, Adverse Events Leading to Permanent Discontinuation of Study 
Treatment or Withdrawal from Study and Adverse events of Special interest   will be 
presented by SOC and PT also summary of drug-related AEs by SOC, PT and maximum 
intensity will be provided.  
The most common reported (≥ 3%) AEs and SAEs will be summarized by overall 
frequency. The Adverse Event will be summarized and presented in data listings using ITT 
population with all AEs (including coding details SOC and PT only) and participants with 
SAEs, AESIs, Fatal AEs and events resulting in study discontinuation will be listed 
separately by participant’s number.  
Note: If there are uncoded adverse events, then the uncoded category will be added in the 
AEs by SOC/PT summary tables. 


212655 
Statistical Analysis Plan 
 25-Apr-24 
V4.0 
 
 
 
 
 
 
CONFIDENTIAL 
Page 25 of 39 
15. 
Vital Signs 
15.1 
Variables and derivations 
The following vital signs parameters will be reported for this study: 
 
Temperature (c) 
 
Weight (Kgs) 
 
Systolic Blood Pressure (mmHg) 
 
Diastolic Blood Pressure (mmHg) 
 
Pulse (beats per minute) 
15.2 
Analysis 
 
Population: 
Table: ITT 
Listing: ITT 
Statistics: 
Summaries of vital parameters will include descriptive statistics at each assessment for 
the actual and change from baseline (number of participants, mean, SD, median, 
minimum & maximum) (for quantitative measurements). Listing will be presented by 
participant, timepoint and parameter. 


212655 
Statistical Analysis Plan 
 25-Apr-24 
V4.0 
 
 
 
 
 
 
CONFIDENTIAL 
Page 26 of 39 
16. 
Physical and Oropharyngeal Examination 
16.1 
Variables and derivations 
The following physical examination parameters will be reported for this study: 
 
Skin 
 
Cardiovascular 
 
Respiratory 
 
Gastrointestinal 
 
Neurology 
16.2 
Analysis 
 
 
Population: 
Table: ITT 
Listing: ITT 
Statistics: 
The physical examination & oropharyngeal assessment will be presented in data listings 
and summarised as number and percentage (n and %) at all assessment timepoints. 
Physical & oropharyngeal examination data will be classified as normal & abnormal. 


212655 
Statistical Analysis Plan 
 25-Apr-24 
V4.0 
 
 
 
 
 
 
CONFIDENTIAL 
Page 27 of 39 
17. 
Primary Estimand 
17.1 
Incidence of adverse events (AE), serious adverse events (SAE) and adverse events of 
special interest (AESIs) during 12 weeks. 
As per the protocol, estimand will be defined as follows: 
 
Summary measure: Number and percentage of participants experiencing an AEs, SAEs and number 
and percentage of participants experiencing AESIs by system organ class and by preferred term. 
 
Population of interest: COPD patients in India. 
 
Key intercurrent events (ICEs): Discontinuation of treatment (for any reason). 
 
Strategy for intercurrent events: A while on treatment strategy will be used for treatment 
discontinuation. This estimates the percentage of participants experiencing an AE or SAE while taking 
treatment. Participants that test positive for COVID-19 will immediately discontinue study treatment. 
Therefore COVID-19 will be included as the intercurrent event of study treatment discontinuation and 
will be handled with while on treatment strategy for the primary estimand. 
 
Supplementary Estimand: Incidence of adverse events (AE), serious adverse events (SAE) and 
adverse events of special interest (AESIs). 
 
 
A supplementary estimand will be defined using identical properties as for the primary estimand 
(summary measure, population of interest and key intercurrent events), however this supplementary 
estimand will report all AEs regardless of the discontinuation of study treatment. 
 
Strategy for intercurrent events: Treatment policy strategy will be used for treatment 
discontinuation. This summary will therefore be inclusive of all on-treatment and post-treatment 
AEs. 
17.1.1 
Variables and derivations 
For the definition of Adverse events (AE) and Serious adverse event (SAE) refer to the protocol section 10.6. 
Derivations: 
 
The question “Is the adverse event serious” is answered as “Yes” then respective AE will be 
considered as serious AEs. 
 
The question “Is this event an adverse event of special interest (AESI)” is answered as “Yes” then 
respective AE will be considered as AESI. 
 
 


212655 
Statistical Analysis Plan 
 25-Apr-24 
V4.0 
 
 
 
 
 
 
CONFIDENTIAL 
Page 28 of 39 
17.1.2 
Primary estimand analyses 
Population: 
Table: ITT 
Listing: NA 
Statistics: 
 
While on-treatment Policy: Values of the variable up to the time of the intercurrent event. 
This strategy summarises the variable while the patient actually receives their randomised 
treatment. An example of use of this strategy is the standard approach to safety data. 
Adverse events in efficacy trials are usually summarised over the period while a subject 
is receiving the randomised treatment. 
The primary estimand analysis will be performed for participants experiencing an AE, 
AESI & SAE while taking treatment. It will follow while on treatment policy.  But if a subject 
discontinues treatment during this period of Visit 2-Visit 4 then values only before 
discontinuation point will be considered. 
Treatment Policy:  Actual values of the variable regardless of whether the intercurrent 
event has occurred. 
This approach requires collection of data after the intercurrent event of interest (e.g. 
continued collection if a patient discontinues treatment) and corresponds to a full ITT 
approach. If the patient also withdraws from the study, then this becomes a missing data 
problem. The supplementary estimand analysis will be performed for participants 
experiencing AE, AESI & SAE while taking treatment and post treatment. It will follow 
treatment policy.  
Summary will be presented as the number of participants experiencing AE, AESI & SAE 
including the incidence of AEs by alphabetically preferred term (PT) sorted by decreasing 
frequency within the system organ class (SOC). Number and proportion of participants 
with AEs will be presented. Both number of participants, number of event (One participant 
may be counted more than once) and percentage will be provided.  
Note: If there are uncoded adverse events, then the uncoded category will be added in 
the AEs by SOC/PT summary tables. 
For the supplementary analysis refer to the SAP section 14. 


212655 
Statistical Analysis Plan 
 25-Apr-24 
V4.0 
 
 
 
 
 
 
CONFIDENTIAL 
Page 29 of 39 
18. 
Secondary efficacy estimands 
18.1 
Change from baseline in trough FEV1 on Day 85 and Day 28 
As per the protocol, estimand will be defined as follows: 
 
Summary measure: Mean change from baseline in trough FEV1 on Day 85. 
                                  Mean change from baseline in trough FEV1 on Day 28.  
 
Population of interest: COPD patients in India. 
 
Key intercurrent events (ICEs): Discontinuation of treatment. 
 
Strategy for intercurrent events: A hypothetical strategy will be used for treatment discontinuation. 
This estimates the effect under the hypothetical scenario that participants had not discontinued 
treatment. Participants   that test positive for COVID-19 will immediately discontinue study treatment. 
Therefore COVID-19 will be included as the intercurrent event of study treatment discontinuation and 
will be handled with hypothetical strategy for the secondary estimands. 
 
Supplementary Estimands:  
Mean change from baseline in trough FEV1 on Day 85.  
Mean change from baseline in trough FEV1 on Day 28. 
A supplementary estimand will be defined using identical properties (summary measure, population 
of interest and key intercurrent events), however this supplementary estimand will report the actual 
values recorded regardless of the discontinuation of study treatment.  
 
Strategy For ICE under Supplementary Estimands: A supplementary estimand will be estimated 
using treatment policy strategy for the intercurrent event of treatment discontinuation unrelated to the 
COVID-19 pandemic and using hypothetical strategy for the intercurrent event of treatment 
discontinuation related to the COVID-19 pandemic.  
 
Treatment Policy:  Actual values of the variable regardless of whether the intercurrent event has 
occurred. This approach requires collection of data after the intercurrent event of interest (e.g. 
continued collection if a patient discontinues treatment) and corresponds to a full ITT approach. If the 
patient also withdraws from the study, then this becomes a missing data problem. 
18.1.1 
Variables and derivations 
 
Trough FEV1 on Day 85 is defined as the mean of the FEV1 values obtained 24 hours after morning 
dosing on Day 84. 
 
Trough FEV1 on Day 28 is defined as the mean of the FEV1 values obtained prior to dosing on Day 
28 
18.1.2 
Secondary estimand analyses 
Population: 
Table: ITT 
Listing: ITT 
Statistics: 
The mean change in FEV1 values from baseline to Day 28 and Day 85 will be summarized 
using descriptive statistics (mean, median, SD, minimum, maximum, and number with 
missing values).  
Only scheduled spirometry observations will be used for the analysis and unscheduled 
spirometry observations will be presented in data listing. 


212655 
Statistical Analysis Plan 
 25-Apr-24 
V4.0 
 
 
 
 
 
 
CONFIDENTIAL 
Page 30 of 39 
 
 
The MMRM model will be used for analysis of the change in FEV1 values from baseline 
to Day 28 and Day 85. Least-square means, standard error, 95% CI derived from the 
analysis model will be displayed by day for two models within the MMRM output. The first 
model will include change from baseline in FEV1 values as response variable, FEV1 
values at baseline and day as covariates and an interaction between FEV1 values at 
baseline and day.  Day will be specified as the repeated effect, and with SUBJECT option 
to account for the repeated measures within subjects. OM will be used in lsmeans 
statement. An unstructured covariance structure will be used to model the within-
participant variability. If this analysis fails to converge, the following covariance structures 
will be tested in order:  
1. Toeplitz with heterogeneity 
2. Autoregressive with heterogeneity, by day 
3. Compound symmetry with heterogeneous variances, by day  
4. Toeplitz 
5. Autoregressive 
6. Compound symmetry without heterogeneous variances, by day 
 
The first covariance structure that converges will be used. The Kenward-Roger 
approximation will be used to estimate denominator degrees of freedom. Significance 
tests will be based on least-squares mean using Type III sum of squares. 
The second model will use absolute FEV1 values as response variable, whilst all other 
components remain the same as described above.  
Trough FEV1 data collected up to the time of treatment discontinuation will be used in the 
analysis. This estimates effect under the hypothetical scenario that participants do not 
discontinue treatment. Trough FEV1 collected after treatment discontinuation will be set 
to missing. Missing data will be assumed to be missing at random (MAR). 
A supplementary estimand will be estimated using treatment policy strategy for the 
intercurrent event of treatment discontinuation unrelated to the COVID-19 pandemic and 
using hypothetical strategy for the intercurrent event of treatment discontinuation related 
to the COVID-19 pandemic.  
 


212655 
Statistical Analysis Plan 
 25-Apr-24 
V4.0 
 
 
 
 
 
 
CONFIDENTIAL 
Page 31 of 39 
19. 
Other assessments 
The following assessments will only be presented in data listings for the ITT population: 
• Chest X-ray 
• Urine Pregnancy test 
• Inclusion/Exclusion criteria 
• ECG 
• COPD assessment test 
• COVID-19 test 
• Exacerbation assessment 


212655 
Statistical Analysis Plan 
 25-Apr-24 
V4.0 
 
 
 
 
 
 
CONFIDENTIAL 
Page 32 of 39 
20. 
Revision history 
Version 
Date 
Change 
1.0 
06-Jun-2023 
Initial Version 
2.0 
18-Aug-2023 
Listings’ population has been changed ENRL to ITT for section 10.2, 
11.2, 12.2, 13.2, 14.2, 15.2, 16.2, 18.1.2 and 19. 
3.0 
29-Feb-2024 
As per updated eCRF and sponsor requirement, drug compliance 
summary analysis added in section 11. 
In section 18.1.2. clarify about the unscheduled visit observations for 
spirometry test. 
4.0 
25-Apr-2024 
Updated section 18.1.2 to provide clarification on inputs to the 
MMRM model. 
 
 
 


212655 
Statistical Analysis Plan 
 25-Apr-24 
V4.0 
 
 
 
 
 
 
CONFIDENTIAL 
Page 33 of 39 
21. 
Appendix 1: Programming Conventions for Tables, Data Listings and Figures (TLFs) 
21.1 
Paper Size, Orientation and Margins 
The margin, page size and line size specifications as stipulated in Table 23.1 will be used for the presentation 
of all TLFs. 
Table 23.1: Output margin, page size and line size specifications 
 
Landscape 
Portrait 
Margins (Inches): 
Top  
Bottom 
Left 
Right 
 
1.25 
1.25 
0.87 
0.87 
 
1 
1 
1.25 
1 
Header (Inches) 
0.5 
0.5 
Footer (Inches) 
0.5 
0.5 
SAS® specifications: 
PAGESIZE 
LINE SIZE 
 
46 
134 
 
67 
93 
21.2 
Fonts 
The font type “Courier New” should be used as default for tables and data listings, with a font size of 10 The 
font color should be black. No bolding, underlining and italics are permitted. 
Figures should have a default font of “Times Roman,” “Helvetica” or “Courier New.” 
21.3 
Header Information 
Headers should be defined as follows: 
 
The header should be placed at the top of the page (same place on each page). 
 
The sponsor’s name should appear in row 1, left-aligned. 
 
The word “CONFIDENTIAL” should appear in row 1, right aligned. 
 
The protocol number should appear in row 2, left-aligned. 
 
The page identification in the format Page X of Y (where Y is the total number of pages for the TLF) 
should appear in row 2, right aligned. 
 
The TLF identification number should appear in row 3, centered. 
 
The TLF title should start in row 4, centered. 


212655 
Statistical Analysis Plan 
 25-Apr-24 
V4.0 
 
 
 
 
 
 
CONFIDENTIAL 
Page 34 of 39 
 
The TLF population should appear in row 5, centered. The population should be spelled out in full, e.g., 
Safety analysis population in preference to Safety analysis population. 
 
Row 6 should be a continuous row of underscores (‘_’) (the number of underscores should equal the line 
size). 
 
Row 7 should be a blank line. 
 
Mixed case should be used for titles. 
 
Titles should not contain quotation marks or footnote references. 
 
The column headings should be underlined with a row of underscores (‘_’). 
 
Column headings spanning more than one column should be underlined and have underscores on either 
side of the title and should be centered. 
 
Column headings containing numbers should be centered. 
 
Column headings should be in mixed case. 
 
In general, the analysis population count should appear in the column header in the form “(N=XX).” 
21.4 
Table and Data Listing Table, Listing and Figure (TLF) Conventions 
21.4.1 
General 
 
The first row in the body of the table or data listing should be blank. 
 
The left-hand column should start in Column 1. No indenting or centering of the TLF should occur. 
 
Rounding should be done with the SAS® function ROUND. 
 
Numerical values in tables should be rounded, not truncated. 
 
Numerical values should be decimal point aligned. 
 
Text values should be left aligned. 
 
The first letter of a text entry should be capitalized. 
 
The study drug should appear first in tables with treatment group as columns. 
 
All variables contained on the eCRF (which have data present) should appear in the data listings, along 
with all derived data appearing in the corresponding tables. 
 
The width of the TLF should match the line size. 
21.4.2 
Univariate statistics 
 
Statistics should be presented in the same order across tables (i.e., n, mean, SD, minimum, median and 
maximum). 


212655 
Statistical Analysis Plan 
 25-Apr-24 
V4.0 
 
 
 
 
 
 
CONFIDENTIAL 
Page 35 of 39 
 
If the original data has N decimal places, then the summary statistics should have the following decimal 
places: 
o Minimum and maximum = N  
o Mean and Percentiles (e.g., median, Q1 and Q3) =N + 1. 
o SD = N + 2. 
21.4.3 
Frequencies and percentages [n, (m) and %] 
Percent values should be reported inside parentheses with percent symbol, no blank spaces are included 
within the parentheses,  e.g., "(25%)." percentages greater than 0 and less than 1 as "<1%" and those greater 
than 99 and less than 100 as ">99%". Percentages exactly equal to 0% will be shown as blanks in the table. 
So, counts of 0 will be presented as 0 and not as 0 (0%).   
21.4.4 
Confidence intervals (CIs) 
 
CIs should be presented with one additional decimal place as that of the raw data, and SDs and standard 
errors (SEs) with two additional decimal places as that of the raw data. 
 
Confidence intervals are displayed within round brackets and separated by a comma. The lower limit is 
presented first, and the upper limit is presented second. The confidence interval is placed either beside 
or below the corresponding estimate. The estimate and the confidence limits are presented using the 
same degree of precision. 
21.4.5 
P-values 
The precision of calculated p-values is expressed to one more decimal place than the precision of the 
significance criteria. For example, if the significance threshold is 0.05, the calculated p-values are expressed 
to three decimal places; if the significance threshold is 0.025, the calculated p-values are expressed to four 
decimal places. If the p-value is smaller than can be represented in this number of decimal places, use a "<" 
with the smallest printable value (e.g. when presenting p-values to three decimal places and a calculated p-
value is less than 0.001, it is reported as "<0.001," rather than "0.000"). Avoid rounding p-values to the 
nearest decimal place. Instead use the most conservative value (e.g. ceiling) based on the test being 
performed. 
21.4.6 
Ratios 
 
Ratios should be reported with one additional decimal place as that of the raw data. 
21.4.7 
Spacing 
 
There should be a minimum of 1 blank space between columns (preferably 2). 
21.4.8 
Missing values 
 
A “0” should be used to indicate a zero frequency. 


212655 
Statistical Analysis Plan 
 25-Apr-24 
V4.0 
 
 
 
 
 
 
CONFIDENTIAL 
Page 36 of 39 
 
A blank will be used to indicate missing data in data listings. 
21.5 
Figure output conventions 
Figures should be provided in RTF files using the SAS® Output Delivery System (ODS). 
21.6 
Dates and times 
Depending on data available, dates and times will take the form ddMMMyyyy and hh: mm. 
21.7 
Spelling format 
The spelling format to be used is English US.  
21.8 
Presentation of treatment group 
FF/UMEC/VI 
21.9 
Presentation of visits 
 
Pre-screen (Visit 0) 
 
Screen (Visit 1) 
 
Visit 2 
 
Visit 3 
 
Telephonic (Visit 4) 
 
Visit 5 
 
Safety follow-up (Visit 6) 
 
 
 


212655 
Statistical Analysis Plan 
 25-Apr-24 
V4.0 
 
 
 
 
 
 
CONFIDENTIAL 
Page 37 of 39 
22. 
Appendix 2: Partial date conventions and Concomitant medication guidelines 
The whole missing date will not be imputed for this study; only partial date imputation will be performed. 
Conventions pertaining to partial dates are presented. 
Table: Algorithm for partial date imputation 
 
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 in overall survival 
analysis dataset. 
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: 
 
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: 
 
If year of start date = year of study intervention 
start date, then 


212655 
Statistical Analysis Plan 
 25-Apr-24 
V4.0 
 
 
 
 
 
 
CONFIDENTIAL 
Page 38 of 39 
Element 
Reporting Detail 
 
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). 
Missing end 
day and month 
No Imputation 
Completely 
missing 
start/end date 
No imputation 
Concomita
nt 
Medication
s 
 
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: 
 
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: 
 
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. 


212655 
Statistical Analysis Plan 
 25-Apr-24 
V4.0 
 
 
 
 
 
 
CONFIDENTIAL 
Page 39 of 39 
Element 
Reporting Detail 
 
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).  
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 
 
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 screening 
visit. 
 
All participants with imputed age of 39 or 40 years will be source data 
verified, and presence/ absence of protocol deviation on the inclusion 
criteria #1 will be taken into consideration in the derivation for the 
analysis variable age. 
Birth date will be presented in listings as ‘YYYY’.