Conditions: Pulmonary Disease, Chronic Obstructive
Keywords: Umeclidinium Lung function RESPIMAT Chronic obstructive pulmonary disease Triple Therapy Vilanterol HANDIHALER Tiotropium Fluticasone furoate
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 800
Healthy volunteers: no

Brief summary:
COPD is a progressive disease characterized by increasing obstruction to airflow and the progressive development of respiratory symptoms including chronic cough, increased sputum production, dyspnea and wheezing. Once-daily triple therapy of an Inhaled Corticosteroid/ Long-acting Muscarinic Receptor Antagonists/ Long Acting Beta-Agonist (ICS/LAMA/LABA) that is combination of FF/UMEC/VI in a single device is being developed with the aim of providing a new treatment option for the management of advanced COPD. The primary purpose of this study is to evaluate lung function and health related quality of life (HRQoL) after 84 days of treatment with a single inhaler triple therapy combination of FF/ UMEC/VI once daily via the ELLIPTA® dry powder inhaler (DPI) compared with tiotropium once daily via HANDIHALER®, in subjects with COPD. Subjects will be randomized 1:1 to receive FF/UMEC/VI or tiotropium in the morning for 84 days. Subjects will also receive albuterol/salbutamol as a rescue therapy throughout the study. Approximately 848 subjects with advanced COPD will be enrolled in the study. The total study duration will be approximately 17 weeks including, 4-week run-in period, 12-week treatment period and a 1-week follow-up period. ELLIPTA is a registered trademark of GlaxoSmithKline (GSK) group of companies. HANDIHALER and RESPIMAT are registered trademarks of Boeringher Ingelheim.

Detailed description:

Arms:
arm 1: Eligible subjects will receive FF/UMEC/VI at a dose of 100/62.5/25 microgram (mcg) administered once daily in the morning via ELLIPTA along with placebo to match tiotropium administered once daily in the morning via HANDIHALER. Subjects will self-administer 4 puffs of rescue medication (Albuterol/salbutamol) via metered dose inhaler (MDI). arm 2: Eligible subjects will receive Tiotropium at a dose of 18 mcg administered once daily in the morning via HANDIHALER along with placebo to match FF/UMEC/VI administered once daily in the morning via ELLIPTA. Subjects will self-administer 4 puffs of rescue medication (Albuterol/salbutamol) via MDI.

Interventions: intervention 1: FF/UMEC/VI intervention 2: Tiotropium intervention 3: Albuterol/salbutamol intervention 4: Placebo to match FF/UMEC/VI intervention 5: Placebo to match tiotropium intervention 6: ELLIPTA inhaler intervention 7: HANDIHALER intervention 8: MDI
Intervention descriptions: intervention 1: A single inhaler triple therapy of FF/UMEC/VI will be provided via ELLIPTA DPI. FF/UMEC/VI will be available as dry white powder with dosing strengths of 100/25/62.5 mcg per blister. intervention 2: Tiotropium will be provided as a hard gelatin capsule for oral inhalation containing 18 mcg tiotropium bromide blended with lactose, administered via HANDIHALER DPI. intervention 3: Albuterol/salbutamol will be provided as an inhalation via MDI with a spacer or nebules and will be given as a rescue medication throughout the study. intervention 4: Placebo matching FF/UMEC/VI will be available as a dry white powder of lactose or magnesium stearate, administered via ELLIPTA DPI. intervention 5: Placebo will be given as hard gelatin capsule for oral inhalation containing lactose, administered via HANDIHALER DPI. intervention 6: ELLIPTA DPI will contain two individual blister strips with 30 blisters per strip. FF/UMEC/VI and placebo to match FF/UMEC/VI will be administered to the subjects using ELLIPTA DPI. intervention 7: Tiotropium and placebo to match tiotropium will be administered to the subjects using HANDIHALER DPI. intervention 8: Albuterol/salbutamol will be provided as a rescue medication throughout the study using MDI.

Protocol document:
Prot_000.pdf: 
2017N323364_01
CONFIDENTIAL
GlaxoSmithKline group of companies
207626
1
TITLE PAGE
Protocol Title: A Phase IV, 12 week, randomised, double-blind, double-dummy study to 
compare single inhaler triple therapy, fluticasone furoate/umeclidinium/vilanterol
(FF/UMEC/VI), with tiotropium monotherapy based on lung function and symptoms in 
participants with chronic obstructive pulmonary disease
Protocol Number: 207626/ 01
Short Title: A randomised study, comparing FF/UMEC/VI single inhaler triple therapy
versus tiotropium monotherapy in participants with chronic obstructive pulmonary 
disease
Compound Number:
GSK573719+GW642444+GW685698 (GSK2834425)
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information can be found in the Study 
Reference Manual
Regulatory Agency Identifying Number(s): IND number 114873, EudraCT Number
2017-001190-16
Approval Date: 17-JUL-2018
Copyright 2018 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
2019N398531_00


 
2019N398531_00
PPD
PPD


2017N323364_01
CONFIDENTIAL
207626
3
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 1
17-Jul-2018
Original Protocol
11-Oct-2017
Amendment 1 17-July-2018
Overall Rationale for the Amendment: This amendment is required to update the QTc 
stopping criteria to that which was used in the Phase III Trelegy registration studies.  In 
addition, a section describing Smoking Cessation Counselling has been added as does a 
corresponding assessment at the end of study (Visit 4).  Clarified that run-in treatment 
should be collected at Visit 2, study treatment at Visit 3, and albuterol/salbutamol at Visit 
5.  Also, wording regarding suggested order for assessments and procedures has been 
added to the end of the Schedule of Activities section.  Removed reference to Fridericia 
formula in calculation of QTc.  Clarification regarding collecting the CAT assessment 
questionnaire prior to the SGRQ-C has also been provided along with clarification that 
vital signs should be collected before the ECG and prior to spirometry.  Also added 
clarification that CAT and SGRQ-C will both be collected at Visit 3 to mirror the SoA.  
Corrected reporting time regarding pregnancy.  Finally, added wording to Genetics 
Appendix 9 regarding withdraw process and sample destruction process.
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
4
Section # and 
Name
Description of Change
Brief Rationale
Table of Contents
Added Smoking Cessation 
Counselling Section (9.10)
Explained the reasoning for the 
Smoking Cessation Counselling 
and to clarify the visits when this 
counselling will be provided
Section 2
Schedule of 
Activities (SOA) 
Added Smoking Cessation 
Counselling to Visit 4
Added collecting run-in 
treatment at Visit 2
Added collecting study 
treatment at Visit 3
Added collecting 
albuterol/salbutamol at Visit 5 
Added wording regarding 
order for assessments and 
procedures (CAT, SGRQ-C, 
Vitals, ECG, Spirometry, 
Clinical Lab Assessments)
Clarified that Smoking Cessation 
Counselling will also be collected 
at Visit 4
Clarified that run-in medication 
should be collected at Visit 2
Clarified that study treatment 
should be collected at Visit 3
Clarified that rescue medication 
(albuterol/salbutamol) should be 
collected at Visit 5
Clarified the requested order of 
assessments and procedures at 
visits (1 and 2 in particular) when 
a number of assessments and 
procedures are collected and 
performed
Section 6.2
Exclusion Criteria 
13
Removed reference to 
Fridericia formula in 
calculation of QTc
Fridericia and Bazett formulas 
provide equal safety in calculation 
of QTc and either may be used if 
done consistently throughout the 
study
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
5
Section 8.1
QTc Stopping 
Criteria
Updated QTc stopping criteria 
to:
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 of 
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 patient should be 
discontinued from the study
Adapted the QTc stopping criteria 
to be in line with stopping criteria 
from the registration Phase III 
Trelegy Studies
Section 9.1.1
Spirometry
Corrected:  If applicable, after 
completing the health 
outcomes assessments (CAT 
should be administered first 
followed by SGRQ-C)
CAT is a shorter assessment 
questionnaire to complete and the 
participant will already have 
experience completing this at 
Screening Visit 1
Section 9.1.2
SGRQ-C
Corrected to match SoA that  
SGRQ-C will also be collected 
at Visit 3
Added wording regarding 
CAT should be collected prior 
to SGRQ-C 
Clarified that SGRQ-C should 
also be collected at Visit 3 as 
outlined in the SoA
CAT is a shorter assessment 
questionnaire to complete and the 
participant will already have 
experience completing this at 
Screening Visit 1
Section 9.1.3
CAT
Corrected to match SoA that 
CAT will also be collected at 
Visit 3
Added wording regarding 
CAT should be collected prior 
to SGRQ-C 
Clarified that CAT should also be 
collected at Visit 3 as outlined in 
the SoA
CAT is a shorter assessment 
questionnaire to complete and the 
participant will already have 
experience completing this at 
Screening Visit 1
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
6
Section 9.2.9
Pregnancy
Corrected to match Appendix 
3:  If a pregnancy is reported, 
the Investigator should inform 
GSK within 24 hours of 
learning of the pregnancy and 
should follow the procedures 
outlined in Appendix 3
Clarified that the reporting period 
for pregnancy should be within 24 
hours of learning of the pregnancy 
and not 2 weeks as previously 
written
Section 9.4.3
Electrocardiograms
Corrected:  A single 12-lead 
ECG and rhythm strip will be 
recorded after measurement of 
vital signs and prior to 
spirometry
Clarified that the ECG should be 
collected after the vital signs and 
prior to spirometry
Section 9.10
Smoking Cessation 
Counselling
Added Section 9.10
Smoking Cessation 
Counselling
Explained the reasoning and 
expectations for the Smoking 
Cessation Counselling
Appendix 9
Genetics
Added wording for both 
withdraw process and 
destruction process
Explained what should be done if 
a participant withdraws consent 
along with the destruction of 
samples after the storage period or 
on withdrawal of consent
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
7
TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS.............................................................................................................10
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................17
3.
INTRODUCTION....................................................................................................19
3.1.
Study Rationale ..........................................................................................19
3.2.
Background ................................................................................................21
3.3.
Benefit/Risk Assessment ............................................................................23
3.3.1.
Risk Assessment .........................................................................24
3.3.2.
Risk Assessment for Tiotropium Bromide 18 mcg........................35
3.3.3.
Benefit Assessment.....................................................................35
3.3.4.
Overall Benefit:Risk Conclusion...................................................36
4.
OBJECTIVES AND ENDPOINTS...........................................................................37
5.
STUDY DESIGN ....................................................................................................38
5.1.
Overall Design ............................................................................................38
5.2.
Number of Participants ...............................................................................40
5.3.
Participant and Study Completion...............................................................40
5.4.
Scientific Rationale for Study Design ..........................................................40
5.5.
Dose Justification........................................................................................41
6.
STUDY POPULATION...........................................................................................41
6.1.
Inclusion Criteria.........................................................................................41
6.2.
Exclusion Criteria........................................................................................42
6.3.
Randomisation Criteria ...............................................................................47
6.4.
Lifestyle Restrictions...................................................................................47
6.5.
Pre-screening/Screening/Run-in/Randomisation Failures...........................47
7.
TREATMENTS.......................................................................................................48
7.1.
Treatment Groups and Duration .................................................................48
7.1.1.
Medical Devices...........................................................................51
7.2.
Dose Modification .......................................................................................51
7.3.
Method of Treatment Assignment ...............................................................51
7.4.
Blinding.......................................................................................................51
7.5.
Preparation/Handling/Storage/Accountability..............................................52
7.6.
Treatment Compliance................................................................................53
7.7.
Concomitant Therapy..................................................................................53
7.7.1.
Permitted Medications and Non-Drug Therapies..........................53
7.7.1.1.
Permitted COPD Medications.....................................53
7.7.1.2.
Permitted Non-COPD Medications .............................54
7.7.2.
Prohibited Medications and Non-Drug Therapies.........................55
7.8.
Treatment after the End of the Study ..........................................................57
8.
DISCONTINUATION CRITERIA.............................................................................57
8.1.
Discontinuation of Study Treatment ............................................................57
8.1.1.
Rechallenge.................................................................................59
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
8
8.1.1.1.
Study Treatment Restart or Rechallenge....................59
8.2.
Withdrawal from the Study..........................................................................59
8.3.
Lost to Follow Up........................................................................................59
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................60
9.1.
Efficacy Assessments.................................................................................61
9.1.1.
Spirometry ...................................................................................61
9.1.1.1.
Reversibility................................................................62
9.1.2.
SGRQ-C ......................................................................................62
9.1.3.
COPD Assessment Test (CAT)....................................................63
9.1.4.
COPD Exacerbations...................................................................63
9.2.
Adverse Events...........................................................................................63
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................64
9.2.2.
Method of Detecting AEs and SAEs.............................................64
9.2.3.
Follow-up of AEs and SAEs.........................................................64
9.2.4.
Regulatory Reporting Requirements for SAEs .............................65
9.2.5.
Cardiovascular and Death Events................................................65
9.2.6.
Disease-Related Outcomes – COPD exacerbations ....................65
9.2.7.
COPD exacerbations should not be recorded as an 
adverse event, unless they meet the definition of an SAE 
(Appendix 6).Pneumonia .............................................................66
9.2.8.
Sentinel Events............................................................................66
9.2.9.
Pregnancy ...................................................................................67
9.2.10.
Medical Device Incidents (Including Malfunctions).......................67
9.2.10.1.
Time Period for Detecting Medical Device 
Incidents.....................................................................67
9.2.10.2.
Follow-up of Medical Device Incidents........................67
9.2.10.3.
Prompt Reporting of Medical Device Incidents 
to Sponsor..................................................................68
9.2.10.4.
Regulatory Reporting Requirements for 
Medical Device Incidents............................................68
9.3.
Treatment of Overdose...............................................................................68
9.4.
Safety Assessments ...................................................................................68
9.4.1.
Physical Examinations.................................................................69
9.4.2.
Vital Signs....................................................................................69
9.4.3.
Electrocardiograms......................................................................69
9.4.4.
Clinical Safety Laboratory Assessments ......................................69
9.5.
Pharmacokinetics .......................................................................................70
9.6.
Pharmacodynamics ....................................................................................70
9.7.
Genetics .....................................................................................................70
9.8.
Biomarkers .................................................................................................70
9.9.
Medical Resource Utilization and Health Economics ..................................70
9.10.
Smoking Cessation Counselling .................................................................70
10. STATISTICAL CONSIDERATIONS........................................................................71
10.1.
Hypotheses.................................................................................................71
10.2.
Sample Size Determination ........................................................................71
10.3.
Populations for Analyses ............................................................................71
10.4.
Statistical Analyses.....................................................................................72
10.4.1.
Efficacy Analyses.........................................................................72
10.4.2.
Safety Analyses...........................................................................73
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
9
10.4.3.
Other Analyses ............................................................................73
10.4.4.
Interim Analyses ..........................................................................73
10.4.5.
Exploratory Analyses ...................................................................74
11. REFERENCES.......................................................................................................75
12. APPENDICES........................................................................................................78
12.1.
Appendix 1: Abbreviations and Trademarks................................................78
12.2.
Appendix 2: Study Governance Considerations..........................................81
12.3.
Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................85
12.4.
Appendix 4: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................88
12.5.
Appendix 5: COPD Exacerbation Identification, Categorization and 
Treatment Guidelines..................................................................................91
12.5.1.
Guidelines for Identifying COPD Exacerbations...........................91
12.5.2.
COPD Exacerbation Severity.......................................................92
12.5.3.
Treatment of COPD Exacerbations..............................................92
12.5.4.
Guidelines for Treatment with Corticosteroids..............................92
12.5.5.
Guidelines for Treatment with Antibiotics .....................................93
12.5.6.
Onset and Resolution of COPD Exacerbations............................93
12.5.7.
Guideline for assessing multiple mild exacerbations ....................93
12.5.8.
Guideline for assessing exacerbations that increase in 
severity ........................................................................................93
12.6.
Appendix 6: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................94
12.7.
Appendix 7: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .....................................100
12.8.
Appendix 8: Clinical Laboratory Tests.......................................................102
12.9.
Appendix 9: Genetics................................................................................104
12.10. Appendix 10: Country-specific requirements.............................................105
12.11. Appendix 11: Protocol Amendment History...............................................106
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
10
1.
SYNOPSIS
Protocol Title: A Phase IV, 12 week, randomised, double-blind, double dummy study to 
compare single inhaler triple therapy, fluticasone furoate/umeclidinium/vilanterol
(FF/UMEC/VI), with tiotropium monotherapy based on lung function and symptoms in 
participants with chronic obstructive pulmonary disease
Short Title: A randomised study, comparing FF/UMEC/VI single inhaler triple therapy
versus tiotropium monotherapy in participants with chronic obstructive pulmonary 
disease
Rationale:  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.
Population based studies of COPD treatment patterns demonstrate that ‘open’ triple 
therapy (use of ICS/LAMA/LABA delivered via multiple inhalers) is already widely used 
in the real-life management of COPD. In 2011, 26 % of patients in the United States (US)
who were taking controller medicines for the treatment of COPD were taking an ‘open’
triple therapy, typically by adding fluticasone propionate/salmeterol (ICS/LABA) to 
tiotropium (LAMA) or vice versa A study in the United Kingdom (UK) Clinical Practice 
Research Database (CPRD) revealed that over a two-year period of time, 35 % of COPD 
patients initially prescribed a LAMA and 39 % initially prescribed an ICS/LABA stepped 
up to an ‘open’ triple therapy regimen. In the four-year long-term safety study conducted 
with tiotropium, 46 % of patients were receiving a concurrent fixed combination of 
ICS/LABA in addition to tiotropium. 
A number of studies have assessed the use of an ‘open’ triple therapy of fluticasone 
propionate/salmeterol or budesonide/formoterol (ICS/LABA) with tiotropium in 
moderate-severe COPD patients. These studies have reported greater improvements in 
lung function, HRQoL, hospitalization rates and rescue medication use, compared to dual 
(ICS/LABA) or LAMA alone, thus supporting the use of triple therapy in COPD.These 
studies have also shown that the number and type of reported adverse events (AE) were 
generally similar with administration of dual or monotherapy doses for periods of up to 
one year, and were mostly related to their pharmacological mode of action.
GlaxoSmithKline (GSK) is currently developing 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, with the aim of providing 
a new treatment option for the management of symptomatic COPD patients at risk for 
exacerbations which will reduce the exacerbation frequency, allow for a reduced burden 
of polypharmacy, convenience, and increase the potential for improvement in lung 
function, HRQoL and symptom control over established dual/monotherapies.
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
11
GSK conducted a Phase III study comparing once-daily FF/UMEC/VI to twice-daily 
budesonide/formoterol (400/12 mcg) in COPD participants that were symptomatic and at 
risk of an exacerbation despite receiving maintenance therapy (CTT116853). 
FF/UMEC/VI demonstrated statistically significant improvements in trough FEV1, a 
statistically significant reduction in the annual rate of moderate or severe COPD 
exacerbations, and a statistically significant reduction of COPD symptoms (using 
Exacerbations and Chronic Pulmonary Disease – Respiratory Symptoms [EXACT-RS]) 
when compared to budesonide/formoterol. Additionally, clinically meaningful 
improvements from baseline in St. George’s Respiratory Questionnaire (SGRQ) total 
score were observed, with a statistically significant improvement compared to 
budesonide/formoterol. This Phase III study provided compelling efficacy data compared 
with an established ICS/LABA and demonstrated the clinical value of single inhaler 
triple-therapy compared to ICS/LABA therapy in patients with COPD. 
As fixed dose combinations of LAMA/LABA therapy remain relatively new, and ICS 
monotherapy is not indicated for the treatment of COPD, the two most frequent treatment 
pathways that lead to ‘open’ triple therapy are the escalation of therapy from either an 
ICS/LABA fixed dose combination or from LAMA monotherapy. A prior study 
demonstrated that participants with COPD may remain symptomatic despite the use of 
LAMA or LABA monotherapy. Participants that remained symptomatic despite treatment 
with LAMA monotherapy, stepped up to ‘open’ triple therapy by the addition of 
ICS/LABA therapy, which resulted in greater improvements in lung function and 
HRQoL, compared LAMA monotherapy.
The primary purpose of this study is to evaluate lung function and HRQoL after 84 days 
of treatment with a single inhaler triple therapy combination of FF/ UMEC/VI 
(100/62.5/25 mcg) once daily via the ELLIPTA™compared with tiotropium (18 mcg) 
once daily, in a patient population appropriate for triple therapy.
Objectives and Endpoints:
Objectives
Endpoints
Primary
To evaluate the effect of single inhaler 
triple therapy (FF/UMEC/VI) compared 
to tiotropium after 12 weeks of 
treatment on lung function
Primary
Change from baseline in trough FEV1 at 
Week 12 (Day 85)
Secondary 
Change from baseline in trough FEV1
on Day 28 and Day 84
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
12
Objectives
Endpoints
Other
To evaluate the effect of single inhaler 
triple therapy (FF/UMEC/VI) compared 
to tiotropium after 12 weeks of 
treatment on Health Status
Proportion of responders based on the St 
George’s Respiratory Questionnaire 
(SGRQ) Total Score at Week 4 and
Week 12
Change from baseline in SGRQ Total 
Score at Week 4 and Week 12
To evaluate the effect of single inhaler 
triple therapy (FF/UMEC/VI) compared 
to tiotropium after 12 weeks of 
treatment on Health Status
Proportion of responders based on the 
COPD Assessment Test (CAT) Total 
Score at Week 4 and Week 12
Change from baseline in CAT Total 
Score at Week 4 and Week 12
To evaluate the effect of single inhaler 
triple therapy (FF/UMEC/VI) compared 
to tiotropium after 12 weeks of 
treatment on COPD exacerbations
Moderate or severe exacerbation event
Safety
To evaluate the safety profile of single 
inhaler triple therapy (FF/UMEC/VI) 
compared to tiotropium over 12 weeks
of treatment 
Incidence of adverse events

Vital signs
Overall Design:
This is a Phase IV, 12-week, randomised, double-blind, double-dummy, parallel group,
multicentre study evaluating once-daily single inhaler triple therapy (FF/UMEC/VI) 
delivered via the ELLIPTA, compared to once daily tiotropium, in participants with 
COPD. 
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
13
Study design schema
Eligible participants at Screening (Visit 1) will be current or former smokers, with an 
established clinical history of COPD, receiving daily maintenance therapy with 
tiotropium alone for at least 3 months (no ICS or LABA maintenance therapy is allowed 
during the 3 months prior to screening), with a post-bronchodilator FEV1 of <50 % 
predicted (or <80 % predicted with a documented history of at least 2 moderate or 1 
severe [hospitalized] exacerbation in the last 12 months) and a CAT score of 10. 
Participants will be requested to participate in the study for approximately 17 weeks, 
consisting of a 4-week run-in period, 12-week treatment period and a 1-week follow-up 
period. 

Pre-screening: Details about the study and procedures will be explained 
through the informed consent process. The Pre-screening Visit (Visit 0), 
including the informed consent process, must be completed prior to any 
protocol-required changes to a participant’s usual COPD treatment and the 
initiation of any Visit 1 procedures. Participants will continue treatment with 
their regular (i.e. pre-study) tiotropium monotherapy during the pre-screening 
period.

Screening/run-in: Eligible participants will be allowed to continue their usual 
tiotropium monotherapy COPD medication until the day before Screening, Visit 
1.  On the morning of the Screening Visit participants will refrain from taking 
their morning dose of tiotropium. Participants who meet all of the eligibility 
criteria at Visit 1 (Screening), will enter the 4-week run-in period.
Participants will discontinue existing tiotropium medication and will take open-
label tiotropium 18 mcg via the HandiHaler once daily plus placebo via the 
ELLIPTA. Participants will not use any other COPD medications (except for 
those allowed per protocol). 
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
14
During the run-in period participants will also take placebo via the ELLIPTA in 
addition to open-label tiotropium. This will familiarise participants with the use 
of the ELLIPTA device and will help ensure participants are compliant and use 
both devices as instructed.
Participants will be provided with short-acting albuterol/salbutamol to be used 
on an as-needed basis (rescue medication) throughout the study. At Screening, 
each participant will be instructed on the proper use of the ELLIPTA and 
HandiHaler and will self-administer their first doses of their run-in treatment 
during the Screening Visit. On the morning of the other study visits (Visit 2 
onwards), participants will refrain from taking their morning dose of study 
treatment until instructed to do so by clinic personnel. 

Randomisation/treatment: On the morning of the day before the 
Randomisation Visit (Visit 2), participants will take their last dose of run-in 
treatment and will not use any other COPD medications (except for those 
allowed per protocol.  Rescue albuterol/salbutamol can be used throughout the 
study as-needed but must be withheld for at least 4 hours prior to conducting 
spirometry.
At Visit 2 (the Randomisation Visit), participants who meet all of the 
randomisation criteria will be randomised 1:1 to receive one the following 
double-blind study treatments for 84 days:

FF/UMEC/VI 100/62.5/25 mcg via the ELLIPTA once daily in the morning
+ placebo to match tiotropium via HandiHaler once daily in the morning

Tiotropium 18 mcg via HandiHaler once daily in the morning
+ placebo via the ELLIPTA once daily in the morning
Participants may continue their study-supplied rescue albuterol/salbutamol. On 
the morning of Visits 3 and 4, participants will refrain from taking their morning 
dose of study treatment until instructed to do so by clinic personnel. At Visits 2, 
3, and 4 participants will self-administer study treatment whilst at the clinic. 
Participants will take their last dose of study treatment in the clinic on Day 84 
and then return to the clinic on Day 85 (Visit 5) for their final clinical 
assessments. Participants are expected on non-clinic visit days to take their study 
treatment at home in the morning at approximately the same time each day, as 
directed by the clinic. 

Safety/follow-up: A safety follow-up telephone contact or clinic study visit 
(Visit 6) will be conducted approximately 7 days after the participant completes 
all of the protocol-defined procedures for Visit 5/End of Study (EOS) or, if 
applicable, the Study Treatment Discontinuation Visit. A participant will be 
considered to have completed the study when they have completed all phases of 
the study including screening, run-in, the randomised treatment phase, and
safety follow-up.
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
15
Participants that permanently discontinue study treatment are not required to withdraw 
from the study. If for any reason a participant must permanently discontinue study 
treatment, every effort should be made by the Investigator/staff to keep the participant in 
the study and complete all remaining protocol specified clinic visits.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.
A participant will be considered to have completed the study when they have completed 
all phases of the study including screening, run-in, the randomised treatment phase, and
safety follow-up.
Number of Participants:
Approximately 848 participants with advanced COPD will enter the run-in period, in 
order to randomise approximately 780 participants, in order to achieve an estimated 702 
evaluble participants.
Approximately 100 centres globally will be required to recruit the study.
Treatment Groups and Duration:
Participants who meet all the eligibility criteria and who have successfully completed all 
protocol procedures at Screening will enter the 4-week run-in period and will take open-
label tiotropium 18 mcg via the HandiHaler once daily plus placebo via the 
ELLIPTA.Following the run-in period, eligible participants will be randomised (1:1) to 
one of the following double-blind, double-dummy treatment groups for 84 days:
Either:

FF/UMEC/VI 100/62.5/25 mcg via the ELLIPTA once daily in the morning
      +  placebo to match tiotropium via HandiHaler once daily in the morning
or,

Tiotropium 18 mcg via HandiHaler once daily in the morning
       + placebo via the ELLIPTA once daily in the morning
The ELLIPTA contains 30 doses (FF/UMEC/VI or placebo) and participants will be
instructed to administer one dose from their ELLIPTA once daily in the morning.
Tiotropium or matching placebo: Contents of 1 capsule (18 mcg) inhaled once daily 
using HandiHaler device. Note: To ensure drug delivery, two inhalations of the contents 
of each capsule should be performed.
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
16
Key Elements of Analysis Plan:
The primary objective of this study is to compare single inhaler triple therapy 
(FF/UMEC/VI) with tiotropium (TIO) in participants with COPD who have received 
tiotropium and continue to have symptoms as measured by CAT 10. The primary 
endpoint is trough FEV₁ at Week 12 (Day 85). The primary analysis is the comparison of 
this endpoint between FF/UMEC/VI and tiotropium.   
The null hypothesis is that there is no difference between treatment groups.
H0: T1 – T2 = 0
The alternative hypothesis is there is a difference between treatment groups.
H1: T1 – T2 0
where T1 and T2 are the treatment means for FF/UMEC/VI and TIO, respectively.
The primary analyses will be based on the ITT population using only data collected on
treatment, the analysis will evaluate the endpoint of trough FEV1 using a mixed model 
repeated measures (MMRM) analysis, including on-treatment trough FEV1 recorded at 
each of visits, Day 28, Day 84 and Day 85. The model will include covariates of baseline 
FEV1, visit, geographical region, treatment and visit by baseline interaction. A visit by 
treatment interaction term will also be included to allow treatment effects to be estimated 
at each visit separately. The variance-covariance matrix will be assumed unstructured.
Estimated differences between FF/UMEC/VI and tiotropium will be presented together 
with 95 % confidence intervals (CIs) for the difference and p-values.
The details of the statistical analysis methods for the secondary efficacy endpoint will be 
provided in the Reporting and Analysis Plan (RAP). 
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
17
2.
SCHEDULE OF ACTIVITIES (SOA)
Protocol Activity
Pre-
Screen Screen
Treatment
Follow-up
Visit 0
Visit 1 
Screen/ 
Run-in
Visit 2
Randomisation Visit 3
Visit 4
Visit 5
Study 
Treatment 
Discontinuation 
Visit
Visit 6 
Safety
Follow-
up 
Contact
Study Day
-56 to  
-28
Day -28
Day 1
Day 28
Day 84
Day 85
Day 91
Week
-8 to -4
-4
0
4
12
12
13
Window
-3/+8d
(Day -31 
to -21)
-4/+2d 
(Day 24 
to 30)
-4/+2d
(Day 80 
to 86)
-1/+4d
(Day 90 
to 95)
Written Informed 
Consenta,
X
X
Genetic Informed 
Consentb
X
X
Demographyc
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
Smoking History
X
Smoking status
X
X
X
Smoking Cessation 
Counselling
X
X
X
Register Visit in IWRS
X
X
X
X
X
X
X
CATd
X
X
X
X
SGRQ-Cd
X
X
X
Reversibility Testinge
X
Trough Spirometryf
X
X
X
X
Device training and 
registration
X
X
Exacerbation 
Assessment
X
X
X
X
X
X
Physical examinationg
X
X
X
Adverse Events 
Assessment
X
X
X
X
X
X
Vital signsh
X
X
X
ECG
X
Chest X-rayi
X
Oropharyngeal 
examination
X
X
X
X
X
Blood Draw for Genetics 
researchj
X
Hematology/biochemistryk
X
Urine Pregnancy Test l
X
X
X
Hepatitis B and C tests 
X
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
18
Protocol Activity
Pre-
Screen Screen
Treatment
Follow-up
Visit 0
Visit 1 
Screen/ 
Run-in
Visit 2
Randomisation Visit 3
Visit 4
Visit 5
Study 
Treatment 
Discontinuation 
Visit
Visit 6 
Safety
Follow-
up 
Contact
Study Day
-56 to  
-28
Day -28
Day 1
Day 28
Day 84
Day 85
Day 91
Week
-8 to -4
-4
0
4
12
12
13
Window
-3/+8d
(Day -31 
to -21)
-4/+2d 
(Day 24 
to 30)
-4/+2d
(Day 80 
to 86)
-1/+4d
(Day 90 
to 95)
Dispense run-in treatment
X
Dispense study treatment
X
X
Administer run-in 
treatment in clinic m
X
Administer study 
treatment in clinic n
X
X
X
Assess run-in treatment 
compliance
X
Collect run-in treatment
X
Assess study treatment 
compliance
X
X
X
Collect study treatment
X
X
X
Dispense 
albuterol/salbutamol
X
X
X
X
Collect 
albuterol/salbutamol
X
X
X
X
X
Dispense paper Medical 
Problems worksheet
X
X
X
X
X
Review paper Medical 
Problems worksheet
X
X
X
X
X
X
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
19
a.
Informed consent must be conducted at the Pre-screen Visit 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.
Genetics research consent may be obtained at the same time as the study informed consent and must be 
obtained prior to obtaining a genetic blood sample. The sample can be collected at any time after Visit 2, 
providing consent is obtained.
c.
Demography may be captured at either the Pre-screen Visit or Screening Visit.
d.
SGRQ-C and CAT will be completed electronically, and should be conducted in the following order and before 
other study assessments: CAT, SGRQ-C.
e.
At Screening Visit 1 both pre and post-bronchodilator spirometry will be conducted. Participants are required to 
withhold their usual morning doses of their COPD meds including rescue albuterol/salbutamol for the protocol  
designated period prior to reversibility testing.
f.
Pre-bronchodilator spirometry will be performed pre-dose at 30 mins and 5 mins prior to taking the morning         
dose of study treatment, between 6am and 11am and after withholding rescue albuterol/salbutamol for ≥4           
hours.  On Day 85, study drug will not be administered following spirometric assessments. 
g.
Physical examination may include height, weight, blood pressure and temperature
h.
Vital signs must be performed prior to spirometry and prior to taking morning dose of study treatment.
i.
Chest X-ray is required at Screening (or historical x-ray obtained within 3 months prior to Screening) and at         
anytime there is a suspected pneumonia or a mod/severe exacerbation
j.
Genetic consent must be obtained prior to obtaining a blood sample.
k.
Hematology and chemistry panels will include full and differential blood count and liver chemistry. See 
Appendix 8. 
l.
All female Participants of child bearing potential will have a urine pregnancy test at Visits 1, 4 and Study 
Treatment Discontinuation Visit (if applicable).
m.
Participants must withhold their morning dose of existing COPD medication/study treatment and not take their 
treatment until instructed to do so by study staff
n.
Participants must withhold their morning dose of study treatment at each clinic visit and not take their study         
treatment until instructed to do so by study staff
When multiple assessments and procedures are performed suggested order is CAT, 
SGRQ-C, vitals, ECG, spirometry, clinical lab assessments.
3.
INTRODUCTION
3.1.
Study Rationale
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 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].
Population based studies of COPD treatment patterns demonstrate that ‘open’ triple 
therapy (use of ICS/LAMA/LABA delivered via multiple inhalers) is already widely used 
in the real-life management of COPD. In 2011, 26 % of patients in the United States (US)
who were taking controller medicines for the treatment of COPD were taking an ‘open’
triple therapy, typically by adding fluticasone propionate/salmeterol (ICS/LABA) to 
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
20
tiotropium (LAMA) or vice versa [Wolters, 2012]. A study in the United Kingdom (UK)
Clinical Practice Research Database (CPRD) revealed that over a two year period of time, 
35 % of COPD patients initially prescribed a LAMA and 39 % initially prescribed an 
ICS/LABA stepped up to an ‘open’ triple therapy regimen [Wurst, 2013]. In the four year 
long-term safety study conducted with tiotropium, 46 % of patients were receiving a 
concurrent fixed combination of ICS/LABA in addition to tiotropium [Tashkin, 2008]. 
A number of studies have assessed the use of an ‘open’ triple therapy of fluticasone 
propionate/salmeterol or budesonide/formoterol (ICS/LABA) with tiotropium in 
moderate-severe COPD patients. These studies have reported greater improvements in 
lung function, HRQoL, hospitalization rates and rescue medication use, compared to dual 
(ICS/LABA) or LAMA alone, thus supporting the use of triple therapy in COPD [Aaron, 
2007; Cazzola, 2007; Hanania, 2012; Jung, 2012; Siler, 2015; Welte, 2009]. These 
studies have also shown that the number and type of reported adverse events (AE) were 
generally similar with administration of dual or monotherapy doses for periods of up to 
one year, and were mostly related to their pharmacological mode of action.
GlaxoSmithKline (GSK) is currently developing 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, with the aim of providing 
a new treatment option for the management of symptomatic COPD patients at risk for 
exacerbations which will reduce the exacerbation frequency, allow for a reduced burden 
of polypharmacy, convenience, and increase the potential for improvement in lung 
function, HRQoL and symptom control over established dual/monotherapies.
GSK conducted a Phase III study comparing once-daily FF/UMEC/VI to twice-daily 
budesonide/formoterol (400/12 mcg) in COPD participants that were symptomatic and at 
risk of an exacerbation despite receiving maintenance therapy (CTT116853). 
FF/UMEC/VI demonstrated statistically significant improvements in trough FEV1, a 
statistically significant reduction in the annual rate of moderate or severe COPD 
exacerbations, and a statistically significant reduction of COPD symptoms (using 
Exacerbations and Chronic Pulmonary Disease – Respiratory Symptoms [EXACT-RS]) 
when compared to budesonide/formoterol. Additionally, clinically meaningful 
improvements from baseline in St. George’s Respiratory Questionnaire (SGRQ) total 
score were observed, with a statistically significant improvement compared to
budesonide/formoterol [Lipson, 2017]. This Phase III study provided compelling efficacy 
data compared with an established ICS/LABA and demonstrated the clinical value of 
single inhaler triple-therapy compared to ICS/LABA therapy in patients with COPD. 
As fixed dose combinations of LAMA/LABA therapy remain relatively new, and ICS 
monotherapy is not indicated for the treatment of COPD, the two most frequent treatment 
pathways that lead to ‘open’ triple therapy are the escalation of therapy from either an 
ICS/LABA fixed dose combination or from LAMA monotherapy. A prior study 
demonstrated that patients with COPD may remain symptomatic despite the use of 
LAMA or LABA monotherapy [Dransfield, 2011]. Patients that remained symptomatic 
despite treatment with LAMA monotherapy, stepped up to ‘open’ triple therapy by the 
addition of ICS/LABA therapy, which resulted in greater improvements in lung function 
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
21
and HRQoL, compared LAMA monotherapy [Aaron, 2007; Cazzola, 2007; Hanania, 
2012; Jung, 2012; Siler, 2015; Welte, 2009].
The primary purpose of this study is to evaluate lung function and HRQoL after 84 days 
of treatment with a single inhaler triple therapy combination of FF/ UMEC/ VI 
(100/62.5/25 mcg) once daily via the ELLIPTA compared with tiotropium (18 mcg) once 
daily, in a patient population appropriate for triple therapy.
3.2.
Background
Chronic obstructive pulmonary disease is a progressive disease characterised by 
increasing obstruction to airflow and the progressive development of respiratory 
symptoms including chronic cough, increased sputum production, dyspnoea and 
wheezing.  
In 2011, the Global Initiative for Chronic Obstructive Lung Disease [GOLD, 2011]
issued a guideline that outlined a new classification system for COPD, using the ABCD 
assessment tool, which aimed to more comprehensively assess disease severity and guide 
therapy choice, ultimately improving COPD management. A 2013 update to the 2011 
strategy included an additional criterion to characterise patients that have had a 
hospitalised exacerbation as high risk, regardless of GOLD status [GOLD, 2013].
GOLD released a revised guideline in 2017 that separates spirometric grading from the 
determination of overall disease severity and choice of pharmacologic therapy (Table 1) 
[GOLD, 2017]. 
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
22
Table 1
GOLD 2017 Classification
GOLD ABCD
Classification
Risk Class Determinant
Symptom Category 
Determinant*
A:  Low risk, 
less symptoms
≤1 exacerbation, prior year
mMRC <2;  CAT <10
B:  Low risk, 
more symptoms
≤1 exacerbation, prior year
mMRC 2;  CAT ≥10
C:  High risk, 
less symptoms
≥2 exacerbations, prior year OR 1 
leading to hospitalisation, prior 
year
mMRC <2;  CAT <10
D:  High risk, 
more symptoms
≥2 exacerbations, prior year OR 1 
leading to hospitalisation, prior 
year
mMRC 2;  CAT ≥10
* - Symptomatic category determined by either Modified Clinical Research Council (mMRC) or COPD Assessment Test 
(CAT) score.
GOLD Airflow 
Limitation
Severity
FEV1 (% predicted)
GOLD 1 
Mild
80
GOLD 2
Moderate
50 – 79 
GOLD 3
Severe
30 – 49 
GOLD 4
Very Severe
<30
The GOLD 2017 guideline also outlined suggested management strategies for COPD 
based upon disease severity, including escalation as well as de-escalation strategies. For 
milder patients (GOLD Group A), the guidelines encourage active risk reduction (e.g., 
smoking cessation and influenza vaccination) with the addition of bronchodilators.  
However, as disease severity increases, the guidelines recommend an incremental 
approach to pharmacological treatment, involving the use of combinations of drug classes 
with different or complementary mechanisms of action [Celli, 2004; GOLD, 2017].  
Long-acting bronchodilators (LAMAs or LABAs) have been shown to relieve symptoms, 
increase exercise capacity, improve health-related quality of life and reduce COPD 
exacerbations to a greater extent than short acting 2 adrenergic receptor agonists.  For 
advanced cases, or those with repeated exacerbations, the incorporation of ICS or triple 
therapy, is recommended.
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
23
3.3.
Benefit/Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK2834425 (FF/UMEC/VI) can be found in the Investigator’s Brochure (IB).  The 
safety information for tiotropium can be found in the authorised product label.  The 
current safety profile for FF/UMEC/VI (100/62.5/25 mcg), based on data available to 
date, is consistent with the pharmacological classes of the components.  The following 
section outlines the risk of assessment and mitigation strategy for this protocol.
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
24
3.3.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) GSK2834425 (FF/UMEC/VI), GSK573719 (UMEC), GW642444 (vilanterol), GW685698 (fluticasone furoate)
Pneumonia in participants with COPD
Pneumonia is a class concern for any ICS-
containing product for the treatment of 
COPD.  
In a study (CTT116853) in 1810 
randomised COPD participants treated with 
FF/UMEC/VI or budesonide/formoterol 
(BUD/FOR) for up to 24 weeks (Intent-To-
Treat [ITT] Population), or up to 52 weeks 
(subset of 430 participants; EXT 
Population), the incidence of events in the 
pneumonia AEs of special interest (AESI) 
group was 2.2 % and 0.8 % for 
FF/UMEC/VI and BUD/FOR, respectively 
in the ITT Population, and 1.9 % and 1.8 % 
for FF/UMEC/VI and BUD/FOR, 
respectively, in the EXT Population.  There 
was one fatal case of pneumonia in a 
participant who received FF/UMEC/VI.
The incidence of pneumonia with 
FF/UMEC/VI in this study was in line with 
the incidence of pneumonia seen in 24 week 
studies with F/VI (<1-2 % with FF/VI 
100/25) and less than that observed in 52 
week exacerbations studies with FF/VI (6 % 
- 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 
(Section 12.5.2) and to treat appropriately.
- Appropriate exclusion criteria as specified 
in Section 6.2 of the protocol i.e
- Instream review of blinded AE/SAE 
reports. 
- All diagnoses of pneumonia 
(radiographically confirmed or 
unconfirmed) must be reported as an AE or 
SAE (if applicable) as specified in Section 
9.2.7.
- Chest X-ray read required at baseline and 
whenever a participant has suspected 
pneumonia or mod/severe exacerbations 
during the study. 
 
 
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
25
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
with FF/VI 100/25) [Dransfield, 2013].  
Similarly, the incidence of pneumonia with 
FF/UMEC/VI was less than that observed in 
a 12 month exacerbation trial with 
BUD/FOR (6.4 %) [Sharafkhaneh, 2012].
Prior studies with FF/VI have demonstrated 
risk factors associated with a higher risk of 
pneumonia in participants with COPD (e.g., 
advanced age, poor lung function, low body 
mass index (BMI), current smoking, and a 
prior history of pneumonia) [Crim, 2009].
These risk factors were present in some 
participants with pneumonia in study 
CTT116853 with FF/UMEC/VI; however, 
the low number of pneumonia events 
reported in this study precludes drawing any 
definite conclusions about risk factors.  
These risk factors should be taken into 
consideration when using an ICS in 
participants with COPD. Pneumonia risk 
will be important in the benefit-risk 
assessment for FF/UMEC/VI in COPD 
participants, hence a robust risk mitigation 
strategy is being proposed.
Pharmacovigilance Risk Assessment 
Committee (PRAC) recently conducted an 
Article 31 review to evaluate the risk of 
pneumonia with use of ICS in participants 
 
 
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
26
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
with COPD.  The PRAC review confirmed 
that COPD participants treated with ICS are 
at increased risk of pneumonia; however, 
the Committee’s view was that the benefits 
of ICS continue to outweigh their risks.  The 
PRAC also looked whether there were any 
differences in the risk of pneumonia 
between these produces, and did not find 
conclusive evidence of such difference.
Decreased bone mineral density 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 CTT116853, the incidence of 
events in the decreased bone mineral density 
and associated fracture AESI group was 
low, with an incidence of 0.4 % and 0.7 % 
in the FF/UMEC/VI and BUD/FOR 
treatment groups, respectively in the ITT 
Population up to 24 weeks and 0.5 % in 
both treatment groups in the EXT 
Population up to 52 weeks.  The majority of 
- Participants will be informed about the 
risk in the informed consent.
- Investigators are informed of the risk in 
the IB.
- Instream review of blinded AE/SAE 
reports.
 
 
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
27
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
the fractures in both treatment groups were 
traumatic in nature.
Adrenal suppression
Oral corticosteroids are known to have an 
effect on the hypothalamic-pituitary-adrenal 
(HPA) axis leading to reduction in cortisol 
production.  Due to the low dose and low 
systemic exposure with ICS, this potential 
effect is not clear, nor is the possible impact 
of any change in cortisol.
The effect of FF/UMEC/VI on cortisol 
levels has not been studied.  In study 
CTT116853, no events were reported in the 
adrenal suppression AESI group for 
FF/UMEC/VI and BUD/FOR.
With respect to the FF/VI clinical 
development programme, a formal HPA 
study, using 24-hour serum cortisol 
measurements, was performed.  In addition, 
multiple studies with COPD (and asthma) 
participants monitored urinary cortisol.  
These studies did not show a clinically 
relevant effect of FF/VI 100/25 on the HPA 
axis.
Participants that have received oral 
corticosteroids, particularly those who have 
received significant amounts for long 
periods of time, will be more susceptible to 
- Investigators are informed of the risk in 
the IB.
- Instream review of blinded AE/SAE 
reports.
 
 
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
28
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
this risk of adrenal suppression.  
The proposed dose (100 mcg) of inhaled FF 
in this study is unlikely to lead to clinically 
significant changes in the treatment period 
since systemic exposure is low. 
Corticosteroid Associated Eye Disorders
Systemic ocular effects (e.g. cataract and 
glaucoma) may occur with any inhaled 
corticosteroid, particularly at high doses 
prescribed for long periods. However, these 
effects are much less likely to occur with 
inhaled corticosteroids compared with oral 
corticosteroids.
In study CTT116853, the incidence of 
events in the ocular effects AESI group was 
low, with an incidence of 0.1 % and 0.4 % 
in the FF/UMEC/VI and BUD/FOR 
treatment groups, respectively, in the ITT 
Population up to 24 weeks.  There were no 
events reported in the ocular effects AESI in 
the EXT Population up to 52 weeks.
During studies with FF and FF/VI in asthma
participants, and 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 
- 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 6.2 of the protocol.
- Instream review of blinded AE/SAE 
reports
- If a risk is suspected, participants should 
receive appropriate treatment
 
 
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
29
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
assessments in a study with FF/VI, FF and 
FP in participants with asthma.
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 CTT116853 [Lipson, 2017], 
approximately two-thirds of all participants 
reported CV risk factors at baseline.  In this 
study, CV effects were the most frequently 
reported AESI, with a similar incidence 
between FF/UMEC/VI and BUD/FOR 
treatment groups in the ITT Population up 
to 24 weeks (4.5 % and 5.2 %, respectively) 
and the EXT Population up to 52 weeks 
(8.6 % and 10 %, respectively).  Within 
subgroups of CV effects, hypertension was 
reported most frequently and with a 
numerically higher incidence with 
BUD/FOR (2.3 %) compared with 
FF/UMEC/VI (1.3 %) in the ITT Population 
up to 24 weeks, but with a similar incidence 
in the EXT Population up to 52 weeks 
(0.9 % to 1.0 % across treatment groups).  
- 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 6.2 of the protocol, including 
ECG inclusion criteria
- Vital sign assessments (heart rate and 
blood pressure) as per protocol
- Protocol defined stopping criteria as per 
Section 8.1.1
- Instream review of blinded AE/SAE 
reports.
 
 
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
30
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Cardiac arrhythmias were reported the next 
most frequently and occurred with an 
incidence of 1.2 % in both treatment groups 
in the ITT Population up to 24 weeks and 
with an incidence of 1.9 % and 3.6 % in the 
FF/UMEC/VI and BUD/FOR groups in the 
EXT Population up to 52 weeks.
The incidence of serious events in the CV 
effects AESI was low, with an incidence of 
1.0 % and 1.1 % in the FF/UMEC/VI and 
BUD/FOR groups, respectively, in the ITT 
Population to 24 weeks, and 2.9 % and 
1.4 % in the FF/UMEC/VI and BUD/FOR 
groups, respectively, in the EXT Population 
up to 52 weeks.  The absolute numbers of 
fatal events in CV effects AESI was low in 
the study, despite the study enrolling 
participants with a number of CV co-
morbidities at baseline.
A pre-specified Major Adverse Cardiac 
Event (MACE) analysis was conducted in 
CTT116853, with broad MACE defined as: 
ischemic heart disease Standardised 
MedDRA Queries (SMQ) excluding 
fatalities, plus central nervous system 
haemorrhages and cerebrovascular 
conditions SMQ excluding fatalities, plus 
adjudicated cardiovascular deaths.  The 
narrow MACE definition included only the 
 
 
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
31
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
preferred terms of myocardial ischaemia 
and acute myocardial infarction in place of 
the ischaemic heart disease SMQ.  Overall, 
the absolute number of MACE events using 
either the broad or narrow definition was 
low both in the ITT Population up to 24 
weeks and the EXT Population up to 52 
weeks.  No clinically relevant differences 
were observed between FF/UMEC/VI and 
BUD/FOR based on narrow and broad 
MACE analysis both in the ITT Population 
up to 24 weeks and EXT Population up to 
52 weeks.
In study CTT116853, there were no 
emerging safety signals from vital signs, 
ECGs, or Holter data.
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. 
The CV safety profile of FF/UMEC/VI was 
generally consistent with that of FF/VI and 
UMEC/VI.
Hypersensitivity
Hypersensitivity reactions are unlikely to 
- Participants will be informed about the 
risk in the informed consent.  Participants 
 
 
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
32
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
affect the majority of participants.
In study CTT116853, in the ITT Population 
up to 24 weeks, events in the 
hypersensitivity AESI group occurred at 
low incidences in the FF/UMEC/VI and 
BUD/FOR treatment groups (1.1 % in both 
groups).  Similarly, in the EXT Population 
up to 52 weeks, events in the 
hypersensitivity AESI group occurred at 
low incidences (1.4 % and 0.5 % in the 
FF/UMEC/VI and BUD/FOR groups, 
respectively).  On-treatment hypersensitivity 
serious AESI events occurred at low 
frequency.
Risk factors for hypersensitivity are poorly 
understood, but may include exposure to 
infectious diseases during early childhood, 
environmental pollution, allergen level, and 
dietary changes [Niggemann, 2014; De 
Bisschop, 2012].  Although hypersensitivity 
reactions are unlikely to affect the majority 
of participants, there may be a few 
individuals who experience allergic 
reactions; they will need to be managed on a 
case by case basis.
will be advised to seek medical treatment if 
any signs of hypersensitivity occur.
- Investigators are informed of the risk in 
the IB.
- Appropriate exclusion criteria as specified 
in Section 6.2 of the protocol.
- Instream review of blinded AE/SAE 
reports.
Narrow angle glaucoma
Rare reports of angle closure glaucoma 
(which may lead into blindness) have been 
associated with nebulised ipratropium 
- Participants will be informed about the 
risk in the informed consent.
- Investigators are informed of the risk in 
the IB.
 
 
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
33
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
bromide and salbutamol [Packe, 1984].
The incidence of narrow angle glaucoma in 
the COPD population associated with the 
use if inhaled bronchodilators (including 
LAMAs and LABAs) is relatively low.
In CTT116853, in the ITT Population up to 
24 weeks, events in the glaucoma SMQ 
were reported as an incidence of 0.1% to 
0.4 % in the FF/UMEC/VI and BUD/FOR 
arms, respectively.  In the EXT Population 
up to 52 weeks, no events were reported in 
either treatment arm.
In the UMEC/VI development programme, 
there was one report (<1 %) of angle closure 
glaucoma (UMEC/VI 62.5/25 mcg).
- Appropriate exclusion criteria as specified 
in Section 6.2 of the protocol.
- Instream review of blinded AE/SAE 
reports.
Bladder outlet obstruction, dysuria, and 
urinary retention
Bladder outlet obstruction and urinary 
retention are class effects seen with 
antimuscarinics.
In study CTT116853, in the ITT Population 
up to 24 weeks, the incidence of events in 
the urinary retention AESI group was low 
(0.1 % and 0.0 % for FF/UMEC/VI and 
BUD/FOR, respectively) in both treatment 
groups.  There were no events of urinary 
retention reported in either group in the 
EXT Population up to 52 weeks.  There 
were no serious events in the urinary 
- 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 6.2 of the protocol.
- Instream review of blinded AE/SAE 
reports.
 
 
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
34
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
retention AESI group in either treatment 
group in the ITT Population up to 24 weeks 
and the EXT Population up to 52 weeks.
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 CTT 116853, the risk of 
paradoxical bronchospasm was evaluated 
through the AESI of asthma/bronchospasm.  
In the ITT Population up to 24 weeks, one 
participant reported an event in the 
athma/bronchospasm AESI (PT of wheezing 
in a participant on BUD/FOR; non-serious).  
There were no events reported in the EXT 
Population up to 52 weeks.
- Participants will be informed about the 
risk in the informed consent.
- Investigators are informed of the risk in 
the IB.
- Instream review of blinded AE/SAE 
reports.
 
 
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
35
3.3.2.
Risk Assessment for Tiotropium Bromide 18 mcg
Tiotropium is a marketed drug that contains tiotropium bromide (18 mcg). A similar 
profile of undesirable effects as reported for anticholinergics (umeclidinium) may occur
with tiotropium bromide. The most common drug related adverse reactions are 
pharmacologically predictable side effects for anti-cholinergic therapy, such as dry 
mouth, blurred vision, dizziness, headache and cough. Please refer to the authorised 
product label for further information on the risks of using Spiriva Handihaler. In this 
study, tiotropium will be used in line with the recommendations provided in the product 
label. 
Tiotropium is an anticholinergic, therefore the risk mitigation strategy for UMEC
component of GSK2834425 will be applicable for tiotropium. 
3.3.3.
Benefit Assessment
GlaxoSmithKline is developing FF/UMEC/VI in a single inhaler, with the aim of 
providing a new treatment option for the management of symptomatic COPD participants 
at risk for exacerbations which will reduce the exacerbation frequency, allow for a 
reduced burden of polypharmacy, convenience, and increase the potential for 
improvement in lung function, HRQoL, and symptom control over established 
dual/monotherapies.
Current risks have been identified for the FF/UMEC/VI (100/62.5/25 mcg) combination 
based on the known pharmacology of the individual components, FF, UMEC, and VI, 
alone or in combination.  These include key risks of pneumonia and bone 
disorders/fractures from ICS-containing combinations, and the risk of adverse 
cardiovascular effects from LAMA and/or LABA-containing combinations.
In the US, the FF/VI combination is approved for the maintenance treatment of airflow 
obstruction and for reduction of exacerbations in COPD. The UMEC/VI combination is 
approved for maintenance treatment of airflow obstruction in COPD. UMEC is indicated 
for the long-term, once-daily, maintenance treatment of airflow obstruction in 
participants with COPD.
In the EU, the FF/VI combination is approved for the symptomatic treatment of adults 
with COPD with an FEV1 <70 % predicted normal (post-bronchodilaotr) with an 
exacerbation history despite regular bronchodilator therapy.  The UMEC/VI combination 
is approved as a maintenance bronchodilator to relieve symptoms in adult participants 
with COPD. UMEC is approved as a maintenance bronchodilator treatment to relieve 
symptoms in adult participants with COPD.
An appropriate safety monitoring strategy is being proposed for all risks associated with 
the FF/UMEC/VI combination, including the key risks (Section 3.3.1).
Given the clinical experience with FF, UMEC, and VI, and that the associated risks with 
these compounds are anticipated from their known pharmacology, the potential benefit of 
a new therapy option in participants with moderate to severe COPD supports the further 
development of the closed triple combination.
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
36
Tiotropium (18 mcg) is a marketed drug for the COPD indication, and has an established 
benefit:risk profile.  Tiotropium will be used in line with the recommendations provided 
in the product label.
3.3.4.
Overall Benefit:Risk Conclusion
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 and tiotropium 
are justified by the anticipated benefits from active treatments that may be afforded to 
participants with COPD.
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
37
4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
To evaluate the effect of single inhaler 
triple therapy (FF/UMEC/VI) compared 
to Tiotropium after 12 weeks of 
treatment on lung function
Primary
Change from baseline in trough FEV1 at 
Week 12 (Day 85)
Secondary 
Change from baseline in trough FEV1 at 
Week 4 (Day 28) and Week 12 (Day 84)
Other
To evaluate the effect of single inhaler 
triple therapy (FF/UMEC/VI) compared 
to Tiotropium after 12 weeks of 
treatment on Health Status
Proportion of responders based on the St 
George’s Respiratory Questionnaire 
(SGRQ) Total Score at Week 4 and 
Week 12
Change from baseline in SGRQ Total 
Score at Week 4 and Week 12
To evaluate the effect of single inhaler 
triple therapy (FF/UMEC/VI) compared 
to Tiotropium after 12 weeks of 
treatment on Health Status
Proportion of responders based on the 
COPD Assessment Test (CAT) Total 
Score at Week 4 and Week 12
Change from baseline in CAT Total 
Score at Week 4 and Week 12
To evaluate the effect of single inhaler 
triple therapy (FF/UMEC/VI) compared 
to Tiotropium after 12 weeks of 
treatment on COPD exacerbations
Moderate or severe exacerbation event
Safety
To evaluate the safety profile of single 
inhaler triple therapy (FF/UMEC/VI) 
compared to Tiotropium over 12 weeks
of treatment 
Incidence of adverse events

Vital signs
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
38
5.
STUDY DESIGN
5.1.
Overall Design
This is a Phase IV, 12-week, randomised, double-blind, double-dummy, parallel group,
multicentre study evaluating once-daily single inhaler triple therapy (FF/UMEC/VI) 
delivered via the ELLIPTA, compared to once daily tiotropium, in participants with 
COPD. 
Study design schema
Eligible participants at Screening (Visit 1) will be current or former smokers, with an 
established clinical history of COPD, receiving daily maintenance therapy with 
tiotropium alone for at least 3 months (no ICS or LABA maintenance therapy is allowed 
during the 3 months prior to screening), with a post-bronchodilator FEV1 of <50 % 
predicted (or <80 % predicted with a documented history of at least 2 moderate or 1 
severe [hospitalized] exacerbation in the last 12 months) and a CAT score of 10. 
Participants will be requested to participate in the study for approximately 17 weeks, 
consisting of a 4-week run-in period, 12-week treatment period and a 1-week follow-up 
period. 

Pre-screening: Details about the study and procedures will be explained 
through the informed consent process. The Pre-screening Visit (Visit 0), 
including the informed consent process, must be completed prior to any 
protocol-required changes to a participant’s usual COPD treatment and the 
initiation of any Visit 1 procedures. Participants will continue treatment with 
their regular (i.e. pre-study) tiotropium monotherapy during the pre-screening 
period.
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
39

Screening/run-in: Eligible participants will be allowed to continue their usual 
tiotropium monotherapy COPD medication until the day before Screening (Visit 
1).  On the morning of the Screening Visit participants will refrain from taking 
their morning dose of tiotropium. Participants who meet all of the eligibility 
criteria at Visit 1, will enter the 4-week run-in period. 
Participants will discontinue existing tiotropium medication and will take open-
label tiotropium 18 mcg once daily via the HandiHaler plus placebo via the 
ELLIPTA. Participants will not use any other COPD medications (except for 
those allowed per protocol). 
During the run-in period participants will also take placebo via the ELLIPTA in 
addition to open-label tiotropium. This will familiarise participants with the use 
of the ELLIPTA device and will help ensure participants are compliant and use 
both devices as instructed.
Participants will be provided with short-acting albuterol/salbutamol to be used 
on an as-needed basis (rescue medication) throughout the study. At Screening, 
each participant will be instructed on the proper use of the ELLIPTA and 
HandiHaler and will self-administer their first doses of their run-in treatment 
during the Screening Visit. On the morning of the other study visits (Visit 2 
onwards), participants will refrain from taking their morning dose of study 
treatment until instructed to do so by clinic personnel. 

Randomisation/treatment: On the morning of the day before the 
Randomisation Visit (Visit 2), participants will take their last dose of run-in 
treatment and will not use any other COPD medications (except for those 
allowed per protocol) until the end of the study.  Rescue albuterol/salbutamol 
can be used throughout the study as-needed but must be withheld for at least 4 
hours prior to conducting spirometry.
At Visit 2 (the Randomisation Visit), participants who meet all of the 
randomisation criteria (see Section 6.3) will be randomised 1:1 to receive one 
the following double-blind study treatments for 84 days:

FF/UMEC/VI 100/62.5/25 mcg via the ELLIPTA once daily in the morning
+  placebo to match tiotropium via HandiHaler once daily in the morning

Tiotropium 18 mcg via HandiHaler once daily in the morning
+ placebo via the ELLIPTA once daily in the morning
Participants may continue their study-supplied rescue albuterol/salbutamol. On 
the morning of Visits 3 and 4, participants will refrain from taking their morning 
dose of study treatment until instructed to do so by clinic personnel. At Visits 2, 
3, and 4 participants will self-administer study treatment whilst at the clinic. 
Participants will take their last dose of study treatment in the clinic on Day 84 
and then return to the clinic on Day 85 (Visit 5) for their final clinical 
assessments. Participants are expected on non-clinic visit days to take their study 
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
40
treatment at home in the morning at approximately the same time each day, as 
directed by the clinic. 

Safety/follow-up: A safety follow-up telephone contact or clinic visit (Visit 6) 
will be conducted approximately 7 days after the participant completes all of the 
protocol-defined procedures for Visit 5/End of Study (EOS) or, if applicable, the 
Study Treatment Discontinuation Visit. A participant will be considered to have 
completed the study when they have completed all phases of the study including 
screening, run-in, the randomised treatment phase, and safety follow-up.
Participants who permanently discontinue double-blind study treatment are not required 
to withdraw from the study. Participants who have permanently discontinued study 
treatment and have not withdrawn consent are encouraged to continue in the study and
complete all remaining protocol specified clinic visits (see Section 8.1).
5.2.
Number of Participants
Approximately 848 participants with advanced COPD will enter the run-in, in order to 
randomise approximately 780 participants, in order to achieve an estimated 702 evaluble 
participants. See Section 10 for further details.
Approximately 100 centres globally will be required to recruit the study.
5.3.
Participant and Study Completion
A participant is considered to have completed the study if he/she has completed all 
phases of the study including pre-screening, screening, run-in, the randomised treatment 
phase and the safety follow-up. 
The end of the study is defined as the date of the last scheduled procedure shown in the 
Schedule of Activities (SoA) table (see Section 2) for the last participant in the trial 
globally.
5.4.
Scientific Rationale for Study Design
This study will use a multicenter, randomised, double-blind, double-dummy, parallel-
group design. A placebo arm is not included because the primary comparison of interest
is FF/UMEC/VI vs. tiotropium and it is not considered appropriate to include a placebo 
arm in a study in patients with advanced COPD. Eligible participants must have been on 
daily maintenance tiotropium for at least 3 months, and those randomised to tiotropium 
will be essentially continuing their therapy prior to enrollment. Although LAMA 
monotherapy in severe patients is not designated a preferred treatment option, it 
continues to be listed as a treatment option for these patients (GOLD B or D) in the 2017 
GOLD strategy document, and is commonly used in clinical practice. The 4-week run-in 
period is necessary in order to assess participant compliance with and ability to use all of 
the medications together and allow sufficient time for the results of screening 
assessments to be returned to the site, in order to establish participant eligibility.
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
41
5.5.
Dose Justification
The FF/UMEC/VI (100/62.5/25 mcg) dose was selected based on the doses that have 
been licensed for COPD for the FF/VI (100/25 mcg) and UMEC/VI (62.5/25 mcg) dual 
combinations through extensive studies in the mono and dual therapy programmes. It is 
the dose which is currently under regulatory review based on the Phase IIIa 
FF/UMEC/VI registration programme.
The dose selected for tiotropium (18 mcg, once daily) is the dose licensed in the US for 
use in COPD.
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
1. Informed consent: capable of giving signed informed consent prior to study start
which includes compliance with the requirements and restrictions listed in the 
informed consent form (ICF) and in this protocol.
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 3 during the treatment period and until the safety follow-up 
contact after the last dose of study treatment.
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 
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
42
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. Severity of COPD symptoms: A score of ≥10 on the COPD Assessment Test (CAT) 
at Screening (Visit 1).
8. Severity of Disease: 
Participants must demonstrate at Screening:
o
a post-bronchodilator FEV1 <50 % predicted normal
OR
o
a post-bronchodilator FEV1 <80 % predicted normal and a documented 
history of ≥2 moderate exacerbations or one severe (hospitalized) 
exacerbation in the previous 12 months
Participants must also have a measured post albuterol/salbutamol FEV1/forced vital 
capacity (FVC) ratio of <0.70 at screening.
Note: Percent predicted will be calculated using the European Respiratory Society
Global Lung Function Initiative reference equations [Quanjer, 2012].
Note: A documented history of a COPD exacerbation (e.g., medical record 
verification) is a medical record of worsening COPD symptoms that required 
systemic/oral corticosteroids and/or antibiotics (for a moderate exacerbation) or 
hospitalization (for a severe exacerbation). Prior use of antibiotics alone does not 
qualify as an exacerbation history unless the use was associated with treatment of 
worsening symptoms of COPD, such as increased dyspnoea, sputum volume, or 
sputum purulence (colour). Participant verbal reports are not acceptable.
9.
Existing COPD maintenance treatment: participant must have been receiving 
daily maintenance treatment with tiotropium alone (via the Handihaler or Respimat) 
for their COPD for at least 3 months prior to Screening.
Note: Participants taking only as-needed tiotropium are not eligible.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
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).
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
43
3. α1-antitrypsin deficiency: Participants with α1-antitrypsin deficiency as the 
underlying cause of COPD.
4. Other respiratory disorders: Participants with active tuberculosis, lung cancer, and 
clinically significant: bronchiectasis, sarcoidosis, lung fibrosis, pulmonary 
hypertension, interstitial lung disease or other active pulmonary diseases. 
5. Lung resection: Participants who have undergone lung volume reduction surgery 
within the 12 months prior to Screening.
6. Risk Factors for Pneumonia: immune suppression (e.g. advanced human 
immunodeficiency virus [HIV] with high viral load and low CD4 count, lupus on 
immunosuppressants) that in the opinion of the investigator 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).
Participants at potentially high risk for pneumonia (e.g. very low body mass index 
[BMI], severely malnourished, or very low FEV1) will only be included at the 
discretion of the Investigator.
7. 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). 
8. Respiratory tract infection that has not resolved at least 7 days prior to Screening.
9. 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 chest x-ray (e.g. significant cardiomegaly, pleural effusion or scarring). 
All participants will have a chest x-ray at Screening Visit 1 (or historical radiograph 
or computerized tomography [CT] scan obtained within 3 months prior to screening).  
Note: Participants who have experienced pneumonia and/or moderate or severe 
COPD exacerbations within 3 months of screening must provide a post 
pneumonia/exacerbation chest X-ray or have a chest X-ray conducted at Screening.
For sites in Germany: If a chest x-ray (or CT scan) within 3 months prior to Screening 
(Visit 1) is not available, approval to conduct a diagnostic chest x-ray will need to be 
obtained from the Federal Office for Radiation Protection (BfS).
10. 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.
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
44
11. Unstable liver disease: ALT >2x ULN; and bilirubin >1.5x ULN (isolated bilirubin 
>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)
Current active liver or biliary disease (with the exception of Gilbert’s syndrome or 
asymptomatic gallstones or otherwise stable chronic liver disease per investigator 
assessment). 
NOTES: 

Stable chronic liver disease should generally be defined by the absence of 
ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or 
gastric varices, or persistent jaundice, or cirrhosis.

Chronic stable hepatitis B and C (e.g., presence of hepatitis B surface antigen 
(HBsAg) or positive hepatitis C antibody test result at screening or within 3 
months prior to first dose of study treatment) are acceptable if participant
otherwise meets entry criteria.
12. Unstable or life threatening cardiac disease: Participants with any of the following 
at Screening (Visit 1) would be excluded

Myocardial infarction or unstable angina in the last 6 months

Unstable or life threatening cardiac arrhythmia requiring intervention in the last 3
months

New York Heart Association (NYHA) Class IV Heart failure
13. Abnormal and clinically significant 12-lead ECG finding at Visit 1

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 ≥500 msec in participants with 
QRS <120 msec and QTcF ≥530 msec in participants with QRS 
≥120 msec
14. 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.
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
45
15. Cancer: Participants with carcinoma that has not been in complete remission for at 
least 3 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 3 year waiting period if the participant has been considered cured by treatment.
16. Oxygen therapy: Use of long-term oxygen therapy (LTOT) described as resting
oxygen therapy >3 L/min (Oxygen use ≤3 L/min flow is not exclusionary.)
17. Medication prior to spirometry: Participants who are medically unable to withhold
their albuterol/salbutamol for the 4-hour period required prior to spirometry testing at
each study visit.
18. Pulmonary rehabilitation: Participants who have participated in the acute phase of a 
Pulmonary Rehabilitation Programme within 4 weeks prior to screening or 
participants who plan to enter the acute phase of a Pulmonary Rehabilitation 
Programme during the study. Participants who are in the maintenance phase of a 
Pulmonary Rehabilitation Programme are not excluded.
19. Drug/alcohol abuse: Participants with a known or suspected history of alcohol or 
drug abuse within the last 2 years.
20. 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.
21. 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.
22. 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.
23. 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.
24. Medication prior to screening: See Table 4 in Section 7.7.2 for the list of 
medications and associated time intervals prior to Visit 1.
Medication
No use within the following time intervals prior 
to Screening 
Inhaled short-acting anticholinergics
6 hrs
Inhaled short-acting beta2 agonists1 
≥4 hrs
Inhaled short-acting anticholinergics + short-acting 
beta agonist combination
6 hrs
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
46
Medication
No use within the following time intervals prior 
to Screening 
Inhaled Corticosteroids (ICS)
Use as maintenance treatment in the 3 months prior 
to Visit 1 is not permitted.
Maintenance treatment is defined as use for ≥14 
consecutive days (at any time in the 3 months prior 
to Visit 1).
Inhaled Corticosteroids (ICS)/Inhaled long-acting 
beta2-agonist (LABALABA) combinations 
(eg.fluticasone/salmeterol, mometasone 
furoate/formoterol fumarate, budesonide/formoterol 
fumarate; fluticasone furoate/vilanterol
Phosphodiesterase 4 (PDE4) inhibitors (roflumilast)
LABA (e.g., indacaterol, olodaterol)
Long acting muscarinic antagonists2 (LAMA) (eg 
umeclidinium, aclidinium, glycopyrronium)
LAMA/LABA combinations
Theophyllines
Sodium cromoglycate and nedocromil sodium
Anti-leukotrienes
Long term antibiotic therapy
Participants receiving antibiotics for long term 
therapy are not eligible for the study.
(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)
Systemic, oral, parenteral corticosteroids
30 days
(During the study oral/systemic corticosteroids may 
be used for ≤14 days to treat COPD 
exacerbations/pneumonia) 
Intra-articular injections are allowed
Any other investigational drug
30 days or 5 half lives whichever is longer. 
1 (rescue albuterol/salbutamol will be provided and is permitted during the study)                               
2  Does not include tiotropium, which must be taken for at least 3 months prior to screening.
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
47
6.3.
Randomisation Criteria
At the end of the run-in period (Visit 2), study participants must fulfil the following 
additional criteria in order to be randomised into the study and enter the treatment period.
1. CAT score at Randomisation (Visit 2)

Participants with CAT score <10 at Randomisation (Visit 2) will be excluded.
2. Compliance with run-in study medication
Compliance with each run-in study medication will be assessed by the 
Investigator, any participant <80 % or >120 % compliant with either of the two 
inhalers (ELLIPTA or Handihaler) will be excluded.
3. COPD exacerbation or pneumonia

Participants that experiences a moderate or a severe COPD exacerbation or 
pneumonia during the run-in period will be excluded. 
4. Changes in COPD medication

Any participant that requires a change in COPD medication from tiotropium 
(18 mcg) and rescue medication (albuterol/salbutamol) during the run-in period 
will be excluded. This includes a temporary change in COPD medication. 
6.4.
Lifestyle Restrictions

Participants should refrain from smoking 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.
6.5.
Pre-screening/Screening/Run-in/Randomisation Failures
A participant will be assigned a participant number at the time the informed consent is 
signed at Visit 0.
The study site will be responsible for reporting pre-screen failures. The following 
information will be collected in the electronic case report form (eCRF) for participants 
who are pre-screen failures: demographic information including race, age and gender; 
participant number; SAE information only for any SAE considered to be related to study 
participation.
A minimal set of information is required to ensure transparent reporting of screening/run-
in/randomisation 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, screening/run-in/randomisation
failure details, eligibility criteria, and any SAEs. Further details are provided in the study-
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
48
specific eCRF completion guidelines. For the purposes of this study, pre-screening 
failures, screening failures, run-in failures and randomisation failures will be defined as 
follows:
Pre-screening failures: those participants that sign the informed consent document but 
do not have a Visit 1 (Screening) procedure.
Screening failures: those participants that complete at least Visit 1 (Screening) 
procedure but do not enter the run-in period. A participant who completes Visit 1 
assessments and is dispensed the study medication for the run-in period is considered to 
have entered the run-in period.
Run-in failures: those participants that enter the run-in period but do not have any Visit 
2 (Randomisation) procedures, or those participants that complete at least one Visit 2 
(Randomisation) procedure but do not enter the double-blind study treatment period. Any 
participant who completed the run-in period and meets the randomisation criteria and is 
dispensed the double-blind study treatment at Visit 2 is considered to have entered the 
treatment period.
7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participants
according to the study protocol.
7.1.
Treatment Groups and Duration
Participants who meet all the eligibility criteria and who have successfully completed all 
protocol procedures at Screening will enter the 4-week run-in period and will take open-
label tiotropium 18 mcg via the HandiHaler once daily plus placebo via the ELLIPTA. 
Following the run-in period, participants who meet randomisation criteria will be 
randomised (1:1) to one of the following double-blind, double-dummy treatment groups
for 84 days:
Either:
FF/UMEC/VI 100/62.5/25 mcg via the ELLIPTA once daily in the morning
+  placebo to match tiotropium via HandiHaler once daily in the morning
or,
Tiotropium 18 mcg via HandiHaler once daily in the morning
+ placebo via the ELLIPTA once daily in the morning
The ELLIPTA contains 30 doses (FF/UMEC/VI or placebo) and participants will be
instructed to administer one dose from their ELLIPTA once daily in the morning.
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
49
Tiotropium or matching placebo: Contents of 1 capsule (18 mcg) inhaled once daily 
using HandiHaler device. Note: To ensure drug delivery, two inhalations of the contents 
of each capsule should be performed.
Descriptions of the study treatments administered via the ELLIPTA and the Handihaler 
are provided in Table 2 and Table 3 respectively.
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
50
Table 2
Description of FF/UMEC/VI Inhalation Powder in ELLIPTA™
FF/UMEC/VI 
First strip 
Second strip 
GW685698 blended with 
lactose
GW642444 and GSK573719 
blended with lactose and 
magnesium stearate
Dosage Form 
ELLIPTA with 30 doses (2 strips with 30 blisters per strip)
Unit Dose 
Strengths 
100 mcg 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
Placebo to match 
First strip
Second strip
Lactose
Lactose/Magnesium Stearate
Dosage Form
ELLIPTA with 30 doses (2 strips with 30 blisters per strip)
Unit Dose 
Strengths
NA
Dry white powder
Physical 
description
Dry white powder
NA
Route of 
Administration
Inhaled
Table 3
Description of Tiotropium bromide in HandiHaler
Tiotropium 18 mcg
HandiHaler
Dosage form
Capsule
Unit dose strength
18 mcg
Physical description 
Hard gelatin capsule containing 18mcg 
tiotropium bromide blended with lactose
Route of administration
Inhaled
Placebo to match Tiotropium
HandiHaler
Dosage form
Capsule
Unit dose strength
NA
Physical description 
Hard gelatin capsule containing lactose
Route of administration
Inhaled
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
51
7.1.1.
Medical Devices

The GSK ELLIPTA medical device will be provided for use in this study.

The other medical device (not manufactured by or for GSK provided) for use in this
study is the Handihaler.

GSK medical device incidents, including those resulting from malfunctions of the
device, must be detected, documented, and reported by the investigator throughout 
the study. (see Section 9.2.10).
7.2.
Dose Modification
No dose modifications are planned for this study.
7.3.
Method of Treatment Assignment
Participants will be assigned to study treatment in accordance with the randomisation 
schedule. The randomisation code will be generated by using a validated computerised 
system. Participants will be randomised using an Interactive Web Response System 
(IWRS). The study will use central-based randomisation to allocate treatments. Once a 
randomisation number is assigned to a participant it cannot be reassigned to any other 
participant in the study. 
7.4.
Blinding
This will be a double-blind study and the following will apply. 

The Investigator or treating physician may unblind a participant’s treatment 
assignment only in the case of an emergency OR in the event of a serious 
medical condition when knowledge of the study treatment is essential for the 
appropriate clinical management or welfare of the participant as judged by the 
Investigator. 

Investigators have direct access to the participant’s individual study treatment. 

It is preferred (but not required) that the Investigator first contacts the Medical 
Monitor or appropriate GSK study personnel to discuss options before unblinding 
the participant’s treatment assignment. 

If GSK personnel are not contacted before the unblinding, the Investigator must 
notify GSK within 24 hours after unblinding, but without revealing the treatment 
assignment of the unblinded participant, unless that information is important for 
the safety of participants currently in the study. 

The date and event or condition which led to the unblinding (i.e. the primary 
reason) will be recorded in source documentation and in the eCRF. 
Should a participant’s treatment assignment be unblinded then the participant may 
continue the assigned study treatment and be followed-up as per protocol until the 
completion of the Safety Follow-up assessments.
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
52
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any participant with an SAE. If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of the 
report, identifying the participant’s treatment assignment, may be sent to Investigators in 
accordance with local regulations and/or GSK policy. Participants will not be withdrawn 
from the study.
Masking of tiotropium and placebo to tiotropium capsules
This study will use a double-dummy design for dosing, whereby participants will be 
given two inhalers (ELLIPTA and Handihaler). All participants and site personnel 
involved in efficacy and safety assessments will be blinded to assigned treatment during
the study. Tiotropium capsules have trade markings that are not present on the placebo 
capsules. This study has a parallel-group design which ensures the capsule type will be
consistent for each participant for the duration of the study. In addition, tiotropium and 
placebo capsules will be closely matched in colour. Both the tiotropium and placebo 
blister packages will be covered with opaque over-labels with the intent of hiding the 
information on the tiotropium packaging. The HandiHaler dry powder inhalers will be 
covered with labels to mask identifying marks on the inhaler. Investigator and site 
personnel involved in efficacy and safety assessments will be instructed not be present
when a participant administers his/her study medication at clinic visits, to guard against 
the possibility of personnel involved in the collection of efficacy and safety data,
identifying the capsules removed from the blisters. Sites are required to have study 
treatment dosed, dispensed and accounted for by site personnel that are not involved in 
any efficacy or safety assessments.
7.5.
Preparation/Handling/Storage/Accountability
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are 
reported and resolved before use of the study treatment.
Only participants enrolled in the study may receive study treatment and only authorized 
site staff may supply or administer study treatment. All study treatments must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the Investigator and 
authorized site staff.
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
Further guidance and information for the final disposition of unused study treatment are 
provided in the Study Reference Manual (SRM). 
Under normal conditions of handling and administration, study treatment is not expected 
to pose significant safety risks to site staff. Take adequate precautions to avoid direct eye 
or skin contact and the generation of aerosols or mists. In the case of unintentional 
occupations exposure notify the monitor, Medical Monitor and/or GSK study contact.
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
53
A Material Safety Data Sheet (MSDS) describing occupational hazards and 
recommended handling precautions will be provided to the Investigator, where is this 
required by local laws, or is available upon request from GSK.
7.6.
Treatment Compliance
When participants are dosed at the site, they will receive study treatment under medical 
supervision.  The date and time of each dose administered in the clinic will be recorded in 
the eCRF.  The dose of study treatment and study participant identification will be 
confirmed at the time of dosing by a member of the study site staff.  
When participants self-administer study treatment(s) at home, compliance with study 
treatment will be assessed through querying the participant during the site visits and 
recording the number of doses remaining in the ELLIPTA and the number of capsules of 
tiotropium bromide (or matching placebo) dispensed and taken by each participant, in the 
eCRF (see SRM for details).
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 
those participants who continue to be non-compliant.  Participants who continue to be 
non-compliant after multiple visit assessments may be permanently discontinued from 
study treatment after consultation with the GSK clinical team.
7.7.
Concomitant Therapy
All COPD medications used within 3 months prior to screening and during the run-in and 
study treatment periods (including the post-treatment period) should be recorded in the 
eCRF. 
All non-COPD medications taken during the study (after randomisation including post-
treatment) 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 are to be recorded.
Note: Study provided albuterol/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 randomised treatment phase of the study 
(Visit 4) or started after discontinuation of study treatment must be recorded in the eCRF 
up to the safety follow-up (Visit 6). 
7.7.1.
Permitted Medications and Non-Drug Therapies
7.7.1.1.
Permitted COPD Medications
The following COPD medications are permitted during the run-in and study treatment
periods: 
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
54

Study supplied albuterol/salbutamol metered dose inhaler (MDI) or nebules (must be 
withheld for at least 4 hours prior to spirometry testing)

Mucolytics such as acetylcysteine

Long term oxygen therapy.  (To be eligible to enter the study at Visit 1, participants
who are on LTOT must be using at a flow rate of ≤3 liters/minute at rest.  However, 
oxygen therapy may be adjusted as deemed medically necessary at any time during 
the run-in or treatment phases 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 %)

Maintenance phase of pulmonary rehabilitation treatment (participants are not 
allowed to initiate treatment during the study)
The following COPD medications are permitted during the study treatment period: 

Oral or injectable corticosteroids (short course ≤14 days) only for the short term 
treatment of COPD exacerbations and/or pneumonia

Antibiotics (short course ≤14 days) for the short term treatment of COPD 
exacerbations and/or pneumonia

Any COPD medication deemed medically necessary for the short term treatment 
(≤14days) of a moderate/severe COPD exacerbation or pneumonia
7.7.1.2.
Permitted Non-COPD Medications
The following non-COPD medications are permitted during the run-in and study 
treatment periods:

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)
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
55

Systemic and ophthalmic beta-blockers. (Administer with caution as systemic 
beta-blockers block the pulmonary effect of beta-agonists, and may produce severe 
bronchospasm in participants with reversible obstructive airways disease. 
Cardioselective 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 electrocardiogram [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)
7.7.2.
Prohibited Medications and Non-Drug Therapies
Use of the medications listed in Table 4 is not permitted during the study.
Table 4
Concomitant Medications
Medication Prohibited during the randomised treatment period
Inhaled short-acting anticholinergics
Inhaled short-acting beta2 agonists 1
Inhaled short-acting anticholinergic/short-acting beta2-agonist combination products
Inhaled corticosteroids (ICS)
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
56
Medication Prohibited during the randomised treatment period
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 therapy 2
Systemic, oral, parenteral corticosteroids 3
Any other investigational drug
1 (rescue albuterol/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 albuterol/salbutamol, mucolytics and 
oxygen) are prohibited during the run-in and randomised treatment periods of the study 
except during the treatment of a moderate/severe COPD exacerbation or pneumonia. In 
the event of an exacerbation or 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 or pneumonia.  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.
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
57
7.8.
Treatment after the End of the Study
Participants will not receive any additional treatment from GSK after completion of the 
study because other treatment options are available. 
The Investigator is responsible for ensuring that consideration has been given to the post-
study care of the participant’s medical condition.
At the end of the treatment period (Visit 5), or after study treatment Discontinuation 
Visit, or withdrawal from study, participants can resume conventional COPD therapy as 
prescribed by the Investigator.  Post-treatment concomitant medication should be entered 
into the eCRF until the safety follow-up visit for participants that successfully complete 
Visit 5 on study treatment and for participants that withdraw from the study.  For 
participants that discontinue study treatment, post-treatment concomitant medication 
should be entered into the eCRF until they complete the visit/telephone contact at the 
planned Visit 6 date.
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
Participants that permanently stop study treatment should return to the clinic as soon as 
possible, in order to complete the Study Treatment Discontinuation Visit. The evaluations 
and procedures to be completed are outlined in the SoA (Section 2). 
Participants that discontinue study treatment 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 by telephone contact. Ideally, participants 
should return to the clinic to complete Visit 5, to collect important spirometry data, 
however, if this isn’t possible, this visit should also be completed by telephone. A safety 
follow-up phone call (Visit 6) should also be conducted 7 days after Visit 5. 
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 withdrawal from the study

COPD exacerbations 

Concomitant medication

Spirometry (Visit 5 only, if participant consents)
Participants have the right to discontinue study treatment before the end of the study. A 
participant may also be asked to discontinue study treatment at the Investigator’s 
discretion. 
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
58
A participant may be withdrawn from study treatment at any time. A reason for 
premature discontinuation of study treatment (e.g., AE, lack of efficacy, protocol 
deviation, Investigator discretion, consent withdrawn etc.) must be captured in the 
eCRF.Protocol defined criteria for discontinuation of study treatment
A participant must be permanently discontinued from study treatment if any of the 
following stopping criteria are met: 

Liver chemistry stopping and increased monitoring criteria have been designed 
to assure participant safety and evaluate liver event etiology (in alignment with the 
FDA premarketing clinical liver safety guidance). These protocol guidelines are in 
alignment with FDA premarketing clinical liver safety guidance: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM174090.pdf.
Discontinuation of study treatment for abnormal liver tests should be considered by 
the Investigator when a participant meets one of the conditions outlined in the 
algorithm or if the Investigator believes that it is in the best interest of the 
participant.
Liver Safety Algorithms and Required Actions and Follow up Assessments can be 
found in Appendix 4.

Pregnancy: Positive urine pregnancy test.

QTc Stopping Criteria: 
Details on performing ECG assessments can be found in Section 9.4.3

The same QT correction formula must be used for each individual participant
to determine eligibility for and discontinuation from the study.  This formula 
may not be changed or substituted once the participant has been enrolled.
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)
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
59
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.
See the SoA for data to be collected at the time of treatment discontinuation and follow-
up and for any further evaluations that need to be completed.
8.1.1.
Rechallenge
8.1.1.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed.
8.2.
Withdrawal from the Study
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, 
compliance or administrative reasons.
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records.
In the event of early withdrawal from the study, every effort should be made to have the 
participant to return to the clinic for a Study Treatment Discontinuation Visit and Safety 
Follow-up, and to return all study related materials. Assessments to be performed during 
the Study Treatment Discontinuation Visit and the Safety Follow-up contact are 
described in the Schedule of Activities table (Section 2).
Participants that have previously discontinued study treatment (and have already 
completed the Study Treatment Discontinuation Visit) but then decide they no longer 
wish to participate in the study, may withdraw from the study by contacting the site by 
telephone. 
If the participant withdraws from the study at least 7 days after the Study Treatment 
Discontinuation Visit was completed, the safety follow-up contact (Visit 6) can be 
conducted at the time the participant notifies the site of their intention to withdraw from 
the study. Alternatively, the safety follow-up contact should be conducted 7 days after the 
Study Treatment Discontinuation Visit, if the participants consents to be contacted.  
8.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
60

The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow up, the Investigator or designee 
must make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 
9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA (Section 2). 

Protocol waivers or exemptions are not allowed 

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

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.

No study related procedures may be performed until the informed consent form 
has been signed by the participant. A Pre-Screening visit (Visit 0) is required in 
order to administer the informed consent before any changes are made to the 
participant’s current medical regimen.  Selection and modification of the 
participant’s medications prior to study participation is based on the physician’s 
judgment according to sound medical practice, principles, and each participant’s 
needs.  A participant’s treatment must not be changed merely for the purpose of 
enabling the participant’s participation in the study.
During the Pre-Screening visit (Visit 0) the following information will be captured in the 
eCRF for each participant: 

Demographic information including race, age and gender

Participant number

Register visit in IWRS
The additional following critical baseline assessments will be conducted at Screening 
(Visit 1):
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
61

Medical history including COPD history (comprised of COPD type [emphysema 
and/or chronic bronchitis]), smoking history, COPD exacerbations history, 
smoking status and previous and/or current medical conditions.

Demography

Concomitant Medications

COPD exacerbation assessment (documented history of exacerbation(s))

Cardiovascular medical history/risk factors

Inclusion/Exclusion criteria 

Physical examination (including oropharyngeal examination)

Pulse rate, blood pressure measurements

12-lead ECG

Pre- and post-albuterol/salbutamol spirometry (reversibility)

SAE assessment (if related to study participation)

Chest X-Ray or (historical radiograph obtained within 3 months prior to 
screening)

Laboratory assessments (chemistry and hematology, hepatitis and pregnancy 
testing)

CAT

Administer and dispense run-in study treatment
In addition the following procedures must be completed at Screening (Visit 1):

Smoking cessation counseling

Register visit in IWRS

Dispense albuterol/salbutamol
9.1.
Efficacy Assessments
The timings of all efficacy assessments are specified in the SoA (Section 2).
9.1.1.
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 screening and 
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, 
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
62
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.
Spirometry must be performed as follows:

Started approximately between 6:00AM and 11:00AM.

If applicable, after completing the health outcomes assessments (CAT should be 
administered first followed by SGRQ-C)

After withholding albuterol/salbutamol for 4 hours. 

At Screening (Visit 1), before the morning dose of their usual COPD medication.  

At Randomisation (Visit 2) and all treatment visits, before the morning dose of study 
treatment.

Participants should refrain from smoking 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.
A full description of the timing and conduct of spirometry procedures is provided in the 
SRM.
9.1.1.1.
Reversibility
At Visit 1, both pre- and post-albuterol/salbutamol spirometry will be obtained.  Post-
albuterol/salbutamol FEV1 and FEV1/FVC findings will be used to determine participant
eligibility.  
Reversibility testing will be completed as follows:  Following pre-albuterol/salbutamol 
spirometry (three acceptable spirometry efforts), the participant will self-administer 4 
puffs of albuterol/salbutamol MDI using a spacer/valved-holding chamber.  Three 
acceptable spirometry efforts will be obtained approximately 10 to 30 minutes after 
albuterol/salbutamol administration.
9.1.2.
SGRQ-C
The St George’s Respiratory Questionnaire-Chronic Obstructive Pulmonary Disease 
specific (SGRQ-C) will be completed by participants at Randomisation (Visit 2), Day 28
(Visit 3), and Day 84 (Visit 4).  When the SGRQ-C and the COPD Assessment Test 
(CAT) are collected at the same visit, the CAT should be collected prior to the SGRQ-C.
The SGRQ-C [Meguro, 2007] is a disease-specific questionnaire designed to measure the 
impact of respiratory disease and its treatment on a COPD participant’s HRQoL.  As well 
as producing an overall summary score, scores for the individual domains of symptoms, 
activity and impacts are also produced.  It has been used in studies of COPD participants
and has been translated and validated for use in most major languages.  The SGRQ-C is 
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
63
derived from the original SGRQ, and produces scores equivalent to the SGRQ instrument 
[Meguro, 2007].  
9.1.3.
COPD Assessment Test (CAT)
The CAT will be completed by participants at Screening (Visit 1), Randomisation (Visit 
2), Day 28 (Visit 3), and Day 84 (Visit 4).  CAT should be collected prior to SGRQ-C 
when collected at the same visit.
The COPD Assessment Test [Jones, 2009; Jones, 2012] is a validated, short and simple 
patient completed questionnaire which has been developed for use in routine clinical 
practice to measure the health status of patients with COPD. The CAT is an 8-item 
questionnaire suitable for completion by all patients diagnosed with COPD.  When 
completing the questionnaire, participants rate their experience on a 6-point scale, 
ranging from 0 (no impairment) to 5 (maximum impairment) with a scoring range of 0-
40. Higher scores indicate greater disease impact.
9.1.4.
COPD Exacerbations
COPD exacerbation data will be collected from the start of the randomised double blind 
treatment period (Visit 2) until the safety follow up contact at Visit 6. 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.  
Every effort should be made to conduct a chest x-ray within 48 hours of identification of 
a moderate or severe exacerbation. 
All COPD exacerbations will be recorded on the exacerbation page of the eCRF. 
Details on COPD Exacerbation Identification, Categorization and Treatment Guidelines 
are provided in Appendix 5.
9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 6
The Investigator and any designees are responsible for detecting, documenting, and
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study,
or that caused the participant to discontinue the study treatment or withdraw from the 
study (see Section 8). 
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
64
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information

Any SAEs assessed as related to study participation (e.g., study treatment, 
protocol-mandated procedures, or change in existing therapy) or related to a 
GSK product will be recorded from the time a participant consents to participate 
in the study up to and including the safety follow-up contact at Visit 6.

All AEs will be collected from the start of study treatment (Visit 2) until the 
safety follow-up contact at the time points specified in the SoA (Section 2).

Medical occurrences that begin before the start of study treatment but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the eCRF not the AE section. 

All SAEs will be recorded and reported to the sponsor or designee immediately 
and under no circumstance should this exceed 24 hours, as indicated in
Appendix 6. The Investigator will submit any updated SAE data to the sponsor 
or designee within 24 hours of it being available. 

Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the Investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study 
participation, the Investigator must promptly notify the sponsor or designee.

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.
9.2.2.
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. 
9.2.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as 
defined in Section 8.3). Further information on follow-up procedures is given in
Appendix 6.
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
65
9.2.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the Investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are 
met. 

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study treatment 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
Investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to Investigators as necessary.

An Investigator who receives an Investigator safety report describing a SAE or 
other specific safety information eg, summary or listing of SAE) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.
9.2.5.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 6 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the eCRF will 
be required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 
The CV eCRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the eCRF within one week of receipt of a CV Event data query prompting its completion. 
The Death eCRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
9.2.6.
Disease-Related Outcomes – COPD exacerbations
COPD exacerbations are an expected disease-related outcome. 
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
66
9.2.7.
COPD exacerbations should not be recorded as an adverse 
event, unless they meet the definition of an SAE (Appendix 
6).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.
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. Risk factors for pneumonia in participants
with COPD receiving FF/VI included current smokers, participants with a history of prior 
pneumonia, participants with a body mass index <25kg/m2 and participants with an FEV1
<50 % predicted.  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 a moderate or severe exacerbation 
is reported or pneumonia is suspected and recorded in the source documents and on the 
pneumonia page of the eCRF if applicable.
9.2.8.
Sentinel Events
A Sentinel Event is a GSK-defined SAE that is not necessarily drug-related but has been 
associated historically with adverse reactions for other drugs and is therefore worthy of 
heightened pharmacovigilance. Medical monitor review of all SAEs for possible Sentinel 
Events is mandated at GSK.  The medical monitor may request additional clinical 
information on an urgent basis if a possible Sentinel Event is identified on SAE review. 
The current GSK-defined Sentinel Events are listed below:

Acquired Long QT Syndrome

Agranulocytosis/Severe Neutropenia 
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
67

Anaphylaxis & Anaphylactoid Reactions 

Hepatotoxicity

Acute Renal Failure

Seizure

Stevens Johnson Syndrome/Toxic Epidermal Necrolysis
9.2.9.
Pregnancy

Details of all pregnancies in female participants will be collected after the start of 
study treatment and until the safety follow-up contact/visit.

If a pregnancy is reported, the Investigator should inform GSK within 24 hours of
learning of the pregnancy and should follow the procedures outlined in Appendix 3.

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
9.2.10.
Medical Device Incidents (Including Malfunctions)
Medical devices (spacers/holding chambers) are being provided for use in this study. In 
order to fulfil regulatory reporting obligations worldwide, the Investigator is responsible 
for the detection and documentation of events meeting the definitions of incident or 
malfunction that occur during the study with such devices. 
The definition of a Medical Device Incident can be found in Appendix 7
NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Section 9.2 and Appendix 6 of the protocol. 
9.2.10.1.
Time Period for Detecting Medical Device Incidents

Medical device incidents or malfunctions of the device that result in an incident 
will be detected, documented, and reported during all periods of the study in 
which the medical device is used. 

If the Investigator learns of any incident at any time after a participant has been 
discharged from the study, and such incident is considered reasonably related to 
a medical device provided for the study, the Investigator will promptly notify 
the Sponsor.

The method of documenting Medical Device Incidents is provided in Appendix
7.
9.2.10.2.
Follow-up of Medical Device Incidents

All medical device incidents involving an AE will be followed and reported in 
the same manner as other AEs (see Section 9.2). This applies to all participants,
including those who discontinue study treatment or the study.
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
68

The Investigator is responsible for ensuring that follow-up includes any 
supplemental investigations as indicated to elucidate the nature and/or causality 
of the incident.

New or updated information will be recorded on the originally completed form 
with all changes signed and dated by the Investigator.
9.2.10.3.
Prompt Reporting of Medical Device Incidents to Sponsor

Medical device incidents will be reported to the sponsor within 24 hours after 
the Investigator determines that the event meets the protocol definition of a 
medical device incident.

The Medical Device Incident Report Form will be sent to the sponsor 
electronically.

The same individual will be the contact for the receipt of medical device reports 
and SAE.
9.2.10.4.
Regulatory Reporting Requirements for Medical Device Incidents

The Investigator will promptly report all incidents occurring with any medical 
device provided for use in the study in order for the sponsor to fulfil the legal 
responsibility to notify appropriate regulatory authorities and other entities about 
certain safety information relating to medical devices being used in clinical 
studies.

The Investigator, or responsible person according to local requirements (eg, the 
head of the medical institution), will comply with the applicable local regulatory 
requirements relating to the reporting of incidents to the IRB/IEC.
9.3.
Treatment of Overdose
An overdose is defined as a dose greater than the total doses described above which 
results in clinical signs and symptoms.  These should be recorded by the Investigator on 
the AE/SAE eCRF pages.  In the event of an overdose of study treatment, the Investigator
should use clinical judgment in treating the overdose and contact the GSK medical 
monitor.
GSK is not recommending specific treatment guidelines for overdose and toxicity 
management. The Investigator is advised to refer to the relevant document(s) for detailed 
information regarding warnings, precautions, contraindications, adverse events, and other 
significant data pertaining to the study drug being used in this study. Such documents 
may include, but not be limited to, the IB or equivalent document provided by GSK.
9.4.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 2).
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
69
9.4.1.
Physical Examinations

A complete physical examination will include, at a minimum, assessments of the 
Skin, Cardiovascular, Respiratory, Gastrointestinal and Neurological systems.
Height,weight will also be measured and recorded.

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
9.4.2.
Vital Signs

Vital signs will be performed at the time points specified in the SoA table 
(Section 2) prior to conducting spirometry and prior to taking study treatment.

Blood pressure (systolic and diastolic) and pulse measurements will be assessed 
in the sitting position after approximately 5 minutes rest.

A single set of values will be collected and recorded in the source 
documentation and eCRF. 
9.4.3.
Electrocardiograms

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 2). All ECG measurements will be made with 
the participant in a supine position having rested in this position for 
approximately 5 minutes before each reading.

For participants who meet the QTc, protocol defined stopping criteria, triplicate 
ECGs (over a brief period of time) should be performed (Section 8.1.1).

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.
9.4.4.
Clinical Safety Laboratory Assessments

Refer to Appendix 8 for the list of clinical laboratory tests to be performed and 
to the SoA for the timing and frequency. 

The Investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the eCRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the Investigator
to be more severe than expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 5 days after the last dose of study 
treatment should be repeated until the values return to normal or baseline or are 
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
70
no longer considered significantly abnormal by the Investigator or medical 
monitor. 

If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 8, must be 
conducted in accordance with the laboratory manual and the SoA.
9.5.
Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study.
9.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
9.7.
Genetics
Information regarding genetic/ pharmacogenetic (PGx) research is included in
Appendix 9. The IEC/IRB and, where required, the applicable regulatory agency must 
approve the PGx and genetic assessments before these can be conducted.  The 
approval(s) must be in writing and will clearly specify approval of the PGx and genetic 
assessments (i.e., approval of Appendix 9).
In some cases, approval of the PGx and genetic assessments can occur after approval is 
obtained for the rest of the study.  If so, then the written approval will clearly indicate 
approval of the PGx and genetic assessments is being deferred and the study, except for 
PGx and genetic assessments, can be initiated.  When PGx and genetic assessments will 
not be approved, then the approval for the rest of the study will clearly indicate this and 
therefore, PGx and genetic assessments will not be conducted.
9.8.
Biomarkers
Biomarkers are not evaluated in this study.
9.9.
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics parameters are not evaluated in this 
study.
9.10.
Smoking Cessation Counselling
During Visits 1 and 4, or Study Discontinuation, participants will be given smoking 
cessation counselling.  This will include advice regarding the following:

the health effects that smoking may cause

the health benefits that may result with smoking cessation
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
71

discuss anti-smoking strategies that primary care physicians may be able to 
provide if participants do not feel capable of discontinuing smoking

participants may discontinue smoking at any time during the study and will not 
have to be withdrawn from the study if they do so.
The specific information to be discussed with each participant is provided in the SRM.
10.
STATISTICAL CONSIDERATIONS
10.1.
Hypotheses
The primary objective of this study is to compare single inhaler triple therapy 
(FF/UMEC/VI) with tiotropium in participants with COPD who have received tiotropium 
and continue to have symptoms as measured by CAT 10. The primary endpoint is 
trough FEV₁ at Week 24 (Day 85). The primary analysis is the comparison of this 
endpoint between FF/UMEC/VI and tiotropium.   
The null hypothesis is that there is no difference between treatment groups.
H0: T1 – T2 = 0
The alternative hypothesis is there is a difference between treatment groups.
H1: T1 – T2 0
Where T1 and T2 are the treatment means for FF/UMEC/VI and tiotropium, respectively.
10.2.
Sample Size Determination
Sample size calculation is based on the primary endpoint of trough FEV1 at Week 12 
(Day 85) and assumes 90 % power, a two-sided 1 % significance level, an estimate of 
residual standard deviation of 240 mL (based on mixed model repeated measures 
[MMRM] analyses of closed triple Phase IIb study CTT116853 in COPD participants) 
and a treatment difference of 70 mL. Under these assumptions, in total 702 evaluable 
participants (351 per treatment group) will be required.
It is estimated that approximately 10 % of participants will withdraw during the treatment 
period without providing a Day 85 trough assessment and approximately 8 % of 
participants will drop out from the 4 week run-in (including those not meeting 
randomisation criteria). Therefore approximately 848 participants will be enrolled to 4-
week run-in in order to have 780 participants randomised. 
10.3.
Populations for Analyses
For purposes of analysis, the following populations are defined:
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
72
Population
Description
All Subject Enrolled (ASE)

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.
Intent-to Treat
(ITT)

All randomised participants, excluding those who were 
randomised in error. A participant who is recorded as a screen 
or run-in failure and also randomised will be considered to be 
randomised in error. Any other participant who receives a 
randomisation number will be considered to have been 
randomised.

Displays will be based on the treatment to which the participant
was randomised.
10.4.
Statistical Analyses
10.4.1.
Efficacy Analyses
Efficacy analyses will be based on the ITT Population using only data collected on-
treatment, unless otherwise specified.
Endpoint
Statistical Analysis Methods
Primary
The primary endpoint of trough FEV1 on Day 85 will be analysed for the ITT
Population using a mixed model repeated measures (MMRM) analysis, including 
trough FEV1 recorded at each of visits, Day 28, Day 84 and Day 85. The model 
will include covariates of baseline FEV1, visit, geographical region, treatment and 
visit by baseline interaction. A visit by treatment interaction term will also be 
included to allow treatment effects to be estimated at each visit separately. The 
variance-covariance matrix will be assumed unstructured.
Estimated differences between FF/UMEC/VI and tiotropium will be presented 
together with 95 % confidence intervals (CIs) for the difference and p-values.
A “tipping point” sensitivity analysis of trough FEV1 on Day 85 will be conducted 
for the ITT Population. This will explore the impact of missing data by using 
differing assumptions regarding the mean treatment effect in participants who 
discontinue study treatment. Assumptions will include scenarios where 
participants who discontinue FF/UMEC/VI have a lower treatment effect than 
those who discontinue TIO. The analysis results will be used to explore the 
conditions under which the conclusion of superiority no longer holds.
Secondary
Secondary endpoint change from baseline in trough FEV1 on Day 28 and Day 
84 will be part of the primary endpoint analysis (MMRM).
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
73
Endpoint
Statistical Analysis Methods
Secondary endpoint change from baseline in SGRQ total score at Week 4 (Day 
28) and Week 12 (Day 84) will be analysed for the ITT Population using MMRM 
analysis, including covariates of baseline, geographical region, treatment and visit 
by baseline interaction. A visit by treatment interaction term will also be included 
to allow treatment effects to be estimated at each visit separately. The variance-
covariance matrix will be assumed unstructured.Estimated differences between 
FF/UMEC/VI and tiotropium will be presented together with 95 % CI for the 
difference and p-value.
Other
Will be described in the reporting and analysis plan.
10.4.2.
Safety Analyses
All safety analyses will be performed on the ITT Population. 
Endpoint
Statistical Analysis Methods
Primary
There is no primary safety analysis.
Secondary
The following safety endpoints will be analysed descriptively by treatment group:

Incidence of adverse events

Incidence of adverse events of special interest (AESI)  

Vital signs
Details will be described in the reporting and analysis plan
Adverse events (AEs) 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.
10.4.3.
Other Analyses
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).
10.4.4.
Interim Analyses
No interim analysis is planned for this study.
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
74
10.4.5.
Exploratory Analyses
These exploratory analyses may be provided in a separate RAP.
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
75
11.
REFERENCES
Aaron SD, Vandemheen KL, Fergusson D, Maltais F, Bourbeau J, Goldstein R,  et al. 
Tiotropium in Combination with Placebo, Salmeterol, or Fluticasone–Salmeterol for 
Treatment of Chronic Obstructive Pulmonary Disease A Randomized Trial. Ann Intern 
Med 2007; 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.
Crim C, Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, et al.  Pneumonia 
risk in COPD patients receiving inhaled corticosteroids alone or in combination: TORCH 
study results. EUR Respier J 2009;34:641-647.
De Bisschop MB, Bellou A. Anaphylaxis. Curr Opin Crit Care. 2012;18:308-317.
Dransfield MT, Bailey W, Crater G, Emmett A, O'Dell DM, Yawn B. Disease severity 
and symptoms among subjects receiving monotherapy for COPD. Prim Care Resp J 
2011; 20): 46-53.
Dransfield MT, Bourbeau J, Jones PW, Hanania NA, Mahler DA, Vestbo J, et al.  Once-
daily inhaled fluticasone furoate and vilanterol versus vilanterol only for prevention of 
exacerbations of COPD: two replicate double-blind, parallel-group, randomised 
controlled trials. Lancet Respir Med 2013;1:210-223.
Global Strategy for the Diagnosis, Management and Prevention of COPD, Global 
Initiative for Chronic Obstructive Lung Disease (GOLD) 2017. Available from:
heep://www.goldcopd.org/.
Global Strategy for the Diagnosis, Management and Prevention of COPD, Global 
Initiative for Chronic Obstructive Lung Disease (GOLD) 2013. Available from: 
http://www.goldcopd.org/.
GOLD. Global Initiative for Chronic Obstructive Lung Disease (Updated 2011). 
http://www.copdgold.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.
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
76
Jones P, Harding G, Berry P, Wiklund I, Chen W-H, Leidy N. Development and first 
validation of the COPD Assessment Test (CAT) Eur Respir J 2009; 34: 648-654 
Jones PW, Harding G, Wiklund I, Berry P, Tabberer M, Yu R, Leidy N. ‘Tests of the 
Responsiveness of the Chronic Obstructive Pulmonary Disease (COPD) Assessment Test 
(CAT) Following Acute Exacerbation and Pulmonary Rehabilitation. Chest 2012; 142:
134-140
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 randomized 
controlled study. Resp Med 2012; 106: 382-389 
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. [Epub ahead 
of print]
Meguro M, Barley EA, Spencer S, Jones PW. Development and validation of an 
improved COPD-Specific Version of the St. George Respiratory Questionnaire. Chest
2007;132:456-463.
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry. Eur Respir J. 2005;26:319-338.
Niggemann B, Beyer K. Factors augmenting allergic reactions. Allergy 2014;69:1582-
1587.
Packe GE, Cayton RM, Mashhoudi N. Nebulised ipratropium bromide and salbutamol 
causing closed-angle glaucoma. Lancet 1984;2:691.
Quanjer P, Stanojevic S, Cole T, Baur X, Hall G, Culver, BH, et al. Multi-ethnic 
reference values for spirometry for the 3-95-yr age range: The global lung function 2012 
equations. Eur Respi J 2012; 40: 1324-1343.
Sharafkhaneh A, Southard JG, Goldman M, Uryniak T, Martin UJ.  Effect of 
budesonide/formorterol pMDI on COPD exacerbations: A double-blind, randomized 
study. Respir Med 2012;106:257-268.
Siler TM, Kerwin E, Sousa AR, Donald A, Ali R, Church A. Efficacy and safety of 
umeclidinium added to fluticasone furoate/vilanterol in chronic obstructive pulmonary 
disease: results of two randomized studies. Respir Med. 2015; 109: 1155-1163.
Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S, et al A 4-year Trial of 
Tiotropium in Chronic Obstructive Pulmonary Disease. N Engl J Med 2008; 359:1543-
1554.
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
77
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.
Wolters Kluwer's Source Lx Database Hierarchical Regimen Analysis (HRA) 
Application SLED Report With Filtering On Patients Aged 18+ With COPD Only. Data 
from February 2011 through January 2012.
Wurst KE, Bushnell G, Shukla A, Muellerova H, Davis KJ. Factors Associated with 
Time to Triple Therapy in Newly Diagnosed COPD Patients in the UK General Practice 
Research Database. (2013) 29th International Conference on Pharmacoepidemiology and 
Therapeutic Risk Management, Montreal, Canada (August 25-28, 2013).  Abstract 62.
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
78
12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
AE
Adverse Event
AESI
Adverse Event of Special Interest
AF
Atrial Fibrillation
ALT
Alanine Transaminase
ASE
All Subjects Enrolled
AST
Aspartate Transaminase
ATS
American Thoracic Society
BfS
Federal Office for Radiation Protection
BMI
Body Mass Index
BPM
Beats per minute
BUD
Budesonide
BUN
Blood Urea Nitrogen
CAT
COPD Assessment Test
CI
Confidence Interval
CIOMS
Council for International Organizations of Medical Sciences
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic Obstructive Pulmonary Disease
CPRD
Clinical Practice Research Database
CT
Computerized Tomography
CV
Cardiovascular
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EOS
End of study
EXACT-RS
Exacerbations and Chronic Pulmonary Disease –
Respiratory Symptoms tool
FDA
Food and Drug Administration
FEV1
Forced expiratory volume in 1 second
FF
Fluticasone Furoate
FOR
Formoterol
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
HBsAg
Hepatitis B surface antigen
hCG
Human Chorionic Gonadotropin
HCP
Health Care Provider
HIPAA
Health Insurance Portability and Accountability Act
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
79
HIV
Human Immunodeficiency Virus
HPA
Hypothalamic-Pituitary-Adrenal
HPLC
High-Performance Liquid Chromatography
HRQoL
Health related quality of life
HRT
Hormone Replacement Therapy
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
ICS
Inhaled Corticosteroids
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IP
Investigational Product
IRB
Institutional Review Board
IWRS
Interactive Web Response System
ITT
Intent-to-Treat
IUD
Intrauterine Device
IUS
Intrauterine Hormone-Releasing System
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
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
mMRC
Modified Clinical Research Council
MMRM
Mixed-Model Repeated Measures
mPP
Modified Per Protocol
MSDS
Material Safety Data Sheet
msec
Millisecond
NA
Not Applicable
NYHA
New York Heart Association
PDE4
Phosphodiestrase 4 inhibitor
PGx
Pharmacogenetic
QTc
QT interval corrected for heart rate
QTcB
QT interval corrected for heart rate by Bazett’s formula
QTcF
QT interval corrected for heart rate by Fridericia’s formula
RAP
Reporting and Analysis Plan
RBC
Red Blood Cell
RNA
Ribonucleic acid
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
80
SAE
Serious Adverse Event
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic-Pyruvic Transaminase
SGRQ-C
St. George’s Respiratory Questionnaire for COPD patients
SMQ
Standardised MedDRA Query
SoA
Schedule of Activities
SRM
Study Reference Manual
SUSAR
Suspected unexpected serious adverse reaction
TIO
Tiotropium
TQT
Thorough QT
UK
United Kingdom
ULN
Upper Limit of Normal
UMEC
Umeclidinium
US
United States
VI
Vilanterol
WBC
White Blood Cell
WOCBP
Woman of child-bearing potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
ELLIPTA
Respimat
Spiriva Handihaler
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
81
12.2.
Appendix 2: Study Governance Considerations
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (eg, advertisements) must be submitted to an IRB/IEC by 
the Investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study Participantss. 

The Investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, 
the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations
Financial Disclosure
Investigators and sub-Investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
Informed Consent Process

The Investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study. 
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
82

Participants must be informed that their participation is voluntary. Participants
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study 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 or the participant’s 
legally authorized representative. 

Participants who are rescreened are required to sign a new ICF.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant
identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the Investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating Investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
83
Dissemination of Clinical Study Data

Where required by applicable regulatory requirements, an Investigator signatory 
will be identified for the approval of the Clinical Study Report.  The Investigator
will be provided reasonable access to statistical tables, figures, and relevant 
reports and will have the opportunity to review the complete study results at a 
GSK site or other mutually-agreeable location.

GSK will also provide the Investigator with the full summary of the study 
results.  The Investigator is encouraged to share the summary results with the 
study participants, as appropriate.

GSK will provide the Investigator with the randomisation codes for their site 
only after completion of the full statistical analysis.

The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK 
Policy.

A manuscript will be progressed for publication in the scientific literature if the 
results provide important scientific or medical knowledge.
Data Quality Assurance

All participant data relating to the study will be recorded on eCRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct 
by electronically signing the eCRF. 

The Investigator must maintain accurate documentation (source data) that 
supports the information entered in the eCRF. 

The Investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

Study monitors will perform ongoing source data verification to confirm that 
data entered into the eCRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the Investigator for 25 years from the issue of the final 
Clinical Study Report / 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. 
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
84
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 entered in the eCRF that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained. 
The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be 
available.
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The Investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or Investigator may include 
but are not limited to:

Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the Investigator

Discontinuation of further study treatment development
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
85
12.3.
Appendix 3: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s: review of Participants’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 5. 
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
86
Table 5
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: 
a.
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for Participantss in clinical studies. 
b.
Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of 
the contraceptive method. In this case two highly effective methods of contraception should be utilized during the 
treatment period.
Pregnancy Testing

WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive urine pregnancy test 
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
87

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 provided by the central 
laboratory and in accordance with instructions provided in its package insert  
Collection of Pregnancy Information
Female participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy. 

Participants will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK. Generally, follow-up will not be required for longer than 6 to 
8 weeks beyond the estimated delivery date.  

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. 

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the Investigator, will be reported to GSK
as described in Appendix 6. While the Investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 

Any female participant who becomes pregnant while participating in the study 
will immediately discontinue study medication.
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
88
12.4.
Appendix 4: 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
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) 
INR2
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

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/rechallenge participant with 

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.

Blood sample for pharmacokinetic 
analysis, obtained within 72 hours after 
last dose6

Serum creatine phosphokinase and lactate
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
89
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 

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
dehydrogenase.

Fractionate bilirubin, if total 
bilirubin2x ULN

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]). 
NOTE: not required in China

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy eCRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that partcipant 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)   
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
90
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.  
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, and who can be 
monitored weekly for 4 weeks.

Notify the GSK medical monitor within 24 hours
of learning of the abnormality to discuss 
participant safety. 

Participant can continue study treatment  

Participant must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time participant meets the liver chemistry 
stopping criteria, proceed as described above

If ALT decreases from ALT 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, et al. 
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, et al.  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;43:2363-2369.
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
91
12.5.
Appendix 5: COPD Exacerbation Identification, 
Categorization and Treatment Guidelines
12.5.1.
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

Other respiratory related disease
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
92
12.5.2.
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.
12.5.3.
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.
12.5.4.
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

Any course of oral/systemic corticosteroids started within 7 days of finishing a 
previous course will be considered as treatment for a single exacerbation
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
93
12.5.5.
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 
12.5.6.
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.  In determining this resolution date, consideration should be given to diary 
recorded symptoms and/or study participant evaluation.
12.5.7.
Guideline for assessing multiple mild exacerbations
Two mild exacerbations can be combined into one, per the Investigator’s judgement, if a 
participant’s diary reveals that the two mild COPD exacerbations are separated by no 
more than three exacerbation free days.
12.5.8.
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.
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
94
12.6.
Appendix 6: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study treatment, whether or not considered related to the 
study treatment.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the Investigator (ie, not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfill the definition of an AE 
or SAE. 

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. Also, "lack of 
efficacy" or "failure of expected pharmacological action" constitutes an AE or SAE.
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
95
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
96
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the eCRF 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
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
97
Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The Investigator will then record all relevant AE/SAE information in the eCRF.

It is not acceptable for the Investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE eCRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The Investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The Investigator is obligated to assess the relationship between study treatment and 
each occurrence of each AE/SAE.

A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The Investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
98
administration will be considered and investigated.

The Investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment.

For each AE/SAE, the Investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the Investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the Investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK.

The Investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE

The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the Investigator will provide GSK with a copy of any post-mortem 
findings including histopathology.

New or updated information will be recorded in the originally completed eCRF.

The Investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.
Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The Investigator or medically-qualified sub-Investigator must show evidence within 
the eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hours of SAE 
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
99
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 assigned SAE contact by telephone.

Contacts for SAE reporting can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
SAE Reporting to GSK via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the SAE contact.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the Investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
100
12.7.
Appendix 7: Medical Device Incidents: Definition and 
Procedures for Recording, Evaluating, Follow-up, and 
Reporting
Definition and Documentation of Medical Device Incidents
Definitions of a Medical Device Incident
The detection and documentation procedures described in this protocol apply to all GSK 
medical devices provided for use in the study. 
Medical Device Incident Definition

A medical device incident is any malfunction or deterioration in the characteristics 
and/or performance of a device as well as any inadequacy in the labeling or the 
instructions for use which, directly or indirectly, might lead to or might have led to 
the death of a participants/user/other person or to a serious deterioration in his/her 
state of health.

Not all incidents lead to death or serious deterioration in health. The nonoccurrence 
of such a result might have been due to other fortunate circumstances or to the 
intervention of health care personnel.
It is sufficient that:

An incident associated with a device happened and

The incident was such that, if it occurred again, might lead to death or a serious 
deterioration in health.
A serious deterioration in state of health can include any of the following:

Life-threatening illness

Permanent impairment of body function or permanent damage to body structure

Condition necessitating medical or surgical intervention to prevent one of the 
above 

Fetal distress, fetal death, or any congenital abnormality or birth defects
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
101
Examples of incidents

A participant, user, caregiver, or healthcare professional is injured as a result of a 
medical device failure or its misuse.

A participant’s study treatment is interrupted or compromised by a medical device 
failure.

A misdiagnosis due to medical device failure leads to inappropriate treatment.

A participant’s health deteriorates due to medical device failure.
Documenting Medical Device Incidents
Medical Device Incident Documenting

Any medical device incident occurring during the study will be documented in the 
participant’s medical records, in accordance with the Investigator’s normal clinical 
practice, and on the appropriate form.

For incidents fulfilling the definition of an AE or an SAE, the appropriate AE/SAE 
eCRF page will be completed as described in Appendix 6.

The form will be completed as thoroughly as possible and signed by the Investigator
before transmittal to the GSK.

It is very important that the Investigator provides his/her assessment of causality 
(relationship to the medical device provided by GSK) at the time of the initial report 
and describes any corrective or remedial actions taken to prevent recurrence of the 
incident.

A remedial action is any action other than routine maintenance or servicing of a 
medical device where such action is necessary to prevent recurrence of an incident. 
This includes any amendment to the device design to prevent recurrence.
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
102
12.8.
Appendix 8: Clinical Laboratory Tests

All protocol required laboratory assessments (haematology, clinical chemistry 
and urinalysis) must be conducted in accordance with the Laboratory Manual, 
and Protocol SoA (Section 2). Laboratory requisition forms must be completed 
and samples must be clearly labelled with the participant number, protocol 
number, site/centre number, and visit date. Details for the preparation and 
shipment of samples will be provided by the laboratory and are detailed in the 
Laboratory Manual. Reference for all safety parameters will be provided to the 
site by the laboratory responsible for the assessments.

All blood samples which will be taken pre-dose, will be sent to a central 
laboratory for analysis (details provided in the Laboratory Manual). Standard 
reference ranges will be used. 

If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in participant management or 
are considered clinically significant by the Investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the eCRF. 

Refer to the Laboratory Manual for appropriate processing and handling of 
samples to avoid duplicate and/or additional blood draws.

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 6.1 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the Investigator or required by local regulations.
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
103
Table 6
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
Mean Corpuscular 
Volume (MCV)
Mean Corpuscular 
Hemoglobin (MCH)
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Clinical 
Chemistry1
Blood Urea 
Nitrogen (BUN)
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase
(SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase
(SGPT)
Total Protein
Glucose 
[nonfasting]
Calcium
Alkaline 
phosphatase
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only)

Serum/urine human chorionic gonadotropin (hCG) pregnancy test (as 
needed for women of childbearing potential)2
The results of each test must be entered into the eCRF.
NOTES :
1.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 8.1 and Appendix 7 All events of ALT 3 × upper limit of normal (ULN) and 
bilirubin 2 × ULN (>35 % direct bilirubin) or ALT 3 × ULN and international normalized ratio (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).
2.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC.
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
104
12.9.
Appendix 9: Genetics
USE/ANALYSIS OF DNA

Genetic variation may impact a participant’s response to therapy, susceptibility, 
severity and progression of disease. Variable response to therapy may be due to 
genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular 
subtype of the disease being treated. Therefore, where local regulations and IRB/IEC 
allow, a 6 mL blood sample will be collected for DNA analysis.

DNA samples may be used for research related to study treatment or COPD and 
related diseases. They may also be used to develop tests/assays including diagnostic 
tests) related to study treatment or study treatments of this drug class and indication.
Genetic research may consist of the analysis of one or more candidate genes 
(including but not limited to: PIK3CD, PIK3CA, IL10, CHRNA3, CHRNA5, DNAH5, 
SUMF1, and CELSR1) or the analysis of genetic markers throughout the genome [or 
analysis of the entire genome] (as appropriate)

The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to study treatment or study treatments of this class. The 
results of genetic analyses may be reported in the clinical study report or in a 
separate study summary.

In the event of DNA extraction failure, a replacement genetic blood sample may be 
requested from the participant. Signed informed consent will be required to obtain a 
replacement sample unless it was included in the original consent.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained while research on study treatment (or study treatments 
of this class) or indication continues but no longer than 15 years after the last 
participant last visit or other period as per local requirements.

Withdraw Process:  If a participant withdraws consent, the Investigator must 
complete the Genetic Sample Destruction Request Form, which will be provided to 
the site in the Investigator Site File.

Destruction Process:  After the specified storage period of 15 years or on 
withdrawal of consent, samples will be destroyed by incineration.  Samples that are 
sent for testing to vendors are returned or destroyed as part of the formal agreement 
and a full record of chain of custody is maintained.  A laboratory information 
management system (LIMS) is used to track and identify samples for destruction.
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
105
12.10.
Appendix 10: Country-specific requirements
There are currently no country specific requirements. 
 
2019N398531_00


2017N323364_01
CONFIDENTIAL
207626
106
12.11.
Appendix 11: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).
 
2019N398531_00

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
207626
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Effective Date: Should correspond with the date of last RAP approval. For example, if 
the final Lead Author and Programmer Line Managers / Designees approved on different 
days, the date the last person approved is documented as the effective date.
Title
:
Reporting and Analysis Plan for Study 207626:  A Phase IV, 
12 week, randomised, double-blind, double-dummy study to 
compare single inhaler triple therapy, fluticasone 
furoate/umeclidinium/vilanterol (FF/UMEC/VI), with 
tiotropium monotherapy based on lung function and 
symptoms in participants with chronic obstructive pulmonary 
disease
Compound Number 
:
GSK2834425 (GW685698 + GSK573719 + GW642444)
Effective Date 
:
30-JUL-2019
Description:
The purpose of this reporting and analysis plan (RAP) is to describe the planned analyses 
and output to be included in the Clinical Study Report for Protocol 207626.
This document will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable and will serve as a detailed guide for the 
programming team.
RAP Author(s):
Author 
Date
24-Jul-2019
Associate Director, Biostatistics, PAREXEL International
 
2019N398531_00
PPD


CONFIDENTIAL
The GlaxoSmithKline group of companies
207626
2
RAP Team Review Confirmations 
(Method: E-mail)
Reviewer
Date
Lead Study Statistician, Principal Statistician (Respiratory 
Clinical Statistics)
25-Jul-2019
Programming Manager
(Respiratory Clinical Programming)
25-Jul-2019
Medical Director (Safety Evaluation and Risk Management, 
Global Clinical Safety and Pharmacovigilance)
25-Jul-2019
Medical Director (Safety Evaluation and Risk Management, 
Global Clinical Safety and Pharmacovigilance)
24-Jul-2019
Director (Respiratory, Clinical Development)
25-Jul-2019
Clinical Investigation Lead, Clinical Development Director 
(Respiratory Therapy Area Unit)
26-Jul-2019
Clinical Development Operations Manager (Respiratory Projects 
Clinical Platforms and Sciences)
29-Jul-2019
Physician Project Leader, Director (Respiratory Discovery 
Medicine)
25-Jul-2019
Principal Clinical Data Manager (Respiratory Data Management)
25-Jul-2019
 
2019N398531_00
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


CONFIDENTIAL
The GlaxoSmithKline group of companies
207626
3
Reviewer
Date
Director (Respiratory Regulatory Affairs)
29-Jul-2019
Director, Respiratory Patient Centered Outcomes (Value 
Evidence and Outcomes)
29-Jul-2019
Global Medical Affairs Leader, Respiratory (GMAL Trelegy)
27-Jul-2019
Medical Affairs Lead, Respiratory Medical Franchise
29-Jul-2019
Manager, Medical Writing & Clinical Submission Planning
25-Jul-2019
Manager, Medical Writing & Clinical Submission Planning
25-Jul-2019
 
2019N398531_00
PPD
PPD
PPD
PPD
PPD
PPD


CONFIDENTIAL
The GlaxoSmithKline group of companies
207626
4
Clinical Statistics & Clinical Programming Line Approvals 
(Method: Pharma TMF eSignature)
Approver
Date
30-Jul-2019
Lead Statistician Line Manager, Senior Statistics Director 
(Respiratory Clinical Statistics)
 
30-Jul-2019
Programming Manager (Respiratory Clinical Programming)
Copyright 2019 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
2019N398531_00
PPD
PPD


CONFIDENTIAL
207626
5
TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................8
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................8
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................8
2.2.
Study Objectives and Endpoints .................................................................10
2.3.
Study Design ..............................................................................................11
2.4.
Statistical Hypotheses / Statistical Analyses ...............................................13
3.
PLANNED ANALYSES ..........................................................................................14
3.1.
Interim Analyses .........................................................................................14
3.2.
Final Analyses ............................................................................................14
4.
ANALYSIS POPULATIONS ...................................................................................14
4.1.
Protocol Deviations.....................................................................................14
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................16
5.1.
Study Treatment & Sub-group Display Descriptors.....................................16
5.2.
Baseline Definitions ....................................................................................16
5.3.
Multicentre Studies .....................................................................................17
5.4.
Examination of Covariates, Other Strata and Subgroups............................17
5.4.1.
Covariates and Other Strata ........................................................17
5.4.2.
Examination of Subgroups...........................................................17
5.5.
Multiple Comparisons and Multiplicity .........................................................17
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................17
6.
STUDY POPULATION ANALYSES .......................................................................19
6.1.
Overview of Planned Study Population Analyses........................................19
7.
EFFICACY ANALYSES..........................................................................................20
7.1.
Primary Efficacy Analyses ..........................................................................20
7.1.1.
Endpoints / Variables...................................................................20
7.1.2.
Summary Measure ......................................................................20
7.1.3.
Population of Interest...................................................................20
7.1.4.
Strategy for Intercurrent (Post-Randomization) Events ................20
7.1.4.1.
Primary estimand .......................................................20
7.1.4.2.
Supplementary estimand............................................20
7.1.5.
Statistical Analyses / Methods .....................................................21
7.1.5.1.
Statistical Methodology Specification..........................21
7.2.
Secondary Efficacy Analyses......................................................................23
7.3.
Other Efficacy Analyses..............................................................................24
7.3.1.
Endpoints / Variables...................................................................24
7.3.2.
Summary Measure ......................................................................24
7.3.3.
Population of Interest...................................................................24
7.3.4.
Strategy for Intercurrent (Post-Randomization) Events ................24
7.3.5.
Statistical Analyses / Methods .....................................................24
 
2019N398531_00


CONFIDENTIAL
207626
6
7.3.5.1.
Statistical Methodology Specification..........................25
7.3.5.1.1.
SGRQ total score and CAT score...........25
7.3.5.1.2.
Responder according to SGRQ 
and CAT score........................................25
7.3.5.1.3.
Exacerbations.........................................26
8.
SAFETY ANALYSES .............................................................................................27
8.1.
Adverse Events Analyses ...........................................................................27
8.2.
Adverse Events of Special Interest Analyses..............................................28
8.3.
Other Safety Analyses ................................................................................28
9.
REFERENCES.......................................................................................................29
10. APPENDICES........................................................................................................30
10.1.
Appendix 1:  Protocol Deviation Management ............................................30
10.2.
Appendix 2:  Schedule of Activities .............................................................31
10.3.
Appendix 3:  Assessment Windows ............................................................34
10.4.
Appendix 4:  Study Phases and Treatment-Emergent Adverse 
Events ........................................................................................................35
10.4.1.
Study Phases ..............................................................................35
10.4.1.1.
Study Phases for Concomitant Medication .................35
10.4.1.2.
Study Phases for Other Data......................................37
10.4.2.
Treatment-Emergent Flag for Adverse Events and 
Exacerbations..............................................................................38
10.5.
Appendix 5:  Data Display Standards & Handling Conventions...................39
10.5.1.
Reporting Process .......................................................................39
10.5.2.
Reporting Standards....................................................................39
10.6.
Appendix 6:  Derived and Transformed Data ..............................................41
10.6.1.
General........................................................................................41
10.6.2.
Study Population..........................................................................41
10.6.3.
Efficacy........................................................................................46
10.6.4.
Safety ..........................................................................................48
10.7.
Appendix 7:  Reporting Standards for Missing Data....................................51
10.7.1.
Premature Withdrawals................................................................51
10.7.2.
Handling of Missing Data.............................................................51
10.7.2.1.
Handling of Missing Dates..........................................52
10.7.2.2.
Handling of Partial Dates............................................52
10.7.2.3.
Handling of Missing Data for Statistical 
Analysis......................................................................53
10.8.
Appendix 8:  Abbreviations & Trade Marks .................................................54
10.8.1.
Abbreviations...............................................................................54
10.8.2.
Trademarks .................................................................................55
10.9.
Appendix 9:  List of Data Displays ..............................................................56
10.9.1.
Data Display Numbering..............................................................56
10.9.2.
Mock Example Shell Referencing ................................................56
10.9.3.
Deliverables.................................................................................56
10.9.4.
Study Population Tables..............................................................57
10.9.5.
Study Population Figures.............................................................61
10.9.6.
Efficacy Tables ............................................................................62
10.9.7.
Efficacy Figures ...........................................................................64
10.9.8.
Safety Tables...............................................................................65
10.9.9.
Safety Figures .............................................................................68
 
2019N398531_00


CONFIDENTIAL
207626
7
10.9.10. ICH Listings .................................................................................69
10.9.11. Non-ICH Listings..........................................................................71
10.10. Appendix 10:  Example Mock Shells for Data Displays ...............................74
10.10.1. Tables..........................................................................................74
10.10.2. Listings ......................................................................................147
10.10.3. Figures ......................................................................................189
 
2019N398531_00


CONFIDENTIAL
207626
8
1.
INTRODUCTION
NOTE: The RAP may also include any pre-defined analyses for publication purposes.
The purpose of this reporting and analysis plan is to describe the analyses to be included 
in the Clinical Study Report for Study 207626:  A Phase IV, 12-week, randomised, 
double-blind, double-dummy study to compare single inhaler triple therapy, fluticasone 
furoate/umeclidinium/vilanterol (FF/UMEC/VI), with tiotropium monotherapy based on 
lung function and symptoms in participants with chronic obstructive pulmonary disease 
(COPD).
Insert revision chronology as detailed within the protocol.
Protocol Revision Chronology:
2017N323364_00
11-OCT-2017
Original Protocol
2017N323364_01
17-JUL-2018
Protocol amendment 01
2.
SUMMARY OF KEY PROTOCOL INFORMATION
Best Practice: Author to copy from the protocol for applicable RAP sections with 
flexibility to include additional clarification, if required.
Where feasible, every effort should be made to reference the protocol.
Lead RAP author to carefully consider whether information included the RAP would be 
more beneficial rather than referencing the protocol.
Information contained in this section of the RAP may promote greater clarity in defining 
the planned analyses for RAP end-users (i.e. CS, CP & RAP Team, outsourced partners
or regulatory agencies).
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Detail to Include: Outline & fully justify (where applicable) changes to the planned 
protocol analysis.
If there are no changes or deviations from the protocol, then specify within this section.
Changes from the originally-planned statistical analysis specified in the protocol are 
outlined in Table 1.
Table 1
Changes to Protocol-Defined Analysis Plan
Protocol
Reporting & Analysis Plan
Rationale for Change
Section 10.3 (“Populations for 
Analysis”) reads in part, “All 
randomised subjects, excluding 
those who were randomised in error. 
A participant who is recorded as a 
The verbatim protocol text will 
be amended in Section 4 of this 
document to read, “All 
randomised participants, 
excluding those who were 
Clarification of the definition of 
“randomized in error.” 
 
2019N398531_00


CONFIDENTIAL
207626
9
Protocol
Reporting & Analysis Plan
Rationale for Change
screen or run-in failure but was also 
randomised will be considered to be 
randomised in error. Any other 
participant who receives a 
randomisation number will be 
considered to have been 
randomised.”
randomised in error. A 
participant who is recorded as a 
screen or run-in failure and also 
randomised, but did not receive 
a dose of study treatment, will 
be considered to be randomised 
in error. Any other participant
who receives a randomization 
number will be considered to 
have been randomised.”
Use of the word “subject.”
Text in this document will use 
the word “participant” in lieu of 
the word “subject,” except in the 
following cases:
1.
In the phrase “subject 
listing”
2.
In the phrase “subject 
number”
3.
In the definition of and 
abbreviation for the 
protocol-defined All 
Subjects Enrolled 
population
4.
Titles and content of 
prospectively-defined 
statistical output 
generated in GSK’s 
HARP system.
5.
Use as part of the 
syntax in the SAS 
programming 
language.
Decision by GSK’s R&D Clinical 
Data Standards Board (CDSB), 
published on GSK’s Intranet 18th
June 2018.  The text below is 
excerpted from this published 
notice:
Until an industry-wide resolution 
has been achieved, the R&D 
Clinical Data Standards Board 
(CDSB) has decided to continue 
with the discrepant 
terminologies and ask teams to:

Data Quality Lead; add a 
note to the Reviewers 
Guide in submissions that 
the term "Subjects" is used 
to refer to a “Participants” in 
the protocol.

Statistician to add the same 
note to RAPs to say that all 
displays (Tables, Figures & 
Listings) will use the term 
'Subjects'. 
RAP text will refer to 
"Participants" in-line [sic] with 
the master RAP template and 
protocol.
Refinements of descriptions of 
efficacy analyses.
This document identifies the 
primary and supplementary 
estimand, and describes the 
four attributes of each, the 
population (Section 7.1.3, , 
Section 7.3.3), the variable of 
interest (Section 7.1.1, Section 
7.3.1), the intercurrent events of 
interest (Section 7.1.4, Section 
7.3.4), and the summary 
measure(s) of interest (Section 
7.1.2, Section 7.3.2).
Issuance by International 
Conference on Harmonization of 
an addendum to the ICH E9 
guidance that outlines the 
concept of the estimand and its 
four components.  Industry 
adoption of the concepts 
outlined in this addendum 
began after finalization of this 
study protocol.
 
2019N398531_00


CONFIDENTIAL
207626
10
2.2.
Study Objectives and Endpoints
State the study objectives and endpoints EXACTLY as specified in the protocol.
Additional clarification may also be included to further describe objectives / endpoints 
(i.e. if not described in other sections of the RAP). It should be highlighted if this 
additional information is not in the protocol.
Objectives
Endpoints
Primary Objective
Primary Endpoint
To evaluate the effect of single inhaler 
triple therapy (FF/UMEC/VI) compared to 
Tiotropium after 12 weeks of treatment on 
lung function 
Change from baseline in trough forced expiratory volume in 1 
second (FEV1) at Week 12 (Day 85)
Secondary Endpoint
Changes from baseline in trough FEV1 at Week 4 (Day 28) and 
Week 12 (Day 84)
Other Objectives
Other Endpoints
To evaluate the effect of single inhaler 
triple therapy (FF/UMEC/VI) compared to 
Tiotropium after 12 weeks of treatment on 
Health Status

Proportion of responders based on the St George’s 
Respiratory Questionnaire (SGRQ) Total Score at Week 4 
and Week 12

Change from baseline in SGRQ Total Score at Week 4 and 
Week 12
To evaluate the effect of single inhaler 
triple therapy (FF/UMEC/VI) compared to 
Tiotropium after 12 weeks of treatment on 
Health Status

Proportion of responders based on the COPD Assessment 
Test (CAT) Total Score at Week 4 and Week 12

Change from baseline in CAT Total Score at Week 4 and 
Week 12
To evaluate the effect of single inhaler 
triple therapy (FF/UMEC/VI) compared to 
Tiotropium after 12 weeks of treatment on 
COPD exacerbations
Moderate or severe exacerbation events
Safety Objective
Safety Endpoints
To evaluate the safety profile of single 
inhaler triple therapy (FF/UMEC/VI) 
compared to Tiotropium over 12 weeks of 
treatment

Incidence of adverse events

Vital signs
 
2019N398531_00


CONFIDENTIAL
207626
11
2.3.
Study Design
Protocol: Reference protocol where applicable and ONLY include supportive 
information.
For example, any elements which may impact or inform the planned analyses or facilitate 
development, review and execution of the RAP.
Protocol Schematic Recommended: Utilised from the protocol (i.e. use ‘cut’ option 
within .pdf version of the protoocl and paste accordingly) but DO NOT repeat 
information which is apparent from the schematic, instead include bulleted points
(recommended) or text descriptions to capture key study design information.
Points for Consideration: May include the following (and others as appropriate), so as 
to aid understanding of statistical methods and elements impacting analyses:
Design Configuration
Experimental Design (e.g. parallel, crossover, factorial, single group, SMART 
(sequential multiple assignment randomized trial)) and other design elements as required 
(e.g. dose-escalation, multicentre).
Control Method (e.g. placebo, active comparator, low dose, historical, or none [i.e. 
uncontrolled]).
Blind Level (e.g. open-label, single-blind, single-blind (sponsor unblinded), double-
blind, double-blind (sponsor unblinded), matching placebos, double-dummy).
Sequence and Duration of All Study Periods (e.g. including pre-randomization, single-
and double-blind treatment periods, washout, and post-treatment periods)
Sequential Multiple Assignment Randomized Trial (SMART) Designs (e.g. 
highlights that treatment switch can be built into the study design and doesn’t have to be 
a ‘problem’ that is solved during analysis.  SMARTs eliminate confounding with rescue 
therapy through sequential randomization.  It indirectly highlights that one can compare 
treatment policies with specific frontline and rescue therapies, and not just perform an 
ITT analysis. 
Copy of Schedule of Events: If included in the Appendix add a link, otherwise delete.
Dosing Information
Dose Regimens in Each Study Period & Stage (e.g. including frequency of 
administration (e.g., twice daily).
Method & Criteria for Individualizing Dosing (e.g. subject weight or plasma 
concentrations).
 
2019N398531_00


CONFIDENTIAL
207626
12
Rules for Dose Changes: Include flexible dosing; modifications in dosage & frequency 
of dose changes or adjustments; dose reductions, interruptions or tapering and permanent 
discontinuation for reasons of efficacy or safety (e.g., planned interim analysis with 
statistical stopping rules or use of an Independent Data Monitoring Committee [IDMC]), 
re-challenges, and any circumstances for resuming treatment).
Treatment Assignment
Method of Assignment to Treatment (e.g., randomization, stratification, minimisation
or specify as appropriate if not randomized and is open label).
Randomization Procedures (e.g. centralized, site-based or adaptive allocation (i.e. such 
as assignment on the basis of earlier assignment or outcome).
Method of Generating Randomization Schedule & Assignment (e.g. RandAll NG or 
other and whether interactive voice response system was used (i.e. RAMOS NG).
Utilisation of Blocking: To maintain blind, DO NOT includes the block size.
Adapt & expand accordingly to the study design and apply the principal features 
illustrated. 
Overview of Study Design and Key Features
Design 
Features

12-week treatment period

Randomized

Double-blind

Double-dummy

Parallel-group
 
2019N398531_00


CONFIDENTIAL
207626
13
Overview of Study Design and Key Features

1-week safety follow-up

Approximately 848 [participants] with advanced COPD will enter the run-in, in order to 
randomize approximately 780 [participants], in order to achieve an estimated 702 
evaluable [participants].

A study with 702 evaluable [participants] for the primary analysis will have 90% power to 
demonstrate superiority of FF/UMEC/VI to tiotropium based on trough FEV1 at Week 12 
(Day 85), at the two-sided 1% significance level, and estimates of residual standard 
deviation of 240mL and a treatment difference of 70mL.

[Participants] will be provided with short-acting albuterol/salbutamol to be used on an as-
needed basis (rescue medication) throughout the study.

[Participants] who permanently discontinue double-blind study treatment are not required 
to withdraw from the study. [Participants] who have permanently discontinued study 
treatment and have not withdrawn consent will be encouraged to continue in the study 
and complete all remaining protocol specified clinic visits as indicated in the Schedule of 
Activities (Protocol Section 2).
Dosing
Randomized treatments are:

FF/UMEC/VI (100/62.5/25 mcg) via ELLIPTA once daily (QD) in the morning

Tiotropium 18 mcg via HandiHaler QD in the morning
Time & 
Events
Refer to Section 10.2 (“Appendix 2: Schedule of Activities”).
Treatment 
Assignment

4-week run-in on open-label tiotropium (via the HandiHaler) and placebo (via the 
ELLIPTA)

Randomization 1:1 to FF/UMEC/VI or tiotropium
PAREXEL software and Interactive Web Response System (IWRS) will be used to 
generate the randomization schedule and for treatment allocation. Centralized 
randomization will be used.
Interim 
Analysis
No interim analyses are planned.
2.4.
Statistical Hypotheses / Statistical Analyses
The primary objective of this study is to compare single inhaler triple therapy 
(FF/UMEC/VI) with tiotropium in participants with COPD who have received tiotropium 
and continue to have symptoms as measured by a COPD Assessment Test (CAT) score 
≥10. The primary endpoint is the mean change from baseline in trough FEV₁ at Week 12 
(Day 85). The primary analysis is the comparison of this endpoint between FF/UMEC/VI 
and tiotropium.
The null hypothesis is that there is no difference between treatment groups (i.e., H0:  T1 
– T2 = 0) in the mean change from baseline in trough FEV1 at Week 12 (Day 85), and 
the alternative hypothesis is there is a difference between treatment groups (i.e., H1:  T1 
– T2 ≠ 0), where T1 and T2 are the treatment means for FF/UMEC/VI and tiotropium, 
respectively.
 
2019N398531_00


CONFIDENTIAL
207626
14
3.
PLANNED ANALYSES
3.1.
Interim Analyses
No interim analyses are planned.
3.2.
Final Analyses
The final planned primary analyses will be undertaken after the completion of the 
following sequential steps:
1.
All participants have completed the study or have been withdrawn as defined in the 
protocol.
2.
All required database-cleaning activities have been completed and final database 
release has been declared by GSK Data Management.
3.
All criteria for unblinding the randomization codes have been met and the final 
database has been locked. 
4.
Randomization codes have been distributed per PAREXEL and PAREXEL 
Informatics’ standard operating procedures and treatment details have been 
unblinded.
5.
Database freeze has been declared by GSK Data Management.
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
All Subjects 
Enrolled (ASE)
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. 
Study disposition and 
SAEs for non-
randomized 
participants
Intent-To-Treat 
(ITT)
All randomised participants, excluding those who were 
randomised in error. A participant who is recorded as a 
screen or run-in failure and also randomised but who did 
not receive any dose of study treatment will be considered 
to be randomised in error. Any other participant who 
receives a randomisation number will be considered to 
have been randomised. 
Displays will be based on the treatment to which the 
participant was randomised.
Study Population, 
Efficacy, Safety
4.1.
Protocol Deviations
Important protocol deviations (as defined in the Protocol Deviations Specification Form 
[PDSF]), include deviations related to study inclusion/exclusion criteria, conduct of the 
 
2019N398531_00


CONFIDENTIAL
207626
15
trial, patient management, and patient assessment.  All protocol deviations will be tracked 
by the study team throughout the conduct of the study in accordance with the PDSF.
Data will be reviewed prior to unblinding and freezing the database to ensure that all 
deviations are captured and categorised on the protocol deviations dataset.  This dataset 
will be the basis for the summaries and listings of protocol deviations.
Important protocol deviations will be summarized by treatment group.  A separate 
summary and listing of all inclusion and exclusion criterion deviations will also be 
provided.  This summary will be based on data recorded on the inclusion/exclusion page 
of the electronic case report form (eCRF).
 
2019N398531_00


CONFIDENTIAL
207626
16
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
PAREXEL Informatics Randomization and Trial 
Management System
Data Displays for Reporting 
Code
Description
Description
Order in output 
A
FF/UMEC/VI 100/62.5/25 mcg 
ELLIPTA
FF/UMEC/VI 100/62.5/25
1
B
Tiotropium 18 mcg HandiHaler
TIO 18
2
Treatment comparisons will be labelled “FF/UMEC/VI 100/62.5/25 vs. TIO 18”.
5.2.
Baseline Definitions
The baseline value of all endpoints, except as noted in baseline definitions, will be the 
latest pre-first-dose assessment with a non-missing value, including those from 
unscheduled visits.  If time is not collected, Day 1 (Visit 2) assessments are assumed to 
be taken prior to first dose and will be used as baseline.
Baseline Definitions 
Parameter
Study Assessments Collected prior to 
dosing
Baseline Definition
Screening 
(Visit 1)
Day 1 Pre-Dose 
(Visit 2)
Efficacy
Trough FEV1
FVC*
X
X
Day 1, defined as the average of 
the two pre-dose measurements
If one of the measurements is 
missing, then the baseline will be 
the single remaining value.
SGRQ Total Score
X
Day 1
CAT score
X
X
Day 1
Safety 
Vital signs
X
Most recent individual value prior 
to first dose (either Screening or a
repeat test).  Systolic and diastolic 
blood pressure values should 
come from the same assessment.
*: FVC is not a protocol specified efficacy endpoint.
 
2019N398531_00


CONFIDENTIAL
207626
17
5.3.
Multicentre Studies
It is anticipated that approximately 83 sites from the United States and Europe (Poland
and the Russian Federation) will participate in the study.  Therefore, it is likely that many 
centres will enrol very small numbers of participants.  Consequently, all centres within 
each country will be pooled.
Enrolment will be summarized and presented by country and centre.  “Geographical 
region” is denoted in the protocol as a covariate in the statistical models assessing several 
efficacy measures:  for the purposes of these analyses, two geographical regions will be 
defined:  Europe (Poland and the Russian Federation) and the United States.
5.4.
Examination of Covariates, Other Strata and Subgroups
5.4.1.
Covariates and Other Strata
No stratification was used in this study.
Covariates to be included in the statistical analyses as outlined in Section 7 (“Efficacy 
Analyses”) of this document are baseline and geographical region.  Additional covariates 
may also be considered in an ad hoc manner at the discretion of the study team, and if 
considered, would be addressed in the Clinical Study Report.
5.4.2.
Examination of Subgroups
No subgroup analyses are planned.
5.5.
Multiple Comparisons and Multiplicity
Given that there are only two treatments under consideration in this study, there is only 
one treatment comparison, that between FF/UMEC/VI and tiotropium.
No multiplicity adjustments are planned for secondary and other endpoints.
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions
Section Aim: Details have been moved to appendices to facilitate review of the main 
body of the RAP. If appendices are not relevant for the study, they should be deleted and 
the list updated.
Flexibility to include details using sub-sections within this section, if required.
Other considerations for data analyses and data handling conventions are outlined in the 
following Appendices:
 
2019N398531_00


CONFIDENTIAL
207626
18
Section
Component
10.3
Appendix 3: Assessment Windows
10.4
Appendix 4: Study Phases and Treatment Emergent Adverse Events
10.5
Appendix 5: Data Display Standards & Handling Conventions
10.6
Appendix 6: Derived and Transformed Data
10.7
Appendix 7: Reporting Standards for Missing Data
 
2019N398531_00


CONFIDENTIAL
207626
19
6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population summaries will be based on the ITT Population, unless otherwise 
specified.
Study population summaries of participant disposition, protocol deviations, demographic 
and baseline characteristics, prior and concomitant medications, and treatment 
compliance will be based on GSK International Data Standards Library (IDSL) Core 
Data Standards.
 
2019N398531_00


CONFIDENTIAL
207626
20
7.
EFFICACY ANALYSES
7.1.
Primary Efficacy Analyses
The primary efficacy analysis will assess the difference between treatments in the context 
of superiority of FF/UMEC/VI over tiotropium.
7.1.1.
Endpoints / Variables
Where applicable, describe the method for combining measurements to create composite 
variables. Flexibility to include this information in Appendix 6: Derived and Transformed 
Data.
The primary efficacy variable is the mean change from baseline in trough FEV1.
7.1.2.
Summary Measure
The summary measure of interest is the adjusted mean treatment difference in trough 
FEV1 on Day 85.
7.1.3.
Population of Interest 
The primary efficacy analyses will be based on the ITT population.
7.1.4.
Strategy for Intercurrent (Post-Randomization) Events
Discontinuation of randomized study treatment is considered an intercurrent event for the
estimands.
7.1.4.1.
Primary estimand
The primary treatment effect to be estimated will be the hypothetical effect if all 
participants had stayed on their randomised treatment.  Trough FEV1 collected up to the 
time of treatment discontinuation will be used in the analysis.  Trough FEV1 collected 
after treatment discontinuation will be set to missing.  Missing data will be assumed to be 
missing at random (MAR). 
7.1.4.2.
Supplementary estimand
The supplementary treatment effect to be estimated will be the treatment policy effect of 
initial randomised treatment.  All recorded data up to the time of study withdrawal will be 
included in the analysis, regardless of discontinuation of study treatment.  Missing data 
will be assumed to be MAR. This supplementary treatment effect will only be estimated 
if >5% of the ITT subjects discontinued the randomized study treatment and have 
spirometry assessment at Visit 5 .
 
2019N398531_00


CONFIDENTIAL
207626
21
7.1.5.
Statistical Analyses / Methods
Unless otherwise specified, endpoints / variables defined in Section 7.1.1 (“Endpoints / 
Variables”) will be summarised using descriptive statistics, graphically presented (where 
appropriate), and listed.
Trough FEV1 will be summarized based on the estimand strategies detailed in Section 
7.1.4.1 (“Primary estimand”) and Section 7.1.4.2 (“Supplementary estimand”).  
7.1.5.1.
Statistical Methodology Specification
Endpoints / Variables

Primary endpoint: Change from baseline in trough FEV1 at Day 85

Secondary endpoint: Change from baseline in trough FEV1 at Day 28 and Day 84
Model Specification

The primary model of interest is a mixed model repeated measures (MMRM) analysis, including trough 
FEV1 recorded at Day 28, Day 84, and Day 85.  The model will include baseline FEV1, visit, 
geographical region, and treatment as covariates and visit-by-baseline FEV1 and visit-by-treatment 
interaction terms.  The visit-by-treatment interaction term is included to allow treatment effects to be 
estimated at each visit separately.  

The variance-covariance matrix will be assumed to be unstructured.

While missing data are not explicitly imputed in the primary MMRM analyses, there is an underlying 
assumption that the data are missing at random. All available on-treatment assessments will be utilized 
and via modeling of the within-subject correlation structure, the derived treatment differences will be 
adjusted to take into account missing data.

Two models will be fitted; one with a response variable of trough FEV1, and one with a response 
variable of change from baseline in trough FEV1.

The model will utilize the OBSMARGINS (OM) option to generate a dataset with a row for every 
participant-visit combination that contains all the covariates and a macro variable containing the mean 
baseline for the participants included in the analysis. This is used to derive the adjusted means using 
coefficients which are based on the participants in the analysis.
Model Checking & Diagnostics

The Kenward and Roger method (KR) for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used.  In the event 
the model fails to run using the KR method, then the residual method will be used instead.

Distributional assumptions underlying the model used for analysis will be examined by generating a 
normal probability plot of the residuals and a plot of the residuals versus the fitted values (i.e. checking 
the normality assumption and constant variance assumption of the model respectively) to gain 
confidence that the model assumptions are reasonable.  These plots will not be included as part of the 
statistical output detailed in Section 10.9 (Appendix 9: List of Data Displays).
Model Results Presentation

Least square (LS) means and LS mean changes from baseline with their corresponding standard 
errors and 95% confidence intervals (CIs) will be presented for each treatment by visit, together with 
 
2019N398531_00


CONFIDENTIAL
207626
22
estimated treatment differences (FF/UMEC/VI vs. TIO) and the corresponding 95% CIs and p-values.

A plot of LS mean changes from baseline and 95% CIs from the model will be generated for 
each treatment by visit.
Subgroup Analyses
No subgroup analyses are planned.
Supportive Analyses - Interactions
The interactions between treatment and other factors will be investigated in the primary analysis as follows 
by adding interaction terms to the statistical model:
An assessment of whether the effect of treatment on trough FEV1 is modified by either 
geographic region or baseline FEV1 will be made by fitting separate repeated measures 
models, identical to the primary analysis models described above but also including 
additional terms as described below.

The primary analysis model will be used with an additional treatment-by-geographical 
region interaction term and a treatment-by-geographical region-by visit interaction 
term. The p-value for the treatment-by-geographical region interaction at Day 85 will 
be computed using contrast statements.  If that p-value is ≥ 0.10 then the interaction 
will be considered not to be statistically significant. If the p-value is < 0.10, further 
investigation will be undertaken, for example by running the primary analysis by 
geographic region.

The primary analysis model will be used with an additional treatment-by-baseline FEV1
interaction term and a treatment-by-baseline FEV1-by-visit interaction.  The p-value for 
the treatment-by-baseline interaction at Day 85 will be obtained using contrast 
statements.  If that p-value is ≥ 0.10 then the interaction will be considered to be not 
statistically significant. If the p-value is < 0.10, further investigation will be undertaken, 
for example by running the analysis by dichotomous categories of baseline FEV1
values (values above and below the median).
Sensitivity and Supportive Analyses
If the overall rate of discontinuation from study treatment is > 5%, a sensitivity analysis for the 
supplementary estimand (i.e., the Treatment Policy estimand) will be undertaken to address the 
statistical assumptions made in the primary analysis regarding missing data and the primary 
statistical hypothesis.  This sensitivity analysis of the Treatment Policy estimand of trough FEV1 on 
Day 85 will be conducted as follows:
A “tipping point” sensitivity analysis of trough FEV1 at Day 85 will be undertaken for the ITT
Population.  This analysis will explore the impact of missing data by using differing assumptions
regarding the mean treatment effect in participants who discontinue study treatment.  Mean 
treatment effects investigated will range from a change from baseline trough FEV1 of -150 mL to 
+150 mL in increments of 50 mL.  For each value of the assumed mean change from baseline for
FF/UMEC/VI, the full range of values for the assumed mean change from baseline for Tio will be 
investigated, thus including scenarios where participants who discontinue FF/UMEC/VI have a 
lower treatment effect than those who discontinue Tio and vice versa.  The analysis results will be 
used to explore the conditions under which the conclusion of superiority no longer holds.
For each participant with missing data at Day 85, a value will be imputed based
 
2019N398531_00


CONFIDENTIAL
207626
23
on a random draw from a normal distribution with mean equal to the corresponding
assumed mean change from baseline and standard deviation taken from the observed
change from baseline data for the combined treatment arms at the Day 85 visit.  Data for
participants with missing baseline values will not be imputed.  Analysis of the complete Day 85 
dataset will be carried out using an ANCOVA model with covariates of treatment group,
geographical region, region and baseline.  A table will be produced displaying the p-values for the 
treatment difference at Day 85 under the above assumptions for the mean changes from baseline 
in each treatment arm.
7.2.
Secondary Efficacy Analyses
A single statistical model will include data from Days 28, 84, and 85, hence evaluation of 
the secondary efficacy variables of trough FEV1 on Days 28 and 84 will be incorporated 
into the primary efficacy analysis.  See Section 7.1 (“Primary Efficacy Analyses”) for 
details.
 
2019N398531_00


CONFIDENTIAL
207626
24
7.3.
Other Efficacy Analyses
The following efficacy analysis will assess the difference between treatments in the 
context of superiority of FF/UMEC/VI over tiotropium.
7.3.1.
Endpoints / Variables
The following endpoints will be used to assess the superiority of FF/UMEC/VI over 
tiotropium:

SGRQ total score

Proportion of population identified via SGRQ total score as responders

CAT score 

Proportion of population identified via CAT score as responders

Moderate / severe COPD exacerbations
7.3.2.
Summary Measure
The proportions of participants identified as responders based on the SGRQ total score 
and CAT score at Day 28 and Day 84 will be summarized and analysed by visit and 
treatment group.
Mean values and changes from baseline in SGRQ total score and CAT score on Days 28 
and 84 will be summarized by visit and treatment in terms of summary statistics 
including means, standard deviations, medians, minima, 1st and 3rd quartiles, and 
maxima.  The treatment comparison of FF/UMEC/VI to tiotropium will be assessed in 
terms of the mean treatment difference at Day 28 and Day 84.
COPD exacerbations will be summarized by treatment in terms of incidence of on-
treatment and post-treatment events.
7.3.3.
Population of Interest
The summaries and analyses of SGRQ and CAT data and their associated responder 
summaries and analyses, as well as the summaries of exacerbation incidence, will be 
based on the ITT population.
7.3.4.
Strategy for Intercurrent (Post-Randomization) Events
All endpoints will use the same strategy for intercurrent events as defined in Section 7.1.4
for the primary estimand.
7.3.5.
Statistical Analyses / Methods
Relevant displays will be based on GSK data standards and statistical principles.
 
2019N398531_00


CONFIDENTIAL
207626
25
Unless otherwise specified, endpoints and variables defined in Section 7.3.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate), and 
listed.
7.3.5.1.
Statistical Methodology Specification
7.3.5.1.1.
SGRQ total score and CAT score
Endpoint / Variables

Change from baseline in SGRQ total score at Days 28 and 84.

Change from baseline in CAT score at Days 28 and 84.
Model Specification

Similar model to that described above in Section 7.1.5.1 (“Statistical Methodology Specification”) 
for the primary efficacy analysis.  

Two models will be fitted; one with a response variable of SGRQ total score/CAT score and one 
with a response variable of change from baseline in SGRQ total score/CAT score.
7.3.5.1.2.
Responder according to SGRQ and CAT score
Endpoint / Variables

Proportion of responders according to SGRQ total score at Days 28 and 84.

Proportion of responders according to CAT score at Days 28 and 84.
Model Specification

The proportions of responders as determined by SGRQ total score/CAT score will be analyzed 
using a generalized linear mixed mode. The model will include terms for baseline score, 
geographical region, treatment, visit, and visit by baseline and visit by treatment interactions. TIO 
will be used as the reference level for treatment.

The model will be fit with an unstructured variance-covariance matrix with a single model to 
include all visits (Days 28 and 84).  

Computation of CIs for the odds ratios will be based on the individual Wald tests.

See Section 10.7.2.3 (“Handing of Missing Data for Statistical Analysis”) for details on how to 
handle missing data.
Model Checking & Diagnostics

Pearson residuals will be plotted by using PLOTS=RESIDUALPANEL option for the model 
statement in SAS.
Model Results Presentation

The number and percentage of responders and non-responders at each visit will be summarized 
by treatment group. The odds ratio, 95% CI, and p-value will be presented for FF/UMEC/VI vs. 
tiotropium
 
2019N398531_00


CONFIDENTIAL
207626
26
7.3.5.1.3.
Exacerbations
Endpoint
Incidence of moderate/severe exacerbations.
Model Specification
No formal statistical model is proposed.  The annual raw exacerbation rate, together with the total 
treatment exposure, will be summarized by treatment group.
Details of the exacerbations will also be summarized by treatment group and will include the 
following elements:
the number and percent of participants reporting an exacerbation, both overall and by 
severity (mild, moderate, severe, and moderate/severe)
number and percent of participants by number of moderate/severe exacerbations (0, 1, 
>2), 
frequency distribution of treatment for the exacerbation
frequency distribution of severity
frequency distribution of outcome
simple summary of the duration of the exacerbation
On- and post-treatment exacerbations will be summarized separately.
 
2019N398531_00


CONFIDENTIAL
207626
27
8.
SAFETY ANALYSES
The safety analyses will be based on the ITT population, unless otherwise specified.
8.1.
Adverse Events Analyses
Adverse events (AEs) analyses will be based on GSK Core Data Standards.
Serious adverse events (SAEs) associated with study participation will be collected from 
the point of informed consent onward.  All AEs, including all SAEs, will be collected 
starting from randomization, and will be summarised and displayed by randomised 
treatment group.  The onset date of the adverse events relative to the blinded treatment 
start and stop dates will be used to determine in which period an adverse event occurs.
The AE text recorded in the eCRF will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA), and will be reported using the primary System Organ 
Class (SOC) and Preferred Term (PT). The number of participants with one or more 
events of any type will be calculated.  Results will be displayed in the order of decreasing 
frequency, both across SOC and within SOC.  A SOC will not be included if no AEs in 
that SOC are reported.  If the total incidence for any two or more AEs is equal, the events 
will be presented in alphabetical order. 
Adverse events will also be listed, with SOC, event (preferred term), treatment group, 
number of participants with the event, and specific subject numbers.  Demographic 
details (e.g. age, gender and race), as well as details of the individual adverse events, will 
be included in these listings.  Listings will be sorted within participant by the date of 
onset of the AE.
The following by-treatment AE summaries will be provided:

On-treatment AEs

Post-treatment AEs

On-treatment drug-related AEs

Pre-treatment SAEs

On-treatment SAEs

Post-treatment SAEs

On-treatment fatal AEs

On-treatment drug-related SAEs

Pre-treatment SAEs leading to withdrawal from study

On-treatment AEs leading to withdrawal from study

On-treatment AEs leading to discontinuation of study treatment

On-treatment AEs of special interest (AESI)

On-treatment common non-serious AEs

10 most frequent on-treatment AEs in each treatment group
o
In case of ties in frequency, all AEs of that frequency will be displayed

Standard summary for Food and Drug Administration Amendments Act 
(FDAAA) report

Standard summary for European Clinical Trials Database (EudraCT) report
 
2019N398531_00


CONFIDENTIAL
207626
28
In addition, the following listings of AE data will be provided:

Subject numbers for all AEs

Subject numbers for AESI

All AEs

Non-fatal SAEs

Fatal AEs

AEs leading to withdrawal from study

AEs leading to discontinuation of study treatment

Criteria for determining SAEs
8.2.
Adverse Events of Special Interest Analyses
The table in Section 10.6.4 (“Safety”) presents the groups of Adverse Events of Special 
Interest (AESI).  Groups which are not standardized MedDRA queries comprise a 
selection of PTs defined by GSK.  The complete list, including the PTs that contribute to 
each of the groups, will be provided by Safety and Medical Governance using the 
MedDRA version current at the time of reporting.  This list will be finalized prior to 
unblinding.
A comprehensive list of MedDRA terms based on clinical review will be used to identify 
each type of event.  Changes to the MedDRA dictionary may occur between the start of 
the study and the time of reporting.  Furthermore, emerging data from on-going studies 
may highlight additional adverse events of special interest.  Therefore, the list of terms to 
be used for each event of interest and the specific events of interest will be based on the 
safety review team (SRT) agreements in place at the time of reporting.
8.3.
Other Safety Analyses
Summary statistics of vital signs collected at Visit 1 (Screening) and Visit 4 (Week 12), 
and change from screening baseline values will be presented by treatment group. Vital 
signs collected at the Study Treatment Discontinuation Visit and on the Pneumonia 
Details eCRF form will be included in ‘minimum/maximum post-baseline’ summaries 
but will not be summarized separately.
On- and post-treatment bone fractures collected on the Fractures Details eCRF form and 
on- and post-treatment pneumonia assessments collected on the Pneumonia Details eCRF 
form will be summarised separately by treatment group. A summary of chest x-rays (on-
and post-treatment) will include data from the Exacerbation Chest X-ray and Pneumonia 
Chest X-ray eCRF pages.
12-lead ECG findings (normal, abnormal – not clinically significant, abnormal –
clinically significant) collected at Visit 1 (Screening) will be summarized with frequency 
distributions by treatment group. Screening lab results will be summarised with 
descriptive statistics by treatment group.
Any pregnancies reported during the study will be summarized in CSR case narratives. 
Any pregnancy complication or elective termination of a pregnancy for medical reasons 
will be recorded as an AE or SAE and included in summaries and listings of AEs/SAEs.
 
2019N398531_00


CONFIDENTIAL
207626
29
9.
REFERENCES
GlaxoSmithKline Document Number 2017N323364_00, 207626, A Phase IV, 12 week, 
randomised, double-blind, double-dummy study to compare single inhaler triple therapy, 
fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI), with tiotropium 
monotherapy based on lung function and symptoms in participants with chronic 
obstructive pulmonary disease, 11-OCT-2017
GlaxoSmithKline Document Number 2017N323364_01, 207626, A Phase IV, 12 week, 
randomised, double-blind, double-dummy study to compare single inhaler triple therapy, 
fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI), with tiotropium 
monotherapy based on lung function and symptoms in participants with chronic 
obstructive pulmonary disease, 17-JUL-2018
Jones PW and Forde Y. (2016) St. Georges Repository Questionnaire for COPD Patients 
Manual, version 1.3.
Kon, SS, et al.  Minimum clinically important difference for the COPD Assessment Test: 
a prospective analysis.  Lancet Respir Med. 2014;2(3):195-203. 
Meguro M, Barley EA, Spencer S, Jones PW. Development and validation of an improved 
COPD-Specific Version of the St. George Respiratory Questionnaire. Chest 
2007;132(2):456-63.
 
2019N398531_00


CONFIDENTIAL
207626
30
10.
APPENDICES
10.1.
Appendix 1: Protocol Deviation Management
No Per-Protocol Population is defined in this study; hence, no data will be excluded from 
planned analyses due to protocol deviations.  However, protocol deviations will be 
monitored during the study, and important protocol deviations will be identified as 
detailed in the Protocol Deviation Specification Form prior to reporting.  Details of the 
summary and listing of protocol deviations can be found in Section 4.1 (“Protocol 
Deviations”).
 
2019N398531_00


CONFIDENTIAL
207626
31
10.2.
Appendix 2: Schedule of Activities
Protocol Activity 
Pre-Screen 
Screen 
Treatment
Follow-up
Visit 0
Visit 1 
Screen / Run-in 
Visit 2 
Randomization 
Visit 3 
Visit 4 
Visit 5 
Study Treatment 
Discontinuation 
Visit 
Visit 6 Safety 
Follow-up 
Contact 
Study Day 
Day -56 to -28
Day- 28
Day 1
Day 28
Day 84
Day 85 
Day 91 
Week 
-8 to -4 
-4 
0 
4 
12 
12 
13 
Window 
-3 / +8d 
(Day -31 to -21) 
-4 / +2d 
(Day 24 to 
30) 
-4 / +2d 
(Day 80 to 
86) 
-1 / +4d 
(Day 90 to 95) 
Written Informed Consent a
X 
X 
Genetic Informed Consent b
X 
X 
Demography c
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
Smoking History 
X
Smoking status 
X
X 
X 
Smoking Cessation Counselling 
X
X
X 
Register Visit in IWRS 
X 
X 
X 
X 
X 
X 
X 
CAT d
X 
X 
X 
X 
SGRQ-C d
X 
X
X 
Reversibility Testing e
X
Trough Spirometry f
X
X 
X 
X 
Device training and registration 
X 
X 
Exacerbation Assessment 
X 
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 
 
 
 
2019N398531_00


CONFIDENTIAL
207626
32
Protocol Activity 
Pre-Screen 
Screen 
Treatment
Follow-up
Visit 0
Visit 1 
Screen / Run-in 
Visit 2 
Randomization 
Visit 3 
Visit 4 
Visit 5 
Study Treatment 
Discontinuation 
Visit 
Visit 6 Safety 
Follow-up 
Contact 
Oropharyngeal examination
X 
X 
X 
X 
X 
Blood Draw for Genetics research j
X 
Hematology/biochemistry k
X
Urine Pregnancy Test l 
X
X
X
Hepatitis B and C tests 
X
Dispense run-in treatment
X
Dispense study treatment
X
X
Administer run-in treatment in clinic 
m
X
Administer study treatment in clinic n
X
X
X
Assess run-in treatment compliance
X
Collect run-in treatment
X
Assess study treatment compliance
X
X
X
Collect study treatment
X
X
X
Dispense albuterol/salbutamol
X
X
X
X
Collect albuterol/salbutamol
X
X
X
X
X
Dispense paper Medical Problems 
worksheet
X
X
X
X
X
Review paper Medical Problems 
worksheet
X
X
X
X
X
X
a. Informed consent must be conducted at the Pre-screen Visit 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. Genetics research consent may be obtained at the same time as the study informed consent and must be obtained prior to obtaining a genetic blood sample. The sample can be
collected at any time after Visit 2, providing consent is obtained. 
c. Demography may be captured at either the Pre-screen Visit or Screening Visit. 
d. SGRQ-C and CAT will be completed electronically, and should be conducted in the following order and before other study assessments: CAT, SGRQ-C. 
e. At Screening Visit 1 both pre- and post-bronchodilator spirometry will be conducted. Participants are required to withhold their usual morning doses of their COPD meds including 
rescue albuterol/salbutamol for the protocol designated period prior to reversibility testing. 
 
 
 
2019N398531_00


CONFIDENTIAL
207626
33
f. Pre-bronchodilator spirometry will be performed pre-dose at 30 mins and 5 mins prior to taking the morning dose of study treatment, between 6am and 11am and after withholding 
rescue albuterol/salbutamol for ≥4 hours. On Day 85, study drug will not be administered following spirometric assessments. 
g. Physical examination may include height, weight, blood pressure and temperature.
h. Vital signs must be performed prior to spirometry and prior to taking morning dose of study treatment. 
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. Genetic consent must be obtained prior to obtaining a blood sample. 
k. Hematology and chemistry panels will include full and differential blood count and liver chemistry. See Appendix 8 of the protocol. 
l. All female participants of child bearing potential will have a urine pregnancy test at Visits 1, 4 and Study Treatment Discontinuation Visit (if applicable). 
m. Participants must withhold their morning dose of existing COPD medication/study treatment and not take their treatment until instructed to do so by study staff.
n. Participants must withhold their morning dose of study treatment at each clinic visit and not take their study treatment until instructed to do so by study staff.
When multiple assessments and procedures are performed, suggested order is CAT, SGRQ-C, vitals, ECG, spirometry, clinical lab 
assessments.
 
 
 
2019N398531_00


CONFIDENTIAL
207626
34
10.3.
Appendix 3: Assessment Windows
In instances where multiple measurements have been collected and recorded at the same 
time point, then the first non-missing value will be used as the assessment associated with 
that time point.
In general terms, data will be reported per the nominal time of clinic visits and 
assessments as specified in the protocol. For example, if a participant’s recorded values 
for the Week 4 visit were actually made on the 21st day of treatment, they will be 
presented as Week 4 values in the summary tables.  
Participants that permanently stop study medication early between scheduled clinic visits 
should undergo all assessments listed for the Study Treatment Discontinuation Visit.  
Data collected at this visit will be listed and used in summary or analysis tables as part of 
the ‘worst case post- baseline’ summary/analysis if appropriate.  
 
2019N398531_00


CONFIDENTIAL
207626
35
10.4.
Appendix 4: Study Phases and Treatment-Emergent 
Adverse Events
10.4.1.
Study Phases
Assessments and events will be classified per time of occurrence relative to the start 
and/or stop date of the randomized study treatment. The earliest and latest exposure 
randomized study treatment start and stop dates will be used to determine whether an 
assessment or event was pre-treatment, on-treatment or post-treatment. If it is not 
possible to tell whether an assessment or event was on-treatment, it will be considered as 
on-treatment.  The ‘worst case-post baseline’ derivation for summaries will consider all 
scheduled and unscheduled measurements that have been assigned a treatment phase of 
‘On-treatment’.
10.4.1.1.
Study Phases for Concomitant Medication
COPD medication combinations taken at screening will include all COPD medications 
that were taken on the day of the screening visit, excluding medications that stopped on 
the day of the screening visit.
Treatment phases for summaries of COPD and non-COPD concomitant medications will 
be assigned as follows:
Treatment Phase
Definition
Prior to Screening
Medications taken between date of Screening – 90 days and date of 
Screening (inclusive) defined as:
(conmed start date <= date of Screening or ‘Taken prior to study?’ is 
‘Yes’) and (conmed stop date >= date of Screening – 90 or (conmed 
stop date is completely missing and date of Screening is non-missing)) 
Note: this screening data will only be summarized for COPD 
medications. All screening data will be listed.
Run-in
Medications taken any time between the date of Screening and 
Treatment Start Date (exclusive) defined as:
(conmed start date < randomized treatment start date or randomized 
treatment not started or conmed start date is missing) and (conmed 
stop date > date of Screening or (conmed stop date is completely 
missing and date of Screening is non-missing))  
On-treatment
If randomized treatment stop date > randomized treatment start date 
then this includes medications taken between the randomized treatment 
start date and randomized treatment stop date - 1 (inclusive) defined as 
follows:
(conmed start date < randomized treatment stop date or conmed start 
date is missing) and (conmed stop date >= randomized treatment start 
 
2019N398531_00


CONFIDENTIAL
207626
36
Treatment Phase
Definition
date or (conmed stop date is completely missing and randomized 
treatment start date is non-missing))
If randomized treatment stop date = randomized treatment start date 
then this includes medications taken on the randomized treatment start 
date (which is equal to the randomized treatment stop date) defined as 
follows.
(conmed start date <= randomized treatment stop date or conmed start 
date is missing) and (conmed stop date >= randomized treatment start 
date or (conmed stop date is completely missing and randomized 
reatment start date is non-missing))
Post-treatment
If randomized treatment stop date > randomized treatment start date 
then this includes medications taken between the date of randomized
treatment stop date and the date of study conclusion (inclusive) defined 
as follows:
(conmed start date <= study conclusion date or conmed start date is 
missing) and (conmed stop date >= randomized treatment stop date or 
(conmed stop date is completely missing and randomized treatment
stop date is non-missing))
If randomized treatment stop date = randomized treatment start date 
then this includes medications taken between the date of randomized 
treatment stop date + 1 and the date of study conclusion (inclusive) 
defined as follows.
(conmed start date <= study conclusion date or conmed start date is 
missing) and (conmed stop date > randomized treatment stop date or 
(conmed stop date is completely missing and randomized treatment 
stop date is non-missing))
NOTES: 

A concomitant medication will be classed in every period of the study in which it was taken (e.g., prior to 
screening, run-in, on- treatment, post-treatment). 

See Section 10.7.2.2 for handling of partial dates.
Details of the handling of partial and missing concomitant medication dates can be found 
in Section 10.7.2 (“Handling of Missing Data”).
 
2019N398531_00


CONFIDENTIAL
207626
37
10.4.1.2.
Study Phases for Other Data
Any events/assessments for participants not in the ITT population will be assigned a Pre-
treatment phase.
For all events and assessments where time is recorded, pre-treatment, on-treatment and 
post-treatment phases will be defined as below:
Study Phase
Definition
Pre-Treatment

Event onset date/time or assessment date/time < randomized treatment start 
date/time
On-Treatment

Randomized treatment start date/time ≤ event onset date/time or assessment 
date/time ≤ randomized treatment stop date + 1, or any event/assessment with a 
missing or partial onset date unless there is evidence it was not on-treatment
Post-Treatment

Event onset date/time or assessment date/time ≥ randomized treatment stop date 
+ 2, and event onset date/time or assessment date/time ≤ study conclusion date
For all events and assessments (with the exception of concomitant medications, SGRQ 
and CAT assessments) where time is not recorded, pre-treatment, on-treatment and post-
treatment phases will be defined as below:
Study Phase
Definition
Pre-Treatment

Event onset date or assessment date < randomized treatment start date
On-Treatment

Randomized treatment start date ≤ event onset date or assessment date ≤ 
randomized treatment stop date + 1, or any event/assessment with a missing or 
partial onset date unless there is evidence it was not on-treatment
Post-Treatment

Event onset date or assessment date ≥ randomized treatment stop date + 2 and 
event onset date or assessment date ≤ study conclusion date
For SGRQ and CAT assessments, pre-treatment, on-treatment and post-treatment phases 
will be defined as below:
Study Phase
Definition
Pre-Treatment

Event onset date or assessment date ≤ randomized treatment start date
On-Treatment

Randomized treatment start date < event onset date or assessment date ≤ 
randomized treatment stop date + 1, or any event/assessment with a missing or 
partial onset date unless there is evidence it was not on-treatment
Post-Treatment

Event onset date or assessment date ≥ randomized treatment stop date + 2 and 
event onset date or assessment date ≤ study conclusion date
 
2019N398531_00


CONFIDENTIAL
207626
38
10.4.2.
Treatment-Emergent Flag for Adverse Events and Exacerbations
Flag
Definition
Treatment 
Emergent
Randomized treatment Start Date ≤ AE Start Date ≤ Randomized treatment Stop Date + 
1.
NOTES: 

If the randomized treatment stop date is missing, then the AE will be considered to be On-Treatment.

Time of randomized treatment dosing and start/stop time of AEs should be considered, if collected.
 
2019N398531_00


CONFIDENTIAL
207626
39
10.5.
Appendix 5: Data Display Standards & Handling 
Conventions
10.5.1.
Reporting Process
Software
The currently supported versions of SAS software will be used to program all output described in this document.
Reporting Area
HARP Server
uk1salx00175
HARP Compound
gsk2834425/mid207626/final_01
Analysis Datasets 
Analysis datasets will be created according to CDISC standards (SDTM Implementation Guide Version 3.2 (or 
more recent, if updated after finalization of this document) & Analysis Data Model (ADaM) Implementation 
Guide Version 1.0 (or more recent, if updated after finalization of this document).
Generation of RTF Files
RTF files will be generated from output described in this analysis plan.
10.5.2.
Reporting Standards
General

All data displays (Tables, Listings and Figures) will use the term “Subject” which reflects CDISC and GSK 
Data Display Standards terminology. 

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless otherwise 
stated (IDSL Standards Location: https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 
Formats

Unless otherwise stated, all results will be reported according to the treatment to which the 
participant was randomized. However, there may be additional adhoc displays for individual participants 
using the actual treatment received.

GSK IDSL Statistical Principles (5.03 & 6.06.3) for precision (i.e., the number of decimal places 
reported) will be adopted for reporting of data based on the raw data collected.  

Numeric data will be reported at the precision collected on the eCRF or recorded in the raw dataset if 
from non-eCRF sources.

The reported precision from non eCRF sources will follow the IDSL statistical principles but may 
be adjusted to a clinically interpretable number of decimal places.

Percentages between 1% and 99%, inclusive, will be rounded to integers. Percentages greater 
than 0%, but less than 1%, will be reported as <1%, and percentages greater than 99%, but less 
than 100%, will be reported as >99%.
 
2019N398531_00


CONFIDENTIAL
207626
40
Planned and Actual Time

Reporting for tables, figures, and statistical analyses

Planned time relative to dosing will be used in figures, summaries, statistical analyses, and 
calculation of any derived parameters, unless otherwise stated.  The impact of any major 
deviation from the planned assessment times and/or scheduled visit days on the analyses and 
interpretation of the results will be assessed as appropriate.
Reporting for Data Listings
Planned and actual time relative to randomized study treatment dosing will be shown in listings (Refer 
to IDSL Statistical Principle 5.05.1).  Unscheduled or unplanned readings will be included in the data
listings.  
Unscheduled Visits

Unscheduled visits will not be included in figures or in summary tables except as a part of a 
‘minimum/maximum post-baseline’ assessment.


All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principles 7.01 to 7.13.

The programs for statistical analysis tables will create SAS datasets with the unrounded numbers 
from the statistical models to be used in any graphs.  These datasets will include all LS means, 
standard errors, treatment differences or ratios, and CIs. These analysis datasets will be created 
for all analysis tables regardless of whether a figure is planned as part of SAC.
 
2019N398531_00


CONFIDENTIAL
207626
41
10.6.
Appendix 6: Derived and Transformed Data
10.6.1.
General
Study Day

Calculated as the number of days from treatment start date (i.e., randomised treatment start date):

Reference date = missing                    → Study day = missing

Reference date < treatment start date → Study day = reference date – treatment start date

Reference date ≥ treatment start date → Study day = reference date – treatment start date +1
Randomized Treatment Start and Stop Dates

Randomized treatment start date will be defined as the earliest treatment start date. Randomized treatment 
stop date will be defined as the latest date of randomized treatment exposure date or date of last dose from 
treatment discontinuation eCRF page. Treatment stop date will be imputed as study completion date if the 
date of last dose cannot be confirmed but investigational product is returned at the end of study visit (follow 
up), or if the date of last dose can be confirmed in protocol deviation log to be after study completion date, 
or if subject completes the study and did not return the investigational product at Visit 4 and the last dose 
cannot be confirmed.
10.6.2.
Study Population
Demographics
Age
Age is calculated in the Interactive Web Response System (IWRS) and will be imported from the IWRS into 
the clinical database.
The IWRS will use GSK standard IDSL algorithms to calculate age.  In accordance with GSK policy, only 
year of birth is collected in the IWRS.  To estimate participant age, a complete birthdate will be estimated by 
using the year recorded by the IWRS and assigning month and day values of ’30JUN.’
The birth date will be presented in listings as ‘YYYY.’
Completely missing dates of birth will remain as missing, with no imputation applied.  Consequently, the age 
of the participant will not be calculated and will remain missing.
Age, in whole years, will be calculated based on the Pre-Screening Visit date (or Screening date, if pre-
screening is not evaluated).
Age Category 
Age categories are based on age at Pre-screening and are defined as:

≤64 years

65-74 years

75-84 years

≥85 years
Body Mass Index (BMI)
BMI will be calculated in the eCRF as Weight (kg) / Height (m) 2.
 
2019N398531_00


CONFIDENTIAL
207626
42
Demographics
Race
The high-level Food and Drug Administration (FDA) race categories and designated Asian subcategories 
are:
1.
Black or African Heritage
2.
American Indian or Alaska Native
3.
Asian
a.
Central/South Asian Heritage
b.
Japanese/East Asian Heritage/South East Asian Heritage
c.
Mixed Asian Heritage (only required if data exist)
4.
Native Hawaiian or other Pacific Islander
5.
White
These categories and subcategories will be summarized along with all combinations of high-level categories 
which exist in the data.  All the high-level race categories and the Asian subcategories must appear on the 
display even if there are no participants in a particular category, but combinations that do not exist in the 
data do not need to be represented.  Combinations will be represented as the concatenation of the high-
level category terms, e.g., “White & Asian”.  The designated Asian subcategories will not be summarized as 
combinations with other categories.
In addition, the standard race categories collected on the eCRF page will be summarized along with 
categories for mixed race.  The categories are:
1.
American Indian or Alaska Native
2.
Asian - Central/South Asian Heritage
3.
Asian – East Asian Heritage
4.
Asian – Japanese Heritage
5.
Asian – South East Asian Heritage
6.
Mixed Asian Heritage (only required if data exist)
7.
African American/African Heritage
8.
Native Hawaiian or other Pacific Islander
9.
White – Arabic/North African Heritage
10.
White – White/Caucasian/European Heritage
11.
White – Mixed Race
12.
Mixed Race
“Asian – Mixed Race” is only used if more than one Asian category, but no non-Asian race, is selected.  
Similarly, “White – Mixed Race” is only used if both of the White categories and no non-White races are 
selected.  If multiple races of different types are selected, then the overall “Mixed Race” category is used.
A participant will only be represented in a single category. A participant who selects a combination of races 
will be counted as “Asian – Mixed Race,” “White – Mixed Race,” or “Mixed Race,” but not in each of the 
constituent terms. Therefore, the counts will add up to the total number of participants with a response, and 
the percentages will add to 100%.
Participant Disposition 

For Kaplan-Meier plots of study withdrawal over time and discontinuation from study treatment 
over time, censoring will be performed as follows:
O
For study withdrawal, participants are represented from their Day 1 date to the date of early 
withdrawal from the study (or date of death). Participants that completed the study are 
 
2019N398531_00


CONFIDENTIAL
207626
43
Participant Disposition 
censored at the earliest of the date of completion and Day 85.
O
For discontinuation from study treatment, participants are represented from their Day 1 date 
to the date of discontinuation from study treatment (or date of death). Participants that 
complete study treatment per protocol are censored at the earliest of their study treatment 
stop date and Day 84.
Cardiovascular Risk Factors 

Participants with at least one of the following current or past medical conditions at Screening 
will be classed as having a cardiovascular (CV) risk factor. The number of CV risk factors at 
Screening (0, 1, or >=2) will be derived.       

Angina pectoris

Coronary artery disease

Myocardial infarction

Arrhythmia

Congestive heart failure

Hypertension

Cerebrovascular accident

Diabetes mellitus

Hypercholesterolemia
Smoking Status

Smoking Status at Screening is determined directly from the eCRF.

A participant’s smoking status from Visit 2 (Day 1) onwards will be derived from the smoking 
status at the visit in question and any changes in smoking status from the time of the previous 
assessment (e.g., date of any changes in status were made).  

Only smoking status responses recorded at scheduled visits will be included in the summary 
tables.
 
2019N398531_00


CONFIDENTIAL
207626
44
Treatment compliance
If a dose counter start count is missing, then it will be assumed to be 30.   If any dose counter stop 
is missing, then the treatment compliance will be set to missing for that participant and for that 
inhaler.
Compliance is calculated as follows:

ELLIPTA compliance = (dose counter start – dose counter stop) x 100 / (exposure stop date 
– exposure start date +1)

HandiHaler compliance = (number of capsules dispensed – number of capsules returned) x 
100 / (exposure stop date – exposure start date +1)

Overall Compliance = (compliance for ELLIPTA + compliance for HandiHaler) / 2. 
Overall and individual inhaler compliance will be summarized during both the run-in and randomized 
study treatment periods, and will be categorized as follows:
< 80 %
80 % to < 95 %
95 % to 105 %
>105 % to 120 %
>120 %.
If a participant received a treatment other than the randomized study treatment during the study, the 
compliance will still be calculated using data from all containers received and overall exposure start 
and stop dates.
Medical Conditions and Concomitant Medications
COPD Concomitant Medications

COPD concomitant medications will be grouped into the following RMCs based on pre-defined 
code lists derived from ATC classifications:

Antiinfectives (antibiotics, antifungals, antivirals, antiseptics)

Short-acting anticholinergic

Short-acting beta-2 agonist

Long-acting anticholinergic

Long-acting beta-2 agonist

Xanthine

PDE4 inhibitor

Corticosteroid – inhaled

Corticosteroid – depot

Corticosteroid - systemic oral parenteral and intra-articular

Corticosteroid – other

Leukotriene receptor antagonist

Nedocromil or cromolyn sodium

Mucolytic

Oxygen

Other medication given for exacerbation
 
2019N398531_00


CONFIDENTIAL
207626
45
Medical Conditions and Concomitant Medications

Other COPD medication
COPD Medication combination
COPD medications taken on the day of the Screening visit will be grouped into the following 
categories based on the RMC classification:

ICS

LABA

LAMA

Xanthine

PDE4 Inhibitors

Any combination of the above

Other

None
COPD Exacerbation History
COPD exacerbations reported in the past 12 months will be categorized as 0, 1, 2, ≥3
The number of COPD exacerbations reported in the past 12 months prior to Screening will be 
summarized in three categories: moderate COPD exacerbations, severe COPD exacerbations, and 
moderate/severe COPD exacerbations. 
Moderate COPD exacerbations are defined as exacerbations that required treatment with 
systemic/oral corticosteroids and/or antibiotics (not involving hospitalization).
Severe COPD exacerbations are defined as exacerbations that required in-patient hospitalization.
The total number of moderate/severe COPD exacerbations is defined as the total numbers of 
moderate and severe COPD exacerbations.
 
2019N398531_00


CONFIDENTIAL
207626
46
Reversibility

A participant’s status as reversible to salbutamol is calculated at Screening and is based on the 
difference (absolute change and % change) between a participant’s pre-salbutamol 
assessment of FEV1 and their post-salbutamol assessment FEV1 and is defined as follows:

Reversible, if the difference in FEV1 was ≥ 12% and ≥ 200 mL, or

Non-reversible, if the difference in FEV1 is < 200 mL or else the difference was ≥ 200 mL 
and was < 12 % of the pre-salbutamol FEV1.
GOLD Grade 1-4 at Screening
Participants will be classified into Global Initiative on Obstructive Lung Disease (GOLD) Grades 1-4 
using the post-salbutamol percent predicted FEV1 assessment at Screening:

GOLD Grade 1 (Mild):  percent predicted FEV1 80%

GOLD Grade 2 (Moderate): 50% percent predicted FEV1 < 80%

GOLD Grade 3 (Severe):  30% percent predicted FEV1 < 50%

GOLD Grade 4 (Very Severe): percent predicted FEV1 < 30%
10.6.3.
Efficacy
Lung Function
On-Treatment Trough FEV1
For Day 28 ad Day 84, trough FEV1 is defined as the average of the two pre-dose FEV1 measurements 
recorded before the morning dose of randomized study medication.  If only one pre-dose measurement is 
recorded, then it will serve as the trough value. 
For Day 85, trough FEV1 is defined as the mean of the two planned spirometry FEV1 measurements. If only one 
measurement is recorded, then it will serve as the trough value.
Post-Treatment Trough FEV1
Post-treatment trough FEV1 is defined as the mean of the two planned spirometry FEV1 measurements. If only 
one measurement is recorded, then it will serve as the trough value.
Patient-Reported Outcomes
St George’s Respiratory Questionnaire -- COPD (SGRQ-C) Total Score
The SGRQ-C includes 14 questions with a total of 40 items grouped into three domains (Symptoms, Activity, 
and Impacts).
The details for how to score the SGRQ-C are outlined in the SGRQ-C manual (Jones, 2016).  This 
manual includes details on how to handle missing data.
The SGRQ-C total score will be converted to an SGRQ score as described in the manual.
The change from baseline in total score will be calculated for the converted scores.
If the language of the SGRQ-C assessed at a post-randomization visit is different from the language 
used at Day 1, all SGRQ-C scores at that visit and all subsequent visits will be set to missing.
Missing data will be handled as detailed in the SGRQ-C manual (Jones, 2016).
 
2019N398531_00


CONFIDENTIAL
207626
47
St George’s Respiratory Questionnaire (SGRQ) Responders
SGRQ-C is assessed at randomization and on Days 28 and 84.  The SGRQ-C will be scored to 
produce SGRQ total scores (Jones, 2016).  Responder analyses will be based on the resulting SGRQ 
total scores.
A participant will be considered a responder per the SGRQ if his/her on-treatment SGRQ total score 
has decreased at least 4 units from the baseline SGRQ total score.
A participant will be considered a non-responder if his/her on-treatment SGRQ total score has 
decreased by fewer than 4 units, has not changed, or has increased compared to baseline.
The handling of missing data will be detailed in Section 10.7.2.
When determining if a participant was a responder to SGRQ Total Score,  the Total Score will be 
rounded to 1dp prior to assigning the responder status.
COPD Assessment Test (CAT) Score

The CAT consists of eight items each formatted as a six-point differential scale: 0 (no impact) to 5 (high 
impact). A CAT score will be calculated by summing the non-missing scores on the eight items with a range 
from 0 to 40. 

If one item is missing, then the score for that item is set as the average of the non-missing items. If more 
than one item is missing, then the CAT score will be set to missing. 

If the language of the CAT conducted at a post-baseline visit is different to the language used at Day 1 
baseline, the CAT score for that visit and all subsequent visits will be set to missing.
Since the CAT score at screening is a study entry criterion, screening CAT scores will be categorized as less 
than 10 and 10 or greater, and those categories summarized by treatment group.
COPD Assessment Test (CAT) Responders
A participant will be a considered a responder per the CAT if his/her on-treatment CAT total score has 
decreased at least 2 units from the baseline CAT score.
A participant will be considered a non-responder if his/her on-treatment CAT score has decreased by fewer 
than 2 units, has not changed, or has increased compared to baseline.
The handling of missing data will be detailed in Section 10.7.2
COPD Exacerbations

The duration of the exacerbation will be calculated as (exacerbation resolution date or date of 
death - exacerbation onset date + 1).

The time to the first on-treatment exacerbation will be calculated as (exacerbation onset date of 
first on-treatment exacerbation – date of start of treatment + 1).

For summaries/analyses, participants will be represented from their Day 1 date to the start date of 
their first event up to and including their treatment stop date+1 day.  

Participants that have not withdrawn from study treatment or experienced the event are censored 
at their treatment stop date+1 day.

The event rate for exacerbations will be calculated as the total number of events divided by the 
total annual participant exposure during the time-period of interest
 
2019N398531_00


CONFIDENTIAL
207626
48
10.6.4.
Safety
Exposure
Extent of exposure
Duration of exposure to randomized treatment will be calculated as:

Randomized treatment stop date – randomized treatment start date + 1
Duration of post-treatment time spent in the study will be calculated as:

Study conclusion date – randomized treatment stop date
Duration of total time spent in the study will be calculated as:

Study conclusion date – randomized treatment start date + 1
Exposure Categories
The following exposure categories will be derived for summaries of the ITT population:

≥1 day

≥4 weeks

≥8 weeks

≥12 weeks

11 – 13 weeks.
 
2019N398531_00


CONFIDENTIAL
207626
49
Adverse Events
AEs of Special Interest

AESI have been defined as AEs which have specified areas of interest for FF, VI or UMEC or 
the overall COPD population. The following table presents the AESI groups.  Groups which are 
not SMQs are made up of a selection of preferred terms (PTs) defined by GSK. The complete 
list, including the PTs which contribute to each of the groups will be provided by Safety and 
Medical Governance (SMG) using the MedDRA version current at the time of reporting.  This 
will be finalized prior to unblinding.
AESI Group
AESI Subgroup
Sub-SMQ
Cardiovascular effects
Cardiac arrhythmia
Arrhythmia related investigations, 
signs and symptoms (SMQ)
Bradyarrhythmia terms, 
nonspecific (SMQ)
Conduction defects (SMQ)
Disorders of sinus node function 
(SMQ)
Cardiac arrhythmia terms, 
nonspecific (SMQ)
Supraventricular tachyarrhythmias 
(SMQ)
Tachyarrhythmia terms, 
nonspecific (SMQ)
Ventricular tachyarrhythmias 
(SMQ)
Cardiac failure (SMQ)
Ischaemic heart disease (SMQ)
Hypertension (SMQ)
Central nervous system 
haemorrhages and 
cerebrovascular conditions (SMQ)
Decreased bone mineral density 
and associated fractures
Pneumonia
Infective pneumonia SMQ 
(Narrow)
Lower Respiratory Tract Infection 
(LRTI) excluding pneumonia
Bone Fracture Incidents
If a participant suffers fractures in multiple locations with the same date of fracture, this event is 
considered to be one fracture incident.
In the case of multiple fracture types (traumatic/non-traumatic) contributing to one fracture incident, the 
worst-case fracture type (non-traumatic) will be assigned to the fracture incident. E.g. if a participant
has a traumatic wrist fracture and a non-traumatic foot fracture on the same date, this will be 
considered to be one non-traumatic fracture incident. 
Bone fracture incident event rate will be calculated in the same manner as AE rate.
 
2019N398531_00


CONFIDENTIAL
207626
50
Association of Chest Imaging (X-ray or CT scan) with Pneumonia Event
A chest X-ray is considered associated with pneumonia if it is performed within -7 to +14 days of the 
date of onset of pneumonia or the date of resolution, whichever date falls later. 
Details of pneumonia events are collected on the Pneumonia Details eCRF page. 
Maximum/Minimum Post-Baseline and Worst-Case Post-Baseline
Definition
Reporting Details
Maximum post-baseline 
(pulse rate, systolic and diastolic 
blood pressure)
Maximum on-treatment value over all timepoints
Minimum post-baseline 
(diastolic blood pressure)
Minimum on-treatment value over all timepoints
NOTES:
The treatment phase definitions to be detailed in the full RAP will be used and only assessments within the on-
treatment period will be considered in assessment of maximum/minimum/worst-case post-baseline.
Assessment of maximum/minimum/worst-case post-baseline will include data from scheduled, unscheduled and study 
treatment discontinuation visits (if applicable). Vital signs (pulse rate, systolic blood pressure and diastolic blood 
pressure) collected at an assessment associated with a pneumonia event will also be included in derivation of a 
‘maximum/minimum post-baseline’ assessment.
 
2019N398531_00


CONFIDENTIAL
207626
51
10.7.
Appendix 7: Reporting Standards for Missing Data
10.7.1.
Premature Withdrawals
Element
Reporting Detail
General
A participant is considered to have completed the study if s/he has completed all phases of 
the study including pre-screening, screening, run-in, the randomised treatment phase, and 
the safety follow-up. 
Withdrawn participants will not be replaced in the study.
All available data from participants who are withdrawn from the study will be listed and all 
available planned data will be included in summary tables and figures, unless otherwise 
specified.
10.7.2.
Handling of Missing Data
Element
Reporting Detail
General
Missing data occur when any requested data are not provided, leading to blank fields on 
the collection instrument 
These data will be indicated using a blank in data listings, unless all data for a specific 
visit are missing, in which case the data is excluded from the table. 
Answers such as “Not applicable” and “Not evaluable” are not considered to be missing 
data and should be displayed as such.
Outliers
Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
 
2019N398531_00


CONFIDENTIAL
207626
52
10.7.2.1.
Handling of Missing Dates
Element
Reporting Detail
General
Partial dates will be displayed as captured in data listings.
Adverse 
Events,
exacerbations,
and 
pneumonia
Missing start day:  The first of the month will be used unless it falls before the start 
date of randomized study treatment, in which case the randomized study treatment
start date will be used and hence the event will be considered on-treatment, as 
defined in Section 10.4 (Appendix 4:  Study Phases and Treatment-Emergent 
Adverse Events).
Missing stop day:  The last day of the month will be used unless it falls after the stop 
date of randomized study treatment, in which case the randomized study treatment
stop date will be used.
Completely missing start or end dates will remain missing, with no imputation applied.  
Consequently, time to onset and duration of such events will also be missing.
10.7.2.2.
Handling of Partial Dates
The eCRF allows partial dates (i.e., only month and year) to be recorded for AEs, 
concomitant medications, and exacerbation start and end dates; that is, the day of the 
month may be missing.  In such cases, the following conventions will be applied for 
calculating the time to onset and the duration of the event:
Element
Reporting Detail
Concomitant 
medications
For the purposes of assigning a treatment period in which to report a concomitant 
medication, partial administration start and stop dates recorded in the CRF will be 
imputed using the following conventions:
If the partial date is a start date, 1 will be used for missing days and 'Jan' will be used 
for missing months.
If the partial date is a stop date, either 28, 29, 30, or 31 (depending on the month and 
year) will be used for missing days and 'Dec' will be used for missing months.
The recorded partial date will be displayed in any relevant listings.
Adverse 
events, 
exacerbations,
and 
pneumonia
Any partial dates for adverse events and exacerbations will be raised to data 
management. If the full date cannot be ascertained, the following assumptions will be 
made.
If the partial date is an onset date, 1 will be used for missing days and 'Jan' will be 
used for the month.  However, if these substitutions result in an onset date prior to 
Day 1 and, based on available information, the event could possibly have occurred 
during treatment, then the Day 1 date will be assumed to be the onset date.  The 
event will then be considered to have started on treatment.
 
2019N398531_00


CONFIDENTIAL
207626
53
Element
Reporting Detail
If the partial date is a resolution date, either 28, 29, 30, or 31 (depending on the 
month and year) will be used for missing days and 'Dec' will be used for missing 
months.
The recorded partial date will be displayed in any relevant listings.
10.7.2.3.
Handling of Missing Data for Statistical Analysis
Element
Reporting Detail
Responder 

Participants with a missing baseline will have responder status as missing

Participants with missing post-baseline data at a time point and a subsequent 
non-missing assessment will not be considered a responder or non-responder 
but will be left as missing at that time point

Participants with a missing post-baseline assessment with no subsequent non-
missing assessments will be considered a non-responder for that and all 
subsequent time points.

Participants with a baseline but all missing post-baseline data will be 
considered a non-responder at all time points.
 
2019N398531_00


CONFIDENTIAL
207626
54
10.8.
Appendix 8: Abbreviations & Trade Marks
10.8.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse event
AESI
Adverse events of special interest
ASE
All subjects enrolled
ATC
Anatomical therapeutic chemical
CAT
COPD Assessment Test
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence interval
COPD
Chronic obstructive pulmonary disease
CSV
Comma-separated values
CT
Computerized (axial) tomography
DR
Dry run
eCRF
Electronic case record form
ECG
Electrocardiogram
EudraCT
European Union Drug Regulating Authorities Clinical Trials
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
FEV1
Forced expiratory flow in 1 second
FF
Fluticasone furoate
GOLD
Global Initiative on Obstructive Lung Disease
GSK
GlaxoSmithKline
HARP
Harmonised Analysis and Reporting Platform
ICH
International Conference on Harmonization
ICS
Inhaled corticosteroid
IDSL
Integrated Data Standards Library
ITT
Intent-o-Treat
IWRS
Interactive web response system
KR
Kenward and Roger
LABA
Long-acting beta2 agonist
LAMA
Long-acting muscarinic antagonist 
LS
Least squares
LRTI
Lower respiratory tract infection
MAR
Missing at random
mcg
microgram
MedDRA
Medical Dictionary for Regulatory Activities
mL
Milliliter
PDE4
Phosphodiesterase type 4
PDSF
Protocol deviation specification form
QD
Quaque die (once daily)
R&D
Research and Development
RAP
Reporting and Analysis Plan
 
2019N398531_00


CONFIDENTIAL
207626
55
Abbreviation
Description
RMC
Respiratory Medication Classification
RUCAM
Roussel Uclaf Causality Assessment Method
SAC
Statistical analysis complete
SAE
Serious adverse event
SDTM
Study Data Tabulation Model
SGRQ
St George’s Respiratory Questionnaire
SGRQ-C
St George’s Respiratory Questionnaire - COPD
SI
System Independent
SRT
Safety review team
SOC
System organ class
UMEC
Umeclidinium
VI
Vilanterol
10.8.2.
Trademarks
Trademarks of the GlaxoSmithKline Group 
of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
ELLIPTA
SAS
HandiHaler
 
2019N398531_00


CONFIDENTIAL
207626
56
10.9.
Appendix 9: List of Data Displays
10.9.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.37
1.1 to 1.2
Efficacy
2.1 to 2.23
2.1 to 2.10
Safety
3.1 to 3.34
3.1
Section
Listings
ICH Listings
1 to 21
Other Listings
22 to 48
10.9.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and, if required, example mock-
up displays provided in Section 10.10 (Appendix 10: Example Mock Shells for Data 
Displays).  Output files in the following sections that use standard IDSL examples are 
identified in the “IDSL / Example Shell” column by their IDSL example format code.
Section
Figure
Table
Listing
Study Population
POP_Fnn
POP_Tnn
POP_Lnn
Efficacy
EFF_Fnn
EFF_Tnn
EFF_Lnn
Safety
SAF_Fnn
SAF_Tnn
SAF_Lnn
10.9.3.
Deliverables
Delivery
Description
DR
Dry run prior to source data lock
SAC 
Final statistical analysis complete
Post-SAC
One week after SAC
 
2019N398531_00


CONFIDENTIAL
207626
57
10.9.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
Participant Disposition
1.1.
ASE
POP_T01
Summary of Subject Populations and Reasons for Screen/Run-
in Failure 
DR, SAC
1.2.
ITT
POP_T02
Summary of Attendance at Each Visit
DR, SAC
1.3.
ITT
SD1
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment
DR, SAC
1.4.
ITT
ES1
Summary of Study Status and Reasons for Study Withdrawal 
DR, SAC
1.5.
ASE
DM11
Summary of Age Ranges
Use age ranges in Section 10.6.2.
DR, SAC
1.6.
ASE
NS1
Summary of Number of Subjects Enrolled by Geographical 
Region, Country and Center
DR, SAC
1.7.
ITT
NS1
Summary of Number of Subjects Enrolled by Geographical 
Region, Country, and Center
DR, SAC
1.8.
ASE
IE1
Summary of Inclusion/Exclusion Criteria Deviations for Screen 
Failures
DR, SAC
1.9.
ITT
IE1
Summary of Inclusion/Exclusion Criteria Deviations 
DR, SAC
Protocol Deviation
1.10.
ITT
POP_T03
Summary of Important Protocol Deviations
DR, SAC
Demographic and Baseline Characteristics
1.11.
ITT
DM1
Summary of Demographic Characteristics
Add BMI to IDSL standard
DR, SAC
1.12.
ITT
DM1
Summary of Demographic Characteristics by Country
DR, SAC
1.13.
ITT
DM5
Summary of Race and Racial Combinations
DR, SAC
 
 
 
2019N398531_00


CONFIDENTIAL
207626
58
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
1.14.
ITT
DM6
Summary of Race and Racial Combinations Details
DR, SAC
Medical Conditions
1.15.
ITT
MH4
Summary of Current Medical Conditions
Use classes and conditions as 
collected on eCRF
DR, SAC
1.16.
ITT
MH4
Summary of Past Medical Conditions
Use classes and conditions as 
collected on eCRF
DR, SAC
1.17.
ITT
POP_T04
Summary of Cardiovascular Risk Factors
DR, SAC
1.18.
ITT
POP_T05
Summary of Family History of Cardiovascular Risk Factors
DR, SAC
Disease Characteristics
1.19.
ITT
POP_T06
Summary of Smoking History at Screening
DR, SAC
1.20.
ITT
POP_T07
Summary of Smoking Status at Screening
DR, SAC
1.21.
ITT
POP_T08
Summary of COPD History at Screening
DR, SAC
1.22.
ITT
POP_T09
Summary of COPD Exacerbation History at Screening
DR, SAC
1.23.
ITT
POP_T10
Summary of Screening Lung Function
DR, SAC
1.24.
ITT
POP_T10
Summary of Screening Lung Function by Country
DR, SAC
1.25.
‘ITT
POP_T11
Summary of Reversibility and GOLD Grade (1 – 4) at Screening
DR, SAC
 
 
 
2019N398531_00


CONFIDENTIAL
207626
59
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
1.26.
ITT
POP_T12
Summary of CAT Score and CAT Category at Screening
DR, SAC
Prior and Concomitant Medications
1.27.
ITT
POP_T13
Summary of COPD Concomitant Medications Taken Prior to 
Screening
Include total column; use 
Respiratory Medicines 
Classification (RMC) level 1 
as top-level classification; see 
MID200812 Table 1.34 (
DR, SAC
1.28.
ITT
POP_T14
Summary of COPD Concomitant Medication Combinations 
Taken at Screening
Include total column; use 
RMC as top-level 
classification; see 
CTT1166855 Table 1.67 (in 
SAFIRE)
DR, SAC
1.29.
ITT
POP_T13
Summary of COPD Concomitant Medications Taken during Run-
in for Reasons other than an Exacerbation
Include total column; use 
RMC as top-level 
classification; see 
MID200812 Table 1.34
DR, SAC
1.30.
ITT
POP_T15
Summary of On-Treatment COPD Concomitant Medications 
Taken for Reasons other than an Exacerbation
Include total column; use RMC as 
top-level classification; see 
MID200812 Table 1.35
DR, SAC
1.31.
ITT
POP_T15
Summary of Post-treatment COPD Concomitant Medications 
Taken for Reasons other than an Exacerbation
Include total column; use RMC as 
top-level classification; see 
MID200812 Table 1.36
DR, SAC
 
 
 
2019N398531_00


CONFIDENTIAL
207626
60
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
1.32.
ITT
POP_T13
Summary of Concomitant Medications Taken during Run-in for 
an Exacerbation
Include total column; use RMC as 
top-level classification; see 
MID200812 Table 1.37
DR, SAC
1.33.
ITT
POP_T15
Summary of On-Treatment Concomitant Medications Taken for 
an Exacerbation
Include total column; use RMC as 
top-level classification; see 
MID200812 Table 1.38
DR, SAC
1.34.
ITT
POP_T15
Summary of Post-Treatment Concomitant Medications Taken for 
an Exacerbation
Include total column; use RMC as 
top-level classification; see 
MID200812 Table 1.39
DR, SAC
1.35.
ITT
POP_T16
Summary of On-Treatment Non-COPD Concomitant 
Medications
Include total column; use ATC level 
1 as top-level classification; see 
MID200812 Table 1.40
DR, SAC
1.36.
ITT
POP_T16
Summary of Post-Treatment Non-COPD Concomitant 
Medications 
Include total column; use ATC level 
1 as top-level classification; see 
MID200812 Table 1.41
DR, SAC
Treatment Compliance
1.37.
ITT
POP_T17
Summary of Treatment Compliance (%)
See CTT116855 Table 1.75 (in 
SAFIRE)
DR, SAC
 
 
 
2019N398531_00


CONFIDENTIAL
207626
61
10.9.5.
Study Population Figures
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Participant Disposition
1.1.
ITT
POP_F01
Kaplan-Meier Plot of Time to Study Withdrawal
DR, SAC
1.2.
ITT
POP_F01
Kaplan-Meier Plot of Time to Study Treatment Discontinuation
DR, SAC
 
 
 
2019N398531_00


CONFIDENTIAL
207626
62
10.9.6.
Efficacy Tables
Efficacy: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
Spirometry
2.1.
ITT
EFF_T01
Summary of Baseline FEV1 (L) 
DR, SAC
2.2.
ITT
EFF_T01
Summary of Baseline FEV1 (L) by Country 
DR, SAC
2.3.
ITT
EFF_T02
Summary of Trough FEV1 (L) - Hypothetical Estimand
Includes Days 28, 84, and 85
DR, SAC
2.4.
ITT
EFF_T02
Summary of Trough FEV1 (L) – Treatment Policy Estimand 
Only if overall rate of 
discontinuation from study 
treatment is >5%
DR, SAC
2.5.
ITT
EFF_T02
Summary of Trough FEV1 (L) by Country – Hypothetical 
Estimand
Includes Days 28, 84, and 85
DR, SAC
2.6.
ITT
EFF_T02
Summary of Trough FEV1 (L) by Country – Treatment Policy 
Estimand
Only if overall rate of 
discontinuation from study 
treatment is >5%
DR, SAC
2.7.
ITT
EFF_T03
Analysis of Trough FEV1 (L) - Hypothetical Estimand
Includes Days 28, 84, and 85
DR, SAC
2.8.
ITT
EFF_T03
Analysis of Trough FEV1 (L) – Treatment Policy Estimand
Only if overall rate of 
discontinuation from study 
treatmentis >5%
DR, SAC
2.9.
ITT
EFF_T04
Significance Levels for Interactions of Treatment with 
Geographical Region and Baseline FEV1 for Analysis of Trough 
FEV1 (L) on Day 85 - Hypothetical Estimand
Includes Days 28, 84, and 85
DR, SAC
2.10.
ITT
EFF_T04
Significance Levels for Interactions of Treatment with 
Geographical Region and Baseline FEV1 for Analysis of Trough 
FEV1 (L) on Day 85 - Treatment Policy Estimand
Only if overall rate of 
discontinuation from study 
treatment is >5%
DR, SAC
 
 
 
2019N398531_00


CONFIDENTIAL
207626
63
Efficacy: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
2.11.
ITT
EFF_T05
Tipping Point Sensitivity Analysis: Two-Sided P-values after 
Imputing Varying Day 85 Mean Change from Baseline Trough 
FEV1 (L) – Treatment Policy Estimand
Only if overall rate of 
discontinuation from study 
treatment is >5%. 
Add * before each p-value that is less 
than 0.050
DR, Post-SAC
SGRQ
2.12.
ITT
EFF_T06
Summary of Baseline SGRQ Total and Domain Scores
DR, SAC
2.13.
ITT
EFF_T02
Summary of SGRQ Total and Domain Scores – Hypothetical 
Estimand
DR, SAC
2.14.
ITT
EFF_T03
Analysis of SGRQ Total Score – Hypothetical Estimand
DR, SAC
2.15.
ITT
EFF_T07
Summary and Analysis of Proportion of Responders as Defined 
by SGRQ Total Score – Hypothetical Estimand
DR, SAC
CAT Scores
2.16.
ITT
EFF_T06
Summary of Baseline CAT Score
DR, SAC
2.17.
ITT
EFF_T02
Summary of CAT Score – Hypothetical Estimand
DR, SAC
2.18.
ITT
EFF_T03
Analysis of CAT Score – Hypothetical Estimand
DR, SAC
2.19.
ITT
EFF_T07
Summary and Analysis of Proportion of Responders as Defined 
by CAT Score – Hypothetical Estimand 
DR, SAC
COPD Exacerbations
2.20.
ITT
EFF_T08
Summary of On-Treatment COPD Exacerbations 
DR, SAC
2.21.
ITT
EFF_T09
Summary of On-Treatment Details of COPD Exacerbations
DR, SAC
2.22.
ITT
EFF_T08
Summary of Post-Treatment COPD Exacerbations
DR, SAC
2.23.
ITT
EFF_T09
Summary of Post-Treatment Details of COPD Exacerbations
DR, SAC
 
 
 
2019N398531_00


CONFIDENTIAL
207626
64
10.9.7.
Efficacy Figures
Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
Spirometry
2.1.
ITT
EFF_F01
Box Plot of Change from Baseline in Trough FEV1 (L) on Day 85 
– Hypothetical Estimand
Might be able to squeeze all three 
timepoints onto one graph – would 
be six box plots.
DR, SAC
2.2.
ITT
EFF_F02
Empirical Distribution Function Plot of Change from Baseline in 
Trough FEV1 (L) on Day 85 – Hypothetical Estimand
DR, SAC
2.3.
ITT
EFF_F03
Least Squares Mean (95% CI) Change from Baseline in Trough 
FEV1 (L) – Hypothetical Estimand 
DR, SAC
2.4.
ITT
EFF_F01
Box Plot of Change from Baseline in Trough FEV1 (L) on Day 85 
– Treatment Policy Estimand
Might be able to squeeze all three 
timepoints onto one graph – would 
be six box plots.
DR, SAC
2.5.
ITT
EFF_F02
Empirical Distribution Function Plot of Change from Baseline in 
Trough FEV1 (L) on Day 85 – Treatment Policy Estimand
DR, SAC
2.6.
ITT
EFF_F03
Least Squares Mean (95% CI) Change from Baseline in Trough 
FEV1 (L) – Treatment Policy Estimand 
DR, SAC
SGRQ
2.7.
ITT
EFF_F02
Empirical Distribution Function Plot of Change from Baseline in 
SGRQ Total Score on Day 84 – Hypothetical Estimand
DR, SAC
2.8.
ITT
EFF_F03
Least Squares Mean (95% CI) Change from Baseline in SGRQ 
Total Score – Hypothetical Estimand 
DR, SAC
CAT Score
2.9.
ITT
EFF_F02
Empirical Distribution Function Plot of Change from Baseline in 
CAT Score on Day 84 – Hypothetical Estimand
DR, SAC
2.10.
ITT
EFF_F03
Least Squares Mean (95% CI) Change from Baseline in CAT 
Score – Hypothetical Estimand
DR, SAC
 
 
 
2019N398531_00


CONFIDENTIAL
207626
65
10.9.8.
Safety Tables
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
Exposure
3.1.
ITT
SAF_T01
Summary of Treatment Exposure
DR, SAC
Adverse Events (AEs)
3.2.
ITT
AE13
Overview of On-Treatment Adverse Events
DR, SAC
3.3.
ITT
AE1
Summary of On-Treatment Adverse Events
DR, SAC
3.4.
ITT
AE1
Summary of On-Treatment Adverse Events by Country
DR, SAC
3.5.
ITT
AE1
Summary of Post-Treatment Adverse Events
DR, SAC
3.6.
ITT
AE1
Summary of On-Treatment Drug-Related Adverse Events 
DR, SAC
3.7.
ITT
AE15
Summary of On-Treatment Common (>=3% in Either Treatment 
Group) Non-serious Adverse Events by System Organ Class 
and Preferred Term (Number of Subjects and Occurrences)
DR, SAC
3.8.
ITT
AE3
Summary of the 10 Most Frequent On-treatment Adverse Events 
in each Treatment Group  
For each treatment group, use 
number of events without tie-
breaker to determine the 10 most 
frequent AEs
DR, SAC
3.9.
ITT
AE5A
Summary of On-Treatment Adverse Events by System Organ 
Class and Maximum Intensity
DR, SAC
3.10.
ASE
AE2
Relationship of Adverse Event System Organ Class, Preferred 
Term and Verbatim Text
DR, SAC
Serious and Other Significant Adverse Events
3.11.
ASE
AE1
Summary of Pre-Treatment Serious Adverse Events 
DR, SAC
3.12.
ITT
AE1
Summary of Pre-Treatment Serious Adverse Events 
DR, SAC
3.13.
ITT
AE1
Summary of On-Treatment Serious Adverse Events  
DR, SAC
3.14.
ITT
AE1
Summary of On-Treatment Fatal Serious Adverse Events  
DR, SAC
 
 
 
2019N398531_00


CONFIDENTIAL
207626
66
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
3.15.
ITT
AE1
Summary of Pre-Treatment Serious Adverse Events Leading to 
Withdrawal from Study
DR, SAC
3.16.
ITT
AE1
Summary of On-Treatment Adverse Events Leading to 
Permanent Discontinuation of Study Treatment or Withdrawal 
from Study 
DR, SAC
3.17.
ITT
AE1
Summary of Serious Adverse Events (Serious, Drug-Related 
Serious, Fatal and Drug-Related Serious) by System Organ 
Class and Preferred Term (Number of Subjects and 
Occurrences)
DR, SAC
3.18.
ITT
AE1
Summary of On-Treatment Drug-Related Serious Adverse 
Events   
DR, SAC
3.19.
ITT
AE1
Summary of On-Treatment Drug-Related Fatal Serious Adverse 
Events   
DR, SAC
3.20.
ITT
AE1
Summary of On-Treatment Adverse Events of Special Interest  
DR, SAC
3.21.
ITT
AE1
Summary of On-Treatment Serious Adverse Events of Special 
Interest  
DR, SAC
3.22.
ITT
AE1
Summary of Post-Treatment Serious Adverse Events
DR, SAC
3.23.
ITT
AE1
Summary of Post-Treatment Serious Fatal Adverse Events
DR, SAC
Pneumonia 
3.24.
ITT
SAF_T02
Summary of On-Treatment Pneumonia Incidence
DR, SAC
3.25.
ITT
SAF_T03
Summary of On-Treatment Details of Pneumonia
DR, SAC
3.26.
ITT
SAF_T02
Summary of Post-Treatment Pneumonia Incidence
DR, SAC
3.27.
ITT
SAF_T03
Summary of Post-Treatment Details of Pneumonia
DR, SAC
Bone fractures
3.28.
ITT
SAF_T04
Summary of On-Treatment Bone Fractures
DR, SAC
3.29.
ITT
SAF_T04
Summary of Post-Treatment Bone Fractures
DR, SAC
 
 
 
2019N398531_00


CONFIDENTIAL
207626
67
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
Chest imaging
3.30.
ITT
SAF_T05
Summary of Chest Imaging (X-Ray or CT Scan) 
combine on- and post-treatment
DR, SAC
Labs
3.31.
ITT
SAF_T06
Summary of Blood Chemistry Results at Screening
DR, SAC
3.32.
ITT
SAF_T06
Summary of Hematology Results at Screening
DR, SAC
Vital signs
3.33.
ITT
SAF_T07
Summary of Vital Signs 
DR, SAC
3.34.
ITT
SAF_T07
Summary of Change from Baseline Vital Signs 
DR, SAC
ECGs
3.35.
ITT
SAF_T08
Summary of ECG Findings at Screening
DR, SAC
 
 
 
2019N398531_00


CONFIDENTIAL
207626
68
10.9.9.
Safety Figures
Safety: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Exposure
3.1.
ITT
SAF_F01
Summary of Treatment Exposure
DR, SAC
 
 
 
2019N398531_00


CONFIDENTIAL
207626
69
10.9.10.
ICH Listings
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Subject Disposition
1.
ASE
ES7
Listing of Reasons for Screening / Run-in Failure
DR, SAC
2.
ITT
TA1
Listing of Planned and Actual Treatments
DR, SAC
3.
ITT
SD2
Listing of Reasons for Study Treatment Discontinuation
DR, SAC
4.
ITT
ES2
Listing of Reasons for Study Withdrawal
DR, SAC
5.
ITT
BL1
Listing of Subjects for Whom the Treatment Blind was Broken
DR, SAC
Protocol Deviations
6.
ITT
DV2
Listing of Important Protocol Deviations 
DR, SAC
7.
ASE
IE3
Listing of Subjects with Inclusion/Exclusion Criteria Deviations
for Screen Failures
DR, SAC
8.
ITT
IE3
Listing of Subjects with Inclusion/Exclusion Criteria Deviations
Demographic and Baseline Characteristics
9.
ITT
DM2
Listing of Demographic Characteristics
DR, SAC
10.
ITT
DM9
Listing of Race
DR, SAC
Prior and Concomitant Medications
11.
ITT
CM3
Listing of Concomitant COPD Medications
DR, SAC
12.
ITT
CM3
Listing of Concomitant Non-COPD Medications
DR, SAC
Exposure 
13.
ITT
SAF_L01
Listing of Exposure Data
DR, SAC
 
 
 
2019N398531_00


CONFIDENTIAL
207626
70
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Adverse Events
14.
ASE
AE8
Listing of All Adverse Events
DR, SAC
15.
ASE
AE7
Listing of Subject Numbers for Individual Adverse Events
DR, SAC
Serious and Other Significant Adverse Events
16.
ASE
AE8
Listing of Fatal Serious Adverse Events
DR, SAC
17.
ASE
AE8
Listing of Non-Fatal Serious Adverse Events
DR, SAC
18.
ASE
AE14
Listing of Reasons for Considering as a Serious Adverse Event
DR, SAC
19.
ASE
AE8
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment
DR, SAC
20.
ITT
AE8
Listing of Adverse Events of Special Interest
DR, SAC
Vital signs
21.
ITT
VS4
Listing of All Vital Signs Values 
DR, SAC
 
 
 
2019N398531_00


CONFIDENTIAL
207626
71
10.9.11.
Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Study population
22.
ASE
POP_L18
Listing of Unique Subject ID vs. Study Subject ID
DR, SAC
23.
ASE
POP_L03
Listing of Study Treatment Misallocations
DR, SAC
24.
ITT
POP_L04
Listing of Screening Lung Function, Reversibility Status, and 
GOLD Grade
DR, SAC
25.
ITT
POP_L05
Listing of Medical Conditions
DR, SAC 
26.
ITT
POP_L06
Listing of Family History of Cardiovascular Risk Factors
DR, SAC
27.
ITT
POP_L07
Listing of COPD Duration and Exacerbation History
DR, SAC 
28.
ITT
POP_L08
Listing of Smoking History and Smoking Status
DR, SAC
29.
ITT
POP_L09
Relationship between ATC Level 1, Ingredient, and Verbatim 
Text for Non-COPD Medications
DR, SAC 
30.
ITT
POP_L10
Listing of Treatment Compliance Data
Including both run-in and on-treatment.
DR, SAC
Spirometry
31.
ITT
EFF_L01
Listing of Raw FEV1 (L) and FVC (L) Data
DR, SAC 
COPD exacerbations
32.
ITT
EFF_L02
Listing of COPD Exacerbations
DR, SAC
SGRQ
33.
ITT
EFF_L03
Listing of SGRQ Scores
Include screening scores
DR, SAC
CAT
34.
ITT
EFF_L04
Listing of CAT Scores
Include screening scores
DR, SAC
 
 
 
2019N398531_00


CONFIDENTIAL
207626
72
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Adverse events
35.
ITT
SAF_L02
Listing of AE Terms of Special Interest
DR, SAC
36.
ITT
AE7
Listing of Subject Numbers for On-Treatment Adverse Events of 
Special Interest
DR, SAC
Pneumonia incidence
37.
ITT
SAF_L03
Listing of Pneumonia Data
DR, SAC
Bone fractures
38.
ITT
SAF_L04
Listing of Bone Fracture Data
DR, SAC
Chest imaging (X-ray or CT scan)
39.
ITT
SAF_L05
Listing of Chest Imaging (X-ray or CT scan) Data
DR, SAC
Liver events
40.
ITT
SAF_L06
Listing of Liver Event Results and Time of Event Relative to 
Treatment
DR, SAC
41.
ITT
SAF_L07
Listing of Medical Conditions for Subjects with Liver Stopping 
Events
DR, SAC
42.
ITT
SAF_L08
Listing of Substance Use for Subjects with Liver Stopping 
Events
DR, SAC
43.
ITT
SAF_L09
Listing of Liver Event Information for RUCAM Scores
DR, SAC
44.
ITT
SAF_L10
Listing of Liver Biopsy Details
DR, SAC
45.
ITT
SAF_L11
Listing of Liver Imaging Details
DR, SAC
Inhaler malfunctions
46.
ITT
SAF_L12
Listing of Inhaler Malfunctions
DR, SAC
 
 
 
2019N398531_00


CONFIDENTIAL
207626
73
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Hepatitis B and C tests
47.
ITT
SAF_L14
Listing of Hepatitis B and C Test Results
Hep B & C test results are included 
in datasets with lab data from 
vendor.
DR, SAC
ECG
48.
ITT
SAF_L15
Listing of ECG Data
DR, SAC
Laboratory data
49.
ITT
LB14
Listing of Laboratory Data with Character Results
DR, SAC
 
 
 
2019N398531_00


CONFIDENTIAL
207626
74
10.10.
Appendix 10: Example Mock Shells for Data Displays
10.10.1.
Tables
Example:  POP_T01                                                                      Page 1 of x
Protocol:  207626
Population:  All Subjects Enrolled
Table 1.1
Summary of Subject Populations and Reasons for Screen/Run-in Failure
Population
FF/UMEC/VI 
100/62.5/25
TIO 18
Total
All subjects enrolled
xxx
   Pre-screen failure
xxx (xxx%)
Attended screening visit
xxx (xxx%)
   Screen failure [1]
xxx (xxx%)
   Primary reason for screen failure [1]
      Did not meet inclusion/exclusion criteria
xxx (xxx%)
      Serious adverse event
xxx (xxx%)
      Investigator discretion
xxx (xxx%)
      Withdrew consent
xxx (xxx%)
      Unknown
xxx (xxx%)
   Run-in failure
xxx
   Primary reason for run-in failure [2]
      Serious adverse event
xxx (xxx%)
      Protocol deviation
xxx (xxx%)
 
 
 
2019N398531_00


CONFIDENTIAL
207626
75
      Study closed / terminated
xxx (xxx%)
      Lost to follow-up
xxx (xxx%)
      Investigator discretion
xxx (xxx%)
      Withdrew consent
xxx (xxx%)
     Did not meet continuation criteria
xxx (xxx%)
Randomized 
xxx
xxx
xxx
   Intent-to-Treat
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
[1] Percentages are based on the number of subjects who attended the screening visit.
[2] Percentages are based on the number of subjects who were considered run-in failures.
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
76
Example:  POP_T02                                                                      Page 1 of x
Protocol:  207626
Population:  Intent-to-Treat
Table 1.2
Summary of Attendance at Each Visit
Visit
FF/UMEC/VI 
100/62.5/25
(N=xxx)
TIO 18
N=xxx)
Total
N=xxx)
Pre-Screening
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
Screening / Run-in
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
Day 1 (Randomization)
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
Day 28
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
Day 84
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
Day 85
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
Follow-up
xxx (xxx%)
xxx (xxx%)
xxx (xxx%)
Note:  The pre-screening and screening visits may occur on the same day.
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
77
Example: POP_T03                                                                         Page 1 of 1
Protocol: 207626
Population: Intent-to-Treat
Table 1.10
Summary of Important Protocol Deviations
FF/UMEC/VI 
100/62.5/25
(N=xxx)
TIO 18
   (N=xxx)
Total
(N=xxx)
Any important protocol deviations
xxx (xx%)
xxx (xx%)
xxx (xx%)
Informed consent
xx (xx%)
xx (xx%)
xx (xx%)
Eligibility criteria not met
xx (xx%)
xx (xx%)
xx (xx%)
Not withdrawn after developing withdrawal criteria
xx (xx%)
xx (xx%)
xx (xx%)
Excluded medication
xx (xx%)
xx (xx%)
xx (xx%)
Received incorrect treatment
xx (xx%)
xx (xx%)
xx (xx%)
Note: A subject may have more than one deviation.
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
78
Example:  POP_T04                                                                      Page 1 of 2
Protocol:  207626
Population:  Intent-to-Treat
Table 1.17
Summary of Cardiovascular Risk Factors
FF/UMEC/VI 
100/62.5/25
(N=xxx)
TIO 18
(N=xxx)
Total
(N=xxx)
Any cardiovascular risk factor
   n
xxx
xxx
Xxx
   Yes
xx (xx%)
xx (xx%)
xx (xx%)
   No
xx (xx%)
xx (xx%)
xx (xx%)
   Unknown
xx (xx%)
xx (xx%)
xx (xx%)
Number of cardiovascular risk 
factors
   n
xxx
xxx
Xxx
   0
xx (xx%)
xx (xx%)
xx (xx%)
   1
xx (xx%)
xx (xx%)
xx (xx%)
   >=2
xx (xx%)
xx (xx%)
xx (xx%)
Note:  Cardiovascular risk factors include past or current medical conditions recorded at screening.
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
79
Example:  POP_T04                                                                      Page 2 of 2
Protocol:  207626
Population:  Intent-to-Treat
Table 1.17
Summary of Cardiovascular Risk Factors
FF/UMEC/VI 
100/62.5/25
(N=xxx)
TIO 18
(N=xxx)
Total
(N=xxx)
Cardiovascular risk factors
   Angina pectoris
xx (xx%)
xx (xx%)
xx (xx%)
   Arrhythmia
xx (xx%)
xx (xx%)
xx (xx%)
   Cerebrovascular accident
xx (xx%)
xx (xx%)
xx (xx%)
   Congestive heart failure
xx (xx%)
xx (xx%)
xx (xx%)
   Coronary artery disease
xx (xx%)
xx (xx%)
xx (xx%)
   Diabetes mellitus
xx (xx%)
xx (xx%)
xx (xx%)
   Hypercholesterolemia
xx (xx%)
xx (xx%)
xx (xx%)
   Hypertension
xx (xx%)
xx (xx%)
xx (xx%)
   Myocardial infarction
xx (xx%)
xx (xx%)
xx (xx%)
Note:  Cardiovascular risk factors include past or current medical conditions recorded at screening.
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
80
Example:  POP_T05                                                                      Page 1 of 2
Protocol:  207626
Population:  Intent-to-Treat
Table 1.18
Summary of Family History of Cardiovascular Risk Factors
FF/UMEC/VI 
100/62.5/25
(N=xxx)
TIO 18
(N=xxx)
Total
(N=xxx)
Family history of 
premature coronary 
artery disease (women 
<65 years old or men 
<55 years old)
   n
xxx
xxx
Xxx
   Yes
xx (xx%)
xx (xx%)
xx (xx%)
   No
xx (xx%)
xx (xx%)
xx (xx%)
   Unknown
xx (xx%)
xx (xx%)
xx (xx%)
Family history of 
myocardial infarction
   n
xxx
xxx
Xxx
   Yes
xx (xx%)
xx (xx%)
xx (xx%)
   No
xx (xx%)
xx (xx%)
xx (xx%)
   Unknown
xx (xx%)
xx (xx%)
xx (xx%)
Note:  History in first-degree relatives only (biological parent, sibling, or offspring).
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
81
Example:  POP_T05                                                                      Page 2 of 2
Protocol:  207626
Population:  Intent-to-Treat
Table 1.18
Summary of Family History of Cardiovascular Risk Factors
FF/UMEC/VI 
100/62.5/25
(N=xxx)
TIO 18
(N=xxx)
Total
(N=xxx)
Family history of 
stroke
   n
xxx
xxx
Xxx
   Yes
xx (xx%)
xx (xx%)
xx (xx%)
   No
xx (xx%)
xx (xx%)
xx (xx%)
   Unknown
xx (xx%)
xx (xx%)
xx (xx%)
Note:  History in first-degree relatives only (biological parent, sibling, or offspring).
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
82
Example:  POP_T06                                                                      Page 1 of 2
Protocol:  207626
Population:  Intent-to-Treat
Table 1.19
Summary of Smoking History at Screening
FF/UMEC/VI 
100/62.5/25
(N=xxx)
TIO 18
(N=xxx)
Total
(N=xxx)
Average number of 
cigarettes smoked per 
day
   n
xxx
xxx
xxx
   Mean
xx.x
xx.x
xx.x
   SD
xx.xx
xx xx
xx.xx
   Median
xx.x
xx.x
xx.x
   Min.
  x
  x
  x
   Max.
xx
xx
xx
Number of years during 
which subject has 
smoked tobacco
   n
xxx
xxx
xxx
   Mean
xx.x
xx.x
xx.x
   SD
xx.xx
xx xx
xx.xx
   Median
xx.x
xx.x
xx.x
   Min.
  x
  x
  x
   Max.
xx
xx
xx
[1] Pack-years = (number of cigarettes smoked per day / 20) x number of years smoked
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
83
Example:  POP_T06                                                                      Page 2 of 2
Protocol:  207626
Population:  Intent-to-Treat
Table 1.19
Summary of Smoking History at Screening
FF/UMEC/VI 
100/62.5/25
(N=xxx)
TIO 18
(N=xxx)
Total
(N=xxx)
Number of pack-years 
[1]
   n
xxx
xxx
xxx
   Mean
xx.x
xx.x
xx.x
   SD
xx.xx
xx xx
xx.xx
   Median
xx.x
xx.x
xx.x
   Min.
  x
  x
  x
   Max.
xx
xx
xx
[1] Pack-years = (number of cigarettes smoked per day / 20) x number of years smoked
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
84
Example:  POP_T07                                                                      Page 1 of x
Protocol:  207626
Population:  Intent-to-Treat
Table 1.20
Summary of Smoking Status at Screening
FF/UMEC/VI 
100/62.5/25
(N=xxx)
TIO 18
(N=xxx)
Total
(N=xxx)
n
xx
xx
xx
Current smoker
xx (xx%)
xx (xx%)
xx (xx%)
Former smoker
xx (xx%)
xx (xx%)
xx (xx%)
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
85
Example:  POP_T08                                                                      Page 1 of x
Protocol:  207626
Population:  Intent-to-Treat
Table 1.21
Summary of COPD History at Screening
FF/UMEC/VI 
100/62.5/25
(N=xxx)
TIO 18
(N=xxx)
Total
(N=xxx)
COPD Type
   Chronic bronchitis
xx (xx%)
xx (xx%)
xx (xx%)
   Emphysema
xx (xx%)
xx (xx%)
xx (xx%)
   Chronic bronchitis and 
emphysema
xx (xx%)
xx (xx%)
xx (xx%)
COPD duration (years)
   n
xxx
xxx
xxx
   <1 year
xx (xx%)
xx (xx%)
xx (xx%)
   >=1 to <5 years
xx (xx%)
xx (xx%)
xx (xx%)
   >=5 to <10 years
xx (xx%)
xx (xx%)
xx (xx%)
   >=10 to <15 years
xx (xx%)
xx (xx%)
xx (xx%)
   >=15 to <20 years
xx (xx%)
xx (xx%)
xx (xx%)
   >=20 to <25 years
xx (xx%)
xx (xx%)
xx (xx%)
   >=25 years
xx (xx%)
xx (xx%)
xx (xx%)
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
86
Example:  POP_T09                                                                      Page 1 of x
Protocol:  207626
Population:  Intent-to-Treat
Table 1.22
Summary of COPD Exacerbation History at Screening
FF/UMEC/VI 
100/62.5/25
(N=xxx)
TIO 18
(N=xxx)
Total
(N=xxx)
Number of exacerbations in the 
last 12 months that were managed 
without oral/systemic 
corticosteroids and/or 
antibiotics (not involving 
hospitalization)
   n
xxx
xxx
Xxx
   0
xx (xx%)
xx (xx%)
xx (xx%)
   1
xx (xx%)
xx (xx%)
xx (xx%)
   >=2
xx (xx%)
xx (xx%)
xx (xx%)
Number of exacerbations in the 
last 12 months that required 
oral/systemic corticosteroids 
and/or antibiotics (not involving 
hospitalization)
   n
xxx
xxx
Xxx
   0
xx (xx%)
xx (xx%)
xx (xx%)
   1
xx (xx%)
xx (xx%)
xx (xx%)
   >=2
xx (xx%)
xx (xx%)
xx (xx%)
Number of exacerbations in the 
last 12 months that required 
 
 
 
2019N398531_00


CONFIDENTIAL
207626
87
hospitalization
   n
xxx
xxx
Xxx
   0
xx (xx%)
xx (xx%)
xx (xx%)
   1
xx (xx%)
xx (xx%)
xx (xx%)
   >=2
xx (xx%)
xx (xx%)
xx (xx%)
COPD Type
   Chronic bronchitis
xx (xx%)
xx (xx%)
xx (xx%)
   Emphysema
xx (xx%)
xx (xx%)
xx (xx%)
   Chronic bronchitis and 
emphysema
xx (xx%)
xx (xx%)
xx (xx%)
Note: Number of COPD exacerbations reported in the 12 months prior to the Screening Visit.  
Note:  Moderate exacerbations are defined as those that required treatment with oral/systemic 
corticosteroids and/or antibiotics (not involving hospitalisation). Severe exacerbations are defined 
as those that required in-patient hospitalisation.
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
88
Example:  POP_T10                                                                      Page 1 of 5
Protocol:  207626
Population:  Intent-to-Treat
Table 1.23
Summary of Screening Lung Function
FF/UMEC/VI 
100/62.5/25
(N=xxx)
TIO 18
(N=xxx)
Total
(N=xxx)
Pre-bronchodilator FEV1 (L)
   n
xxx
xxx
xxx
   Mean
xx.xxx
xx.xxx
xx.xxx
   SD
x.xxxx
x.xxxx
x.xxxx
   Median
xx.xxx
xx.xxx
xx.xxx
   Min.
xx.xx
xx.xx
xx.xx
   Max.
xx.xx
xx.xx
xx.xx
Post-bronchodilator FEV1 (L)
   n
xxx
xxx
xxx
   Mean
xx.xxx
xx.xxx
xx.xxx
   SD
x.xxxx
x.xxxx
x.xxxx
   Median
xx.xxx
xx.xxx
xx.xxx
   Min.
xx.xx
xx.xx
xx.xx
   Max.
xx.xx
xx.xx
xx.xx
Programming note:  Same format for Table 1.24 (Summary of Screening Lung Function by Country).
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
89
Example:  POP_T10                                                                      Page 2 of 5
Protocol:  207626
Population:  Intent-to-Treat
Table 1.23
Summary of Screening Lung Function
FF/UMEC/VI 
100/62.5/25
(N=xxx)
TIO 18
(N=xxx)
Total
(N=xxx)
Pre-bronchodilator FVC (L)
   n
xxx
xxx
xxx
   Mean
xx.xxx
xx.xxx
xx.xxx
   SD
x.xxxx
x.xxxx
x.xxxx
   Median
xx.xxx
xx.xxx
xx.xxx
   Min.
xx.xx
xx.xx
xx.xx
   Max.
xx.xx
xx.xx
xx.xx
Post-bronchodilator FVC (L)
   n
xxx
xxx
xxx
   Mean
xx.xxx
xx.xxx
xx.xxx
   SD
x.xxxx
x.xxxx
x.xxxx
   Median
xx.xxx
xx.xxx
xx.xxx
   Min.
xx.xx
xx.xx
xx.xx
   Max.
xx.xx
xx.xx
xx.xx
Programming note:  Same format for Table 1.24 (Summary of Screening Lung Function by Country).
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
90
Example:  POP_T10                                                                     Page 3 of 5
Protocol:  207626
Population:  Intent-to-Treat
Table 1.23
Summary of Screening Lung Function
FF/UMEC/VI 
100/62.5/25
(N=xxx)
TIO 18
(N=xxx)
Total
(N=xxx)
Pre-bronchodilator FEV1/FVC
   n
xxx
xxx
xxx
   Mean
xx.xxx
xx.xxx
xx.xxx
  SD
x.xxxx
x.xxxx
x.xxxx
   Median
xx.xxx
xx.xxx
xx.xxx
   Min.
xx.xx
xx.xx
xx.xx
   Max.
xx.xx
xx.xx
xx.xx
Post-bronchodilator FEV1/FVC
   n
xxx
xxx
xxx
   Mean
xx.xxx
xx.xxx
xx.xxx
   SD
x.xxxx
x.xxxx
x.xxxx
   Median
xx.xxx
xx.xxx
xx.xxx
   Min.
xx.xx
xx.xx
xx.xx
   Max.
xx.xx
xx.xx
xx.xx
Programming note:  Same format for Table 1.24 (Summary of Screening Lung Function by Country).
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
91
Example:  POP_T10                                                                      Page 4 of 5
Protocol:  207626
Population:  Intent-to-Treat
Table 1.23
Summary of Screening Lung Function
FF/UMEC/VI 
100/62.5/25
(N=xxx)
TIO 18
(N=xxx)
Total
(N=xxx)
Predicted FEV1 (L)
   n
xxx
xxx
xxx
   Mean
xx.xxx
xx.xxx
xx.xxx
   SD
x.xxxx
x.xxxx
x.xxxx
   Median
xx.xxx
xx.xxx
xx.xxx
   Min.
xx.xx
xx.xx
xx.xx
   Max.
xx.xx
xx.xx
xx.xx
Percent predicted FEV1 (%)
   n
xxx
xxx
xxx
   Mean
xx.xxx
xx.xxx
xx.xxx
  SD
x.xxxx
x.xxxx
x.xxxx
   Median
xx.xxx
xx.xxx
xx.xxx
   Min.
xx.xx
xx.xx
xx.xx
   Max.
xx.xx
xx.xx
xx.xx
Programming note:  Same format for Table 1.24 (Summary of Screening Lung Function by Country).
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
92
Example:  POP_T10                                                                      Page 5 of 5
Protocol:  207626
Population:  Intent-to-Treat
Table 1.23
Summary of Screening Lung Function
FF/UMEC/VI 
100/62.5/25
(N=xxx)
TIO 18
(N=xxx)
Total
(N=xxx)
Reversibility (%)
   n
xxx
xxx
xxx
   Mean
xx.xxx
xx.xxx
xx.xxx
   SD
x.xxxx
x.xxxx
x.xxxx
   Median
xx.xxx
xx.xxx
xx.xxx
   Min.
xx.xx
xx.xx
xx.xx
   Max.
xx.xx
xx.xx
xx.xx
Programming note:  Same format for Table 1.24 (Summary of Screening Lung Function by Country).
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
93
Example:  POP_T11                                                                      Page 1 of 2
Protocol:  207626
Population:  Intent-to-Treat
Table 1.25
Summary of Reversibility and GOLD Grade (1 – 4) at Screening
FF/UMEC/VI 
100/62.5/25
(N=xxx)
TIO 18
(N=xxx)
Total
(N=xxx)
Gold Grade
   n
xxx
xxx
Xxx
   Grade 1 (mild):  predicted FEV1 >= 80% 
xx (xx%)
xx (xx%)
xx (xx%)
   Grade 2 (moderate):  50% <= predicted FEV1 < 80%
xx (xx%)
xx (xx%)
xx (xx%)
   Grade 3 (severe) 30% <= predicted FEV1 < 50%
xx (xx%)
xx (xx%)
xx (xx%)
   Grade 3 (very severe) predicted FEV1 < 30%
xx (xx%)
xx (xx%)
xx (xx%)
Reversible to salbutamol [1]
   n
xxx
xxx
Xxx
   Reversible
xx (xx%)
xx (xx%)
xx (xx%)
   Not reversible
xx (xx%)
xx (xx%)
xx (xx%)
Exacerbation history in previous year
   N
xxx
xxx
Xxx
   <2 moderate and no severe
xx (xx%)
xx (xx%)
xx (xx%)
   >=2 moderate OR >=1 severe
xx (xx%)
xx (xx%)
xx (xx%)
GOLD grade / exacerbation history in previous year
   
   GOLD 1/2 with >=2 moderate or >=1 severe
   GOLD 3/4 with <2 moderate and no severe
   GOLD 3/4 with >=2 moderate or >=1 severe
 
 
 
2019N398531_00


CONFIDENTIAL
207626
94
[1] “Reversible” is defined as an increase in FEV1 of >=12% AND of >=200mL following administration 
of salbutamol.  “Not reversible” is defined as an increase in FEV1 of <200mL OR an increase of 
>=200mL that is <12% of the pre-salbutamol FEV1.
Note: Moderate exacerbations are defined as exacerbations that required treatment with oral/systemic 
corticosteroids and/or antibiotics (not involving hospitalisation). Severe exacerbations are defined 
as exacerbations that required in-patient hospitalisation.
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
95
Example:  POP_T11                                                                      Page 2 of 2
Protocol:  207626
Population:  Intent-to-Treat
Table 1.25
Summary of Reversibility and GOLD Grade (1 – 4) at Screening
FF/UMEC/VI 
100/62.5/25
(N=xxx)
TIO 18
(N=xxx)
Total
(N=xxx)
GOLD grade / exacerbation history in previous year
   
   GOLD 1/2 with >=2 moderate or >=1 severe
   GOLD 3/4 with <2 moderate and no severe
   GOLD 3/4 with >=2 moderate or >=1 severe
[1] “Reversible” is defined as an increase in FEV1 of >=12% AND of >=200mL following administration 
of salbutamol.  “Not reversible” is defined as an increase in FEV1 of <200mL OR an increase of 
>=200mL that is <12% of the pre-salbutamol FEV1.
Note: Moderate exacerbations are defined as exacerbations that required treatment with oral/systemic 
corticosteroids and/or antibiotics (not involving hospitalisation). Severe exacerbations are defined 
as exacerbations that required in-patient hospitalisation.
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
96
Example:  POP_T12                                                                      Page 1 of x
Protocol:  207626
Population:  Intent-to-Treat
Table 1.26
Summary of CAT Score and CAT Category at Screening
FF/UMEC/VI 
100/62.5/25
(N=xxx)
TIO 18
(N=xxx)
Total
(N=xxx)
CAT score
   n
xxx
xxx
xxx
   Mean
xx.x
xx.x
xx.x
   SD
xx.xx
xx xx
xx.xx
   Median
xx.x
xx.x
xx.x
   Min.
  x
  x
  x
   Max.
xx
xx
xx
CAT category
   n
xxx
xxx
Xxx
   CAT < 10
xx (xx%)
xx (xx%)
xx (xx%)
   CAT >= 10
xx (xx%)
xx (xx%)
xx (xx%)
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
97
Example: POP_T13                                                                                   Page 1 of x
Protocol: 207626
Population: Intent-to-Treat
Table 1.27
Summary of COPD Concomitant Medications Taken Prior to Screening
Respiratory Class
  Ingredient
FF/UMEC/VI
100/62.5/25
  (N=xxx)
TIO 18
  (N=xxx)
Total
(N=xxx)
Any medication
xxx (xx%)
xxx (xx%)
xxx (xx%)
xxxxxxxxxxxxxxx
Any medication
  xx (xx%)
  xx (xx%)
xxx (xx%)
  xxxxxx + xxxxx
  xx (xx%)
  xx (xx%)
xxx (xx%)
  xxxxxxxxxxxx
  xx (xx%)
  xx (xx%)
xxx (xx%)
  xxxxxxx + xxxxx
  xx (xx%)
  xx (xx%)
xxx (xx%)
  xxxxxxxx + xxxxxxxxxx
  xx (xx%)
  xx (xx%)
xxx (xx%)
  xxxxxxxxx
  xx (xx%)
  xx (xx%)
xxx (xx%)
  xxxxxxxxxxxxxxxxxxxx
  xx (xx%)
  xx (xx%)
xxx (xx%)
  xxxxxx + xxxxx
  xx (xx%)
  xx (xx%)
xxx (xx%)
  xxxxxxxxxxxx
  xx (xx%)
  xx (xx%)
xxx (xx%)
  xxxxxxx + xxxxx
  xx (xx%)
  xx (xx%)
xxx (xx%)
  xxxxxxxx + xxxxxxxxxx
  xx (xx%)
xx (xx%)
xxx (xx%)
  xxxxxxxxx
  xx (xx%)
  xx (xx%)
xxx (xx%)
  xxxxxxxxxxxxxxxxxxxx
  xx (xx%)
  xx (xx%)
xxx (xx%)
xxxxxxxxxxxxxxx
Any medication
  xx (xx%)
  xx (xx%)
xxx (xx%)
  xxxxxx + xxxxx
  xx (xx%)
  xx (xx%)
xxx (xx%)
  xxxxxxxxxxxx
  xx (xx%)
  xx (xx%)
xxx (xx%)
  xxxxxxxx + xxxxxxxxxx
  xx (xx%)
  xx (xx%)
xxx (xx%)
  xxxxxxxxx
  xx (xx%)
  xx (xx%)
xxx (xx%)
Programming not:  same format for Table 1.29 (Summary of COPD Concomitant Medications Taken during Run-in for 
Reasons other than an Exacerbation) and Table 1.32 (Summary of COPD Concomitant Medications Taken during Run-
in for an Exacerbation).
 
 
 
2019N398531_00


CONFIDENTIAL
207626
98
Note: Combination products are included in all applicable respiratory classes.
Note: Study provided salbutamol was not recorded as a concomitant medication.
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
99
Example: POP_T14                                                                                   Page 1 of x
Protocol: 207626
Population: Intent-to-Treat
Table 1.28
Summary of COPD Concomitant Medication Combinations Taken Prior to Screening
Medication Combination [1]
  Full Medication Combination [2]
FF/UMEC/VI
100/62.5/25
  (N=xxx)
TIO 18
  (N=xxx)
Total
(N=xxx)
None
  xx (xx%)
  xx (xx%)
xx (xx%)
xxx + xxx + xxx
  xx (xx%)
  xx (xx%)
xx (xx%)
  xxx + xxx + xxx
  xx (xx%)
  xx (xx%)
xx (xx%)
  xxx + xxx + xxx + xxx
  xx (xx%)
  xx (xx%)
xx (xx%)
  xxx + xxx + xxx + xxx
  xx (xx%)
  xx (xx%)
xx (xx%)
  xxx + xxx + xxx
  xx (xx%)
  xx (xx%)
xx (xx%)
  xxx + xxx + xxx + xxx
  xx (xx%)
  xx (xx%)
xx (xx%)
  xxx + xxx + xxx + xxx
  xx (xx%)
  xx (xx%)
xx (xx%)
xxx + xxx
  xx (xx%)
  xx (xx%)
xx (xx%)
  xxx + xxx
  xx (xx%)
  xx (xx%)
xx (xx%)
  xxx + xxx + xxx
  xx (xx%)
  xx (xx%)
xx (xx%)
  xxx + xxx + xxx + xxx
  xx (xx%)
  xx (xx%)
xx (xx%)
  xxx + xxx + xxx
  xx (xx%)
  xx (xx%)
xx (xx%)
  xxx + xxx + xxx + xxx
  xx (xx%)
  xx (xx%)
xx (xx%)
  xxx + xxx + xxx + xxx
  xx (xx%)
  xx (xx%)
xx (xx%)
xxx + xxx
  xx (xx%)
  xx (xx%)
xx (xx%)
  xxx + xxx
  xx (xx%)
  xx (xx%)
xx (xx%)
  xxx + xxx + xxx
  xx (xx%)
  xx (xx%)
xx (xx%)
  xxx + xxx + xxx + xxx
  xx (xx%)
  xx (xx%)
xx (xx%)
  xxx + xxx + xxx
  xx (xx%)
  xx (xx%)
xx (xx%)
  xxx + xxx + xxx + xxx
  xx (xx%)
  xx (xx%)
xx (xx%)
[1] COPD respiratory medication class (RMC) combination based on the individual RMC and any combination of the 
RMCs: ICS, LABA, LAMA, Xanthine and PDE4 Inhibitors.
[2] COPD RMC combination based on all RMCs.
 
 
 
2019N398531_00


CONFIDENTIAL
207626
100
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
101
Example: POP_T15                                                                                   Page 1 of x
Protocol: 207626
Population: Intent-to-Treat
Table 1.30
Summary of On-Treatment COPD Concomitant Medications Taken for Reasons other than an Exacerbation
Respiratory Class
  Ingredient
FF/UMEC/VI
100/62.5/25
  (N=xxx)
TIO 18
  (N=xxx)
Any medication
xxx (xx%)
xxx (xx%)
xxxxxxxxxxxxxxx
Any medication
  xx (xx%)
  xx (xx%)
  xxxxxx + xxxxx
  xx (xx%)
  xx (xx%)
  xxxxxxxxxxxx
  xx (xx%)
  xx (xx%)
  xxxxxxx + xxxxx
  xx (xx%)
  xx (xx%)
  xxxxxxxx + xxxxxxxxxx
  xx (xx%)
  xx (xx%)
  xxxxxxxxx
  xx (xx%)
  xx (xx%)
  xxxxxxxxxxxxxxxxxxxx
  xx (xx%)
  xx (xx%)
  xxxxxx + xxxxx
  xx (xx%)
  xx (xx%)
  xxxxxxxxxxxx
  xx (xx%)
  xx (xx%)
  xxxxxxx + xxxxx
xx (xx%)
  xx (xx%)
  xxxxxxxx + xxxxxxxxxx
  xx (xx%)
  xx (xx%)
  xxxxxxxxx
  xx (xx%)
  xx (xx%)
  xxxxxxxxxxxxxxxxxxxx
  xx (xx%)
  xx (xx%)
xxxxxxxxxxx
Any medication
  xx (xx%)
  xx (xx%)
  xxxxxx + xxxxx
  xx (xx%)
  xx (xx%)
  xxxxxxxxxxxx
  xx (xx%)
  xx (xx%)
  xxxxxxxx + xxxxxxxxxx
  xx (xx%)
  xx (xx%)
  xxxxxxxxx
  xx (xx%)
  xx (xx%)
Programming note:  Same format for Table 1.31 (Summary of Post-Treatment COPD Concomitant Medications Taken 
for Reasons other than an Exacerbation), Table 1.33 (Summary of On-Treatment COPD Concomitant Medications 
Taken for an Exacerbation), and Table 1.34 (Summary of Post-Treatment COPD Concomitant Medications Taken for 
an Exacerbation),
 
 
 
2019N398531_00


CONFIDENTIAL
207626
102
Note: Combination products are included in all applicable respiratory classes.
Note: Study provided salbutamol was not recorded as a concomitant medication.
Note: On-treatment medications include medications stopped on the day of randomization.
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
103
Example: POP_T16                                                                                   Page 1 of x
Protocol: 207626
Population: Intent-to-Treat
Table 1.35
Summary of On-Treatment Non-COPD Concomitant Medications
ATC Level 1
  Ingredient
FF/UMEC/VI
100/62.5/25
  (N=xxx)
TIO 18
  (N=xxx)
Any medication
xxx (xx%)
xxx (xx%)
xxxxxxxxxxxxxxx
Any medication
  xx (xx%)
  xx (xx%)
  xxxxxx + xxxxx
  xx (xx%)
  xx (xx%)
  xxxxxxxxxxxx
  xx (xx%)
  xx (xx%)
  xxxxxxx + xxxxx
  xx (xx%)
  xx (xx%)
  xxxxxxxx + xxxxxxxxxx
  xx (xx%)
  xx (xx%)
  xxxxxxxxx
  xx (xx%)
  xx (xx%)
  xxxxxxxxxxxxxxxxxxxx
  xx (xx%)
  xx (xx%)
  xxxxxx + xxxxx
  xx (xx%)
  xx (xx%)
  xxxxxxxxxxxx
  xx (xx%)
  xx (xx%)
  xxxxxxx + xxxxx
  xx (xx%)
  xx (xx%)
  xxxxxxxx + xxxxxxxxxx
  xx (xx%)
  xx (xx%)
  xxxxxxxxx
  xx (xx%)
  xx (xx%)
  xxxxxxxxxxxxxxxxxxxx
  xx (xx%)
  xx (xx%)
xxxxxxxxxxx
Any medication
  xx (xx%)
  xx (xx%)
  xxxxxx + xxxxx
  xx (xx%)
  xx (xx%)
  xxxxxxxxxxxx
  xx (xx%)
  xx (xx%)
  xxxxxxxx + xxxxxxxxxx
  xx (xx%)
  xx (xx%)
  xxxxxxxxx
  xx (xx%)
  xx (xx%)
Programming note:  Same format for Table 1.36 (Summary of Post-Treatment Non-COPD Concomitant Medications).
Note: Combination products are included in all applicable ATC level 1 categories.
Note: On-treatment medications include medications stopped on the day of randomization.
 
 
 
2019N398531_00


CONFIDENTIAL
207626
104
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
105
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
106
Example:  POP_T17                                                                      Page 1 of x
Protocol:  207626
Population:  Intent-to-Treat
Table 1.37
Summary of Treatment Compliance
FF/UMEC/VI 
100/62.5/25
(N=xxx)
TIO 18
(N=xxx)
Total
(N=xxx)
ELLIPTA compliance (%)
   n
xxx
xxx
xxx
   Mean
xx.x
xx.x
xx.x
   SD
x.xx
x.xx
x.xx
   Median
xx.x
xx.x
xx.x
   Min.
xx.x
xx.x
xx.x
   Max.
xx.x
xx.x
xx.x
   <80%
xx (xx%)
xx (xx%)
xx (xx%)
   >=80% to <95%
xx (xx%)
xx (xx%)
xx (xx%)
   >=95% to <=105%
xx (xx%)
xx (xx%)
xx (xx%)
   >105% to <=120%
xx (xx%)
xx (xx%)
xx (xx%)
   >120%
xx (xx%)
xx (xx%)
xx (xx%)
Programming note:  repeat this section for HANDIHALER compliance (%) and Overall compliance (%).
Note:  High compliance values may be due to the imputation in the denominator of missing treatment 
stop dates with the date study treatment was last known to be taken.
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
107
Example:  EFF_T01                                                                      Page 1 of x
Protocol:  207626
Population:  Intent-to-Treat
Table 2.1
Summary of Baseline FEV1 (L)
FF/UMEC/VI 
100/62.5/25
(N=xxx)
TIO 18
(N=xxx)
All subjects
n
xxx
xxx
Mean
xx.xxx
xx.xxx
SD
x.xxxx
x.xxxx
Min.
xx.xx
xx.xx
Q1
xx.xxx
xx.xxx
Median
xx.xxx
xx.xxx
Q3
xx.xxx
xx.xxx
Max.
xx.xx
xx.xx
Subjects with non-
missing on-treatment 
trough FEV1 data at Day 
85
n
xxx
xxx
Mean
xx.xxx
xx.xxx
SD
x.xxxx
x.xxxx
Min.
xx.xx
xx.xx
Q1
xx.xxx
xx.xxx
Median
xx.xxx
xx.xxx
Q3
xx.xxx
xx.xxx
Max.
xx.xx
xx.xx
Subjects with missing 
 
 
 
2019N398531_00


CONFIDENTIAL
207626
108
on-treatment trough 
FEV1 data at Day 85
n
xxx
xxx
Mean
xx.xxx
xx.xxx
SD
x.xxxx
x.xxxx
Min.
xx.xx
xx.xx
Q1
xx.xxx
xx.xxx
Median
xx.xxx
xx.xxx
Q3
xx.xxx
xx.xxx
Max.
xx.xx
xx.xx
Programming note:  Same format for Table 2.2 (Summary of Baseline FEV1 (L) by Country).
Note:  Baseline is the average of the two pre-dose measurements on Day 1.
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
109
Example:  EFF_T02                                                                      Page 1 of x
Protocol:  207626
Population:  Intent-to-Treat
Table 2.3
Summary of Trough FEV1 (L) - Hypothetical Estimand
                                                             FF/UMEC/VI     
                                                             100/62.5/25      TIO 18
                                                                     (N=xxx)        (N=xxx)
------------------------------------------------------------------------------------------------------------
Day 28     Trough FEV1 (L)              n                            xxx             xxx
                                       Mean                           x.xxx           x.xxx
                                       SD                             x.xxxx          x.xxxx
                                       Min.
     x.xx            x.xx
    Q1
     x.xxx           x.xxx
    Median                         x.xxx           x.xxx
                                       Q3                             x.xxx           x.xxx
                                        Max.                           x.xx            x.xx
          Change from baseline          n                            xxx             xxx
                                        Mean                           x.xxx           x.xxx
                                       SD                             x.xxxx          x.xxxx
                                        Min.
     x.xx            x.xx
    Q1
     x.xxx          x.xxx
    Median                         x.xxx           x.xxx
                                       Q3                             x.xxx           x.xxx
                                        Max.                           x.xx            x.xx
Day 84    Trough FEV1 (L)               n                            xxx             xxx
                                       Mean                           x.xxx           x.xxx
                                       SD                             x.xxxx          x.xxxx
                                       Min.
     x.xx            x.xx
    Q1
     x.xxx           x.xxx
    Median                         x.xxx           x.xxx
                                       Q3                             x.xxx           x.xxx
 
 
 
2019N398531_00


CONFIDENTIAL
207626
110
                                        Max.                           x.xx            x.xx
          Change from baseline          n                            xxx             xxx
                                        Mean                           x.xxx           x.xxx
                                       SD                             x.xxxx          x.xxxx
                                        Min.
     x.xx            x.xx
    Q1
     x.xxx           x.xxx
    Median                         x.xxx           x.xxx
                                       Q3                             x.xxx           x.xxx
    Max.                           x.xx            x.xx
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
111
Example:  EFF_T02                                                                      Page 2 of x
Protocol:  207626
Population:  Intent-to-Treat
Table 2.3
Summary of Trough FEV1 (L) - Hypothetical Estimand
                                                             FF/UMEC/VI     
                                                             100/62.5/25      TIO 18
                                                                     (N=xxx)        (N=xxx)
------------------------------------------------------------------------------------------------------------
Day 85     Trough FEV1 (L)              n                            xxx             xxx
                                       Mean                           x.xxx           x.xxx
                                       SD                             x.xxxx          x.xxxx
                                       Min.
     x.xx            x.xx
    Q1
     x.xxx           x.xxx
    Median                         x.xxx           x.xxx
                                       Q3                             x.xxx           x.xxx
                                        Max.                           x.xx            x.xx
          Change from baseline          n                            xxx             xxx
                                        Mean                           x.xxx           x.xxx
                                       SD                             x.xxxx          x.xxxx
                                        Min.
     x.xx            x.xx
    Q1
     x.xxx           x.xxx
    Median                         x.xxx           x.xxx
                                       Q3                             x.xxx           x.xxx
                                        Max.                           x.xx            x.xx
Programming note:  Same format for Table 2.4 (Summary of Trough FEV1– Treatment Policy Estimand), 
Table 2.5 (Summary of Trough FEV1 by Country – Hypothetical Estimand), and Table 2.6 (Summary of 
Trough FEV1 by Country – Treatment Policy Estimand).
 
 
 
2019N398531_00


CONFIDENTIAL
207626
112
Programming note:  Same format for Table 2.12 (Summary of SGRQ Total and Domain Scores –
Hypothetical Estimand), but will include total score and 3 domain scores (Symptoms, Activity, and 
Impacts) on Days 28 and 84.
Programming note:  Same format for Table 2.17(Summary of CAT Score – Hypothetical Estimand) on Days 
28 and 84.
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
113
Example:  EFF_T03                                                                      Page 1 of 2
Protocol:  207626
Population:  Intent-to-Treat
Table 2.7
Analysis of Trough FEV1 (L) – Hypothetical Estimand
FF/UMEC/VI 
100/62.5/25
(N=xxx)
TIO 18
(N=xxx)
Day 28
   n
Xxx
xxx
   LS mean (SE)
  x.xxx (x.xxxx)
  x.xxx (x.xxxx)
   95% CI
   (x.xxx, x.xxx)
  (x.xxx, x.xxx)
   LS mean change (SE)
  x.xxx (x.xxxx)
  x.xxx (x.xxxx)
   95% CI
   (x.xxx, x.xxx)
  (x.xxx, x.xxx)
   FF/UMEC/VI 100/62.5/25 VS TIO 18
   Difference (SE)
  x.xxx (x.xxxx)
  (x.xxx, x.xxx)
   95% CI
   p-value
      x.xxx
Day 84
   n
Xxx
xxx
   LS mean (SE)
  x.xxx (x.xxxx)
  x.xxx (x.xxxx)
   95% CI
   (x.xxx, x.xxx)
  (x.xxx, x.xxx)
   LS mean change (SE)
  x.xxx (x.xxxx)
  x.xxx (x.xxxx)
   95% CI
   (x.xxx, x.xxx)
  (x.xxx, x.xxx)
   FF/UMEC/VI 100/62.5/25 VS TIO 18
   Difference (SE)
  x.xxx (x.xxxx)
  (x.xxx, x.xxx)
   95% CI
   p-value
      x.xxx
 
 
 
2019N398531_00


CONFIDENTIAL
207626
114
Note: Analysis consists of a repeated measures model with covariates of baseline value,
visit, geographical region, treatment, and interactions of visit with treatment and baseline value.
Programming note:  Same format for Table 2.8 (Analysis of Trough FEV1 – Treatment Policy Estimand).
Programming note:  Same format for Table 2.13 (Analysis of SGRQ Total Score – Hypothetical Estimand) 
on Days 28 and 84 only.
Programming note:  Same format for Table 2.21 (Analysis of CAT Score – Hypothetical Estimand) on 
Days 28 and 84 only.
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
115
Example:  EFF_T03                                                                      Page 2 of 2
Protocol:  207626
Population:  Intent-to-Treat
Table 2.7
Analysis of Trough FEV1 (L) – Hypothetical Estimand
FF/UMEC/VI 
100/62.5/25
(N=xxx)
TIO 18
(N=xxx)
Day 85
   n
xxx
xxx
   LS mean (SE)
  x.xxx (x.xxxx)
  x.xxx (x.xxxx)
   95% CI
   (x.xxx, x.xxx)
  (x.xxx, x.xxx)
   LS mean change (SE)
  x.xxx (x.xxxx)
  x.xxx (x.xxxx)
   95% CI
   (x.xxx, x.xxx)
  (x.xxx, x.xxx)
   FF/UMEC/VI 100/62.5/25 VS TIO 18
   Difference (SE)
  x.xxx (x.xxxx)
  (x.xxx, x.xxx)
   95% CI
   p-value
      x.xxx
Note: Analysis consists of a repeated measures model with covariates of baseline value,
visit, geographical region, treatment, and interactions of visit by treatment and visit by baseline.
Programming note:  Same format for Table 2.8 (Analysis of Trough FEV1 – Treatment Policy Estimand).
Programming note:  Same format for Table 2.13 (Analysis of SGRQ Total Score – Hypothetical Estimand) 
on Days 28 and 84 only.
Programming note:  Same format for Table 2.21 (Analysis of CAT Score – Hypothetical Estimand) on 
Days 28 and 84 only.
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
116
Example:  EFF_T04                                                                      Page 1 of x
Protocol:  207626
Population:  Intent-to-Treat
Table 2.9
Significance Level for Interaction of Treatment with Geographical Region and Baseline FEV1 for 
Analysis of Trough FEV1 (L)on Day 85 – Treatment Policy Estimand
Interaction of treatment with:
p-value [1]
Baseline FEV1
x.xxx
Geographical region
x.xxx
[1] Analysis consists of a repeated measures model with covariates of baseline value,
visit, geographical region, and treatment, as well as visit by treatment and visit by baseline 
interaction.
Note: An interaction is considered statistically significant if the p-value is <0.10.
Programming note:  Same format for Table 2.10 (Significance Level for Interaction of Treatment with 
Geographical Region and Baseline FEV1 for Analysis of Trough FEV1 (L)on Day 85 – Hypothetical 
Estimand)
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
117
Example:  EFF_T05                                                                      Page 1 of x
Protocol:  207626
Population:  Intent-to-Treat
Table 2.11
Tipping Point Sensitivity Analysis:  Two-Sided p-values after Imputing Various Day 85 Mean Changes 
from Baseline Trough FEV1 (L) – Treatment Policy Estimand
TIO 18
FF/UMEC/VI 100/62.5/25
-0.15
-0.10
-0.05
0.00
0.05
0.10
0.15
-0.15
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
-0.10
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
-0.05
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
0.00
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
0.05
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
0.10
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
0.15
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
x.xxx
Note:  Each column and each row represents a step-wise increment in the magnitude of the change from 
baseline in trough FEV1.
Note: Data for subjects with missing baseline values were not imputed.
Note: Multiple imputation at Day 85 followed by Day 28 and Day 84 was calculated for all subjects 
with a missing on-treatment assessment, adjusting for covariates of 
geographical region and treatment. Imputed values were taken from a multivariate normal distribution 
with the assumed mean change from baseline and standard deviation taken from observed data at the 
corresponding time point.
Note: Analysis, including observed and imputed data at Day 85, used an ANCOVA model with
covariates of baseline value, geographical region, and treatment.
Programming note:  Add * before each p-value that is less than 0.050.
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
118
Example:  EFF_T06                                                                      Page 1 of 2
Protocol:  207626
Population:  Intent-to-Treat
Table 2.12
Summary of Baseline SGRQ Total and Domain Scores
FF/UMEC/VI
100/62.5/25
(N=xxx)
TIO 18
(N=xxx)
SGRQ total score
   N
xxx
xxx
   Mean
xx.x
xx.x
   SD
xx.xx
xx.xx
   Min.
x
x
   Q1
xx.x
xx.x
   Median
xx.x
xx.x
   Q3
xx.x
xx.x
   Max.
xx
xx
Symptoms domain
   N
xxx
xxx
   Mean
xx.x
xx.x
   SD
xx.xx
xx xx
   Min.
x
x
   Q1
xx.x
xx.x
   Median
xx.x
xx.x
   Q3
xx.x
xx.x
   Max.
xx
xx
Programming note:  Same format for Table 2.19 (Summary of Baseline CAT Score).
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
119
Example:  EFF_T06                                                                      Page 2 of 2
Protocol:  207626
Population:  Intent-to-Treat
Table 2.12
Summary of Baseline SGRQ Total and Domain Scores
FF/UMEC/VI
100/62.5/25
(N=xxx)
TIO 18
(N=xxx)
Activity domain
   N
xxx
xxx
   Mean
xx.x
xx.x
   SD
xx.xx
xx xx
   Min.
x
x
   Q1
xx.x
xx.x
   Median
xx.x
xx.x
   Q3
xx.x
xx.x
   Max.
xx
xx
Impacts domain
   N
xxx
xxx
   Mean
xx.x
xx.x
   SD
xx.xx
xx xx
   Min.
x
x
   Q1
xx.x
xx.x
   Median
xx.x
xx.x
   Q3
xx.x
xx.x
   Max.
xx
xx
Programming note:  Same format for Table 2.19 (Summary of Baseline CAT Score).
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
120
Example: EFF_T03
Protocol: 207626                                                                                   Page 1 of 2
Population: Intent-to-Treat
Table 2.14
Analysis of SGRQ Total Score – Hypothetical Estimand
                                                                 FF/UMEC/VI         
                                                                 100/62.5/25           TIO 18
                                                                  (N=xxx)            (N=xxx)
------------------------------------------------------------------------------------------------------------
Day 28
  n [1]                                                          xxx                 xxx
  n [2]                                                          xxx                 xxx
  LS Mean (SE)                                                    x.x (x.xx)      x.x (x.xx)
  95% CI                                                          (x.x, x.x)      (x.x, x.x)
  LS Mean Change (SE)                                              x.x (x.xx)      x.x (x.xx)
  95% CI                                                          (x.x, x.x)      (x.x, x.x)
  FF/UMEC/VI 100/62.5/25 VS TIO 18
  Difference (SE)                                                  x.x (x.xx)
  95% CI                                                         (x.x, x.x)
  p-value                                                          x.xxx
[1] Number of subjects with analyzable data for one or more time points.
[2] Number of subjects with analyzable data at the current time point.
Note: Analysis performed using a repeated measures model with covariates of baseline value, visit, 
geographical region, treatment, visit by treatment and visit by baseline interactions.
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
121
Example: EFF_T03
Protocol: 207626                                                                                   Page 2 of 2
Population: Intent-to-Treat
Table 2.14
Analysis of SGRQ Total Score – Hypothetical Estimand
                                                                 FF/UMEC/VI         
                                                                 100/62.5/25          TIO 18
                                                                  (N=xxx)            (N=xxx)
-------------------------------------------------------------------------------------------------------------
Day 84
  n [1]                                                          xxx                 xxx
  n [2]                                                          xxx                 xxx
  LS Mean (SE)                                                    x.x (x.xx)      x.x (x.xx)
  95% CI                                                          (x.x, x.x)      (x.x, x.x)
  LS Mean Change (SE)                                              x.x (x.xx)      x.x (x.xx)
  95% CI                                                          (x.x, x.x)      (x.x, x.x)
  FF/UMEC/VI 100/62.5/25 VS TIO 18
  Difference (SE)                                                  x.x (x.xx)
  95% CI                                                         (x.x, x.x)
  p-value                                                          x.xxx
[1] Number of subjects with analyzable data for one or more time points.
[2] Number of subjects with analyzable data at the current time point.
Note: Analysis performed using a repeated measures model with covariates of baseline value, visit, 
geographical region, treatment, visit by treatment and visit by baseline interactions.
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
122
Example:  EFF_T07                                                                      Page 1 of x
Protocol:  207626
Population:  Intent-to-Treat
Table 2.15
Summary and Analysis of Proportion of Responders as Defined by SGRQ Total Score – Hypothetical 
Estimand
FF/UMEC/VI 
100/62.5/25
(N=xxx)
TIO 18
(N=xxx)
Day 28
   n
xxx
xxx
   Responders 
  xxx (xx%)
  xxx (xx%)
   Non-responders 
  xxx (xx%)
  xxx (xx%)
   FF/UMEC/VI 100/62.5/25 VS TIO 18
   Odds ratio
  x.xx   
(x.xx, x.xx)
   95% CI
   p-value
      x.xxx
Day 84
   n
xxx
xxx
   Responders 
  xxx (xx%)
  xxx (xx%)
   Non-responders 
  xxx (xx%)
  xxx (xx%)
   FF/UMEC/VI 100/62.5/25 VS TIO 18
   Odds ratio
  x.xx
  (x.xx, x.xx)
   95% CI
   p-value
      x.xxx
 
 
 
2019N398531_00


CONFIDENTIAL
207626
123
Note:  Responders are defined as those subjects whose SGRQ total score is 4 units or more below 
baseline.  Non-responders are defined as those subjects whose SGRQ total score is more than 4 units 
below baseline or a missing SGRQ total score at a the timepoint in question and no subsequent on-
treatment scores.  Subjects will not be assigned a responder status at any timepoint if their 
baseline SGRQ total score is missing.  Subjects will not have a responder status assigned at a given 
timepoint if the SGRQ total score at that timepoint is missing.
Note: Analysis is based on a generalized linear mixed model with a logit link function and 
covariates of treatment group, visit, geographical region, baseline SGRQ score, and interactions of 
visit with baseline SGRQ score and with treatment.
Programming note:  same format and same timepoints for Table 2.23 (Summary and Analysis of 
Proportion of Responders as Defined by CAT Score – Hypothetical Estimand).  Highlighted text in 
footnote above should be changed as follows:
SGRQ total score is 4 units => CAT score is 2 units
SGRQ total score is more than 4 units => CAT score is more than 2 units
SGRQ total score => CAT score
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
124
Example:  EFF_T08                                                                      Page 1 of 1
Protocol:  207626
Population:  Intent-to-Treat
Table 2.16
Summary of On-Treatment COPD Exacerbations
FF/UMEC/VI 
100/62.5/25
(N=xxx)
TIO 18
(N=xxx)
n (%)
Rate (#)
n (%)
Rate (%)
Total treatment exposure (subject-years)
xxx.x
xxx.x
Subjects with a mild, moderate, or severe 
COPD exacerbation
xxx (xx)
xxx.x (xx)
xxx (xx)
xxx.x (xx)
Subjects with a mild COPD exacerbation
xxx (xx)
xxx.x (xx
xxx (xx)
xxx.x (xx)
Subjects with a moderate COPD exacerbation
xxx (xx)
xxx.x (xx
xxx (xx)
xxx.x (xx)
Subjects with a severe COPD exacerbation
xxx (xx)
xxx.x (xx
xxx (xx)
xxx.x (xx)
Subjects with a moderate/severe COPD 
exacerbation
xxx (xx)
xxx.x (xx
xxx (xx)
xxx.x (xx)
Total number of moderate/severe COPD 
exacerbations per subject
   n
xxx (xx)
xxx (xx)
   0
xxx (xx)
xxx (xx)
   1
xxx (xx)
xxx (xx)
   2
xxx (xx)
xxx (xx)
>=3
xxx (xx)
xxx (xx)
Subjects with >=2 moderate/severe COPD 
exacerbations
xxx (xx)
xxx (xx)
 
 
 
2019N398531_00


CONFIDENTIAL
207626
125
Note:  n = number of subjects, # = number of COPD exacerbations.
Note:  Rate is the event rate per 1000 subject-years, calculated as the number of events x 1000, 
divided by the total duration at risk.
Note:  Moderate exacerbations are defined as those that required treatment with oral or systemic 
corticosteroids and/or antibiotics (not involving hospitalizations or resulting in death).  Severe 
exacerbations are defined as those that required hospitalization or resulted in death.
Programming note:  Same format for Table 2.18 (Summary of Post-treatment COPD Exacerbations).
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
126
Example:  EFF_T09                                                                      Page 1 of 2
Protocol:  207626
Population:  Intent-to-Treat
Table 2.17
Summary of On-Treatment Details of COPD Exacerbations
FF/UMEC/VI 
100/62.5/25
(N=xxx)
TIO 18
(N=xxx)
Total number of moderate/severe COPD 
exacerbations
xxxx
xxxx
Treatment [1]
   Oral/systemic corticosteroids
xxx (xx)
xxx (xx)
   Antibiotics
xxx (xx)
xxx (xx)
   Emergency room visit
xxx (xx)
xxx (xx)
   Hospitalization
xxx (xx)
xxx (xx)
Severity of Exacerbation
   Mild
xxx (xx)
xxx (xx)
   Moderate
xxx (xx)
xxx (xx)
   Severe
xxx (xx)
xxx (xx)
Outcome
   Resolved
xxx (xx)
xxx (xx)
   Fatal
xxx (xx)
xxx (xx)
   Not resolved
xxx (xx)
xxx (xx)
[1] More than one treatment could have been recorded for a given exacerbation.
 
 
 
2019N398531_00


CONFIDENTIAL
207626
127
Note:  Percentages are calculated using the total number of moderate/severe COPD exacerbations as 
the denominator.
Note:  Rate is the event rate per 1000 subject-years, calculated as the number of events x 1000, 
divided by the total treatment exposure through Day 85.
Programming note:  Same format for Table 2.19 (Summary of Post-Treatment Details of COPD 
Exacerbations).
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
128
Example:  EFF_T09                                                                      Page 2 of 2
Protocol:  207626
Population:  Intent-to-Treat
Table 2.17
Summary of On-Treatment Details of COPD Exacerbations
FF/UMEC/VI 
100/62.5/25
(N=xxx)
TIO 18
(N=xxx)
Duration of exacerbation (days)
   n
xxx
xxx
   Mean
xx.x
xx.x
   SD
xx.xx
xx xx
   Median
xx.x
xx.x
   Min.
x
x
   Max.
xx
xx
[1] Percentages are calculated using the number of exacerbations of any severity as the denominator.
[2] More than one treatment could have been recorded for a given exacerbation.
Note:  Rate is the event rate per 1000 subject-years, calculated as the number of events x 1000, 
divided by the total treatment exposure through Day 85.
Programming note:  Same format for Table 2.19 (Summary of Post-Treatment COPD Exacerbation Details).
The description for the first row in the table should be ‘Total time in study post-treatment 
(subject-years’. 
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
129
Example: SAF_T01                                                                         Page 1 of 1
Protocol: 207626
Population: Intent-to-Treat
Table 3.1
Summary of Exposure
FF/UMEC/VI
100/62.5/25
  (N=xxx)
TIO 18
(N=xxx)
Exposure (days)
  n
xxx
   xxx
  Mean
xx.x
    xx.x
  SD
xx.xx
    xx.xx
  Median
xx.x
    xx.xx
  Min.
xx
    xx
  Max.
xxx
    xxx
Total treatment exposure (subject-years)
xxx.x
   xxx.x
Duration of exposure
  >=1 day
xx (xx%)
    xx (xx%)
  >=4 weeks
xx (xx%)
    xx (xx%)
  >=8 weeks 
xx (xx%)
   xx (xx%)
  >=12 weeks
xx (xx%)
    xx (xx%)
  11-13 weeks
xx (xx%)
    xx (xx%)
Total time in study post-treatment (subject-years)
xxx.x
   xxx.x
 
 
 
2019N398531_00


CONFIDENTIAL
207626
130
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
131
Example:  SAF_T02                                                                      Page 1 of x
Protocol:  207626
Population:  Intent-to-Treat
Table 3.23
Summary of On-Treatment Pneumonia Incidence
FF/UMEC/VI 
100/62.5/25
(N=xxx)
TIO 18
(N=xxx)
n (%)
Rate (%)
n (%)
Rate (%)
Total treatment exposure (subject-years)
xxx.x
xxx.x
Subjects with pneumonia
xxx (xx)
xxx.x (xx)
xxx (xx)
xxx.x (xx)
Subjects with pneumonia supported by X-ray 
or CT scan
xxx (xx)
xxx.x (xx)
xxx (xx)
xxx.x (xx)
Total number (%) of pneumonia cases per 
subject
   n
xxx (xx)
xxx (xx)
   0
xxx (xx)
xxx (xx)
   1
xxx (xx)
xxx (xx)
   >=2
xxx (xx)
xxx (xx)
Note: n=Number of subjects, #=Number of events.
Note: Rate is event rate per 1000 subject-years, calculated as the number of events x 1000, divided 
by the total treatment exposure.
Note: A chest x-ray/CT scan is associated with pneumonia if it is taken during the pneumonia or 
within -7 to +10 days (inclusive) of the date of onset.
Note: Pneumonia is supported by a chest x-ray/CT scan if there is an associated x-ray/CT scan which 
shows the presence of infiltrates.
Note: Summary includes only pneumonia events reported on the pneumonia eCRF page.
 
 
 
2019N398531_00


CONFIDENTIAL
207626
132
Programming note:  Same format for Table 3.25 (Summary of Post-Treatment Pneumonia Incidence).
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
133
Example: SAF_T03                                                                                   Page 1 of 4
Protocol: 207626
Population: Intent-to-Treat
Table 3.26
Summary of On-Treatment Details of Pneumonia
FF/UMEC/VI 
100/62.5/25
  (N=xxx)
TIO 18
  (N=xxx)
Total number of cases of pneumonia
xx
xx
Cases of pneumonia with onset at most 14 days after the start 
of a moderate/severe exacerbation
xx (xx%)
xx (xx%)
Chest x-ray/CT scan taken
xx (xx%)
xx (xx%)
  Findings consistent with diagnosis of pneumonia
xx (xx%)
xx (xx%)
No chest x-ray/CT scan taken
xx (xx%)
xx (xx%)
Hospitalised
xx (xx%)
xx (xx%)
Hospitalised and chest x-ray/CT scan taken
xx (xx%)
xx (xx%)
  Findings consistent with diagnosis of pneumonia
x (xx%)
x (xx%)
No chest x-ray/CT scan taken
x (xx%)
x (xx%)
Fatal
xx (xx%)
xx (xx%)
Fatal and chest x-ray/CT scan taken
xx (xx%)
xx (xx%)
  Findings consistent with diagnosis of pneumonia
xx (xx%)
xx (xx%)
No chest x-ray/CT scan taken
xx (xx%)
xx (xx%)
Note: Table summarizes event counts. Percentages are calculated using the number of cases of pneumonia as the 
denominator.
Note: A chest x-ray/CT scan is associated with pneumonia if it is taken within the duration of the pneumonia 
or within -7 to +10 days (inclusive) of the date of onset.
Note: Summary includes pneumonia events reported on the pneumonia eCRF page.
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
134
Example: SAF_T03                                                                                   Page 2 of 4
Protocol: 207626
Population: Intent-to-Treat
Table 3.25
Summary of On-Treatment Details of Pneumonia
  FF/UMEC/VI
  100/62.5/25
    (N=xxx)
TIO 18
  (N=xxx)
Level of cough
  Increased level
  Usual level
  xx (xx%)
  xx (xx%)
  xx (xx%)
  xx (xx%)
Increased sputum purulence
  Yes
  No
  Unknown
  xx (xx%)
  xx (xx%)
  xx (xx%)
  xx (xx%)
  xx (xx%)
  xx (xx%)
Lung evaluation shows crackles/rales, bronchial or 
bronchovesicular breath sounds
  Yes
  No
  Unknown
  xx (xx%)
  xx (xx%)
  xx (xx%)
  xx (xx%)
  xx (xx%)
  xx (xx%)
Worsening dypsnea
  Yes
  No
  Unknown
  xx (xx%)
  xx (xx%)
  xx (xx%)
  xx (xx%)
  xx (xx%)
  xx (xx%)
Note: Table summarizes event counts. Percentages are calculated using the number of cases of pneumonia as the 
denominator.
Note: A chest x-ray/CT scan is associated with pneumonia if it is taken within the duration of the pneumonia 
or within -7 to +10 days (inclusive) of the date of onset.
Note: Summary includes pneumonia events reported on the pneumonia eCRF page.
 
 
 
2019N398531_00


CONFIDENTIAL
207626
135
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
136
Example: SAF_T03                                                                                   Page 3 of 4
Protocol: 207626
Population: Intent-to-Treat
Table 3.25
Summary of On-Treatment Details of Pneumonia
  FF/UMEC/VI 
  100/62.5/25
    (N=xxx)
TIO 18
  (N=xxx)
Does subject have pleural effusion?
  Yes
  No
  Unknown
  xx (xx%)
  xx (xx%)
  xx (xx%)
  xx (xx%)
  xx (xx%)
  xx (xx%)
Does subject have hypoxemia?
  Yes
  No
  Unknown
  xx (xx%)
  xx (xx%)
  xx (xx%)
  xx (xx%)
  xx (xx%)
  xx (xx%)
WBC count performed at time of event
  Yes
  No
  Unknown
  xx (xx%)
  xx (xx%)
  xx (xx%)
  xx (xx%)
  xx (xx%)
  xx (xx%)
WBC count relative to reference range
High WBC
  Normal WBC
  Low WBC
  xx (xx%)
  xx (xx%)
  xx (xx%)
  xx (xx%)
  xx (xx%)
  xx (xx%)
Note: Table summarizes event counts. Percentages are calculated using the number of cases of pneumonia as the 
denominator.
Note: A chest x-ray/CT scan is associated with pneumonia if it is taken within the duration of the pneumonia 
or within -7 to +10 days (inclusive) of the date of onset.
Note: Summary includes pneumonia events reported on the pneumonia eCRF page.
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
137
Example: SAF_T03                                                                                   Page 4 of 4
Protocol: 207626
Population: Intent-to-Treat
Table 3.25
Summary of On-Treatment Details of Pneumonia
  FF/UMEC/VI 
  100/62.5/25
    (N=xxx)
TIO 18
  (N=xxx)
Was BUN >19mg/dL (7mmol/L)?
  Yes
  No
  Unknown
  xx (xx%)
  xx (xx%)
  xx (xx%)
  xx (xx%)
  xx (xx%)
  xx (xx%)
Was there evidence the subject was confused?
  Yes
  No
  Unknown
  xx (xx%)
  xx (xx%)
  xx (xx%)
  xx (xx%)
  xx (xx%)
  xx (xx%)
Was the subject in an inpatient healthcare setting when 
the pneumonia developed?
  Yes
  No
  Unknown
  xx (xx%)
  xx (xx%)
  xx (xx%)
  xx (xx%)
  xx (xx%)
  xx (xx%)
Was a culture/swab taken?
  Yes
  No
  Unknown
  xx (xx%)
  xx (xx%)
  xx (xx%)
  xx (xx%)
  xx (xx%)
  xx (xx%)
Note: Table summarizes event counts. Percentages are calculated using the number of cases of pneumonia as the 
denominator.
Note: A chest x-ray/CT scan is associated with pneumonia if it is taken within the duration of the pneumonia 
or within -7 to +10 days (inclusive) of the date of onset.
Note: Summary includes pneumonia events reported on the pneumonia eCRF page.
 
 
 
2019N398531_00


CONFIDENTIAL
207626
138
<user ID:  pathname datestamp timestamp>
Programming note:  Same format for Table 3.26 (Summary of Post-Treatment Details of Pneumonia).
 
 
 
2019N398531_00


CONFIDENTIAL
207626
139
Example:  SAF_T04                                                                      Page 1 of x
Protocol:  207626
Population:  Intent-to-Treat
Table 3.27
Summary of On-Treatment Bone Fractures
FF/UMEC/VI 
100/62.5/25
(N=xxx)
TIO 18
(N=xxx)
n (%)
Rate (%)
n (%)
Rate (%)
Total treatment exposure (subject-years)_
xxx.x
xxx.x
Subjects with at least one bone fracture 
incident
xxx (xx)
xxx.x (xx)
xxx (xx)
xxx.x (xx)
Total number (%) of bone fracture 
incidents per subject
   n
xxx (xx)
xxx (xx)
   0
xxx (xx)
xxx (xx)
   1
xxx (xx)
xxx (xx)
   >=2
xxx (xx)
xxx (xx)
Number of fracture incidents which were 
[1]:
   Non-traumatic
xxx (xx)
xxx (xx)
   Traumatic
xxx (xx)
xxx (xx)
Subjects with at least one bone fracture 
xxx (xx)
xxx.x (xx)
xxx (xx)
xxx.x (xx)
Fracture location [2, 3]
   Chest
xxx (xx)
xxx (xx)
   Ankle joint
xxx (xx)
xxx (xx)
 
 
 
2019N398531_00


CONFIDENTIAL
207626
140
   Arm
xxx (xx)
xxx (xx)
   Foot
xxx (xx)
xxx (xx)
   Thoracic vertebra
xxx (xx)
xxx (xx)
[1] Percentages calculated using the number of bone fracture incidents as the denominator.
[2] Percentages calculated using the number of bone fractures as the denominator.
[3] Fracture locations are only displayed when there is at least one fracture in either treatment 
group.
Note:  n = Number of subjects, # = Number of fracture incidents.
Note:  Rate is event rate per 1000 subject-years, calculated as the number of fracture incidents x 
1000, divided by the total treatment exposure.
Note:
Fractures in multiple locations with the same date of fracture are considered to comprise one 
fracture incident.
Programming note:  Same format for Table 3.28 (Summary of Post-Treatment Bone Fractures).
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
141
Example:  SAF_T05                                                                     Page 1 of x
Protocol:  207626
Population:  Intent-to-Treat
Table 3.29 
Summary of Chest Imaging (X-Ray or CT Scan)
FF/UMEC/VI 
100/62.5/25
(N=xxx)
TIO 18
(N=xxx)
Total number chest x-rays/CT scans taken:
   Associated with pneumonia
xxx (xx)
xxx (xx)
   Associated with moderate/severe exacerbation
xxx (xx)
xxx (xx)
   Findings consistent with diagnosis of pneumonia
xxx (xx)
xxx (xx)
Note:  A chest x-ray/CT scan is associated with pneumonia if it is taken during the pneumonia or 
within -7 to +10 days (inclusive) of the date of onset.
Note:  A chest x-ray/CT scan is associated with an exacerbation if it is taken during the 
exacerbation or within -7 to +10 days (inclusive) of the date of onset
Note:  A single x-ray/CT scan can be associated with both pneumonia and an exacerbation.
Note:  Summary includes on- and post-treatment chest x-rays/CT scans which were associated with an 
on-treatment case of pneumonia and/or exacerbation.
Note: Percentages are based on the total number of assessments/events within each summary.
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
142
Example:  SAF_T06                                                                   Page 1 of x 
Protocol:  207626
Population:  Intent-to-Treat
Table 3.30
Summary of Blood Chemistry Results at Screening
Lab test
FF/UMEC/VI 
100/62.5/25
(N=xxx)
TIO 18
(N=xxx)
Albumin (g/L)
   n
xxx
xxx
   Mean
xx.x
xx.x
   SD
xx.xx
xx xx
   Median
xx.x
xx.x
   Min.
x
x
   Max.
xx
Xx
Alanine aminotransferase (IU/L)
   n
xxx
xxx
   Mean
xx.x
xx.x
   SD
xx.xx
xx xx
   Median
xx.x
xx.x
   Min.
x
x
   Max.
xx
Xx
Aspartate aminotransferase (IU/L)
   n
xxx
xxx
   Mean
xx.x
xx.x
   SD
xx.xx
xx xx
   Median
xx.x
xx.x
   Min.
x
x
   Max.
xx
Xx
 
 
 
2019N398531_00


CONFIDENTIAL
207626
143
Programming note:  include all measured blood chemistry parameters.  Only albumin, ALT, and AST are 
shown above for illustrative purposes.
Programming note:  Same format for Table 3.31 (Summary of Hematology Results at Screening).  Include 
all collected hematology parameters.
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
144
Example:  SAF_T07                                                                   Page 1 of x 
Protocol:  207626
Population:  Intent-to-Treat
Table 3.32
Summary of Vital Signs
Treatment
N
Visit
n
Mean
SD
Median
Min.
Max.
Systolic Blood 
Pressure 
(mmHg)
FF/UMEC/VI 
100/62.5/25
xxx
Screening
xxx
xxx.x
xx.xx
xxx.x
xxx
xxx
Day 84
xxx
xxx.x
xx.xx
xxx.x
xxx
xxx
TIO 18
xxx
Screening
xxx
xxx.x
xx.xx
xxx.x
xxx
xxx
Day 84
xxx
xxx.x
xx.xx
xxx.x
xxx
xxx
Diastolic 
Blood Pressure 
(mmHg)
FF/UMEC/VI 
100/62.5/25
xxx
Screening
xxx
xxx.x
xx.xx
xxx.x
xxx
xxx
Day 84
xxx
xxx.x
xx.xx
xxx.x
xxx
xxx
TIO 18
xxx
Screening
xxx
xxx.x
xx.xx
xxx.x
xxx
xxx
Day 84
xxx
xxx.x
xx.xx
xxx.x
xxx
xxx
Heart rate 
(beats/min)
FF/UMEC/VI 
100/62.5/25
xxx
Screening
xxx
xxx.x
xx.xx
xxx.x
xxx
xxx
Day 84
xxx
xxx.x
xx.xx
xxx.x
xxx
xxx
TIO 18
xxx
Screening
xxx
xxx.x
xx.xx
xxx.x
xxx
xxx
Day 84
xxx
xxx.x
xx.xx
xxx.x
xxx
xxx
Programming note: Same format for Table 3.33 (Summary of Change from Baseline Vital Signs), but 
without row for Screening.
Include early withdrawal and unscheduled visit data, if available, in 
both Tables 3.32 and 3.33.
 
 
 
2019N398531_00


CONFIDENTIAL
207626
145
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
146
Example: SAF_T08                                                                                   
Page 1 of 1
Protocol: 207626
Population: Intent-to-Treat
Table 3.34
Summary of ECG Findings at Screening
FF/UMEC/VI 
100/62.5/25
(N=xxx)
TIO 18
  (N=xxx)
n
xxx
xxx
Normal
Abnormal – not clinically significant
Abnormal – clinically significant
Unable to evaluate
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
xx (xx%)
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
147
10.10.2.
Listings
 
 
 
2019N398531_00


CONFIDENTIAL
207626
148
Example: POP_L01                                                                         Page 1 of x
Protocol: 207626
Population: Intent-to-Treat
Listing 11
Listing of COPD Concomitant Medications
Country: xxx
Treatment: xxxxxxxxxxxx
Centre 
ID/ 
Subject
Respiratory 
class/
Ingredient/
Verbatim text/
Indication
Dose/
Units/
Freq/
Route
Date started/
Study day/
Date stopped/
Study day
Taken prior to 
study?/
Ongoing medication?/
Treatment periods
taken in
Administered for an 
exacerbation?/
Exacerbation 
severity/
Exacerbation start 
date
xxxxxx/ 
xxxxxx
xxxxxxxxxxxxx/
xxxxxxxxxxxxxxxx/
xxxxxxxxxxxxx/
xxxxxxxxxxxxxxx
xxxx/
xxxxx/
xxx/
xxxxxxx
xxxxxxxxxx/
xx/
xxxxxxxxxx/
xx
xxx/
xxx/
xxxxxxxxxx
xxx/
xxxxxxxxxxx/
xxxxxxxxxx
Note: Combination products are listed by individual ingredient in all applicable Respiratory 
Medication Classes.
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
149
Example: POP_L02                                                                         Page 1 of x
Protocol: 207626
Population: Intent-to-Treat
Listing 12
Listing of Non-COPD Concomitant Medications
Country: xxx
Treatment: xxxxxxxxxxxx
Centre ID/ 
Subject
ATC level 1/
Ingredient/
Verbatim text/
Indication
Dose/
Units/
Freq/
Route
Date started/
Study day/
Date stopped/
Study day
Taken prior to 
study?/
Ongoing medication?/
Treatment periods
taken in
xxxxxx/
xxxxxxxxx
xxxxxxxxxxxxx/
xxxxxxxxxxxxxxxx/
xxxxxxxxxxxxx/
xxxxxxxxxxxxxxx
xxxx/
xxxxx/
xxx/
xxxxxxx
xxxxxxxxxx/
xx/
xxxxxxxxxx/
xx
xxx/
xxx/
xxxxxxxxxx,
xxxxxxx,
xxxxxxxxxxxxx
Note: Combination products are listed by individual ingredient in all applicable Respiratory 
Medication Classes.
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
150
Example: SAF_L01                                                                                   
Page 1 of x
Protocol: 207626
Population: Intent-to-Treat
Listing 13
Listing of Exposure Data
Country: xxx
Treatment: xxxxxxxxxxxx
Centre ID
Subject
Exposure 
start 
date
Exposure
end date
Date of 
Week 12 
visit
Date of 
study
completion/
withdrawal
Duration
of
exposure 
(days) [1]
Post-treatment
duration
(days) [2]
xxxxxx
xxxxxxxx
xxxxxxx
xxxxxxx
xxxxxxx
xxxxxxxx
xxx
xx
[1]: Calculated as ((exposure end date – exposure start date) + 1).
[2]: Calculated as (date of study completion/withdrawal – exposure end date).
 
 
 
2019N398531_00


CONFIDENTIAL
207626
151
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
152
Example: POP_L18                                                                                   
Page 1 of x
Protocol: 207626
Population: All Subjects Enrolled
Listing 22
Listing of Unique Subject ID vs. Study Subject ID
Country: xxxxxx
Centre ID
Treatment
Unique Subject ID
Study subject ID
xxx
xxxxxxxxx
xxxxxx.xxxxxx
Xxxxxx.xxxxxx
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
153
Example:  POP_L03                                                                   Page 1 of x 
Protocol:  207626
Population:  Intent-to-Treat
Listing 23
Listing of Study Treatment Misallocations
Country:  xxx
Study
Date of dosing
Container
Actual treatment
Treatment
Centre ID
Subject
day [1]
Start [2]
End [2]
number
dispensed
xxx.xxxxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
[1] Day, relative to randomization, on which treatment was dispensed.
[2] Dates on which actual treatment was dispensed or returned.
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
154
Example:  POP_L04                                                                   Page 1 of x 
Protocol:  207626
Population:  Intent-to-Treat
Listing 24
Listing of Screening Lung Function, Reversibility Status, and GOLD Grade
Country:  xxx
Treatment:  xxx
Centre ID:  xxx
Subject
Visit / 
Visit 
date/ 
Study 
day
Planned 
relative 
time
Actual 
time
FEV1
(L)
FVC (L)
Percent 
predicted 
FEV1 (%)
Reversibility 
to salbutamol 
(mL) / )%)
FEV1/FVC
GOLD 
grade
xxx.xxxxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
xxx
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
155
Example:  POP_L05                                                                   Page 1 of x 
Protocol:  207626
Population:  Intent-to-Treat
Listing 25
Listing of Medical Conditions
Country:   xxx
Centre ID
Subject
Treatment
Body system
Condition
Current or Past?
xxxx
xxx.xxxx
xxxx
xxxx
xxxx
Current
xxxx
xxxx
Past
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
156
Example:  POP_L06                                                                   Page 1 of x 
Protocol:  207626
Population:  Intent-to-Treat
Listing 26
Listing of Family History of Cardiovascular Risk Factors
Country:  xxx
Family History [1]
Treatment
Centre ID
Subject
Premature coronary 
artery disease [2]
Myocardial 
infarction
Stroke
xxx
xxx
xxx.xxxx
<yes/no>
<yes/no>
<yes/no>
[1] Family history in first degree relatives only (e.g. biological parent, sibling, or offspring).
[2] Family history of premature coronary artery disease in women < 65 years or men < 55 years in 
first degree relatives only.
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
157
Example:  POP_L07                                                                   Page 1 of x 
Protocol:  207626
Population:  Intent-to-Treat
Listing 27
Listing of COPD Duration and Exacerbation History
Country:  xxx
Number of exacerbations in past 12 months
Treatment
Centre ID
Subject
Moderate
Severe
Total 
moderate/severe
xxx
xxx
xxx.xxxx
x
x
x
Note: Moderate exacerbations are defined as exacerbations that required treatment with oral or 
systemic corticosteroids and/or antibiotics (not involving hospitalization).  Severe exacerbations 
are defined as exacerbations that required in-patient hospitalization.
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
158
Example:  POP_L08                                                                   Page 1 of x 
Protocol:  207626
Population:  Intent-to-Treat
Listing 28
Listing of Smoking History and Smoking Status
Country:  xxx
Treatment:  xxx
Centre ID / 
Subject
Visit
Years smoked 
/ Cigarettes 
per day
Smoking 
pack-years 
[1]
Smoking 
status
Change in 
status?
Status 
change / 
Date change 
made / Study 
day
xxx / xxx.xxx
Screening
xx / xx
xx.x
<current / 
former>
xx / xx / xx
Day 84
xx / xx
xx.x
<current / 
former>
<yes / no>
xx / xx / xx
Programming note:  include early withdrawal and unscheduled visit data if available.
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
159
Example:  POP_L09                                                                   Page 1 of x 
Protocol:  207626
Population:  Intent-to-Treat
Listing 29
Relationship between ATC Level 1, Ingredient, and Verbatim Text for Non-COPD Medications
ATC Level 1
Ingredient
Verbatim text
xxxx
xxx
xxx
xxx
xxx
xxx
xxx
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
160
Example:  POP_L10                                                                   Page 1 of x 
Protocol:  207626
Population:  Intent-to-Treat
Listing 30
Listing of Treatment Compliance Data
Country:  xxx
Treatment:  xxx
Centre ID
Subject
Study Phase
Overall 
compliance (%)
ELLIPTA 
compliance (%)
Handihaler 
compliance (%)
xxx
xxx.xxxx
Run-in
xx.x
xx.x
xxx.
Study 
treatment
Note:  Compliance values for each device are only calculated for subjects with
complete treatment dispensing information.
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
161
Example:  EFF_L01                                                                   Page 1 of x 
Protocol:  207626
Population:  Intent-to-Treat
Listing 31
Listing of Raw FEV1 (L) and FVC (L) Data
Country: xxx
Treatment: xxx
Centre ID: xxx
Subject
Visit/
Visit date/ 
Study day
Study
phase
Planned
relative
time
Actual
time
Baseline
FEV1(L)
FEV1 (L)/
Change
from 
baseline
FEV1 (L)
Baseline
FVC (L)
FVC (L)/
Change
from 
baseline
FVC (L)
xxxxxxxx
xxxxx/
xxxxx/
xxx
xxxxxxxx
xxxxxxxxxxx
xxxxxx
x.xxx
x.xxx
x.xxx
x.xxx
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
162
Example:  EFF_L02                                                                   Page 1 of x 
Protocol:  207626
Population:  Intent-to-Treat
Listing 32
Listing of COPD Exacerbations
Country:  xxx
Treatment:  xxx
Centre ID / 
Subject
Date of onset 
/ Study day
Study phase at 
onset
Date of 
resolution or 
death / 
Duration 
(days)
Outcome
Corticosterois 
taken? / 
Antibiotics 
taken? / 
Visited ER? / 
Hospitalized?
xxxx / 
xxx.xxxx
xxx / xxx
xxx
xxx / xxx
xxx
xxx / xxx / 
xxx / xxx
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
163
Example:  EFF_L03                                                                   Page 1 of x 
Protocol:  207626
Population:  Intent-to-Treat
Listing 33
Listing of SGRQ Scores
Country:  xxx
Treatment:  xxx
Centre 
ID / 
Subject
Language
Visit 
date / 
Study 
day
Study 
phase
Baseline 
symptoms 
score
Symptoms 
score / 
Change 
from 
baseline
Baseline 
activity 
score
Activity 
score / 
Change 
from 
baseline
Baseline 
impacts 
score
Impacts 
score / 
Change 
from 
baseline
xxx / 
xxx.xxxx
xxx
xxx / 
xxx
xxx
xxx
xxx / 
xxx
xxx
xxx / 
xxx
xxx
xxx / 
xxx
Note:  Responders are defined as those subjects whose SGRQ total score is 4 units or more below 
baseline.  Non-responders are defined as those subjects whose SGRQ total score is more than 4 units 
below baseline or a missing SGRQ total score at a the timepoint in question and no subsequent on-
treatment scores.  Subjects will not be assigned a responder status at any timepoint if their 
baseline SGRQ total score is missing.  Subjects will not have a responder status assigned at a given 
timepoint if the SGRQ total score at that timepoint is missing.
Programming note:  Adjust distribution of columns across pages as necessary.
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
164
Example:  EFF_L03                                                                   Page 2 of x 
Protocol:  207626
Population:  Intent-to-Treat
Listing 33
Listing of SGRQ Scores
Country: xxx
Treatment:  xxx
Centre ID / 
Subject
Language
Visit date / 
Study day
Baseline total 
score
Total score / 
Change from 
baseline
Responder? [1]
xxx / xxx.xxxx
xxx
xxx / xxx
xxx
xxx
<yes / no>
Note:  Responders are defined as those subjects whose SGRQ total score is 4 units or more below 
baseline.  Non-responders are defined as those subjects whose SGRQ total score is more than 4 units 
below baseline or a missing SGRQ total score at a the timepoint in question and no subsequent on-
treatment scores.  Subjects will not be assigned a responder status at any timepoint if their 
baseline SGRQ total score is missing.  Subjects will not have a responder status assigned at a given 
timepoint if the SGRQ total score at that timepoint is missing.
Programming note:  Adjust distribution of columns across pages as necessary.
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
165
Example:  EFF_L04                                                                   Page 1 of x 
Protocol:  207626
Population:  Intent-to-Treat
Listing 34
Listing of CAT Scores
Country:  xxx
Treatment:  xxx
Centre ID / 
Subject
Language
Visit date / 
Study day
Baseline CAT 
score
CAT score / 
Change from 
baseline
Responder? [1]
xxx / xxx.xxxx
xxx
xxx / xxx
xxx
xxx
<yes / no>
[1] Responders are defined as those subjects whose CAT score is 2 units or more below baseline.  
Non-responders are defined as those subjects whose CAT score is more than 2 units below baseline or 
who have a missing CAT score at a the timepoint in question and no subsequent on-treatment scores.  
Subjects will not be assigned a responder status at any timepoint if their baseline CAT score is 
missing.  Subjects will not have a responder status assigned at a given timepoint if the CAT score 
at that timepoint is missing.
 
 
 
2019N398531_00


CONFIDENTIAL
207626
166
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
167
Example: SAF_L02                                                                                   
Page 1 of x
Protocol: 207626
Population: Intent-to-Treat
Listing 35
AE Terms of Special Interest
Special Interest Term
Subgroup
Preferred Term
xxxxxxxxx
xxxxxxxx
xxxxxxx
xxxxxxxxxxxx
xxxxxxxxxxxxxx
xxxxxxxxx
xxxxxxxxxxxxxxxx
Note: All of the pre-specified preferred terms that were assigned to special interest terms are 
shown, regardless of whether they actually occurred in the study.
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
168
Example:  SAF_L03                                                                   Page 1 of x 
Protocol:  207626
Population:  Intent-to-Treat
Listing 37
Listing of Pneumonia Data
Country:  xxx
Treatment:  xxx
Centre ID / 
Subject
Date of onset / Study 
phase at onset / 
Supported by X-ray or 
CT scan?
eCRF question
Response
xxx / 
xxx.xxxx
xxx / xxx / xxx / xxx
Level of cough
<yes / no / 
unknown>
Increased sputum purulence?
Did the chest auscultation show evidence of 
crackles / rales and / or bronchial or 
brochovesicular breath sounds?
Worsening dyspnea?
Does subject have pleural effusion?
Does subject have hypoxemia?
Was WBC count assessed at time of event?
Was BUN > 19mg/dL (7mmol / L)?
Was there evidence of subject confusion?
Was subject in an inpatient health care 
setting when pneumonia developed?
Was a culture or swab taken?
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
169
Example:  SAF_L04                                                                   Page 1 of x 
Protocol:  207626
Population:  Intent-to-Treat
Listing 38
Listing of Bone Fracture Data
Country:  xxx
Treatment:  xxx
Centre ID / 
Subject
Fracture date / 
Study phase
Fracture type
Side
Fracture location
xxx / xxx.xxxx
xxx / xxx
xxx
<left / right>
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
170
Example: SAF_L05                                                                                   
Page 1 of x
Protocol: 207626
Population: Intent-to-Treat
Listing 39
Listing of Chest Imaging (X-ray or CT scan) Data
Country: xxx
Treatment: xxx
Centre ID/ 
Subject
Date of image/ 
Study phase/ 
Study day
Associated with
pneumonia
Associated with
moderate/severe
exacerbation
Consistent with
diagnosis of 
pneumonia
xxxxxx/
xxxxxx
xxxxxxx/
xxxxxxxxxx/
xxx
xxx
xxx
xxx
Note: A chest x-ray/CT scan is associated with pneumonia if it is taken during the pneumonia or 
within -7 to +10 days (inclusive) of the date of onset.
Note: A chest x-ray/CT scan is associated with a moderate/severe exacerbation if it is taken during 
the exacerbation or within -7 to +10 days (inclusive) of the date of onset.
 
 
 
2019N398531_00


CONFIDENTIAL
207626
171
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
172
Example: SAF_L06                                                                   Page 1 of x 
Protocol:  207626
Population:  Intent-to-Treat
Listing 40
Listing of Liver Event Results and Time of Event Relative to Treatment
Country:  xxx
Treatment:  xxx
Centre ID 
/ Subject
Age (y) / 
Sex / Race
Maximum 
status of 
the liver 
event
Date first 
detected / 
Study 
phase at 
event 
onset / 
Study day
Days from 
first dose 
to start 
of event
Days from 
last dose 
to start 
of event
Restart / 
rechallenge 
after 
stopping 
criteria 
were met?
Outcome / 
Date 
resolved
xxx / xxx
xxx / xxx 
/ xxx
xxx
xxx / xxx 
/ xxx
xxx
xxx
xxx
xxx / xxx
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
173
Example:  SAF_L07                                                                   Page 1 of x 
Protocol:  207626
Population:  Intent-to-Treat
Listing 41
Listing of Medical Conditions for Subjects with Liver Stopping Events
Country:  xxx
Treatment:  xxx
Centre ID 
/ Subject
Age (y) / 
Sex / Race
Condition
Status
xxx / xxx
xxx / xxx 
/ xxx
Acute Viral Hepatitis A
<current/past/no 
medical condition/not 
assessed>
Acute hepatitis B
Chronic hepatitis B
Hepatitis B carrier
Chronic hepatitis C
Cytomegalovirus hepatitis
Epstein-Barr virus infectious mononucleosis
Herpes simplex hepatitis
Alcoholic liver disease
Non-alcoholic steatohepatitis
Fatty liver
Hepatic cirrhosis
Hemochromatosis
Autoimmune hepatitis
Gallbladder disease
Hepatobiliary cancer
Liver metastasis
Hepatitis E IgM antibody
Drug-related liver disease
Other condition (specify)
 
 
 
2019N398531_00


CONFIDENTIAL
207626
174
Drug allergies
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
175
Example:  SAF_L07                                                                   Page 2 of x 
Protocol:  207626
Population:  Intent-to-Treat
Listing 41
Listing of Medical Conditions for Subjects with Liver Stopping Events
Country:  xxx
Treatment:  xxx
Centre ID 
/ Subject
Age (y) / 
Sex / Race
Condition
Status
xxx / xxx
xxx / xxx 
/ xxx
Rheumatoid arthritis
<current/past/no 
medical condition/not 
assessed>
Psoriasis
Thyroid disease
Inflammatory bowel disease
Lupus
Sjogren’s syndrome
Vilitigi
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
176
Example:  SAF_L08                                                                   Page 1 of x 
Protocol:  207626
Population:  Intent-to-Treat
Listing 42
Listing of Substance Use for Subjects with Liver Stopping Events
Country:  xxx
Treatment:  xxx
Centre ID 
/ Subject
Age (y) / 
Sex / Race
Date of 
assessment
Does subject 
consume alcohol?
If yes, avg number of units consumed 
per week
xxx / xxx
xxx / xxx 
/ xxx
ddMMMyyyy
<yes/no>
xxx
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
177
Example:  SAF_L09                                                                   Page 1 of x 
Protocol:  207626
Population:  Intent-to-Treat
Listing 43
Listing of Liver Event Information for RUCAM Scores
Country:  xxx
Treatment:  xxx
Centre ID 
/ Subject
Age (y) / 
Sex / 
Race
Liver 
stopping 
event date
Serious 
AE? / If 
female, 
pregnant?
Diagnostic 
tests 
performed? 
/ If so, 
normal?
Liver 
biopsies 
performed?
Use of 
herbals, 
supplements, 
ilicit 
drugs? / 
Dietary 
change in 
past week?
Criterion/
criteria met
xxx / xxx
xxx / xxx 
/ xxx
ddMMMyyyy
<yes / no> 
/ <yes / 
no>
<yes / no> 
/ <yes / 
no>
<yes / no>
<yes / no> / 
<yes / no>
list all 
criteria 
checked
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
178
Example:  SAF_L10                                                                   Page 1 of x 
Protocol:  207626
Population:  Intent-to-Treat
Listing 44
Listing of Liver Biopsy Details
Country:  xxx
Treatment:  xxx
Centre 
ID / 
Subject
Age 
(y) / 
Sex / 
Race
Date of 
biopsy
Appx 
size of 
biopsy 
(unit)
Final 
diagnosis
Final 
diagnosis 
details
Liver 
architecture
Liver architecture 
details
xxx / 
xxx
xxx / 
xxx / 
xxx
If “Final 
diagnosis” 
is 
“Abnormal,” 
list all 
conditions 
that apply.
If “Liver 
architecture” is 
“Abnormal,” list all 
conditions that apply
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
179
Example:  SAF_L10                                                                   Page 2 of x 
Protocol:  207626
Population:  Intent-to-Treat
Listing 44
Listing of Liver Biopsy Details
Country:  xxx
Treatment:  xxx
Centre 
ID / 
Subject
Age 
(y) / 
Sex / 
Race
Date 
of 
biopsy
Description 
of liver 
cells or 
hepatocytes
Description 
of liver 
cells or 
hepatocytes 
details
Liver cell or 
hepatocyte 
inclusions or 
vacuoles
Liver cell or 
hepatocyte inclusions 
or vacuoles details
xxx / 
xxx
xxx / 
xxx / 
xxx
If 
“Description 
of liver 
cells or 
hepatocytes” 
is 
“abnormal,” 
list all 
conditions 
that apply.
If “Liver cell or 
hepatocyte inclusions 
or vacuoles,” is 
answered, list all 
conditions that apply
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
180
Example:  SAF_L10                                                                   Page 3 of x 
Protocol:  207626
Population:  Intent-to-Treat
Listing 44
Listing of Liver Biopsy Details
Country:  xxx
Treatment:  xxx
Centre 
ID / 
Subject
Age 
(y) / 
Sex / 
Race
Date 
of 
biopsy
Hepatocyte or 
liver cell 
nuclear 
abnormalities
Hepatocyte or 
liver cell 
nuclear 
abnormalities 
details
Liver or lobular 
infiltrates
Liver or lobular 
infiltrates details
xxx / 
xxx
xxx / 
xxx / 
xxx
If “Hepatocyte 
or liver cell 
abnormalities” 
is “Yes,” list 
all conditions 
that apply.
If “Liver or lobular 
infiltrates” is “Yes,” 
list all conditions 
that apply
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
181
Example:  SAF_L10                                                                   Page 4 of x 
Protocol:  207626
Population:  Intent-to-Treat
Listing 44
Listing of Liver Biopsy Details
Country:  xxx
Treatment:  xxx
Centre 
ID / 
Subject
Age 
(y) / 
Sex / 
Race
Date 
of 
biopsy
Portal tract 
inflammation
Portal tract 
inflammation 
details
Bile ducts
Bile ducts details
xxx / 
xxx
xxx / 
xxx / 
xxx
If “Portal 
tract 
inflammation” 
is “Yes,” 
list all 
conditions 
that apply.
If “Bile ducts” is 
“Abnormal,” list all 
conditions that apply
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
182
Example:  SAF_L10                                                                   Page 5 of x 
Protocol:  207626
Population:  Intent-to-Treat
Listing 44
Listing of Liver Biopsy Details
Country:  xxx
Treatment:  xxx
Centre 
ID / 
Subject
Age 
(y) / 
Sex / 
Race
Date of 
biopsy
Portal veins
Portal veins 
details
Liver infections
Liver infections 
details
xxx / 
xxx
xxx / 
xxx / 
xxx
If “Portal 
veins” is 
“Abnormal,” 
list all 
conditions 
that apply.
If “Liver infections” 
is “Abnormal,” list all 
conditions that apply
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
183
Example:  SAF_L10                                                                   Page 6 of x 
Protocol:  207626
Population:  Intent-to-Treat
Listing 44
Listing of Liver Biopsy Details
Country:  xxx
Treatment: xxx
Centre 
ID / 
Subject
Age 
(y) / 
Sex / 
Race
Date of 
biopsy
Parasites or 
ova
Parasites or 
ova
Histologic 
staining or 
additional 
studies?
Histologic staining or 
additional studies 
details
xxx / 
xxx
xxx / 
xxx / 
xxx
If “Parasites 
or ova” is 
“Yes,” list 
all 
conditions 
that apply.
If “Histologic staining 
or additional studies?” 
is “Yes,” list all 
items that apply.
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
184
Example:  SAF_L11                                                                   Page 1 of x 
Protocol:  207626
Population:  Intent-to-Treat
Listing 45
Listing of Liver Imaging Details
Centre 
ID / 
Subject
Age 
(y) 
/ 
Sex 
/ 
Race
Date of 
hepatic 
or liver 
imaging
Method 
used / 
Adequate 
images?
Liver size / 
texture / 
infiltration 
grade
Accites 
present?
Hepatic 
lesions? 
Biliary 
ductal 
leisions?
Portal or 
hepatic vein 
abnormalities?
xxx / 
xxx
xxx 
/ 
xxx 
/ 
xxx
ddMMMyyyy
xxx / 
xxx
xxx / xxx / 
xxx
xxx
List all 
that 
apply
List all 
that apply
List all that 
apply
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
185
Example:  SAF_L12                                                                   Page 1 of x 
Protocol:  207626
Population:  Intent-to-Treat
Listing 46
Listing of Inhaler Malfunctions
Country:  xxx
Treatment:  xxx
Centre ID
Subject
Age (y) / Sex 
/ Race
Container 
number
Malfunctioning 
device type
Malfunction 
comment / 
Reason for 
device 
malfunction
xxx
xxx.xxxx
xxx / xxx / 
xxx
Xxx
xxx
xxx / xxx
<user ID:  pathname datestamp timestamp>
 
 
 
2019N398531_00


CONFIDENTIAL
207626
186
 
 
 
2019N398531_00


CONFIDENTIAL
207626
187
Example: SAF_L14                                                                   Page 1 of x 
Protocol:  207626
Population:  Intent-to-Treat
Listing 47
Listing of Hepatitis B and C Test Results
Country: xxxxxx
Treatment: xxxxxxxx
Centre ID
Subject
Study phase/
Visit/
Visit date
Hepatitis B
surface antigen
Hepatitis C antibody
xxxxxx
xxxxxx
xxxxxxxxxxx/
xxxxxxxxxx/
xxxxxx
xxxxxxxxxxxxx
xxxxxxxxxxxxxx
 
 
 
2019N398531_00


CONFIDENTIAL
207626
188
Example: SAF_L15                                                                                   
Page 1 of x
Protocol: 207626
Population: Intent-to-Treat
Listing 48
Listing of ECG Data
Country: xxxxxx
Treatment: xxxxxxxx
Centre ID
Subject
Visit/
Visit date/
Study phase/
Study day
Result
Abnormality
xxxxxx
xxxxxx
xxxxxxx/
xxxxxxxx/
xxxxxxxxxx/
xx
<Normal /
Abnormal – not 
clinically significant 
/ Abnormal –
clinically 
significant>
xxxxxxxxxxxxxx
xx
 
 
 
2019N398531_00


CONFIDENTIAL
207626
189
<user ID:  pathname datestamp timestamp>
10.10.3.
Figures
 
 
 
2019N398531_00


CONFIDENTIAL
207626
190
Example:  POP_F01                                                                      Page 1 of x
Protocol:  207626
Population:  Intent-to-Treat
Figure 1.2
Kaplan-Meier Plot of Time to Study Withdrawal
Programming note:  same format for Figure 1.2 (Kaplan-Meier Plot of Time to Study Treatment 
Discontinuation)
 
 
 
2019N398531_00
PPD


CONFIDENTIAL
207626
191
Example:  EFF_F01                                                                      Page 1 of x
Protocol:  207626
Population:  Intent-to-Treat
Figure 2.1
Box Plot of Change from Baseline in Trough FEV1 (L) on Day 85 – Hypothetical Estimand
Programming note:  same format for Figure 2.4 (Box Plot of Change from Baseline in Trough FEV1 (L) on 
Day 85 – Treatment Policy Estimand)
 
 
 
2019N398531_00
PPD


CONFIDENTIAL
207626
192
Example:  EFF_F02                                                                      Page 1 of x
Protocol:  207626
Population:  Intent-to-Treat
Figure 2.2
Empirical Distribution Function Plot of Change from Baseline in Trough FEV1 (L) on Day 85 –
Hypothetical Estimand
Programming note:  same format for Figure 2.5 (Empirical Distribution Function Plot of Change from 
Baseline in Trough FEV1 (L) on Day 85 –- treatment policy estimand), Figure 2.7 (Empirical 
Distribution Function Plot of Change from Baseline in SGRQ Total Score on Day 84 – Hypothetical 
Estimand), and Figure 2.9 (Empirical Distribution Function Plot of Change from Baseline in CAT Score 
on Day 84 – Hypothetical Estimand
 
 
 
2019N398531_00
PPD


CONFIDENTIAL
207626
193
Example:  EFF_F03                                                                      Page 1 of x
Protocol:  207626
Population:  Intent-to-Treat
Figure 2.3
Least Squares Mean (95% CI) Change from Baseline in Trough FEV1 (L) – Hypothetical Estimand
Programming note:  same format for Figure 2.6 (Least Squares Mean (95% CI) Change from Baseline in 
Trough FEV1 (L) – Treatment Policy Estimand), Figure 2.8 (Least Squares Mean (95% CI) Change from 
Baseline in SGRQ Total Score – Hypothetical Estimand), and Figure 2.10 (Least Squares Mean (95% CI) 
Change from Baseline in CAT Score – Hypothetical Estimand
 
 
 
2019N398531_00
PPD


CONFIDENTIAL
207626
194
Programming note:  Footnotes for Figures will be study-specific; those shown above are illustrative 
only.
 
 
 
2019N398531_00


CONFIDENTIAL
207626
195
Example:  SAF_F01                                                                      Page 1 of x
Protocol:  207626
Population:  Intent-to-Treat
Figure 3.1
Summary of Treatment Exposure
9
 
 
 
2019N398531_00
PPD