A Phase IV, 12-week, Randomised, Double-blind, Triple Dummy Study to Compare Single Inhaler Triple Therapy, Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) With Multiple Inhaler Therapy (Budesonide/Formoterol Plus Tiotropium) Based on Lung Function and Symptoms in Participants With Chronic Obstructive Pulmonary Disease
Phase: PHASE4
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: GlaxoSmithKline

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GlaxoSmithKline group of companies
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TITLE PAGE
Protocol Title: A Phase IV, 12-week, randomised, double-blind, triple dummy study to 
compare single inhaler triple therapy, fluticasone furoate/umeclidinium/vilanterol 
(FF/UMEC/VI) with multiple inhaler therapy (budesonide/formoterol plus tiotropium) 
based on lung function and symptoms in participants with chronic obstructive pulmonary 
disease
Protocol Number: 207609/02
Short Title: A randomised study, comparing FF/UMEC/VI single inhaler triple therapy, 
versus multiple inhaler therapy (budesonide/formoterol plus tiotropium) 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 and EudraCT number 
2017-001150-33
Approval Date: 17-JUL-2018
Copyright 2018 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Protocol Amendment 2
17-Jul-2018
Protocol Amendment 1
09-Nov-2017
Original Protocol
12-Oct-2017
Amendment 2 17-Jul-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 it is preferable to 
have the participants stay at the clinic or approved facility during the serial spirometry 
assessments.  Clarified that run-in medication will be collected at Visit 2.  Correction 
made (reference section) regarding prohibited medications within a specified time 
interval during pre-screening and prior to Visit 1.  Also, wording regarding suggested 
order for assessments and procedures has been added to the end of the Schedule of 
Activities (SoA) 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.  Corrected reporting time regarding pregnancy.  
Routine urinalysis assessment has been deleted as this will not be collected during the 
study.  Finally, added wording to Genetics Appendix 9 regarding withdraw process and 
sample destruction process.
 
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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
Synopsis 
and 
Section 5.1
Overall Design
Randomization/treatment
Corrected wording regarding 
participants stay in the clinic 
during serial spirometry 
assessments:  Participants will 
remain available, preferably at 
the clinic or approved facility, for 
at least 24 hours for serial 
spirometry assessments
Clarified, with added flexibility, that 
it is preferred that the participants 
remain available at the clinic or 
approved facility during 24 hour 
serial spirometry instead of will 
remain at the clinic for at least 24 
hours, for serial spirometry 
assessments as previously written
Section 2
Schedule of Activities 
(SoA) 
Added Smoking Cessation 
Counselling to Visit 4
Added collecting run-in treatment 
at Visit 2
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 will 
be collected at Visit 2
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 5.1
Pre-screening
Updated reference section 
regarding medications that are 
prohibited within a specified time 
interval during the pre-screening 
visit and prior to Visit 1
Deleted reference Section 7.7 and 
corrected to Section 6.2.24 
regarding pre-screening and 
medications that are prohibited 
within a specific time interval prior 
to Visit 1
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
Section 8.1.1
Updated QTc stopping criteria to:
an increase in QTc by > 
Adapted the QTc stopping criteria 
to be in line with stopping criteria 
 
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Section # and Name
Description of Change
Brief Rationale
QTc Stopping Criteria
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
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
Added wording regarding CAT 
should be collected prior to 
SGRQ-C 
CAT is a shorter assessment 
questionnaire to complete and the 
participant will already have 
experience completing this at 
Screening Visit 1
Section 9.1.3
CAT
Added wording regarding CAT 
should be collected prior to 
SGRQ-C 
CAT is a shorter assessment 
questionnaire to complete and the 
participant will already have 
experience completing this at 
Screening Visit 1
Section 9.2.9
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
Corrected:  A single 12-lead 
Clarified that the ECG should be 
 
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Section # and Name
Description of Change
Brief Rationale
Electrocardiograms
ECG and rhythm strip will be 
recorded after measurement of 
vital signs and prior to spirometry
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
Section 12.6
Appendix 6
Adverse Events
Removed reference to urinalysis 
as part of safety assessments
Confirmed routine urinalysis isn’t 
required or being collected in the 
study
Section 12.8
Appendix 8 and
Table 8 
Laboratory Assessments
Deleted routine urinalysis from 
Appendix 8 and the Table 8
Confirmed routine urinalysis isn’t 
required or being collected in the 
study
Section 12.9
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
 
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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS.............................................................................................................10
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................19
3.
INTRODUCTION....................................................................................................21
3.1.
Study Rationale ..........................................................................................21
3.2.
Background ................................................................................................22
3.3.
Benefit/Risk Assessment ............................................................................24
3.3.1.
Risk Assessment .........................................................................25
3.3.2.
Risk assessment for Symbicort MDI (Budesonide/ 
Formoterol) 160/4.5 mcg..............................................................36
3.3.3.
Risk Assessment for Spiriva Handihaler (Tiotropium 
Bromide) 18 mcg .........................................................................36
3.3.4.
Benefit Assessment.....................................................................37
3.3.5.
Overall Benefit:Risk Conclusion...................................................37
4.
OBJECTIVES AND ENDPOINTS...........................................................................38
5.
STUDY DESIGN ....................................................................................................39
5.1.
Overall Design ............................................................................................39
5.2.
Number of Participants ...............................................................................41
5.3.
Participant and Study Completion...............................................................42
5.4.
Scientific Rationale for Study Design ..........................................................42
5.5.
Dose Justification........................................................................................42
6.
STUDY POPULATION...........................................................................................42
6.1.
Inclusion Criteria.........................................................................................42
6.2.
Exclusion Criteria........................................................................................44
6.3.
Randomisation Criteria ...............................................................................48
6.4.
Lifestyle Restrictions...................................................................................48
6.5.
Pre-screening/Screening/Run-in/Randomisation Failures...........................48
7.
TREATMENTS.......................................................................................................49
7.1.
Treatment Groups and Duration .................................................................49
7.1.1.
Medical Devices...........................................................................52
7.2.
Dose Modification .......................................................................................52
7.3.
Method of Treatment Assignment ...............................................................52
7.4.
Blinding.......................................................................................................53
7.5.
Preparation/Handling/Storage/Accountability..............................................54
7.6.
Treatment Compliance................................................................................54
7.7.
Concomitant Therapy..................................................................................55
7.7.1.
Permitted Medications and Non-Drug Therapies..........................55
7.7.1.1.
Permitted COPD Medications.....................................55
7.7.1.2.
Permitted Non-COPD Medications .............................56
7.7.2.
Prohibited Medications and Non-Drug Therapies.........................57
7.8.
Treatment after the End of the Study ..........................................................58
 
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8.
DISCONTINUATION CRITERIA.............................................................................59
8.1.
Discontinuation of Study Treatment ............................................................59
8.1.1.
Protocol defined criteria for discontinuation of study 
treatment .....................................................................................59
8.1.2.
Rechallenge.................................................................................60
8.1.2.1.
Study Treatment Restart or Rechallenge....................60
8.2.
Withdrawal from the Study..........................................................................61
8.3.
Lost to Follow Up........................................................................................61
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................62
9.1.
Efficacy Assessments.................................................................................63
9.1.1.
Spirometry ...................................................................................63
9.1.1.1.
24-hour Serial Spirometry...........................................64
9.1.1.2.
Reversibility................................................................64
9.1.1.3.
Peak Inspiratory Flow Rate (PIFR) .............................64
9.1.2.
SGRQ-C ......................................................................................65
9.1.3.
COPD Assessment Test (CAT)....................................................65
9.1.4.
COPD Exacerbations...................................................................65
9.2.
Adverse Events...........................................................................................66
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................66
9.2.2.
Method of Detecting AEs and SAEs.............................................66
9.2.3.
Follow-up of AEs and SAEs.........................................................67
9.2.4.
Regulatory Reporting Requirements for SAEs .............................67
9.2.5.
Cardiovascular and Death Events................................................67
9.2.6.
Disease-Related Outcomes – COPD Exacerbations....................68
9.2.7.
Pneumonia ..................................................................................68
9.2.8.
Sentinel Events............................................................................68
9.2.9.
Pregnancy ...................................................................................69
9.2.10.
Medical Device Incidents (Including Malfunctions).......................69
9.2.10.1.
Time Period for Detecting Medical Device 
Incidents.....................................................................69
9.2.10.2.
Follow-up of Medical Device Incidents........................70
9.2.10.3.
Prompt Reporting of Medical Device Incidents
to Sponsor..................................................................70
9.2.10.4.
Regulatory Reporting Requirements for 
Medical Device Incidents............................................70
9.3.
Treatment of Overdose...............................................................................70
9.4.
Safety Assessments ...................................................................................71
9.4.1.
Physical Examinations.................................................................71
9.4.2.
Vital Signs....................................................................................71
9.4.3.
Electrocardiograms......................................................................71
9.4.4.
Clinical Safety Laboratory Assessments ......................................71
9.5.
Pharmacokinetics .......................................................................................72
9.6.
Pharmacodynamics ....................................................................................72
9.7.
Genetics .....................................................................................................72
9.8.
Biomarkers .................................................................................................72
9.9.
Medical Resource Utilization and Health Economics ..................................72
9.10.
Smoking Cessation Counselling .................................................................72
10. STATISTICAL CONSIDERATIONS........................................................................73
10.1.
Hypotheses.................................................................................................73
 
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10.2.
Sample Size Determination ........................................................................73
10.3.
Populations for Analyses ............................................................................75
10.4.
Statistical Analyses.....................................................................................76
10.4.1.
Efficacy Analyses.........................................................................76
10.4.2.
Safety Analyses...........................................................................77
10.4.3.
Other Analyses ............................................................................78
10.4.4.
Interim Analyses ..........................................................................78
10.4.5.
Exploratory Analyses ...................................................................78
11. REFERENCES.......................................................................................................79
12. APPENDICES........................................................................................................82
12.1.
Appendix 1: Abbreviations and Trademarks................................................82
12.2.
Appendix 2: Study Governance Considerations..........................................85
12.3.
Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................89
12.4.
Appendix 4: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................92
12.5.
Appendix 5: COPD Exacerbation Identification, Categorization and 
Treatment Guidelines..................................................................................96
12.5.1.
Guidelines for Identifying COPD Exacerbations...........................96
12.5.2.
COPD Exacerbation Severity.......................................................97
12.5.3.
Treatment of COPD Exacerbations..............................................97
12.5.4.
Guidelines for Treatment with Corticosteroids..............................97
12.5.5.
Guidelines for Treatment with Antibiotics .....................................98
12.5.6.
Onset and Resolution of COPD Exacerbations............................98
12.5.7.
Guideline for assessing multiple mild exacerbations ....................98
12.5.8.
Guideline for assessing exacerbations that increase in 
severity ........................................................................................98
12.6.
Appendix 6: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................99
12.7.
Appendix 7: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .....................................105
12.8.
Appendix 8: Clinical Laboratory Tests.......................................................107
12.9.
Appendix 9: Genetics................................................................................109
12.10. Appendix 10: Country-specific requirements.............................................110
12.11. Appendix 11: Protocol Amendment History...............................................111
 
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1.
SYNOPSIS
Protocol Title: A Phase IV, 12-week, randomised, double-blind, triple dummy study to 
compare single inhaler triple therapy, fluticasone furoate/umeclidinium/vilanterol 
(FF/UMEC/VI) with multiple inhaler therapy (budesonide/formoterol plus tiotropium) 
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 multiple inhaler therapy (budesonide/formoterol plus tiotropium) 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 
inhaled corticosteroids plus a long-acting β2-adrenergic receptor agonist (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 exacerbation 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 LAMA 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 of 
exacerbations which will reduce the exacerbation frequency, allow for a reduced burden 
 
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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 
Symbicort MDI (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 [E-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. 
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 a multiple inhaler 
combination therapy of Symbicort Metered Dose Inhaler (MDI) (budesonide/formoterol 
320/9 mcg) twice daily plus Spiriva HandiHaler (tiotropium 18 mcg) once daily. The 
study will inform healthcare providers that patients can be effectively and safely switched 
to FF/UMEC/VI single inhaler therapy from a multiple inhaler triple therapy regimen of 
Symbicort MDI and Spiriva Handihaler.
Objectives and Endpoints:
Objectives
Endpoints
Primary
To evaluate the effects of single inhaler 
triple therapy (FF/UMEC/VI) compared 
to multiple inhaler triple combination 
therapy with budesonide/formoterol plus 
tiotropium after 12 weeks of treatment 
on lung function
Primary
Weighted mean change from baseline in 
FEV1 over 0-24 hours at Week 12
Secondary

Change from baseline in trough FEV1
on Day 2, Day 28, Day 84 and Day 85
Weighted mean change from baseline in 
FEV1 over 0-24 hours on Day 1
 
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Objectives
Endpoints
Other

To evaluate the effects of single inhaler 
triple therapy (FF/UMEC/VI) 
compared to multiple inhaler triple 
combination therapy with 
budesonide/formoterol plus 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 effects of single inhaler 
triple therapy (FF/UMEC/VI) compared 
to multiple inhaler triple combination 
therapy with budesonide/formoterol plus 
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 effects of single inhaler 
triple therapy (FF/UMEC/VI) compared 
to multiple inhaler triple combination 
therapy with budesonide/formoterol plus 
tiotropium after 12 weeks of treatment 
on COPD exacerbations
Moderate or severe exacerbation event
Assess how inspiratory airflow 
limitation affects ability to use the 
ELLIPTA
Peak Inspiratory Flow Rate (PIFR) at 
Screening (Week -4)
Safety
To evaluate the safety profile of single 
inhaler triple therapy (FF/UMEC/VI) 
compared to multiple inhaler triple 
combination therapy with 
budesonide/formoterol plus tiotropium
over 12 weeks of treatment
Incidence of adverse events

Vital signs
Overall Design:
This is a Phase IV, 12-week, randomised, double-blind, triple-dummy, parallel group, 
multicentre study evaluating single inhaler triple therapy (FF/UMEC/VI) once daily via 
the ELLIPTA, compared to multiple inhaler triple combination therapy budesonide/ 
formoterol MDI (320/9 mcg) twice daily plus once daily tiotropium (18 mcg), in 
participants with COPD. 
 
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Study design schema
Eligible participants at Screening (V1) will be current or former smokers, with an 
established clinical history of COPD, receiving daily maintenance COPD therapy for at 
least 3 months, with a post-bronchodilator FEV1 of <50% predicted (or <80% predicted 
with a documented history of at least 2 moderate or 1 severe [hospitalised] exacerbation 
in the last 12 months) and a CAT score of ≥10 at Visit 1 and at Visit 2. 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) COPD medication(s) during the pre-screening 
period, except for medications that are prohibited within a specified time 
interval prior to Visit 1.

Screening/run-in: Eligible participants will be allowed to continue their usual 
COPD medications until the day before Screening, Visit 1.  On the morning of 
the Screening Visit participants will refrain from taking their morning dose of 
their usual COPD medications. Participants who meet all of the eligibility 
criteria at Visit 1, will enter the 4-week run-in period during which they will 
discontinue all existing COPD medications and receive their run-in treatment:
budesonide/formoterol (320/9 mcg) twice daily plus tiotropium (18 mcg) once 
daily plus placebo via the ELLIPTA. Participants will not use any other COPD 
medications (except for those allowed per protocol). 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, MDI and HandiHaler and will 
 
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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 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 will discontinue their run-in treatments and will be 
randomised in 1:1 ratio to receive one the following double-blind study 
treatments for 84 days:
Either:
FF/UMEC/VI 100/62.5/25 mcg via the ELLIPTA once daily in the morning
+ placebo to match budesonide/formoterol via MDI, two inhalations twice daily 
+  placebo to match tiotropium via HandiHaler once daily in the morning
or,
Budesonide/formoterol 320/9 mcg via MDI, twice daily*
+ tiotropium 18mcg via HandiHaler once daily in the morning
+ placebo via the ELLIPTA once daily in the morning
*Participants are required to take two inhalations of budesonide/formoterol 
160/4.5 mcg, via the MDI in the morning and two inhalations in the evening. 
The total dose is therefore 320/9 mcg twice daily. 
At Visit 2 participants will refrain from taking their morning doses of run-in 
study medication and will self-administer study treatment at the clinic, when 
instructed to do so. Participants will remain available, preferably at the clinic or 
approved facility, for at least 24 hours for serial spirometry assessments.
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 3, and 4 participants will self-administer study treatment whilst at the 
clinic. Participants will take their last doses of study treatment in the clinic on 
Day 84 (Visit 4, when instructed to do so by clinic personnel), and preferably 
continue to remain at the clinic or approved facility until at least 24 hours after 
their last morning dose, for their clinical assessments, which include serial 
spirometry assessments. On non-clinic visit days participants are expected to 
take their study treatment at home each day in the morning and in the evening at 
approximately the same time, as directed by the clinic. 

Safety/follow-up: A safety follow-up telephone contact or clinic visit (Visit 5) 
will be conducted approximately 7 days after the participant completes all of the 
 
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protocol-defined procedures for Visit 4/End of Study (EOS) or, if applicable, the 
Study Treatment Discontinuation Visit. 
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 800 participants with advanced COPD will enter the run-in period, in 
order to randomise approximately 732 participants, in order to achieve an estimated 620
evaluable participants in modified per-protocol (mPP) population at Week 12, assuming 
10 % premature discontinuation of study treatment and 5% protocol deviation.
Approximately 80 centres globally will be required to recruit participants in 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 
budesonide/formoterol (320/9 mcg) twice daily plus tiotropium (18 mcg) 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, triple-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 budesonide/formoterol via MDI, two inhalations twice daily 
+  placebo to match tiotropium via HandiHaler once daily in the morning
or,

Budesonide/formoterol 160/4.5 mcg via MDI, two inhalations twice daily*
+ tiotropium 18mcg via HandiHaler once daily in the morning
+ placebo via the ELLIPTA once daily in the morning
*Participants are required to take two inhalations of budesonide/formoterol 160/4.5 mcg, 
via the MDI in the morning and two inhalations in the evening. The total dose is therefore 
320/9 mcg twice daily. 
 
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Dosing schedule for run-in and treatment periods
ELLIPTA
(1 inhalation)
MDI
(2 puffs)
HandiHaler
(1 capsule inhaled 
twice)
Active
Placebo
Active
Placebo
Active
Placebo
Run-in
am
Y
Y
Y
pm
Y
Treatment
FF/UMEC/VI group
am
Y
Y
Y
pm
Y
Budesonide/formoterol 
+ tiotropium group
am
Y
Y
Y
pm
Y
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.
Symbicort MDI contains 120 doses: budesonide/formoterol 160/4.5 mcg, two inhalations 
twice daily.
Tiotropium: 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.
Key Elements of Analysis Plan:
The null hypothesis is that the difference in 0-24 hour Weighted Mean (WM) FEV1
between treatment groups is less than or equal to a pre-specified non-inferiority margin 
Δ:
H0: T1 – T2 ≤ -Δ
The alternative hypothesis is that the difference between treatment groups is greater than 
the margin.
H1: T1 – T2 > -Δ
where T1 and T2 are the treatment means for FF/UMEC/VI and budesonide/formoterol + 
tiotropium (BUD/FOR+TIO), respectively.
The non-inferiority margin has been set at 50 mL.
 
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The primary analysis population will be the modified per-protocol (mPP) population, 
comprising all participants randomised to treatment except those randomised in error, 
who do not have a full protocol deviation or other event considered to impact efficacy.
The primary analysis will be performed for mPP population using on-treatment data. The 
primary analysis will evaluate the endpoint of 0-24 hour WM FEV1 on Day 84 using a 
mixed model repeated measure (MMRM) analysis, including covariates 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.  Baseline 
FEV1 is the mean of the two assessments made -30 and -5 minutes pre-dose on Treatment 
Day 1.
Estimated differences between FF/UMEC/VI and BUD/FOR+TIO will be presented 
together with 95% confidence intervals (CIs) for the treatment difference and p-value.
Inference to be drawn from the p-values will be as follows:

Analysis with mPP population: If the treatment comparison on the primary 
endpoint has a lower confidence limit below the non-inferiority margin, non-
inferiority is not demonstrated. No inference will be drawn from p-values for 
treatment comparisons on any other endpoints.

Analysis with mPP population: If the treatment comparison on the primary 
endpoint has a lower confidence limit above the non-inferiority margin but below 
0, non-inferiority is established but the p-value will not be used to give an 
indication of the strength of that non-inferiority.  Inference will be drawn from p-
values for treatment comparisons (with Intent-To-Treat [ITT] population) on 
other non-lung function endpoints, ie, SGRQ and CAT which will be called 
statistically significant if <0.05. No inference will be drawn from p-values on 
trough FEV1 endpoint. 

Analysis with ITT population: If the treatment comparison on the primary 
endpoint has a lower confidence limit above 0, superiority is established and the 
p-value can be used to give an indication of the strength of that superiority. 
Inference will be drawn from p-values for treatment comparisons on all other 
endpoints, which will be called statistically significant if <0.05.
A “tipping point” sensitivity analysis of 0-24 hour WM FEV1 on Day 84 will be 
conducted for the mPP Population. This will explore the impact of missing data by using 
differing assumptions regarding the mean treatment effect in participants who discontinue 
study treatment or have data excluded from mPP Population analyses. Assumptions will 
include scenarios where participants who discontinue FF/UMEC/VI have a lower 
treatment effect than those who discontinue BUD/FOR+TIO. The analysis results will be 
used to explore the conditions under which the conclusion of non-inferiority no longer 
holds.
 
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If superiority on primary endpoint is established with ITT population, similar “tipping 
point” sensitivity analysis will be conducted for the ITT population in order to explore 
the conditions under which the conclusion of superiority no longer holds.
The details of the statistical analysis methods for the secondary efficacy endpoints will be 
provided in the Reporting and Analysis Plan (RAP).
 
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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
Study Treatment 
Discontinuation 
Visit
Visit 5 
Safety
Follow-up 
Contact
Study Day
-56 to 
-28
Day -28
Day 1
Day 28
Day 
84-85
Day 91
Week
-8 to -4
-4
0
4
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 & 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 and 
PIFR e
X
Trough FEV1 f
X
24h serial spirometry g
X
X
Inhalation device training
X
X
Exacerbation Assessment
X
X
X
X
X
X
Physical examination h
X
X
X
Adverse Events Assessment
X
X
X
X
X
X
Vital signs i
X
X
X
ECG
X
Chest X-ray j
X
Oropharyngeal examination
X
X
X
X
X
Blood Draw for Genetics 
research k
X
Hematology/biochemistry l
X
Urine Pregnancy Test m
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 n
X
 
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Protocol Activity
Pre-
Screen
Screen
Treatment
Follow-up
Visit 0
Visit 1 
Screen/ 
Run-in
Visit 2
Randomisation Visit 3 Visit 4
Study Treatment 
Discontinuation 
Visit
Visit 5 
Safety
Follow-up 
Contact
Study Day
-56 to 
-28
Day -28
Day 1
Day 28
Day 
84-85
Day 91
Week
-8 to -4
-4
0
4
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)
Administer study treatment in 
clinic o
X
X
X
Assess run-in treatment 
compliance
X
Assess study treatment 
compliance
X
X
X
Collect run-in treatment
X
Collect study treatment
X
X
X
Dispense 
albuterol/salbutamol
X
X
X
X
Collect albuterol/salbutamol
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 IC and must be obtained prior to 
obtaining a genetic blood sample. Participants do not have to participate in the genetic research part of this study, 
it is optional.
c.
Demography may be captured at either the Pre-screen Visit or Screening Visit (for participants who do not have a 
Pre-screen Visit).
d.
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 PIFR spirometry and both pre and post-bronchodilator spirometry will be conducted. PIFR will 
be assessed 10 minutes prior to pre-bronchodilator spirometry. Participants are required to withhold their usual 
morning doses of their COPD meds including rescue albuterol/salbutamol for the protocol designated period prior 
to PIFR spirometry and reversibility testing.
f.
Trough FEV1 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. 
g.
Serial spirometry at Visit 2 and Visit 4 will be done pre-dose at 30 mins and 5 mins and post dose at 5 mins, 15 
mins, 30mins,1hr, 3hrs, 6hrs, 12hrs, 15hrs, 21hrs, 23hrs, 24hrs. Participants that discontinue study treatment but 
remain in the study will complete serial spirometry at Week 12, if they consent to do so.
h.
Physical examination may include height, weight, blood pressure and temperature.
i.
Vital signs, including blood pressure and pulse must be performed prior to spirometry and prior to taking morning 
dose of study treatment.
j.
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.
k.
Genetic consent must be obtained prior to obtaining a blood sample. The sample can be collected at any time 
after Visit 2, providing consent is obtained.
l.
Hematology and chemistry panels will include full and differential blood count and liver chemistry.
 
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m.
All female participants of child bearing potential will have a urine pregnancy test at Visits 1, 4 and Study 
Treatment Discontinuation Visit (if applicable).
n.
Participants must withhold their morning dose of existing COPD medication or study treatment and not take their 
run-in treatment until instructed to do so by study staff.
o.
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 sequence 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 inhaled 
corticosteroids (ICS) plus a long-acting β2-adrenergic receptor agonist (LABA) as second 
line therapy for the most advanced patients with significant symptoms and a high risk of 
exacerbations. Regular treatment with Inhaled Corticosteroid (ICS) containing regimens 
has been reported to improve respiratory symptoms, lung function, health related quality 
of life (HRQoL) and reduce the frequency of COPD exacerbation 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 
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 LAMA 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 
 
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(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 of 
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 
Symbiocort MDI) (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 [E-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. 
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 a multiple inhaler 
combination therapy of Symbicort Metered Dose Inhaler (MDI) (budesonide/formoterol 
320/9 mcg) twice daily plus Spiriva HandiHaler (tiotropium 18 mcg) once daily. The 
study will inform healthcare providers that patients can be switched to FF/UMEC/VI 
single inhaler therapy from a multiple inhaler triple therapy regimen of Symbicort MDI 
and Spiriva Handihaler.
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 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 grades from the 
ABCD assessment tool (Table 1) [GOLD, 2017]. 
 
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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 hospitalization, 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 guidelines 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 [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.
 
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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 budesonide/formoterol and 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 assessment and mitigation strategy 
for this protocol.  
 
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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) [Lipson, 2017] 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 adverse event 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 FF/VI 
(<1-2 % with FF/VI 100/25) and less than that 
observed in 52 week exacerbation studies with 
FF/VI (6 % with FF/VI 100/25) [Dransfield, 2013].  
Similarly, the incidence of pneumonia with 
- 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  
- 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 
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
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 the 
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.
The Pharmacovigilance Risk Assessment 
Committee (PRAC) recently conducted an Article 
31 review to evaluate the risk of pneumonia with 
use of ICSs in patients with COPD. The PRAC 
review confirmed that COPD patients treated 
with inhaled corticosteroids are at increased risk 
of pneumonia; however the Committee’s view 
was that the benefits of ICSs continue to 
outweigh their risks. The PRAC also looked 
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. 
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
whether there were any differences in the risk of 
pneumonia between these products, 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 fractures 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 
the fractures in both treatment groups were 
traumatic in nature.
- 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.
Adrenal suppression
Oral corticosteroids are known to have an effect 
on the hypothalamic-pituitary-adrenal (HPA) axis 
leading to a reduction in cortisol production. Due 
to the low dose and low systemic exposure with 
inhaled corticosteroids, this potential effect is not 
- Investigators are informed of the risk in the IB.
- Instream review of blinded AE/SAE reports.
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
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 
program, 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/VI100/25 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 this risk of 
adrenal suppression. The systemic exposure of 
FF is very low compared to that of oral 
corticosteroids, so any concurrent effect will be 
negligible.
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. 
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
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 ICS 
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 assessments in a study with 
FF/VI, FF and FP in participants with asthma.
- Participants will be informed about the risk in 
the informed consent.
- Investigators are informed of the risk in the IB.
- Appropriate exclusion criteria as specified in 
Section 6.2 of the protocol
- Instream review of blinded AE/SAE reports.
- If a risk is suspected, participants should 
receive appropriate treatment
Serious cardiovascular events
Cardiovasular (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 
- 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 
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
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, cardiovascular 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 
(4.3 % and 5.2 % respectively) and the EXT 
Population up to 52 weeks (8.6 % and 10 % 
respectively).  Within subgroups of 
cardiovascular 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). 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 
Section 6.2 of the protocol, including 
- Electrocardiogram (ECG) inclusion criteria
- Vital sign assessments (heart rate and blood 
pressure) as per protocol.
- Protocol defined stopping criteria as per 
Section 8.1.1.
- Instream review of blinded AE/SAE reports.
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
cardiovascular 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 up 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 
cardiovascular effects AESI was low in the study, 
despite the study enrolling participants with a 
number of CV comorbidities 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 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 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 
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
Population up to 24 weeks and EXT Population 
up to 52 weeks.
In study CTT116853 [Lipson, 2017], 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 cardiovascular safety profile of FF/UMEC/VI 
was generally consistent with that of FF/VI and 
UMEC/VI. 
Hypersensitivity
Hypersensitivity reactions are unlikely to 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 FF/UMEC/VI and 
BUD/FOR arms). On treatment hypersensitivity 
- Participants will be informed about the risk in 
the informed consent. Participants 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.
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
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. 
Narrow angle glaucoma
Rare reports of angle closure glaucoma (which 
may lead into blindness) have been associated 
with nebulised ipratropium bromide and 
salbutamol [Packe, 1984].
The incidence of narrow angle glaucoma in the 
COPD population associated with the use of 
inhaled bronchodilators (including LAMAs and 
LABAs) is relatively low. 
In CTT116853, in the ITT Population up to 24 
weeks, events in the glaucoma SMQ were 
reported at an incidence of 0.1 and 0.4 % in the 
FF/UMEC/VI and BUD/FOR arms respectively. 
In the EXT Population up to 52 weeks, no events 
- 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.
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
were reported in either treatment arm.
In the UMEC/VI development program, there 
was one report (<1 %) of angle closure glaucoma 
(UMEC/VI 62.5/25 mcg).
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 retention AESI 
group in either treatment arm in the ITT 
Population up to 24 weeks and 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.
- Appropriate exclusion criteria as specified in 
Section 6.2 of the protocol
- Instream review of blinded AE/SAE reports.
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 CTT116853, the risk of paradoxical 
bronchospasm was evaluated through the AESI 
of asthma/bronchospasm. In the ITT Population 
- 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.
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
up to 24 weeks, one participant reported an
event in the asthma/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.
 
 
 
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3.3.2.
Risk assessment for Symbicort MDI (Budesonide/ Formoterol) 
160/4.5 mcg
Symbicort is a marketed drug that contains both budesonide (ICS; 160 mcg) and 
formoterol (LABA; 4.5 mcg). Two inhalations from the MDI provide the required 
320/9 mcg dose. The dose (320/9 mcg) and formulation, using an MDI, are approved for 
COPD in the US, the dose and formulation are not approved in Europe. A similar profile 
of undesirable effects as reported for ICSs and LABAs may occur with budesonide and 
formoterol respectively. No increased incidence of adverse reactions has been seen 
following concurrent administration of the two compounds. The most common drug-
related adverse reactions are pharmacologically predictable side-effects of β2
adrenoceptor agonist therapy, such as tremor and palpitations. These tend to be mild and 
usually disappear within a few days of treatment. Please refer to the authorised product 
label for further information about the risks of using Symbicort. In this study, Symbicort 
will be used in line with the recommendations provided in the product label.
Since Symbicort contains an ICS and LABA, the risk mitigation strategies for the FF 
(ICS) and VI (LABA) components of GSK2834425 will be applicable for Symbicort.
3.3.3.
Risk Assessment for Spiriva Handihaler (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, Spiriva Handihaler will be used in line with the recommendations provided in the 
product label. 
Spiriva Handihaler is an anticholinergic, therefore the risk mitigation strategy for UMEC 
component of GSK2834425 will be applicable for Spiriva Handilaler.  
 
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3.3.4.
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 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.
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 bronchodilator treatment of airflow 
obstruction in patients 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-bronchodilator) with an 
exacerbation history despite regular bronchodilator therapy.  The UMEC/VI combination
is approved as a maintenance bronchodilator to relieve symptoms in adult patients with 
COPD. UMEC is approved as a maintenance bronchodilator treatment to relieve 
symptoms in adult patients 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 patients with moderate to severe COPD supports the further 
development of the closed triple combination.
Tiotropium (18 mcg) and budesonide/formoterol (400/12 mcg) are marketed drugs for the 
COPD indication, and have established benefit:risk profiles.  Tiotropium and 
budesonide/formoterol will be used in line with the recommendations provided in the 
product labels.
3.3.5.
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, tiotropium and 
budesonide/formoterol are justified by the anticipated benefits from active treatments that 
may be afforded to patients with COPD.
 
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4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
To evaluate the effects of single inhaler 
triple therapy (FF/UMEC/VI) compared 
to multiple inhaler triple combination 
therapy with budesonide/formoterol plus 
tiotropium after 12 weeks of treatment 
on lung function
Primary
Weighted mean change from baseline in 
FEV1 over 0-24 hours at Week 12
Secondary

Change from baseline in trough FEV1
on Day 2, Day 28, Day 84 and Day 85

Weighted mean change from baseline 
in FEV1 over 0-24 hours on Day 1
Other
To evaluate the effects of single inhaler 
triple therapy (FF/UMEC/VI) compared 
to multiple inhaler triple combination 
therapy with budesonide/formoterol plus 
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 effects of single inhaler 
triple therapy (FF/UMEC/VI) compared 
to multiple inhaler triple combination 
therapy with budesonide/formoterol plus 
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 effects of single inhaler 
triple therapy (FF/UMEC/VI) compared 
to multiple inhaler triple combination 
therapy with budesonide/formoterol plus 
tiotropium after 12 weeks of treatment 
on COPD exacerbations
Moderate or severe exacerbation event
Assess how inspiratory airflow 
limitation affects ability to use the 
ELLIPTA
Peak Inspiratory Flow Rate at Screening 
(Week -4)
 
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Objectives
Endpoints
Safety
To evaluate the safety profile of single 
inhaler triple therapy (FF/UMEC/VI) 
compared to multiple inhaler triple 
combination therapy with 
budesonide/formoterol plus tiotropium 
over 84 days of treatment
Incidence of adverse events
Vital signs
5.
STUDY DESIGN
5.1.
Overall Design
This is a Phase IV, 12-week, randomised, double-blind, triple dummy, parallel group, 
multicentre study evaluating single inhaler triple therapy (FF/UMEC/VI) once daily via 
the ELLIPTA, compared to multiple inhaler triple combination therapy 
budesonide/formoterol (320/9 mcg) twice daily plus once daily tiotropium (18 mcg), in 
participants with COPD. 
Figure 1
Study design schema
Eligible participants at Screening (V1) will be current or former smokers, with an 
established clinical history of COPD, receiving daily maintenance COPD therapy for at
least 3 months, with a post-bronchodilator FEV1 of <50 % predicted (or <80 % predicted 
with a documented history of at least 2 moderate or 1 severe [hospitalised] exacerbation 
in the last 12 months) and a CAT score of ≥10 and Visit 1 and at Visit 2. 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. 
 
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
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) COPD medication(s) during the pre-screening 
period; however, medications that are prohibited within a specified time interval 
prior to Visit 1 are defined in Section 6.2 (24).

Screening/run-in: Eligible participants will be allowed to continue their usual 
COPD medications until the day before Screening, Visit 1.  On the morning of 
the Screening Visit participants will refrain from taking their morning dose of 
their usual COPD medications. Participants who meet all of the eligibility 
criteria at Visit 1, will enter the 4-week run-in period during which they will 
discontinue all existing COPD medications and receive their run-in treatment:
budesonide/formoterol (320/9 mcg) twice daily plus tiotropium (18 mcg) once 
daily plus placebo via the ELLIPTA. Participants will not use any other COPD 
medications (except for those allowed per protocol). 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, MDI 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 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:
Either:
FF/UMEC/VI 100/62.5/25 mcg via the ELLIPTA once daily in the morning
+ placebo to match budesonide/formoterol via MDI, two inhalations twice daily 
+  placebo to match tiotropium via HandiHaler once daily in the morning
or,
Budesonide/formoterol 160/4.5 mcg via MDI, two inhalations twice daily*
+ tiotropium 18 mcg via HandiHaler once daily in the morning
+ placebo via the ELLIPTA once daily in the morning
 
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*Participants are required to take two inhalations of budesonide/formoterol 
160/4.5 mcg, via the MDI in the morning and two inhalations in the evening. 
The total dose is therefore 320/9 mcg twice daily. 
At Visit 2 participants will refrain from taking their morning doses of run-in 
study medication and will self-administer study treatment at the clinic, when 
instructed to do so. Participants will remain available, preferably at the clinic or 
approved facility, for at least 24 hours for serial spirometry assessments.

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. 
Participants will remain at the clinic for at least 24 hours, for serial spirometry 
assessments. At Visits 3 and 4 participants will self-administer study treatment 
whilst at the clinic. Participants will take their last doses of study treatment in 
the clinic on Day 84 (Visit 4, when instructed to do so by clinic personnel), and 
preferably continue to remain at the clinic or approved facility until at least 24 
hours after their last morning dose, for their clinical assessments, which include 
serial spirometry 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, and at the same time each evening, as directed by the clinic. 

Safety/follow-up: A safety follow-up telephone contact or clinic visit (Visit 5) 
will be conducted approximately 7 days after the participant completes all of the 
protocol-defined procedures for Visit 4/End of Study (EOS) or, if applicable, the 
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 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 (see Section 8.1). 
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.
5.2.
Number of Participants
Approximately 800 participants with advanced COPD will enter the run-in period, in 
order to randomise approximately 732 participants in order to achieve an estimated 620 
evaluable participants in the modified per-protocol (mPP) population at Week 12, 
assuming 10 % premature discontinuation of study treatment and 5 % protocol deviation. 
See Section 10 for further details. 
 
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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 table (SoA) (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, triple-dummy, parallel-
group design. A placebo arm is not included because the primary comparison of interest 
is FF/UMEC/VI vs.  Budesonide/formoterol + tiotropium and it is not considered 
appropriate to include a placebo arm in a study in participants with advanced COPD. 
Eligible participants must have been on daily maintenance COPD medications for at least 
3 months. 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.
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 doses selected for the Symbicort MDI (budesonide/formoterol 320/9 mcg, twice 
daily) and Spiriva HandiHaler (tiotropium 18 mcg, once daily) is the doses 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.
 
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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 
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].
 
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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 for their COPD for at least 3 months prior to Screening.
Note: Participants taking only as-needed COPD medications 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).
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). 
 
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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.
11. Unstable liver disease: ALT >2x Upper Limit of Normal (ULN); and bilirubin 
>1.5x ULN (isolated bilirubin >1.5x ULN 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
 
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
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.
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 at screening (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.
 
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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: Use of the following medications within the 
following 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
Long term antibiotic therapy
Participants receiving antibiotics for long term therapy (30 
days) 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)
 
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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. 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 any of the three 
inhalers (ELLIPTA, Handihaler or MDI) will be excluded.
2. COPD exacerbation or pneumonia

Participants that experience a moderate or a severe COPD exacerbation or 
pneumonia during the run-in period will be excluded. 
3. Changes in COPD medication

Any participant that requires any change in COPD medication 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; serious adverse event (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/randomization 
failure details, eligibility criteria, and any SAEs. Further details are provided in the study-
specific eCRF completion guidelines.
For the purposes of this study, pre-screening failures, screening failures and run-in 
failures will be defined as follows:
Pre-screening failures: those participants that sign the informed consent document but 
do not have a Visit 1 (Screening) procedure.
 
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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 are not randomised 
(except those randomised in error).
7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.
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 
budesonide/formoterol (320/9 mcg) twice daily plus tiotropium (18 mcg) once daily plus 
placebo via the ELLIPTA. Following the run-in period, participants who meet the 
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 budesonide/formoterol via MDI, two inhalations twice daily 
+  placebo to match tiotropium via HandiHaler once daily in the morning
or,
Budesonide/formoterol 160/4.5 mcg via MDI, two inhalations twice daily*
+ tiotropium 18 mcg via HandiHaler once daily in the morning
+ placebo via the ELLIPTA once daily in the morning
*Participants are required to take two inhalations of budesonide/formoterol 160/4.5 mcg, 
via the MDI in the morning and two inhalations in the evening. The total dose is therefore 
320/9 mcg twice daily.
 
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Table 2
Dosing schedule for run-in and treatment periods
ELLIPTA
(1 inhalation)
MDI
(2 puffs)
HandiHaler
(1 capsule inhaled 
twice)
Active
Placebo
Active
Placebo
Active
Placebo
Run-in
am
Y
Y
Y
pm
Y
Treatment
Active FF/UMEC/VI
am
Y
Y
Y
pm
Y
Active 
budesonide/formoterol 
+ tiotropium
am
Y
Y
Y
pm
Y
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.
Symbicort MDI contains 120 doses: budesonide/formoterol 160mcg/4.5 mcg, two 
inhalations twice daily.
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, MDI and the 
Handihaler are provided in Table 3, Table 4, and Table 5, respectively.
 
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Table 3
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 
100mcg per blister
25 mcg per blister GW642444, 62.5 
mcg per blister GSK573719
Physical 
description 
Dry white powder
Dry white powder
Route of 
Administration 
Inhaled
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
NA
Physical 
description
Dry white powder
Dry white powder
Route of 
Administration
Inhaled
Table 4
Description of Symbicort MDI
Symbicort 160mcg/4.5 mcg
MDI
Dosage form
MDI with 120 doses
Unit dose strength
Budesonide/ Formoterol 160mcg/4.5mcg
Physical description 
Suspension for inhalation
Route of administraton
Inhaled
Placebo to match Symbicort
Placebo to match MDI
Dosage form
MDI with 120 doses
Unit dose strength
NA
Physical description
Suspension for inhalation
Route of administration
Inhaled
 
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Table 5
Description of Tiotropium bromide in HandiHaler
Spiriva 18 mcg
HandiHaler
Dosage form
Capsule
Unit dose strength
18mcg
Physical description 
Hard gelatin capsule containing 18mcg 
tiotropium bromide blended with lactose
Route of administration
Inhaled
Placebo to match Spiriva
HandiHaler
Dosage form
Capsule
Unit dose strength
NA
Physical description 
Hard gelatin capsule containing lactose
Route of administration
Inhaled
7.1.1.
Medical Devices

The GSK ELLIPTA medical device will be provided for use in this study.

Other medical devices (not manufactured by or for GSK provided for use in this 
study) are the Handihaler and MDI.

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 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. 
 
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7.4.
Blinding
This will be a double-blind study and the following will apply. 

The Investigator or treating physician may unblind a participant’s treatment 
assignment only in the case of an emergency OR in the event of a serious 
medical condition when knowledge of the study treatment is essential for the 
appropriate clinical management or welfare of the participant as judged by the 
Investigator. 

Investigators have direct access to the participant’s individual study treatment. 

It is preferred (but not required) that the Investigator first contacts the Medical 
Monitor or appropriate GSK study personnel to discuss options before unblinding 
the participant’s treatment assignment. 

If GSK personnel are not contacted before the unblinding, the Investigator must 
notify GSK within 24 hours after unblinding, but without revealing the treatment 
assignment of the unblinded participant, unless that information is important for 
the safety of participants currently in the study. 

The date and event or condition which led to the unblinding (i.e. the primary 
reason) will be recorded in source documentation and in the eCRF. 
Should a participant’s treatment assignment be unblinded then the participant may 
continue the assigned study treatment and be followed-up as per protocol until the 
completion of the Safety Follow-up assessments.
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any participant with an SAE. If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of the 
report, identifying the participant’s treatment assignment, may be sent to Investigators in 
accordance with local regulations and/or GSK policy. Participants will not be withdrawn 
from the study.
Masking of tiotropium and placebo to tiotropium capsules
This study will use a triple-dummy design for dosing, whereby participants will be given 
three inhalers (ELLIPTA, MDI 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,
 
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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.
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 MDI, 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 
 
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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 randomization 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 5). 
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 the randomised 
treatment periods: 

Study supplied albuterol/salbutamol 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)

Study provided COPD medications in the run-in and the randomised treatment period 
 
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The following COPD medications are permitted during the randomised 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 randomised 
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)

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] 
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
Diuretics. (Caution is advised in the co-administration of beta-agonists with non-
potassium sparing diuretics as this may result in ECG changes and/or 
hypokalemia)

Use of positive airway pressure for sleep apnea

Oral muscarinic antagonists for the treatment of overactive bladder are permitted 
but should be used with caution as they may exacerbate medical conditions that are 
contraindicated for anticholinergics (e.g., narrow angle glaucoma and bladder 
outflow obstruction)

Cytochrome P450 (CYP)3A4 inhibitors. (Caution should be exercised when 
considering the coadministration of long-term ketoconazole and other known 
strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, 
itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, 
troleandomycin, voriconazole) because increased systemic corticosteroid and 
increased cardiovascular adverse effects may occur)
7.7.2.
Prohibited Medications and Non-Drug Therapies
Use of the medications listed in Table 6 is not permitted during the study.
Table 6
Concomitant Medications
Medication Prohibited during the randomised treatment period
Inhaled short-acting anticholinergics
Inhaled short-acting beta2 agonists1 
Inhaled short-acting anticholinergic/short-acting beta2-agonist combination products
Inhaled corticosteroids (ICS)
Inhaled corticosteroids (ICS)/Inhaled long-acting beta2-agonist (LABA) combinations 
(eg.fluticasone/salmeterol, mometasone furoate/formoterol fumarate, budesonide/formoterol fumarate; 
fluticasone furoate/vilanterol
Phosphodiesterase 4 (PDE4) inhibitors (roflumilast)
LABA (e.g., indacaterol, olodaterol, salmeterol etc.)
Other LAMAs (aclidinium, glycopyrronium, umeclidinium etc.)
LAMA/LABA combinations
Theophyllines
Sodium cromoglycate and nedocromil sodium
 
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Medication Prohibited during the randomised treatment period
Anti-leukotrienes
Long term antibiotic therapy2
Systemic, oral, parenteral corticosteroids3
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 neccessary the Investigator or other health care 
personnel may stop the participant’s study treatment temporarily (≤ 14 days) in order to 
treat the COPD exacerbation.  Participants who require more than two consecutive 14 
day courses of treatment (i.e. antibiotics or corticosteroids) should be evaluated for their 
continuation on study treatment by the Investigator in consultation with the GSK medical 
monitor.
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
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 4), 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 4 on study treatment and for participants that withdraw from the study.  For 
participants that discontinue study treatment, post-treatment concomitant medication 
 
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should be entered into the eCRF until they complete the visit/telephone contact at the 
planned Visit 5 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 4, 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 5) should also be conducted 7 days after Visit 4. 
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 

Serial spirometry (Visit 4 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. 
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.
8.1.1.
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, participants are however encouraged to remain in the 
study and complete limited assessments, as detailed in Section 8.1: 

Liver chemistry stopping and increased monitoring criteria have been designed 
to assure participant safety and evaluate liver event etiology (in alignment with the 
Food and Drug Administration (FDA) premarketing clinical liver safety guidance). 
These protocol guidelines are in alignment with FDA premarketing clinical liver 
safety guidance: 
 
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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)
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.
8.1.2.
Rechallenge
8.1.2.1.
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.
 
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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 SOA (Section 2).
Participants that have previously discontinued study treatment (and have already 
completed the Study Treatment Discontinuation Visit) but 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 5) 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:

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 Participants 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. 
 
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9.
STUDY ASSESSMENTS AND PROCEDURES
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. Sites are required to have study treatment dose, dispensed and accounted for by 
site personnel that are not involved in any efficacy or safety assessments. See Section 7.4
for further details.   

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):

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))
 
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
Cardiovascular medical history/risk factors

Inclusion/Exclusion criteria 

Physical examination (including oropharyngeal examination)

12-lead ECG

Pulse rate, blood pressure measurements 

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  
(including PIFR) and each scheduled clinic visit during the treatment period. For FEV1,
FVC and PIFR determinations, at least 3 acceptable spirometry efforts (with no more 
than 8) should be obtained.  Acceptable spirometry efforts should have a satisfactory start 
of test and end of test (e.g. a plateau in the volume-time curve) and be free from artifacts 
due to cough, early termination, poor effort, obstructed mouthpiece, equipment 
malfunction, or other reasons [Miller, 2005].
The largest FEV1 and FVC from the 3 acceptable efforts should be recorded, even if they 
do not come from the same effort.
 
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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 run-in 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.
24-hour Serial Spirometry
24-hour serial spirometry will be performed by all participants at Randomization (Visit 2) 
and Day 84 (Visit 4). In addition, trough FEV1 data will be collected pre-dose on Day 28 
(Visit 3).
Serial spirometry measurements should be taken as close to the following scheduled 
timepoints as possible:
Pre-dose: 30 mins and 5 mins
Post-dose: 5 mins, 15 mins, 30 mins, 1 hr, 3 hrs, 6 hrs, 12 hrs, 15 hrs, 21 hrs, 23 hrs and 
24 hrs
9.1.1.2.
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.
9.1.1.3.
Peak Inspiratory Flow Rate (PIFR)
PIFR will be completed at Screening (Visit 1) only, approximately 10 minutes prior to 
the start of reversibility testing. Three acceptable spirometry efforts will be obtained. 
 
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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 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 
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 5.
Participants will complete a paper Medical Problems worksheet to record medical 
problems experienced during the study. This paper worksheet must be reviewed by the 
Investigator (or designee) at each visit to the study site to assist in the identification of 
new COPD exacerbations.  
All COPD exacerbations will be recorded in the exacerbation eCRF. 
Every effort should be made to conduct a chest x-ray within 48 hours of identification of 
a moderate or severe exacerbation. 
Details on COPD Exacerbation Identification, Categorization and Treatment Guidelines 
are provided in Appendix 5.
 
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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). 
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 5.

All AEs will be collected from the start of Study Screening (Visit 1) 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. 
 
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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.
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 Medicinal 
Dictionary for Regulatory Activities (MedDRA) terms. The CV information should be 
recorded in the specific cardiovascular section of the CRF within one week of receipt of a 
CV Event data query prompting its completion. 
The Death 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.
 
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9.2.6.
Disease-Related Outcomes – COPD Exacerbations
COPD exacerbations are an expected disease-related outcome. 
COPD exacerbations should not be recorded as an adverse event, unless they meet the 
definition of an SAE (Appendix 6).
9.2.7.
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 <25 kg/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 
 
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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 

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.
 
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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.

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. If the eCRF is unavailable, then a paper version should be 
utilized.

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.
 
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9.4.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 2).
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 and 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 (Section 2) 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.
 
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
All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 5 days after the last dose of study 
treatment should be repeated until the values return to normal or baseline or are 
no longer considered significantly abnormal by the Investigator or medical 
monitor. 

If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 8, must be 
conducted in accordance with the laboratory manual and the SoA (Section 2).
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:
 
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
the health effects that smoking may cause

the health benefits that may result with smoking cessation

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 FF/UMEC/VI with 
budesonide/formoterol + tiotropium (BUD/FOR+TIO) in COPD participants. The 
primary endpoint is 0- 24 hour weighted mean (WM) FEV1 at Week 12 (Day 84). The 
primary analysis is the comparison of this endpoint for FF/UMEC/VI vs. BUD/FOR+TIO 
with mPP population.  The null hypothesis is that the difference in 0-24 hour WM FEV1
between treatment groups is less than or equal to a pre-specified non-inferiority margin 
Δ:
H0: T1 – T2 ≤ -Δ
The alternative hypothesis is that the difference between treatment groups is greater than 
the margin.
H1: T1 – T2 > -Δ
where T1 and T2 are the treatment means for FF/UMEC/VI and BUD/FOR+TIO, 
respectively.
The non-inferiority margin has been set at 50 mL. This non-inferiority margin for 0-24 
hour WM FEV1 has previously been accepted by the FDA (Combivent vs Ipratropium 
head to head study).
If the lower bound of the two-sided 9 5% confidence interval around the (FF/UMEC/VI 
vs. BUD/FOR+TIO,) treatment difference is above -50 mL then FF/UMEC/VI will be 
considered non-inferior to BUD/FOR+TIO. Further treatment comparisons and 
inferences to be made based on P-values are detailed in Section 10.4.1.
10.2.
Sample Size Determination
The sample size calculations use a one-sided 2.5 % significance level and an estimate of 
residual standard deviation (SD) for 0-24 hour WM FEV1 of 230 mL. The estimate of SD 
is based on mixed models repeated measures [MMRM] analyses of past studies in COPD 
with 0-24 hour weighted mean as primary endpoint. A study with 620 evaluable 
 
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participants for the primary analysis will have 90 % power to determine non-inferiority of 
FF/UMEC/VI to BUD/FOR+TIO based on 0-24 hour WM FEV1 at Week 12 (Day 84), 
when the margin of non-inferiority is 50 mL and the true mean treatment difference is 
assumed to be 10 mL.
It is estimated that approximately 15 % of participants who are randomised will either 
discontinue IP or be excluded from the modified Per Protocol population at Week 12 and 
approximately 8 % of participants will drop out from 4-week run-in (including those not 
meeting randomisation criteria). Therefore, approximately 800 participants will be 
enrolled to 4-week run-in in order to have 732 participants to be randomised.
 
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10.3.
Populations for Analyses
For purposes of analysis, the following populations are defined:
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.
Run-in 

All participants who are eligible at Screening and entered Run-in 
period. 
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 randomszed 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.
Modified Per Protocol 
(mPP)

All participants in the ITT Population who do not have a full 
protocol deviation considered to impact efficacy.

Data following a COPD exacerbation or pneumonia will be 
excluded from analysis due to the potential impact of the 
exacerbation or the medications used to treat it.

Participants with partial protocol deviations considered to impact 
efficacy will be included in the mPP Population but will have 
their data excluded from analyses from the time of deviation 
onwards.

This population will only be used for the primary analysis for the 
primary endpoint.
 
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10.4.
Statistical Analyses
10.4.1.
Efficacy Analyses
Endpoint
Statistical Analysis Methods
Primary
The primary endpoint, 0-24 hour WM FEV1 on Day 84 will be analyzed with mPP 
population using mixed model repeated measure (MMRM) analysis, including 
covariates such as 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.   Baseline FEV1 is the mean of 
the two assessments made -30 and -5 minutes predose on Treatment Day 1.
Estimated differences between FF/UMEC/VI and BUD/FOR+TIO will be 
presented together with 95 % confidence intervals (CIs) for the treatment 
difference and P-value. The same analysis will be repeated for the ITT 
Population.
Inference to be drawn from the p-values will be as follows:

Analysis with mPP population: If the treatment comparison on the primary 
endpoint has a lower confidence limit below the non-inferiority margin, 
non-inferiority is not demonstrated. No inference will be drawn from p-
values for treatment comparisons on any other endpoints.

Analysis with mPP population: If the treatment comparison on the primary 
endpoint has a lower confidence limit above the non-inferiority margin but 
below 0, non-inferiority is established but the p-value will not be used to 
give an indication of the strength of that noninferiority.  Inference will be 
drawn from p-values for treatment comparisons (with ITT population) on 
other non-lung function endpoints,i.e, SGRQ and CAT, which will be 
called statistically significant if <0.05. No inference will be drawn from p-
values on trough FEV1 endpoint. Analysis with ITT population: If the 
treatment comparison on the primary endpoint has a lower confidence 
limit above 0, superiority is established and the p-value can be used to 
give an indication of the strength of that superiority. Inference will be 
drawn from p-values for treatment comparisons on all other endpoints, 
which will be called statistically significant if <0.05.
A “tipping point” sensitivity analysis of 0-24hour WM FEV1 on Day 84 will be 
conducted for the mPP Population. This will explore the impact of missing data by 
using differing assumptions regarding the mean treatment effect in participants 
who discontinue study treatment or have data excluded from mPP Population 
analyses. Assumptions will include scenarios where participants who discontinue 
FF/UMEC/VI have a lower treatment effect than those who discontinue 
BUD/FOR+TIO. The analysis results will be used to explore the conditions under 
which the conclusion of non-inferiority no longer holds.
 
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Endpoint
Statistical Analysis Methods
If superiority on primary endpoint is established with ITT population, similar 
“tipping point” sensitivity analysis will be conducted for the ITT population in order 
to explore the conditions under which the conclusion of superiority no longer 
holds.
Secondary

Secondary endpoint change from baseline in trough FEV1 will be 
analysed for the ITT Population using a mixed model repeated measures 
(MMRM) analysis, including trough FEV1 recorded at each of visits, Day 
2, 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 TIO will be presented together 
with 95 % CIs for the difference and p-values.
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 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.
 
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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.
10.4.5.
Exploratory Analyses
These exploratory analyses may be provided in a separate RAP.
 
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11.
REFERENCES
Aaron SD, Vandemheen KL, Fergusson D, Maltais F, Bourbeau J, Goldstein R, Balter M 
et al. (2007) Tiotropium in Combination with Placebo, Salmeterol, or Fluticasone–
Salmeterol for Treatment of Chronic Obstructive Pulmonary Disease A Randomised 
Trial. Ann Intern Med. 146:545-555.
Cazzola M, Andò F, Santus P, Ruggeri P, Di Marco F, Sanduzzi A et al. A pilot study to 
assess the effects of combining fluticasone propionate/salmeterol and tiotropium on the 
airflow obstruction of patients with severe-to-very severe COPD. Pul Pharm Ther 2007 
20:556–561.
Celli BR, MacNee W, ATS/ERS Task Force. Standards for the diagnosis and treatment of 
patients with COPD: A summary of the ATS/ERS position paper.  Eur Respir J 2004; 23: 
932-946.
Christensson C, Thoren A, Lindberg B. Safety of inhaled budesonide: clinical 
manifestations of systemic corticosteroid-related adverse effects. Drug Safety. 
2008;31:965-988.
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(2):641-647.
De Bisschop MB, Bellou A. Anaphylaxis. Current Opinion in Critical Care. 
2012;18(4):308-317.
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: 
http://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.
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 
 
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Jones, PW., Harding, G., Wiklund, I., Berry, P., Tabberer, M., Yu, R., et al. ‘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 randomised 
controlled study. Resp. Med. (2012) 106: 382-389 doi:10.1016/j.rmed.2011.09.004.
Lehouck A, Boonen S, Decramer M, Janssens W. COPD, bone metabolism, and 
osteoporosis. Chest. 2011;139:648-657.
Lipson DA, Barnacle H, Birk R, Brealey N, Locantore N, Lomas DA, et al. FULFIL 
Trial: Once-Daily Triple Therapy in Patients with Chronic Obstructive Pulmonary 
Disease. Am J Respir Crit Care Med 2017;10.1164/rccm.201703-0449OC.
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, Odencrantz J, Standardisation of spirometry. Eur Respir J. 
2005;26:319-388.
Niggemann B, Beyer K. Factors augmenting allergic reactions. Allergy. 
2014;69(12):1582-1587.
Packe GE, Cayton RM, Mashhoudi N. Nebulised ipratropium bromide and salbutamol
causing closed-angle glaucoma. Lancet.1984;22:691.
Quanjer P, Stanojevic S, Cole T, Baur X, Hall G, Culver B, et al. Multi-ethnic reference 
values for spirometry for the 3-95-yr age range: The global lung function 2012 equations. 
Eur Respir J 2012;, 40: 1324-1343.
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(2):257-268.
Siler, TM, Kerwin, E, Sousa, AR, Donald, A, Ali, R, Church, A. (2015) Efficacy and 
safety of umeclidinium added to fluticasone furoate/vilanterol in chronic obstructive 
pulmonary disease: results of two randomized studies. Respir Med. 109(9), 1155-1163.
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.
Weldon D. The effects of corticosteroids on bone growth and bone density. Ann. Allergy 
Asthma Immunol. 2009;103:3-11.
 
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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 (2012) 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. Abstract 62. 
 
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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
BPM
Beats per minute
BMI
Body Mass Index
BUD
Budesonide
BUN
Blood Urea Nitrogen
CAT
COPD Assessment Test
CFR
Code of Federal Regulations
CI
Confidence Interval
CIOMS
Council for International Organizations of Medical Sciences
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic Obstructive Pulmonary Disease
CPRD
Clinical Practice Research Database
CT
Computerized Tomography
CV
Cardiovascular
CYP
Cytochrome P450
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
 
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HCP
Health Care Provider
HIPAA
Health Insurance Portability and Accountability Act
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
IUD
Intrauterine device
IUS
Intrauterine Hormone-Releasing System
IWRS
Interactive Web Response System
ITT
Intent-to-Treat
Kg/m2
Kilograms per meter squared
LABA
Long-Acting Beta-2-Agonists
LAMA
Long-Acting Muscarinic Antagonist
LRTI
Lower Respiratory Tract Infection
LTOT
Long-term oxygen therapy
MACE
Major Adverse Cardiac Event
MAOI
Monoamine Oxidase Inhibitors
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
PRAC
Pharmacovigilance Risk Assessment Committee
QTc
QT interval corrected for heart rate
QTcB
QT interval corrected for heart rate by Bazett’s formula
QTcF
QT interval corrected for heart rate by Fridericia’s formula
 
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RAP
Reporting and Analysis Plan
RBC
Red Blood Cell
RNA
Ribonucleic acid
SAE
Serious Adverse Event
SD
Standard Deviation
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic-Pyruvic Transaminase
SGRQ-C
St. George’s Respiratory Questionnaire for COPD patients
SMQ
Standardised MedDRA Queries
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
VT
Ventricular Tachycardia
WBC
White Blood Cell
WM
Weighted Mean
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
Spiriva Handihaler
Symbicort
 
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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 participants. 

The Investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 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. 

Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
 
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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.
 
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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 physically or 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. 
 
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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
 
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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 participant’s 
medical records, medical examination, or medical history interview.
3. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment.
Contraception Guidance
Female Participants
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in 
Table 7. 
 
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Table 7
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 participants 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 

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 
 
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
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 foetal 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.
 
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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) 
International 
Normalized 
Ratio (INR)2
ALT 3x ULN and INR >1.5, if INR measured
Cannot 
Monitor
ALT 5x ULN but <8x ULN and cannot be monitored weekly for 2 weeks
ALT 3x ULN but <5x ULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3x ULN associated with symptoms (new or worsening) believed to be 
related to  liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue  study treatment 

Report the event to GSK within 24 hours

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 

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
 
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(see MONITORING below)

Do not restart/rechallenge participant with 
study treatment unless allowed per protocol 

If restart/rechallenge not allowed per 
protocol , permanently discontinue study 
treatment and may continue participant in the 
study for any protocol specified follow up 
assessments
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24 
hrs

Monitor participants twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 
recommended
For All other criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24-
72 hrs 

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

Serum creatine phosphokinase and lactate 
dehydrogenase.

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form
including acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG or gamma 
globulins).

Serum acetaminophen adduct HPLC 
assay (quantifies potential acetaminophen 
contribution to liver injury in participants 
with definite or likely acetaminophen use 
in the preceding week [James, 2009]). 
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 participant if ALT 3x ULN and bilirubin 2x ULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3x ULN and bilirubin 2x ULN (>35 % direct bilirubin) or ALT 3x ULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to participants receiving anticoagulants
 
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3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)   
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
5.
If hepatitis delta antibody assay cannot be performed, it can be replaced with a PCR of hepatitis D RNA virus 
(where needed) [Le Gal, 2005].
6.
PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
treatments.  Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
treatment prior to blood sample draw on the eCRF. If the date or time of the last dose is unclear, provide the 
participant’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot 
be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and 
shipping are in the SPM.  
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, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
 
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Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E.  Quantification 
of Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates 
Different Patterns of Virological Response to Interferon Therapy in Chronically Infected 
Patients.  J Clin Microbiol. 2005;43(5):2363–2369. 
 
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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
 
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
Other respiratory related disease
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
 
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
Any course of oral/systemic corticosteroids started within 7 days of finishing a 
previous course will be considered as treatment for a single exacerbation
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.
 
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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 and clinical chemisty) 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.
 
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Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (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.
 
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d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
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
 
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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 
 
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risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated.

The Investigator will also consult the 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.
 
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
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 
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.
 
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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 

Foetal distress, foetal death, or any congenital abnormality or birth defects
 
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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.
 
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12.8.
Appendix 8: Clinical Laboratory Tests

All protocol required laboratory assessments (haematology and clinical 
chemistry) 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.
 
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Table 8
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
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)
The results of each test must be entered into the CRF.
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 x ULN (>35 % direct bilirubin) or ALT 3 x 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).
 
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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 Genetics 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.
 
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12.10.
Appendix 10: Country-specific requirements
There are currently no country specific requirements. 
 
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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).
Amendment 1 09-Nov-2017
Overall Rationale for the Amendment: This amendment is required as the incorrect 
EudraCT number was provided in the Regulator Agency Identifying Number(s) section 
on the title page, in error. In addition, the physical form of Symbicort and matching 
placebo was reported as a solution for inhalation, which is incorrect, the correct physical 
form is a suspension for inhalation. An additional footnote has been added to the 
Schedule of Activities, to provide clarity on the collection of trough FEV1 spirometry on 
Day 28.
Section # and 
Name
Description of Change
Brief Rationale
Title page
EudraCT number updated
The incorrect EudraCT number was 
included in error
Schedule of 
Activities
Footnote (f) added 
To explain that trough FEV1 will be 
performed pre-dose at 30 mins and 5 
mins prior to taking the morning dose of 
study treatment.
Section 7.1
Physical form of Symbicort and 
matching placebo updated
The physical form of Symbicort and 
matching placebo was assumed to be a 
solution for inhalation, as the paperwork 
detailing the physical form wasn’t 
available at the time of protocol 
finalisation. 
 
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TITLE PAGE
Protocol Title: A Phase IV, 12-week, randomised, double-blind, triple dummy study to 
compare single inhaler triple therapy, fluticasone furoate/umeclidinium/vilanterol 
(FF/UMEC/VI) with multiple inhaler therapy (budesonide/formoterol plus tiotropium) 
based on lung function and symptoms in participants with chronic obstructive pulmonary 
disease
Protocol Number: 207609 Amendment 1
Short Title: A randomised study, comparing FF/UMEC/VI single inhaler triple therapy, 
versus multiple inhaler therapy (budesonide/formoterol plus tiotropium) 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 and EudraCT number 
2017-001150-33
Approval Date: 09-NOV-2017
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Protocol Amendment 1
09-Nov-2017
Original Protocol
12-Oct-2017
Amendment 1 09-Nov-2017
Overall Rationale for the Amendment: This amendment is required as the incorrect 
EudraCT number was provided in the Regulator Agency Identifying Number(s) section 
on the title page, in error. In addition, the physical form of Symbicort and matching 
placebo was reported as a solution for inhalation, which is incorrect, the correct physical 
form is a suspension for inhalation. An additional footnote has been added to the 
Schedule of Activities, to provide clarity on the collection of trough FEV1 spirometry on 
Day 28.
Section # and 
Name
Description of Change
Brief Rationale
Title page
EudraCT number updated
The incorrect EudraCT number was 
included in error
Schedule of 
Activities
Footnote (f) added 
To explain that trough FEV1 will be 
performed pre-dose at 30 mins and 5 
mins prior to taking the morning dose of 
study treatment.
Section 7.1
Physical form of Symbicort and 
matching placebo updated
The physical form of Symbicort and 
matching placebo was assumed to be a 
solution for inhalation, as the paperwork 
detailing the physical form wasn’t 
available at the time of protocol 
finalisation.
 
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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS...............................................................................................................7
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................16
3.
INTRODUCTION....................................................................................................18
3.1.
Study Rationale ..........................................................................................18
3.2.
Background ................................................................................................19
3.3.
Benefit/Risk Assessment ............................................................................21
3.3.1.
Risk Assessment .........................................................................22
3.3.2.
Risk assessment for Symbicort MDI (Budesonide/ 
Formoterol) 160/4.5 mcg..............................................................33
3.3.3.
Risk Assessment for Spiriva Handihaler (Tiotropium 
Bromide) 18 mcg .........................................................................33
3.3.4.
Benefit Assessment.....................................................................34
3.3.5.
Overall Benefit:Risk Conclusion...................................................34
4.
OBJECTIVES AND ENDPOINTS...........................................................................35
5.
STUDY DESIGN ....................................................................................................36
5.1.
Overall Design ............................................................................................36
5.2.
Number of Participants ...............................................................................38
5.3.
Participant and Study Completion...............................................................39
5.4.
Scientific Rationale for Study Design ..........................................................39
5.5.
Dose Justification........................................................................................39
6.
STUDY POPULATION...........................................................................................39
6.1.
Inclusion Criteria.........................................................................................39
6.2.
Exclusion Criteria........................................................................................41
6.3.
Randomisation Criteria ...............................................................................44
6.4.
Lifestyle Restrictions...................................................................................45
6.5.
Pre-screening/Screening/Run-in/Randomisation Failures...........................45
7.
TREATMENTS.......................................................................................................46
7.1.
Treatment Groups and Duration .................................................................46
7.1.1.
Medical Devices...........................................................................49
7.2.
Dose Modification .......................................................................................49
7.3.
Method of Treatment Assignment ...............................................................49
7.4.
Blinding.......................................................................................................49
7.5.
Preparation/Handling/Storage/Accountability..............................................51
7.6.
Treatment Compliance................................................................................51
7.7.
Concomitant Therapy..................................................................................52
7.7.1.
Permitted Medications and Non-Drug Therapies..........................52
7.7.1.1.
Permitted COPD Medications.....................................52
7.7.1.2.
Permitted Non-COPD Medications .............................53
7.7.2.
Prohibited Medications and Non-Drug Therapies.........................54
7.8.
Treatment after the End of the Study ..........................................................56
 
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8.
DISCONTINUATION CRITERIA.............................................................................56
8.1.
Discontinuation of Study Treatment ............................................................56
8.1.1.
Protocol defined criteria for discontinuation of study 
treatment .....................................................................................57
8.1.2.
Rechallenge.................................................................................58
8.1.2.1.
Study Treatment Restart or Rechallenge....................58
8.2.
Withdrawal from the Study..........................................................................58
8.3.
Lost to Follow Up........................................................................................59
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................59
9.1.
Efficacy Assessments.................................................................................61
9.1.1.
Spirometry ...................................................................................61
9.1.1.1.
24-hour Serial Spirometry...........................................61
9.1.1.2.
Reversibility................................................................62
9.1.1.3.
Peak Inspiratory Flow Rate (PIFR) .............................62
9.1.2.
SGRQ-C ......................................................................................62
9.1.3.
COPD Assessment Test (CAT)....................................................62
9.1.4.
COPD Exacerbations...................................................................63
9.2.
Adverse Events...........................................................................................63
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................63
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 .............................64
9.2.5.
Cardiovascular and Death Events................................................65
9.2.6.
Disease-Related Outcomes – COPD Exacerbations....................65
9.2.7.
Pneumonia ..................................................................................65
9.2.8.
Sentinel Events............................................................................66
9.2.9.
Pregnancy ...................................................................................66
9.2.10.
Medical Device Incidents (Including Malfunctions).......................66
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..................................................................67
9.2.10.4.
Regulatory Reporting Requirements for 
Medical Device Incidents............................................67
9.3.
Treatment of Overdose...............................................................................68
9.4.
Safety Assessments ...................................................................................68
9.4.1.
Physical Examinations.................................................................68
9.4.2.
Vital Signs....................................................................................68
9.4.3.
Electrocardiograms......................................................................68
9.4.4.
Clinical Safety Laboratory Assessments ......................................69
9.5.
Pharmacokinetics .......................................................................................69
9.6.
Pharmacodynamics ....................................................................................69
9.7.
Genetics .....................................................................................................69
9.8.
Biomarkers .................................................................................................70
9.9.
Medical Resource Utilization and Health Economics ..................................70
10. STATISTICAL CONSIDERATIONS........................................................................70
10.1.
Hypotheses.................................................................................................70
10.2.
Sample Size Determination ........................................................................70
 
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10.3.
Populations for Analyses ............................................................................72
10.4.
Statistical Analyses.....................................................................................73
10.4.1.
Efficacy Analyses.........................................................................73
10.4.2.
Safety Analyses...........................................................................74
10.4.3.
Other Analyses ............................................................................75
10.4.4.
Interim Analyses ..........................................................................75
10.4.5.
Exploratory Analyses ...................................................................75
11. REFERENCES.......................................................................................................76
12. APPENDICES........................................................................................................79
12.1.
Appendix 1: Abbreviations and Trademarks................................................79
12.2.
Appendix 2: Study Governance Considerations..........................................82
12.3.
Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................86
12.4.
Appendix 4: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................89
12.5.
Appendix 5: COPD Exacerbation Identification, Categorization and 
Treatment Guidelines..................................................................................93
12.5.1.
Guidelines for Identifying COPD Exacerbations...........................93
12.5.2.
COPD Exacerbation Severity.......................................................94
12.5.3.
Treatment of COPD Exacerbations..............................................94
12.5.4.
Guidelines for Treatment with Corticosteroids..............................94
12.5.5.
Guidelines for Treatment with Antibiotics .....................................95
12.5.6.
Onset and Resolution of COPD Exacerbations............................95
12.5.7.
Guideline for assessing multiple mild exacerbations ....................95
12.5.8.
Guideline for assessing exacerbations that increase in 
severity ........................................................................................95
12.6.
Appendix 6: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................96
12.7.
Appendix 7: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .....................................102
12.8.
Appendix 8: Clinical Laboratory Tests.......................................................104
12.9.
Appendix 9: Genetics................................................................................106
12.10. Appendix 10: Country-specific requirements.............................................107
12.11. Appendix 11: Protocol Amendment History...............................................108
 
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1.
SYNOPSIS
Protocol Title: A Phase IV, 12-week, randomised, double-blind, triple dummy study to 
compare single inhaler triple therapy, fluticasone furoate/umeclidinium/vilanterol 
(FF/UMEC/VI) with multiple inhaler therapy (budesonide/formoterol plus tiotropium) 
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 multiple inhaler therapy (budesonide/formoterol plus tiotropium) 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 
inhaled corticosteroids plus a long-acting β2-adrenergic receptor agonist (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 exacerbation 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 LAMA 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 of 
exacerbations which will reduce the exacerbation frequency, allow for a reduced burden 
 
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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 
Symbicort MDI (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 [E-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. 
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 a multiple inhaler 
combination therapy of Symbicort Metered Dose Inhaler (MDI) (budesonide/formoterol 
320/9 mcg) twice daily plus Spiriva HandiHaler (tiotropium 18 mcg) once daily. The 
study will inform healthcare providers that patients can be effectively and safely switched 
to FF/UMEC/VI single inhaler therapy from a multiple inhaler triple therapy regimen of 
Symbicort MDI and Spiriva Handihaler.
Objectives and Endpoints:
Objectives
Endpoints
Primary
To evaluate the effects of single
inhaler triple therapy (FF/UMEC/VI) 
compared to multiple inhaler triple 
combination therapy with 
budesonide/formoterol plus tiotropium
after 12 weeks of treatment on lung 
function
Primary
Weighted mean change from baseline in 
FEV1 over 0-24 hours at Week 12
Secondary

Change from baseline in trough FEV1
on Day 2, Day 28, Day 84 and Day 
85
Weighted mean change from baseline 
in FEV1 over 0-24 hours on Day 1
 
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Objectives
Endpoints
Other

To evaluate the effects of single 
inhaler triple therapy (FF/UMEC/VI) 
compared to multiple inhaler triple 
combination therapy with 
budesonide/formoterol plus 
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 effects of single 
inhaler triple therapy (FF/UMEC/VI) 
compared to multiple inhaler triple 
combination therapy with 
budesonide/formoterol plus 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 effects of single 
inhaler triple therapy (FF/UMEC/VI) 
compared to multiple inhaler triple 
combination therapy with 
budesonide/formoterol plus tiotropium
after 12 weeks of treatment on COPD 
exacerbations
Moderate or severe exacerbation event
Assess how inspiratory airflow 
limitation affects ability to use the 
ELLIPTA
Peak Inspiratory Flow Rate (PIFR) at 
Screening (Week -4)
Safety
To evaluate the safety profile of single 
inhaler triple therapy (FF/UMEC/VI) 
compared to multiple inhaler triple 
combination therapy with 
budesonide/formoterol plus tiotropium
over 12 weeks of treatment
Incidence of adverse events

Vital signs
Overall Design:
This is a Phase IV, 12-week, randomised, double-blind, triple-dummy, parallel group, 
multicentre study evaluating single inhaler triple therapy (FF/UMEC/VI) once daily via 
the ELLIPTA, compared to multiple inhaler triple combination therapy budesonide/ 
formoterol MDI (320/9 mcg) twice daily plus once daily tiotropium (18 mcg), in 
participants with COPD. 
 
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Study design schema
Eligible participants at Screening (V1) will be current or former smokers, with an 
established clinical history of COPD, receiving daily maintenance COPD therapy for at 
least 3 months, with a post-bronchodilator FEV1 of <50% predicted (or <80% predicted 
with a documented history of at least 2 moderate or 1 severe [hospitalised] exacerbation 
in the last 12 months) and a CAT score of ≥10 at Visit 1 and at Visit 2. 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) COPD medication(s) during the pre-screening 
period, except for medications that are prohibited within a specified time 
interval prior to Visit 1.

Screening/run-in: Eligible participants will be allowed to continue their usual 
COPD medications until the day before Screening, Visit 1.  On the morning of 
the Screening Visit participants will refrain from taking their morning dose of 
their usual COPD medications. Participants who meet all of the eligibility 
criteria at Visit 1, will enter the 4-week run-in period during which they will 
discontinue all existing COPD medications and receive their run-in treatment:
budesonide/formoterol (320/9 mcg) twice daily plus tiotropium (18 mcg) once 
daily plus placebo via the ELLIPTA. Participants will not use any other COPD 
medications (except for those allowed per protocol). 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, MDI and HandiHaler and will 
 
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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 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 will discontinue their run-in treatments and will be 
randomised in 1:1 ratio to receive one the following double-blind study 
treatments for 84 days:
Either:
FF/UMEC/VI 100/62.5/25 mcg via the ELLIPTA once daily in the morning
+ placebo to match budesonide/formoterol via MDI, two inhalations twice daily 
+  placebo to match tiotropium via HandiHaler once daily in the morning
or,
Budesonide/formoterol 320/9 mcg via MDI, twice daily*
+ tiotropium 18mcg via HandiHaler once daily in the morning
+ placebo via the ELLIPTA once daily in the morning
*Participants are required to take two inhalations of budesonide/formoterol 
160/4.5 mcg, via the MDI in the morning and two inhalations in the evening. 
The total dose is therefore 320/9 mcg twice daily. 
At Visit 2 participants will refrain from taking their morning doses of run-in 
study medication and will self-administer study treatment at the clinic, when 
instructed to do so. Participants will remain at the clinic for at least 24 hours, for 
serial spirometry assessments. 
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 3, and 4 participants will self-administer study treatment whilst at the 
clinic. Participants will take their last doses of study treatment in the clinic on 
Day 84 (Visit 4, when instructed to do so by clinic personnel), and continue to 
remain at the clinic until at least 24 hours after their last morning dose, for their 
clinical assessments, which include serial spirometry assessments. On non-clinic 
visit days participants are expected to take their study treatment at home each 
day in the morning and in the evening at approximately the same time, as 
directed by the clinic. 

Safety/follow-up: A safety follow-up telephone contact or clinic visit (Visit 5) 
will be conducted approximately 7 days after the participant completes all of the 
 
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protocol-defined procedures for Visit 4/End of Study (EOS) or, if applicable, the 
Study Treatment Discontinuation Visit. 
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 800 participants with advanced COPD will enter the run-in period, in 
order to randomise approximately 732 participants, in order to achieve an estimated 620
evaluable participants in modified per-protocol (mPP) population at Week 12, assuming 
10 % premature discontinuation of study treatment and 5% protocol deviation.
Approximately 80 centres globally will be required to recruit participants in 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 
budesonide/formoterol (320/9 mcg) twice daily plus tiotropium (18 mcg) 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, triple-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 budesonide/formoterol via MDI, two inhalations twice daily 
+  placebo to match tiotropium via HandiHaler once daily in the morning
or,

Budesonide/formoterol 160/4.5 mcg via MDI, two inhalations twice daily*
+ tiotropium 18mcg via HandiHaler once daily in the morning
+ placebo via the ELLIPTA once daily in the morning
*Participants are required to take two inhalations of budesonide/formoterol 160/4.5 mcg, 
via the MDI in the morning and two inhalations in the evening. The total dose is therefore 
320/9 mcg twice daily. 
 
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Dosing schedule for run-in and treatment periods
ELLIPTA
(1 inhalation)
MDI
(2 puffs)
HandiHaler
(1 capsule inhaled 
twice)
Active
Placebo
Active
Placebo
Active
Placebo
Run-in
am
Y
Y
Y
pm
Y
Treatment
FF/UMEC/VI group
am
Y
Y
Y
pm
Y
Budesonide/formoterol 
+ tiotropium group
am
Y
Y
Y
pm
Y
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.
Symbicort MDI contains 120 doses: budesonide/formoterol 160/4.5 mcg, two inhalations 
twice daily.
Tiotropium: 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.
Key Elements of Analysis Plan:
The null hypothesis is that the difference in 0-24 hour Weighted Mean (WM) FEV1
between treatment groups is less than or equal to a pre-specified non-inferiority margin 
Δ:
H0: T1 – T2 ≤ -Δ
The alternative hypothesis is that the difference between treatment groups is greater than 
the margin.
H1: T1 – T2 > -Δ
where T1 and T2 are the treatment means for FF/UMEC/VI and budesonide/formoterol + 
tiotropium (BUD/FOR+TIO), respectively.
The non-inferiority margin has been set at 50 mL.
 
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The primary analysis population will be the modified per-protocol (mPP) population, 
comprising all participants randomised to treatment except those randomised in error, 
who do not have a full protocol deviation or other event considered to impact efficacy.
The primary analysis will be performed for mPP population using on-treatment data. The 
primary analysis will evaluate the endpoint of 0-24 hour WM FEV1 on Day 84 using a 
mixed model repeated measure (MMRM) analysis, including covariates 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.  Baseline 
FEV1 is the mean of the two assessments made -30 and -5 minutes pre-dose on Treatment 
Day 1.
Estimated differences between FF/UMEC/VI and BUD/FOR+TIO will be presented 
together with 95% confidence intervals (CIs) for the treatment difference and p-value.
Inference to be drawn from the p-values will be as follows:

Analysis with mPP population: If the treatment comparison on the primary 
endpoint has a lower confidence limit below the non-inferiority margin, non-
inferiority is not demonstrated. No inference will be drawn from p-values for 
treatment comparisons on any other endpoints.

Analysis with mPP population: If the treatment comparison on the primary 
endpoint has a lower confidence limit above the non-inferiority margin but below 
0, non-inferiority is established but the p-value will not be used to give an 
indication of the strength of that non-inferiority.  Inference will be drawn from p-
values for treatment comparisons (with Intent-To-Treat [ITT] population) on 
other non-lung function endpoints, ie, SGRQ and CAT which will be called 
statistically significant if <0.05. No inference will be drawn from p-values on 
trough FEV1 endpoint. 

Analysis with ITT population: If the treatment comparison on the primary 
endpoint has a lower confidence limit above 0, superiority is established and the 
p-value can be used to give an indication of the strength of that superiority. 
Inference will be drawn from p-values for treatment comparisons on all other 
endpoints, which will be called statistically significant if <0.05.
A “tipping point” sensitivity analysis of 0-24 hour WM FEV1 on Day 84 will be 
conducted for the mPP Population. This will explore the impact of missing data by using 
differing assumptions regarding the mean treatment effect in participants who discontinue 
study treatment or have data excluded from mPP Population analyses. Assumptions will 
include scenarios where participants who discontinue FF/UMEC/VI have a lower 
treatment effect than those who discontinue BUD/FOR+TIO. The analysis results will be 
used to explore the conditions under which the conclusion of non-inferiority no longer 
holds.
 
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If superiority on primary endpoint is established with ITT population, similar “tipping 
point” sensitivity analysis will be conducted for the ITT population in order to explore 
the conditions under which the conclusion of superiority no longer holds.
The details of the statistical analysis methods for the secondary efficacy endpoints will be 
provided in the Reporting and Analysis Plan (RAP).
 
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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
Study Treatment 
Discontinuation 
Visit
Visit 5 
Safety
Follow-up 
Contact
Study Day
-56 to  -
28
Day -28
Day 1
Day 28
Day 
84-85
Day 91
Week
-8 to -4
-4
0
4
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 & status
X
X
X
Smoking Cessation 
Counselling
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 and 
PIFR e
X
Trough FEV1 f
X
24h serial spirometry g
X
X
Inhalation device training
X
X
Exacerbation Assessment
X
X
X
X
X
X
Physical examination h
X
X
X
Adverse Events Assessment
X
X
X
X
X
X
Vital signs i
X
X
X
ECG
X
Chest X-ray j
X
Oropharyngeal examination
X
X
X
X
X
Blood Draw for Genetics 
research k
X
Hematology/biochemistry l
X
Urine Pregnancy Test m
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 n
X
 
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Protocol Activity
Pre-
Screen
Screen
Treatment
Follow-up
Visit 0
Visit 1 
Screen/ 
Run-in
Visit 2
Randomisation Visit 3 Visit 4
Study Treatment 
Discontinuation 
Visit
Visit 5 
Safety
Follow-up 
Contact
Study Day
-56 to  -
28
Day -28
Day 1
Day 28
Day 
84-85
Day 91
Week
-8 to -4
-4
0
4
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)
Administer study treatment in 
clinic o
X
X
X
Assess run-in treatment 
compliance
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
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 IC and must be obtained prior to 
obtaining a genetic blood sample. Participants do not have to participate in the genetic research part of this study, 
it is optional.
c.
Demography may be captured at either the Pre-screen Visit or Screening Visit (for participants who do not have a 
Pre-screen Visit).
d.
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 PIFR spirometry and both pre and post-bronchodilator spirometry will be conducted. PIFR will 
be assessed 10 minutes prior to pre-bronchodilator spirometry. Participants are required to withhold their usual 
morning doses of their COPD meds including rescue albuterol/salbutamol for the protocol designated period prior 
to PIFR spirometry and reversibility testing.
f.
Trough FEV1 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. 
g.
Serial spirometry at Visit 2 and Visit 4 will be done pre-dose at 30 mins and 5 mins and post dose at 5 mins, 15 
mins, 30mins,1hr, 3hrs, 6hrs, 12hrs, 15hrs, 21hrs, 23hrs, 24hrs. Participants that discontinue study treatment but 
remain in the study will complete serial spirometry at Week 12, if they consent to do so.
h.
Physical examination may include height, weight, blood pressure and temperature.
i.
Vital signs, including blood pressure and pulse must be performed prior to spirometry and prior to taking morning 
dose of study treatment.
j.
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.
k.
Genetic consent must be obtained prior to obtaining a blood sample. The sample can be collected at any time 
after Visit 2, providing consent is obtained.
l.
Hematology and chemistry panels will include full and differential blood count and liver chemistry.
m.
All female participants of child bearing potential will have a urine pregnancy test at Visits 1, 4 and Study 
Treatment Discontinuation Visit (if applicable).
 
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n.
Participants must withhold their morning dose of existing COPD medication or study treatment and not take their 
run-in treatment until instructed to do so by study staff.
o.
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.
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 inhaled 
corticosteroids (ICS) plus a long-acting β2-adrenergic receptor agonist (LABA) as second 
line therapy for the most advanced patients with significant symptoms and a high risk of 
exacerbations. Regular treatment with Inhaled Coricosteroid (ICS) containing regimens 
has been reported to improve respiratory symptoms, lung function, health related quality 
of life (HRQoL) and reduce the frequency of COPD exacerbation 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 
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 LAMA 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 of 
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. 
 
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GSK conducted a Phase III study comparing once-daily FF/UMEC/VI to twice-daily 
Symbiocort MDI) (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 [E-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. 
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 a multiple inhaler 
combination therapy of Symbicort Metered Dose Inhaler (MDI) (budesonide/formoterol 
320/9 mcg) twice daily plus Spiriva HandiHaler (tiotropium 18 mcg) once daily. The 
study will inform healthcare providers that patients can be switched to FF/UMEC/VI 
single inhaler therapy from a multiple inhaler triple therapy regimen of Symbicort MDI 
and Spiriva Handihaler.
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 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 grades from the 
ABCD assessment tool (Table 1) [GOLD, 2017]. 
 
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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 hospitalization, 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 guidelines 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 [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.
 
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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 budesonide/formoterol and 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 assessment and mitigation strategy 
for this protocol.  
 
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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) [Lipson, 2017] 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 adverse event 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 FF/VI 
(<1-2 % with FF/VI 100/25) and less than that 
observed in 52 week exacerbation studies with 
FF/VI (6 % with FF/VI 100/25) [Dransfield, 2013].  
Similarly, the incidence of pneumonia with 
- 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  
- 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 
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
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 the 
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.
The Pharmacovigilance Risk Assessment 
Committee (PRAC) recently conducted an Article 
31 review to evaluate the risk of pneumonia with 
use of ICSs in patients with COPD. The PRAC 
review confirmed that COPD patients treated 
with inhaled corticosteroids are at increased risk 
of pneumonia; however the Committee’s view 
was that the benefits of ICSs continue to 
outweigh their risks. The PRAC also looked 
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. 
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
whether there were any differences in the risk of 
pneumonia between these products, 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 fractures 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 
the fractures in both treatment groups were 
traumatic in nature.
- 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.
Adrenal suppression
Oral corticosteroids are known to have an effect 
on the hypothalamic-pituitary-adrenal (HPA) axis 
leading to a reduction in cortisol production. Due 
to the low dose and low systemic exposure with 
inhaled corticosteroids, this potential effect is not 
- Investigators are informed of the risk in the IB.
- Instream review of blinded AE/SAE reports.
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
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 
program, 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/VI100/25 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 this risk of 
adrenal suppression. The systemic exposure of 
FF is very low compared to that of oral 
corticosteroids, so any concurrent effect will be 
negligible.
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. 
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
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 ICS 
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 assessments in a study with 
FF/VI, FF and FP in participants with asthma.
- Participants will be informed about the risk in 
the informed consent.
- Investigators are informed of the risk in the IB.
- Appropriate exclusion criteria as specified in 
Section 6.2 of the protocol
- Instream review of blinded AE/SAE reports.
- If a risk is suspected, participants should 
receive appropriate treatment
Serious cardiovascular events
Cardiovasular (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 
- 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 
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
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, cardiovascular 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 
(4.3 % and 5.2 % respectively) and the EXT 
Population up to 52 weeks (8.6 % and 10 % 
respectively).  Within subgroups of 
cardiovascular 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). 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 
Section 6.2 of the protocol, including 
- Electrocardiogram (ECG) inclusion criteria
- Vital sign assessments (heart rate and blood 
pressure) as per protocol.
- Protocol defined stopping criteria as per 
Section 8.1.1.
- Instream review of blinded AE/SAE reports.
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
cardiovascular 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 up 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 
cardiovascular effects AESI was low in the study, 
despite the study enrolling participants with a 
number of CV comorbidities 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 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 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 
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
Population up to 24 weeks and EXT Population 
up to 52 weeks.
In study CTT116853 [Lipson, 2017], 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 cardiovascular safety profile of FF/UMEC/VI 
was generally consistent with that of FF/VI and 
UMEC/VI. 
Hypersensitivity
Hypersensitivity reactions are unlikely to 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 FF/UMEC/VI and 
BUD/FOR arms). On treatment hypersensitivity 
- Participants will be informed about the risk in 
the informed consent. Particpants 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.
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
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. 
Narrow angle glaucoma
Rare reports of angle closure glaucoma (which 
may lead into blindness) have been associated 
with nebulised ipratropium bromide and 
salbutamol [Packe, 1984].
The incidence of narrow angle glaucoma in the 
COPD population associated with the use of 
inhaled bronchodilators (including LAMAs and 
LABAs) is relatively low. 
In CTT116853, in the ITT Population up to 24 
weeks, events in the glaucoma SMQ were 
reported at an incidence of 0.1 and 0.4 % in the 
FF/UMEC/VI and BUD/FOR arms respectively. 
In the EXT Population up to 52 weeks, no events 
- 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.
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
were reported in either treatment arm.
In the UMEC/VI development program, there 
was one report (<1 %) of angle closure glaucoma 
(UMEC/VI 62.5/25 mcg).
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 retention AESI 
group in either treatment arm in the ITT 
Population up to 24 weeks and 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.
- Appropriate exclusion criteria as specified in
Section 6.2 of the protocol
- Instream review of blinded AE/SAE reports.
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 CTT116853, the risk of paradoxical 
bronchospasm was evaluated through the AESI 
of asthma/bronchospasm. In the ITT Population 
- 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.
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
up to 24 weeks, one participant reported an 
event in the asthma/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.
 
 
 
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3.3.2.
Risk assessment for Symbicort MDI (Budesonide/ Formoterol) 
160/4.5 mcg
Symbicort is a marketed drug that contains both budesonide (ICS; 160 mcg) and 
formoterol (LABA; 4.5 mcg). Two inhalations from the MDI provide the required 
320/9 mcg dose. The dose (320/9 mcg) and formulation, using an MDI, are approved for 
COPD in the US, the dose and formulation are not approved in Europe. A similar profile 
of undesirable effects as reported for ICSs and LABAs may occur with budesonide and 
formoterol respectively. No increased incidence of adverse reactions has been seen 
following concurrent administration of the two compounds. The most common drug-
related adverse reactions are pharmacologically predictable side-effects of β2
adrenoceptor agonist therapy, such as tremor and palpitations. These tend to be mild and 
usually disappear within a few days of treatment. Please refer to the authorised product 
label for further information about the risks of using Symbicort. In this study, Symbicort 
will be used in line with the recommendations provided in the product label.
Since Symbicort contains an ICS and LABA, the risk mitigation strategies for the FF 
(ICS) and VI (LABA) components of GSK2834425 will be applicable for Symbicort.
3.3.3.
Risk Assessment for Spiriva Handihaler (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, Spiriva Handihaler will be used in line with the recommendations provided in the 
product label. 
Spiriva Handihaler is an anticholinergic, therefore the risk mitigation strategy for UMEC 
component of GSK2834425 will be applicable for Spiriva Handilaler.  
 
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3.3.4.
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 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.
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 bronchodilator treatment of airflow 
obstruction in patients 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-bronchodilator) with an 
exacerbation history despite regular bronchodilator therapy.  The UMEC/VI combination 
is approved as a maintenance bronchodilator to relieve symptoms in adult patients with 
COPD. UMEC is approved as a maintenance bronchodilator treatment to relieve 
symptoms in adult patients 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 patients with moderate to severe COPD supports the further 
development of the closed triple combination.
Tiotropium (18 mcg) and budesonide/formoterol (400/12 mcg) are marketed drugs for the 
COPD indication, and have established benefit:risk profiles.  Tiotropium and 
budesonide/formoterol will be used in line with the recommendations provided in the 
product labels.
3.3.5.
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, tiotropium and 
budesonide/formoterol are justified by the anticipated benefits from active treatments that 
may be afforded to patients with COPD.
 
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4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
To evaluate the effects of single inhaler 
triple therapy (FF/UMEC/VI) compared 
to multiple inhaler triple combination 
therapy with budesonide/formoterol plus 
tiotropium after 12 weeks of treatment 
on lung function
Primary
Weighted mean change from baseline in 
FEV1 over 0-24 hours at Week 12
Secondary

Change from baseline in trough FEV1
on Day 2, Day 28, Day 84 and Day 85

Weighted mean change from baseline 
in FEV1 over 0-24 hours on Day 1
Other
To evaluate the effects of single inhaler 
triple therapy (FF/UMEC/VI) compared 
to multiple inhaler triple combination 
therapy with budesonide/formoterol plus 
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 effects of single inhaler 
triple therapy (FF/UMEC/VI) compared 
to multiple inhaler triple combination 
therapy with budesonide/formoterol plus 
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 effects of single inhaler 
triple therapy (FF/UMEC/VI) compared 
to multiple inhaler triple combination 
therapy with budesonide/formoterol plus 
tiotropium after 12 weeks of treatment 
on COPD exacerbations
Moderate or severe exacerbation event
Assess how inspiratory airflow 
limitation affects ability to use the 
ELLIPTA
Peak Inspiratory Flow Rate at Screening 
(Week -4)
 
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Objectives
Endpoints
Safety
To evaluate the safety profile of single 
inhaler triple therapy (FF/UMEC/VI) 
compared to multiple inhaler triple 
combination therapy with 
budesonide/formoterol plus tiotropium 
over 84 days of treatment
Incidence of adverse events
Vital signs
5.
STUDY DESIGN
5.1.
Overall Design
This is a Phase IV, 12-week, randomised, double-blind, triple dummy, parallel group, 
multicentre study evaluating single inhaler triple therapy (FF/UMEC/VI) once daily via 
the ELLIPTA, compared to multiple inhaler triple combination therapy 
budesonide/formoterol (320/9 mcg) twice daily plus once daily tiotropium (18 mcg), in 
participants with COPD. 
Figure 1
Study design schema
Eligible participants at Screening (V1) will be current or former smokers, with an 
established clinical history of COPD, receiving daily maintenance COPD therapy for at 
least 3 months, with a post-bronchodilator FEV1 of <50 % predicted (or <80 % predicted 
with a documented history of at least 2 moderate or 1 severe [hospitalised] exacerbation 
in the last 12 months) and a CAT score of ≥10 and Visit 1 and at Visit 2. 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. 
 
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
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) COPD medication(s) during the pre-screening 
period; however, medications that are prohibited within a specified time interval 
prior to Visit 1 are defined in Section 7.7.

Screening/run-in: Eligible participants will be allowed to continue their usual 
COPD medications until the day before Screening, Visit 1.  On the morning of 
the Screening Visit participants will refrain from taking their morning dose of 
their usual COPD medications. Participants who meet all of the eligibility 
criteria at Visit 1, will enter the 4-week run-in period during which they will 
discontinue all existing COPD medications and receive their run-in treatment:
budesonide/formoterol (320/9 mcg) twice daily plus tiotropium (18 mcg) once 
daily plus placebo via the ELLIPTA. Participants will not use any other COPD 
medications (except for those allowed per protocol). 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, MDI 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 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:
Either:
FF/UMEC/VI 100/62.5/25 mcg via the ELLIPTA once daily in the morning
+ placebo to match budesonide/formoterol via MDI, two inhalations twice daily 
+  placebo to match tiotropium via HandiHaler once daily in the morning
or,
Budesonide/formoterol 160/4.5 mcg via MDI, two inhalations twice daily*
+ tiotropium 18 mcg via HandiHaler once daily in the morning
+ placebo via the ELLIPTA once daily in the morning
 
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*Participants are required to take two inhalations of budesonide/formoterol 
160/4.5 mcg, via the MDI in the morning and two inhalations in the evening. 
The total dose is therefore 320/9 mcg twice daily. 
At Visit 2 participants will refrain from taking their morning doses of run-in 
study medication and will self-administer study treatment at the clinic, when 
instructed to do so. Participants will remain at the clinic for at least 24 hours, for 
serial spirometry assessments. 

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. 
Participants will remain at the clinic for at least 24 hours, for serial spirometry 
assessments. At Visits 3 and 4 participants will self-administer study treatment 
whilst at the clinic. Participants will take their last doses of study treatment in 
the clinic on Day 84 (Visit 4, when instructed to do so by clinic personnel), and 
continue to remain at the clinic until at least 24 hours after their last morning 
dose, for their clinical assessments, which include serial spirometry 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, and at the same 
time each evening, as directed by the clinic. 

Safety/follow-up: A safety follow-up telephone contact or clinic visit (Visit 5) 
will be conducted approximately 7 days after the participant completes all of the 
protocol-defined procedures for Visit 4/End of Study (EOS) or, if applicable, the 
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 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 (see Section 8.1). 
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.
5.2.
Number of Participants
Approximately 800 participants with advanced COPD will enter the run-in period, in 
order to randomise approximately 732 participants in order to achieve an estimated 620 
evaluable participants in the modified per-protocol (mPP) population at Week 12, 
assuming 10 % premature discontinuation of study treatment and 5 % protocol deviation. 
See Section 10 for further details. 
 
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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 table (SoA) (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, triple-dummy, parallel-
group design. A placebo arm is not included because the primary comparison of interest 
is FF/UMEC/VI vs.  Budesonide/formoterol + tiotropium and it is not considered 
appropriate to include a placebo arm in a study in participants with advanced COPD. 
Eligible participants must have been on daily maintenance COPD medications for at least 
3 months. 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.
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 doses selected for the Symbicort MDI (budesonide/formoterol 320/9 mcg, twice 
daily) and Spiriva HandiHaler (tiotropium 18 mcg, once daily) is the doses 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.
 
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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 
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].
 
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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 for their COPD for at least 3 months prior to Screening.
Note: Participants taking only as-needed COPD medications 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).
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.
 
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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.
11. Unstable liver disease: ALT >2x Upper Limit of Normal (ULN); and bilirubin 
>1.5x ULN (isolated bilirubin >1.5x ULN 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 
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
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 by Fridericia’s formula (QTcF) 
≥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.
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 at screening (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.
 
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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: Use of the following medications within the 
following 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
Long term antibiotic therapy
Participants receiving antibiotics for long term therapy (30 
days) 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)
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. 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 any of the three 
inhalers (ELLIPTA, Handihaler or MDI) will be excluded.
 
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2. COPD exacerbation or pneumonia

Participants that experience a moderate or a severe COPD exacerbation or 
pneumonia during the run-in period will be excluded. 
3. Changes in COPD medication

Any participant that requires any change in COPD medication 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; serious adverse event (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/randomization 
failure details, eligibility criteria, and any SAEs. Further details are provided in the study-
specific eCRF completion guidelines.
For the purposes of this study, pre-screening failures, screening failures and run-in 
failures will be defined as follows:
Pre-screening failures: those participants that sign the informed consent document but 
do not have a Visit 1 (Screening) procedure.
Screening failures: those participants that complete at least 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 are not randomised 
(except those randomised in error).
 
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7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.
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 
budesonide/formoterol (320/9 mcg) twice daily plus tiotropium (18 mcg) once daily plus 
placebo via the ELLIPTA. Following the run-in period, participants who meet the 
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 budesonide/formoterol via MDI, two inhalations twice daily 
+  placebo to match tiotropium via HandiHaler once daily in the morning
or,
Budesonide/formoterol 160/4.5 mcg via MDI, two inhalations twice daily*
+ tiotropium 18 mcg via HandiHaler once daily in the morning
+ placebo via the ELLIPTA once daily in the morning
*Participants are required to take two inhalations of budesonide/formoterol 160/4.5 mcg, 
via the MDI in the morning and two inhalations in the evening. The total dose is therefore 
320/9 mcg twice daily.
 
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Table 2
Dosing schedule for run-in and treatment periods
ELLIPTA
(1 inhalation)
MDI
(2 puffs)
HandiHaler
(1 capsule inhaled 
twice)
Active
Placebo
Active
Placebo
Active
Placebo
Run-in
am
Y
Y
Y
pm
Y
Treatment
Active FF/UMEC/VI
am
Y
Y
Y
pm
Y
Active 
budesonide/formoterol 
+ tiotropium
am
Y
Y
Y
pm
Y
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.
Symbicort MDI contains 120 doses: budesonide/formoterol 160mcg/4.5 mcg, two 
inhalations twice daily.
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, MDI and the 
Handihaler are provided in Table 3, Table 4, and Table 5, respectively.
 
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Table 3
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 
100mcg per blister
25 mcg per blister GW642444, 62.5 
mcg per blister GSK573719
Physical 
description 
Dry white powder
Dry white powder
Route of 
Administration 
Inhaled
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
NA
Physical 
description
Dry white powder
Dry white powder
Route of 
Administration
Inhaled
Table 4
Description of Symbicort MDI
Symbicort 160mcg/4.5 mcg
MDI
Dosage form
MDI with 120 doses
Unit dose strength
Budesonide/ Formoterol 160mcg/4.5mcg
Physical description 
Suspension for inhalation
Route of administraton
Inhaled
Placebo to match Symbicort
Placebo to match MDI
Dosage form
MDI with 120 doses
Unit dose strength
NA
Physical description
Suspension for inhalation
Route of administration
Inhaled
 
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Table 5
Description of Tiotropium bromide in HandiHaler
Spiriva 18 mcg
HandiHaler
Dosage form
Capsule
Unit dose strength
18mcg
Physical description 
Hard gelatin capsule containing 18mcg 
tiotropium bromide blended with lactose
Route of administration
Inhaled
Placebo to match Spiriva
HandiHaler
Dosage form
Capsule
Unit dose strength
NA
Physical description 
Hard gelatin capsule containing lactose
Route of administration
Inhaled
7.1.1.
Medical Devices

The GSK ELLIPTA medical device will be provided for use in this study.

Other medical devices (not manufactured by or for GSK provided for use in this 
study) are the Handihaler and MDI.

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 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. 
 
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
The Investigator or treating physician may unblind a participant’s treatment 
assignment only in the case of an emergency OR in the event of a serious 
medical condition when knowledge of the study treatment is essential for the 
appropriate clinical management or welfare of the participant as judged by the 
Investigator. 

Investigators have direct access to the participant’s individual study treatment. 

It is preferred (but not required) that the Investigator first contacts the Medical 
Monitor or appropriate GSK study personnel to discuss options before unblinding 
the participant’s treatment assignment. 

If GSK personnel are not contacted before the unblinding, the Investigator must 
notify GSK within 24 hours after unblinding, but without revealing the treatment 
assignment of the unblinded participant, unless that information is important for 
the safety of participants currently in the study. 

The date and event or condition which led to the unblinding (i.e. the primary 
reason) will be recorded in source documentation and in the eCRF. 
Should a participant’s treatment assignment be unblinded then the participant may 
continue the assigned study treatment and be followed-up as per protocol until the 
completion of the Safety Follow-up assessments.
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any participant with an SAE. If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of the 
report, identifying the participant’s treatment assignment, may be sent to Investigators in 
accordance with local regulations and/or GSK policy. Participants will not be withdrawn 
from the study.
Masking of tiotropium and placebo to tiotropium capsules
This study will use a triple-dummy design for dosing, whereby participants will be given 
three inhalers (ELLIPTA, MDI 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.  
 
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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.
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 MDI, 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. 
 
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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 randomization 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 5). 
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 the randomised 
treatment periods: 

Study supplied albuterol/salbutamol 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)

Study provided COPD medications in the run-in and the randomised treatment period 
The following COPD medications are permitted during the randomised treatment
period: 

Oral or injectable corticosteroids (short course ≤14 days) only for the short term 
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
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 randomised 
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)

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 ECG changes and/or 
hypokalemia)

Use of positive airway pressure for sleep apnea
 
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
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 6 is not permitted during the study.
 
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Table 6
Concomitant Medications
Medication Prohibited during the randomised treatment period
Inhaled short-acting anticholinergics
Inhaled short-acting beta2 agonists1 
Inhaled short-acting anticholinergic/short-acting beta2-agonist combination products
Inhaled corticosteroids (ICS)
Inhaled corticosteroids (ICS)/Inhaled long-acting beta2-agonist (LABA) combinations 
(eg.fluticasone/salmeterol, mometasone furoate/formoterol fumarate, budesonide/formoterol fumarate; 
fluticasone furoate/vilanterol
Phosphodiesterase 4 (PDE4) inhibitors (roflumilast)
LABA (e.g., indacaterol, olodaterol, salmeterol etc.)
Other LAMAs (aclidinium, glycopyrronium, umeclidinium etc.)
LAMA/LABA combinations
Theophyllines
Sodium cromoglycate and nedocromil sodium
Anti-leukotrienes
Long term antibiotic therapy2
Systemic, oral, parenteral corticosteroids3
Any other investigational drug
1.
(rescue 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 
 
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increase the risk of overdose. If neccessary the Investigator or other health care 
personnel may stop the participant’s study treatment temporarily (≤ 14 days) in order to 
treat the COPD exacerbation.  Participants who require more than two consecutive 14 
day courses of treatment (i.e. antibiotics or corticosteroids) should be evaluated for their 
continuation on study treatment by the Investigator in consultation with the GSK medical 
monitor.
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
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 4), 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 4 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 5 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 4, 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 5) should also be conducted 7 days after Visit 4. 
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
 
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
COPD exacerbations 

Concomitant medication 

Serial spirometry (Visit 4 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. 
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.
8.1.1.
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, participants are however encouraged to remain in the 
study and complete limited assessments, as detailed in Section 8.1: 

Liver chemistry stopping and increased monitoring criteria have been designed 
to assure participant safety and evaluate liver event etiology (in alignment with the 
Food and Drug Administration (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. 
 
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
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:

QTc>500 msec or uncorrected QT>600 msec

Change from baseline: QTc>60 msec

For participants with underlying bundle branch block, follow the 
discontinuation criteria listed below:

Baseline QTc with Bundle Branch Block <450 msec, Discontinuation 
QTc with Bundle Branch Block >500 msec

Baseline QTc with Bundle Branch Block <450-480  msec, 
Discontinuation QTc with Bundle Branch Block ≥530 msec
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.
8.1.2.
Rechallenge
8.1.2.1.
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 SOA (Section 2).
Participants that have previously discontinued study treatment (and have already 
completed the Study Treatment Discontinuation Visit) but 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 5) can be 
conducted at the time the participant notifies the site of their intention to withdraw from 
 
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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:

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 Participants 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
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. Sites are required to have study treatment dose, dispensed and accounted for by 
site personnel that are not involved in any efficacy or safety assessments. See Section 7.4
for further details.   

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 
 
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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):

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)

12-lead ECG

Pulse rate, blood pressure measurements 

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
 
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
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  
(including PIFR) and each scheduled clinic visit during the treatment period. For FEV1,
FVC and PIFR determinations, at least 3 acceptable spirometry efforts (with no more 
than 8) should be obtained.  Acceptable spirometry efforts should have a satisfactory start 
of test and end of test (e.g. a plateau in the volume-time curve) and be free from artifacts 
due to cough, early termination, poor effort, obstructed mouthpiece, equipment 
malfunction, or other reasons [Miller, 2005].
The largest FEV1 and FVC from the 3 acceptable efforts should be recorded, even if they 
do not come from the same effort.
Spirometry must be performed as follows:

Started approximately between 6:00AM and 11:00AM.

If applicable, after completing the health outcomes assessments (SGRQ-C should be 
administered first followed by CAT) 

After withholding albuterol/salbutamol for 4 hours. 

At Screening (Visit 1), before the morning dose of run-in 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.
24-hour Serial Spirometry
24-hour serial spirometry will be performed by all participants at Randomization (Visit 2) 
and Day 84 (Visit 4). In addition, trough FEV1 data will be collected pre-dose on Day 28 
(Visit 3).
Serial spirometry measurements should be taken as close to the following scheduled 
timepoints as possible:
 
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Pre-dose: 30 mins and 5 mins
Post-dose: 5 mins, 15 mins, 30 mins, 1 hr, 3 hrs, 6 hrs, 12 hrs, 15 hrs, 21 hrs, 23 hrs and 
24 hrs
9.1.1.2.
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.
9.1.1.3.
Peak Inspiratory Flow Rate (PIFR)
PIFR will be completed at Screening (Visit 1) only, approximately 10 minutes prior to 
the start of reversibility testing. Three acceptable spirometry efforts will be obtained. 
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).
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 
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).
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.
 
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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 5.
Participants will complete a paper Medical Problems worksheet to record medical 
problems experienced during the study. This paper worksheet must be reviewed by the 
Investigator (or designee) at each visit to the study site to assist in the identification of 
new COPD exacerbations.  
All COPD exacerbations will be recorded in the exacerbation eCRF. 
Every effort should be made to conduct a chest x-ray within 48 hours of identification of 
a moderate or severe exacerbation. 
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). 
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 5.

All AEs will be collected from the start of Study Screening (Visit 1) 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 
 
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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.
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.
 
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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 Medicinal 
Dictionary for Regulatory Activities (MedDRA) terms. The CV information should be 
recorded in the specific cardiovascular section of the CRF within one week of receipt of a 
CV Event data query prompting its completion. 
The Death 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. 
COPD exacerbations should not be recorded as an adverse event, unless they meet the 
definition of an SAE (Appendix 6).
9.2.7.
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 <25 kg/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 
 
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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 

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 2 weeks 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. 
 
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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.

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. If the eCRF is unavailable, then a paper version should be 
utilized.

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.
 
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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).
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 and 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 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 
 
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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 (Section 2) 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 
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 (Section 2).
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.
 
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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.
10.
STATISTICAL CONSIDERATIONS
10.1.
Hypotheses
The primary objective of this study is to compare FF/UMEC/VI with 
budesonide/formoterol + tiotropium (BUD/FOR+TIO) in COPD participants. The 
primary endpoint is 0- 24 hour weighted mean (WM) FEV1 at Week 12 (Day 84). The 
primary analysis is the comparison of this endpoint for FF/UMEC/VI vs. BUD/FOR+TIO 
with mPP population.  The null hypothesis is that the difference in 0-24 hour WM FEV1
between treatment groups is less than or equal to a pre-specified non-inferiority margin 
Δ:
H0: T1 – T2 ≤ -Δ
The alternative hypothesis is that the difference between treatment groups is greater than 
the margin.
H1: T1 – T2 > -Δ
where T1 and T2 are the treatment means for FF/UMEC/VI and BUD/FOR+TIO, 
respectively.
The non-inferiority margin has been set at 50 mL.This non-inferiority margin for 0-24 
hour WM FEV1 has previously been accepted by the FDA (Combivent vs Ipratropium 
head to head study).
If the lower bound of the two-sided 9 5% confidence interval around the (FF/UMEC/VI 
vs. BUD/FOR+TIO,) treatment difference is above -50 mL then FF/UMEC/VI will be 
considered non-inferior to BUD/FOR+TIO. Further treatment comparisons and 
inferences to be made based on P-values are detailed in Section 10.4.1.
10.2.
Sample Size Determination
The sample size calculations use a one-sided 2.5 % significance level and an estimate of 
residual standard deviation (SD) for 0-24 hour WM FEV1 of 230 mL. The estimate of SD 
is based on mixed models repeated measures [MMRM] analyses of past studies in COPD 
with 0-24 hour weighted mean as primary endpoint. A study with 620 evaluable 
participants for the primary analysis will have 90 % power to determine non-inferiority of 
FF/UMEC/VI to BUD/FOR+TIO based on 0-24 hour WM FEV1 at Week 12 (Day 84), 
 
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when the margin of non-inferiority is 50 mL and the true mean treatment difference is 
assumed to be 10 mL.
It is estimated that approximately 15 % of participants who are randomised will either 
discontinue IP or be excluded from the modified Per Protocol population at Week 12 and 
approximately 8 % of participants will drop out from 4-week run-in (including those not 
meeting randomisation criteria). Therefore, approximately 800 participants will be 
enrolled to 4-week run-in in order to have 732 participants to be randomised.
 
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10.3.
Populations for Analyses
For purposes of analysis, the following populations are defined:
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.
Run-in 

All participants who are eligible at Screening and entered Run-in 
period. 
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 randomszed 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.
Modified Per Protocol 
(mPP)

All participants in the ITT Population who do not have a full 
protocol deviation considered to impact efficacy.

Data following a COPD exacerbation or pneumonia will be 
excluded from analysis due to the potential impact of the 
exacerbation or the medications used to treat it.

Participants with partial protocol deviations considered to impact 
efficacy will be included in the mPP Population but will have 
their data excluded from analyses from the time of deviation 
onwards.

This population will only be used for the primary analysis for the 
primary endpoint.
 
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10.4.
Statistical Analyses
10.4.1.
Efficacy Analyses
Endpoint
Statistical Analysis Methods
Primary
The primary endpoint, 0-24 hour WM FEV1 on Day 84 will be analyzed with mPP 
population using mixed model repeated measure (MMRM) analysis, including 
covariates such as 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.   Baseline FEV1 is the mean of 
the two assessments made -30 and -5 minutes predose on Treatment Day 1.
Estimated differences between FF/UMEC/VI and BUD/FOR+TIO will be 
presented together with 95 % confidence intervals (CIs) for the treatment 
difference and P-value. The same analysis will be repeated for the ITT 
Population.
Inference to be drawn from the p-values will be as follows:

Analysis with mPP population: If the treatment comparison on the primary 
endpoint has a lower confidence limit below the non-inferiority margin, 
non-inferiority is not demonstrated. No inference will be drawn from p-
values for treatment comparisons on any other endpoints.

Analysis with mPP population: If the treatment comparison on the primary 
endpoint has a lower confidence limit above the non-inferiority margin but 
below 0, non-inferiority is established but the p-value will not be used to 
give an indication of the strength of that noninferiority.  Inference will be 
drawn from p-values for treatment comparisons (with ITT population) on 
other non-lung function endpoints,i.e, SGRQ and CAT, which will be 
called statistically significant if <0.05. No inference will be drawn from p-
values on trough FEV1 endpoint. Analysis with ITT population: If the 
treatment comparison on the primary endpoint has a lower confidence 
limit above 0, superiority is established and the p-value can be used to 
give an indication of the strength of that superiority. Inference will be 
drawn from p-values for treatment comparisons on all other endpoints, 
which will be called statistically significant if <0.05.
A “tipping point” sensitivity analysis of 0-24hour WM FEV1 on Day 84 will be 
conducted for the mPP Population. This will explore the impact of missing data by 
using differing assumptions regarding the mean treatment effect in participants 
who discontinue study treatment or have data excluded from mPP Population 
analyses. Assumptions will include scenarios where participants who discontinue 
FF/UMEC/VI have a lower treatment effect than those who discontinue 
BUD/FOR+TIO. The analysis results will be used to explore the conditions under 
which the conclusion of non-inferiority no longer holds.
 
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Endpoint
Statistical Analysis Methods
If superiority on primary endpoint is established with ITT population, similar 
“tipping point” sensitivity analysis will be conducted for the ITT population in order 
to explore the conditions under which the conclusion of superiority no longer 
holds.
Secondary

Secondary endpoint change from baseline in trough FEV1 will be 
analysed for the ITT Population using a mixed model repeated measures 
(MMRM) analysis, including trough FEV1 recorded at each of visits, Day 
2, 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 TIO will be presented together 
with 95 % CIs for the difference and p-values.
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 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.
 
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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.
10.4.5.
Exploratory Analyses
These exploratory analyses may be provided in a separate RAP.
 
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11.
REFERENCES
Aaron SD, Vandemheen KL, Fergusson D, Maltais F, Bourbeau J, Goldstein R, Balter M 
et al. (2007) Tiotropium in Combination with Placebo, Salmeterol, or Fluticasone–
Salmeterol for Treatment of Chronic Obstructive Pulmonary Disease A Randomised 
Trial. Ann Intern Med. 146:545-555.
Cazzola M, Andò F, Santus P, Ruggeri P, Di Marco F, Sanduzzi A et al. A pilot study to 
assess the effects of combining fluticasone propionate/salmeterol and tiotropium on the 
airflow obstruction of patients with severe-to-very severe COPD. Pul Pharm Ther 2007 
20:556–561.
Celli BR, MacNee W, ATS/ERS Task Force. Standards for the diagnosis and treatment of 
patients with COPD: A summary of the ATS/ERS position paper.  Eur Respir J 2004; 23: 
932-946.
Christensson C, Thoren A, Lindberg B. Safety of inhaled budesonide: clinical 
manifestations of systemic corticosteroid-related adverse effects. Drug Safety. 
2008;31:965-988.
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(2):641-647.
De Bisschop MB, Bellou A. Anaphylaxis. Current Opinion in Critical Care. 
2012;18(4):308-317.
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: 
http://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.
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 
 
2019N401866_00

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77
Jones, PW., Harding, G., Wiklund, I., Berry, P., Tabberer, M., Yu, R., et al. ‘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 randomised 
controlled study. Resp. Med. (2012) 106: 382-389 doi:10.1016/j.rmed.2011.09.004.
Lehouck A, Boonen S, Decramer M, Janssens W. COPD, bone metabolism, and 
osteoporosis. Chest. 2011;139:648-657.
Lipson DA, Barnacle H, Birk R, Brealey N, Locantore N, Lomas DA, et al. FULFIL 
Trial: Once-Daily Triple Therapy in Patients with Chronic Obstructive Pulmonary 
Disease. Am J Respir Crit Care Med 2017;10.1164/rccm.201703-0449OC.
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, Odencrantz J, Standardisation of spirometry. Eur Respir J. 
2005;26:319-388.
Niggemann B, Beyer K. Factors augmenting allergic reactions. Allergy. 
2014;69(12):1582-1587.
Packe GE, Cayton RM, Mashhoudi N. Nebulised ipratropium bromide and salbutamol 
causing closed-angle glaucoma. Lancet.1984;22:691.
Quanjer P, Stanojevic S, Cole T, Baur X, Hall G, Culver B, et al. Multi-ethnic reference 
values for spirometry for the 3-95-yr age range: The global lung function 2012 equations. 
Eur Respir J 2012;, 40: 1324-1343.
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(2):257-268.
Siler, TM, Kerwin, E, Sousa, AR, Donald, A, Ali, R, Church, A. (2015) Efficacy and 
safety of umeclidinium added to fluticasone furoate/vilanterol in chronic obstructive 
pulmonary disease: results of two randomized studies. Respir Med. 109(9), 1155-1163.
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.
Weldon D. The effects of corticosteroids on bone growth and bone density. Ann. Allergy 
Asthma Immunol. 2009;103:3-11.
 
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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 (2012) 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. Abstract 62. 
 
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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
BPM
Beats per minute
BMI
Body Mass Index
BUD
Budesonide
BUN
Blood Urea Nitrogen
CAT
COPD Assessment Test
CFR
Code of Federal Regulations
CI
Confidence Interval
CIOMS
Council for International Organizations of Medical Sciences
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic Obstructive Pulmonary Disease
CPRD
Clinical Practice Research Database
CT
Computerized Tomography
CV
Cardiovascular
CYP
Cytochrome P450
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
 
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HCP
Health Care Provider
HIPAA
Health Insurance Portability and Accountability Act
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
IUD
Intrauterine device
IUS
Intrauterine Hormone-Releasing System
IWRS
Interactive Web Response System
ITT
Intent-to-Treat
Kg/m2
Kilograms per meter squared
LABA
Long-Acting Beta-2-Agonists
LAMA
Long-Acting Muscarinic Antagonist
LRTI
Lower Respiratory Tract Infection
LTOT
Long-term oxygen therapy
MACE
Major Adverse Cardiac Event
MAOI
Monoamine Oxidase Inhibitors
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
PRAC
Pharmacovigilance Risk Assessment Committee
QTc
QT interval corrected for heart rate
QTcB
QT interval corrected for heart rate by Bazett’s formula
QTcF
QT interval corrected for heart rate by Fridericia’s formula
 
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RAP
Reporting and Analysis Plan
RBC
Red Blood Cell
RNA
Ribonucleic acid
SAE
Serious Adverse Event
SD
Standard Deviation
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic-Pyruvic Transaminase
SGRQ-C
St. George’s Respiratory Questionnaire for COPD patients
SMQ
Standardised MedDRA Queries
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
VT
Ventricular Tachycardia
WBC
White Blood Cell
WM
Weighted Mean
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
Spiriva Handihaler
Symbicort
 
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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 participants. 

The Investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 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. 

Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
 
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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.
 
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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 physically or 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. 
 
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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
 
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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 participant’s 
medical records, medical examination, or medical history interview.
3. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment.
Contraception Guidance
Female Participants
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in 
Table 7. 
 
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Table 7
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 participants 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 
 
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
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 foetal 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.
 
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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) 
International 
Normalized 
Ratio (INR)2
ALT 3x ULN and INR >1.5, if INR measured
Cannot 
Monitor
ALT 5x ULN but <8x ULN and cannot be monitored weekly for 2 weeks
ALT 3x ULN but <5x ULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3x ULN associated with symptoms (new or worsening) believed to be 
related to  liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue  study treatment 

Report the event to GSK within 24 hours

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 

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
 
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(see MONITORING below)

Do not restart/rechallenge participant with 
study treatment unless allowed per protocol 

If restart/rechallenge not allowed per 
protocol , permanently discontinue study 
treatment and may continue participant in the 
study for any protocol specified follow up 
assessments
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24 
hrs

Monitor participants twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 
recommended
For All other criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24-
72 hrs 

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

Serum creatine phosphokinase and lactate 
dehydrogenase.

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form
including acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG or gamma 
globulins).

Serum acetaminophen adduct HPLC 
assay (quantifies potential acetaminophen 
contribution to liver injury in participants 
with definite or likely acetaminophen use 
in the preceding week [James, 2009]). 
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 participant if ALT 3x ULN and bilirubin 2x ULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3x ULN and bilirubin 2x ULN (>35 % direct bilirubin) or ALT 3x ULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to participants receiving anticoagulants
 
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3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)   
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
5.
If hepatitis delta antibody assay cannot be performed, it can be replaced with a PCR of hepatitis D RNA virus 
(where needed) [Le Gal, 2005].
6.
PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
treatments.  Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
treatment prior to blood sample draw on the eCRF. If the date or time of the last dose is unclear, provide the 
participant’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot 
be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and 
shipping are in the SPM.  
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, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
 
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Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E.  Quantification 
of Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates 
Different Patterns of Virological Response to Interferon Therapy in Chronically Infected 
Patients.  J Clin Microbiol. 2005;43(5):2363–2369. 
 
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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
 
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
Other respiratory related disease
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
 
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
Any course of oral/systemic corticosteroids started within 7 days of finishing a 
previous course will be considered as treatment for a single exacerbation
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.
 
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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.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
 
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assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
 
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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
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.

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
It is not acceptable for the Investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the 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 
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 
 
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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 
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.
 
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
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.
 
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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 

Foetal distress, foetal death, or any congenital abnormality or birth defects
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.
 
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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.
 
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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.
 
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Table 8
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 CRF.
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 x ULN (>35 % direct bilirubin) or ALT 3 x 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.
 
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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.
 
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12.10.
Appendix 10: Country-specific requirements
There are currently no country specific requirements. 
 
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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).
Amendment 1 09-Nov-2017
 
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TITLE PAGE
Protocol Title: A Phase IV, 12-week, randomised, double-blind, triple dummy study to 
compare single inhaler triple therapy, fluticasone furoate/umeclidinium/vilanterol
(FF/UMEC/VI) with multiple inhaler therapy (budesonide/formoterol plus tiotropium)
based on lung function and symptoms in participants with chronic obstructive pulmonary 
disease
Protocol Number: 207609
Short Title: A randomised study, comparing FF/UMEC/VI single inhaler triple therapy, 
versus multiple inhaler therapy (budesonide/formoterol plus tiotropium) 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 and EudraCT number 
2017-001149-28
Approval Date: 12-OCT-2017
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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TABLE OF CONTENTS
PAGE
1.
SYNOPSIS...............................................................................................................6
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................15
3.
INTRODUCTION....................................................................................................17
3.1.
Study Rationale ..........................................................................................17
3.2.
Background ................................................................................................18
3.3.
Benefit/Risk Assessment ............................................................................20
3.3.1.
Risk Assessment .........................................................................21
3.3.2.
Risk assessment for Symbicort MDI (Budesonide/ 
Formoterol) 160/4.5 mcg..............................................................32
3.3.3.
Risk Assessment for Spiriva Handihaler (Tiotropium 
Bromide) 18 mcg .........................................................................32
3.3.4.
Benefit Assessment.....................................................................33
3.3.5.
Overall Benefit:Risk Conclusion...................................................33
4.
OBJECTIVES AND ENDPOINTS...........................................................................34
5.
STUDY DESIGN ....................................................................................................35
5.1.
Overall Design ............................................................................................35
5.2.
Number of Participants ...............................................................................37
5.3.
Participant and Study Completion...............................................................38
5.4.
Scientific Rationale for Study Design ..........................................................38
5.5.
Dose Justification........................................................................................38
6.
STUDY POPULATION...........................................................................................38
6.1.
Inclusion Criteria.........................................................................................38
6.2.
Exclusion Criteria........................................................................................40
6.3.
Randomisation Criteria ...............................................................................43
6.4.
Lifestyle Restrictions...................................................................................44
6.5.
Pre-screening/Screening/Run-in/Randomisation Failures...........................44
7.
TREATMENTS.......................................................................................................45
7.1.
Treatment Groups and Duration .................................................................45
7.1.1.
Medical Devices...........................................................................48
7.2.
Dose Modification .......................................................................................48
7.3.
Method of Treatment Assignment ...............................................................48
7.4.
Blinding.......................................................................................................48
7.5.
Preparation/Handling/Storage/Accountability..............................................50
7.6.
Treatment Compliance................................................................................50
7.7.
Concomitant Therapy..................................................................................51
7.7.1.
Permitted Medications and Non-Drug Therapies..........................51
7.7.1.1.
Permitted COPD Medications.....................................51
7.7.1.2.
Permitted Non-COPD Medications .............................52
7.7.2.
Prohibited Medications and Non-Drug Therapies.........................53
7.8.
Treatment after the End of the Study ..........................................................55
8.
DISCONTINUATION CRITERIA.............................................................................55
8.1.
Discontinuation of Study Treatment ............................................................55
 
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8.1.1.
Protocol defined criteria for discontinuation of study 
treatment .....................................................................................56
8.1.2.
Rechallenge.................................................................................57
8.1.2.1.
Study Treatment Restart or Rechallenge....................57
8.2.
Withdrawal from the Study..........................................................................57
8.3.
Lost to Follow Up........................................................................................58
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................58
9.1.
Efficacy Assessments.................................................................................60
9.1.1.
Spirometry ...................................................................................60
9.1.1.1.
24-hour Serial Spirometry...........................................60
9.1.1.2.
Reversibility................................................................61
9.1.1.3.
Peak Inspiratory Flow Rate (PIFR) .............................61
9.1.2.
SGRQ-C ......................................................................................61
9.1.3.
COPD Assessment Test (CAT)....................................................61
9.1.4.
COPD Exacerbations...................................................................62
9.2.
Adverse Events...........................................................................................62
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................62
9.2.2.
Method of Detecting AEs and SAEs.............................................63
9.2.3.
Follow-up of AEs and SAEs.........................................................63
9.2.4.
Regulatory Reporting Requirements for SAEs .............................63
9.2.5.
Cardiovascular and Death Events................................................64
9.2.6.
Disease-Related Outcomes – COPD Exacerbations....................64
9.2.7.
Pneumonia ..................................................................................64
9.2.8.
Sentinel Events............................................................................65
9.2.9.
Pregnancy ...................................................................................65
9.2.10.
Medical Device Incidents (Including Malfunctions).......................65
9.2.10.1.
Time Period for Detecting Medical Device 
Incidents.....................................................................66
9.2.10.2.
Follow-up of Medical Device Incidents........................66
9.2.10.3.
Prompt Reporting of Medical Device Incidents 
to Sponsor..................................................................66
9.2.10.4.
Regulatory Reporting Requirements for 
Medical Device Incidents............................................66
9.3.
Treatment of Overdose...............................................................................67
9.4.
Safety Assessments ...................................................................................67
9.4.1.
Physical Examinations.................................................................67
9.4.2.
Vital Signs....................................................................................67
9.4.3.
Electrocardiograms......................................................................67
9.4.4.
Clinical Safety Laboratory Assessments ......................................68
9.5.
Pharmacokinetics .......................................................................................68
9.6.
Pharmacodynamics ....................................................................................68
9.7.
Genetics .....................................................................................................68
9.8.
Biomarkers .................................................................................................69
9.9.
Medical Resource Utilization and Health Economics ..................................69
10. STATISTICAL CONSIDERATIONS........................................................................69
10.1.
Hypotheses.................................................................................................69
10.2.
Sample Size Determination ........................................................................69
10.3.
Populations for Analyses ............................................................................71
10.4.
Statistical Analyses.....................................................................................72
 
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10.4.1.
Efficacy Analyses.........................................................................72
10.4.2.
Safety Analyses...........................................................................73
10.4.3.
Other Analyses ............................................................................74
10.4.4.
Interim Analyses ..........................................................................74
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..................................................................................92
12.5.1.
Guidelines for Identifying COPD Exacerbations...........................92
12.5.2.
COPD Exacerbation Severity.......................................................93
12.5.3.
Treatment of COPD Exacerbations..............................................93
12.5.4.
Guidelines for Treatment with Corticosteroids..............................93
12.5.5.
Guidelines for Treatment with Antibiotics .....................................94
12.5.6.
Onset and Resolution of COPD Exacerbations............................94
12.5.7.
Guideline for assessing multiple mild exacerbations ....................94
12.5.8.
Guideline for assessing exacerbations that increase in 
severity ........................................................................................94
12.6.
Appendix 6: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................95
12.7.
Appendix 7: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .....................................101
12.8.
Appendix 8: Clinical Laboratory Tests.......................................................103
12.9.
Appendix 9: Genetics................................................................................105
12.10. Appendix 10: Country-specific requirements.............................................106
 
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1.
SYNOPSIS
Protocol Title: A Phase IV, 12-week, randomised, double-blind, triple dummy study to 
compare single inhaler triple therapy, fluticasone furoate/umeclidinium/vilanterol
(FF/UMEC/VI) with multiple inhaler therapy (budesonide/formoterol plus tiotropium)
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 multiple inhaler therapy (budesonide/formoterol plus tiotropium) 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 
inhaled corticosteroids plus a long-acting β2-adrenergic receptor agonist (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 exacerbation 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 LAMA 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 of
exacerbations which will reduce the exacerbation frequency, allow for a reduced burden 
 
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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 
Symbicort MDI (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 [E-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. 
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 a multiple inhaler 
combination therapy of Symbicort Metered Dose Inhaler (MDI) (budesonide/formoterol 
320/9 mcg) twice daily plus Spiriva HandiHaler (tiotropium 18 mcg) once daily. The 
study will inform healthcare providers that patients can be effectively and safely switched 
to FF/UMEC/VI single inhaler therapy from a multiple inhaler triple therapy regimen of 
Symbicort MDI and Spiriva Handihaler.
Objectives and Endpoints:
Objectives
Endpoints
Primary
To evaluate the effects of single 
inhaler triple therapy (FF/UMEC/VI) 
compared to multiple inhaler triple 
combination therapy with 
budesonide/formoterol plus tiotropium
after 12 weeks of treatment on lung 
function
Primary
Weighted mean change from baseline in 
FEV1 over 0-24 hours at Week 12
Secondary

Change from baseline in trough FEV1
on Day 2, Day 28, Day 84 and Day 
85
Weighted mean change from baseline 
in FEV1 over 0-24 hours on Day 1
 
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Objectives
Endpoints
Other

To evaluate the effects of single 
inhaler triple therapy (FF/UMEC/VI) 
compared to multiple inhaler triple 
combination therapy with 
budesonide/formoterol plus 
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 effects of single 
inhaler triple therapy (FF/UMEC/VI) 
compared to multiple inhaler triple 
combination therapy with 
budesonide/formoterol plus 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 effects of single 
inhaler triple therapy (FF/UMEC/VI) 
compared to multiple inhaler triple 
combination therapy with 
budesonide/formoterol plus tiotropium
after 12 weeks of treatment on COPD 
exacerbations
Moderate or severe exacerbation event
Assess how inspiratory airflow 
limitation affects ability to use the 
ELLIPTA
Peak Inspiratory Flow Rate (PIFR) at 
Screening (Week -4)
Safety
To evaluate the safety profile of single 
inhaler triple therapy (FF/UMEC/VI) 
compared to multiple inhaler triple 
combination therapy with 
budesonide/formoterol plus tiotropium
over 12 weeks of treatment
Incidence of adverse events

Vital signs
Overall Design:
This is a Phase IV, 12-week, randomised, double-blind, triple-dummy, parallel group,
multicentre study evaluating single inhaler triple therapy (FF/UMEC/VI) once daily via 
the ELLIPTA, compared to multiple inhaler triple combination therapy budesonide/ 
formoterol MDI (320/9 mcg) twice daily plus once daily tiotropium (18 mcg), in 
participants with COPD.
 
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Study design schema
Eligible participants at Screening (V1) will be current or former smokers, with an 
established clinical history of COPD, receiving daily maintenance COPD therapy for at 
least 3 months, with a post-bronchodilator FEV1 of <50% predicted (or <80% predicted 
with a documented history of at least 2 moderate or 1 severe [hospitalised] exacerbation 
in the last 12 months) and a CAT score of ≥10 at Visit 1 and at Visit 2. 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) COPD medication(s) during the pre-screening 
period, except for medications that are prohibited within a specified time 
interval prior to Visit 1.

Screening/run-in: Eligible participants will be allowed to continue their usual 
COPD medications until the day before Screening, Visit 1.  On the morning of 
the Screening Visit participants will refrain from taking their morning dose of 
their usual COPD medications. Participants who meet all of the eligibility 
criteria at Visit 1, will enter the 4-week run-in period during which they will 
discontinue all existing COPD medications and receive their run-in treatment:
budesonide/formoterol (320/9 mcg) twice daily plus tiotropium (18 mcg) once 
daily plus placebo via the ELLIPTA. Participants will not use any other COPD 
medications (except for those allowed per protocol). 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, MDI and HandiHaler and will 
 
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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 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 will discontinue their run-in treatments and will be 
randomised in 1:1 ratio to receive one the following double-blind study 
treatments for 84 days:
Either:
FF/UMEC/VI 100/62.5/25 mcg via the ELLIPTA once daily in the morning
+ placebo to match budesonide/formoterol via MDI, two inhalations twice daily 
+  placebo to match tiotropium via HandiHaler once daily in the morning
or,
Budesonide/formoterol 320/9 mcg via MDI, twice daily*
+ tiotropium 18mcg via HandiHaler once daily in the morning
+ placebo via the ELLIPTA once daily in the morning
*Participants are required to take two inhalations of budesonide/formoterol 
160/4.5 mcg, via the MDI in the morning and two inhalations in the evening. 
The total dose is therefore 320/9 mcg twice daily. 
At Visit 2 participants will refrain from taking their morning doses of run-in 
study medication and will self-administer study treatment at the clinic, when 
instructed to do so. Participants will remain at the clinic for at least 24 hours, for 
serial spirometry assessments.
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 3, and 4 participants will self-administer study treatment whilst at the 
clinic. Participants will take their last doses of study treatment in the clinic on 
Day 84 (Visit 4, when instructed to do so by clinic personnel), and continue to 
remain at the clinic until at least 24 hours after their last morning dose, for their 
clinical assessments, which include serial spirometry assessments. On non-clinic 
visit days participants are expected to take their study treatment at home each 
day in the morning and in the evening at approximately the same time, as 
directed by the clinic. 

Safety/follow-up: A safety follow-up telephone contact or clinic visit (Visit 5) 
will be conducted approximately 7 days after the participant completes all of the 
 
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protocol-defined procedures for Visit 4/End of Study (EOS) or, if applicable, the 
Study Treatment Discontinuation Visit. 
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 800 participants with advanced COPD will enter the run-in period, in 
order to randomise approximately 732 participants, in order to achieve an estimated 620
evaluable participants in modified per-protocol (mPP) population at Week 12, assuming 
10 % premature discontinuation of study treatment and 5% protocol deviation.
Approximately 80 centres globally will be required to recruit participants in 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 
budesonide/formoterol (320/9 mcg) twice daily plus tiotropium (18 mcg) 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, triple-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 budesonide/formoterol via MDI, two inhalations twice daily 
+ placebo to match tiotropium via HandiHaler once daily in the morning
or,

Budesonide/formoterol 160/4.5 mcg via MDI, two inhalations twice daily*
+ tiotropium 18mcg via HandiHaler once daily in the morning
+ placebo via the ELLIPTA once daily in the morning
*Participants are required to take two inhalations of budesonide/formoterol 160/4.5 mcg, 
via the MDI in the morning and two inhalations in the evening. The total dose is therefore 
320/9 mcg twice daily. 
 
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Dosing schedule for run-in and treatment periods
ELLIPTA
(1 inhalation)
MDI
(2 puffs)
HandiHaler
(1 capsule inhaled 
twice)
Active
Placebo
Active
Placebo
Active
Placebo
Run-in
am
Y
Y
Y
pm
Y
Treatment
FF/UMEC/VI group
am
Y
Y
Y
pm
Y
Budesonide/formoterol
+ tiotropium group
am
Y
Y
Y
pm
Y
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.
Symbicort MDI contains 120 doses: budesonide/formoterol 160/4.5 mcg, two inhalations 
twice daily.
Tiotropium: 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.
Key Elements of Analysis Plan:
The null hypothesis is that the difference in 0-24 hour Weighted Mean (WM) FEV1
between treatment groups is less than or equal to a pre-specified non-inferiority margin 
Δ:
H0: T1 – T2 ≤ -Δ
The alternative hypothesis is that the difference between treatment groups is greater than 
the margin.
H1: T1 – T2 > -Δ
where T1 and T2 are the treatment means for FF/UMEC/VI and budesonide/formoterol + 
tiotropium (BUD/FOR+TIO), respectively.
The non-inferiority margin has been set at 50 mL.
 
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The primary analysis population will be the modified per-protocol (mPP) population, 
comprising all participants randomised to treatment except those randomised in error, 
who do not have a full protocol deviation or other event considered to impact efficacy.
The primary analysis will be performed for mPP population using on-treatment data. The 
primary analysis will evaluate the endpoint of 0-24 hour WM FEV1 on Day 84 using a 
mixed model repeated measure (MMRM) analysis, including covariates 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.  Baseline 
FEV1 is the mean of the two assessments made -30 and -5 minutes pre-dose on Treatment 
Day 1.
Estimated differences between FF/UMEC/VI and BUD/FOR+TIO will be presented 
together with 95% confidence intervals (CIs) for the treatment difference and p-value.
Inference to be drawn from the p-values will be as follows:

Analysis with mPP population: If the treatment comparison on the primary 
endpoint has a lower confidence limit below the non-inferiority margin, non-
inferiority is not demonstrated. No inference will be drawn from p-values for 
treatment comparisons on any other endpoints.

Analysis with mPP population: If the treatment comparison on the primary 
endpoint has a lower confidence limit above the non-inferiority margin but below 
0, non-inferiority is established but the p-value will not be used to give an 
indication of the strength of that non-inferiority.  Inference will be drawn from p-
values for treatment comparisons (with Intent-To-Treat [ITT] population) on 
other non-lung function endpoints, ie, SGRQ and CAT which will be called 
statistically significant if <0.05. No inference will be drawn from p-values on 
trough FEV1 endpoint. 

Analysis with ITT population: If the treatment comparison on the primary 
endpoint has a lower confidence limit above 0, superiority is established and the 
p-value can be used to give an indication of the strength of that superiority. 
Inference will be drawn from p-values for treatment comparisons on all other 
endpoints, which will be called statistically significant if <0.05.
A “tipping point” sensitivity analysis of 0-24 hour WM FEV1 on Day 84 will be 
conducted for the mPP Population. This will explore the impact of missing data by using 
differing assumptions regarding the mean treatment effect in participants who discontinue 
study treatment or have data excluded from mPP Population analyses. Assumptions will
include scenarios where participants who discontinue FF/UMEC/VI have a lower 
treatment effect than those who discontinue BUD/FOR+TIO. The analysis results will be 
used to explore the conditions under which the conclusion of non-inferiority no longer 
holds.
 
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If superiority on primary endpoint is established with ITT population, similar “tipping 
point” sensitivity analysis will be conducted for the ITT population in order to explore 
the conditions under which the conclusion of superiority no longer holds.
The details of the statistical analysis methods for the secondary efficacy endpoints will be 
provided in the Reporting and Analysis Plan (RAP).
 
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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
Study Treatment 
Discontinuation 
Visit
Visit 5 
Safety
Follow-up 
Contact
Study Day
-56 to -
28
Day -28
Day 1
Day 28
Day 
84-85
Day 91
Week
-8 to -4
-4
0
4
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 & status
X
X
X
Smoking Cessation 
Counselling
X
X
Register Visit in IWRS
X
X
X
X
X
X
X
CAT d
X
X
X
X
SGRQ-Cd
X
X
X
Reversibility Testing and 
PIFR e
X
Trough FEV1 
X
24h serial spirometry f
X
X
Inhalation device training
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
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
 
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Protocol Activity
Pre-
Screen
Screen
Treatment
Follow-up
Visit 0
Visit 1 
Screen/ 
Run-in
Visit 2
Randomisation Visit 3 Visit 4
Study Treatment 
Discontinuation 
Visit
Visit 5 
Safety
Follow-up 
Contact
Study Day
-56 to -
28
Day -28
Day 1
Day 28
Day 
84-85
Day 91
Week
-8 to -4
-4
0
4
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)
Administer study treatment in 
clinic n
X
X
X
Assess run-in treatment 
compliance
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
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 IC and must be obtained prior to 
obtaining a genetic blood sample. Participants do not have to participate in the genetic research part of this study, 
it is optional.
c.
Demography may be captured at either the Pre-screen Visit or Screening Visit (for participants who do not have a 
Pre-screen Visit).
d.
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 PIFR spirometry and both pre and post-bronchodilator spirometry will be conducted. PIFR will 
be assessed 10 minutes prior to pre-bronchodilator spirometry. Participants are required to withhold their usual 
morning doses of their COPD meds including rescue albuterol/salbutamol for the protocol designated period prior 
to PIFR spirometry and reversibility testing.
f.
Serial spirometry at Visit 2 and Visit 4 will be done pre-dose at 30 mins and 5 mins and post dose at 5 mins, 15 
mins, 30mins,1hr, 3hrs, 6hrs, 12hrs, 15hrs, 21hrs, 23hrs, 24hrs. Participants that discontinue study treatment but 
remain in the study will complete serial spirometry at Week 12, if they consent to do so.
g.
Physical examination may include height, weight, blood pressure and temperature.
h.
Vital signs, including blood pressure and pulse 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. The sample can be collected at any time 
after Visit 2, providing consent is obtained.
k.
Hematology and chemistry panels will include full and differential blood count and liver chemistry.
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 or study treatment and not take their 
run-in treatment until instructed to do so by study staff.
 
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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.
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 inhaled 
corticosteroids (ICS) plus a long-acting β2-adrenergic receptor agonist (LABA) as second 
line therapy for the most advanced patients with significant symptoms and a high risk of 
exacerbations. Regular treatment with Inhaled Coricosteroid (ICS) containing regimens 
has been reported to improve respiratory symptoms, lung function, health related quality 
of life (HRQoL) and reduce the frequency of COPD exacerbation 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 
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 LAMA 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 of
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 
Symbiocort MDI) (budesonide/formoterol) 400/12 mcg in COPD participants that were 
 
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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 [E-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. 
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 a multiple inhaler 
combination therapy of Symbicort Metered Dose Inhaler (MDI) (budesonide/formoterol 
320/9 mcg) twice daily plus Spiriva HandiHaler (tiotropium 18 mcg) once daily. The 
study will inform healthcare providers that patients can be switched to FF/UMEC/VI 
single inhaler therapy from a multiple inhaler triple therapy regimen of Symbicort MDI
and Spiriva Handihaler.
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 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 grades from the 
ABCD assessment tool (Table 1) [GOLD, 2017]. 
 
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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 hospitalization, 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 guidelines 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 [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.
 
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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 budesonide/formoterol and 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 assessment and mitigation strategy 
for this protocol.  
 
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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) [Lipson, 2017] 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 adverse event 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 FF/VI 
(<1-2 % with FF/VI 100/25) and less than that 
observed in 52 week exacerbation studies with 
FF/VI (6 % with FF/VI 100/25) [Dransfield, 2013].  
Similarly, the incidence of pneumonia with 
- 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  
- 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 
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
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 the 
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.
The Pharmacovigilance Risk Assessment 
Committee (PRAC) recently conducted an Article 
31 review to evaluate the risk of pneumonia with 
use of ICSs in patients with COPD. The PRAC 
review confirmed that COPD patients treated 
with inhaled corticosteroids are at increased risk 
of pneumonia; however the Committee’s view 
was that the benefits of ICSs continue to 
outweigh their risks. The PRAC also looked 
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. 
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
whether there were any differences in the risk of 
pneumonia between these products, 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 fractures 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 
the fractures in both treatment groups were 
traumatic in nature.
- 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.
Adrenal suppression
Oral corticosteroids are known to have an effect 
on the hypothalamic-pituitary-adrenal (HPA) axis
leading to a reduction in cortisol production. Due 
to the low dose and low systemic exposure with 
inhaled corticosteroids, this potential effect is not 
- Investigators are informed of the risk in the IB.
- Instream review of blinded AE/SAE reports.
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
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 
program, 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/VI100/25 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 this risk of 
adrenal suppression. The systemic exposure of 
FF is very low compared to that of oral 
corticosteroids, so any concurrent effect will be 
negligible.
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. 
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
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 ICS
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 assessments in a study with 
FF/VI, FF and FP in participants with asthma.
- Participants will be informed about the risk in 
the informed consent.
- Investigators are informed of the risk in the IB.
- Appropriate exclusion criteria as specified in 
Section 6.2 of the protocol
- Instream review of blinded AE/SAE reports.
- If a risk is suspected, participants should 
receive appropriate treatment
Serious cardiovascular events
Cardiovasular (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 
- 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 
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
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, cardiovascular 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 
(4.3 % and 5.2 % respectively) and the EXT 
Population up to 52 weeks (8.6 % and 10 % 
respectively).  Within subgroups of 
cardiovascular 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). 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 
Section 6.2 of the protocol, including 
- Electrocardiogram (ECG) inclusion criteria
- Vital sign assessments (heart rate and blood 
pressure) as per protocol.
- Protocol defined stopping criteria as per 
Section 8.1.1.
- Instream review of blinded AE/SAE reports.
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
cardiovascular 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 up 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 
cardiovascular effects AESI was low in the study, 
despite the study enrolling participants with a 
number of CV comorbidities 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 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 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 
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
Population up to 24 weeks and EXT Population 
up to 52 weeks.
In study CTT116853 [Lipson, 2017], 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 cardiovascular safety profile of FF/UMEC/VI 
was generally consistent with that of FF/VI and 
UMEC/VI. 
Hypersensitivity
Hypersensitivity reactions are unlikely to 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 FF/UMEC/VI and 
BUD/FOR arms). On treatment hypersensitivity 
- Participants will be informed about the risk in 
the informed consent. Particpants 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.
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
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. 
Narrow angle glaucoma
Rare reports of angle closure glaucoma (which 
may lead into blindness) have been associated 
with nebulised ipratropium bromide and 
salbutamol [Packe, 1984].
The incidence of narrow angle glaucoma in the 
COPD population associated with the use of 
inhaled bronchodilators (including LAMAs and 
LABAs) is relatively low. 
In CTT116853, in the ITT Population up to 24 
weeks, events in the glaucoma SMQ were 
reported at an incidence of 0.1 and 0.4 % in the 
FF/UMEC/VI and BUD/FOR arms respectively. 
In the EXT Population up to 52 weeks, no events 
- 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.
 
 
 
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Potential Risk of Clinical Significance
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Mitigation Strategy
were reported in either treatment arm.
In the UMEC/VI development program, there 
was one report (<1 %) of angle closure glaucoma 
(UMEC/VI 62.5/25 mcg).
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 retention AESI 
group in either treatment arm in the ITT 
Population up to 24 weeks and 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.
- Appropriate exclusion criteria as specified in 
Section 6.2 of the protocol
- Instream review of blinded AE/SAE reports.
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 CTT116853, the risk of paradoxical 
bronchospasm was evaluated through the AESI 
of asthma/bronchospasm. In the ITT Population 
- 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.
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
up to 24 weeks, one participant reported an 
event in the asthma/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.
 
 
 
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3.3.2.
Risk assessment for Symbicort MDI (Budesonide/ Formoterol)
160/4.5 mcg
Symbicort is a marketed drug that contains both budesonide (ICS; 160 mcg) and 
formoterol (LABA; 4.5 mcg). Two inhalations from the MDI provide the required 
320/9 mcg dose. The dose (320/9 mcg) and formulation, using an MDI, are approved for 
COPD in the US, the dose and formulation are not approved in Europe. A similar profile
of undesirable effects as reported for ICSs and LABAs may occur with budesonide and 
formoterol respectively. No increased incidence of adverse reactions has been seen 
following concurrent administration of the two compounds. The most common drug-
related adverse reactions are pharmacologically predictable side-effects of β2
adrenoceptor agonist therapy, such as tremor and palpitations. These tend to be mild and 
usually disappear within a few days of treatment. Please refer to the authorised product 
label for further information about the risks of using Symbicort. In this study, Symbicort 
will be used in line with the recommendations provided in the product label.
Since Symbicort contains an ICS and LABA, the risk mitigation strategies for the FF 
(ICS) and VI (LABA) components of GSK2834425 will be applicable for Symbicort.
3.3.3.
Risk Assessment for Spiriva Handihaler (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, Spiriva Handihaler will be used in line with the recommendations provided in the 
product label. 
Spiriva Handihaler is an anticholinergic, therefore the risk mitigation strategy for UMEC 
component of GSK2834425 will be applicable for Spiriva Handilaler. 
 
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3.3.4.
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 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.
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 bronchodilator treatment of airflow 
obstruction in patients 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-bronchodilator) with an 
exacerbation history despite regular bronchodilator therapy.  The UMEC/VI combination 
is approved as a maintenance bronchodilator to relieve symptoms in adult patients with 
COPD. UMEC is approved as a maintenance bronchodilator treatment to relieve 
symptoms in adult patients 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 patients with moderate to severe COPD supports the further 
development of the closed triple combination.
Tiotropium (18 mcg) and budesonide/formoterol (400/12 mcg) are marketed drugs for the 
COPD indication, and have established benefit:risk profiles.  Tiotropium and 
budesonide/formoterol will be used in line with the recommendations provided in the 
product labels.
3.3.5.
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, tiotropium and 
budesonide/formoterol are justified by the anticipated benefits from active treatments that 
may be afforded to patients with COPD.
 
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4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
To evaluate the effects of single inhaler 
triple therapy (FF/UMEC/VI) compared 
to multiple inhaler triple combination 
therapy with budesonide/formoterol plus 
tiotropium after 12 weeks of treatment 
on lung function
Primary
Weighted mean change from baseline in 
FEV1 over 0-24 hours at Week 12
Secondary

Change from baseline in trough FEV1
on Day 2, Day 28, Day 84 and Day 85

Weighted mean change from baseline 
in FEV1 over 0-24 hours on Day 1
Other
To evaluate the effects of single inhaler 
triple therapy (FF/UMEC/VI) compared 
to multiple inhaler triple combination 
therapy with budesonide/formoterol plus 
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 effects of single inhaler 
triple therapy (FF/UMEC/VI) compared 
to multiple inhaler triple combination 
therapy with budesonide/formoterol plus 
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 effects of single inhaler 
triple therapy (FF/UMEC/VI) compared 
to multiple inhaler triple combination 
therapy with budesonide/formoterol plus 
tiotropium after 12 weeks of treatment 
on COPD exacerbations
Moderate or severe exacerbation event
Assess how inspiratory airflow 
limitation affects ability to use the 
ELLIPTA
Peak Inspiratory Flow Rate at Screening 
(Week -4)
 
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Objectives
Endpoints
Safety
To evaluate the safety profile of single 
inhaler triple therapy (FF/UMEC/VI) 
compared to multiple inhaler triple 
combination therapy with 
budesonide/formoterol plus tiotropium 
over 84 days of treatment
Incidence of adverse events
Vital signs
5.
STUDY DESIGN
5.1.
Overall Design
This is a Phase IV, 12-week, randomised, double-blind, triple dummy, parallel group,
multicentre study evaluating single inhaler triple therapy (FF/UMEC/VI) once daily via 
the ELLIPTA, compared to multiple inhaler triple combination therapy 
budesonide/formoterol (320/9 mcg) twice daily plus once daily tiotropium (18 mcg), in 
participants with COPD. 
Figure 1
Study design schema
Eligible participants at Screening (V1) will be current or former smokers, with an 
established clinical history of COPD, receiving daily maintenance COPD therapy for at 
least 3 months, with a post-bronchodilator FEV1 of <50 % predicted (or <80 % predicted 
with a documented history of at least 2 moderate or 1 severe [hospitalised] exacerbation 
in the last 12 months) and a CAT score of ≥10 and Visit 1 and at Visit 2. 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. 
 
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
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) COPD medication(s) during the pre-screening 
period; however, medications that are prohibited within a specified time interval 
prior to Visit 1 are defined in Section 7.7.

Screening/run-in: Eligible participants will be allowed to continue their usual 
COPD medications until the day before Screening, Visit 1.  On the morning of 
the Screening Visit participants will refrain from taking their morning dose of 
their usual COPD medications. Participants who meet all of the eligibility 
criteria at Visit 1, will enter the 4-week run-in period during which they will 
discontinue all existing COPD medications and receive their run-in treatment:
budesonide/formoterol (320/9 mcg) twice daily plus tiotropium (18 mcg) once 
daily plus placebo via the ELLIPTA. Participants will not use any other COPD 
medications (except for those allowed per protocol). 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, MDI 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 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:
Either:
FF/UMEC/VI 100/62.5/25 mcg via the ELLIPTA once daily in the morning
+ placebo to match budesonide/formoterol via MDI, two inhalations twice daily 
+  placebo to match tiotropium via HandiHaler once daily in the morning
or,
Budesonide/formoterol 160/4.5 mcg via MDI, two inhalations twice daily*
+ tiotropium 18 mcg via HandiHaler once daily in the morning
+ placebo via the ELLIPTA once daily in the morning
 
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*Participants are required to take two inhalations of budesonide/formoterol 
160/4.5 mcg, via the MDI in the morning and two inhalations in the evening. 
The total dose is therefore 320/9 mcg twice daily. 
At Visit 2 participants will refrain from taking their morning doses of run-in 
study medication and will self-administer study treatment at the clinic, when 
instructed to do so. Participants will remain at the clinic for at least 24 hours, for 
serial spirometry assessments.

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.
Participants will remain at the clinic for at least 24 hours, for serial spirometry 
assessments. At Visits 3 and 4 participants will self-administer study treatment 
whilst at the clinic. Participants will take their last doses of study treatment in 
the clinic on Day 84 (Visit 4, when instructed to do so by clinic personnel), and 
continue to remain at the clinic until at least 24 hours after their last morning 
dose, for their clinical assessments, which include serial spirometry 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, and at the same 
time each evening, as directed by the clinic. 

Safety/follow-up: A safety follow-up telephone contact or clinic visit (Visit 5) 
will be conducted approximately 7 days after the participant completes all of the 
protocol-defined procedures for Visit 4/End of Study (EOS) or, if applicable, the 
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 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 (see Section 8.1). 
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.
5.2.
Number of Participants
Approximately 800 participants with advanced COPD will enter the run-in period, in 
order to randomise approximately 732 participants in order to achieve an estimated 620
evaluable participants in the modified per-protocol (mPP) population at Week 12, 
assuming 10 % premature discontinuation of study treatment and 5 % protocol deviation.
See Section 10 for further details. 
 
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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 table (SoA) (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, triple-dummy, parallel-
group design. A placebo arm is not included because the primary comparison of interest
is FF/UMEC/VI vs. Budesonide/formoterol + tiotropium and it is not considered 
appropriate to include a placebo arm in a study in participants with advanced COPD.
Eligible participants must have been on daily maintenance COPD medications for at least 
3 months. 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.
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 doses selected for the Symbicort MDI (budesonide/formoterol 320/9 mcg, twice 
daily) and Spiriva HandiHaler (tiotropium 18 mcg, once daily) is the doses 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.
 
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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 
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].
 
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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 for their COPD for at least 3 months prior to Screening.
Note: Participants taking only as-needed COPD medications 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).
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.
 
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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.
11. Unstable liver disease: ALT >2x Upper Limit of Normal (ULN); and bilirubin 
>1.5x ULN (isolated bilirubin >1.5x ULN 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
 
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
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 by Fridericia’s formula (QTcF)
≥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.
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 at screening (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.
 
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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: Use of the following medications within the
following 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
Long term antibiotic therapy
Participants receiving antibiotics for long term therapy (30 
days) 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)
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. 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 any of the three 
inhalers (ELLIPTA, Handihaler or MDI) will be excluded.
 
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2. COPD exacerbation or pneumonia

Participants that experience a moderate or a severe COPD exacerbation or 
pneumonia during the run-in period will be excluded. 
3. Changes in COPD medication

Any participant that requires any change in COPD medication 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; serious adverse event (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/randomization
failure details, eligibility criteria, and any SAEs. Further details are provided in the study-
specific eCRF completion guidelines.
For the purposes of this study, pre-screening failures, screening failures and run-in 
failures will be defined as follows:
Pre-screening failures: those participants that sign the informed consent document but 
do not have a Visit 1 (Screening) procedure.
Screening failures: those participants that complete at least 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 are not randomised 
(except those randomised in error).
 
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7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.
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 
budesonide/formoterol (320/9 mcg) twice daily plus tiotropium (18 mcg) once daily plus 
placebo via the ELLIPTA. Following the run-in period, participants who meet the 
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 budesonide/formoterol via MDI, two inhalations twice daily 
+  placebo to match tiotropium via HandiHaler once daily in the morning
or,
Budesonide/formoterol 160/4.5 mcg via MDI, two inhalations twice daily*
+ tiotropium 18 mcg via HandiHaler once daily in the morning
+ placebo via the ELLIPTA once daily in the morning
*Participants are required to take two inhalations of budesonide/formoterol 160/4.5 mcg, 
via the MDI in the morning and two inhalations in the evening. The total dose is therefore 
320/9 mcg twice daily.
 
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Table 2
Dosing schedule for run-in and treatment periods
ELLIPTA
(1 inhalation)
MDI
(2 puffs)
HandiHaler
(1 capsule inhaled 
twice)
Active
Placebo
Active
Placebo
Active
Placebo
Run-in
am
Y
Y
Y
pm
Y
Treatment
Active FF/UMEC/VI
am
Y
Y
Y
pm
Y
Active 
budesonide/formoterol 
+ tiotropium
am
Y
Y
Y
pm
Y
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.
Symbicort MDI contains 120 doses: budesonide/formoterol 160mcg/4.5 mcg, two 
inhalations twice daily.
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, MDI and the 
Handihaler are provided in Table 3, Table 4, and Table 5, respectively.
 
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Table 3
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 
100mcg per blister
25 mcg per blister GW642444, 62.5 
mcg per blister GSK573719
Physical 
description 
Dry white powder
Dry white powder
Route of 
Administration 
Inhaled
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
NA
Physical 
description
Dry white powder
Dry white powder
Route of 
Administration
Inhaled
Table 4
Description of Symbicort MDI
Symbicort 160mcg/4.5 mcg
MDI
Dosage form
MDI with 120 doses
Unit dose strength
Budesonide/ Formoterol 160mcg/4.5mcg
Physical description 
Solution for inhalation
Route of administraton
Inhaled
Placebo to match Symbicort
Placebo to match MDI
Dosage form
MDI with 120 doses
Unit dose strength
NA
Physical description
Solution for inhalation
Route of administration
Inhaled
 
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Table 5
Description of Tiotropium bromide in HandiHaler
Spiriva 18 mcg
HandiHaler
Dosage form
Capsule
Unit dose strength
18mcg
Physical description 
Hard gelatin capsule containing 18mcg 
tiotropium bromide blended with lactose
Route of administration
Inhaled
Placebo to match Spiriva
HandiHaler
Dosage form
Capsule
Unit dose strength
NA
Physical description 
Hard gelatin capsule containing lactose
Route of administration
Inhaled
7.1.1.
Medical Devices

The GSK ELLIPTA medical device will be provided for use in this study.

Other medical devices (not manufactured by or for GSK provided for use in this
study) are the Handihaler and MDI.

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 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. 
 
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
The Investigator or treating physician may unblind a participant’s treatment 
assignment only in the case of an emergency OR in the event of a serious 
medical condition when knowledge of the study treatment is essential for the 
appropriate clinical management or welfare of the participant as judged by the 
Investigator. 

Investigators have direct access to the participant’s individual study treatment. 

It is preferred (but not required) that the Investigator first contacts the Medical 
Monitor or appropriate GSK study personnel to discuss options before unblinding 
the participant’s treatment assignment. 

If GSK personnel are not contacted before the unblinding, the Investigator must 
notify GSK within 24 hours after unblinding, but without revealing the treatment 
assignment of the unblinded participant, unless that information is important for 
the safety of participants currently in the study. 

The date and event or condition which led to the unblinding (i.e. the primary 
reason) will be recorded in source documentation and in the eCRF. 
Should a participant’s treatment assignment be unblinded then the participant may 
continue the assigned study treatment and be followed-up as per protocol until the 
completion of the Safety Follow-up assessments.
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any participant with an SAE. If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of the 
report, identifying the participant’s treatment assignment, may be sent to Investigators in 
accordance with local regulations and/or GSK policy. Participants will not be withdrawn 
from the study.
Masking of tiotropium and placebo to tiotropium capsules
This study will use a triple-dummy design for dosing, whereby participants will be given 
three inhalers (ELLIPTA, MDI 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. 
 
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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.
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 MDI, 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.
 
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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 randomization 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 5). 
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 the randomised
treatment periods: 

Study supplied albuterol/salbutamol 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)

Study provided COPD medications in the run-in and the randomised treatment period 
The following COPD medications are permitted during the randomised treatment
period: 

Oral or injectable corticosteroids (short course ≤14 days) only for the short term
treatment of COPD exacerbations and/or pneumonia
 
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
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 randomised 
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)

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 ECG changes and/or 
hypokalemia)

Use of positive airway pressure for sleep apnea
 
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
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 6 is not permitted during the study.
 
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Table 6
Concomitant Medications
Medication Prohibited during the randomised treatment period
Inhaled short-acting anticholinergics
Inhaled short-acting beta2 agonists1 
Inhaled short-acting anticholinergic/short-acting beta2-agonist combination products
Inhaled corticosteroids (ICS)
Inhaled corticosteroids (ICS)/Inhaled long-acting beta2-agonist (LABA) combinations 
(eg.fluticasone/salmeterol, mometasone furoate/formoterol fumarate, budesonide/formoterol fumarate; 
fluticasone furoate/vilanterol
Phosphodiesterase 4 (PDE4) inhibitors (roflumilast)
LABA (e.g., indacaterol, olodaterol, salmeterol etc.)
Other LAMAs (aclidinium, glycopyrronium, umeclidinium etc.)
LAMA/LABA combinations
Theophyllines
Sodium cromoglycate and nedocromil sodium
Anti-leukotrienes
Long term antibiotic therapy2
Systemic, oral, parenteral corticosteroids3
Any other investigational drug
1.
(rescue 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 
 
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increase the risk of overdose. If neccessary the Investigator or other health care 
personnel may stop the participant’s study treatment temporarily (≤ 14 days) in order to 
treat the COPD exacerbation.  Participants who require more than two consecutive 14 
day courses of treatment (i.e. antibiotics or corticosteroids) should be evaluated for their 
continuation on study treatment by the Investigator in consultation with the GSK medical 
monitor.
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
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 4), 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 4 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 5 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 4, 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 5) should also be conducted 7 days after Visit 4.
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
 
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
COPD exacerbations 

Concomitant medication 

Serial spirometry (Visit 4 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. 
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.
8.1.1.
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, participants are however encouraged to remain in the 
study and complete limited assessments, as detailed in Section 8.1: 

Liver chemistry stopping and increased monitoring criteria have been designed 
to assure participant safety and evaluate liver event etiology (in alignment with the 
Food and Drug Administration (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. 
 
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
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:

QTc>500 msec or uncorrected QT>600 msec

Change from baseline: QTc>60 msec

For participants with underlying bundle branch block, follow the 
discontinuation criteria listed below:

Baseline QTc with Bundle Branch Block <450 msec, Discontinuation 
QTc with Bundle Branch Block >500 msec

Baseline QTc with Bundle Branch Block <450-480  msec, 
Discontinuation QTc with Bundle Branch Block ≥530 msec
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.
8.1.2.
Rechallenge
8.1.2.1.
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 SOA (Section 2).
Participants that have previously discontinued study treatment (and have already 
completed the Study Treatment Discontinuation Visit) but 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 5) can be 
conducted at the time the participant notifies the site of their intention to withdraw from 
 
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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:

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 Participants 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
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. Sites are required to have study treatment dose, dispensed and accounted for by 
site personnel that are not involved in any efficacy or safety assessments. See Section 7.4
for further details.   

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 
 
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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):

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)

12-lead ECG

Pulse rate, blood pressure measurements

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
 
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
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  
(including PIFR) and each scheduled clinic visit during the treatment period. For FEV1,
FVC and PIFR determinations, at least 3 acceptable spirometry efforts (with no more 
than 8) should be obtained.  Acceptable spirometry efforts should have a satisfactory start 
of test and end of test (e.g. a plateau in the volume-time curve) and be free from artifacts 
due to cough, early termination, poor effort, obstructed mouthpiece, equipment 
malfunction, or other reasons [Miller, 2005].
The largest FEV1 and FVC from the 3 acceptable efforts should be recorded, even if they 
do not come from the same effort.
Spirometry must be performed as follows:

Started approximately between 6:00AM and 11:00AM.

If applicable, after completing the health outcomes assessments (SGRQ-C should be 
administered first followed by CAT)

After withholding albuterol/salbutamol for 4 hours. 

At Screening (Visit 1), before the morning dose of run-in 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.
24-hour Serial Spirometry
24-hour serial spirometry will be performed by all participants at Randomization (Visit 2) 
and Day 84 (Visit 4). In addition, trough FEV1 data will be collected pre-dose on Day 28 
(Visit 3).
Serial spirometry measurements should be taken as close to the following scheduled 
timepoints as possible:
 
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Pre-dose: 30 mins and 5 mins
Post-dose: 5 mins, 15 mins, 30 mins, 1 hr, 3 hrs, 6 hrs, 12 hrs, 15 hrs, 21 hrs, 23 hrs and 
24 hrs
9.1.1.2.
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.
9.1.1.3.
Peak Inspiratory Flow Rate (PIFR)
PIFR will be completed at Screening (Visit 1) only, approximately 10 minutes prior to 
the start of reversibility testing. Three acceptable spirometry efforts will be obtained. 
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).
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 
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).
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.
 
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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 5.
Participants will complete a paper Medical Problems worksheet to record medical 
problems experienced during the study. This paper worksheet must be reviewed by the 
Investigator (or designee) at each visit to the study site to assist in the identification of 
new COPD exacerbations.  
All COPD exacerbations will be recorded in the exacerbation eCRF. 
Every effort should be made to conduct a chest x-ray within 48 hours of identification of 
a moderate or severe exacerbation. 
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). 
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 5.

All AEs will be collected from the start of Study Screening (Visit 1) 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 
 
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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.
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.
 
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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 Medicinal 
Dictionary for Regulatory Activities (MedDRA) terms. The CV information should be 
recorded in the specific cardiovascular section of the CRF within one week of receipt of a 
CV Event data query prompting its completion. 
The Death 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. 
COPD exacerbations should not be recorded as an adverse event, unless they meet the 
definition of an SAE (Appendix 6).
9.2.7.
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 <25 kg/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 
 
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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 

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 2 weeks 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. 
 
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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.

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. If the eCRF is unavailable, then a paper version should be 
utilized.

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.
 
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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).
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 and 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 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 
 
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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 (Section 2) 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 
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 (Section 2).
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.
 
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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.
10.
STATISTICAL CONSIDERATIONS
10.1.
Hypotheses
The primary objective of this study is to compare FF/UMEC/VI with 
budesonide/formoterol + tiotropium (BUD/FOR+TIO) in COPD participants. The 
primary endpoint is 0- 24 hour weighted mean (WM) FEV1 at Week 12 (Day 84). The 
primary analysis is the comparison of this endpoint for FF/UMEC/VI vs. BUD/FOR+TIO
with mPP population.  The null hypothesis is that the difference in 0-24 hour WM FEV1
between treatment groups is less than or equal to a pre-specified non-inferiority margin 
Δ:
H0: T1 – T2 ≤ -Δ
The alternative hypothesis is that the difference between treatment groups is greater than 
the margin.
H1: T1 – T2 > -Δ
where T1 and T2 are the treatment means for FF/UMEC/VI and BUD/FOR+TIO, 
respectively.
The non-inferiority margin has been set at 50 mL.This non-inferiority margin for 0-24 
hour WM FEV1 has previously been accepted by the FDA (Combivent vs Ipratropium 
head to head study).
If the lower bound of the two-sided 9 5% confidence interval around the (FF/UMEC/VI
vs. BUD/FOR+TIO,) treatment difference is above -50 mL then FF/UMEC/VI will be 
considered non-inferior to BUD/FOR+TIO. Further treatment comparisons and 
inferences to be made based on P-values are detailed in Section 10.4.1.
10.2.
Sample Size Determination
The sample size calculations use a one-sided 2.5 % significance level and an estimate of 
residual standard deviation (SD) for 0-24 hour WM FEV1 of 230 mL. The estimate of SD 
is based on mixed models repeated measures [MMRM] analyses of past studies in COPD
with 0-24 hour weighted mean as primary endpoint. A study with 620 evaluable 
participants for the primary analysis will have 90 % power to determine non-inferiority of 
FF/UMEC/VI to BUD/FOR+TIO based on 0-24 hour WM FEV1 at Week 12 (Day 84), 
 
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when the margin of non-inferiority is 50 mL and the true mean treatment difference is 
assumed to be 10 mL.
It is estimated that approximately 15 % of participants who are randomised will either 
discontinue IP or be excluded from the modified Per Protocol population at Week 12 and 
approximately 8 % of participants will drop out from 4-week run-in (including those not 
meeting randomisation criteria). Therefore, approximately 800 participants will be 
enrolled to 4-week run-in in order to have 732 participants to be randomised.
 
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10.3.
Populations for Analyses
For purposes of analysis, the following populations are defined:
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.
Run-in 

All participants who are eligible at Screening and entered Run-in 
period. 
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 randomszed 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.
Modified Per Protocol 
(mPP)

All participants in the ITT Population who do not have a full 
protocol deviation considered to impact efficacy.

Data following a COPD exacerbation or pneumonia will be 
excluded from analysis due to the potential impact of the 
exacerbation or the medications used to treat it.

Participants with partial protocol deviations considered to impact 
efficacy will be included in the mPP Population but will have 
their data excluded from analyses from the time of deviation 
onwards.

This population will only be used for the primary analysis for the 
primary endpoint.
 
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10.4.
Statistical Analyses
10.4.1.
Efficacy Analyses
Endpoint
Statistical Analysis Methods
Primary
The primary endpoint, 0-24 hour WM FEV1 on Day 84 will be analyzed with mPP 
population using mixed model repeated measure (MMRM) analysis, including 
covariates such as 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.   Baseline FEV1 is the mean of 
the two assessments made -30 and -5 minutes predose on Treatment Day 1.
Estimated differences between FF/UMEC/VI and BUD/FOR+TIO will be 
presented together with 95 % confidence intervals (CIs) for the treatment 
difference and P-value. The same analysis will be repeated for the ITT 
Population.
Inference to be drawn from the p-values will be as follows:

Analysis with mPP population: If the treatment comparison on the primary 
endpoint has a lower confidence limit below the non-inferiority margin, 
non-inferiority is not demonstrated. No inference will be drawn from p-
values for treatment comparisons on any other endpoints.

Analysis with mPP population: If the treatment comparison on the primary 
endpoint has a lower confidence limit above the non-inferiority margin but 
below 0, non-inferiority is established but the p-value will not be used to 
give an indication of the strength of that noninferiority.  Inference will be 
drawn from p-values for treatment comparisons (with ITT population) on 
other non-lung function endpoints,i.e, SGRQ and CAT, which will be 
called statistically significant if <0.05. No inference will be drawn from p-
values on trough FEV1 endpoint. Analysis with ITT population: If the 
treatment comparison on the primary endpoint has a lower confidence 
limit above 0, superiority is established and the p-value can be used to 
give an indication of the strength of that superiority. Inference will be 
drawn from p-values for treatment comparisons on all other endpoints, 
which will be called statistically significant if <0.05.
A “tipping point” sensitivity analysis of 0-24hour WM FEV1 on Day 84 will be 
conducted for the mPP Population. This will explore the impact of missing data by 
using differing assumptions regarding the mean treatment effect in participants 
who discontinue study treatment or have data excluded from mPP Population 
analyses. Assumptions will include scenarios where participants who discontinue 
FF/UMEC/VI have a lower treatment effect than those who discontinue 
BUD/FOR+TIO. The analysis results will be used to explore the conditions under 
which the conclusion of non-inferiority no longer holds.
 
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Endpoint
Statistical Analysis Methods
If superiority on primary endpoint is established with ITT population, similar 
“tipping point” sensitivity analysis will be conducted for the ITT population in order 
to explore the conditions under which the conclusion of superiority no longer 
holds.
Secondary

Secondary endpoint change from baseline in trough FEV1 will be 
analysed for the ITT Population using a mixed model repeated measures 
(MMRM) analysis, including trough FEV1 recorded at each of visits, Day
2, 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 TIO will be presented together 
with 95 % CIs for the difference and p-values.
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 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.
 
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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.
10.4.5.
Exploratory Analyses
These exploratory analyses may be provided in a separate RAP.
 
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11.
REFERENCES
Aaron SD, Vandemheen KL, Fergusson D, Maltais F, Bourbeau J, Goldstein R, Balter M 
et al. (2007) Tiotropium in Combination with Placebo, Salmeterol, or Fluticasone–
Salmeterol for Treatment of Chronic Obstructive Pulmonary Disease A Randomised 
Trial. Ann Intern Med. 146:545-555.
Cazzola M, Andò F, Santus P, Ruggeri P, Di Marco F, Sanduzzi A et al. A pilot study to 
assess the effects of combining fluticasone propionate/salmeterol and tiotropium on the 
airflow obstruction of patients with severe-to-very severe COPD. Pul Pharm Ther 2007 
20:556–561.
Celli BR, MacNee W, ATS/ERS Task Force. Standards for the diagnosis and treatment of 
patients with COPD: A summary of the ATS/ERS position paper.  Eur Respir J 2004; 23: 
932-946.
Christensson C, Thoren A, Lindberg B. Safety of inhaled budesonide: clinical 
manifestations of systemic corticosteroid-related adverse effects. Drug Safety. 
2008;31:965-988.
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(2):641-647.
De Bisschop MB, Bellou A. Anaphylaxis. Current Opinion in Critical Care. 
2012;18(4):308-317.
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: 
http://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.
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 
 
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Jones, PW., Harding, G., Wiklund, I., Berry, P., Tabberer, M., Yu, R., et al. ‘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 randomised 
controlled study. Resp. Med. (2012) 106: 382-389 doi:10.1016/j.rmed.2011.09.004.
Lehouck A, Boonen S, Decramer M, Janssens W. COPD, bone metabolism, and 
osteoporosis. Chest. 2011;139:648-657.
Lipson DA, Barnacle H, Birk R, Brealey N, Locantore N, Lomas DA, et al. FULFIL 
Trial: Once-Daily Triple Therapy in Patients with Chronic Obstructive Pulmonary 
Disease. Am J Respir Crit Care Med 2017;10.1164/rccm.201703-0449OC.
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, Odencrantz J, Standardisation of spirometry. Eur Respir J. 
2005;26:319-388.
Niggemann B, Beyer K. Factors augmenting allergic reactions. Allergy. 
2014;69(12):1582-1587.
Packe GE, Cayton RM, Mashhoudi N. Nebulised ipratropium bromide and salbutamol
causing closed-angle glaucoma. Lancet.1984;22:691.
Quanjer P, Stanojevic S, Cole T, Baur X, Hall G, Culver B, et al. Multi-ethnic reference 
values for spirometry for the 3-95-yr age range: The global lung function 2012 equations. 
Eur Respir J 2012;, 40: 1324-1343.
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(2):257-268.
Siler, TM, Kerwin, E, Sousa, AR, Donald, A, Ali, R, Church, A. (2015) Efficacy and 
safety of umeclidinium added to fluticasone furoate/vilanterol in chronic obstructive 
pulmonary disease: results of two randomized studies. Respir Med. 109(9), 1155-1163.
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.
Weldon D. The effects of corticosteroids on bone growth and bone density. Ann. Allergy 
Asthma Immunol. 2009;103:3-11.
 
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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 (2012) 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. Abstract 62. 
 
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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
BPM
Beats per minute
BMI
Body Mass Index
BUD
Budesonide
BUN
Blood Urea Nitrogen
CAT
COPD Assessment Test
CFR
Code of Federal Regulations
CI
Confidence Interval
CIOMS
Council for International Organizations of Medical Sciences
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic Obstructive Pulmonary Disease
CPRD
Clinical Practice Research Database
CT
Computerized Tomography
CV
Cardiovascular
CYP
Cytochrome P450
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
 
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HCP
Health Care Provider
HIPAA
Health Insurance Portability and Accountability Act
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
IUD
Intrauterine device
IUS
Intrauterine Hormone-Releasing System
IWRS
Interactive Web Response System
ITT
Intent-to-Treat
Kg/m2
Kilograms per meter squared
LABA
Long-Acting Beta-2-Agonists
LAMA
Long-Acting Muscarinic Antagonist
LRTI
Lower Respiratory Tract Infection
LTOT
Long-term oxygen therapy
MACE
Major Adverse Cardiac Event
MAOI
Monoamine Oxidase Inhibitors
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
PRAC
Pharmacovigilance Risk Assessment Committee
QTc
QT interval corrected for heart rate
QTcB
QT interval corrected for heart rate by Bazett’s formula
QTcF
QT interval corrected for heart rate by Fridericia’s formula
 
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RAP
Reporting and Analysis Plan
RBC
Red Blood Cell
RNA
Ribonucleic acid
SAE
Serious Adverse Event
SD
Standard Deviation
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic-Pyruvic Transaminase
SGRQ-C
St. George’s Respiratory Questionnaire for COPD patients
SMQ
Standardised MedDRA Queries
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
VT
Ventricular Tachycardia
WBC
White Blood Cell
WM
Weighted Mean
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
Spiriva Handihaler
Symbicort
 
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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 participants. 

The Investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 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. 

Participants must be informed that their participation is voluntary. Participants
or their legally authorized representative will be required to sign a statement of 
 
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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.
 
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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 physically or 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. 
 
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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
 
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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 participant’s 
medical records, medical examination, or medical history interview.
3. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment.
Contraception Guidance
Female Participants
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in
Table 7. 
 
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Table 7
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 participants 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 
 
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
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 foetal 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.
 
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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) 
International 
Normalized 
Ratio (INR)2
ALT 3x ULN and INR >1.5, if INR measured
Cannot 
Monitor
ALT 5x ULN but <8x ULN and cannot be monitored weekly for 2 weeks
ALT 3x ULN but <5x ULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3x ULN associated with symptoms (new or worsening) believed to be 
related to  liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue  study treatment 

Report the event to GSK within 24 hours

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 

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
 
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(see MONITORING below)

Do not restart/rechallenge participant with 
study treatment unless allowed per protocol 

If restart/rechallenge not allowed per 
protocol , permanently discontinue study 
treatment and may continue participant in the 
study for any protocol specified follow up 
assessments
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24 
hrs

Monitor participants twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 
recommended
For All other criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24-
72 hrs 

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

Serum creatine phosphokinase and lactate 
dehydrogenase.

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form
including acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG or gamma 
globulins).

Serum acetaminophen adduct HPLC 
assay (quantifies potential acetaminophen 
contribution to liver injury in participants 
with definite or likely acetaminophen use 
in the preceding week [James, 2009]). 
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 participant if ALT 3x ULN and bilirubin 2x ULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3x ULN and bilirubin 2x ULN (>35 % direct bilirubin) or ALT 3x ULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to participants receiving anticoagulants
 
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3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)   
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
5.
If hepatitis delta antibody assay cannot be performed, it can be replaced with a PCR of hepatitis D RNA virus 
(where needed) [Le Gal, 2005].
6.
PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
treatments.  Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
treatment prior to blood sample draw on the eCRF. If the date or time of the last dose is unclear, provide the 
participant’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot 
be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and 
shipping are in the SPM.  
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, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
 
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Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E.  Quantification 
of Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates 
Different Patterns of Virological Response to Interferon Therapy in Chronically Infected 
Patients.  J Clin Microbiol. 2005;43(5):2363–2369.
 
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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
 
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
Other respiratory related disease
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
 
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
Any course of oral/systemic corticosteroids started within 7 days of finishing a 
previous course will be considered as treatment for a single exacerbation
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.
 
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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.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
 
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assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
 
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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
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.
 
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
It is not acceptable for the Investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the 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 
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 
 
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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 
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.
 
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
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.
 
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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 

Foetal distress, foetal death, or any congenital abnormality or birth defects
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.
 
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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.
 
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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.
 
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Table 8
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 CRF.
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 x ULN (>35 % direct bilirubin) or ALT 3 x 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.
 
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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.
 
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12.10.
Appendix 10: Country-specific requirements
There are currently no country specific requirements. 
 
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