A Phase IV, 12 Week, Randomised, Double-blind, Double-dummy Study to Compare Single Inhaler Triple Therapy, Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI), With Tiotropium Monotherapy Based on Lung Function and Symptoms in Participants With Chronic Obstructive Pulmonary Disease
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, double-dummy study to 
compare single inhaler triple therapy, fluticasone furoate/umeclidinium/vilanterol
(FF/UMEC/VI), with tiotropium monotherapy based on lung function and symptoms in 
participants with chronic obstructive pulmonary disease
Protocol Number: 207626/ 01
Short Title: A randomised study, comparing FF/UMEC/VI single inhaler triple therapy
versus tiotropium monotherapy in participants with chronic obstructive pulmonary 
disease
Compound Number:
GSK573719+GW642444+GW685698 (GSK2834425)
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information can be found in the Study 
Reference Manual
Regulatory Agency Identifying Number(s): IND number 114873, EudraCT Number
2017-001190-16
Approval Date: 17-JUL-2018
Copyright 2018 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 1
17-Jul-2018
Original Protocol
11-Oct-2017
Amendment 1 17-July-2018
Overall Rationale for the Amendment: This amendment is required to update the QTc 
stopping criteria to that which was used in the Phase III Trelegy registration studies.  In 
addition, a section describing Smoking Cessation Counselling has been added as does a 
corresponding assessment at the end of study (Visit 4).  Clarified that run-in treatment 
should be collected at Visit 2, study treatment at Visit 3, and albuterol/salbutamol at Visit 
5.  Also, wording regarding suggested order for assessments and procedures has been 
added to the end of the Schedule of Activities section.  Removed reference to Fridericia 
formula in calculation of QTc.  Clarification regarding collecting the CAT assessment 
questionnaire prior to the SGRQ-C has also been provided along with clarification that 
vital signs should be collected before the ECG and prior to spirometry.  Also added 
clarification that CAT and SGRQ-C will both be collected at Visit 3 to mirror the SoA.  
Corrected reporting time regarding pregnancy.  Finally, added wording to Genetics 
Appendix 9 regarding withdraw process and sample destruction process.
 
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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
Section 2
Schedule of 
Activities (SOA) 
Added Smoking Cessation 
Counselling to Visit 4
Added collecting run-in 
treatment at Visit 2
Added collecting study 
treatment at Visit 3
Added collecting 
albuterol/salbutamol at Visit 5 
Added wording regarding 
order for assessments and 
procedures (CAT, SGRQ-C, 
Vitals, ECG, Spirometry, 
Clinical Lab Assessments)
Clarified that Smoking Cessation 
Counselling will also be collected 
at Visit 4
Clarified that run-in medication 
should be collected at Visit 2
Clarified that study treatment 
should be collected at Visit 3
Clarified that rescue medication 
(albuterol/salbutamol) should be 
collected at Visit 5
Clarified the requested order of 
assessments and procedures at 
visits (1 and 2 in particular) when 
a number of assessments and 
procedures are collected and 
performed
Section 6.2
Exclusion Criteria 
13
Removed reference to 
Fridericia formula in 
calculation of QTc
Fridericia and Bazett formulas 
provide equal safety in calculation 
of QTc and either may be used if 
done consistently throughout the 
study
 
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Section 8.1
QTc Stopping 
Criteria
Updated QTc stopping criteria 
to:
an increase in QTc by 
> 60 msec from 
baseline or 
development of a QTc 
> 530 msec (based on 
an average of 
triplicate ECGs)
NOTE:  These criteria should 
be based on the average of 
QTc value of triplicate ECGs.  
For example, if an ECG 
demonstrates a prolonged QT 
interval, two more ECGs will 
be obtained over a brief period 
and then the averaged QTc 
value of the three ECGs will 
be used to determine whether 
the patient should be 
discontinued from the study
Adapted the QTc stopping criteria 
to be in line with stopping criteria 
from the registration Phase III 
Trelegy Studies
Section 9.1.1
Spirometry
Corrected:  If applicable, after 
completing the health 
outcomes assessments (CAT 
should be administered first 
followed by SGRQ-C)
CAT is a shorter assessment 
questionnaire to complete and the 
participant will already have 
experience completing this at 
Screening Visit 1
Section 9.1.2
SGRQ-C
Corrected to match SoA that  
SGRQ-C will also be collected 
at Visit 3
Added wording regarding 
CAT should be collected prior 
to SGRQ-C 
Clarified that SGRQ-C should 
also be collected at Visit 3 as 
outlined in the SoA
CAT is a shorter assessment 
questionnaire to complete and the 
participant will already have 
experience completing this at 
Screening Visit 1
Section 9.1.3
CAT
Corrected to match SoA that 
CAT will also be collected at 
Visit 3
Added wording regarding 
CAT should be collected prior 
to SGRQ-C 
Clarified that CAT should also be 
collected at Visit 3 as outlined in 
the SoA
CAT is a shorter assessment 
questionnaire to complete and the 
participant will already have 
experience completing this at 
Screening Visit 1
 
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Section 9.2.9
Pregnancy
Corrected to match Appendix 
3:  If a pregnancy is reported, 
the Investigator should inform 
GSK within 24 hours of 
learning of the pregnancy and 
should follow the procedures 
outlined in Appendix 3
Clarified that the reporting period 
for pregnancy should be within 24 
hours of learning of the pregnancy 
and not 2 weeks as previously 
written
Section 9.4.3
Electrocardiograms
Corrected:  A single 12-lead 
ECG and rhythm strip will be 
recorded after measurement of 
vital signs and prior to 
spirometry
Clarified that the ECG should be 
collected after the vital signs and 
prior to spirometry
Section 9.10
Smoking Cessation 
Counselling
Added Section 9.10
Smoking Cessation 
Counselling
Explained the reasoning and 
expectations for the Smoking 
Cessation Counselling
Appendix 9
Genetics
Added wording for both 
withdraw process and 
destruction process
Explained what should be done if 
a participant withdraws consent 
along with the destruction of 
samples after the storage period or 
on withdrawal of consent
 
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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS.............................................................................................................10
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................17
3.
INTRODUCTION....................................................................................................19
3.1.
Study Rationale ..........................................................................................19
3.2.
Background ................................................................................................21
3.3.
Benefit/Risk Assessment ............................................................................23
3.3.1.
Risk Assessment .........................................................................24
3.3.2.
Risk Assessment for Tiotropium Bromide 18 mcg........................35
3.3.3.
Benefit Assessment.....................................................................35
3.3.4.
Overall Benefit:Risk Conclusion...................................................36
4.
OBJECTIVES AND ENDPOINTS...........................................................................37
5.
STUDY DESIGN ....................................................................................................38
5.1.
Overall Design ............................................................................................38
5.2.
Number of Participants ...............................................................................40
5.3.
Participant and Study Completion...............................................................40
5.4.
Scientific Rationale for Study Design ..........................................................40
5.5.
Dose Justification........................................................................................41
6.
STUDY POPULATION...........................................................................................41
6.1.
Inclusion Criteria.........................................................................................41
6.2.
Exclusion Criteria........................................................................................42
6.3.
Randomisation Criteria ...............................................................................47
6.4.
Lifestyle Restrictions...................................................................................47
6.5.
Pre-screening/Screening/Run-in/Randomisation Failures...........................47
7.
TREATMENTS.......................................................................................................48
7.1.
Treatment Groups and Duration .................................................................48
7.1.1.
Medical Devices...........................................................................51
7.2.
Dose Modification .......................................................................................51
7.3.
Method of Treatment Assignment ...............................................................51
7.4.
Blinding.......................................................................................................51
7.5.
Preparation/Handling/Storage/Accountability..............................................52
7.6.
Treatment Compliance................................................................................53
7.7.
Concomitant Therapy..................................................................................53
7.7.1.
Permitted Medications and Non-Drug Therapies..........................53
7.7.1.1.
Permitted COPD Medications.....................................53
7.7.1.2.
Permitted Non-COPD Medications .............................54
7.7.2.
Prohibited Medications and Non-Drug Therapies.........................55
7.8.
Treatment after the End of the Study ..........................................................57
8.
DISCONTINUATION CRITERIA.............................................................................57
8.1.
Discontinuation of Study Treatment ............................................................57
8.1.1.
Rechallenge.................................................................................59
 
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8.1.1.1.
Study Treatment Restart or Rechallenge....................59
8.2.
Withdrawal from the Study..........................................................................59
8.3.
Lost to Follow Up........................................................................................59
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................60
9.1.
Efficacy Assessments.................................................................................61
9.1.1.
Spirometry ...................................................................................61
9.1.1.1.
Reversibility................................................................62
9.1.2.
SGRQ-C ......................................................................................62
9.1.3.
COPD Assessment Test (CAT)....................................................63
9.1.4.
COPD Exacerbations...................................................................63
9.2.
Adverse Events...........................................................................................63
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................64
9.2.2.
Method of Detecting AEs and SAEs.............................................64
9.2.3.
Follow-up of AEs and SAEs.........................................................64
9.2.4.
Regulatory Reporting Requirements for SAEs .............................65
9.2.5.
Cardiovascular and Death Events................................................65
9.2.6.
Disease-Related Outcomes – COPD exacerbations ....................65
9.2.7.
COPD exacerbations should not be recorded as an 
adverse event, unless they meet the definition of an SAE 
(Appendix 6).Pneumonia .............................................................66
9.2.8.
Sentinel Events............................................................................66
9.2.9.
Pregnancy ...................................................................................67
9.2.10.
Medical Device Incidents (Including Malfunctions).......................67
9.2.10.1.
Time Period for Detecting Medical Device 
Incidents.....................................................................67
9.2.10.2.
Follow-up of Medical Device Incidents........................67
9.2.10.3.
Prompt Reporting of Medical Device Incidents 
to Sponsor..................................................................68
9.2.10.4.
Regulatory Reporting Requirements for 
Medical Device Incidents............................................68
9.3.
Treatment of Overdose...............................................................................68
9.4.
Safety Assessments ...................................................................................68
9.4.1.
Physical Examinations.................................................................69
9.4.2.
Vital Signs....................................................................................69
9.4.3.
Electrocardiograms......................................................................69
9.4.4.
Clinical Safety Laboratory Assessments ......................................69
9.5.
Pharmacokinetics .......................................................................................70
9.6.
Pharmacodynamics ....................................................................................70
9.7.
Genetics .....................................................................................................70
9.8.
Biomarkers .................................................................................................70
9.9.
Medical Resource Utilization and Health Economics ..................................70
9.10.
Smoking Cessation Counselling .................................................................70
10. STATISTICAL CONSIDERATIONS........................................................................71
10.1.
Hypotheses.................................................................................................71
10.2.
Sample Size Determination ........................................................................71
10.3.
Populations for Analyses ............................................................................71
10.4.
Statistical Analyses.....................................................................................72
10.4.1.
Efficacy Analyses.........................................................................72
10.4.2.
Safety Analyses...........................................................................73
 
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10.4.3.
Other Analyses ............................................................................73
10.4.4.
Interim Analyses ..........................................................................73
10.4.5.
Exploratory Analyses ...................................................................74
11. REFERENCES.......................................................................................................75
12. APPENDICES........................................................................................................78
12.1.
Appendix 1: Abbreviations and Trademarks................................................78
12.2.
Appendix 2: Study Governance Considerations..........................................81
12.3.
Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................85
12.4.
Appendix 4: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................88
12.5.
Appendix 5: COPD Exacerbation Identification, Categorization and 
Treatment Guidelines..................................................................................91
12.5.1.
Guidelines for Identifying COPD Exacerbations...........................91
12.5.2.
COPD Exacerbation Severity.......................................................92
12.5.3.
Treatment of COPD Exacerbations..............................................92
12.5.4.
Guidelines for Treatment with Corticosteroids..............................92
12.5.5.
Guidelines for Treatment with Antibiotics .....................................93
12.5.6.
Onset and Resolution of COPD Exacerbations............................93
12.5.7.
Guideline for assessing multiple mild exacerbations ....................93
12.5.8.
Guideline for assessing exacerbations that increase in 
severity ........................................................................................93
12.6.
Appendix 6: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................94
12.7.
Appendix 7: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .....................................100
12.8.
Appendix 8: Clinical Laboratory Tests.......................................................102
12.9.
Appendix 9: Genetics................................................................................104
12.10. Appendix 10: Country-specific requirements.............................................105
12.11. Appendix 11: Protocol Amendment History...............................................106
 
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1.
SYNOPSIS
Protocol Title: A Phase IV, 12 week, randomised, double-blind, double dummy study to 
compare single inhaler triple therapy, fluticasone furoate/umeclidinium/vilanterol
(FF/UMEC/VI), with tiotropium monotherapy based on lung function and symptoms in 
participants with chronic obstructive pulmonary disease
Short Title: A randomised study, comparing FF/UMEC/VI single inhaler triple therapy
versus tiotropium monotherapy in participants with chronic obstructive pulmonary 
disease
Rationale:  Chronic obstructive pulmonary disease (COPD) guidelines advocate the use 
of long-acting muscarinic receptor antagonists (LAMA) added to the combination of an 
inhaled corticosteroid (ICS) plus a long-acting β2-adrenergic receptor agonists (LABA) as 
second line therapy for the most advanced patients with significant symptoms and a high 
risk of exacerbations. Regular treatment with ICS-containing regimens has been reported 
to improve respiratory symptoms, lung function, health related quality of life (HRQoL) 
and reduce the frequency of COPD exacerbations in patients with a forced expiratory 
flow in 1 second (FEV1) <60 % predicted.
Population based studies of COPD treatment patterns demonstrate that ‘open’ triple 
therapy (use of ICS/LAMA/LABA delivered via multiple inhalers) is already widely used 
in the real-life management of COPD. In 2011, 26 % of patients in the United States (US)
who were taking controller medicines for the treatment of COPD were taking an ‘open’
triple therapy, typically by adding fluticasone propionate/salmeterol (ICS/LABA) to 
tiotropium (LAMA) or vice versa A study in the United Kingdom (UK) Clinical Practice 
Research Database (CPRD) revealed that over a two-year period of time, 35 % of COPD 
patients initially prescribed a LAMA and 39 % initially prescribed an ICS/LABA stepped 
up to an ‘open’ triple therapy regimen. In the four-year long-term safety study conducted 
with tiotropium, 46 % of patients were receiving a concurrent fixed combination of 
ICS/LABA in addition to tiotropium. 
A number of studies have assessed the use of an ‘open’ triple therapy of fluticasone 
propionate/salmeterol or budesonide/formoterol (ICS/LABA) with tiotropium in 
moderate-severe COPD patients. These studies have reported greater improvements in 
lung function, HRQoL, hospitalization rates and rescue medication use, compared to dual 
(ICS/LABA) or LAMA alone, thus supporting the use of triple therapy in COPD.These 
studies have also shown that the number and type of reported adverse events (AE) were 
generally similar with administration of dual or monotherapy doses for periods of up to 
one year, and were mostly related to their pharmacological mode of action.
GlaxoSmithKline (GSK) is currently developing a once-daily ‘closed’ triple therapy of a 
ICS/LAMA/LABA combination [fluticasone furoate (FF)/umeclidinium 
(UMEC)/vilanterol (VI) (100/62.5/25 mcg)] in a single inhaler, with the aim of providing 
a new treatment option for the management of symptomatic COPD patients at risk for 
exacerbations which will reduce the exacerbation frequency, allow for a reduced burden 
of polypharmacy, convenience, and increase the potential for improvement in lung 
function, HRQoL and symptom control over established dual/monotherapies.
 
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GSK conducted a Phase III study comparing once-daily FF/UMEC/VI to twice-daily 
budesonide/formoterol (400/12 mcg) in COPD participants that were symptomatic and at 
risk of an exacerbation despite receiving maintenance therapy (CTT116853). 
FF/UMEC/VI demonstrated statistically significant improvements in trough FEV1, a 
statistically significant reduction in the annual rate of moderate or severe COPD 
exacerbations, and a statistically significant reduction of COPD symptoms (using 
Exacerbations and Chronic Pulmonary Disease – Respiratory Symptoms [EXACT-RS]) 
when compared to budesonide/formoterol. Additionally, clinically meaningful 
improvements from baseline in St. George’s Respiratory Questionnaire (SGRQ) total 
score were observed, with a statistically significant improvement compared to 
budesonide/formoterol. This Phase III study provided compelling efficacy data compared 
with an established ICS/LABA and demonstrated the clinical value of single inhaler 
triple-therapy compared to ICS/LABA therapy in patients with COPD. 
As fixed dose combinations of LAMA/LABA therapy remain relatively new, and ICS 
monotherapy is not indicated for the treatment of COPD, the two most frequent treatment 
pathways that lead to ‘open’ triple therapy are the escalation of therapy from either an 
ICS/LABA fixed dose combination or from LAMA monotherapy. A prior study 
demonstrated that participants with COPD may remain symptomatic despite the use of 
LAMA or LABA monotherapy. Participants that remained symptomatic despite treatment 
with LAMA monotherapy, stepped up to ‘open’ triple therapy by the addition of 
ICS/LABA therapy, which resulted in greater improvements in lung function and 
HRQoL, compared LAMA monotherapy.
The primary purpose of this study is to evaluate lung function and HRQoL after 84 days 
of treatment with a single inhaler triple therapy combination of FF/ UMEC/VI 
(100/62.5/25 mcg) once daily via the ELLIPTA™compared with tiotropium (18 mcg) 
once daily, in a patient population appropriate for triple therapy.
Objectives and Endpoints:
Objectives
Endpoints
Primary
To evaluate the effect of single inhaler 
triple therapy (FF/UMEC/VI) compared 
to tiotropium after 12 weeks of 
treatment on lung function
Primary
Change from baseline in trough FEV1 at 
Week 12 (Day 85)
Secondary 
Change from baseline in trough FEV1
on Day 28 and Day 84
 
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Objectives
Endpoints
Other
To evaluate the effect of single inhaler 
triple therapy (FF/UMEC/VI) compared 
to tiotropium after 12 weeks of 
treatment on Health Status
Proportion of responders based on the St 
George’s Respiratory Questionnaire 
(SGRQ) Total Score at Week 4 and
Week 12
Change from baseline in SGRQ Total 
Score at Week 4 and Week 12
To evaluate the effect of single inhaler 
triple therapy (FF/UMEC/VI) compared 
to tiotropium after 12 weeks of 
treatment on Health Status
Proportion of responders based on the 
COPD Assessment Test (CAT) Total 
Score at Week 4 and Week 12
Change from baseline in CAT Total 
Score at Week 4 and Week 12
To evaluate the effect of single inhaler 
triple therapy (FF/UMEC/VI) compared 
to tiotropium after 12 weeks of 
treatment on COPD exacerbations
Moderate or severe exacerbation event
Safety
To evaluate the safety profile of single 
inhaler triple therapy (FF/UMEC/VI) 
compared to tiotropium over 12 weeks
of treatment 
Incidence of adverse events

Vital signs
Overall Design:
This is a Phase IV, 12-week, randomised, double-blind, double-dummy, parallel group,
multicentre study evaluating once-daily single inhaler triple therapy (FF/UMEC/VI) 
delivered via the ELLIPTA, compared to once daily tiotropium, in participants with 
COPD. 
 
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Study design schema
Eligible participants at Screening (Visit 1) will be current or former smokers, with an 
established clinical history of COPD, receiving daily maintenance therapy with 
tiotropium alone for at least 3 months (no ICS or LABA maintenance therapy is allowed 
during the 3 months prior to screening), with a post-bronchodilator FEV1 of <50 % 
predicted (or <80 % predicted with a documented history of at least 2 moderate or 1 
severe [hospitalized] exacerbation in the last 12 months) and a CAT score of 10. 
Participants will be requested to participate in the study for approximately 17 weeks, 
consisting of a 4-week run-in period, 12-week treatment period and a 1-week follow-up 
period. 

Pre-screening: Details about the study and procedures will be explained 
through the informed consent process. The Pre-screening Visit (Visit 0), 
including the informed consent process, must be completed prior to any 
protocol-required changes to a participant’s usual COPD treatment and the 
initiation of any Visit 1 procedures. Participants will continue treatment with 
their regular (i.e. pre-study) tiotropium monotherapy during the pre-screening 
period.

Screening/run-in: Eligible participants will be allowed to continue their usual 
tiotropium monotherapy COPD medication until the day before Screening, Visit 
1.  On the morning of the Screening Visit participants will refrain from taking 
their morning dose of tiotropium. Participants who meet all of the eligibility 
criteria at Visit 1 (Screening), will enter the 4-week run-in period.
Participants will discontinue existing tiotropium medication and will take open-
label tiotropium 18 mcg via the HandiHaler once daily plus placebo via the 
ELLIPTA. Participants will not use any other COPD medications (except for 
those allowed per protocol). 
 
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During the run-in period participants will also take placebo via the ELLIPTA in 
addition to open-label tiotropium. This will familiarise participants with the use 
of the ELLIPTA device and will help ensure participants are compliant and use 
both devices as instructed.
Participants will be provided with short-acting albuterol/salbutamol to be used 
on an as-needed basis (rescue medication) throughout the study. At Screening, 
each participant will be instructed on the proper use of the ELLIPTA and 
HandiHaler and will self-administer their first doses of their run-in treatment 
during the Screening Visit. On the morning of the other study visits (Visit 2 
onwards), participants will refrain from taking their morning dose of study 
treatment until instructed to do so by clinic personnel. 

Randomisation/treatment: On the morning of the day before the 
Randomisation Visit (Visit 2), participants will take their last dose of run-in 
treatment and will not use any other COPD medications (except for those 
allowed per protocol.  Rescue albuterol/salbutamol can be used throughout the 
study as-needed but must be withheld for at least 4 hours prior to conducting 
spirometry.
At Visit 2 (the Randomisation Visit), participants who meet all of the 
randomisation criteria will be randomised 1:1 to receive one the following 
double-blind study treatments for 84 days:

FF/UMEC/VI 100/62.5/25 mcg via the ELLIPTA once daily in the morning
+ placebo to match tiotropium via HandiHaler once daily in the morning

Tiotropium 18 mcg via HandiHaler once daily in the morning
+ placebo via the ELLIPTA once daily in the morning
Participants may continue their study-supplied rescue albuterol/salbutamol. On 
the morning of Visits 3 and 4, participants will refrain from taking their morning 
dose of study treatment until instructed to do so by clinic personnel. At Visits 2, 
3, and 4 participants will self-administer study treatment whilst at the clinic. 
Participants will take their last dose of study treatment in the clinic on Day 84 
and then return to the clinic on Day 85 (Visit 5) for their final clinical 
assessments. Participants are expected on non-clinic visit days to take their study 
treatment at home in the morning at approximately the same time each day, as 
directed by the clinic. 

Safety/follow-up: A safety follow-up telephone contact or clinic study visit 
(Visit 6) will be conducted approximately 7 days after the participant completes 
all of the protocol-defined procedures for Visit 5/End of Study (EOS) or, if 
applicable, the Study Treatment Discontinuation Visit. A participant will be 
considered to have completed the study when they have completed all phases of 
the study including screening, run-in, the randomised treatment phase, and
safety follow-up.
 
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Participants that permanently discontinue study treatment are not required to withdraw 
from the study. If for any reason a participant must permanently discontinue study 
treatment, every effort should be made by the Investigator/staff to keep the participant in 
the study and complete all remaining protocol specified clinic visits.However, a 
participant may voluntarily withdraw from participation in this study at any time. The 
Investigator may also, at his or her discretion, withdraw a participant from further study 
participation. Participants who are withdrawn from the study will not be replaced.
A participant will be considered to have completed the study when they have completed 
all phases of the study including screening, run-in, the randomised treatment phase, and
safety follow-up.
Number of Participants:
Approximately 848 participants with advanced COPD will enter the run-in period, in 
order to randomise approximately 780 participants, in order to achieve an estimated 702 
evaluble participants.
Approximately 100 centres globally will be required to recruit the study.
Treatment Groups and Duration:
Participants who meet all the eligibility criteria and who have successfully completed all 
protocol procedures at Screening will enter the 4-week run-in period and will take open-
label tiotropium 18 mcg via the HandiHaler once daily plus placebo via the 
ELLIPTA.Following the run-in period, eligible participants will be randomised (1:1) to 
one of the following double-blind, double-dummy treatment groups for 84 days:
Either:

FF/UMEC/VI 100/62.5/25 mcg via the ELLIPTA once daily in the morning
      +  placebo to match tiotropium via HandiHaler once daily in the morning
or,

Tiotropium 18 mcg via HandiHaler once daily in the morning
       + placebo via the ELLIPTA once daily in the morning
The ELLIPTA contains 30 doses (FF/UMEC/VI or placebo) and participants will be
instructed to administer one dose from their ELLIPTA once daily in the morning.
Tiotropium or matching placebo: Contents of 1 capsule (18 mcg) inhaled once daily 
using HandiHaler device. Note: To ensure drug delivery, two inhalations of the contents 
of each capsule should be performed.
 
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Key Elements of Analysis Plan:
The primary objective of this study is to compare single inhaler triple therapy 
(FF/UMEC/VI) with tiotropium (TIO) in participants with COPD who have received 
tiotropium and continue to have symptoms as measured by CAT 10. The primary 
endpoint is trough FEV₁ at Week 12 (Day 85). The primary analysis is the comparison of 
this endpoint between FF/UMEC/VI and tiotropium.   
The null hypothesis is that there is no difference between treatment groups.
H0: T1 – T2 = 0
The alternative hypothesis is there is a difference between treatment groups.
H1: T1 – T2 0
where T1 and T2 are the treatment means for FF/UMEC/VI and TIO, respectively.
The primary analyses will be based on the ITT population using only data collected on
treatment, the analysis will evaluate the endpoint of trough FEV1 using a mixed model 
repeated measures (MMRM) analysis, including on-treatment trough FEV1 recorded at 
each of visits, Day 28, Day 84 and Day 85. The model will include covariates of baseline 
FEV1, visit, geographical region, treatment and visit by baseline interaction. A visit by 
treatment interaction term will also be included to allow treatment effects to be estimated 
at each visit separately. The variance-covariance matrix will be assumed unstructured.
Estimated differences between FF/UMEC/VI and tiotropium will be presented together 
with 95 % confidence intervals (CIs) for the difference and p-values.
The details of the statistical analysis methods for the secondary efficacy endpoint will be 
provided in the Reporting and Analysis Plan (RAP). 
 
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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
Visit 5
Study 
Treatment 
Discontinuation 
Visit
Visit 6 
Safety
Follow-
up 
Contact
Study Day
-56 to  
-28
Day -28
Day 1
Day 28
Day 84
Day 85
Day 91
Week
-8 to -4
-4
0
4
12
12
13
Window
-3/+8d
(Day -31 
to -21)
-4/+2d 
(Day 24 
to 30)
-4/+2d
(Day 80 
to 86)
-1/+4d
(Day 90 
to 95)
Written Informed 
Consenta,
X
X
Genetic Informed 
Consentb
X
X
Demographyc
X
X
Medical History, including 
cardiovascular history
X
COPD and Exacerbation 
History
X
Concomitant Medication 
Assessment
X
X
X
X
X
X
X
Inclusion/Exclusion 
Criteria
X
X
Smoking History
X
Smoking status
X
X
X
Smoking Cessation 
Counselling
X
X
X
Register Visit in IWRS
X
X
X
X
X
X
X
CATd
X
X
X
X
SGRQ-Cd
X
X
X
Reversibility Testinge
X
Trough Spirometryf
X
X
X
X
Device training and 
registration
X
X
Exacerbation 
Assessment
X
X
X
X
X
X
Physical examinationg
X
X
X
Adverse Events 
Assessment
X
X
X
X
X
X
Vital signsh
X
X
X
ECG
X
Chest X-rayi
X
Oropharyngeal 
examination
X
X
X
X
X
Blood Draw for Genetics 
researchj
X
Hematology/biochemistryk
X
Urine Pregnancy Test l
X
X
X
Hepatitis B and C tests 
X
 
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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
Visit 5
Study 
Treatment 
Discontinuation 
Visit
Visit 6 
Safety
Follow-
up 
Contact
Study Day
-56 to  
-28
Day -28
Day 1
Day 28
Day 84
Day 85
Day 91
Week
-8 to -4
-4
0
4
12
12
13
Window
-3/+8d
(Day -31 
to -21)
-4/+2d 
(Day 24 
to 30)
-4/+2d
(Day 80 
to 86)
-1/+4d
(Day 90 
to 95)
Dispense run-in treatment
X
Dispense study treatment
X
X
Administer run-in 
treatment in clinic m
X
Administer study 
treatment in clinic n
X
X
X
Assess run-in treatment 
compliance
X
Collect run-in treatment
X
Assess study treatment 
compliance
X
X
X
Collect study treatment
X
X
X
Dispense 
albuterol/salbutamol
X
X
X
X
Collect 
albuterol/salbutamol
X
X
X
X
X
Dispense paper Medical 
Problems worksheet
X
X
X
X
X
Review paper Medical 
Problems worksheet
X
X
X
X
X
X
 
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a.
Informed consent must be conducted at the Pre-screen Visit prior to performing any study procedures                 
including the changing or withholding of medications. The informed consent may be given at Screening Visit 1 if 
the participant does not take or has not taken any protocol excluded medications. The Pre-screen and 
Screening Visits can occur on the same day.
b.
Genetics research consent may be obtained at the same time as the study informed consent and must be 
obtained prior to obtaining a genetic blood sample. The sample can be collected at any time after Visit 2, 
providing consent is obtained.
c.
Demography may be captured at either the Pre-screen Visit or Screening Visit.
d.
SGRQ-C and CAT will be completed electronically, and should be conducted in the following order and before 
other study assessments: CAT, SGRQ-C.
e.
At Screening Visit 1 both pre and post-bronchodilator spirometry will be conducted. Participants are required to 
withhold their usual morning doses of their COPD meds including rescue albuterol/salbutamol for the protocol  
designated period prior to reversibility testing.
f.
Pre-bronchodilator spirometry will be performed pre-dose at 30 mins and 5 mins prior to taking the morning         
dose of study treatment, between 6am and 11am and after withholding rescue albuterol/salbutamol for ≥4           
hours.  On Day 85, study drug will not be administered following spirometric assessments. 
g.
Physical examination may include height, weight, blood pressure and temperature
h.
Vital signs must be performed prior to spirometry and prior to taking morning dose of study treatment.
i.
Chest X-ray is required at Screening (or historical x-ray obtained within 3 months prior to Screening) and at         
anytime there is a suspected pneumonia or a mod/severe exacerbation
j.
Genetic consent must be obtained prior to obtaining a blood sample.
k.
Hematology and chemistry panels will include full and differential blood count and liver chemistry. See 
Appendix 8. 
l.
All female Participants of child bearing potential will have a urine pregnancy test at Visits 1, 4 and Study 
Treatment Discontinuation Visit (if applicable).
m.
Participants must withhold their morning dose of existing COPD medication/study treatment and not take their 
treatment until instructed to do so by study staff
n.
Participants must withhold their morning dose of study treatment at each clinic visit and not take their study         
treatment until instructed to do so by study staff
When multiple assessments and procedures are performed suggested order is CAT, 
SGRQ-C, vitals, ECG, spirometry, clinical lab assessments.
3.
INTRODUCTION
3.1.
Study Rationale
Chronic obstructive pulmonary disease (COPD) guidelines advocate the use of long-
acting muscarinic receptor antagonists (LAMA) added to the combination of an inhaled 
corticosteroid (ICS) plus a long-acting β2-adrenergic receptor agonists (LABA) as second 
line therapy for the most advanced patients with significant symptoms and a high risk of 
exacerbations. Regular treatment with ICS-containing regimens has been reported to 
improve respiratory symptoms, lung function, health related quality of life (HRQoL) and 
reduce the frequency COPD exacerbations in patients with a forced expiratory flow in 1 
second (FEV1) <60 % predicted [Aaron, 2007; Cazzola, 2007; Hanania, 2012; Jung, 
2012; Siler, 2015; Welte, 2009].
Population based studies of COPD treatment patterns demonstrate that ‘open’ triple 
therapy (use of ICS/LAMA/LABA delivered via multiple inhalers) is already widely used 
in the real-life management of COPD. In 2011, 26 % of patients in the United States (US)
who were taking controller medicines for the treatment of COPD were taking an ‘open’
triple therapy, typically by adding fluticasone propionate/salmeterol (ICS/LABA) to 
 
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tiotropium (LAMA) or vice versa [Wolters, 2012]. A study in the United Kingdom (UK)
Clinical Practice Research Database (CPRD) revealed that over a two year period of time, 
35 % of COPD patients initially prescribed a LAMA and 39 % initially prescribed an 
ICS/LABA stepped up to an ‘open’ triple therapy regimen [Wurst, 2013]. In the four year 
long-term safety study conducted with tiotropium, 46 % of patients were receiving a 
concurrent fixed combination of ICS/LABA in addition to tiotropium [Tashkin, 2008]. 
A number of studies have assessed the use of an ‘open’ triple therapy of fluticasone 
propionate/salmeterol or budesonide/formoterol (ICS/LABA) with tiotropium in 
moderate-severe COPD patients. These studies have reported greater improvements in 
lung function, HRQoL, hospitalization rates and rescue medication use, compared to dual 
(ICS/LABA) or LAMA alone, thus supporting the use of triple therapy in COPD [Aaron, 
2007; Cazzola, 2007; Hanania, 2012; Jung, 2012; Siler, 2015; Welte, 2009]. These 
studies have also shown that the number and type of reported adverse events (AE) were 
generally similar with administration of dual or monotherapy doses for periods of up to 
one year, and were mostly related to their pharmacological mode of action.
GlaxoSmithKline (GSK) is currently developing a once-daily ‘closed’ triple therapy of a 
ICS/LAMA/LABA combination [fluticasone furoate (FF)/umeclidinium 
(UMEC)/vilanterol (VI) (100/62.5/25 mcg)] in a single inhaler, with the aim of providing 
a new treatment option for the management of symptomatic COPD patients at risk for 
exacerbations which will reduce the exacerbation frequency, allow for a reduced burden 
of polypharmacy, convenience, and increase the potential for improvement in lung 
function, HRQoL and symptom control over established dual/monotherapies.
GSK conducted a Phase III study comparing once-daily FF/UMEC/VI to twice-daily 
budesonide/formoterol (400/12 mcg) in COPD participants that were symptomatic and at 
risk of an exacerbation despite receiving maintenance therapy (CTT116853). 
FF/UMEC/VI demonstrated statistically significant improvements in trough FEV1, a 
statistically significant reduction in the annual rate of moderate or severe COPD 
exacerbations, and a statistically significant reduction of COPD symptoms (using 
Exacerbations and Chronic Pulmonary Disease – Respiratory Symptoms [EXACT-RS]) 
when compared to budesonide/formoterol. Additionally, clinically meaningful 
improvements from baseline in St. George’s Respiratory Questionnaire (SGRQ) total 
score were observed, with a statistically significant improvement compared to
budesonide/formoterol [Lipson, 2017]. This Phase III study provided compelling efficacy 
data compared with an established ICS/LABA and demonstrated the clinical value of 
single inhaler triple-therapy compared to ICS/LABA therapy in patients with COPD. 
As fixed dose combinations of LAMA/LABA therapy remain relatively new, and ICS 
monotherapy is not indicated for the treatment of COPD, the two most frequent treatment 
pathways that lead to ‘open’ triple therapy are the escalation of therapy from either an 
ICS/LABA fixed dose combination or from LAMA monotherapy. A prior study 
demonstrated that patients with COPD may remain symptomatic despite the use of 
LAMA or LABA monotherapy [Dransfield, 2011]. Patients that remained symptomatic 
despite treatment with LAMA monotherapy, stepped up to ‘open’ triple therapy by the 
addition of ICS/LABA therapy, which resulted in greater improvements in lung function 
 
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and HRQoL, compared LAMA monotherapy [Aaron, 2007; Cazzola, 2007; Hanania, 
2012; Jung, 2012; Siler, 2015; Welte, 2009].
The primary purpose of this study is to evaluate lung function and HRQoL after 84 days 
of treatment with a single inhaler triple therapy combination of FF/ UMEC/ VI 
(100/62.5/25 mcg) once daily via the ELLIPTA compared with tiotropium (18 mcg) once 
daily, in a patient population appropriate for triple therapy.
3.2.
Background
Chronic obstructive pulmonary disease is a progressive disease characterised by 
increasing obstruction to airflow and the progressive development of respiratory 
symptoms including chronic cough, increased sputum production, dyspnoea and 
wheezing.  
In 2011, the Global Initiative for Chronic Obstructive Lung Disease [GOLD, 2011]
issued a guideline that outlined a new classification system for COPD, using the ABCD 
assessment tool, which aimed to more comprehensively assess disease severity and guide 
therapy choice, ultimately improving COPD management. A 2013 update to the 2011 
strategy included an additional criterion to characterise patients that have had a 
hospitalised exacerbation as high risk, regardless of GOLD status [GOLD, 2013].
GOLD released a revised guideline in 2017 that separates spirometric grading from the 
determination of overall disease severity and choice of pharmacologic therapy (Table 1) 
[GOLD, 2017]. 
 
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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 hospitalisation, prior 
year
mMRC <2;  CAT <10
D:  High risk, 
more symptoms
≥2 exacerbations, prior year OR 1 
leading to hospitalisation, prior 
year
mMRC 2;  CAT ≥10
* - Symptomatic category determined by either Modified Clinical Research Council (mMRC) or COPD Assessment Test 
(CAT) score.
GOLD Airflow 
Limitation
Severity
FEV1 (% predicted)
GOLD 1 
Mild
80
GOLD 2
Moderate
50 – 79 
GOLD 3
Severe
30 – 49 
GOLD 4
Very Severe
<30
The GOLD 2017 guideline also outlined suggested management strategies for COPD 
based upon disease severity, including escalation as well as de-escalation strategies. For 
milder patients (GOLD Group A), the guidelines encourage active risk reduction (e.g., 
smoking cessation and influenza vaccination) with the addition of bronchodilators.  
However, as disease severity increases, the guidelines recommend an incremental 
approach to pharmacological treatment, involving the use of combinations of drug classes 
with different or complementary mechanisms of action [Celli, 2004; GOLD, 2017].  
Long-acting bronchodilators (LAMAs or LABAs) have been shown to relieve symptoms, 
increase exercise capacity, improve health-related quality of life and reduce COPD 
exacerbations to a greater extent than short acting 2 adrenergic receptor agonists.  For 
advanced cases, or those with repeated exacerbations, the incorporation of ICS or triple 
therapy, is recommended.
 
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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 tiotropium can be found in the authorised product label.  The 
current safety profile for FF/UMEC/VI (100/62.5/25 mcg), based on data available to 
date, is consistent with the pharmacological classes of the components.  The following 
section outlines the risk of assessment and mitigation strategy for this protocol.
 
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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) in 1810 
randomised COPD participants treated with 
FF/UMEC/VI or budesonide/formoterol 
(BUD/FOR) for up to 24 weeks (Intent-To-
Treat [ITT] Population), or up to 52 weeks 
(subset of 430 participants; EXT 
Population), the incidence of events in the 
pneumonia AEs of special interest (AESI) 
group was 2.2 % and 0.8 % for 
FF/UMEC/VI and BUD/FOR, respectively 
in the ITT Population, and 1.9 % and 1.8 % 
for FF/UMEC/VI and BUD/FOR, 
respectively, in the EXT Population.  There 
was one fatal case of pneumonia in a 
participant who received FF/UMEC/VI.
The incidence of pneumonia with 
FF/UMEC/VI in this study was in line with 
the incidence of pneumonia seen in 24 week 
studies with F/VI (<1-2 % with FF/VI 
100/25) and less than that observed in 52 
week exacerbations studies with FF/VI (6 % 
- Participants will be informed of the risk in 
the informed consent.
- Investigators are informed of the risk in 
the IB
- Investigators will be instructed to remain 
vigilant for the possible development of 
pneumonia in participants with COPD as the 
clinical features of such infections overlap 
with the symptoms of COPD exacerbations. 
For suspected cases of pneumonia, 
investigators will be encouraged to arrange 
a chest x-ray within 48 hours of diagnosis 
(Section 12.5.2) and to treat appropriately.
- Appropriate exclusion criteria as specified 
in Section 6.2 of the protocol i.e
- Instream review of blinded AE/SAE 
reports. 
- All diagnoses of pneumonia 
(radiographically confirmed or 
unconfirmed) must be reported as an AE or 
SAE (if applicable) as specified in Section 
9.2.7.
- Chest X-ray read required at baseline and 
whenever a participant has suspected 
pneumonia or mod/severe exacerbations 
during the study. 
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
with FF/VI 100/25) [Dransfield, 2013].  
Similarly, the incidence of pneumonia with 
FF/UMEC/VI was less than that observed in 
a 12 month exacerbation trial with 
BUD/FOR (6.4 %) [Sharafkhaneh, 2012].
Prior studies with FF/VI have demonstrated 
risk factors associated with a higher risk of 
pneumonia in participants with COPD (e.g., 
advanced age, poor lung function, low body 
mass index (BMI), current smoking, and a 
prior history of pneumonia) [Crim, 2009].
These risk factors were present in some 
participants with pneumonia in study 
CTT116853 with FF/UMEC/VI; however, 
the low number of pneumonia events 
reported in this study precludes drawing any 
definite conclusions about risk factors.  
These risk factors should be taken into 
consideration when using an ICS in 
participants with COPD. Pneumonia risk 
will be important in the benefit-risk 
assessment for FF/UMEC/VI in COPD 
participants, hence a robust risk mitigation 
strategy is being proposed.
Pharmacovigilance Risk Assessment 
Committee (PRAC) recently conducted an 
Article 31 review to evaluate the risk of 
pneumonia with use of ICS in participants 
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
with COPD.  The PRAC review confirmed 
that COPD participants treated with ICS are 
at increased risk of pneumonia; however, 
the Committee’s view was that the benefits 
of ICS continue to outweigh their risks.  The 
PRAC also looked whether there were any 
differences in the risk of pneumonia 
between these produces, and did not find 
conclusive evidence of such difference.
Decreased bone mineral density and 
associated fractures 
Reduction in bone density, and the 
subsequent risk of fractures, is a known 
potential risk with corticosteroids.  There 
may be a modest increase in risk of fracture 
among participants with COPD treated with 
ICS, but the results are not consistent across 
individual studies [Christensson, 2008; 
Lehouck, 2011; Weldon, 2009].
In study CTT116853, the incidence of 
events in the decreased bone mineral density 
and associated fracture AESI group was 
low, with an incidence of 0.4 % and 0.7 % 
in the FF/UMEC/VI and BUD/FOR 
treatment groups, respectively in the ITT 
Population up to 24 weeks and 0.5 % in 
both treatment groups in the EXT 
Population up to 52 weeks.  The majority of 
- Participants will be informed about the 
risk in the informed consent.
- Investigators are informed of the risk in 
the IB.
- Instream review of blinded AE/SAE 
reports.
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
the fractures in both treatment groups were 
traumatic in nature.
Adrenal suppression
Oral corticosteroids are known to have an 
effect on the hypothalamic-pituitary-adrenal 
(HPA) axis leading to reduction in cortisol 
production.  Due to the low dose and low 
systemic exposure with ICS, this potential 
effect is not clear, nor is the possible impact 
of any change in cortisol.
The effect of FF/UMEC/VI on cortisol 
levels has not been studied.  In study 
CTT116853, no events were reported in the 
adrenal suppression AESI group for 
FF/UMEC/VI and BUD/FOR.
With respect to the FF/VI clinical 
development programme, a formal HPA 
study, using 24-hour serum cortisol 
measurements, was performed.  In addition, 
multiple studies with COPD (and asthma) 
participants monitored urinary cortisol.  
These studies did not show a clinically 
relevant effect of FF/VI 100/25 on the HPA 
axis.
Participants that have received oral 
corticosteroids, particularly those who have 
received significant amounts for long 
periods of time, will be more susceptible to 
- Investigators are informed of the risk in 
the IB.
- Instream review of blinded AE/SAE 
reports.
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
this risk of adrenal suppression.  
The proposed dose (100 mcg) of inhaled FF 
in this study is unlikely to lead to clinically 
significant changes in the treatment period 
since systemic exposure is low. 
Corticosteroid Associated Eye Disorders
Systemic ocular effects (e.g. cataract and 
glaucoma) may occur with any inhaled 
corticosteroid, particularly at high doses 
prescribed for long periods. However, these 
effects are much less likely to occur with 
inhaled corticosteroids compared with oral 
corticosteroids.
In study CTT116853, the incidence of 
events in the ocular effects AESI group was 
low, with an incidence of 0.1 % and 0.4 % 
in the FF/UMEC/VI and BUD/FOR 
treatment groups, respectively, in the ITT 
Population up to 24 weeks.  There were no 
events reported in the ocular effects AESI in 
the EXT Population up to 52 weeks.
During studies with FF and FF/VI in asthma
participants, and with FF/VI and UMEC/VI 
in COPD participants, no associated effect 
on ocular disorders was observed. In 
addition, no effects on lens opacification 
were observed on formal ophthalmic 
- Participants will be informed about the 
risk in the informed consent.
- Investigators are informed of the risk in 
the IB.
- Appropriate exclusion criteria as specified 
in Section 6.2 of the protocol.
- Instream review of blinded AE/SAE 
reports
- If a risk is suspected, participants should 
receive appropriate treatment
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
assessments in a study with FF/VI, FF and 
FP in participants with asthma.
Serious cardiovascular events
Cardiovascular (CV) effects are a potential 
class effect associated with anti-muscarinic 
and beta-agonist therapies.
In the COPD population, there is a high 
prevalence of concurrent CV disease and the 
prevalence of CV co-morbidities increases 
with worsening severity of COPD.
In study CTT116853 [Lipson, 2017], 
approximately two-thirds of all participants 
reported CV risk factors at baseline.  In this 
study, CV effects were the most frequently 
reported AESI, with a similar incidence 
between FF/UMEC/VI and BUD/FOR 
treatment groups in the ITT Population up 
to 24 weeks (4.5 % and 5.2 %, respectively) 
and the EXT Population up to 52 weeks 
(8.6 % and 10 %, respectively).  Within 
subgroups of CV effects, hypertension was 
reported most frequently and with a 
numerically higher incidence with 
BUD/FOR (2.3 %) compared with 
FF/UMEC/VI (1.3 %) in the ITT Population 
up to 24 weeks, but with a similar incidence 
in the EXT Population up to 52 weeks 
(0.9 % to 1.0 % across treatment groups).  
- Participants will be informed about the 
risk in the informed consent.
- Investigators are informed of the risk in 
the IB.
- Appropriate exclusion criteria as specified 
in Section 6.2 of the protocol, including 
ECG inclusion criteria
- Vital sign assessments (heart rate and 
blood pressure) as per protocol
- Protocol defined stopping criteria as per 
Section 8.1.1
- Instream review of blinded AE/SAE 
reports.
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Cardiac arrhythmias were reported the next 
most frequently and occurred with an 
incidence of 1.2 % in both treatment groups 
in the ITT Population up to 24 weeks and 
with an incidence of 1.9 % and 3.6 % in the 
FF/UMEC/VI and BUD/FOR groups in the 
EXT Population up to 52 weeks.
The incidence of serious events in the CV 
effects AESI was low, with an incidence of 
1.0 % and 1.1 % in the FF/UMEC/VI and 
BUD/FOR groups, respectively, in the ITT 
Population to 24 weeks, and 2.9 % and 
1.4 % in the FF/UMEC/VI and BUD/FOR 
groups, respectively, in the EXT Population 
up to 52 weeks.  The absolute numbers of 
fatal events in CV effects AESI was low in 
the study, despite the study enrolling 
participants with a number of CV co-
morbidities at baseline.
A pre-specified Major Adverse Cardiac 
Event (MACE) analysis was conducted in 
CTT116853, with broad MACE defined as: 
ischemic heart disease Standardised 
MedDRA Queries (SMQ) excluding 
fatalities, plus central nervous system 
haemorrhages and cerebrovascular 
conditions SMQ excluding fatalities, plus 
adjudicated cardiovascular deaths.  The 
narrow MACE definition included only the 
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
preferred terms of myocardial ischaemia 
and acute myocardial infarction in place of 
the ischaemic heart disease SMQ.  Overall, 
the absolute number of MACE events using 
either the broad or narrow definition was 
low both in the ITT Population up to 24 
weeks and the EXT Population up to 52 
weeks.  No clinically relevant differences 
were observed between FF/UMEC/VI and 
BUD/FOR based on narrow and broad 
MACE analysis both in the ITT Population 
up to 24 weeks and EXT Population up to 
52 weeks.
In study CTT116853, there were no 
emerging safety signals from vital signs, 
ECGs, or Holter data.
The effect of FF/UMEC/VI on the QT 
interval has not been evaluated in a 
thorough QT (TQT) study. TQT studies for 
FF/VI and UMEC/VI did not show 
clinically relevant effects on QT interval at 
clinical doses of FF, UMEC and VI. 
The CV safety profile of FF/UMEC/VI was 
generally consistent with that of FF/VI and 
UMEC/VI.
Hypersensitivity
Hypersensitivity reactions are unlikely to 
- Participants will be informed about the 
risk in the informed consent.  Participants 
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
affect the majority of participants.
In study CTT116853, in the ITT Population 
up to 24 weeks, events in the 
hypersensitivity AESI group occurred at 
low incidences in the FF/UMEC/VI and 
BUD/FOR treatment groups (1.1 % in both 
groups).  Similarly, in the EXT Population 
up to 52 weeks, events in the 
hypersensitivity AESI group occurred at 
low incidences (1.4 % and 0.5 % in the 
FF/UMEC/VI and BUD/FOR groups, 
respectively).  On-treatment hypersensitivity 
serious AESI events occurred at low 
frequency.
Risk factors for hypersensitivity are poorly 
understood, but may include exposure to 
infectious diseases during early childhood, 
environmental pollution, allergen level, and 
dietary changes [Niggemann, 2014; De 
Bisschop, 2012].  Although hypersensitivity 
reactions are unlikely to affect the majority 
of participants, there may be a few 
individuals who experience allergic 
reactions; they will need to be managed on a 
case by case basis.
will be advised to seek medical treatment if 
any signs of hypersensitivity occur.
- Investigators are informed of the risk in 
the IB.
- Appropriate exclusion criteria as specified 
in Section 6.2 of the protocol.
- Instream review of blinded AE/SAE 
reports.
Narrow angle glaucoma
Rare reports of angle closure glaucoma 
(which may lead into blindness) have been 
associated with nebulised ipratropium 
- Participants will be informed about the 
risk in the informed consent.
- Investigators are informed of the risk in 
the IB.
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
bromide and salbutamol [Packe, 1984].
The incidence of narrow angle glaucoma in 
the COPD population associated with the 
use if inhaled bronchodilators (including 
LAMAs and LABAs) is relatively low.
In CTT116853, in the ITT Population up to 
24 weeks, events in the glaucoma SMQ 
were reported as an incidence of 0.1% to 
0.4 % in the FF/UMEC/VI and BUD/FOR 
arms, respectively.  In the EXT Population 
up to 52 weeks, no events were reported in 
either treatment arm.
In the UMEC/VI development programme, 
there was one report (<1 %) of angle closure 
glaucoma (UMEC/VI 62.5/25 mcg).
- Appropriate exclusion criteria as specified 
in Section 6.2 of the protocol.
- Instream review of blinded AE/SAE 
reports.
Bladder outlet obstruction, dysuria, and 
urinary retention
Bladder outlet obstruction and urinary 
retention are class effects seen with 
antimuscarinics.
In study CTT116853, in the ITT Population 
up to 24 weeks, the incidence of events in 
the urinary retention AESI group was low 
(0.1 % and 0.0 % for FF/UMEC/VI and 
BUD/FOR, respectively) in both treatment 
groups.  There were no events of urinary 
retention reported in either group in the 
EXT Population up to 52 weeks.  There 
were no serious events in the urinary 
- Participants will be informed about the 
risk in the informed consent.
- Investigators are informed of the risk in 
the IB.
- Appropriate exclusion criteria as specified 
in Section 6.2 of the protocol.
- Instream review of blinded AE/SAE 
reports.
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
retention AESI group in either treatment 
group in the ITT Population up to 24 weeks 
and the EXT Population up to 52 weeks.
Paradoxical bronchospasm
The phenomenon of paradoxical 
bronchospasm may occur in association 
with all inhaled medication and may vary 
from mild to life threatening.
In study CTT 116853, the risk of 
paradoxical bronchospasm was evaluated 
through the AESI of asthma/bronchospasm.  
In the ITT Population up to 24 weeks, one 
participant reported an event in the 
athma/bronchospasm AESI (PT of wheezing 
in a participant on BUD/FOR; non-serious).  
There were no events reported in the EXT 
Population up to 52 weeks.
- Participants will be informed about the 
risk in the informed consent.
- Investigators are informed of the risk in 
the IB.
- Instream review of blinded AE/SAE 
reports.
 
 
 
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3.3.2.
Risk Assessment for Tiotropium Bromide 18 mcg
Tiotropium is a marketed drug that contains tiotropium bromide (18 mcg). A similar 
profile of undesirable effects as reported for anticholinergics (umeclidinium) may occur
with tiotropium bromide. The most common drug related adverse reactions are 
pharmacologically predictable side effects for anti-cholinergic therapy, such as dry 
mouth, blurred vision, dizziness, headache and cough. Please refer to the authorised 
product label for further information on the risks of using Spiriva Handihaler. In this 
study, tiotropium will be used in line with the recommendations provided in the product 
label. 
Tiotropium is an anticholinergic, therefore the risk mitigation strategy for UMEC
component of GSK2834425 will be applicable for tiotropium. 
3.3.3.
Benefit Assessment
GlaxoSmithKline is developing FF/UMEC/VI in a single inhaler, with the aim of 
providing a new treatment option for the management of symptomatic COPD participants 
at risk for exacerbations which will reduce the exacerbation frequency, allow for a 
reduced burden of polypharmacy, convenience, and increase the potential for 
improvement in lung function, HRQoL, and symptom control over established 
dual/monotherapies.
Current risks have been identified for the FF/UMEC/VI (100/62.5/25 mcg) combination 
based on the known pharmacology of the individual components, FF, UMEC, and VI, 
alone or in combination.  These include key risks of pneumonia and bone 
disorders/fractures from ICS-containing combinations, and the risk of adverse 
cardiovascular effects from LAMA and/or LABA-containing combinations.
In the US, the FF/VI combination is approved for the maintenance treatment of airflow 
obstruction and for reduction of exacerbations in COPD. The UMEC/VI combination is 
approved for maintenance treatment of airflow obstruction in COPD. UMEC is indicated 
for the long-term, once-daily, maintenance treatment of airflow obstruction in 
participants with COPD.
In the EU, the FF/VI combination is approved for the symptomatic treatment of adults 
with COPD with an FEV1 <70 % predicted normal (post-bronchodilaotr) with an 
exacerbation history despite regular bronchodilator therapy.  The UMEC/VI combination 
is approved as a maintenance bronchodilator to relieve symptoms in adult participants 
with COPD. UMEC is approved as a maintenance bronchodilator treatment to relieve 
symptoms in adult participants with COPD.
An appropriate safety monitoring strategy is being proposed for all risks associated with 
the FF/UMEC/VI combination, including the key risks (Section 3.3.1).
Given the clinical experience with FF, UMEC, and VI, and that the associated risks with 
these compounds are anticipated from their known pharmacology, the potential benefit of 
a new therapy option in participants with moderate to severe COPD supports the further 
development of the closed triple combination.
 
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Tiotropium (18 mcg) is a marketed drug for the COPD indication, and has an established 
benefit:risk profile.  Tiotropium will be used in line with the recommendations provided 
in the product label.
3.3.4.
Overall Benefit:Risk Conclusion
Taking into account the measures taken to minimize risk to participants participating in 
this study, the potential risks identified in association with FF/UMEC/VI and tiotropium 
are justified by the anticipated benefits from active treatments that may be afforded to 
participants with COPD.
 
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4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
To evaluate the effect of single inhaler 
triple therapy (FF/UMEC/VI) compared 
to Tiotropium after 12 weeks of 
treatment on lung function
Primary
Change from baseline in trough FEV1 at 
Week 12 (Day 85)
Secondary 
Change from baseline in trough FEV1 at 
Week 4 (Day 28) and Week 12 (Day 84)
Other
To evaluate the effect of single inhaler 
triple therapy (FF/UMEC/VI) compared 
to Tiotropium after 12 weeks of 
treatment on Health Status
Proportion of responders based on the St 
George’s Respiratory Questionnaire 
(SGRQ) Total Score at Week 4 and 
Week 12
Change from baseline in SGRQ Total 
Score at Week 4 and Week 12
To evaluate the effect of single inhaler 
triple therapy (FF/UMEC/VI) compared 
to Tiotropium after 12 weeks of 
treatment on Health Status
Proportion of responders based on the 
COPD Assessment Test (CAT) Total 
Score at Week 4 and Week 12
Change from baseline in CAT Total 
Score at Week 4 and Week 12
To evaluate the effect of single inhaler 
triple therapy (FF/UMEC/VI) compared 
to Tiotropium after 12 weeks of 
treatment on COPD exacerbations
Moderate or severe exacerbation event
Safety
To evaluate the safety profile of single 
inhaler triple therapy (FF/UMEC/VI) 
compared to Tiotropium over 12 weeks
of treatment 
Incidence of adverse events

Vital signs
 
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5.
STUDY DESIGN
5.1.
Overall Design
This is a Phase IV, 12-week, randomised, double-blind, double-dummy, parallel group,
multicentre study evaluating once-daily single inhaler triple therapy (FF/UMEC/VI) 
delivered via the ELLIPTA, compared to once daily tiotropium, in participants with 
COPD. 
Study design schema
Eligible participants at Screening (Visit 1) will be current or former smokers, with an 
established clinical history of COPD, receiving daily maintenance therapy with 
tiotropium alone for at least 3 months (no ICS or LABA maintenance therapy is allowed 
during the 3 months prior to screening), with a post-bronchodilator FEV1 of <50 % 
predicted (or <80 % predicted with a documented history of at least 2 moderate or 1 
severe [hospitalized] exacerbation in the last 12 months) and a CAT score of 10. 
Participants will be requested to participate in the study for approximately 17 weeks, 
consisting of a 4-week run-in period, 12-week treatment period and a 1-week follow-up 
period. 

Pre-screening: Details about the study and procedures will be explained 
through the informed consent process. The Pre-screening Visit (Visit 0), 
including the informed consent process, must be completed prior to any 
protocol-required changes to a participant’s usual COPD treatment and the 
initiation of any Visit 1 procedures. Participants will continue treatment with 
their regular (i.e. pre-study) tiotropium monotherapy during the pre-screening 
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
Screening/run-in: Eligible participants will be allowed to continue their usual 
tiotropium monotherapy COPD medication until the day before Screening (Visit 
1).  On the morning of the Screening Visit participants will refrain from taking 
their morning dose of tiotropium. Participants who meet all of the eligibility 
criteria at Visit 1, will enter the 4-week run-in period. 
Participants will discontinue existing tiotropium medication and will take open-
label tiotropium 18 mcg once daily via the HandiHaler plus placebo via the 
ELLIPTA. Participants will not use any other COPD medications (except for 
those allowed per protocol). 
During the run-in period participants will also take placebo via the ELLIPTA in 
addition to open-label tiotropium. This will familiarise participants with the use 
of the ELLIPTA device and will help ensure participants are compliant and use 
both devices as instructed.
Participants will be provided with short-acting albuterol/salbutamol to be used 
on an as-needed basis (rescue medication) throughout the study. At Screening, 
each participant will be instructed on the proper use of the ELLIPTA and 
HandiHaler and will self-administer their first doses of their run-in treatment 
during the Screening Visit. On the morning of the other study visits (Visit 2 
onwards), participants will refrain from taking their morning dose of study 
treatment until instructed to do so by clinic personnel. 

Randomisation/treatment: On the morning of the day before the 
Randomisation Visit (Visit 2), participants will take their last dose of run-in 
treatment and will not use any other COPD medications (except for those 
allowed per protocol) until the end of the study.  Rescue albuterol/salbutamol 
can be used throughout the study as-needed but must be withheld for at least 4 
hours prior to conducting spirometry.
At Visit 2 (the Randomisation Visit), participants who meet all of the 
randomisation criteria (see Section 6.3) will be randomised 1:1 to receive one 
the following double-blind study treatments for 84 days:

FF/UMEC/VI 100/62.5/25 mcg via the ELLIPTA once daily in the morning
+  placebo to match tiotropium via HandiHaler once daily in the morning

Tiotropium 18 mcg via HandiHaler once daily in the morning
+ placebo via the ELLIPTA once daily in the morning
Participants may continue their study-supplied rescue albuterol/salbutamol. On 
the morning of Visits 3 and 4, participants will refrain from taking their morning 
dose of study treatment until instructed to do so by clinic personnel. At Visits 2, 
3, and 4 participants will self-administer study treatment whilst at the clinic. 
Participants will take their last dose of study treatment in the clinic on Day 84 
and then return to the clinic on Day 85 (Visit 5) for their final clinical 
assessments. Participants are expected on non-clinic visit days to take their study 
 
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treatment at home in the morning at approximately the same time each day, as 
directed by the clinic. 

Safety/follow-up: A safety follow-up telephone contact or clinic visit (Visit 6) 
will be conducted approximately 7 days after the participant completes all of the 
protocol-defined procedures for Visit 5/End of Study (EOS) or, if applicable, the 
Study Treatment Discontinuation Visit. A participant will be considered to have 
completed the study when they have completed all phases of the study including 
screening, run-in, the randomised treatment phase, and safety follow-up.
Participants who permanently discontinue double-blind study treatment are not required 
to withdraw from the study. Participants who have permanently discontinued study 
treatment and have not withdrawn consent are encouraged to continue in the study and
complete all remaining protocol specified clinic visits (see Section 8.1).
5.2.
Number of Participants
Approximately 848 participants with advanced COPD will enter the run-in, in order to 
randomise approximately 780 participants, in order to achieve an estimated 702 evaluble 
participants. See Section 10 for further details.
Approximately 100 centres globally will be required to recruit the study.
5.3.
Participant and Study Completion
A participant is considered to have completed the study if he/she has completed all 
phases of the study including pre-screening, screening, run-in, the randomised treatment 
phase and the safety follow-up. 
The end of the study is defined as the date of the last scheduled procedure shown in the 
Schedule of Activities (SoA) table (see Section 2) for the last participant in the trial 
globally.
5.4.
Scientific Rationale for Study Design
This study will use a multicenter, randomised, double-blind, double-dummy, parallel-
group design. A placebo arm is not included because the primary comparison of interest
is FF/UMEC/VI vs. tiotropium and it is not considered appropriate to include a placebo 
arm in a study in patients with advanced COPD. Eligible participants must have been on 
daily maintenance tiotropium for at least 3 months, and those randomised to tiotropium 
will be essentially continuing their therapy prior to enrollment. Although LAMA 
monotherapy in severe patients is not designated a preferred treatment option, it 
continues to be listed as a treatment option for these patients (GOLD B or D) in the 2017 
GOLD strategy document, and is commonly used in clinical practice. The 4-week run-in 
period is necessary in order to assess participant compliance with and ability to use all of 
the medications together and allow sufficient time for the results of screening 
assessments to be returned to the site, in order to establish participant eligibility.
 
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5.5.
Dose Justification
The FF/UMEC/VI (100/62.5/25 mcg) dose was selected based on the doses that have 
been licensed for COPD for the FF/VI (100/25 mcg) and UMEC/VI (62.5/25 mcg) dual 
combinations through extensive studies in the mono and dual therapy programmes. It is 
the dose which is currently under regulatory review based on the Phase IIIa 
FF/UMEC/VI registration programme.
The dose selected for tiotropium (18 mcg, once daily) is the dose licensed in the US for 
use in COPD.
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
1. Informed consent: capable of giving signed informed consent prior to study start
which includes compliance with the requirements and restrictions listed in the 
informed consent form (ICF) and in this protocol.
2. Type of participant: Outpatient.
3. Age: Participants 40 years of age or older at Screening (Visit 1).
4. Gender: Male or female participants.
Female participants: 
A female participant is eligible to participate if she is not pregnant, not breastfeeding, and 
at least one of the following conditions applies:

Not a woman of childbearing potential (WOCBP) 
OR

A WOCBP who agrees to follow the contraceptive guidance in 
Appendix 3 during the treatment period and until the safety follow-up 
contact after the last dose of study treatment.
5. COPD Diagnosis: An established clinical history of COPD in accordance with the
definition by the American Thoracic Society/European Respiratory Society [Celli, 
2004].
6. Smoking History: Current or former cigarette smokers with a history of cigarette
smoking of ≥10 pack-years at Screening (Visit 1) [number of pack years = (number of 
 
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cigarettes per day / 20) x number of years smoked (e.g., 20 cigarettes per day for 10 
years, or 10 cigarettes per day for 20 years)]. Previous smokers are defined as those 
who have stopped smoking for at least 6 months prior to Visit 1. Note: Pipe and/or 
cigar use cannot be used to calculate pack-year history.
7. Severity of COPD symptoms: A score of ≥10 on the COPD Assessment Test (CAT) 
at Screening (Visit 1).
8. Severity of Disease: 
Participants must demonstrate at Screening:
o
a post-bronchodilator FEV1 <50 % predicted normal
OR
o
a post-bronchodilator FEV1 <80 % predicted normal and a documented 
history of ≥2 moderate exacerbations or one severe (hospitalized) 
exacerbation in the previous 12 months
Participants must also have a measured post albuterol/salbutamol FEV1/forced vital 
capacity (FVC) ratio of <0.70 at screening.
Note: Percent predicted will be calculated using the European Respiratory Society
Global Lung Function Initiative reference equations [Quanjer, 2012].
Note: A documented history of a COPD exacerbation (e.g., medical record 
verification) is a medical record of worsening COPD symptoms that required 
systemic/oral corticosteroids and/or antibiotics (for a moderate exacerbation) or 
hospitalization (for a severe exacerbation). Prior use of antibiotics alone does not 
qualify as an exacerbation history unless the use was associated with treatment of 
worsening symptoms of COPD, such as increased dyspnoea, sputum volume, or 
sputum purulence (colour). Participant verbal reports are not acceptable.
9.
Existing COPD maintenance treatment: participant must have been receiving 
daily maintenance treatment with tiotropium alone (via the Handihaler or Respimat) 
for their COPD for at least 3 months prior to Screening.
Note: Participants taking only as-needed tiotropium are not eligible.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
1. Pregnancy: Women who are pregnant or lactating or are planning on becoming
pregnant during the study.
2. Asthma: Participants with a current diagnosis of asthma. (Participants with a prior 
history of asthma are eligible if they have a current diagnosis of COPD).
 
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3. α1-antitrypsin deficiency: Participants with α1-antitrypsin deficiency as the 
underlying cause of COPD.
4. Other respiratory disorders: Participants with active tuberculosis, lung cancer, and 
clinically significant: bronchiectasis, sarcoidosis, lung fibrosis, pulmonary 
hypertension, interstitial lung disease or other active pulmonary diseases. 
5. Lung resection: Participants who have undergone lung volume reduction surgery 
within the 12 months prior to Screening.
6. Risk Factors for Pneumonia: immune suppression (e.g. advanced human 
immunodeficiency virus [HIV] with high viral load and low CD4 count, lupus on 
immunosuppressants) that in the opinion of the investigator would increase risk of 
pneumonia or other risk factors for pneumonia (e.g. neurological disorders affecting 
control of the upper airway, such as Parkinson’s Disease, Myasthenia Gravis).
Participants at potentially high risk for pneumonia (e.g. very low body mass index 
[BMI], severely malnourished, or very low FEV1) will only be included at the 
discretion of the Investigator.
7. Pneumonia and/or moderate or severe COPD exacerbation that has not resolved
at least 14 days prior to Screening and at least 30 days following the last dose of
oral/systemic corticosteroids (if applicable). 
8. Respiratory tract infection that has not resolved at least 7 days prior to Screening.
9. Abnormal Chest x-ray: Chest x-ray (posteroanterior and lateral) reveals evidence of
pneumonia or a clinically significant abnormality not believed to be due to the
presence of COPD, or another condition that would hinder the ability to detect an
infiltrate on chest x-ray (e.g. significant cardiomegaly, pleural effusion or scarring). 
All participants will have a chest x-ray at Screening Visit 1 (or historical radiograph 
or computerized tomography [CT] scan obtained within 3 months prior to screening).  
Note: Participants who have experienced pneumonia and/or moderate or severe 
COPD exacerbations within 3 months of screening must provide a post 
pneumonia/exacerbation chest X-ray or have a chest X-ray conducted at Screening.
For sites in Germany: If a chest x-ray (or CT scan) within 3 months prior to Screening 
(Visit 1) is not available, approval to conduct a diagnostic chest x-ray will need to be 
obtained from the Federal Office for Radiation Protection (BfS).
10. Other diseases/abnormalities: Participants with historical or current evidence of
clinically significant cardiovascular, neurological, psychiatric, renal, hepatic,
immunological, gastrointestinal, urogenital, nervous system, musculoskeletal, skin,
sensory, endocrine (including uncontrolled diabetes or thyroid disease) or
haematological abnormalities that are uncontrolled. Significant is defined as any
disease that, in the opinion of the Investigator, would put the safety of the participant
at risk through participation, or which would affect the efficacy or safety analysis if 
the disease/condition exacerbated during the study.
 
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11. Unstable liver disease: ALT >2x ULN; and bilirubin >1.5x ULN (isolated bilirubin 
>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)
Current active liver or biliary disease (with the exception of Gilbert’s syndrome or 
asymptomatic gallstones or otherwise stable chronic liver disease per investigator 
assessment). 
NOTES: 

Stable chronic liver disease should generally be defined by the absence of 
ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or 
gastric varices, or persistent jaundice, or cirrhosis.

Chronic stable hepatitis B and C (e.g., presence of hepatitis B surface antigen 
(HBsAg) or positive hepatitis C antibody test result at screening or within 3 
months prior to first dose of study treatment) are acceptable if participant
otherwise meets entry criteria.
12. Unstable or life threatening cardiac disease: Participants with any of the following 
at Screening (Visit 1) would be excluded

Myocardial infarction or unstable angina in the last 6 months

Unstable or life threatening cardiac arrhythmia requiring intervention in the last 3
months

New York Heart Association (NYHA) Class IV Heart failure
13. Abnormal and clinically significant 12-lead ECG finding at Visit 1

The Investigator will determine the clinical significance of each abnormal ECG 
finding in relation to the participant’s medical history and exclude participants 
who would be at undue risk by participating in the trial. 

An abnormal and clinically significant finding that would preclude a participant
from entering the trial is defined as a 12-lead ECG tracing that is interpreted at, 
but not limited to, any of the following:
i. Atrial fibrillation (AF) with rapid ventricular rate >120 beats per 
minute (BPM)
ii. Sustained and non-sustained ventricular tachycardia (VT)
iii. Second degree heart block Mobitz type II and third degree heart 
block (unless pacemaker or defibrillator had been inserted)
iv. QT interval corrected for heart rate ≥500 msec in participants with 
QRS <120 msec and QTcF ≥530 msec in participants with QRS 
≥120 msec
14. Contraindications: A history of allergy or hypersensitivity to any corticosteroid,
anticholinergic/muscarinic receptor antagonist, β2-agonist, lactose/milk protein or
magnesium stearate or a medical condition such as narrow-angle glaucoma, prostatic
hypertrophy or bladder neck obstruction that, in the opinion of the Investigator,
contraindicates study participation.
 
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15. Cancer: Participants with carcinoma that has not been in complete remission for at 
least 3 years. Participants who have had carcinoma in situ of the cervix, squamous 
cell carcinoma and basal cell carcinoma of the skin would not be excluded based on 
the 3 year waiting period if the participant has been considered cured by treatment.
16. Oxygen therapy: Use of long-term oxygen therapy (LTOT) described as resting
oxygen therapy >3 L/min (Oxygen use ≤3 L/min flow is not exclusionary.)
17. Medication prior to spirometry: Participants who are medically unable to withhold
their albuterol/salbutamol for the 4-hour period required prior to spirometry testing at
each study visit.
18. Pulmonary rehabilitation: Participants who have participated in the acute phase of a 
Pulmonary Rehabilitation Programme within 4 weeks prior to screening or 
participants who plan to enter the acute phase of a Pulmonary Rehabilitation 
Programme during the study. Participants who are in the maintenance phase of a 
Pulmonary Rehabilitation Programme are not excluded.
19. Drug/alcohol abuse: Participants with a known or suspected history of alcohol or 
drug abuse within the last 2 years.
20. Non-compliance: Participants at risk of non-compliance, or unable to comply with 
the study procedures. Any infirmity, disability, or geographic location that would 
limit compliance for scheduled visits.
21. Questionable validity of consent: Participants with a history of psychiatric disease,
intellectual deficiency, poor motivation or other conditions that will limit the validity
of informed consent to participate in the study.
22. Affiliation with Investigator site: study Investigators, sub-Investigators, study
coordinators, employees of a participating Investigator or study site, or immediate
family members of the aforementioned that is involved with this study.
23. Inability to read: In the opinion of the Investigator, any participant who is unable to
read and/or would not be able to complete study related materials.
24. Medication prior to screening: See Table 4 in Section 7.7.2 for the list of 
medications and associated time intervals prior to Visit 1.
Medication
No use within the following time intervals prior 
to Screening 
Inhaled short-acting anticholinergics
6 hrs
Inhaled short-acting beta2 agonists1 
≥4 hrs
Inhaled short-acting anticholinergics + short-acting 
beta agonist combination
6 hrs
 
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Medication
No use within the following time intervals prior 
to Screening 
Inhaled Corticosteroids (ICS)
Use as maintenance treatment in the 3 months prior 
to Visit 1 is not permitted.
Maintenance treatment is defined as use for ≥14 
consecutive days (at any time in the 3 months prior 
to Visit 1).
Inhaled Corticosteroids (ICS)/Inhaled long-acting 
beta2-agonist (LABALABA) combinations 
(eg.fluticasone/salmeterol, mometasone 
furoate/formoterol fumarate, budesonide/formoterol 
fumarate; fluticasone furoate/vilanterol
Phosphodiesterase 4 (PDE4) inhibitors (roflumilast)
LABA (e.g., indacaterol, olodaterol)
Long acting muscarinic antagonists2 (LAMA) (eg 
umeclidinium, aclidinium, glycopyrronium)
LAMA/LABA combinations
Theophyllines
Sodium cromoglycate and nedocromil sodium
Anti-leukotrienes
Long term antibiotic therapy
Participants receiving antibiotics for long term 
therapy are not eligible for the study.
(Antibiotics are allowed for the short term treatment 
(≤14 days) of an exacerbation or for short term 
treatment (≤14 days) of other acute infections during 
the study)
Systemic, oral, parenteral corticosteroids
30 days
(During the study oral/systemic corticosteroids may 
be used for ≤14 days to treat COPD 
exacerbations/pneumonia) 
Intra-articular injections are allowed
Any other investigational drug
30 days or 5 half lives whichever is longer. 
1 (rescue albuterol/salbutamol will be provided and is permitted during the study)                               
2  Does not include tiotropium, which must be taken for at least 3 months prior to screening.
 
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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. CAT score at Randomisation (Visit 2)

Participants with CAT score <10 at Randomisation (Visit 2) will be excluded.
2. Compliance with run-in study medication
Compliance with each run-in study medication will be assessed by the 
Investigator, any participant <80 % or >120 % compliant with either of the two 
inhalers (ELLIPTA or Handihaler) will be excluded.
3. COPD exacerbation or pneumonia

Participants that experiences a moderate or a severe COPD exacerbation or 
pneumonia during the run-in period will be excluded. 
4. Changes in COPD medication

Any participant that requires a change in COPD medication from tiotropium 
(18 mcg) and rescue medication (albuterol/salbutamol) during the run-in period 
will be excluded. This includes a temporary change in COPD medication. 
6.4.
Lifestyle Restrictions

Participants should refrain from smoking for 1 hour prior to each pulmonary function   
test.

Participants should abstain from drinking beverages with high levels of caffeine such 
as tea and coffee for 2 hours prior to each pulmonary function test.
6.5.
Pre-screening/Screening/Run-in/Randomisation Failures
A participant will be assigned a participant number at the time the informed consent is 
signed at Visit 0.
The study site will be responsible for reporting pre-screen failures. The following 
information will be collected in the electronic case report form (eCRF) for participants 
who are pre-screen failures: demographic information including race, age and gender; 
participant number; SAE information only for any SAE considered to be related to study 
participation.
A minimal set of information is required to ensure transparent reporting of screening/run-
in/randomisation failure participants to meet the Consolidated Standards of Reporting 
Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screening/run-in/randomisation
failure details, eligibility criteria, and any SAEs. Further details are provided in the study-
 
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specific eCRF completion guidelines. For the purposes of this study, pre-screening 
failures, screening failures, run-in failures and randomisation failures will be defined as 
follows:
Pre-screening failures: those participants that sign the informed consent document but 
do not have a Visit 1 (Screening) procedure.
Screening failures: those participants that complete at least Visit 1 (Screening) 
procedure but do not enter the run-in period. A participant who completes Visit 1 
assessments and is dispensed the study medication for the run-in period is considered to 
have entered the run-in period.
Run-in failures: those participants that enter the run-in period but do not have any Visit 
2 (Randomisation) procedures, or those participants that complete at least one Visit 2 
(Randomisation) procedure but do not enter the double-blind study treatment period. Any 
participant who completed the run-in period and meets the randomisation criteria and is 
dispensed the double-blind study treatment at Visit 2 is considered to have entered the 
treatment period.
7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participants
according to the study protocol.
7.1.
Treatment Groups and Duration
Participants who meet all the eligibility criteria and who have successfully completed all 
protocol procedures at Screening will enter the 4-week run-in period and will take open-
label tiotropium 18 mcg via the HandiHaler once daily plus placebo via the ELLIPTA. 
Following the run-in period, participants who meet randomisation criteria will be 
randomised (1:1) to one of the following double-blind, double-dummy treatment groups
for 84 days:
Either:
FF/UMEC/VI 100/62.5/25 mcg via the ELLIPTA once daily in the morning
+  placebo to match tiotropium via HandiHaler once daily in the morning
or,
Tiotropium 18 mcg via HandiHaler once daily in the morning
+ placebo via the ELLIPTA once daily in the morning
The ELLIPTA contains 30 doses (FF/UMEC/VI or placebo) and participants will be
instructed to administer one dose from their ELLIPTA once daily in the morning.
 
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Tiotropium or matching placebo: Contents of 1 capsule (18 mcg) inhaled once daily 
using HandiHaler device. Note: To ensure drug delivery, two inhalations of the contents 
of each capsule should be performed.
Descriptions of the study treatments administered via the ELLIPTA and the Handihaler 
are provided in Table 2 and Table 3 respectively.
 
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Table 2
Description of FF/UMEC/VI Inhalation Powder in ELLIPTA™
FF/UMEC/VI 
First strip 
Second strip 
GW685698 blended with 
lactose
GW642444 and GSK573719 
blended with lactose and 
magnesium stearate
Dosage Form 
ELLIPTA with 30 doses (2 strips with 30 blisters per strip)
Unit Dose 
Strengths 
100 mcg per blister
25 mcg per blister GW642444, 62.5 
mcg per blister GSK573719
Physical
description 
Dry white powder
Dry white powder
Route of 
Administration 
Inhaled
Placebo to match 
First strip
Second strip
Lactose
Lactose/Magnesium Stearate
Dosage Form
ELLIPTA with 30 doses (2 strips with 30 blisters per strip)
Unit Dose 
Strengths
NA
Dry white powder
Physical 
description
Dry white powder
NA
Route of 
Administration
Inhaled
Table 3
Description of Tiotropium bromide in HandiHaler
Tiotropium 18 mcg
HandiHaler
Dosage form
Capsule
Unit dose strength
18 mcg
Physical description 
Hard gelatin capsule containing 18mcg 
tiotropium bromide blended with lactose
Route of administration
Inhaled
Placebo to match Tiotropium
HandiHaler
Dosage form
Capsule
Unit dose strength
NA
Physical description 
Hard gelatin capsule containing lactose
Route of administration
Inhaled
 
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7.1.1.
Medical Devices

The GSK ELLIPTA medical device will be provided for use in this study.

The other medical device (not manufactured by or for GSK provided) for use in this
study is the Handihaler.

GSK medical device incidents, including those resulting from malfunctions of the
device, must be detected, documented, and reported by the investigator throughout 
the study. (see Section 9.2.10).
7.2.
Dose Modification
No dose modifications are planned for this study.
7.3.
Method of Treatment Assignment
Participants will be assigned to study treatment in accordance with the randomisation 
schedule. The randomisation code will be generated by using a validated computerised 
system. Participants will be randomised using an Interactive Web Response System 
(IWRS). The study will use central-based randomisation to allocate treatments. Once a 
randomisation number is assigned to a participant it cannot be reassigned to any other 
participant in the study. 
7.4.
Blinding
This will be a double-blind study and the following will apply. 

The Investigator or treating physician may unblind a participant’s treatment 
assignment only in the case of an emergency OR in the event of a serious 
medical condition when knowledge of the study treatment is essential for the 
appropriate clinical management or welfare of the participant as judged by the 
Investigator. 

Investigators have direct access to the participant’s individual study treatment. 

It is preferred (but not required) that the Investigator first contacts the Medical 
Monitor or appropriate GSK study personnel to discuss options before unblinding 
the participant’s treatment assignment. 

If GSK personnel are not contacted before the unblinding, the Investigator must 
notify GSK within 24 hours after unblinding, but without revealing the treatment 
assignment of the unblinded participant, unless that information is important for 
the safety of participants currently in the study. 

The date and event or condition which led to the unblinding (i.e. the primary 
reason) will be recorded in source documentation and in the eCRF. 
Should a participant’s treatment assignment be unblinded then the participant may 
continue the assigned study treatment and be followed-up as per protocol until the 
completion of the Safety Follow-up assessments.
 
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GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any participant with an SAE. If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of the 
report, identifying the participant’s treatment assignment, may be sent to Investigators in 
accordance with local regulations and/or GSK policy. Participants will not be withdrawn 
from the study.
Masking of tiotropium and placebo to tiotropium capsules
This study will use a double-dummy design for dosing, whereby participants will be 
given two inhalers (ELLIPTA and Handihaler). All participants and site personnel 
involved in efficacy and safety assessments will be blinded to assigned treatment during
the study. Tiotropium capsules have trade markings that are not present on the placebo 
capsules. This study has a parallel-group design which ensures the capsule type will be
consistent for each participant for the duration of the study. In addition, tiotropium and 
placebo capsules will be closely matched in colour. Both the tiotropium and placebo 
blister packages will be covered with opaque over-labels with the intent of hiding the 
information on the tiotropium packaging. The HandiHaler dry powder inhalers will be 
covered with labels to mask identifying marks on the inhaler. Investigator and site 
personnel involved in efficacy and safety assessments will be instructed not be present
when a participant administers his/her study medication at clinic visits, to guard against 
the possibility of personnel involved in the collection of efficacy and safety data,
identifying the capsules removed from the blisters. Sites are required to have study 
treatment dosed, dispensed and accounted for by site personnel that are not involved in 
any efficacy or safety assessments.
7.5.
Preparation/Handling/Storage/Accountability
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are 
reported and resolved before use of the study treatment.
Only participants enrolled in the study may receive study treatment and only authorized 
site staff may supply or administer study treatment. All study treatments must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the Investigator and 
authorized site staff.
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
Further guidance and information for the final disposition of unused study treatment are 
provided in the Study Reference Manual (SRM). 
Under normal conditions of handling and administration, study treatment is not expected 
to pose significant safety risks to site staff. Take adequate precautions to avoid direct eye 
or skin contact and the generation of aerosols or mists. In the case of unintentional 
occupations exposure notify the monitor, Medical Monitor and/or GSK study contact.
 
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A Material Safety Data Sheet (MSDS) describing occupational hazards and 
recommended handling precautions will be provided to the Investigator, where is this 
required by local laws, or is available upon request from GSK.
7.6.
Treatment Compliance
When participants are dosed at the site, they will receive study treatment under medical 
supervision.  The date and time of each dose administered in the clinic will be recorded in 
the eCRF.  The dose of study treatment and study participant identification will be 
confirmed at the time of dosing by a member of the study site staff.  
When participants self-administer study treatment(s) at home, compliance with study 
treatment will be assessed through querying the participant during the site visits and 
recording the number of doses remaining in the ELLIPTA and the number of capsules of 
tiotropium bromide (or matching placebo) dispensed and taken by each participant, in the 
eCRF (see SRM for details).
Participants who are non-compliant should be re-educated on the importance of treatment 
compliance. Every effort will be made to keep participants in the study and to re-educate 
those participants who continue to be non-compliant.  Participants who continue to be 
non-compliant after multiple visit assessments may be permanently discontinued from 
study treatment after consultation with the GSK clinical team.
7.7.
Concomitant Therapy
All COPD medications used within 3 months prior to screening and during the run-in and 
study treatment periods (including the post-treatment period) should be recorded in the 
eCRF. 
All non-COPD medications taken during the study (after randomisation including post-
treatment) and any changes to concomitant medications will be recorded in the eCRF.  
The minimum requirement is that the drug name, reason for use, dose (including unit), 
frequency, route and the dates of administration are to be recorded.
Note: Study provided albuterol/salbutamol should not be recorded in the eCRF however 
non-study supplied albuterol/salbutamol will be recorded in the eCRF.  
Medications initiated after completion of the randomised treatment phase of the study 
(Visit 4) or started after discontinuation of study treatment must be recorded in the eCRF 
up to the safety follow-up (Visit 6). 
7.7.1.
Permitted Medications and Non-Drug Therapies
7.7.1.1.
Permitted COPD Medications
The following COPD medications are permitted during the run-in and study treatment
periods: 
 
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
Study supplied albuterol/salbutamol metered dose inhaler (MDI) or nebules (must be 
withheld for at least 4 hours prior to spirometry testing)

Mucolytics such as acetylcysteine

Long term oxygen therapy.  (To be eligible to enter the study at Visit 1, participants
who are on LTOT must be using at a flow rate of ≤3 liters/minute at rest.  However, 
oxygen therapy may be adjusted as deemed medically necessary at any time during 
the run-in or treatment phases of the study). Oxygen therapy must be captured on the 
concomitant medication page of the eCRF.  Supplemental oxygen is recommended 
for participants who exhibit oxyhemoglobin desaturation with rest or exertion (e.g.
SaO2 ≤88 %)

Maintenance phase of pulmonary rehabilitation treatment (participants are not 
allowed to initiate treatment during the study)
The following COPD medications are permitted during the study treatment period: 

Oral or injectable corticosteroids (short course ≤14 days) only for the short term 
treatment of COPD exacerbations and/or pneumonia

Antibiotics (short course ≤14 days) for the short term treatment of COPD 
exacerbations and/or pneumonia

Any COPD medication deemed medically necessary for the short term treatment 
(≤14days) of a moderate/severe COPD exacerbation or pneumonia
7.7.1.2.
Permitted Non-COPD Medications
The following non-COPD medications are permitted during the run-in and study 
treatment periods:

Medications for rhinitis (e.g. intranasal corticosteroids, antihistamines, cromolyn, 
nedocromil, nasal decongestants)

Topical and ophthalmic corticosteroids

Localized corticosteroid injections (e.g. intra-articular and epidural)

Vaccinations (Influenza vaccine, Pneumonia vaccine, Shingles vaccine, etc.) 
(Administration of influenza and pneumonia vaccines should be considered based 
on clinical discretion of the Investigator and local/national guidelines. Current 
influenza vaccines and pneumonia vaccines will be captured on the concomitant 
medication pages of the eCRF)

Allergy immunotherapy

Antibiotics for short-term treatment (≤14 days) of acute infections. (Long term 
treatment with antibiotics is not allowed)
 
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
Systemic and ophthalmic beta-blockers. (Administer with caution as systemic 
beta-blockers block the pulmonary effect of beta-agonists, and may produce severe 
bronchospasm in participants with reversible obstructive airways disease. 
Cardioselective beta-blockers should be considered, although they also should be 
administered with caution)

Smoking cessation treatments 

Cough suppressants 

Tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs). (Administer 
with extreme caution as they may potentiate the effects of beta-agonists on the 
cardiovascular system, including QT interval corrected for heart rate [QTc]
prolongation)

Diuretics. (Caution is advised in the co-administration of beta-agonists with non-
potassium sparing diuretics as this may result in electrocardiogram [ECG] changes 
and/or hypokalemia)

Use of positive airway pressure for sleep apnea

Oral muscarinic antagonists for the treatment of overactive bladder are permitted 
but should be used with caution as they may exacerbate medical conditions that are 
contraindicated for anticholinergics (e.g., narrow angle glaucoma and bladder 
outflow obstruction)

Cytochrome P450 (CYP)3A4 inhibitors. (Caution should be exercised when 
considering the coadministration of long-term ketoconazole and other known 
strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, 
itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, 
troleandomycin, voriconazole) because increased systemic corticosteroid and 
increased cardiovascular adverse effects may occur)
7.7.2.
Prohibited Medications and Non-Drug Therapies
Use of the medications listed in Table 4 is not permitted during the study.
Table 4
Concomitant Medications
Medication Prohibited during the randomised treatment period
Inhaled short-acting anticholinergics
Inhaled short-acting beta2 agonists 1
Inhaled short-acting anticholinergic/short-acting beta2-agonist combination products
Inhaled corticosteroids (ICS)
 
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Medication Prohibited during the randomised treatment period
Inhaled corticosteroids (ICS)/Inhaled long-acting beta2-agonist (LABA) combinations 
(eg.fluticasone/salmeterol, mometasone furoate/formoterol fumarate, budesonide/formoterol fumarate; 
fluticasone furoate/vilanterol
Phosphodiesterase 4 (PDE4) inhibitors (roflumilast)
LABA (e.g., indacaterol, olodaterol, salmeterol etc.)
Other LAMAs (aclidinium, glycopyrronium, umeclidinium etc.)
LAMA/LABA combinations
Theophyllines
Sodium cromoglycate and nedocromil sodium
Anti-leukotrienes
Long term antibiotic therapy 2
Systemic, oral, parenteral corticosteroids 3
Any other investigational drug
1 (rescue albuterol/salbutamol will be provided and is permitted during the study)      
2 (Antibiotics are allowed for the short term treatment (≤14 days) of an exacerbation or for short term 
treatment (≤14 days) of other acute infections during the study)
3 (During the study oral/systemic corticosteroids may be used for ≤14 days to treat COPD 
exacerbations/pneumonia). Intra-articular injections are allowed.
Note: Topical and ophthalmic corticosteroids, and localized corticosteroid injections 
(intra-articular and epidural) are allowed.
NOTE: All COPD medications (except for rescue albuterol/salbutamol, mucolytics and 
oxygen) are prohibited during the run-in and randomised treatment periods of the study 
except during the treatment of a moderate/severe COPD exacerbation or pneumonia. In 
the event of an exacerbation or pneumonia, sites should attempt to follow protocol 
treatment guidelines, however, treatment with any medication that the health care 
provider deems necessary is allowed.  Caution is advised in using a LABA or LAMA to 
treat a participant currently taking study treatment as these additional medications may 
increase the risk of overdose. If necessary the Investigator or other health care 
personnel may stop the participant’s study treatment temporarily (≤14 days) in order to 
treat the COPD exacerbation or pneumonia.  Participants who require more than two 
consecutive 14 day courses of treatment (i.e. antibiotics or corticosteroids) should be 
evaluated for their continuation on study treatment by the Investigator in consultation 
with the GSK medical monitor.
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
 
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7.8.
Treatment after the End of the Study
Participants will not receive any additional treatment from GSK after completion of the 
study because other treatment options are available. 
The Investigator is responsible for ensuring that consideration has been given to the post-
study care of the participant’s medical condition.
At the end of the treatment period (Visit 5), or after study treatment Discontinuation 
Visit, or withdrawal from study, participants can resume conventional COPD therapy as 
prescribed by the Investigator.  Post-treatment concomitant medication should be entered 
into the eCRF until the safety follow-up visit for participants that successfully complete 
Visit 5 on study treatment and for participants that withdraw from the study.  For 
participants that discontinue study treatment, post-treatment concomitant medication 
should be entered into the eCRF until they complete the visit/telephone contact at the 
planned Visit 6 date.
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
Participants that permanently stop study treatment should return to the clinic as soon as 
possible, in order to complete the Study Treatment Discontinuation Visit. The evaluations 
and procedures to be completed are outlined in the SoA (Section 2). 
Participants that discontinue study treatment are encouraged to remain in the study and 
every effort should be made by the Investigator/staff to keep the participant in the study, 
to collect important efficacy and safety data by telephone contact. Ideally, participants 
should return to the clinic to complete Visit 5, to collect important spirometry data, 
however, if this isn’t possible, this visit should also be completed by telephone. A safety 
follow-up phone call (Visit 6) should also be conducted 7 days after Visit 5. 
The Investigator/site staff should contact the participant by telephone at the protocol 
designated visit time intervals to collect the following:

SAEs 

AEs assessed as related to study participation

AEs resulting in withdrawal from the study

COPD exacerbations 

Concomitant medication

Spirometry (Visit 5 only, if participant consents)
Participants have the right to discontinue study treatment before the end of the study. A 
participant may also be asked to discontinue study treatment at the Investigator’s 
discretion. 
 
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A participant may be withdrawn from study treatment at any time. A reason for 
premature discontinuation of study treatment (e.g., AE, lack of efficacy, protocol 
deviation, Investigator discretion, consent withdrawn etc.) must be captured in the 
eCRF.Protocol defined criteria for discontinuation of study treatment
A participant must be permanently discontinued from study treatment if any of the 
following stopping criteria are met: 

Liver chemistry stopping and increased monitoring criteria have been designed 
to assure participant safety and evaluate liver event etiology (in alignment with the 
FDA premarketing clinical liver safety guidance). These protocol guidelines are in 
alignment with FDA premarketing clinical liver safety guidance: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM174090.pdf.
Discontinuation of study treatment for abnormal liver tests should be considered by 
the Investigator when a participant meets one of the conditions outlined in the 
algorithm or if the Investigator believes that it is in the best interest of the 
participant.
Liver Safety Algorithms and Required Actions and Follow up Assessments can be 
found in Appendix 4.

Pregnancy: Positive urine pregnancy test.

QTc Stopping Criteria: 
Details on performing ECG assessments can be found in Section 9.4.3

The same QT correction formula must be used for each individual participant
to determine eligibility for and discontinuation from the study.  This formula 
may not be changed or substituted once the participant has been enrolled.
Safety ECGs and other non-protocol specified ECGs are an exception.

For example, if a participant is eligible for the protocol based on QT 
interval corrected for heart rate by Bazett’s formula (QTcB), then QTcB 
must be used for discontinuation of this individual participant as well.

Once the QT correction formula has been chosen for a participant’s 
eligibility, the same formula must continue to be used for that participant
for all QTc data being collected for data analysis.  

The QTc should be based on averaged QTc values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording period.

For this study, the following QTc stopping criteria will apply and lead to 
withdrawal from study treatment:

an increase in QTc by > 60 msec from baseline or

development of a QTc > 530 msec (based on an average of triplicate 
ECGs)
 
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NOTE: These criteria should be based on the average QTc value of triplicate 
ECGs.  For example, if an ECG demonstrates a prolonged QT interval, two 
more ECGs will be obtained over a brief period and then the averaged QTc 
value of the three ECGs will be used to determine whether the participant should 
be discontinued from the study.
See the SoA for data to be collected at the time of treatment discontinuation and follow-
up and for any further evaluations that need to be completed.
8.1.1.
Rechallenge
8.1.1.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed.
8.2.
Withdrawal from the Study
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, 
compliance or administrative reasons.
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records.
In the event of early withdrawal from the study, every effort should be made to have the 
participant to return to the clinic for a Study Treatment Discontinuation Visit and Safety 
Follow-up, and to return all study related materials. Assessments to be performed during 
the Study Treatment Discontinuation Visit and the Safety Follow-up contact are 
described in the Schedule of Activities table (Section 2).
Participants that have previously discontinued study treatment (and have already 
completed the Study Treatment Discontinuation Visit) but then decide they no longer 
wish to participate in the study, may withdraw from the study by contacting the site by 
telephone. 
If the participant withdraws from the study at least 7 days after the Study Treatment 
Discontinuation Visit was completed, the safety follow-up contact (Visit 6) can be 
conducted at the time the participant notifies the site of their intention to withdraw from 
the study. Alternatively, the safety follow-up contact should be conducted 7 days after the 
Study Treatment Discontinuation Visit, if the participants consents to be contacted.  
8.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:
 
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
The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow up, the Investigator or designee 
must make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 
9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA (Section 2). 

Protocol waivers or exemptions are not allowed 

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.

No study related procedures may be performed until the informed consent form 
has been signed by the participant. A Pre-Screening visit (Visit 0) is required in 
order to administer the informed consent before any changes are made to the 
participant’s current medical regimen.  Selection and modification of the 
participant’s medications prior to study participation is based on the physician’s 
judgment according to sound medical practice, principles, and each participant’s 
needs.  A participant’s treatment must not be changed merely for the purpose of 
enabling the participant’s participation in the study.
During the Pre-Screening visit (Visit 0) the following information will be captured in the 
eCRF for each participant: 

Demographic information including race, age and gender

Participant number

Register visit in IWRS
The additional following critical baseline assessments will be conducted at Screening 
(Visit 1):
 
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
Medical history including COPD history (comprised of COPD type [emphysema 
and/or chronic bronchitis]), smoking history, COPD exacerbations history, 
smoking status and previous and/or current medical conditions.

Demography

Concomitant Medications

COPD exacerbation assessment (documented history of exacerbation(s))

Cardiovascular medical history/risk factors

Inclusion/Exclusion criteria 

Physical examination (including oropharyngeal examination)

Pulse rate, blood pressure measurements

12-lead ECG

Pre- and post-albuterol/salbutamol spirometry (reversibility)

SAE assessment (if related to study participation)

Chest X-Ray or (historical radiograph obtained within 3 months prior to 
screening)

Laboratory assessments (chemistry and hematology, hepatitis and pregnancy 
testing)

CAT

Administer and dispense run-in study treatment
In addition the following procedures must be completed at Screening (Visit 1):

Smoking cessation counseling

Register visit in IWRS

Dispense albuterol/salbutamol
9.1.
Efficacy Assessments
The timings of all efficacy assessments are specified in the SoA (Section 2).
9.1.1.
Spirometry
Spirometry measurements will be obtained using spirometry equipment that meets or 
exceeds the minimal performance recommendations of the American Thoracic Society 
(ATS) [Miller, 2005].  All sites will use standardised spirometry equipment provided by 
an external vendor.  All participants will have spirometry performed at screening and 
each scheduled clinic visit during the treatment period. For FEV1 and FVC 
determinations, at least 3 acceptable spirometry efforts (with no more than 8) should be 
obtained.  Acceptable spirometry efforts should have a satisfactory start of test and end of 
test (e.g. a plateau in the volume-time curve) and be free from artifacts due to cough, 
 
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early termination, poor effort, obstructed mouthpiece, equipment malfunction, or other 
reasons [Miller, 2005].
The largest FEV1 and FVC from the 3 acceptable efforts should be recorded, even if they 
do not come from the same effort.
Spirometry must be performed as follows:

Started approximately between 6:00AM and 11:00AM.

If applicable, after completing the health outcomes assessments (CAT should be 
administered first followed by SGRQ-C)

After withholding albuterol/salbutamol for 4 hours. 

At Screening (Visit 1), before the morning dose of their usual COPD medication.  

At Randomisation (Visit 2) and all treatment visits, before the morning dose of study 
treatment.

Participants should refrain from smoking for 1 hour prior to each pulmonary function   
test.

Participants should abstain from drinking beverages with high levels of caffeine such 
as tea and coffee for 2 hours prior to each pulmonary function test.
A full description of the timing and conduct of spirometry procedures is provided in the 
SRM.
9.1.1.1.
Reversibility
At Visit 1, both pre- and post-albuterol/salbutamol spirometry will be obtained.  Post-
albuterol/salbutamol FEV1 and FEV1/FVC findings will be used to determine participant
eligibility.  
Reversibility testing will be completed as follows:  Following pre-albuterol/salbutamol 
spirometry (three acceptable spirometry efforts), the participant will self-administer 4 
puffs of albuterol/salbutamol MDI using a spacer/valved-holding chamber.  Three 
acceptable spirometry efforts will be obtained approximately 10 to 30 minutes after 
albuterol/salbutamol administration.
9.1.2.
SGRQ-C
The St George’s Respiratory Questionnaire-Chronic Obstructive Pulmonary Disease 
specific (SGRQ-C) will be completed by participants at Randomisation (Visit 2), Day 28
(Visit 3), and Day 84 (Visit 4).  When the SGRQ-C and the COPD Assessment Test 
(CAT) are collected at the same visit, the CAT should be collected prior to the SGRQ-C.
The SGRQ-C [Meguro, 2007] is a disease-specific questionnaire designed to measure the 
impact of respiratory disease and its treatment on a COPD participant’s HRQoL.  As well 
as producing an overall summary score, scores for the individual domains of symptoms, 
activity and impacts are also produced.  It has been used in studies of COPD participants
and has been translated and validated for use in most major languages.  The SGRQ-C is 
 
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derived from the original SGRQ, and produces scores equivalent to the SGRQ instrument 
[Meguro, 2007].  
9.1.3.
COPD Assessment Test (CAT)
The CAT will be completed by participants at Screening (Visit 1), Randomisation (Visit 
2), Day 28 (Visit 3), and Day 84 (Visit 4).  CAT should be collected prior to SGRQ-C 
when collected at the same visit.
The COPD Assessment Test [Jones, 2009; Jones, 2012] is a validated, short and simple 
patient completed questionnaire which has been developed for use in routine clinical 
practice to measure the health status of patients with COPD. The CAT is an 8-item 
questionnaire suitable for completion by all patients diagnosed with COPD.  When 
completing the questionnaire, participants rate their experience on a 6-point scale, 
ranging from 0 (no impairment) to 5 (maximum impairment) with a scoring range of 0-
40. Higher scores indicate greater disease impact.
9.1.4.
COPD Exacerbations
COPD exacerbation data will be collected from the start of the randomised double blind 
treatment period (Visit 2) until the safety follow up contact at Visit 6. Participants will 
complete a paper Medical Problems worksheet to record medical problems experienced 
during the study. This paper worksheet must be reviewed by the Investigator (or 
designee) at each visit to the study site to assist in the identification of new COPD 
exacerbations.  
Every effort should be made to conduct a chest x-ray within 48 hours of identification of 
a moderate or severe exacerbation. 
All COPD exacerbations will be recorded on the exacerbation page of the eCRF. 
Details on COPD Exacerbation Identification, Categorization and Treatment Guidelines 
are provided in Appendix 5.
9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 6
The Investigator and any designees are responsible for detecting, documenting, and
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study,
or that caused the participant to discontinue the study treatment or withdraw from the 
study (see Section 8). 
 
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9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information

Any SAEs assessed as related to study participation (e.g., study treatment, 
protocol-mandated procedures, or change in existing therapy) or related to a 
GSK product will be recorded from the time a participant consents to participate 
in the study up to and including the safety follow-up contact at Visit 6.

All AEs will be collected from the start of study treatment (Visit 2) until the 
safety follow-up contact at the time points specified in the SoA (Section 2).

Medical occurrences that begin before the start of study treatment but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the eCRF not the AE section. 

All SAEs will be recorded and reported to the sponsor or designee immediately 
and under no circumstance should this exceed 24 hours, as indicated in
Appendix 6. The Investigator will submit any updated SAE data to the sponsor 
or designee within 24 hours of it being available. 

Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the Investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study 
participation, the Investigator must promptly notify the sponsor or designee.

The method of recording, evaluating, and assessing causality of AEs and SAEs
and the procedures for completing and transmitting SAE reports are provided in
Appendix 6.
9.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
Participants will be issued with a paper Medical Problems worksheet to record any 
medical problems experienced during the study. This paper worksheet will be used to 
assist participant recall in discussions with the Investigator (or designee), for site staff to 
then enter as appropriate in the eCRF. 
9.2.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as 
defined in Section 8.3). Further information on follow-up procedures is given in
Appendix 6.
 
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9.2.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the Investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are 
met. 

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study treatment 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
Investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to Investigators as necessary.

An Investigator who receives an Investigator safety report describing a SAE or 
other specific safety information eg, summary or listing of SAE) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.
9.2.5.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 6 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the eCRF will 
be required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 
The CV eCRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the eCRF within one week of receipt of a CV Event data query prompting its completion. 
The Death eCRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
9.2.6.
Disease-Related Outcomes – COPD exacerbations
COPD exacerbations are an expected disease-related outcome. 
 
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9.2.7.
COPD exacerbations should not be recorded as an adverse 
event, unless they meet the definition of an SAE (Appendix 
6).Pneumonia
All suspected pneumonias will require confirmation as defined by the presence of new 
infiltrate(s) on chest x-ray AND at least 2 of the following signs and symptoms: 

Increased cough 

Increased sputum purulence (colour) or production 

Auscultatory findings of adventitious sounds (e.g. egophony, bronchial breath 
sounds, rales, etc.)

Dyspnoea or tachypnea

Fever (oral temperature >37.5 °C)

Elevated white blood cells (WBC) (>10,000/mm3 or >15 % immature forms)

Hypoxemia (HbO2 saturation <88 % or at least 2 % lower than baseline value)
All pneumonias must be captured on the AE/SAE page of the eCRF and on the 
pneumonia page of the eCRF.
The Investigators and site staff should remain vigilant for the possible development of 
pneumonia in participants with COPD as the clinical features of such infections overlap 
with the symptoms of COPD exacerbations. Risk factors for pneumonia in participants
with COPD receiving FF/VI included current smokers, participants with a history of prior 
pneumonia, participants with a body mass index <25kg/m2 and participants with an FEV1
<50 % predicted.  For all suspected cases of pneumonia, Investigators are strongly 
encouraged to confirm the diagnosis (this includes obtaining a chest x-ray) and to initiate 
appropriate therapy as promptly as possible. All diagnoses of pneumonia 
(radiographically confirmed or unconfirmed) must be reported as an AE or SAE (if 
applicable).
Note: Pulse oximetry should be measured at any time a moderate or severe exacerbation 
is reported or pneumonia is suspected and recorded in the source documents and on the 
pneumonia page of the eCRF if applicable.
9.2.8.
Sentinel Events
A Sentinel Event is a GSK-defined SAE that is not necessarily drug-related but has been 
associated historically with adverse reactions for other drugs and is therefore worthy of 
heightened pharmacovigilance. Medical monitor review of all SAEs for possible Sentinel 
Events is mandated at GSK.  The medical monitor may request additional clinical 
information on an urgent basis if a possible Sentinel Event is identified on SAE review. 
The current GSK-defined Sentinel Events are listed below:

Acquired Long QT Syndrome

Agranulocytosis/Severe Neutropenia 
 
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
Anaphylaxis & Anaphylactoid Reactions 

Hepatotoxicity

Acute Renal Failure

Seizure

Stevens Johnson Syndrome/Toxic Epidermal Necrolysis
9.2.9.
Pregnancy

Details of all pregnancies in female participants will be collected after the start of 
study treatment and until the safety follow-up contact/visit.

If a pregnancy is reported, the Investigator should inform GSK within 24 hours of
learning of the pregnancy and should follow the procedures outlined in Appendix 3.

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
9.2.10.
Medical Device Incidents (Including Malfunctions)
Medical devices (spacers/holding chambers) are being provided for use in this study. In 
order to fulfil regulatory reporting obligations worldwide, the Investigator is responsible 
for the detection and documentation of events meeting the definitions of incident or 
malfunction that occur during the study with such devices. 
The definition of a Medical Device Incident can be found in Appendix 7
NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Section 9.2 and Appendix 6 of the protocol. 
9.2.10.1.
Time Period for Detecting Medical Device Incidents

Medical device incidents or malfunctions of the device that result in an incident 
will be detected, documented, and reported during all periods of the study in 
which the medical device is used. 

If the Investigator learns of any incident at any time after a participant has been 
discharged from the study, and such incident is considered reasonably related to 
a medical device provided for the study, the Investigator will promptly notify 
the Sponsor.

The method of documenting Medical Device Incidents is provided in Appendix
7.
9.2.10.2.
Follow-up of Medical Device Incidents

All medical device incidents involving an AE will be followed and reported in 
the same manner as other AEs (see Section 9.2). This applies to all participants,
including those who discontinue study treatment or the study.
 
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
The Investigator is responsible for ensuring that follow-up includes any 
supplemental investigations as indicated to elucidate the nature and/or causality 
of the incident.

New or updated information will be recorded on the originally completed form 
with all changes signed and dated by the Investigator.
9.2.10.3.
Prompt Reporting of Medical Device Incidents to Sponsor

Medical device incidents will be reported to the sponsor within 24 hours after 
the Investigator determines that the event meets the protocol definition of a 
medical device incident.

The Medical Device Incident Report Form will be sent to the sponsor 
electronically.

The same individual will be the contact for the receipt of medical device reports 
and SAE.
9.2.10.4.
Regulatory Reporting Requirements for Medical Device Incidents

The Investigator will promptly report all incidents occurring with any medical 
device provided for use in the study in order for the sponsor to fulfil the legal 
responsibility to notify appropriate regulatory authorities and other entities about 
certain safety information relating to medical devices being used in clinical 
studies.

The Investigator, or responsible person according to local requirements (eg, the 
head of the medical institution), will comply with the applicable local regulatory 
requirements relating to the reporting of incidents to the IRB/IEC.
9.3.
Treatment of Overdose
An overdose is defined as a dose greater than the total doses described above which 
results in clinical signs and symptoms.  These should be recorded by the Investigator on 
the AE/SAE eCRF pages.  In the event of an overdose of study treatment, the Investigator
should use clinical judgment in treating the overdose and contact the GSK medical 
monitor.
GSK is not recommending specific treatment guidelines for overdose and toxicity 
management. The Investigator is advised to refer to the relevant document(s) for detailed 
information regarding warnings, precautions, contraindications, adverse events, and other 
significant data pertaining to the study drug being used in this study. Such documents 
may include, but not be limited to, the IB or equivalent document provided by GSK.
9.4.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 2).
 
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9.4.1.
Physical Examinations

A complete physical examination will include, at a minimum, assessments of the 
Skin, Cardiovascular, Respiratory, Gastrointestinal and Neurological systems.
Height,weight will also be measured and recorded.

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
9.4.2.
Vital Signs

Vital signs will be performed at the time points specified in the SoA table 
(Section 2) prior to conducting spirometry and prior to taking study treatment.

Blood pressure (systolic and diastolic) and pulse measurements will be assessed 
in the sitting position after approximately 5 minutes rest.

A single set of values will be collected and recorded in the source 
documentation and eCRF. 
9.4.3.
Electrocardiograms

A single 12-lead ECG and rhythm strip will be recorded after measurement of 
vital signs and prior to spirometry. Recordings will be made at the time-points 
defined in the SoA table (Section 2). All ECG measurements will be made with 
the participant in a supine position having rested in this position for 
approximately 5 minutes before each reading.

For participants who meet the QTc, protocol defined stopping criteria, triplicate 
ECGs (over a brief period of time) should be performed (Section 8.1.1).

The Investigator, a designated sub-Investigator or other appropriately trained
site personnel will be responsible for performing each 12-lead ECG. The 
Investigator must provide his/her dated signature on the original paper tracing, 
attesting to the authenticity of the ECG machine interpretation.
9.4.4.
Clinical Safety Laboratory Assessments

Refer to Appendix 8 for the list of clinical laboratory tests to be performed and 
to the SoA for the timing and frequency. 

The Investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the eCRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the Investigator
to be more severe than expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 5 days after the last dose of study 
treatment should be repeated until the values return to normal or baseline or are 
 
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no longer considered significantly abnormal by the Investigator or medical 
monitor. 

If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 8, must be 
conducted in accordance with the laboratory manual and the SoA.
9.5.
Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study.
9.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
9.7.
Genetics
Information regarding genetic/ pharmacogenetic (PGx) research is included in
Appendix 9. The IEC/IRB and, where required, the applicable regulatory agency must 
approve the PGx and genetic assessments before these can be conducted.  The 
approval(s) must be in writing and will clearly specify approval of the PGx and genetic 
assessments (i.e., approval of Appendix 9).
In some cases, approval of the PGx and genetic assessments can occur after approval is 
obtained for the rest of the study.  If so, then the written approval will clearly indicate 
approval of the PGx and genetic assessments is being deferred and the study, except for 
PGx and genetic assessments, can be initiated.  When PGx and genetic assessments will 
not be approved, then the approval for the rest of the study will clearly indicate this and 
therefore, PGx and genetic assessments will not be conducted.
9.8.
Biomarkers
Biomarkers are not evaluated in this study.
9.9.
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics parameters are not evaluated in this 
study.
9.10.
Smoking Cessation Counselling
During Visits 1 and 4, or Study Discontinuation, participants will be given smoking 
cessation counselling.  This will include advice regarding the following:

the health effects that smoking may cause

the health benefits that may result with smoking cessation
 
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
discuss anti-smoking strategies that primary care physicians may be able to 
provide if participants do not feel capable of discontinuing smoking

participants may discontinue smoking at any time during the study and will not 
have to be withdrawn from the study if they do so.
The specific information to be discussed with each participant is provided in the SRM.
10.
STATISTICAL CONSIDERATIONS
10.1.
Hypotheses
The primary objective of this study is to compare single inhaler triple therapy 
(FF/UMEC/VI) with tiotropium in participants with COPD who have received tiotropium 
and continue to have symptoms as measured by CAT 10. The primary endpoint is 
trough FEV₁ at Week 24 (Day 85). The primary analysis is the comparison of this 
endpoint between FF/UMEC/VI and tiotropium.   
The null hypothesis is that there is no difference between treatment groups.
H0: T1 – T2 = 0
The alternative hypothesis is there is a difference between treatment groups.
H1: T1 – T2 0
Where T1 and T2 are the treatment means for FF/UMEC/VI and tiotropium, respectively.
10.2.
Sample Size Determination
Sample size calculation is based on the primary endpoint of trough FEV1 at Week 12 
(Day 85) and assumes 90 % power, a two-sided 1 % significance level, an estimate of 
residual standard deviation of 240 mL (based on mixed model repeated measures 
[MMRM] analyses of closed triple Phase IIb study CTT116853 in COPD participants) 
and a treatment difference of 70 mL. Under these assumptions, in total 702 evaluable 
participants (351 per treatment group) will be required.
It is estimated that approximately 10 % of participants will withdraw during the treatment 
period without providing a Day 85 trough assessment and approximately 8 % of 
participants will drop out from the 4 week run-in (including those not meeting 
randomisation criteria). Therefore approximately 848 participants will be enrolled to 4-
week run-in in order to have 780 participants randomised. 
10.3.
Populations for Analyses
For purposes of analysis, the following populations are defined:
 
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Population
Description
All Subject Enrolled (ASE)

All participants for whom a record exists in the study database, 
including screen failures and any participant who was not 
screened but experienced an SAE between the date of informed 
consent and the planned date of the Screening visit.
Intent-to Treat
(ITT)

All randomised participants, excluding those who were 
randomised in error. A participant who is recorded as a screen 
or run-in failure and also randomised will be considered to be 
randomised in error. Any other participant who receives a 
randomisation number will be considered to have been 
randomised.

Displays will be based on the treatment to which the participant
was randomised.
10.4.
Statistical Analyses
10.4.1.
Efficacy Analyses
Efficacy analyses will be based on the ITT Population using only data collected on-
treatment, unless otherwise specified.
Endpoint
Statistical Analysis Methods
Primary
The primary endpoint of trough FEV1 on Day 85 will be analysed for the ITT
Population using a mixed model repeated measures (MMRM) analysis, including 
trough FEV1 recorded at each of visits, Day 28, Day 84 and Day 85. The model 
will include covariates of baseline FEV1, visit, geographical region, treatment and 
visit by baseline interaction. A visit by treatment interaction term will also be 
included to allow treatment effects to be estimated at each visit separately. The 
variance-covariance matrix will be assumed unstructured.
Estimated differences between FF/UMEC/VI and tiotropium will be presented 
together with 95 % confidence intervals (CIs) for the difference and p-values.
A “tipping point” sensitivity analysis of trough FEV1 on Day 85 will be conducted 
for the ITT Population. This will explore the impact of missing data by using 
differing assumptions regarding the mean treatment effect in participants who 
discontinue study treatment. Assumptions will include scenarios where 
participants who discontinue FF/UMEC/VI have a lower treatment effect than 
those who discontinue TIO. The analysis results will be used to explore the 
conditions under which the conclusion of superiority no longer holds.
Secondary
Secondary endpoint change from baseline in trough FEV1 on Day 28 and Day 
84 will be part of the primary endpoint analysis (MMRM).
 
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Endpoint
Statistical Analysis Methods
Secondary endpoint change from baseline in SGRQ total score at Week 4 (Day 
28) and Week 12 (Day 84) will be analysed for the ITT Population using MMRM 
analysis, including covariates of baseline, geographical region, treatment and visit 
by baseline interaction. A visit by treatment interaction term will also be included 
to allow treatment effects to be estimated at each visit separately. The variance-
covariance matrix will be assumed unstructured.Estimated differences between 
FF/UMEC/VI and tiotropium will be presented together with 95 % CI for the 
difference and p-value.
Other
Will be described in the reporting and analysis plan.
10.4.2.
Safety Analyses
All safety analyses will be performed on the ITT Population. 
Endpoint
Statistical Analysis Methods
Primary
There is no primary safety analysis.
Secondary
The following safety endpoints will be analysed descriptively by treatment group:

Incidence of adverse events

Incidence of adverse events of special interest (AESI)  

Vital signs
Details will be described in the reporting and analysis plan
Adverse events (AEs) will be coded using the standard GSK dictionary, Medical 
Dictionary for Regulatory Activities (MedDRA), and grouped by body system. The 
number and percentage of participants experiencing at least one AE of any type, AEs 
within each body system and AEs within each preferred term will be presented for each 
treatment group. Separate summaries will be provided for all AEs, drug related AEs, fatal 
AEs, non-fatal SAEs, adverse events of special interest (AESIs) and AEs leading to 
withdrawal. Deaths and SAEs, if applicable, will be documented in case narrative format.
10.4.3.
Other Analyses
Full details of the analyses to be performed on the primary and other efficacy endpoints 
will be given in the Reporting and Analysis Plan (RAP).
10.4.4.
Interim Analyses
No interim analysis is planned for this study.
 
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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,  et al. 
Tiotropium in Combination with Placebo, Salmeterol, or Fluticasone–Salmeterol for 
Treatment of Chronic Obstructive Pulmonary Disease A Randomized Trial. Ann Intern 
Med 2007; 146:545-555.
Cazzola M, Andò F, Santus P, Ruggeri P, Di Marco F, Sanduzzi A, et al.  A pilot study to 
assess the effects of combining fluticasone propionate/salmeterol and tiotropium on the 
airflow obstruction of patients with severe-to-very severe COPD. Pul Pharm Ther 2007; 
20:556–561.
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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
BMI
Body Mass Index
BPM
Beats per minute
BUD
Budesonide
BUN
Blood Urea Nitrogen
CAT
COPD Assessment Test
CI
Confidence Interval
CIOMS
Council for International Organizations of Medical Sciences
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic Obstructive Pulmonary Disease
CPRD
Clinical Practice Research Database
CT
Computerized Tomography
CV
Cardiovascular
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EOS
End of study
EXACT-RS
Exacerbations and Chronic Pulmonary Disease –
Respiratory Symptoms tool
FDA
Food and Drug Administration
FEV1
Forced expiratory volume in 1 second
FF
Fluticasone Furoate
FOR
Formoterol
FSH
Follicle Stimulating Hormone
FVC
Forced Vital Capacity
GCP
Good clinical practice
GCSP
Global Clinical Safety and Pharmacovigilance
GOLD
Global Initiative for Chronic Obstructive Lung Disease
GSK
GlaxoSmithKline
HBsAg
Hepatitis B surface antigen
hCG
Human Chorionic Gonadotropin
HCP
Health Care Provider
HIPAA
Health Insurance Portability and Accountability Act
 
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HIV
Human Immunodeficiency Virus
HPA
Hypothalamic-Pituitary-Adrenal
HPLC
High-Performance Liquid Chromatography
HRQoL
Health related quality of life
HRT
Hormone Replacement Therapy
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
ICS
Inhaled Corticosteroids
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IP
Investigational Product
IRB
Institutional Review Board
IWRS
Interactive Web Response System
ITT
Intent-to-Treat
IUD
Intrauterine Device
IUS
Intrauterine Hormone-Releasing System
Kg/m2
Kilograms per meter squared
LABA
Long-Acting Beta-2-Agonists
LAMA
Long-Acting Muscarinic Antagonist
LRTI
Lower Respiratory Tract Infection
LTOT
Long-term oxygen therapy
MACE
Major Adverse Cardiac Event
MAOI
Monoamine Oxidase Inhibitors
MedDRA
Medicinal Dictionary for Regulatory Activities
mcg
Microgram
MCHC
Mean Corpuscular Hemoglobin Concentration
MCV
Mean Corpuscular Volume
MDI
Metered Dose Inhaler
min
Minute
mL
Milliliter
mMRC
Modified Clinical Research Council
MMRM
Mixed-Model Repeated Measures
mPP
Modified Per Protocol
MSDS
Material Safety Data Sheet
msec
Millisecond
NA
Not Applicable
NYHA
New York Heart Association
PDE4
Phosphodiestrase 4 inhibitor
PGx
Pharmacogenetic
QTc
QT interval corrected for heart rate
QTcB
QT interval corrected for heart rate by Bazett’s formula
QTcF
QT interval corrected for heart rate by Fridericia’s formula
RAP
Reporting and Analysis Plan
RBC
Red Blood Cell
RNA
Ribonucleic acid
 
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SAE
Serious Adverse Event
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic-Pyruvic Transaminase
SGRQ-C
St. George’s Respiratory Questionnaire for COPD patients
SMQ
Standardised MedDRA Query
SoA
Schedule of Activities
SRM
Study Reference Manual
SUSAR
Suspected unexpected serious adverse reaction
TIO
Tiotropium
TQT
Thorough QT
UK
United Kingdom
ULN
Upper Limit of Normal
UMEC
Umeclidinium
US
United States
VI
Vilanterol
WBC
White Blood Cell
WOCBP
Woman of child-bearing potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
ELLIPTA
Respimat
Spiriva Handihaler
 
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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 Participantss. 

The Investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, 
the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations
Financial Disclosure
Investigators and sub-Investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
Informed Consent Process

The Investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study. 
 
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
Participants must be informed that their participation is voluntary. Participants
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study centre. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative. 

Participants who are rescreened are required to sign a new ICF.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant
identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the Investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating Investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
 
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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 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 Participants’s 
medical records, medical examination, or medical history interview.
3. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment.
Contraception Guidance
Female Participants
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in
Table 5. 
 
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Table 5
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1 % per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing ) hormonal contraception associated with 
inhibition of ovulationb

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulation

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.) 
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the Participants.)
NOTES: 
a.
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for Participantss in clinical studies. 
b.
Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of 
the contraceptive method. In this case two highly effective methods of contraception should be utilized during the 
treatment period.
Pregnancy Testing

WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive urine pregnancy test 
 
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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 fetal status (presence or 
absence of anomalies) or indication for procedure. 

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. 

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the Investigator, will be reported to GSK
as described in Appendix 6. While the Investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 

Any female participant who becomes pregnant while participating in the study 
will immediately discontinue study medication.
 
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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) 
INR2
ALT 3x ULN and INR>1.5, if INR measured
Cannot 
Monitor
ALT 5x ULN but <8x ULN and cannot be monitored weekly for 2 weeks
ALT 3x ULN but <5x ULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3x ULN associated with symptoms (new or worsening) believed to be 
related to  liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue  study treatment 

Report the event to GSK within 24 hours

Complete the liver event eCRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the participant until liver chemistries 
resolve , stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge participant with 

Viral hepatitis serology4

Only in those with underlying chronic 
hepatitis B at study entry (identified by 
positive hepatitis B surface antigen) 
quantitative hepatitis B DNA and hepatitis 
delta antibody5.

Blood sample for pharmacokinetic 
analysis, obtained within 72 hours after 
last dose6

Serum creatine phosphokinase and lactate
 
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study treatment unless allowed per protocol 

If restart/rechallenge not allowed per 
protocol , permanently discontinue study 
treatment and may continue participant in the 
study for any protocol specified follow up 
assessments
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 
hrs

Monitor participants twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 
recommended
For All other criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24-
72 hrs 

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
dehydrogenase.

Fractionate bilirubin, if total 
bilirubin2x ULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form
including acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG or gamma 
globulins).

Serum acetaminophen adduct HPLC 
assay (quantifies potential acetaminophen 
contribution to liver injury in participants 
with definite or likely acetaminophen use 
in the preceding week [James, 2009]). 
NOTE: not required in China

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy eCRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that partcipant if ALT 3x ULN and bilirubin 2x ULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3x ULN and bilirubin 2x ULN (>35% direct bilirubin) or ALT 3x ULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to participants receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)   
 
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4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
5.
If hepatitis delta antibody assay cannot be performed,, it can be replaced with a PCR of hepatitis D RNA virus 
(where needed) [Le Gal, 2005].
6.
PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
treatments.  Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
treatment prior to blood sample draw on the eCRF. If the date or time of the last dose is unclear, provide the 
participant’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot 
be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and 
shipping are in the SPM.  
Phase III-IV liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 5x ULN and <8x ULN and
bilirubin <2x ULN without symptoms 
believed to be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 2 weeks.
OR
ALT 3x ULN and <5x ULN and
bilirubin <2x ULN without symptoms 
believed to be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks.

Notify the GSK medical monitor within 24 hours
of learning of the abnormality to discuss 
participant safety. 

Participant can continue study treatment  

Participant must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time participant meets the liver chemistry 
stopping criteria, proceed as described above

If ALT decreases from ALT 5x ULN and
<8x ULN to ≥3x ULN but <5x ULN, continue to 
monitor liver chemistries weekly. 

If, after 4 weeks of monitoring, ALT <3x ULN and 
bilirubin <2x ULN, monitor participants twice 
monthly until liver chemistries normalize or return 
to within baseline.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, et al. 
Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose 
and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, et al.  Quantification of 
Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates Different 
Patterns of Virological Response to Interferon Therapy in Chronically Infected Patients.  
J Clin Microbiol. 2005;43:2363-2369.
 
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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

Other respiratory related disease
 
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12.5.2.
COPD Exacerbation Severity
Each COPD exacerbation will be categorized based on severity as follows:
Mild:  Worsening symptoms of COPD that are self-managed by the participant.  
Mild exacerbations are not associated with the use of corticosteroids or 
antibiotics.
Moderate:  Worsening symptoms of COPD that require treatment with 
oral/systemic corticosteroids and/or antibiotics.
Severe: Worsening symptoms of COPD that require treatment with in-patient 
hospitalization.
Every effort should be made to conduct a chest x-ray within 48 hours of 
identification of a moderate or severe exacerbation. 
Details of an exacerbation should be recorded in the exacerbation page of the eCRF. 
However, exacerbations should not be recorded in the AE section of the eCRF unless 
they meet the definition of an SAE. (Pneumonia must be recorded in the AE or SAE 
section of the eCRF and on the Pneumonia page of the eCRF.)
Use of antibiotics for the treatment of upper or lower respiratory tract infections will not 
be considered a COPD exacerbation unless the participant experiences worsening 
symptoms of COPD which match the definition of an exacerbation as given above.
12.5.3.
Treatment of COPD Exacerbations
All medications used for the treatment of exacerbations must be recorded in the source 
documents and the exacerbation page of the eCRF.  All sites should follow the protocol 
treatment guidelines (as outlined below), but any medications deemed medically 
necessary may be used to treat a COPD exacerbation. However, caution is advised in 
using a LABA or LAMA to treat a participant currently taking IP as these additional 
medications may increase the risk of overdose. If necessary the PI or other health care 
personnel may stop the participant’s study treatment temporarily in order to treat the 
COPD exacerbation.
12.5.4.
Guidelines for Treatment with Corticosteroids
If in the opinion of the Investigator/treating physician the exacerbation is severe enough 
to warrant the need for oral or systemic corticosteroids (with or without antibiotics) the 
following guidelines should be used.

The duration of treatment with oral/systemic corticosteroids should be 14 days (dose 
and type according to local practice) 

The duration of treatment with oral/systemic corticosteroids should not exceed 14 
days unless approval is given by the sponsor or representative

Any course of oral/systemic corticosteroids started within 7 days of finishing a 
previous course will be considered as treatment for a single exacerbation
 
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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.
 
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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.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
 
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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 
risk factors, as well as the temporal relationship of the event to study treatment 
 
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administration will be considered and investigated.

The Investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment.

For each AE/SAE, the Investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the Investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the Investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK.

The Investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE

The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the Investigator will provide GSK with a copy of any post-mortem 
findings including histopathology.

New or updated information will be recorded in the originally completed eCRF.

The Investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.
Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The Investigator or medically-qualified sub-Investigator must show evidence within 
the eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hours of SAE 
 
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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 

Fetal distress, fetal 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, 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 6
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
Mean Corpuscular 
Volume (MCV)
Mean Corpuscular 
Hemoglobin (MCH)
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Clinical 
Chemistry1
Blood Urea 
Nitrogen (BUN)
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase
(SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase
(SGPT)
Total Protein
Glucose 
[nonfasting]
Calcium
Alkaline 
phosphatase
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only)

Serum/urine human chorionic gonadotropin (hCG) pregnancy test (as 
needed for women of childbearing potential)2
The results of each test must be entered into the eCRF.
NOTES :
1.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 8.1 and Appendix 7 All events of ALT 3 × upper limit of normal (ULN) and 
bilirubin 2 × ULN (>35 % direct bilirubin) or ALT 3 × ULN and international normalized ratio (INR) >1.5, if INR 
measured, which may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis).
2.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC.
 
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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 Genetic Sample Destruction Request Form, which will be provided to 
the site in the Investigator Site File.

Destruction Process:  After the specified storage period of 15 years or on 
withdrawal of consent, samples will be destroyed by incineration.  Samples that are 
sent for testing to vendors are returned or destroyed as part of the formal agreement 
and a full record of chain of custody is maintained.  A laboratory information 
management system (LIMS) is used to track and identify samples for destruction.
 
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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).
 
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