Clinical trial NCT03034967
Conditions: Pulmonary Disease, Chronic Obstructive
Keywords: HCRU exacerbations SGRQ CXCR2 antagonist GSK1325756 Danirixin COPD
Sponsor: GlaxoSmithKline
Start date: 2017-04-25; Completion date: 2018-10-05
Enrollment: 614 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Danirixin (DNX) is a selective CXC chemokine receptor (CXCR2) antagonist being developed as a potential anti-inflammatory agent for the treatment of COPD. This is a Phase 2, randomized, double-blind (Sponsor Open) study. The primary objective of the study is to evaluate the clinical activity and safety of danirixin compared with placebo in participants with COPD. Following baseline assessments collected over a 7 day period participants will be randomized (1:1:1:1:1:1) to receive one of five dose strengths of danirixin (5 milligram \[mg\], 10 mg, 25 mg, 35 mg and 50 mg) or placebo. Study treatment will be administered orally twice daily for 24 weeks. Participants will continue with their standard of care inhaled medications (i.e. long acting bronchodilators with or without inhaled corticosteroids) while receiving study treatment. Follow up will continue up to 28 days post last dose. Approximately 700 participants will be screened with a target of 540 participants completing 24 weeks of treatment and key study assessments.

Detailed description:

Arms: arm 1: Eligible participants will receive danirixin 5 mg tablet with food twice daily along with standard care of treatment for 24 weeks. arm 2: Eligible participants will receive danirixin 10 mg tablet with food twice daily along with standard care of treatment for 24 weeks. arm 3: Eligible participants will receive danirixin 25 mg tablet with food twice daily along with standard care of treatment for 24 weeks. arm 4: Eligible participants will receive danirixin 35 mg tablet with food twice daily along with standard care of treatment for 24 weeks. arm 5: Eligible participants will receive danirixin 50 mg tablet with food twice daily along with standard care of treatment for 24 weeks. arm 6: Eligible participants will receive placebo tablet with food twice daily along with standard care of treatment for 24 weeks.
Interventions: intervention 1: Danirixin intervention 2: Danirixin matching placebo intervention 3: Standard of care intervention 4: Rescue medication
Intervention descriptions: intervention 1: Danirixin is available as 5, 10, 25, 35 and 50 mg white, film-coated, oval or round shaped tablets for oral administration. intervention 2: Danirixin matching placebo will be available as white, film-coated, oval or round shaped tablets for oral administration. intervention 3: Participants will continue with their standard of care inhaled medications (i.e. long acting bronchodilators with or without inhaled corticosteroids) during the study treatment. intervention 4: Participants will continue to use rescue medication(s). The following rescue medications may be used: short acting beta agonists, short acting muscarinic antagonists, or short acting combination bronchodilators.

Protocol documents:
Prot_001.pdf: 
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GlaxoSmithKline group of companies
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TITLE PAGE
Protocol Title: Randomised, Double-Blind (Sponsor Open), Placebo-Controlled, Multi-
centre, Dose Ranging Study to Evaluate the Efficacy and Safety of Danirixin Tablets 
Administered Twice Daily Compared with Placebo for 24 Weeks in Adult Participants 
with Chronic Obstructive Pulmonary Disease (COPD)
Protocol Number: 205724 Amendment 1
Short Title: Danirixin Dose Ranging Study in Participants with COPD
Compound Number:
GSK1325756
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 will be provided in the Study 
Reference Manual
Regulatory Agency Identifying Number(s): IND: 108168; EudraCT: 2016-003675-21
Approval Date: 31-OCT-2017
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.


PPD
PPD
PPD


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 1
31-Oct-2017
Original Protocol
28-Nov-2016
Amendment 1: 31-Oct-2017
Overall Rationale for the Amendment: This amendment adds a second, optional, 
detailed pharmacokinetic profiling at Visit 10 in a subset of participants to allow for a 
better understanding of danirixin pharmacokinetics.  This amendment also removes the 
Participant Exit Interview from the exploratory endpoints.  Additionally, this amendment 
provides additional information and clarification for the following: spirometry 
assessments, exclusion for cancers other than lung cancer, permitted use of supplemental 
oxygen, permitted uses of chronic steroids, participant numbering requirement for re-
screening, additional text to explain the timing of the planned interim analysis and 
updates to the analysis populations.


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Section # 
and Name
Description of Change
Brief Rationale
Table 1 –
Schedule of 
Activities
Added Pulse Oximetry to 
Eligibility Assessments
To provide clarification for the 
eligibility assessment
Table 1 –
Schedule of 
Activities
Added additional, detailed PK 
profiling in a subset or 
participants at Visit 10
(additional text was added to 
footnote n)
To provide an additional PK profile to 
improve the understanding of 
danirixin PK
Table 1 –
Schedule of 
Activities
Removed Participant Exit 
Interview and associated 
footnote from Schedule of 
Activities
A completed analysis of Exit 
Interviews conducted as part of the 
danirixin phase IIa study (study 
200163) did not demonstrate 
sufficient evidence that the 
complexity and cost of including Exit 
Interview was justified as very limited 
additional information beyond that 
obtained with other scheduled 
participant questionnaires was 
obtained. Study Team decided to 
remove as an exploratory endpoint.
Section 3.1 
– Study 
Rationale
Exit Interview removed
See above for detailed explanation for 
removal of the Exit Interview
Section 4 –
Objectives 
and 
Endpoints
Added additional text to clarify 
assessment of the E-RS:COPD 
endpoint
To provide clarification of primary 
endpoint analysis
Section 4 –
Objectives 
and 
Endpoints
Exit Interview removed as an 
exploratory endpoint
See above for detailed explanation of 
rationale for removal of Exit 
Interview as an exploratory endpoint
Section 5.1 
– Overall 
Study 
Design
Provided additional 
explanatory text to describe 
interim analyses.
Provides clarification for purpose and 
timing of interim analyses
Section 6.1 
– Inclusion 
Criteria
Corrected typographical error 
in inclusion criterion 4
To correct typographical error


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Section # 
and Name
Description of Change
Brief Rationale
Section 6.2 
– Exclusion 
Criteria
Provided additional 
explanatory text for exclusion 
criterion 1
Provided explanatory text to clarify 
assessment of history of tuberculosis 
and other cancers
Section 6.2 
– Exclusion 
Criteria
Added new exclusion criterion 
26 to clarify prohibited oxygen 
use (also describes allowed 
oxygen use)
Provided text to clarify oxygen use 
study participants
Section 6.4 
– Screen 
Failure
Revised text to indicate that if 
a participant is rescreened they 
must be assigned a new 
participant number at the time 
of rescreening
This change was made to be 
consistent with the current GSK SOP 
requirements for rescreening a clinical 
trial participant
Section 6.5 
– Run In 
Failures
Additional text added to 
describe what to do if a COPD 
exacerbation occurs between 
Visit 2 and Visit 3
Provide clarification on what to do if 
a COPD exacerbation occurs between 
Visit 2 and Visit 3
Section 7.7 
–
Concomitant 
Therapy
Provided additional text to 
define chronic use of systemic 
corticosteroids
Provided definition of chronic use of 
systemic corticosteroids to clarify 
conditions of prohibited use from the 
screening visit until after completion 
of the follow up visit
Section 7.7 
–
Concomitant 
Therapy
Provided additional text to 
clarify use of oxygen
Added text clarifies the permitted uses 
of intermittent oxygen.
Section 
9.1.8 – Exit 
Interview
This subsection was removed 
since the Exit Interview was
removed as an exploratory 
endpoint.
See above for detailed explanation
Section 
9.1.9
Clinically Important 
Deterioration (CID)
This section renumbered to Section 
9.1.8 with removal of the Exit 
Interview Assessment.
Section 
9.2.8.3
Corrected spelling of Form and 
Medical in 2nd bullet of this 
section.
Correction of typographical error
Section 
9.4.6 –
This section added to provide 
in the protocol more detail for 
Adds spirometry testing detail to the 
protocol some of which was 


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Section # 
and Name
Description of Change
Brief Rationale
Spirometry 
Testing
the spirometry testing
previously in the Study Reference 
Manual (SRM).  The SRM will be 
update to avoid duplicate information.  
For spirometry testing, investigators 
should use the information in the 
protocol and the SRM.
Section 10.4 
–
Populations 
for Analysis
Modified Intent to Treat 
(mITT) population definition 
added to Populations for 
Analysis; Intent to Treat (ITT) 
and Safety Populations 
removed from Populations for 
Analysis
To perform analysis based on actual 
treatment instead of randomised 
treatment. This is a dose-ranging 
study and therefore the primary 
interest is on outcomes based on 
actual treatment.
Section 10.4 
–
Populations 
for Analysis
Definition of the PK 
Population changed to include 
all participants in the mITT 
population
PK population will be based on actual 
treatment instead of randomized 
treatment.
Section 
10.5.1.1 –
Primary 
Analysis
Revised text to indicate 
primary endpoint will use the 
mITT population,
See above for explanation
Section 
10.5.1.2
Text revised to indicate that 
analyses for secondary efficacy 
endpoints will use the mITT 
population, unless otherwise
noted
Revised text explains that mITT 
population will be used for the 
analyses of secondary efficacy 
endpoints, unless otherwise noted
Section 
10.5.2
Text revised to indicate that all 
safety endpoints will be 
performed on the mITT 
population
Revised text explains which 
population will be used for analysis of 
all safety endpoints
Section 
10.5.4
Additional text was added to 
provide additional information 
for the conduct of interim 
analyses.
To provide additional detail to 
describe the conduct of interim 
analyses.
Section 
10.5.4.2
Corrected spelling of 
parameter.
Correction of typographical error
Section 
10.5.4.2
Last paragraph of this section 
was amended.
Futility Interim Analysis will contain 
outputs for the primary endpoint and 


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Section # 
and Name
Description of Change
Brief Rationale
some key secondary endpoints –
details will be provided in the RAP
Section 
10.5.4.3 –
Strategic 
Planning 
Analyses
Revised text provides 
additional information for 
when the Strategic Planning 
interim analysis will be 
conducted
Additional text better defines the 
timing of the Strategic Planning 
interim analysis
Section 
10.5.4.4
This section added to provide 
additional text to describe 
interim analyses
Additional text to describe interim 
analyses
Section 11 –
References
Added Miller MR et al (2005) 
reference
Reference added to support additional 
spirometry text in Section 9.4.6
Section 12.1 
– Appendix 
1
ITT abbreviation removed; 
mITT abbreviation added
Changes reflect changes to 
Populations for Analysis changes 
made to section 10.5.1.2
Section 12.3 
– Appendix 
3
Publication Policy text revised 
to indicate that interim 
analyses may be disclosed 
externally
Provide text to explain that results of 
interim analyses may be disclosed 
externally
Section 12.3 
– Appendix 
3
Additional text added to 
Committees Structure section 
to indicate that results of 
interim analyses may be shared 
within GSK.
To provide additional explanation for 
sharing of results of interim analyses.
Section 12. 
3 –
Appendix 3
Typographical error corrected 
in third bullet of Dissemination 
of Clinical Study Data 
subsection
Correction of typographical error


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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS.............................................................................................................11
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................13
3.
INTRODUCTION....................................................................................................19
3.1.
Study Rationale ..........................................................................................20
3.2.
Background ................................................................................................20
3.3.
Benefit/Risk Assessment ............................................................................21
3.3.1.
Risk Assessment .........................................................................22
3.3.2.
Benefit Assessment.....................................................................26
3.3.3.
Overall Benefit:Risk Conclusion...................................................26
4.
OBJECTIVES AND ENDPOINTS...........................................................................26
5.
STUDY DESIGN ....................................................................................................28
5.1.
Overall Design ............................................................................................28
5.2.
Number of Participants ...............................................................................30
5.3.
Participant and Study Completion...............................................................30
5.4.
Scientific Rationale for Study Design ..........................................................30
5.5.
Dose Justification........................................................................................31
6.
STUDY POPULATION...........................................................................................32
6.1.
Inclusion Criteria.........................................................................................33
6.2.
Exclusion Criteria........................................................................................34
6.3.
Lifestyle Restrictions...................................................................................37
6.3.1.
Meals and Dietary Restrictions ....................................................37
6.3.2.
Activity .........................................................................................37
6.4.
Screen Failures...........................................................................................37
6.5.
Run In Failures ...........................................................................................37
7.
TREATMENTS.......................................................................................................38
7.1.
Treatments Administered............................................................................38
7.1.1.
Medical Devices...........................................................................39
7.2.
Dose Modification .......................................................................................39
7.3.
Method of Treatment Assignment ...............................................................39
7.4.
Blinding.......................................................................................................40
7.5.
Preparation/Handling/Storage/Accountability..............................................40
7.6.
Treatment Compliance................................................................................41
7.7.
Concomitant Therapy..................................................................................41
7.8.
Treatment after the End of the Study ..........................................................43
8.
DISCONTINUATION CRITERIA.............................................................................43
8.1.
Discontinuation of Study Treatment ............................................................43
8.1.1.
Liver Chemistry Stopping Criteria ................................................43
8.1.2.
QTc Stopping Criteria ..................................................................44
8.1.3.
Neutrophil Stopping Criteria.........................................................44
8.1.4.
Temporary Discontinuation ..........................................................44


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8.1.5.
Study Treatment Restart..............................................................45
8.2.
Withdrawal from the Study..........................................................................45
8.3.
Lost to Follow Up........................................................................................45
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................46
9.1.
Efficacy Assessments.................................................................................46
9.1.1.
EXACT and E-RS:COPD.............................................................46
9.1.2.
COPD Exacerbations...................................................................47
9.1.3.
SGRQ-C ......................................................................................48
9.1.4.
CAT .............................................................................................49
9.1.5.
PROactive ...................................................................................49
9.1.6.
Patient Global Rating of Severity and Global Rating of 
Change in Disease Severity.........................................................49
9.1.7.
Patient Global Rating of Activity Limitation and Global 
Impression of Change in Activity Limitation..................................50
9.1.8.
Clinically Important Deterioration (CID)........................................50
9.2.
Adverse Events...........................................................................................50
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................50
9.2.2.
Method of Detecting AEs and SAEs.............................................51
9.2.3.
Follow-up of AEs and SAEs.........................................................51
9.2.4.
Regulatory Reporting Requirements for SAEs .............................51
9.2.5.
Cardiovascular and Death Events................................................51
9.2.6.
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as SAEs...............................................52
9.2.7.
Pregnancy ...................................................................................52
9.2.8.
Medical Device Incidents (Including Malfunctions).......................52
9.2.8.1.
Time Period for Detecting Medical Device 
Incidents.....................................................................53
9.2.8.2.
Follow-up of Medical Device Incidents........................53
9.2.8.3.
Prompt Reporting of Medical Device Incidents 
to Sponsor..................................................................53
9.2.8.4.
Regulatory Reporting Requirements for 
Medical Device Incidents............................................54
9.3.
Treatment of Overdose...............................................................................54
9.4.
Safety Assessments ...................................................................................54
9.4.1.
Physical Examinations.................................................................54
9.4.2.
Vital Signs....................................................................................55
9.4.3.
Electrocardiograms......................................................................55
9.4.4.
Clinical Safety Laboratory Assessments ......................................55
9.4.5.
Pneumonia ..................................................................................56
9.4.6.
Spirometry Testing.......................................................................56
9.5.
Pharmacokinetics .......................................................................................57
9.6.
Pharmacodynamics ....................................................................................58
9.7.
Genetics .....................................................................................................58
9.8.
Biomarkers .................................................................................................58
9.9.
Health Economics OR Medical Resource Utilization and Health 
Economics..................................................................................................58
10. STATISTICAL CONSIDERATIONS........................................................................59
10.1.
Hypothesis..................................................................................................59
10.2.
Sample Size Determination ........................................................................59


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10.2.1.
Sample Size Re-estimation..........................................................63
10.3.
Randomization............................................................................................63
10.4.
Populations for Analyses ............................................................................63
10.5.
Statistical Analyses.....................................................................................64
10.5.1.
Efficacy Analyses.........................................................................64
10.5.1.1.
Primary Analysis.........................................................64
10.5.1.2.
Key Secondary Analyses............................................66
10.5.1.3.
HCRU Exacerbations .................................................66
10.5.1.4.
Time to First HCRU Exacerbation...............................66
10.5.2.
Safety Analyses...........................................................................66
10.5.3.
PK and PK/PD Analyses..............................................................66
10.5.4.
Interim Analyses ..........................................................................67
10.5.4.1.
Interim PK Analysis ....................................................67
10.5.4.2.
Futility Analysis...........................................................67
10.5.4.3.
Strategic Planning Analysis ........................................68
10.5.4.4.
Additional Interims......................................................68
11. REFERENCES.......................................................................................................69
12. APPENDICES........................................................................................................73
12.1.
Appendix 1: Abbreviations and Trademarks................................................73
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................77
12.3.
Appendix 3: Study Governance Considerations..........................................79
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................84
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................89
12.6.
Appendix 6: Genetics..................................................................................93
12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................94
12.8.
Appendix 8: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................97
12.9.
Appendix 9: Neutrophil Safety and Study Treatment Restart ......................99
12.10. Appendix 10: Country Specific Requirements...........................................101
12.11. Appendix 11: Protocol Amendment History...............................................102


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1.
SYNOPSIS
Protocol Title: Randomised, Double-Blind (Sponsor Open), Placebo-Controlled, Multi-
centre, Dose Ranging Study to Evaluate the Efficacy and Safety of Danirixin Tablets 
Administered Twice Daily Compared with Placebo for 24 Weeks in Adult Participants 
with Chronic Obstructive Pulmonary Disease (COPD)
Short Title: Danirixin Dose Ranging Study in Participants with COPD
Rationale: The primary aims of this study are to evaluate the clinical activity and safety 
of 5 doses of danirixin compared with placebo in participants with COPD.  The study is 
intended to support subsequent decisions regarding the progression of danirixin in the 
COPD indication, including the selection of doses and appropriate endpoints for use in 
pivotal studies.
Objectives and Endpoints:
Objective
Endpoint
Primary

To characterize the dose response of 
danirixin compared with placebo on 
the incidence and severity of 
respiratory symptoms in participants 
with COPD

To compare the safety of danirixin 
with placebo in participants with 
COPD

Change from baseline in respiratory 
symptoms measured by the 
Evaluating Respiratory Symptoms in 
COPD (E-RS:COPD) daily diary at 
month 6: total score and subscales 
(i.e. breathlessness, cough and 
sputum, and chest symptoms

Adverse events (AE), clinical 
laboratory values, vital signs, 
electrocardiogram (ECG)
Key Secondary

To characterize the dose response of 
danirixin compared with placebo on 
the annual rate of moderate/severe 
COPD exacerbations in participants 
with COPD

To further characterize the clinical 
activity of danirixin compared to 
placebo in participants with COPD

Annual rate of Healthcare Resource 
Utilization (HCRU)-defined COPD 
exacerbations

Time to first HCRU-defined COPD 
exacerbation

Change from baseline for the St. 
George’s Respiratory Questionnaire 
(SGRQ) total score (derived from 
SGRQ-C)


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Overall Design: This is a double-blind (Sponsor Open), placebo-controlled, parallel 
group study that will evaluate the dose response of danirixin compared with placebo on 
respiratory symptoms, COPD exacerbations, healthcare-related quality of life and 
physical activity.  The safety of danirixin compared with placebo is also an important 
objective of the study.  Following the completion of baseline assessments collected over a 
7 day period (i.e. EXACT/E-RS:COPD, physical activity, and rescue medication use), 
participants will be randomized (1:1:1:1:1:1) to receive one of five dose strengths of 
danirixin or placebo for 24 weeks.  Three interim analyses are planned for the study.  The 
first interim analysis will be an analysis of danirixin pharmacokinetics, and will be 
conducted after approximately 10 participants in each treatment group who are 
participating in the PK substudy have completed Visit 3. A futility analysis interim based 
on the E-RS:COPD endpoint and will be conducted after approximately 150 participants 
have completed 3 months of study treatment.  An additional interim analysis will be 
conducted approximately 12-15 months after the beginning of the study, or when 450 
participants have completed 6 months of study treatment, whichever is earlier.  This 
interim analysis will be used to support GSK decisions regarding the further development 
of danirixin and will include clinical activity assessments and key safety assessments 
available at the time it is conducted. Additional informal summaries of danirixin 
exposure and efficacy data may be undertaken during the conduct of the study.
Number of Participants:
Approximately 700 participants will be screened to achieve approximately 600 
randomized participants.  It is anticipated that approximately 540 participants will 
complete 24 weeks of treatment and key study assessments (dropout rate estimated to be 
approximately 10%).  
Treatment Groups and Duration:
Participants will be randomized to one of six parallel groups and will receive study 
treatment twice daily for 24 weeks:

Placebo

5 mg danirixin (as hydrobromide hemihydrate salt)

10 mg danirixin (as hydrobromide hemihydrate salt)

25 mg danirixin (as hydrobromide hemihydrate salt)

35 mg danirixin (as hydrobromide hemihydrate salt)

50 mg danirixin (as hydrobromide hemihydrate salt)


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2.
SCHEDULE OF ACTIVITIES (SOA)
Table 1
Schedule of Activities
Procedure
Pre-
Screeninga
(Visit 0)
Screeninga
(Visit 1)
Study Visits
2
3
4
5
6
7
8
9
10
Early 
Withdrawal
Follow Up
(up to 28 days 
post last dose)
Study Day
-7
1
14
28
56
84
112
140
168
Assessment Window
-30 d
0d
+ 
3d
3d
3d
3d
3d
3d
3d
3d
Eligibility 
Informed consent
X
Genetic Sample 
Informed Consentb
X
Demography
X
COPD Exacerbation 
History
X
Pre-Screening 
Fibrinogenc
X
Smoking Historyd
X
Smoking Statusd
X
X
Inclusion and 
Exclusion criteria
X
Medical historye
X
Full physical 
examination including 
height and weight
X
Chest x-ray (CXR)f
X


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Procedure
Pre-
Screeninga
(Visit 0)
Screeninga
(Visit 1)
Study Visits
2
3
4
5
6
7
8
9
10
Early 
Withdrawal
Follow Up
(up to 28 days 
post last dose)
Study Day
-7
1
14
28
56
84
112
140
168
Assessment Window
-30 d
0d
+ 
3d
3d
3d
3d
3d
3d
3d
3d
HIV, Hepatitis B and 
C screeningg
X
Pulse Oximetry
X
Additional Eligibility and In Study Assessments
Verify Eligibilityh
X
X
Brief Physical
X
X
X
X
X
Urine or serum
pregnancy testi
X
X
X
X
X
X
X
X
X
Laboratory 
assessments (clinical 
chemistry (includes 
liver chemistries), 
hematology, 
urinalysis) 
X
X
X
X
X
X
Additional Liver 
chemistries only
X
X
X
12-lead ECG
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
Spirometry
X
X
X
X
X
Randomization
X
Dispense Study 
Medication
X
X
X
X
X
X


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Procedure
Pre-
Screeninga
(Visit 0)
Screeninga
(Visit 1)
Study Visits
2
3
4
5
6
7
8
9
10
Early 
Withdrawal
Follow Up
(up to 28 days 
post last dose)
Study Day
-7
1
14
28
56
84
112
140
168
Assessment Window
-30 d
0d
+ 
3d
3d
3d
3d
3d
3d
3d
3d
Dispense log pad and 
provide training
X
Dispense MDI sensors 
and provide training
X
Dispense physical 
activity monitor and 
provide training
X
Study treatment
=====================================
Study treatment 
compliance (ediary)
=====================================
Collect IP
============================
X
X
Collect MDI sensors
X
X
Collect physical 
activity monitor
X
X
Collect log pad
X
X
Adverse Event (AE) 
review
=====================================
X
X
Serious Adverse 
Event (SAE) review
================================================================
X
X
Concomitant 
medication review
X
X
X
X
X
X
X
X
X
X
X
X
X


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Procedure
Pre-
Screeninga
(Visit 0)
Screeninga
(Visit 1)
Study Visits
2
3
4
5
6
7
8
9
10
Early 
Withdrawal
Follow Up
(up to 28 days 
post last dose)
Study Day
-7
1
14
28
56
84
112
140
168
Assessment Window
-30 d
0d
+ 
3d
3d
3d
3d
3d
3d
3d
3d
Clinical Outcomes Assessments
COPD Exacerbations
===========================================
X
X
EXACT-PROj
===========================================
Rescue Medication 
Usek
===========================================
SGRQ-C
X
X
X
X
COPD Assessment 
Test
X
X
X
X
PROactive 
Questionnairel
X
X
X
Physical Activity 
Monitorl
X
X
X
Participant Global 
Impression of COPD 
Severity
X
Participant Impression 
of Change in COPD 
Severity
X
X
X
X
X
X
X
X
Participant Global 
Impression of Activity 
Limitation
X


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Procedure
Pre-
Screeninga
(Visit 0)
Screeninga
(Visit 1)
Study Visits
2
3
4
5
6
7
8
9
10
Early 
Withdrawal
Follow Up
(up to 28 days 
post last dose)
Study Day
-7
1
14
28
56
84
112
140
168
Assessment Window
-30 d
0d
+ 
3d
3d
3d
3d
3d
3d
3d
3d
Participant Impression 
of Change in Activity 
Limitation
X
X
X
X
X
X
X
X
Genetic, Pharmacokinetic and Biomarker Blood Collections
Blood sample for 
Genetics
X
Blood sample for 
pharmacokinetics 
(PK)m
X
X
X
X
Blood sample for  
Fibrinogen
X
X
X
X
Blood sample for CRP
X
X
X
X
Blood Sample for 
Exploratory
Biomarkers
X
X
X
X


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Procedure
Pre-
Screeninga
(Visit 0)
Screeninga
(Visit 1)
Study Visits
2
3
4
5
6
7
8
9
10
Early 
Withdrawal
Follow Up
(up to 28 days 
post last dose)
Study Day
-7
1
14
28
56
84
112
140
168
Assessment Window
-30 d
0d
+ 
3d
3d
3d
3d
3d
3d
3d
3d
a.
Pre-screening and screening visits may be completed on the same day.
b.
Agreeing to the genetic sample consent is not required for study participation.
c.
A pre-screening plasma fibrinogen measurement is only required for participants with 1 COPD exacerbation in the prior year.
d.
Smoking status /history assessed at screening: smoking status rechecked at Visit 2
e.
Includes substance usage, past and present medical conditions and family history of premature CV disease.
f. 
See inclusion/exclusion criteria for CXR screening requirement
g. 
Hepatitis B (HBsAg) and Hepatitis C (HepC antibody) testing is required. If testing otherwise performed within 3 months prior to the first dose of 
study treatment, testing at screening is not required.  Hepatitis C RNA testing is optional; however a confirmatory negative Hepatitis C RNA test must 
be obtained, to be able to enrol participants with positive Hepatitis C antibody due to prior resolved disease.
h.
Participant’s clinical status should be reviewed.
i.
Pregnancy testing only required for women of child bearing potential (WOCBP).  A positive urine pregnancy test requires confirmation with a serum 
pregnancy test.
j.
E-RS:COPD is a subset of EXACT-PRO and is not a separate assessment.
k.
Rescue medication use will be assessed via e-diary and MDI sensor.
l. 
The Clinic Visit PROactive Physical Activity in COPD tool will be assessed in a subset of approximately 50% of study participants
m.
Pre-dose PK samples will be collected in all participants at Visits 3, 6, 7, and 10.  In a subset of participants (approx. 50 participants at each dose 
level) at Visit 3, PK samples will be collected at pre-dose, 0.5, 1, 2, 4, 6, 8, 10, 12 hours post-dose.  In a subset of participants (approx.. 50 
participants at each dose level) at Visit 10, PK samples will be collected at pre-dose, 0.5. 1. 2. 4. 6, 8, 10, 12 hours post-dose.
Note: The timing and number of planned study assessments, including safety, pharmacokinetic, and biomarker assessments, may be 
altered during the course of the study based on newly available data (e.g., to obtain data closer to the time of peak plasma 
concentrations) to ensure appropriate monitoring. Any changes in the timing or addition of time points for any planned study 
assessments must be documented and approved by the relevant study team member and then archived in the sponsor and site study 
files, but will not constitute a protocol amendment. The IRB/IEC will be informed of any safety issues that require alteration of the 
safety monitoring scheme or amendment of the ICF.


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3.
INTRODUCTION
The inflammation associated with COPD is characterized by a prominent infiltration of 
neutrophils in lung tissue and the airways.  Neutrophils and other inflammatory cells are 
recruited to the lung in response to various chemotactic factors, including chemokines.  
Specifically, there is a large body of evidence that the CXCR2 chemokine receptor plays 
a pivotal role in neutrophil recruitment to the lung.  For neutrophils, chemokine binding 
to the CXCR2 results in chemotaxis and cell activation, ultimately resulting in the release 
of a number of inflammatory mediators and proteases that are thought to contribute to the 
progressive fibrosis, airway stenosis, and destruction of the lung parenchyma 
characteristic of COPD.    
Selective antagonism of the interaction between CXCR2 and its ligands is a potential 
strategy for reducing the inflammation in COPD [Chapman, 2009].  A reduction in tissue 
and airway neutrophilia is expected to result in downstream effects on mucus 
hypersecretion, lung inflammation, and tissue destruction that are hypothesized to 
underlie the development and worsening of respiratory symptoms and decline in lung 
function that occurs in COPD.
Molecules with CXCR2 antagonist activity have been shown to reduce the influx of 
neutrophils into the lungs in healthy participants (e.g. ozone or LPS challenge models) 
and to reduce sputum and tissue neutrophils in the lungs of patients with severe, 
neutrophilic asthma, COPD and bronchiectasis in association with improvements in 
measures of disease activity in some, but not all, studies [O'Byrne, 2016; Holz, 2010; 
Watz, 2016; Lazaar, 2011; Nair, 2012; Rennard, 2015]. Overall, the results of the 
reported clinical studies with CXCR2 antagonists suggest that careful selection of the 
target patient population is important to achieving clinical benefit.
Danirixin is a selective CXCR2 antagonist being developed as a potential anti-
inflammatory agent for the treatment of COPD and other inflammatory diseases and 
influenza.  Danirixin has demonstrated potent antagonism of CXCR2 activity both in 
vitro and in vivo in preclinical studies [GlaxoSmithKline Document No. 
YM2010/00163/07]. 
Clinical pharmacology studies in healthy volunteers demonstrated the pharmacodynamic 
activity of danirixin (inhibition of ex vivo CXCL1-induced CD11b expression on 
peripheral blood neutrophils).  Danirixin has also been tested in a Phase IIa study in 
symptomatic participants with mild to moderate COPD at risk for exacerbation (GSK 
Study No. 200163) [GlaxoSmithKline Document No. 2013N180289_03].  In study 
200163, twice daily dosing with danirixin free base (75 mg bid) or placebo given on top 
of standard of care inhaled maintenance treatments was tested for one year.  An interim 
analysis of clinical endpoints from study 200163 demonstrated that danirixin, compared 
to placebo, reduced respiratory symptoms as measured with E-RS:COPD [Miller, 2016].


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3.1.
Study Rationale
This protocol describes a Phase IIb dose-ranging study evaluating the clinical activity and 
safety of danirixin compared with placebo in participants with COPD that have current 
respiratory symptoms including cough, increased sputum production, and dyspnoea.  
Study participants will continue with their standard of care inhaled medications (i.e. long 
acting bronchodilators with or without inhaled corticosteroids) while receiving study 
treatment.  In this study, 5 doses of danirixin and placebo are being evaluated (danirixin 
or placebo will be taken orally twice daily).  
The primary objectives of the study are to evaluate the dose response of danirixin 
compared with placebo on respiratory symptoms assessed by the E-RS:COPD patient 
reported outcome (PRO) tool and assess the safety of danirixin compared with placebo.  
Key secondary objectives include an evaluation of danirixin compared with placebo on 
healthcare resource utilization (HRCU) defined COPD exacerbations, health status, 
physical activity, and rescue medication use.  Exploratory objectives will include blood 
biomarkers to investigate the impact of danirixin on biomarkers of extracellular matrix 
turnover and remodeling.  
3.2.
Background
COPD is a major cause of disability, morbidity, and mortality, resulting in millions of 
deaths annually worldwide contributing significantly to health care costs [Mathers, 2006; 
Lopez-Campos, 2016; Vastava, 2015; GOLD, 2016].  The morbidity and mortality of 
COPD are continuing to increase and worldwide, by the year 2020, COPD is expected to 
be the third leading cause of death and fifth leading cause of disability [Mathers, 2006; 
Lopez-Campos, 2016].  The airflow limitation that characterizes COPD is primarily due 
to small airways disease and parenchymal destruction associated with an excessive 
inflammatory response in the lung, mainly caused by cigarette smoking [Celli, 2004].  
COPD is characterized by symptoms of chronic and, in many patients, progressive 
breathlessness (or dyspnea), cough and sputum production.  Many COPD patients also 
suffer from periodic worsening of their COPD symptoms that is beyond the typical day to 
day variation [Hurst, 2010].  These episodes of worsening symptoms (COPD 
exacerbations) account for a significant proportion of COPD-related and total health care 
costs.  Despite several available therapies that have been shown to reduce COPD 
exacerbations and respiratory symptoms, many COPD patients continue to experience a 
high burden of respiratory symptoms and COPD exacerbations resulting in a continuing 
unmet medical need [Vestbo, 2016].  Additionally, there is growing recognition that a 
high percentage of COPD patients with mild airflow limitation as well as smokers with 
preserved lung function suffer from a high burden of symptoms and COPD exacerbations 
with a subsequent impact on health status [Woodruff, 2016].  Therapies that effectively 
further reduce COPD exacerbations and improve respiratory symptoms could have a 
substantial impact on healthcare utilization and most importantly result in an 
improvement in COPD patients’ quality of life.
The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines for the 
treatment and management of patients with COPD recommend that the management of 
current respiratory symptoms and subsequent worsening of symptoms resulting in COPD 


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exacerbations should be an important component of COPD patient management [GOLD, 
2016].
Danirixin is being evaluated as an addition to standard of care inhaled therapies (i.e. long 
acting bronchodilators and long acting bronchodilator/corticosteroid combination 
therapies) and is targeting those COPD patients that continue to have a burden of 
respiratory symptoms and COPD exacerbations despite management with currently 
available COPD treatments.
3.3.
Benefit/Risk Assessment
More detailed information about the potential benefits and risks of danirixin may be 
found in the danirixin Investigator’s Brochure [GlaxoSmithKline Document No. 
YM2010/00163/07].


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3.3.1.
Risk Assessment
Investigational Product (IP) [Danirixin, GSK1325756]
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Testicular effects and male fertility
The most sensitive species is the rat. 
Testicular effects present at doses ≥150
mg/kg/day in the rat include spermatid 
degeneration, seminiferous tubular 
degeneration and secondary epididymal 
changes, including oligo/aspermia and/or 
epididymal intratubular cellular debris.  The 
no observed adverse effect level (NOAEL) 
in this study, based on the microscopic 
findings in the testis, was 50 mg/kg/day for 
male rats.  The systemic exposure margins 
for the NOAEL for testicular effects in the 
rat is 7.3-fold for an oral clinical dose of 50 
mg BID free base tablet.
The testicular effects seen in the rat have 
also been shown to directly impact on male 
fertility and the NOAEL for these 
reproductive effects was 100 mg/kg/day. 
Refer to IB Section 4.4 for full details
No adverse events related to testicular 
effects have been observed in clinical 
studies to date.
Standard safety monitoring will be 
employed.
The potential risk of testicular injury has 
been conveyed in the informed consent.
Pharmacokinetic parameters will be 
monitored in clinical studies to ensure 
appropriate safety margins (2-fold 
NOAEL). PK modelling predicts that in a 
participant receiving 50 mg BID of the HBr 
salt, the risk of exposure exceeding the 2-
fold margin for AUC(0-24) for the NOAEL 
of testicular effects is low.


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Investigational Product (IP) [Danirixin, GSK1325756]
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Impairment of host defense.
Host defense has not been studied directly 
in nonclinical studies. However, data in 
nonclinical species have not identified an 
increased risk of infection with danirixin.  
Nonclinical studies in mice and ferrets with 
two CXCR2 antagonists in the same 
chemical class as danirixin have not shown 
an increase in infections in challenge 
models (e.g., influenza viral load).  
Secondary bacterial infections after viral 
infection have not been directly evaluated in 
nonclinical studies.
The data from clinical studies including 
healthy participants, COPD and influenza 
patients thus far show no evidence that 
participants taking danirixin have an 
increased infection rate compared with 
participants taking placebo.
Neutropenia has been reported in clinical 
trials of other CXCR2 antagonists.  No 
instances of neutropenia have been reported 
in nonclinical studies with danirixin.  In 
healthy volunteer studies and a phase 2a 
study in patients with Influenza (GSK Study 
Monitoring of neutrophil count.
Stopping criteria: in participants with a 
confirmed absolute neutrophil count 0.5 x 
109/L product will be discontinued and 
neutrophil count will be monitored until 
return to normal. Participants may be 
restarted on study treatment as detailed in 
Appendix 9.
Ongoing assessment of AE/SAEs related to 
infection.
Closely monitor, collect information on and 
characterize infection events such as 
pneumonia, and use adjudication as 
appropriate.


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Investigational Product (IP) [Danirixin, GSK1325756]
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
201682, GlaxoSmithKline Document No. 
2014N205875_00), decreased neutrophil 
counts have been observed in subjects 
receiving either placebo or danirixin; no 
instances of danirixin-related neutropenia 
have been reported in clinical studies to 
date. In healthy subjects, the data are 
confounded by the observation of low 
neutrophil counts before dosing or at 
follow-up, and were not dose-related, while 
in patients with influenza, neutrophil counts 
recovered while receiving danirixin, 
coincident with resolution of the viral 
infection. There have been no reports of 
neutrophil count decreases below the lower 
limit of normal in patients with COPD who 
were treated with danirixin for one year.   
These data support the conclusion that a 
causal association of neutropenia with 
danirixin cannot be definitively established.


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Investigational Product (IP) [Danirixin, GSK1325756]
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Reproductive toxicology (Embryofetal 
development)
In a rat embryofetal development study, an 
oral dose of 300 mg/kg/day resulted in fetal 
skeletal variations in the skull (reductions in 
ossification). There were no test article-
related effects on numbers of corpora lutea, 
implantations, embryofetal survival,
placental morphology, gravid uterine 
weight, sex ratio, fetal body weight, or fetal 
morphology (external and visceral).
As danirixin HBr has shown the potential to 
cause fetal malformations, danirixin or 
danirixin HBr must not be administered to 
pregnant women or nursing mothers. 
Women of childbearing potential should 
only be included in clinical trials with the 
use of appropriate precautions against 
pregnancy.
Male participants with female partners of
child-bearing potential must comply with 
the contraception requirements.
Study Procedures
None
Other 
Not applicable


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3.3.2.
Benefit Assessment

All participants will undergo a thorough medical assessment during the study. 
Participants will have frequent study clinic visits for the evaluation of their 
disease symptoms. During these visits, participants will have spirometry, ECG, 
vital signs monitoring, and physical examinations. Monitoring for worsening of 
their disease will also take place.  

Participants may benefit from the knowledge that they are contributing to the 
process of developing a new treatment in an area of unmet need, even if not 
directly beneficial for them

All participants will continue with changes to their medications, where medically 
appropriate, to receive established standard of care.  
3.3.3.
Overall Benefit:Risk Conclusion
Danirixin has demonstrated potent antagonism of CXCR2 activity both in vitro and in 
vivo in preclinical and clinical studies. Its potency and duration of action supports its 
potential use as an oral, anti-inflammatory agent in the treatment of COPD with 
anticipated potential for bringing benefit to a serious condition that affects the lives of 
millions and contributes to significant morbidity and mortality.
In clinical trials completed to date danirixin has been well-tolerated and most adverse 
events (AEs) were mild to moderate in intensity. The most commonly observed AEs have 
been nasopharyngitis, headache and diarrhea following administration of danirixin or 
placebo.  There have been no treatment related clinically significant changes in vital signs 
and ECG at any dose of danirixin.  
Taking into account the measures taken to minimize risks to participants in this study, the 
potential risks identified in association with danirixin are justified by the anticipated 
benefits that may be afforded to participants with COPD.
4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To characterize the dose response of 
danirixin compared with placebo on 
the incidence and severity of
respiratory symptoms in participants 
with COPD

To compare the safety of danirixin 
with placebo in participants with 
COPD

Change from baseline in respiratory 
symptoms measured by E-RS:COPD 
daily diary at month 6: total score and 
subscales (i.e. breathlessness, cough 
and sputum, and chest symptoms)

Adverse events (AE), clinical 
laboratory values, vital signs, 
electrocardiogram (ECG)


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Objectives
Endpoints
Secondary

To characterize the dose response of 
danirixin compared with placebo on 
the annual rate of moderate/severe 
COPD exacerbations in participants 
with COPD

To further characterize the clinical 
activity of danirixin compared to 
placebo in participants with COPD

Healthcare Resource Utilization 
(HCRU)-defined COPD exacerbations

E-RS:COPD Responder Analysis 
(including subscales)

Number of Exacerbations of Chronic 
Pulmonary Disease (EXACT) tool 
defined events

Time to first EXACT event

EXACT event severity

EXACT event duration for all events

Time to first HCRU-defined COPD 
exacerbation

Time to first severe HCRU-defined 
COPD exacerbation

HCRU-defined exacerbation duration

Change from baseline for the St. 
George’s Respiratory Questionnaire 
(SGRQ) total score (derived from 
SGRQ-C)

SGRQ responder analysis

Change for baseline COPD 
Assessment Test (CAT) total score

CAT responder analysis

Lung function (FEV1, FEV1 % 
predicted, FVC, FEV1/FVC ratio)

Rescue medication use

Participant experience of physical 
activity (subset of approximately 50% 
of participants) measured using 
PROactive Clinic Visit Tool (C-PPAC)


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Objectives
Endpoints

To characterize the 
pharmacokinetics of danirixin in 
participants with COPD

Danirixin concentration and standard 
pharmacokinetic parameters for 
danirixin (e.g. AUC, Cmax, Tmax), 
using dried blood spot data
Tertiary/Exploratory

To further explore study participants 
experience with study treatment and 
overall experience with the study

To characterize the effect of 
danirixin on lung matrix 
destruction/remodelling

Comparison between dried blood 
spot and wet whole blood analysis of 
danirixin concentrations in patients 
with COPD

To characterise danirixin exposure-
response relationships for various 
safety parameters,if appropriate

Time to first Clinically Important 
Deterioration (CID)

SGRQ domains

Blood/serum/plasma biomarkers that 
are indicative of extracellular matrix 
turnover/remodelling (e.g. elastin and 
collagen neo-epitopes)

Danirixin concentration and standard 
pharmacokinetic parameters for 
danirixin (e.g. AUC, Cmax, Tmax) 

Danirixin systemic exposure and 
various efficacy/PD/safety parameters, 
if appropriate
5.
STUDY DESIGN
5.1.
Overall Design
A study schematic is shown in Figure 1. This is a parallel group study.  Following 
screening and successful completion of the EXACT daily diary (all participants), rescue 
medication use daily diary (all participants) and PROactive baseline measurements 
(questionnaire and participant experience of physical activity) over study days -7 to 1, 
participants will be randomized (1:1:1:1:1:1) to receive one of five dose strengths of 
danirixin (5 mg, 10 mg, 25 mg, 35 mg and 50 mg) or placebo.  Study treatment will be 
administed twice daily for 24 weeks.  The PROactive baseline measurements will only be 
collected for those participants selected for the physical activity monitoring subgroup.  
Participants who do not properly complete (i.e. are not adherent with the requirements for 
completing and recording) the required baseline assessments (i.e. EXACT/E-RS:COPD 
daily diary, physical activity monitoring portion of PROactive, and daily rescue 
medication use baseline measurements) will not be randomized and will not be eligible 
for rescreening.


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A minimum of three interim analyses are planned for the study.  The first interim analysis 
will be an evaluation of danirixin pharmacokinetics after 10 participants in each treatment 
group participating in the PK substudy have completed Visit 3.
A futility analysis interim based on the E-RS:COPD endpoint and will be conducted after 
approximately 150 participants have completed 3 months of study treatment. 
An additional interim analysis will be conducted approximately 12-15 months after the 
beginning of the study, or when 450 participants have completed 6 months of treatment, 
whichever is earlier.  This interim analysis will be used to support GSK decisions 
regarding the further development of danirixin, and will include E-RS:COPD dose 
response modelling, secondary endpoints of HCRU-defined exacerbations and SGRQ 
total score along with all available safety data.  No changes will be made to the study 
based on the results of this interim analysis.  
Additional informal assessments of danirixin exposure and efficacy data may be 
undertaken during the conduct of the study as data becomes available. No decisions 
regarding study conduct will be made based on these informal assessments.
Outputs containing unblinded treatment assignments will be created for these interim 
analyses and will only be made available to a limited number of GSK staff.  Full details 
will be included in the study data dissemination plan.
No Independent Data Monitoring Committee (IDMC) will be utilized for this study.  
While the study is being conducted, core members of the study team will be unblinded 
(with the exception of those study team members who will directly interact with study 
sites, e.g. Operations and Science Leader and Data Quality Leader).  There will be 
ongoing review of safety data and clinical outcomes.  Only the study statistician will have 
access to individual participant treatment assignments, other core team members will 
review aggregate summaries by study treatments.  A study charter will specify which 
team members will have access to unblinded data while the study is ongoing, the 
frequency of planned data reviews and the data to be included in the data reviews.  The 
study charter will also state how interim results will be communicated outside the study 
team.  A safety review team will meet approximately every 3 months (or as needed based 
on emerging data) to review available safety information.  


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Figure 1
Study Schematic
5.2.
Number of Participants
Approximately 700 participants will be screened to achieve approximately 600 
randomized participants.  It is anticipated that approximately 540 participants will 
complete 24 weeks of treatment and key study assessment (the dropout rate is estimated 
to be approximately 10% based on previous experience with studies enrolling similar 
participants).  
For the analysis of study assessments, several analysis populations will be defined.  
Details of the evaluable participants for each planned analysis population are included in 
Section 10.4. 
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 the last study visit and the last scheduled procedure shown 
in the Schedule of Activities (Table 1).
The end of the study is defined as the date of the last visit of the last participant in the 
study. 
5.4.
Scientific Rationale for Study Design
This study will use a multicenter, randomized, parallel-group design. This is a well-
established design to evaluate the efficacy and safety of an investigational drug. Twenty-
four weeks should be adequate to demonstrate efficacy based on E-RS:COPD, as well as 
to collect adequate safety measurements before going into larger phase III trials. 
Danirixin has already been clinically investigated over one year treatment duration (GSK 
Study No. 200163, GlaxoSmithKline Document No. 2013N180289_03). 


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By evaluating a range of doses from 5 mg to 50 mg of danirixin, it will be possible to 
assess the dose response of danirixin as well as the potential effects of danirixin on 
biomarker and safety endpoints. The data will provide useful information in determining 
the therapeutic index of danirixin and in selecting the minimal effective and safe dose to 
be carried forward in the Phase III COPD program.
PK samples from randomized participants will also be collected in this study.  Defining 
the optimum dose for later stages of development can be made more efficiently by 
understanding the variability in the pharmacokinetics of a drug. In addition, the study will 
evaluate the relationship between danirixin blood concentrations and biomarker and 
safety endpoints. 
A placebo arm is included to measure the absolute effect of each dose tested, thereby 
allowing a robust determination of the dose-response. Inclusion of a placebo arm will 
also allow a more robust exploration of the therapeutic index of danirixin.
5.5.
Dose Justification
Five doses of danirixin (5 mg, 10 mg, 25 mg, 35 mg and 50 mg) are planned for 
evaluation in this study. The doses to be investigated have been selected based on 
integrating information available from:

Dose-exposure-biomarker response using inhibition of ex vivo CXCL1-induced 
CD11b expression on peripheral blood neutrophils over the dose range of 0-400 
mg in healthy volunteer participants

Evidence of reduced respiratory symptoms in mild to moderate COPD 
participants in the Phase IIa study (GSK study 200163) 
In the early clinical studies, danirixin was administered as a free base tablet, whereas the 
danirixin formulation to be used in this study will be a hydrobromide salt tablet. The 
hydrobromide tablet has approximately twice the bioavailability of the free base tablet in 
healthy elderly participants (GSK Study No. 201037, GlaxoSmithKline Document No. 
2015N248339_00 ).  Predicted steady-state exposures and multiples of blood ex vivo
CXCL1-induced CD11b pharmacology at the proposed danirixin doses are presented in 
Table 2. 


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Table 2
Predicted steady state systemic exposure and multiples of blood ex 
vivo CXCL1-induced pharmacology following twice daily of 
administration of danirixin
a.
Model derived based on PK data in healthy elderly participants from GSK Study No. 201037 
(GlaxoSmithKline Document No. 2015N248339_00).
b.
Model predicted population mean IC50=78.5 ng/mL (95% CI: 37.3, 120), sigmoidal Emax model of 
DNX PK-ex vivo CXCL1-induced CD11b expression on peripheral blood neutrophils in healthy 
participants.
The predicted multiples of ex vivo CXCL1-induced CD11b inhibition achieved at 24 h 
post steady-state, together with the terminal elimination half-life of danirixin support the 
twice daily dosing regimen.
Based on the biomarker results described for danirixin and the anticipated higher 
exposure from the hydrobromide tablet, doses of 5 mg, 10 mg, 25 mg and 35 mg were 
selected to span the dose range and allow efficient estimation of the dose response curve 
in this mild/moderate COPD population. Fifty mg twice daily is included as a supra-
therapeutic dose but where there is a low possibility of AUC(0-24) exposure exceeding a 
2-fold margin for the no observed adverse effect level (NOAEL) for testicular effects.
The risk of exposure exceeding the 2-fold margin for AUC(0-24) for the NOAEL of 
testicular effects is considered low. Based on PK modeling, the predicted AUC (0-24) for 
a dose of 50 mg BD is 13.7 ug.hr/mL (6.7, 27.6). This provides 2.5-fold cover over the 
NOAEL/2 and approximately 5-fold cover over the NOAEL.
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
Dose 
(mg)
Predicted steady-state median (5th, 95th
percentile)a
Cavg 
multiple of 
IC50b
Cmin 
multiple of 
IC50b
AUC(0-24) 
steady-state
(g.h/mL)
Cavg
(ng/mL)
Cmin
(ng/mL)
5
1.37 
(0.69, 2.78)
57.2
(28.6, 116)
27.8
(6.8, 92.1)
0.7
0.4
10
2.74 
(1.34, 5.53)
114 
(56.0, 230)
54.8
(13.6, 180)
1.5
0.7
25
6.85
(3.36, 13.8)
285
(140, 576)
137
(34.0, 450)
3.6
1.7
35
9.59
(4.70, 19.3)
399
(196, 806)
192
(47.6, 630)
5.1
2.4
50
13.7
(6.71, 27.6)
571
(280, 1152)
274
(68.0, 900)
7.3
3.5


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6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1. Participant must be 40 to 80 years of age inclusive, at the time of signing the 
informed consent.
Type of Participant and Disease Characteristics
2. Participants who have COPD (postbronchodilator FEV1/FVC ratio < 0.7 and FEV1 
% predicted 40%) based on American Thoracic Society (ATS)/European 
Respiratory Society (ERS) current guidelines [Celli, 2004].  Participants with a 
historical diagnosis of asthma may be included so long as they have a current 
diagnosis of COPD.
3. History of respiratory symptoms including chronic cough, mucus hypersecretion, and 
dyspnea on most days for at least the previous 3 months prior to screening.
4. Participants with a documented history of COPD exacerbation(s) in the 12 months 
prior to study participation (screening) meeting at least one of the following criteria:

2 COPD exacerbations resulting in prescription for antibiotics and/or oral 
corticosteroids or hospitalization or extended observation in a hospital emergency 
room or outpatient center

1 COPD exacerbation resulting in prescription for antibiotics and/or oral 
corticosteroids or hospitalization or extended observation in a hospital emergency 
room or outpatient center and a plasma fibrinogen concentration at screening 3 
g/L (300 mg/dL)
5. Smoking history: current and former smokers with a cigarette smoking history of 
10 pack years (1 pack year = 20 cigarettes smoked per day for 1 year or equivalent).  
Current smokers are defined as those who are currently smoking cigarettes (i.e. have 
smoked at least one cigarette daily or most days for the month prior to Visit 1).  
Former 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 smoking 
pack-year history.
6. Participants must have the ability and willingness to use an electronic diary (log pad) 
on a daily basis.
Weight
7. Body weight 45 kg


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Sex
8. Male or female.
a. Male participants:
A male participant must agree to use contraception as detailed in Appendix 5 of this 
protocol during the treatment period and for at least 60 hours after the last dose of 
study treatment, corresponding to approximately 6 half-lives (which is the time 
needed to eliminate any teratogenic study treatment) and to refrain from donating 
sperm during this period.
b. Female participants: 
A female participant is eligible to participate if she is not pregnant (see Appendix 5), 
not breastfeeding, and at least one of the following conditions applies:
i.
Not a woman of childbearing potential (WOCBP) as defined in Appendix 5
OR
ii. A WOCBP who agrees to follow the contraceptive guidance in Appendix 5
during the treatment period and for at least 60 hours after the last dose of 
study treatment.
Informed Consent
9. Capable of giving signed informed consent as described in Appendix 3 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Diagnosis of other clinically relevant lung diseases (other than COPD), e.g. 
sarcoidosis, tuberculosis, pulmonary fibrosis, severe bronchiectasis or lung cancer.

A participant with a history of tuberculosis may be considered for eligibility if 
he/she has documented completion of a course of antibiotic therapy (eg, INH) and 
has no evidence of latent TB infection.  A chest x-ray ideally would be available 
for review by the medical monitor but is not required. All cases of prior TB must 
be discussed with the medical monitor.

For cancers other than lung cancer, participants may be considered for eligibility 
if the carcinoma has been in remission for at least 5 years.  Participants who have 
had carcinoma in situ of the cervix, squamous cell carcinoma or basal cell 
carcinoma of the skin would not need to be excluded based on the 5 year waiting 
period if the participant has been considered cured by treatment.
2. Alpha-1-antitrypsin deficiency as the underlying cause of COPD


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3. Pulse oximetry < 88% at rest at screening.  Participants should be tested while 
breathing room air.  However, participants living at high altitudes (above 5000 feet or 
1500 meters above sea level) who are receiving supplemental oxygen can be included 
provided they are receiving the equivalent of < 4 L/min and screening pulse oximetry 
is measured while on their usual oxygen settings.
4. Less than 14 days have elapsed from the completion of a course of antibiotics or oral 
corticosteroids for a recent COPD exacerbation.
5. A peripheral blood neutrophil count < 1.5 x 109/L.
6. Diagnosis of pneumonia (chest X-ray or CT confirmed) within the 3 months prior to 
screening.
7. Chest x-ray (posterior-anterior with lateral) or CT scan reveals evidence of a 
clinically significant abnormality not believed to be due to the presence of COPD 
(historic results up to 1 year prior to screening may be used).  For sites in Germany: If 
a chest x-ray (or CT scan) within 1 year prior to screening is not available, approval 
to conduct a diagnostic chest x-ray will need to be obtained from the Federal Office 
of Radiation Protection (BfS).
8. History or current evidence of other clinically significant medical condition that is 
uncontrolled on permitted therapies.  Significant is defined as any disease that, in the 
opinion of the Investigator, would put the safety of the participant at risk through 
study participation, or that would affect the safety analysis or other analysis if the 
disease/condition worsened during the study.
9. Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert’s syndrome or asymptomatic gallstones).
10. Abnormal and clinically significant 12-lead ECG finding. 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 study.  An abnormal and clinically significant finding that would 
preclude a participant from entering the study is defined as a 12-lead tracing that is 
interpreted as, but not limited to, any of the following:
a.
AF with rapid ventricular rate > 120 bpm
b. sustained or non-sustained VT
c.
second degree heart block Mobitz type II and third degree heart block (unless 
pacemaker or defibrillator has been implanted)
d. QTcF 500 msec in participants with QRS < 120 msec and QTcF 530 msec 
in participants with QRS 120 msec
11. Previous lung surgery (e.g. lobectomy, pneumonectomy) or lung volume reduction 
procedure.
Prior/Concomitant Therapy
12. Current or expected chronic use of macrolide antibiotics during the study period for 
the prevention of COPD exacerbations.  Examples of chronic use include, but are not 
limited to, daily or two to three times per week use for at least 3 months.


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13. Oral or injectable CYP3A4 or BRCP (breast cancer resistance protein) substrates with 
a narrow therapeutic index (CYP3A4 substrates include, but are not limited to, 
alfenatil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, 
quinidine, sirolimus, tacrolimus, and theophylline; BCRP substrates include, but are 
not limited to, topotecan.)  The Investigator should consult with the Medical Monitor 
if necessary.
14. Current or expected use of phosphodiesterase-4 inhibitors (e.g. roflumilast).  
Participants currently receiving roflumilast may be included if they are able to 
discontinue use from 30 days prior to screening through the completion of the follow 
up visit.
Prior/Concurrent Clinical Study Experience
15. Participation in a previous clinical trial and has received an investigational product 
within any of the following time periods prior to the first dosing day in the current 
study: 30 days, 5 half lives, or twice the duration of the biological effect of the 
investigational product (whichever is longer).
16. Participation in a previous clinical trial with danirixin within 1 year prior to the first 
dosing day in the current study
17. Exposure to more than four investigational products within 1 year prior to the first 
dosing day in the current study.
Diagnostic assessments
18. Alanine transferase (ALT) > 2x upper limit of normal (ULN); bilirubin > 1.5xULN 
(isolated bilirubin > 1.5xULN is acceptable if bilirubin is fractionated and direct 
bilirubin <35%).
19. A positive test for HIV antibody.
20. A positive pre-study hepatitis B surface antigen or positive hepatitis C antibody result 
within 3 months prior to screening.
Other Exclusions
21. Pulmonary rehabilitation: Participants who have taken part in the acute phase of a 
pulmonary rehabilitation program within 4 weeks prior to screening or participants 
who plan to enter the acute phase of a pulmonary rehabilitation program during the 
study.  Participants who are in the maintenance phase of a pulmonary rehabilitation 
program are not excluded.
22. A history of allergy or hypersensitivity to any of the ingredients in the study 
treatment.
23. A known or suspected history of alcohol or drug abuse within the 2 years prior to 
screening.
24. 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.


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25. Affiliation with the study site: study investigators, sub-investigators, study 
coordinators, employees of a study investigator, sub-investigator or study site, or 
immediate family member of any of the above that are involved with the study.
26. Oxygen therapy:  Chronic treatment with long-term oxygen therapy (LTOT) or 
nocturnal oxygen therapy required for > 15 hours a day.  Oxygen prn use (i.e.<15   
hours per day) is not exclusionary.  Oxygen use during an exacerbation is permitted.  
6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions
No meal or dietary restrictions are required for participation in this study.  Danirixin must 
be taken with food.  Specific dosing instructions will be provided in the Study Reference 
Manual (SRM) and will be provided to all study participants.
6.3.2.
Activity
Participants should abstain from strenuous exercise for 24 hours before each blood 
collection for clinical laboratory tests. 
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized in the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria and any serious adverse 
events (SAEs).
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened up to two additional times if the investigator judges the participant can 
meet the eligibility criteria. Any rescreened participant must satisfy all of the protocol 
specified inclusion/exclusion requirements at the re-screening visit.  Rescreened 
participants should be assigned a new participant number at the time of rescreening.
6.5.
Run In Failures
A run in failure is defined as a participant who consents to participate in the clinical 
study, satisfies all eligibility criteria, but who does not properly complete the required 
baseline assessments for the daily EXACT diary, daily rescue medication use, and the 
physical activity monitoring portion of PROactive baseline (if selected to participate in 
the physical activity subgroup) over 7 days beginning with Visit 2.  A participant who is 
selected to participate in the physical activity subgroup and does not complete the 
baseline physical activity monitoring portion of PROactive baseline but does complete 
the daily EXACT diary and daily rescue medication use baseline assessments will still be 
eligible for participation in the study but will be not be included in the physical activity 


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subgroup.  Participants who are run in failures will not be randomized to any study 
treatment and are not eligible for rescreening.
A successful EXACT baseline assessment is defined as completion of all 14 questions of 
the EXACT questionnaire on at least 4 of the 7 days. Successful rescue medication use 
recording is defined as recording of rescue medication use in the daily diary on at least 4 
of the 7 days along with electronic data capture from the MDI sensor device. For 
participants in the physical activity subgroup a successful baseline determination is 
defined as recording of physical activity for at least 8 hours per day on at least 3 of the 7 
days and completion of the PROactive questionnaire at Visit 3.
During the time period between Visit 2 and Visit 3 if a participant has a moderate or 
severe COPD exacerbation (one that requires treatment with systemic corticosteroids 
and/or antibiotics or requires hospitalization), the patient should not be randomized and 
should be withdrawn. In this case, the participant may be rescreened at a later date if the 
investigator judges the participant can meet the eligibility criteria. A participant with a 
mild COPD exacerbation would not need to be withdrawn.
7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo or medical device(s) intended to be administered to a study participant according 
to the study protocol.
7.1.
Treatments Administered
Table 3
Treatments Administered
Study Treatment Name:
Danirixin 
(GSK1325756H, the 
hydrobromide 
hemihydrate salt)
Placebo
Dosage formulation:
White Film coated tablets 
(oval or round shaped). 
Refer to Investigator’s 
Brochure for presentation 
and excipients
White Film coated tablets 
(oval or round shaped). 
Refer to Investigator’s 
Brochure for presentation 
and excipients
Unit dose strength(s)/Dosage 
level(s):
5, 10, 25, 35 and 50 mg 
(of free base equivalent)
N/A
Route of Administration 
Oral
Oral
Dosing instructions:
One tablet to be taken 
twice daily with food
One tablet to be taken 
twice daily with food


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Study Treatment Name:
Danirixin 
(GSK1325756H, the 
hydrobromide 
hemihydrate salt)
Placebo
Packaging and Labeling
Study Treatment will be 
provided in a HDPE 
bottle with desiccant. 
Each bottle will be 
labeled as required per 
country requirement.
Study Treatment will be 
provided in a HDPE 
bottle with desiccant. 
Each bottle will be 
labeled as required per 
country requirement.
Manufacturer
GSK
GSK
7.1.1.
Medical Devices

Subject to availability and any local restrictions on use, MDI sensor devices 
(manufactured by and purchased from Propeller Health) are being provided by 
GSK for this study.  These devices are fitted onto rescue medication MDI devices 
to electronically record rescue medication usage.  The MDI sensor devices have 
US FDA 510(k) clearance to market (Class II medical device) and European 
Union CE marking (Class I medical device).

Subject to availability and any local restrictions on use, ActiGraph GT9X physical 
activity monitors (manufactured by and purchased from ActiGraph, LLC) are 
being provided by GSK for the subset of participants that will be included in the 
physical activity monitoring subgroup.  The device is a tri-axial accelerometer.  
The participant wears the devices for the period of time that physical activity is 
being monitored.

Additional descriptive information and instructions for the eMDI and physical 
activity monitoring devices are provided in the SRM.

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).
7.2.
Dose Modification
No individual participant dose modifications or adjustments are allowed.
7.3.
Method of Treatment Assignment

This study will use an Interactive Web Response System (IWRS).  All 
participants will be centrally randomized using the IWRS.  Before the study is 
initiated, the log in information and directions for the IWRS will be provided to 
each site.


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
Participant randomization will be stratified by smoking status (i.e. current 
smoker or former smoker).

Study treatment will be dispensed to participants at the study visits summarized 
in the SOA.  

Returned study treatment should not be re-dispensed to any participant. 
7.4.
Blinding
This will be a double-blind (sponsor open) study.  Study participants, all study site staff, 
and all members of the GSK study team, with the exception of the study statistics and 
programming team, will be blinded to individual participant treatment assignment.  As 
defined in the study charter and RAP, defined and named members of the GSK study 
team will have access to unblinded, aggregate summaries of study treatment results.
A participant will be withdrawn if the participant’s treatment code is unblinded by the 
investigator or treating physician. The primary reason for discontinuation (the event or 
condition which led to the unblinding) will be recorded in the CRF.
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.
7.5.
Preparation/Handling/Storage/Accountability

The investigator or designee must confirm and document 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 of records).

Further guidance and information for the final disposition of unused study 
treatment are provided in the SRM. 

Precaution will be taken to avoid direct contact with the study treatment.  Under 
normal conditions of handling and administration, study treatment is not expected 
to pose significant safety risks to site staff.  In the case of unintentional 
occupational exposure notify the monitor, Medical Monitor and/or GSK study 
contact.


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
A Material Safety Data Sheet (MSDS)/equivalent document describing 
occupational hazards and recommended handling precautions either will be 
provided to the investigator, where this is required by local laws, or is available 
upon request from GSK.
7.6.
Treatment Compliance

When participants are dosed at the site, they will receive study treatment directly 
from the investigator or designee, under medical supervision.  The date and time of 
each dose administered in the clinic will be recorded in the source documents.  The 
dose of study treatment and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person 
administering the study treatment.  

When participants self-administer study treatment(s) at home, compliance with study 
treatment administration will be assessed through querying the participant during the 
site visits and documented in the source documents and CRF.  In addition, 
participants will be asked to confirm study administration each day in the daily 
ediary.  

Study participants who are not compliant with study treatment administration 
requirements should be re-educated on the importance of treatment compliance.  
Every effort should be made to keep participants in the study.  Participants who 
continue to be non-compliant after several attempts to re-educate may be 
discontinued after consultation with the GSK study team.  

A record of the number of tablets dispensed to and taken by each participant must be 
maintained and reconciled with study treatment and compliance records.  Treatment 
start and stop dates, including dates for treatment delays and/or dose reductions will 
also be recorded in the CRF.
7.7.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrolment or receives during the study must be recorded along with:

reason for use

dates of administration including start and end dates

dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
The following COPD medications are permitted during the study, at the discretion of the 
GSK Medical Monitor and/or Investigator:

Inhaled COPD maintenance medications (e.g. long acting bronchodilator 
medications (i.e. LAMA, LABA) and long-acting bronchodilator combination 


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therapies (e.g. LAMA/LABA) and long-acting bronchodilator/inhaled steroid 
combination (ICS) therapies (e.g. LABA/ICS, LAMA/LABA/ICS)

Short courses of oral corticosteroids and/or antibiotics (including macrolides) 
are permitted for the acute treatment of exacerbations of COPD and should not 
exceed 21 days.  This use must be recorded as an HCRU exacerbation event.  
The following medications are prohibited from the screening visit until after completion 
of the follow up visit:

Chronic use of macrolide antibiotics for the prevention of COPD exacerbations.  
Examples of chronic use include daily or two-three times per week for at least 3 
months.

Oral or injectable CYP3A4 or BCRP substrates with narrow therapeutic index 
(CYP3A4 substrates include, but are not limited to, alfentanil, cyclosporine, 
dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, 
tacrolimus, and theophylline; BCRP substrates include, but are not limited to, 
topotecan.

Phosphodiesterase-4 inhibitors (e.g. roflumilast)

Broad spectrum phosphodiesterase inhibitors (e.g. theophylline)

Chronic use of systemic corticosteroids, i.e. long term (i.e. greater than 3 
weeks), daily use of systemic corticosteroids. Chronic use of intranasal, 
intraocular and topical (for dermatological conditions) corticosteroids is 
allowed.
GSK will not supply rescue medication.  Participants may continue to use and should 
obtain rescue medication(s) through via their usual route. The following rescue 
medications may be used:

Short acting beta agonists (SABA) (e.g., albuterol/salbutamol)

Short acting muscarinic antagonists (SAMA) (e.g., ipratropium)

Short acting combination (SABA/SAMA) bronchodilations, (e.g. Duoneb, 
Combivent)
The use of rescue medications is allowable at any time during the study. Participants 
should record in the daily e-diary the number of puffs of rescue medication(s) over each 
24 hour period.  Data from the MDI sensor device will be electronically captured and 
transmitted to GSK.
Oxygen for intermittent use or PRN therapy ≤15 hours per day is allowed.  Long term 
oxygen therapy or nocturnal oxygen therapy required for >15 hours is excluded 
throughout the study.
Annual influenza vaccine is recommended for patients with COPD but is not required for 
participation in this study.  Influenza vaccination is permitted during the study and should 
be based on applicable local or national guidelines.  Pneumococcal vaccine may also be 
administered, when indicated, based on applicable local or national guidelines.  


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Additional vaccinations may be administered when indicated.  Any vaccination 
administered during the study should be recorded as a concomitant therapy.
7.8.
Treatment after the End of the Study
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the participant.
GSK will not provide post-study treatment.  There are no plans to provide the study 
treatment for compassionate use following study completion.
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
8.1.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to assure 
participant safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). These protocol guidelines are in alignment 
with FDA premarketing clinical liver safety guidance [FDA, 2009].
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 
below or if the investigator believes that it is in the best interest of the participant. 


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Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 7. 
8.1.2.
QTc Stopping Criteria

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.

For example, if a participant is eligible for the protocol based on 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.  Safety ECGs and other non-protocol specified 
ECGs are an exception.  

The QTc should be based on single or averaged QTc values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording period. 
A participant who meets either bulleted criteria based on the average of triplicate ECG 
readings will be withdrawn from study treatment:

QTc > 500 msec OR Uncorrected QT > 600 msec

Change from baseline of QTc > 60 msec
For patients with underlying bundle branch block, follow the discontinuation criteria 
listed below:
Baseline QTc with Bundle Branch Block
Discontinuation QTc with Bundle 
Branch Block
< 450 msec
> 500 msec
450 – 480 msec
≥ 530 msec
See the SoA (Table 1) for data to be collected at the time of treatment discontinuation and 
follow-up and for any further evaluations that need to be completed.
8.1.3.
Neutrophil Stopping Criteria
A participant with a peripheral blood neutrophil count 0.5 x 109/L that is confirmed on 
repeat testing will be instructed to suspend dosing.  The neutrophil count should be 
monitored daily until it returns to within the baseline value, as detailed in Appendix 9.
8.1.4.
Temporary Discontinuation
Temporary discontinuation of study treatment is allowed for up to 14 days when 
medically necessary, e.g. for hospitalization for a COPD exacerbation, other medical 


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condition requiring hospitalization, or reduction in peripheral blood neutrophil counts  
0.5 x 109/L.  Temporary discontinuation for any other reason should be discussed with 
the GSK Medical Monitor.
8.1.5.
Study Treatment Restart
Study treatment restart after liver chemistry stopping criteria are met by any participant in 
this study is not allowed. Refer to Appendix 7 for full guidance for required actions and 
follow-up assessments to undertake if liver stopping criteria are met. 
Study treatment restart after neutrophil stopping criteria are met can be considered once 
the neutrophil count has returned to within baseline and provided that no more than 14 
days have elapsed since study medication was halted. The Investigator must obtain 
approval from the GSK Medical Monitor prior to restarting study treatment.  See 
Appendix 9 for the procedure to be followed for study treatment restart after neutrophil 
stopping criteria are met.
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, 
behavioural, 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.

Refer to the SoA for data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed.
8.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the 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 


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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 (Table 1). 

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. 

Procedures conducted as part of the participant’s routine clinical management 
(e.g., blood count) and obtained before signing of ICF may be utilized for 
screening or baseline purposes provided the procedure met the protocol-
specified criteria and was performed within the time frame defined in the SoA.

The maximum amount of blood collected from each participant over the 
duration of the study, including any extra assessments that may be required, will 
not exceed 500 mL.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.
9.1.
Efficacy Assessments
9.1.1.
EXACT and E-RS:COPD
The Exacerbations of Chronic Pulmonary Disease Tool (EXACT) is a 14 item patient 
reported outcome instrument designed to capture information on the occurrence, 
frequency, severity, and duration of exacerbations of disease in patients with COPD 
[Jones, 2011; Leidy, 2010; Leidy, 2011].  EXACT captures information on the severity of 
the respiratory and systemic manifestations of a COPD exacerbation as reported by the 
patient.  The instrument is to be completed daily (typically at bedtime) using an 
electronic diary.  The daily recording of information allows an assessment of underlying 
day to day variability of a patient’s symptoms and facilitates the detection of symptom 
worsening indicative of a COPD exacerbation.  The total score for EXACT ranges from 0 
– 100, higher scores indicate more severe symptoms.  The entire instrument is intended to 
be completed in about 3 minutes or less (typically the time required for completion 
decreases as the patient becomes more familiar with the tool and the electronic diary).


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The Evaluating Respiratory Symptoms in COPD (E-RS:COPD) tool consists of 11 items 
from the 14 item EXACT instrument [Leidy, 2014a; Leidy, 2014b]. E-RS:COPD is 
intended to capture information related to the respiratory symptoms of COPD, i.e. 
breathlessness, cough & sputum production, chest tightness and chest congestion.  E-
RS:COPD has a scoring range of 0 – 40, higher scores indicate more severe symptoms.  
Three subscales of E-RS are used to describe different symptoms, dyspnea, cough and 
sputum, and chest symptoms.  
E-RS: COPD has recently been recognized as a drug development tool by FDA and EMA 
[EMA, 2015; FDA, 2016].
9.1.2.
COPD Exacerbations
An exacerbation of COPD is defined by a worsening of symptoms. 
The following are symptoms used to determine an exacerbation of COPD:
Worsening of two or more of the following major symptoms for at least two consecutive 
days:

Dyspnea

Spontaneous sputum volume

Sputum purulence
OR
Worsening of any one of the above major symptoms together with any one of the 
following minor symptoms for at least two consecutive days:

Sore throat

Cold (nasal discharge and/or nasal congestion)

Fever (oral temperature > 37.5 oC) 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 as soon as possible 
and report to the study clinic as required

If the participant is unable to contact their study investigator or research 
coordinator, they should contact their primary care provider (or other health care 
provider) and contact their study site as soon as possible

Continue to record their symptoms and rescue medication use in their daily 
ediary


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
If the participant seeks emergency/acute care for worsening respiratory 
symptoms he/she should request the caring health care provider to contact the 
study investigator or research coordinator as soon as possible

COPD exacerbations will be classified according to severity as follows:

A COPD exacerbation is defined as a mild exacerbation if it is self-managed by 
the participant.  Mild exacerbations are not associated with the use of antibiotics 
and/or systemic corticosteroids

A COPD exacerbation is defined as a moderate exacerbation if it requires a new 
prescription for antibiotics and/or systemic corticosteroids

A COPD exacerbation is defined as a severe exacerbation if it requires 
hospitalization, an emergency room visit, or extended observation in an 
outpatient centre
Details of an exacerbation should be recorded in the exacerbation page of the eCRF.  
Exacerbations will not be reported according to the standard process for expedited 
reporting of SAEs to GSK (even though the event may meet the definition of an SAE) as 
they are considered Disease Related Events (DREs).  Only when the event is, in the 
Investigator’s opinion, of greater intensity, or duration than expected for the individual 
participant, or the Investigator considers that there is a reasonable possibility that the 
event is related to study treatment should it be reported as an SAE (See Section 9.2).  
(Pneumonia must be recorded in the AE or SAE section of the eCRF and on the 
pneumonia page of the eCRF (See Section 9.4.5)).
All medications used for the treatment of exacerbations must be recorded in the source 
documents and the exacerbation page of the eCRF.  If necessary, the PI or other health 
care personnel may stop the participant’s study treatment temporarily in order to treat the 
COPD exacerbation.  The reason for temporarily stopping study treatment and duration 
should be recorded in the eCRF.
The date of onset and the date of resolution will be recorded in the source documents and 
the eCRF.

The date of onset is the first day (of at least 2 consecutive days) or worsening 
symptoms described above.

The date of resolution should be based on when the Investigator or participant 
determines that the COPD symptoms have returned to near pre-exacerbation 
levels or to a new baseline.
9.1.3.
SGRQ-C
The St. George’s Respiratory Questionnaire-Chronic Obstructive Pulmonary Disease 
specific tool (SGRQ-C) is a disease-specific questionnaire designed to measure the 
impact of respiratory disease and its treatment on a COPD patient’s HRQoL [Meguro, 
2007].  As well as producing an overall summary score, scores for the individual domains 
of symptoms, activity and impacts are also produced.  The SGRQ-C has been used in 
numerous previous studies of COPD participants and has been translated and validated 


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for use in most major languages.  The SGRQ-C is derived from the original SGRQ and 
produces scores equivalent to the original SGRQ instrument [Jones, 1992].
9.1.4.
CAT
The COPD Assessment Test is a 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 [Jones, 2009; Jones, 2012].  When completing the 
questionnaire, participants rate their experience on a 6-point scale, ranging from 0 
(maximum impairment) to 5 (no impairment) with a scoring range of 0-40. Higher scores 
indicate greater disease impact.
The CAT consists of 8 items (cough, sputum, chest tightness, breathlessness, going up 
hills/stairs, activity limitation at home, confidence leaving the home, and sleep and 
energy).  Individual items are scored from 0 to 5 with a total score range from 0 – 40, 
higher scores indicate worse health status.
9.1.5.
PROactive
The PROactive tools, developed under the EU Innovative Medicines Initiative, measure 
patient experience of Physical Activity in COPD. The tools consist of a patient reported 
questionnaire combined with output from an activity monitor [Dobbels, 2014; Gimeno-
Santos, 2015; Williams, 2012; Rabinovich, 2013; Gimeno-Santos, 2011]. The Clinical 
Visit PROactive Physical Activity in COPD (C-PPAC) tool is a designed for intermittent 
use within a clinical study. The 12 item questionnaire has a seven day recall period and 
participant responses are combined with two activity monitor data outputs covering the 
same period. The PROactive tools are scored from 0 to 100 with higher scores indicating 
greater disease impact, two subscales of amount and difficulty can be used to support the 
total score. 
The C-PPAC tool will be implemented in a subset of approx. 50% of participants.  
Participants will be randomly selected from each study site participating in the physical 
activity subgroup.
9.1.6.
Patient Global Rating of Severity and Global Rating of Change in 
Disease Severity
Participants will complete the Global Rating of COPD Severity at randomisation and at 
final study visit or IP Discontinuation Visit.  This single global question will ask subjects 
to rate their severity of COPD on a four point scale (mild, moderate, severe, very severe). 
Participants will complete a Global Rating of Change in COPD (overall disease) question 
at all Visits subsequent to randomisation including the final Visit (or Early Withdrawal 
(EW) Visit). Response options will be on a 7 point Likert scale ranging from much better 
to much worse. Asking at each Visit allows for early detection of response as well as 
continued response.


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9.1.7.
Patient Global Rating of Activity Limitation and Global 
Impression of Change in Activity Limitation
Subjects will complete the Global Rating of Activity Limitation at randomisation and at 
final visit or EW Visit. This single global question will ask subjects to rate their activity 
limitation on a four-point scale (not limited, slightly limited, limited, very limited).
Subjects will complete a Global Impression of Change in Activity Limitation question at 
all Visits subsequent to randomisation including the final Visit (or EW Visit). Response 
options will be on a 7 point Likert scale ranging from much better to much worse.
9.1.8.
Clinically Important Deterioration (CID)
A clinically important deterioration is a composite endpoint defined as at least one of the 
following events: (1) a decrease of 100 mL from baseline in trough FEV1, (2) a 
deterioration in health-related quality of life defined as a 4-unit increase from baseline 
in SGRQ total score, or (3) the occurrence of an on-treatment moderate or severe COPD 
exacerbation [Singh, 2016].
9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4.
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 (see Section 8). 
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from Visit 0 (i.e. from the time the informed consent 
is signed by the participant) until the follow up visit at the time points specified 
in the SoA (Section 2).

All AEs will be collected from the start of Visit 3 (study treatment 
randomization visit) until the follow-up visit 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 case report form (CRF) not the AE section.

All SAEs will be recorded and reported to the sponsor or designee within 24 
hours, as indicated in Appendix 4. The investigator will submit any updated 
SAE data to the sponsor within 24 hours of it being available.

Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she 


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considers the event to be reasonably related to the study treatment or study 
participation, the investigator must promptly notify the sponsor.

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 4.
9.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the participant is the preferred method to inquire 
about AE occurrence. 
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 4.
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 e.g., 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 4 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will 
be required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 


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The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
9.2.6.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
The following disease related events (DREs) are common in participants with COPD and 
can be serious/life threatening:

COPD exacerbations
Because these events are typically associated with the disease under study, they will not 
be reported according to the standard process for expedited reporting of SAEs to GSK 
(even though the event may meet the definition of an SAE).  These events will be 
recorded on the DRE page in the participant’s CRF within 72 hours after the investigator 
becomes aware of the event.  These DREs will be monitored by the Safety Review Team 
(SRT) on a routine basis as described in Appendix 3.  
NOTE: However, if either of the following conditions applies, then the event must be 
recorded and reported as an SAE (instead of a DRE): 

The event is, in the investigator’s opinion, of greater intensity, frequency, or 
duration than expected for the individual participant, or

The investigator considers that there is a reasonable possibility that the event 
was related to treatment with the investigational product
9.2.7.
Pregnancy

Details of all pregnancies in female participants and female partners of male 
participants will be collected after the start of study treatment and until 60 hours after 
the last dose of study treatment.

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 5

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
9.2.8.
Medical Device Incidents (Including Malfunctions)
Medical devices are being provided for use in this study for the purposes of monitoring 
inhaled rescue medication use and for evaluating physical activity. In order to fulfill 
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. 


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The definition of a Medical Device Incident can be found in Appendix 8.
NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Section 9.2 and Appendix 4. 
9.2.8.1.
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 8.
9.2.8.2.
Follow-up of Medical Device Incidents

All medical device incidents involving an AE will be followed and reported in 
the same manner as other AEs (see Section 9.2). This applies to all participants, 
including those who discontinue study treatment or the study.

The investigator is responsible for ensuring that follow-up includes any 
supplemental investigations as indicated to elucidate the nature and/or causality 
of the incident.

New or updated information will be recorded on the originally completed form 
with all changes signed and dated by the investigator.
9.2.8.3.
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.

Complete the Medical Device Incident Form for each participant who has a 
medical device incident with GSK medical devices provided for use during the 
study period.  All of the header information in the form must be completed 
before sending to GSK.  Original documents should be filed in the site study 
file.  A copy of the form must also be sent to the GKS study monitor.  Contact 
details will be included in the SRM.  A copy of the form must also be sent to the 
GSK study monitor.  Contact details will be included in the SRM.  For incidents 
fulfilling the definition of an AE or SAE, the appropriate pages of the CRF must 
be completed.  If there is an SAE, the completed CRF pages should be sent 
together with the Medical Device Incident Form.  If the participant is withdrawn 
due to a medical device incident, ensure the Study Conclusion page is 
completed.

The same individual will be the contact for the receipt of medical device reports 
and SAEs.


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9.2.8.4.
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 fulfill the legal 
responsibility to notify appropriate regulatory authorities and other entities about 
certain safety information relating to medical devices being used in clinical 
studies.

The investigator, or responsible person according to local requirements (e.g., 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
For this study, any dose of study treatment 4 tablets in a day will be considered an 
overdose.
GSK does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator/treating physician should:
1. Contact the Medical Monitor immediately.
2. Closely monitor the participant for AE/SAE and laboratory abnormalities until study 
treatment can no longer be detected systemically (at least 3 days).
3. Obtain a plasma sample for PK analysis as soon as possible from the date of the last 
dose of study treatment if requested by the Medical Monitor (determined on a case-
by-case basis).
4. Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.
9.4.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Table 1).
9.4.1.
Physical Examinations

A complete physical examination will include, at a minimum, assessments of the 
skin, cardiovascular, respiratory, gastrointestinal and neurological systems. 
Height and weight will also be measured and recorded.

A brief physical examination will include, at a minimum, assessments of the 
skin, lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.


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9.4.2.
Vital Signs

Vital signs will be measured in a semi-supine position after 5 minutes rest and 
will include systolic and diastolic blood pressure, pulse, temperature and 
respiratory rate. Three readings of blood pressure and pulse will be taken. The 
first reading should be rejected. The second and third readings should be 
averaged to give the measurement to be recorded in the CRF. A single 
measurement of respiratory rate and oral temperature is adequate.
9.4.3.
Electrocardiograms

For participant screening and pre-dose on Day 1, triplicate ECG measurements 
should be collected.  For all subsequent ECG assessments, single measurement 
are to be collected. 12-lead ECG will be obtained as outlined in the SoA using 
an ECG machine that automatically calculates the heart rate and measures PR, 
QRS, QT, and QTc intervals. Refer to Section 8.1.2 for QTc withdrawal criteria 
and additional QTc readings that may be necessary.

At each time point at which triplicate ECG are required, 3 individual ECG 
tracings should be obtained as closely as possible in succession, but no more 
than 2 minutes apart. The full set of triplicates should be completed in less than 
5 minutes.
9.4.4.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 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 CRF. 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 abnormal and clinically significant 
during participation in the study or within 3 days after the last dose of study 
treatment should be repeated until the values return to normal or baseline or are 
no longer considered significantly abnormal by the investigator or medical 
monitor. 

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA (Table 1).

If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in participant 
management or are considered clinically significant by the investigator (e.g., 
SAE or AE), then the results must be recorded in the CRF.


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9.4.5.
Pneumonia
All suspected pneumonias will require confirmation as defined by the presence or 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.)

Dyspnea or tachypnea

Fever (oral temperature > 37.5 oC)

Elevated white blood cell count (WBC) (> 10 x 109/L or > 15% immature 
forms)

Hypoxemia (Hb O2 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 Investigator and site staff should remain vigilant for the possible development of 
pneumonia in participants as the clinical features of such infections overlap with the 
symptoms of COPD exacerbations.  For all suspected cases of pneumonia, Investigators 
are strongly encouraged to confirm the diagnosis (this includes obtaining a chest x-ray) 
and to initiate appropriate therapy as promptly as possible.  Any microbiology or virology 
tests performed to determine etiology should be reported on the pneumonia eCRF page.  
All diagnoses of pneumonia (radiographically confirmed or unconfirmed) must be 
reported as an AE or SAE (if applicable).
9.4.6.
Spirometry Testing
Spirometry assessments will be obtained using spirometry equipment that meets or 
exceeds the minimal performance recommendations of the ATS/ERS [Miller, 2005].  All 
participants will have spirometry performed at Visits 1, 3, 7, 10 and where necessary 
Early Withdrawal.  For each spirometry assessment, both pre- and post-bronchodilator 
measurements will be performed.  For each FEV1 and FVC determination, at least 3 
acceptable spirometry efforts should be obtained.  Acceptable spirometry efforts should 
have a satisfactory start of the test and end of the test (i.e. a plateau in the volume-time 
curve) and be free from artifacts due to cough, early termination, poor effort, obstructed 
mouthpiece, equipment malfunction, or other reasons.  The largest FEV1 and FVC from 
the 3 acceptable efforts should be recorded, even if they do not come from the same 
effort.
For each spirometry assessment, the following guidelines should be followed:

Spirometry procedure conducted between 6:00 AM and 11:00 AM

Where applicable, after completion of other visit assessments (e.g. participant 
questionnaires and blood collections)


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
Short acting bronchodilators (i.e. rescue medications) should not be used for at 
least 4 hours prior to the spirometry assessment

The morning dose of any inhaled maintenance treatment should be withheld until 
the completion of the spirometry assessment

Participants should refrain from smoking for at least 1 hour prior to each 
spirometry assessment

Participants should abstain from consuming beverages with high levels of caffeine 
(including tea and coffee) for at least 2 hours prior to each spirometry assessment
Post-Bronchodilator Spirometry Testing

Following pre-bronchodilator spirometry assessment, post-bronchodilator 
spirometry is measured.  Following measurement of pre-bronchodilator 
spirometry, post-bronchodilator spirometry is performed 15 5 minutes after 4 
puffs of short acting beta-agonist administered using a valved spacer (i.e. 100 g 
per puff of salbutamol or albuterol; other short acting bronchodilators may also be 
sued, e.g. iprotropium bromide, 4 x 40 g) - according to the ATS/ERS
guidelines.

Similar to pre-bronchodilator spirometry testing, 3 acceptable spirometry efforts 
should be obtained and the highest FEV1 and FVC from the acceptable efforts 
should be recorded.
Additional details for the requirements and conduct of spirometry assessments are 
provided in the SRM.
9.5.
Pharmacokinetics

Whole blood samples of approximately 2 mL will be collected for measurement 
of whole blood concentrations of danirixin (performed under the control of GSK 
Platform Technology and Science Department of In Vitro In Vivo Translation
Third Party Resourcing (PTS-IVIVT/TPR)) as specified in the SoA (Table 1).  
Instructions for the collection, processing, storage and shipping of biological 
samples will be provided by the sponsor in the SRM. The actual date and time 
(24-hour clock time) of each sample will be recorded.

Samples will be used to evaluate the PK of danirixin at Visit 3 and 10. Each 
whole blood sample will be used to prepare 4 dried blood spots which will be 
analysed for danirixin concentrations and reported as primary data. The 
remaining whole blood will be retained and approximately 20% of the wet whole 
blood samples collected in Visit 3 will also be analysed for danirixin 
concentrations to provide an analytical comparison between dried blood spots and 
wet whole blood sample results. Samples collected for analyses of danirixin 
whole blood may also be used to evaluate safety or efficacy aspects related to 
concerns arising during or after the study.


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
Any remaining whole blood will be stored and may be analyzed for other 
compound-related metabolites and the results reported under a separate protocol.
Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.
9.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
9.7.
Genetics
A 6 mL whole blood sample for DNA isolation will be collected from participants who 
have consented to participate in the genetics analysis component of the study. 
Participation in the genetics analysis is optional. Participants who do not wish to 
participate in the genetic research may still participate in the study.
See Appendix 6 for Information regarding genetic research. Details on procedures for 
collection and shipment and destruction of these samples can be found in the SRM.
9.8.
Biomarkers

Collection of samples for biomarker research is also part of this study. The 
following samples for biomarker research will be collected from all participants 
in this study as specified in the SoA:
‒
peripheral venous blood samples for the preparation of serum and 
plasma

Samples will be tested for biomarkers that are indicative of inflammation (i.e. 
CRP and fibrinogen), extracellular matrix turnover and remodelling to evaluate 
their association with the observed clinical responses or to help understand the 
underlying biological responses to danirixin.

In addition, with the participant’s consent, samples will be stored and may be 
used to investigate additional biomarkers thought to play a role in COPD disease 
progression or to evaluate their association with observed clinical responses to 
danirixin

Samples also may be used for research to develop methods or support 
identification of prognostic/diagnostic biomarkers associated with clinical 
outcomes in COPD and related diseases.
9.9.
Health Economics OR Medical Resource Utilization and 
Health Economics
Parameters for specific use in Health Economics analysis or Medical Resource 
Utilization and Health Economics are not evaluated in this study.


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10.
STATISTICAL CONSIDERATIONS
10.1.
Hypothesis
The primary efficacy endpoint is the change from baseline of E-RS:COPD total score at 
month 6.  The primary objective of the study is to study the dose response and select an 
appropriate dose for future drug development programs.
A model based probability inference approach in Bayesian framework will be used to 
guide decision-making around dose selection. The posterior probability of the change 
from baseline of E-RS:COPD for each active dose being less than placebo will be used.
10.2.
Sample Size Determination
In order to evaluate the impact of different sample sizes, various simulations were 
undertaken to understand the following questions around the change in baseline of E-
RS:COPD scores at 6 months:

What is the 90% confidence interval half width for the estimate of the treatment 
effect of the 5 mg, 25 mg, 35 mg, and 50 mg doses?

What is the probability that the point estimate of difference from placebo is less 
than -1.5 for the 5 mg, 25mg, 35mg and 50 mg doses?

What is the probability that the two-sided 90% confidence interval of the 
treatment effect excludes 0 for 5 mg, 25 mg, 35 mg and 50 mg doses?  

What is the probability that the two-sided 90% confidence interval of the 
treatment effect difference from placebo excludes 0 for 5 mg, 25 mg, 35 mg and 
50 mg doses?  
There are 3 scenarios considered for the simulations, each based on different assumptions 
of the effect for each of the 6 treatment arms.  No model assumptions were made to 
generate these values.  The scenarios are found in Table 4 and Figure 2. The assumed 
between participant standard deviation is 6.5 which is based on interim data from the 
200163 study.  For each scenario, 10,000 iterations of simulations were run.


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Table 4
Assumptions Used for Sample Size Calculations
Scenario 1
Scenario 2
Scenario 3
Placebo
0
0
0
5 mg
-0.5
-0.333
-0.5
10 mg
-1
-0.667
-0.75
25 mg
-2
-1.333
-2
35 mg
-2.5
-1.667
-2
50 mg
-3
-2
-2
Figure 2
Simulation scenarios with best fit sigmoidal Emax model


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The Emax model will be used for the primary analysis and was the basis for estimation of 
the simulated data.  The more general 4 parameter version of this model is defined as:
y(dose) = E0 + Emax [ dosem / (ED50m + dosem) ]
where y( ) represents the E-RS:COPD change from baseline, E0 is the mean response at 
dose = 0, Emax is the maximum dose effect (at dose = ), ED50 is the dose that yields a 
mean response of E0 + Emax / 2, and m is the slope parameter allowing for sigmoidal dose 
response relationships.
Results of the sample size simulations are presented in Figure 3, Figure 4, Figure 5 and 
Figure 6,with the lowest danirixin dose (5 mg) and the 3 highest doses (25 mg, 35 mg, 50 
mg).
Figure 3
Half width of the 90% confidence interval for the 5 mg, 25 mg, 35 mg 
and 50 mg doses


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Figure 4
Proportion of simulations in which the point estimate of difference 
from placebo is less than -1.5 for doses of 5 mg, 25 mg, 35 mg and 
50 mg
Figure 5
Proportion of simulations in which the 90% confidence interval 
exclused 0 for doses of 5 mg, 25 mg, 35 mg and 50 mg


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Figure 6
Proportion of simulations in which the 90% confidence interval of 
difference from placebo excludes 0 for doses of 5 mg, 25 mg, 35 mg 
and 50 mg
Based on the simulations a sample size of at least n = 600 will allow for adequate 
precision in estimation of the 35 mg dose as well as sufficient proportion with 90% 
confidence interval difference from placebo excluding 0 (over 80% for the 35 mg dose 
under all scenarios) and proportion with 90% confidence interval of dose estimate 
excluding 0 (over 80% for all higher doses and scenarios except 25 mg under scenario 2).
10.2.1.
Sample Size Re-estimation
At the time of the interim analysis for futility, sample size re-estimation may be 
considered by the study team if the assumptions driving the sample size calculations are 
shown to be incorrect (e.g., variability is higher than expected).  No more than 100 
additional participants will be considered.
10.3.
Randomization
Participants will be randomized equally (1:1:1:1:1:1) to the six treatment arms of 
placebo, 5 mg, 10 mg, 25 mg, 35 mg and 50 mg danirixin.  Randomization will be 
stratified by smoking status (current vs. former).
10.4.
Populations for Analyses
For purposes of analysis, the following populations are defined:


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Population
Description
All Participants
This population will comprise all participants screened and 
for whom a record exists on the study database and will be 
used for the tabulation and listing of reasons for withdrawal 
before randomization and listings of AEs and SAEs for 
nonrandomized participants.
Modified Intent To Treat 
(mITT)
This population will comprise all participants randomized to 
treatment and who received at least one dose of study 
medication. Randomized subjects will be assumed to have 
received study medication unless definitive evidence to the 
contrary exists. A true Intent-to-treat analysis would use the 
randomized treatment, but this population will be ‘modified’ 
in that all data summaries and analyses for this population 
will be based on the actual treatment received, if it is different 
to the randomized treatment. This will constitute the primary 
population for all analyses of efficacy and safety. 
If any subject received more than one treatment during a 
treatment period, their data will be reported according to the 
treatment they received for the longest period of time.
PK
This population will comprise all participants in the mITT 
population for whom a pharmacokinetic sample was obtained 
and analyzed while on treatment with DNX.
10.5.
Statistical Analyses
Analysis methods for key endpoints are described below.  Unless otherwise stated, all 
statistical testing will be two-sided and all confidence intervals or Bayesian credible 
intervals will be 90% two-sided.
Further details on all analyses will be described in the reporting and analysis plan (RAP).
10.5.1.
Efficacy Analyses
10.5.1.1.
Primary Analysis
The primary endpoint is 6 month change from baseline using the mITT population.
Baseline values of E-RS: COPD will be defined as the daily average of scores for the 7 
days prior to randomization.  Days with missing values will not count towards the 
average.  A minimum of 4 days will be needed and participants without sufficient days 
will not be randomized.
Individual monthly E-RS:COPD means will be defined as the average E-RS:COPD 
scores during the following study days:


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
Month 1: days 1-28

Month 2: days 29-56

Month 3: days 57-84

Month 4: days 85-112

Month 5: days 113-140

Month 6: days 141-168
Days with missing values will not factor into the calculations.  Participants will require a 
minimum number of 10 observations within a month, otherwise the monthly mean will be 
considered missing for that patient. 
The primary analysis will be Emax (4 parameter) modeling of the dose-response curve 
for the primary efficacy endpoint of month 6 change from baseline.  Smoking status will 
be included as a covariate in this model, allowing the asymptote values of the dose-
response relation for smokers to differ from those of the non-smokers. This model 
formulation will require estimation of at most six parameters. Simpler models nested 
within this general formulation will be also considered, comprising formulations of the 
mean dose-response relation allowing for a fixed difference between smokers and non-
smokers (parallel curves model), no difference between smokers and non-smokers and 
the Emax model restriction m=1. Model fitness will be measured using standard 
goodness of fit analysis. This analysis will allow for an assessment of the extent to which 
the variability of the trial data will be captured using the proposed model and what dose-
response specification allows the best interpretation of the data.    
The dose-response model will be fitted to the data using Bayesian techniques using the 
function uniform prior (FUP). The rationale for this choice of inference is that the FUP 
shrinks the dose-response towards a flat line throughout the dose range, therefore 
providing more conservative estimates of the dose-response relation compared to
maximum likelihood.
Standard Bayesian diagnostic plots will be produced to aid in the interpretation of results. 
Based on the selected model, 90% two sided Bayesian credible interval for all treatment 
arms, all pairwise differences between each danirixin dose and placebo, as well as 
between active danirixin doses, will be generated.  
Other models of dose response such as quadratic and log linear will be considered as 
alternative analysis option if the Emax model does not fit the data well.  Similar analysis 
with the final model using the endpoint includes months 1-6 and months 3-6 will be fit.  
A longitudinal mixed effects model will be also be fit with dose as a categorical variable 
to explore the time trend of E-RS:COPD.  Each of the three E-RS:COPD subscales
(breathlessness, cough and sputum, and chest symptoms) will be analysed using similar 
methods for the primary analysis and longitudinal analysis.  Details of these sensitivity 
analyses will be further described in the RAP.


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10.5.1.2.
Key Secondary Analyses
All analyses for other efficacy endpoints will use the mITT Population, unless otherwise 
noted. Dose will be treated as a categorical variable and no dose response modelling will 
be done unless otherwise stated.  The treatment comparisons of interest will be between 
individual danirixin doses and placebo and between different danirixin doses.  Smoking 
status (current vs former) will be included as a covariate in all analyses.  All Bayesian 
analyses will use non-informative priors.  Further details will be described in the RAP. 
10.5.1.3.
HCRU Exacerbations
The number of events associated with HCRU-defined exacerbations will be analyzed 
using generalised linear models assuming a negative binomial distribution for the 
underlying exacerbation rate with a log link and an offset to account for the length of 
time in study for each participant. The exacerbation rates for the danirixin and placebo 
groups, along with the ratio in exacerbation rates danirixin/placebo, will be estimated and 
corresponding 95% credible intervals will be produced. 
10.5.1.4.
Time to First HCRU Exacerbation
Time to first HCRU exacerbation will be defined from the date of randomization.  
Participants without an exacerbation and participants who withdraw from the study prior 
to any observed exacerbations will be censored at the time of last contact.  Survival will 
be summarized by treatment groups through Kaplan-Meier curves.  Treatment arms will 
be compared using a stratified log-rank test.  Time to first severe HCRU exacerbation 
will be analysed in a similar manner.
10.5.2.
Safety Analyses
All safety endpoints will be tabulated or plotted by treatment group and will be 
performed on the mITT Population. Further details will be described in the RAP.
10.5.3.
PK and PK/PD Analyses
Pharmacokinetic data will be presented in graphical and/or tabular form and will be 
summarized descriptively. For participants in the PK subset non-compartmental PK 
parameters (e.g. AUC(0-12), Cmax and tmax) will be calculated as data permit. The 
pharmacokinetic data from this study may be combined with historic DNX 
pharmacokinetic data for the purposes of population pharmacokinetic modelling which 
may be reported separately from the main clinical study report. The goal of this analysis 
is to characterize the population pharmacokinetics of DNX administered orally in 
subjects with COPD. The influence of subject demographics, baseline characteristics, 
including disease activity, and co-medication on the pharmacokinetics of DNX in this 
population will be investigated. DNX blood concentration-time data will be subjected to 
nonlinear mixed effects modelling using the program NONMEM to develop a population 
PK model [FDA, 1999].  Further details will be described in the RAP.


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Exploratory analysis using scatter plots will be conducted to investigate the relationship 
between blood exposure to danirixin (PK) and efficacy/PD/safety endpoints as data 
permit. If appropriate PK/PD modelling will be attempted to describe any relationship 
including longitudinal efficacy, PD, and/or safety variables versus systemic exposure (or 
dose) and may be combined with historic data. The results of any PK/PD modelling may
be reported separately from the main clinical study report. Further details will be 
described in the RAP.
10.5.4.
Interim Analyses
All interim analyses will be based on unblinded data. The randomization schedules and 
unblinded datasets will be stored on internal restricted drives. The GSK study team, with 
the exception of the statistics and programming team, will not have access to an 
unblinded randomization schedule during the course of the trial. Further details are 
described in the RAP and study charter.
10.5.4.1.
Interim PK Analysis
After approximately 10 participants in the PK subset for each treatment group have 
completed Visit 3, an interim evaluation of danirixin pharmacokinetic parameters will be 
undertaken.  The purpose of the interim PK analysis is to determine if danirixin 
exposures are within the expected range.
10.5.4.2.
Futility Analysis
An interim analysis will be conducted to allow for the possibility of stopping early for 
futility.  The expected pace of recruitment will be 12 months.  Therefore, by the time a 
sufficient number of participants have been recruited and have accrued 6 months of data, 
a futility analysis will not be practical.  We will therefore consider futility analyses based 
on the 3 month data using the assumption that the response will be consistent from month 
3 onwards.  Under this assumption, which is consistent with the Phase IIa study, this is a 
valid futility approach.
Once approximately 150 participants have completed 3 months of treatment, the 3 
parameter Emax model will be fit to the change from baseline of E-RS:COPD. If the 
posterior predictive probability of difference from placebo being less than 0 is below 
30% for all danirixin doses, the study may be stopped for futility.
Based on simulated data, the expected number of participants with completed 6 month 
data at the time of this analysis will be too small to warrant any analysis (expected 
number < 10).  However, if the recruitment differs greatly from expectations, and enough 
participants have completed 6 months of treatment, the 6 month change from baseline 
endpoint may also be explored.  
No early stopping for efficacy will be considered.  Outputs featuring unblinded treatment 
assignments will be created for this interim analysis but will not be shared outside of the 
study team unless the decision is made to halt the study for futility.


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10.5.4.3.
Strategic Planning Analysis
The study will have an interim analysis for administrative purposes approximately 12-15 
months after the beginning of the study, or when 450 participants have completed 6 
months of study treatment, whichever is earlier.  This analysis will be used to aid in the 
planning of future studies and for a better understanding of benefit/risk profile of 
danirixin.  This interim analysis will look at the primary endpoint of E-RS:COPD dose 
response modelling, key secondary endpoints of HCRU exacerbations and SGRQ score, 
key safety endpoints around hepatotoxicity, neutrophils, pneumonia and other infections 
and PK data.  No changes will be made to this study based on the results of this interim 
analysis.  Outputs featuring unblinded treatment assignments will be created for this 
interim analysis, reviewed by the study team and potentially shared with selective GSK 
personnel (to be included in the study results dissemination plan).
Further details of the outputs including key safety outputs that will be produced will be 
described in the RAP. 
10.5.4.4.
Additional Interims
Additional informal summaries of danirixin exposure and efficacy data may be 
undertaken during the conduct of the study.


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11.
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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
List of Abbreviations
AE
Adverse Event
ALT
Alanine Aminotransferase (SGPT)
AST
Aspartate Aminotransferase (SGOT)
ATS
American Thoracic Society
AUC
Area under the concentration-time curve
BfS
Federal Office of Radiation Protection (Germany)
BID
Twice daily
BRCP
Breast cancer resistance protein
BUN
Blood urea nitrogen
CAT
COPD Assessment Test
CD
Cluster of differentiation
CFR
Code of Federal Regulations (United States)
CI
Confidence Interval
CID
Clinically important deterioration
CIL
Clinical Investigation Leader
Cmax
Maximum observed concentration
CONSORT
Consolidated standards of reporting trials
COPD
Chronic Obstructive Pulmonary Disease
CPMS
Clinical Pharmacokinetics Modelling and Simulation
C-PPAC
Clinic Visit PROactive Physical Activity in COPD 
Tool
CRF
Case Report Form
CT
Computed Tomography
CV
Cardiovascular
CXCR
CXC Chemokine Receptor
CXR
Chest X-Ray
dL
Deciliter
DNA
Deoxyribonucleic acid
DNX
Danirixin
DRE
Disease Related Event
E0
Effect at zero concentration
ECG
Electrocardiogram


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eCRF
Electronic Case Report Form
ED50
Dose causing 50% of the maximum achievable 
response
EMA
European Medicines Agency
Emax
Maximum response achievable
eMDI
Electronic metered dose inhaler
EXACT-PRO
Exacerbations of Chronic Pulmonary Disease-Patient 
Reported Outcome
E-RS:COPD
Evaluting Respiratory Symptoms in Chronic 
Obstructive Pulmonary Disease
EW
Early Withdrawal
FDA
Food and Drug Administation (United States)
FEV1
Forced Expiratory Volume in one second
FVC
Forced Vital Capacity
FSH
Follicle Stimulation Hormone
FUP
Function Uniform Prior
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GGT
Gamma glutamyltransferase
GOLD
Global Initiative for Chronic Obstructive Lung 
Disease
GSK
GlaxoSmithKline
HBsAG
Hepatitis B surface antigen
HCRU
Healthcare Resource Utilization
hCG
Human chorionic gonadotrophin
HDPE
High density polyethylene
Hep B
Hepatitis B
Hep C
Hepatitis C
hsCRP
High sensitivity C-reactive protein
HIV
Human immunodeficiency virus
HPLC
High performance liquid chromatography
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization of 
Technical Requirements for Registration of 
Pharmaceuticals for Human Use
ICS
Inhaled corticosteroid
IDMC
Independent Data Monitoring Committee


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IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IgM
Immunoglobulin M
INR
International normalized ratio
IP
Investigational Product
IRB
Institutional Review Board
IUD
Intrauterine device
IUS
Intrauterine hormone releasing system
IVIVT
In vitro In vivo Translation
IWRS
Interactive Web Response System
kg
Kilogram
L
Liter
LABA
Long acting 2 receptor agonist
LAMA
Long acting muscarinic receptor antagonist
LH
Leutinizing Hormone
LTOT
Long term oxygen therapy
MCV
Mean corpuscular volume
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin count
MDI
Metered dose inhaler
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligrams
mITT
Modified Intent to treat
mL
Milliliter
MM
Medical monitor
MSDS
Material Safety Data Sheet
msec
Millisecond
NOAEL
No observed adverse effect level
O2
Oxygen
PK
Pharmacokinetics
PR
PR interval; duration in milliseconds from the 
beginning of the P wave to onset of ventricular 
depolarization (R)
PRO
Patient Reported Outcome
PTS
Platform Technology and Science
QRS
QRS interval; duration in milliseconds of the QRS 
complex


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QT
QT interval; duraction in milliseconds between the 
start of the Q wave and the end of the T wave
QTcF
QT interval corrected for heart rate (Friderica 
formula)
RAP
Reporting and Analysis Plan
RBC
Red blood cells
RNA
Ribonucleic acid
SABA
Short-acting 2 Receptor Agonist
SAE
Serious Adverse Event
SAMA
Short-acting Muscarinic Receptor Agonist
SGRQ
St George’s Respiratory Questionnaire
SGRQ-C
SGRQ for COPD patients
SRM
Study Reference Manual
SRT
Safety Review Team
SOA
Schedule of Activities
SUSAR
Suspected unexpected serious adverse reaction
t½
Terminal phase half-life
TB
Tuberculosis
tmax
Time to reach Cmax
TPR
Third Party Resourcing
ULN
Upper limit of normal
g
Microgram
VT
Ventricular tachycardia
WBC
White blood cells
WOCBP
Women of child bearing potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
CAT
Combivent
Duoneb
E-RS:COPD
EXACT


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12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 5  Protocol-Required Safety Laboratory Assessments 
will be performed by the central laboratory, except as noted.

Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either study treatment administration and/or 
response evaluation. If a local sample is required, it is important that the sample 
for central analysis is obtained at the same time. Additionally, if the local 
laboratory results are used to make either a study treatment decision or response 
evaluation, the results must be entered into the CRF.

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 6.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 5
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
MCV
MCH
MCHC
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Clinical 
Chemistry1
BUN
Potassium
Chloride
Bicarbonate
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 (fasting 
required for 
screening)
Calcium
Alkaline 
phosphatase
Routine 
Urinalysis

Specific gravity


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Laboratory 
Assessments
Parameters

pH, glucose, protein, blood, ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

Plasma fibrinogen (a screening plasma fibrinogen is only needed for 
participants with 1 COPD exacerbation in the prior year)

Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only)

Serum or urine human chorionic gonadotropin (hCG) pregnancy test (as 
needed for women of childbearing potential)2

HIV antibody, hepatitis B surface antigen (HBsAg), and hepatitis C virus 
antibody3

All study-required laboratory assessments will be performed by a central 
laboratory, with the exception of urine testing   
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 hCG testing will be standard for the protocol unless serum testing is required by local 
regulation or IRB/IEC.
3.
Hepatitis C RNA is optional however a confirmatory negative Hepatitis C RNA test must be obtained, 
to be able to enrol participants with positive Hepatitis C antibody due to prior resolved disease
Laboratory results that could unblind the study will not be reported to investigative sites 
or other blinded personnel until the study has been unblinded.


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12.3.
Appendix 3: Study Governance Considerations
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (eg, advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study. 

Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 


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informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative. 

Participants who are rescreened are required to sign a new ICF.

The ICF may contain a separate section that addresses the use of the remaining 
mandatory samples for optional exploratory research in accordance with GSK 
SOP-GSKF-410.  The investigator of authorized designee will explain to each 
participant the objectives of the exploratory research.  Participants will be told 
that they are free to refuse to participate and may withdraw their consent at any 
time and for any reason during the storage period.  A separate signature will be 
required to document a participant’s agreement to allow any remaining 
specimens to be used for exploratory research.  Participants who decline will not 
provide this separate signature.
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.
Committees Structure

A study charter will be created to describe important governance aspects while 
the study is being conducted.

The core GSK study team (this will include the Clinical Investigation Leader 
(CIL), Medical Monitor (MM), study statistician, GCSP physician, GCSP 
scientist, and CPMS representative) will have access to unblinded, aggregate 
summaries for study treatments.  Only the study statistician will have access to 
individual participant treatment assignments.  Study team members who interact 


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with study site staff will remain blinded until the study is completed.  Complete 
details will be included in the study charter.  Results of the interim analyses may 
be shared with and discussed with selective GSK personnel (to be included in 
the study results dissemination plan).

The SRT will include the Safety Development Leader, GCSP scientist, MM, 
CIL and study statistician but will extend to other functions as required. The 
SRT will provide a proactive, aggregate and holistic evaluation of the safety 
data of danirixin. Further details are included in the SRT charter.
Publication Policy

The results of this study, including the results of interim analyses, may be 
published, presented at scientific meetings or otherwise shared externally (e.g. 
via a GSK press release or other communication). 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.
Dissemination of Clinical Study Data

This study will be registered and study information from this protocol will be 
posted on publicly available clinical trial registers before enrolment of study 
participants begins.

The results summary of this study will be posted to the GSK Clinical Study 
Register and other publicly available clinical trial registers within 8 months of 
the primary study completion date.

A manuscript reporting the study results will be submitted to a peer reviewed 
journal within 18 months of the last participant’s last visit. 
Data Quality Assurance

All participant data relating to the study will be recorded on electronic Case 
Report Report (eCRF) unless transmitted to the sponsor or designee 
electronically (eg, laboratory data). The investigator is responsible for verifying 
that data entries are accurate and correct by physically or electronically signing 
the CRF/eCRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF/eCRF. 


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
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 CRF/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 after from the issue of the 
final Clinical Study Report (CSR) or 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. 
Data Management

For this study subject data will be entered into GSK-defined eCRFs, transmitted 
electronically to GSK or designee and combined with data provided from other 
sources in a validated data system.

Management of clinical data will be performed in accordance with applicable 
GSK standards and data cleaning procedures to ensure the integrity of the data, 
e.g. removing errors and inconsistencies in the data.

Adverse events and concomitant medication terms will be coded using the 
Medical Dictionary for Regulatory Activities (MeDRA) and an internal validated 
medication dictionary, GSKDrug.

CRFs (including queries and audit trails) will be retained by GSK and copies will 
be sent to the investigator to maintain as the investigator copy.  Subject initials 
will not be collected or transmitted to GSK according to GSK policy.
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available.


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
Definition of what constitutes source data can be found in the SRM.
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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12.4.
Appendix 4: 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. 
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 


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


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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 CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
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 CRF.

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 CRF 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 


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participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
each occurrence of each AE/SAE.

A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 


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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 CRF.

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 for more than 24 hours, then the site will use 
the paper SAE data collection tool and fax or email the paper form to GSK and the 
Medical Monitor.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor/SAE coordinator by telephone or e-mail.

Contacts for SAE reporting can be found in the SRM.


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12.5.
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
3. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment.
Contraception Guidance
Male participants
Male participants with female partners of child-bearing potential are eligible to 
participate if they agree to ONE of the following during the protocol-defined time 
frame in Section 6.1: 

Are abstinent from penile-vaginal intercourse as their usual and preferred 
lifestyle (abstinent on a long term and persistent basis) and agree to remain 
abstinent 

Agree to use a male condom plus an additional method of contraception with a 
failure rate of <1% per year as described in Table 6  when having penile-vaginal 
intercourse with a woman of childbearing potential 


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
Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of 
penile penetration during the protocol-defined time frame 

Refrain from donating sperm for the duration of study and for at least 60 hours 
after the last dose of study treatment.
Female participants
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in 
Table 6.
Table 6
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulationb

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 participant.)
NOTES: 
a: Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with 
local regulations regarding the use of contraceptive methods for participants in clinical studies. 
b: Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of the 
contraceptive method. In this case two highly effective methods of contraception should be utilized during the 
treatment period and for at least 60 hours after the last dose of study treatment 


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Pregnancy Testing

WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive urine or serum pregnancy test. 

Additional pregnancy testing will be performed at approximately monthly intervals 
during the study treatment period, after the last dose of study treatment and as 
required locally. 

Pregnancy testing, with a high sensitivity test will be performed using the test kit 
provided by the central laboratory and approved by the sponsor and in accordance 
with instructions provided in the test kit package insert.  
Collection of Pregnancy Information
Male participants with partners who become pregnant

Investigator will attempt to collect pregnancy information on any male participant’s 
female partner of a male study participant who becomes pregnant while participating 
in this study. This applies only to participants who receive study treatment.

After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the partner’s 
pregnancy. 

Partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure. 
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. 

Participant 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. 


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
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 4. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 
Any female participant who becomes pregnant while participating will discontinue 
study treatment and be withdrawn from the study.  


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12.6.
Appendix 6: 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 blood sample will be collected for DNA analysis.

DNA samples may be used for research related to danirixin or COPD and related 
diseases. They may also be used to develop tests/assays (including diagnostic tests) 
related to danirixin treatment, and COPD (and related diseases). Genetic research 
may consist of the analysis of one or more candidate genes or the analysis of genetic 
markers throughout the genome (as appropriate).

DNA samples may be analyzed if it is hypothesized that this may help further 
understand the clinical data. 

The samples also may be analyzed as part of a multi-study assessment of genetic 
factors involved in the response to danirixin 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.

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 danirixin (or study treatments of this 
class) or COPD and related diseases continues but no longer than 15 years after the last 
participant last visit or other period as per local requirements. 


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12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments
Phase II liver chemistry stopping and increased monitoring criteria have been 
designed to assure participant safety and evaluate liver event etiology 
Phase II liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin)
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot 
Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed 
to be related to liver injury or hypersensitivity
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Immediately discontinue study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver chemistry 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 study treatment unless allowed per 
protocol and GSK Medical Governance 
approval is granted (see below)

If restart/rechallenge not allowed per 
protocol or not granted, permanently 

Viral hepatitis serology4

Obtain INR and recheck with each 
liver chemistry assessment until the 
transaminases values show 
downward trend

Obtain blood sample for 
pharmacokinetic (PK) analysis, up 
to 72 h after last dose5

Serum creatine phosphokinase 
(CPK) and lactate dehydrogenase 
(LDH).

Fractionate bilirubin, if total 
bilirubin 2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or 
worsening of clinical symptoms of 


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discontinue study treatment and continue 
participant in the study for any protocol 
specified follow up assessments 
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, 
AST, alkaline phosphatase, bilirubin) and 
perform liver event follow up assessments 
within  24 hrs

Monitor participants twice weekly until 
liver chemistries resolve, stabilize or return 
to within baseline 

A specialist or hepatology consultation is 
recommended
For All other criteria: 

Repeat liver chemistries (include ALT, 
AST, alkaline phosphatase, bilirubin) and 
perform liver event follow up assessments 
within  24-72 hrs 

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
liver injury, or hypersensitivity, on 
the AE report form

Record use of concomitant 
medications on the concomitant 
medications report form including 
acetaminophen, herbal remedies, 
other over the counter medications.

Record alcohol use on the liver 
event alcohol intake case report 
form (CRF) page 
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin 
G (IgG) or gamma globulins.

Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver 
injury in participants with definite 
or likely acetaminophen use in the 
preceding week [James, 2009]. 

Liver imaging (ultrasound, 
magnetic resonance, or 
computerised tomography) and /or 
liver biopsy to evaluate liver 
disease; complete Liver Imaging 
and/or Liver Biopsy CRF pages.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that participant if ALT 3xULN and bilirubin 2xULN.. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to participants receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen (HbsAg) 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 


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5.
PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
treatments.)  Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
treatment prior to PK blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the 
participant’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot 
be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and 
shipping are in the SRM.  
Phase II liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 3xULN and <5xULN and bilirubin 
<2xULN, without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks

Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss participant 
safety. 

Participant can continue study treatment  

Participant must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time participant meets the liver chemistry 
stopping criteria, proceed as described above

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor participants twice monthly 
until liver chemistries normalize or return to within 
baseline.
Reference
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.


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12.8.
Appendix 8: 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 (see Section 7.1.1 for the list of GSK 
medical devices to be used in this 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 participant/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 
CRF page will be completed as described in Appendix 4.

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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12.9.
Appendix 9: Neutrophil Safety and Study Treatment Restart
Neutrophil Stopping Criteria: Absolute neutrophil count (ANC) 0.5 x 109 /L
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Immediately discontinue study treatment 

Report the event to GSK within 24 hours

Complete an SAE data collection tool if the 
event also meets the criteria for an SAE

Monitor the participant until neutrophil 
count stabilizes or returns to within 
baseline (see MONITORING below)

Do not restart participant with study 
treatment unless allowed per protocol and 
GSK Medical Governance approval is 
granted (see RESTART below)
MONITORING:

Treatment of any suspected infections1

Repeat CBC within  24 hrs

Monitor CBC daily until neutrophil count 
resolves, stabilizes or returns to within 
baseline 

Record the appearance or 
worsening of any clinical 
symptoms on the AE report form1

Obtain blood sample for 
pharmacokinetic (PK) analysis 
within 12 hours  after last dose2

Record use of concomitant 
medications on the concomitant 
medications report form 
RESTART

Restart of study medication must be 
approved by the GSK Medical Monitor

Restart may be attempted ONLY if all 
three criteria are met:
The neutrophil count is 1.5 x 109/L 
for at least 48 hours

At least 7 days have elapsed since the 
suspension of study treatment 
No sign or symptom of associated 
infection has been identified

Check the CBC within 24-48 hours 
after re-starting study medication, 
monitor twice weekly for two 
weeks, and monthly thereafter.

If the ANC drops below 1.0 x 
109/L on restart, the participant 
should be permanently 
discontinued from study treatment 
and withdrawn from the study.


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1.
New or worsening symptoms believed to be related to neutropenia such as (but not limited
to): sudden onset of fever or malaise, stomatitis, odynophagia, periodontal infection, skin 
abscesses, signs or symptoms of sinusitis and otitis, symptoms of pneumonia (eg, cough, 
dyspnea), perirectal pain and irritation, hypotension or signs of septic shock. 
2.
Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
treatment prior to PK blood sample draw on the CRF. If the date or time of the last dose is 
unclear, provide the participant’s best approximation. If the date/time of the last dose cannot 
be approximated OR a PK sample cannot be collected in the time period indicated above, do 
not obtain a PK sample. Instructions for sample handling and shipping are in the SRM.


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12.10.
Appendix 10: Country Specific Requirements
Korea - Investigational Product Label
PPD


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12.11.
Appendix 11: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).
Amendment 1: 31-Oct-2017


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TITLE PAGE
Protocol Title: Randomised, Double-Blind (Sponsor Open), Placebo-Controlled, Multi-
centre, Dose Ranging Study to Evaluate the Efficacy and Safety of Danirixin Tablets 
Administered Twice Daily Compared With Placebo for 24 Weeks in Adult Participants 
With Chronic Obstructive Pulmonary Disease (COPD)
Protocol Number: 205724
Short Title: Danirixin Dose Ranging Study in Participants with COPD
Compound Number:
GSK1325756
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 will be provided in the Study 
Reference Manual
Regulatory Agency Identifying Number(s): IND: 108168; EudraCT: 2016-003675-21
Approval Date: 28-NOV-2016
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.


PPD
PPD
PPD


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TABLE OF CONTENTS
PAGE
1.
SYNOPSIS...............................................................................................................6
2.
SCHEDULE OF ACTIVITIES (SOA).........................................................................8
3.
INTRODUCTION....................................................................................................14
3.1.
Study Rationale ..........................................................................................15
3.2.
Background ................................................................................................15
3.3.
Benefit/Risk Assessment ............................................................................16
3.3.1.
Risk Assessment .........................................................................17
3.3.2.
Benefit Assessment.....................................................................21
3.3.3.
Overall Benefit:Risk Conclusion...................................................21
4.
OBJECTIVES AND ENDPOINTS...........................................................................21
5.
STUDY DESIGN ....................................................................................................23
5.1.
Overall Design ............................................................................................23
5.2.
Number of Participants ...............................................................................25
5.3.
Participant and Study Completion...............................................................25
5.4.
Scientific Rationale for Study Design ..........................................................25
5.5.
Dose Justification........................................................................................26
6.
STUDY POPULATION...........................................................................................27
6.1.
Inclusion Criteria.........................................................................................28
6.2.
Exclusion Criteria........................................................................................29
6.3.
Lifestyle Restrictions...................................................................................31
6.3.1.
Meals and Dietary Restrictions ....................................................31
6.3.2.
Activity .........................................................................................32
6.4.
Screen Failures...........................................................................................32
6.5.
Run In Failures ...........................................................................................32
7.
TREATMENTS.......................................................................................................32
7.1.
Treatments Administered............................................................................33
7.1.1.
Medical Devices...........................................................................33
7.2.
Dose Modification .......................................................................................34
7.3.
Method of Treatment Assignment ...............................................................34
7.4.
Blinding.......................................................................................................34
7.5.
Preparation/Handling/Storage/Accountability..............................................35
7.6.
Treatment Compliance................................................................................35
7.7.
Concomitant Therapy..................................................................................36
7.8.
Treatment after the End of the Study ..........................................................37
8.
DISCONTINUATION CRITERIA.............................................................................37
8.1.
Discontinuation of Study Treatment ............................................................37
8.1.1.
Liver Chemistry Stopping Criteria ................................................37
8.1.2.
QTc Stopping Criteria ..................................................................38
8.1.3.
Neutrophil Stopping Criteria.........................................................39
8.1.4.
Temporary Discontinuation ..........................................................39
8.1.5.
Study Treatment Restart..............................................................39
8.2.
Withdrawal from the Study..........................................................................39


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8.3.
Lost to Follow Up........................................................................................40
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................40
9.1.
Efficacy Assessments.................................................................................41
9.1.1.
EXACT and E-RS:COPD.............................................................41
9.1.2.
COPD Exacerbations...................................................................41
9.1.3.
SGRQ-C ......................................................................................43
9.1.4.
CAT .............................................................................................43
9.1.5.
PROactive ...................................................................................43
9.1.6.
Patient Global Rating of Severity and Global Rating of 
Change in Disease Severity.........................................................44
9.1.7.
Patient Global Rating of Activity Limitation and Global 
Impression of Change in Activity Limitation..................................44
9.1.8.
Exit Interview ...............................................................................44
9.1.9.
Clinically Important Deterioration (CID)........................................45
9.2.
Adverse Events...........................................................................................45
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................45
9.2.2.
Method of Detecting AEs and SAEs.............................................46
9.2.3.
Follow-up of AEs and SAEs.........................................................46
9.2.4.
Regulatory Reporting Requirements for SAEs .............................46
9.2.5.
Cardiovascular and Death Events................................................46
9.2.6.
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as SAEs...............................................47
9.2.7.
Pregnancy ...................................................................................47
9.2.8.
Medical Device Incidents (Including Malfunctions).......................47
9.2.8.1.
Time Period for Detecting Medical Device 
Incidents.....................................................................48
9.2.8.2.
Follow-up of Medical Device Incidents........................48
9.2.8.3.
Prompt Reporting of Medical Device Incidents 
to Sponsor..................................................................48
9.2.8.4.
Regulatory Reporting Requirements for 
Medical Device Incidents............................................48
9.3.
Treatment of Overdose...............................................................................50
9.4.
Safety Assessments ...................................................................................50
9.4.1.
Physical Examinations.................................................................50
9.4.2.
Vital Signs....................................................................................50
9.4.3.
Electrocardiograms......................................................................51
9.4.4.
Clinical Safety Laboratory Assessments ......................................51
9.4.5.
Pneumonia ..................................................................................52
9.5.
Pharmacokinetics .......................................................................................52
9.6.
Pharmacodynamics ....................................................................................53
9.7.
Genetics .....................................................................................................53
9.8.
Biomarkers .................................................................................................53
9.9.
Health Economics OR Medical Resource Utilization and Health 
Economics..................................................................................................53
10. STATISTICAL CONSIDERATIONS........................................................................54
10.1.
Hypothesis..................................................................................................54
10.2.
Sample Size Determination ........................................................................54
10.2.1.
Sample Size Re-estimation..........................................................58
10.3.
Randomization............................................................................................58


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10.4.
Populations for Analyses ............................................................................58
10.5.
Statistical Analyses.....................................................................................59
10.5.1.
Efficacy Analyses.........................................................................59
10.5.1.1.
Primary Analysis.........................................................59
10.5.1.2.
Key Secondary Analyses............................................60
10.5.1.3.
HCRU Exacerbations .................................................61
10.5.1.4.
Time to First HCRU Exacerbation...............................61
10.5.2.
Safety Analyses...........................................................................61
10.5.3.
PK and PK/PD Analyses..............................................................61
10.5.4.
Interim Analyses ..........................................................................62
10.5.4.1.
Interim PK Analysis ....................................................62
10.5.4.2.
Futility Analysis...........................................................62
10.5.4.3.
Strategic Planning Analysis ........................................62
11. REFERENCES.......................................................................................................64
12. APPENDICES........................................................................................................68
12.1.
Appendix 1: Abbreviations and Trademarks................................................68
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................72
12.3.
Appendix 3: Study Governance Considerations..........................................74
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................79
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................84
12.6.
Appendix 6: Genetics..................................................................................88
12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................89
12.8.
Appendix 8: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................92
12.9.
Appendix 9: Neutrophil Safety and Study Treatment Restart ......................94
12.10. Appendix 10: Country Specific Requirements.............................................96


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1.
SYNOPSIS
Protocol Title: Randomised, Double-Blind (Sponsor Open), Placebo-Controlled, Multi-
centre, Dose Ranging Study to Evaluate the Efficacy and Safety of Danirixin Tablets 
Administered Twice Daily Compared With Placebo for 24 Weeks in Adult Participants
With Chronic Obstructive Pulmonary Disease (COPD)
Short Title: Danirixin Dose Ranging Study in Participants with COPD
Rationale: The primary aims of this study are to evaluate the clinical activity and safety 
of 5 doses of danirixin compared with placebo in participants with COPD.  The study is 
intended to support subsequent decisions regarding the progression of danirixin in the 
COPD indication, including the selection of doses and appropriate endpoints for use in 
pivotal studies.
Objectives and Endpoints:
Objective
Endpoint
Primary

To characterize the dose response of 
danirixin compared with placebo on 
the incidence and severity of 
respiratory symptoms in participants 
with COPD

To compare the safety of danirixin 
with placebo in participants with 
COPD

Change from baseline in respiratory 
symptoms measured by the 
Evaluating Respiratory Symptoms in 
COPD (E-RS:COPD) daily diary: 
total score and subscales (i.e. 
breathlessness, cough and sputum, 
and chest symptoms

Adverse events (AE), clinical 
laboratory values, vital signs, 
electrocardiogram (ECG)
Key Secondary

To characterize the dose response of 
danirixin compared with placebo on 
the annual rate of moderate/severe 
COPD exacerbations in participants 
with COPD

To further characterize the clinical 
activity of danirixin compared to 
placebo in participants with COPD

Annual rate of Healthcare Resource 
Utilization (HCRU)-defined COPD 
exacerbations

Time to first HCRU-defined COPD 
exacerbation

Change from baseline for the St. 
George’s Respiratory Questionnaire 
(SGRQ) total score (derived from 
SGRQ-C)


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Overall Design: This is a double-blind (Sponsor Open), placebo-controlled, parallel 
group study that will evaluate the dose response of danirixin compared with placebo on 
respiratory symptoms, COPD exacerbations, healthcare-related quality of life and 
physical activity.  The safety of danirixin compared with placebo is also an important 
objective of the study.  Following the completion of baseline assessments collected over a 
7 day period (i.e. EXACT/E-RS:COPD, physical activity, and rescue medication use), 
participants will be randomized (1:1:1:1:1:1) to receive one of five dose strengths of 
danirixin or placebo for 24 weeks.  Three interim analyses are planned for the study.  The 
first interim analysis will be an analysis of danirixin pharmacokinetics and and will be 
conducted after approximately 10 participants in each treatment group have completed 
Visit 3. The second interim analysis will be a futility analysis based on the E-RS:COPD 
endpoint and will be conduced after approximately 150 participants have completed 3 
months of study treatment.  The third interim analysis will be conducted after 
approximately 450 participants have completed 6 months of study treatment.  The third
interim analysis will be used to support GSK decisions regarding the further development 
of danirixin.  This interim analysis will include all clinical activity assessments and safety
assessments available at the time it is conducted.
Number of Participants:
Approximately 700 participants will be screened to achieve approximately 600 
randomized participants.  It is anticipated that approximately 540 participants will 
complete 24 weeks of treatment and key study assessments (dropout rate estimated to be 
approximately 10%).  
Treatment Groups and Duration:
Participants will be randomized to one of six parallel groups and will receive study 
treatment twice daily for 24 weeks:

Placebo

5 mg danirixin (as hydrobromide hemihydrate salt)

10 mg danirixin (as hydrobromide hemihydrate salt)

25 mg danirixin (as hydrobromide hemihydrate salt)

35 mg danirixin (as hydrobromide hemihydrate salt)

50 mg danirixin (as hydrobromide hemihydrate salt)


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2.
SCHEDULE OF ACTIVITIES (SOA)
Table 1
Schedule of Activities
Procedure
Pre-
Screeninga
(Visit 0)
Screeninga
(Visit 1)
Study Visits
2
3
4
5
6
7
8
9
10
Early 
Withdrawal
Follow Up
(up to 28 days 
post last dose)
Study Day
-7
1
14
28
56
84
112
140
168
Assessment Window
-30 d
+/-
0d
+ 
3d
+/-
3d
+/-
3d
+/-
3d
+/-
3d
+/-
3d
+/-
3d
+/-
3d
Eligibility 
Informed consent
X
Genetic Sample 
Informed Consentb
X
Demography
X
COPD Exacerbation 
History
X
Pre-Screening 
Fibrinogenc
X
Smoking Historyd
X
Smoking Statusd
X
X
Inclusion and 
Exclusion criteria
X
Medical historye
X
Full physical 
examination including 
height and weight
X
Chest x-ray (CXR)f
X


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Procedure
Pre-
Screeninga
(Visit 0)
Screeninga
(Visit 1)
Study Visits
2
3
4
5
6
7
8
9
10
Early 
Withdrawal
Follow Up
(up to 28 days 
post last dose)
Study Day
-7
1
14
28
56
84
112
140
168
Assessment Window
-30 d
+/-
0d
+ 
3d
+/-
3d
+/-
3d
+/-
3d
+/-
3d
+/-
3d
+/-
3d
+/-
3d
HIV, Hepatitis B and 
C screeningg
X
Additional Eligibility and In Study Assessments
Verify Eligibilityh
X
X
Brief Physical
X
X
X
X
X
Urine or serum
pregnancy testi
X
X
X
X
X
X
X
X
X
Laboratory 
assessments (clinical 
chemistry (includes 
liver chemistries), 
hematology, 
urinalysis) 
X
X
X
X
X
X
Additional Liver 
chemistries only
X
X
X
12-lead ECG
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
Spirometry
X
X
X
X
X
Randomization
X
Dispense Study 
Medication
X
X
X
X
X
X


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Procedure
Pre-
Screeninga
(Visit 0)
Screeninga
(Visit 1)
Study Visits
2
3
4
5
6
7
8
9
10
Early 
Withdrawal
Follow Up
(up to 28 days 
post last dose)
Study Day
-7
1
14
28
56
84
112
140
168
Assessment Window
-30 d
+/-
0d
+ 
3d
+/-
3d
+/-
3d
+/-
3d
+/-
3d
+/-
3d
+/-
3d
+/-
3d
Dispense log pad and 
provide training
X
Dispense MDI sensors 
and provide training
X
Dispense physical 
activity monitor and 
provide training
X
Study treatment
=====================================
Study treatment 
compliance (ediary)
=====================================
Collect IP
============================
X
X
Collect MDI sensors
X
X
Collect physical 
activity monitor
X
X
Collect log pad
X
X
Adverse Event (AE)
review
=====================================
X
X
Serious Adverse 
Event (SAE) review
================================================================
X
X
Concomitant 
medication review
X
X
X
X
X
X
X
X
X
X
X
X
X


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Procedure
Pre-
Screeninga
(Visit 0)
Screeninga
(Visit 1)
Study Visits
2
3
4
5
6
7
8
9
10
Early 
Withdrawal
Follow Up
(up to 28 days 
post last dose)
Study Day
-7
1
14
28
56
84
112
140
168
Assessment Window
-30 d
+/-
0d
+ 
3d
+/-
3d
+/-
3d
+/-
3d
+/-
3d
+/-
3d
+/-
3d
+/-
3d
Clinical Outcomes Assessments
COPD Exacerbations
===========================================
X
X
EXACT-PROj
===========================================
Rescue Medication 
Usek
===========================================
SGRQ-C
X
X
X
X
COPD Assessment 
Test
X
X
X
X
PROactive 
Questionnairel
X
X
X
Physical Activity 
Monitorl
X
X
X
Participant Global 
Impression of COPD 
Severity
X
Participant Impression 
of Change in COPD 
Severity
X
X
X
X
X
X
X
X
Participant Global 
Impression of Activity 
Limitation
X


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Procedure
Pre-
Screeninga
(Visit 0)
Screeninga
(Visit 1)
Study Visits
2
3
4
5
6
7
8
9
10
Early 
Withdrawal
Follow Up
(up to 28 days 
post last dose)
Study Day
-7
1
14
28
56
84
112
140
168
Assessment Window
-30 d
+/-
0d
+ 
3d
+/-
3d
+/-
3d
+/-
3d
+/-
3d
+/-
3d
+/-
3d
+/-
3d
Participant Impression 
of Change in Activity 
Limitation
X
X
X
X
X
X
X
X
Exit Interviewm
X
X
Genetic, Pharmacokinetic and Biomarker Blood Collections
Blood sample for 
Genetics
X
Blood sample for 
pharmacokinetics
(PK)n
X
X
X
X
Blood sample for  
Fibrinogen
X
X
X
X
Blood sample for CRP
X
X
X
X
Blood Sample for 
Exploratory
Biomarkers
X
X
X
X
a.
Pre-screening and screening visits may be completed on the same day.
b.
Agreeing to the genetic sample consent is not required for study participation.
c.
A pre-screening plasma fibrinogen measurement is only required for participants with 1 COPD exacerbation in the prior year.
d.
Smoking status /history assessed at screening: smoking status rechecked at Visit 2
e.
Includes substance usage, past and present medical conditions and family history of premature CV disease.
f. 
See inclusion/exclusion criteria for CXR screening requirement
g.
Hepatitis B (HBsAg) and Hepatitis C (HepC antibody) testing is required. If testing otherwise performed within 3 months prior to the first dose of study 
treatment, testing at screening is not required.  Hepatitis C RNA testing is optional; however a confirmatory negative Hepatitis C RNA test must be obtained, 
to be able to enrol participants with positive Hepatitis C antibody due to prior resolved disease.


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h.
Participant’s clinical status should be reviewed.
i.
Pregnancy testing only required for women of child bearing potential (WOCBP).  A positive urine pregnancy test requires confirmation with a serum 
pregnancy test.
j.
E-RS:COPD is a subset of EXACT-PRO and is not a separate assessment.
k.
Rescue medication use will be assessed via e-diary and MDI sensor.
l.
The Clinic Visit PROactive Physical Activity in COPD tool will be assessed in a subset of approximately 50% of study participants
m.
An Exit Interview will be collected in approximately 15 – 20% of study participants.
n.
Pre-dose PK samples will be collected in all participants at Visits 3, 6, 7, and 10.  In a subset of participants (approx. 50 participants at each dose level) at 
Visit 3, PK samples will be collected at pre-dose, 0.5, 1, 2, 4, 6, 8, 10, 12 hours post-dose.
Note: The timing and number of planned study assessments, including safety, pharmacokinetic, and biomarker assessments, may be 
altered during the course of the study based on newly available data (e.g., to obtain data closer to the time of peak plasma 
concentrations) to ensure appropriate monitoring. Any changes in the timing or addition of time points for any planned study 
assessments must be documented and approved by the relevant study team member and then archived in the sponsor and site study 
files, but will not constitute a protocol amendment. The IRB/IEC will be informed of any safety issues that require alteration of the 
safety monitoring scheme or amendment of the ICF.


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3.
INTRODUCTION
The inflammation associated with COPD is characterized by a prominent infiltration of 
neutrophils in lung tissue and the airways.  Neutrophils and other inflammatory cells are 
recruited to the lung in response to various chemotactic factors, including chemokines.  
Specifically, there is a large body of evidence that the CXCR2 chemokine receptor plays 
a pivotal role in neutrophil recruitment to the lung.  For neutrophils, chemokine binding 
to the CXCR2 results in chemotaxis and cell activation, ultimately resulting in the release 
of a number of inflammatory mediators and proteases that are thought to contribute to the 
progressive fibrosis, airway stenosis, and destruction of the lung parenchyma 
characteristic of COPD.    
Selective antagonism of the interaction between CXCR2 and its ligands is a potential 
strategy for reducing the inflammation in COPD [Chapman, 2009].  A reduction in tissue 
and airway neutrophilia is expected to result in downstream effects on mucus 
hypersecretion, lung inflammation, and tissue destruction that are hypothesized to 
underlie the development and worsening of respiratory symptoms and decline in lung 
function that occurs in COPD.
Molecules with CXCR2 antagonist activity have been shown to reduce the influx of 
neutrophils into the lungs in healthy participants (e.g. ozone or LPS challenge models) 
and to reduce sputum and tissue neutrophils in the lungs of patients with severe, 
neutrophilic asthma, COPD and bronchiectasis in association with improvements in 
measures of disease activity in some, but not all, studies [O'Byrne, 2016; Holz, 2010; 
Watz, 2016; Lazaar, 2011; Nair, 2012; Rennard, 2015]. Overall, the results of the 
reported clinical studies with CXCR2 antagonists suggest that careful selection of the 
target patient population is important to achieving clinical benefit.
Danirixin is a selective CXCR2 antagonist being developed as a potential anti-
inflammatory agent for the treatment of COPD and other inflammatory diseases and 
influenza.  Danirixin has demonstrated potent antagonism of CXCR2 activity both in 
vitro and in vivo in preclinical studies [GlaxoSmithKline Document No. 
YM2010/00163/07].
Clinical pharmacology studies in healthy volunteers demonstrated the pharmacodynamic 
activity of danirixin (inhibition of ex vivo CXCL1-induced CD11b expression on 
peripheral blood neutrophils).  Danirixin has also been tested in a Phase IIa study in 
symptomatic participants with mild to moderate COPD at risk for exacerbation (GSK 
Study No. 200163) [GlaxoSmithKline Document No. 2013N180289_03].  In study 
200163, twice daily dosing with danirixin free base (75 mg bid) or placebo given on top 
of standard of care inhaled maintenance treatments was tested for one year.  An interim 
analysis of clinical endpoints from study 200163 demonstrated that danirixin, compared 
to placebo, reduced respiratory symptoms as measured with E-RS:COPD [Miller, 2016].


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3.1.
Study Rationale
This protocol describes a Phase IIb dose-ranging study evaluating the clinical activity and 
safety of danirixin compared with placebo in participants with COPD that have current 
respiratory symptoms including cough, increased sputum production, and dyspnoea.  
Study participants will continue with their standard of care inhaled medications (i.e. long 
acting bronchodilators with or without inhaled corticosteroids) while receiving study 
treatment.  In this study, 5 doses of danirixin and placebo are being evaluated (danirixin 
or placebo will be taken orally twice daily).  
The primary objectives of the study are to evaluate the dose response of danirixin 
compared with placebo on respiratory symptoms assessed by the E-RS:COPD patient 
reported outcome (PRO) tool and assess the safety of danirixin compared with placebo.  
Key secondary objectives include an evaluation of danirixin compared with placebo on 
healthcare resource utilization (HRCU) defined COPD exacerbations, health status, 
physical activity, and rescue medication use.  Exploratory objectives will include a 
participant exit interview and blood biomarkers to investigate the impact of danirixin on 
biomarkers of extracellular matrix turnover and remodeling.  
3.2.
Background
COPD is a major cause of disability, morbidity, and mortality, resulting in millions of 
deaths annually worldwide contributing significantly to health care costs [Mathers, 2006; 
Lopez-Campos, 2016; Vastava, 2015; GOLD, 2016].  The morbidity and mortality of 
COPD are continuing to increase and worldwide, by the year 2020, COPD is expected to 
be the third leading cause of death and fifth leading cause of disability [Mathers, 2006; 
Lopez-Campos, 2016].  The airflow limitation that characterizes COPD is primarily due 
to small airways disease and parenchymal destruction associated with an excessive 
inflammatory response in the lung, mainly caused by cigarette smoking [Celli, 2004].  
COPD is characterized by symptoms of chronic and, in many patients, progressive 
breathlessness (or dyspnea), cough and sputum production.  Many COPD patients also 
suffer from periodic worsening of their COPD symptoms that is beyond the typical day to 
day variation [Hurst, 2010].  These episodes of worsening symptoms (COPD 
exacerbations) account for a significant proportion of COPD-related and total health care 
costs.  Despite several available therapies that have been shown to reduce COPD 
exacerbations and respiratory symptoms, many COPD patients continue to experience a 
high burden of respiratory symptoms and COPD exacerbations resulting in a continuing 
unmet medical need [Vestbo, 2016].  Additionally, there is growing recognition that a 
high percentage of COPD patients with mild airflow limitation as well as smokers with 
preserved lung function suffer from a high burden of symptoms and COPD exacerbations 
with a subsequent impact on health status [Woodruff, 2016].  Therapies that effectively
further reduce COPD exacerbations and improve respiratory symptoms could have a 
substantial impact on healthcare utilization and most importantly result in an
improvement in COPD patients’ quality of life.
The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines for the 
treatment and management of patients with COPD recommend that the management of 
current respiratory symptoms and subsequent worsening of symptoms resulting in COPD 


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exacerbations should be an important component of COPD patient management [GOLD, 
2016] .
Danirixin is being evaluated as an addition to standard of care inhaled therapies (i.e. long 
acting bronchodilators and long acting bronchodilator/corticosteroid combination 
therapies) and is targeting those COPD patients that continue to have a burden of 
respiratory symptoms and COPD exacerbations despite management with currently 
available COPD treatments.
3.3.
Benefit/Risk Assessment
More detailed information about the potential benefits and risks of danirixin may be 
found in the danirixin Investigator’s Brochure [GlaxoSmithKline Document No. 
YM2010/00163/07].


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3.3.1.
Risk Assessment
Investigational Product (IP) [Danirixin, GSK1325756]
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Testicular effects and male fertility
The most sensitive species is the rat. 
Testicular effects present at doses ≥150 
mg/kg/day in the rat include spermatid 
degeneration, seminiferous tubular 
degeneration and secondary epididymal 
changes, including oligo/aspermia and/or 
epididymal intratubular cellular debris.  The 
no observed adverse effect level (NOAEL) 
in this study, based on the microscopic 
findings in the testis, was 50 mg/kg/day for 
male rats.  The systemic exposure margins 
for the NOAEL for testicular effects in the 
rat is 7.3-fold for an oral clinical dose of 50 
mg BID free base tablet.
The testicular effects seen in the rat have 
also been shown to directly impact on male 
fertility and the NOAEL for these 
reproductive effects was 100 mg/kg/day.
Refer to IB Section 4.4 for full details
No adverse events related to testicular 
effects have been observed in clinical 
studies to date.
Standard safety monitoring will be 
employed.
The potential risk of testicular injury has 
been conveyed in the informed consent.
Pharmacokinetic parameters will be 
monitored in clinical studies to ensure 
appropriate safety margins (2-fold 
NOAEL). PK modelling predicts that in a 
participant receiving 50 mg BID of the HBr 
salt, the risk of exposure exceeding the 2-
fold margin for AUC(0-24) for the NOAEL 
of testicular effects is low.


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Investigational Product (IP) [Danirixin, GSK1325756]
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Impairment of host defense.
Host defense has not been studied directly 
in nonclinical studies. However, data in 
nonclinical species have not identified an 
increased risk of infection with danirixin.  
Nonclinical studies in mice and ferrets with 
two CXCR2 antagonists in the same
chemical class as danirixin have not shown 
an increase in infections in challenge 
models (e.g., influenza viral load).  
Secondary bacterial infections after viral 
infection have not been directly evaluated in 
nonclinical studies.
The data from clinical studies including 
healthy participants, COPD and influenza 
patients thus far show no evidence that 
participants taking danirixin have an 
increased infection rate compared with 
participants taking placebo.
Neutropenia has been reported in clinical 
trials of other CXCR2 antagonists.  No 
instances of neutropenia have been reported 
in nonclinical studies with danirixin.  In 
healthy volunteer studies and a phase 2a 
study in patients with Influenza (GSK Study 
Monitoring of neutrophil count.
Stopping criteria: in participants with a 
confirmed absolute neutrophil count 0.5 x 
109/L product will be discontinued and 
neutrophil count will be monitored until 
return to normal. Participants may be 
restarted on study treatment as detailed in 
Appendix 9.
Ongoing assessment of AE/SAEs related to 
infection.
Closely monitor, collect information on and 
characterize infection events such as 
pneumonia, and use adjudication as 
appropriate.


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Investigational Product (IP) [Danirixin, GSK1325756]
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
201682, GlaxoSmithKline Document No. 
2014N205875_00), decreased neutrophil 
counts have been observed in subjects 
receiving either placebo or danirixin; no 
instances of danirixin-related neutropenia 
have been reported in clinical studies to 
date. In healthy subjects, the data are 
confounded by the observation of low 
neutrophil counts before dosing or at 
follow-up, and were not dose-related, while 
in patients with influenza, neutrophil counts 
recovered while receiving danirixin, 
coincident with resolution of the viral 
infection. There have been no reports of 
neutrophil count decreases below the lower 
limit of normal in patients with COPD who 
were treated with danirixin for one year.   
These data support the conclusion that a 
causal association of neutropenia with 
danirixin cannot be definitively established.


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Investigational Product (IP) [Danirixin, GSK1325756]
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Reproductive toxicology (Embryofetal 
development)
In a rat embryofetal development study, an 
oral dose of 300 mg/kg/day resulted in fetal 
skeletal variations in the skull (reductions in 
ossification). There were no test article-
related effects on numbers of corpora lutea, 
implantations, embryofetal survival,
placental morphology, gravid uterine weight, sex 
ratio, fetal body weight, or fetal morphology 
(external and visceral).
As danirixin HBr has shown the potential to 
cause fetal malformations, danirixin or 
danirixin HBr must not be administered to 
pregnant women or nursing mothers. 
Women of childbearing potential should 
only be included in clinical trials with the 
use of appropriate precautions against 
pregnancy.
Male participants with female partners of 
child-bearing potential must comply with 
the contraception requirements.
Study Procedures
None
Other 
Not applicable


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3.3.2.
Benefit Assessment

All participants will undergo a thorough medical assessment during the study. 
Participants will have frequent study clinic visits for the evaluation of their 
disease symptoms. During these visits, participants will have spirometry, ECG, 
vital signs monitoring, and physical examinations. Monitoring for worsening of 
their disease will also take place.  

Participants may benefit from the knowledge that they are contributing to the 
process of developing a new treatment in an area of unmet need, even if not 
directly beneficial for them

All participants will continue with changes to their medications, where medically 
appropriate, to receive established standard of care.  
3.3.3.
Overall Benefit:Risk Conclusion
Danirixin has demonstrated potent antagonism of CXCR2 activity both in vitro and in 
vivo in preclinical and clinical studies. Its potency and duration of action supports its 
potential use as an oral, anti-inflammatory agent in the treatment of COPD with 
anticipated potential for bringing benefit to a serious condition that affects the lives of 
millions and contributes to significant morbidity and mortality.
In clinical trials completed to date danirixin has been well-tolerated and most adverse 
events (AEs) were mild to moderate in intensity The most commonly observed AEs have 
been nasopharyngitis, headache and diarrhea following administration of danirixin or 
placebo. There have been no treatment related clinically significant changes in vital signs 
and ECG at any dose of danirixin.  
Taking into account the measures taken to minimize risks to participants in this study, the 
potential risks identified in association with danirixin are justified by the anticipated 
benefits that may be afforded to participants with COPD.
4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To characterize the dose response of 
danirixin compared with placebo on 
the incidence and severity of 
respiratory symptoms in participants 
with COPD

To compare the safety of danirixin
with placebo in participants with 
COPD

Change from baseline in respiratory 
symptoms measured by E-RS:COPD 
daily diary: total score and subscales 
(i.e. breathlessness, cough and sputum, 
and chest symptoms)

Adverse events (AE), clinical 
laboratory values, vital signs, 
electrocardiogram (ECG)


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Objectives
Endpoints
Secondary

To characterize the dose response of 
danirixin compared with placebo on 
the annual rate of moderate/severe 
COPD exacerbations in participants 
with COPD

To further characterize the clinical 
activity of danirixin compared to 
placebo in participants with COPD

To characterize the 

Healthcare Resource Utilization 
(HCRU)-defined COPD exacerbations

E-RS:COPD Responder Analysis
(including subscales)

Number of Exacerbations of Chronic 
Pulmonary Disease (EXACT) tool
defined events

Time to first EXACT event

EXACT event severity

EXACT event duration for all events

Time to first HCRU-defined COPD 
exacerbation

Time to first severe HCRU-defined 
COPD exacerbation

HCRU-defined exacerbation duration

Change from baseline for the St. 
George’s Respiratory Questionnaire 
(SGRQ) total score (derived from 
SGRQ-C)

SGRQ responder analysis

Change for baseline COPD 
Assessment Test (CAT) total score

CAT responder analysis

Lung function (FEV1, FEV1 % 
predicted, FVC, FEV1/FVC ratio)

Rescue medication use

Participant experience of physical 
activity (subset of approximately 50% 
of participants) measured using 
PROactive Clinic Visit Tool (C-PPAC)


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Objectives
Endpoints
pharmacokinetics of danirixin in 
participants with COPD

Danirixin concentration and standard 
pharmacokinetic parameters for 
danirixin (e.g. AUC, Cmax, Tmax), 
using dried blood spot data
Tertiary/Exploratory

To further explore study participants 
experience with study treatment and 
overall experience with the study

To characterize the effect of 
danirixin on lung matrix 
destruction/remodelling

Comparison between dried blood 
spot and wet whole blood analysis of 
danirixin concentrations in patients 
with COPD

To characterise danirixin exposure-
response relationships for various 
safety parameters,if appropriate

Time to first Clinically Important 
Deterioration (CID)

SGRQ domains

Responses to a participant Exit 
Interview at the end of treatment (in a 
subset of 15 – 20% of participants)

Blood/serum/plasma biomarkers that 
are indicative of extracellular matrix 
turnover/remodelling (e.g. elastin and 
collagen neo-epitopes)

Danirixin concentration and standard 
pharmacokinetic parameters for 
danirixin (e.g. AUC, Cmax, Tmax) 

Danirixin systemic exposure and 
various efficacy/PD/safety parameters, 
if appropriate
5.
STUDY DESIGN
5.1.
Overall Design
A study schematic is shown in Figure 1. This is a parallel group study.  Following 
screening and successful completion of the EXACT daily diary (all participants), rescue 
medication use daily diary (all participants) and PROactive baseline measurements 
(questionnaire and participant experience of physical activity) over study days -7 to 1, 
participants will be randomized (1:1:1:1:1:1) to receive one of five dose strengths of 
danirixin (5 mg, 10 mg, 25 mg, 35 mg and 50 mg) or placebo.  Study treatment will be 
administed twice daily for 24 weeks.  The PROactive baseline measurements will only be 
collected for those participants selected for the physical activity monitoring subgroup.  
Participants who do not properly complete (i.e. are not adherent with the requirements for 
completing and recording) the required baseline assessments (i.e. EXACT/E-RS:COPD


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daily diary, physical activity monitoring portion of PROactive, and daily rescue 
medication use baseline measurements) will not be randomized and will not be eligible 
for rescreening.
Three interim analyses are planned for the study.  The first interim analysis will be an 
evaluation of danirixin pharmacokinetics after 10 participants in each treatment group 
have completed Visit 3.
The second interim analysis will be a futility analysis based on the E-RS:COPD endpoint 
and will be conducted after approximately 150 participants have completed 3 months of 
study treatment.  
The third interim analysis will be conducted after approximately 450 participants have 
completed 6 months of treatment.  The second interim will be used to support GSK 
decisions regarding the further development of danirixin.  This interim analysis will 
include the E-RS:COPD dose response modelling, secondary endpoints of HCRU-
defined exacerbations and SGRQ total score along with all available safety data.  No 
changes will be made to the study based on the results of the second interim analysis.  
Outputs containing unblinded treatment assignments will be created for this interim 
analysis and will only be made available to a limited number of GSK staff.  Full details 
will be included in the study data dissemination plan.
No Independent Data Monitoring Committee (IDMC) will be utilized for this study.  
While the study is being conducted, core members of the study team will be unblinded 
(with the exception of those study team members who will directly interact with study 
sites, e.g. Operations and Science Leader and Data Quality Leader).  There will be 
ongoing review of safety data and clinical outcomes.  Only the study statistician will have 
access to individual participant treatment assignments, other core team members will 
review aggregate summaries by study treatments.  A study charter will specify which 
team members will have access to unblinded data while the study is ongoing, the 
frequency of planned data reviews and the data to be included in the data reviews.  The 
study charter will also state how interim results will be communicated outside the study 
team.  A safety review team will meet approximately every 3 months (or as needed based 
on emerging data) to review available safety information.  


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Figure 1
Study Schematic
5.2.
Number of Participants
Approximately 700 participants will be screened to achieve approximately 600
randomized participants.  It is anticipated that approximately 540 participants will 
complete 24 weeks of treatment and key study assessment (the dropout rate is estimated 
to be approximately 10% based on previous experience with studies enrolling similar 
participants).  
For the analysis of study assessments, several analysis populations will be defined.  
Details of the evaluable participants for each planned analysis population are included in 
Section 10.4. 
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 the last study visit and the last scheduled procedure shown 
in the Schedule of Activities (Table 1).
The end of the study is defined as the date of the last visit of the last participant in the 
study.
5.4.
Scientific Rationale for Study Design
This study will use a multicenter, randomized, parallel-group design. This is a well-
established design to evaluate the efficacy and safety of an investigational drug. Twenty-
four weeks should be adequate to demonstrate efficacy based on E-RS:COPD, as well as 
to collect adequate safety measurements before going into larger phase III trials. 
Danirixin has already been clinically investigated over one year treatment duration (GSK 
Study No. 200163, GlaxoSmithKline Document No. 2013N180289_03). 


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By evaluating a range of doses from 5 mg to 50 mg of danirixin, it will be possible to 
assess the dose response of danirixin as well as the potential effects of danirixin on 
biomarker and safety endpoints. The data will provide useful information in determining 
the therapeutic index of danirixin and in selecting the minimal effective and safe dose to 
be carried forward in the Phase III COPD program.
PK samples from randomized participants will also be collected in this study. Defining 
the optimum dose for later stages of development can be made more efficiently by 
understanding the variability in the pharmacokinetics of a drug. In addition, the study will 
evaluate the relationship between danirixin blood concentrations and biomarker and 
safety endpoints. 
A placebo arm is included to measure the absolute effect of each dose tested, thereby 
allowing a robust determination of the dose-response. Inclusion of a placebo arm will 
also allow a more robust exploration of the therapeutic index of danirixin.
5.5.
Dose Justification
Five doses of danirixin (5 mg, 10 mg, 25 mg, 35 mg and 50 mg) are planned for 
evaluation in this study. The doses to be investigated have been selected based on 
integrating information available from:

Dose-exposure-biomarker response using inhibition of ex vivo CXCL1-induced 
CD11b expression on peripheral blood neutrophils over the dose range of 0-400
mg in healthy volunteer participants

Evidence of reduced respiratory symptoms in mild to moderate COPD 
participants in the Phase IIa study (GSK study 200163) 
In the early clinical studies, danirixin was administered as a free base tablet, whereas the 
danirixin formulation to be used in this study will be a hydrobromide salt tablet. The 
hydrobromide tablet has approximately twice the bioavailability of the free base tablet in 
healthy elderly participants (GSK Study No. 201037, GlaxoSmithKline Document No. 
2015N248339_00 ).  Predicted steady-state exposures and multiples of blood ex vivo
CXCL1-induced CD11b pharmacology at the proposed danirixin doses are presented in 
Table 2.


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Table 2
Predicted steady state systemic exposure and multiples of blood ex 
vivo CXCL1-induced pharmacology following twice daily of 
administration of danirixin
Model derived based on PK data in healthy elderly participants from GSK Study No. 201037
(GlaxoSmithKline Document No. 2015N248339_00).
Model predicted population mean IC50=78.5 ng/mL (95% CI: 37.3, 120), sigmoidal Emax model of DNX 
PK-ex vivo CXCL1-induced CD11b expression on peripheral blood neutrophils in healthy participants.
The predicted multiples of ex vivo CXCL1-induced CD11b inhibition achieved at 24 h 
post steady-state, together with the terminal elimination half-life of danirixin support the 
twice daily dosing regimen.
Based on the biomarker results described for danirixin and the anticipated higher 
exposure from the hydrobromide tablet,  doses of 5 mg, 10 mg, 25 mg and 35 mg were 
selected to span the dose range and allow efficient estimation of the dose response curve 
in this mild/moderate COPD population. Fifty mg twice daily is included as a supra-
therapeutic dose but where there is a low possibility of AUC(0-24) exposure exceeding a 
2-fold margin for the no observed adverse effect level (NOAEL) for testicular effects.
The risk of exposure exceeding the 2-fold margin for AUC(0-24) for the NOAEL of 
testicular effects is considered low. Based on PK modeling, the predicted AUC (0-24) for 
a dose of 50 mg BD is 13.7 ug.hr/mL (6.7, 27.6). This provides 2.5-fold cover over the 
NOAEL/2 and approximately 5-fold cover over the NOAEL.
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
Dose 
(mg)
Predicted steady-state median (5th, 95th
percentile)a
Cavg 
multiple of 
IC50b
Cmin 
multiple of 
IC50b
AUC(0-24) 
steady-state
(g.h/mL)
Cavg
(ng/mL)
Cmin
(ng/mL)
5
1.37 
(0.69, 2.78)
57.2
(28.6, 116)
27.8
(6.8, 92.1)
0.7
0.4
10
2.74 
(1.34, 5.53)
114 
(56.0, 230)
54.8
(13.6, 180)
1.5
0.7
25
6.85
(3.36, 13.8)
285
(140, 576)
137
(34.0, 450)
3.6
1.7
35
9.59
(4.70, 19.3)
399
(196, 806)
192
(47.6, 630)
5.1
2.4
50
13.7
(6.71, 27.6)
571
(280, 1152)
274
(68.0, 900)
7.3
3.5


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6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1. Participant must be 40 to 80 years of age inclusive, at the time of signing the 
informed consent.
Type of Participant and Disease Characteristics
2. Participants who have COPD (postbronchodilator FEV1/FVC ratio < 0.7 and FEV1 
% predicted 40%) based on American Thoracic Society (ATS)/European 
Respiratory Society (ERS) current guidelines [Celli, 2004].  Participants with a 
historical diagnosis of asthma may be included so long as they have a current 
diagnosis of COPD.
3. History of respiratory symptoms including chronic cough, mucus hypersecretion, and 
dyspnea on most days for at least the previous 3 months prior to screening.
4. Participants with a documented history of COPD exacerbation(s) in the 12 months 
prior to study participation (screening) meeting at least one of the following criteria:

2 COPD exacerbations resulting in prescription for antibiotics and/or oral 
corticosteroids or hospitalization or extended observation in a hospital emergency 
room or outpatient center

1 COPD exacerbation resulting in prescription for antibiotics and/or oral 
corticosteroids of hospitalization or extended observation in a hospital emergency 
room or outpatient center and a plasma fibrinogen concentration at screening 3 
g/L (300 mg/dL)
5. Smoking history: current and former smokers with a cigarette smoking history of 
10 pack years (1 pack year = 20 cigarettes smoked per day for 1 year or equivalent).  
Current smokers are defined as those who are currently smoking cigarettes (i.e. have 
smoked at least one cigarette daily or most days for the month prior to Visit 1).  
Former 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 smoking 
pack-year history.
6. Participants must have the ability and willingness to use an electronic diary (log pad) 
on a daily basis.
Weight
7. Body weight 45 kg


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Sex
8. Male or female.
a. Male participants:
A male participant must agree to use contraception as detailed in Appendix 5 of this 
protocol during the treatment period and for at least 60 hours after the last dose of 
study treatment, corresponding to approximately 6 half-lives (which is the time 
needed to eliminate any teratogenic study treatment) and to refrain from donating 
sperm during this period.
b. Female participants: 
A female participant is eligible to participate if she is not pregnant (see Appendix 5), 
not breastfeeding, and at least one of the following conditions applies:
(i)
Not a woman of childbearing potential (WOCBP) as defined in Appendix 5
OR
(ii)
A WOCBP who agrees to follow the contraceptive guidance in Appendix 5
during the treatment period and for at least 60 hours after the last dose of 
study treatment.
Informed Consent
9. Capable of giving signed informed consent as described in Appendix 3 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Diagnosis of other clinically relevant lung diseases (other than COPD), e.g. 
sarcoidosis, tuberculosis, pulmonary fibrosis, severe bronchiectasis or lung cancer.
2. Alpha-1-antitrypsin deficiency as the underlying cause of COPD
3. Pulse oximetry < 88% at rest at screening.  Participants should be tested while 
breathing room air.  However, participants living at high altitudes (above 5000 feet or 
1500 meters above sea level) who are receiving supplemental oxygen can be included 
provided they are receiving the equivalent of < 4 L/min and screening pulse oximetry 
is measured while on their usual oxygen settings.
4. Less than 14 days have elapsed from the completion of a course of antibiotics or oral 
corticosteroids for a recent COPD exacerbation.
5. A peripheral blood neutrophil count < 1.5 x 109/L.
6. Diagnosis of pneumonia (chest X-ray or CT confirmed) within the 3 months prior to 
screening.


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7. Chest x-ray (posterior-anterior with lateral) or CT scan reveals evidence of a 
clinically significant abnormality not believed to be due to the presence of COPD 
(historic results up to 1 year prior to screening may be used).  For sites in Germany: If 
a chest x-ray (or CT scan) within 1 year prior to screening is not available, approval 
to conduct a diagnostic chest x-ray will need to be obtained from the Federal Office 
of Radiation Protection (BfS).
8. History or current evidence of other clinically significant medical condition that is 
uncontrolled on permitted therapies.  Significant is defined as any disease that, in the 
opinion of the Investigator, would put the safety of the participant at risk through 
study participation, or that would affect the safety analysis or other analysis if the 
disease/condition worsened during the study.
9. Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert’s syndrome or asymptomatic gallstones).
10. Abnormal and clinically significant 12-lead ECG finding. 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 study.  An abnormal and clinically significant finding that would 
preclude a participant from entering the study is defined as a 12-lead tracing that is 
interpreted as, but not limited to, any of the following:
a.
AF with rapid ventricular rate > 120 bpm
b. sustained or non-sustained VT
c.
second degree heart block Mobitz type II and third degree heart block (unless 
pacemaker or defibrillator has been implanted)
d. QTcF 500 msec in participants with QRS < 120 msec and QTcF 530 msec 
in participants with QRS 120 msec
11. Previous lung surgery (e.g. lobectomy, pneumonectomy) or lung volume reduction 
procedure.
Prior/Concomitant Therapy
12. Current or expected chronic use of macrolide antibiotics during the study period for 
the prevention of COPD exacerbations.  Examples of chronic use include, but are not 
limited to, daily or two to three times per week use for at least 3 months.
13. Oral or injectable CYP3A4 or BRCP (breast cancer resistance protein) substrates with 
a narrow therapeutic index (CYP3A4 substrates include, but are not limited to, 
alfenatil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, 
quinidine, sirolimus, tacrolimus, and theophylline; BCRP substrates include, but are 
not limited to, topotecan.)  The Investigator should consult with the Medical Monitor 
if necessary.
14. Current or expected use of phosphodiesterase-4 inhibitors (e.g. roflumilast).  
Participants currently receiving roflumilast may be included if they are able to 
discontinue use from 30 days prior to screening through the completion of the follow 
up visit.


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Prior/Concurrent Clinical Study Experience
15. Participation in a previous clinical trial and has received an investigational product 
within any of the following time periods prior to the first dosing day in the current 
study: 30 days, 5 half lives, or twice the duration of the biological effect of the 
investigational product (whichever is longer).
16. Participation in a previous clinical trial with danirixin within 1 year prior to the first 
dosing day in the current study
17. Exposure to more than four investigational products within 1 year prior to the first 
dosing day in the current study.
Diagnostic assessments
18. Alanine transferase (ALT) > 2x upper limit of normal (ULN); bilirubin > 1.5xULN 
(isolated bilirubin > 1.5xULN is acceptable if bilirubin is fractionated and direct 
bilirubin <35%).
19. A positive test for HIV antibody.
20. A positive pre-study hepatitis B surface antigen or positive hepatitis C antibody result 
within 3 months prior to screening.
Other Exclusions
21. Pulmonary rehabilitation: Participants who have taken part in the acute phase of a 
pulmonary rehabilitation program within 4 weeks prior to screening or participants 
who plan to enter the acute phase of a pulmonary rehabilitation program during the 
study.  Participants who are in the maintenance phase of a pulmonary rehabilitation 
program are not excluded.
22. A history of allergy or hypersensitivity to any of the ingredients in the study 
treatment.
23. A known or suspected history of alcohol or drug abuse within the 2 years prior to 
screening.
24. Inability to read: in the opinion of the Investigator, any participant who is unable to 
read and/or would not be able to complete study related materials.
25. Affiliation with the study site: study investigators, sub-investigators, study 
coordinators, employees of a study investigator, sub-investigator or study site, or 
immediate family member of any of the above that are involved with the study.
6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions
No meal or dietary restrictions are required for participation in this study.  Danirixin must 
be taken with food.  Specific dosing instructions will be provided in the Study Reference 
Manual (SRM) and will be provided to all study participants.


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6.3.2.
Activity
Participants should abstain from strenuous exercise for 24 hours before each blood 
collection for clinical laboratory tests. 
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized in the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria and any serious adverse 
events (SAEs).
Individuals who do not meet the criteria for participation in this study (screen failure)
may be rescreened up to two additional times if the investigator judges the participant can 
meet the eligibility criteria. Any rescreened participant must satisfy all of the protocol 
specified inclusion/exclusion requirements at the re-screening visit.  Rescreened 
participants should be assigned the same participant number as for the initial screening.
6.5.
Run In Failures
A run in failure is defined as a participant who consents to participate in the clinical 
study, satisfies all eligibility criteria,  but who does not properly complete the required 
baseline assessments for the daily EXACT diary, daily rescue medication use, and the 
physical activity monitoring portion of PROactive baseline (if selected to participate in 
the physical activity subgroup) over 7 days beginning with Visit 2.  A participant who is 
selected to participate in the physical activity subgroup and does not complete the 
baseline physical activity monitoring portion of PROactive baseline but does complete 
the daily EXACT diary and daily rescue medication use baseline assessments will still be 
eligible for participation in the study but will be not be included in the physical activity 
subgroup.  Participants who are run in failures will not be randomized to any study 
treatment and are not eligible for rescreening.
A successful EXACT baseline assessment is defined as completion of all 14 questions of 
the EXACT questionnaire on at least 4 of the 7 days. Successful rescue medication use 
recording is defined as recording of rescue medication use in the daily diary on at least 4 
of the 7 days along with electronic data capture from the MDI sensor device. For 
participants in the physical activity subgroup a successful baseline determination is 
defined as recording of physical activity for at least 8 hours per day on at least 3 of the 7 
days and completion of the PROactive questionnaire at Visit 3.
7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo or medical device(s) intended to be administered to a study participant according 
to the study protocol.


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7.1.
Treatments Administered
Table 3
Treatments Administered
Study Treatment Name:
Danirixin 
(GSK1325756H, the 
hydrobromide 
hemihydrate salt)
Placebo
Dosage formulation:
White Film coated tablets 
(oval or round shaped). 
Refer to Investigator’s 
Brochure for presentation 
and excipients
White Film coated tablets 
(oval or round shaped). 
Refer to Investigator’s 
Brochure for presentation 
and excipients
Unit dose strength(s)/Dosage 
level(s):
5, 10, 25, 35 and 50 mg 
(of free base equivalent)
N/A
Route of Administration 
Oral
Oral
Dosing instructions:
One tablet to be taken 
twice daily with food
One tablet to be taken 
twice daily with food
Packaging and Labeling
Study Treatment will be 
provided in a HDPE 
bottle with desiccant. 
Each bottle will be 
labeled as required per 
country requirement.
Study Treatment will be 
provided in a HDPE 
bottle with desiccant. 
Each bottle will be 
labeled as required per 
country requirement.
Manufacturer
GSK
GSK
7.1.1.
Medical Devices

Subject to availability and any local restrictions on use, MDI sensor devices 
(manufactured by and purchased from Propeller Health) are being provided by 
GSK for this study.  These devices are fitted onto rescue medication MDI devices
to electronically record rescue medication usage.  The MDI sensor devices have 
US FDA 510(k) clearance to market (Class II medical device) and European 
Union CE marking (Class I medical device).

Subject to availability and any local restrictions on use, ActiGraph GT9X physical 
activity monitors (manufactured by and purchased from ActiGraph, LLC) are 
being provided by GSK for the subset of participants that will be included in the 
physical activity monitoring subgroup.  The device is a tri-axial accelerometer.  
The participant wears the devices for the period of time that physical activity is 
being monitored.


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
Additional descriptive information and instructions for the eMDI and physical 
activity monitoring devices are provided in the SRM.

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).
7.2.
Dose Modification
No individual participant dose modifications or adjustments are allowed.
7.3.
Method of Treatment Assignment

This study will use an Interactive Web Response System (IWRS).  All 
participants will be centrally randomized using the IWRS.  Before the study is 
initiated, the log in information and directions for the IWRS will be provided to 
each site.

Participant randomization will be stratified by smoking status (i.e. current 
smoker or former smoker).

Study treatment will be dispensed to participants at the study visits summarized 
in the SOA.  

Returned study treatment should not be re-dispensed to any participant. 
7.4.
Blinding
This will be a double-blind (sponsor open) study.  Study participants, all study site staff, 
and all members of the GSK study team, with the exception of the study statistician, will 
be blinded to individual participant treatment assignment.  As defined in the study 
charter, core members of the GSK study team will have access to unblinded, aggregate 
summaries of study treatment results.
A participant will be withdrawn if the participant’s treatment code is unblinded by the 
investigator or treating physician. The primary reason for discontinuation (the event or 
condition which led to the unblinding) will be recorded in the CRF.
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.


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7.5.
Preparation/Handling/Storage/Accountability

The investigator or designee must confirm and document 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 of records).

Further guidance and information for the final disposition of unused study 
treatment are provided in the SRM. 

Precaution will be taken to avoid direct contact with the study treatment.  Under 
normal conditions of handling and administration, study treatment is not expected 
to pose significant safety risks to site staff.  In the case of unintentional 
occupational exposure notify the monitor, Medical Monitor and/or GSK study 
contact.

A Material Safety Data Sheet (MSDS)/equivalent document describing 
occupational hazards and recommended handling precautions either will be 
provided to the investigator, where this is required by local laws, or is available 
upon request from GSK.
7.6.
Treatment Compliance

When participants are dosed at the site, they will receive study treatment directly 
from the investigator or designee, under medical supervision.  The date and time of 
each dose administered in the clinic will be recorded in the source documents.  The 
dose of study treatment and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person 
administering the study treatment.  

When participants self-administer study treatment(s) at home, compliance with study 
treatment administration will be assessed through querying the participant during the 
site visits and documented in the source documents and CRF.  In addition, 
participants will be asked to confirm study administration each day in the daily 
ediary.  

Study participants who are not compliant with study treatment administration 
requirements should be re-educated on the importance of treatment compliance.  
Every effort should be made to keep participants in the study.  Participants who 
continue to be non-compliant after several attempts to re-educate may be 
discontinued after consultation with the GSK study team.  


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
A record of the number of tablets dispensed to and taken by each participant must be 
maintained and reconciled with study treatment and compliance records.  Treatment 
start and stop dates, including dates for treatment delays and/or dose reductions will 
also be recorded in the CRF.
7.7.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrolment or receives during the study must be recorded along with:

reason for use

dates of administration including start and end dates

dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
The following COPD medications are permitted during the study, at the discretion of the 
GSK Medical Monitor and/or Investigator:

Inhaled COPD maintenance medications (e.g. long acting bronchodilator 
medications (i.e. LAMA, LABA) and long-acting bronchodilator combination 
therapies (e.g. LAMA/LABA) and long-acting bronchodilator/inhaled steroid 
combination (ICS) therapies (e.g. LABA/ICS, LAMA/LABA/ICS)

Short courses of oral corticosteroids and/or antibiotics (including macrolides) 
are permitted for the acute treatment of exacerbations of COPD and should not 
exceed 21 days.  This use must be recorded as an HCRU exacerbation event.  
The following medications are prohibited from the screening visit until after completion 
of the follow up visit:

Chronic use of macrolide antibiotics for the prevention of COPD exacerbations.  
Examples of chronic use include daily or two-three times per week for at least 3 
months.

Oral or injectable CYP3A4 or BCRP substrates with narrow therapeutic index 
(CYP3A4 substrates include, but are not limited to, alfentanil, cyclosporine, 
dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, 
tacrolimus, and theophylline; BCRP substrates include, but are not limited to, 
topotecan.

Phosphodiesterase-4 inhibitors (e.g. roflumilast)

Broad spectrum phosphodiesterase inhibitors (e.g. theophylline)


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GSK will not supply rescue medication.  Participants may continue to use and should 
obtain rescue medication(s) through via their usual route. The following rescue 
medications may be used:

Short acting beta agonists (SABA)(e.g., albuterol/salbutamol)

Short acting muscarinic antagonists (SAMA)(e.g., ipratropium)

Short acting combination (SABA/SAMA) bronchodilations, (e.g. Duoneb, 
Combivent)
The use of rescue medications is allowable at any time during the study. Participants 
should record in the daily e-diary the number of puffs of rescue medication(s) over each 
24 hour period. Data from the MDI sensor device will be electronically captured and 
transmitted to GSK.
Annual influenza vaccine is recommended for patients with COPD but is not required for 
participation in this study.  Influenza vaccination is permitted during the study and should 
be based on applicable local or national guidelines.  Pneumococcal vaccine may also be 
administered, when indicated, based on applicable local or national guidelines.  
Additional vaccinations may be administered when indicated.  Any vaccination 
administered during the study should be recorded as a concomitant therapy.
7.8.
Treatment after the End of the Study
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the participant.
GSK will not provide post-study treatment.  There are no plans to provide the study 
treatment for compassionate use following study completion.
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
8.1.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to assure 
participant safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). These protocol guidelines are in alignment 
with FDA premarketing clinical liver safety guidance [FDA, 2009].
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 
below or if the investigator believes that it is in the best interest of the participant. 


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Liver Safety Required Actions and Follow up Assessments Section can be found in
Appendix 7. 
8.1.2.
QTc Stopping Criteria

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.

For example, if a participant is eligible for the protocol based on 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.  Safety ECGs and other non-protocol specified 
ECGs are an exception.  

The QTc should be based on single or averaged QTc values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording period. 
A participant who meets either bulleted criteria based on the average of triplicate ECG 
readings will be withdrawn from study treatment:

QTc > 500 msec OR Uncorrected QT > 600 msec

Change from baseline of QTc > 60 msec


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For patients with underlying bundle branch block, follow the discontinuation criteria 
listed below:
Baseline QTc with Bundle Branch Block
Discontinuation QTc with Bundle 
Branch Block
< 450 msec
> 500 msec
450 – 480 msec
≥ 530 msec
See the SoA (Table 1) for data to be collected at the time of treatment discontinuation and 
follow-up and for any further evaluations that need to be completed.
8.1.3.
Neutrophil Stopping Criteria
A participant with a peripheral blood neutrophil count 0.5 x 109/L that is confirmed on 
repeat testing will be instructed to suspend dosing.  The neutrophil count should be 
monitored daily until it returns to within the baseline value, as detailed in Appendix 9.
8.1.4.
Temporary Discontinuation
Temporary discontinuation of study treatment is allowed for up to 14 days when 
medically necessary, e.g. for hospitalization for a COPD exacerbation, other medical 
condition requiring hospitalization, or reduction in peripheral blood neutrophil counts  
0.5 x 109/L.  Temporary discontinuation for any other reason should be discussed with 
the GSK Medical Monitor.
8.1.5.
Study Treatment Restart
Study treatment restart after liver chemistry stopping criteria are met by any participant in
this study is not allowed. Refer to Appendix 7 for full guidance for required actions and 
follow-up assessments to undertake if liver stopping criteria are met. 
Study treatment restart after neutrophil stopping criteria are met can be considered once 
the neutrophil count has returned to within baseline and provided that no more than 14 
days have elapsed since study medication was halted. The Investigator must obtain 
approval from the GSK Medical Monitor prior to restarting study treatment.  See 
Appendix 9 for the procedure to be followed for study treatment restart after neutrophil 
stopping criteria are met.
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, 
behavioural, compliance or administrative reasons.


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
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.

Refer to the SoA for data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed.
8.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the 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 (Table 1). 

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. 

Procedures conducted as part of the participant’s routine clinical management 
(e.g., blood count) and obtained before signing of ICF may be utilized for 


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screening or baseline purposes provided the procedure met the protocol-
specified criteria and was performed within the time frame defined in the SoA.

The maximum amount of blood collected from each participant over the 
duration of the study, including any extra assessments that may be required, will 
not exceed 500 mL.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.
9.1.
Efficacy Assessments
9.1.1.
EXACT and E-RS:COPD
The Exacerbations of Chronic Pulmonary Disease Tool (EXACT) is a 14 item patient 
reported outcome instrument designed to capture information on the occurrence, 
frequency, severity, and duration of exacerbations of disease in patients with COPD
[Jones, 2011; Leidy, 2010; Leidy, 2011].  EXACT captures information on the severity of 
the respiratory and systemic manifestations of a COPD exacerbation as reported by the 
patient.  The instrument is to be completed daily (typically at bedtime) using an 
electronic diary.  The daily recording of information allows an assessment of underlying 
day to day variability of a patient’s symptoms and facilitates the detection of symptom 
worsening indicative of a COPD exacerbation.  The total score for EXACT ranges from 0 
– 100, higher scores indicate more severe symptoms.  The entire instrument is intended to 
be completed in about 3 minutes or less (typically the time required for completion 
decreases as the patient becomes more familiar with the tool and the electronic diary).
The Evaluating Respiratory Symptoms in COPD (E-RS:COPD) tool consists of 11 items 
from the 14 item EXACT instrument [Leidy, 2014a; Leidy, 2014b]. E-RS:COPD is 
intended to capture information related to the respiratory symptoms of COPD, i.e. 
breathlessness, cough & sputum production, chest tightness and chest congestion.  E-
RS:COPD has a scoring range of 0 – 40, higher scores indicate more severe symptoms.  
Three subscales of E-RS are used to describe different symptoms, dyspnea, cough and 
sputum, and chest symptoms.  
E-RS: COPD has recently been recognized as a drug development tool by FDA and EMA
[EMA, 2015; FDA, 2016].
9.1.2.
COPD Exacerbations
An exacerbation of COPD is defined by a worsening of symptoms. 
The following are symptoms used to determine an exacerbation of COPD:
Worsening of two or more of the following major symptoms for at least two consecutive 
days:

Dyspnea

Spontaneous sputum volume


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
Sputum purulence
OR
Worsening of any one of the above major symptoms together with any one of the 
following minor symptoms for at least two consecutive days:

Sore throat

Cold (nasal discharge and/or nasal congestion)

Fever (oral temperature > 37.5 oC) 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 as soon as possible 
and report to the study clinic as required

If the participant is unable to contact their study investigator or research 
coordinator, they should contact their primary care provider (or other health care 
provider) and contact their study site as soon as possible

Continue to record their symptoms and rescue medication use in their daily 
ediary

If the participant seeks emergency/acute care for worsening respiratory 
symptoms he/she should request the caring health care provider to contact the 
study investigator or research coordinator as soon as possible

COPD exacerbations will be classified according to severity as follows:

A COPD exacerbation is defined as a mild exacerbation if it is self-managed by 
the participant.  Mild exacerbations are not associated with the use of antibiotics 
and/or systemic corticosteroids

A COPD exacerbation is defined as a moderate exacerbation if it requires a new 
prescription for antibiotics and/or systemic corticosteroids

A COPD exacerbation is defined as a severe exacerbation if it requires 
hospitalization, an emergency room visit, or extended observation in an 
outpatient centre
Details of an exacerbation should be recorded in the exacerbation page of the eCRF.  
Exacerbations will not be reported according to the standard process for expedited 
reporting of SAEs to GSK (even though the event may meet the definition of an SAE) as 
they are considered Disease Related Events (DREs).  Only when the event is, in the 
Investigator’s opinion, of greater intensity, or duration than expected for the individual 
participant, or the Investigator considers that there is a reasonable possibility that the 
event is related to study treatment should it be reported as an SAE (See Section 9.2).  


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(Pneumonia must be recorded in the AE or SAE section of the eCRF and on the 
pneumonia page of the eCRF (See Section 9.4.5)).
All medications used for the treatment of exacerbations must be recorded in the source 
documents and the exacerbation page of the eCRF.  If necessary the PI or other health 
care personnel may stop the participant’s study treatment temporarily in order to treat the 
COPD exacerbation.  The reason for temporarily stopping study treatment and duration 
should be recorded in the eCRF.
The date of onset and the date of resolution will be recorded in the source documents and 
the eCRF.

The date of onset is the first day (of at least 2 consecutive days) or worsening 
symptoms described above.

The date of resolution should be based on when the Investigator or participant 
determines that the COPD symptoms have returned to near pre-exacerbation 
levels or to a new baseline.
9.1.3.
SGRQ-C
The St. George’s Respiratory Questionnaire-Chronic Obstructive Pulmonary Disease 
specific tool (SGRQ-C) is a disease-specific questionnaire designed to measure the 
impact of respiratory disease and its treatment on a COPD patient’s HRQoL [Meguro, 
2007].  As well as producing an overall summary score, scores for the individual domains 
of symptoms, activity and impacts are also produced.  The SGRQ-C has been used in 
numerous previous studies of COPD participants and has been translated and validated 
for use in most major languages.  The SGRQ-C is derived from the original SGRQ and 
produces scores equivalent to the original SGRQ instrument [Jones, 1992].
9.1.4.
CAT
The COPD Assessment Test is a 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 [Jones, 2009; Jones, 2012].  When completing the 
questionnaire, participants rate their experience on a 6-point scale, ranging from 0 
(maximum impairment) to 5 (no impairment) with a scoring range of 0-40. Higher scores 
indicate greater disease impact.
The CAT consists of 8 items (cough, sputum, chest tightness, breathlessness, going up 
hills/stairs, activity limitation at home, confidence leaving the home, and sleep and 
energy).  Individual items are scored from 0 to 5 with a total score range from 0 – 40, 
higher scores indicate worse health status.
9.1.5.
PROactive
The PROactive tools, developed under the EU Innovative Medicines Initiative, measure 
patient experience of Physical Activity in COPD. The tools consist of a patient reported 
questionnaire combined with output from an activity monitor [Dobbels, 2014; Gimeno-


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Santos, 2015; Williams, 2012; Rabinovich, 2013; Gimeno-Santos, 2011]. The Clinical 
Visit PROactive Physical Activity in COPD (C-PPAC) tool is a designed for intermittent 
use within a clinical study. The 12 item questionnaire has a seven day recall period and 
participant responses are combined with two activity monitor data outputs covering the 
same period. The PROactive tools are scored from 0 to 100 with higher scores indicating 
greater disease impact, two subscales of amount and difficulty can be used to support the 
total score. 
The C-PPAC tool will be implemented in a subset of approx. 50% of participants.  
Participants will be randomly selected from each study site participating in the physical 
activity subgroup.
9.1.6.
Patient Global Rating of Severity and Global Rating of Change in 
Disease Severity
Participants will complete the Global Rating of COPD Severity at randomisation and at 
final study visit or IP Discontinuation Visit.  This single global question will ask subjects 
to rate their severity of COPD on a four point scale (mild, moderate, severe, very severe). 
Participants will complete a Global Rating of Change in COPD (overall disease) question 
at all Visits subsequent to randomisation including the final Visit (or Early Withdrawal
(EW) Visit). Response options will be on a 7 point Likert scale ranging from much better 
to much worse. Asking at each Visit allows for early detection of response as well as 
continued response.
9.1.7.
Patient Global Rating of Activity Limitation and Global 
Impression of Change in Activity Limitation
Subjects will complete the Global Rating of Activity Limitation at randomisation and at 
final visit or EW Visit. This single global question will ask subjects to rate their activity
limitation on a four-point scale (not limited, slightly limited, limited, very limited).
Subjects will complete a Global Impression of Change in Activity Limitation question at 
all Visits subsequent to randomisation including the final Visit (or EW Visit). Response 
options will be on a 7 point Likert scale ranging from much better to much worse.
9.1.8.
Exit Interview
An exit interview will be administered by trained study staff at visit 10 or the EW Visit.  
The questions included in the exit interview are designed to more fully understand the 
participant’s experience with the study medication and the study itself.  Study staff will 
be provided with a semi-structured interview guide and data collection sheet and trained 
on interview administrative techniques.  Responses will be audio-recorded for purposes 
of accurate transcription and analysis. Site training, and transcription and analysis of the 
exit interview data will be conducted by a specialist research organisation. Full guidance 
on implementing the exit interview, including guidance on interview organisation, the 
semi-structured interview script, guidance on conducting the interview and the use of 
interview probes will be included in the SRM.


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A representative subset of participants (approx. 15 – 20% of all participants) will be 
selected to participate in the exit interview. The total number of interviews conducted 
will be driven by analysis of blinded transcripts. This analysis will be conducted in 
batches during the course of the study and interviews will only continue until saturation is 
confirmed.  
9.1.9.
Clinically Important Deterioration (CID)
A clinically important deterioration is a composite endpoint defined as at least one of the 
following events: (1) a decrease of 100 mL from baseline in trough FEV1, (2) a
deterioration in health-related quality of life defined as a 4-unit increase from baseline 
in SGRQ total score, or (3) the occurrence of an on-treatment moderate or severe COPD 
exacerbation [Singh, 2016].
9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4.
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 (see Section 8). 
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from Visit 0 (i.e. from the time the informed consent 
is signed by the participant) until the follow up visit at the time points specified 
in the SoA (Section 2).

All AEs will be collected from the start of Visit 3 (study treatment 
randomization visit) until the follow-up visit 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 case report form (CRF) not the AE section.

All SAEs will be recorded and reported to the sponsor or designee within 24 
hours, as indicated in Appendix 4. The investigator will submit any updated 
SAE data to the sponsor within 24 hours of it being available.

Investigators are not obligated to actively seek 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.

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 4.


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9.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the participant is the preferred method to inquire 
about AE occurrence. 
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 4.
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 e.g., 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 4 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will 
be required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.


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9.2.6.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
The following disease related events (DREs) are common in participants with COPD and 
can be serious/life threatening:

COPD exacerbations
Because these events are typically associated with the disease under study, they will not 
be reported according to the standard process for expedited reporting of SAEs to GSK 
(even though the event may meet the definition of an SAE).  These events will be 
recorded on the DRE page in the participant’s CRF within 72 hours after the investigator 
becomes aware of the event.  These DREs will be monitored by the Safety Review Team 
(SRT) on a routine basis as described in Appendix 3.  
NOTE: However, if either of the following conditions applies, then the event must be 
recorded and reported as an SAE (instead of a DRE): 

The event is, in the investigator’s opinion, of greater intensity, frequency, or 
duration than expected for the individual participant, or

The investigator considers that there is a reasonable possibility that the event 
was related to treatment with the investigational product
9.2.7.
Pregnancy

Details of all pregnancies in female participants and female partners of male 
participants will be collected after the start of study treatment and until 60 hours after 
the last dose of study treatment.

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 5

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
9.2.8.
Medical Device Incidents (Including Malfunctions)
Medical devices are being provided for use in this study for the purposes of monitoring 
inhaled rescue medication use and for evaluating physical activity. In order to fulfill 
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 8.
NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Section 9.2 and Appendix 4. 


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9.2.8.1.
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 8.
9.2.8.2.
Follow-up of Medical Device Incidents

All medical device incidents involving an AE will be followed and reported in 
the same manner as other AEs (see Section 9.2). This applies to all participants, 
including those who discontinue study treatment or the study.

The investigator is responsible for ensuring that follow-up includes any 
supplemental investigations as indicated to elucidate the nature and/or causality 
of the incident.

New or updated information will be recorded on the originally completed form 
with all changes signed and dated by the investigator.
9.2.8.3.
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.

Complete the Medical Device Incident Form for each participant who has a 
medical device incident with GSK medical devices provided for use during the 
study period.  All of the header information in the form must be completed 
before sending to GSK.  Original documents should be filed in the site study 
file.  A copy of the form must also be sent to the GKS study monitor.  Contact 
details will be included in the SRM.  A copy of the form must also be sent to the 
GSK study monitor.  Contact details will be included in the SRM.  For incidents 
fulfilling the definition of an AE or SAE, the appropriate pages of the CRF must 
be completed.  If there is an SAE, the completed CRF pages should be sent 
together with the Medical Device Incident From.  If the participant is withdrawn 
due to a medial device incident, ensure the Study Conclusion page is completed.

The same individual will be the contact for the receipt of medical device reports 
and SAEs.
9.2.8.4.
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 fulfill the legal 
responsibility to notify appropriate regulatory authorities and other entities about 


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certain safety information relating to medical devices being used in clinical 
studies.

The investigator, or responsible person according to local requirements (e.g., the 
head of the medical institution), will comply with the applicable local regulatory 
requirements relating to the reporting of incidents to the IRB/IEC.


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9.3.
Treatment of Overdose
For this study, any dose of study treatment 4 tablets in a day will be considered an 
overdose.
GSK does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator/treating physician should:
1. Contact the Medical Monitor immediately.
2. Closely monitor the participant for AE/SAE and laboratory abnormalities until study 
treatment can no longer be detected systemically (at least 3 days).
3. Obtain a plasma sample for PK analysis as soon as possible from the date of the last 
dose of study treatment if requested by the Medical Monitor (determined on a case-
by-case basis).
4. Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.
9.4.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Table 1).
9.4.1.
Physical Examinations

A complete physical examination will include, at a minimum, assessments of the
skin, cardiovascular, respiratory, gastrointestinal and neurological systems. 
Height and weight will also be measured and recorded.

A brief physical examination will include, at a minimum, assessments of the 
skin, lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
9.4.2.
Vital Signs

Vital signs will be measured in a semi-supine position after 5 minutes rest and 
will include systolic and diastolic blood pressure, pulse, temperature and 
respiratory rate. Three readings of blood pressure and pulse will be taken. The 
first reading should be rejected. The second and third readings should be 
averaged to give the measurement to be recorded in the CRF. A single 
measurement of respiratory rate and oral temperature is adequate.


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9.4.3.
Electrocardiograms

For participant screening and pre-dose on Day 1, triplicate ECG measurements 
should be collected.  For all subsequent ECG assessments, single measurement 
are to be collected. 12-lead ECG will be obtained as outlined in the SoA using 
an ECG machine that automatically calculates the heart rate and measures PR, 
QRS, QT, and QTc intervals. Refer to Section 8.1.2 for QTc withdrawal criteria 
and additional QTc readings that may be necessary.

At each time point at which triplicate ECG are required, 3 individual ECG 
tracings should be obtained as closely as possible in succession, but no more 
than 2 minutes apart. The full set of triplicates should be completed in less than 
5 minutes.
9.4.4.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 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 CRF. 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 abnormal and clinically significant 
during participation in the study or within 3 days after the last dose of study 
treatment should be repeated until the values return to normal or baseline or are 
no longer considered significantly abnormal by the investigator or medical 
monitor. 

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA (Table 1).

If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in participant 
management or are considered clinically significant by the investigator (e.g., 
SAE or AE), then the results must be recorded in the CRF.


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9.4.5.
Pneumonia
All suspected pneumonias will require confirmation as defined by the presence or 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.)

Dyspnea or tachypnea

Fever (oral temperature > 37.5 oC)

Elevated white blood cell count (WBC) (> 10 x 109/L or > 15% immature 
forms)

Hypoxemia (Hb O2 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 Investigator and site staff should remain vigilant for the possible development of 
pneumonia in participants as the clinical features of such infections overlap with the 
symptoms of COPD exacerbations.  For all suspected cases of pneumonia, Investigators 
are strongly encouraged to confirm the diagnosis (this includes obtaining a chest x-ray) 
and to initiate appropriate therapy as promptly as possible.  Any microbiology or virology 
tests performed to determine etiology should be reported on the pneumonia eCRF page.  
All diagnoses of pneumonia (radiographically confirmed or unconfirmed) must be 
reported as an AE or SAE (if applicable).
9.5.
Pharmacokinetics

Whole blood samples of approximately 2 mL will be collected for measurement 
of whole blood concentrations of danirixin (performed under the control of GSK 
Platform Technology and Science Department of In Vitro In Vivo Translation 
Third Party Resourcing (PTS-IVIVT/TPR)) as specified in the SoA (Table 1).  
Instructions for the collection, processing, storage and shipping of biological 
samples will be provided by the sponsor in the SRM. The actual date and time 
(24-hour clock time) of each sample will be recorded.

Samples will be used to evaluate the PK of danirixin. Each whole blood sample 
will be used to prepare 4 dried blood spots which will be analysed for danirixin 
concentrations and reported as primary data. The remaining whole blood will be 
retained and approximately 20% of the wet whole blood samples collected in 
Visit 3 will also be analysed for danirixin concentrations to provide an analytical 
comparison between dried blood spots and wet whole blood sample results. 
Samples collected for analyses of danirixin whole blood may also be used to 
evaluate safety or efficacy aspects related to concerns arising during or after the 
study.


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
Any remaining whole blood will be stored and may be analyzed for other 
compound-related metabolites and the results reported under a separate protocol.
Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.
9.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
9.7.
Genetics
A 6 mL whole blood sample for DNA isolation will be collected from participants who 
have consented to participate in the genetics analysis component of the study. 
Participation in the genetics analysis is optional. Participants who do not wish to 
participate in the genetic research may still participate in the study.
See Appendix 6 for Information regarding genetic research. Details on procedures for 
collection and shipment and destruction of these samples can be found in the SRM.
9.8.
Biomarkers

Collection of samples for biomarker research is also part of this study. The 
following samples for biomarker research will be collected from all participants 
in this study as specified in the SoA:
‒
peripheral venous blood samples for the preparation of serum and 
plasma

Samples will be tested for biomarkers that are indicative of inflammation (i.e. 
CRP and fibrinogen), extracellular matrix turnover and remodelling to evaluate 
their association with the observed clinical responses or to help understand the 
underlying biological responses to danirixin.

In addition, with the participant’s consent, samples will be stored and may be 
used to investigate additional biomarkers thought to play a role in COPD disease 
progression or to evaluate their association with observed clinical responses to 
danirixin

Samples also may be used for research to develop methods or support 
identification of prognostic/diagnostic biomarkers associated with clinical 
outcomes in COPD and related diseases.
9.9.
Health Economics OR Medical Resource Utilization and 
Health Economics
Parameters for specific use in Health Economics analysis or Medical Resource 
Utilization and Health Economics are not evaluated in this study.


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10.
STATISTICAL CONSIDERATIONS
10.1.
Hypothesis
The primary efficacy endpoint is the change from baseline of E-RS:COPD total score at 
month 6.  The primary objective of the study is to study the dose response and select an 
appropriate dose for future drug development programs.
A model based probability inference approach in Bayesian framework will be used to 
guide decision-making around dose selection. The posterior probability of the change 
from baseline of E-RS:COPD for each active dose being less than placebo will be used.
10.2.
Sample Size Determination
In order to evaluate the impact of different sample sizes, various simulations were 
undertaken to understand the following questions around the change in baseline of E-
RS:COPD scores at 6 months:

What is the 90% confidence interval half width for the estimate of the treatment 
effect of the 5 mg, 25 mg, 35 mg, and 50 mg doses?

What is the probability that the point estimate of difference from placebo is less 
than -1.5 for the 5 mg, 25mg, 35mg and 50 mg doses?

What is the probability that the two-sided 90% confidence interval of the 
treatment effect excludes 0 for 5 mg, 25 mg, 35 mg and 50 mg doses?  

What is the probability that the two-sided 90% confidence interval of the 
treatment effect difference from placebo excludes 0 for 5 mg, 25 mg, 35 mg and 
50 mg doses?  
There are 3 scenarios considered for the simulations, each based on different assumptions 
of the effect for each of the 6 treatment arms.  No model assumptions were made to 
generate these values.  The scenarios are found in Table 4 and Figure 2. The assumed 
between participant standard deviation is 6.5 which is based on interim data from the 
200163 study.  For each scenario, 10,000 iterations of simulations were run.


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Table 4
Assumptions Used for Sample Size Calculations
Scenario 1
Scenario 2
Scenario 3
Placebo
0
0
0
5 mg
-0.5
-0.333
-0.5
10 mg
-1
-0.667
-0.75
25 mg
-2
-1.333
-2
35 mg
-2.5
-1.667
-2
50 mg
-3
-2
-2
Figure 2
Simulation scenarios with best fit sigmoidal Emax model


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The Emax model will be used for the primary analysis and was the basis for estimation of 
the simulated data.  The more general 4 parameter version of this model is defined as:
y(dose) = E0 + Emax [ dosem / (ED50
m + dosem) ]
where y( ) represents the E-RS:COPD change from baseline, E0 is the mean response at 
dose = 0, Emax is the maximum dose effect (at dose = ), ED50 is the dose that yields a 
mean response of E0 + Emax / 2, and m is the slope parameter allowing for sigmoidal dose 
response relationships.
Results of the sample size simulations are presented in Figure 3, Figure 4, Figure 5 and 
Figure 6,with the lowest danirixin dose (5 mg) and the 3 highest doses (25 mg, 35 mg, 50
mg).
Figure 3
Half width of the 90% confidence interval for the 5 mg, 25 mg, 35 mg 
and 50 mg doses


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Figure 4
Proportion of simulations in which the point estimate of difference 
from placebo is less than -1.5 for doses of 5 mg, 25 mg, 35 mg and 
50 mg
Figure 5
Proportion of simulations in which the 90% confidence interval 
exclused 0 for doses of 5 mg, 25 mg, 35 mg and 50 mg


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Figure 6
Proportion of simulations in which the 90% confidence interval of 
difference from placebo excludes 0 for doses of 5 mg, 25 mg, 35 mg 
and 50 mg
Based on the simulations a sample size of at least n = 600 will allow for adequate 
precision in estimation of the 35 mg dose as well as sufficient proportion with 90% 
confidence interval difference from placebo excluding 0 (over 80% for the 35 mg dose 
under all scenarios) and proportion with 90% confidence interval of dose estimate 
excluding 0 (over 80% for all higher doses and scenarios except 25 mg under scenario 2).
10.2.1.
Sample Size Re-estimation
At the time of the interim analysis for futility, sample size re-estimation may be 
considered by the study team if the assumptions driving the sample size calculations are 
shown to be incorrect (e.g., variability is higher than expected).  No more than 100 
additional participants will be considered.
10.3.
Randomization
Participants will be randomized equally (1:1:1:1:1:1) to the six treatment arms of 
placebo, 5 mg, 10 mg, 25 mg, 35 mg and 50 mg danirixin.  Randomization will be 
stratified by smoking status (current vs. former).
10.4.
Populations for Analyses
For purposes of analysis, the following populations are defined:


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Population
Description
All Participants
This population will comprise all participants screened and 
for whom a record exists on the study database and will be 
used for the tabulation and listing of reasons for withdrawal 
before randomization and listings of AEs and SAEs for 
nonrandomized participants.
Intent To Treat (ITT)
This population will comprise all participants randomized to 
treatment and who received at least one dose of study 
medication. This will constitute the primary population for all 
analyses of efficacy and safety. Outcomes will be reported 
according to the randomized treatment allocation.
PK
This population will comprise all participants in the ITT 
population for whom a pharmacokinetic sample was obtained 
and analyzed.
Safety
All randomized participants who take at least 1 dose of study 
treatment. Participants will be analyzed according to the 
treatment they actually received.
10.5.
Statistical Analyses
Analysis methods for key endpoints are described below.  Unless otherwise stated, all 
statistical testing will be two-sided and all confidence intervals or Bayesian credible 
intervals will be 90% two-sided.
Further details on all analyses will be described in the reporting and analysis plan (RAP).
10.5.1.
Efficacy Analyses
10.5.1.1.
Primary Analysis
The primary endpoint is 6 month change from baseline using the ITT population.
Baseline values of E-RS:COPD will be defined as the daily average of scores for the 7 
days prior to randomization.  Days with missing values will not count towards the 
average.  A minimum of 4 days will be needed and participants without sufficient days 
will not be randomized.
Individual monthly E-RS:COPD means will be defined as the average E-RS:COPD
scores during the following study days:

Month 1: days 1-28

Month 2: days 29-56

Month 3: days 57-84


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
Month 4: days 85-112

Month 5: days 113-140

Month 6: days 141-168
Days with missing values will not factor into the calculations.  Participants will require a 
minimum number of 10 observations within a month, otherwise the monthly mean will be 
considered missing for that patient. 
The primary analysis will be Emax (4 parameter) modeling of the dose-response curve 
for the primary efficacy endpoint of month 6 change from baseline.  Smoking status will 
be included as a covariate in this model, allowing the asymptote values of the dose-
response relation for smokers to differ from those of the non-smokers. This model 
formulation will require estimation of at most six parameters. Simpler models nested 
within this general formulation will be also considered, comprising formulations of the 
mean dose-response relation allowing for a fixed difference between smokers and non-
smokers (parallel curves model), no difference between smokers and non-smokers and 
the Emax model restriction m=1. Model fitness will be measured using standard 
goodness of fit analysis. This analysis will allow for an assessment of the extent to which 
the variability of the trial data will be captured using the proposed model and what dose-
response specification allows the best interpretation of the data.    
The dose-response model will be fitted to the data using Bayesian techniques using the 
function uniform prior (FUP). The rationale for this choice of inference is that the FUP 
shrinks the dose-response towards a flat line throughout the dose range, therefore 
providing more conservative estimates of the dose-response relation compared to 
maximum likelihood.
Standard Bayesian diagnostic plots will be produced to aid in the interpretation of results. 
Based on the selected model, 90% two sided Bayesian credible interval for all treatment 
arms, all pairwise differences between each danirixin dose and placebo, as well as 
between active danirixin doses, will be generated.  
Other models of dose response such as quadratic and log linear will be considered as 
alternative analysis option if the Emax model does not fit the data well.  Similar analysis 
with the final model using the endpoint includes months 1-6 and months 3-6 will be fit.  
A longitudinal mixed effects model will be also be fit with dose as a categorical variable 
to explore the time trend of E-RS:COPD.  Each of the three E-RS:COPD subscales
(breathlessness, cough and sputum, and chest symptoms) will be analysed using similar 
methods for the primary analysis and longitudinal analysis.  Details of these sensitivity 
analyses will be further described in the RAP.
10.5.1.2.
Key Secondary Analyses
All analyses for other efficacy endpoints will use the ITT Population, unless otherwise 
noted. Dose will be treated as a categorical variable and no dose response modelling will 
be done unless otherwise stated.  The treatment comparisons of interest will be between 
individual danirixin doses and placebo and between different danirixin doses.  Smoking 


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status (current vs former) will be included as a covariate in all analyses.  All Bayesian 
analyses will use non-informative priors.  Further details will be described in the RAP. 
10.5.1.3.
HCRU Exacerbations
The number of events associated with HCRU-defined exacerbations will be analyzed 
using generalised linear models assuming a negative binomial distribution for the 
underlying exacerbation rate with a log link and an offset to account for the length of 
time in study for each participant. The exacerbation rates for the danirixin and placebo 
groups, along with the ratio in exacerbation rates danirixin/placebo, will be estimated and 
corresponding 95% credible intervals will be produced. 
10.5.1.4.
Time to First HCRU Exacerbation
Time to first HCRU exacerbation will be defined from the date of randomization.  
Participants without an exacerbation and participants who withdraw from the study prior 
to any observed exacerbations will be censored at the time of last contact.  Survival will 
be summarized by treatment groups through Kaplan-Meier curves.  Treatment arms will 
be compared using a stratified log-rank test.  Time to first severe HCRU exacerbation 
will be analysed in a similar manner.
10.5.2.
Safety Analyses
All safety endpoints will be tabulated or plotted by treatment group and will be 
performed on the Safety Population. Further details will be described in the RAP.
10.5.3.
PK and PK/PD Analyses
Pharmacokinetic data will be presented in graphical and/or tabular form and will be 
summarized descriptively. For participants in the PK subset non-compartmental PK 
parameters (e.g. AUC(0-12), Cmax and tmax) will be calculated as data permit. The 
pharmacokinetic data from this study may be combined with historic DNX 
pharmacokinetic data for the purposes of population pharmacokinetic modelling which 
may be reported separately from the main clinical study report. The goal of this analysis 
is to characterize the population pharmacokinetics of DNX administered orally in 
subjects with COPD. The influence of subject demographics, baseline characteristics, 
including disease activity, and co-medication on the pharmacokinetics of DNX in this 
population will be investigated. DNX blood concentration-time data will be subjected to 
nonlinear mixed effects modelling using the program NONMEM to develop a population 
PK model [FDA, 1999].  Further details will be described in the RAP.
Exploratory analysis using scatter plots will be conducted to investigate the relationship 
between blood exposure to danirixin (PK) and efficacy/PD/safety endpoints as data 
permit. If appropriate PK/PD modelling will be attempted to describe any relationship 
including longitudinal efficacy, PD, and/or safety variables versus systemic exposure (or 
dose) and may be combined with historic data. The results of any PK/PD modelling may
be reported separately from the main clinical study report. Further details will be 
described in the RAP.


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10.5.4.
Interim Analyses
10.5.4.1.
Interim PK Analysis
After approximately 10 participants in the PK subset for each treatment group have 
completed Visit 3, an interim evaluation of danirixin pharmacokinetic parameters will be 
undertaken.  The purpose of the interim PK analysis is to determine if danirixin 
exposures are within the expected range.
10.5.4.2.
Futility Analysis
An interim analysis will be conducted to allow for the possibility of stopping early for 
futility.  The expected pace of recruitment will be 12 months.  Therefore, by the time a 
sufficient number of participants have been recruited and have accrued 6 months of data, 
a futility analysis will not be practical.  We will therefore consider futility analyses based 
on the 3 month data using the assumption that the response will be consistent from month 
3 onwards.  Under this assumption, which is consistent with the Phase IIa study, this is a 
valid futility approach.
Once approximately 150 participants have completed 3 months of treatment, the 3 
paramter Emax model will be fit to the change from baseline of E-RS:COPD. If the 
posterior predictive probability of difference from placebo being less than 0 is below 
30% for all danirixin doses, the study may be stopped for futility.
Based on simulated data, the expected number of participants with completed 6 month 
data at the time of this analysis will be too small to warrant any analysis (expected 
number < 10).  However, if the recruitment differs greatly from expectations, and enough 
participants have completed 6 months of treatment, the 6 month change from baseline 
endpoint may also be explored.  
No early stopping for efficacy will be considered and only outputs relating to the primary 
endpoint of E-RS:COPD change from baseline will be created.  Outputs featuring 
unblinded treatment assignments will be created for this interim analysis but will not be 
shared outside of the study team unless the decision is made to halt the study for futility.
10.5.4.3.
Strategic Planning Analysis
When 450 participants have completed 6 months of treatment or prematurely withdrawn 
from treatment, the study will have an interim analysis for administrative purposes.  This 
analysis will be used to aid in the planning of future studies and for a better
understanding of benefit/risk profile of danirixin.  This interim analysis will look at the 
primary endpoint of E-RS: COPD dose response modelling, key secondary endpoints of 
HCRU exacerbations and SGRQ score, key safety endpoints around hepatotoxicity, 
neutrophils, pneumonia and other infections and PK data.  No changes will be made to 
this study based on the results of this interim analysis.  Outputs featuring unblinded 
treatment assignments will be created for this interim analysis, reviewed by the study 
team and potentially shared with selective GSK personnel (to be included in the data 
dissemination plan).


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Further details of the outputs including key safety outputs that will be produced will be 
described in the RAP. 


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Obstruct Pulmon Dis. 2016;11:1413-1424. 
Vastava S, Thakur D, Sharma S, Punekar YS. Systematic review of humanistic and 
economic burden of symptomatic chronic obstructive pulmonary disease. Pharmacoecon. 
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Vestbo J, Leather D, Diar Bakerly N, New J, Gibson JM, McCorkindate S, et al. 
Effectiveness of fluticasone furoate-vilanterol for COPD in clinical practice. N Engl J 
Med. 2016;375:1253-1260. 
Watz H, Kirsten A, Pedersen F, Goldmann T, Stellmacher F, Uddin M, et al. Neutrophils 
in bronchial mucosa, sputum and blood after administration of the CXCR2-antagonist 
AZD5069 - an explorative study in neutrophilic asthma. Eur Respir J. 
2016;48(S60):PA4892. 
Williams K, Frei A, Vetsch A, Dobbels F, Puhan MA, Rudell K. Patient-reported 
physical activity questionnaires: a systematic review of content and format. Health Qual 
Life Outcomes. 2012;10:28-45. 
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significance of symptoms in smokers with preserved pulmonary function. N Engl J Med. 
2016;374:1811-1821. 


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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
List of Abbreviations
AE
Adverse Event
ALT
Alanine Aminotransferase (SGPT)
AST
Aspartate Aminotransferase (SGOT)
ATS
American Thoracic Society
AUC
Area under the concentration-time curve
BfS
Federal Office of Radiation Protection (Germany)
BID
Twice daily
BRCP
Breast cancer resistance protein
BUN
Blood urea nitrogen
CAT
COPD Assessment Test
CD
Cluster of differentiation
CFR
Code of Federal Regulations (United States)
CI
Confidence Interval
CID
Clinically important deterioration
CIL
Clinical Investigation Leader
Cmax
Maximum observed concentration
CONSORT
Consolidated standards of reporting trials
COPD
Chronic Obstructive Pulmonary Disease
CPMS
Clinical Pharmacokinetics Modelling and Simulation
C-PPAC
Clinic Visit PROactive Physical Activity in COPD
Tool
CRF
Case Report Form
CT
Computed Tomography
CV
Cardiovascular
CXCR
CXC Chemokine Receptor
CXR
Chest X-Ray
dL
Deciliter
DNA
Deoxyribonucleic acid
DNX
Danirixin
DRE
Disease Related Event
E0
Effect at zero concentration
ECG
Electrocardiogram


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eCRF
Electronic Case Report Form
ED50
Dose causing 50% of the maximum achievable 
response
EMA
European Medicines Agency
Emax
Maximum response achievable
eMDI
Electronic metered dose inhaler
EXACT-PRO
Exacerbations of Chronic Pulmonary Disease-Patient 
Reported Outcome
E-RS:COPD
Evaluting Respiratory Symptoms in Chronic 
Obstructive Pulmonary Disease
EW
Early Withdrawal
FDA
Food and Drug Administation (United States)
FEV1
Forced Expiratory Volume in one second
FVC
Forced Vital Capacity
FSH
Follicle Stimulation Hormone
FUP
Function Uniform Prior
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GGT
Gamma glutamyltransferase
GOLD
Global Initiative for Chronic Obstructive Lung 
Disease
GSK
GlaxoSmithKline
HBsAG
Hepatitis B surface antigen
HCRU
Healthcare Resource Utilization
hCG
Human chorionic gonadotrophin
HDPE
High density polyethylene
Hep B
Hepatitis B
Hep C
Hepatitis C
hsCRP
High sensitivity C-reactive protein
HIV
Human immunodeficiency virus
HPLC
High performance liquid chromatography
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization of 
Technical Requirements for Registration of 
Pharmaceuticals for Human Use
ICS
Inhaled corticosteroid
IDMC
Independent Data Monitoring Committee


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IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IgM
Immunoglobulin M
INR
International normalized ratio
IP
Investigational Product
IRB
Institutional Review Board
ITT
Intent to treat
IUD
Intrauterine device
IUS
Intrauterine hormone releasing system
IVIVT
In vitro In vivo Translation
IWRS
Interactive Web Response System
kg
Kilogram
L
Liter
LABA
Long acting 2 receptor agonist
LAMA
Long acting muscarinic receptor antagonist
LH
Leutinizing Hormone
MCV
Mean corpuscular volume
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin count
MDI
Metered dose inhaler
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligrams
mL
Milliliter
MM
Medical monitor
MSDS
Material Safety Data Sheet
msec
Millisecond
NOAEL
No observed adverse effect level
O2
Oxygen
PK
Pharmacokinetics
PR
PR interval; duration in milliseconds from the 
beginning of the P wave to onset of ventricular 
depolarization (R)
PRO
Patient Reported Outcome
PTS
Platform Technology and Science
QRS
QRS interval; duration in milliseconds of the QRS 
complex


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QT
QT interval; duraction in milliseconds between the 
start of the Q wave and the end of the T wave
QTcF
QT interval corrected for heart rate (Friderica 
formula)
RAP
Reporting and Analysis Plan
RBC
Red blood cells
RNA
Ribonucleic acid
SABA
Short-acting 2 Receptor Agonist
SAE
Serious Adverse Event
SAMA
Short-acting Muscarinic Receptor Agonist
SGRQ
St George’s Respiratory Questionnaire
SGRQ-C
SGRQ for COPD patients
SRM
Study Reference Manual
SRT
Safety Review Team
SOA
Schedule of Activities
SUSAR
Suspected unexpected serious adverse reaction
t½
Terminal phase half-life
tmax
Time to reach Cmax
TPR
Third Party Resourcing
ULN
Upper limit of normal
g
Microgram
VT
Ventricular tachycardia
WBC
White blood cells
WOCBP
Women of child bearing potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
CAT
Combivent
Duoneb
E-RS:COPD
EXACT


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12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 5  Protocol-Required Safety Laboratory Assessments
will be performed by the central laboratory, except as noted.

Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either study treatment administration and/or 
response evaluation. If a local sample is required, it is important that the sample 
for central analysis is obtained at the same time. Additionally, if the local 
laboratory results are used to make either a study treatment decision or response 
evaluation, the results must be entered into the CRF.

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 6.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 5
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
MCV
MCH
MCHC
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Clinical 
Chemistry1
BUN
Potassium
Chloride
Bicarbonate
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 (fasting 
required for 
screening)
Calcium
Alkaline 
phosphatase
Routine 
Urinalysis

Specific gravity


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Laboratory 
Assessments
Parameters

pH, glucose, protein, blood, ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

Plasma fibrinogen (a screening plasma fibrinogen is only needed for 
participants with 1 COPD exacerbation in the prior year)

Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only)

Serum or urine human chorionic gonadotropin (hCG) pregnancy test (as 
needed for women of childbearing potential)2

HIV antibody, hepatitis B surface antigen (HBsAg), and hepatitis C virus 
antibody3

All study-required laboratory assessments will be performed by a central 
laboratory, with the exception of urine testing   
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 hCG testing will be standard for the protocol unless serum testing is required by local 
regulation or IRB/IEC.
3.
Hepatitis C RNA is optional however a confirmatory negative Hepatitis C RNA test must be obtained, 
to be able to enrol participants with positive Hepatitis C antibody due to prior resolved disease
Laboratory results that could unblind the study will not be reported to investigative sites 
or other blinded personnel until the study has been unblinded.


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12.3.
Appendix 3: Study Governance Considerations
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (eg, advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study. 

Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 


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informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative. 

Participants who are rescreened are required to sign a new ICF.

The ICF may contain a separate section that addresses the use of the remaining 
mandatory samples for optional exploratory research in accordance with GSK 
SOP-GSKF-410.  The investigator of authorized designee will explain to each 
participant the objectives of the exploratory research.  Participants will be told 
that they are free to refuse to participate and may withdraw their consent at any 
time and for any reason during the storage period.  A separate signature will be 
required to document a participant’s agreement to allow any remaining 
specimens to be used for exploratory research.  Participants who decline will not 
provide this separate signature.
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.
Committees Structure

A study charter will be created to describe important governance aspects while 
the study is being conducted.

The core GSK study team (this will include the Clinical Investigation Leader 
(CIL), Medical Monitor (MM), study statistician, GCSP physician, GCSP 
scientist, and CPMS representative) will have access to unblinded, aggregate 
summaries for study treatments.  Only the study statistician will have access to 
individual participant treatment assignments.  Study team members who interact 


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with study site staff will remain blinded until the study is completed.  Complete 
details will be included in the study charter.

The SRT will include the Safety Development Leader, GCSP scientist, MM, 
CIL and study statistician but will extend to other functions as requied. The 
SRT will provide a proactive, aggregate and holistic evaluation of the safety 
data of danirixin. Further details are included in the SRT charter.
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.
Dissemination of Clinical Study Data

This study will be registered and study information from this protocol will be 
posted on publicly available clinical trial registers before enrolment of study 
participants begins.

The results summary of this study will be posted to the GSK Clinical Study 
Register and other publicly available clinical trial registers within 8 months of
the primary study completion date.

A manuscript reporting the study results will be submitted to a peer reviewed 
journal within 18 months of the last partcipant’s last visit. 
Data Quality Assurance

All participant data relating to the study will be recorded on electronic Case 
Report Report (eCRF) unless transmitted to the sponsor or designee 
electronically (eg, laboratory data). The investigator is responsible for verifying 
that data entries are accurate and correct by physically or electronically signing
the CRF/eCRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF/eCRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 


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
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 CRF/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 after from the issue of the
final Clinical Study Report (CSR) or 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. 
Data Management

For this study subject data will be entered into GSK-defined eCRFs, transmitted 
electronically to GSK or designee and combined with data provided from other 
sources in a validated data system.

Management of clinical data will be performed in accordance with applicable 
GSK standards and data cleaning procedures to ensure the integrity of the data, 
e.g. removing errors and inconsistencies in the data.

Adverse events and concomitant medication terms will be coded using the 
Medical Dictionary for Regulatory Activities (MeDRA) and an internal validated 
medication dictionary, GSKDrug.

CRFs (including queries and audit trails) will be retained by GSK and copies will 
be sent to the investigator to maintain as the investigator copy.  Subject initials 
will not be collected or transmitted to GSK according to GSK policy.
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available.

Definition of what constitutes source data can be found in the SRM.


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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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12.4.
Appendix 4: 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. 
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 


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


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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 CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
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 CRF.

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 CRF 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 


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participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
each occurrence of each AE/SAE.

A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 


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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 CRF.

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 for more than 24 hours, then the site will use 
the paper SAE data collection tool and fax or email the paper form to GSK and the 
Medical Monitor.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor/SAE coordinator by telephone or e-mail.

Contacts for SAE reporting can be found in the SRM.


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12.5.
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
3. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment.
Contraception Guidance
Male participants
Male participants with female partners of child-bearing potential are eligible to 
participate if they agree to ONE of the following during the protocol-defined time 
frame in Section 6.1: 

Are abstinent from penile-vaginal intercourse as their usual and preferred 
lifestyle (abstinent on a long term and persistent basis) and agree to remain 
abstinent 

Agree to use a male condom plus an additional method of contraception with a 
failure rate of <1% per year as described in Table 6 when having penile-vaginal 
intercourse with a woman of childbearing potential 


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
Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of 
penile penetration during the protocol-defined time frame 

Refrain from donating sperm for the duration of study and for at least 60 hours
after the last dose of study treatment.
Female participants
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in 
Table 6.
Table 6
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing ) hormonal contraception associated with 
inhibition of ovulationb

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulationb

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 participant.)
NOTES: 
a.
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants in clinical studies. 
b.
Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of 
the contraceptive method. In this case two highly effective methods of contraception should be utilized during the 
treatment period and for at least 60 hours after the last dose of study treatment


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Pregnancy Testing

WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive urine or serum pregnancy test.

Additional pregnancy testing will be performed at approximately monthly intervals 
during the study treatment period, after the last dose of study treatment and as 
required locally.

Pregnancy testing, with a high sensitivity test will be performed using the test kit 
provided by the central laboratory and approved by the sponsor and in accordance 
with instructions provided in the test kit package insert.  
Collection of Pregnancy Information
Male participants with partners who become pregnant

Investigator will attempt to collect pregnancy information on any male participant’s 
female partner of a male study participant who becomes pregnant while participating 
in this study. This applies only to participants who receive study treatment.

After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the partner’s 
pregnancy. 

Partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure. 
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. 

Participant 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. 


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
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 4. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 
Any female participant who becomes pregnant while participating will discontinue 
study treatment and be withdrawn from the study.  


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12.6.
Appendix 6: 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 blood sample will be collected for DNA analysis.

DNA samples may be used for research related to danirixin or COPD and related 
diseases. They may also be used to develop tests/assays (including diagnostic tests) 
related to danirixin treatment, and COPD (and related diseases). Genetic research 
may consist of the analysis of one or more candidate genes or the analysis of genetic 
markers throughout the genome (as appropriate).

DNA samples may be analyzed if it is hypothesized that this may help further 
understand the clinical data. 

The samples also may be analyzed as part of a multi-study assessment of genetic 
factors involved in the response to danirixin 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.

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 danirixin (or study treatments of this 
class) or COPD and related diseases continues but no longer than 15 years after the last 
participant last visit or other period as per local requirements.


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12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments
Phase II liver chemistry stopping and increased monitoring criteria have been 
designed to assure participant safety and evaluate liver event etiology 
Phase II liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin)
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot 
Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed 
to be related to liver injury or hypersensitivity
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Immediately discontinue  study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver chemistry 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 study treatment unless allowed per 
protocol and GSK Medical Governance 
approval is granted (see below)

If restart/rechallenge not allowed per 
protocol or not granted, permanently 

Viral hepatitis serology4

Obtain INR and recheck with each 
liver chemistry assessment until the 
transaminases values show 
downward trend

Obtain blood sample for 
pharmacokinetic (PK) analysis, up 
to 72 h after last dose5

Serum creatine phosphokinase 
(CPK) and lactate dehydrogenase 
(LDH).

Fractionate bilirubin, if total 
bilirubin 2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or 
worsening of clinical symptoms of 


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discontinue study treatment and continue 
participant in the study for any protocol 
specified follow up assessments 
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, 
AST, alkaline phosphatase, bilirubin) and 
perform liver event follow up assessments 
within  24 hrs

Monitor participants twice weekly until 
liver chemistries resolve, stabilize or return 
to within baseline 

A specialist or hepatology consultation is 
recommended
For All other criteria: 

Repeat liver chemistries (include ALT, 
AST, alkaline phosphatase, bilirubin) and 
perform liver event follow up assessments 
within  24-72 hrs 

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
liver injury, or hypersensitivity, on 
the AE report form

Record use of concomitant 
medications on the concomitant 
medications report form including 
acetaminophen, herbal remedies, 
other over the counter medications.

Record alcohol use on the liver 
event alcohol intake case report 
form (CRF) page 
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin 
G (IgG) or gamma globulins.

Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver 
injury in participants with definite 
or likely acetaminophen use in the 
preceding week [James, 2009]. 

Liver imaging (ultrasound, 
magnetic resonance, or 
computerised tomography) and /or 
liver biopsy to evaluate liver 
disease; complete Liver Imaging 
and/or Liver Biopsy CRF pages.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that participant if ALT 3xULN and bilirubin 2xULN.. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to participants receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen (HbsAg) 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 


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5.
PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
treatments.)  Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
treatment prior to PK blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the 
participant’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot 
be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and 
shipping are in the SRM.  
Phase II liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 3xULN and <5xULN and bilirubin 
<2xULN, without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks

Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss participant 
safety. 

Participant can continue study treatment  

Participant must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time participant meets the liver chemistry 
stopping criteria, proceed as described above

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor participants twice monthly 
until liver chemistries normalize or return to within 
baseline.
Reference
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.


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12.8.
Appendix 8: 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 (see Section 7.1.1 for the list of GSK 
medical devices to be used in this 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 participant/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 
CRF page will be completed as described in Appendix 4.

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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12.9.
Appendix 9: Neutrophil Safety and Study Treatment Restart
Neutrophil Stopping Criteria: Absolute neutrophil count (ANC) 0.5 x 109 /L
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Immediately discontinue study treatment 

Report the event to GSK within 24 hours

Complete an SAE data collection tool if the 
event also meets the criteria for an SAE

Monitor the participant until neutrophil 
count stabilizes or returns to within 
baseline (see MONITORING below)

Do not restart participant with study 
treatment unless allowed per protocol and 
GSK Medical Governance approval is 
granted (see RESTART below)
MONITORING:

Treatment of any suspected infections1

Repeat CBC within  24 hrs

Monitor CBC daily until neutrophil count 
resolves, stabilizes or returns to within 
baseline 

Record the appearance or 
worsening of any clinical 
symptoms on the AE report form1

Obtain blood sample for 
pharmacokinetic (PK) analysis 
within 12 hours  after last dose2

Record use of concomitant 
medications on the concomitant 
medications report form 
RESTART

Restart of study medication must be 
approved by the GSK Medical Monitor

Restart may be attempted ONLY if all 
three criteria are met:
The neutrophil count is 1.5 x 109/L 
for at least 48 hours

At least 7 days have elapsed since the 
suspension of study treatment 
No sign or symptom of associated 
infection has been identified

Check the CBC within 24-48 hours 
after re-starting study medication, 
monitor twice weekly for two 
weeks, and monthly thereafter.

If the ANC drops below 1.0 x 
109/L on restart, the participant 
should be permanently 
discontinued from study treatment 
and withdrawn from the study.


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1.
New or worsening symptoms believed to be related to neutropenia such as (but not limited 
to): sudden onset of fever or  malaise, stomatitis, odynophagia, periodontal infection, skin 
abscesses, signs or symptoms of sinusitis and otitis, symptoms of pneumonia (eg, cough, 
dyspnea), perirectal pain and irritation, hypotension or signs of septic shock.
2.
Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
treatment prior to PK blood sample draw on the CRF. If the date or time of the last dose is 
unclear, provide the participant’s best approximation. If the date/time of the last dose cannot 
be approximated OR a PK sample cannot be collected in the time period indicated above, do 
not obtain a PK sample. Instructions for sample handling and shipping are in the SRM.


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12.10.
Appendix 10: Country Specific Requirements
Korea - Investigational Product Label
PPD

SAP_000.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
205724
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan
Title
:
Reporting and Analysis Plan for 450 Participant/6 Month 
Strategic Interim and Final Analysis for Study 205724: 
Randomized, Double-Blind (Sponsor Open), Placebo-
Controlled, Multi-centre, Dose Ranging Study to Evaluate 
the Efficacy and Safety of Danirixin Tablets Administered 
Twice Daily Compared with Placebo for 24 Weeks in Adult 
Participants with Chronic Obstructive Pulmonary Disease
Compound Number 
:
GSK1325756
Effective Date 
:
30-OCT-2018
Description:

The purpose of this Reporting and Analysis Plan is to describe the planned 450 
participant/6 month strategic interim and final analyses and output to be included in 
the Clinical Study Report for Protocol 205724.
RAP Author(s):
Approver
Date
Approval Method
25-OCT-2018
eTMF eSignature
Statistics Leader, Clinical Statistics
29-OCT-2018
eTMF eSignature
Director Clinical Pharmacology
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD


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RAP Team Approvals:
Approver
Date
Approval Method
26-OCT-2018
eTMF eSignature
Programming Manager
30-OCT-2018
email
Senior Scientific Director
26-OCT-2018
eTMF eSignature
Clinical Development Manager
26-OCT-2018
eTMF eSignature
Clinical Data Management
26-OCT-2018
email
Patient Reported Outcomes
25-OCT-2018
eTMF eSignature
Global Regulatory Affairs
Statistics Director 
26-OCT-2018
eTMF eSignature
Clinical Statistics and Clinical Programming Line Approvals:
Approver
Date
Approval Method
30-OCT-2018
eTMF eSignature
Statistics Director (Respiratory Clinical Statistics)
26-OCT-2018
eTMF eSignature
Programming Manager (Respiratory Clinical 
Programming)
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................7
1.1.
RAP Amendment..........................................................................................7
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................9
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................9
2.2.
Study Objectives and Endpoints .................................................................10
2.3.
Study Design ..............................................................................................12
2.4.
Statistical Hypotheses.................................................................................13
3.
PLANNED ANALYSES ..........................................................................................14
3.1.
Interim Analyses .........................................................................................14
3.1.1.
Interim PK Analysis......................................................................14
3.1.2.
Futility Analysis............................................................................14
3.1.3.
Strategic Analysis ........................................................................14
3.1.4.
Administrative Interims.................................................................14
3.2.
Final Analyses ............................................................................................15
4.
ANALYSIS POPULATIONS ...................................................................................16
4.1.
Strategic Interim Analysis ...........................................................................16
4.2.
Final Analysis .............................................................................................17
4.3.
Protocol Deviations.....................................................................................17
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................18
5.1.
Study Treatment & Sub-group Display Descriptors.....................................18
5.2.
Baseline Definitions ....................................................................................18
5.3.
Multicentre Studies .....................................................................................19
5.4.
Examination of Covariates, Other Strata and Subgroups............................19
5.4.1.
Covariates and Other Strata ........................................................19
5.4.2.
Examination of Subgroups...........................................................20
5.5.
Multiple Comparisons and Multiplicity .........................................................20
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................20
6.
STUDY POPULATION ANALYSES .......................................................................21
6.1.
Overview of Planned Study Population Analyses........................................21
6.1.1.
Demographic and Baseline Characteristics..................................21
6.1.2.
Prior and Concomitant Medications .............................................21
6.1.3.
Exposure and Treatment Compliance..........................................21
7.
EFFICACY ANALYSES..........................................................................................22
7.1.
Primary Efficacy Analyses ..........................................................................22
7.1.1.
Month 6 E-RS: COPD Total Score Dose-Response 
Analysis .......................................................................................22
7.1.1.1.
Endpoint.....................................................................22
7.1.1.2.
Summary Measure .....................................................23
7.1.1.3.
Population of Interest..................................................23


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7.1.1.4.
Strategy for Intercurrent (Post-Randomization) 
Events ........................................................................23
7.1.1.5.
Statistical Analyses / Methods ....................................23
7.1.1.5.1.
Statistical Methodology 
Specification ...........................................23
7.1.2.
E-RS: COPD Subscale Scores Dose-Response Analysis............25
7.1.3.
E-RS: COPD Total and Subscale Scores Longitudinal 
Analysis .......................................................................................25
7.1.3.1.
Endpoint.....................................................................25
7.1.3.2.
Summary Measure .....................................................25
7.1.3.3.
Population of Interest..................................................25
7.1.3.4.
Strategy for Intercurrent (Post-Randomization) 
Events ........................................................................26
7.1.3.5.
Statistical Analyses / Methods ....................................26
7.1.3.5.1.
Bayesian MMRM Methodology 
Specification ...........................................26
7.1.3.5.2.
Frequentist MMRM Methodology 
Specification ...........................................27
7.2.
Secondary Efficacy Analyses......................................................................28
7.2.1.
Annual Rate of HCRU Exacerbations and Annual Rate of 
EXACT Events.............................................................................29
7.2.1.1.
Endpoint.....................................................................29
7.2.1.2.
Summary Measure .....................................................29
7.2.1.3.
Population of Interest..................................................29
7.2.1.4.
Strategy for Intercurrent (Post-Randomization) 
Events ........................................................................29
7.2.1.5.
Statistical Analyses / Methods ....................................29
7.2.1.5.1.
Statistical Methodology 
Specification ...........................................29
7.2.2.
Time to First HCRU Exacerbation and EXACT Event ..................31
7.2.2.1.
Endpoint.....................................................................31
7.2.2.2.
Summary Measure .....................................................31
7.2.2.3.
Population of Interest..................................................31
7.2.2.4.
Strategy for Intercurrent (Post-Randomization) 
Events ........................................................................31
7.2.2.5.
Statistical Analyses / Methods ....................................32
7.2.2.5.1.
Statistical Methodology 
Specification ...........................................32
7.2.3.
E-RS: COPD Total and Subscale Scores Responder 
Analysis .......................................................................................33
7.2.3.1.
Endpoint.....................................................................33
7.2.3.2.
Summary Measure .....................................................33
7.2.3.3.
Population of Interest..................................................33
7.2.3.4.
Strategy for Intercurrent (Post-Randomization) 
Events ........................................................................33
7.2.3.5.
Statistical Analyses / Methods ....................................33
7.2.3.5.1.
Statistical Methodology 
Specification ...........................................33
7.2.4.
SGRQ Total Score and CAT Score..............................................34
7.2.5.
Rescue Use.................................................................................34
7.2.6.
Physical Activity...........................................................................34
7.3.
Exploratory Efficacy Analyses.....................................................................35


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7.3.1.
E-RS: COPD Total Score.............................................................35
7.3.2.
CAT Score...................................................................................36
7.3.3.
Time to First Clinically Important Deterioration.............................36
7.3.4.
SGRQ Domain Scores.................................................................36
7.3.5.
Participant Global Assessments ..................................................36
8.
SAFETY ANALYSES .............................................................................................37
8.1.
Adverse Events Analyses ...........................................................................37
8.2.
Adverse Events of Special Interest Analyses..............................................37
8.3.
Clinical Laboratory Analyses.......................................................................37
8.4.
Spirometry ..................................................................................................37
8.4.1.
Endpoint ......................................................................................37
8.4.2.
Summary Measure ......................................................................37
8.4.3.
Population of Interest...................................................................37
8.4.4.
Strategy for Intercurrent (Post-Randomization) Events ................38
8.4.5.
Statistical Analyses / Methods .....................................................38
8.4.5.1.
Frequentist MMRM Methodology Specification...........38
8.5.
Other Safety Analyses ................................................................................39
9.
PHARMACOKINETIC ANALYSES.........................................................................39
9.1.
Primary Pharmacokinetic Analyses.............................................................39
9.1.1.
Derived Pharmacokinetic Parameters..........................................39
9.1.2.
Statistical Analyses / Methods .....................................................39
9.2.
Exploratory Pharmacokinetic Analyses .......................................................40
9.2.1.
Derived Pharmacokinetic Parameters..........................................40
9.2.2.
Statistical Analyses / Methods .....................................................40
9.2.2.1.
Statistical Methodology Specification..........................40
10. POPULATION PHARMACOKINETIC ANALYSES .................................................41
11. BIOMARKER ANALYSES......................................................................................41
12. PHARMACOKINETIC / PHARMACODYNAMIC ANALYSES .................................42
12.1.
Statistical Analyses / Methods ....................................................................42
13. REFERENCES.......................................................................................................43
14. APPENDICES........................................................................................................44
14.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................44
14.1.1.
Exclusions from Per Protocol Population .....................................44
14.2.
Appendix 2: Schedule of Activities ..............................................................45
14.2.1.
Protocol Defined Schedule of Events...........................................45
14.3.
Appendix 3: Assessment Windows .............................................................51
14.4.
Appendix 4: Study Phases..........................................................................52
14.4.1.
Study Phases ..............................................................................52
14.4.1.1.
Study Phases for Diary Data ......................................52
14.4.1.2.
Study Phases for Concomitant Medication .................52
14.4.1.3.
Study Phases for Event Data......................................53
14.4.1.4.
Study Phases for Other Data......................................53
14.5.
Appendix 5: Data Display Standards & Handling Conventions....................54
14.5.1.
Reporting Process .......................................................................54
14.5.2.
Reporting Standards....................................................................54


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14.5.3.
Reporting Standards for Pharmacokinetic Data ...........................56
14.6.
Appendix 6: Derived and Transformed Data ...............................................57
14.6.1.
General........................................................................................57
14.6.2.
Study Population..........................................................................57
14.6.3.
Efficacy........................................................................................61
14.6.4.
Safety ..........................................................................................66
14.7.
Appendix 7: Reporting Standards for Missing Data.....................................68
14.7.1.
Premature Withdrawals................................................................68
14.7.2.
Handling of Missing Data.............................................................68
14.7.2.1.
Handling of Missing and Partial Dates ........................68
14.8.
Appendix 8: Values of Potential Clinical Importance ...................................69
14.8.1.
Laboratory Values........................................................................69
14.8.2.
ECG.............................................................................................70
14.8.3.
Vital Signs....................................................................................71
14.9.
Appendix 9: Population Pharmacokinetic Analyses.....................................72
14.9.1.
Population Pharmacokinetic Dataset Specification ......................72
14.9.1.1.
Handling Missing Demographic and Covariate 
Data ...........................................................................72
14.9.1.2.
Handling Missing Dose Times ....................................72
14.9.1.3.
Handling Missing Times of PK Samples .....................72
14.9.1.4.
Handling of PK Data Below the Lower Limit of 
Quantification .............................................................72
14.9.1.5.
Dataset Specification..................................................72
14.10. Appendix 10: Abbreviations & Trade Marks ................................................85
14.10.1. Abbreviations...............................................................................85
14.10.2. Trademarks .................................................................................86
14.11. Appendix 11: List of Data Displays..............................................................87
14.11.1. Data Display Numbering..............................................................87
14.11.2. Deliverables.................................................................................87
14.11.3. Study Population Tables..............................................................88
14.11.4. Study Population Figures.............................................................94
14.11.5. Efficacy Tables ............................................................................95
14.11.6. Efficacy Figures .........................................................................103
14.11.7. Safety Tables.............................................................................109
14.11.8. Safety Figures ...........................................................................114
14.11.9. Pharmacokinetic Tables.............................................................115
14.11.10.Pharmacokinetic Figures ...........................................................116
14.11.11.Pharmacokinetic / Pharmacodynamic Figure.............................119
14.11.12.Biomarker Tables.......................................................................120
14.11.13.Biomarker Figures .....................................................................121
14.11.14.ICH Listings ...............................................................................122
14.11.15.Non-ICH Listings........................................................................126
14.12. Appendix 12: Example Mock Shells for Data Displays ..............................130


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1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the 450 participant/6 
month strategic interim.  This RAP will also describe the final analyses to be included in 
the Clinical Study Report (CSR) for Protocol 205724.
Revision Chronology:
2016N293867_00
28-NOV-2016
Original
2016N293867_01
31-OCT-2017

Adds a second, optional, detailed pharmacokinetic 
profiling at Visit 10 in a subset of participants to allow for 
a better understanding of danirixin pharmacokinetics. 

Removes the Participant Exit Interview from the 
exploratory endpoints. 

Provides additional information and clarification for the 
following: spirometry assessments, exclusion for cancers 
other than lung cancer, permitted use of supplemental 
oxygen, permitted uses of chronic steroids, participant 
numbering requirement for rescreening, additional text to 
explain the timing of the planned interim analysis and 
updates to the analysis populations.
1.1.
RAP Amendment
Revision chronology: 
RAP Section
Amendment Details
GSK1325756-205724 Statistical Analysis Plan Reporting and Analysis Plan Version 001 (31-Aug-
2018)
GSK1325756-205724 Reporting and Analysis Plan Amendment1_Final [Insert Date]
Approvals 

Removed 
 as she has left GSK. Added 
 
 replacement) as an additional approver
2.2 Study Objectives and 
Endpoints

PK endpoints were not assessed in the strategic interim
3.1.3 Strategic Analysis

Updated to past tense
3.2 Final Analysis

Updated to reflect planned unblinding process
4.1 Strategic Interim 
Analysis, 7.1.4.5.1 
Bayesian MMRM 
Methodology Specification
and 7.2.1.5.1 Statistical 
Methodology Specification

ITT and Symptomatic populations not used for final analysis. 

(PP) added to Per Protocol population in the definition table.
6.1.2 Prior and 
Concomitant Medications

Additional concomitant medication table at Month 6
7.1.1 Month 6 E-RS: COPD 
Total Score Dose-
Response Analysis

Clarification of posterior predictive probability of success calculation used 
at the Strategic Interim
PPD
PPD
PPD


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RAP Section
Amendment Details
7.1.2 Month 2-6 E-RS: 
COPD Total Score Dose-
Response Analysis and 
7.1.3.5.2 Frequentist 
ANCOVA Methodology 
Specification and 14.6.3 
Efficacy

Month 2-6 E:RS: COPD Dose Response Analysis not required
7.1.4.5.1 Bayesian MMRM 
Methodology Specification

Updates to Bayesian model specifications to improve convergence and 
mixing
7.1.4.5.3 Frequentist 
MMRM Methodology 
Specification

Additional plots of LS Mean and daily mean E-RS: COPD scores. Plots 
of empirical distribution function for E-RS: COPD Total Scores. 
7.2.1.5.1 Statistical 
Methodology Specification

Additional table for HCRU exacerbations treated with antibiotics.
7.2.4 SGRQ Total Score 
and CAT Score

Additional plot of arithmetic mean and 90% CIs for SGRQ and CAT
7.2.5 Rescue Medication

Additional plots daily rescue medication use
7.3.1 E-RS: COPD Total 
Score

Identify subgroups not required for final SAC
7.3.3 Time to First 
Clinically Important 
Deterioration

8.3 Clinical Laboratory 
Analysis

Remove urinalysis outputs because no PCI ranges are defined for 
urinalysis
8.4.5.1 Frequentist MMRM 
Methodology Specification

Additional summaries of FEV1/FVC ratio and plots of arithmetic mean 
and 90% CIs for all spirometry endpoints.
11 Biomarker Analysis

Additional tables and boxplots in subjects with pneumonia
14.4.1.1 Study Phases for 
Diary Data

Clarify that Diary data phases applies to EXACT events
14.6.2 Study Population

Additional COPD medication combinations table at Month 6
14.6.3 Efficacy

Clarify definitions for Season, time to first, raw annual rate and offset. 
Remove definition of CID as not reporting this exploratory endpoint.
14.6.4 Safety

Clarify definition for character laboratory parameters.  Add definition of 
ICS use for pneumonia table.
14.11 Appendix 11: List of 
Data Displays

Updates to tables and figures.

Remove urinalysis outputs

Remove CID tables


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2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Changes from the originally planned statistical analysis specified in the protocol are 
outlined in Table 1.
Table 1
Changes to Protocol Defined Analysis Plan
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes

All Participants population

All Subjects population 

R&D Clinical Data Standards Board 
(CDSB) recommendation to use the 
term 'Subjects' in all displays (Tables, 
Figures & Listings)

No Intent-to-treat (ITT) 
population 

ITT population defined 
to be used for selected 
efficacy displays

Used for key efficacy displays to 
enable phase III planning

No Per Protocol (PP) 
population

PP population defined 
and used for efficacy 
displays

Remove data from participants who 
had a protocol deviation considered 
to impact efficacy during the 
treatment period.

No Symptomatic population

Symptomatic 
population defined and 
used for selected study 
population and efficacy 
displays

Used to explore the subgroup of 
symptomatic participants. 

No PK2 population

PK2 population defined 
and used for PK dry 
blood spot vs wet 
whole blood

Used to compare dry blood spot with 
wet whole blood

mITT population used for 
efficacy endpoints

PP population used for 
efficacy endpoints

Remove data from participants who 
had a protocol deviation considered 
to impact efficacy during the 
treatment period.

The final Emax model will 
be repeated using months 
1-6 and months 3-6.

The final Emax model 
will be repeated using 
months 2-6.

Team decision to include most 
informative time period.

The protocol states that 
exacerbation rates for the 
danirixin and placebo 
groups, along with the ratio 
in exacerbation rates 
danirixin/placebo, will be 
estimated and 
corresponding 95% credible 
intervals will be produced.

90% credible intervals 
will be produced for all 
Bayesian efficacy 
analyses including 
exacerbation rates.

Inconsistency in protocol.  


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2.2.
Study Objectives and Endpoints
Objectives
Endpoints
Assessed in 
Strategic 
Interim
Primary Objectives
Primary Endpoints

To characterize the dose 
response of danirixin 
compared with placebo on 
the incidence and severity 
of respiratory symptoms 
in participants with 
chronic obstructive 
pulmonary disease 
(COPD)

Change from baseline in respiratory 
symptoms measured by the Evaluating 
Respiratory Symptoms in COPD (E-RS:
COPD) daily diary: total score and 
subscales (i.e. breathlessness, cough and 
sputum, and chest symptoms)
Yes

To compare the safety of 
danirixin with placebo in 
participants with COPD

Adverse events (AE), clinical 
laboratory values, vital signs, 
electrocardiogram (ECG)
Yes[1]
Secondary Objectives
Secondary Endpoints

To characterize the dose 
response of danirixin 
compared with placebo on 
the annual rate of 
moderate/severe COPD 
exacerbations in 
participants with COPD

Healthcare Resource Utilization 
(HCRU)-defined COPD exacerbations
Yes

To further characterize 
the clinical activity of 
danirixin compared to 
placebo in participants 
with COPD

E-RS: COPD Responder Analysis 
(including subscales)
Yes

Number of Exacerbations of Chronic 
Pulmonary Disease (EXACT) tool 
defined events
No

Time to first EXACT event
No

EXACT event severity
No

EXACT event duration for all events
No

Time to first HCRU-defined COPD 
exacerbation
Yes

Time to first severe HCRU-defined 
COPD exacerbation
Yes

HCRU-defined COPD exacerbation 
duration
Yes

Change from baseline for the St. 
George’s Respiratory Questionnaire 
(SGRQ) total score (derived from 
Yes


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Objectives
Endpoints
Assessed in 
Strategic 
Interim
SGRQ-C)

SGRQ responder analysis
Yes

Change from baseline for the COPD 
Assessment Test (CAT) total score
Yes

CAT responder analysis
Yes

Lung function (forced expiratory 
volume in 1 second [FEV1], FEV1 % 
predicted, forced vital capacity [FVC], 
FEV1/FVC ratio)
Yes

Rescue medication use
Yes

Participant experience of physical 
activity (subset of approximately 50% 
of participants) measured using Clinical 
Visit PROactive Physical Activity in 
COPD Tool (C-PPAC)
Yes[2]

To characterize the 
pharmacokinetics of 
danirixin in participants 
with COPD

Danirixin concentration and standard 
pharmacokinetic (PK) parameters for 
danirixin (e.g. AUC, Cmax, Tmax), 
using dried blood spot data
No
Exploratory Objectives
Exploratory Endpoints

To further explore study 
participants’ experience 
with study treatment and 
overall experience with 
the study

Time to first Clinically Important 
Deterioration (CID)
No

SGRQ domains
Yes

To characterize the effect 
of danirixin on lung 
matrix 
destruction/remodelling

Blood/serum/plasma biomarkers that 
are indicative of extracellular matrix 
turnover/remodelling (e.g. elastin and 
collagen neo-epitopes)
No

Comparison between 
dried blood spot and wet 
whole blood analysis of 
danirixin concentrations 
in partipants with COPD

Danirixin concentration and standard 
pharmacokinetic parameters for 
danirixin (e.g. AUC, Cmax, Tmax)
No


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Objectives
Endpoints
Assessed in 
Strategic 
Interim

To characterise danirixin 
exposure-response 
relationships for various 
safety parameters, if 
appropriate

Danirixin systemic exposure and 
various efficacy/pharmacodynamic 
(PD)/safety parameters, if appropriate
No
[1] AEs, serious AEs (SAEs), drug-related AEs, AEs leading to withdrawal, AEs of 
special interest (AESI), laboratory data, ECG 
[2] Summary of C-PPAC questionnaire responses only
2.3.
Study Design
Overview of Study Design and Key Features
Design
Features
This is a parallel group, randomized, double-blind (sponsor open), 
placebo-controlled, multi-centre, dose ranging study.
Dosing
Study treatment will be administered twice daily for 24 weeks.
Time & 
Events
Refer to Appendix 2: Schedule of Activities
Treatment 
Assignment
Participants will be randomized (1:1:1:1:1:1) to receive one of five dose 
strengths of danirixin (5 mg, 10 mg, 25 mg, 35 mg and 50 mg) or placebo.  
Randomization was stratified by smoking status.
Interim 
Analysis
Three specific interim analyses were defined for the study, with the 
protocol allowing for additional administrative interims as required.  
An administrative interim was performed in October 2017 and included 
plots of E-RS: COPD total score (and subscale scores) over time by 
treatment, to aid internal decision-making on the project.
The first protocol specified interim analysis was an evaluation of danirixin 
PK after 10 participants in each treatment group had completed Visit 3 


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Overview of Study Design and Key Features
(Day 1). This analysis was performed in December 2017.
A protocol specified futility interim analysis based on the E-RS: COPD 
endpoint was conducted after approximately 150 participants had 
completed 3 months of study treatment.  This analysis was performed in 
February 2018.
A further protocol specified strategic interim analysis will be conducted 
when approximately 450 participants have completed 6 months of 
treatment.  This strategic interim will be used to support GlaxoSmithKline 
(GSK) decisions regarding additional investment and further development 
of danirixin. It will include endpoints as specified in Section 2.2 and in the 
list of data displays in Appendix 11. No changes will be made to the study 
based on the results of this strategic interim analysis unless a safety 
concern is identified.
Outputs containing unblinded treatment assignments will be created for all 
interim analyses and will only be made available to a limited number of 
GSK staff.  Full details will be included in the study results dissemination 
plan (SRDP).
2.4.
Statistical Hypotheses
The primary efficacy endpoint is the change from baseline of E-RS: COPD total score at 
Month 6.  The primary objective of the study is to characterize the dose response of 
danirixin and select appropriate dose(s) for future drug development.
A model based probability inference approach in Bayesian framework will be used to 
guide decision-making around dose selection. The posterior probability that the change 
from baseline of E-RS: COPD total score for each active dose is less than placebo will be 
derived.
No formal statistical hypothesis will be tested in the primary efficacy analysis.


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3.
PLANNED ANALYSES
3.1.
Interim Analyses
3.1.1.
Interim PK Analysis
After approximately 10 participants in the PK subset for each treatment group had
completed Visit 3 (Day 1), an interim evaluation of danirixin PK parameters was
undertaken.  The purpose of the interim PK analysis was to determine if danirixin 
exposures were within the expected range.  No formal HARP outputs were produced.
3.1.2.
Futility Analysis
An interim analysis was conducted to allow for the possibility of stopping early for 
futility after approximately 150 participants had completed 3 months of treatment.  This 
is described in a separate RAP.  Outputs featuring unblinded treatment assignments were 
created and shared with the study team and those listed in the Study Results 
Dissemination Plan (SRDP).
3.1.3.
Strategic Analysis
When approximately 450 participants had completed 6 months of treatment, a further 
interim analysis was performed for strategic planning purposes, as described in this RAP.  
This analysis was planned to be used to aid in the planning of future studies and for a 
better understanding of benefit/risk profile of danirixin.  No changes were made to the
study based on the results of this strategic interim analysis.
The analyses were performed after the completion of the following sequential steps:
1.
The date of the planned Visit 10 for the 450th completed participant (01AUG2018) 
had been met.
2.
All required database cleaning activities had been completed by Data Management 
(DM) on data collected up until 01AUG18.  Data collected between 02AUG2018 
and 5SEP2018 (DBR) for ongoing subjects was not cleaned.
3.
Unblinded randomization schedules were released by Randomization coordinator.
Data was reported in System Independent (SI) format. Outputs featuring unblinded 
treatment assignments were created for this strategic interim analysis, reviewed by the 
study team and shared with selective GSK personnel (to be included in the SRDP).
3.1.4.
Administrative Interims
Administrative assessments of danirixin exposure, efficacy and spirometry data may be 
undertaken during the conduct of the study as data becomes available. No decisions 
regarding study conduct will be made based on these assessments.  The reporting team 
will have access to the unblinded participant treatment assignments.  The unblinded study 
team (as defined in the 205724 Study Charter) will have access to unblinded aggregate 
data grouped by study treatment assignment.


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An administrative interim was performed in October 2017 and included plots of E-RS: 
COPD total score (and the subgroups) over time by treatment, to aid internal decision-
making on the project.
3.2.
Final Analyses
The final planned analyses for this Clinical Data Interchange Standards Consortium 
(CDISC) study will be performed after the completion of the following sequential steps:
1.
All participants have completed the study as defined in the protocol.
2.
SI data to Study Data Tabulation Model (SDTM) data conversion has been 
completed by Accenture and quality control (QC) of blinded SDTM has been 
completed by CDAD and DM. DM will provide the blinded SI PC dataset to 
Accenture.
3.
All required database cleaning activities have been completed and final SI Source 
Data Lock (SDL) has been declared by DM.
4.
Study is unblinded
Randomization schedules and container data are released in RANDALL NG.
SMS2000 data is released in HARP
5.
The SDTMs (including the PK) are unblinded by clinical programming (or 
representative) using the interim unblinding process. 
6.
Database freeze (DBF) on unblinded SDTM datasets is declared by DM.


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4.
ANALYSIS POPULATIONS
4.1.
Strategic Interim Analysis
Population
Definition / Criteria
Analyses Evaluated
All Subjects 
(ALLSUB)

All participants screened and for whom a 
record exists on the study database.

Participant disposition

Reasons for withdrawal prior to 
randomization

Inclusion/exclusion/randomization 
criteria deviations for non-
randomized participants

AEs and SAEs for non-
randomized participants
Intent-to-treat 
(ITT)

All randomized participants apart from those 
who were randomized in error (i.e. were also 
recorded as screen or run-in failures and did 
not receive a dose of study treatment).

Any participant who receives a treatment 
randomization number will be considered to 
have been randomized.

Randomized participants will be assumed to 
have received study medication unless 
definitive evidence to the contrary exists.

Data will be reported according to the 
randomized treatment.

Selected efficacy displays as 
described in Section 7

Strategic Interim only
Modified 
Intent-To-
Treat (mITT)

Same as the Intent-to-treat population, but 
this population will be ‘modified’ in that all 
data summaries and analyses for this 
population will be based on the actual 
treatment received, if it is different to the 
randomized treatment.

If any participant received more than one 
treatment during a treatment period, their data 
will be reported according to the treatment 
they received for the longest period of time.

Study Population

Safety
Per Protocol
(PP)

All participants from the mITT population who 
did not have a protocol deviation considered 
to impact efficacy

Efficacy
Symptomatic

All participants in the PP population who have 
Chronic Mucus Hypersecretion (CMH) 
according to baseline SGRQ (see Section 
14.6.2) and baseline E-RS: COPD total score 
(see Section 5.2) >=10.

Study Population

Selected efficacy displays as 
described in Section 7

Strategic Interim only
Refer to Appendix 11: List of Data Displays which details the population used for each display.


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4.2.
Final Analysis
The final analysis will use the same populations as above, plus additional populations as 
defined below.
Population
Definition / Criteria
Analyses Evaluated
PK

All participants in the mITT population who had at least 1 
non-missing PK assessment (Non-quantifiable [NQ] 
values will be considered as non-missing values) 
obtained and analysed whilst on treatment with danirixin.

PK
PK2

All participants in the PK population who had at least 1 
non-missing PK assessment (NQ values will be 
considered as non-missing values) obtained and 
analysed whilst on treatment with danirixin from a dry 
blood spot sample and corresponding wet whole blood 
sample.

PK Dry Blood Spot 
vs Wet Whole 
Blood
Refer to Appendix 11: List of Data Displays which details the population used for each display.
In the event one or more investigators are withdrawn from the study due to concerns over 
protocol deviation then a further population will be defined which will consist of all 
participants in the PP population excluding participants from those investigative sites. 
This population will be used to perform additional sensitivity analysis for the primary 
efficacy endpoint only and will only be defined if the combined enrolment at these sites 
exceeds ≥ 2% of the overall PP study enrolment. No other analyses will be repeated.
4.3.
Protocol Deviations
Protocol Deviations (PDs) will be tracked by the study team throughout the conduct of 
the study in accordance with the Protocol Deviation Management Plan (6JUL2018, 
V2.0):

Data will be reviewed prior to SDL to ensure all important deviations are captured 
and categorised on the protocol deviations dataset. 

Participants who received an incorrect treatment container will be captured as an 
important protocol deviation. Whether or not the incorrect container contained 
incorrect treatment will be identified following DBF in the analysis dataset and 
the PD will be flagged accordingly. 

This dataset will be the basis for the summaries and listings of protocol 
deviations.

Important protocol deviations (including deviations related to study 
inclusion/exclusion criteria, conduct of the trial, participant management or 
participant assessment) will be summarised and listed.

A separate summary and listing of all inclusion/exclusion criteria deviations will 
also be provided. This summary will be based on data as recorded on the 
inclusion/exclusion page of the electronic case report form (eCRF).


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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG
Data Displays for Reporting 
Code
Description
Description
Order in TLF 
D5
Danirixin 5mg
DNX 5mg
2
D10
Danirixin 10mg
DNX 10mg 
3
D25
Danirixin 25mg
DNX 25mg 
4
D35
Danirixin 35mg
DNX 35mg 
5
D50
Danirixin 50mg
DNX 50mg 
6
PO
Placebo oval
Placebo
1
PR
Placebo round
Placebo
1
Treatment comparisons will be displayed as in the danirixin dose column with the 
descriptor: Column vs Placebo.
5.2.
Baseline Definitions
Any assessments made after the start of study treatment will not be included in the 
derivation of baseline.  Assessments made on the same day as the start of treatment are 
assumed to be taken prior to first dose.
If baseline data are missing, no derivation will be performed and baseline will be set to 
missing.
Parameter
Baseline Used in Data Display
E-RS: COPD total and 
subscale scores
Mean score during a stable period between (Latest of (7 days before Study 
treatment start date (Day 1) and day of Visit 1 (Screening)) and day before Day 1 
of study treatment.  Data must be present on at least 4 days
EXACT (for 
determining EXACT 
events)
Defined according to the EXACT User Manual v8.0 (Evidera, 2016a)
SGRQ total and 
domain scores
Day 1
CAT score
Day 1
Rescue use (diary card 
and sensor data, mean 
number of 
puffs/occasions per 
day and percentage of 
rescue-free days)
Mean score during a stable period between (Latest of (7 days before Study 
treatment start date (Day 1) and day of Visit 1 (Screening)) and day before Day 1 
of study treatment.  Data must be present on at least 4 days.
PROactive score
A PROactive Total Score and two domain scores (amount and difficulty) will be 
derived using data from the C-PPAC questionnaire on Day 1 and physical activity 


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Parameter
Baseline Used in Data Display
monitor worn between Visit 2 and Visit 3 (7 days). The activity monitor must have 
been worn for at least 3 days with >=8 hours wearing (the 3 days do not need to 
be consecutive). Further details of the derivation are described in Section 14.6.3
and in the IMI PROactive user manual (14JUN16). 
Blood pressure (BP)
Latest pre-dose assessment with a non-missing value for both systolic and 
diastolic BP, including those from unscheduled visits
Pulse rate, laboratory 
data, ECG
Latest pre-dose assessment with a non-missing value for the individual 
assessment, including those from unscheduled visits
Post-bronchodilator 
(BD) FEV1, post-BD 
FVC
Day 1
5.3.
Multicentre Studies
In this multicentre global study, enrolment will be summarized by country and 
investigative site.  Country will be included as a fixed effect in statistical models and 
treatment by country interaction investigated as described in Section 7 and Section 8.  
Results will be presented for all countries combined except as specified in Section 7.
5.4.
Examination of Covariates, Other Strata and Subgroups
5.4.1.
Covariates and Other Strata
The covariates and other strata listed below will be used in statistical models and 
treatment by covariate/stratum investigated as defined in Section 7, Section 14.6.2 and
Section 14.6.3.
Category
Details
Strata
Smoking status
Covariates
Treatment, visit/Month, baseline, smoking status at screening, country, gender,
exacerbation history (≤1, ≥2 moderate/severe), post-bronchodilator % predicted FEV1, 
CMH status at baseline, season of data collection.


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5.4.2.
Examination of Subgroups
The subgroups listed below will be used in statistical analyses as described in Section 7.
Subgroup
Categories 
Season
Spring, Summer, Fall, Winter (see Section 14.6.3)
Country
Australia, Canada, Germany, Korea, Netherlands, Poland, Romania, 
Spain, US
Exacerbation history
History of ≥2 moderate/severe exacerbations vs <2 moderate/severe 
exacerbation
COPD medication at Baseline
ICS+LABA+LAMA vs. ICS+LABA vs. LABA+LAMA vs. Other COPD 
medication
ERS10
Baseline E-RS: COPD Total Score <10, ≥10
CAT10
Baseline CAT Score <10, ≥10
Smoking status at Screening
Current, Former
% predicted FEV1 at Screening
<50%, ≥50%
CMH status at baseline
CMH+, CMH- (see Section 14.6.2)
5.5.
Multiple Comparisons and Multiplicity
No multiplicity adjustment will be made for this study, as the primary objective of the 
study is to model the danirixin dose response and use it to select Phase III dose(s).
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
14.3
Appendix 3: Assessment Windows
14.4
Appendix 4: Study Phases
14.5
Appendix 5: Data Display Standards & Handling Conventions
14.6
Appendix 6: Derived and Transformed Data
14.7
Appendix 7: Reporting Standards for Missing Data
14.8
Appendix 8: Values of Potential Clinical Importance


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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
Study population displays including analyses of participant disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure and treatment compliance will be based on GSK Core Data Standards.  
Results will be presented for each treatment and overall.
Details of the planned displays including the population to be used for each display and 
which displays are produced for the strategic interim are presented in Appendix 11.  
Additional details are provided below.
6.1.1.
Demographic and Baseline Characteristics
The summary of exacerbation history at Screening will include the number and 
percentage of participants reporting mild, moderate, severe and moderate/severe 
exacerbations (0, 1, >=2; see Section 14.6.2) in the 12 months prior to screening.
6.1.2.
Prior and Concomitant Medications
Non-COPD medication tables will report by Anatomical Therapeutic Chemical (ATC) 
level 1 classification and ingredient. Multi-ingredient non-COPD medications will be 
presented according to their combination ATC classification rather than the 
classifications of the ingredients.
COPD medication tables will report by respiratory medication class (RMC) and 
ingredient (See Section 14.6.2). The number and percentage of participants taking each 
medication in the RMC categories (defined in Section 14.6.2) will be presented. 
The number and percentage of subjects taking each medication in the RMC categories 
ICS, LABA, LAMA, PDE4 inhibitors, Xanthines, Anti-IgE, Anti-IL5 and combinations 
of these RMCs on the day of the Screening visit, at Baseline (Day 1) and at Month 6 will 
be presented.
6.1.3.
Exposure and Treatment Compliance
Calculation of treatment compliance will be based on the number of tablets dispensed and 
returned as described in Section 14.6.2. Calculation of diary compliance will be based on 
the number of days with non-missing E-RS: COPD total score as described in Section 
14.6.2.  Percentage treatment and diary compliance will be summarized categorically and 
with descriptive statistics.


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7.
EFFICACY ANALYSES
Details of the planned displays including the population to be used for each display and 
which displays are produced for the strategic interim are presented in Appendix 11.  
Additional details are provided below.
For this study, no data were scheduled to be collected after discontinuation of study 
treatment, therefore accounting for non-recorded missing data following study 
withdrawal is addressed by the strategy for the intercurrent event of treatment 
discontinuation.
7.1.
Primary Efficacy Analyses
7.1.1.
Month 6 E-RS: COPD Total Score Dose-Response Analysis
The estimand is the effect of actual treatment in the population of participants who did 
not experience a protocol deviation considered to impact efficacy and completed six 
months of treatment.
A Bayesian dose response model will be applied to the change from baseline to Month 6 
and used to estimate the treatment difference between placebo and each dose.
The dose-response model will be fitted using Bayesian techniques with non-informative 
priors for E0 and Emax and a functional uniform prior (FUP) for ED50 and the slope 
parameter, m (Bornkamp, 2014). The rationale for this choice of inference is that the FUP 
shrinks the dose-response towards a flat line throughout the dose range, therefore 
providing more conservative estimates of the dose-response relationship compared to 
maximum likelihood.
For the strategic interim, the posterior predictive probability of success (PPS) at the end 
of the study will be calculated for each dose using the formula suggested by Spiegelhalter 
et al. (Spiegelhalter, 2004) as follows:
Where m is the average number of participants with Month 6 data in the placebo and 
comparative dose arm, n is the average number of participants yet to be observed
(assuming 90% of participants, rounded to the nearest integer, in each treatment group 
will provide month 6 data at end of study. If the actual number of participants at month 6 
exceeds this, the actual number will be used), 
is the posterior mean difference from 
the fitted model, and 
is the standard deviation (SD) of the posterior mean 
difference.
7.1.1.1.
Endpoint
Change from baseline in Month 6 E-RS: COPD total score as defined in Section 14.6.3.


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7.1.1.2.
Summary Measure
For the strategic interim, the summary measure is the posterior predictive probability of 
success for each danirixin dose, where success is the probability that a true difference 
from placebo is less than 0 is >95% at Month 6.
For the final analysis, the summary measure is the posterior probability that a true 
difference from placebo is less than 0 at Month 6 for each danirixin dose.
7.1.1.3.
Population of Interest 
PP population.
7.1.1.4.
Strategy for Intercurrent (Post-Randomization) Events
For the primary efficacy analysis, the intercurrent event of interest is occurrence of a 
protocol deviation considered to impact efficacy during the treatment period (see 
Appendix 1). An ‘as treated’ strategy will be used to account for this event - only Month 
6 E-RS: COPD data (see Section 14.6.3) collected prior to the occurrence of a protocol 
deviation considered to impact efficacy will be used in the analysis.
The intercurrent event of treatment discontinuation is accounted for in the endpoint 
definition as only data at Month 6 will be used.
7.1.1.5.
Statistical Analyses / Methods
7.1.1.5.1.
Statistical Methodology Specification
Endpoint / Variables

Change from baseline in Month 6 E-RS: COPD total score
Model Specification
Bayesian dose response model:

Models of the following form will be considered:
Response=E0+ Emax* f(dose)
o
Log-linear model: f(dose)=log(dose+0.01), where 0.01 is an offset to allow the 
model to fit for zero dose (placebo).
o
3-parameter emax model: f(dose)=dose/(dose+ed50)
o
4-parameter emax model: f(dose)=dose^m/(dose^m+ED50^m)
Where:
o
E0 = the response at dose = 0 (placebo),
o
Emax = the maximal response over placebo,
o
ED50= the dose that yields 50% of the maximal response,
o
m= dose-response slope parameter.

The log-linear, 3-parameter emax and 4-parameter emax model will be fitted without adjusting 
for covariates. If possible, covariates (i.e., baseline, smoking status, country) will be included in 
the E0 and Emax terms of the model for the final analysis

Normal non-informative priors will be used for the E0 and Emax parameters with mean 0 and 
SD 100. A FUP will be used for the ED50 and m parameters (Bornkamp, 2014), where the 


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prior density for the FUP is based on all the parameters in the model.  An inverse -gamma prior 
with shape of 0.001 and scale of 0.001 will be used for the residual variance.

Parameters will be blocked such that the MCMC procedure samples from E0 and Emax first, 
then the ED50 and m parameters and then finally the residual variance parameter. 

For the functional uniform priors, the density will be calculated for values of dose from 0.0001 
to 50 in steps of 5 (i.e. 0.0001, 5.0001, 10.0001,…, 50.0001).

3 MCMC chains will be fitted using the following starting values (as required for the parameters 
in each particular model):
Parameter
Chain 1
Chain 2
Chain 3
E0
Posterior mean for placebo from 
MMRM at Month 6 (See Section 7.1.3)
-15
15
Emax
Posterior mean for 50mg dose from 
MMRM at Month 6 (See Section 7.1.3)
15
-15
ED50
25
10
50
M
1
2
4
Residual variance
6
8
10

100,000 MCMC samples will be generated using a thin of 50 to leave 2000 retained samples, 
and after a burn-in of 10,000 samples for each of the three sets of starting values.  All post-
burn-in samples from the 3 chains will be used for inference. The number of samples 
generated and the thin may be increased to reduce the ratio of the MCSE to the posterior SD, 
as deemed necessary.

The seeds used to for the three chains were generated using the ranuni function in SAS and 
are listed in Section 14.5.2.

The best fitting model will be the model with the smallest average DIC over the 3 chains where 
convergence is deemed to have been achieved.  If the best fitting model is one that adjusts for 
covariates, all outputs will be presented adjusting for the mean in the observed covariate. 

Production and QC will be deemed to have agreement if the QC value is the following range:

if a number is reported to 0dp and there is a difference of 1 (number of participants must 
agree)

if a number is reported to 1dp and there is a difference of 0.1

if a number is reported to 2dp and there is a difference of 0.01

if a number is reported to 3dp and there is a difference of 0.001

if a number is reported to 4dp and there is a difference of 0.0001
Model Checking & Diagnostics

Posterior density plots and plots of the posterior samples (chains) will be produced for all the 
parameters in the model.

The posterior density for the adjusted mean change from baseline in E-RS: COPD total score 
in each treatment group and differences versus placebo for each danirixin dose will be plotted.

The Gelman-Rubin R estimate from the three chains will be calculated for all parameters in the 
model and the differences from placebo for each danirixin dose.
Model Results Presentation
The following will be presented for each analysis based on the best fitting model using all post-burn 
in samples available.

The posterior mean, median, SD and 90% credible interval (CrI) for the change from baseline 
in E-RS: COPD total score for each treatment group.

The posterior mean and 90% CrI for the difference from placebo for each danirixin dose.


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
The posterior probability that difference from placebo is less than 0, -0.5, -1, -1.5 and -2 for 
each danirixin dose.

For the strategic interim, the posterior predictive probability of success for each danirixin dose, 
where success is the probability that the difference from placebo is less than 0 is >95%.

A figure of the fitted mean dose response model with the 90% CrI for all possible doses in the 
dose range, overlaid with the Month 6 adjusted posterior means and 90% CrI from the 
longitudinal model in Section 7.1.3.
Sensitivity and Supportive Analyses

At the strategic interim, a supportive analysis will be conducted to estimate the effect of actual 
treatment in the population of participants who were confirmed as having CMH according to 
SGRQ, were symptomatic at baseline, did not experience a protocol deviation considered to 
impact efficacy, and completed six months of treatment.  The population used will be the 
Symptomatic population; all other details will be the same as for the primary analysis.
7.1.2.
E-RS: COPD Subscale Scores Dose-Response Analysis
The primary analysis described in Section 7.1.1 will be repeated for the three E-RS:
COPD subscale scores of breathlessness, cough and sputum and chest symptoms.
7.1.3.
E-RS: COPD Total and Subscale Scores Longitudinal Analysis
The estimand is the effect of actual treatment in the population of participants who did 
not experience a protocol deviation considered to impact efficacy.  A supportive analysis 
will be performed to assess the effect of randomized treatment in all randomized and 
dosed participants.
A Bayesian mixed effects analysis with repeated measures (MMRM) will be performed 
on the monthly E-RS: COPD total and subscale scores.
A frequentist MMRM analysis will be performed on the monthly E-RS: COPD total 
scores and repeated to assess the impact of various covariates.
7.1.3.1.
Endpoint
Change from baseline in monthly mean E-RS: COPD total and subscale scores as defined 
in Section 14.6.3.
7.1.3.2.
Summary Measure
For the Bayesian MMRM the summary measure is the adjusted posterior mean difference 
from placebo for each danirixin dose.
For the frequentist MMRM the summary measure is the adjusted mean difference from 
placebo for each danirixin dose.
7.1.3.3.
Population of Interest
PP population.


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7.1.3.4.
Strategy for Intercurrent (Post-Randomization) Events
A ‘hypothetical’ strategy will be used to account for the intercurrent events of occurrence 
of a protocol deviation considered to impact efficacy during the treatment period (see 
Appendix 1) and treatment discontinuation, to estimate the effect if participants had not 
deviated from the protocol and remained on treatment. Only E-RS: COPD data prior to 
the occurrence of a protocol deviation considered to impact efficacy or treatment 
discontinuation will be used in the analysis. Subsequent data up to Month 6 will be 
assumed to be missing at random (MAR). 
7.1.3.5.
Statistical Analyses / Methods
7.1.3.5.1.
Bayesian MMRM Methodology Specification
Endpoint / Variables

Change from baseline in monthly E-RS: COPD total and subscale scores
Model Specification

Bayesian mixed models repeated measures approach.

The model will include treatment*visit, baseline*visit, country and smoking status parameters.   
Note that the model will not include an intercept.  Visit will consist of six levels (Month 1-Month 
6), and Treatment will consist of six levels (placebo and 5 active doses). If the model does not 
run, the country covariate will be removed.

The priors for the mean vector for each of the parameters (i.e covariates) will each follow a 
normal distribution with mean 0 and SD 1000.  The prior for the variance-covariance will follow 
an inverse Wishart distribution with degrees of freedom equal to the number of visits and an 
identity scale array.  150,000 samples will be generated with a thin of 75 after a burn-in of 
10,000 samples.  The number of samples or thin may be increased as needed to reduce the 
MCSE/SD<0.01 as deemed necessary.

Three chains will be used to calculate the gelman-rubin R statistic:
o
Chain 1: The starting value for all covariates in the model will be 0.
o
Chain 2: The starting value for all covariates in the model will be 2.
o
Chain 3: The starting value for all covariates in the model will be -2.

The seeds used to for the three chains were generated using the ranuni function in SAS and 
are listed in Section 14.5.2.

All post-burn-in samples will be used when creating outputs.
Model Checking & Diagnostics

Posterior density plots and plots of the posterior samples (chains) will be produced for all the 
parameters in the model.

The posterior density for the adjusted mean change from baseline in E-RS: COPD score in 
each treatment group and differences versus placebo for each danirixin dose will be plotted.

The Gelman-Rubin R estimate from the three chains will be calculated for all parameters in the 
model and the differences from placebo for each danirixin dose.

Distributional assumptions underlying the model used for analyses using MMRM will be 
examined by obtaining a normal probability plot of the residuals and a plot of the residuals 
versus the fitted values (i.e. checking the normality assumption and constant variance 
assumption of the model respectively) to gain confidence that the model assumptions are 


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reasonable. Plots of residuals versus covariates and baseline versus response will also be 
examined.
Model Results Presentation

The adjusted posterior mean change from baseline and the associated 90% equi-tailed CrI for 
each Month for each treatment.

The adjusted mean difference from placebo and the associated 90% equi-tailed CrI for each 
Month for each danirixin dose.

The probability that each treatment difference is less than 0, -0.5, -1, -1.5 and -2 for each 
month for each danirixin dose.

A figure of the posterior mean and 90% equi-tail CrI for each Month for each treatment.
Sensitivity and Supportive Analyses

At the strategic interim a supportive analysis of monthly E-RS: COPD total score will be 
conducted to estimate the effect of actual treatment in the population of participants who were 
confirmed as having CMH according to SGRQ, were symptomatic at baseline, and did not 
experience a protocol deviation considered to impact efficacy.  The population used will be the 
Symptomatic population; all other details will be the same as for the primary analysis.

At the strategic interim a further supportive analysis will be conducted to estimate the effect of 
the randomized treatment.  The population used will be the ITT (according to randomized 
treatment). A ‘treatment policy’ strategy will be used to account for the intercurrent event of 
occurrence of a protocol deviation considered to impact efficacy during the treatment period 
(see Appendix 1). All E-RS: COPD data up the time of treatment discontinuation or Month 6 
(see Section 14.6.3) will be used in the analysis, regardless of any protocol deviation. A 
‘hypothetical’ strategy will be used to account for the intercurrent event of treatment 
discontinuation. Data after treatment discontinuation will be considered MAR.
7.1.3.5.2.
Frequentist MMRM Methodology Specification
Endpoint / Variables

Change from baseline in monthly E-RS: COPD total score
Model Specification

The following covariates will be included in the model: baseline, country, smoking status at 
screening, treatment, Month, Month*baseline and Month*treatment interactions, where Month 
is nominal. Month will consist of six levels (Month 1-Month 6), and treatment will consist of six 
levels (placebo and 5 active doses)

Two models will be fitted; one with a response variable of E-RS: COPD Total Score, and one 
with a response variable of change from baseline in E-RS: COPD Total Score.

An unstructured covariance structure for the R matrix will be used by specifying ‘type=UN’ on 
the REPEATED line.

The Kenward and Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used. If this 
method does not run, the residual method will be used instead

The OM option will be used to derive the least square (LS) means using coefficients which are 
based on the participants used in the analysis. The OM option requires an OM dataset which 
has a row for every participant-visit combination that contains all of the covariates used in the 
model and a macro variable containing the mean baseline for the participants used in the 


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analysis.
Model Checking & Diagnostics

Distributional assumptions underlying the model used for analyses using MMRM will be 
examined by obtaining a normal probability plot of the residuals and a plot of the residuals 
versus the fitted values (i.e. checking the normality assumption and constant variance 
assumption of the model respectively) to gain confidence that the model assumptions are 
reasonable. Plots of residuals versus covariates and baseline versus response will also be 
examined.
Model Results Presentation

LS mean and LS mean changes from baseline with their corresponding standard errors (SEs) 
for each Month and each treatment

Estimated treatment differences from placebo and corresponding 90% confidence intervals 
(CIs) and p-values for each Month and each danirixin dose.

A figure of LS mean changes from baseline and 90% CIs for each treatment by Month will be 
generated.

A figure of LS mean and 90% CIs for each treatment by Month will be generated.

The type III tests of fixed effects from the model will be presented.
Summary Results Presentation

A figure of daily mean E-RS: COPD total and subscale scores over time (Days -7 to 168) for 
the PP population.

A figure of daily mean E-RS: COPD total and subscale scores over time by completer status 
(Days -7 to 168) for the PP population.

A figure of daily mean change from baseline E-RS: COPD total and subscale scores over time 
for the PP population.

A figure of daily mean (SE) change from baseline E-RS: COPD total and subscale scores 
over time for each dose and placebo in a separate panel.  This figure will be produced for the 
PP and Symptomatic populations (Strategic interim only).

A figure of daily mean (SE) E-RS: COPD total and subscale scores over time (Days -7 to 
168) for each dose and placebo in a separate panel.  This figure will be produced for the PP 
population.

Summary statistics for baseline E-RS: COPD total and subscale scores for each treatment and 
overall for participants with non-missing score for each Month, for the PP and Symptomatic
(Strategic interim only) population.

Summary statistics for raw and change from baseline monthly mean E-RS: COPD total and 
subscale scores for each month for each treatment, for the PP and Symptomatic population
(Strategic interim only).

Empirical distribution function plot of E-RS: COPD Total Scores at Baseline and at Month 6.
7.2.
Secondary Efficacy Analyses
The estimand is the effect of actual treatment in the population of participants who did 
not experience a protocol deviation considered to impact efficacy.


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A supportive analysis will be conducted to estimate the treatment policy effect of the 
randomized treatment on the annual rate of HCRU exacerbations in all randomized and 
dosed participants.
7.2.1.
Annual Rate of HCRU Exacerbations and Annual Rate of EXACT 
Events
7.2.1.1.
Endpoint
Annual rate of moderate/severe HCRU exacerbations as defined in Section 14.6.3.
Annual rate of EXACT events as defined in Section 14.6.3.  
7.2.1.2.
Summary Measure
Rate ratio (also expressed as percentage rate reduction) for each danirixin dose vs. 
placebo
7.2.1.3.
Population of Interest
PP population
7.2.1.4.
Strategy for Intercurrent (Post-Randomization) Events
The intercurrent events of interest are occurrence of a protocol deviation considered to 
impact efficacy during the treatment period (see Appendix 1) and treatment 
discontinuation. An ‘as treated’ strategy will be used to account for these events to 
estimate the effect if participants had not deviated from the protocol and remained on 
treatment. Only HCRU exacerbations/EXACT events prior to the occurrence of a 
protocol deviation considered to impact efficacy will be used in the analysis.
7.2.1.5.
Statistical Analyses / Methods
7.2.1.5.1.
Statistical Methodology Specification
Endpoint / Variables

Annual rate of On-treatment moderate/severe HCRU exacerbations

Annual rate of On-treatment EXACT events
Model Specification

Bayesian generalized linear model assuming a negative binomial distribution for the 
underlying exacerbation rate with a log link function

Terms in the model:
o
Response: number of on-treatment, moderate/severe HCRU exacerbations or EXACT 
events per participant.
o
Categorical: treatment group, gender, exacerbation history (≤1, ≥2 moderate/severe),
smoking status (screening), country
o
Continuous: post-bronchodilator % predicted FEV1 (Screening)
o
An offset to account for the length of time on treatment for each participant will be 


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included in the model as loge (length of time) as defined in Section 14.6.3.
o
Non-informative priors will be used for all modelling parameters. Wherever possible 
conjugate priors will be utilised.
o
All the terms in the model will follow a normal distribution with a mean of 0 and a SD of 
100, except for dispersion which follows a gamma distribution with shape and inverse 
scale of 0.001. 

Three chains will be used to calculate the gelman-rubin R statistic:
o
Chain 1: The starting value for all covariates in the model will be the maximum 
likelihood estimation (MLE), except dispersion which will be 0.1.
o
Chain 2: The starting value for all covariates in the model will be 130% of the MLE, 
except for dispersion which will be 0.2.
o
Chain 3: The starting value for all covariates in the model will be 70% of the MLE, 
except for dispersion which will be 0.4.

The seeds used to for the three chains were generated using the ranuni function in SAS and 
are listed in Section 14.5.2.

Burn-in 2000, thin 5, and 10,000 MCMC samples will be generated for 2000 retained samples
Model Checking & Diagnostics

The fit of the regression models will be examined using “Q-Q” plots of the standardized 
residuals. Interpretation of these plots will be aided by the addition of simulated envelopes as 
proposed by Atkinson (Atkinson, 1985).

The Gelman-Rubin R estimate will be calculated for all parameters in the model and the rate 
ratios vs. placebo for each danirixin dose.

Autocorrelation plots will be visually inspected to assess degree of autocorrelation (should 
decline rapidly and show no oscillation patterns).
Model Results Presentation

Model estimated median exacerbation/event rate and associated 90% CrI for each treatment 
group

Median rate ratio and associated 90% CrI, percent reduction in annual exacerbation/event rate 
and associated 90% CI for each danirixin dose vs. placebo

The probability that the true exacerbation rate ratio is less than 1, 0.9 and 0.8 for each danirixin 
dose will be presented

A figure of the rate ratios and associated 90% CrIs for each danirixin dose vs. placebo
Summary Results Presentation
For HCRU exacerbations:

Number and percent of participants reporting an exacerbation (mild, moderate, severe and
moderate/severe), number and percent of participants with each number of moderate/severe
exacerbations (0, 1, ≥2), the total number of exacerbations per treatment and annual raw
exacerbation rate (as defined in Section 14.6.3).  This table will be repeated for HCRU 
exacerbations that were treated with Antibiotics and will include the number and percentage of 
participants who were receiving ICS treatment at the time of the exacerbation.

For each moderate/severe exacerbation, the outcome, severity, duration, whether the
exacerbation led to hospitalization, systemic/oral corticosteroids being taken, antibiotics being 
taken, or emergency room visit.
For EXACT events:

Number and percent of participants reporting an EXACT-defined event, number and percent of 


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participants with each number of EXACT-defined events (0, 1, ≥2), the number of EXACT-
defined events and annual raw event rate (as defined in Section 14.6.3) will be summarized for 
all events and for recovered, censored and persistent worsening events separately for each 
treatment group.  The duration and severity (indicated by the maximum observed value and 
duration) will be reported for all events.  
Sensitivity and Supportive Analyses

At the strategic interim a supportive analysis of HCRU exacerbations will be conducted to 
estimate the effect of the randomized treatment.  The population used will be the ITT 
(according to randomized treatment). A ‘treatment policy’ strategy will be used to account for 
the intercurrent event of occurrence of a protocol deviation considered to impact efficacy during 
the treatment period (see Appendix 1). All on-treatment exacerbations up the time of treatment 
discontinuation will be used in the analysis, regardless of any protocol deviation. An ‘as treated’ 
strategy will be used to account for the intercurrent event of treatment discontinuation – no 
exacerbations will be recorded after treatment discontinuation/study withdrawal.
7.2.2.
Time to First HCRU Exacerbation and EXACT Event
7.2.2.1.
Endpoint
Time to first moderate/severe HCRU exacerbation as defined in Section 14.6.3.
Time to first severe HCRU exacerbation as defined in Section 14.6.3.
Time to first EXACT event as defined in Section 14.6.3.  
7.2.2.2.
Summary Measure
Hazard ratio (also expressed as percentage risk reduction) for each danirixin dose vs. 
placebo)
7.2.2.3.
Population of Interest 
PP population
7.2.2.4.
Strategy for Intercurrent (Post-Randomization) Events
The intercurrent events of interest are occurrence of a protocol deviation considered to 
impact efficacy during the treatment period (see Appendix 1) and treatment 
discontinuation. An ‘as treated’ strategy will be used to account for these events to 
estimate the effect if participants had not deviated from the protocol and remained on 
treatment. Only first exacerbations/EXACT events prior to the occurrence of a protocol 
deviation considered to impact efficacy will be used in the analysis.


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7.2.2.5.
Statistical Analyses / Methods
7.2.2.5.1.
Statistical Methodology Specification
Endpoint / Variables

Time to first On-treatment moderate/severe HCRU exacerbation

Time to first On-treatment severe HCRU exacerbation

Time to first On-treatment EXACT event
Model Specification

Bayesian proportional hazards model

Terms in the model:
o
Response: time to first on-treatment, moderate/severe HCRU exacerbation or EXACT 
event
o
Categorical: treatment group, gender, exacerbation history (≤1, ≥2 moderate/severe), 
smoking status (screening), country
o
Continuous: post-bronchodilator % predicted FEV1 (Screening)
o
Non-informative priors will be used for all modelling parameters. Wherever possible 
conjugate priors will be utilised.
o
All the terms in the model will follow a normal distribution with a mean of 0 and a SD of 
100

The ‘exact’ method will be used for handling ties. If the analysis will not run using the ‘exact’
method, then the ‘Efron’ method for handling ties will be used instead.

Three chains will be used to calculate the gelman-rubin R statistic:
o
Chain 1: The starting value for all covariates in the model will be the MLE, except 
dispersion which will be 0.1.
o
Chain 2: The starting value for all covariates in the model will be 130% of the MLE, 
except for dispersion which will be 0.2.
o
Chain 3: The starting value for all covariates in the model will be 70% of the MLE, 
except for dispersion which will be 0.4.

The seeds used to for the three chains were generated using the ranuni function in SAS and 
are listed in Section 14.5.2.

Burn-in 2000, thin 5, and 10,000 MCMC samples will be generated for 2000 retained samples

Kaplan-Meier survivor functions will be obtained for each treatment group using PROC 
LIFETEST with a TIME statement.
Model Checking & Diagnostics

The proportional hazards assumption will be examined by obtaining the Kaplan-Meier 
estimates of the survival function S(t) over time separately for each treatment group. In 
addition, the ln {-ln[S(t)]} plot will be produced.
Model Results Presentation

Hazard ratio and the percent reduction in risk for each danirixin dose compared with placebo 
with associated 90% CrI.

The probability of having an event, 90% CrI and first quartile and median time to event for each 
treatment group will be presented.

The probability that the true hazard ratio is less than 1 for each danirixin dose will be 
presented.


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
Kaplan-Meier curves showing the probability of having an event over time for each treatment 
group separately plotted on the same figure
7.2.3.
E-RS: COPD Total and Subscale Scores Responder Analysis
7.2.3.1.
Endpoint
Response according to E-RS: COPD total score, subscale scores, SGRQ total score or 
CAT score as defined in Section 14.6.3.
7.2.3.2.
Summary Measure
Ratio of odds of being a responder vs. not for each danirixin dose vs. placebo
7.2.3.3.
Population of Interest 
PP population
7.2.3.4.
Strategy for Intercurrent (Post-Randomization) Events
A ‘hypothetical’ strategy will be used to account for the intercurrent events of occurrence 
of a protocol deviation considered to impact efficacy during the treatment period (see 
Appendix 1) and treatment discontinuation, to estimate the effect if participants had not 
deviated from the protocol and remained on treatment. Only response data prior to the 
occurrence of a protocol deviation considered to impact efficacy or treatment 
discontinuation will be used in the analysis. Subsequent data up to Month 6 will be 
assumed to be missing at random (MAR). 
7.2.3.5.
Statistical Analyses / Methods
7.2.3.5.1.
Statistical Methodology Specification
Endpoint / Variables

Response according to E-RS: COPD total score, subscale scores, SGRQ total score or CAT 
score
Model Specification

Generalized linear mixed model

Terms in the model:
o
Dependent : response (yes/no)
o
Categorical : treatment group, smoking status (screening), country, visit/month
o
Continuous : baseline
o
Interaction : baseline*visit/month, treatment group*visit/month

The model will be fit with an unstructured variance-covariance matrix with one single model to 
include all visits/months where the assessment in question is scheduled to be performed.

Computation of confidence intervals for the odds ratios is based on the individual Wald tests.


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Model Checking & Diagnostics

Pearson residuals will be plotted by using PLOTS=PEARSONPANEL option for the model 
statement in SAS.
Model Results Presentation

Number and percentage of responders and non-responders for each treatment at each 
visit/month

Odds ratio for comparison of each danrixin dose with placebo, with associated 90% CI and p-
value
7.2.4.
SGRQ Total Score and CAT Score
SGRQ total score and CAT score at each visit will be analysed using the same 
methodology as for E-RS: COPD total and subscale scores longitudinal analysis (as 
described in Section 7.1.3.5.1).  Visit will be substituted for Month. A figure of mean and 
90% CIs for each treatment over time will be generated for SGRQ Total Score and CAT 
Score.
7.2.5.
Rescue Use
The monthly mean number of puffs of rescue use per day according to diary card data 
and the monthly mean number of occasions of rescue use per day according to sensor 
data and the monthly percentage of rescue-free days according to diary card data and 
according to sensor data will be analysed using the same methodology as for E-RS:
COPD total and subscale scores longitudinal analysis (as described in Section 7.1.3.5.2).
A figure of daily mean number of puffs of rescue medication per day using diary data 
over time and daily mean number of occasions of rescue medication per day using sensor 
data over time will be generated for the PP population.
Additional analysis of rescue use according to sensor data may be performed and will be 
defined in a separate RAP.
7.2.6.
Physical Activity
Assessment of physical activity during clinical visits (C-PPAC) has been developed to 
capture experience of physical activity in participants with COPD. This physical activity 
data will be combined with activity monitor data to assess physical activity experience 
according to the IMI PROactive User Guide (14JUN16). A PROactive Total Score and 
two domain scores (amount and difficulty) will be derived.  
Raw and change from baseline PROactive Total Score and Domain scores (Amount and 
Difficulty) will be summarized.
For the strategic interim, the responses to the C-PPAC questions at each visit will be 
summarized.
Additional analysis of activity monitor data may be performed and will be defined in a 
separate RAP.


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7.3.
Exploratory Efficacy Analyses
7.3.1.
E-RS: COPD Total Score
For the final analysis the list of subgroups may be amended.
Exploratory Statistical Analyses
Model Specification
For the PP population, an assessment of whether the effect of treatment on E-RS: COPD Total Score is 
modified by:
o
Baseline E-RS: COPD Total Score (continuous) (Strategic Interim only)
o
Smoking Status at Screening 
o
Country (Strategic Interim only)  
will be made by fitting separate repeated measures models, identical to the MMRM model described in 
Section 7.1.3.5.2 but also including additional terms for the treatment by factor interaction.
An assessment will be made of whether the effect of treatment on E-RS: COPD Total Score is modified 
by the following factors (as defined in Section 5.4.2):
o
Percent Predicted FEV1 at Screening (continuous)
o
Baseline CAT Score (continuous)
o
Exacerbation history (Strategic Interim only)
o
COPD Medication at Baseline (Strategic Interim only)
o
CMH status at baseline (Strategic Interim only)
o
Season (Strategic Interim only)
This will be made by fitting separate repeated measures models, identical to the model described above 
but also including additional terms for the factor and the treatment by factor interaction.
If an interaction from these analyses is significant at the 10% level it implies that the effect of treatment on 
E-RS: COPD Total Score is modified by the factor. The analysis will be run by each level of the factors as 
listed below regardless of significance level (excluding any groups with sparse data):
o
Baseline E-RS: COPD Total Score <10, ≥10 (Strategic Interim only)
o
Smoking Status at Screening - Former, Current 
o
Country (Strategic Interim only)
o
Percent Predicted FEV1 at Screening <50, ≥50
o
Baseline CAT Score <10, ≥10
o
Exacerbation history (history of ≥2 moderate/severe exacerbations, <2 moderate/severe 
exacerbation) (Strategic Interim only)
o
COPD Medication at Baseline (ICS+LABA+LAMA vs. ICS+LABA vs. LABA+LAMA vs. Other 
COPD medication) (Strategic Interim only)
o
CMH +, - (Strategic Interim only)
o
Season (The estimates from this model will be presented for each season.) (Strategic 
Interim only)
Model Checking & Diagnostics

Distributional assumptions underlying the model used for analyses using MMRM will be examined by 
obtaining a normal probability plot of the residuals and a plot of the residuals versus the fitted values 
(i.e. checking the normality assumption and constant variance assumption of the model respectively) 
to gain confidence that the model assumptions are reasonable.  Plots of residuals versus covariates 
and baseline versus response will also be examined.


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Exploratory Statistical Analyses
Model Results Presentation

The interaction p-values from the interactions of treatment with the factors above will be presented.

Comparisons of each danirixin dose with placebo for each level of each categorical subgroup.

LS Mean changes from baseline estimates for each treatment by visit (except for season) along with 
90% CIs will be obtained for each level of the subgroup.

LS Mean changes from baseline estimates for each treatment along with 90% CIs will be obtained 
for each level of the season subgroup.  

LS Mean changes from baseline estimates and 90% CIs will be plotted against treatment in separate 
panels for each level of the factor for Month 6 (except for season).LS Mean changes from baseline 
estimates and 90% CIs will be plotted by treatment for each level of the season subgroup.    

If an interaction between treatment and factor is significant at the 10% level an additional plot of LS 
Mean changes from baseline and 90% CIs against treatment by Month will be produced with a 
separate plot for each level of the factor (except for season).
7.3.2.
CAT Score
CAT score will be analysed using the same methodology as for E-RS: COPD total scores 
exploratory statistical analysis (as described in Section 7.3.1).  
7.3.3.
Time to First Clinically Important Deterioration
Following the Strategic Interim, the study team decided not to report this exploratory 
endpoint.
7.3.4.
SGRQ Domain Scores
Raw and change from baseline SGRQ domain scores will be summarized.
7.3.5.
Participant Global Assessments
Participant global assessments of severity, change in severity, activity limitation and 
change in activity limitation will be summarized.


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8.
SAFETY ANALYSES
Details of the planned displays including the population to be used for each display and 
which displays are produced for the strategic interim are presented in Appendix 11.  
Additional details are provided below.
The estimand is the effect of actual treatment in the population of participants who were 
randomized and dosed.  All collected data will be included in reporting as described 
below.  Non-recorded missing data following study withdrawal will not be imputed.
8.1.
Adverse Events Analyses
Adverse events analyses including the analysis of AEs, SAEs and other significant AEs 
will be based on GSK Core Data Standards.
8.2.
Adverse Events of Special Interest Analyses
AESI have been defined as AEs which have specified areas of interest for the COPD 
population.  A list of Standardized Medical Dictionary for Regulatory Activities 
(MedDRA) Queries (SMQs) and other groupings for AESI is provided in Section 14.6.4
8.3.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, Hematology 
laboratory testsand liver function tests will be based on GSK Core Data Standards.
8.4.
Spirometry
The estimand is the effect of actual treatment in the population of participants who were 
randomised and dosed.
A frequentist MMRM analysis will be performed on spirometry data.
8.4.1.
Endpoint
Change from baseline in post-BD FEV1 
Change from baseline in post-BD FVC
8.4.2.
Summary Measure
The summary measure is the adjusted mean difference from placebo for each danirixin 
dose.
8.4.3.
Population of Interest 
mITT population.


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8.4.4.
Strategy for Intercurrent (Post-Randomization) Events
The intercurrent event of interest is treatment discontinuation. A ‘hypothetical’ strategy 
will be used to account for this event. All recorded data up to the time of treatment
discontinuation will be included in the analysis. Subsequent data up to Day 168 will be 
assumed to be missing at random (MAR). 
8.4.5.
Statistical Analyses / Methods
8.4.5.1.
Frequentist MMRM Methodology Specification
Endpoint / Variables

Change from baseline in post-BD FEV1

Change from baseline in post-BD FVC
Model Specification

The following covariates will be included in the model: baseline, country, smoking status at 
screening, treatment, Visit, Visit *baseline and Visit *treatment interactions, where Visit is 
nominal. Visit will consist of two levels (Day 84 and 168), and treatment will consist of six levels 
(placebo and 5 active doses)

Two models will be fitted; one with a response variable (FEV1 or FVC), and one with a 
response variable of change from baseline (FEV1 or FVC).

An unstructured covariance structure for the R matrix will be used by specifying ‘type=UN’ on 
the REPEATED line.

The Kenward and Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used. If this 
method does not run, the residual method will be used instead

The OM option will be used to derive the least square (LS) means using coefficients which are 
based on the participants used in the analysis. The OM option requires an OM dataset which 
has a row for every participant-visit combination that contains all of the covariates used in the 
model and a macro variable containing the mean baseline for the participants used in the 
analysis.
Model Checking & Diagnostics

Distributional assumptions underlying the model used for analyses using MMRM will be 
examined by obtaining a normal probability plot of the residuals and a plot of the residuals 
versus the fitted values (i.e. checking the normality assumption and constant variance 
assumption of the model respectively) to gain confidence that the model assumptions are 
reasonable. Plots of residuals versus covariates and baseline versus response will also be 
examined.
Model Results Presentation

LS mean and LS mean changes from baseline with their corresponding standard errors (SEs) 
for each visit and each treatment

Estimated treatment differences from placebo and corresponding 90% confidence intervals 
(CIs) and p-values for each visit and each danirixin dose.

A figure of LS mean changes from baseline and 90% CIs for each treatment by visit will be 
generated.

The type III tests of fixed effects from the model will be presented.


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Summary Results Presentation

Summary statistics for baseline post-BD FEV1, FVC and FEV1/FVC for each treatment and 
overall for participants with non-missing assessments for each Visit, for the mITT population.

Summary statistics for raw and change from baseline post-BD FEV1, FVC and FEV1/FVC for 
each visit for each treatment, for the mITT population.

A figure of mean and 90% CIs for each treatment by visit (including baseline, Day 84 and Day 
168) will be generated for post-BD FEV1, FVC and FEV1/FVC.
8.5.
Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified.
9.
PHARMACOKINETIC ANALYSES
9.1.
Primary Pharmacokinetic Analyses
9.1.1.
Derived Pharmacokinetic Parameters
PK parameters will be calculated by standard non-compartmental analysis according to 
current working practices and using the currently supported version of WinNonlin. All 
calculations of non-compartmental parameters will be based on actual sampling times. 
PK parameters listed will be determined from the blood concentration-time (dry blood 
spot) data at Visit 3 and 10, as data permits for participants in the PK sub-set collecting 
PK samples at pre-dose, 0.5. 1. 2. 4. 6, 8, 10, 12 hours post-dose.
Parameter
Parameter Description
AUC(0-t)
Area under the concentration-time curve from time zero to the time of the last quantifiable 
concentration (C(t)) will be calculated using the linear trapezoidal rule for each incremental 
trapezoid and the log trapezoidal rule for each decremental trapezoid.
Cmax
Maximum observed concentration, determined directly from the concentration-time data.
Tmax
Time to reach Cmax, determined directly from the concentration-time data.
Tlast
Time of last quantifiable concentration
NOTES:

Additional parameters may be included as required.
9.1.2.
Statistical Analyses / Methods
No formal statistical analysis of the dry blood spot PK concentrations or PK parameters 
will be performed. Details of the planned displays are provided in Appendix 11 and will 
be based on GSK Data Standards and statistical principles.


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9.2.
Exploratory Pharmacokinetic Analyses
9.2.1.
Derived Pharmacokinetic Parameters
Note: Approximately 20% of the wet whole blood samples collected at Visit 3 will be 
analysed for danirixin concentrations to provide an analytical comparison between dried 
blood spot and wet whole blood sample results. The expectation is that samples selected 
will mainly come from those samples provided by participants in the PK sub-set (i.e.
collecting samples over 12 hours) and be distributed across danirixin treatment groups.
PK parameters will be calculated by standard non-compartmental analysis according to 
current working practices and using the currently supported version of WinNonlin. All 
calculations of non-compartmental parameters will be based on actual sampling times. 
PK parameters listed will be determined from the blood concentration-time (wet whole 
blood) data at Visit 3, as data permits.
Parameter
Parameter Description
AUC(0-t)
Area under the concentration-time curve from time zero to the time of the last quantifiable 
concentration (C(t)) will be calculated using the linear trapezoidal rule for each incremental 
trapezoid and the log trapezoidal rule for each decremental trapezoid.
Cmax
Maximum observed concentration, determined directly from the concentration-time data.
Tmax
Time to reach Cmax, determined directly from the concentration-time data.
Tlast
Time of last quantifiable concentration
NOTES:

Additional parameters may be included as required.
9.2.2.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 11 and will be based on GSK 
Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 9.2.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
9.2.2.1.
Statistical Methodology Specification
An extension of the Bland and Altman approach [Bland, 1986; Bland, 1999] will be used 
to quantify the agreement between the assay methods using log-transformed data, 
including hematocrit in the model. Age and weight will also be added one at a time in a 
model building approach and their significance in the model will be assessed. Limits of 
agreement and the coefficient of variation will be assessed to determine the agreement of 
the assay methods and whether wet whole blood assay is comparable to dry blood spot
assay. 
A sensitivity analysis will be performed excluding dry blood spot concentrations above 
the assay higher level of quantification of 1000 ng/mL.


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Endpoint / Variables

Log-transformed Danirixin blood concentration and pharmacokinetic parameter (Cmax and 
AUC(0-t)) data
Model Specification

The Bland and Altman method will be used.

The following covariates will be included in the model: haematocrit, age and weight.
Model Results Presentation

Separate outputs will be produced for Danirixin concentration and pharmacokinetic parameters 
(although both will be analyzed using the same model)

Estimates of intercept and slope on log-scale for Danirixin concentration and pharmacokinetic 
parameters, bias at concentration is 0, %CVw, geometric means and limit of agreement at 
concentration is 0.

Comparative plots of individual blood concentration and pharmacokinetic parameter data.

Supportive SAS output from statistical analysis.
Sensitivity and Supportive Analyses

A sensitivity analysis excluding dry blood spot concentrations above the assay HLOQ of 1000 
ng/mL will be performed.
10.
POPULATION PHARMACOKINETIC ANALYSES
PK data from this study may be combined with historic data for the purposes of
population PK (PopPK) modelling which would be the subject of a separate analysis plan 
and would be presented separately from the main CSR.
To support this analysis a PopPK dataset will be generated. The details for the dataset 
specifications are provided in Appendix 9.
11.
BIOMARKER ANALYSES
C-reactive protein and fibrinogen data will be summarized in the same way as laboratory 
data. Summary tables and boxplots for each treatment by visit (including screening, 
baseline, Day 84 and Day 168) will be generated for the mITT populations and also for 
the subset of subjects who have an event in the ‘Infective pneumonia’ SMQ.
Exploratory biomarker analysis will be the subject of a separate RAP.


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12.
PHARMACOKINETIC / PHARMACODYNAMIC
ANALYSES
Graphical assessment of the relationship between individual danirixin exposure and PD 
endpoints will be conducted.
Contingent on any PK/PD relationship(s) being identified from the graphical assessment 
a PK/PD dataset will be generated. The details for the methodology and dataset 
specifications will be provided in a separate document after review of the graphical 
assessment of the relationship between PK and PD endpoints.
12.1.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 11 and will be based on GSK 
Data Standards and statistical principles.


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13.
REFERENCES
Atkinson, AC. (1985) Plots, Transformations and Regression. Clarendon Press.
Bland JM, Altman DG. (1986). Statistical methods for assessing agreement between two
methods of clinical measurement. Lancet, i, 307-310
Bland JM, Altman DG. (1999). Measuring agreement in method comparison studies.
Statistical Methods in Medical Research 1999; 8: 135-160.
Bornkamp, B. (2014). Practical considerations for using functional uniform prior 
distributions for dose-response estimation in clinical trials. Biometrical Journal, 947–962.
Chong J, Leung, B and Poole P. Phosphodiesterase 4 inhibitors for chronic obstructive 
pulmonary disease. Cochrane Database Syst. Rev. 2013; Issue 11
Crim C, Dransfield MT, Bourbeau J, et al. Pneumonia risk with inhaled fluticasone 
furoate and vilanterol compared with vilanterol alone in patients with COPD. Ann. Am. 
Thorac. Soc. 2015; 12(1): 27-34
Drummond MB, et al. Inhaled corticosteroids in patients with stable chronic obstructive 
pulmonary disease: a systemic review and meta-analysis. JAMA. 2008; 300(20): 2407 -
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EMA press release. PRAC reviews known risk of pneumonia with inhaled corticosteroids 
for chronic obstructive pulmonary disease. 2016
Evidera (2016a) The Exacerbations of Chronic Pulmonary Disease Tool (EXACT) 
Patient-Reported Outcomes (PRO), User Manual (Version 8.0).
Evidera (2016b) Evaluating Respiratory Symptoms (E-RS™) in COPD (E-RS™: COPD), 
User Manual (Version 5.0) 
IMI PROactive in COPD Daily and Clinical Instruments D-PPAC and C-PPAC User 
Guide (14JUN16)
Jones PW and Forde Y. (2016) St. Georges Respiratory Questionnaire for COPD Patients 
Manual, version 1.3
Spencer S, Karner C, Cates CJ, Evans DJ. Inhaled corticosteroids versus long-acting 
beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database of 
Systematic Reviews 2011, Issue 12. 
Spiegelhalter, D. J., Abrams, K. R., & Myles, J. P. (2004). Bayesian approaches to 
clinical trials and health-care evaluation. John Wiley & Sons.


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14.
APPENDICES
14.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
14.1.1.
Exclusions from Per Protocol Population
A participant meeting any of the following criteria will be excluded from the Per Protocol 
population:
Number
Exclusion Description
01
Inclusion #2 – FEV1/FVC ratio >=0.70 or % predicted FEV1<40% at Screening
02
Inclusion #4 – <2 historical exacerbations or one historical exacerbation with screening 
fibrinogen <3 g/L
03
Inclusion #5 - Smoking history of <10 pack years at Screening
04
Exclusion #4 - Screening visit is less than 14 days since the completion of a course of 
antibiotics or oral steroids for a COPD exacerbation
05
Exclusion #14 - Use of PDE4 inhibitors within 30 days of Screening
06
Exclusion #26 - Oxygen use that is not PRN at Screening
At the strategic interim a participant meeting any of the following criteria will be 
excluded from the Per Protocol population:
Number
Exclusion Description
07
Xanthines at any time between the day after screening and end of treatment
08
PDE4 inhibitors at any time between screening and end of treatment
09
Chronic use (more than 3 months) of erythromycin or azithromycin for between screening 
and end of treatment
10
Participants who stopped study medication for more than 14 days 
11
Blind broken
For the final analysis a participant meeting any of the following criteria will have data 
excluded from the time of the deviation.  If a prohibited medication is taken prior to 
randomisation the participant will be excluded from the Per Protocol population.
Number
Exclusion Description
07
Xanthines at any time between the day after screening and end of treatment
08
PDE4 inhibitors at any time between screening and end of treatment
09
Chronic use (more than 3 months) of erythromycin or azithromycin between screening and 
end of treatment
10
Participants who stopped study medication for more than 14 days will be excluded from the 
PP analyses from the time they stopped taking study medication.
11
Data excluded from date of breaking of blind.


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14.2.
Appendix 2: Schedule of Activities
14.2.1.
Protocol Defined Schedule of Events
Procedure
Pre-
Screeninga
(Visit 0)
Screeninga
(Visit 1)
Study Visits
2
3
4
5
6
7
8
9
10
Early 
Withdrawal
Follow Up
(up to 28 days 
post last dose)
Study Day
-7
1
14
28
56
84
112
140
168
Assessment Window
-30 d
  
0d
+
3d

3d
  
3d
  
3d
  
3d
  
3d
   
3d
  
3d
Eligibility 
Informed consent
X
Genetic Sample 
Informed Consentb
X
Demography
X
COPD Exacerbation 
History
X
Pre-Screening 
Fibrinogenc
X
Smoking Historyd
X
Smoking Statusd
X
X
Inclusion and 
Exclusion criteria
X
Medical historye
X
Full physical 
examination including 
height and weight
X


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Procedure
Pre-
Screeninga
(Visit 0)
Screeninga
(Visit 1)
Study Visits
2
3
4
5
6
7
8
9
10
Early 
Withdrawal
Follow Up
(up to 28 days 
post last dose)
Study Day
-7
1
14
28
56
84
112
140
168
Assessment Window
-30 d
  
0d
+
3d

3d
  
3d
  
3d
  
3d
  
3d
   
3d
  
3d
Chest x-ray (CXR)f
X
HIV, Hepatitis B and 
C screeningg
X
Pulse Oximetry
X
Additional Eligibility and In Study Assessments
Verify Eligibilityh
X
X
Brief Physical
X
X
X
X
X
Urine or serum
pregnancy testi
X
X
X
X
X
X
X
X
X
Laboratory 
assessments (clinical 
chemistry (includes 
liver chemistries), 
hematology, 
urinalysis) 
X
X
X
X
X
X
Additional Liver 
chemistries only
X
X
X
12-lead ECG
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
Spirometry
X
X
X
X
X
Randomization
X


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Procedure
Pre-
Screeninga
(Visit 0)
Screeninga
(Visit 1)
Study Visits
2
3
4
5
6
7
8
9
10
Early 
Withdrawal
Follow Up
(up to 28 days 
post last dose)
Study Day
-7
1
14
28
56
84
112
140
168
Assessment Window
-30 d
  
0d
+
3d

3d
  
3d
  
3d
  
3d
  
3d
   
3d
  
3d
Dispense Study 
Medication
X
X
X
X
X
X
Dispense log pad and 
provide training
X
Dispense MDI sensors 
and provide training
X
Dispense physical 
activity monitor and 
provide training
X
Study treatment
=====================================
Study treatment 
compliance (ediary)
=====================================
Collect IP
============================
X
X
Collect MDI sensors
X
X
Collect physical 
activity monitor
X
X
Collect log pad
X
X
Adverse Event (AE) 
review
=====================================
X
X
Serious Adverse 
Event (SAE) review
================================================================
X
X


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Procedure
Pre-
Screeninga
(Visit 0)
Screeninga
(Visit 1)
Study Visits
2
3
4
5
6
7
8
9
10
Early 
Withdrawal
Follow Up
(up to 28 days 
post last dose)
Study Day
-7
1
14
28
56
84
112
140
168
Assessment Window
-30 d
  
0d
+
3d

3d
  
3d
  
3d
  
3d
  
3d
   
3d
  
3d
Concomitant 
medication review
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Outcomes Assessments
COPD Exacerbations
===========================================
X
X
EXACT-PROj
===========================================
Rescue Medication 
Usek
===========================================
SGRQ-C
X
X
X
X
COPD Assessment 
Test
X
X
X
X
PROactive 
Questionnairel
X
X
X
Physical Activity 
Monitorl
X
X
X
Participant Global 
Impression of COPD 
Severity
X
Participant Impression 
of Change in COPD 
Severity
X
X
X
X
X
X
X
X


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Procedure
Pre-
Screeninga
(Visit 0)
Screeninga
(Visit 1)
Study Visits
2
3
4
5
6
7
8
9
10
Early 
Withdrawal
Follow Up
(up to 28 days 
post last dose)
Study Day
-7
1
14
28
56
84
112
140
168
Assessment Window
-30 d
  
0d
+
3d

3d
  
3d
  
3d
  
3d
  
3d
   
3d
  
3d
Participant Global 
Impression of Activity 
Limitation
X
Participant Impression 
of Change in Activity 
Limitation
X
X
X
X
X
X
X
X
Genetic, Pharmacokinetic and Biomarker Blood Collections
Blood sample for 
Genetics
X
Blood sample for 
pharmacokinetics 
(PK)m
X
X
X
X
Blood sample for 
Fibrinogen
X
X
X
X
Blood sample for CRP
X
X
X
X
Blood Sample for 
Exploratory
Biomarkers
X
X
X
X


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Procedure
Pre-
Screeninga
(Visit 0)
Screeninga
(Visit 1)
Study Visits
2
3
4
5
6
7
8
9
10
Early 
Withdrawal
Follow Up
(up to 28 days 
post last dose)
Study Day
-7
1
14
28
56
84
112
140
168
Assessment Window
-30 d
  
0d
+
3d

3d
  
3d
  
3d
  
3d
  
3d
   
3d
  
3d
a.
Pre-screening and screening visits may be completed on the same day.
b.
Agreeing to the genetic sample consent is not required for study participation.
c.
A pre-screening plasma fibrinogen measurement is only required for participants with 1 COPD exacerbation in the prior year.
d.
Smoking status /history assessed at screening: smoking status rechecked at Visit 2
e.
Includes substance usage, past and present medical conditions and family history of premature CV disease.
f. 
See inclusion/exclusion criteria for CXR screening requirement
g. 
Hepatitis B (HBsAg) and Hepatitis C (HepC antibody) testing is required. If testing otherwise performed within 3 months prior to the first dose of 
study treatment, testing at screening is not required.  Hepatitis C RNA testing is optional; however a confirmatory negative Hepatitis C RNA test must 
be obtained, to be able to enrol participants with positive Hepatitis C antibody due to prior resolved disease.
h.
Participant’s clinical status should be reviewed.
i.
Pregnancy testing only required for women of child bearing potential (WOCBP).  A positive urine pregnancy test requires confirmation with a serum 
pregnancy test.
j.
E-RS: COPD is a subset of EXACT-PRO and is not a separate assessment.
k.
Rescue medication use will be assessed via e-diary and MDI sensor.
l. 
The Clinic Visit PROactive Physical Activity in COPD tool will be assessed in a subset of approximately 50% of study participants
m.
Pre-dose PK samples will be collected in all participants at Visits 3, 6, 7, and 10.  In a subset of participants (approx. 50 participants at each dose 
level) at Visit 3, PK samples will be collected at pre-dose, 0.5, 1, 2, 4, 6, 8, 10, 12 hours post-dose.  In a subset of participants (approx.. 50 
participants at each dose level) at Visit 10, PK samples will be collected at pre-dose, 0.5. 1. 2. 4. 6, 8, 10, 12 hours post-dose.


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14.3.
Appendix 3: Assessment Windows
In general, data will be reported according to the nominal time of clinic visits and 
assessments as specified in the protocol. For example, if a participant recorded values for 
the Day 28 visit that were actually made on the 21st day of treatment, they will be 
presented as Day 28 values in the summary tables.
Participants that withdraw from the study at the time of a scheduled study visit will have 
data collected in the eCRF as part of the scheduled study visit. In order to collect all 
questionnaires that are scheduled to be performed at the Early Withdrawal (EW) Visit, 
eDiary data is reported as an EW Visit. If the date of the EW diary assessment is the 
same as the date of a scheduled visit date from the eCRF and there is no diary data 
present at the scheduled visit in question, the EW diary data will be listed, summarized 
and analysed as part of the scheduled visit (if the diary data was scheduled to be 
performed at the visit in question).


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14.4.
Appendix 4: Study Phases
14.4.1.
Study Phases
Assessments and events collected outside scheduled study visits will be classified into 
study phases according to the time of occurrence relative to the start and/or stop date of 
study treatment.  The ‘worst case-post baseline’ derivation for summaries will consider 
all scheduled and unscheduled measurements that have been assigned a treatment phase 
of ‘On-treatment’.
14.4.1.1.
Study Phases for Diary Data
Diary data (including EXACT events) treatment states are specified in Section 14.6.3.
14.4.1.2.
Study Phases for Concomitant Medication
COPD medication combinations taken at screening will include all COPD medications 
that were taken on the day of the screening visit, excluding medications that stopped on 
the day of the screening visit.
Treatment phases for summaries of COPD and non-COPD concomitant medications will 
be assigned as follows:
Study Phase
Definition
Prior
Medications taken on or before the day before treatment start date defined as:
(conmed start date < treatment start date or ‘Taken prior to study?’ is ‘Yes’ or study 
treatment not started or conmed start date is missing)
Note: prior concomitant medication data will only be summarized for COPD 
medications. All screening data will be listed.
On-treatment
If study treatment stop date > study treatment start date then this includes medications 
taken between the study treatment start date and study treatment stop date - 1 
(inclusive) defined as follows:
(conmed start date < study treatment stop date or conmed start date is missing) and 
(conmed stop date >= study treatment start date or (conmed stop date is completely 
missing and study treatment start date is non-missing))
If study treatment stop date = study treatment start date then this includes medications 
taken on the study treatment start date (which is equal to the study treatment stop 
date) defined as follows.
(conmed start date <= study treatment stop date or conmed start date is missing) and 
(conmed stop date >= study treatment start date or (conmed stop date is completely 
missing and study treatment start date is non-missing))
Post-treatment
If study treatment stop date > study treatment start date then this includes medications 
taken after the study treatment stop date defined as follows:
(conmed stop date >= study treatment stop date or (conmed stop date is completely 
missing and study treatment stop date is non-missing))
If study treatment stop date = study treatment start date then this includes medications 
taken after the study treatment stop date + 1 defined as follows.
(conmed stop date > study treatment stop date or (conmed stop date is completely 
missing and study treatment stop date is non-missing))


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NOTES: 

A concomitant medication will be classed in every period of the study in which it was taken.

See Section 14.7.2.1 for handling of partial dates.

If the study treatment stop date is missing, it will be imputed as described in Section 14.6.1.
14.4.1.3.
Study Phases for Event Data 
Classification of a HCRU exacerbation/AE as having onset on-treatment will be made 
with reference to the study treatment start and stop dates and the event onset date. If the 
event onset date is missing, then the event will be considered on-treatment. 
Study Phase
Definition
Pre-treatment
If onset date is prior to treatment start date
Start Date < Study Treatment Start Date
On-treatment
If onset date is on or after treatment start date & on or before treatment stop date + 3.
Study Treatment Start Date ≤ Start Date ≤ Study Treatment Stop Date + 3 days
Post-treatment
If onset date is after treatment stop date + 3.
Start Date > Study Treatment Stop Date + 3 days
Note: assume on-treatment unless there is evidence to the contrary 
14.4.1.4.
Study Phases for Other Data 
All data collected at scheduled study visits after Day 1 will be considered on-treatment. 
Any data collected at unscheduled visits (ie, laboratory data, vital signs, ECGs, 
spirometry, CAT and SGRQ) will be classified as on-treatment based on the study 
treatment start date (and time, if available) and study treatment stop date and the date 
(and time, if available) of the visit/assessment. If the visit/assessment date is missing, 
then the event will be considered on-treatment. 
Study Phase
Definition
Pre-treatment
If assessment/visit date (and time) is on or prior to treatment start date (and time)
Assessment/Visit Date (and time) ≤ Study Treatment Start Date (and time)
On-treatment
If assessment/visit date (and time) is after treatment start date (and time) & on or 
before treatment stop date + 3.
Study Treatment Start Date (and time) < Assessment/Visit Date (and time) ≤ Study 
Treatment Stop Date + 3 days
Post-treatment
If assessment/visit date is after treatment stop date + 3.
Assessment/Visit Date > Study Treatment Stop Date + 3 days
Note: assume on-treatment unless there is evidence to the contrary 


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14.5.
Appendix 5: Data Display Standards & Handling 
Conventions
14.5.1.
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
: uk1salx00175
HARP Compound
: GSK1325756
Analysis Datasets 

Analysis datasets will be created according to Legacy GSK A&R dataset standards for the strategic 
interim and CDISC standards (SDTM IG Version 3.2 & ADaM IG Version 1.1].
Generation of RTF Files

RTF files will be generated for strategic interim and final reporting efforts
14.5.2.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: 
https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):

4.03 to 4.24: General Principles

5.01 to 5.08: Principles Relating to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 
Formats

GSK IDSL Statistical Principle 4.24 for decimal places (DP’s) will be adopted for reporting of data based 
on the raw data collected, unless otherwise stated.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but may be
adjusted to a clinically interpretable number of DP’s.
o
E-RS: COPD and SGRQ will have a min and max to 1 decimal places (dp) and then follow 
IDSL standards for reporting other summary statistics.
o
CAT will have a min and max to 0 dp and then follow IDSL standards for reporting other 
summary statistics. 

Categories will be based on rounded values to the precision collected on the eCRF, i.e., categories of 
% predicted FEV1 will be based on the rounded (to 1 dp) values of the variable FEV1PDPC

Summaries of continuous data will include number of participants, mean, SD, median, minimum and
maximum and for C-RP and fibrinogen outputs the 25th and 75th percentile.

Percentages between 1% and 99%, inclusive, will be rounded to integers. Percentages greater than 
0%, but less than 1%, will be reported as <1%, and percentages greater than 99%, but less than 100%, 
will be reported as >99%.
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.


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
Actual time will be used for calculation of times to events and Kaplan-Meier plots.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the participant’s listings. 
Unscheduled Visits

Unscheduled visits will not be included in summary tables and/or figures except as part of a 
maximum/minimum/worst case post-baseline assessment or if they are assigned as the baseline 
assessment as detailed in Section 5.2.

All unscheduled visits will be included in listings.
Cardiovascular Event Reports

Laboratory results, ECG results/findings and vital signs measurements collected as part of 
cardiovascular event reports will not be included in any tables, listings or any minimum/maximum post-
baseline assessments.
Time to Event Results

For all time to event analyses, the first quartile and median time to event will be presented. If less than 
25% of participants experienced the event within a treatment group then the first quartile will be 
displayed as NA (not applicable) for that treatment. If less than 50% of participants experienced the 
event within a treatment group then the median will be displayed as NA for that treatment.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.
Seeds for Bayesian Analyses

The seeds used to for the Bayesian analyses were generated using the ranuni function in SAS.  The 
same seeds should be applied for all endpoints and populations. 
Chain
Seed
1
2619
2
413
3
9243


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14.5.3.
Reporting Standards for Pharmacokinetic Data
Pharmacokinetic Concentration Data
PC Windows Non-
Linear (WNL) File
PC WNL file (CSV format) for the non-compartmental analysis by Clinical 
Pharmacology Modelling and Simulation function will be created according to 
GUI_51487 and PKOne documents. 
Note: Concentration values will be imputed as per GUI_51487
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.
Refer to IDSL Statistical Principle 6.06.1.
Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics/analysis and summarized graphical displays only. 
Additionally, include geometric mean and 90% CI for the summary of blood 
concentration data.
NONMEM/Pop PK 
File
PopPK file (CSV format) for the PopPK analysis by Clinical Pharmacology 
Modelling and Simulation function will be created according to the data specification 
detailed in Appendix 9.
Pharmacokinetic Parameter Derivation
PK Parameter to be 
Derived by 
Programmer
None
Pharmacokinetic Parameter Data
Is NQ impacted PK 
Parameters Rule 
Being Followed
No. 
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.


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14.6.
Appendix 6: Derived and Transformed Data
14.6.1.
General
Multiple Measurements at One Analysis Time Point

Mean of the measurements will be calculated and used in any derivation of summary statistics but if 
listed, all data will be presented.

Participants having both High and Low values for Potential Clinical Importance criteria at any post-
baseline visit for safety parameters will be counted in both the High and Low categories of “Worst case
post-baseline” row of related summary tables. 
Study Day

Calculated as the number of days from First Dose Date:

Ref Date = Missing              → Study Day = Missing 

Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date

Ref Data ≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1
Study Treatment Stop Date

If the study treatment stop date is missing, it will be imputed as follows:

If any of EW Visit date, Visit 10 (Day 168) date or date of death are non-missing then the study 
treatment stop date will be imputed as the minimum of (EW Visit date, Visit 10 (Day 168) date, date 
of death, date that all study treatment containers were returned).

For all other missing treatment stop dates, the last recorded exposure start or stop date will be 
used.

For ongoing participants at the strategic interim, treatment stop date will be imputed as 5SEP2018
Study Completion Definition

A participant is considered to have completed the study if they have not withdrawn and attended Visit 
10. 
14.6.2.
Study Population
Demographics
Age

GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed as 
follows:
o
Any participant with a missing day will have this imputed as day ‘15’. 
o
Any participant with a missing date and month will have this imputed as ‘30th June’.

Birth date will be presented in listings as ‘YYYY’.

Age will be calculated based on the Pre-screening visit date.

Age group categories are 18-64, 65-74, 75-84, >=85
Body Mass Index (BMI)

Calculated as Weight (kg) / [Height (m)2]


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Baseline Characteristics
% Predicted Normal FEV1 at Screening

The following categories will be derived: <50%, >=50%
Smoking Status

If the last smoked date (SUSMLSDT) is missing and a partial date (SUSMLSD) is not missing, then the 
following imputation should be applied to the partial smoking date for use in the reclassification of 
smoking status calculation:

'01' will be used for the day and 'Jan' will be used for the month.

Former smokers will be reclassified as current smokers if screening date – last smoked date < 183 days.
Chronic Mucus Hypersecretion

A participant is considered to have CMH (CMH+) if baseline SGRQ Q1(cough) = Most or several 
days a week AND baseline SGRQ Q2 (phlegm) = Most or several days a week. 

A participant is considered not to have CMH (CMH-) if baseline SGRQ Q1(cough) not equal to 
Most or several days a week OR baseline SGRQ Q2(phlegm) not equal to Most or several days a week 
and both questions are non-missing at baseline.

Otherwise participants are considered to have a missing CMH status.
Baseline E-RS: COPD Total Score Categories

The following categories will be derived for baseline E-RS: COPD Total Score
o
<8, >=8
o
<10, >=10
o
<12, >=12
Exacerbation History Categories

Exacerbations (historical) will be classified as follows:

Mild: Managed without oral/systemic corticosteroids and/or antibiotics (not involving 
hospitalisation) 

Moderate: Requiring oral/systemic corticosteroids and/or antibiotics (not involving hospitalisation) 

Severe: Requiring hospitalisation 

Moderate/severe: Requiring oral/systemic corticosteroids and/or antibiotics or hospitalisation.

The total number of moderate/severe exacerbations will be categorized as ≤1, ≥2 for inclusion as 
a covariate in statistical models.
GOLD Grade 1-4 at Screening

Participants will be classified into Global Initiative on Obstructive Lung Disease (GOLD) Grades 
1-4 using the post-bronchodilator percent predicted FEV1 assessment at Screening: 
o
GOLD Grade 1 (Mild):  percent predicted FEV1 80%
o
GOLD Grade 2 (Moderate): 50%percent predicted FEV1 <80%
o
GOLD Grade 3 (Severe):  30%percent predicted FEV1 <50%
o
GOLD Grade 4 (Very Severe): percent predicted FEV1 <30%  
GOLD Grade A-D at Screening

Participants will be classified into GOLD Grades A-D definitions as follows:
A. Low risk, less symptoms: baseline CAT < 10 AND GOLD Grade 1-2 AND ≤1
exacerbation; (no hospitalizations for exacerbations), prior year.
B. Low risk, more symptoms: baseline CAT >= 10 AND GOLD Grade 1-2 AND ≤1
exacerbation (no hospitalizations for exacerbations), prior year
C. High risk, less symptoms: baseline CAT < 10 AND either GOLD Grade 3-4 OR ≥2
exacerbations, prior year OR >=1 exacerbation leading to hospitalization, prior
year
D. High risk, more symptoms: baseline CAT >= 10 AND either GOLD Grade 3-4 OR ≥2
exacerbations, prior year OR >=1 exacerbation leading to hospitalization, prior year


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Baseline Characteristics
Participant Disposition

For Kaplan-Meier plots of study withdrawal over time, censoring will be performed as follows:
o
Participants are represented from their Day 1 date to the date of early withdrawal from the study (or 
date of death). Participants that completed the study are censored at the earliest of the date of 
completion and Day 168.
Medical Conditions and Concomitant Medications
Respiratory Medication Class

COPD concomitant medications will be grouped into the following RMCs based on pre-defined code lists 
derived from ATC classifications:
o
Androgens and Estrogens
o
Anti-IgE, Anti-IL5
o
Anticholinergic
o
Antiinfectives (antibiotics, antiseptics only)
o
Antimycotics
o
Antivirals
o
Beta 2 Agonist
o
Corticosteroid – Inhaled
o
Corticosteroid – Depot
o
Corticosteroid – Systemic, oral, parenteral and intra-articular
o
Corticosteroid – Other
o
Leukotriene Receptor Antagonist
o
Long-acting anticholinergic
o
Long-acting beta-2 agonist
o
Mucolytics
o
Nedocromil or Cromolyn Sodium
o
Oxygen
o
PDE4 Inhibitors
o
Short-acting anticholinergic
o
Short-acting beta-2 agonist
o
Xanthine
o
Other medication given for exacerbation
o
Other COPD medication
COPD Medication Combination

COPD medications will be summarized at the following time points:
o
At Screening: Taken on the day of the Screening visit excluding medications that stopped 
on the day of the Screening visit
o
At Baseline: Taken on the day of start of treatment
o
At Month 6: Taken during Month 6 (Study Day 141 to earliest of (Study day 168 and day 
before study treatment stop date))

Medication combinations of all RMC categories will be derived.  Medications will be summarized based 
on individual and combinations of the following RMC categories, with or without other medications:
o
ICS
o
LABA
o
LAMA
o
Xanthine
o
PDE4 inhibitor
o
Anti-IgE, Anti-IL5


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Medical Conditions and Concomitant Medications
Cardiovascular Risk Factors

Subjects with at least one of the following current or past medical conditions at Screening will be classed 
as having cardiovascular (CV) risk factor at screening.  The number of CV risk factors at Screening (0, 1, 
or >=2) will be derived.
o
Coronary artery disease
o
Myocardial infarction
o
Arrithymia
o
Congestive heart failure
o
Hypertension
o
Cerebrovascular accident
o
Hypercholesterolemia
o
Diabetes mellitus
Compliance
Treatment Compliance
Compliance= (tablets issued–tablets returned) x 100 / 2 x (treatment stop date – treatment start date +1)
If any count of tablets returned is missing overall compliance will be set to missing.

Compliance will be categorized as follows:
< 80 %
80 % to < 95 %
95 % to 105 %
>105 % to 120 %
>120 %

If a participant received a treatment other than the randomized treatment during the study, the 
compliance will still be calculated using data from all containers received and overall treatment start and 
stop dates.
Daily Diary Compliance
Overall compliance= (number of days with non-missing data between study treatment start and the earliest of 
(Study day 168 and day before study treatment stop)) x 100 / (Earliest of (Study day 168 and day before 
study treatment stop date) – treatment start date +1)

Overall compliance will be categorized as follows:
< 50 %
50 % to < 60 %
60 % to < 70 %
70 % to < 80 %
80 % to < 90 %
90 % to 100 %
Baseline and Monthly compliance= number of days with non-missing data between periods defined in 
Section 14.6.3  

Baseline compliance will be categorized as follows: Number of days completed <4, 4

Monthly compliance will be categorized as follows: Number of days completed <10, 10-20, >20


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Exposure
Exposure to Study Treatment
Duration of exposure to study treatment is calculated as (treatment stop date – treatment start date +1).
The following exposure categories will be derived:
≥1 day, ≥4 weeks, ≥8 weeks, ≥12 weeks, ≥16 weeks, ≥20 weeks and ≥24 weeks. An additional 
category of 23-25 weeks will also be summarized.
14.6.3.
Efficacy
Daily eDiary endpoints
General
Participants were instructed to complete the daily eDiary in the evening (typically at bedtime).  The 
parameters collected include rescue use and EXACT-PRO scores.
The tables below show which daily eDiary records are used to calculate the daily eDiary parameters for each 
period.  Any diary data collected after the minimum of (Day 168 and the day before study treatment stop 
date) will not be slotted. 
To be used for rescue use endpoints and E-RS: COPD total and subscale scores:
Period
First day
Last day
Baseline[1]
Latest of (7 days before Study 
treatment start date (Day 1) and 
day of Visit 1 (Screening))
Day before Day 1 of study 
treatment
Month 1[1]
Study day 1 
Study day 28
Month 2[1]
Study day 29
Study day 56
Month 3[1]
Study day 57
Study day 84
Month 4[1]
Study day 85
Study day 112
Month 5[1]
Study day 113
Study day 140
Month 6[1]
Study day 141
Earliest of (Study day 168 and day 
before study treatment stop date)
[1] The denominator for baseline and monthly mean scores is the number of days with a non-missing 
score; this is also used to determine whether or not a baseline (>=4 days) or monthly mean (>=10 
days) is calculated.
EXACT PRO

The EXACT-PRO (Evidera, 2016a) is a 14-item daily diary (typically completed at bedtime) 

The daily E-RS: COPD total score (and subscales) will be computed according to the E-RS in COPD 
user manual (Evidera, 2016b). 

The monthly mean for E-RS: COPD total score, and the subscale scores RS-Breathlessness, RS-Cough 
and Sputum, and RS-Chest Symptoms will be calculated as the mean of the daily scores in the monthly 
intervals defined above.

Mean monthly score = (sum of daily scores/# diary days completed).

A participant must have at least 10 days of diary data in any month to contribute a non-missing monthly 
mean of daily values; otherwise the monthly mean for that month will be considered missing.

A participant must have at least 4 days of diary data in the 7 days prior to treatment start date to 
contribute a non-missing mean of daily values for baseline; otherwise baseline will be considered 
missing.

If missing values occur for individual items, the E-RS: COPD total score and E-RS: COPD subscale 


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Daily eDiary endpoints
score that contain the item will be set to missing on that day.
Responders according to E-RS: COPD Total and Subscale Scores

A participant will be considered as a responder according to E-RS: COPD total score if their monthly 
mean change from baseline E-RS: COPD total score ≤ -2.0.

A participant will be considered as a non-responder according to E-RS: COPD total score if their monthly 
mean change from baseline E-RS: COPD total score >-2.0.

A participant will be considered as a responder according to E=RS: COPD breathlessness score if their 
month mean change from baseline E-RS: COPD breathlessness score ≤ -1.0.

A participant will be considered as a non-responder according to E-RS: COPD breathlessness score if 
their monthly mean change from baseline E-RS: COPD breathlessness score >-1.0.

A participant will be considered as a responder according to E-RS: COPD cough & sputum score if their 
monthly mean change from baseline E-RS: COPD cough & sputum score ≤ -0.70.

A participant will be considered as a non-responder according to E-RS: COPD cough & sputum score if 
their monthly mean change from baseline E-RS: COPD cough & sputum score >-0.70.

A participant will be considered as a responder according to E-RS: COPD chest symptoms score if their 
monthly mean change from baseline E-RS: COPD chest symptoms score ≤ -0.70.

A participant will be considered as a non-responder according to E-RS: COPD chest symptoms score if 
their monthly mean change from baseline E-RS: COPD chest symptoms score >-0.70.

If the monthly mean E-RS: COPD score is missing then response status will be missing.
Season

For each participant and each month, season will be assigned based on the first date with a non-missing 
daily score in the monthly mean E-RS: COPD total score. 

Australia will add 6 months to the first day of the monthly mean E-RS: COPD total score before season 
is assigned.

If the month of the first day of the monthly mean score period is:

Dec, Jan or Feb then season is Winter

Mar, Apr or May then season is Spring

Jun, Jul or Aug then season is Summer

Sep, Oct or Nov then season is Fall
Mean Number of Rescue Puffs per Day and Percentage Rescue Free Days

If a participant has more than one daily diary record for any given day, the worst case response on that 
day for each endpoint will be used in the summaries and analyses. i.e. the maximum number of puffs of 
rescue use reported will be counted for the day in question and used to determine if it was a recue-free 
day.

A rescue-free day is defined as a day where the total puffs is 0.

For each summary period, the mean number of puffs per day and the percentage of rescue free days, 
will be calculated, using the number of days with non-missing values for the endpoint as denominator.

Rescue use will be summarized over the periods defined above.


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HCRU Exacerbations
Duration

The duration of the exacerbation will be calculated as (exacerbation resolution date or date of death -
exacerbation onset date + 1).
Severity

Each HCRU exacerbation will be categorized based on severity as follows:
o
Mild: no treatment with oral/systemic corticosteroids and/or antibiotics and not involving 
hospitalisation, an emergency room visit or resulting in death  
o
Moderate: required treatment with oral/systemic corticosteroids and/or antibiotics (not 
involving hospitalisation, an emergency room visit or resulting in death).
o
Severe: required in-patient hospitalization, an emergency room visit, or resulted in death
Time to First Exacerbation

The time to first on-treatment Moderate/Severe HCRU exacerbation will be calculated as exacerbation 
onset date of first on-treatment moderate or severe on-treatment exacerbation – date of start of 
treatment +1

Participants will be represented from their treatment start date to their first on-treatment moderate or 
severe exacerbation or date of censoring.

For the strategic interim analysis, participants that have not experienced an on-treatment exacerbation 
are censored at the earliest of (treatment stop date + 3, date of death, or the interim cut-off date, 
1AUG2018). 

For the final analysis, participants that have not experienced an on-treatment exacerbation are censored 
at the earliest of (treatment stop date + 3, date of death, date of exclusion from the per protocol 
population (if analysis is in Per Protocol population))
Raw Annual Rate

Raw annual rate is the event rate per 1000 participant-years, calculated as the number of events x 1000, 
divided by the total duration at risk (minimum(treatment stop date + 1, date of death, date of exclusion 
from the per protocol population (if analysis is in Per Protocol population)) – treatment start date + 1).
Offset Variable

For analyses of exacerbation rate, the offset variable will be defined as the logarithm of the ((minimum 
(date of end of study treatment + 3, date of death, date of exclusion from the per protocol population (if 
analysis is in Per Protocol population)) – date of start of treatment + 1)/365.25)
EXACT Events
General

The daily EXACT-PRO scores will be computed according to the EXACT-PRO user manual (Evidera, 
2016a) and used to identify EXACT-defined events, including the frequency, duration and severity of the 
events.

Events will be categorized as recovered, censored, or persistent worsening (according to the manual).
Time to First Event

The time to first on-treatment EXACT event will be calculated as the onset date of the first on-treatment 
EXACT event – date of start of treatment +1

Participants will be represented from their treatment start date to their first EXACT event or date of 
censoring. 

For the final analysis, participants that have not experienced an EXACT event are censored at the 
earliest of (Day 168, treatment stop date - 1, date of death, or date of final EXACT-PRO assessment, 
date of exclusion from the per protocol population (if analysis is in Per Protocol population))


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Raw Annual Rate

Raw annual rate is the event rate per 1000 participant-years, calculated as the total number of EXACT-
defined events x 1000, divided by the total duration at risk (minimum(Day 168, treatment stop date - 1, 
date of death, date of final EXACT-PRO assessment, date of exclusion from the per protocol population 
(if analysis is in Per Protocol population)) – treatment start date + 1).
Offset Variable

For analyses of EXACT event rate, the offset variable will be defined as the logarithm of the ((minimum 
(Day 168, treatment stop date - 1, date of death, date of final EXACT-PRO assessment, date of 
exclusion from the per protocol population (if analysis is in Per Protocol population)) – date of start of 
treatment + 1)/365.25)
CAT
CAT Score

The CAT consists of eight items each formatted as a six-point differential scale: 0 (no impact) to 5 (high 
impact). A CAT score will be calculated by summing the non-missing scores on the eight items.  The 
score can have values ranging from 0 to 40. 

If one item is missing, then the score for that item is set as the average of the non-missing items. If more 
than one item is missing, then the CAT score will be set to missing. 

If the language of the CAT conducted at a post-baseline visit is different to the language used at 
baseline, the CAT score for that visit and all subsequent visits will be set to missing.

If there is more than one response to a question at a visit or duplicate questionnaires, the CAT score for 
that visit will be set to missing.
Responders according to CAT Score

A participant will be considered as a responder according to CAT score if their change from baseline 
CAT score ≤ -2.0.

A participant will be considered as a non-responder according to CAT score if their change from baseline 
CAT score >-2.0.

If CAT score is missing at a visit, the response status will be missing at that visit.
Season

For each participant and each visit, season will be assigned based on visit date. 

Australia will add 6 months to the visit date before season is assigned.

If the month of the visit is:

Dec, Jan or Feb then season is Winter

Mar, Apr or May then season is Spring

Jun, Jul or Aug then season is Summer

Sep, Oct or Nov then season is Fall
SGRQ
SGRQ Domain and Total Scores

The SGRQ-C contains 14 questions with a total of 40 items grouped into three domains (Symptoms, 
Activity and Impacts). 

Details for how to score the SGRQ-C, including handling of missing data or multiple responses to 
questions, are outlined in the SGRQ-C manual (Jones, 2016).

SGRQ-C domains and total scores will be converted to SGRQ scores as described in the manual.

Changes from baseline in domain and total score will be calculated for the converted scores.

If the language of the SGRQ-C conducted at a post-baseline visit is different to the language used at 
baseline, all SGRQ scores at that visit and all subsequent visits will be set to missing.


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Responders according to SGRQ Total Score

A participant will be considered as a responder according to SGRQ total score if their change from 
baseline SGRQ total score ≤ -4.0.

A participant will be considered as a non-responder according to SGRQ total score if their change from 
baseline SGRQ total score >-4.0.

If SGRQ total score is missing at a visit, the response status will be missing at that visit.

Change from baseline SGRQ total score will be rounded to 1dp prior to assigning responder status.
Rescue Use via Sensor
Mean Number of Occasions and Percentage Rescue Free Days via Sensor

The mean number of occasions of rescue per day and the percentage of rescue-free days will be 
calculated over the same time periods and using the same assumptions as rescue use via diary.

Rescue-free Days - days within the diary data collection period with no recorded rescue inhaler usage 
by the sensor will be assigned a rescue inhaler usage of 0. 
PROactive
General

A PROactive Total Score and two domain scores (amount and difficulty) are derived using data from the 
C-PPAC questionnaire and a physical activity monitor worn for 7 days prior to the questionnaire. 

To derive the PROactive score at each visit the following is required:
o
Response to valid (i.e., no missing items) C-PPAC questionnaire
o
Median values of steps/day and VMU/min on at least 3 days of the 7 days prior to the 
C-PPAC questionnaire with >=8 hours wearing (the 3 days do not need to be 
consecutive).

The C-PPAC questionnaire contains 14 items (12 questions and 2 scores from the activity monitor 
outputs) each scored from 0 to 4.

The amount domain is calculated using 2 items from the C-PPAC questionnaire (amount of walking 
outside and chores outside) and 2 activity monitor outputs (vector magnitude units per minute (VMU/min) 
and steps/day).

The difficulty domain is calculated using 10 items from the C-PPAC questionnaire.

Each domain score is based on the addition of items (0-15 for amount and 0-40 for difficulty) and then 
scaled from 0-100.

The total score is calculated as (amount+difficulty)/2

Further details for how to score and scale the domain and total scores are outlined in the IMI PROactive 
user guide (14JUN16).


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14.6.4.
Safety
Adverse Events
AEs of Special Interest

AESI are defined as events in the ‘Infective pneumonia’ SMQ in the MedDRA version current at the time of 
reporting.

Subjects receiving ICS (RMC - Corticosteroid – Inhaled) for at least 7 days at the time of Pneumonia onset.
Maximum/Minimum Post-Baseline and Worst-Case Post-Baseline
Definition
Reporting Details
Maximum post-baseline
(QTcF, QTc B, PR interval, ECG 
heart rate, pulse rate, systolic BP, 
diastolic BP and laboratory tests)
Change from baseline of maximum value over all time-points after Day 1 
Minimum post-baseline
(Diastolic BP and laboratory tests 
that do not have a lower limit = 0)
Change from baseline of minimum value over all time-points after Day 1 
Worst case post-baseline
(ECG findings)

‘Abnormal’ if any on-treatment assessment is evaluated as 
‘Abnormal’

‘Unable to evaluate’ if all on-treatment assessments are ‘Unable to 
evaluate’

‘Normal’ if any on-treatment assessment is evaluated as ‘Normal’ 
and there are no on-treatment assessments evaluated as 
‘Abnormal’
NOTES :

The treatment phase definitions specified in Section 14.4.1.4 will be used and only assessments within the on-
treatment period will be considered in assessment of minimum/maximum/worst-case post-baseline.

Assessment of minimum/maximum/worst-case post-baseline will include on-treatment data from scheduled, 
unscheduled and study treatment discontinuation visits (if applicable) 
Laboratory Parameters
General

NQ laboratory results will be treated as missing in summary displays.  However, the results will be listed 
as received (e.g. ‘<x’ or ‘>x’).

If numeric laboratory results are missing but a character result has been recorded, ie. <X, (the numeric 
part of the character value)/2 will be used to assign the PCI ranges. 

A ‘worst case post-baseline’ change classification will be derived, in which participants will be counted in 
the ‘to low’ and ‘to high’ categories if they reported a change from an ‘in range’ baseline to a value 
below or above the PCI criteria (respectively) at any scheduled or unscheduled on-treatment visit. 
Participants who did not report a change to a value outside the PCI criteria at any visit after the start of 
study treatment will be counted in the ‘to w/in range or no change’ category. 
Multiple Measurements for On-Treatment Visits for Safety

Participants having both high and low values relative to PCI criteria at post-baseline visits for safety 
parameters will be counted in both the high and low categories of the “worst case post-baseline” row of 
related summary tables.


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ECG
General

The QTc data was collected via machine derived values (QTCB/QTCF) or manually derived values 
(QTCBC/QTCFC). For the purposes of reporting the following variable should be combined:
-
Combine QTCF with QTCFC 

If both QTCF and QTCFC are missing (and QT and RR are non-missing then the QTcF interval will be 
derived as follows:
-
QTcF interval (msec) = QT/[(RR/1000)**(1/3)]
-
If RR interval is not collected and the corrected QT interval by Bazett’s method (QTcB) is collected, 
then RR interval (msec) will be derived prior to deriving QTcF as follows: RR interval (msec) = 
1000*[(QT/QTcB)**2]

If QTcF intervals are collected they will not be rederived.
ECG Categories
Maximum and maximum increase in d QTcF values will be reported in categories as below. In subjects who 
have QTc above 450 at baseline, decreases that result in a QTc that remains above 450 will be considered 
No Change.
ECG Parameter
Units
Category
Absolute
Absolute QTcF Interval
msec
No Change or Decrease to <=450
Increase To >450 to <=480
Increase To >480 to <=500
Increase To >500
Change from Baseline
Change from Baseline QTcF
msec
Increase of <=30 ms
Increase of 31-60 msec
Increase of >60 msec
Assessment of maximum post-baseline will include on-treatment data from scheduled, unscheduled and 
study treatment discontinuation visits (if applicable)


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14.7.
Appendix 7: Reporting Standards for Missing Data
14.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Participant study completion (i.e. as specified in the protocol) was defined as 
completion of all phases of the study including the last study visit and the last 
scheduled procedure shown in the Schedule of Activities (Appendix 2). 

For the purposes of reporting, a participant is considered to have completed the study if 
they have not withdrawn and attended Visit 10.

Withdrawn participants were not replaced in the study.

All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified.

Data from the Early Withdrawal visit will not be included in any summaries or analyses 
except as part of a worst case post-baseline assessment.
14.7.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank fields on 
the collection instrument:
o
These data will be indicated by the use of a “blank” in participant listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such.
Outliers

If outliers are identified, analyses may be repeated excluding the outlying data.

Any participants/data excluded from summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
14.7.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in participant listing displays.
Adverse 
Events

Completely missing start or end dates will remain missing, with no imputation applied. 
Consequently, time to onset and duration of such events will be missing.
Concomitant 
Medications

Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will be 
used for the month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month.

The recorded partial date will be displayed in listings.


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14.8.
Appendix 8: Values of Potential Clinical Importance
14.8.1.
Laboratory Values
The following table identifies a range of potential clinical importance (PCI) for each 
laboratory analyte.  Limits with an ‘x’ are multipliers of the central laboratory normal 
range.  Values above and below this range will be considered of PCI.
Hematology Analyte 
(units)
Effect
COPD Patients
Low
High
Platelet Count (x109/L)
0.90x
1.10x
Red Blood Cell Count 
(x1012/L)
0.93x
1.07x
White Blood Cell Count 
(x109/L)
0.70x
1.60x
Reticulocyte Count (%)
>4%
Hemoglobin (g/L)
Males
0.85x
1.20x
Females
0.85x
1.20x
Hematocrit (Ratio of 1)
Males
0.50x
1.30x
Females
0.50x
1.30x
MCV (fL)
0.25x
2.00x
MCH (pg)
0.85x
1.20x
MCHC (g/dL)
0.85x
1.10x
Neutrophils (%)
0.65x
1.50x
Lymphocytes (%)
0.80x
1.20x
Monocytes (%)
0.80x
1.60x
Eosinophils (%)
2.00x
Basophils (%)
5.00x
Note: Multipliers are identified by “x”, otherwise actual comparison values are provided with units.


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Chemistry Analyte
Effect
COPD Patients
Low
High
BUN (mmol/L)
0.70x
1.60x
Creatinine (mol/L)
1.30x
(or >27 mol/L increase from 
baseline)
Glucose fasting (mmol/L)
<0.6x
>4x
Sodium (mmol/L)
0.80x
1.15x
Potassium (mmol/L)
0.75x
1.30x
Chloride (mmol/L)
0.90x
1.10x
Bicarbonate (mmol/L)
<18 mmol/L
>32 mmol/L
Calcium (mmol/L)
0.85x
1.08x
GGT (U/L)
0.85x
1.10x
Uric Acid (mg/dL)
Males
<2.1 mg/dL
>8.5 mg/dL
Females
<2.0 mg/dL
>7.0 mg/dL
Albumin (mmol/L)
0.90x
1.50x
Total Protein (mg/dL)
1.25x
Note: Multipliers are identified by “x”, otherwise actual comparison values are provided with units.
Liver Function Test Analyte
Effect
PCI Range
Unit
ALT/SGPT
High
≥ 3x ULN
U/L
AST/SGOT
High
≥ 3x ULN
U/L
Alkaline Phosphatase
High
≥ 2x ULN
U/L
Total Bilirubin
High
≥ 2x ULN
mol/L
Direct Bilirubin
High
≥ 2x ULN
mol/L
Total Bilirubin + ALT
High
≥ 2x ULN Total Billirubin
+
≥ 3x ULN ALT
mol/L
U/L
14.8.2.
ECG
ECG Parameter
PCI Range
Unit
Absolute QTc Interval (QTcB, QTcF)
>530
msec
Increase from Baseline QTc
>60
msec
QT Interval
<300 or >500
msec
PR Interval
<120 or >240
msec
QRS Interval
<70 or >125
msec
RR Interval
<375 or >1714
msec
Heart Rate
<35 or >120
bpm


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14.8.3.
Vital Signs
Vital Sign Parameter
PCI Range
Unit
Systolic BP
<90 or >160
mmHg
Diastolic BP
<40 or >110
mmHg
Heart Rate
<35 or >120
bpm
Respiration Rate
<8 or >30
breaths 
/min


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14.9.
Appendix 9: Population Pharmacokinetic Analyses
14.9.1.
Population Pharmacokinetic Dataset Specification
14.9.1.1.
Handling Missing Demographic and Covariate Data 
Missing demographic and covariate data will not be imputed. 
14.9.1.2.
Handling Missing Dose Times
Missing dose time information will be handled on a case by case basis by imputing this 
information based on prior dosing times or based on recorded PK collection times. The 
details of these imputations will be described in the report.
14.9.1.3.
Handling Missing Times of PK Samples
Missing times for PK will be handled on a case by case basis by imputing this 
information based on the dose time and/or times of other PK. The details of these 
imputations will be described in the report.
14.9.1.4.
Handling of PK Data Below the Lower Limit of Quantification
Any PK data below the lower limit of quantification will be set to missing.
14.9.1.5.
Dataset Specification
General description and rules:

Missing or unknown values in covariates, if not to be imputed, will be assigned -99.

The dataset is sorted by STUD, SUBJID, DATE, RTFD, EVID descending.

The data items (columns) in the analysis-ready data file will be provided in the same 
order as follows.

NQ concentration values will be included as detailed for the CONC variable.

Non-numerical concentration values (such as NS, NR, NA) will not be included.

Placebo participants will not be included.

The dataset will be a comma delimited ASCII text file and will be named:
o
NM.compound.study.PK.v1.csv
o
Where “compound” is the compound name (e.g. GSK1234567) and “study” is 
the study number (e.g. 205724).


CONFIDENTIAL
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Variable
Label 
(Variable 
description)
Type
Units
Missing 
value
Codes/Derivation/Notes
ID
NONMEM 
participant
identifier
Integer
None
Never
Sequential participant identifier 
across study after data is sorted 
by STUD, SUBJID, DATE, RTFD, 
EVID.
Numbering to start at 1.
To be entered in all rows for each 
participant.
STUDYID
Unique 
identifier for a 
study
Char
None
Never
205724 for all records
STUD
Study ID
Num
None
Never
205724 for all records
SUBJID
Participant
identifier for 
study
Num
None
Never
Participant identifier, which must 
be unique within the study. The 
identification number of the 
participant as recorded on the 
CRF.
Exclude placebo participants.
Include participants who have 
received IP and have at least one 
measurable drug concentration.
To be entered in all rows for each 
participant.
COUNTRY
Country
Char
None
Never
Country of the investigational site 
in which the participant
participated in the trial; e.g. USA.
To be entered in all rows for each 
participant.
SITEID
Unique 
identifier for a 
study site
Char
None
Never
e.g. 
 any lead zero should 
not be included.
To be entered in all rows for each 
participant.
CONC
Drug 
Concentration 
Num
ng/mL
Never
CONC=0 for 
DOSE_GSK1325756 records.
No sample (NS), insufficient 
sample (IS) and no result (NR) 
records will be excluded from 
dataset.
CONC=’.’ for PK_GSK1325756 
records < LOQ (i.e. if drug conc is 
NQ).
LNCONC
Natural log of 
CONC 
column 
Num
ng/mL
Never
Natural log of CONC column.
If CONC=0, then LNCONC=’.’.
LLQ
Lower Limit of 
quantification
Num
ng/mL
Never
LLQ=5 or from source data if 
different.
To be entered in all rows for each 
participant.
PPD


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Variable
Label 
(Variable 
description)
Type
Units
Missing 
value
Codes/Derivation/Notes
LNLLQ
Natural log of 
LLQ column
Num
ng/mL
Never
Natural log of LLQ column.
If LLQ=0, then LNLLQ=’.’.
MATRIX
Sample matrix
Num
None
Never
MATRIX=1 (blood).
MATRTEXT
Sample matrix 
text
Char
None
Never
Text corresponding to code for 
MATRIX. 
Enter ‘Blood’ for all rows.
LABL
Label 
describing the 
record
Char
None
Never
LABL explains the type of 
measurement for CONC for the 
current record.
LABL=DOSE_GSK1325756 for 
dose record. 
LABL=PK_GSK1325756 for 
blood concentration record.
DATE
Date of 
Record 
MM/DD/YYYY
None
Never
Date of record.
DATETIME
Date and time 
of record
MM/DD/YYYY 
HH:MM:SS
None
Never
Date and time of record.
DAY
Study day 
number of 
record
Num
None
Never
Day of study relative to first IP 
dose.
NDAY
Nominal day
Num
day
Never
Schedule visit day of study 
relative to first IP dose.
NOMT
Nominal time 
since FIRST 
IP dose
Num
h
Never
Nominal time of study relative to 
first IP dose.
NOMT=0 for first dosing record 
only. 
NOMTLD
Nominal time 
since latest IP 
dose 
Num
h
Never
Nominal time of study relative to 
last IP dose prior to sample. 
NOMTLD=0 for dosing records.
RTFD
Relative time 
from FIRST IP 
dose 
Num
h
Never
Actual time from FIRST dose of 
IP.
RTLD
Relative time 
from latest IP 
dose  
Num
h
Never
Actual time from last dose of IP 
prior to sample.
When 
LABL=DOSE_GSK1325756, 
RTLD=0.
For pre-dose PK sample Visit 6, 7 
and 10, RTLD is relative to the 
previous dose. 
DOSE
Dose amount
Num
mg
Never
DOSE=5, 10, 25, 35 or 50 per 
treatment administered.
To be entered in all rows for each 
participant.
DRUG
Name of drug
Char
None
Never
DRUG=GSK1325756.
To be entered in all rows for each 
participant.


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Variable
Label 
(Variable 
description)
Type
Units
Missing 
value
Codes/Derivation/Notes
REG
Dosing 
Regimen 
Integer
None
Never
REG=2 for BD.
To be entered in all rows for each 
participant.
REGTEXT
Participant
dose regimen 
text
Char
None
Never
REGTXT=BD, text corresponding 
to code for REG. 
To be entered in all rows for each 
participant.
ROUT
Route of 
administration
Integer
None
Never
ROUT=1 for PO.
To be entered in all rows for each 
participant.
ROUTTEXT
Participant
route of 
administration 
text
Char
None
Never
ROUTTEXT=PO, text 
corresponding to code for ROUT.
To be entered in all rows for each 
participant.
CNC
NONMEM 
Country code
Integer
None
Never
Australia, Canada, Germany, 
Korea, Netherlands, Poland, 
Romania, Spain, US. 
Assign integer as appropriate for 
each country. Eg. 1=US
To be entered in all rows for each 
participant.
CMT
NONMEM 
Compartment 
code
Integer
None
Never
CMT=1 for DOSE_GSK1325756 
records.
CMT=2 for PK_GSK1325756 
records.
EVID
NONMEM 
Event ID
Integer
None
Never
EVID=1 for LABL= 
DOSE_GSK1325756.
EVID=0 for LABL= 
PK_GSK1325756.
AMT
NONMEM 
Amount of 
drug 
administered
Num
mg
Never
AMT=0 for LABL= 
PK_GSK1325756 records.
AMT=5, 10, 25, 35 or 50 (ass 
appropriate) for LABL= 
DOSE_GSK1325756 records.
II
NONMEM 
Inter-dose 
interval
Integer
h
Never
II=0 for LABL= PK_GSK1325756.
II=12 for LABL= 
DOSE_GSK1325756, except
II=0 for LABL= 
DOSE_GSK1325756 on Day 1 
only.
SS
Steady-state 
data item
Integer
None
Never
SS=0 for LABL= 
PK_GSK1325756 records.
SS=1 for LABL= 
DOSE_GSK1325756 records, 
except
SS=0 for LABL= 
DOSE_GSK1325756 records on 
Day 1 only.


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Variable
Label 
(Variable 
description)
Type
Units
Missing 
value
Codes/Derivation/Notes
RATE
NONMEM 
Rate of drug 
infusion
Integer
None
Never
RATE=0 for LABL= 
PK_GSK1325756 records.
RATE=-2 for LABL= 
DOSE_GSK1325756 records.
MDV
NONMEM 
Missing data 
value
Integer
None
Never
MDV=1 for LABL= 
DOSE_GSK1325756 records.
MDV=0 for LABL= 
PK_GSK1325756 records.
MDV=1 for LABL= 
PK_GSK1325756 records < LOQ 
(NQ).
VIS
Visit number
Integer
None
Never
From source data.
POP
Population
Integer
None
Never
POP=1, for COPD.
To be entered in all rows for each 
participant.
POPTEXT
Participant
population 
text
Char
None
Never
POPTEXT=COPD, text 
corresponding to code for POP.
To be entered in all rows for each 
participant.
COH
Cohort
Integer
None
Never
COH=1.
To be entered in all rows for each 
participant.
AGE
Participant
Age
Integer
year
If missing 
impute 
with -99
From source data.
To be entered in all rows for each 
participant.
SEX
Participant
gender 
Integer
None
Never
0=Male, 1=Female
To be entered in all rows for each 
participant.
SEXTEXT
Participant
gender text
Char
None
Never
Text corresponding to code for 
SEX, e.g. MALE or FEMALE). To 
be entered in all rows for each 
participant.
BMI
Baseline Body 
Mass Index
Num
kg/m2
If missing 
impute 
with -99
Ensure consistent with S&P 
formula. E.g. Formula: 
Weight(kg)/(height(m)**2)
To be entered in all rows for each 
participant.
BSA
Baseline Body 
Surface Area
Num
m2
If missing 
impute 
with -99
Formula: BSA (m2) = 0.024265 • 
Height(cm)0.3964 • Weight(kg)0.5378
Ensure consistent to with S&P 
formula.
To be entered in all rows for each 
participant.
WT
Baseline 
Participant
weight
Num
kg
If missing 
impute 
with -99
From source data.
To be entered in all rows for each 
participant.


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Variable
Label 
(Variable 
description)
Type
Units
Missing 
value
Codes/Derivation/Notes
HT
Baseline 
Participant
height
Num
m
If missing 
impute 
with -99
From source data.
To be entered in all rows for each 
participant.
RACE1
Participant
race code1
Integer
None
Never
From source data e.g.
1=African American / African 
Heritage
2=American Indian or Alaska 
Native
3=Asian – Central / South Asian 
Heritage
4=Asian – East Asian Heritage
5=Asian – Japanese Heritage
6=Asian – South East Asian 
Heritage
7=Asian – Mixed Race
8=Native Hawaiian or other 
Pacific Islander
9=White – Arabic / North African 
Heritage
10=White – White / Caucasian / 
European Heritage
11=White – Mixed Race
12=Mixed Race
To be entered in all rows for each 
participant.
RACE1TXT
Participant
race 1 text
Char
None
Never
Text corresponding to code for 
RACE1
To be entered in all rows for each 
participant.
RACE2
Participant
race code2
Integer
None
Never
1=East Asian: Asian – East Asian 
Heritage & Asian – Japanese 
Heritage
2=White: White – Arabic / North 
African Heritage White – White / 
Caucasian / European Heritage
3=African: African American / 
African Heritage; 
4=Other: American Indian or 
Alaska Native; Asian – Central / 
South Asian Heritage; Asian –
South East Asian Heritage; Asian 
– Mixed Race; Native Hawaiian 
or other Pacific Islander; White –
Mixed Race & Mixed Race
To be entered in all rows for each 
participant.


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Variable
Label 
(Variable 
description)
Type
Units
Missing 
value
Codes/Derivation/Notes
RACE2TXT
Participant
race 2 text
Char
None
Never
Text corresponding to code for 
RACE2
To be entered in all rows for each 
participant.
ETHN
Participant
ethnicity
Num
None
Never
From source data definition. 
E.g 1=Hispanic or Latino, 2=Non-
Hispanic
To be entered in all rows for each 
participant.
ETHNTEXT
Participant
ethnicity text
Char
None
Never
Text corresponding to code for 
ETHN.
To be entered in all rows for each 
participant.
REGN
Region for 
participant
Num
None
Never
1 = East Asia (to include Japan, 
South Korea and Taiwan)
2 = Rest of the World (to include 
all other countries)
To be entered in all rows for each 
participant.
SMOK
Participant
smoking 
status
Integer
None
Never
0=Non-smoker, 1=Smoker, 
2=Former smoker
To be entered in all rows for each 
participant.
SMOKTEXT
Participant
smoking 
status text
Char
None
Never
Text corresponding to code for 
SMOK.
To be entered in all rows for each 
participant.
CMED1
COPD 
conmeds 
identifier
Num
None
Never
0 = no concomitant use
1 = intermittent use
2 = continuous use
To be entered in all rows for each 
participant.
CMED1TXT
Participant
CMED1 text
Char
None
Never
Text corresponding to code for 
CMED1.
To be entered in all rows for each 
participant.
CRCL
Baseline 
Creatinine 
Clearance 
Num
mL/min
If missing 
impute 
with -99
From source data.
OR Specify appropriate formula 
e.g.
Creatinine Clearance will be 
calculated based on the 
Cockcroft-Gault equation.

CrCL (ml/min) = [140 –
AGE (in 
years)]*Weight(kg)*0.85 
(for female particpants) / 


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Variable
Label 
(Variable 
description)
Type
Units
Missing 
value
Codes/Derivation/Notes
[72* Serum Creatinine 
(micromol/L) * 0.0113

CrCL (mL/min) = (140 –
Age (yr)) * IBW (kg) / (72 
• SCr (µmol/L) * 0.0113) 
* [0.85 if female], where 
IBW (kg) = 50 (kg) [ - 4.5 
(kg) if female]+ 2.3 (kg) * 
(HT (inch) - 60)

Delete one as 
appropriate and ensure 
consistency with S&P 
formula

To be entered in all rows 
for each participant.
CMED2
Gastric acid 
reducing 
conmeds 
identifier
Num
None
Never
0 = no concomitant use
1 = intermittent use
2 = continuous use
To be entered in all rows for each 
participant.
CMED2TXT
Participant
CMED2 text
Char
None
Never
Text corresponding to code for 
CMED2.
To be entered in all rows for each 
participant.
CMED3
Identifier for 
on-treatment 
gastric acid 
increasing 
concomitant 
medication
Num
None
Never
0 = no concomitant use
1 = intermittent use
2 = continuous use
To be entered in all rows for each 
participant.
CMED3TXT
Participant
concomitant 
medication 
text
Char
None
Never
Text corresponding to code for 
CMED3.
To be entered in all rows for each 
participant.
CMED4
P-gp inhibitor 
conmeds 
identifier
Num
None
Never
0 = no concomitant use
1 = intermittent use
2 = continuous use
To be entered in all rows for each 
participant.
CMED4TXT
Participant
CMED4 text
Char
None
Never
Text corresponding to code for 
CMED4.
To be entered in all rows for each 
participant.
CMED5
Identifier for 
on-treatment 
p-gp inducer 
concomitant 
medication
Num
None
Never
0 = no concomitant use
1 = intermittent use
2 = continuous use
To be entered in all rows for each 
participant.


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Variable
Label 
(Variable 
description)
Type
Units
Missing 
value
Codes/Derivation/Notes
CMED5TXT
Participant
concomitant 
medication 
text
Char
None
Never
Text corresponding to code for 
CMED5.
To be entered in all rows for each 
participant.
ALB
Baseline
Albumin
Num
Specify
If missing 
impute 
with -99
Baseline defined in the source 
dataset
To be entered in all rows for each 
participant.
TBIL
Baseline Total 
bilirubin
Num
Specify
If missing 
impute 
with -99
Baseline defined in the source 
dataset
To be entered in all rows for each 
participant.
TFIB
Baseline 
Fibrinogen
Num
Specify
If missing 
impute 
with -99
Baseline defined in the source 
dataset
To be entered in all rows for each 
participant.
Current Therapies for COPD: CMED1
Therapy
Efficacy Claims
Main Safety Concerns
Long-acting β2-agonists (LABAs)
Formoterol
Indacaterol
Salmeterol
Olodaterol
Bronchodilator treatment to 
relieve symptoms in patients 
with COPD. Not used alone, 
generally in combination 
with inhaled corticosteroids 
and LAMAs. 
Adverse reactions related to β 
receptor agonist pharmacology 
e.g. tremor, tachycardia, 
hypokalaemia, hyperglycaemia. 
Use of indacaterol has been 
associated with post-inhalation 
cough.
Hypersensitivity reactions can 
occur with ICS, LAMA and LABAs, 
but are unlikely to affect the 
majority of patients. 
Cardiovascular effects have also 
been associated with use of 
muscarinic antagonists and β2
agonists in patients with COPD.


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Therapy
Efficacy Claims
Main Safety Concerns
Long acting anti-muscarinic antagonists (LAMAs)
Tiotropium
Aclidinium Bromide
Glycopyrronium bromide
Umeclidinium
Bronchodilator treatment to 
relieve symptoms in patients 
with COPD. Same as 
above.
Adverse reactions related to anti-
muscarinic pharmacology. The 
most commonly reported adverse 
effects include dry mouth, GI 
effects and upper respiratory 
system infection.
Hypersensitivity reactions can 
occur with ICS, LAMA and LABAs, 
but are unlikely to affect the 
majority of patients
Cardiovascular effects have also 
been associated with use of 
muscarinic antagonists and β2
agonists in patients with COPD. 
Long acting combination bronchodilators
Albuterol/ipratropium bromide 
Vilanterol/umeclidinium 
Olodaterol/tiotropium 
Indacaterol/glycopyrrolate
Formoterol/glycopyrrolate
Formoterol/aclidinium
Bronchodilator treatment 
superior to LABA or 
LAMA alone relieving 
symptoms in patients with 
COPD.
Adverse reactions related to β 
receptor agonist and anti-
muscarinic pharmacology
Methylxanthines
Theophylline
Aminophylline
Bronchodilator effects and 
claimed anti-inflammatory 
effects.
Dose-related toxicity including the 
development of atrial and 
ventricular arrhythmias and grand 
mal seizures. 
Inhaled glucocorticosteroids 
Beclomethasone
Budesonide
Fluticasone propionate
Fluticasone furoate
Mometasone
Anti-inflammatory effects; 
normally used in 
combination with LAMAs 
and LABAs
The class effects of inhaled 
corticosteroids can include oral 
candidiasis, hoarse voice, skin 
bruising and increased risk of 
pneumonia. Systemic 
corticosteroid class effects 
including hypothalamic-pituitary-
adrenal (HPA) axis suppression, 
decrease in bone mineral density 
and ocular disorders (e.g. 
glaucoma and cataracts).
Pneumonia is a recognized class 


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Therapy
Efficacy Claims
Main Safety Concerns
risk with the use of inhaled 
corticosteroid (ICS) in COPD 
[Spencer, 2011; Drummond, 
2008], however, the benefit of ICS 
continue to outweigh the risks 
[EMA, 2016]
Hypersensitivity reactions can 
occur with ICS, LAMA and LABAs, 
but are unlikely to affect the 
majority of patients.
Inhaled glucocorticosteroids (ICS, in combination with inhaled bronchodilators)
Formoterol/budesonide
Salmeterol/Fluticasone 
propionate
Vilanterol/Fluticasone Furoate
Formoterol/beclomethasone
Formoterol/mometasone
An inhaled corticosteroid 
combined with a LABA is 
more effective than the 
individual components in 
reducing exacerbations and 
improving lung function and 
health status.
As described for LABAs and 
inhaled glucocorticosteriods 
above.
Crim et al. (2015) pneumonia was 
shown to be more frequent in 
patients who received 
fluticasone/vilanterol than those 
who received vilanterol alone. 
Inhaled glucocorticosteroids (ICS, in combination with inhaled LABA and LAMA)
Fluticasone 
Furoate/Umeclidium/Vilanterol
Adding a LAMA to existing 
LABA/ICS improves lung 
function and patient 
reported outcomes in 
particular, exacerbation risk. 
As described for LABAs, LAMAs 
and inhaled corticosteroids above. 
Phospodiesterase-4 inhibitors
Roflumilast
Reduction of exacerbations 
in patients with severe 
COPD. 
Modest improvement in 
FEV1 (versus placebo) and 
small improvements in 
SCRQ and COPD-related 
systems. No significant 
changes in exercise 
tolerance with PDE4 
inhibitors. Unclear benefit on 
modifying FEV1 decline, 
hospitalization or mortality in 
COPD. [Chong J et al. 
2013].  
Weight loss, abdominal pain, 
diarrhoea, nausea, headache and 
sleep disturbances. Caution for 
use is advised in patients with 
depression.


CONFIDENTIAL
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Therapy
Efficacy Claims
Main Safety Concerns
Antibiotics
Macrolides (e.g. azithromycin, 
erythromycin)
Regular use of may reduce 
exacerbation rate. 
Azithromycin or 
erythromycin for one year in 
patients prone to 
exacerbations reduced the 
risk of exacerbations 
compared to usual care.
Azithromycin use associated with 
increased incidence of bacterial 
resistance and impaired hearing.
CMED2: Gastric acid reducing conmeds


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NDAY: For deriving the nominal day which is the planned day, DAY specific 
information is not available in EXPOSURE dataset. VISIT variable and the time and 
events table might have to be taken into account to find the exact plan of events.
NOMT: It is twice daily dosing with inter-dose interval given to be 12 hours. Therefore, 
to find the planned time of event since the first dose in hours, again the VISIT variable 
and time and events will have to be considered.
NOMTLD: In case of PK_GSK1325756 records, the planned time point variable will 
give the value of this variable for all the post-dose records. For the pre-dose records, this 
variable will have missing values since there is no fixed time point since the previous 
dose for pre-dose records.
RTFD: The time difference between the first dose of the subject and the current dose 
(when LABL=DOSE_GSK1325756) should be calculated in hours. The time difference 
between the first dose of the subject and the PK sample collection time (when 
LABL=PK_GSK1325756) should be calculated in hours.
RTLD: The latest dose prior to the PK sample collection time will have to be found out 
and the time difference between that dose and the PK sample collection time will be 
calculated in hours.


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14.10.
Appendix 10: Abbreviations & Trade Marks
14.10.1.
Abbreviations
Abbreviation
Description
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALLSUB
All Subjects
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical Classification
BD
Bronchodilator
BP
Blood Pressure
BUN
Blood urea nitrogen
C-PPAC
Clinical Visit PROactive Physical Activity in COPD
CAT
COPD Assessment Test
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CID
Clinically Important Deterioration
CMH
Chronic Mucus Hypersecretion
CrI
Credible Interval
COPD
Chronic Obstructive Pulmonary Disease
CSR
Clinical Study Report
DBF
Database Freeze
DM
Data Management
DP
Decimal Places
E-RS: COPD
Evaluating Respiratory Symptoms in COPD
ECG
Electrocardiogram
eCRF
Electronic Case Record Form
EW
Early Withdrawal
EXACT
Exacerbations of Chronic Pulmonary Disease Tool
FEV1
Forced Expiratory Volume in 1 Second
FUP
Functional Uniform Prior
FVC
Forced Vital Capacity
GGT
Gamma-glutamyl transferase
GOLD
Global Initiative for Obstructive Lung Disease
GSK
GlaxoSmithKline
HCRU
Healthcare Resource Utilization
IDSL
Integrated Data Standards Library
LS
Least Squares
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCSE
Monte Carlo Standard Error
MCV
Microtic cell volume
MedDRA
Medical Dictionary for Regulatory Activities
mITT
Modified Intent-to-treat


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Abbreviation
Description
MLE
Maximum likelihood estimate
MMRM
Mixed Model Repeated Measures
NQ
Non-quantifiable
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PK
Pharmacokinetic
PopPK
Population PK
QC
Quality Control
RAP
Reporting & Analysis Plan
RMC
Respiratory Medication Class
SAE
Serious Adverse Event
SD
Standard Deviation
SE
Standard Error
SDL
Source Data Lock
SDTM
Study Data Tabulation Model
SGOT
Serum glutamic oxalocaetic transaminase
SGPT
Siamane glutamate pyruvate transaminase
SGRQ
St. George’s Respiratory Questionnaire
SGRQ-C
SGRQ for COPD patients
SI
System Independent
SMQ
Standardized MedDRA Query
SRDP
Study Results Dissemination Plan
ULN
Upper limit of normal
14.10.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
NONE
NONMEM 
SAS
WinNonlin


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14.11.
Appendix 11: List of Data Displays
14.11.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Strategic Interim Statistical Analysis Complete
Section
Tables
Figures
Study Population
1.1 to 1.20
Efficacy
2.1 to 2.52
2.1 to 2.35
Conditional Efficacy
2.36 to 2.xx
Safety
3.1 to 3.23
3.1 to 3.6
Pharmacokinetic
Pharmacokinetic / Pharmacodynamic
Biomarker
6.1 to 6.2
6.1 to 6.2
Section
Listings
ICH Listings
1 to 1
Other Listings
2 to 2
Final Statistical Analysis Complete (Including Post SAC)
Section
Tables
Figures
Study Population
1.1 to 1.43
1.1 
Efficacy
2.1 to 2.49
2.1 to 2.32
Conditional Efficacy
2.33 to 2.xx
Safety
3.1 to 3.37
3.1 to 3.11
Pharmacokinetic
4.1 to 4.8
4.1 to 4.13
Pharmacokinetic / Pharmacodynamic
5.1 to 5.4
Biomarker
6.1 to 6.4
6.1 to 6.4
Section
Listings
ICH Listings
1 to 36
Other Listings
37 to 69
14.11.2.
Deliverables
In all displays the term "Subjects" is used to refer to “Participants”.
Delivery [Priority]
Description
StInt
Strategic Interim Statistical Analysis Complete
SAC
Final Statistical Analysis Complete
Post SAC
Additional outputs provided after SAC


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14.11.3.
Study Population Tables
Study Population Tables
StInt
No.
SAC
No.
Population
IDSL / Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Participant Disposition
1.1
1.1
mITT
ES1
Summary of Subject Disposition for the Subject
Conclusion Record
ICH E3, FDAAA, EudraCT
Include number of ongoing 
participants for strategic 
interim
StInt, SAC
1.2
All Subjects
ES6
Summary of Screening Status and Reasons for 
Screen Failure
Journal Requirements
SAC
1.3
All Subjects
NS1
Summary of Number of Subjects by Country and 
Site ID
EudraCT/Clinical 
Operations
SAC
1.2
1.4
mITT
NS1
Summary of Number of Subjects by Country and 
Site ID
StInt, SAC
1.3
1.5
PP
NS1
Summary of Number of Subjects by Country and 
Site ID
StInt, SAC
1.4
1.6
mITT
Summary of Attendance at Each Clinic Visit
StInt, SAC
Protocol Deviation
1.7
mITT
DV1
Summary of Important Protocol Deviations
ICH E3
SAC
1.8
All Subjects
IE2
Summary of Inclusion/ Exclusion/ Randomization 
Criteria Deviations for Screen or Run-in failures
Add a row “Number of 
Screen Failures” above 
“any criteria deviations”.
Percentage will be based 
on number of screen 
failures
SAC


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Study Population Tables
StInt
No.
SAC
No.
Population
IDSL / Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.9
mITT
IE1
Summary of Inclusion/ Exclusion/ Randomization 
Criteria Deviations for the Modified Intent-to-treat 
Population
SAC
Population Analysed
1.5
1.10
All Subjects
SP1 
Summary of Study Populations
IDSL
Number of participants who 
were in the All Participants 
population, who were 
randomized, the number in 
the ITT population
(Strategic interim only), the 
number in the mITT 
population.  Of those in the 
mITT, the number and 
percentage of participants 
in the PP, Symptomatic
(Strategic interim only), PK 
and PK2 populations
StInt, SAC
1.11
mITT
SP2 
Summary of Exclusions from the Per Protocol 
Population
IDSL
SAC
Demographic and Baseline Characteristics
1.6
1.12
mITT
DM1 
Summary of Demographic Characteristics
ICH E3, FDAAA, EudraCT
StInt, SAC
1.7
1.13
PP
DM1 
Summary of Demographic Characteristics
ICH E3, FDAAA, EudraCT
StInt, SAC
1.14
All Subjects
DM11
Summary of Age Ranges
EudraCT
SAC
1.15
mITT
DM6
Summary of Race and Racial Combinations
ICH E3, FDA, FDAAA, 
EudraCT
SAC


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Study Population Tables
StInt
No.
SAC
No.
Population
IDSL / Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.16
All Subjects
EMA Table 1
Summary of Number of Subjects Enrolled by 
Country
EMA Reporting Package. 
Macro: EMA_COUNTRY
SAC
1.17
All Subjects
EMA Table 2
Summary of Number of Subjects Enrolled by Age 
Category
EMA Reporting Package. 
Macro: EMA_AGEGRP
SAC
1.8
1.18
mITT
SU1
Summary of Smoking History and Smoking Status at 
Screening
Include smoking status, 
smoking pack years, 
cigarettes smoked/day
StInt, SAC
1.9
1.19
PP
SU1
Summary of Smoking History and Smoking Status at 
Screening
Include smoking status, 
smoking pack years, 
cigarettes smoked/day
StInt, SAC
1.10
Symptomatic
SU1
Summary of Smoking History and Smoking Status at 
Screening
Include smoking status, 
smoking pack years, 
cigarettes smoked/day
StInt
1.20
mITT
SP_T12
Summary of COPD History at Screening
SAC
1.11
1.21
mITT
SP_T13
Summary of HCRU Exacerbation History at 
Screening
See notes in Section 14.6.3
StInt, SAC
1.12
1.22
PP
SP_T13
Summary of HCRU Exacerbation History at 
Screening
See notes in Section 14.6.3
StInt, SAC
1.13
1.23
mITT
Summary of Screening Spirometry Measures
Pre-BD FEV1 (L), Post-BD 
FEV1 (L), Predicted normal 
FEV1 (L), Percent 
predicted normal post-BD 
FEV1 (%), Percent 
predicted normal post-BD 
FEV1: <50%, >=50%, Post-
BD FVC (L), Post-BD 
FEV1/FVC
StInt, SAC


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Study Population Tables
StInt
No.
SAC
No.
Population
IDSL / Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.14
1.24
PP
Summary of Screening Spirometry Measures
Pre-BD FEV1 (L), Post-BD 
FEV1 (L), Predicted normal 
FEV1 (L), Percent 
predicted normal post-BD 
FEV1 (%), Percent 
predicted normal post-BD 
FEV1: <50%, >=50%, Post-
BD FVC (L), Post-BD 
FEV1/FVC
StInt, SAC
1.25
mITT
Summary of GOLD Stages at Screening
GOLD 1-4 and GOLD A-D
SAC
1.15
1.26
mITT
Summary of Baseline Symptomatic Characteristics
Proportion of participants 
with CMH according to 
SGRQ, with baseline E-RS: 
COPD total score </>=10, 
with baseline CAT Score 
</>=10, with 
ICS+LABA+LAMA vs. 
ICS+LABA vs. 
LABA+LAMA vs. Other 
COPD medication 
StInt, SAC


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Study Population Tables
StInt
No.
SAC
No.
Population
IDSL / Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.16
1.27
PP
Summary of Baseline Symptomatic Characteristics
Proportion of participants 
with CMH according to 
SGRQ, with baseline E-RS: 
COPD total score </>=10, 
with baseline CAT Score 
</>=10, with 
ICS+LABA+LAMA vs. 
ICS+LABA vs. 
LABA+LAMA vs. Other 
COPD medication 
StInt, SAC
Prior and Concomitant Medications
1.28
mITT
CM1
Summary of COPD Concomitant Medications Taken 
Pre-treatment
Use RMC instead of ATC 
Level 1
SAC
1.29
mITT
CM1
Summary of COPD Concomitant Medications Taken 
On-Treatment, Medications Given for Reasons 
Other than an Exacerbation
Use RMC instead of ATC 
Level 1
SAC
1.30
mITT
CM1
Summary of COPD Concomitant Medications Taken 
Post-treatment
Use RMC instead of ATC 
Level 1
SAC
1.31
mITT
CM1
Summary of On-treatment COPD Concomitant 
Medications Given for an Exacerbation
Use RMC instead of ATC 
Level 1
SAC
1.17
1.32
mITT
Summary of COPD Concomitant Medication 
Combinations Taken at Screening
Number and percentage of 
participants taking each 
medication in the RMC 
combination defined in 
Section 14.6.2
StInt, SAC


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Study Population Tables
StInt
No.
SAC
No.
Population
IDSL / Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.18
1.33
mITT
Summary of COPD Concomitant Medication 
Combinations Taken at Baseline
Number and percentage of 
participants taking each 
medication in the RMC 
combination defined in 
Section 14.6.2
StInt, SAC
1.19
Symptomatic
Summary of COPD Concomitant Medication 
Combinations Taken at Baseline
Number and percentage of 
participants taking each 
medication in the RMC 
combination defined in 
Section 14.6.2
StInt
1.34
PP
Summary of COPD Concomitant Medication 
Combinations Taken at Month 6
Number and percentage of 
participants taking each 
medication in the RMC 
combination defined in 
Section 14.6.2 during 
Month 6
Post SAC
1.35
mITT
CM1
Summary of On-treatment Non-COPD Concomitant 
Medications
Use ATC Level 1
SAC
1.36
mITT
CM1
Summary of Post-treatment Non-COPD 
Concomitant Medications
Use ATC Level 1
SAC
Past and Current Medical History
1.37
mITT
MH4
Summary of Past Medical Conditions
ICH E3
SAC
1.38
mITT
MH4
Summary of Current Medical Conditions
SAC
1.39
mITT
Table 1.23
Study 
GSK2834425/CTT116853
Summary of Cardiovascular History/Risk Factors
SAC


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Study Population Tables
StInt
No.
SAC
No.
Population
IDSL / Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.20
1.40
mITT
FH1
Summary of Family History of Cardiovascular Risk 
Factors
StInt, SAC
Exposure and Treatment Compliance
1.41
mITT
IP1
Summary of Treatment Compliance
SAC
1.42
mITT
Summary of Daily Diary Compliance
SAC
1.43
mITT
EX1 
Summary of Exposure to Study Treatment
ICH E3
SAC
14.11.4.
Study Population Figures
Study Population Figures
SAC
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Disposition of Subjects
1.1.
mITT
Kaplan-Meier Plot of Time to Study Withdrawal
SAC


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14.11.5.
Efficacy Tables
Efficacy: Tables
StInt
No.
SAC
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
E-RS: COPD
2.1
2.1
PP
PD4
Summary of Baseline E-RS: COPD Scores
Endpoints: E-RS: COPD total and 
subscale scores
Include total column
StInt, SAC
2.2
Symptomatic
PD4
Summary of Baseline E-RS: COPD Scores
Endpoints: E-RS: COPD total and 
subscale scores
Include total column
StInt
2.3
2.2
PP
PD4
Summary of Monthly Mean E-RS: COPD 
Scores
Endpoints: E-RS: COPD total and 
subscale scores
Include raw and change from baseline 
scores for participants with non-missing 
E-RS data for each month
StInt, SAC
2.4
Symptomatic
PD4
Summary of Monthly Mean E-RS: COPD 
Scores
Endpoints: E-RS: COPD total and 
subscale scores
Include raw and change from baseline 
scores for participants with non-missing 
E-RS data for each month
StInt
2.5
2.3
PP
Bayesian Dose Response Analysis of Change 
from Baseline E-RS: COPD Scores at Month 6
Endpoint: Month 6 E-RS: COPD total and 
subscale scores
StInt, SAC
2.6
Symptomatic
Bayesian Dose Response Analysis of Change 
from Baseline E-RS: COPD Total Score at 
Month 6
Endpoint: Month 6 E-RS: COPD total 
score
StInt


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Efficacy: Tables
StInt
No.
SAC
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.7
2.4
PP
Bayesian Analysis of Change from Baseline 
Monthly Mean E-RS: COPD Scores up to 
Month 6
Bayesian MMRM on Change from 
Baseline 
Endpoints: E-RS: COPD total and 
subscale scores
StInt, SAC
2.8
Symptomatic
Bayesian Analysis of Change from Baseline 
Monthly Mean E-RS: COPD Scores up to 
Month 6
Bayesian MMRM on Change from 
Baseline 
Endpoints: E-RS: COPD total and 
subscale scores
StInt
2.9
ITT
Bayesian Analysis of Change from Baseline 
Monthly Mean E-RS: COPD Scores up to 
Month 6
Bayesian MMRM on Change from 
Baseline 
Endpoints: E-RS: COPD total and 
subscale scores
StInt
2.10
2.5
PP
Analysis of Change from Baseline Monthly 
Mean E-RS: COPD Total Score up to Month 6
Frequentist MMRM 
Endpoints: E-RS: COPD total score
StInt, SAC
2.11
2.6
PP 
Type III Tests of Fixed Effects for Analysis of 
Change from Baseline Monthly Mean E-RS:
COPD Total Score up to Month 6
Frequentist MMRM 
Endpoints: E-RS: COPD total score
StInt, SAC
2.12
2.7
PP
Analysis of Proportion of Responders 
According to Monthly Mean E-RS: COPD
Scores up to Month 6
Responder Analysis
Generalized linear model
Endpoints: E-RS: COPD total and 
subscale scores
StInt, SAC
2.13
2.8
PP
Analysis of Change from Baseline Monthly 
Mean E-RS: COPD Total Score up to Month 6: 
Interaction of Treatment with Other Factors
Frequentist MMRM 
Endpoints: E-RS: COPD total score
StInt, SAC


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Efficacy: Tables
StInt
No.
SAC
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.14
PP
Analysis of Change from Baseline Monthly 
Mean E-RS: COPD Total Score up to Month 6 
by Baseline E-RS: COPD Total Score (<10, 
>=10)
Frequentist MMRM 
Endpoints: E-RS: COPD total score
StInt
2.15
2.9
PP
Analysis of Change from Baseline Monthly 
Mean E-RS: COPD Total Score up to Month 6 
by Smoking Status at Screening (Current, 
Former)
Frequentist MMRM 
Endpoints: E-RS: COPD total score
StInt, SAC
2.16
PP
Analysis of Change from Baseline Monthly 
Mean E-RS: COPD Total Score up to Month 6 
by Country
Frequentist MMRM 
Endpoints: E-RS: COPD total score
StInt
2.17
2.10
PP
Analysis of Change from Baseline Monthly 
Mean E-RS: COPD Total Score up to Month 6 
by % Predicted FEV1 at Screening (<50, >=50)
Frequentist MMRM 
Endpoints: E-RS: COPD total score
StInt, SAC
2.18
2.11
PP
Analysis of Change from Baseline Monthly 
Mean E-RS: COPD Total Score up to Month 6 
by Baseline CAT Score (<10, >=10)
Frequentist MMRM 
Endpoints: E-RS: COPD total score
StInt, SAC
2.19
PP
Analysis of Change from Baseline Monthly 
Mean E-RS: COPD Total Score up to Month 6 
by Exacerbation History (>=2 moderate/severe 
vs. 1 moderate/severe, prior year)
Frequentist MMRM 
Endpoints: E-RS: COPD total score
StInt
2.20
PP
Analysis of Change from Baseline Monthly 
Mean E-RS: COPD Total Score up to Month 6 
by COPD Medication Grouping at Baseline 
(ICS+LABA+LAMA, ICS+LABA, LABA+LAMA, 
Other)
Frequentist MMRM 
Endpoints: E-RS: COPD total score
StInt


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Efficacy: Tables
StInt
No.
SAC
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.21
PP
Analysis of Change from Baseline Monthly 
Mean E-RS: COPD Total Score up to Month 6 
by CMH Status at Baseline
Frequentist MMRM 
Endpoints: E-RS: COPD total score
StInt
2.22
PP
Analysis of Change from Baseline Monthly 
Mean E-RS: COPD Total Score up to Month 6 
by Season
Frequentist MMRM 
Endpoints: E-RS: COPD total score
StInt
2.12
Summary of Responders to E-RS: COPD Total 
Score, SGRQ and CAT at Month 6
Include categories for E-RS, SGRQ, 
CAT, E-RS+SGRQ, E-RS+CAT. 
SGRQ+CAT, E-RS+SGRQ+CAT, None, 
Missing
Post SAC
Exacerbations
2.23
2.13
PP
Summary of On-treatment HCRU
Exacerbations
StInt, SAC
2.14
PP
Summary of On-treatment Details of 
Moderate/Severe HCRU Exacerbations
SAC
2.15
PP
Summary of On-treatment HCRU 
Exacerbations Treated with Antibiotics
Include row for how many subjects were 
receiving ICS for at least 7 days at the 
time of exacerbation
Post SAC
2.24
2.16
PP
Bayesian Analysis of On-treatment 
Moderate/Severe HCRU Exacerbations 
Bayesian generalized linear model
StInt, SAC
2.25
ITT
Bayesian Analysis of On-treatment 
Moderate/Severe HCRU Exacerbations 
Bayesian generalized linear model
StInt, 
2.26
2.17
PP
Summary and Bayesian Analysis of Time to 
First On-treatment Moderate/Severe HCRU
Exacerbation
Bayesian proportional hazards model
StInt, SAC


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Efficacy: Tables
StInt
No.
SAC
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.27
2.18
PP
Summary and Bayesian Analysis of Time to 
First On-treatment Severe HCRU Exacerbation
Bayesian proportional hazards model
StInt, SAC
EXACT Events
2.19
PP
Summary of On-treatment EXACT Events
SAC
2.20
PP
Bayesian Analysis of On-treatment EXACT 
Events
Bayesian generalized linear model
SAC
2.21
PP
Summary and Bayesian Analysis of Time to 
First On-treatment EXACT Events
Bayesian proportional hazards model
SAC
SGRQ
2.28
2.22
PP
PD4
Summary of Baseline SGRQ Scores
Include total column
Total and domain scores
StInt, SAC
2.29
2.23
PP
PD4
Summary of SGRQ Scores
Include raw and change from baseline
Total and domain scores
StInt, SAC
2.30
2.24
PP
Bayesian Analysis of Change from Baseline
SGRQ Total Score up to Month 6
Bayesian MMRM on Change from 
Baseline 
Endpoints: SGRQ Total Score
StInt, SAC
2.31
2.25
PP
Analysis of Proportion of Responders 
According to SGRQ Total Scores up to Month 6
Responder Analysis
Generalized linear model
StInt, SAC
CAT
2.32
2.26
PP
PD4
Summary of Baseline CAT Score
Include total column
StInt, SAC
2.33
2.27
PP
PD4
Summary of CAT Score
Include raw and change from baseline
StInt, SAC


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Efficacy: Tables
StInt
No.
SAC
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.34
2.28
PP
Bayesian Analysis of Change from Baseline 
CAT Score up to Month 6
Bayesian MMRM on Change from 
Baseline 
Endpoints: CAT Score
StInt, SAC
2.35
2.29
PP
Analysis of Proportion of Responders 
According to CAT Score up to Month 6
Responder Analysis
Generalized linear model
StInt, SAC
2.36
2.30
PP
Analysis of Change from Baseline CAT Score 
up to Month 6: Interaction of Treatment with 
Other Factors
Frequentist MMRM 
Endpoints: CAT Score
StInt, SAC
2.37
PP
Analysis of Change from Baseline CAT Score 
up to Month 6 by Baseline E-RS: COPD Total 
Score (<10, >=10)
Frequentist MMRM 
Endpoints: CAT Score
StInt
2.38
2.31
PP
Analysis of Change from Baseline CAT Score 
up to Month 6 by Smoking Status at Screening 
(Current, Former)
Frequentist MMRM 
Endpoints: CAT Score
StInt, SAC
2.39
PP
Analysis of Change from Baseline CAT Score
up to Month 6 by Country
Frequentist MMRM 
Endpoints: CAT Score
StInt
2.40
2.32
PP
Analysis of Change from Baseline CAT Score
up to Month 6 by % Predicted FEV1 at 
Screening (<50, >=50)
Frequentist MMRM 
Endpoints: CAT Score
StInt, SAC
2.41
2.33
PP
Analysis of Change from CAT Score up to 
Month 6 by Baseline CAT Score (<10, >=10)
Frequentist MMRM 
Endpoints: CAT Score
StInt, SAC
2.42
PP
Analysis of Change from CAT Score up to 
Month 6 by Exacerbation History (>=2 
moderate/severe vs. 1 moderate/severe, prior 
year)
Frequentist MMRM 
Endpoints: CAT Score
StInt


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Efficacy: Tables
StInt
No.
SAC
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.43
PP
Analysis of Change from Baseline CAT Score
up to Month 6 by COPD Medication Grouping 
at Baseline (ICS+LABA+LAMA, ICS+LABA, 
LABA+LAMA, Other)
Frequentist MMRM 
Endpoints: CAT Score
StInt
2.44
PP
Analysis of Change from Baseline CAT Score 
up to Month 6 by CMH Status at Baseline
Frequentist MMRM 
Endpoints: CAT Score
StInt
2.45
PP
Analysis of Change from Baseline CAT Score
up to Month 6 by Season
Frequentist MMRM 
Endpoints: CAT Score
StInt
Rescue Use
2.46
2.34
PP
PD4
Summary of Baseline Mean Number of Puffs of 
Rescue Medication per Day using Diary Data
Include total column
StInt, SAC
2.47
2.35
PP
PD4
Summary of Monthly Mean Number of Puffs of 
Rescue Medication per Day using Diary Data 
up to Month 6
Include raw and change from baseline
StInt, SAC
2.48
2.36
PP
Analysis of Change from Baseline in Monthly 
Mean Number of Puffs of Rescue Medication 
per Day using Diary Data up to Month 6
MMRM on Change from Baseline 
StInt, SAC
2.49
2.37
PP
PD4
Summary of Baseline Percentage Rescue-free 
Days using Diary Data
Include total column
StInt, SAC
2.50
2.38
PP
PD4
Summary of Percentage Rescue-free Days 
using Diary Data up to Month 6
Include raw and change from baseline
StInt, SAC
2.51
2.39
PP
Analysis of Change from Baseline in 
Percentage Rescue-free Days using Diary Data 
up to Month 6
MMRM on Change from Baseline 
StInt, SAC


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Efficacy: Tables
StInt
No.
SAC
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.40
PP
PD4
Summary of Baseline Mean Number of 
Occasions of Rescue Medication per Day using 
Sensor Data
Include total column
SAC
2.41
PP
PD4
Summary of Monthly Mean Number of 
Occasions of Rescue Medication per Day using 
Sensor Data up to Month 6
Include raw and change from baseline
SAC
2.42
PP
Analysis of Change from Baseline Monthly 
Mean Number of Occasions of Rescue 
Medication per Day using Sensor Data up to 
Month 6
MMRM on Change from Baseline 
SAC
2.43
PP
PD4
Summary of Baseline Percentage Rescue-free 
Days using Sensor Data
Include total column
SAC
2.44
PP
PD4
Summary of Percentage Rescue-free Days 
using Sensor Data up to Month 6
Include raw and change from baseline
SAC
2.45
PP
Analysis of Change from Baseline Percentage 
Rescue-free Days using Sensor Data up to 
Month 6
MMRM on Change from Baseline 
SAC
Physical Activity
2.46
PP
PD4
Summary of Baseline PROactive Score
Include total column
Endpoints: PROactive Total Score and 
domain scores
SAC
2.47
PP
PD4
Summary of PROactive Score up to Month 6
Include raw and change from baseline
Endpoints: PROactive Total Score and 
domain scores
SAC


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Efficacy: Tables
StInt
No.
SAC
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.52
PP
Summary of Responses to C-PPAC 
Questionnaire at Each Visit
StInt
Subject Global Assessments
2.48
PP
PD4
Summary of Subject Global Assessments at 
Baseline
Include total column
Endpoints: severity, activity limitation
SAC
2.49
PP
PD4
Summary of Subject Global Assessments
Endpoints: severity, change in severity, 
activity limitation and change in activity 
limitation
SAC
14.11.6.
Efficacy Figures
Efficacy: Figures
StInt
No.
SAC No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
E-RS: COPD
2.1
PP
Daily Mean E-RS: COPD Scores over Time
Total and subscale scores
Day -7 to Day 168
Post SAC
2.2
PP
Daily Mean E-RS: COPD Scores over Time by 
Completion Status
Total and subscale scores
Day -7 to Day 168
One page for completers and one page 
for subjects who withdrew
Post SAC
2.1
2.3
PP
Daily Mean Change from Baseline in E-RS: COPD 
Scores over Time
Total and subscale scores
StInt, SAC


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Efficacy: Figures
StInt
No.
SAC No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.2
2.4
PP
Daily Mean (SE) Change from Baseline in E-RS: 
COPD over Time by Dose
Total and subscale scores; one panel for 
each DNX dose to include DNX and 
placebo data
StInt, SAC
2.3
Symptomatic
Daily Mean (SE) Change from Baseline in E-RS: 
COPD over Time by Dose
Total and subscale scores; one panel for 
each DNX dose to include DNX and 
placebo data
StInt
2.5
PP
Daily Mean (SE) E-RS: COPD over Time by Dose
Total and subscale scores
Day -7 to Day 168
Post SAC
2.4
2.6
PP
Bayesian Dose Response Model for E-RS: COPD 
Scores at Month 6
Total and subscale scores; overlaid with 
mean/CI from Bayesian longitudinal 
model
StInt, SAC
2.5
Symptomatic
Bayesian Dose Response Model for E-RS: COPD 
Total Score at Month 6
Total score; overlaid with mean/CI from 
Bayesian longitudinal model
StInt
2.6
2.7
PP
Posterior Mean (90% CrI) Change from Baseline in E-
RS: COPD Scores over Time
Total and subscale scores
StInt, SAC
2.7
Symptomatic
Posterior Mean (90% CrI) Change from Baseline in E-
RS: COPD Total Score over Time
Total score
StInt
2.8
ITT
Posterior Mean (90% CrI) Change from Baseline in E-
RS: COPD Total Score over Time
Total score
StInt
2.9
2.8
PP
Adjusted Mean (90% CI) Change from Baseline in E-
RS: COPD Total Score over Time
Total score
StInt, SAC
2.9
PP
Adjusted Mean (90% CI) E-RS: COPD Total Score 
over Time
Total score
Post SAC


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Efficacy: Figures
StInt
No.
SAC No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.10
PP
Least Squares Mean (90% CI) Change from Baseline 
in E-RS:COPD Total Score at Month 6 by Baseline E-
RS: COPD Total Score (<10, >=10)
One panel for each factor on the same 
page
StInt
2.11
2.10
PP
Least Squares Mean (90% CI) Change from Baseline 
in E-RS: COPD Total Score at Month 6 by Smoking 
Status at Screening (Current, Former)
One panel for each factor on the same 
page
StInt, SAC
2.12
PP
Least Squares Mean (90% CI) Change from Baseline 
in E-RS: COPD Total Score at Month 6 by Country
One panel for each factor, 4 panels per 
page
StInt
2.13
2.11
PP
Least Squares Mean (90% CI) Change from Baseline 
in E-RS: COPD Total Score at Month 6 by % 
Predicted FEV1 at Screening (<50, >=50)
One panel for each factor on the same 
page
StInt, SAC
2.14
2.12
PP
Least Squares Mean (90% CI) Change from Baseline 
in E-RS: COPD Total Score at Month 6 by Baseline 
CAT Score (<10, >=10)
One panel for each factor on the same 
page
StInt, SAC
2.15
PP
Least Squares Mean (90% CI) Change from Baseline 
in E-RS: COPD Total Score at Month 6 by 
Exacerbation History (>=2 moderate/severe vs. <2 
moderate/severe, prior year)
One panel for each factor on the same 
page
StInt
2.16
PP
Least Squares Mean (90% CI) Change from Baseline 
in E-RS: COPD Total Score at Month 6 by COPD 
Medication Grouping at Baseline (ICS+LABA+LAMA, 
ICS+LABA, LABA+LAMA, Other)
One panel for each factor on the same 
page
StInt
2.17
PP
Least Squares Mean (90% CI) Change from Baseline 
in E-RS: COPD Total Score at Month 6 by CMH 
Status at Baseline
One panel for each factor on the same 
page
StInt


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Efficacy: Figures
StInt
No.
SAC No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.18
PP
Least Squares Mean (90% CI) Change from Baseline 
in E-RS: COPD Total Score at Month 6 by Season
All factors on one plot
StInt
2.13
PP
Empirical Distribution Function Plot of E-RS: COPD 
Total Scores at Baseline
Total and subscale scores
Post SAC
2.14
PP
Empirical Distribution Function Plot of E-RS: COPD 
Total Scores at Month 6
Total and subscale scores
Post SAC
Exacerbations
2.19
2.15
PP
Median Rate Ratio (90% CrI) of On-treatment 
Moderate/Severe HCRU Exacerbations
StInt, SAC
2.20
ITT
Median Rate Ratio (90% CrI) of On-treatment 
Moderate/Severe HCRU Exacerbations
StInt
2.21
2.16
PP
Kaplan-Meier Plot of Time to First On-treatment 
Moderate/Severe HCRU Exacerbation
StInt, SAC
2.22
2.17
PP
Kaplan-Meier Plot of Time to First On-treatment 
Severe HCRU Exacerbation
StInt, SAC
EXACT Events
2.18
PP
Median Rate Ratio (90% CrI) of On-treatment EXACT 
Events
SAC
2.19
PP
Kaplan-Meier Plot of Time to First On-treatment 
EXACT Event
SAC
SGRQ
2.23
2.20
PP
Posterior Mean (90% CrI) Change from Baseline in 
SGRQ Total Score over Time
StInt, SAC
2.21
PP
Mean (90% CI) SGRQ Total Score over Time
Baseline, Day 84 and 168
Post SAC


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Efficacy: Figures
StInt
No.
SAC No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
CAT
2.24
2.22
PP
Posterior Mean (90% CrI) Change from Baseline in 
CAT Score over Time
StInt, SAC
2.23
PP
Mean (90% CI) CAT Score over Time
Baseline, Day 84 and 168
Post SAC
2.25
PP
Least Squares Mean (90% CI) Change from Baseline 
in CAT Score at Month 6 by Baseline E-RS: COPD 
Total Score (<10, >=10)
One panel for each factor
StInt
2.26
2.24
PP
Least Squares Mean (90% CI) Change from Baseline 
in CAT Score at Month 6 by Smoking Status at 
Screening (Current, Former)
One panel for each factor
StInt, SAC
2.27
PP
Least Squares Mean (90% CI) Change from Baseline 
in CAT Score at Month 6 by Country
One panel for each factor
StInt
2.28
2.25
PP
Least Squares Mean (90% CI) Change from Baseline 
in CAT Score at Month 6 by % Predicted FEV1 at 
Screening (<50, >=50)
One panel for each factor
StInt, SAC
2.29
2.26
PP
Least Squares Mean (90% CI) Change from Baseline 
in CAT Score at Month 6 by Baseline CAT Score 
(<10, >=10)
One panel for each factor
StInt, SAC
2.30
PP
Least Squares Mean (90% CI) Change from Baseline 
in CAT Score at Month 6 by Exacerbation History 
(>=2 moderate/severe vs. 1 moderate/severe, prior 
year)
One panel for each factor
StInt


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Efficacy: Figures
StInt
No.
SAC No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.31
PP
Least Squares Mean (90% CI) Change from Baseline 
in CAT Score at Month 6 by COPD Medication 
Grouping at Baseline (ICS+LABA+LAMA, ICS+LABA, 
LABA+LAMA, Other)
One panel for each factor
StInt
2.32
PP
Least Squares Mean (90% CI) Change from Baseline 
in CAT Score at Month 6 by CMH Status at Baseline
One panel for each factor
StInt
2.33
PP
Least Squares Mean (90% CI) Change from Baseline 
in CAT Score at Month 6 by Season
All factors on one plot
StInt
Rescue Use
2.27
PP
Daily Mean Number of Puffs of Rescue Medication 
per Day using Diary Data over Time
Day -7 to Day 168
Post SAC
2.34
2.28
PP
Least Squares Mean (90% CI) Change from Baseline 
in Mean Number of Puffs of Rescue Use per Day 
using Diary Data over Time
StInt, SAC
2.35
2.29
PP
Least Squares Mean (90% CI) Change from Baseline 
in Percentage of Rescue-free Days using Diary Data
over Time
StInt, SAC
2.30
PP
Daily Mean Number of Occasions of Rescue 
Medication per Day using Sensor Data over Time
Day -7 to Day 168
Post SAC
2.31
PP
Least Squares Mean (90% CI) Change from Baseline 
in Mean Number of Occasions of Rescue Use per 
Day using Sensor Data over Time
SAC
2.32
PP
Least Squares Mean (90% CI) Change from Baseline 
in Percentage of Rescue-free Days using Sensor 
Data over Time
SAC


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Efficacy: Figures
StInt
No.
SAC No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Conditional E-RS: COPD
2.36-
2.43
2.33-
2.35
PP
Least Squares Mean (90% CI) Change from Baseline 
in E-RS: COPD Total Score over Time by Factor
Produced if an interaction between 
treatment and factor is significant at the 
10% level Where Factor is defined in 
Section 7.3.1
One panel for each factor
StInt, SAC
Continue 
from 
above
Continue 
from 
above
PP
Least Squares Mean (90% CI) Change from Baseline 
in CAT Score over Time by Factor
Produced if an interaction between 
treatment and factor is significant at the 
10% level Where Factor is defined in 
Section 7.3.1
One panel for each factor
StInt, SAC
14.11.7.
Safety Tables
Safety: Tables
StInt
No.
SAC 
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
3.1
3.1
mITT
AE1
Summary of On-treatment Adverse Events by System 
Organ Class and Preferred Term
ICH E3
StInt, SAC
3.2
3.2
mITT
AE3
Summary of Common (>=5%) On-treatment Adverse 
Events by Overall Frequency
ICH E3
StInt, SAC


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Safety: Tables
StInt
No.
SAC 
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.3
3.3
mITT
AE1/AE3
Summary All On-treatment Drug-Related Adverse Events 
by [System Organ Class and] Preferred Term
ICH E3
Use AE1 for interim with text in [] in title
Use AE3 for final reporting with text in [] 
omitted.
StInt, SAC
3.4
mITT
AE15
Summary of Common (>=5%) Non-serious On-treatment 
Adverse Events by System Organ Class and Preferred 
Term (Number of Subject and Occurrences)
FDAAA, EudraCT
SAC
3.5
mITT
AE1
Summary of Post-treatment Adverse Events
SAC
3.6
ALLSUB
AE2
Relationship of Adverse Event System Organ Class, 
Preferred Term and Verbatim Text
SAC
3.7
mITT
AE5A
Summary of All On-treatment Adverse Events by Maximum 
Intensity by System Organ Class and Preferred Term
ICH E3
SAC
3.8
mITT
AE5A
Summary of On-treatment Drug-Related Adverse Events 
by Maximum Intensity by System Organ Class and 
Preferred Term
ICH E3
SAC
Serious and Other Significant Adverse Events
3.9
mITT
AE16
Summary of On-treatment Serious Adverse Events by 
System Organ Class and Preferred Term (Number of 
Subjects and Occurrences)
FDAAA, EudraCT
SAC
3.10
ALLSUB
AE1/AE3
Summary of Pre-treatment Serious Adverse Events by 
[System Organ Class and] Preferred Term
SAC
3.4
3.11
mITT
AE1/AE3
Summary of On-treatment Serious Adverse Events by 
[System Organ Class and] Preferred Term
Use AE1 for interim with text in [] in title
Use AE3 for final reporting with text in [] 
omitted.
StInt, SAC


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Safety: Tables
StInt
No.
SAC 
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.5
3.12
mITT
AE1/AE3
Summary of On-treatment Fatal Serious Adverse Events 
by [System Organ Class and] Preferred Term
Use AE1 for interim with text in [] in title
Use AE3 for final reporting with text in [] 
omitted.
StInt, SAC
3.6
3.13
mITT
AE1/AE3
Summary of On-treatment Adverse Events Leading to 
Permanent Discontinuation of Study Treatment or 
Withdrawal from Study by [System Organ Class and]
Preferred Term
IDSL
Use AE1 for interim with text in [] in title
Use AE3 for final reporting with text in [] 
omitted.
StInt, SAC
3.7
3.14
mITT
Summary of On-treatment Adverse Events of Special 
Interest
StInt, SAC
3.15
mITT
Summary of On-treatment Pneumonia (AE and SAE) by 
ICS
AE and SAE
Subjects who have an event in the 
‘Infective pneumonia’ SMQ
By subjects receiving ICS for at least 7 
days at the time on pneumonia onset.
Post SAC
Laboratory: Chemistry 
3.8
3.16
mITT
LB1
Summary of Chemistry Changes from Baseline 
ICH E3, include change from baseline of 
min/max value
StInt, SAC
3.9
3.17
mITT
LB17
Summary of Worst Case Chemistry Results by Potential 
Clinical Importance Criteria
ICH E3
StInt, SAC
Laboratory: Hematology
3.10
3.18
mITT
LB1
Summary of Hematology Changes from Baseline
ICH E3, include change from baseline of 
min/max value
StInt, SAC
3.11
3.19
mITT
LB17
Summary of Worst Case Hematology by Potential Clinical 
Importance Criteria
ICH E3
StInt, SAC


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Safety: Tables
StInt
No.
SAC 
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Laboratory: Hepatobiliary (Liver)
3.12
3.20
mITT
LIVER1
Summary/Listing of Liver Monitoring/Stopping Event 
Reporting
IDSL – if there are very small number of 
events this summary will be replaced 
with a listing. Table title to be 
determined by content.
StInt, SAC
3.13
3.21
mITT
LIVER10
Summary/Listing of Hepatobiliary Laboratory Abnormalities
IDSL – if there are very small number of 
events this summary will be replaced 
with a listing. Table title to be 
determined by content.
StInt, SAC
ECG
3.22
mITT
EG1
Summary of ECG Findings 
IDSL, include min/max value
SAC
3.23
mITT
EG2
Summary of Change from Baseline in ECG Values by Visit
IDSL include change from baseline of 
min/max value
SAC
3.14
3.24
mITT
EG10
Summary of Maximum QTcF Values Post-Baseline 
Relative to Baseline by Category
IDSL 
StInt, SAC
3.15
3.25
mITT
EG11
Summary of Maximum Increase in QTcF Values Post-
Baseline Relative to Baseline by Category
IDSL 
StInt, SAC
Vital Signs
3.26
mITT
VS1
Summary of Change from Baseline in Vital Signs
ICH E3, include change from baseline of 
min/max value
SAC
3.27
mITT
VS7
Summary of Worst Case Vital Signs Results by Potential 
Clinical Importance Criteria
IDSL
SAC


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Safety: Tables
StInt
No.
SAC 
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Spirometry
3.16
3.28
mITT
Summary of Baseline Post-Bronchodilator FEV1 (L)
Post bronchodilator FEV1 
Include total column
StInt, SAC
3.17
3.29
mITT
Summary of Post-Bronchodilator FEV1 (L)
Post bronchodilator FEV1 
Include raw and change from baseline
StInt, SAC
3.18
3.30
mITT
Analysis of Change from Baseline Post-Bronchodilator 
FEV1 (L) up to Month 6
Frequentist MMRM 
Endpoints: Post bronchodilator FEV1
StInt, SAC
3.19
3.31
mITT
Type III Tests of Fixed Effects for Analysis of Change from 
Baseline Post-Bronchodilator FEV1 (L)
Frequentist MMRM 
Endpoints: Post bronchodilator FEV1
StInt, SAC
3.20
3.32
mITT
Summary of Baseline Post-Bronchodilator FVC (L)
Post bronchodilator FVC 
Include total column
StInt, SAC
3.21
3.33
mITT
Summary of Post-Bronchodilator FVC (L)
Post bronchodilator FVC 
Include raw and change from baseline
StInt, SAC
3.22
3.34
mITT
Analysis of Change from Baseline Post-Bronchodilator 
FVC (L) up to Month 6
Frequentist MMRM 
Endpoints: Post bronchodilator FVC
StInt, SAC
3.23
3.35
mITT
Type III Tests of Fixed Effects for Analysis of Change from 
Baseline Post-Bronchodilator FVC (L)
Frequentist MMRM 
Endpoints: Post bronchodilator FVC
StInt, SAC
3.36
mITT
Summary of Baseline Post-Bronchodilator FEV1/FVC
Post bronchodilator FEV1/FVC 
Include total column
Post SAC
3.37
mITT
Summary of Post-Bronchodilator FEV1/FVC
Post bronchodilator FEV1 
Include raw and change from baseline
Day 84 and 168
Post SAC


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14.11.8.
Safety Figures
Safety: Figures
StInt
No.
SAC 
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events
3.1
mITT
AE10
Plot of Common (>=5%) On-Treatment Adverse Events and 
Relative Risk
IDSL
One page per active 
treatment compared to 
placebo
Include AEs which have 
>=5% incidence in any 
treatment group
SAC
Laboratory
3.1
3.2
mITT
LIVER14
Scatter Plot of Maximum Post-Baseline vs. Baseline for ALT
IDSL
StInt, SAC
3.2
3.3
mITT
LIVER9
Scatter Plot of Maximum Post-Baseline ALT vs. Maximum Post-
Baseline Total Bilirubin
IDSL
StInt, SAC
3.3
3.4
mITT
Plot of Mean (95% CI) Neutrophil Counts over Time
StInt, SAC
3.5
mITT
Plot of Mean (95% CI) Neutrophil Counts over Time for Subjects 
with Pneumonia
Post SAC
Spirometry
3.6
mITT
Mean (90% CI) Post-Bronchodilator FEV1 (L) over Time
Baseline, Day 84 and 168
Post SAC
3.4
3.7
mITT
Adjusted Mean (90% CI) Change from Baseline Post-
Bronchodilator FEV1 (L) over Time
StInt, SAC
3.8
mITT
Mean (90% CI) Post-Bronchodilator FVC (L) over Time
Baseline, Day 84 and 168
Post SAC
3.5
3.9
mITT
Adjusted Mean (90% CI) Change from Baseline Post-
Bronchodilator FVC (L) over Time
StInt, SAC


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Safety: Figures
StInt
No.
SAC 
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.10
mITT
Mean (90% CI) Post-Bronchodilator FEV1/FVC Ratio over Time
Baseline, Day 84 and 168
Post SAC
ECG
3.6
3.11
mITT
Boxplot of Change from Baseline in QTcF by Time and Treatment
StInt, SAC
14.11.9.
Pharmacokinetic Tables
SAC 
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
4.1
PK
PKCT1
Summary of Danirixin Whole Blood Pharmacokinetic 
Concentration-Time Data (Dry Blood Spot)
Include geometric mean and 90% 
CI for the summary of blood 
concentration data
SAC
4.2
PK
PKPT4
Summary of Derived Danirixin Whole Blood Pharmacokinetic 
Parameters (Dry Blood Spot)
SAC
4.3
PK2
Table 3.10
Study 201037
Summary of Statistical Analysis of Log-Transformed Danirixin 
Concentration-Time Data
Dry Blood Spot vs Wet Whole Blood Samples - Bland Altman 
Analysis
SAC
4.4
PK2
Table 3.12
Study 201037
Summary of Statistical Analysis of Log-Transformed Danirixin 
Pharmacokinetic Parameters
Dry Blood Spot vs Wet Whole Blood Samples - Bland Altman 
Analysis
SAC
4.5
PK2
Table 3.11
Study 201037
Summary of Statistical Analysis of Log-Transformed Danirixin 
Pharmacokinetic Parameters
Dry Blood Spot vs Wet Whole Blood Samples
SAC


CONFIDENTIAL
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116
SAC 
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
4.6
PK2
Table 3.10
Study 201037
Summary of Statistical Analysis of Log-Transformed Danirixin 
Concentration-Time Data
Sensitivity Analysis: Dry Blood Spot vs Wet Whole Blood 
Samples - Bland Altman Analysis
excluding dry blood spot 
concentrations above the assay 
HLOQ of 1000 ng/mL
SAC
4.7
PK2
Table 3.12
Study 201037
Summary of Statistical Analysis of Log-Transformed Danirixin 
Pharmacokinetic Parameters
Sensitivity Analysis: Dry Blood Spot vs Wet Whole Blood 
Samples - Bland Altman Analysis
excluding dry blood spot 
concentrations above the assay 
HLOQ of 1000 ng/mL
SAC
4.8
PK2
Table 3.11
Study 201037
Summary of Statistical Analysis of Log-Transformed Danirixin 
Pharmacokinetic Parameters
Sensitivity Analysis: Dry Blood Spot vs Wet Whole Blood 
Samples
excluding dry blood spot 
concentrations above the assay 
HLOQ of 1000 ng/mL
SAC
14.11.10. Pharmacokinetic Figures
SAC 
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
[Priority]
4.1
PK
PKCF1p
Individual Whole Blood Danirixin Concentration-Time Plots by 
Subject (Linear and Semi-log) (Dry Blood Spot)
1. X-axis displays actual relative 
time
2. Include line for LLQ along with 
footnote defining LLQ value
3. Include values below LLQ
4. Overlay Visit 3, 6, 7 and 10.
SAC
4.2
PK
PKCF6
Individual Whole Blood Danirixin Concentration-Time Plots by 
Day (Linear and Semi-log) (Dry Blood Spot)
1. X-axis displays actual relative 
time
2. Include line for LLQ along with 
footnote defining LLQ value
3. Include values below LLQ
SAC


CONFIDENTIAL
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SAC 
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
[Priority]
4.3
PK
PKCF4
Mean (SD) Whole Blood Danirixin Concentration-Time Plots 
(Linear and Semi-log) (Dry Blood Spot)
1. Include the full SD bars at each 
time point
2. X-axis displays planned relative 
time
3. Include line for LLQ along with 
footnote defining LLQ value
4. Overlay Visit 3, 6, 7 and 10.
SAC
4.4
PK
PKCF5
Median (Range) Whole Blood Danirixin Concentration-Time 
Plots (Linear and Semi-log) (Dry Blood Spot)
1. Include bars for range at each 
time point
2. X-axis displays planned relative 
time
3. Include like for LLQ along with 
footnote defining LLQ value
4. Overlay Visit 3, 6, 7 and 10.
SAC
4.5
PK
PK27
Median (Range) Pre-Dose Whole Blood Danirixin 
Concentration Versus Day (Linear and Semi-log) (Dry Blood 
Spot)
1. Include bars for range at each 
time point
2. X-axis displays Visit
3. Include like for LLQ along with 
footnote defining LLQ value
4. Visit include 3, 6, 7 and 10.
SAC
4.6
PK
Figure 11.206
Study 200163
Individual Whole Blood Pharmacokinetic Parameters 
(+Geometric Mean and 95% CI) versus Demographics
Demographics: Age, Weight, 
Gender.
By day.
SAC
4.7
PK
Scatter Plot of Whole Blood Danirixin Concentration-by Day 
(Dry Blood Spot)
Post SAC
4.8
PK2
Figure 3.10
Study 201037
Individual Subject Danirixin Blood Concentration-Time Plot 
(Linear and Semi-Log) by Subject 
Dry Blood Spot vs Wet Whole Blood Samples
SAC


CONFIDENTIAL
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118
SAC 
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
[Priority]
4.9
PK2
Figure 3.8
Study 2010137
Comparative Plot of Individual Subject Danirixin Blood 
Concentrations 
Dry Blood Spot vs Wet Whole Blood Samples
SAC
4.10
PK2
Figure 3.9
Study 201037
Bland-Altman Plot of Individual Subject Log-Transformed 
Danirixin Blood Concentrations
Dry Blood Spot vs Wet Whole Blood Samples
SAC
4.11
PK2
Figure 3.10
Study 201037
Individual Subject Danirixin Blood Concentration-Time Plot 
(Linear and Semi-Log) by Subject 
Sensitivity Analysis: Dry Blood Spot vs Wet Whole Blood 
Samples
excluding dry blood spot 
concentrations above the assay 
HLOQ of 1000 ng/mL
SAC
4.12
PK2
Figure 3.8
Study 2010137
Comparative Plot of Individual Subject Danirixin Blood 
Concentrations 
Sensitivity Analysis: Dry Blood Spot vs Wet Whole Blood 
Samples
excluding dry blood spot 
concentrations above the assay 
HLOQ of 1000 ng/mL
SAC
4.13
PK2
Figure 3.9
Study 201037
Bland-Altman Plot of Individual Subject Log-Transformed 
Danirixin Blood Concentrations
Sensitivity Analysis: Dry Blood Spot vs Wet Whole Blood 
Samples
excluding dry blood spot 
concentrations above the assay 
HLOQ of 1000 ng/mL
SAC


CONFIDENTIAL
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14.11.11. Pharmacokinetic / Pharmacodynamic Figure
Pharmacokinetic / Pharmacodynamic: Figures
SAC
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
5.1
PK
Scatter plot of PD endpoint versus Danirixin Concentration
(Trough)
CAT Total Score 
Include Placebo imputed as DNX 
conc=0ng/mL, include DNX 
conc=NQ imputed as LLOQ/2, 
where LLOQ=5ng/mL
By Day
Different symbol for each treatment
Post SAC
5.2
PK
Scatter plot of Safety versus Danirixin Concentration (Trough)
Blood Neutrophil Count and C-
reactive Protein (CRP)
Highlight subjects with an on-
treatment event in the ‘Infective 
pneumonia’ SMQ. Add footnote 
‘Note: Pneumonia may have 
occurred at any time during the 
study’
Include Placebo imputed as DNX 
conc=0ng/mL, include DNX 
conc=NQ imputed as LLOQ/2, 
where LLOQ=5ng/mL
By Day
Different symbol for each treatment
Post SAC
5.3
PK
Quartile plot of Danirixin Concentration versus PD endpoint
CAT Total Score 
Post SAC
5.4
PK
Quartile plot of Danirixin Concentration versus Safety endpoint
Blood Neutrophil Count and C-
reactive Protein (CRP)
Post SAC


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14.11.12. Biomarker Tables
Biomarker: Tables
StInt
No.
SAC 
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Biomarkers
6.1
6.1
mITT
LB1
Summary of C-reactive Protein (CRP) Changes from 
Baseline
ICH E3
StInt, SAC
6.2
6.2
mITT
LB1
Summary of Fibrinogen Changes from Baseline
ICH E3
StInt, SAC
6.3
mITT
Summary of C-reactive Protein (CRP) for Subjects with 
Pneumonia
Screening, Baseline, Day 84 
and 168
Subjects who have an event in 
the ‘Infective pneumonia’ SMQ
Post SAC
6.4
mITT
Summary of Fibrinogen for Subjects with Pneumonia
Screening, Baseline, Day 84 
and 168
Subjects who have an event in 
the ‘Infective pneumonia’ SMQ
Post SAC


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14.11.13. Biomarker Figures
Biomarker: Figures
StInt
No.
SAC 
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Biomarkers
6.1
6.1
mITT
Boxplot of C-reactive Protein (CRP) by Time and 
Treatment
Screening, Baseline, Day 84 
and 168
StInt, SAC
6.2
6.2
mITT
Boxplot of Fibrinogen by Time and Treatment
Screening, Baseline, Day 84 
and 168
StInt, SAC
6.2
mITT
Boxplot of C-reactive Protein (CRP) over Time for 
Subjects with Pneumonia
Screening, Baseline, Day 84 
and 168
Subjects who have an event in 
the ‘Infective pneumonia’ SMQ
Post SAC
6.4
mITT
Boxplot of Fibrinogen over Time for Subjects with 
Pneumonia
Screening, Baseline, Day 84 
and 168
Subjects who have an event in 
the ‘Infective pneumonia’ SMQ
Post SAC


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14.11.14. ICH Listings
ICH: Listings
StInt
No.
SAC 
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1
ALLSUB
ES7
Listing of Reasons for Screen Failure
Journal Guidelines
SAC
2
mITT
ES2
Listing of Reasons for Study Withdrawal
ICH E3
SAC
3
mITT
SD2
Listing of Reasons for Study Treatment Discontinuation
ICH E3
SAC
4
mITT
BL1 
Listing of Subjects for Whom the Treatment Blind was 
Broken
ICH E3
SAC
5
mITT
TA1 
Listing of Planned and Actual Treatments
IDSL
SAC
Protocol Deviations
6
mITT
DV2
Listing of Important Protocol Deviations 
ICH E3
Listing also includes analysis 
population exclusions.
SAC
7
ALLSUB
IE3 
Listing of Screen Failure Subjects with Inclusion/Exclusion 
Criteria Deviations
ICH E3
SAC
8
mITT
IE3
Listing of Subjects with Inclusion/Exclusion Criteria 
Deviations
ICH E3
SAC


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ICH: Listings
StInt
No.
SAC 
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Populations Analysed
9
mITT
SP3
Listing of Subjects Excluded from Any Population
ICH E3
ITT (Strategic interim only), 
mITT, PP, Symptomatic
(Strategic interim only), PK and 
PK2 population
SAC
Demographic and Baseline Characteristics
10
mITT
DM2 
Listing of Demographic Characteristics
ICH E3
SAC
11
miTT
DM9 
Listing of Race
ICH E3
SAC
Prior and Concomitant Medications
12
mITT
CP_CM3 
Listing of Non-COPD Concomitant Medications
IDSL
SAC
13
mITT
CP_CM3
Listing of COPD Concomitant Medications
SAC
Exposure and Treatment Compliance
14
mITT
EX3 
Listing of Exposure Data
ICH E3
SAC
EXACT Scores
15
mITT
Listing of E-RS: COPD Daily Scores
Total and subscale scores
SAC
Adverse Events
1
16
mITT
AE8 
Listing of All Adverse Events
ICH E3
StInt, SAC
17
mITT
AE7
Listing of Subject Numbers for Individual Adverse Events
ICH E3
SAC
18
mITT
AE2
Listing of Relationship Between Adverse Event System 
Organ Classes, Preferred Terms, and Verbatim Text
IDSL
SAC


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ICH: Listings
StInt
No.
SAC 
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Serious and Other Significant Adverse Events
19
mITT
AE8 / 
AE8CPa
Listing of Fatal Serious Adverse Events
ICH E3
SAC
20
mITT
AE8 / 
AE8CPa
Listing of Non-Fatal Serious Adverse Events
ICH E3
SAC
21
mITT
AE14
Listing of Reasons for Considering as a Serious Adverse 
Event
ICH E3
SAC
22
mITT
AE8 / AECP8 
Listing of Adverse Events Leading to Withdrawal from 
Study / Permanent Discontinuation of Study Treatment
ICH E3
SAC
23
mITT
AE8 / AECP8 
Listing of Drug-Related Adverse Events
ICH E3
SAC
24
mITT
AE8 / AECP8 
Listing of Adverse Events of Special Interest
ICH E3
SAC
Hepatobiliary (Liver)
25
mITT
MH2
Listing of Medical Conditions for Subjects with Liver 
Stopping Events
IDSL
SAC
26
mITT
SU2
Listing of Substance Use for Subjects with Liver Stopping 
Events
IDSL
SAC
All Laboratory
27
mITT
LB5 
Listing of Chemistry Data for Subjects with Any Value of 
Potential Clinical Importance
ICH E3
SAC
28
mITT
LB5 
Listing of Haematology Data for Subjects with Any Value of 
Potential Clinical Importance
ICH E3
SAC
29
mITT
LB5 
Listing of Chemistry Values of Potential Clinical 
Importance
SAC


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ICH: Listings
StInt
No.
SAC 
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
30
mITT
LB5 
Listing of Haematology Values of Potential Clinical 
Importance
SAC
31
mITT
LB14
Listing of Laboratory Data with Character Results
ICH E3
SAC
ECG
32
mITT
EG3 
Listing of All ECG Values for Subjects with Any Value of 
Potential Clinical Importance
SAC
33
mITT
EG3 
Listing of ECG Values of Potential Clinical Importance
SAC
34
mITT
EG5
Listing of All ECG Findings for Subjects with an Abnormal 
ECG Finding
SAC
35
mITT
EG5 
Listing of Abnormal ECG Findings
SAC
Vital Signs
36
mITT
VS4 
Listing of All Vital Signs Data for Subjects with Any Value 
of Potential Clinical Importance
IDSL
SAC


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14.11.15. Non-ICH Listings
Non-ICH: Listings
StInt 
No.
SAC
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
37.
ALLSUB
ES9
Listing of Subjects Who Were Rescreened
Include Inclusion/ Exclusion/ 
Randomization Criteria 
Deviations
SAC
38.
ALLSUB
Listing of Study Treatment Misallocations
SAC
Demographic and Baseline Characteristics
39.
mITT
Listing of Smoking History and Smoking Status
SAC
40.
mITT
Listing of COPD History and Exacerbation History
SAC
41.
mITT
Listing of Screening Spirometry Measures and GOLD 
Stages at Screening
Include % predicted category 
(</>=50%)
SAC
42.
mITT
Listing of Baseline Symptomatic Characteristics
Contents as for table
SAC
Past and Current Medical History
43.
mITT
Listing of Medical Conditions
SAC
44.
mITT
Listing of Family History of Cardiovascular Risk Factors
SAC
45.
mITT
Listing of Percent Oxygen in Blood
SAC
Treatment Compliance
46.
mITT
Listing of Treatment Compliance
SAC


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Non-ICH: Listings
StInt 
No.
SAC
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
E-RS: COPD 
47.
mITT
Listing of E-RS: COPD Baseline and Monthly Mean 
Scores
Include baseline and baseline 
category (</>=10) 
Total and subscale scores
Include change from baseline 
and season
SAC
Exacerbations
48.
mITT
Listing of HCRU Exacerbation Data
SAC
EXACT Events
49.
mITT
Listing of EXACT Event Data
SAC
SGRQ
50.
mITT
Listing of SGRQ Scores
Total and domain scores
Baseline, absolute and change 
from baseline
SAC
CAT
51.
mITT
Listing of CAT Scores
Total score
Baseline, absolute and change 
from baseline and season
SAC
Rescue Use
52.
mITT
Listing of Derived Rescue Use from Diary 
Monthly means
Absolute, baseline and change 
from baseline
SAC


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Non-ICH: Listings
StInt 
No.
SAC
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
53.
mITT
Listing of Derived Rescue Use from Sensor 
Monthly means
Baseline, absolute and change 
from baseline
SAC
Physical Activity
54.
mITT
Listing of C-PPAC Questionnaire Responses
SAC
55.
mITT
Listing of Activity Monitor Data
SAC
56.
mITT
Listing of PROactive Scores
Total and domain scores
Baseline, absolute and change 
from baseline
SAC
Subject Global Assessments
57.
mITT
Listing of Subject Global Assessments
SAC
Biomarkers
58.
mITT
Listing of Biomarkers
SAC
ECG
2.
59.
mITT
Listing of Subjects with Maximum Post-Baseline QTcF 
increasing to over 500 msec or by 60 msec from Baseline
StInt, SAC
PK
60.
PK
PKCL1P
Listing of Danirixin Blood Concentration-Time Data – Dry 
Blood Spot Samples
SAC
61.
PK
PKPL1P
Listing of Danirixin Blood Pharmacokinetic Parameter –
Dry Blood Spot Samples
SAC
62.
PK2
PKCL1P
Listing of Danirixin Blood Concentration-Time Data – Wet 
Whole Blood Samples
SAC


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Non-ICH: Listings
StInt 
No.
SAC
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
63.
PK2
PKPL1P
Listing of Danirixin Blood Pharmacokinetic Parameter –
Wet Whole Blood Samples
SAC
64.
PK2
Listing 40
Study 
201037
Supportive SAS Output from Statistical Analysis of Log-
Transformed Danirixin Blood Pharmacokinetic 
Concentration Data - Bland Altman Analysis
SAC
65.
PK2
Listing 42
Study 
2101037
Supportive SAS Output from Statistical Analysis of Log-
Transformed Danirixin Pharmacokinetic Parameters -
Bland Altman Analysis
SAC
66.
PK2
Listing 41
Study 
201037
Supportive SAS Output from Statistical Analysis of Log-
Transformed Danirixin Pharmacokinetic Parameters
SAC
67.
PK2
Listing 40
Study 
201037
Supportive SAS Output from Statistical Analysis of Log-
Transformed Sensitivity Analysis: Danirixin Blood 
Pharmacokinetic Concentration Data - Bland Altman 
Analysis
excluding dry blood spot 
concentrations above the assay 
HLOQ of 1000 ng/mL
SAC
68.
PK2
Listing 42
Study 
2101037
Supportive SAS Output from Statistical Analysis of Log-
Transformed Sensitivity Analysis: Danirixin
Pharmacokinetic Parameters - Bland Altman Analysis
excluding dry blood spot 
concentrations above the assay 
HLOQ of 1000 ng/mL
SAC
69.
PK2
Listing 41
Study 
201037
Supportive SAS Output from Statistical Analysis of Log-
Transformed Sensitivity Analysis: Danirixin
Pharmacokinetic Parameters
excluding dry blood spot 
concentrations above the assay 
HLOQ of 1000 ng/mL
SAC


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14.12.
Appendix 12: Example Mock Shells for Data Displays
Mock shells will be created in a separate document.