A Randomized, Double-blind, Sponsor Open, Placebo-controlled, 52 Week Study Evaluating the Effect of Danirixin (GSK1325756) on Lung Function and Health Related Quality of Life in Participants With Mild to Moderate Chronic Obstructive Pulmonary Disease (COPD)
Phase: PHASE2
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: GlaxoSmithKline

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TITLE PAGE
Protocol Title: A randomized, double-blind, Sponsor open, placebo-controlled, 52 week 
study evaluating the effect of danirixin (GSK1325756) on lung function and health 
related quality of life in participants with mild to moderate Chronic Obstructive 
Pulmonary Disease (COPD).
Protocol Number: 205864 Amendment 3
Short Title: Danirixin Pilot Study for Disease Progression
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
Approval Date: 18-MAY-2018
Copyright 2018 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 3
18-May-2018
Amendment 2
24-Jul-2017
Amendment 1
17-May-2017
Original Protocol
21-Mar-2017
Amendment 1: 17-MAY-2017
Overall Rationale for the Amendment: This amendment excludes the enrolment of 
women of childbearing potential and clarifies the testing required for determination of 
post menopausal status in specific situations.
Section # 
and Name
Description of Change
Brief Rationale
Table 1 –
Schedule of 
Activities

Remove pregnancy testing

Added missing check 
marks

Updated screening period

Not required as no longer enrolling 
WOCBP

Error in original protocol

Required to allow for screening lab 
tests
Section 6.1
Inclusion 
Criteria
Update to only allow females to 
participate if they are not women of 
childbearing potential (WOCBP)
To remove additional burden on female 
subjects of childbearing potential requiring 
additional visits for pregnancy testing only.  
Section 12.2 
– Appendix 2
Clinical 
Laboratory 
Tests
Update Table 6 – Protocol-
Required Safety Laboratory 
Assessments to remove pregnancy 
testing
Removed pregnancy testing based on the 
exclusion of WOCBP
Section 12.5 
– Appendix 5
Contraceptive 
Guidance and 
Collection of 
Pregnancy 
Information

Adding clarification on 
determination of post 
menopausal state in the 
absence of 12 months of 
amenorrhea

Updated wording to be in 
line with exclusion of 
WOCBP

Current wording in template is not 
clear on testing required

Clarification of wording
 
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Amendment 2: 24-JUL-2017
Overall Rationale for the Amendment:
Section # 
and Name
Description of Change
Brief Rationale
Section 3.3.1
Risk 
Assessment
Removal of the following text from 
the mitigation strategy of the 
reproductive toxicology section:
“Male participants with female 
partners of child-bearing 
potential must comply with the 
contraception requirements.”
Additional data available demonstrating 
absence of genotoxic effects
Section 7.1.1 
and Section 
9.2.8
Medical 
Devices and 
Medical 
Device 
Incidents
Update to add mobile spirometer 
(MicroDiary) as a medical device
This device is being used in the study and 
was inadvertently omitted from the 
previous versions of the protocol
Section 6.1 
and Section 
12.5 
(Appendix 5)
Inclusion 
Criteria and 
Contraceptive 
Guidance and 
Collection of 
Pregnancy 
Information
Removal of requirement for male 
contraception with partners of 
WOCBP
Additional data available demonstrating 
absence of genotoxic effects
 
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Amendment 3: 18-MAY-2018
Overall Rationale for the Amendment:
Section # 
and Name
Description of Change
Brief Rationale
Section 2 
Schedule of 
Activities
Updated Smoking history to 
reflect that it is captured only 
at V1 and smoking status is 
captured at both V1 and V2; 
also updated Screening visit 
window to up to 32 days
Correcting error from original version
and discussion with investigators
Section 4 
Objectives 
and 
Endpoints
Updated to match the obectives 
and endpoints in the synopsis
Correcting error from original version
Section 5.1
Updated screening period from 
up to 28 days to up to 32 days
Based on discussion with 
investigators
Section 6 
Study 
Population
Updated to reflect that cohorts 
in addition to COPDGene may 
be used to support recruitment. 
Removed the use of the 
Random Forest data in patient 
selection and changed history 
of lung function decline from 
20mL/yr to 15 mL/yr.  
Changed inclusion criteria 
from weight >45kg to body 
mass index ≥ 21.
Based on discussion with 
investigators 
Appendix 5
Removed pregnancy testing 
requirements
Overisight from previous amendment 
when WOCBP were excluded. No 
pregnancy testing needed with this 
exclusion criteria.
 
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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS...............................................................................................................9
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................11
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...........................................................................22
5.
STUDY DESIGN ....................................................................................................23
5.1.
Overall Design ............................................................................................23
5.2.
Number of Participants ...............................................................................23
5.3.
Participant and Study Completion...............................................................23
5.4.
Scientific Rationale for Study Design ..........................................................24
5.5.
Dose Justification........................................................................................24
6.
STUDY POPULATION...........................................................................................25
6.1.
Inclusion Criteria.........................................................................................25
6.2.
Exclusion Criteria........................................................................................26
6.3.
Lifestyle Restrictions...................................................................................28
6.3.1.
Meals and Dietary Restrictions ....................................................28
6.3.2.
Activity .........................................................................................28
6.4.
Screen Failures...........................................................................................28
7.
TREATMENTS.......................................................................................................29
7.1.
Treatments Administered............................................................................29
7.1.1.
Medical Devices...........................................................................29
7.2.
Dose Modification .......................................................................................30
7.3.
Method of Treatment Assignment ...............................................................30
7.4.
Blinding.......................................................................................................30
7.5.
Preparation/Handling/Storage/Accountability..............................................31
7.6.
Treatment Compliance................................................................................31
7.7.
Concomitant Therapy..................................................................................32
7.8.
Treatment after the End of the Study ..........................................................33
8.
DISCONTINUATION CRITERIA.............................................................................33
8.1.
Discontinuation of Study Treatment ............................................................33
8.1.1.
Liver Chemistry Stopping Criteria ................................................33
8.1.2.
QTc Stopping Criteria ..................................................................34
8.1.3.
Neutrophil Stopping Criteria.........................................................35
8.1.4.
Temporary Discontinuation ..........................................................35
8.1.5.
Study Treatment Restart..............................................................35
 
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8.2.
Withdrawal from the Study..........................................................................35
8.3.
Lost to Follow Up........................................................................................36
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................37
9.1.
Efficacy Assessments.................................................................................37
9.1.1.
FEV1 ............................................................................................37
9.1.1.1.
Clinic Spirometry ........................................................37
9.1.1.2.
Mobile Spirometry ......................................................37
9.1.2.
SGRQ-C ......................................................................................37
9.1.3.
CAT .............................................................................................38
9.1.4.
COPD Exacerbations...................................................................38
9.1.5.
Patient Global Rating of Severity and Global Rating of 
Change in Disease Severity.........................................................38
9.2.
Adverse Events...........................................................................................39
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................39
9.2.2.
Method of Detecting AEs and SAEs.............................................39
9.2.3.
Follow-up of AEs and SAEs.........................................................39
9.2.4.
Regulatory Reporting Requirements for SAEs .............................40
9.2.5.
Cardiovascular and Death Events................................................40
9.2.6.
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as SAEs...............................................40
9.2.7.
Pregnancy ...................................................................................41
9.2.8.
Medical Device Incidents (Including Malfunctions).......................41
9.2.8.1.
Time Period for Detecting Medical Device 
Incidents.....................................................................41
9.2.8.2.
Follow-up of Medical Device Incidents........................42
9.2.8.3.
Prompt Reporting of Medical Device Incidents 
to Sponsor..................................................................42
9.2.8.4.
Regulatory Reporting Requirements for 
Medical Device Incidents............................................42
9.3.
Treatment of Overdose...............................................................................43
9.4.
Safety Assessments ...................................................................................43
9.4.1.
Physical Examinations.................................................................43
9.4.2.
Vital Signs....................................................................................43
9.4.3.
Electrocardiograms......................................................................44
9.4.4.
Clinical Safety Laboratory Assessments ......................................44
9.4.5.
Pneumonia ..................................................................................44
9.5.
Pharmacokinetics .......................................................................................45
9.6.
Pharmacodynamics ....................................................................................45
9.7.
Genetics .....................................................................................................45
9.8.
Biomarkers .................................................................................................45
9.9.
Health Economics OR Medical Resource Utilization and Health 
Economics..................................................................................................46
10. STATISTICAL CONSIDERATIONS........................................................................46
10.1.
Sample Size Determination ........................................................................46
10.2.
Randomization............................................................................................49
10.3.
Populations for Analyses ............................................................................49
10.4.
Statistical Analyses.....................................................................................49
10.4.1.
Efficacy Analyses.........................................................................49
10.4.2.
Safety Analyses...........................................................................51
 
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10.4.3.
Other Analyses ............................................................................51
10.4.4.
Interim Analyses ..........................................................................51
11. REFERENCES.......................................................................................................52
12. APPENDICES........................................................................................................55
12.1.
Appendix 1: Abbreviations and Trademarks................................................55
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................59
12.3.
Appendix 3: Study Governance Considerations..........................................61
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................65
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................71
12.6.
Appendix 6: Genetics..................................................................................74
12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................75
12.8.
Appendix 8: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................78
12.9.
Appendix 9: Neutrophil Safety and Study Treatment Restart ......................80
12.10. Appendix 10: Country-specific requirements...............................................82
12.11. Appendix 11 Protocol Amendment History..................................................83
 
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1.
SYNOPSIS
Protocol Title: A randomized, double-blind, Sponsor open, placebo-controlled, 52 week 
study evaluating the effect of danirixin (GSK1325756) on lung function and health 
related quality of life in participants with mild to moderate Chronic Obstructive 
Pulmonary Disease (COPD).
Short Title: Danirixin Pilot Study for Disease Progression in COPD
Rationale:  This is a pilot study to investigate the effect of danirixin hydrobromide (HBr) 
35mg tablets on lung function and health related quality of life (HRQoL)  in participants 
with mild to moderate airflow obstruction and a demonstrated history of decline in FEV1. 
This study aims to assess whether danirixin has the potential to impact disease 
progression in participants with COPD and with a demonstrated history of disease 
progression measured by lung function. 
Objectives and Endpoints:
Objective
Endpoint
Primary

To assess whether danirixin HBr 35mg 
tablets impact disease progression
compared with placebo

Rate of decline in FEV1

Change from baseline in St. George’s 
Respiratory Questionnaire (SGRQ)  
total score (derived from SGRQ-C)
Secondary

To further characterize the safety of 
danirixin HBr 35mg tablets compared 
with placebo in participants with mild 
to moderate airflow limitation

Adverse events

Vital Signs

ECG

Clinical Laboratory Assessments 
(hematology, clinical chemistry, 
urinalysis)

To further characterize the clinical 
activity of danirixin HBr 35mg tablets 
compared with  placebo

Time to first HCRU COPD 
exacerbation

Change from baseline in FEV1

SGRQ responder analysis

SGRQ domains

COPD Assessment Test (CAT)

Rescue medication use 
 
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Overall Design:
This is a Phase 2 study to investigate the potential impact of danirixin HBr 35mg tablets 
compared with placebo on disease progression in participants with mild to moderate 
airflow obstruction.  The study will also assess the enrichment strategy of enrolling 
participants identified from the COPDGene study.  These participants have been 
identified by COPDGene investigators based on data collected over the initial 5 year 
period.  The participants were identified based on a Random Forest analysis and a 
demonstrated decline of at least 20mL/yr over the initial 5 year period. 
Number of Participants:
Approximately 130 participants will be screened to enrol 100 participants in this study.  It 
is anticipated that approximately 85 participants will complete the 52 weeks of treatment 
(assuming a 15% drop out rate).
Treatment Groups and Duration:
Participants will receive either placebo or danirixin 35mg tablets (as hydrobromide 
hemihydrate salt) twice daily for 52 weeks (12months).
 
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2.
SCHEDULE OF ACTIVITIES (SOA)
Table 1
Schedule of activities
Screening/
Visit1a
Visit 2
Visit 3  
Visit 
4
Visit 5
Visit 
6
Visit 
7
Visit 8
Visit 9
Visit 
10
Visit 11
Visit 12
EW
FU
Up to 28 
days 
post last 
dose
up to
-32 days
Week 
0 /
D1
Week 2/ 
D14
Week 4/ 
D28
Week 8/ 
D56
Week 12/ 
D84
Week 16 
/ D112
Week 20 
/ D140 
Week 
24 
/D168
Week 32 
/D224
Week 40 
/ D280
Week 52 
/ D364
Assessment window
+3d
±3d
±3d
±3d
±3d
±3d
±3d
±3d
±6d
±6d
±6d
±6d
Eligibility
Informed Consent
X
Genetics Informed Consentb
X
Demography
X
Inclusion and Exclusion Criteria
X
Smoking Statusc
X
X
Smoking Historyc
X
Medical Historyd
X
Full physical
X
Chest X-ray (historical within 1 year 
acceptable)
X
HIV, Hepatitis B and C screeninge
X
Additional Eligibility and In Study Assessments
Verify Eligibilityf
X
X
Brief physical
X
X
X
X
X
Laboratory assessments (clinical chemistry,
including liver chemistries), hematology, 
urinalysis
X
X
X
X
X
X
Additional Liver chemistries only
X
X
X
X
X
X
X
12 lead ECG
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
 
 
 
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Screening/
Visit1a
Visit 2
Visit 3  
Visit 
4
Visit 5
Visit 
6
Visit 
7
Visit 8
Visit 9
Visit 
10
Visit 11
Visit 12
EW
FU
Up to 28 
days 
post last 
dose
up to
-32 days
Week 
0 /
D1
Week 2/ 
D14
Week 4/ 
D28
Week 8/ 
D56
Week 12/ 
D84
Week 16 
/ D112
Week 20 
/ D140 
Week 
24 
/D168
Week 32 
/D224
Week 40 
/ D280
Week 52 
/ D364
Assessment window
+3d
±3d
±3d
±3d
±3d
±3d
±3d
±3d
±6d
±6d
±6d
±6d
Office spirometry (centralized)
X
X
X
X
X
X
X
X
X
X
X
X
X
Home spirometry  - (weekly)
X
X
X
Randomization
X
Dispense study medication
X
X
X
X
X
X
X
X
X
Dispense log pad and provide training
X
Dispense MDI sensors and provide training
X
Study Treatment
Study Treatment Compliance (ediary)
Collect IP 
Collect MDI sensors
X
X
Collect log pad
X
X
AE review
X
X
SAE review
X
X
Concomitant medication review
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Outcomes Assessments
COPD exacerbation review
X
X
X
X
X
X
X
X
X
X
X
X
Rescue medication Use
SGRQ-C
X
X
X
X
X
X
COPD Assessment Test (CAT)
X
X
X
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
X
X
X
 
 
 
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Screening/
Visit1a
Visit 2
Visit 3  
Visit 
4
Visit 5
Visit 
6
Visit 
7
Visit 8
Visit 9
Visit 
10
Visit 11
Visit 12
EW
FU
Up to 28 
days 
post last 
dose
up to
-32 days
Week 
0 /
D1
Week 2/ 
D14
Week 4/ 
D28
Week 8/ 
D56
Week 12/ 
D84
Week 16 
/ D112
Week 20 
/ D140 
Week 
24 
/D168
Week 32 
/D224
Week 40 
/ D280
Week 52 
/ D364
Assessment window
+3d
±3d
±3d
±3d
±3d
±3d
±3d
±3d
±6d
±6d
±6d
±6d
Genetic, Pharmacokinetic and Biomarker Blood Collections
Blood sample for Genetics
X
Blood sample for CRP
X
X
X
X
Blood sample for exploratory biomarkers
X
X
X
X
a
Informed consent may be signed prior to screening visit in the case that any changes in medications are necessary
b
Agreeing to genetic sample consent is not required for study participation
c
Smoking status/history assessed at screening; smoking status re-checked at Visit 2
d
Includes substance usage, past and present medical conditions and family history of premature CV disease
e
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.
f
Participant’s clinical status should be reviewed
The timing and number of planned study assessments, including safety and biomarker assessments may be altered during the course of the study based on newly available data to 
ensure appropriate data collection.  Any changes in the timing or addition of time points for any planned study assess 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 Number 
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 
[GlaxoSmithKline Document Number 2013N180289_03 Study ID 200163].  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.  Analyses 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 pilot study to investigate the effect of danirixin HBr 35mg 
tablets on lung function and health related quality of life (HRQoL) in participants with 
mild to moderate airflow obstruction identified from the COPDGene cohort. 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.
Specifically, this study aims to assess whether or not danirixin has the potential to impact 
disease progression in participants with a demonstrated history of decline in FEV1 based 
on 5 year data from COPDGene and support the conduct of a larger Phase III study for 
disease progression. In addition to lung function and HRQoL, this study will assess 
moderate/severe COPD exacerbations, health status (CAT), and rescue medication use.
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 and, 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 
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 
 
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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 Number 
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.
PK modelling predicts that in a participant 
receiving 35 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 participants
receiving either placebo or danirixin; no 
instances of danirixin-related neutropenia 
have been reported in clinical studies to 
date. In healthy participants, 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.
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 or 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.
 
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4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To assess whether danirixin HBr 
35mg tablets impacts disease 
progression compared with placebo

Rate of decline in FEV1

Change from baseline in St. George’s 
Respiratory Questionnaire (SGRQ) 
total score (derived from SGRQ-C)
Secondary

To further characterize the safety of 
danirixin HBr 35mg tablets compared 
with placebo in participants with mild 
to moderate airflow limitation

To further characterize the clinical 
activity of danirixin HBr 35mg tablets
compared to placebo

Adverse events (AE), clinical 
laboratory values, vital signs, 
electrocardiogram (ECG), and/or other 
safety biomarkers

Time to first HCRU COPD 
exacerbation

Change from baseline in FEV1

SGRQ responder analysis

SGRQ domains

COPD Assessment Test (CAT)

Rescue medication use
Exploratory

To characterize the effect of 
danirixin on lung matrix 
destruction/remodelling and 
inflammation

Further characterize efficacy of 
danirixin
Blood/serum/plasma biomarkers that 
are indicative of extracellular matrix 
turnover/remodelling (e.g. elastin and 
collagen neo-epitopes) and 
inflammation (e.g. CRP)

Global assessment of COPD severity 
 
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5.
STUDY DESIGN
5.1.
Overall Design
A study schematic is shown in Figure 1. This is a parallel group study.  Following 
screening and assessment of rescue medication use via a daily diary over study days -32
to 1, participants will be randomized (1:1) to receive either danirixin 35mg tablets or 
placebo.  Study treatment will be administered twice daily for 52 weeks [Figure 1].  
There will be no pre-specified interim analysis for this study.  An interim analysis may be 
performed if it is determined that the enrolment is slow enough to allow it to be 
informative. There will be no IDMC for this study. An internal safety review team will 
meet approximately every 3 months (or as needed based on emerging data) to review 
available safety information. 
Figure 1
Study Schematic
5.2.
Number of Participants
Approximately 130 participants will be screened to achieve 100 randomized in this study.  
It is anticipated that approximately 85 participants will complete the 12 months of 
treatment (assuming a 15% drop out rate).
For the analysis of study assessments, several analysis populations are defined in Section 
10.3.  
5.3.
Participant and Study Completion
A participant is considered to have completed the study if he/she has completed all
planned study visits 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. 
Screening
1
1 If changes to medication are required, consent must be signed prior to any 
changes being made and may occur prior to the Screening Visit
2 Follow-up visit to occur within 28days of last dose of study medication
Up to 
32 days
R
Placebo (n=50)
Danirixin, 35mg 
(n=50)
Follow-up
2
52 weeks
 
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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.  With the 
use of an enriched population, it is anticipated that one year of treatment will be sufficient 
to detect a trend in altering disease progression.   Danirixin has already been clinically 
investigated over one year treatment duration (GlaxoSmithKline Document Number 
2013N180289_03 Study ID 200163).  
The data from this study will provide useful information in determining whether or not to 
progress to a Phase III study to explore an indication for slowing disease progression. 
5.5.
Dose Justification
One dose of danirixin is proposed for this study, 35mg tablets BID.  This dose was 
selected based on integrating information on:

Dose-exposure-biomarker response using inhibition of ex vivo CXCL1-induced 
CD11b expression on peripheral blood neutrophils over the dose range of 0-400mg 
(free base tablet) in healthy volunteers (GSK Study No. CX3 112483).

Evidence of reduced respiratory symptoms and improvement in health status in mild 
to moderate COPD participants from interim data in the Phase IIa study (GSK Study 
No. 200163).

Relative bioavailability study comparing danirixin free base vs HBr (GSK Study No. 
201037).
In the previous 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 (GlaxoSmithKline Document Number 
2015N248339_00, Study ID 201037). Thus the danirixin (hydrobromide tablet) 35mg 
BID dose for investigation in this study is expected to provide steady-state systemic 
exposure approximately equivalent to the 75mg BID (free base tablet) used in Study 
200163. Predicted steady-state exposures and multiples of blood ex vivo CXCL1-induced 
CD11b pharmacology at the proposed danirixin doses are presented in Table 2.
Table 2
Predicted steady state systemic exposure and multiples of blood ex 
vivo CXCL1-induced pharmacology following twice daily of 
administration of danirixin
Dose 
(mg)
Predicted# steady-state median (5th, 95th
percentile)
Cavg 
multiple of 
IC50*
Cmin 
multiple of 
IC50*
AUC(0-24) 
steady-state
(ug.h/mL)
Cavg
(ng/mL)
Cmin
(ng/mL)
35
9.59
(4.70, 19.3)
399
(196, 806)
192
(47.6, 630)
5.1
2.4
 
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#Model derived based on PK data in healthy elderly participants from GSK Study No. 201037 
(GlaxoSmithKline Document Number. 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.
6.
STUDY POPULATION
This study will identify specific COPD patients most likely to decline from well 
established cohorts like COPDGene [NCT00608764].  This study will be an ancillary 
study within COPDGene and any other relevant cohort investigating the enrichment 
strategy for assessing disease progression. These potential participants will be identified 
by COPDGene investigators based on data collected over the initial 5 year period.  The 
participants were identified based on a demonstrated decline of at least 15mL/yr over the 
initial 5 year period. Once participants are identified from the COPDGene dataset, the 
following criteria will be verified at initial study visit following signing of consent.  
Equivalent cirteria may be identified within other cohorts if necessary to broaden 
recruitment pool. 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1.
Participant must be 40 to 76 years of age inclusive, at the time of signing the 
informed consent.
Type of Participant and Disease Characteristics
2.
At the screening visit, the subject must have an FEV1 >40% of the predicted 
normal.
3.
Participants with a prior history of asthma are eligible if they have a current 
diagnosis of COPD
Weight
4.
Body Mass Index 21
5.
Sex
Male or female
Female participants: 
A female participant is eligible to participate if she is not a woman of childbearing 
potential (WOCBP) as defined in Section 12.5 (Appendix 5)
 
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Informed Consent
6. Capable of giving signed informed consent as described in Section 12.3 (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 disease (other than COPD), e.g. 
sarcoidosis, tuberculosis, pulmonary fibrosis, severe bronchiectasis or lung cancer
2. COPD due to alpha-1-antitrypsin deficiency 
3. Pulse oximetry < 88% at rest at screening.  Participants should be tested while 
breathing room air.  However, participants living at high altitudes (above 5000 ft or 
1500 m above sea level) who are receiving supplemental oxygen can be included 
provided they are receiving the equivalent of < 4L/min and screening oximetry is 
measured while on their usual settings.
4. Less than 14 days have elapsed from completion of a course of antibiotics or oral 
corticosteroids for a recent COPD exacerbation
5. Participants with a peripheral blood neutrophil count < 1 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 with lateral) or CT scan reveals evidence of a clinically 
significant abnormality not believed to be due to the presence of COPD (historic data 
up to 1 year may be used).  
8. History or current evidence of clinically significant renal disease, diabetes 
mellitus/metabolic syndrome, hypertension, or any other clinically significant 
cardiovascular, neurological, immunological, endocrine, or haematological 
abnormality 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 participants 
at risk through study participation, or which would affect the safety analysis or other 
analysis if the disease/condition exacerbated during the study.
9. History of sensitivity to any of the study medications, or components thereof or a 
history of drug or other allergy that, in the opinion of the investigator of GSK medical 
monitor, contraindicates their participation.
10. Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert’s syndrome or asymptomatic gallstones).
11. Abnormal and clinically significant 12-lead ECG finding.  The investigator will 
determine the clinical significance of each abnormal ECG finding in relation to the 
subject’s medical history and exclude participants who would be at undue risk by 
participating in the trial.  An abnormal and clinically significant finding that would 
 
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preclude a subject from entering the trial is defined as a 12-lead tracing that is 
interpreted as, but not limited to, any of the following:
‒
AF with rapid ventricular rate > 120 bpm;
‒
sustained or non-sustained VT
‒
second degree heat block Mobitz type II and third degree heart block (unless 
pacemaker or defibrillator has been implanted)
‒
QTcF 500 msec in patients with QRS < 120 msec and QTcF 530 msec in 
patients with QRS 120 msec
12. Previous lung surgery (e.g. lobectomy, pneumonectomy) or lung volume reduction 
procedure.
Prior/Concomitant Therapy
13. 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.
14. 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.
15. 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
16. 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).
17. Participation in a previous clinical trial with danirixin within 1 year prior to the first 
dosing day in the current study
18. Exposure to more than four investigational products within 1 year prior to the first 
dosing day in the current study.
Diagnostic assessments
19. Alanine transferase (ALT) > 2x upper limit of normal (ULN) and bilirubin > 
1.5xULN (isolated bilirubin > 1.5xULN is acceptable if bilirubin is fractionated and 
direct bilirubin <35%).
20. A positive test for HIV antibody.
 
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21. A positive pre-study hepatitis B surface antigen or positive hepatitis C antibody result 
within 3 months prior to screening. Note: 
22. Participants with positive Hepatitis C antibody due to prior resolved disease can be 
enrolled, only if a confirmatory negative Hepatitis C RNA PCR test is obtained.
Other Exclusions
23. 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.
24. A history of allergy or hypersensitivity to any of the ingredients in the study 
treatment.
25. A known or suspected history of alcohol or drug abuse within the 2 years prior to 
screening.
26. 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.
27. 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.
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 not be rescreened unless discussed with the medical monitor. 
 
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7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.
7.1.
Treatments Administered
Study Treatment Name:
Danirixin 
(GSK1325756H, the 
hydrobromide 
hemihydrate salt)
Placebo
Dosage formulation:
White Film coated 
tablets (oval shaped). 
Refer to Investigator’s 
Brochure for 
presentation and 
excipients
White Film coated 
tablets (oval shaped). 
Refer to 
Investigator’s 
Brochure for 
presentation and 
excipients
Unit dose strength(s)/Dosage level(s):
35mg tablets (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).
 
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Mobile spirometers (MicroDiary, manufactured by and purchased from CareFusion) are 
also being provided by GSK for this study. These devices allow participants to conduct 
spirometry assessments at home. The MicroDiary has US FDA 510(k) clearance to 
market (Class II medical device) and European Union CE marking (Class I medical 
device).
Additional descriptive information and instructions for the eMDI monitoring devices and 
mobile spirometers 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 study.  Study participants, all study site staff, and all members 
of the GSK study team will be blinded to individual participant treatment assignment.  
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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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)
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)
 
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
Short acting combination (SABA/SAMA) bronchodilators, (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: Liver Safety: Required Actions and Follow-up Assessments). 
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 (Section 12.7) 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.
 
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
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. 
 
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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.
FEV1
9.1.1.1.
Clinic Spirometry
Spirometry using FEV1 and FVC measurements (FEV%, and FVC% and FEV1/FVC will 
be calculated) will be performed in triplicate at time points listed in the SoA (Table 1).  
Spirometry assessments should be performed in accordance with ATS/ERS guidelines as 
outlined in the SRM.
9.1.1.2.
Mobile Spirometry
Spirometry will also be performed weekly by the participants using a mobile spirometer 
at home.  Details will be outlined in the SRM.
9.1.2.
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 
 
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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 SGRQ scores equivalent to the original SGRQ instrument [Jones, 1992].
9.1.3.
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.
9.1.4.
COPD Exacerbations
An exacerbation of COPD is defined by a worsening of symptoms requiring additional 
treatment or hospitalization. 
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 based on the Investigator’s judgement.
9.1.5.
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 
final study visit or IP Discontinuation Visit.  This single global question will ask 
participants 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 every visit following randomization (or Early Withdrawal (EW) Visit). Response 
 
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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.
9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4 (Section 12.4).
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 the time the informed consent is signed by the 
participant until the follow up visit at the time points specified in the SoA
(Table 1).

All AEs will be collected from the start of study treatment (randomization visit) 
until the follow-up visit at the time points specified in the SoA (Table 1).

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 must be reported immediately and not more than 24 hrs to the sponsor, 
as indicated in Appendix 4 (Section 12.4). 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 (Section 12.4).
9.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
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 
 
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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 Section 12.4 (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. 
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 Section 12.3 (Appendix 3).  
 
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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 
Section 12.5 (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 measuring spirometry at home. 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 Section 12.8 (Appendix 8).
NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Section 9.2 and Section 12.4 (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 within 24 hours of determining a device-related event.

The method of documenting Medical Device Incidents is provided in Section 
12.8 (Appendix 8).
 
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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 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.
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.
 
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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.
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, 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 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 measurements 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 10 minutes.
9.4.4.
Clinical Safety Laboratory Assessments
Refer to Section 12.2 (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 Section 12.2, 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.
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.)
 
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
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
Pharmacokinetic parameters are not evaluated in this study.
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 Section 12.6 (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), 
extracellular matrix turnover and remodelling to evaluate their association with the 
observed clinical responses or to help understand the underlying biological responses to 
danirixin.
 
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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
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study.
10.
STATISTICAL CONSIDERATIONS
The objective of this study is to investigate the effect of danirixin HBr 35mg tablets on 
COPD disease progression. There are no formal hypothesis tests associated with this 
objective and no formal significance tests. The information acquired from this study will 
primarily be used to assess whether or not danirixin impacts disease progression and to 
quantify the effect that danirixin has on disease progression, specifically change in lung 
function as measured by FEV1 decline and change in health-related quality of life as 
measured by SGRQ total score to further support disease understanding and future 
studies. 
10.1.
Sample Size Determination
Sample size is based primarily on feasibility for this study. Since there is much 
uncertainty around the magnitude of the difference in the decline in FEV1 and change in 
SGRQ along with the between-subject variability for the specific patient population, the 
proposed sample size is unavoidably imprecise. Sample size may be adjusted using the 
predictions of final study outcome based on simulations and possible interim analyses. It 
is anticipated that screening 130 participants will allow for approximately 100 
participants to enrol. 
In order to observe the effect of different sample sizes, various simulations were done to 
assess the impact of sample sizes of 50, 100, 150 and 200 with a 1:1 allocation to each 
treatment group [Table 3]. The assumed variability for rate of decline in FEV1 and 
change in SGRQ is 25 and 10, respectively.  The correlation between rate of decline in 
FEV1 and change in SGRQ is assumed to be -0.2. [Nagai, 2015] 
Table 3
Assumptions used for the Simulations
Treatment Effect Assumptions
(δFEV1, δSGRQ)
Variability Assumptions
(σFEV1, σSGRQ)
Sample Size
Null
(0,0)
(25,10)
N={50,100,150,200}
Alternate 1 
(5,-1)
(25,10)
N={50,100,150,200}
Alternate 2
(5,0) 
(25,10)
N={50,100,150,200}
Alternate 3
(0,-1)
(25,10)
N={50,100,150,200}
 
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Data from a bivariate normal distribution were simulated under the four different 
treatment effect assumptions for samples sizes of 50, 100, 150, and 200. The samples 
from the posterior probability distribution from the MCMC approximation were divided 
into four regions based on δFEV1 and δSGRQ treatment effect cut-off values; δFEV1≥0 and 
δSGRQ ≤0, δFEV1≥0 and δSGRQ>0, δFEV1<0 and δSGRQ≤0, and δFEV1<0 and δSGRQ>0. Based 
on a 70% threshold, the proportion of the 1000 simulations meeting the requirement 
P(δFEV1≥0 & δSGRQ≤0) ≥70% were considered a success based on the joint definition 
[Figure 2, Table 4]. If P(δFEV1≥0 & δSGRQ≤0) < 70%, success could further be defined 
based on each endpoint independently where P(δFEV1 ≥0) ≥ 80% or P(δSGRQ ≤0) ≥ 80%. 
Figure 2
Total Probability of Success
Table 4
Total Probability of Success (Figure 2)
N=50
N=100
N=150
N=200
(5,-1)
57.4
68.5
75.1
81.4
(5,0)
52.5
62.6
67.8
74.5
(0,-1)
42.6
46.2
48.9
53.0
(0,0)
34.9
33.9
33.3
31.5
 
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Figure 3
Half Width of the 95% Confidence Interval of δFEV1 Point Estimate
Figure 4
Half Width of the 95% Confidence Interval of δSGRQ Point Estimate
Based on the simulations, under the assumption of an expected treatment difference of 
(5,-1) which is the most probable scenario, the marginal increase for the total probability 
of success is greatest when increasing the sample size from 50 to 100 (Figure 2). The half 
widths of the 95% CI of the point estimate of the marginal treatment differences for FEV1
(Figure 3) and SGRQ (Figure 4) have the greatest reduction from a sample size of 50 to 
100. A sample size of 100 will allow for an adequate level of confidence in the study 
success while also considering the precision of the treatment effect differences. 
 
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10.2.
Randomization
Participants will be randomized equally (1:1) to the two treatment arms of placebo and 35 
mg danirixin HBr.  Randomization will be stratified by smoking status (current vs. 
former).
10.3.
Populations for Analyses
For purposes of analysis, the following populations are defined:
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.
Per-Protocol (PP) 
Population
This population will comprise of all patients in the ITT 
population who are not major protocol violators.
Safety
All randomized participants who take at least 1 dose of study 
treatment. Participants will be analyzed according to the 
treatment they actually received.
10.4.
Statistical Analyses
Treatment comparisons using all endpoints will be made using appropriate statistical 
techniques. Analysis methods for key endpoints are described below. Main analysis will 
use ITT unless noted. Further details on all analyses will be described in the reporting and 
analysis plan (RAP).
10.4.1.
Efficacy Analyses
The total probability of success will be defined as a combination of a joint and 
conditional statement. The joint probability of success will be defined as the probability 
of the difference in the rate of decline in FEV1 between danirixin and placebo is greater 
than or equal to 0 and the difference in the change in SGRQ total score from baseline 
between danirixin and placebo is less than or equal to 0 is greater than 70%. If the joint 
probability of success is less than 70%, success can further be defined based on each 
endpoint independently, where either the difference in the rate of decline in FEV1 is
 
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greater than or equal to 0 is greater than 80% or the difference in the change in SGRQ 
total score is less than or equal to 0 is greater than 80%. 
Endpoint
Statistical Analysis Methods
Primary
Rate of decline in FEV1 and change from baseline in SGRQ total score
Exploratory
Will be described in detail in the RAP
Lung Function Decline: Rate of Decline of FEV1 (mL/yr)
The rate of decline of FEV1 will be derived from a repeated measures random 
coefficients model. Post-baseline FEV1 will be modelled including terms for age, sex, 
smoking status, FEV1 at baseline, and BMI along with treatment group, time and 
treatment by time interaction as fixed effects.  Subject will be a random effect. Time will 
be defined as the number of days since start of treatment. Only FEV1 values measured 
after baseline will be used in the model. Based on the results of previous studies, the 
study team will determine the time point at which post-baseline spirometry assessments 
will be included in the model to account for the initial treatment response. The estimate 
of the rate of FEV1 decline will be the slope of the parameter estimate of the treatment by 
time interaction term in the model. Contrasts will be calculated for the difference in 
treatment by time interaction between danirixin and placebo treatment groups to estimate 
the treatment difference. 
FEV1 = Treatment group + age + sex +smoking status+FEV1_BL+BMI+ time + 
treatment*time 
The rate of decline for each subject, the estimate of the slope parameter of the treatment 
by time interaction term, will be used as a co-primary endpoint for the joint analysis 
using both FEV1 and SGRQ. 
HRQoL: SGRQ
A co-primary endpoint of interest is change in SGRQ total score (derived from SGRQ-C) 
from baseline. Change in SGRQ total scores from baseline will be derived using a mixed 
model with repeated measures (MMRM) including fixed effects of treatment group, age, 
sex, smoking status, BMI, baseline SGRQ score, time as a categorical variable and a 
treatment by time interaction term. Subject will be a random effect. Estimated treatment 
differences at the end of one year will be obtained. The difference of the least square 
mean change from baseline at 12 months will be derived. The adjusted SGRQ total score 
 
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change from baseline will used as the other co-primary endpoint for the joint analysis 
using both FEV1 and SGRQ. 
Joint Analysis
The joint analysis will use the ITT population with all available FEV1 rate of decline and 
change in SGRQ data.
The rate of decline (the slope parameter from the random coefficients model) of FEV1, 
along with the change in SGRQ from the MMRM model will be extracted for each 
subject. These values will then be used to obtain MCMC approximations of the joint 
posterior distribution of the treatment differences between FEV1 decline and change in 
SGRQ between the danirixin and placebo groups. Based on the samples from the 
posterior distribution, the proportion of samples falling within certain treatment 
difference regions will be calculated and the probability of success will be derived. 
10.4.2.
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.
10.4.3.
Other Analyses
Exploratory biomarker analyses will be described in the RAP.
10.4.4.
Interim Analyses
Conducting an interim analysis or futility assessment may not be practical due to an 
expected fast recruitment period. By the time enough data will accumulate for any 
meaningful interim analysis to support changes to the study design, recruitment of all 
study participants will have concluded. However, if recruitment takes a longer than 
anticipated, an interim analysis to reassess the variability assumptions, estimate the 
probability of success at the end of study, and confirm the directionality of the endpoints 
may be conducted.  
The RAP will describe the potential interim analyses in greater detail.
 
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11.
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Eur Respir J. 2004;23:932-946. 
Chapman RW, Philips JE, Hipkin RW, Curran AK, Lundell D, Fine JS. CXCR2 
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GlaxoSmithKline Document Number YM2010/00163/07. Danirixin Investigator's 
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GOLD. From the Global Strateby for the Diagnosis, Management and Prevention of 
COPD, Global Initiative for Chronic Obstructive Lung Disease. Global Initiative for 
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Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Leidy NK. Development and first 
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Jones PW, Harding G, Wiklund I, Berry P, Tabberer M, Yu R et al. Tests of the 
responsiveness of the chronic obstructive pulmonary disease (COPD) assessment test 
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Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure of health 
status for chronic airflow limitation. The St. George's Respiratory Questionnaire. Am Rev 
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Lazaar AL, Sweeney LE, MacDonald AJ et al. SB-656933, a novel CXCR2 selective 
antagnoist, inhibits ex vivo neutrophil activation and ozone-induced airway inflammation 
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Lopez-Campos JL, Tan W, Soriano JB. Global burden of COPD. Respirology. 
2016;21:14-23.
Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 
to 2030. PLoS Med. 2006;3:e442. 
Meguro M, Barley EA, Spencer S et al. Development and validation of an improved 
COPD-specific version of the St. George Respiratory Questionnaire. Chest. 
2007;132:456-463. 
Miller B, Tal-Singer R, Lazaar A, Leidy N, Watz H, Collins D, et al. Assessing 
symptoms in COPD: use of the E-RS daily digital diary in early drug development. Eur 
Respir J. 2016;48(S60):PA1047. 
Nagai, K., Makita, H., Suzuki, M., Shimizu, K., Konno, S., Ito, Y. M., & Nishimura, M. 
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trial. Clin Exp Allergy. 2012;42:1097-2103. 
O'Byrne PM, Metev H, Puu M et al. Efficacy and safety of a CXCR2 antagonist, 
AZD5069, in patients with uncontrolled persistent asthma: a randomised, double-blind, 
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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 
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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. 
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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
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
eCRF
Electronic Case Report Form
ED50
Dose causing 50% of the maximum achievable response
 
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EMA
European Medicines Agency
Emax
Maximum response achievable
eMDI
Electronic metered dose inhaler
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
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
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
 
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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
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
 
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SGRQ
St George’s Respiratory Questionnaire
SGRQ-C
SGRQ-C 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
 
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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

pH, glucose, protein, blood, ketones by dipstick
 
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Laboratory 
Assessments
Parameters

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only)

HIV antibody, hepatitis B surface antigen (HBsAg), and hepatitis C virus 
antibody2

All study-required laboratory assessments will be performed by a central 
laboratory   
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.
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.
 
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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 
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 remaining 
mandatory samples for optional exploratory research in accordance with SOP-
GSKF-410. The investigator or 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 to 
participate 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.
 
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Committees Structure

A study charter will be created to describe important governance aspects while the 
study is being conducted.

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 participant’s last visit. 
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (eg, laboratory 
data). The investigator is responsible for verifying that data entries are accurate 
and correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

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 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 study completion 
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. 
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.
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. 

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. Also, "lack of 
efficacy" or "failure of expected pharmacological action" constitutes an AE or SAE.
 
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Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a) Results in death
b) Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
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.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
 
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normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
Is a congenital anomaly/birth defect
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
 
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Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the 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 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study 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.
 
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
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 
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 (see next section).

The site will enter the SAE data into the electronic system as soon as it becomes 
available.
 
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
After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor/SAE coordinator by telephone.

Contacts for SAE reporting 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 and confirmatory testing with additional FSH and 
estradiol measurements is required.

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.
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 will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected 
 
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
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 not routinely attempt to collect pregnancy information on any male 
participant’s female partner(s) who becomes pregnant while the male participant is 
participating in this study; however, voluntary reports of such incidents will be 
captured through the GSK standard reporting mechanism. This applies only to male 
participants who receive double-blind study treatment.

If pregnancy information for a male participant’s female partner(s) is voluntarily 
reported, 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. 

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 
 
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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 will 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 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 will be analyzed if it is hypothesized that this may help further 
understand the clinical data. 

The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to danirixin 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 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).
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
No country specific requirements
 
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12.11.
Appendix 11 Protocol Amendment History
Amendment 1
Table 1
Schedule of activities
Original text:
Screening/
Visit1a
Visit 
2
Visit 
3  
Visit 
4
Visit 
5
Visit 
6  
Visit 
7
Visit 
8  
Visit 
9
Visit 
10  
Visit 
11
Visit 
12
EW
FU
Up to 
28 
days 
post 
last 
dose
up to
-7 days
Week 
0 /
D1
Week 
2/ 
D14
Week 
4/ 
D28
Week 
8/ 
D56
Week 
12/ 
D84
Week 
16 / 
D112
Week 
20 / 
D140 
Week 
24 
/D168
Week 
32 
/D224
Week 
40 / 
D280
Week 
52 / 
D364
Assessment 
window
+3d ±3d ±3d ±3d ±3d ±3d ±3d ±3d
±6d ±6d ±6d
±6d
Urine or 
serum 
Pregnancy 
testg
X
X
X
HIV, 
Hepatitis B 
and C 
screeninge
AE review
SAE review
Revised text:
Screening/
Visit1a
Visit 
2
Visit 
3  
Visit 
4
Visit 
5
Visit 
6  
Visit 
7
Visit 
8  
Visit 
9
Visit 
10  
Visit 
11
Visit 
12
EW
FU
Up to 
28 
days 
post 
last 
dose
up to
-28 days
Week 
0 /
D1
Week 
2/ 
D14
Week 
4/ 
D28
Week 
8/ 
D56
Week 
12/
D84
Week 
16 / 
D112
Week 
20 / 
D140 
Week 
24 
/D168
Week 
32 
/D224
Week 
40 / 
D280
Week 
52 / 
D364
Assessment 
window
+3d ±3d ±3d ±3d ±3d ±3d ±3d ±3d
±6d ±6d ±6d
±6d
HIV, 
Hepatitis B 
and C 
screeninge
X
AE review
X
X
SAE review
X
X
 
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Section 5.1
Overall Design
Original text:
A study schematic is shown in Figure 1. This is a parallel group study.  Following 
screening and assessment of rescue medication use via a daily diary over study days -7 to 
1, participants will be randomized (1:1) to receive either danirixin 35mg tablets or 
placebo.  Study treatment will be administered twice daily for 52 weeks [Figure 1].  
There will be no pre-specified interim analysis for this study.  An interim analysis may be 
performed if it is determined that the enrolment is slow enough to allow it to be 
informative. There will be no IDMC for this study. An internal safety review team will 
meet approximately every 3 months (or as needed based on emerging data) to review 
available safety information. 
Figure 1
Study Schematic
Amended text:
A study schematic is shown in Figure 1. This is a parallel group study.  Following 
screening and assessment of rescue medication use via a daily diary over study days -28
to 1, participants will be randomized (1:1) to receive either danirixin 35mg tablets or 
placebo.  Study treatment will be administered twice daily for 52 weeks [Figure 1].  
There will be no pre-specified interim analysis for this study.  An interim analysis may be 
performed if it is determined that the enrolment is slow enough to allow it to be 
informative. There will be no IDMC for this study. An internal 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
Section 6.1
Inclusion Criteria
Original text:
2
Male or female
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.
Female participants: 
A female participant is eligible to participate if she is not pregnant (see Section 12.5; 
Appendix 5), not breastfeeding, and at least one of the following conditions applies:
i.
Not a woman of childbearing potential (WOCBP) as defined in Section 12.5
(Appendix 5)
OR
ii. A WOCBP who agrees to follow the contraceptive guidance in Section 12.5
(Appendix 5) during the treatment period and for at least 60 hours after the 
last dose of study treatment.
 
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Revised text:
3
Male or female
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.
Female participants: 
A female participant is eligible to participate if she is not a woman of childbearing 
potential (WOCBP) as defined in Section 12.5 (Appendix 5)
Section 12.2 Appendix 2: 
Original text:
Table 7
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
 
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Laboratory 
Assessments
Parameters
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other
Screening 
Tests

Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only)

Serum 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
 
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Amended text:
Table 8
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

pH, glucose, protein, blood, ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only)

HIV antibody, hepatitis B surface antigen (HBsAg), and hepatitis C virus 
antibody2

All study-required laboratory assessments will be performed by a central 
laboratory
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 
 
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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.
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
Section 12.5 Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information
Original text:
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 9
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.)
 
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Amended text:
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 and confirmatory 
testing with additional FSH and estradiol measurements is required.

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 

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.
 
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Table 10
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.)
 
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Amendment 2
Original text:
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
Standard safety monitoring will be 
employed.
The potential risk of testicular injury has 
been conveyed in the informed consent.
PK modelling predicts that in a participant 
receiving 35 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
No adverse events related to testicular 
effects have been observed in clinical 
studies to date.
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 
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
in nonclinical studies with danirixin.  In 
healthy volunteer studies and a phase 2a 
study in patients with Influenza (GSK Study 
201682, GlaxoSmithKline Document No.
2014N205875_00), decreased neutrophil 
counts have been observed in participants
receiving either placebo or danirixin; no 
instances of danirixin-related neutropenia 
have been reported in clinical studies to 
date. In healthy participants, 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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Amended text:
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 
Standard safety monitoring will be 
employed.
The potential risk of testicular injury has 
been conveyed in the informed consent.
PK modelling predicts that in a participant 
receiving 35 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
studies to date.
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 
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
study in patients with Influenza (GSK Study 
201682, GlaxoSmithKline Document No.
2014N205875_00), decreased neutrophil 
counts have been observed in participants
receiving either placebo or danirixin; no 
instances of danirixin-related neutropenia 
have been reported in clinical studies to 
date. In healthy participants, 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.
Study Procedures
None
Other 
Not applicable
 
 
 
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Section 6.1
Inclusion Criteria
Original text:
Sex
6.
Male or female
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.
Female participants: 
A female participant is eligible to participate if she is not a woman of childbearing 
potential (WOCBP) as defined in Section 12.5 (Appendix 5)
Revised text:
7.
Male or female
Female participants: 
A female participant is eligible to participate if she is not a woman of childbearing 
potential (WOCBP) as defined in Section 12.5 (Appendix 5)
7.1.1 Medical Devices
Original text:
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).
Additional descriptive information and instructions for the eMDI 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).
Revised text:
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 
 
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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).
Mobile spirometers (MicroDiary, manusfactured by and purchased from CareFusion) are 
also being provided by GSK for this study. These devices allow participants to conduct 
spirometry assessments at home. The MicroDiary has US FDA 510(k) clearance to 
market (Class II medical device) and European Union CE marking (Class I medical 
device).
Additional descriptive information and instructions for the eMDI monitoring devices and 
mobile spirometers 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).
9.2.8 Medical Device Incidents (Including Malfunctions)
Original text:
Medical devices are being provided for use in this study for the purposes of monitoring 
inhaled rescue medication use. 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.
Revised text:
Medical devices are being provided for use in this study for the purposes of monitoring 
inhaled rescue medication use and measuring spirometry at home. 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.
12.5
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information
Original text:
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 
 
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
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 

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.
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.)
 
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Revised text:
Text deleted.
12.5
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information
Original text:
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. 
Revised text:
Collection of Pregnancy Information
Male participants with partners who become pregnant

Investigator will not routinely attempt to collect pregnancy information on any 
male participant’s female partner(s) who becomes pregnant while the male 
participant is participating in this study; however, voluntary reports of such 
incidents will be captured through the GSK standard reporting mechanism. This 
applies only to male participants who receive double-blind study treatment.

If pregnancy information for a male participant’s female partner(s) is voluntarily 
reported, 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
 
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
Generally, follow-up will be no longer than 6 to 8 weeks following the 
estimateddelivery date. Any termination of the pregnancy will be reported 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure.
 
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Amendment 03
Original text:
Schedule of Activities (only section relevant for the change):
Screening/
Visit1a
Visit 
2
up to
-28 days
Week 
0 /
D1
Assessment window
+3d
Eligibility
Informed Consent
X
Genetics Informed Consentb
X
Demography
X
Inclusion and Exclusion 
Criteria
X
Smoking Statusc
X
Smoking Historyc
X
X
Amended text:
Schedule of Activities (only section relevant for the change):
Screening/
Visit1a
Visit 
2
up to
-32 days
Week 
0 /
D1
Assessment window
+3d
Eligibility
Informed Consent
X
Genetics Informed Consentb
X
Demography
X
Inclusion and Exclusion 
Criteria
X
Smoking Statusc
X
X
Smoking Historyc
X
Original text:
3.1
Study Rationale
This protocol describes a pilot study to investigate the effect of danirixin HBr 35mg 
tablets on lung function and health related quality of life (HRQoL) in participants with 
mild to moderate airflow obstruction identified from the COPDGene cohort. 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.
 
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Specifically, this study aims to assess whether or not danirixin has the potential to impact 
disease progression in participants with a COPD progression score indicating they are 
likely to decline based on 5 year data from COPDGene and support the conduct of a 
larger Phase III study for disease progression. In addition to lung function and HRQoL, 
this study will assess moderate/severe COPD exacerbations, health status (CAT), and 
rescue medication use.
Amended text:
3.1
Study Rationale
This protocol describes a pilot study to investigate the effect of danirixin HBr 35mg 
tablets on lung function and health related quality of life (HRQoL) in participants with 
mild to moderate airflow obstruction identified from the COPDGene cohort. 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.
Specifically, this study aims to assess whether or not danirixin has the potential to impact 
disease progression in participants with a demonstrated history of decline in FEV1 based 
on 5 year data from COPDGene and support the conduct of a larger Phase III study for 
disease progression. In addition to lung function and HRQoL, this study will assess 
moderate/severe COPD exacerbations, health status (CAT), and rescue medication use.
Original text (relevant section only):
4.1
Objectives and Endpoints
Objectives
Endpoints
Primary

To assess whether danirixin HBr 
35mg tablets impacts disease 
progression compared with placebo

Rate of decline in FEV1

Change from baseline in St. George’s 
Respiratory Questionnaire (SGRQ) 
total score (derived from SGRQ-C)

To further characterize the safety of 
danirixin HBr 35mg tablets
compared with placebo in 
participants with mild to moderate 
airflow limitation

Adverse events (AE), clinical 
laboratory values, vital signs, 
electrocardiogram (ECG), and/or other 
safety biomarkers
 
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Amended text (relevant section only)
4.1
Objectives and Endpoints
Objectives
Endpoints
Primary

To assess whether danirixin HBr 
35mg tablets impacts disease 
progression compared with placebo

Rate of decline in FEV1

Change from baseline in St. George’s 
Respiratory Questionnaire (SGRQ) 
total score (derived from SGRQ-C)
Secondary

To further characterize the safety of 
danirixin HBr 35mg tablets
compared with placebo in 
participants with mild to moderate 
airflow limitation

Adverse events (AE), clinical 
laboratory values, vital signs, 
electrocardiogram (ECG), and/or other 
safety biomarkers
Original text:
5.1
Overall Design
A study schematic is shown in Figure 1. This is a parallel group study.  Following 
screening and assessment of rescue medication use via a daily diary over study days -28
to 1, participants will be randomized (1:1) to receive either danirixin 35mg tablets or 
placebo.  Study treatment will be administered twice daily for 52 weeks [Figure 1].  
There will be no pre-specified interim analysis for this study.  An interim analysis may be 
performed if it is determined that the enrolment is slow enough to allow it to be 
informative. There will be no IDMC for this study. An internal 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 5
Study Schematic
Amended text:
5.1
Overall Design
A study schematic is shown in Figure 1. This is a parallel group study.  Following 
screening and assessment of rescue medication use via a daily diary over study days -32
to 1, participants will be randomized (1:1) to receive either danirixin 35mg tablets or 
placebo.  Study treatment will be administered twice daily for 52 weeks [Figure 1].  
There will be no pre-specified interim analysis for this study.  An interim analysis may be 
performed if it is determined that the enrolment is slow enough to allow it to be 
informative. There will be no IDMC for this study. An internal 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 6
Study Schematic
Original text:
6
Study Population
This study will identify specific patients most likely to decline from the well established 
COPDGene cohort [NCT00608764].  This study will be an ancillary study within 
COPDGene investigating the enrichment strategy for assessing disease progression. 
These potential participants have been identified by COPDGene investigators based on 
data collected over the initial 5 year period.  The participants were identified based on a 
Random Forest analysis and a demonstrated decline of at least 20mL/yr over the initial 5 
year period. Once participants are identified from the COPDGene dataset, the following 
criteria will be verified at initial study visit following signing of consent.
Amended text:
6
Study Population
This study will identify specific COPD patients most likely to decline from well 
established cohorts like COPDGene [NCT00608764].  This study will be an ancillary 
study within COPDGene and any other relevant cohort investigating the enrichment 
strategy for assessing disease progression. These potential participants will be identified 
by COPDGene investigators based on data collected over the initial 5 year period.  The 
participants were identified based on a demonstrated decline of at least 15mL/yr over the 
initial 5 year period. Once participants are identified from the COPDGene dataset, the 
following criteria will be verified at initial study visit following signing of consent.  
Equivalent cirteria may be identified within other cohorts if necessary to broaden 
recruitment pool. 
Screening
1
1 If changes to medication are required, consent must be signed prior to 
any changes being made and may occur prior to the Screening Visit
2 Follow-up visit to occur within 28days of last dose of study medication
Up to 
32 days
R
Placebo (n=50)
Danirixin, 35mg 
(n=50)
Follow-up
2
52 weeks
 
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Original text:
Inclusion Criteria
Weight
4. Body weight >45kg
Amended text:
Weight
4, Body Mass Index ≥ 21
Original text:
Exclusion Criteira
Diagnostic assessments
19. 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%).
20. A positive test for HIV antibody.
21. A positive pre-study hepatitis B surface antigen or positive hepatitis C antibody result 
within 3 months prior to screening.
Amended text:
Exclusion Criteria
19. Alanine transferase (ALT) > 2x upper limit of normal (ULN) and bilirubin > 
1.5xULN (isolated bilirubin > 1.5xULN is acceptable if bilirubin is fractionated and 
direct bilirubin <35%).
20. A positive test for HIV antibody.
21. A positive pre-study hepatitis B surface antigen or positive hepatitis C antibody result 
within 3 months prior to screening.  
Note: 
Participants with positive Hepatitis C antibody due to prior resolved disease can be 
 
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Original text:
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 and confirmatory testing with additional FSH and 
estradiol measurements is required.

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.
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 will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected.
 
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Amended text:
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 and confirmatory testing with additional FSH and 
estradiol measurements is required.

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.
 
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GlaxoSmithKline group of companies
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TITLE PAGE
Protocol Title: A randomized, double-blind, Sponsor open, placebo-controlled, 52 week 
study evaluating the effect of danirixin (GSK1325756) on lung function and health 
related quality of life in participants with mild to moderate Chronic Obstructive 
Pulmonary Disease (COPD).
Protocol Number: 205864 Amendment 2
Short Title: Danirixin Pilot Study for Disease Progression
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
Approval Date: 24-JUL-2017
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 2
24-Jul-2017
Amendment 1
17-May-2017
Original Protocol
21-Mar-2017
Amendment 1: 17-MAY-2017
Overall Rationale for the Amendment: This amendment excludes the enrolment of 
women of childbearing potential and clarifies the testing required for determination of 
post menopausal status in specific situations.
Section # 
and Name
Description of Change
Brief Rationale
Table 1 –
Schedule of 
Activities

Remove pregnancy testing

Added missing check 
marks

Updated screening period

Not required as no longer enrolling 
WOCBP

Error in original protocol

Required to allow for screening lab 
tests
Section 6.1
Inclusion 
Criteria
Update to only allow females to 
participate if they are not women of 
childbearing potential (WOCBP)
To remove additional burden on female 
subjects of childbearing potential requiring 
additional visits for pregnancy testing only.  
Section 12.2 
– Appendix 2
Clinical 
Laboratory 
Tests
Update Table 6 – Protocol-
Required Safety Laboratory 
Assessments to remove pregnancy 
testing
Removed pregnancy testing based on the 
exclusion of WOCBP
Section 12.5 
– Appendix 5
Contraceptive 
Guidance and 
Collection of 
Pregnancy 
Information

Adding clarification on 
determination of post 
menopausal state in the 
absence of 12 months of 
amenorrhea

Updated wording to be in 
line with exclusion of 
WOCBP

Current wording in template is not 
clear on testing required

Clarification of wording
 
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Amendment 2: 24-JUL-2017
Overall Rationale for the Amendment:
Section # 
and Name
Description of Change
Brief Rationale
Section 3.3.1
Risk 
Assessment
Removal of the following text from 
the mitigation strategy of the 
reproductive toxicology section:
“Male participants with female 
partners of child-bearing 
potential must comply with the 
contraception requirements.”
Additional data available demonstrating 
absence of genotoxic effects
Section 7.1.1 
and Section 
9.2.8
Medical 
Devices and 
Medical 
Device 
Incidents
Update to add mobile spirometer 
(MicroDiary) as a medical device
This device is being used in the study and 
was inadvertently omitted from the 
previous versions of the protocol
Section 6.1 
and Section 
12.5 
(Appendix 5)
Inclusion 
Criteria and 
Contraceptive 
Guidance and 
Collection of 
Pregnancy 
Information
Removal of requirement for male 
contraception with partners of 
WOCBP
Additional data available demonstrating 
absence of genotoxic effects
 
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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS...............................................................................................................8
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................10
3.
INTRODUCTION....................................................................................................13
3.1.
Study Rationale ..........................................................................................13
3.2.
Background ................................................................................................14
3.3.
Benefit/Risk Assessment ............................................................................15
3.3.1.
Risk Assessment .........................................................................16
3.3.2.
Benefit Assessment.....................................................................20
3.3.3.
Overall Benefit:Risk Conclusion...................................................20
4.
OBJECTIVES AND ENDPOINTS...........................................................................21
5.
STUDY DESIGN ....................................................................................................22
5.1.
Overall Design ............................................................................................22
5.2.
Number of Participants ...............................................................................22
5.3.
Participant and Study Completion...............................................................23
5.4.
Scientific Rationale for Study Design ..........................................................23
5.5.
Dose Justification........................................................................................23
6.
STUDY POPULATION...........................................................................................24
6.1.
Inclusion Criteria.........................................................................................24
6.2.
Exclusion Criteria........................................................................................25
6.3.
Lifestyle Restrictions...................................................................................27
6.3.1.
Meals and Dietary Restrictions ....................................................27
6.3.2.
Activity .........................................................................................27
6.4.
Screen Failures...........................................................................................28
7.
TREATMENTS.......................................................................................................28
7.1.
Treatments Administered............................................................................29
7.1.1.
Medical Devices...........................................................................29
7.2.
Dose Modification .......................................................................................30
7.3.
Method of Treatment Assignment ...............................................................30
7.4.
Blinding.......................................................................................................30
7.5.
Preparation/Handling/Storage/Accountability..............................................30
7.6.
Treatment Compliance................................................................................31
7.7.
Concomitant Therapy..................................................................................31
7.8.
Treatment after the End of the Study ..........................................................33
8.
DISCONTINUATION CRITERIA.............................................................................33
8.1.
Discontinuation of Study Treatment ............................................................33
8.1.1.
Liver Chemistry Stopping Criteria ................................................33
8.1.2.
QTc Stopping Criteria ..................................................................34
8.1.3.
Neutrophil Stopping Criteria.........................................................35
8.1.4.
Temporary Discontinuation ..........................................................35
8.1.5.
Study Treatment Restart..............................................................35
 
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8.2.
Withdrawal from the Study..........................................................................35
8.3.
Lost to Follow Up........................................................................................36
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................37
9.1.
Efficacy Assessments.................................................................................37
9.1.1.
FEV1 ............................................................................................37
9.1.1.1.
Clinic Spirometry ........................................................37
9.1.1.2.
Mobile Spirometry ......................................................37
9.1.2.
SGRQ-C ......................................................................................37
9.1.3.
CAT .............................................................................................38
9.1.4.
COPD Exacerbations...................................................................38
9.1.5.
Patient Global Rating of Severity and Global Rating of 
Change in Disease Severity.........................................................38
9.2.
Adverse Events...........................................................................................39
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................39
9.2.2.
Method of Detecting AEs and SAEs.............................................39
9.2.3.
Follow-up of AEs and SAEs.........................................................39
9.2.4.
Regulatory Reporting Requirements for SAEs .............................40
9.2.5.
Cardiovascular and Death Events................................................40
9.2.6.
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as SAEs...............................................40
9.2.7.
Pregnancy ...................................................................................41
9.2.8.
Medical Device Incidents (Including Malfunctions).......................41
9.2.8.1.
Time Period for Detecting Medical Device 
Incidents.....................................................................41
9.2.8.2.
Follow-up of Medical Device Incidents........................42
9.2.8.3.
Prompt Reporting of Medical Device Incidents 
to Sponsor..................................................................42
9.2.8.4.
Regulatory Reporting Requirements for 
Medical Device Incidents............................................42
9.3.
Treatment of Overdose...............................................................................42
9.4.
Safety Assessments ...................................................................................43
9.4.1.
Physical Examinations.................................................................43
9.4.2.
Vital Signs....................................................................................43
9.4.3.
Electrocardiograms......................................................................43
9.4.4.
Clinical Safety Laboratory Assessments ......................................44
9.4.5.
Pneumonia ..................................................................................44
9.5.
Pharmacokinetics .......................................................................................45
9.6.
Pharmacodynamics ....................................................................................45
9.7.
Genetics .....................................................................................................45
9.8.
Biomarkers .................................................................................................45
9.9.
Health Economics OR Medical Resource Utilization and Health 
Economics..................................................................................................46
10. STATISTICAL CONSIDERATIONS........................................................................46
10.1.
Sample Size Determination ........................................................................46
10.2.
Randomization............................................................................................49
10.3.
Populations for Analyses ............................................................................49
10.4.
Statistical Analyses.....................................................................................49
10.4.1.
Efficacy Analyses.........................................................................49
10.4.2.
Safety Analyses...........................................................................51
 
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10.4.3.
Other Analyses ............................................................................51
10.4.4.
Interim Analyses ..........................................................................51
11. REFERENCES.......................................................................................................52
12. APPENDICES........................................................................................................55
12.1.
Appendix 1: Abbreviations and Trademarks................................................55
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................59
12.3.
Appendix 3: Study Governance Considerations..........................................61
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................65
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................71
12.6.
Appendix 6: Genetics..................................................................................74
12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................75
12.8.
Appendix 8: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................78
12.9.
Appendix 9: Neutrophil Safety and Study Treatment Restart ......................80
12.10. Appendix 10: Country-specific requirements...............................................82
12.11. Appendix 11 Protocol Amendment History..................................................83
 
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1.
SYNOPSIS
Protocol Title: A randomized, double-blind, Sponsor open, placebo-controlled, 52 week 
study evaluating the effect of danirixin (GSK1325756) on lung function and health 
related quality of life in participants with mild to moderate Chronic Obstructive 
Pulmonary Disease (COPD).
Short Title: Danirixin Pilot Study for Disease Progression in COPD
Rationale:  This is a pilot study to investigate the effect of danirixin hydrobromide (HBr) 
35mg tablets on lung function and health related quality of life (HRQoL)  in participants 
with mild to moderate airflow obstruction and a demonstrated history of decline in FEV1. 
This study aims to assess whether danirixin has the potential to impact disease 
progression in participants with COPD and with a demonstrated history of disease 
progression measured by lung function. 
Objectives and Endpoints:
Objective
Endpoint
Primary

To assess whether danirixin HBr 35mg 
tablets impact disease progression
compared with placebo

Rate of decline in FEV1

Change from baseline in St. George’s 
Respiratory Questionnaire (SGRQ)  
total score (derived from SGRQ-C)
Secondary

To further characterize the safety of 
danirixin HBr 35mg tablets compared 
with placebo in participants with mild 
to moderate airflow limitation

Adverse events

Vital Signs

ECG

Clinical Laboratory Assessments 
(hematology, clinical chemistry, 
urinalysis)

To further characterize the clinical 
activity of danirixin HBr 35mg tablets 
compared with  placebo

Time to first HCRU COPD 
exacerbation

Change from baseline in FEV1

SGRQ responder analysis

SGRQ domains

COPD Assessment Test (CAT)

Rescue medication use 
Overall Design:
This is a Phase 2 study to investigate the potential impact of danirixin HBr 35mg tablets 
compared with placebo on disease progression in participants with mild to moderate 
 
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airflow obstruction.  The study will also assess the enrichment strategy of enrolling 
participants identified from the COPDGene study.  These participants have been 
identified by COPDGene investigators based on data collected over the initial 5 year 
period.  The participants were identified based on a Random Forest analysis and a 
demonstrated decline of at least 20mL/yr over the initial 5 year period. 
Number of Participants:
Approximately 130 participants will be screened to enrol 100 participants in this study.  It 
is anticipated that approximately 85 participants will complete the 52 weeks of treatment 
(assuming a 15% drop out rate).
Treatment Groups and Duration:
Participants will receive either placebo or danirixin 35mg tablets (as hydrobromide 
hemihydrate salt) twice daily for 52 weeks (12months).
 
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2.
SCHEDULE OF ACTIVITIES (SOA)
Table 1
Schedule of activities
Screening/
Visit1a
Visit 2
Visit 3  
Visit 
4
Visit 5
Visit 
6
Visit 
7
Visit 8
Visit 9
Visit 
10
Visit 11
Visit 12
EW
FU
Up to 28 
days 
post last 
dose
up to
-28 days
Week 
0 /
D1
Week 2/ 
D14
Week 4/ 
D28
Week 8/ 
D56
Week 12/ 
D84
Week 16 
/ D112
Week 20 
/ D140 
Week 
24 
/D168
Week 32 
/D224
Week 40 
/ D280
Week 52 
/ D364
Assessment window
+3d
±3d
±3d
±3d
±3d
±3d
±3d
±3d
±6d
±6d
±6d
±6d
Eligibility
Informed Consent
X
Genetics Informed Consentb
X
Demography
X
Inclusion and Exclusion Criteria
X
Smoking Statusc
X
Smoking Historyc
X
X
Medical Historyd
X
Full physical
X
Chest X-ray (historical within 1 year 
acceptable)
X
HIV, Hepatitis B and C screeninge
X
Additional Eligibility and In Study Assessments
Verify Eligibilityf
X
X
Brief physical
X
X
X
X
X
Laboratory assessments (clinical chemistry, 
including liver chemistries), hematology, 
urinalysis
X
X
X
X
X
X
Additional Liver chemistries only
X
X
X
X
X
X
X
12 lead ECG
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
 
 
 
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Screening/
Visit1a
Visit 2
Visit 3  
Visit 
4
Visit 5
Visit 
6
Visit 
7
Visit 8
Visit 9
Visit 
10
Visit 11
Visit 12
EW
FU
Up to 28 
days 
post last 
dose
up to
-28 days
Week 
0 /
D1
Week 2/ 
D14
Week 4/ 
D28
Week 8/ 
D56
Week 12/ 
D84
Week 16 
/ D112
Week 20 
/ D140 
Week 
24 
/D168
Week 32 
/D224
Week 40 
/ D280
Week 52 
/ D364
Assessment window
+3d
±3d
±3d
±3d
±3d
±3d
±3d
±3d
±6d
±6d
±6d
±6d
Office spirometry (centralized)
X
X
X
X
X
X
X
X
X
X
X
X
X
Home spirometry  - (weekly)
X
X
X
Randomization
X
Dispense study medication
X
X
X
X
X
X
X
X
X
Dispense log pad and provide training
X
Dispense MDI sensors and provide training
X
Study Treatment
Study Treatment Compliance (ediary)
Collect IP 
Collect MDI sensors
X
X
Collect log pad
X
X
AE review
X
X
SAE review
X
X
Concomitant medication review
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Outcomes Assessments
COPD exacerbation review
X
X
X
X
X
X
X
X
X
X
X
X
Rescue medication Use
SGRQ-C
X
X
X
X
X
X
COPD Assessment Test (CAT)
X
X
X
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
X
X
X
 
 
 
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Screening/
Visit1a
Visit 2
Visit 3  
Visit 
4
Visit 5
Visit 
6
Visit 
7
Visit 8
Visit 9
Visit 
10
Visit 11
Visit 12
EW
FU
Up to 28 
days 
post last 
dose
up to
-28 days
Week 
0 /
D1
Week 2/ 
D14
Week 4/ 
D28
Week 8/ 
D56
Week 12/ 
D84
Week 16 
/ D112
Week 20 
/ D140 
Week 
24 
/D168
Week 32 
/D224
Week 40 
/ D280
Week 52 
/ D364
Assessment window
+3d
±3d
±3d
±3d
±3d
±3d
±3d
±3d
±6d
±6d
±6d
±6d
Genetic, Pharmacokinetic and Biomarker Blood Collections
Blood sample for Genetics
X
Blood sample for CRP
X
X
X
X
Blood sample for exploratory biomarkers
X
X
X
X
a
Informed consent may be signed prior to screening visit in the case that any changes in medications are necessary
b
Agreeing to genetic sample consent is not required for study participation
c
Smoking status/history assessed at screening; smoking status re-checked at Visit 2
d
Includes substance usage, past and present medical conditions and family history of premature CV disease
e
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.
f
Participant’s clinical status should be reviewed
The timing and number of planned study assessments, including safety and biomarker assessments may be altered during the course of the study based on newly available data to 
ensure appropriate data collection.  Any changes in the timing or addition of time points for any planned study assess 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 Number 
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 
[GlaxoSmithKline Document Number 2013N180289_03 Study ID 200163].  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.  Analyses of 
clinical endpoints from study 200163 demonstrated that danirixin, compared to placebo, 
reduced respiratory symptoms as measured with E-RS:COPD [Miller, 2016].
3.1.
Study Rationale
This protocol describes a pilot study to investigate the effect of danirixin HBr 35mg 
tablets on lung function and health related quality of life (HRQoL) in participants with 
 
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mild to moderate airflow obstruction identified from the COPDGene cohort. 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.
Specifically, this study aims to assess whether or not danirixin has the potential to impact 
disease progression in participants with a COPD progression score indicating they are 
likely to decline based on 5 year data from COPDGene and support the conduct of a 
larger Phase III study for disease progression. In addition to lung function and HRQoL, 
this study will assess moderate/severe COPD exacerbations, health status (CAT), and 
rescue medication use.
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 and, 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 
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.  
 
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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 Number 
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.
PK modelling predicts that in a participant 
receiving 35 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 participants
receiving either placebo or danirixin; no 
instances of danirixin-related neutropenia 
have been reported in clinical studies to 
date. In healthy participants, 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.
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 
or 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.
 
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4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To assess whether danirixin HBr 
35mg tablets impacts disease 
progression compared with placebo

Rate of decline in FEV1

Change from baseline in St. George’s 
Respiratory Questionnaire (SGRQ) 
total score (derived from SGRQ-C)

To further characterize the safety of 
danirixin HBr 35mg tablets
compared with placebo in 
participants with mild to moderate 
airflow limitation

Adverse events (AE), clinical 
laboratory values, vital signs, 
electrocardiogram (ECG), and/or other 
safety biomarkers
Secondary

To further characterize the clinical 
activity of danirixin HBr 35mg tablets
compared to placebo

Time to first HCRU COPD 
exacerbation

Change from baseline in FEV1

SGRQ responder analysis

SGRQ domains

COPD Assessment Test (CAT)

Rescue medication use
Exploratory

To characterize the effect of 
danirixin on lung matrix 
destruction/remodelling and 
inflammation

Further characterize efficacy of 
danirixin
Blood/serum/plasma  biomarkers that 
are indicative of extracellular matrix 
turnover/remodelling (e.g. elastin and 
collagen neo-epitopes) and 
inflammation (e.g. CRP)

Global assessment of COPD severity 
 
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5.
STUDY DESIGN
5.1.
Overall Design
A study schematic is shown in Figure 1. This is a parallel group study.  Following 
screening and assessment of rescue medication use via a daily diary over study days -28
to 1, participants will be randomized (1:1) to receive either danirixin 35mg tablets or 
placebo.  Study treatment will be administered twice daily for 52 weeks [Figure 1].  
There will be no pre-specified interim analysis for this study.  An interim analysis may be 
performed if it is determined that the enrolment is slow enough to allow it to be 
informative. There will be no IDMC for this study. An internal safety review team will 
meet approximately every 3 months (or as needed based on emerging data) to review 
available safety information. 
Figure 1
Study Schematic
5.2.
Number of Participants
Approximately 130 participants will be screened to achieve 100 randomized in this study.  
It is anticipated that approximately 85 participants will complete the 12 months of 
treatment (assuming a 15% drop out rate).
For the analysis of study assessments, several analysis populations are defined in Section 
10.3.  
 
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5.3.
Participant and Study Completion
A participant is considered to have completed the study if he/she has completed all
planned study visits 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.  With the 
use of an enriched population, it is anticipated that one year of treatment will be sufficient 
to detect a trend in altering disease progression.   Danirixin has already been clinically 
investigated over one year treatment duration (GlaxoSmithKline Document Number 
2013N180289_03 Study ID 200163).  
The data from this study will provide useful information in determining whether or not to 
progress to a Phase III study to explore an indication for slowing disease progression. 
5.5.
Dose Justification
One dose of danirixin is proposed for this study, 35mg tablets BID.  This dose was 
selected based on integrating information on:

Dose-exposure-biomarker response using inhibition of ex vivo CXCL1-induced 
CD11b expression on peripheral blood neutrophils over the dose range of 0-400mg 
(free base tablet) in healthy volunteers (GSK Study No. CX3 112483).

Evidence of reduced respiratory symptoms and improvement in health status in mild 
to moderate COPD participants from interim data in the Phase IIa study (GSK Study 
No. 200163).

Relative bioavailability study comparing danirixin free base vs HBr (GSK Study No. 
201037).
In the previous 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 (GlaxoSmithKline Document Number 
2015N248339_00, Study ID 201037). Thus the danirixin (hydrobromide tablet) 35mg 
BID dose for investigation in this study is expected to provide steady-state systemic 
exposure approximately equivalent to the 75mg BID (free base tablet) used in Study 
200163. 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 Number. 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.
6.
STUDY POPULATION
This study will identify specific patients most likely to decline from the well established 
COPDGene cohort [NCT00608764].  This study will be an ancillary study within 
COPDGene investigating the enrichment strategy for assessing disease progression. 
These potential participants have been identified by COPDGene investigators based on 
data collected over the initial 5 year period.  The participants were identified based on a 
Random Forest analysis and a demonstrated decline of at least 20mL/yr over the initial 5 
year period. Once participants are identified from the COPDGene dataset, the following 
criteria will be verified at initial study visit following signing of consent.
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1.
Participant must be 40 to 76 years of age inclusive, at the time of signing the 
informed consent.
Type of Participant and Disease Characteristics
2.
At the screening visit, the subject must have an FEV1 >40% of the predicted normal.
3.
Participants with a prior history of asthma are eligible if they have a current 
diagnosis of COPD
Dose 
(mg)
Predicted# steady-state median (5th, 95th
percentile)
Cavg 
multiple of 
IC50*
Cmin 
multiple of 
IC50*
AUC(0-24) 
steady-state
(ug.h/mL)
Cavg
(ng/mL)
Cmin
(ng/mL)
35
9.59
(4.70, 19.3)
399
(196, 806)
192
(47.6, 630)
5.1
2.4
 
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Weight
4.
Body weight 45 kg
Sex
5.
Male or female
Female participants: 
A female participant is eligible to participate if she is not a woman of childbearing 
potential (WOCBP) as defined in Section 12.5 (Appendix 5)
Informed Consent
6. Capable of giving signed informed consent as described in Section 12.3 (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 disease (other than COPD), e.g. 
sarcoidosis, tuberculosis, pulmonary fibrosis, severe bronchiectasis or lung cancer
2. COPD due to alpha-1-antitrypsin deficiency 
3. Pulse oximetry < 88% at rest at screening.  Participants should be tested while 
breathing room air.  However, participants living at high altitudes (above 5000 ft or 
1500 m above sea level) who are receiving supplemental oxygen can be included 
provided they are receiving the equivalent of < 4L/min and screening oximetry is 
measured while on their usual settings.
4. Less than 14 days have elapsed from completion of a course of antibiotics or oral 
corticosteroids for a recent COPD exacerbation
5. Participants with a peripheral blood neutrophil count < 1 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 with lateral) or CT scan reveals evidence of a clinically 
significant abnormality not believed to be due to the presence of COPD (historic data 
up to 1 year may be used).  
8. History or current evidence of clinically significant renal disease, diabetes 
mellitus/metabolic syndrome, hypertension, or any other clinically significant 
cardiovascular, neurological, immunological, endocrine, or haematological 
abnormality 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 participants 
 
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at risk through study participation, or which would affect the safety analysis or other 
analysis if the disease/condition exacerbated during the study.
9. History of sensitivity to any of the study medications, or components thereof or a 
history of drug or other allergy that, in the opinion of the investigator of GSK medical 
monitor, contraindicates their participation.
10. Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert’s syndrome or asymptomatic gallstones).
11. Abnormal and clinically significant 12-lead ECG finding.  The investigator will 
determine the clinical significance of each abnormal ECG finding in relation to the 
subject’s medical history and exclude participants who would be at undue risk by 
participating in the trial.  An abnormal and clinically significant finding that would 
preclude a subject from entering the trial is defined as a 12-lead tracing that is 
interpreted as, but not limited to, any of the following:
‒
AF with rapid ventricular rate > 120 bpm;
‒
sustained or non-sustained VT
‒
second degree heat block Mobitz type II and third degree heart block (unless 
pacemaker or defibrillator has been implanted)
‒
QTcF 500 msec in patients with QRS < 120 msec and QTcF 530 msec in 
patients with QRS 120 msec
12. Previous lung surgery (e.g. lobectomy, pneumonectomy) or lung volume reduction 
procedure.
Prior/Concomitant Therapy
13. 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.
14. 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.
15. 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
16. 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 
 
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study: 30 days, 5 half lives, or twice the duration of the biological effect of the 
investigational product (whichever is longer).
17. Participation in a previous clinical trial with danirixin within 1 year prior to the first 
dosing day in the current study
18. Exposure to more than four investigational products within 1 year prior to the first 
dosing day in the current study.
Diagnostic assessments
19. 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%).
20. A positive test for HIV antibody.
21. A positive pre-study hepatitis B surface antigen or positive hepatitis C antibody result 
within 3 months prior to screening.
Other Exclusions
22. 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.
23. A history of allergy or hypersensitivity to any of the ingredients in the study 
treatment.
24. A known or suspected history of alcohol or drug abuse within the 2 years prior to 
screening.
25. Inability to read: in the opinion of the Investigator, any participant who is unable to 
read and/or would not be able to complete study related materials.
26. 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.
6.3.2.
Activity
Participants should abstain from strenuous exercise for 24 hours before each blood 
collection for clinical laboratory tests. 
 
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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 not be rescreened unless discussed with the medical monitor. 
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
Study Treatment Name:
Danirixin 
(GSK1325756H, the 
hydrobromide 
hemihydrate salt)
Placebo
Dosage formulation:
White Film coated
tablets (oval shaped). 
Refer to Investigator’s 
Brochure for 
presentation and 
excipients
White Film coated 
tablets (oval shaped). 
Refer to 
Investigator’s 
Brochure for 
presentation and 
excipients
Unit dose strength(s)/Dosage level(s):
35mg tablets (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).
Mobile spirometers (MicroDiary, manufactured by and purchased from CareFusion) are 
also being provided by GSK for this study. These devices allow participants to conduct 
spirometry assessments at home. The MicroDiary has US FDA 510(k) clearance to 
market (Class II medical device) and European Union CE marking (Class I medical 
device).
 
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Additional descriptive information and instructions for the eMDI monitoring devices and 
mobile spirometers 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 study.  Study participants, all study site staff, and all members 
of the GSK study team will be blinded to individual participant treatment assignment.  
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 
 
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(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.  
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
 
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
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)
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) bronchodilators, (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 
 
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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: Liver Safety: Required Actions and Follow-up Assessments). 
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 (Section 12.7) 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.
 
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
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. 
 
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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.
FEV1
9.1.1.1.
Clinic Spirometry
Spirometry using FEV1 and FVC measurements (FEV%, and FVC% and FEV1/FVC will 
be calculated) will be performed in triplicate at time points listed in the SoA (Table 1).  
Spirometry assessments should be performed in accordance with ATS/ERS guidelines as 
outlined in the SRM.
9.1.1.2.
Mobile Spirometry
Spirometry will also be performed weekly by the participants using a mobile spirometer 
at home.  Details will be outlined in the SRM.
9.1.2.
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 
 
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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 SGRQ scores equivalent to the original SGRQ instrument [Jones, 1992].
9.1.3.
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.
9.1.4.
COPD Exacerbations
An exacerbation of COPD is defined by a worsening of symptoms requiring additional 
treatment or hospitalization. 
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 based on the Investigator’s judgement.
9.1.5.
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 
final study visit or IP Discontinuation Visit.  This single global question will ask 
participants 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 every visit following randomization (or Early Withdrawal (EW) Visit). Response 
 
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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.
9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4 (Section 12.4).
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 the time the informed consent is signed by the 
participant until the follow up visit at the time points specified in the SoA
(Table 1).

All AEs will be collected from the start of study treatment (randomization visit) 
until the follow-up visit at the time points specified in the SoA (Table 1).

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 must be reported immediately and not more than 24 hrs to the sponsor, 
as indicated in Appendix 4 (Section 12.4). 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 (Section 12.4).
9.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
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 
 
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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 Section 12.4 (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. 
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 Section 12.3 (Appendix 3).  
 
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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 
Section 12.5 (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 measuring spirometry at home. 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 Section 12.8 (Appendix 8).
NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Section 9.2 and Section 12.4 (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 Section 
12.8 (Appendix 8).
 
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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 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.
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.
 
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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.
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, 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 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 measurements 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.
 
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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 10 minutes.
9.4.4.
Clinical Safety Laboratory Assessments
Refer to Section 12.2 (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 Section 12.2, 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.
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)
 
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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
Pharmacokinetic parameters are not evaluated in this study.
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 Section 12.6 (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), 
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.
 
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9.9.
Health Economics OR Medical Resource Utilization and 
Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study.
10.
STATISTICAL CONSIDERATIONS
The objective of this study is to investigate the effect of danirixin HBr 35mg tablets on 
COPD disease progression. There are no formal hypothesis tests associated with this 
objective and no formal significance tests. The information acquired from this study will 
primarily be used to assess whether or not danirixin impacts disease progression and to 
quantify the effect that danirixin has on disease progression, specifically change in lung 
function as measured by FEV1 decline and change in health-related quality of life as 
measured by SGRQ total score to further support disease understanding and future 
studies. 
10.1.
Sample Size Determination
Sample size is based primarily on feasibility for this study. Since there is much 
uncertainty around the magnitude of the difference in the decline in FEV1 and change in 
SGRQ along with the between-subject variability for the specific patient population, the 
proposed sample size is unavoidably imprecise. Sample size may be adjusted using the 
predictions of final study outcome based on simulations and possible interim analyses. It 
is anticipated that screening 130 participants will allow for approximately 100 
participants to enrol. 
In order to observe the effect of different sample sizes, various simulations were done to 
assess the impact of sample sizes of 50, 100, 150 and 200 with a 1:1 allocation to each 
treatment group [Table 3]. The assumed variability for rate of decline in FEV1 and 
change in SGRQ is 25 and 10, respectively.  The correlation between rate of decline in 
FEV1 and change in SGRQ is assumed to be -0.2. [Nagai, 2015] 
Table 3
Assumptions used for the Simulations
Treatment Effect Assumptions
(δFEV1, δSGRQ)
Variability Assumptions
(σFEV1, σSGRQ)
Sample Size
Null
(0,0)
(25,10)
N={50,100,150,200}
Alternate 1 
(5,-1)
(25,10)
N={50,100,150,200}
Alternate 2
(5,0) 
(25,10)
N={50,100,150,200}
Alternate 3
(0,-1)
(25,10)
N={50,100,150,200}
Data from a bivariate normal distribution were simulated under the four different 
treatment effect assumptions for samples sizes of 50, 100, 150, and 200. The samples 
from the posterior probability distribution from the MCMC approximation were divided 
into four regions based on δFEV1 and δSGRQ treatment effect cut-off values; δFEV1≥0 and 
δSGRQ ≤0, δFEV1≥0 and δSGRQ>0, δFEV1<0 and δSGRQ≤0, and δFEV1<0 and δSGRQ>0. Based 
on a 70% threshold, the proportion of the 1000 simulations meeting the requirement 
P(δFEV1≥0 & δSGRQ≤0) ≥70% were considered a success based on the joint definition 
 
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[Figure 2, Table 4]. If P(δFEV1≥0 & δSGRQ≤0) < 70%, success could further be defined 
based on each endpoint independently where P(δFEV1 ≥0) ≥ 80% or P(δSGRQ ≤0) ≥ 80%. 
Figure 2
Total Probability of Success
Table 4
Total Probability of Success (Figure 2)
N=50
N=100
N=150
N=200
(5,-1)
57.4
68.5
75.1
81.4
(5,0)
52.5
62.6
67.8
74.5
(0,-1)
42.6
46.2
48.9
53.0
(0,0)
34.9
33.9
33.3
31.5
 
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Figure 3
Half Width of the 95% Confidence Interval of δFEV1 Point Estimate
Figure 4
Half Width of the 95% Confidence Interval of δSGRQ Point Estimate
Based on the simulations, under the assumption of an expected treatment difference of 
(5,-1) which is the most probable scenario, the marginal increase for the total probability 
of success is greatest when increasing the sample size from 50 to 100 (Figure 2). The half 
widths of the 95% CI of the point estimate of the marginal treatment differences for FEV1
(Figure 3) and SGRQ (Figure 4) have the greatest reduction from a sample size of 50 to 
100. A sample size of 100 will allow for an adequate level of confidence in the study 
success while also considering the precision of the treatment effect differences. 
 
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10.2.
Randomization
Participants will be randomized equally (1:1) to the two treatment arms of placebo and 35 
mg danirixin HBr.  Randomization will be stratified by smoking status (current vs. 
former).
10.3.
Populations for Analyses
For purposes of analysis, the following populations are defined:
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.
Per-Protocol (PP) 
Population
This population will comprise of all patients in the ITT 
population who are not major protocol violators.
Safety
All randomized participants who take at least 1 dose of study 
treatment. Participants will be analyzed according to the 
treatment they actually received.
10.4.
Statistical Analyses
Treatment comparisons using all endpoints will be made using appropriate statistical 
techniques. Analysis methods for key endpoints are described below. Main analysis will 
use ITT unless noted. Further details on all analyses will be described in the reporting and 
analysis plan (RAP).
10.4.1.
Efficacy Analyses
The total probability of success will be defined as a combination of a joint and 
conditional statement. The joint probability of success will be defined as the probability 
of the difference in the rate of decline in FEV1 between danirixin and placebo is greater 
than or equal to 0 and the difference in the change in SGRQ total score from baseline 
between danirixin and placebo is less than or equal to 0 is greater than 70%. If the joint 
probability of success is less than 70%, success can further be defined based on each 
endpoint independently, where either the difference in the rate of decline in FEV1 is
 
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greater than or equal to 0 is greater than 80% or the difference in the change in SGRQ 
total score is less than or equal to 0 is greater than 80%. 
Endpoint
Statistical Analysis Methods
Primary
Rate of decline in FEV1 and change from baseline in SGRQ total score
Exploratory
Will be described in detail in the RAP
Lung Function Decline: Rate of Decline of FEV1 (mL/yr)
The rate of decline of FEV1 will be derived from a repeated measures random 
coefficients model. Post-baseline FEV1 will be modelled including terms for age, sex, 
smoking status, FEV1 at baseline, and BMI along with treatment group, time and 
treatment by time interaction as fixed effects.  Subject will be a random effect. Time will 
be defined as the number of days since start of treatment. Only FEV1 values measured 
after baseline will be used in the model. Based on the results of previous studies, the 
study team will determine the time point at which post-baseline spirometry assessments 
will be included in the model to account for the initial treatment response. The estimate 
of the rate of FEV1 decline will be the slope of the parameter estimate of the treatment by 
time interaction term in the model. Contrasts will be calculated for the difference in 
treatment by time interaction between danirixin and placebo treatment groups to estimate 
the treatment difference. 
FEV1 = Treatment group + age + sex +smoking status+FEV1_BL+BMI+ time + 
treatment*time 
The rate of decline for each subject, the estimate of the slope parameter of the treatment 
by time interaction term, will be used as a co-primary endpoint for the joint analysis 
using both FEV1 and SGRQ. 
HRQoL: SGRQ
A co-primary endpoint of interest is change in SGRQ total score (derived from SGRQ-C) 
from baseline. Change in SGRQ total scores from baseline will be derived using a mixed 
model with repeated measures (MMRM) including fixed effects of treatment group, age, 
sex, smoking status, BMI, baseline SGRQ score, time as a categorical variable and a 
treatment by time interaction term. Subject will be a random effect. Estimated treatment 
differences at the end of one year will be obtained. The difference of the least square 
mean change from baseline at 12 months will be derived. The adjusted SGRQ total score 
 
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change from baseline will used as the other co-primary endpoint for the joint analysis 
using both FEV1 and SGRQ. 
Joint Analysis
The joint analysis will use the ITT population with all available FEV1 rate of decline and 
change in SGRQ data.
The rate of decline (the slope parameter from the random coefficients model) of FEV1, 
along with the change in SGRQ from the MMRM model will be extracted for each 
subject. These values will then be used to obtain MCMC approximations of the joint 
posterior distribution of the treatment differences between FEV1 decline and change in 
SGRQ between the danirixin and placebo groups. Based on the samples from the 
posterior distribution, the proportion of samples falling within certain treatment 
difference regions will be calculated and the probability of success will be derived. 
10.4.2.
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.
10.4.3.
Other Analyses
Exploratory biomarker analyses will be described in the RAP.
10.4.4.
Interim Analyses
Conducting an interim analysis or futility assessment may not be practical due to an 
expected fast recruitment period. By the time enough data will accumulate for any 
meaningful interim analysis to support changes to the study design, recruitment of all 
study participants will have concluded. However, if recruitment takes a longer than 
anticipated, an interim analysis to reassess the variability assumptions, estimate the 
probability of success at the end of study, and confirm the directionality of the endpoints 
may be conducted.  
The RAP will describe the potential interim analyses in greater detail.
 
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11.
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Eur Respir J. 2004;23:932-946. 
Chapman RW, Philips JE, Hipkin RW, Curran AK, Lundell D, Fine JS. CXCR2 
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FDA. Guidance for Industry. Center for Drug Evaluation and Research, United States 
Food and Drug Administration; 2009. Drug-induced liver injury: premarketing clinical 
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GlaxoSmithKline Document Number 2013N180289_03 Study ID 200163. A two part, 
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GlaxoSmithKline Document Number 2014N205875_00 Study ID 201682. A 
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GlaxoSmithKline Document Number 2015N248339_00 Study ID 201037. A single 
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evaluate the relative bioavailability of hydrobromide salt and free base immediate release 
tablet formulations of danirixin in the fed state, and to evaluate the effect of food and 
gastric acid secretion suppression on danirixin pharmacokinetics following administration 
of hydrobromide salt tablets. Report Date 01-Jun-2016. 
GlaxoSmithKline Document Number YM2010/00163/07. Danirixin Investigator's 
Brochure, Version 09. Report Date 14-Apr-2016. 
GOLD. From the Global Strateby for the Diagnosis, Management and Prevention of 
COPD, Global Initiative for Chronic Obstructive Lung Disease. Global Initiative for 
Chronic Obstructive Lung Disease, Available from: http://www.copdgold.org; 2016. 
Holz O, Khalilieh S, Ludwig-Sengpiel A, Watz H, Stryszak P, Soni P, et al. SCH527123, 
a novel CXCR2 antagonist, inhibits ozone-induced neutrophilia in healthy subjects. Eur 
Respir J. 2010;35:564-570. 
Hurst JA, Vestbo J, Anzueto A, Locantore N, Mullerova, Tal-Singer R, et al. 
Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 
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Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Leidy NK. Development and first 
validation of the COPD Assessment Test (CAT). Eur Respir J. 2009;34:648-654. 
 
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Jones PW, Harding G, Wiklund I, Berry P, Tabberer M, Yu R et al. Tests of the 
responsiveness of the chronic obstructive pulmonary disease (COPD) assessment test 
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Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure of health 
status for chronic airflow limitation. The St. George's Respiratory Questionnaire. Am Rev 
Respir Dis. 1992;145:1321-1327. 
Lazaar AL, Sweeney LE, MacDonald AJ et al. SB-656933, a novel CXCR2 selective 
antagnoist, inhibits ex vivo neutrophil activation and ozone-induced airway inflammation 
in humans. Br J Clin Pharmacol. 2011;72:282-293.  
Lopez-Campos JL, Tan W, Soriano JB. Global burden of COPD. Respirology. 
2016;21:14-23.
Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 
to 2030. PLoS Med. 2006;3:e442. 
Meguro M, Barley EA, Spencer S et al. Development and validation of an improved 
COPD-specific version of the St. George Respiratory Questionnaire. Chest. 
2007;132:456-463. 
Miller B, Tal-Singer R, Lazaar A, Leidy N, Watz H, Collins D, et al. Assessing 
symptoms in COPD: use of the E-RS daily digital diary in early drug development. Eur 
Respir J. 2016;48(S60):PA1047. 
Nagai, K., Makita, H., Suzuki, M., Shimizu, K., Konno, S., Ito, Y. M., & Nishimura, M. 
Differential changes in quality of life components over 5 years in chronic obstructive 
pulmonary disease patients. International Journal of Chronic Obstructive Pulmonary 
Disease. 2015; 10: 745–757. 
Nair P, Gaga M, Zervas E et al. Safety and efficacy of a CXCR2 antagnoist in patients 
with severe asthma and sputum neutrophils: a randomized, placebo-controlled clinical 
trial. Clin Exp Allergy. 2012;42:1097-2103. 
O'Byrne PM, Metev H, Puu M et al. Efficacy and safety of a CXCR2 antagonist, 
AZD5069, in patients with uncontrolled persistent asthma: a randomised, double-blind, 
placebo-controlled trial. Lancet Respir Med. 2016;4:797-806. 
Rennard SI, Dale DC, Donohue JF et al. CXCR2 antagonist MK-7123 - a phase 2 proof-
of-concept trial for chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 
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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. 
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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
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
eCRF
Electronic Case Report Form
ED50
Dose causing 50% of the maximum achievable response
 
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EMA
European Medicines Agency
Emax
Maximum response achievable
eMDI
Electronic metered dose inhaler
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
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
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
 
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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
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
 
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SGRQ
St George’s Respiratory Questionnaire
SGRQ-C
SGRQ-C 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
 
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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

pH, glucose, protein, blood, ketones by dipstick
 
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Laboratory 
Assessments
Parameters

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only)

HIV antibody, hepatitis B surface antigen (HBsAg), and hepatitis C virus 
antibody2

All study-required laboratory assessments will be performed by a central 
laboratory   
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.
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.
 
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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 
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 remaining 
mandatory samples for optional exploratory research in accordance with SOP-
GSKF-410. The investigator or 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 to 
participate 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.
 
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Committees Structure

A study charter will be created to describe important governance aspects while the 
study is being conducted.

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 participant’s last visit. 
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (eg, laboratory 
data). The investigator is responsible for verifying that data entries are accurate 
and correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

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 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 study completion 
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. 
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.
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. 

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. Also, "lack of 
efficacy" or "failure of expected pharmacological action" constitutes an AE or SAE.
 
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Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a) Results in death
b) Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
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.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
 
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normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
Is a congenital anomaly/birth defect
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
 
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Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the 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 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study 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.
 
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
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 
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 (see next section).

The site will enter the SAE data into the electronic system as soon as it becomes 
available.
 
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
After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor/SAE coordinator by telephone.

Contacts for SAE reporting 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 and confirmatory testing with additional FSH and 
estradiol measurements is required.

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.
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 will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected 
 
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
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 not routinely attempt to collect pregnancy information on any male 
participant’s female partner(s) who becomes pregnant while the male participant is 
participating in this study; however, voluntary reports of such incidents will be 
captured through the GSK standard reporting mechanism. This applies only to male 
participants who receive double-blind study treatment.

If pregnancy information for a male participant’s female partner(s) is voluntarily 
reported, 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. 

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 
 
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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 will 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 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 will be analyzed if it is hypothesized that this may help further 
understand the clinical data. 

The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to danirixin 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 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).
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
No country specific requirements
 
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12.11.
Appendix 11 Protocol Amendment History
Amendment 1
Table 1
Schedule of activities
Original text:
Screening/
Visit1a
Visit 
2
Visit 
3  
Visit 
4
Visit 
5
Visit 
6  
Visit 
7
Visit 
8  
Visit 
9
Visit 
10  
Visit 
11
Visit 
12
EW
FU
Up to 
28 
days 
post 
last 
dose
up to
-7 days
Week 
0 /
D1
Week 
2/ 
D14
Week 
4/ 
D28
Week 
8/ 
D56
Week 
12/ 
D84
Week 
16 / 
D112
Week 
20 / 
D140 
Week 
24 
/D168
Week 
32 
/D224
Week 
40 / 
D280
Week 
52 / 
D364
Assessment 
window
+3d ±3d ±3d ±3d ±3d ±3d ±3d ±3d
±6d ±6d ±6d
±6d
Urine or 
serum 
Pregnancy 
testg
X
X
X
HIV, 
Hepatitis B 
and C 
screeninge
AE review
SAE review
Revised text:
Screening/
Visit1a
Visit 
2
Visit 
3  
Visit 
4
Visit 
5
Visit 
6  
Visit 
7
Visit 
8  
Visit 
9
Visit 
10  
Visit 
11
Visit 
12
EW
FU
Up to 
28 
days 
post 
last 
dose
up to
-28 days
Week 
0 /
D1
Week 
2/ 
D14
Week 
4/ 
D28
Week 
8/ 
D56
Week 
12/
D84
Week 
16 / 
D112
Week 
20 / 
D140 
Week 
24 
/D168
Week 
32 
/D224
Week 
40 / 
D280
Week 
52 / 
D364
Assessment 
window
+3d ±3d ±3d ±3d ±3d ±3d ±3d ±3d
±6d ±6d ±6d
±6d
HIV, 
Hepatitis B 
and C 
screeninge
X
AE review
X
X
 
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SAE review
X
X
Section 5.1
Overall Design
Original text:
A study schematic is shown in Figure 1. This is a parallel group study.  Following 
screening and assessment of rescue medication use via a daily diary over study days -7 to 
1, participants will be randomized (1:1) to receive either danirixin 35mg tablets or 
placebo.  Study treatment will be administered twice daily for 52 weeks [Figure 1].  
There will be no pre-specified interim analysis for this study.  An interim analysis may be 
performed if it is determined that the enrolment is slow enough to allow it to be 
informative. There will be no IDMC for this study. An internal safety review team will 
meet approximately every 3 months (or as needed based on emerging data) to review 
available safety information. 
Figure 1
Study Schematic
Amended text:
A study schematic is shown in Figure 1. This is a parallel group study.  Following 
screening and assessment of rescue medication use via a daily diary over study days -28
to 1, participants will be randomized (1:1) to receive either danirixin 35mg tablets or 
placebo.  Study treatment will be administered twice daily for 52 weeks [Figure 1].  
There will be no pre-specified interim analysis for this study.  An interim analysis may be 
performed if it is determined that the enrolment is slow enough to allow it to be 
informative. There will be no IDMC for this study. An internal safety review team will 
 
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meet approximately every 3 months (or as needed based on emerging data) to review 
available safety information. 
Figure 1
Study Schematic
Section 6.1
Inclusion Criteria
Original text:
2
Male or female
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.
Female participants: 
A female participant is eligible to participate if she is not pregnant (see Section 12.5; 
Appendix 5), not breastfeeding, and at least one of the following conditions applies:
i.
Not a woman of childbearing potential (WOCBP) as defined in Section 12.5
(Appendix 5)
OR
 
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ii. A WOCBP who agrees to follow the contraceptive guidance in Section 12.5
(Appendix 5) during the treatment period and for at least 60 hours after the 
last dose of study treatment.
Revised text:
3
Male or female
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.
Female participants: 
A female participant is eligible to participate if she is not a woman of childbearing 
potential (WOCBP) as defined in Section 12.5 (Appendix 5)
Section 12.2 Appendix 2: 
Original text:
Table 7
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 
Calcium
Alkaline 
 
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Laboratory 
Assessments
Parameters
required for 
screening)
phosphatase
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only)

Serum 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
 
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Amended text:
Table 8
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

pH, glucose, protein, blood, ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only)

HIV antibody, hepatitis B surface antigen (HBsAg), and hepatitis C virus 
antibody2

All study-required laboratory assessments will be performed by a central 
laboratory
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 
 
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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.
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
Section 12.5 Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information
Original text:
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 9
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.)
 
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Amended text:
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 and confirmatory 
testing with additional FSH and estradiol measurements is required.

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 

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.
 
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Table 10
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.)
 
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Amendment 2
Original text:
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
Standard safety monitoring will be 
employed.
The potential risk of testicular injury has 
been conveyed in the informed consent.
PK modelling predicts that in a participant 
receiving 35 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
No adverse events related to testicular 
effects have been observed in clinical 
studies to date.
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 
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
in nonclinical studies with danirixin.  In 
healthy volunteer studies and a phase 2a 
study in patients with Influenza (GSK Study 
201682, GlaxoSmithKline Document No.
2014N205875_00), decreased neutrophil 
counts have been observed in participants
receiving either placebo or danirixin; no 
instances of danirixin-related neutropenia 
have been reported in clinical studies to 
date. In healthy participants, 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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Amended text:
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 
Standard safety monitoring will be 
employed.
The potential risk of testicular injury has 
been conveyed in the informed consent.
PK modelling predicts that in a participant 
receiving 35 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
studies to date.
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 
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
study in patients with Influenza (GSK Study 
201682, GlaxoSmithKline Document No.
2014N205875_00), decreased neutrophil 
counts have been observed in participants
receiving either placebo or danirixin; no 
instances of danirixin-related neutropenia 
have been reported in clinical studies to 
date. In healthy participants, 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.
Study Procedures
None
Other 
Not applicable
 
 
 
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Section 6.1
Inclusion Criteria
Original text:
Sex
4.
Male or female
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.
Female participants: 
A female participant is eligible to participate if she is not a woman of childbearing 
potential (WOCBP) as defined in Section 12.5 (Appendix 5)
Revised text:
5.
Male or female
Female participants: 
A female participant is eligible to participate if she is not a woman of childbearing 
potential (WOCBP) as defined in Section 12.5 (Appendix 5)
7.1.1 Medical Devices
Original text:
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).
Additional descriptive information and instructions for the eMDI 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).
Revised text:
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 
 
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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).
Mobile spirometers (MicroDiary, manusfactured by and purchased from CareFusion) are 
also being provided by GSK for this study. These devices allow participants to conduct
spirometry assessments at home. The MicroDiary has US FDA 510(k) clearance to 
market (Class II medical device) and European Union CE marking (Class I medical 
device).
Additional descriptive information and instructions for the eMDI monitoring devices and 
mobile spirometers 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).
9.2.8 Medical Device Incidents (Including Malfunctions)
Original text:
Medical devices are being provided for use in this study for the purposes of monitoring 
inhaled rescue medication use. 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.
Revised text:
Medical devices are being provided for use in this study for the purposes of monitoring 
inhaled rescue medication use and measuring spirometry at home. 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.
12.5
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information
Original text:
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 
 
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
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 

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.
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.)
 
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Revised text:
Text deleted.
12.5
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information
Original text:
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. 
Revised text:
Collection of Pregnancy Information
Male participants with partners who become pregnant

Investigator will not routinely attempt to collect pregnancy information on any 
male participant’s female partner(s) who becomes pregnant while the male 
participant is participating in this study; however, voluntary reports of such 
incidents will be captured through the GSK standard reporting mechanism. This 
applies only to male participants who receive double-blind study treatment.

If pregnancy information for a male participant’s female partner(s) is voluntarily 
reported, 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
 
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
Generally, follow-up will be no longer than 6 to 8 weeks following the 
estimateddelivery date. Any termination of the pregnancy will be reported 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure
 
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TITLE PAGE
Protocol Title: A randomized, double-blind, Sponsor open, placebo-controlled, 52 week 
study evaluation the effect of danirixin (GSK1325756) on lung function and health 
related quality of life in participants with mild to moderate Chronic Obstructive 
Pulmonary Disease (COPD).
Protocol Number: 205864 Amendment 1
Short Title: Danirixin Pilot Study for Disease Progression
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
Approval Date: 17-MAY-2017
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 1
17-May-2017
Original Protocol
21-Mar-2017
Amendment 1 17-May-2017
Overall Rationale for the Amendment: This amendment excludes the enrolment of 
women of childbearing potential and clarifies the testing required for determination of 
post menopausal status in specific situations.
Section # 
and Name
Description of Change
Brief Rationale
Table 1 –
Schedule of 
Activities

Remove pregnancy testing

Added missing check 
marks

Updated screening period

Not required as no longer enrolling 
WOCBP

Error in original protocol

Required to allow for screening lab 
tests
Section 6.1
Inclusion 
Criteria
Update to only allow females to 
participate if they are not women of 
childbearing potential (WOCBP)
To remove additional burden on female 
subjects of childbearing potential requiring 
additional visits for pregnancy testing only.  
Section 12.2 
– Appendix 2
Clinical 
Laboratory 
Tests
Update Table 6 – Protocol-
Required Safety Laboratory 
Assessments to remove pregnancy 
testing
Removed pregnancy testing based on the 
exclusion of WOCBP
Section 12.5 
– Appendix 5
Contraceptive 
Guidance and 
Collection of 
Pregnancy 
Information

Adding clarification on 
determination of post 
menopausal state in the 
absence of 12 months of 
amenorrhea

Updated wording to be in 
line with exclusion of 
WOCBP

Current wording in template is not 
clear on testing required

Clarification of wording
 
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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS...............................................................................................................7
2.
SCHEDULE OF ACTIVITIES (SOA).........................................................................9
3.
INTRODUCTION....................................................................................................12
3.1.
Study Rationale ..........................................................................................12
3.2.
Background ................................................................................................13
3.3.
Benefit/Risk Assessment ............................................................................14
3.3.1.
Risk Assessment .........................................................................15
3.3.2.
Benefit Assessment.....................................................................19
3.3.3.
Overall Benefit:Risk Conclusion...................................................19
4.
OBJECTIVES AND ENDPOINTS...........................................................................20
5.
STUDY DESIGN ....................................................................................................21
5.1.
Overall Design ............................................................................................21
5.2.
Number of Participants ...............................................................................21
5.3.
Participant and Study Completion...............................................................22
5.4.
Scientific Rationale for Study Design ..........................................................22
5.5.
Dose Justification........................................................................................22
6.
STUDY POPULATION...........................................................................................23
6.1.
Inclusion Criteria.........................................................................................23
6.2.
Exclusion Criteria........................................................................................24
6.3.
Lifestyle Restrictions...................................................................................26
6.3.1.
Meals and Dietary Restrictions ....................................................26
6.3.2.
Activity .........................................................................................27
6.4.
Screen Failures...........................................................................................27
7.
TREATMENTS.......................................................................................................27
7.1.
Treatments Administered............................................................................28
7.1.1.
Medical Devices...........................................................................28
7.2.
Dose Modification .......................................................................................29
7.3.
Method of Treatment Assignment ...............................................................29
7.4.
Blinding.......................................................................................................29
7.5.
Preparation/Handling/Storage/Accountability..............................................29
7.6.
Treatment Compliance................................................................................30
7.7.
Concomitant Therapy..................................................................................30
7.8.
Treatment after the End of the Study ..........................................................32
8.
DISCONTINUATION CRITERIA.............................................................................32
8.1.
Discontinuation of Study Treatment ............................................................32
8.1.1.
Liver Chemistry Stopping Criteria ................................................32
8.1.2.
QTc Stopping Criteria ..................................................................33
8.1.3.
Neutrophil Stopping Criteria.........................................................34
8.1.4.
Temporary Discontinuation ..........................................................34
8.1.5.
Study Treatment Restart..............................................................34
 
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8.2.
Withdrawal from the Study..........................................................................34
8.3.
Lost to Follow Up........................................................................................35
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................36
9.1.
Efficacy Assessments.................................................................................36
9.1.1.
FEV1 ............................................................................................36
9.1.1.1.
Clinic Spirometry ........................................................36
9.1.1.2.
Mobile Spirometry ......................................................36
9.1.2.
SGRQ-C ......................................................................................36
9.1.3.
CAT .............................................................................................37
9.1.4.
COPD Exacerbations...................................................................37
9.1.5.
Patient Global Rating of Severity and Global Rating of 
Change in Disease Severity.........................................................37
9.2.
Adverse Events...........................................................................................38
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................38
9.2.2.
Method of Detecting AEs and SAEs.............................................38
9.2.3.
Follow-up of AEs and SAEs.........................................................38
9.2.4.
Regulatory Reporting Requirements for SAEs .............................39
9.2.5.
Cardiovascular and Death Events................................................39
9.2.6.
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as SAEs...............................................39
9.2.7.
Pregnancy ...................................................................................40
9.2.8.
Medical Device Incidents (Including Malfunctions).......................40
9.2.8.1.
Time Period for Detecting Medical Device 
Incidents.....................................................................40
9.2.8.2.
Follow-up of Medical Device Incidents........................41
9.2.8.3.
Prompt Reporting of Medical Device Incidents 
to Sponsor..................................................................41
9.2.8.4.
Regulatory Reporting Requirements for 
Medical Device Incidents............................................41
9.3.
Treatment of Overdose...............................................................................42
9.4.
Safety Assessments ...................................................................................42
9.4.1.
Physical Examinations.................................................................42
9.4.2.
Vital Signs....................................................................................42
9.4.3.
Electrocardiograms......................................................................43
9.4.4.
Clinical Safety Laboratory Assessments ......................................43
9.4.5.
Pneumonia ..................................................................................43
9.5.
Pharmacokinetics .......................................................................................44
9.6.
Pharmacodynamics ....................................................................................44
9.7.
Genetics .....................................................................................................44
9.8.
Biomarkers .................................................................................................44
9.9.
Health Economics OR Medical Resource Utilization and Health 
Economics..................................................................................................45
10. STATISTICAL CONSIDERATIONS........................................................................45
10.1.
Sample Size Determination ........................................................................45
10.2.
Randomization............................................................................................48
10.3.
Populations for Analyses ............................................................................48
10.4.
Statistical Analyses.....................................................................................48
10.4.1.
Efficacy Analyses.........................................................................48
10.4.2.
Safety Analyses...........................................................................51
 
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10.4.3.
Other Analyses ............................................................................51
10.4.4.
Interim Analyses ..........................................................................51
11. REFERENCES.......................................................................................................52
12. APPENDICES........................................................................................................55
12.1.
Appendix 1: Abbreviations and Trademarks................................................55
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................59
12.3.
Appendix 3: Study Governance Considerations..........................................61
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................65
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................71
12.6.
Appendix 6: Genetics..................................................................................75
12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................76
12.8.
Appendix 8: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................79
12.9.
Appendix 9: Neutrophil Safety and Study Treatment Restart ......................81
12.10. Appendix 10: Country-specific requirements...............................................83
12.11. Appendix 11 Protocol Amendment History..................................................84
 
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1.
SYNOPSIS
Protocol Title: A randomized, double-blind, Sponsor open, placebo-controlled, 52 week 
study evaluating the effect of danirixin (GSK1325756) on lung function and health 
related quality of life in participants with mild to moderate Chronic Obstructive 
Pulmonary Disease (COPD).
Short Title: Danirixin Pilot Study for Disease Progression in COPD
Rationale:  This is a pilot study to investigate the effect of danirixin hydrobromide (HBr) 
35mg tablets on lung function and health related quality of life (HRQoL)  in participants 
with mild to moderate airflow obstruction and a demonstrated history of decline in FEV1. 
This study aims to assess whether danirixin has the potential to impact disease 
progression in participants with COPD and with a demonstrated history of disease 
progression measured by lung function. 
Objectives and Endpoints:
Objective
Endpoint
Primary

To assess whether danirixin HBr 35mg 
tablets impact disease progression
compared with placebo

Rate of decline in FEV1

Change from baseline in St. George’s 
Respiratory Questionnaire (SGRQ)  
total score (derived from SGRQ-C)
Secondary

To further characterize the safety of 
danirixin HBr 35mg tablets compared 
with placebo in participants with mild 
to moderate airflow limitation

Adverse events

Vital Signs

ECG

Clinical Laboratory Assessments 
(hematology, clinical chemistry, 
urinalysis)

To further characterize the clinical 
activity of danirixin HBr 35mg tablets 
compared with  placebo

Time to first HCRU COPD 
exacerbation

Change from baseline in FEV1

SGRQ responder analysis

SGRQ domains

COPD Assessment Test (CAT)

Rescue medication use 
Overall Design:
This is a Phase 2 study to investigate the potential impact of danirixin HBr 35mg tablets 
compared with placebo on disease progression in participants with mild to moderate 
 
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airflow obstruction.  The study will also assess the enrichment strategy of enrolling 
participants identified from the COPDGene study. These participants have been 
identified by COPDGene investigators based on data collected over the initial 5 year 
period.  The participants were identified based on a Random Forest analysis and a 
demonstrated decline of at least 20mL/yr over the initial 5 year period. 
Number of Participants:
Approximately 130 participants will be screened to enrol 100 participants in this study.  It 
is anticipated that approximately 85 participants will complete the 52 weeks of treatment 
(assuming a 15% drop out rate).
Treatment Groups and Duration:
Participants will receive either placebo or danirixin 35mg tablets (as hydrobromide 
hemihydrate salt) twice daily for 52 weeks (12months).
 
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2.
SCHEDULE OF ACTIVITIES (SOA)
Table 1
Schedule of activities
Screening/
Visit1a
Visit 2
Visit 3  
Visit 
4
Visit 5
Visit 
6
Visit 
7
Visit 8
Visit 9
Visit 
10
Visit 11
Visit 12
EW
FU
Up to 28 
days 
post last 
dose
up to
-28 days
Week 
0 /
D1
Week 2/ 
D14
Week 4/ 
D28
Week 8/ 
D56
Week 12/ 
D84
Week 16 
/ D112
Week 20 
/ D140 
Week 
24 
/D168
Week 32 
/D224
Week 40 
/ D280
Week 52 
/ D364
Assessment window
+3d
±3d
±3d
±3d
±3d
±3d
±3d
±3d
±6d
±6d
±6d
±6d
Eligibility
Informed Consent
X
Genetics Informed Consentb
X
Demography
X
Inclusion and Exclusion Criteria
X
Smoking Statusc
X
Smoking Historyc
X
X
Medical Historyd
X
Full physical
X
Chest X-ray (historical within 1 year 
acceptable)
X
HIV, Hepatitis B and C screeninge
X
Additional Eligibility and In Study Assessments
Verify Eligibilityf
X
X
Brief physical
X
X
X
X
X
Laboratory assessments (clinical chemistry, 
including liver chemistries), hematology, 
urinalysis
X
X
X
X
X
X
Additional Liver chemistries only
X
X
X
X
X
X
X
12 lead ECG
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
 
 
 
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Screening/
Visit1a
Visit 2
Visit 3  
Visit 
4
Visit 5
Visit 
6
Visit 
7
Visit 8
Visit 9
Visit 
10
Visit 11
Visit 12
EW
FU
Up to 28 
days 
post last 
dose
up to
-28 days
Week 
0 /
D1
Week 2/ 
D14
Week 4/ 
D28
Week 8/ 
D56
Week 12/ 
D84
Week 16 
/ D112
Week 20 
/ D140 
Week 
24 
/D168
Week 32 
/D224
Week 40 
/ D280
Week 52 
/ D364
Assessment window
+3d
±3d
±3d
±3d
±3d
±3d
±3d
±3d
±6d
±6d
±6d
±6d
Office spirometry (centralized)
X
X
X
X
X
X
X
X
X
X
X
X
X
Home spirometry  - (weekly)
X
X
X
Randomization
X
Dispense study medication
X
X
X
X
X
X
X
X
X
Dispense log pad and provide training
X
Dispense MDI sensors and provide training
X
Study Treatment
Study Treatment Compliance (ediary)
Collect IP 
Collect MDI sensors
X
X
Collect log pad
X
X
AE review
X
X
SAE review
X
X
Concomitant medication review
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Outcomes Assessments
COPD exacerbation review
X
X
X
X
X
X
X
X
X
X
X
X
Rescue medication Use
SGRQ-C
X
X
X
X
X
X
COPD Assessment Test (CAT)
X
X
X
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
X
X
X
 
 
 
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Screening/
Visit1a
Visit 2
Visit 3  
Visit 
4
Visit 5
Visit 
6
Visit 
7
Visit 8
Visit 9
Visit 
10
Visit 11
Visit 12
EW
FU
Up to 28 
days 
post last 
dose
up to
-28 days
Week 
0 /
D1
Week 2/ 
D14
Week 4/ 
D28
Week 8/ 
D56
Week 12/ 
D84
Week 16 
/ D112
Week 20 
/ D140 
Week 
24 
/D168
Week 32 
/D224
Week 40 
/ D280
Week 52 
/ D364
Assessment window
+3d
±3d
±3d
±3d
±3d
±3d
±3d
±3d
±6d
±6d
±6d
±6d
Genetic, Pharmacokinetic and Biomarker Blood Collections
Blood sample for Genetics
X
Blood sample for CRP
X
X
X
X
Blood sample for exploratory biomarkers
X
X
X
X
a
Informed consent may be signed prior to screening visit in the case that any changes in medications are necessary
b
Agreeing to genetic sample consent is not required for study participation
c
Smoking status/history assessed at screening; smoking status re-checked at Visit 2
d
Includes substance usage, past and present medical conditions and family history of premature CV disease
e
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.
f
Participant’s clinical status should be reviewed
The timing and number of planned study assessments, including safety and biomarker assessments may be altered during the course of the study based on newly available data to 
ensure appropriate data collection.  Any changes in the timing or addition of time points for any planned study assess 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 Number 
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 
[GlaxoSmithKline Document Number 2013N180289_03 Study ID 200163].  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.  Analyses of 
clinical endpoints from study 200163 demonstrated that danirixin, compared to placebo, 
reduced respiratory symptoms as measured with E-RS:COPD [Miller, 2016].
3.1.
Study Rationale
This protocol describes a pilot study to investigate the effect of danirixin HBr 35mg 
tablets on lung function and health related quality of life (HRQoL) in participants with 
 
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mild to moderate airflow obstruction identified from the COPDGene cohort. 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.
Specifically, this study aims to assess whether or not danirixin has the potential to impact 
disease progression in participants with a COPD progression score indicating they are 
likely to decline based on 5 year data from COPDGene and support the conduct of a 
larger Phase III study for disease progression. In addition to lung function and HRQoL, 
this study will assess moderate/severe COPD exacerbations, health status (CAT), and 
rescue medication use.
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 and, 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 
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.  
 
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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 Number 
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.
PK modelling predicts that in a participant 
receiving 35 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 participants
receiving either placebo or danirixin; no 
instances of danirixin-related neutropenia 
have been reported in clinical studies to 
date. In healthy participants, 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 
or 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.
 
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4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To assess whether danirixin HBr 
35mg tablets impacts disease 
progression compared with placebo

Rate of decline in FEV1

Change from baseline in St. George’s 
Respiratory Questionnaire (SGRQ) 
total score (derived from SGRQ-C)

To further characterize the safety of 
danirixin HBr 35mg tablets
compared with placebo in 
participants with mild to moderate 
airflow limitation

Adverse events (AE), clinical 
laboratory values, vital signs, 
electrocardiogram (ECG), and/or 
other safety biomarkers
Secondary

To further characterize the clinical 
activity of danirixin HBr 35mg tablets
compared to placebo

Time to first HCRU COPD 
exacerbation

Change from baseline in FEV1

SGRQ responder analysis

SGRQ domains

COPD Assessment Test (CAT)

Rescue medication use
Exploratory

To characterize the effect of 
danirixin on lung matrix 
destruction/remodelling and 
inflammation

Further characterize efficacy of 
danirixin
Blood/serum/plasma  biomarkers that 
are indicative of extracellular matrix 
turnover/remodelling (e.g. elastin and 
collagen neo-epitopes) and 
inflammation (e.g. CRP)

Global assessment of COPD severity 
 
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5.
STUDY DESIGN
5.1.
Overall Design
A study schematic is shown in Figure 1. This is a parallel group study.  Following 
screening and assessment of rescue medication use via a daily diary over study days -28
to 1, participants will be randomized (1:1) to receive either danirixin 35mg tablets or 
placebo.  Study treatment will be administered twice daily for 52 weeks [Figure 1].  
There will be no pre-specified interim analysis for this study.  An interim analysis may be 
performed if it is determined that the enrolment is slow enough to allow it to be 
informative. There will be no IDMC for this study. An internal safety review team will 
meet approximately every 3 months (or as needed based on emerging data) to review 
available safety information. 
Figure 1
Study Schematic
5.2.
Number of Participants
Approximately 130 participants will be screened to achieve 100 randomized in this study.  
It is anticipated that approximately 85 participants will complete the 12 months of 
treatment (assuming a 15% drop out rate).
For the analysis of study assessments, several analysis populations are defined in Section 
10.3.  
 
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5.3.
Participant and Study Completion
A participant is considered to have completed the study if he/she has completed all
planned study visits 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.  With the 
use of an enriched population, it is anticipated that one year of treatment will be sufficient 
to detect a trend in altering disease progression.   Danirixin has already been clinically 
investigated over one year treatment duration (GlaxoSmithKline Document Number 
2013N180289_03 Study ID 200163).  
The data from this study will provide useful information in determining whether or not to 
progress to a Phase III study to explore an indication for slowing disease progression. 
5.5.
Dose Justification
One dose of danirixin is proposed for this study, 35mg tablets BID.  This dose was 
selected based on integrating information on:

Dose-exposure-biomarker response using inhibition of ex vivo CXCL1-induced 
CD11b expression on peripheral blood neutrophils over the dose range of 0-400mg 
(free base tablet) in healthy volunteers (GSK Study No. CX3 112483).

Evidence of reduced respiratory symptoms and improvement in health status in mild 
to moderate COPD participants from interim data in the Phase IIa study (GSK Study 
No. 200163).

Relative bioavailability study comparing danirixin free base vs HBr (GSK Study No. 
201037).
In the previous 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 (GlaxoSmithKline Document Number 
2015N248339_00, Study ID 201037). Thus the danirixin (hydrobromide tablet) 35mg 
BID dose for investigation in this study is expected to provide steady-state systemic 
exposure approximately equivalent to the 75mg BID (free base tablet) used in Study 
200163. 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 Number. 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.
6.
STUDY POPULATION
This study will identify specific patients most likely to decline from the well established 
COPDGene cohort [NCT00608764].  This study will be an ancillary study within 
COPDGene investigating the enrichment strategy for assessing disease progression. 
These potential participants have been identified by COPDGene investigators based on 
data collected over the initial 5 year period.  The participants were identified based on a 
Random Forest analysis and a demonstrated decline of at least 20mL/yr over the initial 5 
year period. Once participants are identified from the COPDGene dataset, the following 
criteria will be verified at initial study visit following signing of consent.
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1.
Participant must be 40 to 76 years of age inclusive, at the time of signing the 
informed consent.
Type of Participant and Disease Characteristics
2.
At the screening visit, the subject must have an FEV1 >40% of the predicted normal.
3.
Participants with a prior history of asthma are eligible if they have a current 
diagnosis of COPD
Dose 
(mg)
Predicted# steady-state median (5th, 95th
percentile)
Cavg 
multiple of 
IC50*
Cmin 
multiple of 
IC50*
AUC(0-24) 
steady-state
(ug.h/mL)
Cavg
(ng/mL)
Cmin
(ng/mL)
35
9.59
(4.70, 19.3)
399
(196, 806)
192
(47.6, 630)
5.1
2.4
 
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Weight
4.
Body weight 45 kg
Sex
5.
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 a woman of childbearing 
potential (WOCBP) as defined in Section 12.5 (Appendix 5)
Informed Consent
6. Capable of giving signed informed consent as described in Section 12.3 (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 disease (other than COPD), e.g. 
sarcoidosis, tuberculosis, pulmonary fibrosis, severe bronchiectasis or lung cancer
2. COPD due to alpha-1-antitrypsin deficiency 
3. Pulse oximetry < 88% at rest at screening.  Participants should be tested while 
breathing room air.  However, participants living at high altitudes (above 5000 ft or 
1500 m above sea level) who are receiving supplemental oxygen can be included 
provided they are receiving the equivalent of < 4L/min and screening oximetry is 
measured while on their usual settings.
4. Less than 14 days have elapsed from completion of a course of antibiotics or oral 
corticosteroids for a recent COPD exacerbation
5. Participants with a peripheral blood neutrophil count < 1 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 with lateral) or CT scan reveals evidence of a clinically 
significant abnormality not believed to be due to the presence of COPD (historic data 
up to 1 year may be used).  
 
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8. History or current evidence of clinically significant renal disease, diabetes 
mellitus/metabolic syndrome, hypertension, or any other clinically significant 
cardiovascular, neurological, immunological, endocrine, or haematological 
abnormality 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 participants 
at risk through study participation, or which would affect the safety analysis or other 
analysis if the disease/condition exacerbated during the study.
9. History of sensitivity to any of the study medications, or components thereof or a 
history of drug or other allergy that, in the opinion of the investigator of GSK medical 
monitor, contraindicates their participation.
10. Current of chronic history of liver disease, or know hepatic or biliary abnormalities 
(with the exception of Gilbert’s syndrome or asymptomatic gallstones).
11. Abnormal and clinically significant 12-lead ECG finding.  The investigator will 
determine the clinical significance of each abnormal ECG finding in relation to the 
subject’s medical history and exclude participants who would be at undue risk by 
participating in the trial.  An abnormal and clinically significant finding that would 
preclude a subject from entering the trial is defined as a 12-lead tracing that is 
interpreted as, but not limited to, any of the following:
‒
AF with rapid ventricular rate > 120 bpm;
‒
sustained or non-sustained VT
‒
second degree heat block Mobitz type II and third degree heart block (unless 
pacemaker or defibrillator has been implanted)
‒
QTcF 500 msec in patients with QRS < 120 msec and QTcF 530 msec in 
patients with QRS 120 msec
12. Previous lung surgery (e.g. lobectomy, pneumonectomy) or lung volume reduction 
procedure.
Prior/Concomitant Therapy
13. 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.
14. 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.
15. 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
16. 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).
17. Participation in a previous clinical trial with danirixin within 1 year prior to the first 
dosing day in the current study
18. Exposure to more than four investigational products within 1 year prior to the first 
dosing day in the current study.
Diagnostic assessments
19. 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%).
20. A positive test for HIV antibody.
21. A positive pre-study hepatitis B surface antigen or positive hepatitis C antibody result 
within 3 months prior to screening.
Other Exclusions
22. 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.
23. A history of allergy or hypersensitivity to any of the ingredients in the study 
treatment.
24. A known or suspected history of alcohol or drug abuse within the 2 years prior to 
screening.
25. Inability to read: in the opinion of the Investigator, any participant who is unable to 
read and/or would not be able to complete study related materials.
26. 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 not be rescreened unless discussed with the medical monitor. 
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
Study Treatment Name:
Danirixin 
(GSK1325756H, the 
hydrobromide 
hemihydrate salt)
Placebo
Dosage formulation:
White Film coated 
tablets (oval shaped). 
Refer to Investigator’s 
Brochure for 
presentation and 
excipients
White Film coated 
tablets (oval shaped). 
Refer to 
Investigator’s 
Brochure for 
presentation and 
excipients
Unit dose strength(s)/Dosage level(s):
35mg tablets (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).
Additional descriptive information and instructions for the eMDI monitoring devices are 
provided in the SRM.
 
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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 study.  Study participants, all study site staff, and all members 
of the GSK study team will be blinded to individual participant treatment assignment.  
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 
 
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(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.  
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
 
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
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)
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) bronchodilators, (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 
 
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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: Liver Safety: Required Actions and Follow-up Assessments). 
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 (Section 12.7) 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. 
 
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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.
FEV1
9.1.1.1.
Clinic Spirometry
Spirometry using FEV1 and FVC measurements (FEV%, and FVC% and FEV1/FVC will 
be calculated) will be performed in triplicate at time points listed in the SoA (Table 1).  
Spirometry assessments should be performed in accordance with ATS/ERS guidelines as 
outlined in the SRM.
9.1.1.2.
Mobile Spirometry
Spirometry will also be performed weekly by the participants using a mobile spirometer 
at home.  Details will be outlined in the SRM.
9.1.2.
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 
 
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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 SGRQ scores equivalent to the original SGRQ instrument [Jones, 1992].
9.1.3.
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.
9.1.4.
COPD Exacerbations
An exacerbation of COPD is defined by a worsening of symptoms requiring additional 
treatment or hospitalization. 
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 based on the Investigator’s judgement.
9.1.5.
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 
final study visit or IP Discontinuation Visit.  This single global question will ask 
participants 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 every visit following randomization (or Early Withdrawal (EW) Visit). Response 
 
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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.
9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4 (Section 12.4).
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 the time the informed consent is signed by the 
participant until the follow up visit at the time points specified in the SoA
(Table 1).

All AEs will be collected from the start of study treatment (randomization visit) 
until the follow-up visit at the time points specified in the SoA (Table 1).

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 must be reported immediately and not more than 24 hrs to the sponsor, 
as indicated in Appendix 4 (Section 12.4). 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 (Section 12.4).
9.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
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 
 
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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 Section 12.4 (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. 
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 
 
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becomes aware of the event.  These DREs will be monitored by the Safety Review Team 
(SRT) on a routine basis as described in Section 12.3 (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 Section 12.5
(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. 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 Section 12.8 (Appendix 8).
NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Section 9.2 and Section 12.4 (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 
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
The method of documenting Medical Device Incidents is provided in Section 
12.8 (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 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.
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.
 
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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.
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, 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 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 measurements 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 10 minutes.
9.4.4.
Clinical Safety Laboratory Assessments
Refer to Section 12.2 (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 Section 12.2, 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.
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.)
 
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
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
Pharmacokinetic parameters are not evaluated in this study.
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 Section 12.6 (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), 
extracellular matrix turnover and remodelling to evaluate their association with the 
 
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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
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study.
10.
STATISTICAL CONSIDERATIONS
The objective of this study is to investigate the effect of danirixin HBr 35mg tablets on 
COPD disease progression. There are no formal hypothesis tests associated with this 
objective and no formal significance tests. The information acquired from this study will 
primarily be used to assess whether or not danirixin impacts disease progression and to
quantify the effect that danirixin has on disease progression, specifically change in lung 
function as measured by FEV1 decline and change in health-related quality of life as 
measured by SGRQ total score to further support disease understanding and future 
studies. 
10.1.
Sample Size Determination
Sample size is based primarily on feasibility for this study. Since there is much 
uncertainty around the magnitude of the difference in the decline in FEV1 and change in 
SGRQ along with the between-subject variability for the specific patient population, the 
proposed sample size is unavoidably imprecise. Sample size may be adjusted using the 
predictions of final study outcome based on simulations and possible interim analyses. It 
is anticipated that screening 130 participants will allow for approximately 100 
participants to enrol. 
In order to observe the effect of different sample sizes, various simulations were done to 
assess the impact of sample sizes of 50, 100, 150 and 200 with a 1:1 allocation to each 
treatment group [Table 3]. The assumed variability for rate of decline in FEV1 and 
change in SGRQ is 25 and 10, respectively.  The correlation between rate of decline in 
FEV1 and change in SGRQ is assumed to be -0.2. [Nagai, 2015] 
 
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Table 3
Assumptions used for the Simulations
Treatment Effect Assumptions
(δFEV1, δSGRQ)
Variability Assumptions
(σFEV1, σSGRQ)
Sample Size
Null
(0,0)
(25,10)
N={50,100,150,200}
Alternate 1 
(5,-1)
(25,10)
N={50,100,150,200}
Alternate 2
(5,0) 
(25,10)
N={50,100,150,200}
Alternate 3
(0,-1)
(25,10)
N={50,100,150,200}
Data from a bivariate normal distribution were simulated under the four different 
treatment effect assumptions for samples sizes of 50, 100, 150, and 200. The samples 
from the posterior probability distribution from the MCMC approximation were divided 
into four regions based on δFEV1 and δSGRQ treatment effect cut-off values; δFEV1≥0 and 
δSGRQ ≤0, δFEV1≥0 and δSGRQ>0, δFEV1<0 and δSGRQ≤0, and δFEV1<0 and δSGRQ>0. Based 
on a 70% threshold, the proportion of the 1000 simulations meeting the requirement 
P(δFEV1≥0 & δSGRQ≤0) ≥70% were considered a success based on the joint definition 
[Figure 2, Table 4]. If P(δFEV1≥0 & δSGRQ≤0) < 70%, success could further be defined 
based on each endpoint independently where P(δFEV1 ≥0) ≥ 80% or P(δSGRQ ≤0) ≥ 80%. 
Figure 2
Total Probability of Success
Table 4
Total Probability of Success (Figure 2)
N=50
N=100
N=150
N=200
(5,-1)
57.4
68.5
75.1
81.4
(5,0)
52.5
62.6
67.8
74.5
(0,-1)
42.6
46.2
48.9
53.0
(0,0)
34.9
33.9
33.3
31.5
 
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Figure 3
Half Width of the 95% Confidence Interval of δFEV1 Point Estimate
Figure 4
Half Width of the 95% Confidence Interval of δSGRQ Point Estimate
Based on the simulations, under the assumption of an expected treatment difference of 
(5,-1) which is the most probable scenario, the marginal increase for the total probability 
of success is greatest when increasing the sample size from 50 to 100 (Figure 2). The half 
widths of the 95% CI of the point estimate of the marginal treatment differences for FEV1
(Figure 3) and SGRQ (Figure 4) have the greatest reduction from a sample size of 50 to 
100. A sample size of 100 will allow for an adequate level of confidence in the study 
success while also considering the precision of the treatment effect differences. 
 
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10.2.
Randomization
Participants will be randomized equally (1:1) to the two treatment arms of placebo and 35 
mg danirixin HBr.  Randomization will be stratified by smoking status (current vs. 
former).
10.3.
Populations for Analyses
For purposes of analysis, the following populations are defined:
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.
Per-Protocol (PP) 
Population
This population will comprise of all patients in the ITT 
population who are not major protocol violators.
Safety
All randomized participants who take at least 1 dose of study 
treatment. Participants will be analyzed according to the 
treatment they actually received.
10.4.
Statistical Analyses
Treatment comparisons using all endpoints will be made using appropriate statistical 
techniques. Analysis methods for key endpoints are described below. Main analysis will 
use ITT unless noted. Further details on all analyses will be described in the reporting and 
analysis plan (RAP).
10.4.1.
Efficacy Analyses
The total probability of success will be defined as a combination of a joint and 
conditional statement. The joint probability of success will be defined as the probability 
of the difference in the rate of decline in FEV1 between danirixin and placebo is greater 
than or equal to 0 and the difference in the change in SGRQ total score from baseline 
between danirixin and placebo is less than or equal to 0 is greater than 70%. If the joint 
probability of success is less than 70%, success can further be defined based on each 
endpoint independently, where either the difference in the rate of decline in FEV1 is 
 
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greater than or equal to 0 is greater than 80% or the difference in the change in SGRQ 
total score is less than or equal to 0 is greater than 80%. 
 	
 = 	 ≥0 &  ≤0 ≥70%
+ 	 ≥0  ≥80%|	 ≥0 &  ≤0 < 70%
+	 ≤0  ≥80%|	 ≥0 &  ≤0 < 70%
Endpoint
Statistical Analysis Methods
Primary
Rate of decline in FEV1 and change from baseline in SGRQ total score
Exploratory
Will be described in detail in the RAP
 
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Lung Function Decline: Rate of Decline of FEV1 (mL/yr)
The rate of decline of FEV1 will be derived from a repeated measures random 
coefficients model. Post-baseline FEV1 will be modelled including terms for age, sex, 
smoking status, FEV1 at baseline, and BMI along with treatment group, time and 
treatment by time interaction as fixed effects.  Subject will be a random effect. Time will 
be defined as the number of days since start of treatment. Only FEV1 values measured 
after baseline will be used in the model. Based on the results of previous studies, the 
study team will determine the time point at which post-baseline spirometry assessments 
will be included in the model to account for the initial treatment response. The estimate 
of the rate of FEV1 decline will be the slope of the parameter estimate of the treatment by 
time interaction term in the model. Contrasts will be calculated for the difference in 
treatment by time interaction between danirixin and placebo treatment groups to estimate
the treatment difference. 
FEV1 = Treatment group + age + sex +smoking status+FEV1_BL+BMI+ time + 
treatment*time 
The rate of decline for each subject, the estimate of the slope parameter of the treatment 
by time interaction term, will be used as a co-primary endpoint for the joint analysis 
using both FEV1 and SGRQ. 
HRQoL: SGRQ
A co-primary endpoint of interest is change in SGRQ total score (derived from SGRQ-C) 
from baseline. Change in SGRQ total scores from baseline will be derived using a mixed 
model with repeated measures (MMRM) including fixed effects of treatment group, age, 
sex, smoking status, BMI, baseline SGRQ score, time as a categorical variable and a 
treatment by time interaction term. Subject will be a random effect. Estimated treatment 
differences at the end of one year will be obtained. The difference of the least square 
mean change from baseline at 12 months will be derived. The adjusted SGRQ total score 
change from baseline will used as the other co-primary endpoint for the joint analysis
using both FEV1 and SGRQ. 
Joint Analysis
The joint analysis will use the ITT population with all available FEV1 rate of decline and 
change in SGRQ data.
The rate of decline (the slope parameter from the random coefficients model) of FEV1, 
along with the change in SGRQ from the MMRM model will be extracted for each 
subject. These values will then be used to obtain MCMC approximations of the joint 
posterior distribution of the treatment differences between FEV1 decline and change in 
SGRQ between the danirixin and placebo groups. Based on the samples from the 
posterior distribution, the proportion of samples falling within certain treatment 
difference regions will be calculated and the probability of success will be derived. 
 
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10.4.2.
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.
10.4.3.
Other Analyses
Exploratory biomarker analyses will be described in the RAP.
10.4.4.
Interim Analyses
Conducting an interim analysis or futility assessment may not be practical due to an 
expected fast recruitment period. By the time enough data will accumulate for any 
meaningful interim analysis to support changes to the study design, recruitment of all 
study participants will have concluded. However, if recruitment takes a longer than 
anticipated, an interim analysis to reassess the variability assumptions, estimate the 
probability of success at the end of study, and confirm the directionality of the endpoints 
may be conducted.  
The RAP will describe the potential interim analyses in greater detail.
 
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11.
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Eur Respir J. 2004;23:932-946. 
Chapman RW, Philips JE, Hipkin RW, Curran AK, Lundell D, Fine JS. CXCR2 
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GlaxoSmithKline Document Number 2013N180289_03 Study ID 200163. A two part, 
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gastric acid secretion suppression on danirixin pharmacokinetics following administration 
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GlaxoSmithKline Document Number YM2010/00163/07. Danirixin Investigator's 
Brochure, Version 09. Report Date 14-Apr-2016. 
GOLD. From the Global Strateby for the Diagnosis, Management and Prevention of 
COPD, Global Initiative for Chronic Obstructive Lung Disease. Global Initiative for 
Chronic Obstructive Lung Disease, Available from: http://www.copdgold.org; 2016. 
Holz O, Khalilieh S, Ludwig-Sengpiel A, Watz H, Stryszak P, Soni P, et al. SCH527123, 
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Hurst JA, Vestbo J, Anzueto A, Locantore N, Mullerova, Tal-Singer R, et al. 
Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 
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Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Leidy NK. Development and first 
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Jones PW, Harding G, Wiklund I, Berry P, Tabberer M, Yu R et al. Tests of the 
responsiveness of the chronic obstructive pulmonary disease (COPD) assessment test 
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Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure of health 
status for chronic airflow limitation. The St. George's Respiratory Questionnaire. Am Rev 
Respir Dis. 1992;145:1321-1327. 
Lazaar AL, Sweeney LE, MacDonald AJ et al. SB-656933, a novel CXCR2 selective 
antagnoist, inhibits ex vivo neutrophil activation and ozone-induced airway inflammation 
in humans. Br J Clin Pharmacol. 2011;72:282-293.  
Lopez-Campos JL, Tan W, Soriano JB. Global burden of COPD. Respirology. 
2016;21:14-23.
Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 
to 2030. PLoS Med. 2006;3:e442. 
Meguro M, Barley EA, Spencer S et al. Development and validation of an improved 
COPD-specific version of the St. George Respiratory Questionnaire. Chest. 
2007;132:456-463. 
Miller B, Tal-Singer R, Lazaar A, Leidy N, Watz H, Collins D, et al. Assessing 
symptoms in COPD: use of the E-RS daily digital diary in early drug development. Eur 
Respir J. 2016;48(S60):PA1047. 
Nagai, K., Makita, H., Suzuki, M., Shimizu, K., Konno, S., Ito, Y. M., & Nishimura, M. 
Differential changes in quality of life components over 5 years in chronic obstructive 
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Nair P, Gaga M, Zervas E et al. Safety and efficacy of a CXCR2 antagnoist in patients 
with severe asthma and sputum neutrophils: a randomized, placebo-controlled clinical 
trial. Clin Exp Allergy. 2012;42:1097-2103. 
O'Byrne PM, Metev H, Puu M et al. Efficacy and safety of a CXCR2 antagonist, 
AZD5069, in patients with uncontrolled persistent asthma: a randomised, double-blind, 
placebo-controlled trial. Lancet Respir Med. 2016;4:797-806. 
Rennard SI, Dale DC, Donohue JF et al. CXCR2 antagonist MK-7123 - a phase 2 proof-
of-concept trial for chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 
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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 
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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. 
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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
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
eCRF
Electronic Case Report Form
ED50
Dose causing 50% of the maximum achievable 
response
 
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EMA
European Medicines Agency
Emax
Maximum response achievable
eMDI
Electronic metered dose inhaler
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
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
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
 
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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
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
 
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SAMA
Short-acting Muscarinic Receptor Agonist
SGRQ
St George’s Respiratory Questionnaire
SGRQ-C
SGRQ-C 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
 
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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

Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only)

HIV antibody, hepatitis B surface antigen (HBsAg), and hepatitis C virus 
antibody2

All study-required laboratory assessments will be performed by a central 
laboratory   
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.
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.
 
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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 
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 remaining 
mandatory samples for optional exploratory research in accordance with SOP-
GSKF-410. The investigator or 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 to participate 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.
 
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Committees Structure

A study charter will be created to describe important governance aspects while 
the study is being conducted.

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 participant’s last visit. 
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (eg, laboratory 
data). The investigator is responsible for verifying that data entries are accurate 
and correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that
supports the information entered in the CRF. 

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 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 study completion 
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. 
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.
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. 

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. Also, "lack of 
efficacy" or "failure of expected pharmacological action" constitutes an AE or SAE.
 
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Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
 
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normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the 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
 
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Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the 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 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study 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.
 
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
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 
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 (see next section).

The site will enter the SAE data into the electronic system as soon as it becomes 
available.
 
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
After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor/SAE coordinator by telephone.

Contacts for SAE reporting 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 and confirmatory testing with additional FSH and 
estradiol measurements is required.

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 
 
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
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 

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.
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.)
 
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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
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 will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected 

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 
 
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be forwarded to GSK Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date.  

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. 

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK
as described in Appendix 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 will 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 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 will be analyzed if it is hypothesized that this may help further 
understand the clinical data. 

The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to danirixin 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 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).
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
No country specific requirements
 
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12.11.
Appendix 11 Protocol Amendment History
Table 1
Schedule of activities
Original text:
Screening/
Visit1a
Visit 
2
Visit 
3  
Visit 
4
Visit 
5
Visit 
6  
Visit 
7
Visit 
8  
Visit 
9
Visit 
10  
Visit 
11
Visit 
12
EW
FU
Up to 
28 
days 
post 
last 
dose
up to
-7 days
Week 
0 /
D1
Week 
2/ 
D14
Week 
4/ 
D28
Week 
8/ 
D56
Week 
12/ 
D84
Week 
16 / 
D112
Week 
20 / 
D140 
Week 
24 
/D168
Week 
32 
/D224
Week 
40 / 
D280
Week 
52 / 
D364
Assessment 
window
+3d ±3d ±3d ±3d ±3d ±3d ±3d ±3d
±6d ±6d ±6d
±6d
Urine or 
serum 
Pregnancy 
testg
X
X
X
HIV, 
Hepatitis B 
and C 
screeninge
AE review
SAE review
Revised text:
Screening/
Visit1a
Visit 
2
Visit 
3  
Visit 
4
Visit 
5
Visit 
6  
Visit 
7
Visit 
8  
Visit 
9
Visit 
10  
Visit 
11
Visit 
12
EW
FU
Up to 
28 
days 
post 
last 
dose
up to
-28 days
Week 
0 /
D1
Week 
2/ 
D14
Week 
4/ 
D28
Week 
8/ 
D56
Week 
12/ 
D84
Week 
16 / 
D112
Week 
20 / 
D140 
Week 
24 
/D168
Week 
32 
/D224
Week 
40 / 
D280
Week 
52 / 
D364
Assessment 
window
+3d ±3d ±3d ±3d ±3d ±3d ±3d ±3d
±6d ±6d ±6d
±6d
HIV, 
Hepatitis B 
and C 
screeninge
X
AE review
X
X
SAE review
X
X
 
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Section 5.1
Overall Design
Original text:
A study schematic is shown in Figure 1. This is a parallel group study.  Following 
screening and assessment of rescue medication use via a daily diary over study days -7 to 
1, participants will be randomized (1:1) to receive either danirixin 35mg tablets or 
placebo.  Study treatment will be administered twice daily for 52 weeks [Figure 1].  
There will be no pre-specified interim analysis for this study.  An interim analysis may be 
performed if it is determined that the enrolment is slow enough to allow it to be 
informative. There will be no IDMC for this study. An internal safety review team will 
meet approximately every 3 months (or as needed based on emerging data) to review 
available safety information. 
Figure 1
Study Schematic
Amended text:
A study schematic is shown in Figure 1. This is a parallel group study.  Following 
screening and assessment of rescue medication use via a daily diary over study days -28
to 1, participants will be randomized (1:1) to receive either danirixin 35mg tablets or 
placebo.  Study treatment will be administered twice daily for 52 weeks [Figure 1].  
There will be no pre-specified interim analysis for this study.  An interim analysis may be 
performed if it is determined that the enrolment is slow enough to allow it to be 
informative. There will be no IDMC for this study. An internal 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
Section 6.1
Inclusion Criteria
Original text:
2. Male or female
g.
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.
h.
Female participants: 
A female participant is eligible to participate if she is not pregnant (see Section 12.5; 
Appendix 5), not breastfeeding, and at least one of the following conditions applies:
i.
Not a woman of childbearing potential (WOCBP) as defined in Section 12.5
(Appendix 5)
OR
ii. A WOCBP who agrees to follow the contraceptive guidance in Section 12.5
(Appendix 5) during the treatment period and for at least 60 hours after the 
last dose of study treatment.
 
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Revised text:
3. Male or female
i.
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.
j.
Female participants: 
A female participant is eligible to participate if she is not a woman of childbearing 
potential (WOCBP) as defined in Section 12.5 (Appendix 5)
 
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Section 12.2 Appendix 2: 
Original text:
Table 7
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

pH, glucose, protein, blood, ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only)

Serum 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   
 
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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
Amended text:
Table 8
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

pH, glucose, protein, blood, ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 

Follicle-stimulating hormone and estradiol (as needed in women of non-
 
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Laboratory 
Assessments
Parameters
Screening 
Tests
childbearing potential only)

HIV antibody, hepatitis B surface antigen (HBsAg), and hepatitis C virus 
antibody2

All study-required laboratory assessments will be performed by a central 
laboratory
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.
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
Section 12.5 Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information
Original text:
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, 
 
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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 

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 9
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 
 
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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.)
Amended text:
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 and confirmatory 
testing with additional FSH and estradiol measurements is required.

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.
 
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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 

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.
Table 10
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 
 
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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.)
 
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GlaxoSmithKline group of companies
205864
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TITLE PAGE
Protocol Title: A randomized, double-blind, Sponsor open, placebo-controlled, 52 week 
study evaluating the effect of danirixin (GSK1325756) on lung function and health 
related quality of life in participants with mild to moderate Chronic Obstructive 
Pulmonary Disease (COPD).
Protocol Number: 205864
Short Title: Danirixin Pilot Study for Disease Progression in 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
Approval Date: 21-MAR-2017
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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TABLE OF CONTENTS
PAGE
1.
SYNOPSIS...............................................................................................................6
2.
SCHEDULE OF ACTIVITIES (SOA).........................................................................8
3.
INTRODUCTION....................................................................................................11
3.1.
Study Rationale ..........................................................................................11
3.2.
Background ................................................................................................12
3.3.
Benefit/Risk Assessment ............................................................................13
3.3.1.
Risk Assessment .........................................................................14
3.3.2.
Benefit Assessment.....................................................................18
3.3.3.
Overall Benefit:Risk Conclusion...................................................18
4.
OBJECTIVES AND ENDPOINTS...........................................................................19
5.
STUDY DESIGN ....................................................................................................20
5.1.
Overall Design ............................................................................................20
5.2.
Number of Participants ...............................................................................20
5.3.
Participant and Study Completion...............................................................21
5.4.
Scientific Rationale for Study Design ..........................................................21
5.5.
Dose Justification........................................................................................21
6.
STUDY POPULATION...........................................................................................22
6.1.
Inclusion Criteria.........................................................................................22
6.2.
Exclusion Criteria........................................................................................23
6.3.
Lifestyle Restrictions...................................................................................26
6.3.1.
Meals and Dietary Restrictions ....................................................26
6.3.2.
Activity .........................................................................................26
6.4.
Screen Failures...........................................................................................26
7.
TREATMENTS.......................................................................................................26
7.1.
Treatments Administered............................................................................27
7.1.1.
Medical Devices...........................................................................27
7.2.
Dose Modification .......................................................................................28
7.3.
Method of Treatment Assignment ...............................................................28
7.4.
Blinding.......................................................................................................28
7.5.
Preparation/Handling/Storage/Accountability..............................................28
7.6.
Treatment Compliance................................................................................29
7.7.
Concomitant Therapy..................................................................................29
7.8.
Treatment after the End of the Study ..........................................................31
8.
DISCONTINUATION CRITERIA.............................................................................31
8.1.
Discontinuation of Study Treatment ............................................................31
8.1.1.
Liver Chemistry Stopping Criteria ................................................31
8.1.2.
QTc Stopping Criteria ..................................................................32
8.1.3.
Neutrophil Stopping Criteria.........................................................33
8.1.4.
Temporary Discontinuation ..........................................................33
8.1.5.
Study Treatment Restart..............................................................33
8.2.
Withdrawal from the Study..........................................................................33
8.3.
Lost to Follow Up........................................................................................34
 
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9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................35
9.1.
Efficacy Assessments.................................................................................35
9.1.1.
FEV1 ............................................................................................35
9.1.1.1.
Clinic Spirometry ........................................................35
9.1.1.2.
Mobile Spirometry ......................................................35
9.1.2.
SGRQ-C ......................................................................................35
9.1.3.
CAT .............................................................................................36
9.1.4.
COPD Exacerbations...................................................................36
9.1.5.
Patient Global Rating of Severity and Global Rating of 
Change in Disease Severity.........................................................36
9.2.
Adverse Events...........................................................................................37
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................37
9.2.2.
Method of Detecting AEs and SAEs.............................................37
9.2.3.
Follow-up of AEs and SAEs.........................................................37
9.2.4.
Regulatory Reporting Requirements for SAEs .............................38
9.2.5.
Cardiovascular and Death Events................................................38
9.2.6.
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as SAEs...............................................38
9.2.7.
Pregnancy ...................................................................................39
9.2.8.
Medical Device Incidents (Including Malfunctions).......................39
9.2.8.1.
Time Period for Detecting Medical Device 
Incidents.....................................................................39
9.2.8.2.
Follow-up of Medical Device Incidents........................40
9.2.8.3.
Prompt Reporting of Medical Device Incidents 
to Sponsor..................................................................40
9.2.8.4.
Regulatory Reporting Requirements for 
Medical Device Incidents............................................40
9.3.
Treatment of Overdose...............................................................................41
9.4.
Safety Assessments ...................................................................................41
9.4.1.
Physical Examinations.................................................................41
9.4.2.
Vital Signs....................................................................................41
9.4.3.
Electrocardiograms......................................................................42
9.4.4.
Clinical Safety Laboratory Assessments ......................................42
9.4.5.
Pneumonia ..................................................................................42
9.5.
Pharmacokinetics .......................................................................................43
9.6.
Pharmacodynamics ....................................................................................43
9.7.
Genetics .....................................................................................................43
9.8.
Biomarkers .................................................................................................43
9.9.
Health Economics OR Medical Resource Utilization and Health 
Economics..................................................................................................44
10. STATISTICAL CONSIDERATIONS........................................................................44
10.1.
Sample Size Determination ........................................................................44
10.2.
Randomization............................................................................................47
10.3.
Populations for Analyses ............................................................................47
10.4.
Statistical Analyses.....................................................................................47
10.4.1.
Efficacy Analyses.........................................................................47
10.4.2.
Safety Analyses...........................................................................50
10.4.3.
Other Analyses ............................................................................50
10.4.4.
Interim Analyses ..........................................................................50
 
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11. REFERENCES.......................................................................................................51
12. APPENDICES........................................................................................................54
12.1.
Appendix 1: Abbreviations and Trademarks................................................54
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................58
12.3.
Appendix 3: Study Governance Considerations..........................................60
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................64
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................70
12.6.
Appendix 6: Genetics..................................................................................74
12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................75
12.8.
Appendix 8: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................78
12.9.
Appendix 9: Neutrophil Safety and Study Treatment Restart ......................80
12.10. Appendix 10: Country-specific requirements...............................................82
 
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1.
SYNOPSIS
Protocol Title: A randomized, double-blind, Sponsor open, placebo-controlled, 52 week 
study evaluating the effect of danirixin (GSK1325756) on lung function and health 
related quality of life in participants with mild to moderate Chronic Obstructive 
Pulmonary Disease (COPD).
Short Title: Danirixin Pilot Study for Disease Progression in COPD
Rationale:  This is a pilot study to investigate the effect of danirixin hydrobromide (HBr)
35mg tablets on lung function and health related quality of life (HRQoL)  in participants
with mild to moderate airflow obstruction and a demonstrated history of decline in FEV1. 
This study aims to assess whether danirixin has the potential to impact disease 
progression in participants with COPD and with a demonstrated history of disease 
progression measured by lung function. 
Objectives and Endpoints:
Objective
Endpoint
Primary

To assess whether danirixin HBr 35mg 
tablets impact disease progression
compared with placebo

Rate of decline in FEV1

Change from baseline in St. George’s 
Respiratory Questionnaire (SGRQ) 
total score (derived from SGRQ-C)
Secondary

To further characterize the safety of 
danirixin HBr 35mg tablets compared 
with placebo in participants with mild 
to moderate airflow limitation

Adverse events

Vital Signs

ECG

Clinical Laboratory Assessments 
(hematology, clinical chemistry, 
urinalysis)

To further characterize the clinical 
activity of danirixin HBr 35mg tablets
compared with placebo

Time to first HCRU COPD 
exacerbation

Change from baseline in FEV1

SGRQ responder analysis

SGRQ domains

COPD Assessment Test (CAT)

Rescue medication use 
Overall Design:
This is a Phase 2 study to investigate the potential impact of danirixin HBr 35mg tablets
compared with placebo on disease progression in participants with mild to moderate 
 
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airflow obstruction.  The study will also assess the enrichment strategy of enrolling 
participants identified from the COPDGene study.  These participants have been 
identified by COPDGene investigators based on data collected over the initial 5 year 
period.  The participants were identified based on a Random Forest analysis and a 
demonstrated decline of at least 20mL/yr over the initial 5 year period. 
Number of Participants:
Approximately 130 participants will be screened to enrol 100 participants in this study.  It 
is anticipated that approximately 85 participants will complete the 52 weeks of treatment 
(assuming a 15% drop out rate).
Treatment Groups and Duration:
Participants will receive either placebo or danirixin 35mg tablets (as hydrobromide 
hemihydrate salt) twice daily for 52 weeks (12months).
 
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2.
SCHEDULE OF ACTIVITIES (SOA)
Table 1
Schedule of activities
Screening/
Visit1a
Visit 2
Visit 3  
Visit 
4
Visit 5
Visit 
6
Visit 
7
Visit 8
Visit 9
Visit 
10
Visit 11
Visit 12
EW
FU
Up to 28 
days 
post last 
dose
up to
-7 days
Week 
0 /
D1
Week 2/ 
D14
Week 4/ 
D28
Week 8/ 
D56
Week 12/ 
D84
Week 16 
/ D112
Week 20 
/ D140 
Week 
24 
/D168
Week 32 
/D224
Week 40 
/ D280
Week 52 
/ D364
Assessment window
+3d
±3d
±3d
±3d
±3d
±3d
±3d
±3d
±6d
±6d
±6d
±6d
Eligibility
Informed Consent
X
Genetics Informed Consentb
X
Demography
X
Inclusion and Exclusion Criteria
X
Smoking Statusc
X
Smoking Historyc
X
X
Medical Historyd
X
Full physical
X
Chest X-ray (historical within 1 year 
acceptable)
X
HIV, Hepatitis B and C screeninge
Additional Eligibility and In Study Assessments
Verify Eligibilityf
X
X
Brief physical
X
X
X
X
X
Urine or serum Pregnancy testg
X
X
X
Laboratory assessments (clinical chemistry, 
including liver chemistries), hematology, 
urinalysis
X
X
X
X
X
X
Additional Liver chemistries only
X
X
X
X
X
X
X
12 lead ECG
X
X
X
X
X
X
X
 
 
 
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Screening/
Visit1a
Visit 2
Visit 3  
Visit 
4
Visit 5
Visit 
6
Visit 
7
Visit 8
Visit 9
Visit 
10
Visit 11
Visit 12
EW
FU
Up to 28 
days 
post last 
dose
up to
-7 days
Week 
0 /
D1
Week 2/ 
D14
Week 4/ 
D28
Week 8/ 
D56
Week 12/ 
D84
Week 16 
/ D112
Week 20 
/ D140 
Week 
24 
/D168
Week 32 
/D224
Week 40 
/ D280
Week 52 
/ D364
Assessment window
+3d
±3d
±3d
±3d
±3d
±3d
±3d
±3d
±6d
±6d
±6d
±6d
Vital Signs
X
X
X
X
X
X
X
Office spirometry (centralized)
X
X
X
X
X
X
X
X
X
X
X
X
X
Home spirometry  - (weekly)
X
X
X
Randomization
X
Dispense study medication
X
X
X
X
X
X
X
X
X
Dispense log pad and provide training
X
Dispense MDI sensors and provide training
X
Study Treatment
Study Treatment Compliance (ediary)
Collect IP 
Collect MDI sensors
X
X
Collect log pad
X
X
AE review
SAE review
Concomitant medication review
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Outcomes Assessments
COPD exacerbation review
X
X
X
X
X
X
X
X
X
X
X
X
Rescue medication Use
SGRQ-C
X
X
X
X
X
X
COPD Assessment Test (CAT)
X
X
X
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
X
X
X
 
 
 
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Screening/
Visit1a
Visit 2
Visit 3  
Visit 
4
Visit 5
Visit 
6
Visit 
7
Visit 8
Visit 9
Visit 
10
Visit 11
Visit 12
EW
FU
Up to 28 
days 
post last 
dose
up to
-7 days
Week 
0 /
D1
Week 2/ 
D14
Week 4/ 
D28
Week 8/ 
D56
Week 12/ 
D84
Week 16 
/ D112
Week 20 
/ D140 
Week 
24 
/D168
Week 32 
/D224
Week 40 
/ D280
Week 52 
/ D364
Assessment window
+3d
±3d
±3d
±3d
±3d
±3d
±3d
±3d
±6d
±6d
±6d
±6d
Genetic, Pharmacokinetic and Biomarker Blood Collections
Blood sample for Genetics
X
Blood sample for CRP
X
X
X
X
Blood sample for exploratory biomarkers
X
X
X
X
a
Informed consent may be signed prior to screening visit in the case that any changes in medications are necessary
b
Agreeing to genetic sample consent is not required for study participation
c
Smoking status/history assessed at screening; smoking status re-checked at Visit 2
d
Includes substance usage, past and present medical conditions and family history of premature CV disease
e
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.
f
Participant’s clinical status should be reviewed
g
Pregnancy testing is only required for women of child bearing potential (WOCBP). A positive urine pregnancy test requires confirmation with a serum pregnancy test.
The timing and number of planned study assessments, including safety and biomarker assessments may be altered during the course of the study based on newly available data to 
ensure appropriate data collection.  Any changes in the timing or addition of time points for any planned study assess 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 Number 
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 
[GlaxoSmithKline Document Number 2013N180289_03 Study ID 200163].  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.  Analyses of 
clinical endpoints from study 200163 demonstrated that danirixin, compared to placebo, 
reduced respiratory symptoms as measured with E-RS:COPD [Miller, 2016].
3.1.
Study Rationale
This protocol describes a pilot study to investigate the effect of danirixin HBr 35mg 
tablets on lung function and health related quality of life (HRQoL) in participants with 
 
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mild to moderate airflow obstruction identified from the COPDGene cohort. 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.
Specifically, this study aims to assess whether or not danirixin has the potential to impact 
disease progression in participants with a COPD progression score indicating they are 
likely to decline based on 5 year data from COPDGene and support the conduct of a 
larger Phase III study for disease progression. In addition to lung function and HRQoL, 
this study will assess moderate/severe COPD exacerbations, health status (CAT), and 
rescue medication use.
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 and, 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 
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.  
 
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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 Number 
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.
PK modelling predicts that in a participant 
receiving 35 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 participants
receiving either placebo or danirixin; no 
instances of danirixin-related neutropenia 
have been reported in clinical studies to 
date. In healthy participants, 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 
or 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.
 
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4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To assess whether danirixin HBr 
35mg tablets impacts disease 
progression compared with placebo

Rate of decline in FEV1

Change from baseline in St. George’s 
Respiratory Questionnaire (SGRQ)
total score (derived from SGRQ-C)

To further characterize the safety of 
danirixin HBr 35mg tablets
compared with placebo in 
participants with mild to moderate 
airflow limitation

Adverse events (AE), clinical 
laboratory values, vital signs, 
electrocardiogram (ECG), and/or 
other safety biomarkers
Secondary

To further characterize the clinical 
activity of danirixin HBr 35mg tablets
compared to placebo

Time to first HCRU COPD 
exacerbation

Change from baseline in FEV1

SGRQ responder analysis

SGRQ domains

COPD Assessment Test (CAT)

Rescue medication use
Exploratory

To characterize the effect of 
danirixin on lung matrix 
destruction/remodelling and 
inflammation

Further characterize efficacy of 
danirixin
Blood/serum/plasma  biomarkers that 
are indicative of extracellular matrix 
turnover/remodelling (e.g. elastin and 
collagen neo-epitopes) and 
inflammation (e.g. CRP)

Global assessment of COPD severity 
 
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5.
STUDY DESIGN
5.1.
Overall Design
A study schematic is shown in Figure 1. This is a parallel group study.  Following 
screening and assessment of rescue medication use via a daily diary over study days -7 to 
1, participants will be randomized (1:1) to receive either danirixin 35mg tablets or 
placebo.  Study treatment will be administered twice daily for 52 weeks [Figure 1].  
There will be no pre-specified interim analysis for this study.  An interim analysis may be 
performed if it is determined that the enrolment is slow enough to allow it to be 
informative. There will be no IDMC for this study. An internal safety review team will 
meet approximately every 3 months (or as needed based on emerging data) to review 
available safety information. 
Figure 1
Study Schematic
5.2.
Number of Participants
Approximately 130 participants will be screened to achieve 100 randomized in this study.  
It is anticipated that approximately 85 participants will complete the 12 months of 
treatment (assuming a 15% drop out rate).
For the analysis of study assessments, several analysis populations are defined in Section 
10.3.  
 
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5.3.
Participant and Study Completion
A participant is considered to have completed the study if he/she has completed all
planned study visits 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.  With the 
use of an enriched population, it is anticipated that one year of treatment will be sufficient 
to detect a trend in altering disease progression.   Danirixin has already been clinically 
investigated over one year treatment duration (GlaxoSmithKline Document Number 
2013N180289_03 Study ID 200163).  
The data from this study will provide useful information in determining whether or not to 
progress to a Phase III study to explore an indication for slowing disease progression. 
5.5.
Dose Justification
One dose of danirixin is proposed for this study, 35mg tablets BID.  This dose was 
selected based on integrating information on:

Dose-exposure-biomarker response using inhibition of ex vivo CXCL1-induced 
CD11b expression on peripheral blood neutrophils over the dose range of 0-400mg 
(free base tablet) in healthy volunteers (GSK Study No. CX3 112483).

Evidence of reduced respiratory symptoms and improvement in health status in mild 
to moderate COPD participants from interim data in the Phase IIa study (GSK Study 
No. 200163).

Relative bioavailability study comparing danirixin free base vs HBr (GSK Study No. 
201037).
In the previous 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 (GlaxoSmithKline Document Number 
2015N248339_00, Study ID 201037). Thus the danirixin (hydrobromide tablet) 35mg 
BID dose for investigation in this study is expected to provide steady-state systemic 
exposure approximately equivalent to the 75mg BID (free base tablet) used in Study 
200163. 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 Number. 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.
6.
STUDY POPULATION
This study will identify specific patients most likely to decline from the well established 
COPDGene cohort [NCT00608764].  This study will be an ancillary study within 
COPDGene investigating the enrichment strategy for assessing disease progression. 
These potential participants have been identified by COPDGene investigators based on 
data collected over the initial 5 year period.  The participants were identified based on a 
Random Forest analysis and a demonstrated decline of at least 20mL/yr over the initial 5 
year period. Once participants are identified from the COPDGene dataset, the following 
criteria will be verified at initial study visit following signing of consent.
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1. Participant must be 40 to 76 years of age inclusive, at the time of signing the 
informed consent.
Type of Participant and Disease Characteristics
2. At the screening visit, the subject must have an FEV1 >40% of the predicted normal.
3. Participants with a prior history of asthma are eligible if they have a current diagnosis 
of COPD
Dose 
(mg)
Predicted# steady-state median (5th, 95th
percentile)
Cavg 
multiple of 
IC50*
Cmin 
multiple of 
IC50*
AUC(0-24) 
steady-state
(ug.h/mL)
Cavg
(ng/mL)
Cmin
(ng/mL)
35
9.59
(4.70, 19.3)
399
(196, 806)
192
(47.6, 630)
5.1
2.4
 
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Weight
4. Body weight 45 kg
Sex
5. 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 Section 12.5; 
Appendix 5), not breastfeeding, and at least one of the following conditions applies:
(i)
Not a woman of childbearing potential (WOCBP) as defined in Section 12.5
(Appendix 5)
OR
(ii)
A WOCBP who agrees to follow the contraceptive guidance in Section 12.5
(Appendix 5) during the treatment period and for at least 60 hours after the 
last dose of study treatment.
Informed Consent
6.
Capable of giving signed informed consent as described in Section 12.3 (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 disease (other than COPD), e.g. 
sarcoidosis, tuberculosis, pulmonary fibrosis, severe bronchiectasis or lung cancer
2. COPD due to alpha-1-antitrypsin deficiency 
3. Pulse oximetry < 88% at rest at screening.  Participants should be tested while 
breathing room air.  However, participants living at high altitudes (above 5000 ft or 
1500 m above sea level) who are receiving supplemental oxygen can be included 
provided they are receiving the equivalent of < 4L/min and screening oximetry is 
measured while on their usual settings.
4. Less than 14 days have elapsed from completion of a course of antibiotics or oral 
corticosteroids for a recent COPD exacerbation
 
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5. Participants with a peripheral blood neutrophil count < 1 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 with lateral) or CT scan reveals evidence of a clinically 
significant abnormality not believed to be due to the presence of COPD (historic data 
up to 1 year may be used).  
8. History or current evidence of clinically significant renal disease, diabetes 
mellitus/metabolic syndrome, hypertension, or any other clinically significant 
cardiovascular, neurological, immunological, endocrine, or haematological 
abnormality 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 participants
at risk through study participation, or which would affect the safety analysis or other 
analysis if the disease/condition exacerbated during the study.
9. History of sensitivity to any of the study medications, or components thereof or a 
history of drug or other allergy that, in the opinion of the investigator of GSK medical 
monitor, contraindicates their participation.
10. Current of chronic history of liver disease, or know hepatic or biliary abnormalities 
(with the exception of Gilbert’s syndrome or asymptomatic gallstones).
11. Abnormal and clinically significant 12-lead ECG finding.  The investigator will 
determine the clinical significance of each abnormal ECG finding in relation to the 
subject’s medical history and exclude participants who would be at undue risk by 
participating in the trial.  An abnormal and clinically significant finding that would 
preclude a subject from entering the trial is defined as a 12-lead tracing that is 
interpreted as, but not limited to, any of the following:
‒
AF with rapid ventricular rate > 120 bpm;
‒
sustained or non-sustained VT
‒
second degree heat block Mobitz type II and third degree heart block (unless 
pacemaker or defibrillator has been implanted)
‒
QTcF 500 msec in patients with QRS < 120 msec and QTcF 530 msec in 
patients with QRS 120 msec
12. Previous lung surgery (e.g. lobectomy, pneumonectomy) or lung volume reduction 
procedure.
Prior/Concomitant Therapy
13. 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.
14. 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 
 
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not limited to, topotecan.)  The Investigator should consult with the Medical Monitor 
if necessary.
15. 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
16. 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).
17. Participation in a previous clinical trial with danirixin within 1 year prior to the first 
dosing day in the current study
18. Exposure to more than four investigational products within 1 year prior to the first 
dosing day in the current study.
Diagnostic assessments
19. 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%).
20. A positive test for HIV antibody.
21. A positive pre-study hepatitis B surface antigen or positive hepatitis C antibody result 
within 3 months prior to screening.
Other Exclusions
22. 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.
23. A history of allergy or hypersensitivity to any of the ingredients in the study 
treatment.
24. A known or suspected history of alcohol or drug abuse within the 2 years prior to 
screening.
25. Inability to read: in the opinion of the Investigator, any participant who is unable to 
read and/or would not be able to complete study related materials.
26. 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.
 
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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 not be rescreened unless discussed with the medical monitor. 
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
Study Treatment Name:
Danirixin 
(GSK1325756H, the 
hydrobromide 
hemihydrate salt)
Placebo
Dosage formulation:
White Film coated 
tablets (oval shaped). 
Refer to Investigator’s 
Brochure for 
presentation and 
excipients
White Film coated 
tablets (oval shaped). 
Refer to 
Investigator’s 
Brochure for 
presentation and 
excipients
Unit dose strength(s)/Dosage level(s):
35mg tablets (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).
Additional descriptive information and instructions for the eMDI monitoring devices are 
provided in the SRM.
 
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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 study.  Study participants, all study site staff, and all members 
of the GSK study team will be blinded to individual participant treatment assignment.  
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 
 
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(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.  
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
 
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
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)
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) bronchodilators, (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 
 
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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: Liver Safety: Required Actions and Follow-up Assessments). 
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 (Section 12.7) 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. 
 
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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.
FEV1
9.1.1.1.
Clinic Spirometry
Spirometry using FEV1 and FVC measurements (FEV%, and FVC% and FEV1/FVC will 
be calculated) will be performed in triplicate at time points listed in the SoA (Table 1).  
Spirometry assessments should be performed in accordance with ATS/ERS guidelines as 
outlined in the SRM.
9.1.1.2.
Mobile Spirometry
Spirometry will also be performed weekly by the participants using a mobile spirometer 
at home.  Details will be outlined in the SRM.
9.1.2.
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 
 
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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 SGRQ scores equivalent to the original SGRQ instrument [Jones, 1992].
9.1.3.
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.
9.1.4.
COPD Exacerbations
An exacerbation of COPD is defined by a worsening of symptoms requiring additional 
treatment or hospitalization. 
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 based on the Investigator’s judgement.
9.1.5.
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 
final study visit or IP Discontinuation Visit.  This single global question will ask 
participants 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 every visit following randomization (or Early Withdrawal (EW) Visit). Response 
 
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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.
9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4 (Section 12.4).
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 the time the informed consent is signed by the 
participant until the follow up visit at the time points specified in the SoA
(Table 1).

All AEs will be collected from the start of study treatment (randomization visit) 
until the follow-up visit at the time points specified in the SoA (Table 1).

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 must be reported immediately and not more than 24 hrs to the sponsor, 
as indicated in Appendix 4 (Section 12.4). 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 (Section 12.4).
9.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
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 
 
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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 Section 12.4 (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. 
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 
 
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becomes aware of the event.  These DREs will be monitored by the Safety Review Team 
(SRT) on a routine basis as described in Section 12.3 (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 Section 12.5
(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. 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 Section 12.8 (Appendix 8).
NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Section 9.2 and Section 12.4 (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.
 
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
The method of documenting Medical Device Incidents is provided in Section 
12.8 (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 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.
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.
 
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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.
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, 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 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 measurements 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 10 minutes.
9.4.4.
Clinical Safety Laboratory Assessments
Refer to Section 12.2 (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 Section 12.2, 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.
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 
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
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
Pharmacokinetic parameters are not evaluated in this study.
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 Section 12.6 (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), 
extracellular matrix turnover and remodelling to evaluate their association with the 
 
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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 
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study. 
10. 
STATISTICAL CONSIDERATIONS 
The objective of this study is to investigate the effect of danirixin HBr 35mg tablets on 
COPD disease progression. There are no formal hypothesis tests associated with this 
objective and no formal significance tests. The information acquired from this study will 
primarily be used to assess whether or not danirixin impacts disease progression and to 
quantify the effect that danirixin has on disease progression, specifically change in lung 
function as measured by FEV1 decline and change in health-related quality of life as 
measured by SGRQ total score to further support disease understanding and future 
studies.  
10.1. 
Sample Size Determination 
Sample size is based primarily on feasibility for this study. Since there is much 
uncertainty around the magnitude of the difference in the decline in FEV1 and change in 
SGRQ along with the between-subject variability for the specific patient population, the 
proposed sample size is unavoidably imprecise. Sample size may be adjusted using the 
predictions of final study outcome based on simulations and possible interim analyses. It 
is anticipated that screening 130 participants will allow for approximately 100 
participants to enrol.  
In order to observe the effect of different sample sizes, various simulations were done to 
assess the impact of sample sizes of 50, 100, 150 and 200 with a 1:1 allocation to each 
treatment group [Table 3]. The assumed variability for rate of decline in FEV1 and 
change in SGRQ is 25 and 10, respectively.  The correlation between rate of decline in 
FEV1 and change in SGRQ is assumed to be -0.2. [Nagai, 2015]  
 
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Table 3 
Assumptions used for the Simulations 
 
Treatment Effect Assumptions 
(δFEV1, δSGRQ) 
Variability Assumptions 
(σFEV1, σSGRQ) 
Sample Size 
Null 
(0,0) 
(25,10) 
N={50,100,150,200} 
Alternate 1  
(5,-1) 
(25,10) 
N={50,100,150,200} 
Alternate 2 
(5,0)  
(25,10) 
N={50,100,150,200} 
Alternate 3 
(0,-1) 
(25,10) 
N={50,100,150,200} 
 
Data from a bivariate normal distribution were simulated under the four different 
treatment effect assumptions for samples sizes of 50, 100, 150, and 200. The samples 
from the posterior probability distribution from the MCMC approximation were divided 
into four regions based on δFEV1 and δSGRQ treatment effect cut-off values; δFEV1≥0 and 
δSGRQ ≤0, δFEV1≥0 and δSGRQ>0, δFEV1<0 and δSGRQ≤0, and δFEV1<0 and δSGRQ>0. Based 
on a 70% threshold, the proportion of the 1000 simulations meeting the requirement 
P(δFEV1≥0 & δSGRQ≤0) ≥ 70% were considered a success based on the joint definition 
[Figure 2, Table 4]. If P(δFEV1≥0 & δSGRQ≤0) < 70%, success could further be defined 
based on each endpoint independently where P(δFEV1 ≥ 0) ≥ 80% or P(δSGRQ ≤ 0) ≥ 80%.  
Figure 2 
Total Probability of Success 
 
 
Table 4 
Total Probability of Success (Figure 2) 
 
N=50 
N=100 
N=150 
N=200 
(5,-1) 
57.4 
68.5 
75.1 
81.4 
(5,0) 
52.5 
62.6 
67.8 
74.5 
(0,-1) 
42.6 
46.2 
48.9 
53.0 
(0,0) 
34.9 
33.9 
33.3 
31.5 
 
 
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Figure 3
Half Width of the 95% Confidence Interval of δFEV1 Point Estimate
Figure 4
Half Width of the 95% Confidence Interval of δSGRQ Point Estimate
Based on the simulations, under the assumption of an expected treatment difference of 
(5,-1) which is the most probable scenario, the marginal increase for the total probability 
of success is greatest when increasing the sample size from 50 to 100 (Figure 2). The half 
widths of the 95% CI of the point estimate of the marginal treatment differences for FEV1
(Figure 3) and SGRQ (Figure 4) have the greatest reduction from a sample size of 50 to 
100. A sample size of 100 will allow for an adequate level of confidence in the study 
success while also considering the precision of the treatment effect differences. 
 
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10.2.
Randomization
Participants will be randomized equally (1:1) to the two treatment arms of placebo and 35 
mg danirixin HBr.  Randomization will be stratified by smoking status (current vs. 
former).
10.3.
Populations for Analyses
For purposes of analysis, the following populations are defined:
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.
Per-Protocol (PP) 
Population
This population will comprise of all patients in the ITT 
population who are not major protocol violators.
Safety
All randomized participants who take at least 1 dose of study 
treatment. Participants will be analyzed according to the 
treatment they actually received.
10.4.
Statistical Analyses
Treatment comparisons using all endpoints will be made using appropriate statistical 
techniques. Analysis methods for key endpoints are described below. Main analysis will 
use ITT unless noted. Further details on all analyses will be described in the reporting and 
analysis plan (RAP).
10.4.1.
Efficacy Analyses
The total probability of success will be defined as a combination of a joint and 
conditional statement. The joint probability of success will be defined as the probability 
of the difference in the rate of decline in FEV1 between danirixin and placebo is greater 
than or equal to 0 and the difference in the change in SGRQ total score from baseline 
between danirixin and placebo is less than or equal to 0 is greater than 70%. If the joint 
probability of success is less than 70%, success can further be defined based on each 
endpoint independently, where either the difference in the rate of decline in FEV1 is 
 
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greater than or equal to 0 is greater than 80% or the difference in the change in SGRQ
total score is less than or equal to 0 is greater than 80%. 
 	
 = 	 ≥0 &  ≤0 ≥70%
+ 	 ≥0  ≥80%|	 ≥0 &  ≤0 < 70%
+	 ≤0  ≥80%|	 ≥0 &  ≤0 < 70%
Endpoint
Statistical Analysis Methods
Primary
Rate of decline in FEV1 and change from baseline in SGRQ total score
Exploratory
Will be described in detail in the RAP
 
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Lung Function Decline: Rate of Decline of FEV1 (mL/yr)
The rate of decline of FEV1 will be derived from a repeated measures random 
coefficients model. Post-baseline FEV1 will be modelled including terms for age, sex, 
smoking status, FEV1 at baseline, and BMI along with treatment group, time and 
treatment by time interaction as fixed effects.  Subject will be a random effect. Time will 
be defined as the number of days since start of treatment. Only FEV1 values measured 
after baseline will be used in the model. Based on the results of previous studies, the 
study team will determine the time point at which post-baseline spirometry assessments 
will be included in the model to account for the initial treatment response. The estimate 
of the rate of FEV1 decline will be the slope of the parameter estimate of the treatment by 
time interaction term in the model. Contrasts will be calculated for the difference in 
treatment by time interaction between danirixin and placebo treatment groups to estimate 
the treatment difference. 
FEV1 = Treatment group + age + sex +smoking status+FEV1_BL+BMI+ time + 
treatment*time 
The rate of decline for each subject, the estimate of the slope parameter of the treatment 
by time interaction term, will be used as a co-primary endpoint for the joint analysis 
using both FEV1 and SGRQ. 
HRQoL: SGRQ
A co-primary endpoint of interest is change in SGRQ total score (derived from SGRQ-C) 
from baseline. Change in SGRQ total scores from baseline will be derived using a mixed 
model with repeated measures (MMRM) including fixed effects of treatment group, age, 
sex, smoking status, BMI, baseline SGRQ score, time as a categorical variable and a 
treatment by time interaction term. Subject will be a random effect. Estimated treatment 
differences at the end of one year will be obtained. The difference of the least square 
mean change from baseline at 12 months will be derived. The adjusted SGRQ total score 
change from baseline will used as the other co-primary endpoint for the joint analysis 
using both FEV1 and SGRQ. 
Joint Analysis
The joint analysis will use the ITT population with all available FEV1 rate of decline and 
change in SGRQ data.
The rate of decline (the slope parameter from the random coefficients model) of FEV1, 
along with the change in SGRQ from the MMRM model will be extracted for each 
subject. These values will then be used to obtain MCMC approximations of the joint 
posterior distribution of the treatment differences between FEV1 decline and change in 
SGRQ between the danirixin and placebo groups. Based on the samples from the 
posterior distribution, the proportion of samples falling within certain treatment 
difference regions will be calculated and the probability of success will be derived. 
 
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10.4.2.
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.
10.4.3.
Other Analyses
Exploratory biomarker analyses will be described in the RAP.
10.4.4.
Interim Analyses
Conducting an interim analysis or futility assessment may not be practical due to an 
expected fast recruitment period. By the time enough data will accumulate for any 
meaningful interim analysis to support changes to the study design, recruitment of all 
study participants will have concluded. However, if recruitment takes a longer than 
anticipated, an interim analysis to reassess the variability assumptions, estimate the 
probability of success at the end of study, and confirm the directionality of the endpoints 
may be conducted.  
The RAP will describe the potential interim analyses in greater detail.
 
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11.
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Eur Respir J. 2004;23:932-946. 
Chapman RW, Philips JE, Hipkin RW, Curran AK, Lundell D, Fine JS. CXCR2 
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FDA. Guidance for Industry. Center for Drug Evaluation and Research, United States 
Food and Drug Administration; 2009. Drug-induced liver injury: premarketing clinical 
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GlaxoSmithKline Document Number 2013N180289_03 Study ID 200163. A two part, 
phase IIa, randomized, placebo-controlled study to investigate the safety, tolerability, 
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(GSK1325756) in symptomatic COPD subjects with mild to moderate airflow limitation 
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GlaxoSmithKline Document Number 2014N205875_00 Study ID 201682. A 
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GlaxoSmithKline Document Number 2015N248339_00 Study ID 201037. A single 
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evaluate the relative bioavailability of hydrobromide salt and free base immediate release 
tablet formulations of danirixin in the fed state, and to evaluate the effect of food and 
gastric acid secretion suppression on danirixin pharmacokinetics following administration 
of hydrobromide salt tablets. Report Date 01-Jun-2016. 
GlaxoSmithKline Document Number YM2010/00163/07. Danirixin Investigator's 
Brochure, Version 09. Report Date 14-Apr-2016. 
GOLD. From the Global Strateby for the Diagnosis, Management and Prevention of 
COPD, Global Initiative for Chronic Obstructive Lung Disease. Global Initiative for 
Chronic Obstructive Lung Disease, Available from: http://www.copdgold.org; 2016. 
Holz O, Khalilieh S, Ludwig-Sengpiel A, Watz H, Stryszak P, Soni P, et al. SCH527123, 
a novel CXCR2 antagonist, inhibits ozone-induced neutrophilia in healthy subjects. Eur 
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Hurst JA, Vestbo J, Anzueto A, Locantore N, Mullerova, Tal-Singer R, et al. 
Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 
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Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Leidy NK. Development and first 
validation of the COPD Assessment Test (CAT). Eur Respir J. 2009;34:648-654. 
 
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Jones PW, Harding G, Wiklund I, Berry P, Tabberer M, Yu R et al. Tests of the 
responsiveness of the chronic obstructive pulmonary disease (COPD) assessment test 
(CAT) following acute exacerbation and pulmonary rehabilitation. Chest. 2012;142:134-
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Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure of health 
status for chronic airflow limitation. The St. George's Respiratory Questionnaire. Am Rev 
Respir Dis. 1992;145:1321-1327. 
Lazaar AL, Sweeney LE, MacDonald AJ et al. SB-656933, a novel CXCR2 selective 
antagnoist, inhibits ex vivo neutrophil activation and ozone-induced airway inflammation 
in humans. Br J Clin Pharmacol. 2011;72:282-293.  
Lopez-Campos JL, Tan W, Soriano JB. Global burden of COPD. Respirology. 
2016;21:14-23.
Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 
to 2030. PLoS Med. 2006;3:e442. 
Meguro M, Barley EA, Spencer S et al. Development and validation of an improved 
COPD-specific version of the St. George Respiratory Questionnaire. Chest. 
2007;132:456-463. 
Miller B, Tal-Singer R, Lazaar A, Leidy N, Watz H, Collins D, et al. Assessing 
symptoms in COPD: use of the E-RS daily digital diary in early drug development. Eur 
Respir J. 2016;48(S60):PA1047. 
Nagai, K., Makita, H., Suzuki, M., Shimizu, K., Konno, S., Ito, Y. M., & Nishimura, M. 
Differential changes in quality of life components over 5 years in chronic obstructive 
pulmonary disease patients. International Journal of Chronic Obstructive Pulmonary 
Disease. 2015; 10: 745–757. 
Nair P, Gaga M, Zervas E et al. Safety and efficacy of a CXCR2 antagnoist in patients 
with severe asthma and sputum neutrophils: a randomized, placebo-controlled clinical 
trial. Clin Exp Allergy. 2012;42:1097-2103. 
O'Byrne PM, Metev H, Puu M et al. Efficacy and safety of a CXCR2 antagonist, 
AZD5069, in patients with uncontrolled persistent asthma: a randomised, double-blind, 
placebo-controlled trial. Lancet Respir Med. 2016;4:797-806. 
Rennard SI, Dale DC, Donohue JF et al. CXCR2 antagonist MK-7123 - a phase 2 proof-
of-concept trial for chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 
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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. 
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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
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
eCRF
Electronic Case Report Form
ED50
Dose causing 50% of the maximum achievable 
response
 
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EMA
European Medicines Agency
Emax
Maximum response achievable
eMDI
Electronic metered dose inhaler
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
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
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
 
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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
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
 
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SAMA
Short-acting Muscarinic Receptor Agonist
SGRQ
St George’s Respiratory Questionnaire
SGRQ-C
SGRQ-C 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
 
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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

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.
 
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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 
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 remaining 
mandatory samples for optional exploratory research in accordance with SOP-
GSKF-410. The investigator or 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 to participate 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. 
 
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Committees Structure 
• A study charter will be created to describe important governance aspects while the 
study is being conducted. 
• 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 participant’s last visit.  
Data Quality Assurance 
• 
All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (eg, laboratory 
data). The investigator is responsible for verifying that data entries are accurate 
and correct by physically or electronically signing the CRF.  
• 
The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF.  
• 
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 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 study completion 
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. 
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.
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. 

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. Also, "lack of 
efficacy" or "failure of expected pharmacological action" constitutes an AE or SAE.
 
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Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
 
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normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the 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
 
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Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the 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
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study 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.
 
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
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 
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 (see next section).

The site will enter the SAE data into the electronic system as soon as it becomes 
available.
 
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
After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor/SAE coordinator by telephone.

Contacts for SAE reporting 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.)
 
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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
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 will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected 

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 
 
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be forwarded to GSK Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date.  

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. 

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK
as described in Appendix 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 will 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 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 will be analyzed if it is hypothesized that this may help further 
understand the clinical data. 

The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to danirixin 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 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).
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
No country specific requirements
 
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