Clinical trial NCT03250689
Conditions: Pulmonary Disease, Chronic Obstructive
Keywords: Danirixin CXCR2 NETs GSK1325756 COPD HBr
Sponsor: GlaxoSmithKline
Start date: 2017-11-15; Completion date: 2018-10-08
Enrollment: 19 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The inflammation associated with COPD is characterized by a prominent infiltration of neutrophils in lung tissue and airways. The CXC chemokine receptor type 2 (CXCR2) plays a pivotal role in neutrophil recruitment to the lungs resulting in progressive fibrosis, airway stenosis, and destruction of the lung parenchyma characteristic of COPD. There is a paucity of novel therapies that target these symptoms, and there are no currently available therapies that modify disease progression in COPD. Danirixin (GSK1325756) is a selective CXCR2 antagonist being developed as a potential anti-inflammatory agent for the treatment of COPD and influenza. This study is a mechanistic study which aims to evaluate the effect of danirixin in reducing neutrophil extracellular traps (NETs) formation (or NETosis). Subjects will be randomized (3:1) to receive danirixin hydrobromide (HBr) 35 milligram (mg) orally twice daily or matching placebo for 14 days. Subjects may continue to use rescue medication(s) and inhaled COPD maintenance medication(s) during the study. The study will consist of a screening period of up to 30 days, a 2 week treatment period, and a 1-week follow-up visit via phone call. Approximately 50 subjects will be screened to obtain approximately 24 subjects to complete the study.

Detailed description:

Arms: arm 1: Eligible subjects will receive danirixin 35 mg tablet with food twice daily for 14 Days. arm 2: Eligible subjects will receive placebo tablet with food twice daily for 14 Days.
Interventions: intervention 1: Danirixin intervention 2: Placebo intervention 3: Rescue medication intervention 4: Inhaled COPD maintenance medication
Intervention descriptions: intervention 1: Danirixin will be available as 35 mg oval shaped, white film coated HBr embossed tablets. intervention 2: Placebo will be available as oval shaped, white film coated tablets. intervention 3: Subjects may continue to use rescue medication(s) anytime during the study. The following rescue medications may be used: short acting beta agonists, short acting muscarinic antagonists, or short acting combination bronchodilators. intervention 4: Subjects may continue to use inhaled COPD maintenance medication(s) during the study, at the discretion of the GSK Medical Monitor and/or Investigator. The following maintenance medications may be used: long acting bronchodilator medications (e.g. long-acting muscarinic antagonist \[LAMA\], long-acting beta-agonist \[LABA\]) and long-acting bronchodilator combination therapies (e.g. LAMA/LABA) and long-acting bronchodilator/inhaled corticosteroid steroid combination (ICS) therapies (e.g. LABA/ICS, LAMA/LABA/ICS)

Protocol documents:
Prot_000.pdf: 
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TITLE PAGE
Protocol Title: Randomized double blind (sponsor unblind) study evaluating the effect
of 14 days of treatment with danirixin (GSK1325756) on neutrophil extracellular traps 
(NETs) formation in participants with stable chronic obstructive pulmonary disease 
(COPD)
Protocol Number: 207551
Short Title: Randomized study evaluating the effect of danirixin on neutrophil 
extracellular traps (NETs) 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 Can be found in the Study Reference 
Manual
Regulatory Agency Identifying Number(s): EudraCT number 2017-001069-25
Approval Date: 16-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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TABLE OF CONTENTS
PAGE
1.
SYNOPSIS...............................................................................................................6
2.
SCHEDULE OF ACTIVITIES (SOA).........................................................................9
3.
INTRODUCTION....................................................................................................11
3.1.
Study Rationale ..........................................................................................11
3.2.
Background ................................................................................................11
3.3.
Benefit/Risk Assessment ............................................................................13
3.3.1.
Risk Assessment .........................................................................14
3.3.2.
Benefit Assessment.....................................................................17
3.3.3.
Overall Benefit:Risk Conclusion...................................................17
4.
OBJECTIVES AND ENDPOINTS...........................................................................17
5.
STUDY DESIGN ....................................................................................................19
5.1.
Overall Design ............................................................................................19
5.2.
Number of Participants ...............................................................................20
5.3.
Participant and Study Completion...............................................................20
5.4.
Scientific Rationale for Study Design ..........................................................20
5.5.
Dose Justification........................................................................................20
6.
STUDY POPULATION...........................................................................................21
6.1.
Inclusion Criteria.........................................................................................21
6.2.
Exclusion Criteria........................................................................................22
6.3.
Lifestyle Restrictions...................................................................................24
6.3.1.
Meals and Dietary Restrictions ....................................................24
6.3.2.
Caffeine, Alcohol, and Tobacco ...................................................24
6.3.3.
Activity .........................................................................................24
6.4.
Screen Failures...........................................................................................24
7.
TREATMENTS.......................................................................................................25
7.1.
Treatments Administered............................................................................25
7.2.
Dose Modification .......................................................................................25
7.3.
Method of Treatment Assignment ...............................................................26
7.4.
Blinding.......................................................................................................26
7.5.
Preparation/Handling/Storage/Accountability. .............................................26
7.6.
Treatment Compliance................................................................................27
7.7.
Concomitant Therapy..................................................................................28
7.8.
Treatment after the End of the Study ..........................................................29
8.
DISCONTINUATION CRITERIA.............................................................................29
8.1.
Discontinuation of Study Treatment ............................................................29
8.1.1.
Liver Chemistry Stopping Criteria ................................................29
8.1.2.
Neutrophil Stopping Criteria.........................................................30
8.1.3.
QTc Stopping Criteria ..................................................................30
8.1.4.
Temporary Discontinuation ..........................................................31
8.1.5.
Rechallenge.................................................................................31
8.1.5.1.
Study Treatment Restart or Rechallenge....................31
8.2.
Withdrawal from the Study..........................................................................31
 
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8.3.
Lost to Follow Up........................................................................................32
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................32
9.1.
Efficacy Assessments.................................................................................33
9.1.1.
Induced Sputum samples ............................................................33
9.1.2.
Biomarkers ..................................................................................33
9.1.3.
Measurement of volatile organic compounds (VOCs) ..................34
9.2.
Adverse Events...........................................................................................34
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................34
9.2.2.
Method of Detecting AEs and SAEs.............................................35
9.2.3.
Follow-up of AEs and SAEs.........................................................35
9.2.4.
Regulatory Reporting Requirements for SAEs .............................35
9.2.5.
Cardiovascular and Death Events................................................35
9.2.6.
Pregnancy ...................................................................................36
9.3.
Treatment of Overdose...............................................................................36
9.4.
Safety Assessments ...................................................................................36
9.4.1.
Physical Examinations.................................................................37
9.4.2.
Vital Signs....................................................................................37
9.4.3.
Electrocardiograms......................................................................37
9.4.4.
Clinical Safety Laboratory Assessments ......................................37
9.4.5.
Spirometry ...................................................................................38
9.5.
Pharmacokinetics .......................................................................................38
9.6.
Genetics .....................................................................................................38
9.7.
Biomarkers .................................................................................................39
9.8.
Health Economics OR Medical Resource Utilization and Health 
Economics..................................................................................................39
10. STATISTICAL CONSIDERATIONS........................................................................39
10.1.
Sample Size Determination ........................................................................39
10.2.
Populations for Analyses ............................................................................40
10.3.
Statistical Analyses.....................................................................................40
10.3.1.
Efficacy Analyses.........................................................................40
10.3.2.
Safety Analyses...........................................................................41
10.3.3.
Pharmacokinetic Analyses...........................................................41
10.3.4.
Other Analyses ............................................................................41
10.3.5.
Interim Analyses ..........................................................................42
10.3.6.
Data Management .......................................................................42
11. REFERENCES.......................................................................................................43
12. APPENDICES........................................................................................................45
12.1.
Appendix 1: Abbreviations and Trademarks................................................45
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................47
12.3.
Appendix 3: Study Governance Considerations..........................................49
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................53
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................59
12.6.
Appendix 6: Genetics..................................................................................63
12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................64
 
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12.8.
Appendix 8: Neutrophil Safety.....................................................................67
12.9.
Appendix 9: Medication Adherence Platform ..............................................68
 
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1.
SYNOPSIS
Protocol Title: Randomized double blind (sponsor unblind) study evaluating the effect 
of 14 days of treatment with danirixin (GSK1325756) on neutrophil extracellular traps 
(NETs) formation in participants with stable chronic obstructive pulmonary disease 
(COPD)
Short Title: Randomized study evaluating the effect of danirixin on neutrophil 
extracellular traps (NETs) in COPD
Rationale:
Danirixin (DNX) is a potent selective CXC chemokine receptor type 2 (CXCR2) 
antagonist being developed as a potential anti-inflammatory agent for the treatment of 
chronic obstructive pulmonary disease (COPD) and influenza. Clinical pharmacology 
studies in healthy volunteers demonstrated the pharmacodynamic activity of danirixin 
(inhibition of ex vivo chemokine (C-X-C motif) ligand 1 [CXCL1]-induced CD11b 
expression on peripheral blood neutrophils and inhibition of neutrophil trafficking after 
ozone challenge).  The current study is a mechanistic study to evaluate the effect of 
danirixin on neutrophil extracellular traps (NETs) formation. NETs consist of 
decondensed chromatin coated in antimicrobial and granular proteins. Whilst NETs can 
have a protective role against bacterial dissemination, excessive NET formation can 
cause host tissue damage, and could form one mechanism for disease progression in 
COPD.  This study specifically aims to test the hypothesis that danirixin may reduce NET 
formation (NETosis) in participants with COPD; this study will help to better understand 
the pharmacology of danirixin and is the first study of its kind in COPD.
Objectives and Endpoints:
Objectives
Endpoints
Primary

To assess the change from baseline 
in NETs formation in participants 
with COPD following 14 days 
treatment with  danirixin 
hydrobromide (HBr) 35mg twice 
daily

Reduction in sputum NETs (quantified by 
Histone-elastase complexes)
Secondary

To assess the change from baseline 
in NETs formation in participants 
with COPD following 14 days 
treatment with  danirixin HBr 35mg
twice daily

Reduction in sputum NETS (quantified by 
Deoxyribonucleic acid [DNA]-elastase 
complexes)

Reduction in sputum NET area 
quantification by microscopy

To further characterize the safety of 
danirixin HBr 35mg twice daily 
compared with placebo in 

Adverse events

Vital Signs

ECG
 
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Objectives
Endpoints
participants with COPD

Spirometry

Clinical Laboratory Assessments 
(hematology, clinical chemistry, 
urinalysis)

To assess the effects of danirixin 
HBr 35mg twice daily on NETosis-
associated biomarkers in sputum and 
peripheral blood 

Change from baseline in sputum resistin 
levels

Change from baseline in the ratio of 
sputum NETs to sputum neutrophils

Change from baseline in sputum elastase 
activity

Change from baseline in peripheral blood 
neutrophil NET formation (DNA release, 
microscopy)

Characterise the population 
pharmacokinetic (PK) profile of 
approximately 14 days of dosing of 
danirixin HBr 35mg twice daily in 
participants with COPD

Model specific PK parameters of 
danirixin (e.g., oral clearance, oral steady-
state volume of distribution).
Further exploratory analyses related to the above endpoints may be performed.
Overall Design:
This is a double blind (sponsor unblind), parallel group study, with two groups 
randomized to 14 days of treatment with either danirixin 35mg HBr or matching placebo. 
The target population will be individuals with COPD who have evidence of existing 
elevated sputum NETosis.
There will be no Independent Data Monitoring Committee.
Number of Participants:
Approximately 50 participants will be screened to randomize 24 evaluable participants 
(18 in the treatment arm and 6 in the placebo arm). If a subject prematurely discontinues
the study or is unable to complete all study assessments, additional subjects may be 
enrolled as replacement subjects at the discretion of the sponsor in consultation with the 
investigator. Additional subjects may be enrolled to improve the statistical properties of 
the end of study decision criteria (i.e., the probability of a positive outcome) based on the 
observed variability at an interim analysis. It is expected that the dropout rate in the study 
should be <10% given the study duration. Enrolment is not expected to exceed a 
maximum of 32 participants.
 
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Treatment Groups and Duration:
The study will consist of a screening/baseline period of up to 30 days, a 2 week treatment 
period, and a 1-week follow-up visit.  The study duration, including screening and 
follow-up, is not expected to exceed 2 months for participants in the study.
Study treatment will consist of two groups: danirixin 35mg HBr orally twice daily or 
matching placebo. 
 
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2.
SCHEDULE OF ACTIVITIES (SOA)
Procedure
Pre-Screening 
and Screening1
Treatment Period
(14 days)
Follow-up
Phone call
Unscheduled 
visit 2
Notes
V0
V1
V2
V3
V 4
V5
Day
Day -30 to  -1
D 1
D 7
D14
D 21
As required
Assessment window
1d
1d
3d
As required
Written, informed consent
X
Inclusion and exclusion criteria
X
Recheck clinical status before randomization.
Demography, Medical history
X
Baseline COPD assessment test (CAT) score
X
Adverse event (AE)/Serious adverse event ( SAE)  
review
X
=============
X
X
Concomitant medication review
X
=============
X
X
Full physical examination including height and weight
X
X
Vital signs
X
X
X
X
X
X
Volatile organic compound (VOC) measurement 
X3
X3,4
X5
X3
X3
X
Spirometry
X
X
X
X
Induced Sputum Samples (including biomarker samples)
X
X 4
X
X
X
X
Spirometry post-Sputum Induction 
X
X 4
X
X
X
X
Triplicate 12-lead ECG
X
X
X
X
Chest X-ray (historical within 1 year acceptable)
X
HIV, Hepatitis B and C screening
X6
Laboratory assessments (clinical chemistry including 
liver chemistries, haematology, biomarkers) 
X
X
X
X
Pharmacokinetic (PK) sample
X7
X8
X7
X
See footnotes for timings of PK sampling
Genetic sample
X9
Pre-dose (baseline) sample. 
Urinary Pregnancy test (WOCBP only)
X10
X10
X10
X10
Urinalysis (including biomarker samples)
X
X
X
X
Randomization
X
All baseline assessments at V2 should be 
completed prior to randomization
Study treatment
X

X
 
 
 
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Procedure
Pre-Screening 
and Screening1
Treatment Period
(14 days)
Follow-up
Phone call
Unscheduled 
visit 2
Notes
V0
V1
V2
V3
V 4
V5
Dispense study medication
X
Monitor IP compliance (via manual counting and App)
X
X
X
Digital App monitoring to begin at V2
Collect IP 
X

The timing and number of planned study assessments, including safety, pharmacokinetic, pharmacodynamic/biomarker or other assessments may be altered during the course 
of the study based on newly available data (e.g., to obtain data closer to the time of peak plasma concentrations) to ensure appropriate monitoring. 

Any changes in the timing or addition of time points for any planned study assessments must be documented and approved by the relevant study team member and then 
archived in the sponsor and site study files, but will not constitute a protocol amendment. The IRB/IEC will be informed of any safety issues that require alteration of the safety 
monitoring scheme or amendment of the Informed consent form (ICF).

Safety assessments should be performed in the following order where applicable/ possible: vital signs, ECG measurements, blood samples and spirometry.
1.
Screening visit is split into pre-screening on visit 0 and screening on visit 1 although the visits may be performed on the same day. This is to a) enable participants to 
potentially have more than one attempt at sputum induction for meeting eligibility and b) to only collect minimal screening data for subjects who fail on the basis of the elevated 
NETs since that is the key inclusion criteria that may not be known from medical records.
2.
Unscheduled visits may be used to collect information related to adverse events, for follow up of any safety assessments, and also to complete assessments where
participants were not able to perform these within the visit window for any reason. It is not necessary to carry out all of the assessments listed under an unscheduled visit at a 
single visit; the assessments performed should be driven by the need for the visit.
3.
VOC measurement should be undertaken prior to sputum induction at these visits.
4.
Sputum induction (and associated VOC measurement and safety spirometry) at visit 1 is only necessary if participant unable to give sample at visit 0. Where the participant is 
judged by the investigator to have a borderline sputum NETs level ( <0.5 units/ml) at visit 0, they will be invited to give a second sputum sample on visit 1 to re-assess 
eligibility.
5.
VOC measurements should be undertaken at the following timepoints at this visits:  prior to sputum induction,and 4 hours post dose
6.
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 Ribonucleic acid (RNA) testing is optional; however a confirmatory negative Hepatitis C RNA test must be obtained, to be able to enroll
participants with positive Hepatitis C antibody due to prior resolved disease.
7.
At visits 2 and 4, PK samples should be collected at the following time-points: pre-dose, 0.5, 1, 2 and 4 hours post-dose.
8.
At visit 3 only a pre-dose PK sample should be collected.
9.
Agreeing to genetic sample consent is not required for overall study participation. Informed consent for genetic sample must be obtained prior to taking sample.
10. Pregnancy testing only required for women of child bearing potential (WOCBP). A positive urine pregnancy test requires confirmation with a serum pregnancy test.
 
 
 
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3.
INTRODUCTION
The inflammation associated with chronic obstructive pulmonary disease (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 CXC chemokine receptor type 2 (CXCR2) chemokine receptor plays a pivotal 
role in neutrophil recruitment to the lung. For neutrophils, chemokine binding to the 
CXCR2 receptor 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.
Danirixin is a selective CXCR2 antagonist being developed as a potential anti-
inflammatory agent for the treatment of COPD and influenza. Danirixin has demonstrated 
potent antagonism of CXCR2 activity both in vitro and in vivo in preclinical studies 
[GlaxoSmithKline Document No. YM2010/00163/08]. 
Clinical pharmacology studies in healthy volunteers demonstrated the pharmacodynamic 
activity of danirixin (inhibition of ex vivo CXCL1-induced CD11b expression on 
peripheral blood neutrophils). In a Phase IIa study in symptomatic participants with mild 
to moderate COPD at risk for exacerbation (GSK Study No. 200163) [GlaxoSmithKline 
Document No. 2013N180289_03], danirixin reduced respiratory symptoms as measured 
with E-RS:COPD, compared to placebo [Miller, 2016].
3.1.
Study Rationale
The aim of this study is to better understand the mechanism of action of danirixin, and to 
understand whether danirixin impacts neutrophil function via effects on neutrophil 
extracellular traps (NETs) formation in sputum and in peripheral blood in vivo, since in 
vitro experiments have suggested that CXCR2 antagonism reduces NETs formation in 
peripheral blood neutrophils from COPD patients [Pedersen, 2017], with NETs formation 
being proposed as one mechanism for disease progression in COPD. 
This study specifically aims to test the hypothesis that twice daily administration of 
danirixin HBr 35mg reduces NET formation in participants with COPD and is the first 
study of its kind in COPD. Reduction of NET formation has potential application in a 
host of chronic lung diseases, infections and autoimmune disease, thus supporting 
development of danirixin across a wide range of indications.
3.2.
Background
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. There is a paucity of novel therapies that target these 
symptoms, and there are no currently available therapies that modify disease progression 
 
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in COPD. There are no licensed CXCR2 antagonists currently available, with one other
compound (AZD5069) currently under development for indications other than COPD.
The current study is a mechanistic study to better understand the pharmacology of 
danirixin and to assess the effect of danirixin on neutrophil extracellular traps (NETs) 
formation (or NETosis). NETs consist of decondensed chromatin coated in antimicrobial 
and granular proteins that are extruded in the extracellular space by neutrophils as a 
defensive mechanism in response to microorganisms, soluble factors and host molecules 
[Pires, 2016]. 
Whilst NETs can have a protective role against bacterial dissemination [Brinkmann, 
2004] excessive NETosis can cause host damage, with the lung being especially
vulnerable to damage from NETs. For example, following infection with the H1N1 virus 
in animal models, NETs expressing MMP-9 were found entangled with alveoli, causing 
increased alveolar capillary damage and small airway obstruction, suggesting a link 
between these DNA lattices and lung damage [Narasaraju, 2011]. There is differential 
activation of NETosis pathways and responses in reaction to different pathogens and 
triggers [Delgado-Rizo, 2017] hence consideration of both the host microbiome and 
infectious species are important. COPD patients colonized with Haemophilus Influenzae
appear more susceptible to NETosis [Dicker, 2017], therefore identification of host 
microbiome subspecies could be important for targeting patients for treatment with 
CXCR2 antagonists. Detection of the lung microbiome has been explored via breath 
analysis of volatile organic compounds (VOC),and may provide a non-invasive method 
to identify people with COPD who are colonized with Haemophilus Influenzae [Shafiek, 
2015]
In addition to infectious disease, massive NET formation has also been reported in 
autoimmune diseases, inflammatory disease, and several lung diseases [Delgado-Rizo,
2017], including COPD, and could form one mechanism for disease progression 
[Grabcanovic-Musija, 2015; Dicker, 2017].
Blocking CXCR2 on neutrophils has been shown to decrease NET formation in some 
inflammatory in vitro and murine models [Marcos, 2010]. In peripheral blood neutrophils 
derived from COPD patients, in vitro treatment with CXCRs antagonists showed a 
reduction in NETs formation [Pedersen, 2017].
This study specifically aims to test the hypothesis that danirixin may reduce NET 
formation (NETosis) in participants with COPD, to improve our understanding of its 
pharmacology in humans, and the definition of target patient population for subsequent 
clinical trials. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of 
GSK1325756 is provided in the Investigator’s Brochure. 
 
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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 No. 
YM2010/00163/08].
 
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3.3.1.
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) GSK 1325756
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 twice daily
dosing (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 area under the concentration 
curve from pre-dose to 24 hours post-dose 
(AUC[0-24] for the NOAEL of testicular 
effects is low.
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 
Monitoring of peripheral blood neutrophil 
count.
Stopping criteria: in participants with a 
confirmed absolute neutrophil count ≤ 0.5 x
109/L product will be discontinued and 
 
 
 
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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
(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 201682, GlaxoSmithKline 
Document No. 2014N205875_00), decreased neutrophil 
counts have been observed in subjects receiving either 
placebo or danirixin; no instances of danirixin-related 
neutropenia have been reported in clinical studies to date. 
In healthy subjects, the data are confounded by the 
observation of low neutrophil counts before dosing or at 
follow-up, and were not dose-related, while in patients with 
influenza, neutrophil counts recovered while receiving 
danirixin, coincident with resolution of the viral infection. 
There have been no reports of neutrophil count decreases 
below the lower limit of normal in patients with COPD 
neutrophil count will be monitored until 
return to normal. 
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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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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.
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 elated 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
Sputum Induction
During induction of sputum, the hypertonicity of saline, the 
rate and volume of administration can potentially cause 
bronchoconstriction and clinically important dyspnoea in 
some patients with COPD, with a resulting fall in forced 
expiratory volume in one second FEV1 of >10%. 
Participants
will 
be 
dosed 
with 
bronchodilators prior to sputum induction 
and will have a post-induction spirometry 
measure at 15 minutes, and will be treated 
with bronchodilators if there is evidence of 
bronchospasm.
Other
None
 
 
 
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3.3.2.
Benefit Assessment

All participants will undergo a thorough medical assessment during the study.
Participants will have study clinic visits for the evaluation of their disease symptoms. 
During these visits, participants will have spirometry, ECG, vital signs monitoring, 
and physical examinations. 

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.
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. To date no significant 
risks have been identified for danirixin from toxicology data or completed and ongoing 
clinical studies.  While the potential for AEs related to testicular effects or impaired 
neutrophil response cannot be dismissed, no such effects have been observed in healthy 
subjects, or in subjects with COPD or influenza.  Data regarding host response outcomes 
in COPD and influenza are limited, but no increase in infections have been observed to 
date.
Taking into account the measures taken to minimize risks to participants in this study, the 
potential risks identified in association with danirixin are justified by the anticipated 
benefits that may be afforded to participants with COPD.
4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To assess the change from baseline 
in NETs formation in participants 
with COPD following 14 days 
treatment with  danirixin HBr 35mg 
twice daily

Reduction in sputum NETs (quantified by 
Histone-elastase complexes)
Secondary

To assess the change from baseline 
in NETs formation in participants 
with COPD following 14 days 
treatment with  danirixin HBr 35mg
twice daily

Reduction in sputum NETS (quantified by 
Deoxyribonucleic acid [DNA]-elastase 
complexes)

Reduction in sputum NET area 
quantification by microscopy

To further characterize the safety of 
danirixin HBr 35mg twice daily
compared with placebo in 

Adverse events

Vital Signs

ECG
 
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Objectives
Endpoints
participants with COPD

Spirometry

Clinical Laboratory Assessments 
(hematology, clinical chemistry, 
urinalysis)

To assess the effects of danirixin 
HBr 35mg twice daily on NETosis-
associated biomarkers in sputum and 
peripheral blood 

Change from baseline in sputum resistin 
levels

Change from baseline in the ratio of 
sputum NETs to sputum neutrophils

Change from baseline in sputum elastase 
activity

Change from baseline in peripheral blood 
neutrophil NET formation (DNA release, 
microscopy)

Characterise the population 
pharmacokinetic (PK) profile of 
approximately 14 days of dosing of 
danirixin HBr 35mg twice daily in 
participants with COPD

Model specific PK parameters of 
danirixin (e.g., oral clearance, oral steady-
state volume of distribution).
Exploratory

To explore the relationships between 
NETs formation and lung 
microbiome composition 

Characterize sputum microbiome 
composition and diversity

To explore volatile organic 
compound (VOC) profile in 
participants with COPD

Characterize relationship between lung
microbiome and exhaled volatile organic 
compounds (VOCs) in stable COPD 

To explore variability of exhaled VOCs

To explore the effects of danirixin 
HBr 35mg twice daily on neutrophil 
activity and exploratory biomarkers

Changes from baseline in ex-vivo 
neutrophil phagocytosis of bacteria by 
flow cytometry

Changes in exploratory urine, sputum and 
blood biomarkers (e.g. plasma fibrinogen, 
serum C-reactive protein, serum IL-8 or 
sputum mucin)

To explore the effects of an App on 
adherence to treatment with danirixin 
or placebo

Characterize treatment adherence in 
relation to monitoring via App and
explore relationship to PK parameters
 
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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, participants will be randomized (3:1) to receive danirixin 35 mg or placebo. 
Study treatment will be administered twice daily for 2 weeks. 
Based on the observed variability at an interim analysis, additional subjects may be 
enrolled to improve the statistical properties of the end of study decision criteria (i.e., the 
probability of a positive outcome). Outputs containing unblinded treatment assignments 
will be created for this interim analysis will only be made available to a limited number 
of GSK staff. Full details will be included in the study data dissemination plan. No 
Independent Data Monitoring Committee (IDMC) will be utilized for this study.
While the study is being conducted, core members of the study team will be unblinded 
(with the exception of those study team members who will directly interact with study 
sites, e.g. Operations and Science Leader and Data Quality Leader). There will be 
ongoing review of safety data and clinical outcomes. Only the study statistician will have 
access to individual participant treatment assignments, other core team members will 
review aggregate summaries by study treatments. A study charter will specify which 
team members will have access to unblinded data while the study is ongoing and the data 
to be included in the data reviews. 
The danirixin safety review team will perform ongoing safety review and will meet at 
least once while the study is ongoing and as needed based on emerging data to review 
available safety information.
Figure 1
Study Schematic
   30 days
Placebo, BD 
(~6 participants)
Screening 
period 
R
Danirixin 35mg BD 
(~18participants
14 days
Early 
Withdrawal
/ Follow-up
*R=Randomization 
Notes:

Early Withdrawal visit to occur as soon as possible (ASAP) after decision to 
withdraw by either investigator or participant

Follow up phone-call to occur within 7 days of last dose of study medication
 
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5.2.
Number of Participants
Approximately 50 participants will be screened to obtain approximately 24 subjects who 
are randomized and also complete the primary endpoint assessment at Day 14.  It is 
anticipated that less than 10% of participants will drop out of the study given the short 
duration of treatment.  
A maximum of 32 participants will be randomized such that approximately 24 evaluable 
participants complete the study. An evaluable participant is one that completes all 
assessments related to the primary endpoint at visits 0 - 4 (see Section 10.1 for further 
details). 
If participants prematurely discontinue the study, additional replacement participants may 
be recruited and assigned to the same treatment sequence at the discretion of the Sponsor 
in consultation with the investigator.
5.3.
Participant and Study Completion
A participant is considered to have completed the study if he/she has completed all
phases of the study including the last visit.
The end of the study is defined as the date of the last visit of the last participant in the 
study in the trial.
5.4.
Scientific Rationale for Study Design
This study is designed as a mechanistic study to evaluate the effect of danixirin in 
reducing NET formation. NET formation has been studied across several human studies, 
however consensus has not been reached on identification of NETs, which relies upon 
detection of DNA. Presence of bacterial DNA can confound results from sputum, 
therefore detection of histone elastase complexes is increasingly recognised as a specific 
and robust assay for detection of NETosis, and is used as the primary endpoint. The 
duration of treatment, 2 weeks, is adequate to see treatment effect given that neutrophil 
lifespan is 1-2 days.
5.5.
Dose Justification
One dose of danirixin is proposed for this study, 35mg twice daily.  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 in healthy volunteers

Evidence of reduced respiratory symptoms in mild to moderate COPD participants in 
the Phase IIa study (200163) 

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Analysis of the percent inhibition achieved across the pooled data from studies in healthy 
volunteers indicated that the maximum possible inhibition of CXCL1-induced CD11b 
activated neutrophil expression had been achieved following oral administration of 
danirixin at a nominal dose of 200 mg BID.
In Phase IIa COPD study (200163), a dose of danirixin (free base) 75 mg BID resulted in 
a reduction in respiratory symptoms compared to placebo.
The danirixin formulation to be used in this study (207551) will be a hydrobromide salt 
tablet.  The hydrobromide tablet has approximately twice the exposure of the free base 
tablet in healthy elderly participants (GSK Study No. 201037). Based on the anticipated 
higher exposure from the hydrobromide tablet, the 35 mg twice daily dose  was selected 
for this study to maximize the potential to see any impact on NET formation.
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1.
Participant must be 50 to 75 years of age inclusive, at the time of signing the 
informed consent.
Type of Participant and Disease Characteristics
2.
Diagnosis of COPD with mild to moderate airflow obstruction (post-bronchodilator 
FEV1/ Forced Vital Capacity (FVC) ratio <0.7 and FEV1% predicted (pred) ≥40% at 
screening) based on the Quanjer reference equations, with spirometry conducted 
according to American Thoracic Society (ATS)/European Respiratory Society (ERS) 
current guidelines.
3.
Elevated sputum neutrophil extracellular traps based on screening assay for histone-
elastase complexes of >0.5 units/ml sputum. Two further screening samples can be 
submitted for analysis within 30day screening period if previous samples do not pass 
criteria.
4.
Able to produce at least 1ml of sputum sample at the screening visit with nebulised 
saline induction
5.
Current smokers and former smokers with a cigarette smoking history of 10 pack
years (1 pack year = 20 cigarettes smoked per day for 1 year or equivalent). Former
smokers are defined as those who have stopped smoking for at least 6 months prior
to Visit 1.
 
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Weight
6.
Body weight 45 kg
Sex
7.
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, corresponding to
approximately 6 half-lives (which is the time needed to eliminate any  teratogenic 
treatments  after the last dose of study treatment and refrain from donating sperm 
during this period.
b. Female participants: 
A female participant is eligible to participate if she is not pregnant (see Appendix 5),
not breastfeeding, and at least one of the following conditions applies:
(i)
Not a woman of childbearing potential (WOCBP) as defined in Appendix 5
OR
(ii)
A WOCBP who agrees to follow the contraceptive guidance in Appendix 5
during the treatment period and for at least 60 hours after the last dose of 
study treatment.
Informed Consent
8.
Capable of giving signed informed consent as described in Appendix 3 which
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
Primary clinical diagnoses of any of the following relevant lung diseases; asthma, 
sarcoidosis, tuberculosis, pulmonary fibrosis, severe bronchiectasis or lung cancer
2.
Known alpha-1-antitrypsin deficiency 
3.
Pulse oximetry <88% at rest at screening.  Participants should be tested while 
breathing room air.
4.
Participants on long term oxygen therapy (defined as >15 hours/day of oxygen use)
5.
Unstable co-morbidities (eg cardiovascular disease, active malignancy) which in the 
opinion of the Investigator would make the participant unsuitable to be enrolled in 
the study. This includes any abnormality identified on screening bloods or screening 
ECG which in the opinion of the Investigator would make the participant unsuitable 
for the study. 
 
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6.
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.
7.
Current or chronic history of liver disease, or know hepatic or biliary abnormalities 
(with the exception of Gilbert’s syndrome or asymptomatic gallstones).
8.
Participants with a known or suspected history of alcohol or drug abuse within the 
last 2 years
Prior/Concomitant Therapy
9.
Antibiotic use concurrently or within 28 days preceding the screening visit, including 
current or planned chronic use of macrolide antibiotics during the study period for 
the prevention of COPD exacerbations.  Examples of chronic use include daily or 
two-three times per week for at least 3 months
10. Systemic immunosuppressive medication, including current oral corticosteroids at a 
dose >5mg, concurrently or within 28 days preceding the screening visit.
11. Oral or injectable Cytochrome P450 (CYP) 3A4 or Breast Cancer Resistance Protein 
(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: Methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, 
sulfasalazine, topotecan..
12. Current use of phosphodiesterase-4 inhibitors: Roflumilast, Crisaborole and 
Apremilast
13. Current use of Raloxifene
14. Current use of low molecular weight heparin
Prior/Concurrent Clinical Study Experience
15. The participant has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dosing day in the current 
study: 30 days, 5 half lives, or twice the duration of the biological effect of the 
investigational product (whichever is longer).
16. Exposure to more than four investigational products within 12 months prior to the 
first dosing day.
Diagnostic assessments
17. Participants with a peripheral blood neutrophil count < 1.0 x 109/L at screening
18. Diagnosis of pneumonia (chest X-ray or computed tomography [CT] confirmed) 
within the 3 months prior to screening
19. 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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20. Abnormal and clinically significant 12-lead ECG finding at screening.  The 
investigator will determine the clinical significance of each abnormal ECG finding in 
relation to the participant’s medical history and exclude participants who would be at 
undue risk by participating in the trial.  An abnormal and clinically significant 
finding that would preclude a participant from entering the trial is defined as a 12-
lead tracing that is interpreted as, but not limited to, any of the following:

AF with rapid ventricular rate > 120 beats per minute (bpm);

sustained or non-sustained ventricular tachycardia (VT)

second degree heart block Mobitz type II and third degree heart block 
(unless pacemaker or defibrillator has been implanted)

QT interval corrected for heart rate by Fridericia’s formula (QTcF)
500 msec in participants with QRS <120 msec and QTcF 530 
millisecond (msec) in participants with QRS 120 msec
Other Exclusions
21. Affiliation with a study site: study investigators, sub-investigators, study 
coordinators, employees of a study investigator, sub-investigator or study site, or 
immediate family members of any of the above that is involved with the study.
6.3.
Lifestyle Restrictions
No restrictions are required.
6.3.1.
Meals and Dietary Restrictions
No meal or dietary restrictions are required for participation in this study, but participants 
should have fasted for 6 hours prior to each visit.  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.
Caffeine, Alcohol, and Tobacco
Participants should refrain from alcohol for 24 hours prior to each study visit, and avoid 
caffeine for 6 hours prior to each visit. Participants should avoid changes to their tobacco 
habit for the duration of the study, and, where applicable, try to refrain from smoking for 
4 hours before each visit.
6.3.3.
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 
 
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requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any SAEs.
Individuals who do not meet the criteria for participation in this study (screen failure) or 
have an exacerbation of COPD in the screening period (run-in failure) may be rescreened
once. If rescreening is performed, subjects are assigned a different unique subject 
Identification (ID) number for the re-screening, and all the screening procedures must be 
repeated. 
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
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 HBr
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 Labelling
Study Treatment will be 
provided in a High-
density polyethylene
(HDPE) bottle with 
desiccant. Each bottle 
will be labelled as 
required per country 
requirement.
Study Treatment will be 
provided in a HDPE 
bottle with desiccant. 
Each bottle will be 
labelled as required per 
country requirement.
Manufacturer
GSK
GSK
7.2.
Dose Modification
No individual participant dose modifications or adjustments are allowed.
 
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7.3.
Method of Treatment Assignment
All participants will be centrally randomized using an Interactive Voice/Web Response 
System (IVRS/IWRS). Before the study is initiated, the telephone number and call-in 
directions for the IVRS and/or the log in information & directions for the IWRS will be 
provided to each site.
Study treatment will be dispensed at study visit 2 (see SoA). Returned study treatment 
should not be re-dispensed to the participants.
7.4.
Blinding
The IVRS/IWRS will be programmed with blind-breaking instructions. The blind may be 
broken by the investigator or treating physician in the case of an emergency, or if, in the 
opinion of the investigator, it is in the participant’s best interest for the investigator to 
know the study treatment assignment. The investigator is encouraged to discuss with the 
GSK Medical Monitor or appropriate GSK study personnel before the blind is broken. If 
GSK is not notified before the blind is broken, they must be notified as soon as possible 
after breaking the blind. The date and reason that the blind was broken must be recorded 
in the source documentation and electronic case report form (eCRF), as applicable.
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.
1.
The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment.
2.
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.
3.
The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records).
4.
Further guidance and information for the final disposition of unused study treatment 
are provided in the Study Reference Manual or other specified location.
5.
Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  
 
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6.
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 
danirixin or placebo will be assessed through querying the participant during the site 
visits and documented in the source documents and case report form (CRF).  A 
record of the number of danirixin or placebo tablets dispensed to and taken by each 
participant must be maintained and reconciled with study treatment and compliance 
records.  Treatment start and stop dates will also be recorded in the CRF.
Compliance at each visit will be determined as follows:
(# dispensed - # returned) x 100 / (# days since last visit)

Participants estimated to have taken less than 80% or more than 120% of study 
treatment tablets at two consecutive visits will be considered noncompliant. All 
attempts should be made to improve the participant’s compliance in taking study 
treatment at visit 3.

Treatment compliance may additionally be assessed via a digital application (a 
medication adherence monitoring Platform) for all participants in the study.  The 
Platform uses artificial intelligence on smartphones to confirm treatment ingestion. 
In addition, built-in reminders and a communication system allow real-time 
intervention in case of drug interruptions. Use of this platform will in no way 
supersede or replace the physician and/or prescribed medication protocol of the 
participants. Since the platform does not change the treatment protocol of the 
participants, but rather encourages adherence to the study treatment to the predefined 
protocol, use of this platform presents minimal risk to the participants. Consenting to 
use of the Platform is optional for participation in the study.
The monitoring Platform requires that all participants take each dose of the study
treatment while using a smartphone. The platform will be provided to participants 
preloaded on a smartphone, or participants can download the platform onto their own 
mobile device during V2. 
When at home, participants will receive reminders within predefined windows to self-
administer the study treatment using the front-facing webcam on their smartphone. The 
application on the smartphone will make an automated determination of whether the 
participant has properly ingested their treatment at the prescribed time. There is no need 
for a healthcare provider to review the administration, nor would a healthcare provider 
 
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need to be available at the time the participant takes their treatment. Further information 
on the Platform in available in Appendix 9 .
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. long-acting muscarinic antagonist [LAMA], long-acting beta-
agonist [LABA]) and long-acting bronchodilator combination therapies (e.g. 
LAMA/LABA) and long-acting bronchodilator/inhaled corticosteroid steroid 
combination (ICS) therapies (e.g. LABA/ICS, LAMA/LABA/ICS)
The following medications are prohibited from the screening visit until after completion 
of the follow up visit:

Systemic immunosuppressive medication, including current oral corticosteroids 
at a dose >5 mg, concurrently or within 28 days preceding the screening visit.

Acute or chronic use of antibiotics, including macrolides for the prevention or 
treatment 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 includeMethotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, 
rosuvastatin, sulfasalazine, topotecan.

Current use of phosphodiesterase-4 inhibitors: Roflumilast, Crisaborole and 
Apremilast

Broad spectrum phosphodiesterase inhibitors (e.g. theophylline)

Raloxifene

Low molecular weight heparin
 
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GSK will not supply rescue medication.  Participants may continue to use and should 
obtain rescue medication(s) through via their usual route. The following rescue 
medications may be used:

Short acting beta agonists (SABA)(e.g., albuterol/salbutamol)

Short acting muscarinic antagonists (SAMA)(e.g., ipratropium)

Short acting combination (SABA/SAMA) bronchodilations, (e.g. Duoneb, 
Combivent)
The use of rescue medications is allowable at any time during the study. 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
A participant who discontinues study treatment should return to the clinic only for safety 
assessments as part of an unscheduled visit (physical examination, 12-lead ECG, vitals, 
blood tests, urinalysis and concomitant medication review) and to return IP as detailed in 
the SoA and Section 9.4.
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.
Discontinuation of study treatment for abnormal liver tests is required when:

a participant meets one of the conditions outlined in the algorithm
OR

when in the presence of abnormal liver chemistries not meeting protocol-
specified stopping rules, the investigator believes study treatment 
discontinuation  is in the best interest of the participant. 
 
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Phase II Liver Chemistry Stopping and Increased Monitoring Algorithm
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 7
8.1.2.
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 discontinue treatment and withdraw from the study.  
The neutrophil count should be monitored daily until it returns to within the baseline 
value, as detailed in Appendix 8.
8.1.3.
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 QT interval 
corrected for heart rate by Bazett's formula (QTcB), then QTcB must be used for 
discontinuation of this individual participant as well.

Once the QT correction formula has been chosen for a participant’s eligibility, 
the same formula must continue to be used for that participant for all QT 
 
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interval corrected for heart rate (QTc) data being collected for data analysis.  
Safety ECGs and other non-protocol specified ECGs are an exception.  

The QTc should be based on single or averaged QTc values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording period.  
A participant who meets either bulleted criteria based on the average of triplicate ECG 
readings will be withdrawn from study treatment:

QTc >500 msec OR Uncorrected QT >600 msec

Change from baseline of QTc >60 msec
For participants 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 for data to be collected at the time of treatment discontinuation and follow-
up and for any further evaluations that need to be completed.
8.1.4.
Temporary Discontinuation
Withdrawal of study treatment requires withdrawal from the study.
8.1.5.
Rechallenge
8.1.5.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed.
8.2.
Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, 
or may be withdrawn at any time at the discretion of the investigator for safety, 
behavioral, compliance or administrative reasons.

If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent.

If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records.
 
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
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.
Any participant who experiences a COPD exacerbation (i.e., associated with 
antibiotic or steroid use) will be permanently discontinued from study 
treatment and should return to the clinic for follow-up if possible.  Only the 
safety assessments scheduled for the follow-up visit should be conducted in 
these participants as described in the SoA (Section 2).
8.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 
9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA. 

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 (eg, 
blood count) and obtained before signing of ICF may be utilized for screening or 
 
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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.
Induced Sputum samples
Participants should have pre-treatment with a short-acting bronchodilator prior to sputum 
induction where they have not conducted post-bronchodilator spirometry prior to sputum 
induction. Sputum  induction  will be performed  using  3%  saline  given  as  3  
nebulisations [Singh, 2010]. Where 3% saline is insufficient to obtain a sufficiently large 
sputum sample, 4.5% saline will be administered as 3 nebulisations. This process may 
take from 10 to more than 20 minutes, depending on the participant and the concentration 
of salt. Sputum induction can be terminated at any time if participants are able to produce 
a sputum sample of sufficient volume. The participant should be monitored for 15 
minutes following the procedure; if any respiratory distress or wheezing is present, a 
short-acting bronchodilator should be administered. Safety spirometry is required for 15 
minutes after end of the procedure (see Section 9.4.5), and a short-acting bronchodilator 
should be administered if there is any evidence of bronchospasm.
A minimum of 1ml of sputum will be collected. Remaining sputum may be stored for 
future biomarker analysis (see Section 9.1.2)
9.1.2.
Biomarkers
Sputum will be used to assess NET formation via a range of measures: Histone-elastase 
complexes, DNA-elastase complexes, NET area quantification by microscopy, ratio of 
sputum NETs to sputum neutrophils. Additionally, sputum will also be analyzed for 
resistin levels, elastase activity, microbiome composition and diversity and ex-vivo 
neutrophil phagocytosis of bacteria by flow cytometry, as samples permit. 
Blood will be used for the assessment of NET formation in peripheral blood and to 
explore biomarkers associated with disease activity such as plasma fibrinogen and C-
reactive protein (CRP).
Storage of biomarkers for future research is an optional part of this study, and 
participants will be asked for written consent for storage, which they can withdraw at any 
time. Blood, urine and sputum samples for biomarker research will be collected from 
participants in this study where possible as specified in the SoA. 
Since collection of biomarkers is optional, separate collection procedures are not 
essential, i.e. sputum collection is through any remaining sputum from induction, and a 
further sputum induction is not necessary. Similarly, blood and urine will be collected for 
storage at the same time as taking clinical measurements for the study; where remnant 
 
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volumes are insufficient for storage, further attempts at collection are entirely voluntary 
for participants.
In addition, with the participant’s consent, samples will be stored and analysis may be 
performed on biomarker variants thought to play a role in NETosis to evaluate their 
association with observed clinical responses to danirixin.
Other samples may be used for research to develop methods, assays, prognostics and/or 
companion diagnostics related to danirixin, disease process, pathways associated with 
disease state, and/or mechanism of action of the study treatment.
9.1.3.
Measurement of volatile organic compounds (VOCs)
Exhaled breath samples through normal tidal breathing will be collected via a ReCIVA 
(Owlstone Medical, Cambridge, UK) collection device, which connects a disposable face 
mask onto multiple sorbent tubes that bind VOCs. The sorbent tubes will be stored and 
later subject to analysis via one or more devices that measure patterns of exhaled VOCs,
such as eNoses or Field asymmetric ion mobility spectrometry (FAIMS) devices, and 
may also be subject to gas chromatography mass spectrometry for comparison. Exhaled 
breath samples should be collected at the timepoints specified in the SoA, and samples 
should be collected prior to administration of bronchodilators and sputum induction (with 
the exception of the samples taken at 4 hours post dose). Further sampling considerations 
are detailed in the SRM.
9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4.
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study,
or that caused the participant to discontinue the study treatment (see Section 8). 
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the signing of the ICF until the follow-up visit
at the time points specified in the SoA (Section 2).

All AEs will be collected from the signing of the ICF until the follow-up visit at 
the time points specified in the SoA (Section 2).

Medical occurrences that begin before the start of study treatment but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the CRF not the AE section.

All SAEs will be recorded and reported to the sponsor or designee immediately 
and under no circumstances should this exceed 24 hours, as indicated in
Appendix 4. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.
 
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
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
9.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the participant is the preferred method to inquire 
about AE occurrence. 
9.2.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and non serious AEs of special 
interest (as defined in Appendix 4) will be followed until the event is resolved, stabilized, 
otherwise explained, or the participant is lost to follow-up (as defined in Section 8.3). 
Further information on follow-up procedures is given in Appendix 4.
9.2.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are 
met. 

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study treatment 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or 
other specific safety information eg, summary or listing of SAE) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.
9.2.5.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 4 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will 
 
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be required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
9.2.6.
Pregnancy

Details of all pregnancies in female participants and, if indicated, female partners of 
male participants will be collected after the start of study treatment and until 60 
hours after the end of treatment.

If a pregnancy is reported, the investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 5

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
9.3.
Treatment of Overdose
For this study, any dose of danirixin greater than 70 mg within a 24-hour time period 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 if 
applicable, for at least 3 days following overdose.
3.
Obtain a plasma sample for PK analysis 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.
 
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9.4.1.
Physical Examinations

A complete physical examination will include, at a minimum, assessments of the 
Skin, Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. 
Height and weight (with participants wearing no shoes) will also be measured 
and recorded.

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
9.4.2.
Vital Signs

Pulse rate, respiratory rate, and blood pressure will be assessed.

Seated blood pressure and pulse measurements will be assessed with a 
completely automated device. Manual techniques will be used only if an 
automated device is not available.

Blood pressure and pulse measurements should be preceded by at least 5 
minutes of rest for the participant in a quiet setting without distractions (eg, 
television, cell phones).

Vital signs (to be taken before blood collection for laboratory tests) will consist 
of 1 pulse and 3 blood pressure measurements (3 consecutive blood pressure 
readings will be recorded at intervals of at least 1 minute). The average of the 3 
blood pressure readings will be recorded on the CRF.
9.4.3.
Electrocardiograms

Triplicate 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 8.1.3 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 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.
 
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
All laboratory tests with values considered clinically significantly abnormal 
during participation in the study should be repeated until the values return to 
normal or baseline or are no longer considered significantly abnormal by the 
investigator or medical monitor. 

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
9.4.5.
Spirometry
Post-bronchodilator spirometry using FEV1 and FVC measurements (FEV1%pred, and 
FVC%pred and FEV1/FVC will be calculated based on Quanjer reference equations 
[Quanjer, 2012]) will be at time points listed in the SoA. Spirometry assessments should 
be performed in accordance with ATS/ERS guidelines as outlined in the SRM.
9.5.
Pharmacokinetics
Blood samples for pharmacokinetic analysis of danirixin (approximately 1ml) will be 
collected at the time points indicated in SoA. The actual date and time of each blood 
sample collection will be recorded. The timing of PK samples may be altered and/or PK 
samples may be obtained at additional time points to ensure thorough PK monitoring. 
Processing, storage and shipping procedures are provided in the SRM.
Blood analysis will be performed under the management of Platform Technology and 
Science (PTS)/In vitro In Vivo Translation (IVIVT)/Third Party Resourcing (TPR), 
GlaxoSmithKline. Concentrations of DNX will be determined in the blood samples using 
the currently approved analytical methodology. 
Raw data will be stored at the bioanalytical site (detailed in the SRM).
Once the blood has been analyzed for DNX, any remaining blood may be analyzed 
qualitatively for other circulating metabolites and the results reported under a separate 
PTS-IVIVT, GlaxoSmithKline protocol.
9.6.
Genetics
A 6 mL blood sample for DNA isolation will be collected from participants who have 
consented to participate in the genetics analysis component of the study. Participation is 
optional. Participants who do not wish to participate in the genetic research may still 
participate in the study.
In the event of DNA extraction failure, a replacement genetic blood sample may be
requested from the participant. Signed informed consent will be required to obtain a 
replacement sample unless it was included in the original consent.
 
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See Appendix 6 for Information regarding genetic research. Details on processes for 
collection and shipment and destruction of these samples can be found in the study 
reference manual.
9.7.
Biomarkers
See Section 9.1.2 for information on biomarker collection and analysis.
9.8.
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
10.1.
Sample Size Determination
Approximately 50 subjects will be enrolled in the study to obtain approximately 24 
subjects who are randomized and also complete the primary endpoint assessment at Day 
14.  Subjects who are withdrawn may be replaced.  Subjects will be randomized at a ratio 
of 3:1 for Danirixin:placebo.
While the sample size has been determined by feasibility, consideration has been made 
regarding the probability of observing a reduction in sputum NETs (quantified by 
Histone-elastase complexes).  Observational data from an external cohort of COPD 
patients (not yet published) was used to quantify variability of the measurement and used 
for simulations.  Other ex vivo data [Pedersen, 2017] using another CXCR2 receptor 
antagonist and a different assay method had demonstrated a 40% reduction in median 
spontaneous NET formation. 
Danirixin effect is modelled through a parameter, ρ, which indicates the extent Danirixin 
attenuates the true mean sputum NETs value under treatment with placebo. If ρ = 1, then 
there is no Danirixin effect; if ρ < 1, then Danirixin reduces the mean sputum NETs value 
by that amount (e.g. if ρ = 0.7 then Danirixin reduces mean sputum NETs by 30%.) 
A mixture prior was utilized. One centred on no effect (ρ = 1), the other centred on an 
effect with ρ = 0.7, with both normally distributed with the same standard deviation 
(0.182, based on historical data).  It was assumed that under the no effect case, the 
probability that ρ is less than 0.7 is 5% and under the effect case, the probability that ρ is 
greater than 1.0 is 5%. The mixture prior used equal weight for each scenario. 
Based on this prior, the following probabilities for the study were estimated: 

The probability to observe a mean Danirixin sputum NETs value, which is lower 
than that observed in the historical data set, is 69.3%.
 
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
The study has a 70% probability of success of being at least 50% certain, after the 
study, that the true mean sputum NETs values for Danirixin are lower than 
Placebo 
These estimates are contingent on assumptions about Danirixin effects; the ones selected 
are a priori plausible but may change once data from the study is available. Changes to 
sample size may be made based on the accruing information about effect size and 
variability once sufficient data is available.
10.2.
Populations for Analyses

For purposes of analysis, the following populations are defined:
Population
Description
Enrolled 
All participants who sign the ICF
This population will be used for tables/listings of reasons for 
withdrawal before randomization and listings of AEs and SAEs for 
non-randomized subjects.
Randomized
This population (also considered as the Intent-to-Treat (ITT) 
Population) will consist of all subjects randomized to treatment who 
receive at least one dose of study medication.  This will constitute 
the primary population for all analyses.
Primary Completer
This population will consist of all subjects in the Randomized 
population who have completed the assessments supporting the 
primary endpoint (sputum NETs).
Safety
All participants in the Randomized population who take at least one
dose of study treatment. Participants will be analyzed according to 
the treatment they actually received.

Subjects who withdraw from the study and are replaced will be part of the 
Enrolled, Randomized and (if applicable) Safety populations.

The primary analysis for the study (mean reduction in sputum NETs) will use the 
Primary Completer population.
10.3.
Statistical Analyses
10.3.1.
Efficacy Analyses
The Primary Completer population will be used for the primary analysis of sputum NETs.  
A mixed effects model with repeated measures will be used for the sputum NETs data.  
The mean and corresponding 95% credible interval will be calculated for the Danirixin 
 
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treatment arm at Day 14.  The posterior probability that the true mean reduction from 
baseline for the Danirixin treatment group in sputum NETs is greater than a 0%, 15%, 
30% and 40% reduction will be calculated, as appropriate, depending on the observed 
data.
Additionally, the mean and corresponding 95% credible interval for the difference 
between Danirixin and placebo at Day 14 will be produced. The posterior probability that 
the true relative reduction from baseline in sputum NETs is greater than a 0%, 15%, 30% 
and 40% reduction will be calculated, as appropriate, depending on the observed data.  
The existing reference data may be used to construct the prior distribution for the placebo 
arm instead of a non-informative prior.  A non-informative prior will be utilized for the 
other parameters in the statistical model as appropriate to their distribution.
Other efficacy data will be presented in tabular and/or graphical format and summarized 
descriptively. Full details of the analyses to be performed on all efficacy endpoints will 
be described in the reporting and analysis plan (RAP).
10.3.2.
Safety Analyses
The Safety population will be used for all safety analyses.  Safety data will be presented 
in tabular and/or graphical format and summarized descriptively. Full details of the 
analyses to be performed on all safety endpoints will be given in the RAP.
10.3.3.
Pharmacokinetic Analyses
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacokinetics 
Modelling & Simulation department within GlaxoSmithKline. Blood danirixin 
concentration-time data will be analyzed by non-compartmental methods with 
WinNonlin 5.2.or later. Calculations will be based on the actual sampling times recorded 
during the study. From the blood concentration-time data, the following pharmacokinetic 
parameters will be determined, as data permit: maximum observed blood concentration 
(Cmax), time to Cmax (tmax), area under the blood concentration-time curve [AUC(0-t)], 
time of last observed concentration (tlast). The RAP will describe the planned analyses in 
greater detail.
PK data from this study may be combined with historic data for the purposes of 
population PK modelling which would be the subject of a separate analysis plan and 
would be presented separately from the main clinical study report (CSR). 
10.3.4.
Other Analyses
Biomarker and exploratory analyses will be described in the RAP.  
Population analyses for volatile organic compounds will be the subject of a separate 
analysis plan and presented separately from the main clinical study report (CSR).
 
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10.3.5.
Interim Analyses
An interim analysis of the primary endpoint may be performed at the discretion of the 
sponsor to make a determination whether to enrol additional subjects beyond the target of 
24 evaluable participants, based on the determination of the posterior probability of a 
reduction in sputum NETs in the Danirixin arm..  All available data for evaluable subjects 
for sputum NETs using the histone elastase assay will be included in the analysis.  
The RAP will describe the planned interim analyses in greater detail.
10.3.6.
Data Management

For this study subject data will be entered into GSK defined CRFs, transmitted
electronically to GSK or designee and combined with data provided from other
sources in a validated data system.

Management of clinical data will be performed in accordance with applicableGSK
standards and data cleaning procedures to ensure the integrity of the data, e.g.
removing errors and inconsistencies in the data.

Adverse events and concomitant medications terms will be coded using MedDRA
(Medical Dictionary for Regulatory Activities) and an internal validated medication
dictionary, GSK Drug.
CRFs (including queries and audit trails) will be retained by GSK, and copies will be sent 
to the investigator to maintain as the investigator copy. Subject initials andday/month of 
birth will not be collected or transmitted to GSK according to GSK.
 
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11.
REFERENCES
Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS,et al. 
Neutrophil extracellular traps kill bacteria. Science. 2004;3:1532-35
Delgado-Rizo V, Martinez-Guzman MA, Iniguez-Gutierrez L, Garcia-Orozco A, 
Alvarado-Navarro A, Fafutis-Morris M. Neutrophil extracellular traps and its 
implications in inflammation: an overview. Front Immunol. 2017;8:81
Dicker AJ, Crichton ML, Pumphrey EG, Cassidy AJ, Suarez-Cuartin G, Sibila O. 
Neutrophil Extracellular Traps are associated with disease severity and microbiota 
diversity in Chronic Obstructive Pulmonary Disease. Jour Aller and Clin Imm. 2017; doi: 
10.1016/j.jaci.2017.04.022.
GlaxoSmithKline Document No. 2013N180289_03. A Two Part, Phase IIa, Randomized, 
Placebo-Controlled Study to Investigate the Safety, Tolerability, Pharmacokinetics, 
Pharmacodynamics, and Clinical Efficacy of Oral Danirixin (GSK1325756) in 
Symptomatic COPD Subjects with Mild to Moderate Airflow Limitation at Risk for 
Exacerbations.  2015
GlaxoSmithKline Document No. 2014N205875_00. A randomized, double-blind, 
placebo controlled study to evaluate the safety, tolerability and clinical effect of oral 
danirixin (GSK1325756) in the treatment of healthy adults with acute, uncomplicated 
influenza (201682).  2014
GlaxoSmithKline Document No. YM2010/00163/08. Danirixin Investigator's Brochure.  
2017
Grabcanovic-Musija F, Obermayer A, Stoiber W, Krautgartner W-D, Steinbacher P, 
Winterberg N, et al. Neutrophil extracellular trap (NET) formation characterises stable 
and exacerbated COPD and correlates with airflow limitation. Respir Res. 2015;16:59
Marcos V,  Zhou Z  Yildirim AO,  Bohla A, Hector A, Vitkov L, et al. CXCR2 mediates 
NADPH oxidase-independent neutrophil extracellular trap formation in cystic fibrosis 
airway inflammation. Nature Med. 2010;16:1018–23
Miller BE, 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 Resp Jour. 
2016; 48: PA1047
Narasaraju T, Yang E, Samy RP, Ng HH, Poh WP, Liew A, et al. Excessive Neutrophils 
and Neutrophil Extracellular Traps Contribute to Acute Lung Injury of Influenza 
Pneumonitis. Am Jour Path. 2011; 179:199–210
Pedersen F, Waschki B, Marwitz S, Goldmann T, Kirsten A, Rabe KF, et al. The 
Chemokine Receptor CXCR2 Regulates Formation of Neutrophil Extracellular Traps in 
COPD Patients. Am Thoracic Society Conf 2017. P1207.
 
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Pires RH, Felix SB, Delcea M. The architecture of neutrophil extracellular traps investigated 
by atomic force microscopy. Nanoscale. 2016; 8: 14193-14202
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL et al. Multi-ethnic reference values for 
spirometry for the 3-95 year age range: the global lung function 2012 equations. Eur Resp
J. 2012;40: 1324-43
Shafiek H, Fiorentino F, Merino JL, López C, Oliver A, Segura J, et al. Using the
Electronic Nose to Identify Airway Infection during COPD Exacerbations. PLOS ONE.
2015;10: e0135199.
Singh D, Edwards L, Tal-Singer R, Rennard S. Sputum neutrophils as a biomarker in 
COPD: findings from the ECLIPSE study. Resp Research. 2010;11:77
 
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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
AE
Adverse Event
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
ASAP
As soon as possible
ATS
American Thoracic Society
AUC(0-24)
Area under the concentration curve from pre-dose to 24 
hours post-dose
BID
Twice daily dosing
BPM
Beats per minutes
CONSORT
Consolidated Standards of Reporting Trials
BCRP
Breast Cancer Resistance Protein
COPD
Chronic Obstructive Pulmonary Disease
CRF
Case Report Form
CRP
C-reactive protein
CSR
Clinical study report
CT
Computed tomography
CV
Cardiovascular
CXCL1
chemokine (C-X-C motif) ligand 1
CXCR2
CXC chemokine receptor type 2
CYP3A4
cytochrome P-450 isoenzyme 3A4 
DNA
Deoxyribonucleic acid
DNX
Danirixin
ECG
Electrocardiogram
eCRF
Electronic case report form
ERS
European Respiratory Society
FAIMS
Field asymmetric ion mobility spectrometry
FDA
United States Food and Drug Administration
FEV1
The amount of air which can be forcibly exhaled from the 
lungs in the first second of a forced exhalation also known 
as forced expiratory volume in one second
FSH
Follicle Stimulating Hormone
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GFR
Glomerular Filtration Rate
GSK
GlaxoSmithKline
Hep C
Hepatitis C
HBr
Hydrobromide
HBsAg
Hepatitis B Surface Antigen
HDPE
High-density polyethylene
IB
Investigator's Brochure
HIV
Human Immunodeficiency Virus
 
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ICH
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use
ICS
Inhaled corticosteroid
ID
Identification
IDSL
Integrated Data Standards Library
IEC
Independent Ethics Committee
ITT
Intent-to-treat
IRB
Institutional Review Board
IVRS/IWRS
Interactive Voice/Web Response System
LABA
Long-acting beta-agonist
LAMA
Long-acting muscarinic antagonist
MedDRA
Medical Dictionary for Regulatory Activities
MSDS
Material Safety Data Sheet
NETs
Neutrophil extracellular traps
NETosis
NET formation
NOAEL
No observed adverse effect level
PK
Pharmacokinetic
Pred
Predicted
PTS-DMPK
Platform Technology and Science- Drug Metabolism and 
Pharmacokinetics
QTc
QT interval corrected for heart rate
QTcB
QT interval corrected for heart rate by Bazett's formula
QTcF
QT interval corrected for heart rate by Fridericia’s formula
RAP
Reporting and Analysis Plan
RNA
Ribonucleic acid
SABA
Short acting beta agonists
SAE
Serious Adverse Event
SAMA
Short acting muscarinic antagonists
SRM
Study Reference Manual
SRT
Safety Review Team
SoA
Schedule of Activity
SUSAR
Suspected unexpected serious adverse reactions
ULN
Upper Limit of Normal (reference range for laboratory)
VOC
Volatile organic compound
VT
Ventricular tachycardia
WOCBP
Woman of child bearing potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
ReCIVA
 
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12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 1 will be performed by the local laboratory. 

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 6 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 1
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
MCV
MCH
%Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Fibrinogen
Clinical 
Chemistry1
BUN
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT)
Total Protein
Glucose [non-
fasting]
Calcium
Alkaline 
phosphatase
C-reactive protein
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte 
esterase by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

Follicle-stimulating hormone (as needed in women of non-childbearing 
potential only)

Urine human chorionic gonadotropin (hCG) pregnancy test (as needed for 
women of childbearing potential)2

Serology [(HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis 
 
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Laboratory 
Assessments
Parameters
C virus antibody) [if applicable] 
The results of each test must be entered into the CRF.
NOTES :
1.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 8.1 and Appendix 7 All events of ALT 3 × upper limit of normal (ULN) and 
bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (INR) >1.5, if INR 
measured, which may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis).
2.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC.
 
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12.3.
Appendix 3: Study Governance Considerations
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (eg, advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study. 
 
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
Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study 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.
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 
 
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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
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. 

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 from the issue of the final 
Clinical Study Report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without 
written notification to the sponsor. 

Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report.  The investigator 
will be provided reasonable access to statistical tables, figures, and relevant 
reports and will have the opportunity to review the complete study results at a 
GSK site or other mutually-agreeable location.

GSK will also provide the investigator with the full summary of the study 
results.  The investigator is encouraged to share the summary results with the 
study subjects, as appropriate.

GSK will provide the investigator with the randomization codes for their site 
only after completion of the full statistical analysis.
 
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
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK 
Policy.
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 SRM.
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study treatment development
 
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12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study treatment, whether or not considered related to the 
study treatment.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfill the definition of an AE 
or SAE. 
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
 
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the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
 
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f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
 
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requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
each occurrence of each AE/SAE.

A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated.

The investigator will also consult the 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 
 
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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, then the site will use the paper SAE data 
collection tool  in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hours of SAE 
entry into the eCRF.

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the SAE coordinator by telephone.

Contacts for SAE reporting can be found in study reference manual.
 
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SAE Reporting to GSK via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the SAE coordinator.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in the study reference manual.
 
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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 2 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.

In addition male participants must refrain from donating sperm for duration of 
study and for 60 hours after study completion or from last dose.
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 2.
Table 2
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 pregnancy test 

Additional pregnancy testing is not required during the treatment period, but is 
required 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.
Collection of Pregnancy Information
Male participants with partners who become pregnant

Investigator will attempt to collect pregnancy information on any male participant’s 
female partner of a male study participant who becomes pregnant while participating 
in this study. This applies only to participants who receive study treatment.

After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the partner’s 
pregnancy. 

Partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure. 
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date.  

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 
 
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
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 
treatment and will 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, COPD and related 
diseases, or neutrophil extracellular traps. They may also be used to develop 
tests/assays including diagnostic tests) related to danirixin and other CXCR2 
antagonists, and COPD. Genetic research may consist of the analysis of one or more 
candidate genes or the analysis of genetic markers throughout the genome [or 
analysis of the entire 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 continues but no longer than 15 years after the last subject last visit 
or other period as per local requirements.
 
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12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments 
Phase II liver chemistry stopping and increased monitoring criteria have been 
designed to assure participant safety and evaluate liver event etiology 
Phase II liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin)
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot 
Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed 
to be related to liver injury or hypersensitivity
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Immediately discontinue  study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver chemistry event follow up 
assessments 

Monitor the participant until liver 
chemistries resolve, stabilize, or return to 
within baseline (see MONITORING
below)

Do not restart/rechallenge participant 
with study treatment unless allowed per 
protocol and GSK Medical Governance 
approval is granted (see below)

If restart/rechallenge not allowed per 
protocol or not granted, permanently 

Viral hepatitis serology4

Obtain INR and recheck with each 
liver chemistry assessment until the 
transaminases values show 
downward trend

Obtain blood sample for 
pharmacokinetic (PK) analysis, up 
to 72 h after last dose5

Serum creatine phosphokinase 
(CPK) and lactate dehydrogenase 
(LDH).

Fractionate bilirubin, if total 
bilirubin 2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or 
worsening of clinical symptoms of 
 
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discontinue study treatment and continue 
participant in the study for any protocol 
specified follow up assessments 
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, 
AST, alkaline phosphatase, bilirubin) and 
perform liver event follow up assessments 
within  24 hrs

Monitor participants twice weekly until 
liver chemistries resolve, stabilize or return 
to within baseline 

A specialist or hepatology consultation is 
recommended
For All other criteria: 

Repeat liver chemistries (include ALT, 
AST, alkaline phosphatase, bilirubin) and 
perform liver event follow up assessments 
within  24-72 hrs 

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
liver injury, or hypersensitivity, on 
the AE report form

Record use of concomitant 
medications on the concomitant 
medications report form including 
acetaminophen, herbal remedies, 
other over the counter medications.

Record alcohol use on the liver 
event alcohol intake case report 
form (CRF) page 
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin 
G (IgG) or gamma globulins.

Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver 
injury in participants with definite 
or likely acetaminophen use in the 
preceding week [James, 2009]. 

Liver imaging (ultrasound, 
magnetic resonance, or 
computerised tomography) and /or 
liver biopsy to evaluate liver 
disease; complete Liver Imaging 
and/or Liver Biopsy CRF pages.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that participant if ALT 3xULN and bilirubin 2xULN.. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to participants receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen (HbsAg) and Hepatitis B Core Antibody (IgM); 
Hepatitis C RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, 
obtain heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
 
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5.
PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
treatments.)  Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
treatment prior to PK blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the 
participant’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot 
be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and 
shipping are in the SRM.  
Phase II liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 3xULN and <5xULN and bilirubin 
<2xULN, without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks

Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss participant 
safety. 

Participant can continue study treatment  

Participant must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time participant meets the liver chemistry 
stopping criteria, proceed as described above

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor participants twice monthly 
until liver chemistries normalize or return to within 
baseline.
Reference
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
 
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12.8.
Appendix 8: Neutrophil Safety 
Neutrophil Stopping Criteria: Absolute neutrophil count (ANC) 0.5 x 109 /L
(peripheral blood)
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 
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 
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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12.9.
Appendix 9: Medication Adherence Platform
After the device confirms proper treatment ingestion, video recordings will be encrypted 
and transmitted to a secure centralized location for further analysis, including testing for 
duplicate enrolment. The captured data and video is reviewable through a roles and rules 
restricted system ensuring privacy of the information. All video images and data captured 
by the AiCure application will be held in encrypted format, both within the application 
itself and on the secure servers used to validate the Study; those servers are located in the 
U.S., and therefore your data will be stored and processed in the U.S. The system has 
been designed to support compliance with applicable regulations to protect the privacy 
and security of healthcare information, including the Data Protection Act 1998. 
Phone numbers of the participants may also be collected and stored in an encrypted 
manner. Storing the phone numbers will allow for direct communication with 
participants, including automated messaging from the Platform device and contact by 
healthcare providers or other monitoring personnel.  At no time is the phone number 
visible to healthcare providers or monitoring personnel.  Individuals outside the clinical 
sites will not be provided with participant names, nor will they be given access to 
participant medical records.
The Platform Provider will protect participants’ personal information to the full extent 
required by law.  However, information from this Study, including de-identified video 
recording(s) of participant performance of various actions, may be submitted to the Study 
site, and potentially to the U.S. Food and Drug Administration (FDA). Both information 
obtained by the application, and information in the participant Informed Consent, may be 
examined by the Study site or the Study site’s representatives, and may also be reviewed 
by the FDA and other regulatory agencies, Institutional Review Board(s) and or Ethics 
Committee(s). A depersonalized version of the Study data may be generated and retained 
by the Platform Provider for use beyond the term of the trial. This will be utilized solely 
to improve the operation of the Platform, categorize adherence activity by disease state or 
other useful categories, and/or for regulatory filings by the Platform Provider to support 
future applications for the Platform Provider’s product. Individuals who are not 
associated with the care and treatment of participants will not have access to participant 
identity or any medical records. The Platform Provider may also retain a copy of Study 
data in disaggregated (ie identifiable participant) format beyond the term of the trial for 
the above purposes where the relevant participant has provided express written 
authorization for the Platform Provider to do this. Any such authorization shall be 
entirely voluntary on the part of the participant and separate from participation in the 
Study.  
 
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SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
207551
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for a Randomized double blind 
(sponsor unblind) study evaluating the effect of 14 days of 
treatment with danirixin (GSK1325756) on neutrophil 
extracellular traps (NETs) formation in participants with 
stable chronic obstructive pulmonary disease (COPD)
Compound Number 
:
GSK1325756
Effective Date 
:
14-NOV-2018
Description:

The purpose of this RAP is to describe planned efficacy and safety analyses and 
output to be included in the Clinical Study Report (CSR) for Protocol 207551.

This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable.
RAP Author(s):
Approver
Date
Approval Method
13-NOV-2018
e-mail
Statistician (Respiratory Clinical Statistics)
14-NOV-2018
e-mail
Programming Manager (Respiratory Clinical 
Programming)
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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The GlaxoSmithKline group of companies
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RAP Team Approvals:
Approver
Date
Approval Method
13-NOV-2018
e-mail
Physician (CIL)
13-NOV-2018
e-mail
Principal Clinical Research Scientist (OSL)
13-NOV-2018
e-mail
Principal Data Manager (DQL)
Clinical Statistics and Clinical Programming Line Approvals:
Approver
Date
Approval Method
 
Project Statistician (Respiratory Clinical 
Statistics)
On behalf of 
14-NOV-2018
e-Signature
Line Manager (Respiratory Clinical Statistics)
Project Programmer (Respiratory Clinical 
Statistics)
On behalf of 
14-NOV-2018
e-Signature
Line Manager (Respiratory Clinical Statistics)
 
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TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................6
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................6
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................6
2.2.
Study Objective(s) and Endpoint(s)...............................................................7
2.3.
Study Design ................................................................................................8
2.4.
Statistical Hypotheses / Statistical Analyses .................................................8
3.
PLANNED ANALYSES ............................................................................................9
3.1.
Interim Analyses ...........................................................................................9
3.2.
Final Analyses ..............................................................................................9
4.
ANALYSIS POPULATIONS .....................................................................................9
4.1.
Protocol Deviations.....................................................................................10
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................12
5.1.
Study Treatment & Sub-group Display Descriptors.....................................12
5.2.
Baseline Definitions ....................................................................................12
5.3.
Examination of Covariates, Other Strata and Subgroups............................12
5.3.1.
Covariates and Other Strata ........................................................12
5.4.
Multiple Comparisons and Multiplicity .........................................................13
5.5.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................13
6.
STUDY POPULATION ANALYSES .......................................................................14
6.1.
Overview of Planned Study Population Analyses........................................14
7.
EFFICACY ANALYSES..........................................................................................15
7.1.
Primary Efficacy Analyses ..........................................................................15
7.1.1.
Endpoint / Variables.....................................................................15
7.1.2.
Summary Measure ......................................................................15
7.1.3.
Population of Interest...................................................................15
7.1.4.
Strategy for Intercurrent (Post-Randomization) Events ................15
7.1.5.
Statistical Analyses / Methods .....................................................15
7.1.5.1.
Statistical Methodology Specification..........................15
7.2.
Secondary Efficacy Analyses......................................................................16
7.2.1.
Endpoint / Variables.....................................................................16
7.2.2.
Summary Measure ......................................................................16
7.2.3.
Population of Interest...................................................................16
7.2.4.
Statistical Analyses / Methods .....................................................16
7.2.5.
Endpoint / Variables.....................................................................16
7.2.6.
Summary Measure ......................................................................16
7.2.7.
Population of Interest...................................................................16
7.2.8.
Statistical Analyses / Methods .....................................................17
7.2.8.1.
Statistical Methodology Specification..........................17
7.3.
Exploratory Efficacy Analyses.....................................................................17
7.3.1.
Endpoint / Variables.....................................................................17
 
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8.
SAFETY ANALYSES .............................................................................................19
8.1.
Adverse Events Analyses ...........................................................................19
8.2.
Adverse Events of Special Interest Analyses..............................................19
8.3.
Clinical Laboratory Analyses.......................................................................19
8.4.
Other Safety Analyses ................................................................................19
9.
PHARMACOKINETIC ANALYSES.........................................................................20
9.1.
Primary Pharmacokinetic Analyses.............................................................20
9.1.1.
Endpoint / Variables.....................................................................20
9.1.1.1.
Drug Concentration Measures....................................20
9.1.1.2.
Derived Pharmacokinetic Parameters.........................20
10. POPULATION PHARMACOKINETIC (POPPK) ANALYSES..................................21
11. REFERENCES.......................................................................................................22
12. APPENDICES........................................................................................................23
12.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................23
12.1.1.
Exclusions from Per Protocol Population .....................................23
12.2.
Appendix 2: Schedule of Activities ..............................................................24
12.2.1.
Protocol Defined Schedule of Events...........................................24
12.3.
Appendix 3: Assessment Windows .............................................................26
12.3.1.
Definitions of Assessment Windows for Analyses........................26
12.4.
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................27
12.4.1.
Study Phases ..............................................................................27
12.4.1.1.
Study Phases for Concomitant Medication .................27
12.4.2.
Treatment Emergent Flag for Adverse Events .............................27
12.5.
Appendix 5: Data Display Standards & Handling Conventions....................28
12.5.1.
Reporting Process .......................................................................28
12.5.2.
Reporting Standards....................................................................28
12.5.3.
Reporting Standards for Pharmacokinetic....................................29
12.6.
Appendix 6: Derived and Transformed Data ...............................................30
12.6.1.
General........................................................................................30
12.6.2.
Study Population..........................................................................30
12.6.3.
Efficacy........................................................................................31
12.6.4.
Dataset to Protocol Mapping........................................................31
12.7.
Appendix 7: Reporting Standards for Missing Data.....................................33
12.7.1.
Premature Withdrawals................................................................33
12.7.2.
Handling of Missing Data.............................................................33
12.7.2.1.
Handling of Missing and Partial Dates ........................33
12.8.
Appendix 8: Values of Potential Clinical Importance ...................................34
12.8.1.
Laboratory Values........................................................................34
12.8.2.
ECG.............................................................................................35
12.8.3.
Vital Signs....................................................................................35
12.9.
Appendix 9: Population Pharmacokinetic (PopPK) Analyses ......................36
12.9.1.
Population Pharmacokinetic (PopPK) Dataset 
Specification ................................................................................36
12.9.1.1.
Handling Missing Demographic and Covariate 
Data ...........................................................................36
12.9.1.2.
Handling Missing Dose Times ....................................36
 
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12.9.1.3.
Handling Missing Times of PK Samples .....................36
12.9.1.4.
Handling of PK Data Below the Lower Limit of 
Quantification .............................................................36
12.9.1.5.
Dataset Specification..................................................36
12.10. Appendix 10: Abbreviations & Trade Marks ................................................48
12.10.1. Abbreviations...............................................................................48
12.10.2. Trademarks .................................................................................49
12.11. Appendix 11: List of Data Displays..............................................................50
12.11.1. Data Display Numbering..............................................................50
12.11.2. Mock Example Shell Referencing ................................................50
12.11.3. Deliverables.................................................................................50
12.11.4. Study Population Tables..............................................................51
12.11.5. Efficacy Tables ............................................................................54
12.11.6. Efficacy Figures ...........................................................................56
12.11.7. Safety Tables...............................................................................58
12.11.8. Pharmacokinetic Tables...............................................................61
12.11.9. Pharmacokinetic Figures .............................................................62
12.11.10.ICH Listings .................................................................................64
12.11.11.Non-ICH Listings..........................................................................67
12.12. Appendix 12: Example Mock Shells for Data Displays ................................69
 
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1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol
Revision Chronology:
2017N314013_00
16-MAY-2017
Original
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes

Enrolled - All participants 
who sign informed 
consent

Enrolled - All 
participants who sign 
informed consent 
and for whom a 
record exists on the 
study database

Align with standard Enrolled 
population definition.

Randomised

mITT population 
defined to be used for 
selected displays

Used for key displays 

Primary completer

Population definition 
refined

To allow for missing data and 
increase clarity

Safety

mITT population used 
for safety reporting

Safety population not required.

PK population

PK population defined 

Used for PK displays

Endpoint - Model specific 
PK parameters of danirixin 
(e.g., oral clearance, oral 
steady state volume of 
distribution).

Danirixin concentration 
and standard 
pharmacokinetic (PK) 
parameters for 
danirixin (e.g. AUC, 
Cmax, tmax)

Updated due to small number of 
participants with PK data

Endpoints - serum IL-8 or 
sputum mucin

Removed

Not collected

Primary analysis Bayesian

Primary analysis 
Frequentist

The primary analysis has been 
simplified as the historical data could 
not be used as a prior.

Modified Primary 
Completer 

Population defined 

Defined to allow for a sensitivity 
around the definitions of quality for 
the samples 
 
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2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To assess the change from 
baseline in NETs formation in 
participants with COPD following 
14 days of treatment with danirixin 
hydrobromide (HBr) 35mg twice 
daily

Reduction in sputum NETs (quantified by Histone-
elastase complexes)
Secondary Objectives
Secondary Endpoints

To assess the change from 
baseline in NETs formation in 
participants with COPD following 
14 days of treatment with danirixin 
HBr 35mg twice daily

Reduction in sputum NETS (quantified by 
Deoxyribonucleic acid [DNA]-elastase complexes)

Reduction in sputum NET area quantification by 
microscopy

To further characterize the safety 
of danirixin HBr 35mg tablets 
compared with placebo in 
participants with COPD

Adverse events

Vital Signs

ECG 

Spirometry

To assess the effects of danirixin 
HBr 35mg twice daily on NETosis-
associated biomarkers in sputum 
and peripheral blood

Change from baseline in sputum resistin levels 

Change from baseline in the ratio of sputum NETs 
to sputum neutrophils

Change from baseline in sputum elastase activity

Change from baseline in peripheral blood 
neutrophil NET formation (DNA release)

Characterise the population 
pharmacokinetic (PK) profile of 
approximately 14 days of dosing 
of danirixin HBr 35mg twice daily
in participants with COPD

Danirixin concentration and standard 
pharmacokinetic (PK) parameters for danirixin 
(e.g. AUC, Cmax, tmax)
Exploratory Objectives
Exploratory Endpoints

To explore the relationships 
between NETs formation and lung 
microbiome composition

Characterize sputum microbiome composition and 
diversity

To explore volatile organic 
compound (VOC) profile in 
participants with COPD

Characterize relationship between lung 
microbiome and exhaled volatile organic 
compounds (VOCs) in stable COPD

To explore variability of exhaled VOCs

To explore the effects of danirixin 
Changes from baseline in ex-vivo neutrophil 
 
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Objectives
Endpoints
HBr 35mg twice daily on 
neutrophil activity and 
exploratory biomarkers
phagocytosis of bacteria by flow cytometry

Changes in exploratory urine, sputum and blood 
biomarkers (e.g. plasma fibrinogen, serum C-
reactive protein)
2.3.
Study Design
Overview of Study Design and Key Features
Design Features

Single centre, randomized, double-blind, sponsor open, placebo-
controlled, 14-day mechanistic study evaluating the effect of danirixin 
in reducing NET formation. 
Dosing

Study treatment will be administered twice daily for 14 days.  
Treatment 
Assignment

Participants will be randomized (3:1) to receive either danirixin HBr 
35mg or placebo. 

GSK RandAll NG used to generate randomisation schedules.
Interim Analysis

No formal interim analysis will be preformed 
2.4.
Statistical Hypotheses / Statistical Analyses
The objective of this study is to assess whether danirixin impacts NET formation in 
participants with COPD. There will be no formal hypotheses tests and significant tests. 
Model based results for the primary endpoint of reduction in sputum NETs (quantified by 
Histone-elastase complexes) adjusted for baselin, will be used. 
 
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3.
PLANNED ANALYSES
3.1.
Interim Analyses
There is no formal interim analysis planned for this study. Although, blinded data looks 
were performed at 12 participants and 19 participants. The purpose of the data looks is to 
check data quality. The data showed that 6 participants had poor quality data. The team 
decided to replace all 6 participants; approximately 30 participants will be enrolled. 
3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
After decision to terminate DNX in COPD the study was stopped early.  19 subjects 
had completed the study.
2.
All required database cleaning activities have been completed and final database 
release (DBR) 
3.
All criteria for unblinding the randomization codes have been met. 
4.
Randomization codes have been distributed according to RandAll NG procedures.
5.
Database freeze (DBF) has been declared by Data Management.
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Enrolled
All participants who sign informed consent and for 
whom a record exists on the study database.  This 
population will be used for the tables/listings of 
reasons for withdrawal before randomization and 
listings of AEs and SAEs for non-randomized 
participants.

Subject Disposition

Reasons for 
withdrawal before 
randomization.

Inclusion, exclusion, 
and randomization 
criteria deviations
Modified ITT
All randomized participants who receive at least 
one dose of study treatment. Participants will be 
analysed according to the treatment they actually 
received. If a participant received more than one 
treatment during the treatment period, they will be 
reported according to the treatment taken the most 
based on doses taken from each container.

Study population

Efficacy

Safety
Primary 
Completer 
All participants in the Modified ITT population who 
have completed the assessments supporting the 
primary endpoint (sputum NETs).

In the case where the modified ITT and 
the primary completer population are the 

Sputum NETs

Secondary NETs 
analyses 
 
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Population
Definition / Criteria
Analyses Evaluated
same, the primary completer population 
will not be defined and all output will be 
done on the Modified ITT population. 

Participants need sputum samples of 
acceptable quality at screening/baseline 
and day 14. 

Acceptable quality samples have viable 
leukocytes >50% and coded as acceptable 
or good in MISPQL
Modified Primary 
Completer
All participants in the Modified ITT population who 
have completed the assessments supporting the 
primary endpoint (sputum NETs). 

In the case where the modified ITT and 
the primary completer population are the 
same, the primary completer population 
will not be defined and all output will be 
done on the Modified ITT population. 

Participants need sputum samples of 
reasonable quality at screening/baseline 
and day 14. 
Reasonable quality samples have viable 
leukocytes >50% and coded as acceptable, good 
or poor quality in MISPQL
This population will only be use if this increases 
the available sample from the Primary completer 
population by 20%. 

Secondary NETs 
analyses
PK 
All participants in the mITT population who had at 
least 1 non-missing PK assessment (Non-
quantifiable [NQ] values will be considered as non-
missing values) obtained and analysed whilst on 
treatment with danirixin.

PK
NOTES :  Please refer to Appendix 11: List of Data Displays which details the population to be used for each displays 
being generated.
4.1.
Protocol Deviations
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed.
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan 17Aug2017 Final V1.0.
o Data will be reviewed prior to freezing the database to ensure all important 
deviations are captured and categorised on the protocol deviations dataset. 
 
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o This dataset will be the basis for the summaries and listings of protocol 
deviations.
A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion 
page of the eCRF.
 
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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG System
Data Displays for Reporting 
Code
Description
Description
Order in TLF 
PBO
Placebo
Placebo
1
DNX
GSK1325756 (danirixin) 35mg 
HBr
DNX 35mg BD
2
Treatment comparisons will be displayed as follows using the descriptors as specified:
1.
Danirixin vs. Placebo
5.2.
Baseline Definitions
Parameter
Study Assessments Considered as Baseline
Baseline Used in 
Data Display
Screening (Visit 0 / Visit 1)
Day 1 (Visit 2)
Induced sputum variables
X
X
Baseline
Vital signs
X
Baseline
Spirometry variables
X
Baseline 
ECG [mean of triplicate]
X
Baseline
Clinical Laboratory Assessments
X
Baseline
For labs, vitals and ECG, use the most recent value prior to dosing. In cases where the 
induced sputum from day 1 does not meet quality standards, the sample from screening
can be used. 
5.3.
Examination of Covariates, Other Strata and Subgroups
5.3.1.
Covariates and Other Strata
Other covariates will be included for specific analyses as detailed in model specifications 
in Section 7.1 and Section 7.2.
Category
Details
Covariates
Treatment, baseline
 
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5.4.
Multiple Comparisons and Multiplicity
No adjustment for multiplicity is required for this study, as the primary analysis involves 
an estimation approach, rather than hypothesis testing.
5.5.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
12.3
Appendix 3: Assessment Windows
12.4
Appendix 4: Study Phases and Treatment Emergent Adverse Events
12.5
Appendix 5: Data Display Standards & Handling Conventions
12.6
Appendix 6: Derived and Transformed Data
12.7
Appendix 7: Reporting Standards for Missing Data
12.8
Appendix 8: Values of Potential Clinical Importance
 
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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the modified ITT population, unless 
otherwise specified.
Study population analyses including analyses of subject’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure and treatment compliance will be based on GSK Core Data Standards.  
Details of the planned displays are presented in Appendix 11: List of Data Displays.
 
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7.
EFFICACY ANALYSES
7.1.
Primary Efficacy Analyses
7.1.1.
Endpoint / Variables
The primary endpoint will be the percent change (relative to baseline) in sputum NETs, 
quantified by Histone-elastase complexes, for danirixin.
7.1.2.
Summary Measure
Mean and 95% confidence interval will be calculated for the danirixin and placebo arms
at day 7 and 14.  
7.1.3.
Population of Interest 
The primary efficacy analysis will be based on the Primary Completer population, unless 
the primary completer populations is the same as the mITT population. In that case the 
mITT population will be used for all analysis. Participants with poor quality sputum 
samples should also be excluded from the analysis.
7.1.4.
Strategy for Intercurrent (Post-Randomization) Events
No intercurrent events are considered of interest in this analysis. Data for the endpoint 
will be complete for the specific population
7.1.5.
Statistical Analyses / Methods 
Unless otherwise specified, endpoints / variables defined in Section 7.1.1 will be 
summarised using descriptive statistics, graphically presented and listed.
7.1.5.1.
Statistical Methodology Specification
Endpoint / Variables

Sputum NETs quantified by Histone-elastase complexes
Model Specification

The ratio of post-baseline NETs values to baseline NETS values will be log transformed prior 
to analysis. Note: 
.


Where i is the index for each participant and j is the index for day 
Model Checking & Diagnostics

The mixed effect model will control for treatment, baseline, and day. 

An unstructured symmetric covariance structure will be used. Although if there are issues with 
convergence auto-regressive lag 1 can be used. 

It may be necessary to exclude placebo data from the analysis due to small cell size. 

The Kenward and Rodger method for approximating the denominator degrees of freedom and 
 
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correcting for bias in the estimated variance-covariance of the fixed effects will be used 

If there are any departure from the distributional assumptions, alternative models will be 
explored using appropriate transformed data. Residual plots will be checked. 
Model Results Presentation

Refer to Appendix 12 for detailed description of tables, figures, and listings  
7.2.
Secondary Efficacy Analyses
7.2.1.
Endpoint / Variables
The endpoint will be the change (relative to baseline) in sputum NETs, quantified by 
DNA-elastase and microscopy sputum resistin levels, ratio of sputum NETs to sputum 
neutrophils, sputum neutrophils, and sputum elastase activity. The mapping to dataset 
values are as follows. NETs quantified by microscopy are mean percent NETs per field. 
For a mapping of protocol variables to dataset variables (see Dataset to Protocol Mapping
)
7.2.2.
Summary Measure
Unadjusted mean and standard error will be calculated for the danirixin and placebo arms 
at baseline, day 7 and 14. Unadjusted mean and standard error will be calculated for the 
percent change from baseline and absolute change from baseline for danirixin and 
placebo arms at day 7 and 14. 
7.2.3.
Population of Interest 
Same as above, for NETs quantified by histone-elastase. 
7.2.4.
Statistical Analyses / Methods
Unadjusted means and standard errors will be calculated. 
7.2.5.
Endpoint / Variables
Change from baseline in peripheral blood neutrophil NET formation. 
7.2.6.
Summary Measure
Unadjusted mean and standard error will be calculated for the danirixin and placebo arms 
at baseline, day 7 and 14. Unadjusted mean and standard error will be calculated for the 
percent change from baseline danirixin and placebo arms at day 7 and 14
7.2.7.
Population of Interest 
The mITT population will be used.
 
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7.2.8.
Statistical Analyses / Methods
7.2.8.1.
Statistical Methodology Specification
Unadjusted means and standard errors will be calculated.
7.3.
Exploratory Efficacy Analyses
7.3.1.
Endpoint / Variables
Exploratory endpoints include volatile organic compounds (VOC), ex-vivo neutrophil 
phagocytosis of bacteria by flow cytometry, and blood biomarkers. The blood biomarkers 
are plasma fibrinogen, serum C-reactive protein. Only VOCs from Cyranose, ex-vivo 
neutrophil phagocytosis and blood biomarkers will be part of SAC. No formal statistical 
analysis will be used to summarize the blood biomarkers, only unadjusted means. The 
urine will be stored for a two-year period, during which if there is a biomarker assay that 
comes forth that will support danirixin development program, analysis may be run. 
The between tube, within day, and between day variability of the Cyaronose device will 
calculated using a multilevel multivariate model. Day will be the top level, followed by 
time of day, and tube. An unstructured covariance should be used to model the 
relationship between sensors, but the same covariance structure should be used across all 
tubes. Assume a constant variance between morning and afternoon and between days. 
Below is the model diagram for a single subject. 
 
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In the case where the multilevel multivariate model does not converge then treat each 
sensor as independent and just run the multilevel model. If the multilevel models do not 
coverage, day and time of day can be collapsed into a single time level, in which we will 
only provide the variability of time rather than within day and between day. 
Sputum microbiome, VOCs, and the relationship there in, will be investigated, but not 
included in the SAC due to the length of time needed to analysed the microbiome. The 
sputum microbiome will be analysed by Dundee. A secondary RAP to investigate VOCs 
and sputum microbiome will be written by the Computational Biology group to detail the 
analysis for this data. The results of this analysis will be written up in a report and added 
as an addendum to the CPSR. 
 
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8.
SAFETY ANALYSES
The safety analyses will be based on the mITT population.
8.1.
Adverse Events Analyses
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs)
and other significant AEs will be based on GSK Core Data Standards. The details of the 
planned displays are provided in Appendix 11: List of Data Displays.
8.2.
Adverse Events of Special Interest Analyses
A comprehensive list of MedDRA terms based on clinical review will be used to identify 
each type of event. SRT, safety review team, has decided the Infective Pneumonia SMQ 
will used to identify AESI. The details of the planned displays are provided in Appendix 
11: List of Data Displays.
8.3.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, 
Haematology laboratory tests, Urinalysis, and liver function tests will be based on GSK 
Core Data Standards. The details of the planned displays are in Appendix 11: List of Data 
Displays. The blood biomarkers, plasma fibrinogen and serum C-reactive protein, will be 
in the efficacy outputs. 
8.4.
Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. The details of the 
planned displays are presented in Appendix 11: List of Data Displays. Summaries of 
spirometry will also be created.
 
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9.
PHARMACOKINETIC ANALYSES
9.1.
Primary Pharmacokinetic Analyses
9.1.1.
Endpoint / Variables
9.1.1.1.
Drug Concentration Measures
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 12.5.3
Reporting Standards for Pharmacokinetic)
9.1.1.2.
Derived Pharmacokinetic Parameters
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
per current working practices and using the currently supported version of WinNonlin. 
All calculations of non-compartmental parameters will be based on actual sampling 
times. The pharmacokinetic parameters listed below will be determined from the blood 
concentration-time data on Day 1 and Day 14, as data permits.
Parameter
Parameter Description
AUC(0-t)
Area under the concentration-time curve from time zero to the time of the last 
quantifiable concentration (C(t)) will be calculated using the linear trapezoidal rule 
for each incremental trapezoid and the log trapezoidal rule for each decremental 
trapezoid.
Cmax*
Maximum observed concentration, determined directly from the concentration-time 
data.
tmax
Time to reach Cmax, determined directly from the concentration-time data.
tlast
Time of last quantifiable concentration
NOTES:

Additional parameters may be included as required.
Unless otherwise specified, endpoints / variables defined in Section 9.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
 
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10.
POPULATION PHARMACOKINETIC (POPPK) 
ANALYSES
PK data from this study may be combined with historic data for the purposes of 
population PK modelling which would be the subject of a separate analysis plan and 
would be presented separately from the main clinical study report (CSR).
To support this analysis a PopPK dataset will be generated. The details for the dataset 
specifications are provided in Section 12.8 Appendix 9.
 
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11.
REFERENCES
GlaxoSmithKline Document Number 2017N314013_00, Protocol: Randomized double 
blind (sponsor unblind) study evaluating the effect of 14 days of treatment with danirixin 
(GSK1325756) on neutrophil extracellular traps (NETs) formation in participants with 
stable chronic obstructive pulmonary disease (COPD), 16 May 2017
 
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12.
APPENDICES
12.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
12.1.1.
Exclusions from Per Protocol Population
No per protocol analysis is defined in this study. 
 
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12.2.
Appendix 2: Schedule of Activities
12.2.1.
Protocol Defined Schedule of Events
Table 1
Schedule of activities
Procedure
Pre-Screening 
and Screening1
Treatment Period
(14 days)
Follow-up
Phone call
Unscheduled 
visit 2
Notes
V0
V1
V2
V3
V 4
V5
Day
Day -30 to -1
D 1
D 7
D14
D 21
As required
Assessment window
1d
1d
3d
As required
Written, informed consent
X
Inclusion and exclusion criteria
X
Recheck clinical status before randomization.
Demography, Medical history
X
Baseline COPD assessment test (CAT) score
X
Adverse event (AE)/Serious adverse event (SAE) review
X
=============
X
X
Concomitant medication review
X
=============
X
X
Full physical examination including height and weight
X
X
Vital signs
X
X
X
X
X
X
Volatile organic compound (VOC) measurement 
X3
X3,4
X5
X3
X3
X
Spirometry
X
X
X
X
Induced Sputum Samples (including biomarker samples)
X
X 4
X
X
X
X
Spirometry post-Sputum Induction 
X
X 4
X
X
X
X
Triplicate 12-lead ECG
X
X
X
X
Chest X-ray (historical within 1 year acceptable)
X
HIV, Hepatitis B and C screening
X6
Laboratory assessments (clinical chemistry including 
liver chemistries, haematology, biomarkers) 
X
X
X
X
Pharmacokinetic (PK) sample
X7
X8
X7
X
See footnotes for timings of PK sampling
Genetic sample
X9
Pre-dose (baseline) sample. 
Urinary Pregnancy test (WOCBP only)
X10
X10
X10
X10
 
 
 
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Procedure
Pre-Screening 
and Screening1
Treatment Period
(14 days)
Follow-up
Phone call
Unscheduled 
visit 2
Notes
V0
V1
V2
V3
V 4
V5
Urinalysis (including biomarker samples)
X
X
X
X
Randomization
X
All baseline assessments at V2 should be 
completed prior to randomization
Study treatment
X

X
Dispense study medication
X
Monitor IP compliance (via manual counting and App)
X
X
X
Digital App monitoring to begin at V2
Collect IP 
X

The timing and number of planned study assessments, including safety, pharmacokinetic, pharmacodynamic/biomarker or other assessments may be altered during the course 
of the study based on newly available data (e.g., to obtain data closer to the time of peak plasma concentrations) to ensure appropriate monitoring. 

Any changes in the timing or addition of time points for any planned study assessments must be documented and approved by the relevant study team member and then 
archived in the sponsor and site study files, but will not constitute a protocol amendment. The IRB/IEC will be informed of any safety issues that require alteration of the safety 
monitoring scheme or amendment of the Informed consent form (ICF).

Safety assessments should be performed in the following order where applicable/ possible: vital signs, ECG measurements, blood samples and spirometry.
1.
Screening visit is split into pre-screening on visit 0 and screening on visit 1 although the visits may be performed on the same day.  This is to a) enable participants to 
potentially have more than one attempt at sputum induction for meeting eligibility and b) to only collect minimal screening data for subjects who fail on the basis of the elevated 
NETs since that is the key inclusion criteria that may not be known from medical records.
2.
Unscheduled visits may be used to collect information related to adverse events, for follow up of any safety assessments, and also to complete assessments where 
participants were not able to perform these within the visit window for any reason. It is not necessary to carry out all of the assessments listed under an unscheduled visit at a 
single visit; the assessments performed should be driven by the need for the visit.
3.
VOC measurement should be undertaken prior to sputum induction at these visits.
4.
Sputum induction (and associated VOC measurement and safety spirometry) at visit 1 is only necessary if participant unable to give sample at visit 0. Where the participant is 
judged by the investigator to have a borderline sputum NETs level ( <0.5 units/ml) at visit 0, they will be invited to give a second sputum sample on visit 1 to re-assess 
eligibility. 
5.
VOC measurements should be undertaken at the following timepoints at this visits:  prior to sputum induction,and 4 hours post dose
6.
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 Ribonucleic acid (RNA) testing is optional; however a confirmatory negative Hepatitis C RNA test must be obtained, to be able to enroll 
participants with positive Hepatitis C antibody due to prior resolved disease.
7.
At visits 2 and 4, PK samples should be collected at the following time-points: pre-dose, 0.5, 1, 2 and 4 hours post-dose.
8.
At visit 3 only a pre-dose PK sample should be collected.
9.
Agreeing to genetic sample consent is not required for overall study participation. Informed consent for genetic sample must be obtained prior to taking sample.
10. Pregnancy testing only required for women of child bearing potential (WOCBP). A positive urine pregnancy test requires confirmation with a serum pregnancy t
 
 
 
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12.3.
Appendix 3: Assessment Windows
12.3.1.
Definitions of Assessment Windows for Analyses
Use nominal time of assessment. 
 
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12.4.
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events
12.4.1.
Study Phases
Assessments and events will be classified according to the time of occurrence relative to 
treatment start date.
Study Phase
Definition
Pre-Treatment 
Date ≤ Study Treatment Start Date
On-Treatment
Study Treatment Start Date < Date ≤ Study Treatment Stop Date +1
Post-Treatment
Date > Study Treatment Stop Date +1
12.4.1.1.
Study Phases for Concomitant Medication
Study Phase
Definition
Prior
If medication end date is not missing and is before date of start of treatment
Concomitant
Any medication that is not a prior
NOTES: 

Please refer to Appendix 7: Reporting Standards for Missing Data for handling of missing and partial dates for 
concomitant medication. Use the rules in this table if concomitant medication date is completely missing.
12.4.2.
Treatment Emergent Flag for Adverse Events
Flag
Definition
Treatment 
Emergent

If AE onset date is on or after treatment start date & on or before treatment stop 
date. 

Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment Stop Date +1
NOTES: 

If the study treatment stop date is missing, then the AE will be considered to be On-Treatment.

Time of study treatment dosing and start/stop time of AEs should be considered, if collected.
 
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12.5.
Appendix 5: Data Display Standards & Handling 
Conventions
12.5.1.
Reporting Process
Software

The currently supported versions of SAS Studio 3.6 (Basic Edition) will be used.
Reporting Area
HARP Server
: \\UK1SALX00175.CORPNET2.com
HARP Compound
: \arprod\gsk1325756
Analysis Datasets 

Analysis datasets will be created according to Legacy GSK A&R dataset standards.
Generation of RTF Files

RTF files will be generated for final analysis outputs
12.5.2.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 

Do not include subject level listings or figures in the main body of the GSK Clinical Study Report. All 
subject level listings should be located in the modular appendices as ICH or non-ICH listings
Formats

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected, unless otherwise stated.

Numeric data will be reported at the precision collected on the eCRF or provided by vendor.

The reported precision from non eCRF sources will follow the IDSL statistical principles but may be
adjusted to a clinically interpretable number of DP’s.

For NETs the individual data will be provided according to the appropriate level of precision for the 
listings.
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the participant’s listings. 
 
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Unscheduled Visits

Unscheduled visits will not be included in summary tables and/or figures.

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.
12.5.3.
Reporting Standards for Pharmacokinetic
Pharmacokinetic Concentration Data
PC Windows Non-
Linear (WNL) File
PC WNL file (CSV format) for the non compartmental analysis by Clinical 
Pharmacology Modelling and Simulation function will be created according to 
GUI_51487 and PKONE document. 
Note: Concentration values will be imputed as per GUI_51487
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.
Refer to IDSL Statistical Principle 6.06.1.
Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics/analysis and summarized graphical displays only. 
Additionally, include geometric mean and 90% CI for the summary of blood 
concentration data
NONMEM/Pop PK 
File
Pop-PK file (CSV format) for the POP-PK analysis by Clinical Pharmacology 
Modelling and Simulation function will be created according to the data specification 
detailed in Appendix 9.
NONMEM/PK/PD 
File
Not applicable.
Pharmacokinetic Parameter Derivation
PK Parameter to be 
Derived by 
Programmer
None.
Pharmacokinetic Parameter Data
Is NQ impacted PK 
Parameters Rule 
Being Followed
No. 
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.
 
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12.6.
Appendix 6: Derived and Transformed Data
12.6.1.
General
Multiple Measurements at One Analysis Time Point

Mean of the measurements will be calculated and used in any derivation of summary statistics but if 
listed, all data will be presented.

If there are two values within a time window (as per Section 12.3.1) the value closest to the target day 
for that window will be used. If values are the same distance from the target, then the mean will be 
taken.
o
For NETs: If there are unscheduled visits between screening and visit 2 use the last 
unscheduled visit prior to visit 2. 

Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance summary 
tables.
Study Day

Calculated as the number of days from First Dose Date:

Ref Date = Missing              → Study Day = Missing 

Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date

Ref Data ≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1    
12.6.2.
Study Population
Treatment Compliance

Treatment compliance will be calculated based on the formula:  
Treatment Compliance = Number of Actual Doses / (Planned Treatment Duration in Days * 
Frequency)

Frequency is 2 for BID Treatment compliance could be greater than 100% if there are events of 
overdose. 

Planned Treatment Duration is defined as 14 days
Extent of Exposure

Number of days of exposure to study drug will be calculated based on the formula:  
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 1
Age 

Age will be calculated based off the date participants signed consent forms

GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed as 
follows:
o
Any participant with a missing day will have this imputed as day ‘15’. 
o
Any participant with a missing date and month will have this imputed as ‘30th June’.

Birth date will be presented in listings as ‘YYYY’.
Smoking Status 

If the last smoked date (SUSMLSDT) is missing and a partial date (SUSMLSD) is not missing, then the 
following imputation should be applied to the partial smoking date for use in the reclassification of 
smoking status calculation:
o
'01' will be used for the day and 'Jan' will be used for the month.
 
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Treatment Compliance

Former smokers will be reclassified as current smokers if screening date – last smoked date < 183 
days.
12.6.3.
Efficacy
Change from Baseline 

Change from Baseline will be calculated based on the formula: 
Change from Baseline = Value – Value on day 1  

Use the most recent pre-dose value for baseline. In the case where there is a bad sample on 
day 1 use screening 

12.6.4.
Dataset to Protocol Mapping 
Protocol Variable
BICAT
(BIOMARK)
MITEST
(MICROSCOPY)
MITSTD 
(MICROSCOPY)
SPECTYPE 
(MICROSCOPY)
Reduction in sputum NET 
area quantification by 
microscopy
AK005
26
C13278
Reduction in sputum NETs 
(quantified by
Histone-elastase 
complexes)
HISTELAS
C13278
Reduction in sputum NETS 
(quantified by
Deoxyribonucleic acid 
[DNA]-elastase
complexes)
DNAELAS
C13278
Change from baseline in 
sputum resistin
levels
RESIST
C13278
Change from baseline in 
the ratio of
sputum NETs to sputum 
neutrophils
AW002
C13278
Change from baseline in 
sputum elastase
activity
ELASTASE
C13278
 
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Protocol Variable
BICAT
(BIOMARK)
MITEST
(MICROSCOPY)
MITSTD 
(MICROSCOPY)
SPECTYPE 
(MICROSCOPY)
Change from baseline in 
peripheral blood
neutrophil NET formation 
(DNA release,
microscopy)
AK005
8
C12434
 
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12.7.
Appendix 7: Reporting Standards for Missing Data
12.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Participant study completion (i.e. as specified in the protocol) was defined as those 
who have completed the assessments supporting the primary endpoint

Withdrawn participants may be replaced in the study.

All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified.
12.7.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank fields on 
the collection instrument:
o
These data will be indicated by the use of a “blank” in participant listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such.
Outliers

Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
12.7.2.1. Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in participant listing displays.
Adverse
Events

The eCRF allows for the possibility of partial dates (i.e., only month and year) to be 
recorded for AE start and end dates; that is, the day of the month may be missing. In 
such a case, the following conventions will be applied for calculating the time to onset 
and the duration of the event:
o
Missing Start Day: First of the month will be used unless this is before the start 
date of study treatment; in this case the study treatment start date will be used and 
hence the event is considered On-treatment as per Appendix 4: Study Phases and 
Treatment Emergent Adverse Events.
o
Missing Stop Day: Last day of the month will be used, unless this is after the stop 
date of study treatment; in this case the study treatment stop date will be used.

Completely missing start or end dates will remain missing, with no imputation applied. 
Consequently, time to onset and duration of such events will be missing.

If treatment phase for an AE is missing due to missing dates class as on-treatment 
Concomitant 
Medications/
Medical 
History

Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will be 
used for the month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day (dependent 
on the month and year) and 'Dec' will be used for the month.

The recorded partial date will be displayed in listings.
 
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12.8.
Appendix 8: Values of Potential Clinical Importance
12.8.1.
Laboratory Values
Hematology Analyte 
(units)
Effect
COPD Patients
Low
High
Platelet Count (x109/L)
0.90x
1.10x
Red Blood Cell Count 
(x1012/L)
0.93x
1.07x
White Blood Cell Count  
(x109/L)
0.70x
1.60x
Hemoglobin (g/L)
Males
0.85x
1.20x
Females
0.85x
1.20x
Hematocrit (Ratio of 1)
Males
0.50x
1.30x
Females
0.50x
1.30x
MCV (fL)
0.25x
2.00x
MCH (pg)
0.85x
1.20x
Neutrophils (10^9/L)
<1.0
>10
Lymphocytes (10^9/L)
<1.2
>11.2
Monocytes (10^9/L)
<0.16
>2.6
Eosinophils (10^9/L)
>1.2
Basophils (10^9/L)
>0.85
Note: Multipliers are identified by “x”, otherwise actual comparison values are provided with units.
Chemistry Analyte
Effect
COPD Patients
Low
High
BUN (mmol/L)
0.70x
1.60x
Creatinine (mol/L)
1.30x
(or >27 mol/L increase from 
baseline)
Glucose (mmol/L)
1.20x
Sodium (mmol/L)
0.80x
1.15x
Potassium (mmol/L)
0.75x
1.30x
Calcium (mmol/L)
Males
0.85x
1.08x
Females
<0.499 mmol/l
>1.7465 mmol/l
Total Protein (mg/dL)
1.25x
Note: Multipliers are identified by “x”, otherwise actual comparison values are provided with units.
 
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Liver Function Test Analyte
Effect
PCI Range
Unit
ALT/SGPT
High
≥ 3x ULN
U/L
AST/SGOT
High
≥ 3x ULN
U/L
Alkaline Phosphatase
High
≥ 2x ULN
U/L
Direct Bilirubin
High
≥ 1.5x ULN
mol/L
12.8.2.
ECG
ECG Parameter
PCI Range
Unit
Absolute QTc Interval (QTcB, QTcF)
<300 or >500
msec
QT Interval
<300 or >500
msec
PR Interval
<120 or >210
msec
QRS Interval
<70 or >125
msec
Heart Rate
<35 or >120
bpm
Values based on the mean of triplicate 
12.8.3.
Vital Signs
Vital Sign Parameter
PCI Range
Unit
Systolic Blood Pressure
<90 or >160
mmHg
Diastolic Blood Pressure
<40 or >110
mmHg
Heart Rate
<35 or >120
bpm
Respiration Rate
<8 or >30
breaths 
/min
 
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12.9.
Appendix 9: Population Pharmacokinetic (PopPK) Analyses
12.9.1.
Population Pharmacokinetic (PopPK) Dataset Specification
12.9.1.1.
Handling Missing Demographic and Covariate Data 
Missing demographic and covariate data will not be imputed. 
12.9.1.2.
Handling Missing Dose Times
Missing dose time information will be handled on a case by case basis by imputing this 
information based on prior dosing times or based on recorded PK collection times. The 
details of these imputations will be described in the report.
12.9.1.3.
Handling Missing Times of PK Samples
Missing times for PK will be handled on a case by case basis by imputing this 
information based on the dose time and/or times of other PK. The details of these 
imputations will be described in the report.
12.9.1.4.
Handling of PK Data Below the Lower Limit of Quantification
Any PK data below the lower limit of quantification will be set to missing.
12.9.1.5.
Dataset Specification
General description and rules:

Missing or unknown values in covariates, if not to be imputed, will be assigned -99.

The dataset is sorted by STUD, SUBJID, DATE, CTIM, EVID descending.

The data items (columns) in the analysis-ready data file will be provided the same 
order as follows.

Non-quantifiable (NQ) concentration values will be included as detailed for the 
CONC variable.

Non-numerical concentration values (such as NS, NR, NA) will not be included.

Placebo subjects will not be included.

The dataset will be a comma delimited ASCII text file and will be named:
o
NM.compound.study.PK.v1.csv
o
Where “compound” is the compound name (e.g. GSK1234567) and “study” is 
the study number (e.g. 207551).
 
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Variable
Label 
(Variable 
description)
Type
Units
Missing 
value
Codes/Derivation/Notes
ID
NONMEM 
subject 
identifier
Integer
None
Never
Sequential subject identifier 
across study after data is sorted 
by STUD, SUBJID, DATE, RTFD, 
EVID.
Numbering to start at 1.
To be entered in all rows for each 
subject.
STUDYID
Unique 
identifier for a 
study
Char
None
Never
207551 for all records
STUD
Study ID
Num
None
Never
207551 for all records
SUBJID
Subject 
identifier for 
study
Char
None
Never
Subject identifier, which must be 
unique within the study. The 
identification number of the 
subject as recorded on the CRF.
Exclude placebo subjects.
Include subjects who have 
received IP and have at least one 
measureable drug concentration.
To be entered in all rows for each 
subject.
COUNTRY
Country
Char
None
Never
Country of the investigational site 
in which the subject participated 
in the trial; e.g. USA.
To be entered in all rows for each 
subject.
SITEID
Unique 
identifier for a 
study site
Num
None
Never
e.g. 
 any lead zero should 
not be included.
To be entered in all rows for each 
subject.
CONC
Drug 
Concentration 
Num
ng/mL
Never
CONC=0 for PK_GSK1325756 
records.
No sample (NS), insufficient 
sample (IS) and no result (NR) 
records will be excluded from 
dataset.
CONC=’.’ for PK_GSK1325756 
records < LOQ (i.e. if drug conc is 
NQ).
LNCONC
Natural log of 
CONC 
column 
Num
ng/mL
Never
Natural log of CONC column.
If CONC=0, then LNCONC=’.’.
LLQ
Lower Limit of 
quantification
Num
ng/mL
Never
LLQ=5 or from source data if 
different.
To be entered in all rows for each 
 
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Variable
Label 
(Variable 
description)
Type
Units
Missing 
value
Codes/Derivation/Notes
subject.
LNLLQ
Natural log of 
LLQ column
Num
ng/mL
Never
Natural log of LLQ column.
If LLQ=0, then LNLLQ=’.’.
MATRIX
Sample matrix
Num
None
Never
MATRIX=1 (blood).
MATRTEXT
Sample matrix 
text
Char
None
Never
Text corresponding to code for 
MATRIX. 
Enter ‘Blood’ for all rows.
LABL
Label 
describing the 
record
Char
None
Never
LABL explains the type of 
measurement for CONC for the 
current record.
LABL=DOSE_GSK1325756 for 
dose record. 
LABL=PK_GSK1325756 for 
blood concentration record.
DATE
Date of 
Record 
MM/DD/YYYY
None
Never
Date of record.
DATETIME
Date and time 
of record
MM/DD/YYYY 
HH:MM:SS
None
Never
Date and time of record.
DAY
Study day 
number of 
record
Num
None
Never
Day of study relative to first IP 
dose.
NDAY
Nominal day
Num
day
Never
Schedule visit day of study 
relative to first IP dose.
NOMT
Nominal time 
since FIRST 
IP dose
Num
h
Never
Nominal time of study relative to 
first IP dose.
NOMT=0 for first dosing record 
only. 
NOMTLD
Nominal time 
since LAST IP 
dose prior to 
sample
Num
h
Never
Nominal time of study relative to 
last IP dose prior to sample. 
NOMTLD=0 for dosing records.
RTFD
Relative time 
from FIRST IP 
dose to 
current 
sample time
Num
h
Never
Actual time from FIRST dose of 
IP.
RTLD
Relative time 
from LAST IP 
dose  prior to 
sample
Num
h
Never
Actual time from last dose of IP 
prior to sample.
When 
LABL=DOSE_GSK1325756, 
RTLD=0.
For pre-dose PK sample on Day 
7, RTLD is relative to the 
previous dose. 
DOSE
Dose amount
Num
mg
Never
DOSE=35.
To be entered in all rows for each 
subject.
 
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Variable
Label 
(Variable 
description)
Type
Units
Missing 
value
Codes/Derivation/Notes
DRUG
Name of drug
Char
None
Never
DRUG=GSK1325756.
To be entered in all rows for each 
subject.
REG
Dosing 
Regimen 
Integer
None
Never
REG=2 for BD.
To be entered in all rows for each 
subject.
REGTEXT
Subject dose 
regimen text
Char
None
Never
REGTXT=BD, text corresponding 
to code for REG. 
To be entered in all rows for each 
subject.
ROUT
Route of 
administration
Integer
None
Never
ROUT=1 for PO.
To be entered in all rows for each 
subject.
ROUTTEXT
Subject route 
of 
administration 
text
Char
None
Never
ROUTTEXT=PO, text 
corresponding to code for ROUT.
To be entered in all rows for each 
subject.
CMT
NONMEM 
Compartment 
code
Integer
None
Never
CMT=1 for DOSE_GSK1325756 
records.
CMT=2 for PK_GSK1325756 
records.
EVID
NONMEM 
Event ID
Integer
None
Never
EVID=1 for LABL= 
DOSE_GSK1325756.
EVID=0 for LABL= 
PK_GSK1325756.
AMT
NONMEM 
Amount of 
drug 
administered
Num
mg
Never
AMT=0 for LABL= 
PK_GSK1325756 records.
AMT=35 for LABL= 
DOSE_GSK1325756 records.
II
NONMEM 
Inter-dose 
interval
Integer
h
Never
II=0 for LABL= PK_GSK1325756.
II=12 for LABL= 
DOSE_GSK1325756, except
II=0 for LABL= 
DOSE_GSK1325756 on Day 1 
only.
SS
Steady-state 
data item
Integer
None
Never
SS=0 for LABL= 
PK_GSK1325756 records.
SS=1 for LABL= 
DOSE_GSK1325756 records, 
except
SS=0 for LABL= 
DOSE_GSK1325756 records on 
Day 1 only.
RATE
NONMEM 
Rate of drug 
infusion
Integer
None
Never
RATE=0 for LABL= 
PK_GSK1325756 records.
RATE=-2 for LABL= 
DOSE_GSK1325756 records.
 
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Variable
Label 
(Variable 
description)
Type
Units
Missing 
value
Codes/Derivation/Notes
MDV
NONMEM 
Missing data 
value
Integer
None
Never
MDV=1 for LABL= 
DOSE_GSK1325756 records.
MDV=0 for LABL= 
PK_GSK1325756 records.
MDV=1 for LABL= 
PK_GSK1325756 records < LOQ 
(NQ).
VIS
Visit number
Integer
None
Never
From source data.
POP
Population
Integer
None
Never
POP=1, for COPD.
To be entered in all rows for each 
subject.
POPTEXT
Subject 
population 
text
Char
None
Never
POPTEXT=COPD, text 
corresponding to code for POP.
To be entered in all rows for each 
subject.
COH
Cohort
Integer
None
Never
COH=1.
To be entered in all rows for each 
subject.
AGE
Subject Age
Integer
year
If missing 
impute 
with -99
From source data.
To be entered in all rows for each 
subject.
SEX
Subject 
gender 
Integer
None
Never
0=Male, 1=Female
To be entered in all rows for each 
subject.
SEXTEXT
Subject 
gender text
Char
None
Never
Text corresponding to code for 
SEX, e.g. MALE or FEMALE). To 
be entered in all rows for each 
subject.
BMI
Baseline Body 
Mass Index
Num
kg/m2
If missing 
impute 
with -99
Ensure consistent with S&P 
formula. E.g. Formula: 
Weight(kg)/(height(m)**2)
To be entered in all rows for each 
subject.
BSA
Baseline Body 
Surface Area
Num
m2
If missing 
impute 
with -99
Formula: BSA (m2) = 0.024265 • 
Height(cm)0.3964 • Weight(kg)0.5378
Ensure consistent to with S&P 
formula.
To be entered in all rows for each 
subject.
WT
Baseline 
Subject 
weight
Num
kg
If missing 
impute 
with -99
From source data.
To be entered in all rows for each 
subject.
HT
Baseline 
Subject height
Num
m
If missing 
impute 
with -99
From source data.
To be entered in all rows for each 
subject.
RACE1
Subject race 
code1
Integer
None
Never
From source data e.g.
1=African American / African 
 
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Variable
Label 
(Variable 
description)
Type
Units
Missing 
value
Codes/Derivation/Notes
Heritage
2=American Indian or Alaska 
Native
3=Asian – Central / South Asian 
Heritage
4=Asian – East Asian Heritage
5=Asian – Japanese Heritage
6=Asian – South East Asian 
Heritage
7=Asian – Mixed Race
8=Native Hawaiian or other 
Pacific Islander
9=White – Arabic / North African 
Heritage
10=White – White / Caucasian / 
European Heritage
11=White – Mixed Race
12=Mixed Race
To be entered in all rows for each 
subject.
RACE1TXT
Subject race 
text
Char
None
Never
Text corresponding to code for 
RACE1
To be entered in all rows for each 
subject.
RACE2
Subject race 
code2
Integer
None
Never
1=East Asian: Asian – East Asian 
Heritage & Asian – Japanese 
Heritage
2=White: White – Arabic / North
African Heritage White – White / 
Caucasian / European Heritage
3=African: African American / 
African Heritage; 
4=Other: American Indian or 
Alaska Native; Asian – Central / 
South Asian Heritage; Asian –
South East Asian Heritage; Asian 
– Mixed Race; Native Hawaiian 
or other Pacific Islander; White –
Mixed Race & Mixed Race
To be entered in all rows for each 
subject.
RACE2TXT
Subject race 
text
Char
None
Never
Text corresponding to code for 
RACE2
To be entered in all rows for each 
subject.
ETHN
Subject 
ethnicity
Num
None
Never
From source data definition. 
E.g 1=Hispanic or Latino, 2=Non-
 
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Variable
Label 
(Variable 
description)
Type
Units
Missing 
value
Codes/Derivation/Notes
Hispanic
To be entered in all rows for each 
subject.
ETHNTEXT
Subject 
ethnicity text
Char
None
Never
Text corresponding to code for 
ETHN.
To be entered in all rows for each 
subject.
REGN
Region for 
subject
Num
None
Never
1 = East Asia (to include Japan, 
South Korea and Taiwan)
2 = Rest of the World (to include 
all other countries)
To be entered in all rows for each 
subject.
SMOK
Subject 
smoking 
status
Integer
None
Never
0=Non-smoker, 1=Smoker, 
2=Former smoker
To be entered in all rows for each 
subject. Smoking status at 
baseline. 
SMOKTEXT
Subject 
smoking 
status text
Char
None
Never
Text corresponding to code for 
SMOK.
To be entered in all rows for each 
subject.
CMED1
Identifier for 
on-treatment 
COPD 
concomitant 
medication
Num
None
Never
0 = no concomitant use
1 = intermittent use
2 = continuous use
To be entered in all rows for each 
subject.
CMED1TEXT
Subject 
CMED1 text
Char
None
Never
Text corresponding to code for 
CMED1.
To be entered in all rows for each 
subject.
CRCL
Baseline 
Creatinine 
Clearance 
Num
mL/min
If missing 
impute 
with -99
From source data.
OR Specify appropriate formula 
e.g.
Creatinine Clearance will be 
calculated based on the 
Cockcroft-Gault equation.

CrCL (ml/min) = [140 –
AGE (in 
years)]*Weight(kg)*0.85 
(for female patients) / 
[72* Serum Creatinine 
(micromol/L) * 0.0113

Delete one as 
appropriate and ensure 
consistency with S&P 
 
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Variable
Label 
(Variable 
description)
Type
Units
Missing 
value
Codes/Derivation/Notes
formula

To be entered in all rows 
for each subject.
CMED2
Identifier for
on-treatment 
gastric acid 
reducing 
concomitant 
medication
Num
None
Never
0 = no concomitant use
1 = intermittent use
2 = continuous use
To be entered in all rows for each 
subject.
CMED2TEXT
Subject 
concomitant 
medication 
text
Char
None
Never
Text corresponding to code for 
CMED2.
To be entered in all rows for each 
subject.
CMED3
Identifier for 
on-treatment 
gastric acid 
increasing 
concomitant 
medication
Num
None
Never
0 = no concomitant use
1 = intermittent use
2 = continuous use
To be entered in all rows for each 
subject.
CMED3TEXT
Subject 
concomitant 
medication 
text
Char
None
Never
Text corresponding to code for 
CMED3.
To be entered in all rows for each 
subject.
CMED4
Identifier for 
on-treatment 
p-gp inhibitor 
concomitant 
medication
Num
None
Never
0 = no concomitant use
1 = intermittent use
2 = continuous use
To be entered in all rows for each 
subject.
CMED4TEXT
Subject 
CMED4 text
Char
None
Never
Text corresponding to code for 
CMED4.
To be entered in all rows for each 
subject.
CMED5
Identifier for 
on-treatment 
p-gp inducer 
concomitant 
medication
Num
None
Never
0 = no concomitant use
1 = intermittent use
2 = continuous use
To be entered in all rows for each 
subject.
CMED5TEXT
Subject 
concomitant 
medication 
text
Char
None
Never
Text corresponding to code for 
CMED5.
To be entered in all rows for each 
subject.
TBIL
Baseline Total 
bilirubin
Num
Specify
If missing 
impute 
with -99
Baseline defined in the source 
dataset
To be entered in all rows for each 
subject.
TFIB
Baseline 
Fibrinogen
Num
Specify
If missing 
impute 
Baseline defined in the source 
dataset
 
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Variable
Label 
(Variable 
description)
Type
Units
Missing 
value
Codes/Derivation/Notes
with -99
To be entered in all rows for each 
subject.
Current Therapies for COPD:  CMED1
Long-acting β2-agonists (LABAs)
Formoterol
Indacaterol
Salmeterol
Olodaterol
Long acting anti-muscarinic antagonists (LAMAs)
Tiotropium
Aclidinium Bromide
Glycopyrronium bromide
Umeclidinium
Long acting combination bronchodilators
Albuterol/ipratropium bromide 
Vilanterol/umeclidinium 
Olodaterol/tiotropium 
Indacaterol/glycopyrrolate
Formoterol/glycopyrrolate
Formoterol/aclidinium
Methylxanthines
Theophylline
Aminophylline
Bronchodilator effects and 
claimed anti-inflammatory 
effects.
Dose-related toxicity including the 
development of atrial and 
ventricular arrhythmias and grand 
mal seizures. 
Inhaled glucocorticosteroids 
Beclomethasone
Budesonide
Fluticasone propionate
Fluticasone furoate
Mometasone
 
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Inhaled glucocorticosteroids (ICS, in combination with inhaled bronchodilators)
Formoterol/budesonide
Salmeterol/Fluticasone 
propionate
Vilanterol/Fluticasone Furoate
Formoterol/beclomethasone
Formoterol/mometasone
Inhaled glucocorticosteroids (ICS, in combination with inhaled LABA and LAMA)
Fluticasone 
Furoate/Umeclidium/Vilanterol
Phospodiesterase-4 inhibitors
Roflumilast
Antibiotics
Macrolides (e.g. azithromycin, 
erythromycin)
 
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CMED2: Gastric acid reducing conmeds
NDAY: For deriving the nominal day which is the planned day, DAY specific 
information is not available in EXPOSURE dataset. VISIT variable and the time and 
events table might have to be taken into account to find the exact plan of events.
NOMT: It is twice daily dosing with inter-dose interval given to be 12 hours. Therefore, 
to find the planned time of event since the first dose in hours, again the VISIT variable 
and time and events will have to be considered.
NOMTLD: In case of PK_GSK1325756 records, the planned time point variable will 
give the value of this variable for all the post-dose records. For the pre-dose records, this 
variable will have missing values since there is no fixed time point since the previous 
dose for pre-dose records.
RTFD: The time difference between the first dose of the subject and the current dose 
(when LABL=DOSE_GSK1325756) should be calculated in hours. The time difference 
 
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between the first dose of the subject and the PK sample collection time (when 
LABL=PK_GSK1325756) should be calculated in hours.
RTLD: The latest dose prior to the PK sample collection time will have to be found out 
and the time difference between that dose and the PK sample collection time will be 
calculated in hours.
 
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12.10.
Appendix 10: Abbreviations & Trade Marks
12.10.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
AIC
Akaike's Information Criteria
A&R
Analysis and Reporting 
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CPMS
Clinical Pharmacology Modelling & Simulation
CS
Clinical Statistics
CSR
Clinical Study Report
CTR
Clinical Trial Register
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
DBF
Database Freeze
DBR
Database Release
DOB
Date of Birth
DP
Decimal Places
eCRF
Electronic Case Record Form
EMA
European Medicines Agency
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
GSK
GlaxoSmithKline
IA
Interim Analysis
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
IMMS
International Modules Management System
IP
Investigational Product
ITT
Intent-To-Treat
MMRM
Mixed Model Repeated Measures
mITT
Modified Intent to Treat 
NETs
Neutrophil Extracellular Traps
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PP
Per Protocol
PopPK
Population PK
QC
Quality Control
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RAMOS
Randomization & Medication Ordering System 
 
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Abbreviation
Description
SAC
Statistical Analysis Complete
SDSP
Study Data Standardization Plan
SDTM
Study Data Tabulation Model
SOP
Standard Operation Procedure
TA
Therapeutic Area
TFL
Tables, Figures & Listings 
12.10.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
None
WinNonlin
SAS
 
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12.11.
Appendix 11: List of Data Displays
12.11.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.21
Efficacy
2.1 to 2.22
2.1 to 2.18
Safety
3.1 to 3.14
Pharmacokinetic
4.1 to 4.2
4.1 to 4.6
Section
Listings
ICH Listings
1 to 30
Other Listings
31 to 44
12.11.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced by the name of the table or figure and if 
required example mock-up displays provided in Appendix 12: Example Mock Shells for 
Data Displays.
12.11.3.
Deliverables
Delivery [Priority] [1]
Description
SAC [X]
Final Statistical Analysis Complete
D
Will be part of the abbreviated dry run
NOTES: 
1.
Indicates priority (i.e. order) in which displays will be generated for the reporting effort
 
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12.11.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
mITT
ES1
Summary of Subject Disposition for the Subject Conclusion 
Record
ICH E3, FDAAA, EudraCT, Use latest 
screening 
SAC [2]
1.2.
mITT
SD1
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment
ICH E3
SAC [2]
1.3.
Enrolled
ES6
Summary of Screening Status and Reasons for Screen Failure
Journal Requirements, Use latest 
screening. If a subject is rescreened 
only use final re-screen 
SAC [2]
1.4.
Enrolled
NS1
Summary of Number of Subject by Country and Site ID
EudraCT/Clinical Operations
SAC [2]
1.5.
mITT
NS1
Summary of Number of Subject by Country and Site ID
EudraCT/Clinical Operations
SAC [2]
1.6.
Primary 
Completer
NS1
Summary of Number of Subject by Country and Site ID
EudraCT/Clinical Operations. If the 
primary completer and mITT population 
are the same do not recreate 
SAC [2]
Protocol Deviation
1.7.
mITT
DV1
Summary of Important Protocol Deviations
ICH E3
SAC [2]
1.8.
Enrolled
IE1
Summary of Inclusion/Exclusion Criteria Deviations for Screen 
or Run-in failures
SAC [2]
1.9.
mITT
IE1 
Summary of Inclusion/Exclusion Criteria Deviations for the 
Modified Intent-to-treat Population
SAC [2]
 
 
 
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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Population Analysed
1.10.
Enrolled
SP1 
Summary of Study Populations 
IDSL
Number of participants who were in the 
Enrolled population, who were 
randomized, the number in the mITT 
population. Of those in the mITT, the 
number and percentage of participants 
in the primary completer population
SAC [2]
Demographic and Baseline Characteristics
1.11.
mITT
DM1 
Summary of Demographic Characteristics
ICH E3, FDAAA, EudraCT
SAC [2]
1.12.
Primary 
Completer
DM1 
Summary of Demographic Characteristics
ICH E3, FDAAA, EudraCT
SAC [2]
1.13.
Enrolled
DM11
Summary of Age Ranges
EudraCT
SAC [2]
1.14.
mITT
PD4
Summary of Screening and Baseline Spirometry Measures
Pre-BD FEV1 (L), Post-BD FEV1 (L), 
Predicted normal FEV1 (L), Percent 
predicted normal post-BD FEV1 (%), 
Percent predicted normal post-BD 
FEV1: <50%, >=50%, Post-BD FVC 
(L), Post-BD FEV1/FVC 
Footnote: Subjects are only supposed 
to have a Post Sputum Induction FEV1 
at baseline if participant was unable to 
give a sample at Pre-Screening. The 
pre-screening and screening samples 
for this measure are combined.
SAC [2]
1.15.
mITT
SU1
Summary of Smoking History and Smoking Status at Screening  
Include smoking status, smoking pack 
years, cigarettes smoked/day
SAC [2]
1.16.
mITT
DM6
Summary of Race and Racial Combinations
ICH E3, FDA, FDAAA, EudraCT
SAC [2]
 
 
 
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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Prior and Concomitant Medications
1.17.
mITT
MH4
Summary of Current Medical Conditions
ICH E3 
SAC [2]
1.18.
mITT
MH4
Summary of Past Medical Conditions
ICH E3
SAC [2]
1.19.
mITT
CM1
Summary of Concomitant Medications
ICH E3
SAC [2]
1.20.
mITT
CM1
Summary of COPD Concomitant Medications Taken Pre-
treatment
SAC [2]
1.21.
mITT
CM1
Summary of COPD Concomitant Medications Taken Post-
treatment
SAC [2]
 
 
 
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12.11.5.
Efficacy Tables
Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
NETs 
2.1
Primary 
Completer
Summary of Adjusted Mean Change from Baseline of NETs 
Quantified by Histone-Elastase
D, SAC [2]
2.2
Primary 
Completer
Summary of Unadjusted Means of NETs
Histone, DNA, and microscopy
quantified 
D, SAC [1]
2.3
Modified 
Primary 
Completer 
Summary of Unadjusted Means of NETs for the Modified 
Primary Population
Histone, DNA, and microscopy 
quantified. This population will only be 
use if this increases the available 
sample from the Primary completer 
population by 20%.
SAC [2]
2.4
Primary 
Completer
Summary Unadjusted Mean Change from Baseline of NETs
Include percent change from baseline 
D, SAC [2]
2.5
Primary 
Completer
Summary of the Ratio of Sputum NETs to Sputum Neutrophils 
D, SAC [2]
2.6
Primary 
Completer
Summary of Change from Baseline in the Ratio of Sputum NETs 
to Sputum Neutrophils 
D, SAC [2]
2.7
Primary 
Completer
Summary of Sputum Neutrophils 
D, SAC [1]
2.8
Primary 
Completer
Summary of Change from Baseline in Sputum Neutrophils 
D, SAC [2]
2.9
mITT
Summary of Peripheral Blood Neutrophil NETs Formation
Will be measured by DNA release and 
microscopy, summarise no PMA and 
PMA values septately, but include both 
on the table. Only collected at baseline 
and day 14 
D, SAC [1]
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.10
mITT
Summary of Change from Baseline in Peripheral Blood 
Neutrophil NETs Formation
Will be measured by DNA release and 
Microscopy 
D, SAC [2]
2.11
mITT
Summary of Sputum Quality
Number of subjects with Insufficient 
Tissue, Poor Quality, Acceptable, and 
Good Quality samples see MISPQL 
variable for quality flag 
Mean and SD of Squamous epithelial 
cells. Mean and SD of Viable 
Leukocytes. 
D, SAC [2]
2.12
Primary 
Completer 
Summary of Sputum Quality
Number of subjects with Insufficient 
Tissue, Poor Quality, Acceptable, and 
Good Quality samples see MISPQL 
variable for quality flag 
Mean and SD of Squamous epithelial 
cells. Mean and SD of Viable 
Leukocytes . 
D, SAC [2]
CAT
2.13
mITT
Summary of Baseline CAT
SAC [2]
Biomarker
2.14
Primary 
Completer
Summary of Change from Baseline Sputum Resistin Levels 
D, SAC [2]
2.15
Primary 
Completer
Summary of Sputum Resistin Levels
D, SAC [2]
2.16
Primary 
Completer
Summary of Change from Baseline in Sputum Elastase Activity 
D, SAC [2]
2.17
Primary 
Completer
Summary of Sputum Elastase Activity 
D, SAC [2]
 
 
 
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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.18
mITT
Summary of Change from Baseline in Ex-Vivo Neutrophil 
Phagocytosis of Bacteria by Flow Cytometry 
D, SAC [2]
2.19
mITT
Summary of Ex-Vivo Neutrophil Phagocytosis of Bacteria by 
Flow Cytometry 
D, SAC [2]
2.20
mITT
Summary of Change from Baseline of Blood Biomarkers
Include plasma fibrinogen and serum 
C-reactive protein. For values below the 
LLQ use X/2
D, SAC [2]
2.21
mITT
Summary of Blood Biomarkers
Include plasma fibrinogen and serum 
C-reactive protein. For values below the 
LLQ use X/2
D, SAC [2]
Exploratory 
2.22
mITT
Summary of VOCs Variablity 
SAC [2]
12.11.6.
Efficacy Figures
Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
NETs
2.1
Primary 
Completer 
Adjusted Mean (95% CI) Change from Baseline of NETs 
Quantified by Histone-Elastase
D, SAC [2]
2.2
Primary 
Completer
Unadjusted Mean and (95% CI) Change from Baseline of NETs 
Quantified by Histone-Elastase, DNA-Elastase, and Microscopy
Please add text below indicating the 
number of subjects in each quality 
category. Percentage change. 
D, SAC [2]
 
 
 
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Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.3
Modified 
Primary 
Completer 
Unadjusted Mean and (95% CI) Change from Baseline of NETs 
Quantified by Histone-Elastase, DNA-Elastase, and Microscopy 
for the Modified Primary Population
Please add text below indicating the 
number of subjects in each quality 
category. Percentage change. This 
population will only be use if this 
increases the available sample from the 
Primary completer population by 20%.
SAC [2]
2.4
Primary 
Completer 
Spaghetti Plot of Change from Baseline of NETs
D, SAC [2]
2.5
Primary 
Completer 
Spaghetti Plot of NETs
D, SAC [2]
2.6
Modified 
Primary 
Completer 
Spaghetti Plot of NETs for the Modified Primary Population 
This population will only be use if this 
increases the available sample from the 
Primary completer population by 20%.
SAC [2]
2.7
Primary 
Completers
Spaghetti and Boxplot of Baseline and Day 14 of NETs 
Quantified by Histone Elastase 
D, SAC [2]
2.8
Primary 
Completers
Spaghetti and Boxplot of Baseline and Day 14 of Neutrophils 
D, SAC [2]
2.9
mITT
Spaghetti and Boxplot of Baseline and Day 14 of Peripheral 
Blood NETs  
For no PMA values only. Will be 
measured by DNA release and 
microscopy 
D, SAC [2]
2.10
Primary 
Completer 
Spaghetti Plot of Change from Baseline in the Ratio of Sputum 
NETs to Sputum Neutrophils 
D, SAC [2]
2.11
Primary 
Completer 
Spaghetti Plot of Ratio of Sputum NETs to Sputum Neutrophils 
D, SAC [2]
 
 
 
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Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.12
mITT 
Spaghetti Plot of Change from PMA in Peripheral Blood 
Neutrophil NETs Formation
Facet the plot by the change that 
occurs on day -1 and on day 14. Will be 
measure by DNA release and 
microscopy 
D, SAC [2]
2.13
mITT
Spaghetti and Boxplot of Peripheral Blood Neutrophil NETs 
Formation
D, SAC [2] 
2.14
mITT
Boxplot of Change from Baseline in Peripheral Blood Neutrophil
NETs Formation
For Placebo and treatment 
D, SAC [2]
2.15
Primary 
Completer
Spaghetti Plot of Change from Baseline of Sputum Neutrophils 
D, SAC [2]
2.16
Primary 
Completer
Spaghetti Plot of Sputum Neutrophils 
D, SAC [2]
Biomarkers 
2.17
mITT
Mean and (95% CI) of Change from Baseline in Ex-Vivo 
Neutrophil Phagocytosis of Bacteria by Flow Cytometry 
SAC [2]
2.18
mITT
Mean and (95% CI) of Change from Baseline of Blood 
Biomarkers
SAC [2]
12.11.7.
Safety Tables
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
3.1.
mITT
AE1CP 
Summary of All Adverse Events by System Organ Class and 
Preferred Term
ICH E3
SAC [2]
 
 
 
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.2.
mITT
AE1 
Summary of Adverse Events of Special Interest 
the specific events of interest will be 
based on the safety review team (SRT) 
agreements in place at the time of 
reporting
SAC [2]
3.3.
mITT
AE1CP
Summary All Drug-Related Adverse Events by System Organ 
Class and Preferred Term
ICH E3
SAC [2]
3.4.
mITT
AE15
Summary of Common (>=5%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Participant 
and Occurrences)
FDAAA, EudraCT
SAC [2]
Serious and Other Significant Adverse Events
3.5.
mITT
Summary of Change from Baseline of Spirometry
SAC [2]
3.6.
mITT
Summary of Spirometry
SAC [2]
3.7.
mITT
AE16
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Participants and Occurrences)
FDAAA, EudraCT
SAC [2]
Laboratory: Chemistry 
3.8.
mITT
LB1
Summary of Chemistry Changes from Baseline 
ICH E3
SAC [2]
Laboratory: Hematology
3.9.
mITT
LB1
Summary of Hematology Changes from Baseline
ICH E3
SAC [2]
Laboratory: Urinalysis
3.10.
mITT
LB1
Summary of Urine Concentration Changes from Baseline
ICH E3
SAC [2]
Laboratory: Hepatobiliary (Liver)
3.11.
mITT
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting
IDSL
SAC [2]
ECG
3.12.
mITT
EG1
Summary of ECG Findings 
IDSL 
SAC [2]
 
 
 
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.13.
mITT
EG2
Summary of Change from Baseline in ECG Values by Visit
IDSL 
SAC [2]
Vital Signs
3.14.
mITT
VS1
Summary of Change from Baseline in Vital Signs
ICH E3
SAC [2]
 
 
 
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12.11.8.
Pharmacokinetic Tables
Pharmacokinetic: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Whole Blood Pk
4.1.
PK
PKCT1
Summary of Danirixin Whole Blood Pharmacokinetic 
Concentration-Time Data
SAC[2]
4.2.
PK
PKPT4
Summary of Derived Danirixin Whole Blood Pharmacokinetic 
Parameters
SAC[2]
 
 
 
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12.11.9.
Pharmacokinetic Figures
Pharmacokinetic: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
4.1.
PK
PKCF1p
Individual Whole Blood Danirixin Concentration-Time Plots by 
Subject (Linear and Semi-log)
1. X-axis displays actual relative 
time
2. Include line for LLQ along with 
footnote defining LLQ value
3. Include values below LLQ
4. Overlay Day 1 and 14
SAC [2]
4.2.
PK
PKCF6
Individual Whole Blood Danirixin Concentration-Time Plots by 
Day (Linear and Semi-log)
1. X-axis displays actual relative 
time
2. Include line for LLQ along with 
footnote defining LLQ value
3. Include values below LLQ
SAC [2]
4.3.
PK
PKCF4
Mean (SD) Whole Blood Danirixin Concentration-Time Plots 
(Linear and Semi-log)
1. Include the full SD bars at each 
time point
2. X-axis displays planned relative 
time
3. Include line for LLQ along with 
footnote defining LLQ value
SAC [2]
4.4.
PK
PKCF5
Median (Range) Whole Blood Danirixin Concentration-Time 
Plots (Linear and Semi-log)
1. Include bars for range at each 
time point
2. X-axis displays planned relative 
time
3. Include like for LLQ along with 
footnote defining LLQ value
SAC [2]
 
 
 
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Pharmacokinetic: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
4.5.
PK
Scatter plot of Efficacy versus Danirixin Concentration 
(Trough)
Spumtum Neutrophil Count and 
Peripheral Blood Neutrophil 
Count Include Placebo imputed 
as DNX conc=0ng/mL, include 
DNX conc=NQ imputed as 
LLOQ/2, where LLOQ=5ng/mL
By Day
SAC [2]
4.6.
PK
Scatter plot of Safety versus Danirixin Concentration 
(Trough)
C-reactive Protein (CRP)
Include Placebo imputed as DNX 
conc=0ng/mL, include DNX 
conc=NQ imputed as LLOQ/2, 
where LLOQ=5ng/mL
By Day
SAC [2]
 
 
 
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12.11.10. ICH Listings
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.
Screened
ES7
Listing of Reasons for Screen Failure
Journal Guidelines
SAC [2]
2.
Enrolled
ES2 
Listing of Reasons for Study Withdrawal
ICH E3
SAC [2]
3.
mITT
SD2
Listing of Reasons for Study Treatment Discontinuation
ICH E3
SAC [2]
4.
mITT
BL1
Listing of Subjects for Whom the Treatment Blind was Broken
ICH E3
SAC [2]
5.
mITT
TA1 
Listing of Planned and Actual Treatments
IDSL
SAC [2]
Protocol Deviations
6.
mITT
DV2
Listing of Important Protocol Deviations 
ICH E3
SAC [2]
7.
mITT
IE3 
Listing of Subjects with Inclusion/Exclusion Criteria Deviations
ICH E3, Add a flag if subject got 
randomized and dosed 
SAC [2]
Populations Analysed
8.
Enrolled
SP3
Listing of Participants Excluded from Any Population
ICH E3
SAC [2]
Demographic and Baseline Characteristics
9.
mITT
DM2
Listing of Demographic Characteristics
ICH E3
SAC [2]
10.
mITT
DM9 
Listing of Race
ICH E3
SAC [2]
11.
mITT
Listing of Change in Smoking Status from Screening  
SAC [2]
Prior and Concomitant Medications
12.
mITT
CP_CM3 
Listing of Concomitant Medications
IDSL
SAC [2]
Exposure and Treatment Compliance
13.
mITT
EX3
Listing of Exposure Data
ICH E3
SAC [2]
 
 
 
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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events
14.
mITT
AE8CP
Listing of All Adverse Events
ICH E3
SAC [2]
15.
mITT
AE8CP
Listing of Adverse Events of Special Interest 
ICH E3
SAC [2]
16.
Enrolled
AE8CP
Listing of All Adverse Events for Subject not in mITT
ICH E3
SAC [2]
17.
mITT
AE7
Listing of Subject Numbers for Individual Adverse Events
ICH E3
SAC [2]
18.
mITT
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text
IDSL
SAC [2]
Serious and Other Significant Adverse Events
19.
mITT
AE7
Listing of Adverse Event of Special Interest
the specific events of interest will be 
based on the safety review team (SRT) 
agreements in place at the time of 
reporting
SAC [2]
20.
mITT
AE8CPa
Listing of Fatal Serious Adverse Events
ICH E3
SAC [2]
21.
mITT
AE8CPa
Listing of Non-Fatal Serious Adverse Events
ICH E3
SAC [2]
22.
mITT
AE14
Listing of Reasons for Considering as a Serious Adverse Event
ICH E3
SAC [2]
23.
mITT
AE8
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment
ICH E3
SAC [2]
Hepatobiliary (Liver)
24.
mITT
MH2
Listing of Medical Conditions for Subjects with Liver Stopping
Events
IDSL
SAC [2]
25.
mITT
SU2
Listing of Substance Use for Subjects with Liver Stopping 
Events
IDSL
SAC [2]
 
 
 
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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
All Laboratory
26.
mITT
LB5 
Listing of All Laboratory Data for Subjects with Any Value of 
Potential Clinical Importance
ICH E3
SAC [2]
27.
mITT
LB5 / LB6
Listing of Laboratory Values 
IDSL
SAC [2]
28.
mITT
UR2A
Listing of Urinalysis Data for Subjects with Any Value of 
Potential Clinical Importance
ICH E3, Use IDSL standard range 
SAC [2]
ECG
29.
mITT
EG3 / EG4
Listing of ECG Values 
IDSL
SAC [2]
Vital Signs
30.
mITT
VS4 / VS5
Listing of Vital Signs
IDSL
SAC [2]
 
 
 
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12.11.11. Non-ICH Listings  
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
NETs
31.
Primary 
Completer
Listing of NETs 
Include Change from Baseline 
SAC [2]
32.
Primary 
Completer
Listing of the Ratio of Sputum NETs to Sputum Neutrophils 
Include Change from Baseline
SAC [2]
33.
mITT
Listing of Peripheral Blood Neutrophil NETs Formation 
Include Change from Baseline
SAC [2]
34.
Primary 
Completer
Listing of Sputum Quality Measures
Quality measure, viability of 
leukocytes, and Squamous epithelial 
cells
SAC [2]
Spirometry 
35.
mITT
Listing of Spirometry  
Include Change from Baseline
SAC [2]
36.
mITT
Listing of Baseline CAT 
Flag to indicate if they are part of the 
primary completer population
SAC [2]
Exploratory 
37.
mITT
Listing of Treatment Adherence 
SAC [2]
38.
mITT
Listing of VOCs
SAC [2]
Biomarker
39.
Primary 
Completer
Listing of Sputum Resistin
Include Change from Baseline
SAC [2]
40.
Primary 
Completer
Listing of Sputum Elastase 
Include Change from Baseline
SAC [2] 
41.
mITT
Listing of Ex-Vivo Neutrophil Phagocytosis of Bacteria by Flow 
Cytometry 
Include Change from Baseline
SAC [2]
 
 
 
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Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
42.
mITT
Listing of Blood Biomarkers
Include plasma fibrinogen and serum 
C-reactive protein. Include Change 
from Baseline
SAC [2] 
PK
43.
PK
PKCL1P
Listing of Danirixin Whole Blood Pharmacokinetic 
Concentration-Time Data
SAC [2]
44.
PK
PKPL1P
Listing of Derived Danirixin Whole Blood Pharmacokinetic 
Parameters
SAC [2]
 
 
 
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12.12.
Appendix 12: Example Mock Shells for Data Displays
Available Upon Request
 
 
 
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