Conditions: Pulmonary Disease, Chronic Obstructive
Keywords: Danirixin Healthy Food effect Relative Bioavailability Hydrobromide Salt
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 40
Healthy volunteers: yes

Brief summary:
This 2-part study will be carried out on healthy elderly subjects to evaluate relative bioavailability of danirixin formulations. Part A will support the selection of the formulation and Part B will assess food effect, bioavailability and pharmacokinetic (PK) profile of selected formulation from Part A. Danirixin is currently administered with food, therefore the investigation of food effect for the selected formulation could potentially enable dosing without food. Approximately 16 subjects will be included in Part A and approximately 24 subjects will be included in Part B. Both parts will include a screening phase, treatment phase with in-between washout period and a follow-up phase.

Detailed description:

Arms:
arm 1: Subjects will receive a single oral dose of 50 mg danirixin reference and test formulations with food and 240 mL of water in a cross-over manner. arm 2: Subjects will receive a single oral dose of 50 mg danirixin formulation (selected in Part A) in fasted or fed state in a cross-over manner. arm 3: Subjects will receive a single oral dose of 50 mg danirixin formulation (selected in Part A) along with once daily 40 mg OMP capsule in fasted or fed state in a cross-over manner.

Interventions: intervention 1: Danirixin intervention 2: Omeprazole
Intervention descriptions: intervention 1: Danirixin is being developed as a potential anti-inflammatory agent for the treatment of chronic obstructive pulmonary disorder (COPD) and other inflammatory diseases and influenza. Danirixin reference (600 mg) or test formulation (475 or 600 mg or 600 mg with 5 percent HPMC) immediate release tablets will be administered by oral route in a cross-over manner. intervention 2: Omeprazole is used as an antacid. OMP 40 mg delayed-release capsule will be administered by oral route to randomized subjects.

Protocol document:
Prot_001.pdf: 
2017N316476_01
CONFIDENTIAL
GlaxoSmithKline group of companies
207573
1
TITLE PAGE
Protocol Title: A Two Part, Randomized, Open-label, Cross over Study in Healthy 
Elderly Participants to Evaluate the Relative Bioavailability of Hydrobromide Salt Tablet 
Formulations of Danirixin in the Fed and Fasted States, and to Evaluate the Effect of 
Food and Gastric Acid Secretion Suppression on Danirixin Pharmacokinetics Following 
Administration of Hydrobromide Salt Tablets.
Protocol Number: 207573 / 01
Short Title: GSK1325756 Relative Bioavailability Study in Healthy Elderly Participants 
Compound Number:
GSK1325756
Study Phase: I
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information can be found in the Study 
Reference Manual.
Regulatory Agency Identifying Number(s): IND:108168
Approval Date: 22-FEB-2018
Copyright 2018 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
2018N378719_00


 
2018N378719_00
PPD
PPD
PPD


2017N316476_01
CONFIDENTIAL
207573
3
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
List dates of original protocol and all amendments in reverse chronological order.
Document
Date
DNG Number
Amendment -01
22-FEB-2018
2017N316476_01
Original Protocol
21-Dec-2017
2017N316476_00
Amendment 22-FEB-2018
Overall Rationale for the Amendment: This amendment modifies the design of Part A 
incorporating a fasted group for each of the 4 treatments in addition to the fed groups.  
Additional clarifications have been made where necessary throughout  the protocol.
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
4
Section # and 
Name
Description of Change
Brief Rationale
Synopsis
(Section 1) –
and 
throughout 
document

Changed Strata/Stratum to 
Group

Prevent confusion over the use of 
the term stratum/strata which is 
generally related to randomization
Synopsis 
(Section 1)

Updated Part A from a 
single group to two groups

Update study design to have fed 
and fasted groups in Part A
Synopsis 
(Section 1)

Clarified OMP dosing and 
completion of OMP diary

Provide additional clarity on timing 
of OMP dosing relative to 
screening visit and completion of 
diary
Schedule of 
Activities 
(Section 2)

Updated Part A from a 
single group to two groups

Update study design to have fed 
and fasted groups in Part A
Schedule of 
Activities 
(Section 2)

Update minor 
inconsistencies in the table 
and footnotes

Correct minor inconsistencies
Schedule of 
Activities 
(Section 2)

Changed Strata/Stratum to 
Group

Prevent confusion over the use of 
the term stratum/strata which is 
generally related to randomization
Schedule of 
Activities 
(Section 2)

Clarified OMP dosing

Provide additional clarity on timing 
of OMP dosing relative to 
screening visit
Objectives and 
Endpoints 
(Section 4)

Updated Part A from a 
single group to two groups

Update study design to have fed 
and fasted groups in Part A
Overall Design 
(Section 5.1)

Updated Part A from a 
single group to two groups

Update study design to have fed 
and fasted groups in Part A
Overall Design 
(Section 5.1)

Clarified OMP dosing

Provide additional clarity on timing 
of OMP dosing relative to 
screening visit
Number of 

Updated Part A from a 

Update study design to have fed 
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
5
Section # and 
Name
Description of Change
Brief Rationale
Participants 
(Section 5.2)
single group to two groups
and fasted groups in Part A
Exclusion 
Criteria
(Section 6.2)

Removal of exclusion 
criteria related to TB

Included in original protocol in error
Exclusion 
Criteria
(Section 6.2)

Changed pregnancy test 
from urine to serum

Error in original protocol
Exclusion
Criteria
(Section 6.2)

Updated details related to 
prohibited and allowed 
concomitant medications

Clarified the information in the 
original protocol
Exclusion 
Criteria
(Section 6.2)

Removed exclusion criteria 
related to presence of 
HBcAb

Study drug is not an 
immunosuppressant; therefore, 
criteria is not applicable.
Method of 
treatment 
assignment
(Section 7.3)

Updated to include the 
addition of fed and fasted 
groups in Part A

Updated based on revised study 
design
Statistical 
Considerations
and Sample 
size
determination
(Section 10
and 10.1)

Updated to reflect revised 
study design

Updated based on revised study 
design
All sections

Additional minor 
clarifications added

To clarify protocol
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
6
TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS...............................................................................................................8
2.
SCHEDULE OF ACTIVITIES (SOA) PART A (GROUP 1 AND GROUP 2) 
AND PART B (GROUP 1) ......................................................................................15
3.
INTRODUCTION....................................................................................................23
3.1.
Study Rationale ..........................................................................................23
3.2.
Background ................................................................................................24
3.3.
Benefit/Risk Assessment ............................................................................25
3.3.1.
Risk Assessment .........................................................................26
3.3.2.
Benefit Assessment.....................................................................30
3.3.3.
Overall Benefit:Risk Conclusion...................................................30
4.
OBJECTIVES AND ENDPOINTS...........................................................................30
5.
STUDY DESIGN ....................................................................................................31
5.1.
Overall Design ............................................................................................31
5.2.
Number of Participants ...............................................................................33
5.3.
Participant and Study Completion...............................................................33
5.4.
Scientific Rationale for Study Design ..........................................................33
5.5.
Dose Justification........................................................................................33
6.
STUDY POPULATION...........................................................................................34
6.1.
Inclusion Criteria.........................................................................................34
6.2.
Exclusion Criteria........................................................................................35
6.3.
Lifestyle Restrictions...................................................................................38
6.3.1.
Meals and Dietary Restrictions ....................................................38
6.3.2.
Caffeine, Alcohol, and Tobacco ...................................................38
6.3.3.
Activity .........................................................................................38
6.4.
Screen Failures...........................................................................................38
7.
TREATMENTS.......................................................................................................39
7.1.
Treatments Administered............................................................................39
7.2.
Dose Modification .......................................................................................41
7.3.
Method of Treatment Assignment ...............................................................41
7.4.
Blinding.......................................................................................................41
7.5.
Preparation/Handling/Storage/Accountability..............................................41
7.6.
Treatment Compliance................................................................................42
7.7.
Concomitant Therapy..................................................................................42
7.8.
Treatment after the End of the Study ..........................................................44
8.
DISCONTINUATION CRITERIA.............................................................................44
8.1.
Discontinuation of Study Treatment ............................................................44
8.1.1.
Liver Chemistry Stopping Criteria ................................................44
8.1.2.
QTc Stopping Criteria ..................................................................45
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
7
8.1.3.
Neutrophil Stopping Criteria.........................................................45
8.2.
Withdrawal from the Study..........................................................................45
8.3.
Lost to Follow Up........................................................................................46
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................46
9.1.
Efficacy.......................................................................................................47
9.2.
Adverse Events...........................................................................................47
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................47
9.2.2.
Method of Detecting AEs and SAEs.............................................48
9.2.3.
Follow-up of AEs and SAEs.........................................................48
9.2.4.
Regulatory Reporting Requirements for SAEs .............................48
9.2.5.
Pregnancy ...................................................................................49
9.3.
Treatment of Overdose...............................................................................49
9.4.
Safety Assessments ...................................................................................49
9.4.1.
Physical Examinations.................................................................49
9.4.2.
Vital Signs....................................................................................50
9.4.3.
Electrocardiograms......................................................................50
9.4.4.
Clinical Safety Laboratory Assessments ......................................50
9.5.
Pharmacokinetics .......................................................................................51
9.6.
Pharmacodynamics ....................................................................................51
9.7.
Genetics .....................................................................................................51
9.8.
Biomarkers .................................................................................................51
10. STATISTICAL CONSIDERATIONS........................................................................51
10.1.
Sample Size Determination ........................................................................52
10.1.1.
Sample Size Sensitivity................................................................53
10.1.2.
Sample Size Re-estimation or Adjustment...................................53
10.2.
Populations for Analyses ............................................................................53
10.3.
Statistical Analyses.....................................................................................54
10.3.1.
Pharmacokinetic Analyses...........................................................54
11. REFERENCES.......................................................................................................55
12. APPENDICES........................................................................................................57
12.1.
Appendix 1: Abbreviations and Trademarks................................................57
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................59
12.3.
Appendix 3: Study Governance Considerations..........................................61
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................65
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................70
12.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................74
12.7.
Appendix 7: Neutrophil Safety and Study Treatment Restart ......................76
12.8.
Appendix 8: Protocol Amendment History...................................................78
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
8
1.
SYNOPSIS
Protocol Title:
A Two Part, Randomized, Open-label, Cross over Study in Healthy Elderly Participants
to Evaluate the Relative Bioavailability of Hydrobromide Salt Tablet Formulations of 
Danirixin in the Fed and Fasted States, and to Evaluate the Effect of Food and Gastric 
Acid Secretion Suppression on Danirixin Pharmacokinetics Following Administration of 
Hydrobromide Salt Tablets.
Short Title:
GSK1325756 Relative Bioavailability Study in Healthy Elderly Participants
Rationale:
Part A of this study will provide an understanding of the PK of 3 test tablet formulations 
of the HBr salt of danirixin in healthy elderly participants in fed and fasted conditions in 
comparison to the current HBr salt tablet formulation. The current formulation is a 
hemihydrate salt tablet formulation manufactured using roller compaction (RC). The test 
formulations are manufactured by direct compression (DC) and will investigate the 
performance of these DC tablets, as well as the inclusion of the excipient hydroxypropyl 
methylcellulose (HPMC). Formulation selection for Part B will occur following review of 
the PK data collected in Part A.
Part B of this study will provide an understanding of the PK using the selected 
formulation from Part A in the fed and fasted state; during gastric acid suppression and in 
the monohydrate state under fed conditions in a population of healthy elderly 
participants. Danirixin is currently administered with food, therefore the investigation of 
food effect for the selected formulation could potentially enable dosing without food. 
Additionally, omeprazole (OMP) is being administered with the selected formulation to 
investigate a potential PK interaction as gastric pH has been shown to alter PK exposure 
and this study will further enable us to investigate OMPs influence in the presence and 
absence of food. Finally, the monohydrate tablet simulates a hemihydrate to monohydrate 
tablet in stressed conditions.
The outcome of this study will contribute to the selection of the most appropriate 
formulation/dosing regimen for future studies.
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
9
Objectives and Endpoints:
Objectives
Endpoints
Part A:

To estimate the relative bioavailability 
of danirixin after single dose 
administration of HBr tablet (RC), the 
reference treatment, relative to the test
formulations of the HBr tablet (DC 
475, DC 600 and HPMC 600), in 
healthy elderly subjects in the fed and 
fasted states.

To provide safety and tolerability 
information for oral administration of 
the different formulations of danirixin 
HBr tablets in elderly subjects.

Danirixin PK parameters: AUC(0-inf) 
and Cmax. 

AEs/SAEs, vital signs, ECGs, and 
clinical laboratory parameters 

To estimate the secondary 
pharmacokinetic parameters of 
danirixin after single dose 
administration of HBr tablet (RC), the 
reference treatment, relative to the test
formulations of the HBr tablet (DC 
475, DC 600 and HPMC 600), in 
healthy elderly subjects in the fed and 
fasted states.

Danirixin PK parameters: AUC(0-t), 
AUC(0-24), tmax, t1/2, tlast and tlag.
Part B:

To estimate the effect of food on the 
single dose pharmacokinetics of the 
danirixin HBr tablet formulation 
selected from Part A in healthy elderly 
subjects.

To estimate the effect of OMP on the 
single dose pharmacokinetics of the 
danirixin HBr tablet formulation
selected from Part A in healthy elderly 
subjects in various fed and fasted 
states.

To estimate the relative bioavailability 
of danirixin after single dose 
administration of HBr tablet (RC), the 
reference treatment, relative to the test 

Danirixin PK parameters: 
AUC(0-inf), AUC(0-t), AUC(0-24),
Cmax, tmax, t1/2, tlast and tlag. 

Danirixin PK parameters: AUC(0-inf), 
AUC(0-t), AUC(0-24), Cmax, tmax, 
t1/2, tlast and tlag. 

Danirixin PK parameters: AUC(0-inf), 
AUC(0-t), AUC(0-24), Cmax, tmax, 
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
10
Objectives
Endpoints
formulation of the HBr tablet
(MONO), in healthy elderly subjects in 
the fed state.

To provide safety and tolerability 
information for oral administration of 
danirixin HBr tablets in elderly 
subjects.
t1/2, tlast and tlag. 

AEs/SAEs, vital signs, ECGs, and 
clinical laboratory parameters
Overall Design:
This is a Phase I, two part (Part A and Part B each part contains 2 Groups), randomized, 
open-label, single dose, cross-over study conducted with healthy elderly participants. Part 
A will support the selection of the formulation and Part B will address the Proton Pump 
Inhibitor (PPI) effect, food effect and PK of the monohydrate.
Part A
In Part A, approximately 16 healthy elderly participants will be enrolled such that 
approximately 13 subjects complete dosing and critical assessments for all planned 
treatment periods. The 16 participants will be randomized and designated to go into one 
of two (2) groups, Group 1 and Group 2. Group 1 will be administered danirixin in the 
fed state in all treatment periods. Group 2 will be administered danirixin in the fasted
state in all treatment periods. Participants will undergo a screening period ~30 days prior 
to the first dose of study treatment, followed by 4 treatment periods with at least a 5 day 
washout period between each treatment and a follow-up period of 3-10 days following 
the last dose of danirixin. 
Eligible participants will be admitted to the clinical facilities on Day -1 of each treatment 
period. 
On Day 1 of each treatment period, following completion of the required pre-dose 
measurements and procedures, the investigator or authorized study unit personnel will 
administer a single oral dose of 50 mg danirixin to each participant in the unit. Following 
dosing, participants will undergo clinical safety assessments and serial PK assessments at 
timepoints specified in the Section 2. Participants will be discharged from the unit 
approximately 24 hours following dosing at the Investigator’s discretion. 
Participants will return back to the unit on an outpatient basis approximately 48 hours 
post dose for the 48 hour post dose assessments and be discharged once the assessments 
are complete at the investigator’s discretion. Three to ten days following the last dose of 
danirixin, participants will return to the clinic for the final follow-up visit. Refer to 
Section 2 for study assessments and timepoints. 
A minimum washout period of 5 days is required between dosing in each treatment 
period. A study design schematic for Part A is presented in Table 1.
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
11
Table 1
Part A Group 1 and 2 Study Design
Screening
Period  
Within 30
Days of 
Day 1
Treatment 
Period 1
5- Day 
Washout
Treatment 
Period 2
5 Day 
Washout
Treatment 
Period 3
5 Day 
Washout
Treatment 
Period 4
Early 
Discontinuation/ 
Follow-Up Visit 
3-10 days after 
last dose of 
DNX
Part B
In Part B, approximately 24 healthy elderly participants will be enrolled such that 
approximately 20 subjects (10 subjects per group) complete dosing and critical 
assessments for all planned treatment periods in Group 1 and 2. 
In Part B Group 2 eligible participants will take omeprazole (OMP), 40 mg from Day -4
relative to treatment period 1, Day 1 first dose of danirixin through all periods and 
washouts until the final treatment period 3 PK assessment (48hr post dose). Participants
will be provided with a participant diary to document daily recordings of OMP dosing 
occurring outside of the unit.
For Part B Group 2, once screened, eligible participants will be instructed to return to the 
clinic on Day -4 relative to the first dose of danirixin on Day 1 (Period 1) for a 
qualification visit. During this visit, clinical safety assessments will be performed as 
specified in the Section 2 Schedule of Activities of the protocol. Once assessments are 
complete, eligible participants will be administered a single of dose of OMP in the clinic. 
Participants will be discharged with OMP and will take OMP on Day -3 and Day -2 at 
home. OMP will be administered in the clinic on Day -1, Day 1, Day 2 and Day 3 of each 
treatment period. OMP will be taken on an outpatient daily bases on all other days through
each period until the Period 3 post dose 48h PK assessment. 
For Group 1 and 2, eligible participants will be admitted to the clinical facilities on Day -
1 of each treatment period.
On Day 1 of each treatment period, following completion of the required pre-dose 
measurements and procedures, the investigator or authorized study unit personnel will 
administer a single oral dose of 50 mg danirixin to each participant in the unit. Following 
dosing, participants will undergo clinical safety assessments and serial PK assessments at 
timepoints specified in the Section 2. Participants will be discharged from the unit
approximately 24 hours following dosing at the Investigator’s discretion. 
Participants will return back to the unit on an outpatient basis approximately 48 hours 
post dose for the 48 hour post dose assessments and be discharged once the assessments 
are complete at the investigator’s discretion. Three to ten days following the last dose of 
danirixin, participants will return to the clinic for the final follow-up visit. Refer to 
Section 2 for study assessments and timepoints.
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
12
A minimum washout period of 5 days is required between dosing in each treatment 
period. Study design schematics are presented in Table 2 and Table 3 for Part B Group 1 
and 2, respectively.
Table 2
Part B Group 1 Study Design
Screenin
g
Period  
Within 30
Days of 
Day 1
Treatme
nt Period 
1
5- Day 
Washo
ut
Treatme
nt Period 
2
5 Day 
Washo
ut
Treatme
nt Period 
3
5 Day 
Washo
ut
Treatme
nt Period 
4
Early 
Discontinuatio
n Follow-Up 
Visit 3-10
days after last 
dose of DNX
Table 3
Part B Group 2 Study Design
Screening 
Period 
Within 30 
Days of 
Day 1 
Day -4
Treatment 
Period 1
5- Day 
Washout
Treatment 
Period 2
5 Day 
Washout
Treatment 
Period 3 
Early 
Discontinuation
Follow-Up Visit 
3 - 10 days 
after last dose 
of DNX
OMP taken daily through all treatment and washout periods, ending with 
final assessments for Treatment period 3
Number of Participants:
In Part A, approximately 16 participants will be randomized such that approximately 13
evaluable participants complete the study. Participants will be randomized and designated
to go into one of two (2) groups, Group 1 and Group 2. There will be approximately 8 
participants in each group. 
In Part B, a total of approximately 24 participants (12 participants per group) will be 
randomized per group such that approximately 10 evaluable participants complete each 
group. 
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
13
Table 4
Part A Treatment Descriptions
Treatment Arm
Description
Danirixin Dosing Regimen (or 
Frequency)
A
1 x 50 mg danirixin HBr tablet (600 mg RC 
formulation) reference formulation; fed state 
high fat meal (heavy)
single dose
B
1 x 50 mg danirixin HBr tablet (475mg DC 
formulation); fed state high fat meal (heavy)
single dose
C
1 x 50 mg danirixin HBr tablet (600 mg DC 
formulation); fed state high fat meal (heavy)
single dose
D
1 x 50 mg danirixin HBr tablet (600 mg DC 
tablet formulation with 5% HPMC); fed state 
high fat meal (heavy)
single dose
AO
1 x 50 mg danirixin HBr tablet (600 mg RC 
formulation) reference formulation; fasted
single dose
BO
1 x 50 mg danirixin HBr tablet (475mg DC 
formulation); fasted
single dose
CO
1 x 50 mg danirixin HBr tablet (600 mg DC 
formulation); fasted
single dose
DO
1 x 50 mg danirixin HBr tablet (600 mg DC 
tablet formulation with 5% HPMC); fasted
single dose
Table 5
Part B Group 1 Treatment Descriptions (without OMP)
Treatment Arm
Description
Danirixin Dosing Regimen (or 
Frequency)
E
1 x danirixin Selected 
formulation; fasted  
single dose
F
1 x danirixin Selected 
formulation; fed state normal 
meal (light)
single dose
G
1 x danirixin selected 
formulation; fed state high fat 
meal (heavy)
single dose
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
14
Treatment Arm
Description
Danirixin Dosing Regimen (or 
Frequency)
H
1 x 50 mg danirixin 
monohydrate formulation; fed 
state high fat meal (heavy) 
single dose
Table 6
Part B Group 2 Treatment Descriptions (with OMP)
Treatment Arm
Description
Danirixin Dosing Regimen (or 
Frequency)
I
1 x danirixin selected 
formulation; fasted with 40mg 
OMP  
single dose
J
1 x danirixin selected 
formulation; fed state normal 
meal (light) with 40mg OMP
single dose
K
1 x danirixin selected 
formulation; fed state high fat 
meal (heavy) with 40mg OMP  
single dose
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
15
2.
SCHEDULE OF ACTIVITIES (SOA) PART A (GROUP 1 AND GROUP 2) AND PART B (GROUP
1)
Periods 1-4
Procedure
Screenin
g (up to 
30 days 
prior to 
Day 1) 1
Study Day (Treatment Periods 1-4) 2
Early 
Discontinuatio
n /Follow-up
(3 to 10 days 
post-last 
dose)
Da
y -1 
1
Pre-dose
0h
0.5h
1h
1.5h
2h
3h
4h
6h
8h
10h
12h
24h
48h
Informed 
Consent 
X
Inclusion and 
Exclusion 
Criteria
X
X
Demographics
X
Full Physical 
Exam including 
Height and 
Weight
X
Brief Physical 
Exam
X
X
Medical 
History 
(includes 
substance 
usage)
X
X
Pregnancy 
Test, 
(WOCBP)3
X
X
 
 
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
16
Procedure
Screenin
g (up to 
30 days 
prior to 
Day 1) 1
Study Day (Treatment Periods 1-4) 2
Early 
Discontinuatio
n /Follow-up
(3 to 10 days 
post-last 
dose)
Da
y -1 
1
Pre-dose
0h
0.5h
1h
1.5h
2h
3h
4h
6h
8h
10h
12h
24h
48h
FSH and 
estradiol
(if needed)
X
HIV, Hep B 
and Hep C 
Screen
X
Urine Drug 
Screen
X
X
Alcohol 
Screen-
Breathalyzer
X
X
Urine Cotinine 
Screen
X
X
Admission to 
Unit
X
Laboratory 
Assessments 
(include liver 
chemistries) 
X
X
X
12-lead ECG 4
X
X
X
X
Vital Signs5
X
X
X
X
X
Randomization
X
 
 
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
17
Procedure
Screenin
g (up to 
30 days 
prior to 
Day 1) 1
Study Day (Treatment Periods 1-4) 2
Early 
Discontinuatio
n /Follow-up
(3 to 10 days 
post-last 
dose)
Da
y -1 
1
Pre-dose
0h
0.5h
1h
1.5h
2h
3h
4h
6h
8h
10h
12h
24h
48h
Meal 6
X
Danirixin
Administration,
7
X
Pharmacokinet
ic Sampling
X
X
X
X
X
X
X
X
X
X
X
X
X
SAE Review 
================================================================================================================
AE Review
X
==================================================================================================
Concomitant 
Medication 
Review
X
===================================================================================================
Discharge
X
1.
Screening must be performed within 30 days prior to receiving the dose of Danirixin on Day 1 of period 1.
2.
Treatment periods1-4 will include a minimum 5 day wash-out from day of dosing between each treatment
3.
Serum pregnancy test (where applicable) will be performed at the screening visit and a urine pregnancy test at all other time points specified.
4.
Triplicate ECGs at screening and on Day -1 of each treatment period only. Single ECGs at other timepoints (performed at a similar time of day as Day 1 Pre-dose), unless a 
reading meets the QTc stopping criteria, in which case two further measurements will be taken at the same time point and the average values captured. 
5.
Triplicate BP and HR at screening and pre-dose on Day 1 of each treatment period only. Single measurements at other timepoints (performed at a similar time of day as Day 1 
Pre-dose). HR and BP assessments only performed at the 24 and 48 hr post dose and early discontinuation/follow-up visit timepoints. 
 
 
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
18
6.
Meal (where applicable) to be started and completed 30 minutes prior to of danirixin dosing. Meal to consist of 900-1000 calories and be composed of proper caloric content of 
protein/fat/carbohydrates per FDA guidance and subjects will be required to consume at least 90% of meal. 
7.
When danirixin dosing occurs in the fasted state, subjects will be provided with a light snack and then will fast from all food and drink (except water) from 10 hours prior to dosing
until 4hrs post-dose on Day 1 in each treatment period at which time lunch will be provided. An evening meal will be provided at approximately 9 h post dose. At all other times 
during residency in the clinic, meals will be provided at appropriate times.
 
 
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
19
Part B – Group 2
Periods 1-3
Procedure
Study Day (Treatment Periods -1-3) 2
Early 
Disconti
nuation
/Follow-
up (3 to 
10 days 
post-last 
dose)
Screening
(Up to 30 
days prior 
to Day 1) 1
Qualification 
Visit 
Day -49
Day 
-1
1
Pre-dose
0h
0.5h
1h
1.5h
2h
3h
4h
6h
8h
10h
12h
24h
48h
Informed Consent
X
Inclusion and 
Exclusion
X
X
Demographics
X
Full Physical Exam 
including Height and 
Weight
X
Brief Physical Exam
X
X
Medical History 
(includes substance 
usage)
X
X
Pregnancy Test,3           
(WOCBP)
X
X
X
 
 
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
20
Procedure
Study Day (Treatment Periods -1-3) 2
Early 
Disconti
nuation
/Follow-
up (3 to 
10 days 
post-last 
dose)
Screening
(Up to 30 
days prior 
to Day 1) 1
Qualification 
Visit 
Day -49
Day 
-1
1
Pre-dose
0h
0.5h
1h
1.5h
2h
3h
4h
6h
8h
10h
12h
24h
48h
FSH and estradiol
(if needed)
X
HIV, Hep B and Hep C 
Screen
X
Urine Drug Screen
X
X
X
Alcohol Screen-
Breathalyzer 
X
X
X
Urine Cotinine Screen
X
X
X
Admission to Unit
X
Laboratory 
Assessments (include 
liver chemistries) 
X
X
X
12-lead ECG 4
X
X
X
X
Vital Signs 5
X
X
X
X
X
Randomization
X
 
 
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
21
Procedure
Study Day (Treatment Periods -1-3) 2
Early 
Disconti
nuation
/Follow-
up (3 to 
10 days 
post-last 
dose)
Screening
(Up to 30 
days prior 
to Day 1) 1
Qualification 
Visit 
Day -49
Day 
-1
1
Pre-dose
0h
0.5h
1h
1.5h
2h
3h
4h
6h
8h
10h
12h
24h
48h
Meal6
X
Danirixin
Administration7
X
Omeprazole 
Administration 8
X
X
X
X
X
Diary Card completion 
for Omeprazole Dosing
===============================================================================================
Pharmacokinetic 
Sampling
X
X
X
X
X
X
X
X
X
X
X
X
X
SAE Review
======================================================================================================================
AE Review
X
==========================================================================
Concomitant 
Medication Review
X
============================================================= ==============
 
 
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
22
Procedure
Study Day (Treatment Periods -1-3) 2
Early 
Disconti
nuation
/Follow-
up (3 to 
10 days 
post-last 
dose)
Screening
(Up to 30 
days prior 
to Day 1) 1
Qualification 
Visit 
Day -49
Day 
-1
1
Pre-dose
0h
0.5h
1h
1.5h
2h
3h
4h
6h
8h
10h
12h
24h
48h
Discharge
X
1.
Screening must be performed within 30 days prior to receiving the dose of Danirixin on Day 1 of period 1.
2.
Treatment periods1-3 will include a minimum 5 day wash-out from day of dose between each treatment.
3.
Serum pregnancy test (where applicable) will be performed at the screening visit and a urine pregnancy test at all other time points specified.
4.
Triplicate ECGs at screening and on Day -1 of each treatment period only. Single ECGs at other timepoints (performed at a similar time of day as Day 1 Pre-dose), unless a 
reading meets the QTc stopping criteria, in which case two further measurements will be taken at the same time point and the average values captured. 
5.
Triplicate BP and HR assessments at screening and pre-dose on Day 1 of each treatment period only. Single measurements at other timepoints (performed at a similar time 
of day as Day 1 Pre-dose). HR and BP assessments only performed at the 24 and 48 hr post dose and early discontinuation/follow-up visit timepoints. 
6.
Meal (where applicable) to be started and completed within 30 minutes prior to danirixin dosing. Normal and high fat meal will be described in the SRM. 
7.
When danirixin dosing occurs in the fasted state, subjects will be provided with a light snack and then will fast from all food and drink (except water) from 10 hours prior to 
dose until 4 hr post-dose on Day 1 in each treatment period at which time lunch will be provided. An evening meal will be provided at approximately 9 h post dose. At all other 
times during residency in the clinic, meals will be provided at appropriate times.
8.
OMP will be taken starting on Day -4 continuing daily through all treatment and washout periods until the day of the Period 3, 48hour PK assessment.
9.
The Day -4 Qualification visit only applies to period 1.
 
 
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
23
3.
INTRODUCTION
The inflammation associated with COPD is characterized by a prominent infiltration of 
neutrophils in lung tissue and the airways.  Neutrophils and other inflammatory cells are 
recruited to the lung in response to various chemotactic factors, including chemokines.  
Specifically, there is a large body of evidence that the CXCR2 chemokine receptor plays 
a pivotal role in neutrophil recruitment to the lung.  For neutrophils, chemokine binding 
to the CXCR2 results in chemotaxis and cell activation, ultimately resulting in the release 
of a number of inflammatory mediators and proteases that are thought to contribute to the 
progressive fibrosis, airway stenosis, and destruction of the lung parenchyma 
characteristic of COPD.    
Selective antagonism of the interaction between CXCR2 and its ligands is a potential 
strategy for reducing the inflammation in COPD [Chapman, 2009].  A reduction in tissue 
and airway neutrophilia is expected to result in downstream effects on mucus 
hypersecretion, lung inflammation, and tissue destruction that are hypothesized to 
underlie the development and worsening of respiratory symptoms and decline in lung 
function that occurs in COPD.
Molecules with CXCR2 antagonist activity have been shown to reduce the influx of 
neutrophils into the lungs in healthy participants (e.g. ozone or LPS challenge models) 
and to reduce sputum and tissue neutrophils in the lungs of patients with severe, 
neutrophilic asthma, COPD and bronchiectasis in association with improvements in 
measures of disease activity in some, but not all, studies [O'Byrne, 2016; Holz, 2010;
Watz, 2016, Lazaar 2011; Nair, 2012; Rennard, 2015]. Overall, the results of the reported 
clinical studies with CXCR2 antagonists suggest that careful selection of the target 
patient population is important to achieving clinical benefit.
Danirixin is a selective CXCR2 antagonist being developed as a potential anti-
inflammatory agent for the treatment of COPD and other inflammatory diseases and 
influenza.  Danirixin has demonstrated potent antagonism of CXCR2 activity both in 
vitro and in vivo in preclinical studies [GlaxoSmithKline Document Number, 
YM2010/00163/07]. 
3.1.
Study Rationale
Part A of this study will provide an understanding of the PK of 3 test tablet formulations 
of the HBr salt of danirixin in healthy elderly subjects in fed and fasted conditions in 
comparison to the current HBr salt tablet formulation. The current formulation is a 
hemihydrate salt tablet formulation manufactured using roller compaction (RC). The test 
formulations are manufactured by direct compression (DC) and will investigate the 
performance of these smaller DC tablets, as well as the inclusion of the excipient 
hydroxypropyl methylcellulose (HPMC). Formulation selection for Part B will occur 
following review of the PK data collected in Part A.
Part B of this study will provide an understanding of the PK using the selected 
formulation from Part A in the fed and fasted state; during gastric acid suppression and in 
the monohydrate state under fed conditions in a population of healthy elderly subjects. 
Danirixin is currently administered with food, therefore the investigation of food effect 
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
24
for the selected formulation could potentially enable dosing without food. Additionally,
OMP is being administered with the selected formulation to investigate PK interaction
potential as gastric pH has been shown to alter PK exposure and this study will further 
enable us to investigate OMPs influence in the presence and absence of food. Finally, the 
monohydrate tablet simulates a hemihydrate to monohydrate tablet in stressed conditions.
The outcome of this study will contribute to the selection of the most appropriate 
formulation/dosing regimen for future studies.
3.2.
Background
COPD is a major cause of disability, morbidity, and mortality, resulting in millions of 
deaths annually worldwide contributing significantly to health care costs [Mathers, 2006;
Lopez-Campos, 2016; Vastava, 2015; GOLD, 2016].  The morbidity and mortality of 
COPD are continuing to increase and worldwide and, by the year 2020, COPD is 
expected to be the third leading cause of death and fifth leading cause of disability
[Mathers, 2006; Lopez-Campos, 2016].  The airflow limitation that characterizes COPD 
is primarily due to small airways disease and parenchymal destruction associated with an 
excessive inflammatory response in the lung, mainly caused by cigarette smoking [Celli, 
2004].  COPD is characterized by symptoms of chronic and, in many patients, 
progressive breathlessness (or dyspnea), cough and sputum production.  Many COPD 
patients also suffer from periodic worsening of their COPD symptoms that is beyond the 
typical day to day variation [Hurst, 2010].  These episodes of worsening symptoms 
(COPD exacerbations) account for a significant proportion of COPD-related and total 
health care costs.  Despite several available therapies that have been shown to reduce 
COPD exacerbations and respiratory symptoms, many COPD patients continue to 
experience a high burden of respiratory symptoms and COPD exacerbations resulting in a 
continuing unmet medical need [Vestbo, 2016].  Additionally, there is growing 
recognition that a high percentage of COPD patients with mild airflow limitation as well 
as smokers with preserved lung function suffer from a high burden of symptoms and 
COPD exacerbations with a subsequent impact on health status [Woodruff, 2016].  
Therapies that effectively further reduce COPD exacerbations and improve respiratory 
symptoms could have a substantial impact on healthcare utilization and most importantly 
result in an improvement in COPD patients’ quality of life.
The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines for the 
treatment and management of patients with COPD recommend that the management of 
current respiratory symptoms and subsequent worsening of symptoms resulting in COPD 
exacerbations should be an important component of COPD patient management [GOLD, 
2016].  
Danirixin is being evaluated as an addition to standard of care inhaled therapies (i.e. long 
acting bronchodilators and long acting bronchodilator/corticosteroid combination 
therapies) and is targeting those COPD patients that continue to have a burden of 
respiratory symptoms and COPD exacerbations despite management with currently 
available COPD treatments.
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
25
3.3.
Benefit/Risk Assessment
More detailed information about the potential benefits and risks of danirixin may be 
found in the danirixin Investigator’s Brochure [GlaxoSmithKline Document Number,
YM2010/00163/07].
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
26
3.3.1.
Risk Assessment
Investigational Product (IP) [Danirixin, GSK1325756]
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Testicular effects and male fertility
Clinical exposure limits will be based on the 
NOAELs for testicular toxicity; other 
findings described above occurred at non-
tolerated doses and/or at systemic exposures 
well in excess of the maximum oral or 
maximum predicted intravenous exposure in 
human subjects or were considered non-
adverse and monitorable. Exposure margins 
derived from the 26 and 39 week toxicology 
studies in rats and dogs, respectively, with 
DNX are considered sufficient to support 
oral and intravenous infusion administration 
of DNX in single and repeat-dose clinical 
studies under the proposed dosing regimens.
Clear NOAELs for testicular effects were 
established in the rat at 50 mg/kg/day and at 
10 mg/kg/day in the dog after oral 
administration of DNX. These doses 
resulted in systemic exposures which are 7.7 
and 23.5-fold respectively the exposure for 
an oral clinical dose of 75 mg BID (AUC0-
24 of 8.734 µg.h/mL) and 3 and 9.3-fold 
respectively for the maximum proposed 
Standard safety monitoring will be 
employed.
The potential risk of testicular injury has 
been conveyed in the informed consent.
Pharmacokinetic parameters will be 
monitored in clinical studies to ensure 
appropriate safety margins.
 
 
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
27
Investigational Product (IP) [Danirixin, GSK1325756]
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
intravenous infusion clinical dose of 50 mg 
BID (AUC0-24 of 21.94 µg.h/mL).
Impairment of host defense.
Host defense has not been studied directly 
in nonclinical studies. However, data in 
nonclinical species have not identified an 
increased risk of infection with danirixin.  
Nonclinical studies in mice and ferrets with 
two CXCR2 antagonists in the same 
chemical class as danirixin have not shown 
an increase in infections in challenge 
models (e.g., influenza viral load).  
Secondary bacterial infections after viral 
infection have not been directly evaluated in 
nonclinical studies.
The data from clinical studies including 
healthy participants, COPD and influenza 
patients thus far show no evidence that 
participants taking danirixin have an 
increased infection rate compared with 
participants taking placebo.
Neutropenia has been reported in clinical 
trials of other CXCR2 antagonists.  No 
instances of neutropenia have been reported 
in nonclinical studies with danirixin.  In 
Monitoring of neutrophil count.
Stopping criteria: in participants with a 
confirmed absolute neutrophil count 0.5 x 
109/L product will be discontinued and 
neutrophil count will be monitored until 
return to normal. Participants may be 
restarted on study treatment as detailed in
Appendix 7.
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.
 
 
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
28
Investigational Product (IP) [Danirixin, GSK1325756]
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
healthy volunteer studies and a phase 2a 
study in patients with Influenza (GSK Study 
201682, GlaxoSmithKline Document No.
2014N205875_00), decreased neutrophil 
counts have been observed in participants
receiving either placebo or danirixin; no 
instances of danirixin-related neutropenia 
have been reported in clinical studies to 
date. In healthy participants, the data are 
confounded by the observation of low 
neutrophil counts before dosing or at 
follow-up, and were not dose-related, while 
in patients with influenza, neutrophil counts 
recovered while receiving danirixin, 
coincident with resolution of the viral 
infection. There have been no reports of 
neutrophil count decreases below the lower 
limit of normal in patients with COPD who 
were treated with danirixin for one year.   
These data support the conclusion that a 
causal association of neutropenia with 
danirixin cannot be definitively established.
 
 
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
29
Investigational Product (IP) [Danirixin, GSK1325756]
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Reproductive toxicology (Embryofetal 
development)
In a rat embryofetal development study, an 
oral dose of 300 mg/kg/day resulted in fetal 
skeletal variations in the skull (reductions in 
ossification). There were no test article-
related effects on numbers of corpora lutea, 
implantations, embryofetal survival,
placental morphology, gravid uterine 
weight, sex ratio, fetal body weight, or fetal 
morphology (external and visceral).
As danirixin HBr has shown the potential to 
cause fetal malformations, danirixin or 
danirixin HBr must not be administered to 
pregnant women or nursing mothers. 
Women of childbearing potential should 
only be included in clinical trials with the 
use of appropriate precautions against 
pregnancy.
Study Procedures
None
Other 
Not applicable
 
 
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
30
3.3.2.
Benefit Assessment
There is no direct medical benefit to the subjects from taking part in this study. The
information obtained from this study will be important in selection of appropriate 
formulations and doses/dosing regimens for subsequent studies in patient populations. 
3.3.3.
Overall Benefit:Risk Conclusion
Appropriate measures have been taken to minimize the risk to subjects in this study 
through eligibility criteria and consideration of burden relative to study procedures.  It is 
acceptable to conduct this study in healthy elderly participants, because whilst they will 
receive no direct medical benefit, the risks from the study treatment and procedures are 
minimal.  The study will be conducted in a fully equipped clinical research facility with 
access to hospital emergency facilities.
4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Part A:

To estimate the relative bioavailability 
of danirixin after single dose 
administration of HBr tablet (RC), the 
reference treatment, relative to the test 
formulations of the HBr tablet (DC 
475, DC 600 and HPMC 600), in 
healthy elderly subjects in the fed and 
fasted states.

To provide safety and tolerability 
information for oral administration of 
the different formulations of danirixin 
HBr tablets in elderly subjects.

Danirixin PK parameters: AUC(0-inf) 
and Cmax. 

AEs/SAEs, vital signs, ECGs, and 
clinical laboratory parameters 

To estimate the secondary 
pharmacokinetic parameters of 
danirixin after single dose 
administration of HBr tablet (RC), the 
reference treatment, relative to the test
formulations of the HBr tablet (DC 
475, DC 600 and HPMC 600), in 
healthy elderly subjects in the fed and 
fasted states.

Danirixin PK parameters: AUC(0-t), 
AUC(0-24), tmax, t1/2, tlast and tlag.
Part B:

To estimate the effect of food on the 

Danirixin PK parameters: 
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
31
Objectives
Endpoints
single dose pharmacokinetics of the 
danirixin HBr tablet formulation 
selected from Part A in healthy elderly 
subjects.

To estimate the effect of OMP on the 
single dose pharmacokinetics of the 
danirixin HBr tablet formulation
selected from Part A in healthy elderly 
subjects in various fed and fasted 
states.

To estimate the relative bioavailability 
of danirixin after single dose 
administration of HBr tablet (RC), the 
reference treatment, relative to the test 
formulation of the HBr tablet
(MONO), in healthy elderly subjects in 
the fed state.

To provide safety and tolerability 
information for oral administration of 
danirixin HBr tablets in elderly 
subjects.
AUC(0-inf), AUC(0-t), AUC(0-24),
Cmax, tmax, t1/2, tlast and tlag. 

Danirixin PK parameters: AUC(0-inf), 
AUC(0-t), AUC(0-24), Cmax, tmax, 
t1/2, tlast and tlag. 

Danirixin PK parameters: AUC(0-inf), 
AUC(0-t), AUC(0-24), Cmax, tmax, 
t1/2, tlast and tlag. 

AEs/SAEs, vital signs, ECGs, and 
clinical laboratory parameters
5.
STUDY DESIGN
5.1.
Overall Design
This is a Phase I, two part (Part A and Part B each part contains 2 Groups), randomized, 
open-label, single dose, cross-over study conducted with healthy elderly participants. Part 
A will support the selection of the formulation and Part B will address the PPI effect, 
food effect and PK of the monohydrate.
Part A
In Part A, approximately 16 healthy elderly participants will be enrolled such that 
approximately 13 subjects complete dosing and critical assessments for all planned 
treatment periods. The 16 participants will be randomized and designated to go into one 
of two (2) groups, Group 1 and Group 2. Group 1 will be administered danirixin in the 
fed state in all treatment periods. Group 2 will be administered danirixin in the fasted 
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
32
state in all treatment periods. Participants will undergo a screening period ~30 days prior 
to the first dose of study treatment, followed by 4 treatment periods with at least a 5 day 
washout period between each treatment and a follow-up period of 3-10 days following 
the last dose of danirixin. 
Eligible participants will be admitted to the clinical facilities on Day -1 of each treatment 
period. 
On Day 1 of each treatment period, following completion of the required pre-dose 
measurements and procedures, the investigator or authorized study unit personnel will 
administer a single oral dose of 50 mg danirixin to each participant in the unit. Following 
dosing, participants will undergo clinical safety assessments and serial PK assessments at 
timepoints specified in the Section 2. Participants will be discharged from the unit 
approximately 24 hours following dosing at the Investigator’s discretion. 
Participants will return back to the unit on an outpatient basis approximately 48 hours 
post dose for the 48 hour post dose assessments and be discharged once the assessments 
are complete at the investigator’s discretion. Three to ten days following the last dose of 
danirixin, participants will return to the clinic for the final follow-up visit. Refer to 
Section 2 for study assessments and timepoints. 
A minimum washout period of 5 days is required between dosing in each treatment 
period. A study design schematic for Part A is presented in Table 1.
Part B
In Part B, approximately 24 healthy elderly participants will be enrolled such that 
approximately 20 subjects (10 subjects per group) complete dosing and critical 
assessments for all planned treatment periods in Group 1 and 2. 
In Part B Group 2 eligible participants will take omeprazole (OMP), 40 mg from Day -4
relative to the treatment period 1, Day 1 first dosing of danirixin through all periods and 
washouts until the final treatment period 3 PK assessment (48hr). Participants will be 
provided with a participant diary to document daily recordings of OMP dosing occurring 
outside of the unit.
For Part B Group 2, once screened, eligible participants will be instructed to return to the 
clinic on Day -4 relative to the first dose of danirixin on Day 1 for a qualification visit. 
During this visit, clinical safety assessments will be performed as specified in the Section 
2 Schedule of Activities of the protocol. Once assessments are complete, eligible
participants will be administered a single of dose of OMP in the clinic. Participants will be 
discharged with OMP and will take OMP on Day -3 and Day -2 at home. OMP be 
administered in the clinic on Day -1, Day 1, Day 2 and Day 3 of each treatment period. 
OMP will be taken on an outpatient daily bases on all other days through each period until
the Period 3 post dose 48h PK assessment. 
For Group 1 and 2 eligible participants will be admitted to the clinical facilities on Day -1 
of each treatment period. 
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
33
On Day 1 of each treatment period, following completion of the required pre-dose 
measurements and procedures, the investigator or authorized study unit personnel will 
administer a single oral dose of 50 mg danirixin to each participant in the unit. Following 
dosing, participants will undergo clinical safety assessments and serial PK assessments at 
timepoints specified in the Section 2. Participants will be discharged from the unit 
approximately 24 hours following dosing at the Investigator’s discretion. 
Participants will return back to the unit on an outpatient basis approximately 48 hours 
post dose for the 48 hour post dose assessments and be discharged once the assessments 
are complete at the investigator’s discretion. Three to ten days following the last dose of 
danirixin participants will return to the clinic for the final follow-up visit. Refer to 
Section 2 for study assessments and timepoints.
A minimum washout period of 5 days is required between dosing in each treatment 
period. Study design schematics are presented in Table 2 and Table 3 for Part B Group 1 
and 2, respectively.
5.2.
Number of Participants
In Part A, approximately 16 participants will be randomized such that approximately 13
evaluable participants complete the study. Part A will have two (2) groups of participants, 
Group 1 and Group 2. There will be approximately 8 participants in each group. 
In Part B, approximately 24 participants (12 participants per group) will be randomized 
such that approximately 10 evaluable participants complete each group.
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 final follow-up visit for the part for which they were 
enrolled.
The end of the study is defined as the date of the last visit of the last participant in the 
study.
5.4.
Scientific Rationale for Study Design
This study will use a single dose, open label, cross-over design. This is a well-established 
design to evaluate the relative bioavailability of new formulations of an investigational 
drug. 
5.5.
Dose Justification
The oral dose strength of 50 mg danirixin HBr will be administered as a single dose in all 
the treatment periods in the present study. This is a clinically relevant danirixin dose level 
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
34
and was also the dose used in Clinical Study 201037 [GlaxoSmithKline Document 
Number, 2015N248339_00].
In Group 2 of Part B, subjects will take an oral dose of 40 mg OMP QD in the morning 
for four days prior to the initial danirixin dosing day until 48 hrs after the final danirixin 
dosing day. On the danirixin dosing days, the OMP will be taken in the morning with the 
dose of danirixin.  This omeprazole dose strength and regimen is the same as that 
administered during Clinical Study 201037 [GlaxoSmithKline Document Number, 
2015N248339_00]. The co-administration of 40 mg OMP with danirixin 50 mg in the 
present study is not expected to influence the pharmacokinetics of OMP. The selection of 
the OMP dose and dosing frequency is justified based on efficacy and safety data from 
the package insert. The 40 mg q24h dose of OMP was selected as it is a therapeutic dose 
that is expected to achieve maximal acid suppression and identify an interaction if one 
exists. The onset of effect occurs within 1 hr of administration with maximum effect of a 
single dose occurring within 2 hrs. Following repeated once daily doses, the inhibitory 
effect of OMP on acid secretion increases, reaching a plateau after four days [Sachs, 
1995; Stedman, 2000].
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1.
Participant must be 65 to 80 years of age inclusive, at the Screening Visit.
Type of Participant and Disease Characteristics
2.
Participants who are healthy, as determined by a responsible and experienced 
physician, based on a medical evaluation including medical history, physical 
examination, laboratory tests and cardiac monitoring or a subject with a clinical 
abnormality or laboratory parameters outside the reference range for the population being 
studied may be included if the investigator and the GSK Medical Monitor agree that the 
finding is unlikely to introduce risk factors and will not interfere with the study 
procedures and objectives. Additionally, laboratory assessments that are specifically 
listed in the inclusion or exclusion criteria and are outside of the reference range can be 
repeated once during the screening period.
Weight
3.
Body weight ≥50 kg and body mass index (BMI) within the range 19 - 34 kg/m2 
(inclusive).
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
35
Sex
4.
Male or female
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
5.
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.
Diagnostic Assessments and Other Criteria
6.
Aspartate aminotransferase (AST), ALT, alkaline phosphatase and bilirubin ≤ 1.5 × 
ULN (isolated bilirubin > 1.5 × ULN is acceptable if bilirubin is fractionated and 
direct bilirubin < 35%).
7.
Resting BP of ≤ 160/90 mm Hg, irrespective of anti-hypertensive medication status 
for the subject.
8.
Able and willing to consume the Food and Drug Administration (FDA) defined high 
fat meal [Food and Drug Administration, 2013] within 30 minutes in each of the four
treatment periods where study treatment is administered in a fed state.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
Significant history of or current cardiovascular, respiratory, hepatic, renal, 
gastrointestinal, endocrine, hematological, or neurological disorders capable of 
significantly altering the absorption, metabolism, or elimination of drugs; 
constituting a risk when taking the study treatment; or interfering with the 
interpretation of data.
2.
Lymphoma, leukemia, or any malignancy within the past 5 years except for basal 
cell or squamous epithelial carcinomas of the skin that have been resected with no 
evidence of metastatic disease for 3 years
3.
Breast cancer within the past 10 years
4.
Alanine transaminase (ALT) >1.5x upper limit of normal (ULN) 
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
36
5.
Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%). 
6.
Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones)
7.
QTc >450 msec
NOTES: 
The QTc is the QT interval corrected for heart rate according to Bazett’s formula 
(QTcB), Fridericia’s formula (QTcF), and/or another method, machine-read or 
manually over-read.
The specific formula that will be used to determine eligibility and discontinuation 
for an individual subject should be determined prior to initiation of the study. In 
other words, several different formulae cannot be used to calculate the QTc for 
an individual subject and then the lowest QTc value used to include or 
discontinue the subject from the trial.

For purposes of data analysis, QTcB, QTcF, another QT correction formula, or a 
composite of available values of QTc will be used as specified in the Reporting 
and Analysis Plan (RAP).
Prior/Concomitant Therapy
8.
Use of prescription or non-prescription drugs, including vitamins, herbal and dietary 
supplements (including St John’s Wort) within 7 days (or 14 days if the drug is a 
potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose 
of study treatment until completion of the last study assessment, unless in the 
opinion of the investigator and GSK Medical Monitor, the medication will not 
interfere with the study procedures or compromise subject safety. Some examples of 
exceptions (permitted medications) are:
a. Stable dose of anti-hypertensive medication for at least 3 months prior
to the screening visit.
b. Stable dose of lipid-lowering medications (statins or fibrates) for at
least 3 months prior to the screening visit.
This list is not meant to be all inclusive.
9.
Use of proton pump inhibitors and histamine receptor 2 antagonists 
Other short acting antacid medications (such as TUMS, Maalox, Mylanta, etc) can be 
used between periods but must be stopped 24 hours prior to dosing
Prior/Concurrent Clinical Study Experience
10. Participation in the study would result in loss of blood or blood products in excess of 
500 mL within 3 months
11. The subject 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 
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
37
study: 3 months, 5 half-lives or twice the duration of the biological effect of the 
investigational product (whichever is longer).
12. Exposure to more than 4 new chemical entities within 12 months prior to the first 
dosing day.
13. Participation in a previous clinical trial with danirixin within 1 year prior to the first
dosing day in the current study
Diagnostic assessments
14. Female Subjects: Positive serum beta-human chorionic gonadotropin (β-hCG) test at 
screening.
15. Presence of Hepatitis B surface antigen (HBsAg) and/or Positive Hepatitis C 
antibody test result at screening.
NOTE:  Subjects with positive Hepatitis C antibody due to prior resolved disease can 
be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained
16. Positive Hepatitis C RNA test result at screening or within 3 months prior to first 
dose of study treatment
17. Positive pre-study drug/alcohol screen
18. Positive human immunodeficiency virus (HIV) antibody test
19. Regular use of known drugs of abuse
Other Exclusions
20. Regular alcohol consumption within 6 months prior to the study defined as: 

an average weekly intake of >21 units for males or >14 units for females.  One 
unit is equivalent to 8 g of alcohol: a half-pint (~240 ml) of beer, 1 glass (125 ml) 
of wine or 1 (25 ml) measure of spirits. 
21. Consumption of red wine, Seville oranges, grapefruit or grapefruit juice and/or 
pummelos, citrus fruits, grapefruit hybrids or fruit juices from 7 days prior to the first 
dose of study treatment until collection of the final blood sample.
22. Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or 
nicotine-containing products within 90 days prior to screening.
23. Sensitivity to heparin or heparin-induced thrombocytopenia
24. Sensitivity to any of the study treatments, or components thereof, or drug or other 
allergy that, in the opinion of the investigator or medical monitor, contraindicates 
participation in the study
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
38
6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions

Refrain from consumption of Seville oranges, grapefruit or grapefruit juice, and/or 
pummelos, exotic citrus fruits, grapefruit hybrids, or fruit juices from 7 days before 
the start of study treatment until completion of all study procedures in each study 
period after the final dose. Specific dosing instructions will be provided in the Study 
Reference Manual (SRM) and will be provided to all study participants by the site 
staff at each visit.
6.3.2.
Caffeine, Alcohol, and Tobacco

During each treatment period, subjects will abstain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, tea, cola drinks and chocolate) for 24 
hours prior to the start of dosing until collection of the final pharmacokinetic or 
clinical laboratory sample during each treatment period.

During each dosing session, subjects will abstain from alcohol for 24 hours prior to 
the start of dosing until collection of the final pharmacokinetic and clinical 
laboratory sample during each session. 

Use of tobacco- or nicotine-containing products is prohibited, as detailed in the
  exclusion criteria (Section 6.2).

When dosing occurs in the fasted state, subjects will be provided with a light snack 
and then will fast from all food and drink (except water) from midnight on the 
evening of Day -1 until 4 h post-dose on Day 1 at which time a meal will be provided. 
An evening meal will be provided at approximately 9 h post dose. 

At all other times during residency in the clinic, meals and snacks will be provided at 
appropriate times.

When dosing occurs in the fed state, subjects will be given a high-fat or low-fat diet 
before study treatment administration.  
6.3.3.
Activity
Participants will abstain from strenuous exercise for 48 hours before each blood 
collection for clinical laboratory tests. Participants may participate in light recreational 
activities during studies (eg, watching television, reading).
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently entered in the study. A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
39
demography, screen failure details, eligibility criteria, and any serious adverse events 
(SAEs).
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened if, in the opinion of the investigator, the reason for screen failure is 
temporary and it can be reasonably expected to resolve. Any rescreens must take place 
within the planned screening period so as to not cause any undue prolongation of the 
planned study completion.
Any re-screened participant must meet all the protocol specific inclusion/exclusion 
requirements at the re-screen visit. All screening procedures must be repeated for subjects 
that are re-screened. If a subject screen fails prior to randomization, he/she can be re-
screened once if the site staff feels the subject meets eligibility criteria.
Rescreened participants will be assigned a unique screening number for each time they 
are screened and will receive a participant number when enrolled.
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
GSK will provide the danirixin study treatment.  The study site will be responsible to 
provide the omeprazole for Part 2, Group 2.
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
40
Study Treatment 
Name:
Danirixin 
(GSK1325756H, 
the hydrobromide 
hemihydrate salt)
Reference
Danirixin
(GSK1325756
H, the 
hydrobromide 
hemihydrate 
salt)
Danirixin 
(GSK1325756
H, the 
hydrobromide 
monohydrate 
salt)
PRILOSEC 
(omeprazole)
Dosage 
formulation:
Immediate 
release tablet
Immediate 
release 
tablet
Immediate 
release tablet
Delayed-Release 
capsule
Unit dose 
strength(s)/Dosa
ge level(s):
50mg
50mg
50mg
40mg
Manufacturing 
process
Roller 
Compaction (RC)
Direct 
Compression 
(DC)
Direct 
Compression
(DC)
NA
Tablet Size
600mg
475 and 
600mg
600mg
NA
Presence of 
excipient, HPMC
No
Only in 
600mg
TBC based on 
outcome of part 
A
NA
Route of 
Administration 
Oral
Oral
Oral
Oral
Dosing 
instructions:
With food and 
240 mL (8 oz) 
water, unless 
explicitly defined 
by protocol
With food and 
240 mL (8 oz) 
water, unless 
explicitly 
defined by 
protocol
With food and 
240 mL (8 oz) 
water
Per label 
Packaging and 
Labelling
Study 
Treatment will 
be provided in a 
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.
Study 
Treatment will 
be provided in 
a HDPE bottle 
with 
desiccant. 
Each bottle 
will be 
labelled as 
required per 
country 
requirement.
Over the counter 
product
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
41
Manufacturer
GSK
GSK
GSK
Over the counter 
product
7.2.
Dose Modification
There will be no dose modifications.
7.3.
Method of Treatment Assignment
In Part A, participants will be randomised to a treatment sequence including treatments 
A-D or AO - DO [Table 4]. Participants randomised to a treatment sequence including 
treatments A-D will comprise Group 1 and participants randomised to a treatment 
sequence including treatments AO-DO will comprise Group 2. In Part B, Group 1, 
participants will be randomised to a treatment sequence including treatments E-H [Table 
5], and those in Part B, Group 2 will be randomised to a treatment sequence including 
treatments I-K [Table 6].   This will be done in accordance with the randomization 
schedule generated by the study statistician, prior to the start of the study, using validated 
internal software. Study treatment will be dispensed to participants at the study visits 
summarized in the Section 2.  
7.4.
Blinding
This is an open-label study.
7.5.
Preparation/Handling/Storage/Accountability
No special preparation of study treatment is required. Danirixin tablets will be provided 
in multi-dose bottles and packaged with a desiccant. The monohydrate formulation will 
require storage in a humidity chamber, details will be provided in the study reference 
manual.
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].
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
42

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.

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 the individual dose for a participant is prepared from a bulk supply, the 
preparation of the dose will be confirmed by a second member of the study site staff. 

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.  Study site personnel will examine each 
participant’s mouth to ensure that the study treatment was ingested.

Participants self-administer OMP at home, compliance with OMP will be assessed 
through the participant diary that the participant will complete. Additionally, the 
participant will be queried at the site visit and documented in the source documents 
and CRF.  A record of the number of OMP 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.
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 
informed consent 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
Permitted Medications and Non-Drug Therapies
The following medications have been pre-approved for concomitant use:
A stable dose of anti-hypertensive medication for at least 3 months prior to the 
screening visit is permitted

A stable dose of lipid-lowering medications (statins or fibrates) for at least 3 months
prior to the screening visit is permitted.
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
43

Other short acting antacid medications (such as TUMS, Maalox, Mylanta, etc) can be 
used between periods but must be stopped 24 hours prior to dosing

Standard doses of vitamins

A stable dose of thyroid replacement therapy medications

A stable dose of topical or oral hormone replacement therapy medications

Occasional use of acetaminophen for patient complaints of discomfort (e.g. headache, 
achiness) during clinic visits at the investigator’s discretion with consideration of 
proximity to dosing.

Emergency equipment and drugs will be available within the clinical unit. In the
unlikely event that they are required, their use will be documented.
Prohibited Medications and Non-Drug Therapies
Subjects must be advised that no medication should be discontinued without the 
approval of their primary or treating physician.
Subjects must abstain from the use of prescription or non-prescription drugs, 
including:

proton pump inhibitors

histamine receptor 2 antagonists
  antacid medications (except as indicated above) 
  greater than recommended use of vitamins
  herbal and dietary supplements (including St John’s Wort)
oral or injectable CYP3A4 or BRCP (breast cancer resistance protein) substrates 
with a narrow therapeutic index (CYP3A4 substrates include, but are not limited 
to, alfenatil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, 
quinidine, sirolimus, tacrolimus, and theophylline; BCRP substrates include, but 
are not limited to, topotecan.)
within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives 
(whichever is longer) prior to the first dose of study treatment until completion of the 
last study assessment, unless in the opinion of the investigator and GSK Medical 
Monitor, the medication will not interfere with the study procedures or compromise 
subject safety.
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
44
7.8.
Treatment after the End of the Study
Participants will not receive any additional treatment from GSK after the completion of 
the study.
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
8.1.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). These protocol guidelines are in alignment 
with FDA premarketing clinical liver safety guidance:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Discontinuation of study treatment for abnormal liver tests should be considered by the 
investigator when a participant meets one of the conditions outlined in the algorithm
below or if the investigator believes that it is in the best interest of the participant.
Study treatment will be discontinued for a participant if liver chemistry stopping criteria 
are met:
Phase I Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments  section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 6.
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
45
8.1.2.
QTc Stopping Criteria

The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study.  This formula may not 
be changed or substituted once the participant has been enrolled.

For example, if a participant is eligible for the protocol based on QTcB, then 
QTcB must be used for discontinuation of this individual participant as well.

Once the QT correction formula has been chosen for a participant’s eligibility, 
the same formula must continue to be used for that participant for all QTc data 
being collected for data analysis.  Safety ECGs and other non-protocol specified 
ECGs are an exception.  

The QTc should be based on single or averaged QTc values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording period.  
A subject that meets either bulleted criterion based on the average of triplicate ECG 
readings will be withdrawn from study treatment.  

QTc or QTcB or QTcF > 500 msec,

Change from baseline: QTc >60 msec
See the Section 2 for data to be collected at the time of treatment discontinuation and 
follow-up and for any further evaluations that need to be completed.
8.1.3.
Neutrophil Stopping Criteria
A participant with a peripheral blood neutrophil count 0.5 x 109/L that is confirmed on 
repeat testing will be instructed to suspend dosing.  The neutrophil count should be 
monitored daily until it returns to within the baseline value, as detailed in Appendix 7.
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.

Refer to the Section 2 for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be 
completed.
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
46
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 
baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the time frame defined in the Section 2.
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
47
The following points must be noted: 

If assessments are scheduled for the same nominal time, the assessments should 
occur in the following order:
1. 12-lead ECG
2. vital signs
3. blood draws.  
Note: The timing of the assessments should allow the blood draw to occur at the 
exact nominal time.

The timing and number of planned study assessments, including PK and safety 
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. 

The change in timing or addition of time points for any planned study 
assessments must be documented in a Note to File which is approved by the 
relevant GSK study team members (e.g. medical monitor and GCSP) and then 
archived in the study sponsor and site study files, but this will not constitute a 
protocol amendment. 

The IRB will be informed of any safety issues that require alteration of the 
safety monitoring scheme or amendment of the Informed Consent Form. 

No more than 500 mL of blood will be collected over the duration of the study.
9.1.
Efficacy
This study is a single dose PK study and therefore there is no efficacy endpoint.
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 (see Appendix 4). 
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 start of treatment until the follow-up visit at 
the time points specified in the SoA (Section 2).
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
48

Medical occurrences that begin before the start of study treatment but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the case report form (CRF) not the AE section.

All SAEs will be recorded and reported to the sponsor or designee within 24 
hours, as indicated in Appendix 4. The investigator will submit any updated 
SAE data to the sponsor within 24 hours of it being available.

Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she
considers the event to be reasonably related to the study treatment or study 
participation, the investigator must promptly notify the sponsor.

The method of recording, evaluating, and assessing causality of AEs and SAEs
and the procedures for completing and transmitting SAE reports are provided in
Appendix 4.
9.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
9.2.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as 
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.
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
49

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.
Pregnancy

Details of all pregnancies in female participants will be collected after the start of 
study treatment and until 60 hours after the last dose of study treatment.

If a pregnancy is reported, the investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 5.

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
9.3.
Treatment of Overdose
For this study, any dose of study treatment 4 tablets in a day will be considered an 
overdose.
GSK does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator/treating physician should:
1.
Contact the Medical Monitor immediately.
2.
Closely monitor the participant for AE/SAE and laboratory abnormalities until 
danirixin can no longer be detected systemically (at least 3 days).
3.
Obtain a sample for PK analysis within 4 days from the date of the last dose of study 
treatment if requested by the Medical Monitor (determined on a case-by-case basis).
4.
Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.
9.4.
Safety Assessments
Planned time points for all safety assessments are provided in the Section 2.
9.4.1.
Physical Examinations

A complete physical examination will include, at a minimum, assessments of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. Height 
and weight will also be measured and recorded.
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
50

A brief physical examination will include, at a minimum, assessments of the 
skin, lungs, cardiovascular system, and abdomen (auscultation and palpation of 
the abdomen including examination of the liver and spleen).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
9.4.2.
Vital Signs

Oral temperature, pulse rate, respiratory rate, and blood pressure will be 
assessed. Heart Rate and Blood Pressure will be assessed at 24 and 48 hours 
post dose and at the early termination/final follow-up visit only. 

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) at time points 
specified in Section 2. The average of the 3 blood pressure readings will be 
recorded on the CRF.

Vital signs will be measured in a semi-supine position after 5 minutes rest and 
will include temperature, systolic and diastolic blood pressure, and pulse and 
respiratory rate.
9.4.3.
Electrocardiograms

Single 12-lead ECG will be obtained as outlined in the SoA (Section 2) using an 
ECG machine that automatically calculates the heart rate and measures PR, 
QRS, QT, and QTc intervals. Refer to Section [8.1.2] for QTc withdrawal 
criteria and additional QTc readings that may be necessary.
9.4.4.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory tests to be performed and 
to the SoA for the timing and frequency. 

The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 3 days after the last dose of study 
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
51
treatment should be repeated until the values return to normal or baseline or are 
no longer considered significantly abnormal by the investigator or medical 
monitor. 

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the Section 2.

If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in participant 
management or are considered clinically significant by the investigator (eg, SAE 
or AE or dose modification), then the results must be recorded in the CRF.
9.5.
Pharmacokinetics

Whole blood samples of approximately 2 mL will be collected for measurement 
of whole blood concentrations of danirixin (performed under the control of GSK 
Platform Technology and Science Department of In Vitro In Vivo Translation 
Third Party Resourcing (PTS-IVIVT/TPR) as specified in the Section 2.
Instructions for the collection and handling of biological samples will be provided 
by the sponsor in the SRM. The actual date and time (24-hour clock time) of each 
sample will be recorded.

Samples will be used to evaluate the PK of danirixin. Each whole blood sample
will be used to prepare 4 dried blood spots which will be analysed for danirixin 
concentrations.  Samples collected for analyses of danirixin whole blood may also 
be used to evaluate safety or efficacy aspects related to concerns arising during or 
after the study.
9.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
9.7.
Genetics
Genetics are not evaluated in this study.
9.8.
Biomarkers
Biomarkers are not evaluated in this study.
10.
STATISTICAL CONSIDERATIONS
No formal hypothesis will be tested. For each pharmacokinetic endpoint, point estimates 
and corresponding 90% confidence intervals will be constructed for the ratio of the 
geometric mean of the test treatment to the geometric mean of the reference treatment, 
(test)/(reference).
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
52
The following comparisons of interest will be constructed:
Part
Question
Comparison
Part A
Group 1
Formulation
fed
475mg DC tablet formulation versus 600mg RC 
formulation (reference) 
600mg DC tablet formulation versus reference
600mg DC tablet with 5% HPMC versus reference
Part A
Group 2
Formulation
fasted
475mg DC tablet formulation versus 600mg RC 
formulation (reference)
600mg DC tablet formulation versus reference
600mg DC tablet with 5% HPMC versus reference
Part A
Group 1 & 
2
Food effect
600mg RC formulation fed versus fasted
475mg DC tablet formulation fed versus fasted
600mg DC tablet formulation fed versus fasted
600mg DC tablet with 5% HPMC fed versus fasted
Part B
Group 1
Food effect
No OMP
High fat meal (heavy) versus Fasted
Normal meal (light) versus Fasted
High fat meal (heavy) versus Normal meal (light)
Part B
Group 2
Food effect
With OMP
High fat meal (heavy) versus Fasted
Normal meal (light) versus Fasted
High fat meal (heavy) versus Normal meal (light)
Part B
Group 1 & 
2
Drug 
interaction
Fasted with OMP versus Fasted without OMP
Normal meal (light) with OMP versus Normal meal (light)  
without OMP
High fat meal (heavy) with OMP versus High fat meal 
(heavy) without OMP
Part B
Group 1
Pharm Dev
Monohydrate with high fat meal versus High fat meal 
(heavy)
10.1.
Sample Size Determination
The sample size is primarily based on feasibility. Approximately 60 participants will be 
enrolled in the study to obtain approximately 8 randomized participants (6 completers) in
each group in Part A and approximately 12 randomized subjects (10 completers) in each 
group in Part B.  
The within-subject variability for AUC(0-inf), AUC(0-t) and Cmax of danirixin [GSK
Study 201037, GlaxoSmithKline Document Number 2015N248339_00] was estimated to 
be 37.3%, 39.3% and 44.7%, respectively. Based upon the largest within-subject 
coefficient of variation (44.7% for Cmax of danirixin) and a sample size of 6 subjects 
completing each group in part A of the study, it is estimated that the half-width of the 
90% confidence interval for the ratio of geometric means for the comparison of interest 
should be no more than 42% of the point estimates. Assuming an observed ratio of one, 
the corresponding 90% confidence interval for the ratio of geometric means would be 
0.70 to 1.42.
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
53
A PK interim analysis is planned at the completion of Part A to select the formulation for 
evaluation in Part B.
10.1.1.
Sample Size Sensitivity
The figure below shows the half width of the 90% CI for a range of within-subject 
coefficient of variations for various sample sizes.
Figure 1
Plot of half width of 90% CI by within-subject coefficient of 
variations
10.1.2.
Sample Size Re-estimation or Adjustment
No sample size re-estimation will be performed.
10.2.
Populations for Analyses
For purposes of analysis, the following populations are defined:
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
54
Population
Description
All Participants 
All participants who receive at least one dose of study 
medication. This population will be used for the study 
population and safety analyses.
PK
All participants for whom a pharmacokinetic sample was 
obtained and analyzed. This will be the population used for 
all the pharmacokinetic displays.
10.3.
Statistical Analyses
Final analyses will be performed after the completion of the study and final dataset 
authorization. 
Data will be listed and summarized separately for each part of the study according to 
GlaxoSmithKline reporting standards where applicable. 
Complete details will be documented in the Reporting and Analysis Plan (RAP).
10.3.1.
Pharmacokinetic Analyses
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to GlaxoSmithKline current working practices. . 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), AUC(0-inf), AUC(0-24)], lag time before 
observation of first blood concentration (tlag), time of last observed blood concentration 
(tlast), and apparent terminal phase half-life (t1/2).
Pharmacokinetic data will be listed and presented in graphical form and will be 
summarized descriptively. Complete details will be documented in the Reporting and 
Analysis Plan (RAP).
The point estimates of the geometric least squares (GLS) mean ratio for the PK 
parameters (AUC and Cmax) and the associated 90% CIs will be provided for treatment 
comparisons (test:reference). The PK parameters will be log-transformed prior to analysis 
and treatment comparisons will be expressed as ratios on the original scale.
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
55
11.
REFERENCES
Celli BR, MacNee W. Standards for the diagnosis and treatment of patients with COPD. 
Eur Respir J. 2004;23:932-946. 
Chapman RW, Philips JE, Hipkin RW, Curran AK, Lundell D, Fine JS. CXCR2 
antagonists for the treatment of pulmonary disease. Pharmacol Ther. 2009;121:55-68. 
FDA. Guidance for Industry. Center for Drug Evaluation and Research, United States 
Food and Drug Administration; 2009. Drug-induced liver injury: premarketing clinical 
evaluation. 
Food and Drug Administration (FDA). Bioequivalence Studies with Pharmacokinetic 
Endpoints for Drugs Submitted Under an ANDA Draft Guidance. 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidanc
es/ucm377465.pdf . DEC 2013
GlaxoSmithKline Document Number 2014N205875_00 Study ID 201682. 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. Report Date 21-Nov-2014
GlaxoSmithKline Document Number 2015N248339_00 Study ID 201037. A single 
centre, open-label, 5-period, cross over, randomized study in healthy elderly subjects to 
evaluate the relative bioavailability of hydrobromide salt and free base immediate release 
tablet formulations of danirixin in the fed state, and to evaluate the effect of food and 
gastric acid secretion suppression on danirixin pharmacokinetics following administration 
of hydrobromide salt tablets. Report Date 01-Jun-2016
GlaxoSmithKline Document Number YM2010/00163/07. Danirixin Investigator's 
Brochure, Version 09. Report Date 14-Apr-2016. 
GOLD. From the Global Strategy for the Diagnosis, Management and Prevention of 
COPD, Global Initiative for Chronic Obstructive Lung Disease. Global Initiative for 
Chronic Obstructive Lung Disease, Available from: http://www.copdgold.org; 2016. 
Holz O, Khalilieh S, Ludwig-Sengpiel A, Watz H, Stryszak P, Soni P, et al. SCH527123, 
a novel CXCR2 antagonist, inhibits ozone-induced neutrophilia in healthy subjects. Eur 
Respir J. 2010;35:564-570. 
Hurst JA, Vestbo J, Anzueto A, Locantore N, Mullerova, Tal-Singer R, et al. 
Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 
2010;363:1128-1138. 
Lazaar AL, Sweeney LE, MacDonald AJ et al. SB-656933, a novel CXCR2 selective 
antagnoist, inhibits ex vivo neutrophil activation and ozone-induced airway inflammation 
in humans. Br J Clin Pharmacol. 2011;72:282-293.  
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
56
Lopez-Campos JL, Tan W, Soriano JB. Global burden of COPD. Respirology. 
2016;21:14-23.
Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 
to 2030. PLoS Med. 2006;3:e442. 
Nagai, K., Makita, H., Suzuki, M., Shimizu, K., Konno, S., Ito, Y. M., & Nishimura, M. 
Differential changes in quality of life components over 5 years in chronic obstructive 
pulmonary disease patients. International Journal of Chronic Obstructive Pulmonary 
Disease. 2015; 10: 745–757. 
Nair P, Gaga M, Zervas E et al. Safety and efficacy of a CXCR2 antagnoist in patients 
with severe asthma and sputum neutrophils: a randomized, placebo-controlled clinical 
trial. Clin Exp Allergy. 2012;42:1097-2103. 
O'Byrne PM, Metev H, Puu M et al. Efficacy and safety of a CXCR2 antagonist, 
AZD5069, in patients with uncontrolled persistent asthma: a randomised, double-blind, 
placebo-controlled trial. Lancet Respir Med. 2016;4:797-806. 
Rennard SI, Dale DC, Donohue JF et al. CXCR2 antagonist MK-7123 - a phase 2 proof-
of-concept trial for chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 
2015;191:1001-1011. 
Sachs G, Shin JM, Briving C, et al. The pharmacology of the gastric acid pump: the 
H+,K+ ATPase. Annu Rev Pharmacol Toxicol 1995; 35: 277 305.
Stedman CAM, Barclay ML. Alimentary Pharmacology & Therapeutics Volume 
14, Issue 8, pages 963–978, August 2000.
Vastava S, Thakur D, Sharma S, Punekar YS. Systematic review of humanistic and 
economic burden of symptomatic chronic obstructive pulmonary disease. Pharmacoecon. 
2015;33:467-488. 
Vestbo J, Leather D, Diar Bakerly N, New J, Gibson JM, McCorkindate S, et al. 
Effectiveness of fluticasone furoate-vilanterol for COPD in clinical practice. N Engl J 
Med. 2016;375:1253-1260. 
Watz H, Kirsten A, Pedersen F, Goldmann T, Stellmacher F, Uddin M, et al. Neutrophils 
in bronchial mucosa, sputum and blood after administration of the CXCR2-antagonist 
AZD5069 - an explorative study in neutrophilic asthma. Eur Respir J. 
2016;48(S60):PA4892. 
Woodruff PG, Barr RG, Bleecker F, Christenson SA, Couper D, Curtis JL, et al. Clinical 
significance of symptoms in smokers with preserved pulmonary function. N Engl J Med. 
2016;374:1811-1821.
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
57
12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
  AE
Adverse Event
ALT
Alanine aminotransferase (SGPT)
AST
Aspartate aminotransferase (SGOT)
AUC
Area under concentration-time curve
AUC(0-24)
Area under the concentration-time curve from time zero (pre-
dose) to 24 hours post dose 
AUC(0-inf) 
Area under the concentration-time curve from time zero (pre-
dose) extrapolated to infinite time
AUC(0-t)
Area under the concentration-time curve from time zero (pre-
dose) to last time of quantifiable concentration within a 
subject across all treatments
BCG
Bacillus Calmette-Guerin
BID
Twice a Day
BMI
Body Mass Index
BUN
Blood Urea Nitrogen
CIOMS
Council for International Organizations of Medical Sciences
CPK 
Creatine Phosphokinase
Cmax,
Maximum Observed Concentration
CONSORT
Consolidated Standards of Reporting Trials 
COPD
Chronic Obstructive Pulmonary Disease
CRF
Case Report Form
CSR
Clinical Study Report
DC
Direct Compression 
DNX
Danirixin
ECG
Electrocardiogram
FDA
Food and Drug Administration
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GCSP
Global Clinical Safety Pharmacovigilance
GLS
Geometric Least Squares
GOLD
Global Initiative for Chronic Obstructive Lung Disease
GSK1325756
Danirixin
HBcAb 
Hepatitis B core antibody 
HBr 
Hydrobromide
HBsAg
Hepatitis B surface antigen 
HBsAg
Hepatitis B Surface Antigen
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HIV
Human Immunodeficiency Virus
HPMC
Hydroxypropyl Methylcellulose 
ICF
Informed Consent Form 
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
58
IEC
Independent Ethics Committees
IRB
Institutional Review Boards 
Kg
Kilogram 
LDH
Lactate Dehydrogenase LDH
MCH
Mean Corpuscular Hemoglobin
MCV
Mean Corpuscular Volume
Mg
Milligram 
MSDS
Material Safety Data Sheet 
NOAEL
No-Observed-Adverse-Effect-Level
OMP
Omeprazole 
PPI
Proton Pump Inhibitors
PK
Pharmacokinetic 
RAP
Reporting and Analysis Plan
RBC
Red Blood Cells 
RC
Roller Compaction
SAE
Serious Adverse Event
SOA
Schedule of Activities 
SRM
Study Reference Manual 
SUSAR
Suspected Unexpected Serious Adverse Reactions
t1/2,
Terminal phase half-life
TB
tuberculosis
tlag
Lag time before observation of drug concentrations in 
sampled matrix
tlast
Time of last quantifiable concentration
tmax,
Time of occurrence of Cmax
TST
tuberculin skin test
ULN
Upper Limit of Normal
WBC
While Blood Cells
WOCBP
Woman of Childbearing Potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
Not Applicable
Not Applicable
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
59
12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 7 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 7
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
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 [fasting
Calcium
Alkaline 
phosphatase, 
Albumin
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 and estradiol (as needed in women of non-
childbearing potential only)

Breathalizer alcohol screen and a urine drug screen to include at minimum: 
amphetamines, barbiturates, cocaine, opiates, cannabinoids and 
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
60
Laboratory 
Assessments
Parameters
benzodiazepines.

Serum or 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 C virus antibody
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.
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
61
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. 
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
62

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.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
63
Dissemination of Clinical Study Data

This study will be registered and study information from this protocol will be 
posted on publicly available clinical trial registers before enrolment of study 
participants begins.

The results summary of this study will be posted to the GSK Clinical Study 
Register and other publicly available clinical trial registers within 8 months of 
the primary study completion date.

A manuscript reporting the study results will be submitted to a peer reviewed 
journal within 18 months of the last participant’s last visit. 
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (eg, laboratory 
data). The investigator is responsible for verifying that data entries are accurate 
and correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

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. 
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.
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
64

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 Appendix 3.
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
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
65
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.

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. Also, "lack of 
efficacy" or "failure of expected pharmacological action" constitutes an AE or SAE.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
66

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
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
67
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.
Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes 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.
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
68
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 
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.
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
69
Reporting of SAEs 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 (e.g., InForm).

If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper SAE data collection tool (see next section).

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

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 medical monitor or SAE coordinator by telephone.

Contacts for SAE reporting can be found in the study procedures manual.
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
70
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
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 8.
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
71
Table 8
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulationb

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.)
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the participant.)
NOTES: 
a.
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants in clinical studies. 
b.
Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of 
the contraceptive method. In this case two highly effective methods of contraception should be utilized during the 
treatment period and for at least 60 hours after the last dose of study treatment 
Pregnancy Testing

WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive urine or serum pregnancy test 

Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected 
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
72

Pregnancy testing, with a sensitivity of 5 mIU/mL will be performed using the test 
kit provided by the central laboratory and in accordance with instructions provided in 
its package insert.  
Collection of Pregnancy Information
Male participants with partners who become pregnant

Investigator will not routinely attempt to collect pregnancy information on any male 
participant’s female partner(s) who becomes pregnant while the male participant is 
participating in this study; however, voluntary reports of such incidents will be 
captured through the GSK standard reporting mechanism. This applies only to male 
participants who receive double-blind study treatment.

If pregnancy information for a male participant’s female partner(s) is voluntarily 
reported, after obtaining the necessary signed informed consent from the pregnant 
female partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the partner’s 
pregnancy.

Partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date.  

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. 

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
73
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 be withdrawn 
from the study.
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
74
12.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments
Phase I liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT≥3xULN
If ALT≥3xULN AND bilirubin1,2 2xULN (>35% direct bilirubin) or INR >1.5, 
Report as an SAE.
See additional Actions and Follow Up Assessments listed below
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

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 event follow up assessments 

Monitor the subject until liver chemistries 
resolve, stabilise, or return to within baseline 
(see MONITORING below)
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN  or INR 
>1.5

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 
hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilise or return to 
within baseline

A specialist or hepatology consultation is 
recommended
If ALT≥3xULN AND bilirubin < 2xULN  and 
INR ≤1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24-
72 hrs

Viral hepatitis serology3

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Obtain blood sample for pharmacokinetic 
(PK) analysis, obtained up to 72 hours 
after last dose4 

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 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
If ALT≥3xULN AND bilirubin 2xULN  or 
INR >1.5:

Anti-nuclear antibody, anti-smooth muscle 
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
75
Liver Chemistry Stopping Criteria 

Monitor subjects weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
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 subjects with definite or likely 
acetaminophen use in the preceding week 
[James, 2009]. NOTE: not required in 
China.

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject 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 subjects receiving anticoagulants
3.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
76
12.7.
Appendix 7: Neutrophil Safety and Study Treatment Restart
Neutrophil Stopping Criteria: Absolute neutrophil count (ANC) 0.5 x 109 /L
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Immediately discontinue study treatment 

Report the event to GSK within 24 hours

Complete an SAE data collection tool if the 
event also meets the criteria for an SAE

Monitor the participant until neutrophil 
count stabilizes or returns to within 
baseline (see MONITORING below)

Do not restart participant with study 
treatment unless allowed per protocol and 
GSK Medical Governance approval is 
granted (see RESTART below)
MONITORING:

Treatment of any suspected infections1

Repeat CBC within  24 hrs

Monitor CBC daily until neutrophil count 
resolves, stabilizes or returns to within 
baseline 

Record the appearance or 
worsening of any clinical 
symptoms on the AE report form1

Obtain blood sample for 
pharmacokinetic (PK) analysis 
within 12 hours  after last dose2

Record use of concomitant 
medications on the concomitant 
medications report form 
RESTART

Restart of study medication must be 
approved by the GSK Medical Monitor

Restart may be attempted ONLY if all 
three criteria are met:
The neutrophil count is 1.5 x 109/L 
for at least 48 hours

At least 7 days have elapsed since the 
suspension of study treatment 
No sign or symptom of associated 
infection has been identified

Check the CBC within 24-48 hours 
after re-starting study medication, 
monitor twice weekly for two 
weeks, and monthly thereafter.

If the ANC drops below 1.0 x 
109/L on restart, the participant 
should be permanently 
discontinued from study treatment 
and withdrawn from the study.
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 
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
77
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.
 
2018N378719_00


2017N316476_01
CONFIDENTIAL
207573
78
12.8.
Appendix 8: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
GlaxoSmithKline group of companies
207573
1
TITLE PAGE
Protocol Title: A Two Part, Randomized, Open-label, Cross over Study in Healthy 
Elderly Participants to Evaluate the Relative Bioavailability of Hydrobromide Salt Tablet 
Formulations of Danirixin in the Fed and Fasted States, and to Evaluate the Effect of 
Food and Gastric Acid Secretion Suppression on Danirixin Pharmacokinetics Following 
Administration of Hydrobromide Salt Tablets.
Protocol Number: 207573
Short Title: GSK1325756 Relative Bioavailability Study in Healthy Elderly Participants 
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): IND:108168
Approval Date: 21-DEC-2017
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
2018N378719_00


 
2018N378719_00
PPD
PPD
PPD


2017N316476_00
CONFIDENTIAL
207573
3
TABLE OF CONTENTS
PAGE
1.
SYNOPSIS...............................................................................................................5
2.
SCHEDULE OF ACTIVITIES (SOA) PART A AND PART B STRATUM 1..............12
3.
INTRODUCTION....................................................................................................18
3.1.
Study Rationale ..........................................................................................18
3.2.
Background ................................................................................................19
3.3.
Benefit/Risk Assessment ............................................................................20
3.3.1.
Risk Assessment .........................................................................21
3.3.2.
Benefit Assessment.....................................................................25
3.3.3.
Overall Benefit:Risk Conclusion...................................................25
4.
OBJECTIVES AND ENDPOINTS...........................................................................25
5.
STUDY DESIGN ....................................................................................................26
5.1.
Overall Design ............................................................................................26
5.2.
Number of Participants ...............................................................................28
5.3.
Participant and Study Completion...............................................................28
5.4.
Scientific Rationale for Study Design ..........................................................28
5.5.
Dose Justification........................................................................................28
6.
STUDY POPULATION...........................................................................................29
6.1.
Inclusion Criteria.........................................................................................29
6.2.
Exclusion Criteria........................................................................................30
6.3.
Lifestyle Restrictions...................................................................................32
6.3.1.
Meals and Dietary Restrictions ....................................................32
6.3.2.
Caffeine, Alcohol, and Tobacco ...................................................33
6.3.3.
Activity .........................................................................................33
6.4.
Screen Failures...........................................................................................33
7.
TREATMENTS.......................................................................................................34
7.1.
Treatments Administered............................................................................34
7.2.
Dose Modification .......................................................................................35
7.3.
Method of Treatment Assignment ...............................................................36
7.4.
Blinding.......................................................................................................36
7.5.
Preparation/Handling/Storage/Accountability..............................................36
7.6.
Treatment Compliance................................................................................37
7.7.
Concomitant Therapy..................................................................................37
7.8.
Treatment after the End of the Study ..........................................................38
8.
DISCONTINUATION CRITERIA.............................................................................39
8.1.
Discontinuation of Study Treatment ............................................................39
8.1.1.
Liver Chemistry Stopping Criteria ................................................39
8.1.2.
QTc Stopping Criteria ..................................................................40
8.1.3.
Neutrophil Stopping Criteria.........................................................40
8.2.
Withdrawal from the Study..........................................................................40
8.3.
Lost to Follow Up........................................................................................41
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................41
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
4
9.1.
Efficacy.......................................................................................................42
9.2.
Adverse Events...........................................................................................42
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................42
9.2.2.
Method of Detecting AEs and SAEs.............................................43
9.2.3.
Follow-up of AEs and SAEs.........................................................43
9.2.4.
Regulatory Reporting Requirements for SAEs .............................43
9.2.5.
Pregnancy ...................................................................................44
9.3.
Treatment of Overdose...............................................................................44
9.4.
Safety Assessments ...................................................................................44
9.4.1.
Physical Examinations.................................................................44
9.4.2.
Vital Signs....................................................................................45
9.4.3.
Electrocardiograms......................................................................45
9.4.4.
Clinical Safety Laboratory Assessments ......................................45
9.5.
Pharmacokinetics .......................................................................................46
9.6.
Pharmacodynamics ....................................................................................46
9.7.
Genetics .....................................................................................................46
9.8.
Biomarkers .................................................................................................46
10. STATISTICAL CONSIDERATIONS........................................................................46
10.1.
Sample Size Determination ........................................................................47
10.1.1.
Sample Size Sensitivity................................................................47
10.1.2.
Sample Size Re-estimation or Adjustment...................................48
10.2.
Populations for Analyses ............................................................................48
10.3.
Statistical Analyses.....................................................................................48
10.3.1.
Pharmacokinetic Analyses...........................................................49
11. REFERENCES.......................................................................................................50
12. APPENDICES........................................................................................................53
12.1.
Appendix 1: Abbreviations and Trademarks................................................53
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................55
12.3.
Appendix 3: Study Governance Considerations..........................................57
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................61
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................66
12.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................70
12.7.
Appendix 7: Neutrophil Safety and Study Treatment Restart ......................72
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
5
1.
SYNOPSIS
Protocol Title:
A Two Part, Randomized, Open-label, Cross over Study in Healthy Elderly Participants
to Evaluate the Relative Bioavailability of Hydrobromide Salt Tablet Formulations of 
Danirixin in the Fed and Fasted States, and to Evaluate the Effect of Food and Gastric 
Acid Secretion Suppression on Danirixin Pharmacokinetics Following Administration of 
Hydrobromide Salt Tablets.
Short Title:
GSK1325756 Relative Bioavailability Study in Healthy Elderly Participants
Rationale:
Part A of this study will provide an understanding of the PK of 3 test tablet formulations 
of the HBr salt of danirixin in healthy elderly participants in fed conditions in comparison 
to the current HBr salt tablet formulation. The current formulation is a hemihydrate salt 
tablet formulation manufactured using roller compaction (RC). The test formulations are 
manufactured by direct compression (DC) and will investigate the performance of these 
DC tablets, as well as the inclusion of the excipient hydroxypropyl methylcellulose 
(HPMC). Formulation selection for Part B will occur following review of the PK data 
collected in Part A.
Part B of this study will provide an understanding of the PK using the selected 
formulation from Part A in the fed and fasted state; during gastric acid suppression and in 
the monohydrate state under fed conditions in a population of healthy elderly 
participants. Danirixin is currently administered with food, therefore the investigation of 
food effect for the selected formulation could potentially enable dosing without food. 
Additionally, omeprazole (OMP) is being administered with the selected formulation to 
investigate a potential PK interaction as gastric pH has been shown to alter PK exposure 
and this study will further enable us to investigate OMPs influence in the presence and 
absence of food. Finally, the monohydrate tablet simulates a hemihydrate to monohydrate 
tablet in stressed conditions.
The outcome of this study will contribute to the selection of the most appropriate 
formulation/dosing regimen for future studies.
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
6
Objectives and Endpoints:
Objectives
Endpoints
Part A:

To estimate the relative bioavailability 
of danirixin after single dose 
administration of HBr tablet (RC), the 
reference treatment, relative to the test
formulations of the HBr tablet (DC 
475, DC 600 and HPMC 600), in 
healthy elderly subjects in the fed 
state.

To provide safety and tolerability 
information for oral administration of 
the different formulations of danirixin 
HBr tablets in elderly subjects.

Danirixin PK parameters: AUC(0-inf) 
and Cmax. 

AEs/SAEs, vital signs, ECGs, and 
clinical laboratory parameters 

To estimate the secondary 
pharmacokinetic parameters of 
danirixin after single dose 
administration of HBr tablet (RC), the 
reference treatment, relative to the test
formulations of the HBr tablet (DC 
475, DC 600 and HPMC 600), in 
healthy elderly subjects in the fed 
state.

Danirixin PK parameters: AUC(0-t), 
AUC(0-24), tmax, t1/2, tlast and tlag.
Part B:

To estimate the effect of food on the 
single dose pharmacokinetics of the 
danirixin HBr tablet formulation 
selected from Part A in healthy elderly 
subjects.

To estimate the effect of OMP on the 
single dose pharmacokinetics of the 
danirixin HBr tablet formulation
selected from Part A in healthy elderly 
subjects in various fed and fasted 
states.

To estimate the relative bioavailability 
of danirixin after single dose 

Danirixin PK parameters: 
AUC(0-inf), AUC(0-t), AUC(0-24),
Cmax, tmax, t1/2, tlast and tlag. 

Danirixin PK parameters: AUC(0-inf), 
AUC(0-t), AUC(0-24), Cmax, tmax, 
t1/2, tlast and tlag. 

Danirixin PK parameters: AUC(0-inf), 
AUC(0-t), AUC(0-24), Cmax, tmax, 
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
7
Objectives
Endpoints
administration of HBr tablet (RC), the 
reference treatment, relative to the test 
formulation of the HBr tablet
(MONO), in healthy elderly subjects in 
the fed state.

To provide safety and tolerability 
information for oral administration of 
the different formulations of danirixin 
HBr tablets in elderly subjects.
t1/2, tlast and tlag. 

AEs/SAEs, vital signs, ECGs, and 
clinical laboratory parameters
Overall Design:
This is a Phase I, two part (Part A and Part B which contains 2 Strata), randomized, open-
label, single dose, cross-over study conducted with healthy elderly participants. Part A 
will support the selection of the formulation and Part B will address the PPI effect, food 
effect and PK of the monohydrate.
Part A
In Part A, approximately 16 healthy elderly participants will be enrolled such that 
approximately 13 subjects complete dosing and critical assessments for all planned 
treatment periods. Participants will undergo a screening period ~30 days prior to the first 
dose of study treatment, followed by 4 treatment periods with at least a 5day washout 
period between each treatment and a follow-up period of 3-10 days following the last 
dose of danirixin. 
Eligible participants will be admitted to the clinical facilities on Day -1 of each treatment 
period. 
On Day 1 of each treatment period, following completion of the required pre-dose 
measurements and procedures, the investigator or authorized study unit personnel will 
administer a single oral dose of 50 mg danirixin to each participant in the unit. Following 
dosing, participants will undergo clinical safety assessments and serial PK assessments at 
timepoints specified in the Section 2. Participants will be discharged from the unit 
approximately 24 hours following dosing at the Investigator’s discretion. 
Participants will return back to the unit on an outpatient basis approximately 48 hours 
post dose for the 48 hour post dose assessments and be discharged once the assessments 
are complete at the investigator’s discretion. Three to ten days following the 48 hour 
clinic visit for the final treatment period, participants will return to the clinic for the 
follow-up visit. Refer to Section 2 for study assessments and timepoints. 
 
2018N378719_00


2017N316476_00 
CONFIDENTIAL 
 
 
 
207573 
 
8 
 
A minimum washout period of 5 days is required between dosing in each treatment 
period. A study design schematic for Part A is presented in Table 1. 
Table 1 
Part A Study Design 
Screening 
Period   
Within 30 
Days of 
Day 1 
Treatment 
Period 1 
5- Day 
Washout 
Treatment 
Period 2 
5 Day 
Washout 
Treatment 
Period 3 
5 Day 
Washout 
Treatment 
Period 4 
Follow-
Up Visit 
3-10 
days 
after 
last 
dose of 
DNX 
 
Part B 
 
In Part B, approximately 24 healthy elderly participants will be enrolled such that 
approximately 20 subjects (10 subjects per strata) complete dosing and critical 
assessments for all planned treatment periods in Strata 1 and 2.  
In Part B Stratum 2 eligible participants will take omeprazole (OMP), 40 mg from Day -4 
to day of final PK assessment (48hr) for treatment period 3. Participants will be provided 
with a participant diary to document daily recordings of OMP dosing occurring outside of 
the unit. 
Eligible participants will be admitted to the clinical facilities on Day -1 of each treatment 
period.  
On Day 1 of each treatment period, following completion of the required pre-dose 
measurements and procedures, the investigator or authorized study unit personnel will 
administer a single oral dose of 50 mg danirixin to each participant in the unit. Following 
dosing, participants will undergo clinical safety assessments and serial PK assessments at 
timepoints specified in the Section 2. Participants will be discharged from the unit 
approximately 24 hours following dosing at the Investigator’s discretion.  
Participants will return back to the unit on an outpatient basis approximately 48 hours 
post dose for the 48 hour post dose assessments and be discharged once the assessments 
are complete at the investigator’s discretion. Three to ten days following the 48 hour 
clinic visit for the final treatment period, participants will return to the clinic for the 
follow-up visit. Refer to Section 2 for study assessments and timepoints. 
A minimum washout period of 5 days is required between dosing in each treatment 
period. Study design schematics are presented in Table 2 and Table 3 for Part B Strata 1 
and 2, respectively. 
 
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
9
Table 2
Part B Stratum 1 Study Design
Screening
Period  
Within 30
Days of 
Day 1
Treatment 
Period 1
5- Day 
Washout
Treatment 
Period 2
5 Day 
Washout
Treatment 
Period 3
5 Day 
Washout
Treatment 
Period 4
Follow-
Up 
Visit
3-10
days 
after 
last 
dose 
of DNX
Table 3
Part B Strata 2 Study Design
Screening 
Period 
Within 30
Days of 
Day 1 
Day -4
Treatment 
Period 1
5- Day 
Washout
Treatment 
Period 2
5 Day 
Washout
Treatment 
Period 3 
Follow-Up 
Visit 
3 - 10 days 
after last dose 
of DNX
OMP taken daily ending with final assessments for Treatment period 3
Number of Participants:
In Part A, 16 participants will be randomized such that approximately 13 evaluable 
participants complete the study. 
In Part B, a total of 24 participants (12 participants per strata) will be randomized per 
stratum such that approximately 10 evaluable participants complete each strata. 
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
10
Table 4
Part A Treatment Descriptions
Treatment Arm
Description
Danirixin Dosing Regimen (or 
Frequency)
A
1 x 50 mg danirixin HBr tablet (600 mg RC 
formulation) reference formulation; fed state 
high fat meal (heavy)
single dose
B
1 x 50 mg danirixin HBr tablet (475mg DC 
formulation); fed state high fat meal (heavy)
single dose
C
1 x 50 mg danirixin HBr tablet (600 mg DC 
formulation); fed state high fat meal (heavy)
single dose
D
1 x 50 mg danirixin HBr tablet (600 mg DC 
tablet formulation with 5% HPMC); fed state 
high fat meal (heavy)
single dose
Table 5
Part B Stratum 1 Treatment Descriptions (without OMP)
Treatment Arm
Description
Danirixin Dosing Regimen (or 
Frequency)
E
1 x danirixin Selected 
formulation; fasted  
single dose
F
1 x danirixin Selected 
formulation; fed state normal 
meal (light)
single dose
G
1 x danirixin selected 
formulation; fed state high fat 
meal (heavy)
single dose
H
1 x 50 mg danirixin 
monohydrate formulation; fed 
state high fat meal (heavy) 
single dose
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
11
Table 6
Part B Stratum 2 Treatment Descriptions (with OMP)
Treatment Arm
Description
Danirixin Dosing Regimen (or 
Frequency)
I
1 x danirixin selected 
formulation; fasted with 40mg 
OMP  
single dose
J
1 x danirixin selected 
formulation; fed state normal 
meal (light) with 40mg OMP
single dose
K
1 x danirixin selected 
formulation; fed state high fat 
meal (heavy) with 40mg OMP  
single dose
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
12
2.
SCHEDULE OF ACTIVITIES (SOA) PART A AND PART B STRATUM 1
Periods 1-4
Procedure
Screening 
(up to 30 
days prior 
to Day 1) 1
Study Day (Treatment Periods 1-4) 2
Follow-
up
(3 to 10 
days 
post-
last 
dose)
Day -1 
1
Pre-dose
0h
0.5h
1h
1.5h
2h
3h
4h
6h
8h
10h
12h
24h
48h
Informed 
Consent 
X
Inclusion and 
Exclusion Criteria
X
X
Demographics
X
Full Physical 
Exam including 
Height and 
Weight
X
Brief Physical 
Exam
X
X
Medical History 
(includes 
substance 
usage)
X
X
Pregnancy Test, 
(WOCBP)3
X
X
X
FSH and 
estradiol
(if needed)
X
TB Screen 
X
 
 
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
13
Procedure
Screening 
(up to 30 
days prior 
to Day 1) 1
Study Day (Treatment Periods 1-4) 2
Follow-
up
(3 to 10 
days 
post-
last 
dose)
Day -1 
1
Pre-dose
0h
0.5h
1h
1.5h
2h
3h
4h
6h
8h
10h
12h
24h
48h
HIV, Hep B and 
Hep C Screen
X
Urine 
Drug/Alcohol  
Screen
X
X
Urine Cotinine 
Screen
X
X
Admission to Unit
X
Laboratory 
Assessments 
(include liver 
chemistries) 
X
X
X
X
12-lead ECG
X4
X4
X4
X
Vital Signs
X5
X5
X5
X5
X
Randomization
X
Meal
X6,7
Danirixin
Administration
X
Pharmacokinetic 
Sampling
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
14
Procedure
Screening 
(up to 30 
days prior 
to Day 1) 1
Study Day (Treatment Periods 1-4) 2
Follow-
up
(3 to 10 
days 
post-
last 
dose)
Day -1 
1
Pre-dose
0h
0.5h
1h
1.5h
2h
3h
4h
6h
8h
10h
12h
24h
48h
SAE Review 
=====================================================================================================================
AE Review
X
========================================================================================================

Concomitant 
Medication 
Review
X
========================================================================================================

Discharge
X
1.
Screening must be performed within 30 days prior to receiving the dose of Danirixin on Day 1 of period 1.
2.
Treatment periods1-4 will include a minimum 5 wash-out from day of last dose in between each treatment
3.
Serum pregnancy test will be performed at the screening visit and a urine pregnancy test at all other time points specified.
4.
Triplicate ECGs at screening and pre-dose on Day 1 only. Single ECGs at other timepoints (performed at a similar time of day as Day 1 Pre-dose), unless a reading meets the 
QTc stopping criteria, in which case two further measurements will be taken at the same time point and the average values captured. 
5.
Triplicate vital signs at screening and pre-dose on Day 1 only. Single vital signs at other timepoints (performed at a similar time of day as Day 1 Pre-dose).
6.
Meal to be started and completed within 30 minutes of danirixin dosing. Meal to consist of 900-1000 calories and be composed of proper caloric content of 
protein/fat/carbohydrates per FDA guidance and subjects will be required to consume at least 90% of meal. 
7.
When danirixin dosing occurs in the fasted state, subjects will be provided with a light snack and then will fast from all food and drink (except water) from 10 hours pre-dose until 4 
h post-dose on Day 1 in each treatment period at which time lunch will be provided. An evening meal will be provided at approximately 9 h post dose. At all other times during 
residency in the clinic, meals will be provided at appropriate times.
 
 
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
15
Part B – Stratum 2
Periods 1-3
Procedure
Study Day (Treatment Periods -1-3) 2
Follow-up
(3 to 10 days post-last dose)
Screening 1 
(Up to 30 
days prior 
to Day 1)
Day -4 
to -2 
Day 
-1
1
Pre-dose
0h
0.5h
1h
1.5h
2h
3h
4h
6h
8h
10h
12h
24h
48h
Informed Consent
X
Inclusion and 
Exclusion
X
X
Demographics
X
Full Physical Exam 
including Height and 
Weight
X
Brief Physical Exam
X
X
Medical History 
(includes substance 
usage)
X
X
Pregnancy Test,            
(WOCBP)3
X
X
X
FSH and estradiol
(if needed)
X
TB Screen 
X
 
 
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
16
Procedure
Study Day (Treatment Periods -1-3) 2
Follow-up
(3 to 10 days post-last dose)
Screening 1 
(Up to 30 
days prior 
to Day 1)
Day -4 
to -2 
Day 
-1
1
Pre-dose
0h
0.5h
1h
1.5h
2h
3h
4h
6h
8h
10h
12h
24h
48h
HIV, Hep B and Hep C 
Screen
X
Drug/Alcohol Screen
X
X
Urine Cotinine Screen
X
X
Admission to Unit
X
Laboratory 
Assessments (include 
liver chemistries) 
X
X
X
X
12-lead ECG
X4
X4
X4
X
Vital Signs
X5
X5
X5
X5
X5
X
Randomization
X
Meal
X6,7
Danirixin
Administration
X
Omeprazole 
Administration 8
X
X
X
X
x
x
Diary Card completion 
for Omeprazole Dosing
X
X
X
Pharmacokinetic 
Sampling
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
17
Procedure
Study Day (Treatment Periods -1-3) 2
Follow-up
(3 to 10 days post-last dose)
Screening 1 
(Up to 30 
days prior 
to Day 1)
Day -4 
to -2 
Day 
-1
1
Pre-dose
0h
0.5h
1h
1.5h
2h
3h
4h
6h
8h
10h
12h
24h
48h
SAE Review
==================================================================================================
AE Review
X
==========================================================================
Concomitant 
Medication Review
X
============================================================= ==============
Discharge
X
1.
Treatment periods1-3 will include a minimum 5 wash-out from day of last dose in between each treatment
2.
Serum pregnancy test will be performed at the screening visit and a urine pregnancy test at all other time points specified.
3.
Triplicate ECGs at screening and pre-dose on Day 1 only. Single ECGs at other timepoints (performed at a similar time of day as Day 1 Pre-dose), unless a reading meets 
the QTc stopping criteria, in which case two further measurements will be taken at the same time point and the average values captured. 
4.
Triplicate vital signs at screening and pre-dose on Day 1 only. Single vital signs at other timepoints (performed at a similar time of day as Day 1 Pre-dose).
5.
Meal to be started and completed within 30 minutes of danirixin dosing. Normal and high fat meal will be described in the SRM. 
6.
When danirixin dosing occurs in the fasted state, subjects will be provided with a light snack and then will fast from all food and drink (except water) from 10 hours pre-dose 
until 4 h post-dose on Day 1 in each treatment period at which time lunch will be provided. An evening meal will be provided at approximately 9 h post dose. At all other times 
during residency in the clinic, meals will be provided at appropriate times.
7.
OMP will be taken starting on Day -4 continuing daily through the day of the 48hour PK assessment for period 3
 
 
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
18
3.
INTRODUCTION
The inflammation associated with COPD is characterized by a prominent infiltration of 
neutrophils in lung tissue and the airways.  Neutrophils and other inflammatory cells are 
recruited to the lung in response to various chemotactic factors, including chemokines.  
Specifically, there is a large body of evidence that the CXCR2 chemokine receptor plays 
a pivotal role in neutrophil recruitment to the lung.  For neutrophils, chemokine binding 
to the CXCR2 results in chemotaxis and cell activation, ultimately resulting in the release 
of a number of inflammatory mediators and proteases that are thought to contribute to the 
progressive fibrosis, airway stenosis, and destruction of the lung parenchyma 
characteristic of COPD.    
Selective antagonism of the interaction between CXCR2 and its ligands is a potential 
strategy for reducing the inflammation in COPD [Chapman, 2009].  A reduction in tissue 
and airway neutrophilia is expected to result in downstream effects on mucus 
hypersecretion, lung inflammation, and tissue destruction that are hypothesized to 
underlie the development and worsening of respiratory symptoms and decline in lung 
function that occurs in COPD.
Molecules with CXCR2 antagonist activity have been shown to reduce the influx of 
neutrophils into the lungs in healthy participants (e.g. ozone or LPS challenge models) 
and to reduce sputum and tissue neutrophils in the lungs of patients with severe, 
neutrophilic asthma, COPD and bronchiectasis in association with improvements in 
measures of disease activity in some, but not all, studies [O'Byrne, 2016; Holz, 2010;
Watz, 2016, Lazaar 2011; Nair, 2012; Rennard, 2015]. Overall, the results of the reported 
clinical studies with CXCR2 antagonists suggest that careful selection of the target 
patient population is important to achieving clinical benefit.
Danirixin is a selective CXCR2 antagonist being developed as a potential anti-
inflammatory agent for the treatment of COPD and other inflammatory diseases and 
influenza.  Danirixin has demonstrated potent antagonism of CXCR2 activity both in 
vitro and in vivo in preclinical studies [GlaxoSmithKline Document Number, 
YM2010/00163/07]. 
3.1.
Study Rationale
Part A of this study will provide an understanding of the PK of 3 test tablet formulations 
of the HBr salt of danirixin in healthy elderly subjects in fed conditions in comparison to 
the current HBr salt tablet formulation. The current formulation is a hemihydrate salt
tablet formulation manufactured using roller compaction (RC). The test formulations are 
manufactured by direct compression (DC) and will investigate the performance of these 
smaller DC tablets, as well as the inclusion of the excipient hydroxypropyl 
methylcellulose (HPMC). Formulation selection for Part B will occur following review of 
the PK data collected in Part A.
Part B of this study will provide an understanding of the PK using the selected 
formulation from Part A in the fed and fasted state; during gastric acid suppression and in 
the monohydrate state under fed conditions in a population of healthy elderly subjects. 
Danirixin is currently administered with food, therefore the investigation of food effect 
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
19
for the selected formulation could potentially enable dosing without food. Additionally,
OMP is being administered with the selected formulation to investigate PK interaction
potential as gastric pH has been shown to alter PK exposure and this study will further 
enable us to investigate OMPs influence in the presence and absence of food. Finally, the 
monohydrate tablet simulates a hemihydrate to monohydrate tablet in stressed conditions.
The outcome of this study will contribute to the selection of the most appropriate 
formulation/dosing regimen for future studies.
3.2.
Background
COPD is a major cause of disability, morbidity, and mortality, resulting in millions of 
deaths annually worldwide contributing significantly to health care costs [Mathers, 2006;
Lopez-Campos, 2016; Vastava, 2015; GOLD, 2016].  The morbidity and mortality of 
COPD are continuing to increase and worldwide and, by the year 2020, COPD is 
expected to be the third leading cause of death and fifth leading cause of disability
[Mathers, 2006; Lopez-Campos, 2016].  The airflow limitation that characterizes COPD 
is primarily due to small airways disease and parenchymal destruction associated with an 
excessive inflammatory response in the lung, mainly caused by cigarette smoking [Celli, 
2004].  COPD is characterized by symptoms of chronic and, in many patients, 
progressive breathlessness (or dyspnea), cough and sputum production.  Many COPD 
patients also suffer from periodic worsening of their COPD symptoms that is beyond the 
typical day to day variation [Hurst, 2010].  These episodes of worsening symptoms 
(COPD exacerbations) account for a significant proportion of COPD-related and total 
health care costs.  Despite several available therapies that have been shown to reduce 
COPD exacerbations and respiratory symptoms, many COPD patients continue to 
experience a high burden of respiratory symptoms and COPD exacerbations resulting in a 
continuing unmet medical need [Vestbo, 2016].  Additionally, there is growing 
recognition that a high percentage of COPD patients with mild airflow limitation as well 
as smokers with preserved lung function suffer from a high burden of symptoms and 
COPD exacerbations with a subsequent impact on health status [Woodruff, 2016].  
Therapies that effectively further reduce COPD exacerbations and improve respiratory 
symptoms could have a substantial impact on healthcare utilization and most importantly 
result in an improvement in COPD patients’ quality of life.
The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines for the 
treatment and management of patients with COPD recommend that the management of 
current respiratory symptoms and subsequent worsening of symptoms resulting in COPD 
exacerbations should be an important component of COPD patient management [GOLD, 
2016].  
Danirixin is being evaluated as an addition to standard of care inhaled therapies (i.e. long 
acting bronchodilators and long acting bronchodilator/corticosteroid combination 
therapies) and is targeting those COPD patients that continue to have a burden of 
respiratory symptoms and COPD exacerbations despite management with currently 
available COPD treatments.
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
20
3.3.
Benefit/Risk Assessment
More detailed information about the potential benefits and risks of danirixin may be 
found in the danirixin Investigator’s Brochure [GlaxoSmithKline Document Number,
YM2010/00163/07].
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
21
3.3.1.
Risk Assessment
Investigational Product (IP) [Danirixin, GSK1325756]
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Testicular effects and male fertility
Clinical exposure limits will be based on the 
NOAELs for testicular toxicity; other 
findings described above occurred at non-
tolerated doses and/or at systemic exposures 
well in excess of the maximum oral or 
maximum predicted intravenous exposure in 
human subjects or were considered non-
adverse and monitorable. Exposure margins 
derived from the 26 and 39 week toxicology 
studies in rats and dogs, respectively, with 
DNX are considered sufficient to support 
oral and intravenous infusion administration 
of DNX in single and repeat-dose clinical 
studies under the proposed dosing regimens.
Clear NOAELs for testicular effects were 
established in the rat at 50 mg/kg/day and at 
10 mg/kg/day in the dog after oral 
administration of DNX. These doses 
resulted in systemic exposures which are 7.7 
and 23.5-fold respectively the exposure for 
an oral clinical dose of 75 mg BID (AUC0-
24 of 8.734 µg.h/mL) and 3 and 9.3-fold 
respectively for the maximum proposed 
Standard safety monitoring will be 
employed.
The potential risk of testicular injury has 
been conveyed in the informed consent.
Pharmacokinetic parameters will be 
monitored in clinical studies to ensure 
appropriate safety margins.
 
 
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
22
Investigational Product (IP) [Danirixin, GSK1325756]
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
intravenous infusion clinical dose of 50 mg 
BID (AUC0-24 of 21.94 µg.h/mL).
Impairment of host defense.
Host defense has not been studied directly 
in nonclinical studies. However, data in 
nonclinical species have not identified an 
increased risk of infection with danirixin.  
Nonclinical studies in mice and ferrets with 
two CXCR2 antagonists in the same 
chemical class as danirixin have not shown 
an increase in infections in challenge 
models (e.g., influenza viral load).  
Secondary bacterial infections after viral 
infection have not been directly evaluated in 
nonclinical studies.
The data from clinical studies including 
healthy participants, COPD and influenza 
patients thus far show no evidence that 
participants taking danirixin have an 
increased infection rate compared with 
participants taking placebo.
Neutropenia has been reported in clinical 
trials of other CXCR2 antagonists.  No 
instances of neutropenia have been reported 
in nonclinical studies with danirixin.  In 
Monitoring of neutrophil count.
Stopping criteria: in participants with a 
confirmed absolute neutrophil count 0.5 x 
109/L product will be discontinued and 
neutrophil count will be monitored until 
return to normal. Participants may be 
restarted on study treatment as detailed in
Appendix 7.
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.
 
 
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
23
Investigational Product (IP) [Danirixin, GSK1325756]
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
healthy volunteer studies and a phase 2a 
study in patients with Influenza (GSK Study 
201682, GlaxoSmithKline Document No.
2014N205875_00), decreased neutrophil 
counts have been observed in participants
receiving either placebo or danirixin; no 
instances of danirixin-related neutropenia 
have been reported in clinical studies to 
date. In healthy participants, the data are 
confounded by the observation of low 
neutrophil counts before dosing or at 
follow-up, and were not dose-related, while 
in patients with influenza, neutrophil counts 
recovered while receiving danirixin, 
coincident with resolution of the viral 
infection. There have been no reports of 
neutrophil count decreases below the lower 
limit of normal in patients with COPD who 
were treated with danirixin for one year.   
These data support the conclusion that a 
causal association of neutropenia with 
danirixin cannot be definitively established.
 
 
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
24
Investigational Product (IP) [Danirixin, GSK1325756]
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Reproductive toxicology (Embryofetal 
development)
In a rat embryofetal development study, an 
oral dose of 300 mg/kg/day resulted in fetal 
skeletal variations in the skull (reductions in 
ossification). There were no test article-
related effects on numbers of corpora lutea, 
implantations, embryofetal survival,
placental morphology, gravid uterine 
weight, sex ratio, fetal body weight, or fetal 
morphology (external and visceral).
As danirixin HBr has shown the potential to 
cause fetal malformations, danirixin or 
danirixin HBr must not be administered to 
pregnant women or nursing mothers. 
Women of childbearing potential should 
only be included in clinical trials with the 
use of appropriate precautions against 
pregnancy.
Study Procedures
None
Other 
Not applicable
 
 
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
25
3.3.2.
Benefit Assessment
There is no direct medical benefit to the subjects from taking part in this study. The
information obtained from this study will be important in selection of appropriate 
formulations and doses/dosing regimens for subsequent studies in patient populations. 
3.3.3.
Overall Benefit:Risk Conclusion
Appropriate measures have been taken to minimize the risk to subjects in this study 
through eligibility criteria and consideration of burden relative to study procedures.  It is 
acceptable to conduct this study in healthy elderly participants, because whilst they will 
receive no direct medical benefit, the risks from the study treatment and procedures are 
minimal.  The study will be conducted in a fully equipped clinical research facility with 
access to hospital emergency facilities.
4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Part A:

To estimate the relative bioavailability 
of danirixin after single dose 
administration of HBr tablet (RC), the 
reference treatment, relative to the test
formulations of the HBr tablet (DC 
475, DC 600 and HPMC 600), in 
healthy elderly subjects in the fed 
state.

To provide safety and tolerability 
information for oral administration of 
the different formulations of danirixin 
HBr tablets in elderly subjects.

Danirixin PK parameters: AUC(0-inf) 
and Cmax. 

AEs/SAEs, vital signs, ECGs, and 
clinical laboratory parameters 

To estimate the secondary 
pharmacokinetic parameters of 
danirixin after single dose 
administration of HBr tablet (RC), the 
reference treatment, relative to the test
formulations of the HBr tablet (DC
475, DC 600 and HPMC 600), in 
healthy elderly subjects in the fed 
state.

Danirixin PK parameters: AUC(0-t), 
AUC(0-24), tmax, t1/2, tlast and tlag.
Part B:

To estimate the effect of food on the 

Danirixin PK parameters: 
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
26
Objectives
Endpoints
single dose pharmacokinetics of the 
danirixin HBr tablet formulation 
selected from Part A in healthy elderly 
subjects.

To estimate the effect of OMP on the 
single dose pharmacokinetics of the 
danirixin HBr tablet formulation
selected from Part A in healthy elderly 
subjects in various fed and fasted 
states.

To estimate the relative bioavailability 
of danirixin after single dose 
administration of HBr tablet (RC), the 
reference treatment, relative to the test 
formulation of the HBr tablet
(MONO), in healthy elderly subjects in 
the fed state.

To provide safety and tolerability 
information for oral administration of 
the different formulations of danirixin 
HBr tablets in elderly subjects.
AUC(0-inf), AUC(0-t), AUC(0-24),
Cmax, tmax, t1/2, tlast and tlag. 

Danirixin PK parameters: AUC(0-inf), 
AUC(0-t), AUC(0-24), Cmax, tmax, 
t1/2, tlast and tlag. 

Danirixin PK parameters: AUC(0-inf), 
AUC(0-t), AUC(0-24), Cmax, tmax, 
t1/2, tlast and tlag. 

AEs/SAEs, vital signs, ECGs, and 
clinical laboratory parameters
5.
STUDY DESIGN
5.1.
Overall Design
This is a Phase I, two part (Part A and Part B which contains 2 Strata), randomized, open-
label, single dose, cross-over study conducted with healthy elderly participants. Part A 
will support the selection of the formulation and Part B will address the PPI effect, food 
effect and PK of the monohydrate.
Part A
In Part A, approximately 16 healthy elderly participants will be enrolled such that 
approximately 13 subjects complete dosing and critical assessments for all planned 
treatment periods. Participants will undergo a screening period ~30 days prior to the first 
dose of study treatment, followed by 4 treatment periods with at least a 5 day washout 
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
27
period between each treatment and a follow-up period of  3-10 days following the last 
dose of danirixin. 
Eligible participants will be admitted to the clinical facilities on Day -1 of each treatment 
period. 
On Day 1 of each treatment period, following completion of the required pre-dose 
measurements and procedures, the investigator or authorized study unit personnel will 
administer a single oral dose of 50 mg danirixin to each participant in the unit. Following 
dosing, participants will undergo clinical safety assessments and serial PK assessments at 
timepoints specified in the Section 2. Participants will be discharged from the unit 
approximately 24 hours following dosing at the Investigator’s discretion. 
Participants will return back to the unit on an outpatient basis approximately 48 hours 
post dose for the 48 hour post dose assessments and be discharged once the assessments 
are complete at the investigator’s discretion. Three to ten days following the 48 hour 
clinic visit for the final treatment period, participants will return to the clinic for the 
follow-up visit. Refer to Section 2 for study assessments and timepoints. 
A minimum washout period of 5 days is required between dosing in each treatment 
period. A study design schematic for Part A is presented in Table 1.
Part B
In Part B, approximately 24 healthy elderly participants will be enrolled such that 
approximately 20 subjects (10 subjects per strata) complete dosing and critical 
assessments for all planned treatment periods in Strata 1 and 2. 
In Part B Stratum 2 eligible participants will take omeprazole (OMP), 40 mg from Day -4 
to day of final PK assessment (48hr) for treatment period 3. Participants will be provided 
with a participant diary to document daily recordings of OMP dosing occurring outside of 
the unit.
Eligible participants will be admitted to the clinical facilities on Day -1 of each treatment 
period. 
On Day 1 of each treatment period, following completion of the required pre-dose 
measurements and procedures, the investigator or authorized study unit personnel will 
administer a single oral dose of 50 mg danirixin to each participant in the unit. Following 
dosing, participants will undergo clinical safety assessments and serial PK assessments at 
timepoints specified in the Section 2. Participants will be discharged from the unit 
approximately 24 hours following dosing at the Investigator’s discretion. 
Participants will return back to the unit on an outpatient basis approximately 48 hours 
post dose for the 48 hour post dose assessments and be discharged once the assessments 
are complete at the investigator’s discretion. Three to ten days following the 48 hour 
clinic visit for the final treatment period, participants will return to the clinic for the 
follow-up visit. Refer to Section 2 for study assessments and timepoints.
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
28
A minimum washout period of 5 days is required between dosing in each treatment 
period. Study design schematics are presented in Table 2 and Table 3 for Part B Strata 1 
and 2, respectively.
5.2.
Number of Participants
In Part A, 16 participants will be randomized such that approximately 13 evaluable 
participants complete the study. 
In Part B, a total of 24 participants (12 participants per strata) will be randomized per 
stratum such that approximately 10 evaluable participants complete each strata.
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 follow-up visit for the part for which they were enrolled.
The end of the study is defined as the date of the last visit of the last participant in the 
study.
5.4.
Scientific Rationale for Study Design
This study will use a single dose, open label, cross-over design. This is a well-established 
design to evaluate the relative bioavailability of new formulations of an investigational 
drug. 
5.5.
Dose Justification
The oral dose strength of 50 mg danirixin HBr will be administered as a single dose in all 
the treatment periods in the present study. This is a clinically relevant danirixin dose level 
and was also the dose used in Clinical Study 201037 [GlaxoSmithKline Document 
Number, 2015N248339_00].
In stratum 2 of Part B, subjects will take an oral dose of 40 mg OMP QD in the morning 
for four days prior to the initial danirixin dosing day until 48 hrs after the final danirixin 
dosing day. On the danirixin dosing days, the OMP will be taken in the morning with the 
dose of danirixin.  This omeprazole dose strength and regimen is the same as that 
administered during Clinical Study 201037 [GlaxoSmithKline Document Number, 
2015N248339_00]. The co-administration of 40 mg OMP with danirixin 50 mg in the 
present study is not expected to influence the pharmacokinetics of OMP. The selection of 
the OMP dose and dosing frequency is justified based on efficacy and safety data from 
the package insert. The 40 mg q24h dose of OMP was selected as it is a therapeutic dose 
that is expected to achieve maximal acid suppression and identify an interaction if one 
exists. The onset of effect occurs within 1 hr of administration with maximum effect of a 
single dose occurring within 2 hrs. Following repeated once daily doses, the inhibitory 
effect of OMP on acid secretion increases, reaching a plateau after four days [Sachs, 
1995; Stedman, 2000].
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
29
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1.
Participant must be 65 to 80 years of age inclusive, at the Screening Visit.
Type of Participant and Disease Characteristics
2.
Participants who are healthy, as determined by a responsible and experienced 
physician, based on a medical evaluation including medical history, physical 
examination, laboratory tests and cardiac monitoring or a subject with a clinical 
abnormality or laboratory parameters outside the reference range for the population being 
studied may be included if the investigator and the GSK Medical Monitor agree that the 
finding is unlikely to introduce risk factors and will not interfere with the study 
procedures and objectives. Additionally, laboratory assessments that are specifically 
listed in the inclusion or exclusion criteria and are outside of the reference range can be 
repeated once during the screening period.
Weight
3.
Body weight ≥50 kg and body mass index (BMI) within the range 19 - 34 kg/m2 
(inclusive).
Sex
4.
Male or female
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.
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
30
Informed Consent
5.
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.
Diagnostic Assessments and Other Criteria
6.
Aspartate aminotransferase (AST), ALT, alkaline phosphatase and bilirubin ≤ 1.5
× ULN (isolated bilirubin > 1.5 × ULN is acceptable if bilirubin is fractionated
and direct bilirubin < 35%).
7. Resting BP of ≤ 160/90 mm Hg, irrespective of anti-hypertensive medication
status for the subject.
8. Able to consume the Food and Drug Administration (FDA) defined high fat meal
[Food and Drug Administration, 2013] within 30 minutes in each of the four
treatment periods where study treatment is administered in a fed state.
6.2.
Exclusion Criteria.
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
Significant history of or current cardiovascular, respiratory, hepatic, renal, 
gastrointestinal, endocrine, hematological, or neurological disorders capable of 
significantly altering the absorption, metabolism, or elimination of drugs; 
constituting a risk when taking the study treatment; or interfering with the 
interpretation of data.
2.
Evidence of active or latent tuberculosis (TB) as documented by medical history and 
examination, chest x-rays (posterior anterior and lateral), and TB testing: either a 
positive tuberculin skin test (TST; defined as a skin induration <5 mm at 48 to 72 
hours, regardless of Bacillus Calmette-Guerin (BCG) or other vaccination history) or 
a positive (not indeterminate) QuantiFERON®-TB Gold test. NOTE: The choice to 
perform a TST or a QuantiFERON-TB Gold test will be made by the investigator 
according to local licensing and standard of care. The QuantiFERON-TB Gold test 
can only be used in countries where it is licensed, and the use of this test is 
dependent on previous treatment(s). This test may not be suitable if previous 
treatment(s) produced significant immunosuppression.
3.
Lymphoma, leukemia, or any malignancy within the past 5 years except for basal 
cell or squamous epithelial carcinomas of the skin that have been resected with no 
evidence of metastatic disease for 3 years
4.
Breast cancer within the past 10 years
5.
Alanine transaminase (ALT) >1.5x upper limit of normal (ULN) 
6.
Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%). 
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
31
7.
Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones)
8.
QTc >450 msec 
NOTES: 
The QTc is the QT interval corrected for heart rate according to Bazett’s formula 
(QTcB), Fridericia’s formula (QTcF), and/or another method, machine-read or 
manually over-read. 
The specific formula that will be used to determine eligibility and discontinuation 
for an individual subject should be determined prior to initiation of the study. In 
other words, several different formulae cannot be used to calculate the QTc for 
an individual subject and then the lowest QTc value used to include or 
discontinue the subject from the trial.

For purposes of data analysis, QTcB, QTcF, another QT correction formula, or a 
composite of available values of QTc will be used as specified in the Reporting 
and Analysis Plan (RAP).
Prior/Concomitant Therapy
9.
Use of prescription or non-prescription drugs, including proton pump inhibitors, 
histamine receptor 2 antagonists, systemic antacid medications (unless these can
be held during the study), vitamins, herbal and dietary supplements (including St
John’s Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer)
or 5 half-lives (whichever is longer) prior to the first dose of study treatment until
completion of the last study assessment , unless in the opinion of the
investigator and GSK Medical Monitor, the medication will not interfere with the
study procedures or compromise subject safety. Some examples of exceptions
(permitted medications) are:
a. Stable dose of anti-hypertensive medication for at least 3 months prior
to the screening visit.
b. Stable dose of lipid-lowering medications (statins or fibrates) for at
least 3 months prior to the screening visit.
c. Antacids up to 24 hours prior to dosing
This list is not meant to be all inclusive.
Prior/Concurrent Clinical Study Experience
10. Participation in the study would result in loss of blood or blood products in excess of 
500 mL within 3 months
11. The subject 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: 3 months, 5 half-lives or twice the duration of the biological effect of the 
investigational product (whichever is longer).
12. Exposure to more than 4 new chemical entities within 12 months prior to the first 
dosing day.
13. Participation in a previous clinical trial with danirixin within 1 year prior to the first
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
32
dosing day in the current study
Diagnostic assessments
14. Female Subjects: Positive urine beta-human chorionic gonadotropin (β-hCG) test at 
screening.
15. Presence of Hepatitis B surface antigen (HBsAg) at screening Positive Hepatitis C 
antibody test result at screening.
NOTE:  Subjects with positive Hepatitis C antibody due to prior resolved disease can 
be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained
16. Positive Hepatitis C RNA test result at screening or within 3 months prior to first 
dose of study treatment
NOTE: Test is optional and subjects with negative Hepatitis C antibody test are not 
required to also undergo Hepatitis C RNA testing
17. For potent immunosuppressive agents, presence of the Hepatitis B core antibody 
(HBcAb) should also lead to exclusion from the study even if HBsAg is negative
18. Positive pre-study drug/alcohol screen
19. Positive human immunodeficiency virus (HIV) antibody test
20. Regular use of known drugs of abuse
Other Exclusions
21. Regular alcohol consumption within 6 months prior to the study defined as: 

an average weekly intake of >21 units for males or >14 units for females.  One 
unit is equivalent to 8 g of alcohol: a half-pint (~240 ml) of beer, 1 glass (125 ml) 
of wine or 1 (25 ml) measure of spirits. 
22. Consumption of red wine, Seville oranges, grapefruit or grapefruit juice and/or 
pummelos, citrus fruits, grapefruit hybrids or fruit juices from 7 days prior to the first 
dose of study treatment until collection of the final blood sample.
23. Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or 
nicotine-containing products within 90 days prior to screening.
24. Sensitivity to heparin or heparin-induced thrombocytopenia
25. Sensitivity to any of the study treatments, or components thereof, or drug or other 
allergy that, in the opinion of the investigator or medical monitor, contraindicates 
participation in the study
6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions

Refrain from consumption of Seville oranges, grapefruit or grapefruit juice, and/or 
pummelos, exotic citrus fruits, grapefruit hybrids, or fruit juices from 7 days before 
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
33
the start of study treatment until completion of all study procedures in each study 
period after the final dose. Specific dosing instructions will be provided in the Study 
Reference Manual (SRM) and will be provided to all study participants by the site 
staff at each visit.
6.3.2.
Caffeine, Alcohol, and Tobacco

During each treatment period, subjects will abstain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, tea, cola drinks and chocolate) for 24 
hours prior to the start of dosing until collection of the final pharmacokinetic or 
clinical laboratory sample during each treatment period.

During each dosing session, subjects will abstain from alcohol for 24 hours prior to 
the start of dosing until collection of the final pharmacokinetic and clinical 
laboratory sample during each session. 

Use of tobacco- or nicotine-containing products is prohibited, as detailed in the
  exclusion criteria (Section 6.2).

When dosing occurs in the fasted state, subjects will be provided with a light snack 
and then will fast from all food and drink (except water) from midnight on the 
evening of Day -1 until 4 h post-dose on Day 1 at which time a meal will be provided. 
An evening meal will be provided at approximately 9 h post dose. 

At all other times during residency in the clinic, meals and snacks will be provided at 
appropriate times.

When dosing occurs in the fed state, subjects will be given a high-fat or low-fat diet 
before study treatment administration.  
6.3.3.
Activity
Participants will abstain from strenuous exercise for 48 hours before each blood 
collection for clinical laboratory tests. Participants may participate in light recreational 
activities during studies (eg, watching television, reading).
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently entered in the study. A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any serious adverse events 
(SAEs).
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened if, in the opinion of the investigator, the reason for screen failure is 
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
34
temporary and it can be reasonably expected to resolve. Any rescreens must take place 
within the planned screening period so as to not cause any undue prolongation of the 
planned study completion.
Any re-screened participant must meet all the protocol specific inclusion/exclusion 
requirements at the re-screen visit. All screening procedures must be repeated for subjects 
that are re-screened. If a subject screen fails prior to randomization, he/she can be re-
screened once if the site staff feels the subject meets eligibility criteria.
Rescreened participants will be assigned a unique screening number for each time they 
are screened and will receive a participant number when enrolled.
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
GSK will provide the danirixin study treatment.  The study site will be responsible to 
provide the omeprazole for Part 2, stratum 2.
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
35
Study Treatment 
Name:
Danirixin 
(GSK1325756H
, the 
hydrobromide 
hemihydrate 
salt)
Reference
Danirixin 
(GSK1325756H, 
the 
hydrobromide 
hemihydrate 
salt)
Danirixin 
(GSK1325756H, 
the 
hydrobromide 
monohydrate 
salt)
PRILOSEC 
(omeprazole)
Dosage 
formulation:
Immediate 
release tablet
Immediate 
release tablet
Immediate 
release tablet
Delayed-Release 
capsule
Unit dose 
strength(s)/Dosag
e level(s):
50mg
50mg
50mg
40mg
Manfacturing 
process
Roller 
Compaction 
(RC)
Direct 
Compression 
(DC)
Direct 
Compression
(DC)
NA
Tablet Size
600mg
475 and 600mg
600mg
NA
Route of 
Administration 
Oral
Oral
Oral
Oral
Dosing 
instructions:
With food and 
240 mL (8 oz) 
water, unless 
explicitly 
defined by 
protocol
With food and 
240 mL (8 oz) 
water, unless 
explicitly defined 
by protocol
With food and 
240 mL (8 oz) 
water
Per label 
Packaging and 
Labelling
Study 
Treatment will 
be provided in 
a 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.
Study 
Treatment will 
be provided in 
a HDPE bottle 
with desiccant. 
Each bottle will 
be labelled as 
required per 
country 
requirement.
Over the counter 
product
Manufacturer
GSK
GSK
GSK
Over the counter 
product
7.2.
Dose Modification
There will be no dose modifications.
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
36
7.3.
Method of Treatment Assignment
In Part 1, participants will be randomised to a treatment sequence including treatments A-
D [Table 4]. In Part 2, participants will be stratified by OMP use. Those stratified to 
stratum 1 will be randomised to a treatment sequence including treatments E-H [Table 5], 
and those in stratum 2 will be randomised to a treatment sequence including treatments I-
K [Table 6].   This will be done in accordance with the randomization schedule generated 
by the study statistician, prior to the start of the study, using validated internal software. 
Study treatment will be dispensed to participants at the study visits summarized in the
Section 2.  
Returned study treatment should not be re-dispensed to any participant.
7.4.
Blinding
This is an open-label study.
7.5.
Preparation/Handling/Storage/Accountability
No special preparation of study treatment is required. Danirixin tablets will be provided 
in multi-dose bottles and packaged with a desiccant. The monohydrate formulation will 
require storage in a humidity chamber, details will be provided in the study reference 
manual.
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].

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.

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.
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
37
7.6.
Treatment Compliance

When the individual dose for a participant is prepared from a bulk supply, the 
preparation of the dose will be confirmed by a second member of the study site staff. 

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.  Study site personnel will examine each 
participant’s mouth to ensure that the study treatment was ingested.

Participants self-administer OMP at home, compliance with OMP will be assessed 
through the participant diary that the participant will complete. Additionally, the 
participant will be queried at the site visit and documented in the source documents 
and CRF.  A record of the number of OMP 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.
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 
informed consent 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
Permitted Medications and Non-Drug Therapies
The following medications have been pre-approved for concomitant use:

A stable dose of anti-hypertensive medication for at least 3 months prior to the 
screening visit is permitted

A stable dose of lipid-lowering medications (statins or fibrates) for at least 3 months
prior to the screening visit is permitted.

Antacids are allowed up to 24 hours prior to start of dosing

Standard doses of vitamins

A stable dose of thyroid replacement therapy medications

A stable dose of topical or oral hormone replacement therapy medications
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
38

Occasional use of acetaminophen for patient complaints of discomfort (e.g. headache, 
achiness) during clinic visits at the investigator’s discretion with consideration of 
proximity to dosing.

Emergency equipment and drugs will be available within the clinical unit. In the
unlikely event that they are required, their use will be documented.
Prohibited Medications and Non-Drug Therapies
Subjects must be advised that no medication should be discontinued without the 
approval of their primary or treating physician.
Subjects must abstain from the use of prescription or non-prescription drugs, 
including:

proton pump inhibitors

histamine receptor 2 antagonists
  antacid medications (except as indicated above) 
  Greater than recommended use of vitamins
herbal and dietary supplements (including St John’s Wort)
oral or injectable CYP3A4 or BRCP (breast cancer resistance protein) substrates 
with a narrow therapeutic index (CYP3A4 substrates include, but are not limited 
to, alfenatil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, 
quinidine, sirolimus, tacrolimus, and theophylline; BCRP substrates include, but 
are not limited to, topotecan.)
within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives 
(whichever is longer) prior to the first dose of study treatment until completion of the 
last study assessment, unless in the opinion of the investigator and GSK Medical 
Monitor, the medication will not interfere with the study procedures or compromise 
subject safety.
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
7.8.
Treatment after the End of the Study
Participants will not receive any additional treatment from GSK after the completion of 
the study.
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
39
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
8.1.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). These protocol guidelines are in alignment 
with FDA premarketing clinical liver safety guidance:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Discontinuation of study treatment for abnormal liver tests should be considered by the 
investigator when a participant meets one of the conditions outlined in the algorithm
below or if the investigator believes that it is in the best interest of the participant.
Study treatment will be discontinued for a participant if liver chemistry stopping criteria 
are met:
Phase I Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments  section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 6.
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
40
8.1.2.
QTc Stopping Criteria

The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study.  This formula may not 
be changed or substituted once the participant has been enrolled.

For example, if a participant is eligible for the protocol based on QTcB, then 
QTcB must be used for discontinuation of this individual participant as well.

Once the QT correction formula has been chosen for a participant’s eligibility, 
the same formula must continue to be used for that participant for all QTc data 
being collected for data analysis.  Safety ECGs and other non-protocol specified 
ECGs are an exception.  

The QTc should be based on single or averaged QTc values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording period.  
A subject that meets either bulleted criterion based on the average of triplicate ECG 
readings will be withdrawn from study treatment.  

QTc, QTcB, QTcF > 500 msec,

Change from baseline: QTc >60 msec
See the Section 2 for data to be collected at the time of treatment discontinuation and 
follow-up and for any further evaluations that need to be completed.
8.1.3.
Neutrophil Stopping Criteria
A participant with a peripheral blood neutrophil count 0.5 x 109/L that is confirmed on 
repeat testing will be instructed to suspend dosing.  The neutrophil count should be 
monitored daily until it returns to within the baseline value, as detailed in Appendix 7.
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.

Refer to the Section 2 for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be 
completed.
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
41
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 
baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the time frame defined in the Section 2.
The following points must be noted: 
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
42

If assessments are scheduled for the same nominal time, the assessments should 
occur in the following order:
1. 12-lead ECG
2. vital signs
3. blood draws.  
Note: The timing of the assessments should allow the blood draw to occur at the 
exact nominal time.

The timing and number of planned study assessments, including PK and safety 
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. 

The change in timing or addition of time points for any planned study 
assessments must be documented in a Note to File which is approved by the 
relevant GSK study team members (e.g. medical monitor and GCSP) and then 
archived in the study sponsor and site study files, but this will not constitute a 
protocol amendment. 

The IRB will be informed of any safety issues that require alteration of the 
safety monitoring scheme or amendment of the Informed Consent Form. 

No more than 500 mL of blood will be collected over the duration of the study.
9.1.
Efficacy
This study is a single dose PK study and therefore there is no efficacy endpoint.
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 (see Appendix 4). 
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 start of treatment until the follow-up visit at 
the time points specified in the SoA (Section 2).

Medical occurrences that begin before the start of study treatment but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the case report form (CRF) not the AE section.
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
43

All SAEs will be recorded and reported to the sponsor or designee within 24 
hours, as indicated in Appendix 4. The investigator will submit any updated 
SAE data to the sponsor within 24 hours of it being available.

Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study 
participation, the investigator must promptly notify the sponsor.

The method of recording, evaluating, and assessing causality of AEs and SAEs
and the procedures for completing and transmitting SAE reports are provided in
Appendix 4.
9.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
9.2.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as 
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.
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
44
9.2.5.
Pregnancy

Details of all pregnancies in female participants will be collected after the start of 
study treatment and until 60 hours after the last dose of study treatment.

If a pregnancy is reported, the investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 5.

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
9.3.
Treatment of Overdose
For this study, any dose of study treatment 4 tablets in a day will be considered an 
overdose.
GSK does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator/treating physician should:
1.
Contact the Medical Monitor immediately.
2.
Closely monitor the participant for AE/SAE and laboratory abnormalities until 
danirixin can no longer be detected systemically (at least 3 days).
3.
Obtain a sample for PK analysis within 4 days from the date of the last dose of study 
treatment if requested by the Medical Monitor (determined on a case-by-case basis).
4.
Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.
9.4.
Safety Assessments
Planned time points for all safety assessments are provided in the Section 2.
9.4.1.
Physical Examinations

A complete physical examination will include, at a minimum, assessments of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. Height 
and weight will also be measured and recorded.

A brief physical examination will include, at a minimum, assessments of the 
skin, lungs, cardiovascular system, and abdomen (auscultation and palpation of 
the abdomen including examination of the liver and spleen).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
45
9.4.2.
Vital Signs

Oral temperature, pulse rate, respiratory rate, and blood pressure will be 
assessed.

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.

Vital signs will be measured in a semi-supine position after 5 minutes rest and 
will include temperature, systolic and diastolic blood pressure, and pulse and 
respiratory rate.
9.4.3.
Electrocardiograms

Single 12-lead ECG will be obtained as outlined in the SoA (Section 2) using an
ECG machine that automatically calculates the heart rate and measures PR, 
QRS, QT, and QTc intervals. Refer to Section [8.1.2] for QTc withdrawal 
criteria and additional QTc readings that may be necessary.
9.4.4.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory tests to be performed and 
to the SoA for the timing and frequency. 

The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 3 days after the last dose of study 
treatment should be repeated until the values return to normal or baseline or are 
no longer considered significantly abnormal by the investigator or medical 
monitor. 

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
46

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the Section 2.

If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in participant 
management or are considered clinically significant by the investigator (eg, SAE 
or AE or dose modification), then the results must be recorded in the CRF.
9.5.
Pharmacokinetics

Whole blood samples of approximately 2 mL will be collected for measurement 
of whole blood concentrations of danirixin (performed under the control of GSK 
Platform Technology and Science Department of In Vitro In Vivo Translation 
Third Party Resourcing (PTS-IVIVT/TPR) as specified in the Section 2.
Instructions for the collection and handling of biological samples will be provided 
by the sponsor in the SRM. The actual date and time (24-hour clock time) of each 
sample will be recorded.

Samples will be used to evaluate the PK of danirixin. Each whole blood sample
will be used to prepare 4 dried blood spots which will be analysed for danirixin 
concentrations.  Samples collected for analyses of danirixin whole blood may also 
be used to evaluate safety or efficacy aspects related to concerns arising during or 
after the study.
9.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
9.7.
Genetics
Genetics are not evaluated in this study.
9.8.
Biomarkers
Biomarkers are not evaluated in this study.
10.
STATISTICAL CONSIDERATIONS
No formal hypothesis will be tested. For each pharmacokinetic endpoint, point estimates 
and corresponding 90% confidence intervals will be constructed for the ratio of the 
geometric mean of the test treatment to the geometric mean of the reference treatment, 
(test)/(reference).
The following comparisons of interest will be constructed:

 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
47
Part
Question
Comparison
Part A
Formulation
475mg DC tablet formulation versus 600mg RC 
formulation (reference)
600mg DC tablet formulation versus reference
600mg DC tablet with 5% HPMC versus reference
Part B
Stratum 1
Food effect
No OMP
High fat meal (heavy) versus Fasted
Normal meal (light) versus Fasted
High fat meal (heavy) versus Normal meal (light)
Part B
Stratum 2
Food effect
With OMP
High fat meal (heavy) versus Fasted
Normal meal (light) versus Fasted
High fat meal (heavy) versus Normal meal (light)
Part B
Strata 1 & 2
Drug 
interaction
Fasted with OMP versus Fasted without OMP
Normal meal (light) with OMP versus Normal meal (light)  
without OMP
High fat meal (heavy) with OMP versus High fat meal 
(heavy) without OMP
Part B
Stratum 1
Pharm Dev
Monohydrate with high fat meal versus High fat meal 
(heavy)

10.1.
Sample Size Determination
The sample size is primarily based on feasibility. Approximately 60 subjects will be 
enrolled in the study to obtain approximately 16 randomized subjects (13 completers) in 
Part A and 12 randomized subjects (10 completers) in each strata of Part B.  
The within-subject variability for AUC(0-inf), AUC(0-t) and Cmax of danirixin [GSK 
Study 201037, GlaxoSmithKline Document Number 2015N248339_00] was estimated to 
be 37.3%, 39.3% and 44.7%, respectively. Based upon the largest within-subject 
coefficient of variation (44.7% for Cmax of danirixin) and a sample size of 13 subjects 
completing part A of the study, it is estimated that the half-width of the 90% confidence 
interval for the ratio of geometric means for the comparison of interest should be no more 
than 23% of the point estimates. Assuming an observed ratio of one, the corresponding 
90% confidence interval for the ratio of geometric means would be 0.81 to 1.23.
An interim analysis is planned at the completion of Part A to select the formulation for 
evaluation in Part B.
10.1.1.
Sample Size Sensitivity
The figure below shows the half width of the 90% CI for a range of within-subject 
coefficient of variations for various sample sizes.
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
48
Figure 1
Plot of half width of 90% CI by within-subject coefficient of 
variations
10.1.2.
Sample Size Re-estimation or Adjustment
No sample size re-estimation will be performed.
10.2.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
All Participants 
All participants who receive at least one dose of study 
medication. This population will be used for the study 
population and safety analyses.
PK
All participants for whom a pharmacokinetic sample was 
obtained and analyzed. This will be the population used for 
all the pharmacokinetic displays.
10.3.
Statistical Analyses
Final analyses will be performed after the completion of the study and final dataset 
authorization. 
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
49
Data will be listed and summarized separately for each part of the study according to 
GlaxoSmithKline reporting standards where applicable. 
Complete details will be documented in the Reporting and Analysis Plan (RAP).
10.3.1.
Pharmacokinetic Analyses
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to GlaxoSmithKline current working practices. . 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), AUC(0-inf), AUC(0-24)], lag time before 
observation of first blood concentration (tlag), time of last observed blood concentration 
(tlast), and apparent terminal phase half-life (t1/2).
Pharmacokinetic data will be listed and presented in graphical form and will be 
summarized descriptively. Complete details will be documented in the Reporting and 
Analysis Plan (RAP).
The point estimates of the geometric least squares (GLS) mean ratio for the PK 
parameters (AUC and Cmax) and the associated 90% CIs will be provided for treatment 
comparisons (test:reference). The PK parameters will be log-transformed prior to analysis 
and treatment comparisons will be expressed as ratios on the original scale.
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
50
11.
REFERENCES
Celli BR, MacNee W. Standards for the diagnosis and treatment of patients with COPD. 
Eur Respir J. 2004;23:932-946. 
Chapman RW, Philips JE, Hipkin RW, Curran AK, Lundell D, Fine JS. CXCR2 
antagonists for the treatment of pulmonary disease. Pharmacol Ther. 2009;121:55-68. 
FDA. Guidance for Industry. Center for Drug Evaluation and Research, United States 
Food and Drug Administration; 2009. Drug-induced liver injury: premarketing clinical 
evaluation. 
Food and Drug Administration (FDA). Bioequivalence Studies with Pharmacokinetic 
Endpoints for Drugs Submitted Under an ANDA Draft Guidance. 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidanc
es/ucm377465.pdf . DEC 2013
GlaxoSmithKline Document Number 2014N205875_00 Study ID 201682. 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. Report Date 21-Nov-2014
GlaxoSmithKline Document Number 2015N248339_00 Study ID 201037. A single 
centre, open-label, 5-period, cross over, randomized study in healthy elderly subjects to 
evaluate the relative bioavailability of hydrobromide salt and free base immediate release 
tablet formulations of danirixin in the fed state, and to evaluate the effect of food and 
gastric acid secretion suppression on danirixin pharmacokinetics following administration 
of hydrobromide salt tablets. Report Date 01-Jun-2016
GlaxoSmithKline Document Number 2015N248339_00 Study ID 201037. A single 
centre, open-label, 5-period, cross over, randomized study in healthy elderly subjects to 
evaluate the relative bioavailability of hydrobromide salt and free base immediate release 
tablet formulations of danirixin in the fed state, and to evaluate the effect of food and 
gastric acid secretion suppression on danirixin pharmacokinetics following administration 
of hydrobromide salt tablets. Report Date 01-Jun-2016. 
GlaxoSmithKline Document Number YM2010/00163/07. Danirixin Investigator's 
Brochure, Version 09. Report Date 14-Apr-2016. 
GOLD. From the Global Strategy for the Diagnosis, Management and Prevention of 
COPD, Global Initiative for Chronic Obstructive Lung Disease. Global Initiative for 
Chronic Obstructive Lung Disease, Available from: http://www.copdgold.org; 2016. 
Holz O, Khalilieh S, Ludwig-Sengpiel A, Watz H, Stryszak P, Soni P, et al. SCH527123, 
a novel CXCR2 antagonist, inhibits ozone-induced neutrophilia in healthy subjects. Eur 
Respir J. 2010;35:564-570. 
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
51
Hurst JA, Vestbo J, Anzueto A, Locantore N, Mullerova, Tal-Singer R, et al. 
Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 
2010;363:1128-1138. 
Lazaar AL, Sweeney LE, MacDonald AJ et al. SB-656933, a novel CXCR2 selective 
antagnoist, inhibits ex vivo neutrophil activation and ozone-induced airway inflammation 
in humans. Br J Clin Pharmacol. 2011;72:282-293.  
Lopez-Campos JL, Tan W, Soriano JB. Global burden of COPD. Respirology. 
2016;21:14-23.
Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 
to 2030. PLoS Med. 2006;3:e442. 
Nagai, K., Makita, H., Suzuki, M., Shimizu, K., Konno, S., Ito, Y. M., & Nishimura, M. 
Differential changes in quality of life components over 5 years in chronic obstructive 
pulmonary disease patients. International Journal of Chronic Obstructive Pulmonary 
Disease. 2015; 10: 745–757. 
Nair P, Gaga M, Zervas E et al. Safety and efficacy of a CXCR2 antagnoist in patients 
with severe asthma and sputum neutrophils: a randomized, placebo-controlled clinical 
trial. Clin Exp Allergy. 2012;42:1097-2103. 
O'Byrne PM, Metev H, Puu M et al. Efficacy and safety of a CXCR2 antagonist, 
AZD5069, in patients with uncontrolled persistent asthma: a randomised, double-blind, 
placebo-controlled trial. Lancet Respir Med. 2016;4:797-806. 
Rennard SI, Dale DC, Donohue JF et al. CXCR2 antagonist MK-7123 - a phase 2 proof-
of-concept trial for chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 
2015;191:1001-1011. 
Sachs G, Shin JM, Briving C, et al. The pharmacology of the gastric acid pump: the 
H+,K+ ATPase. Annu Rev Pharmacol Toxicol 1995; 35: 277 305.
Stedman CAM, Barclay ML. Alimentary Pharmacology & Therapeutics Volume 
14, Issue 8, pages 963–978, August 2000.
Vastava S, Thakur D, Sharma S, Punekar YS. Systematic review of humanistic and 
economic burden of symptomatic chronic obstructive pulmonary disease. Pharmacoecon. 
2015;33:467-488. 
Vestbo J, Leather D, Diar Bakerly N, New J, Gibson JM, McCorkindate S, et al. 
Effectiveness of fluticasone furoate-vilanterol for COPD in clinical practice. N Engl J 
Med. 2016;375:1253-1260. 
Watz H, Kirsten A, Pedersen F, Goldmann T, Stellmacher F, Uddin M, et al. Neutrophils 
in bronchial mucosa, sputum and blood after administration of the CXCR2-antagonist 
AZD5069 - an explorative study in neutrophilic asthma. Eur Respir J. 
2016;48(S60):PA4892. 
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
52
Woodruff PG, Barr RG, Bleecker F, Christenson SA, Couper D, Curtis JL, et al. Clinical 
significance of symptoms in smokers with preserved pulmonary function. N Engl J Med. 
2016;374:1811-1821.
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
53
12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
  AE
Adverse Event
ALT
Alanine aminotransferase (SGPT)
AST
Aspartate aminotransferase (SGOT)
AUC
Area under concentration-time curve
AUC(0-24)
Area under the concentration-time curve from time zero (pre-
dose) to 24 hours post dose 
AUC(0-inf) 
Area under the concentration-time curve from time zero (pre-
dose) extrapolated to infinite time
AUC(0-t)
Area under the concentration-time curve from time zero (pre-
dose) to last time of quantifiable concentration within a 
subject across all treatments
BCG
Bacillus Calmette-Guerin
BID
Twice a Day
BMI
Body Mass Index
BUN
Blood Urea Nitrogen
CIOMS
Council for International Organizations of Medical Sciences
CPK 
Creatine Phosphokinase
Cmax,
Maximum Observed Concentration
CONSORT
Consolidated Standards of Reporting Trials 
COPD
Chronic Obstructive Pulmonary Disease
CRF
Case Report Form
CSR
Clinical Study Report
DC
Direct Compression 
DNX
Danirixin
ECG
Electrocardiogram
FDA
Food and Drug Administration
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GCSP
Global Clinical Safety Pharmacovigilance
GLS
Geometric Least Squares
GOLD
Global Initiative for Chronic Obstructive Lung Disease
GSK1325756
Danirixin
HBcAb 
Hepatitis B core antibody 
HBr 
Hydrobromide
HBsAg
Hepatitis B surface antigen 
HBsAg
Hepatitis B Surface Antigen
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HIV
Human Immunodeficiency Virus
HPMC
Hydroxypropyl Methylcellulose 
ICF
Informed Consent Form 
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
54
IEC
Independent Ethics Committees
IRB
Institutional Review Boards 
Kg
Kilogram 
LDH
Lactate Dehydrogenase LDH
MCH
Mean Corpuscular Hemoglobin
MCV
Mean Corpuscular Volume
Mg
Milligram 
MSDS
Material Safety Data Sheet 
NOAEL
No-Observed-Adverse-Effect-Level
OMP
Omeprazole 
PK
Pharmacokinetic 
RAP
Reporting and Analysis Plan
RBC
Red Blood Cells 
RC
Roller Compaction
SAE
Serious Adverse Event
SOA
Schedule of Activities 
SRM
Study Reference Manual 
SUSAR
Suspected Unexpected Serious Adverse Reactions
t1/2,
Terminal phase half-life
TB
tuberculosis
tlag
Lag time before observation of drug concentrations in 
sampled matrix
tlast
Time of last quantifiable concentration
tmax,
Time of occurrence of Cmax
TST
tuberculin skin test
ULN
Upper Limit of Normal
WBC
While Blood Cells
WOCBP
Woman of Childbearing Potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
None
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
55
12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 7 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 7
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
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 [fasting
Calcium
Alkaline 
phosphatase, 
Albumin
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 and estradiol (as needed in women of non-
childbearing potential only)

Urine/breathalizer alcohol screen and a urine drug screen to include at 
minimum: amphetamines, barbiturates, cocaine, opiates, cannabinoids and 
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
56
Laboratory 
Assessments
Parameters
benzodiazepines.

Serum or 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 C virus antibody
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.
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
57
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. 
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
58

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.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
59
Dissemination of Clinical Study Data

This study will be registered and study information from this protocol will be 
posted on publicly available clinical trial registers before enrolment of study 
participants begins.

The results summary of this study will be posted to the GSK Clinical Study 
Register and other publicly available clinical trial registers within 8 months of 
the primary study completion date.

A manuscript reporting the study results will be submitted to a peer reviewed 
journal within 18 months of the last participant’s last visit. 
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (eg, laboratory 
data). The investigator is responsible for verifying that data entries are accurate 
and correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

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. 
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.
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
60

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 Appendix 3.
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
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
61
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.

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. Also, "lack of 
efficacy" or "failure of expected pharmacological action" constitutes an AE or SAE.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
62

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
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
63
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.
Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes 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.
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
64
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 
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.
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
65
Reporting of SAEs 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 (e.g., InForm).

If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper SAE data collection tool (see next section).

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

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 medical monitor or SAE coordinator by telephone.

Contacts for SAE reporting can be found in the study procedures manual.
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
66
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
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 8.
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
67
Table 8
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing ) hormonal contraception associated with 
inhibition of ovulationb

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulationb

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.)
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the participant.)
NOTES: 
a.
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants in clinical studies. 
b.
Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of 
the contraceptive method. In this case two highly effective methods of contraception should be utilized during the 
treatment period and for at least 60 hours after the last dose of study treatment 
Pregnancy Testing

WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive urine or serum pregnancy test 

Additional pregnancy testing should be performed at monthly intervals during the 
treatment period and at 60 hours after the last dose of study treatment and as required 
locally 
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
68

Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected 

Pregnancy testing, with a sensitivity of 5 mIU/mL will be performed using the test 
kit provided by the central laboratory and in accordance with instructions provided in 
its package insert.  
Collection of Pregnancy Information
Male participants with partners who become pregnant

Investigator will not routinely attempt to collect pregnancy information on any male 
participant’s female partner(s) who becomes pregnant while the male participant is 
participating in this study; however, voluntary reports of such incidents will be 
captured through the GSK standard reporting mechanism. This applies only to male 
participants who receive double-blind study treatment.

If pregnancy information for a male participant’s female partner(s) is voluntarily 
reported, after obtaining the necessary signed informed consent from the pregnant 
female partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the partner’s 
pregnancy.

Partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date.  

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. 

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
69

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 be withdrawn 
from the study.
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
70
12.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments 
Phase I liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT≥3xULN
If ALT≥3xULN AND bilirubin1,2 2xULN (>35% direct bilirubin) or  INR >1.5, 
Report as an SAE.
See additional Actions and Follow Up Assessments listed below
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

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 event follow up assessments 

Monitor the subject until liver chemistries 
resolve, stabilise, or return to within baseline 
(see MONITORING below)
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN  or INR 
>1.5

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 
hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilise or return to 
within baseline

A specialist or hepatology consultation is 
recommended
If ALT≥3xULN AND bilirubin < 2xULN  and 
INR ≤1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24-
72 hrs

Viral hepatitis serology3

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Obtain blood sample for pharmacokinetic 
(PK) analysis, obtained up to 72 hours 
after last dose4 

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 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
If ALT≥3xULN AND bilirubin 2xULN  or 
INR >1.5:

Anti-nuclear antibody, anti-smooth muscle 
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
71
Liver Chemistry Stopping Criteria 

Monitor subjects weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
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 subjects with definite or likely 
acetaminophen use in the preceding week 
[James, 2009]. NOTE: not required in 
China.

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject 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 subjects receiving anticoagulants
3.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
72
12.7.
Appendix 7: Neutrophil Safety and Study Treatment Restart
Neutrophil Stopping Criteria: Absolute neutrophil count (ANC) 0.5 x 109 /L
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Immediately discontinue study treatment 

Report the event to GSK within 24 hours

Complete an SAE data collection tool if the 
event also meets the criteria for an SAE

Monitor the participant until neutrophil 
count stabilizes or returns to within 
baseline (see MONITORING below)

Do not restart participant with study 
treatment unless allowed per protocol and 
GSK Medical Governance approval is 
granted (see RESTART below)
MONITORING:

Treatment of any suspected infections1

Repeat CBC within  24 hrs

Monitor CBC daily until neutrophil count 
resolves, stabilizes or returns to within 
baseline 

Record the appearance or 
worsening of any clinical 
symptoms on the AE report form1

Obtain blood sample for 
pharmacokinetic (PK) analysis 
within 12 hours  after last dose2

Record use of concomitant 
medications on the concomitant 
medications report form 
RESTART

Restart of study medication must be 
approved by the GSK Medical Monitor

Restart may be attempted ONLY if all 
three criteria are met:
The neutrophil count is 1.5 x 109/L 
for at least 48 hours

At least 7 days have elapsed since the 
suspension of study treatment 
No sign or symptom of associated 
infection has been identified

Check the CBC within 24-48 hours 
after re-starting study medication, 
monitor twice weekly for two 
weeks, and monthly thereafter.

If the ANC drops below 1.0 x 
109/L on restart, the participant 
should be permanently 
discontinued from study treatment 
and withdrawn from the study.
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 
 
2018N378719_00


2017N316476_00
CONFIDENTIAL
207573
73
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.
 
2018N378719_00

SAP_000.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
207573
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan
Title
:
Reporting and Analysis Plan for Study 207573: a two part, 
randomized, open-label, cross over study in healthy elderly 
participants to evaluate the relative bioavailability of 
hydrobromide salt tablet formulations of danirixin in the fed and 
fasted states, and to evaluate the effect of food and gastric acid 
secretion suppression on danirixin pharmacokinetics following 
administration of hydrobromide salt tablets.
Compound 
Number 
:
GSK1325756
Effective Date 
:
06-AUG-2018
Description:

The purpose of this Reporting and Analysis Plan is to describe the planned analyses 
and displays to be included in the Clinical Study Report for Protocol 207573.

This Reporting and Analysis Plan will be provided to the study team members to 
convey the content of the final Statistical Analysis Complete deliverable.
RAP Author(s):
Approver
Date
Approval Method
 
03-AUG-2018
eTMF eSigniture
Statistical Leader (Respiratory Clinical 
Statistics)
03-AUG-2018
eTMF eSigniture
Director, Statistics (Respiratory Clinical 
Statistics)
05-AUG-2018
eTMF eSigniture
Director Clinical Pharmacology Modelling 
and Simulation
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
2018N378719_00
PPD
PPD
PPD


CONFIDENTIAL
The GlaxoSmithKline group of companies
207573
2
RAP Team Approvals:
Approver
Date
Approval Method
03-AUG-2018
eTMF eSigniture
Clinical Development Director 
03-AUG-2018
eTMF eSigniture
Programming Manager 
03-AUG-2018
eTMF eSigniture
Operational Study Lead
06-AUG-2018
eTMF eSigniture
Principal Data Manager
03-AUG-2018
eTMF eSigniture
Medical Director, Safety Evaluation and 
Risk Management
Clinical Statistics and Clinical Programming Line Approvals:
Approver
Date
Approval Method
06-AUG-2018
eTMF eSigniture
Head, Respiratory Clinical Statistics
03-AUG-2018
eTMF eSigniture
Programming Manager (Respiratory 
Clinical Programming)
 
2018N378719_00
PPD
PPD
PPD
PPD
PPD
PPD
PPD


CONFIDENTIAL
207573
3
TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................5
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................5
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................5
2.2.
Study Objective(s) and Endpoint(s)...............................................................6
2.3.
Study Design ................................................................................................7
2.4.
Statistical Analyses.......................................................................................9
3.
PLANNED ANALYSES ............................................................................................9
3.1.
Interim Analyses ...........................................................................................9
3.2.
Final Analyses ..............................................................................................9
4.
ANALYSIS POPULATIONS ...................................................................................10
4.1.
Protocol Deviations.....................................................................................10
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................11
5.1.
Study Treatment Display Descriptors..........................................................11
5.2.
Baseline Definitions ....................................................................................12
5.3.
Multiple Comparisons and Multiplicity .........................................................13
5.4.
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.
PHARMACOKINETIC ANALYSES.........................................................................15
7.1.
Primary Pharmacokinetic Parameter Analyses ...........................................15
7.1.1.
Endpoint / Variables.....................................................................15
7.1.1.1.
Drug Concentration Measures....................................15
7.1.1.2.
Derived Pharmacokinetic Parameters.........................15
7.1.2.
Summary Measure ......................................................................16
7.1.3.
Population of Interest...................................................................16
7.1.4.
Strategy for Intercurrent Events ...................................................16
7.1.5.
Statistical Analyses / Methods .....................................................17
7.1.5.1.
Statistical Methodology Specification..........................17
7.2.
Secondary Pharmacokinetic Parameter Analyses.......................................18
7.2.1.
Endpoint / Variables.....................................................................18
7.2.2.
Summary Measure ......................................................................18
7.2.3.
Population of Interest...................................................................18
7.2.4.
Strategy for Intercurrent Events ...................................................18
7.2.5.
Statistical Analyses / Methods .....................................................19
7.2.5.1.
Statistical Methodology Specification..........................19
8.
SAFETY ANALYSES .............................................................................................20
8.1.
Adverse Events Analyses ...........................................................................20
8.2.
Clinical Laboratory Analyses.......................................................................20
8.3.
Other Safety Analyses ................................................................................20
 
2018N378719_00


CONFIDENTIAL
207573
4
9.
REFERENCES.......................................................................................................21
10. APPENDICES........................................................................................................22
10.1.
Appendix 1: Protocol Deviation Management .............................................22
10.2.
Appendix 2: Schedule of Activities ..............................................................23
10.2.1.
Protocol Defined Schedule of Events...........................................23
10.3.
Appendix 3: Assessment Windows .............................................................31
10.4.
Appendix 4: Study Phases..........................................................................32
10.4.1.
Study Phases for Treatment Period .............................................32
10.4.2.
Study Phases for Adverse Event Data.........................................32
10.4.3.
Study Phases for Concomitant Medication...................................32
10.5.
Appendix 5: Data Display Standards & Handling Conventions....................33
10.5.1.
Reporting Process .......................................................................33
10.5.2.
Reporting Standards....................................................................33
10.5.3.
Reporting Standards for Pharmacokinetics..................................34
10.6.
Appendix 6: Derived and Transformed Data ...............................................35
10.6.1.
General........................................................................................35
10.6.2.
Study Population..........................................................................35
10.6.3.
Safety ..........................................................................................36
10.7.
Appendix 7: Reporting Standards for Missing Data.....................................37
10.7.1.
Premature Withdrawals................................................................37
10.7.2.
Handling of Missing Data.............................................................37
10.7.2.1.
Handling of Missing and Partial Dates ........................38
10.8.
Appendix 8: Values of Potential Clinical Importance ...................................39
10.8.1.
Laboratory Values........................................................................39
10.8.2.
ECG.............................................................................................40
10.8.3.
Vital Signs....................................................................................40
10.9.
Appendix 9: Abbreviations & Trade Marks ..................................................41
10.9.1.
Abbreviations...............................................................................41
10.9.2.
Trademarks .................................................................................42
10.10. Appendix 10: List of Data Displays..............................................................43
10.10.1. Data Display Numbering..............................................................43
10.10.2. Mock Example Shell Referencing ................................................43
10.10.3. Deliverables.................................................................................43
10.10.4. Study Population Tables..............................................................44
10.10.5. Pharmacokinetic Tables...............................................................47
10.10.6. Pharmacokinetic Figures .............................................................48
10.10.7. Safety Tables...............................................................................50
10.10.8. ICH Listings .................................................................................52
10.10.9. Non-ICH Listings..........................................................................55
10.11. Appendix 11: Example Mock Shells for Data Displays ................................56
 
2018N378719_00


CONFIDENTIAL
207573
5
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 207573: a two part, randomized, open-
label, cross over study in healthy elderly participants to evaluate the relative 
bioavailability of hydrobromide salt tablet formulations of danirixin in the fed and fasted 
states, and to evaluate the effect of food and gastric acid secretion suppression on 
danirixin pharmacokinetics following administration of hydrobromide salt tablets..
Revision Chronology:
2017N316476_00
21-DEC-2017
Original
2017N316476_01
22-FEB-2018
To modify the design of Part A incorporating a fasted group for 
each of the 4 treatments in addition to the fed groups. Additional 
clarifications have been made where necessary throughout the 
protocol.
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Changes from the originally planned statistical analysis specified in the protocol are 
outlined in Table 1.
Table 1
Changes to Protocol Defined Analysis Plan
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes

All Participants 
population

All Subjects population

R&D Clinical Data Standards 
Board (CDSB) recommendation to 
use the term 'Subjects' in all 
displays (Tables, Figures & 
Listings)

All Subjects (ALLSUB) 
Population includes all 
participants who receive 
at least one dose of 
study medication. This 
population will be used 
for the study population 
and safety analyses.

All Subjects Population 
includes all participants who 
were screened and for whom 
a record exists on the study 
database.  This population 
will be used for summaries 
including participants who 
were not randomised

Allows summaries including 
participants who were not 
randomised and is consistent with
other studies in the development 
program.

No modified Intent-to-
treat (mITT) population

mITT population defined to be 
used for study population and 
safety displays

Replaced ALLPAR population 
which is now defined differently as 
above, and is consistent with 
other studies in the development 
program.
 
2018N378719_00


CONFIDENTIAL
207573
6
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes

No exclusions from 
analysis were specified

Exclusion of data from 
analysis is detailed in Section 
7.1.4 Strategy for Intercurrent 
Events and Section 7.2.4
Strategy for Intercurrent 
Events.

Pharmacokinetic (PK) data would 
be affected by incorrect 
meal/formulation, incomplete 
meals,  non-compliance with OMP
and inadequate PK concentration 
profile.
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Part
Primary Objectives
Primary Endpoints
To estimate the relative bioavailability of 
danirixin after single dose administration of 
hydrobromide (HBr) tablet (Roller Compaction 
[RC]), the reference treatment, relative to the 
test formulations of the HBr tablet (Direct 
Comparession [DC] 475, DC 600 and 
hydroxypropyl methylcellulose [HPMC] 600), in 
healthy elderly participants in the fed and fasted 
states.
Danirixin PK parameters: area under 
the concentration-time curve from time 
zero (predose) extrapolated to infinite 
time (AUC[0-inf]) and maximum 
observed concentration (Cmax).
Part A
To provide safety and tolerability information for 
oral administration of the different formulations 
of danirixin HBr tablets in elderly participants.
Adverse events (AEs)/serious AEs 
(SAEs), vital signs, 
electrocardiograms (ECGs), and 
clinical laboratory parameters
Part A
Secondary Objectives
Secondary Endpoints
To estimate the secondary pharmacokinetic 
parameters of danirixin after single dose 
administration of HBr tablet (RC), the reference 
treatment, relative to the test formulations of the 
HBr tablet (DC 475, DC 600 and HPMC 600), in 
healthy elderly participants in the fed and fasted
states.
Danirixin PK parameters: area under 
the concentration-time curve from time 
zero (predose) to last time of 
quantifiable concentration within a 
participant across all treatments 
(AUC[0-t]), area under the 
concentration-time curve from time 
zero (predose) to 24 hours post dose 
(AUC[0-24]), time of occurrence of 
Cmax (tmax), terminal phase half-life
(t1/2), time of last quantifiable 
concentration (tlast) and lag time 
before observation of drug 
concentrations in sampled matrix 
(tlag).
Part A
To estimate the effect of food on the single dose 
pharmacokinetics of the danirixin HBr tablet 
formulation selected from Part A in healthy 
elderly participants.
Danirixin PK parameters: AUC(0-inf), 
AUC(0-t), AUC(0-24), Cmax, tmax, 
t1/2, tlast and tlag.
Part B
To estimate the effect of OMP on the single 
dose pharmacokinetics of the danirixin HBr 
tablet formulation selected from Part A in 
healthy elderly participants in various fed and 
fasted states.
Danirixin PK parameters: AUC(0-inf), 
AUC(0-t), AUC(0-24), Cmax, tmax, 
t1/2, tlast and tlag.
Part B
 
2018N378719_00


CONFIDENTIAL
207573
7
Objectives
Endpoints
Part
To estimate the relative bioavailability of 
danirixin after single dose administration of HBr 
tablet (RC), the reference treatment, relative to 
the test formulation of the HBr tablet (MONO), in 
healthy elderly participants in the fed state.
Danirixin PK parameters: AUC(0-inf), 
AUC(0-t), AUC(0-24), Cmax, tmax, 
t1/2, tlast and tlag.
Part B
To provide safety and tolerability information for 
oral administration of danirixin HBr tablets in 
elderly participants.
AEs/SAEs, vital signs, ECGs, and 
clinical laboratory parameters
Part B
2.3.
Study Design
Overview of Study Design and Key Features
Part A Group 1 and 2 
Screening
Period  
Within 30 
Days of 
Day 1
Treatment 
Period 1
5- Day 
Washout
Treatment 
Period 2
5 Day 
Washout
Treatment 
Period 3
5 Day 
Washout
Treatment 
Period 4
Early 
Discontinuation/ 
Follow-Up Visit  
3-10 days after 
last dose of 
danirixin (DNX)
Part B Group 1 
Screening
Period  
Within 30 
Days of 
Day 1
Treatment 
Period 1
5- Day 
Washout
Treatment 
Period 2
5 Day 
Washout
Treatment 
Period 3
5 Day 
Washout
Treatment 
Period 4
Early 
Discontinuation 
Follow-Up Visit 
3-10 days after 
last dose of 
DNX
Part B Group 2 
Screening 
Period 
Within 30 
Days of Day
1 
Day -4
Treatment 
Period 1
5- Day 
Washout
Treatment 
Period 2
5 Day 
Washout
Treatment 
Period 3 
Early Discontinuation 
Follow-Up Visit 3 - 10 
days after last dose of 
DNX
OMP taken daily through all treatment and washout periods, ending with 
final assessments for Treatment period 3
Design
Features

This is a Phase I, two part (Part A and Part B; each part contains 2 Groups), randomized, 
open-label, single dose, cross-over study conducted with healthy elderly participants. Part 
A will support the selection of the formulation and Part B will address the Proton Pump 
Inhibitor (PPI) effect, food effect and PK of the monohydrate.
Dosing

On Day 1 of each treatment period, following completion of the required pre-dose 
measurements and procedures, the investigator or authorized study unit personnel 
administered a single oral dose of 50 mg danirixin to each participant in the unit.

In Part B Group 2, all participants took OMP from Day -4 relative to treatment period 1, 
through all periods and washouts until the final treatment period 3 PK assessment (48hr 
post dose).
 
2018N378719_00


CONFIDENTIAL
207573
8
Overview of Study Design and Key Features
Time & 
Events

Refer to Appendix 2: Schedule of Activities
Treatment 
Assignment

In Part A, 16 participants were randomised to a treatment sequence including treatments 
A-D or AO-DO (Section 5.1: Study Treatment Display Descriptors). Participants 
randomised to a treatment sequence including treatments A-D comprised Group 1 and 
participants randomised to a treatment sequence including treatments AO-DO comprised
Group 2.  Equal numbers of participants were randomized to each of the following 
sequences:
ABCD
BDAC
CADB
DCBA
AOBOCODO
BODOAOCO
COAODOBO
DOCOBOAO

In Part B, Group 1, 12 participants were randomised to a treatment sequence including 
treatments E-H (Section 5.1: Study Treatment Display Descriptors). Equal numbers of 
participants were randomized to each of the following sequences:
EFGH
EGFH
FGEH
FEGH
GEFH
GFEH

In Part B, Group 2, 12 participants were randomised to a treatment sequence including 
treatments I-K (Section 5.1: Study Treatment Display Descriptors). Equal numbers of 
participants were randomized to each of the following sequences:
IJK
IKJ
JKI
JIK
KIJ
KJI

GSK RandAll NG was used to generate the randomisation schedules.

Study treatment was dispensed to participants at the study visits according to the 
randomisation schedule.
Interim 
Analysis

An interim PK analysis is planned at the end of Part A. PK parameters AUC(0-inf), AUC(0-
t), AUC(0-24) and Cmax will be derived using nominal times. The formulation to be 
investigated in Part B will be dependent on the PK profile, relative bioavailability and 
between-participant variability of the test formulations (DC 475, DC 600 and HPMC 600) 
compared to the reference formulation (RC).
 
2018N378719_00


CONFIDENTIAL
207573
9
2.4.
Statistical Analyses
No formal hypothesis will be tested. For each PK endpoint and each treatment 
comparison described in Section 5.1 Study Treatment Display Descriptors, point 
estimates and corresponding 90% confidence intervals (CIs) will be constructed for the 
ratio of the geometric mean of the test treatment to the geometric mean of the reference 
treatment, (test)/(reference).
3.
PLANNED ANALYSES
3.1.
Interim Analyses
An interim PK analysis is planned at the end of Part A. PK parameters AUC(0-inf), 
AUC(0-t), AUC(0-24) and Cmax will be derived using nominal times (see Section 
7.1.1.2: Derived Pharmacokinetic Parameters). The formulation to be investigated in Part 
B will be dependent on the PK profile, relative bioavailability and between-participant
variability of the test formulations (DC 475, DC 600 and HPMC 600) compared to the 
reference formulation (RC). The analysis will be documented in a short report which will 
be stored in the study Trial Master File, together will the associated analysis outputs and 
Quality Control documentation.
3.2.
Final Analyses
The final planned study population, safety and PK concentration summaries will be 
performed after the completion of the following sequential steps:
1.
All participants have completed the study as defined in the protocol.
2.
All required database cleaning activities have been completed and final Source Data 
Lock (SDL) has been declared by data management (DM).
3.
Study is unblinded

Randomization schedules are released in RANDALL NG and GSK create and 
quality control (QC) unblinded RANDALL dataset.

SMS2000 data is released in HARP
4.
Unblinded RANDALL dataset and SMS2000 file are released to IQVIA by GSK via 
secure external alliance portal (EAP)
5.
Study Data Tabulation Model (SDTM) data conversion has been completed by 
IQVIA including unblinding activities and QC of unblinded SDTM has been 
completed by DM.
6.
Database freeze (DBF) on unblinded study population, safety and PC SDTM datasets 
has been declared by DM.
Following this, the PK parameter analyses will be performed after the PP SDTM domain 
is available.
 
2018N378719_00


CONFIDENTIAL
207573
10
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
All Subjects
(ALLSUB)

All participants who were screened and for whom 
a record exist on the study database

Participant disposition

Reasons for withdrawal 
prior to randomization

Inclusion/exclusion criteria 
deviations for non-
randomized participants

AEs and SAEs for non-
randomized participants
Modified Intent-
to-treat (mITT)

All randomized participants apart from those who 
were randomized in error (i.e. were also recorded 
as screen failures and did not receive a dose of 
study treatment).

Any participant who receives a treatment 
randomization number will be considered to have 
been randomized.

Randomized participants will be assumed to have 
received study medication unless definitive 
evidence to the contrary exists.

If a participant received an incorrect meal or 
formulation, by-treatment summaries will use the 
meal/formulation actually received.

Study population

Safety
Pharmacokinetic 
(PK)

All participants for whom a pharmacokinetic 
sample was obtained and analysed 

PK
Refer to Appendix 10: List of Data Displays which details the population used for each display.
If the PK and mITT populations include the same participants then the PK analysis will be run on the mITT population 
and data will be excluded as detailed in Section 7
4.1.
Protocol Deviations
Protocol deviations (PDs) will be handled as described in Appendix 1: Protocol Deviation
Management.  A Per Protocol population will not be defined.
 
2018N378719_00


CONFIDENTIAL
207573
11
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment Display Descriptors
All participants will receive DNX 50mg in each treatment period.  The term ‘treatment’ 
refers to the combination of formulation and meal as identified below.
Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting 
Code
Description
Description
Order in TLF 
A
DNX 50mg 600RC High fat Formulation 
1
DNX 50mg 600RC High fat – A
1
B
DNX 50mg 475DC High fat Formulation 
4
DNX 50mg 475DC High fat – B
2
C
DNX 50mg 600DC High fat Formulation 
2
DNX 50mg 600DC High fat – C
3
D
DNX 50mg 600DC 5%HPMC High fat 
Formulation 3
DNX 50mg 600DC 5%HPMC High fat
– D
4
AO
DNX 50mg 600RC Fasted Formulation 
1
DNX 50mg 600RC Fasted – AO
5
BO
DNX 50mg 475DC Fasted Formulation 
4
DNX 50mg 475DC Fasted – BO
6
CO
DNX 50mg 600DC Fasted Formulation 
2
DNX 50mg 600DC Fasted – CO
7
DO
DNX 50mg 600DC 5%HPMC Fasted 
Formulation 3
DNX 50mg 600DC 5%HPMC Fasted -
DO
8
E
DNX 50mg Fasted
DNX 50mg Fasted – E
9
F
DNX 50mg Normal meal
DNX 50mg Normal meal – F
10
G
DNX 50mg High fat
DNX 50mg High fat – G
11
H
DNX 50mg MONO High fat
DNX 50mg MONO High fat – H
12
I
DNX 50mg Fasted OMP
DNX 50mg Fasted OMP – I
13
J
DNX 50mg Normal meal OMP
DNX 50mg Normal meal OMP – J
14
K
DNX 50mg High fat OMP
DNX 50mg High fat OMP - K
15
Treatment comparisons will be displayed as follows using the comparison column as 
specified:
Part
Question
Comparison
Comparison Description
Part A
Group 1
Formulation in 
the fed state
475mg DC tablet formulation versus 600mg 
RC formulation (reference) 
B vs A 
600mg DC tablet formulation versus 
reference
C vs A 
600mg DC tablet with 5% HPMC versus 
reference
D vs A
Part A
Group 2
Formulation in 
the fasted state
475mg DC tablet formulation versus 600mg 
RC formulation (reference)
BO vs AO 
600mg DC tablet formulation versus 
reference
CO vs AO 
 
2018N378719_00


CONFIDENTIAL
207573
12
Part
Question
Comparison
Comparison Description
600mg DC tablet with 5% HPMC versus 
reference
DO vs AO 
Part A
Group 1 & 2
Food effect
600mg RC formulation fed versus fasted
A vs AO
475mg DC tablet formulation fed versus 
fasted
B vs BO
600mg DC tablet formulation fed versus 
fasted
C vs CO
600mg DC tablet with 5% HPMC fed versus 
fasted
D vs DO
Part B
Group 1
Food effect, no 
OMP
High fat meal (heavy) versus fasted
G vs E
Normal meal (light) versus fasted
F vs E
High fat meal (heavy) versus normal meal 
(light)
G vs F
Part B
Group 2
Food effect 
with OMP
High fat meal (heavy) versus fasted
K vs I
Normal meal (light) versus fasted
J vs I
High fat meal (heavy) versus normal meal 
(light)
K vs J
Part B
Group 1 & 2
Drug 
interaction
Fasted with OMP versus fasted without OMP
I vs E
Normal meal (light) with OMP versus normal 
meal (light) without OMP
J vs F
High fat meal (heavy) with OMP versus high 
fat meal (heavy) without OMP
K vs G
Part B
Group 1
Pharmaceutical 
development
Monohydrate with high fat meal versus high 
fat meal (heavy)
H vs G
5.2.
Baseline Definitions
Any assessments made after the time of the study treatment dose will not be included in 
the derivation of baseline.  Assessments made on the same day as dosing with a missing 
time are assumed to be taken prior to first dose.
If baseline data are missing, no derivation will be performed and baseline will be set to 
missing.
Parameter
Baseline Used in Data Display
ECG values
The average of the triplicate readings made on Day -1 of each treatment period will 
be calculated and used as period baseline.  Any reading made after the time of 
dosing will not be included in the calculation.
Vital signs (pulse 
rate, systolic and 
diastolic blood 
pressure)
The average of the triplicate readings made pre-dose on Day 1 of each treatment 
period as recorded on the electronic case report form (eCRF) will be used as period 
baseline
Laboratory data
The assessment made on Day -1 of the first treatment period will be used as a study 
baseline
 
2018N378719_00


CONFIDENTIAL
207573
13
5.3.
Multiple Comparisons and Multiplicity
No adjustments for multiplicity will be made.
5.4.
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
10.3
Appendix 3: Assessment Windows
10.4
Appendix 4: Study Phases
10.5
Appendix 5: Data Display Standards & Handling Conventions
10.6
Appendix 6: Derived and Transformed Data
10.7
Appendix 7: Reporting Standards for Missing Data
10.8
Appendix 8: Values of Potential Clinical Importance
 
2018N378719_00


CONFIDENTIAL
207573
14
6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
Study population analyses including analyses of participant disposition, protocol 
deviations, demographic and baseline characteristics, relevant medical history and
concomitant medications will be based on GlaxoSmithKline (GSK) Core Data Standards.  
Results will generally be presented for all participants with a Part and Group, not split by 
treatment.  Details of the split for each display are included in Section 10.10.4 Study 
Population Tables.
A summary of the number and percentage of participants who completed each treatment 
period and entered and completed each washout period, along with the reasons for 
withdrawal, will be displayed for each Part and Group separately.  Separate study 
treatment compliance and exposure displays will not be produced as they would contain 
the same information.
Compliance with OMP will be summarized by treatment for treatments I, J and K.
Meal data will be summarized by treatment.
Details of the planned displays including the population to be used for each display are 
presented in Appendix 10: List of Data Displays.
 
2018N378719_00


CONFIDENTIAL
207573
15
7.
PHARMACOKINETIC ANALYSES
7.1.
Primary Pharmacokinetic Parameter Analyses
The primary PK parameter analysis is to compare the relative bioavailability of different 
formulations of danirixin in the fed and fasted states. The primary treatment effect to be 
estimated is the ‘as-treated’ effect of treatment (formulation and meal) in participants 
who consume at least 90% of the meal (in fed participants) and provided an adequate PK 
concentration profile to allow reliable estimation of PK parameters.
7.1.1.
Endpoint / Variables

Log-transformed AUC(0-inf) and Cmax.
The following secondary endpoints which are analysed in the same way as the primary 
endpoints and assess the same outcome are also included in this section:

Log-transformed AUC(0-t), AUC(0-24) and t1/2.
The following parameters will not be log-transformed and will be included in summary 
tables containing untransformed values for the primary endpoint.

tmax, tlag, tlast.
7.1.1.1.
Drug Concentration Measures
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 10.5.3
Reporting Standards for Pharmacokinetics)
7.1.1.2.
Derived Pharmacokinetic Parameters
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of 
WinNonlin. All calculations of non-compartmental parameters will be based on actual 
sampling times. Pharmacokinetic parameters listed will be determined from the blood
concentration-time data, as data permits.  If parameters cannot be determined, a ‘Not 
done’ or ‘Not calculable’ flag will be present in the data.  In addition, parameters affected 
by the other intercurrent events identified in Section 7.1 will also be identified in the data.
 
2018N378719_00


CONFIDENTIAL
207573
16
Parameter
Parameter Description
AUC(0-inf)
Area under the concentration-time curve extrapolated to infinity will be calculated as: 
                                  AUC = AUC(0-t) + C(t) / lambda_z
Cmax
Maximum observed concentration, determined directly from the concentration-time data.
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.
AUC(0-24)
Area under the concentration-time curve from time zero to 24 hours will be calculated using 
the linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule for each 
decremental trapezoid.
Tmax
Time to reach Cmax, determined directly from the concentration-time data.
t1/2*
Apparent terminal half-life will be calculated as: 
                                    t1/2 = ln2 / lambda_z
Tlag
Lag time before observation of drug concentrations in blood
Tlast
Time of last quantifiable concentration
* associated parameters lambda_z, lambda_z_lower, lambda_x_upper, No_points_lambda_z to be listed.
NOTES:

Additional parameters may be included as required.

Lambda_z is the terminal phase rate constant.
7.1.2.
Summary Measure
Relative bioavailability of danirixin after single dose of three formulations of HBr tablet 
(DC) versus HBr tablet (RC) in fed and fasted states.

Fed (treatment comparisons B vs A, C vs A, D vs A)

Fasted (treatment comparisons BO vs AO, CO vs AO, DO vs AO)
7.1.3.
Population of Interest 
PK population.
7.1.4.
Strategy for Intercurrent Events
Participants who experienced the following intercurrent events will have data from the 
relevant treatment period excluded from analysis:
-
Received incorrect formulation or meal
-
Did not consume at least 90% of the meal (in fed participants)
-
Did not provide an adequate PK concentration profile to allow reliable estimation 
of PK parameters
Inclusion of the participant’s remaining data in the analysis effectively uses a missing at 
random assumption to account for the excluded data.
If a participant is included in the PK population but withdrew from the study prior to a 
treatment period, data for that and subsequent periods will not be imputed.  Inclusion of 
the participant’s data prior to withdrawal in the analysis effectively uses a missing at 
random assumption to account for the missing data.
 
2018N378719_00


CONFIDENTIAL
207573
17
7.1.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
7.1.5.1.
Statistical Methodology Specification
Endpoint / Variables

Log-transformed AUC(0-inf) and Cmax in fed and fasted states.

Log-transformed AUC(0-t), AUC(0-24) and t1/2 in fed and fasted states.
Model Specification

Include all Part A data in the model.

Mixed effects model with fixed effect terms for period and treatment (formulation and fed/fasted 
state). Participant will be treated as a random effect in the model.

Point estimates on the loge scale for the least squares (LS) mean for each treatment and the 
LS mean difference between treatments (for comparisons specified in Section 7.1.2: Summary 
Measure), and associated 90% CI for the difference will be constructed using the residual 
variance.  The LS means, LS mean differences and associated 90% CIs will then be back-
transformed to obtain geometric LS mean for each treatment, and LS treatment ratios and 
associated 90% CIs.

The Kenward and Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used.
Model Checking & Diagnostics

Model assumptions will be applied, but appropriate adjustments maybe made based on the 
data.

Distributional assumptions underlying the model used for analysis will be examined by 
obtaining a normal probability plot of the residuals and a plot of the residuals versus the fitted 
values (i.e. checking the normality assumption and constant variance assumption of the model 
respectively) to gain confidence that the model assumptions are reasonable. 

If there are any departures from the distributional assumptions, alternative models will be 
explored using appropriate transformed data.
Model Results Presentation

Separate outputs will be produced for fed and fasted states (although both will be analyzed 
using the same model)

Geometric LS means for each treatment, treatment ratios and associated 90% CIs for each 
parameter.

Estimates of within-participant variability (%CVw) for AUC and Cmax (%CVw represents a 
pooled measure of within-participant variability across treatments).

Comparative plots of individual blood PK parameters by treatment on linear and semi-
logarithmic scales.

Forest plots of geometric mean treatment ratios for AUC and Cmax together with 90% CIs.

Listing of individual blood PK parameter ratios.

Supportive SAS output from statistical analysis.
 
2018N378719_00


CONFIDENTIAL
207573
18
7.2.
Secondary Pharmacokinetic Parameter Analyses
The following analyses will be conducted to assess food effect, PPI effect and 
pharmaceutical development.  The primary treatment effect to be estimated is the ‘as-
treated effect of the treatment (formulation and meal) in participants who consume at 
least 90% of the meal (in fed participants), are OMP compliant (in OMP participants) and 
provided an adequate PK concentration profile to allow reliable estimation of PK 
parameters.
7.2.1.
Endpoint / Variables

Log-transformed AUC( 0-inf) and Cmax.

Log-transformed AUC(0-t), AUC(0-24) and t1/2.
7.2.2.
Summary Measure
Relative bioavailability of danirixin after single dose.

Food effect in test formulation (treatment comparisons A vs AO, B vs BO, C vs 
CO, D vs DO)

Food effect in selected formulation without PPI (treatment comparisons G vs E, F 
vs E, G vs F)

Food effect in selected formulation with PPI (treatment comparisons K vs I, J vs I, 
K vs J)

PPI effect in selected formulation (treatment comparisons I vs E, J vs F, K vs G)

Pharmaceutical development (treatment comparison H vs G)
7.2.3.
Population of Interest
PK population.
7.2.4.
Strategy for Intercurrent Events
Participants who experienced the following intercurrent events will have data from the 
relevant treatment period excluded from analysis:
-
Received incorrect formulation or meal
-
Did not consume at least 90% of the meal (in fed participants)
-
Missed more than one OMP dose between Days -4 and -2 or missed any other OMP 
dose (participants on treatments I, J, K – Section 5.1 Study Treatment Display 
Descriptors)) 
-
Did not provide an adequate PK concentration profile to allow reliable estimation 
of PK parameters
Inclusion of the participant’s remaining data in the analysis effectively uses a missing at 
random assumption to account for the excluded data.
If a participant is included in the PK population but withdrew from the study prior to a 
treatment period, data for that and subsequent periods will not be imputed.  Inclusion of 
 
2018N378719_00


CONFIDENTIAL
207573
19
the participant’s data prior to withdrawal in the analysis effectively uses a missing at 
random assumption to account for the missing data.
7.2.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
7.2.5.1.
Statistical Methodology Specification
Secondary PK analyses will use the same methods as described in Section 7.1: Primary 
Pharmacokinetic Analysis.  The data to be included in each model are described below.
Food Effect in Test Formulations
Treatment Comparisons

A vs AO, B vs BO, C vs CO, D vs DO
Model Specification

From model used for primary PK analysis including all Part A data.
Food Effect in Selected Formulation without PPI
Treatment Comparisons

G vs E, F vs E, G vs F
Food Effect in Selected Formulation with PPI
Treatment Comparisons

K vs I, J vs I, K vs J
PPI Effect in Selected Formulation
Treatment Comparisons

I vs E, J vs F, K vs G
Model Specification

Include all Part B data from periods 1-3.
Pharmaceutical Development
Treatment Comparisons

H vs G
Model Specification

Part B non-OMP treatment arms (E-H) only.

Estimates presented for treatments G and H and difference H vs G.
 
2018N378719_00


CONFIDENTIAL
207573
20
8.
SAFETY ANALYSES
Details of the planned displays including the population to be used for each display are 
presented in Appendix 10 List of Data Displays.
The estimand is the effect of actual treatment in the population of participants who were 
randomized and dosed.  All collected data will be included in reporting as described 
below.  If a participant received the incorrect meal or formulation, data will be reported 
according to the actual meal and formulation received.  If a participant consumed <90% 
of the meal, data will still be reported according to that meal.  If a participant was non-
compliant with OMP dosing, data will still be reported according to the OMP-containing 
treatment. Non-recorded missing data following study withdrawal will not be imputed.
All safety data displays will be split by actual treatment received, except where specified 
below.
8.1.
Adverse Events Analyses
Adverse events analyses including the analysis of AEs, SAEs and other significant AEs 
will be based on GSK Core Data Standards.
8.2.
Clinical Laboratory Analyses
Laboratory displays including chemistry laboratory tests, hematology laboratory tests, 
urinalysis, and liver function tests will be based on GSK Core Data Standards.  
Summaries will include Screening and baseline (see Section 5.2 Baseline Definitions) 
values, and raw and change from baseline values at the Follow-up visit, and will be split 
by Part and Group.
Laboratory data from eligibility screening (follicle stimulating hormone, oestradiol,
human immunodeficiency virus, hepatits B & hepatits C) will not be reported.
8.3.
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.
 
2018N378719_00


CONFIDENTIAL
207573
21
9.
REFERENCES
None.
 
2018N378719_00


CONFIDENTIAL
207573
22
10.
APPENDICES
10.1.
Appendix 1: Protocol Deviation Management
PDs will be tracked by the study team throughout the conduct of the study in accordance 
with the Protocol Deviation Management Plan (PDMP) for the study:

PICTS database is not being used to collect protocol deviations occurring in the 
study. A PD spreadsheet (PD Log) is being used to collect all deviations from the 
protocol and is being managed by the IQVIA Clinical Research Associate. 

Every time there is a deviation, an email is sent to the GSK study team to confirm 
whether it should be classified as important or not, and subsequently updated in the 
spreadsheet.

Participants who received an incorrect formulation or meal, consumed <90% of meal 
or were non-compliance with OMP will be captured as an important protocol 
deviation.

The spreadsheet will be reviewed prior to SDL to ensure all important deviations are 
captured.

At the end of the study, IQVIA will convert this spreadsheet into a SAS dataset which 
will be provided to statistics and programming along with the other datasets.

This dataset will be the basis for the summaries and listings of PDs.

Important PDs (including deviations related to study inclusion/exclusion criteria, 
conduct of the trial, participant management or participant assessment) will be 
summarised and listed.

A separate summary and listing of all inclusion/exclusion criteria deviations will also 
be provided. This summary will be based on data as recorded on the 
inclusion/exclusion page of the electronic case report form (eCRF).

A Per Protocol Population will not be defined.
The following PDs will lead to exclusion from the pharmacokinetic parameter analysis 
outputs for the specific period (tables, statistical analysis and figures).  Exclusions will be 
programmed by statistics and programming from the SDTM data:

incorrect meal/formulation 

non-compliance with OMP (participants on treatments I, J, K – Section 5.1 Study 
Treatment Display Descriptors))

consumed <90% of meal (in fed participants)
In addition, a participant may be excluded from the pharmacokinetic parameter analysis 
outputs for the specific period due to having an inadequate PK concentration profile. This 
will be determined by the Pharmacokineticist during an initial review of the PK 
concentration data prior to derivation of the PK parameters.  In such cases, any data 
identified for exclusion will be provided to statistics and programming and flagged in the 
relevant Analysis Data Model (ADaM) datasets.  This will be documented in the ADaM 
Data Reviewers Guide (ADRG).
 
2018N378719_00


CONFIDENTIAL
207573
23
10.2.
Appendix 2: Schedule of Activities
10.2.1.
Protocol Defined Schedule of Events
Schedule of Activities Part A (Group 1 and Group 2) and Part B (Group 1)
Periods 1-4
Procedure
Screenin
g (up to 
30 days 
prior to 
Day 1) 1
Study Day (Treatment Periods 1-4) 2
Early 
Discontinuatio
n /Follow-up 
(3 to 10 days 
post-last 
dose)
Day 
-1 
1
Pre-dose
0h
0.5h
1h
1.5h
2h
3h
4h
6h
8h
10h
12h
24h
48h
Informed 
Consent 
X
Inclusion and 
Exclusion 
Criteria
X
X
Demographics
X
Full Physical 
Exam including 
Height and 
Weight
X
Brief Physical 
Exam
X
X
Medical 
History 
(includes 
substance 
usage)
X
X
 
 
 
2018N378719_00


CONFIDENTIAL
207573
24
Procedure
Screenin
g (up to 
30 days 
prior to 
Day 1) 1
Study Day (Treatment Periods 1-4) 2
Early 
Discontinuatio
n /Follow-up 
(3 to 10 days 
post-last 
dose)
Day 
-1 
1
Pre-dose
0h
0.5h
1h
1.5h
2h
3h
4h
6h
8h
10h
12h
24h
48h
Pregnancy 
Test, 
(WOCBP)3
X
X
FSH and 
estradiol
(if needed)
X
HIV, Hep B 
and Hep C 
Screen
X
Urine Drug 
Screen
X
X
Alcohol 
Screen-
Breathalyzer 
X
X
Urine Cotinine 
Screen
X
X
Admission to 
Unit
X
Laboratory 
Assessments 
(include liver 
chemistries)
X
X
X
12-lead ECG 4
X
X
X
X
 
 
 
2018N378719_00


CONFIDENTIAL
207573
25
Procedure
Screenin
g (up to 
30 days 
prior to 
Day 1) 1
Study Day (Treatment Periods 1-4) 2
Early 
Discontinuatio
n /Follow-up 
(3 to 10 days 
post-last 
dose)
Day 
-1 
1
Pre-dose
0h
0.5h
1h
1.5h
2h
3h
4h
6h
8h
10h
12h
24h
48h
Vital Signs5
X
X
X
X
X
Randomization
X
Meal 6
X
Danirixin
Administration,
7
X
Pharmacokinet
ic Sampling
X
X
X
X
X
X
X
X
X
X
X
X
X
SAE Review 
================================================================================================================
AE Review
X
==================================================================================================
Concomitant 
Medication 
Review
X
===================================================================================================
Discharge
X
1.
Screening must be performed within 30 days prior to receiving the dose of Danirixin on Day 1 of period 1.
2.
Treatment periods1-4 will include a minimum 5 day wash-out from day of dosing between each treatment
3.
Serum pregnancy test (where applicable) will be performed at the screening visit and a urine pregnancy test at all other time points specified.
 
 
 
2018N378719_00


CONFIDENTIAL
207573
26
4.
Triplicate ECGs at screening and on Day -1 of each treatment period only. Single ECGs at other timepoints (performed at a similar time of day as Day 1 Pre-dose), unless a 
reading meets the QTc stopping criteria, in which case two further measurements will be taken at the same time point and the average values captured. 
5.
Triplicate BP and HR at screening and pre-dose on Day 1 of each treatment period only. Single measurements at other timepoints (performed at a similar time of day as Day 1 
Pre-dose). HR and BP assessments only performed at the 24 and 48 hr post dose and early discontinuation/follow-up visit timepoints. 
6.
Meal (where applicable) to be started and completed 30 minutes prior to of danirixin dosing. Meal to consist of 900-1000 calories and be composed of proper caloric content of 
protein/fat/carbohydrates per FDA guidance and participants will be required to consume at least 90% of meal. 
7.
When danirixin dosing occurs in the fasted state, participants will be provided with a light snack and then will fast from all food and drink (except water) from 10 hours prior to 
dosing until 4hrs post-dose on Day 1 in each treatment period at which time lunch will be provided. An evening meal will be provided at approximately 9 h post dose. At all other 
times during residency in the clinic, meals will be provided at appropriate times.
 
 
 
2018N378719_00


CONFIDENTIAL
207573
27
Part B – Group 2
Periods 1-3
Procedure
Study Day (Treatment Periods -1-3) 2
Early 
Discontinuat
ion /Follow-
up (3 to 10 
days post-
last dose)
Screeni
ng (Up 
to 30 
days 
prior to 
Day 1) 1
Qualificati
on Visit 
Day -49
Da
y 
-1
1
Pre-dose
0h
0.5h
1h
1.5h
2h
3h
4h
6h
8h
10h
12h
24h
48h
Informed 
Consent
X
Inclusion and 
Exclusion
X
X
Demographic
s
X
Full Physical 
Exam 
including 
Height and 
Weight
X
Brief Physical 
Exam
X
X
Medical 
History 
(includes 
X
X
 
 
 
2018N378719_00


CONFIDENTIAL
207573
28
Procedure
Study Day (Treatment Periods -1-3) 2
Early 
Discontinuat
ion /Follow-
up (3 to 10 
days post-
last dose)
Screeni
ng (Up 
to 30 
days 
prior to 
Day 1) 1
Qualificati
on Visit 
Day -49
Da
y 
-1
1
Pre-dose
0h
0.5h
1h
1.5h
2h
3h
4h
6h
8h
10h
12h
24h
48h
substance 
usage)
Pregnancy 
Test,3           
(WOCBP)
X
X
X
FSH and 
estradiol
(if needed)
X
HIV, Hep B 
and Hep C 
Screen
X
Urine Drug 
Screen
X
X
X
Alcohol 
Screen-
Breathalyzer 
X
X
X
Urine 
Cotinine 
Screen
X
X
X
Admission to 
Unit
X
Laboratory 
Assessments 
X
X
X
 
 
 
2018N378719_00


CONFIDENTIAL
207573
29
Procedure
Study Day (Treatment Periods -1-3) 2
Early 
Discontinuat
ion /Follow-
up (3 to 10 
days post-
last dose)
Screeni
ng (Up 
to 30 
days 
prior to 
Day 1) 1
Qualificati
on Visit 
Day -49
Da
y 
-1
1
Pre-dose
0h
0.5h
1h
1.5h
2h
3h
4h
6h
8h
10h
12h
24h
48h
(include liver 
chemistries) 
12-lead ECG 
4
X
X
X
X
Vital Signs 5
X
X
X
X
X
Randomizatio
n
X
Meal6
X
Danirixin
Administratio
n7
X
Omeprazole 
Administratio
n 8
X
X
X
X
X
Diary Card 
completion 
for 
Omeprazole 
Dosing
===============================================================================================
Pharmacokin
etic Sampling
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
2018N378719_00


CONFIDENTIAL
207573
30
Procedure
Study Day (Treatment Periods -1-3) 2
Early 
Discontinuat
ion /Follow-
up (3 to 10 
days post-
last dose)
Screeni
ng (Up 
to 30 
days 
prior to 
Day 1) 1
Qualificati
on Visit 
Day -49
Da
y 
-1
1
Pre-dose
0h
0.5h
1h
1.5h
2h
3h
4h
6h
8h
10h
12h
24h
48h
SAE Review
======================================================================================================================
AE Review
X
==========================================================================
Concomitant 
Medication 
Review
X
============================================================= ==============
Discharge
X
1.
Screening must be performed within 30 days prior to receiving the dose of Danirixin on Day 1 of period 1.
2.
Treatment periods1-3 will include a minimum 5 day wash-out from day of dose between each treatment.
3.
Serum pregnancy test (where applicable) will be performed at the screening visit and a urine pregnancy test at all other time points specified.
4.
Triplicate ECGs at screening and on Day -1 of each treatment period only. Single ECGs at other timepoints (performed at a similar time of day as Day 1 Pre-dose), unless a 
reading meets the QTc stopping criteria, in which case two further measurements will be taken at the same time point and the average values captured. 
5.
Triplicate BP and HR assessments at screening and pre-dose on Day 1 of each treatment period only. Single measurements at other timepoints (performed at a similar time 
of day as Day 1 Pre-dose). HR and BP assessments only performed at the 24 and 48 hr post dose and early discontinuation/follow-up visit timepoints. 
6.
Meal (where applicable) to be started and completed within 30 minutes prior to danirixin dosing. Normal and high fat meal will be described in the SRM. 
7.
When danirixin dosing occurs in the fasted state, participants will be provided with a light snack and then will fast from all food and drink (except water) from 10 hours prior to 
dose until 4 hr post-dose on Day 1 in each treatment period at which time lunch will be provided. An evening meal will be provided at approximately 9 h post dose. At all other 
times during residency in the clinic, meals will be provided at appropriate times.
8.
OMP will be taken starting on Day -4 continuing daily through all treatment and washout periods until the day of the Period 3, 48hour PK assessment. The Day -4 
Qualification visit only applies to period 1.
 
 
 
2018N378719_00


CONFIDENTIAL
207573
31
10.3.
Appendix 3: Assessment Windows
Data will be reported according to the nominal time of clinic visits and assessments as 
specified in the protocol.
 
2018N378719_00


CONFIDENTIAL
207573
32
10.4.
Appendix 4: Study Phases
Assessments and events collected outside scheduled study visits will be classified into 
study phases according to the time of occurrence relative to the start and/or stop date of 
study treatment.
10.4.1.
Study Phases for Treatment Period
A treatment period will be considered complete if study treatment was administered.  The 
washout period will start the day after dosing and stop the day before dosing in the next 
period.
10.4.2.
Study Phases for Adverse Event Data
Classification of an AE/SAE as having onset on-treatment will be made with reference to 
the study treatment dates and the event onset date. If the event onset date is missing, then 
the event will be considered on-treatment. Events with onset up to 1 day after the date of 
a treatment will be considered on-treatment.
Study 
Phase
Definition
Pre-
treatment
Events with onset before the first treatment defined as:
(onset date < first study treatment dose date or no study treatment dose date)
On-treatment
Events with onset on the day of each treatment and up to 1 day afterwards, defined as:
(study treatment dose date <= onset date <= study treatment dose date + 1 or onset date 
missing)
Events that are not pre- or on-treatment will be presented in listings only
10.4.3.
Study Phases for Concomitant Medication
No study phases will be defined for concomitant medications; all concomitant 
medications taken will be summarized together.
 
2018N378719_00


CONFIDENTIAL
207573
33
10.5.
Appendix 5: Data Display Standards & Handling 
Conventions
10.5.1.
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
: uk1salx00175
HARP Compound
: GSK1325756
Analysis Datasets 

Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.2 & ADaM IG 
Version 1.1).
Generation of RTF Files

RTF files will be generated for all tables in the final reporting effort.
10.5.2.
Reporting Standards
General
o
The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: 
https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):

4.03 to 4.24: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 
Formats
o
GSK IDSL Statistical Principle 4.24 for decimal places (DP’s) will be adopted for reporting of data 
based on the raw data collected, unless otherwise stated.
o
Numeric data will be reported at the precision collected on the eCRF.
o
The reported precision from non eCRF sources will follow the IDSL statistical principles but may be
adjusted to a clinically interpretable number of DP’s. 
o
Summaries of continuous data will include number of participants, mean, standard deviation (SD), 
median, minimum and maximum.
o
Percentages between 1% and 99%, inclusive, will be rounded to integers. Percentages greater than 
0%, but less than 1%, will be reported as <1%, and percentages greater than 99%, but less than 
100%, will be reported as >99%.
o
Actual time will be reported as HH:MM. Seconds will not be presented.
Planned and Actual Time
o
Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries and statistical analyses.
Calculation of derived PK parameters will use actual time.

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.
o
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).
 
2018N378719_00


CONFIDENTIAL
207573
34

Unscheduled or unplanned readings will be presented within the participant’s listings. 
Unscheduled Visits
o
Unscheduled visits will not be included in summary tables or figures.
o
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
o
Refer to IDSL Statistical Principals 7.01 to 7.13.
10.5.3.
Reporting Standards for Pharmacokinetics
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
Standards for the Transfer and Reporting of PK Data 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. 
Pharmacokinetic Parameter Derivation
PK Parameter to 
be Derived by 
Programmer
None
Pharmacokinetic Parameter Data
Is Not Quantifiable 
(NQ) impacted PK 
Parameters Rule 
Being Followed
No (PK parameter derivation is not expected to be affected by NQs.)
Descriptive 
Summary Statistics
(Log Transformed 
parameters AUCs,
Cmax, t1/2)
Refer to IDSL PK Display Standards.
N, n, geometric mean, 95% CI of geometric mean, SD of logged data and [between 
or within] geometric coefficient of variation (CVb/w (%)) will be reported.
[1] CVb (%) = √ (exp(SD2) - 1) * 100
(SD = SD of log transformed data) 
[2] CVw (%) = √ (exp(MSE) - 1) * 100 
(MSE = mean square error from mixed effect model of log-transformed data).
Untransformed 
Parameters
Tmax, tlag, and tlast
PK Parameters 
listed only
lambda_z, lambda_z_lower, lambda_x_upper, No_points_lambda_z
 
2018N378719_00


CONFIDENTIAL
207573
35
10.6.
Appendix 6: Derived and Transformed Data
10.6.1.
General
Multiple Measurements at One Analysis Time Point
o
The mean of the triplicate vital sign assessments as recorded on the eCRF will be reported; all 
individual assessments will be listed.
o
The mean of the triplicate ECG assessments will be calculated and reported; all individual assessments 
will be listed.  The baseline ECG assessment will be calculated as described in Section 5.2 Baseline 
Definitions.
o
For any other parameter with multiple measurements at one time point, the mean of the measurements 
will be calculated and used in any derivation of summary statistics but if listed, all data will be 
presented.
Study Day
o
Calculated as the number of days from first study treatment dose date:

Ref date = missing
→ study day = missing 

Ref date < first study treatment dose date
→ study day = ref date – first study treatment dose 
date

Ref date ≥ first study treatment dose date
→ study day = ref ate – (first study treatment dose 
date) + 1
Period Study Day
o
Period day refers to the study day within a period.
o
For period 1, period day will be the same as study day.
o
For period 2, period day will be calculated as (ref date – 2nd treatment dose date + 1).
o
For period 3, period day will be calculated as (ref date – 3rd treatment dose date + 1).
o
For period 4, period day will be calculated as (ref date – 4th treatment dose date + 1).
Study Completion Definition
o
A participant is considered to have completed the study if they have not withdrawn and were dosed in 
their last scheduled treatment period.
10.6.2.
Study Population
Demographic Characteristics
Age
o
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’.
o
Birth date will be presented in listings as ‘YYYY’.
o
Age will be calculated based on the Screening visit date.
Body Mass Index (BMI)
o
Calculated as Weight (kg) / [Height (m)2]
 
2018N378719_00


CONFIDENTIAL
207573
36
Compliance
Compliance with OMP
o
An OMP dose scheduled to be taken in the clinic will be counted if the answer to ‘Did the subject 
receive the correct treatment’ in the OMP dosing section of the eCRF is ‘Yes’.
o
The total number of OMP doses taken will be calculated as the sum of each dose taken in the clinic on 
Days -4, -1, 1, 2, and 3 and the actual number of doses taken at home between Day -4 and Day -1 (as 
recorded in the eCRF).
o
Compliance with OMP will be calculated as:
Total doses taken*100/(number of days between Day -4 and Day 3)
o
Compliance with OMP will be summarized as a continuous variable and also in the categories:
o
<80%
o
80-<120%
o
≥120%
Meals
o
The duration of the meal (in minutes) will be calculated and summarized as a continuous variable.
o
The proportion of the meal consumed will be summarized as a continuous variable and also in the 
categories:
o
<90%
o
90-<95%
o
≥95%
o
The actual time between the start of the meal and the time of dosing will be summarized as a 
continuous variable and also in the categories:
o
<20 min
o
20-<40min
o
≥40 min
10.6.3.
Safety
ECG
ECG Categories
QTcB and QTcF values at each time point will be reported in categories as below
ECG Parameter
Units
Category
Absolute
Absolute QTcF Interval
msec
No Change or Decrease to <=450
Increase To >450 to <=480
Increase To >480 to <=500
Increase To >500
Change from Baseline
Change from Baseline 
QTcF
msec
Increase of <=30 ms
Increase of 31-60 msec
Increase of >60 msec
 
2018N378719_00


CONFIDENTIAL
207573
37
10.7.
Appendix 7: Reporting Standards for Missing Data
10.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Participant study completion was defined in the protocol as completion of all phases of 
the study including the final follow-up visit for the Part for which the participant was 
enrolled.

For the purposes of reporting, a participant is considered to have completed the study if 
they have not withdrawn and have completed their last scheduled treatment period.

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.

AE and concomitant medication data from participants who were withdrawn from the 
study will be listed and included in summary tables.

Laboratory, vital sign and ECG data from an Early Discontinuation visit will not be 
included in any summaries but will be listed.
10.7.2.
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. If all 
data for a specific visit is missing the data is excluded from the table/participant
listing. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such.
Outliers

If outliers are identified, analyses may be repeated excluding the outlying data.

Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
 
2018N378719_00


CONFIDENTIAL
207573
38
10.7.2.1.
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.
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.
Concomitant 
Medications

Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will be used 
for the month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day (dependent 
on the month and year) and 'Dec' will be used for the month.

The recorded partial date will be displayed in listings.
 
2018N378719_00


CONFIDENTIAL
207573
39
10.8.
Appendix 8: Values of Potential Clinical Importance
10.8.1.
Laboratory Values
Hematology Analyte (units)
Low
High
Platelet Count (x109/L)
0.90x
1.10x
Red Blood Cell Count (x1012/L)
0.93x
1.07x
White Blood Cell Count  (x109/L)
0.70x
1.60x
Reticulocyte Count (%)
>4%
Hemoglobin (g/L)
Males
0.85x
1.05x
Females
0.85x
1.15x
Hematocrit (Ratio of 1)
Males
0.80x
1.02x
Females
0.80x
1.15x
Mean Corpuscular Volume (fL)
0.80x
1.20x
Mean Corpuscular Hemoglobin (pg)
0.90x
1.10x
Neutrophils (%)
0.85x
1.50x
Lymphocytes (%)
0.85x
1.50x
Monocytes (%)
0.50x
2.00x
Eosinophils (%)
2.00x
Basophils (%)
5.00x
Chemistry Analyte (units)
Low
High
Blood Urea Nitrogen (mmol/L)
0.70x
1.60x
Creatinine (mol/L)
1.30x
(or >27 mol/L increase from 
baseline)
Glucose  (mmol/L)
0.85x
1.20x
Sodium (mmol/L)
0.95x
1.05x
Potassium (mmol/L)
0.85x
1.10x
Calcium (mmol/L)
0.90x
1.05x
Albumin (mmol/L)
0.90x
1.20x
Total Protein (mg/dL)
1.20x
Note: Multipliers are identified by “x”, otherwise actual comparison values are provided with units.
 
2018N378719_00


CONFIDENTIAL
207573
40
Liver Function Test Analyte (units)
High
Alanine aminotransferase (ALT)/SGPT (U/L)
2x
Aspartate amintransferase/SGOT (U/L)
2x
Alkaline Phosphatase (U/L)
2x
Total Bilirubin (mol/L)
1.5x
Direct Bilirubin (mol/L)
1.5x
Total Bilirubin (mol/L) + ALT (U/L)
≥ 1.5x ULN Total Billirubin + ≥ 2x ULN ALT
10.8.2.
ECG
ECG Parameter (units)
Low
High
Absolute QTc Interval (QTcB, QTcF) (msec)
>450
PR Interval (msec)
<110
>220
QRS Interval (msec)
<75
>110
Change from Baseline QTcF, QTcB
>60
10.8.3.
Vital Signs
Vital Sign Parameter (units)
Low
High
Systolic Blood Pressure (mmHg)
<85
>160
Diastolic Blood Pressure (mmHg)
<50
>100
Heart Rate (bpm)
<50
>110
 
2018N378719_00


CONFIDENTIAL
207573
41
10.9.
Appendix 9: Abbreviations & Trade Marks
10.9.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
ADRG
ADaM Data Reviewers Guide
AE
Adverse Event
ALLSUB
All Subjects
ALT
Alanine aminotransferase
AUC(0-24)
Area under the concentration-time curve from time zero (predose) to 24 hours 
post dose
AUC(0-inf)
Area under the concentration-time curve from time zero (predose) extrapolated to 
infinite time
AUC(0-t)
Area under the concentration-time curve from time zero (predose) to time of last 
quantifiable concentration within a participant across all treatments
BMI
Body Mass Index
BP
Blood pressure 
CDISC
Clinical Data Interchange Standards Consortium
CDSB
Clinical Data Standards Board
CI
Confidence Interval
Cmax
Maximum observed concentration
%CVB
Coefficient of Variation (Between)
%CVw
Coefficient of Variation (Within)
DBF
Database freeze
DC
Direct Compression
DM
Data Management
DNX
Danirixin
DP
Decimal Places
EAP
External alliance portal
ECG
Electrocardiogram
eCRF
Electronic Case Record Form
GSK
GlaxoSmithKline
HBr
Hydrobromide
HPMC
Hydroxypropyl methylcellulose
HR
Heart rate
IDSL
Integrated Data Standards Library
LS
Least squares
mITT
Modified Intent-to-treat
MSE
Mean squared error
NQ
Non-quantifiable
OMP
Omeprazole
PD
Protocol deviation
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PPI
Proton pump inhibitor
 
2018N378719_00


CONFIDENTIAL
207573
42
Abbreviation
Description
QC
Quality control
RAP
Reporting & Analysis Plan
RC
Roller Compaction
SAE
Serious adverse event
SD
Standard deviation
SDL
Source Data Lock
SDTM
Study Data Tabulation Model
t1/2
Terminal phase half-life
tlag
Lab time before observation of drug concentrations in sampled matrix
tlast
Time of last quantifiable concentration
tmax
Time of occurrence of Cmax
WNL
Windows Non Linear
10.9.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
NONE
NONMEM
SAS
WinNonlin
 
2018N378719_00


CONFIDENTIAL
207573
43
10.10.
Appendix 10: List of Data Displays
10.10.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.16
-
Pharmacokinetic
2.1 to 2.10
2.1 to 2.18
Safety
3.1 to 3.20
-
Section
Listings
ICH Listings
1 to 32
Other Listings
33 to 38
10.10.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 11: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
Pharmacokinetic
PK_Fn
PK_Tn
PK_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL /  Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’
10.10.3.
Deliverables
In all displays the term "Subjects" is used to refer to “Participants”.
Delivery
Description
SAC
Final Statistical Analysis Complete
 
2018N378719_00


CONFIDENTIAL
207573
44
10.10.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
mITT
CP_ES1
Summary of Participant Disposition
ICH E3, FDAAA, EudraCT
SAC
1.2.
ALLSUB
NS1
Summary of Number of Subjects Enrolled by Country and Site 
ID
Split by Part and Group, not split by 
treatment
SAC
1.3.
mITT
ES4
Summary of Subject Disposition at Each Study Epoch
ICH E3
For treatment periods, only ‘completed’ 
row is required.  For washouts use all 3 
options as in shell
SAC
1.4.
ALLSUB
ES6
Summary of Screening Status and Reasons for Screen Failure
Journal Requirements
SAC
Protocol Deviation
1.5.
mITT
DV1
Summary of Important Protocol Deviations
ICH E3
Split by Part and Group, not split by 
treatment
SAC
1.6.
ALLSUB
IE2
Summary of Inclusion/ Exclusion Criteria Deviations for Screen 
Failures
Add a row “Number of Screen Failures” 
above “any criteria deviations”.
Percentage will be based on number of
screen failures
SAC
1.7.
mITT
IE2
Summary of Inclusion/ Exclusion Criteria Deviations for the 
Modified Intent-to-treat Population
Split by Part and Group, not split by 
treatment
SAC
 
 
 
2018N378719_00


CONFIDENTIAL
207573
45
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Population Analysed
1.8.
ALLSUB
SP1
Summary of Study Populations 
IDSL
Number of participants who were 
randomized and number in the mITT 
population.  Of those the number and 
percentage of participants in the PK 
population
Split by Part and Group, not split by 
treatment
SAC
1.9.
PK
SP2A
Summary of Exclusions from the Pharmacokinetic Parameter 
Analysis
Split by treatment
SAC
Demographic and Baseline Characteristics
1.10.
mITT
DM3
Summary of Demographic Characteristics
ICH E3, FDAAA, EudraCT
Include BMI
Split by Part and Group, not split by 
treatment
SAC
1.11.
ALLSUB
DM11
Summary of Age Ranges
EudraCT
Include total column
Split by Part and Group, not split by 
treatment
SAC
1.12.
mITT
DM5
Summary of Race and Racial Combinations
ICH E3, FDA, FDAAA, EudraCT
Split by Part and Group, not split by 
treatment
SAC
Medical Conditions
1.13.
mITT
MH1
Summary of Relevant Medical Conditions
Split by Part and Group, not split by 
treatment
SAC
 
 
 
2018N378719_00


CONFIDENTIAL
207573
46
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Prior and Concomitant Medications
1.14.
mITT
CP_CM1
Summary of Concomitant Medications by Generic Term
ICH E3
Medications will be sorted in 
descending order of total incidence 
across treatment groups for generic 
term. If the total incidence for any two 
or more generic terms is equal, the 
events will be presented in alphabetical 
order.
Split by Part and Group, not split by 
treatment
SAC
1.15.
mITT
POP_T1
Summary of Compliance with Omeprazole Therapy
Split by treatment
Includes treatment I-K only
SAC
1.16.
mITT
POP_T2
Summary of Meal Data
Split by treatment
SAC
 
 
 
2018N378719_00


CONFIDENTIAL
207573
47
10.10.5.
Pharmacokinetic Tables
Pharmacokinetic: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.1.
PK
PK01
Summary of Danirixin Blood Pharmacokinetic Concentration-
Time Data
Split by Part, Group and by treatment
SAC
2.2.
PK
PK03
Summary Statistics of Untransformed Derived Danirixin Blood 
Pharmacokinetic Parameters
Split by Part, Group and by treatment
SAC
2.3.
PK
PK05
Summary Statistics of Log-transformed Derived Danirixin Blood 
Pharmacokinetic Parameters
Split by Part, Group and by treatment
SAC
2.4.
PK
201037 Table 
3.6
Summary of Statistical Analysis of Log-transformed Danirixin 
Blood Pharmacokinetic Parameters: Fed State
Part A
SAC
2.5.
PK
201037 Table 
3.6
Summary of Statistical Analysis of Log-transformed Danirixin 
Blood Pharmacokinetic Parameters: Fasted State
Part A
SAC
2.6.
PK
201037 Table 
3.6
Summary of Statistical Analysis of Log-transformed Danirixin 
Blood Pharmacokinetic Parameters: Food Effect in Test 
Formulations
Part A
SAC
2.7.
PK
201037 Table 
3.6
Summary of Statistical Analysis of Log-transformed Danirixin 
Blood Pharmacokinetic Parameters: Food Effect in Selected 
Formulation without Proton Pump Inhibitor
Part B
SAC
2.8.
PK
201037 Table 
3.6
Summary of Statistical Analysis of Log-transformed Danirixin 
Blood Pharmacokinetic Parameters: Food Effect in Selected 
Formulation with Proton Pump Inhibitor
Part B
SAC
2.9.
PK
201037 Table 
3.6
Summary of Statistical Analysis of Log-transformed Danirixin 
Blood Pharmacokinetic Parameters: Proton Pump Inhibitor 
Effect in Selected Formulation
Part B
SAC
 
 
 
2018N378719_00


CONFIDENTIAL
207573
48
Pharmacokinetic: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.10.
PK
201037 Table 
3.6
Summary of Statistical Analysis of Log-transformed Danirixin 
Blood Pharmacokinetic Parameters: Pharmaceutical 
Development
Part B
SAC
10.10.6.
Pharmacokinetic Figures
Pharmacokinetic: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.1.
PK
PK16b
Individual Subject Danirixin Blood Concentration-Time Plot 
(Linear and Semi-log) by Subject
All treatments for one participant on 
same panel
SAC
2.2.
PK
PK24
Individual Subject Danirixin Blood Concentration-Time Plot 
(Linear and Semi-log) by Treatment
All participants for one treatment on 
same panel
SAC
2.3.
PK
PK19
Arithmetic Mean (+SD) Danirixin Blood Concentration-Time Plot 
(Linear and Semi-log)
SAC
2.4.
PK
PK20
Median (Range) Danirixin Blood Concentration-Time Plot 
(Linear and Semi-log)
SAC
2.5.
PK
PK25
Comparative Plot of Individual Subject Danirixin Blood 
Concentration-Time Parameters vs. Treatment: Fed State
Treatments A-D
SAC
2.6.
PK
PK25
Comparative Plot of Individual Subject Danirixin Blood 
Concentration-Time Parameters vs. Treatment: Fasted State
Treatments AO-DO
SAC
2.7.
PK
PK25
Comparative Plot of Individual Subject Danirixin Blood 
Concentration-Time Parameters vs. Treatment: Food Effect in 
Test Formulations
Treatments A, AO, B, BO, C, CO, D, 
DO
SAC
 
 
 
2018N378719_00


CONFIDENTIAL
207573
49
Pharmacokinetic: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.8.
PK
PK25
Comparative Plot of Individual Subject Danirixin Blood 
Concentration-Time Parameters vs. Treatment: Food Effect in 
Selected Formulation without Proton Pump Inhibitor
Treatments E-G
SAC
2.9.
PK
PK25
Comparative Plot of Individual Subject Danirixin Blood 
Concentration-Time Parameters vs. Treatment: Food Effect in 
Selected Formulation with Proton Pump Inhibitor
Treatments I-K
SAC
2.10.
PK
PK25
Comparative Plot of Individual Subject Danirixin Blood 
Concentration-Time Parameters vs. Treatment: Proton 
Pump Inhibitor Effect in Selected Formulation
Treatments E, I, F, J, G, K
SAC
2.11.
PK
PK25
Comparative Plot of Individual Subject Danirixin Blood 
Concentration-Time Parameters vs. Treatment: Pharmaceutical 
Development
Treatments G-H
SAC
2.12.
PK
201037 Figure 
3.7
Geometric Mean (90% CI) Treatment Ratios of Danirixin Blood 
Pharmacokinetic Parameters: Fed State
Treatment comparisons B vs A, C vs 
A, D vs A
SAC
2.13.
PK
201037 Figure 
3.7
Geometric Mean (90% CI) Treatment Ratios of Danirixin Blood 
Pharmacokinetic Parameters: Relative Bioavailability in Fasted 
State
Treatment comparisons BO vs AO, CO 
vs AO, DO vs AO
SAC
2.14.
PK
201037 Figure 
3.7
Geometric Mean (90% CI) Treatment Ratios of Danirixin Blood 
Pharmacokinetic Parameters Food Effect in Test Formulations
Treatment comparisons A vs AO, B vs 
BO, C vs CO, D vs DO
SAC
2.15.
PK
201037 Figure 
3.7
Geometric Mean (90% CI) Treatment Ratios of Danirixin Blood 
Pharmacokinetic Parameters Food Effect in Selected 
Formulation without Proton Pump Inhibitor
Treatment comparisons G vs E, F vs 
E, G vs F
SAC
2.16.
PK
201037 Figure 
3.7
Geometric Mean (90% CI) Treatment Ratios of Danirixin Blood 
Pharmacokinetic Parameters: Food Effect in Selected 
Formulation with Proton Pump Inhibitor
treatment comparisons K vs I, J vs I, K 
vs J
SAC
 
 
 
2018N378719_00


CONFIDENTIAL
207573
50
Pharmacokinetic: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.17.
PK
201037 Figure 
3.7
Geometric Mean (90% CI) Treatment Ratios of Danirixin Blood 
Pharmacokinetic Parameters: Proton Pump Inhibitor Effect in 
Selected Formulation
Treatment comparisons I vs E, J vs F, 
K vs G
SAC
2.18.
PK
201037 Figure 
3.7
Geometric Mean (90% CI) Treatment Ratios of Danirixin Blood 
Pharmacokinetic Parameters: Pharmaceutical Development
Treatment comparison H vs G
SAC
10.10.7.
Safety Tables
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
3.1.
mITT
CP_AE1x
Summary of On-treatment Adverse Events by System Organ 
Class and Preferred Term
ICH E3
SAC
3.2.
mITT
CP_AE1x
Summary All Drug-Related Adverse Events by System Organ 
Class and Preferred Term
ICH E3
SAC
3.3.
mITT
AE15
Summary of Common (>=5%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Subject
and Occurrences)
FDAAA, EudraCT
Use TD_AE4VCTR macro
SAC
Serious and Other Significant Adverse Events
3.4.
mITT
AE16
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Subjects and Occurrences)
FDAAA, EudraCT
Use TD_AE4VCTR macro
SAC
3.5.
mITT
CP_AE1x
Summary of On-treatment Serious Adverse Events by System 
Organ Class and Preferred Term
SAC
 
 
 
2018N378719_00


CONFIDENTIAL
207573
51
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.6.
mITT
CP_AE1x
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study by 
System Organ Class and Preferred Term
IDSL
SAC
Laboratory: Chemistry 
3.7.
mITT
LB1
Summary of Pre-dose Clinical Chemistry Laboratory Values
ICH E3
SAC
Laboratory: Hematology
3.8.
mITT
LB1
Summary of Pre-dose Haematology Laboratory Values
ICH E3
SAC
Laboratory: Urinalysis
3.9.
mITT
200163 Table 
2.17
Summary of Urinalysis Dipstick Data
ICH E3
SAC
Laboratory: Hepatobiliary (Liver)
3.10.
mITT
MH2
Listing of Medical Conditions for Subjects with Liver Stopping 
Events
Only create if there is a liver event
SAC
3.11.
mITT
SU2
Listing of Substance Use for Subjects with Liver Stopping 
Events
Only create if there is a liver event
SAC
3.12.
mITT
LIVER5
Listing of Liver Monitoring/Stopping Event Reporting
Only create if there is a liver event
SAC
3.13.
mITT
LIVER6
Listing of Liver Stopping Event Information for RUCAM Score
Only create if there is a liver event
SAC
3.14.
mITT
LIVER7
Listing of Liver Biopsy Details
Only create if there is a liver event
SAC
3.15.
mITT
LIVER8
Listing of Liver Imaging Details
Only create if there is a liver event
SAC
3.16.
mITT
LIVER13
Listing of Subjects Meeting Hepatobiliary Laboratory Criteria
Only create if there is a liver event
SAC
ECG
3.17.
mITT
CP_EG9
Summary of Change from Baseline in 2h Post-dose ECG Values
IDSL
Include all parameters collected
SAC
 
 
 
2018N378719_00


CONFIDENTIAL
207573
52
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.18.
mITT
CP_EG11
Frequency of QTc Values at 2h Post-dose by Pre-specified 
Categories
IDSL
Include QTcF, QTcB
SAC
3.19.
mITT
CP_EG12
Frequency of Change from Baseline in QTc Values at 2h Post-
dose by Pre-specified Categories
IDSL
Include QTcF, QTcB
SAC
Vital Signs
3.20.
mITT
VS1
Summary of Vital Signs
ICH E3
SAC
10.10.8.
ICH Listings
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.
ALLSUB
ES7
Listing of Reasons for Screen Failure
Journal Guidelines
SAC
2.
mITT
CP_ES10x
Listing of Reasons for Study Withdrawal
ICH E3
SAC
3.
mITT
TA2
Listing of Planned and Actual Treatments
IDSL
SAC
Protocol Deviations
4.
mITT
DV2
Listing of Important Protocol Deviations 
ICH E3
SAC
5.
ALLSUB
IE4
Listing of Screen Failure Subjects with Inclusion/Exclusion 
Criteria Deviations
SAC
6.
mITT
IE4
Listing of Subjects with Inclusion/Exclusion Criteria Deviations
ICH E3
SAC
 
 
 
2018N378719_00


CONFIDENTIAL
207573
53
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Populations Analysed
7.
PK
SP3
Listing of Exclusions from the Pharmacokinetic Analysis
ICH E3
SAC
Demographic and Baseline Characteristics
8.
mITT
DM4
Listing of Demographic Characteristics
ICH E3
SAC
9.
mITT
DM10
Listing of Race
ICH E3
SAC
Prior and Concomitant Medications
10.
mITT
CP_CM4
Listing of Concomitant Medications using Generic Term
IDSL
SAC
11.
PK
POP_L1
Listing of Omeprazole Dosing Times
SAC
Pharmacokinetic
12.
PK
PK08
Listing of Danirixin Blood Concentration-Time Data
SAC
13.
PK
PK14
Listing of Danirixin Blood Pharmacokinetic Parameters
SAC
14.
PK
PK15
Listing of Danirixin Blood Pharmacokinetic Parameter Ratios
SAC
Adverse Events
15.
ALLSUB
AE9
Listing of All Adverse Events
ICH E3
SAC
16.
ALLSUB
AE7
Listing of Subject Numbers for Individual Adverse Events
ICH E3
SAC
17.
ALLSUB
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text
IDSL
SAC
Serious and Other Significant Adverse Events
18.
ALLSUB
AE9a
Listing of Serious Adverse Events
ICH E3
Include fatal and non-fatal SAEs
Add identification of treatment phase 
and treatment
SAC
19.
ALLSUB
AE14
Listing of Reasons for Considering as a Serious Adverse Event
ICH E3
SAC
 
 
 
2018N378719_00


CONFIDENTIAL
207573
54
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
20.
ALLSUB
AE9
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment
ICH E3
SAC
21.
ALLSUB
AE9
Listing of Drug-Related Adverse Events
ICH E3
SAC
All Laboratory
22.
mITT
CP_LB6
Listing of All Clinical Chemistry Laboratory Data for Subjects 
with Any Value of Potential Clinical Importance
ICH E3
SAC
23.
mITT
CP_LB6
Listing of All Haematology Laboratory Data for Subjects with Any 
Value of Potential Clinical Importance
ICH E3
SAC
24.
mITT
CP_LB6
Listing of Clinical Chemistry Abnormalities of Potential Clinical 
Importance
SAC
25.
mITT
CP_LB6
Listing of Haematology Abnormalities of Potential Clinical 
Importance
SAC
26.
mITT
UR2A/UR2B
Listing of Urinalysis Data 
ICH E3
SAC
ECG
27.
mITT
CP_EG4
Listing of All ECG Values for Subjects with Any Value of 
Potential Clinical Importance
IDSL
SAC
28.
mITT
CP_EG4
Listing of ECG Values of Potential Clinical Importance
IDSL
SAC
29.
mITT
CP_EG6
Listing of All ECG Findings for Subjects with an Abnormal ECG 
Finding
IDSL
SAC
30.
mITT
CP_EG6
Listing of Abnormal ECG Findings
IDSL
SAC
Vital Signs
31.
mITT
CP_VS5
Listing of All Vital Signs Data for Subjects with Any Value of 
Potential Clinical Importance
IDSL
SAC
32.
mITT
CP_VS5
Listing of Vital Signs of Potential Clinical Importance
IDSL
SAC
 
 
 
2018N378719_00


CONFIDENTIAL
207573
55
10.10.9.
Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
33.
ALLSUB
POP_L2
Listing of Study Treatment Misallocations
SAC
Past and Current Medical History
34.
mITT
MH3
Listing of Medical Conditions
SAC
Pharmacokinetics
35.
PK
No shell (SAS 
output)
Supportive SAS Output from Statistical Analysis of Log-
Transformed Danirixin Pharmacokinetic Parameters: Relative 
Bioavailability, Fed and Fasted States and Food Effect in Test 
Formulations
SAC
36.
PK
No shell (SAS 
output)
Supportive SAS Output from Statistical Analysis of Log-
Transformed Danirixin Pharmacokinetic Parameters: Food Effect 
in Selected Formulation with and without PPI, and PPI Effect in 
Selected Formulation
SAC
37.
PK
No shell (SAS 
output)
Supportive SAS Output from Statistical Analysis of Log-
Transformed Danirixin Pharmacokinetic 
Parameters:Pharmaceutical Development
SAC
38.
PK
CP_MP1x
Listing of Dosing Times, Meal Start and End Times
Include proportion of meal eaten
SAC
 
 
 
2018N378719_00


CONFIDENTIAL
207573
56
10.11.
Appendix 11: Example Mock Shells for Data Displays
Mock shells will be created in a separate document.
 
 
 
2018N378719_00