Conditions: Inflammatory Bowel Diseases
Keywords: Inflammatory Bowel disease Pro-drug Double-blinded Crossover
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 31
Healthy volunteers: yes

Brief summary:
This study is the first administration of GSK2983559, a selective receptor interacting protein 2 (RIP2) kinase inhibitor, to humans. This will be randomized, double-blinded (sponsor open) and two part study (A and B). Part A of the study is single ascending dose crossover design with two separate cohorts (1 and 2). In Part A, 9 single dose levels will be explored. In Cohort 1, 10 healthy subjects will randomized to receive single oral doses of either GSK2983559 or placebo in a ratio of 4:1 in 5 way cross-over design with 5 treatment periods. In Cohort 2, 8 healthy subjects will be randomized to receive single oral doses of either GSK2983559 or placebo in a ratio of 3:1 in 4 way cross-overs design with 4 treatment periods. In Cohort 2 there will be an additional period (period 5-open label) for assessing GSK2983559 under fed conditions. There will be 48 hours wash-out period between each dose escalation period. Part B is repeat ascending dose sequential group design. It will contain 4 Cohorts of and dosing will be done sequential dosing. Subjects in Part B will receive once daily (QD) dose or twice daily dose (will be decided based upon the pharmacokinetic, safety and tolerability observed in Part A). There will 58 subjects involved in this study. Total duration of Part A will be approximately for 11 Weeks and Part B will be approximately for 15 Weeks.

Detailed description:

Arms:
arm 1: Cohort 1 will be 5-way crossover with 5 treatment periods. Subjects will be randomized in the ratio 4:1 to receive either single dose of GSK2983559 or placebo. arm 2: Cohort 2 will be 4-way crossover design with one additional period of open-label. Subjects will be randomized in the ratio 3:1 to receive either single dose of GSK2983559 or placebo in fasted conditions arm 3: In Cohort 2, treatment period 5 will be open-label period. This open-label period is to determine food effect and subjects will receive GSK2983559 under fed conditions. arm 4: Part B is repeat ascending dose sequential period. There will four cohorts (3-6) of 10 healthy subjects. In each cohort subjects will be randomized to receive GSK2983559 or placebo in ratio 4:1. Subjects will receive GSK2983559 or placebo QD and twice daily dose will be decided based upon the pharmacokinetic, safety and tolerability observed in Part A.

Interventions: intervention 1: GSK2983559 intervention 2: Placebo
Intervention descriptions: intervention 1: GSK2983559 will be available as oral capsules with dose strength of 2-45 milligram (mg), 100 and 114 mg. intervention 2: Placebo oral capsules matching GSK2983559 will be available for subjects.

Protocol document:
Prot_000.pdf: 
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TITLE PAGE
Protocol Title: A single-centre, randomized, double-blind (sponsor open), placebo-
controlled study 
to 
evaluate the safety, 
tolerability, 
pharmacokinetics, and 
pharmacodynamics of GSK2983559, in single (in both fed and fasted states) and repeat 
oral doses in healthy participants
Protocol Number: 205021/ Amendment 01
Short Title: GSK2983559 First time in human study
Compound Number:
GSK2983559
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information can be found in the Study Reference 
Manual
Regulatory Agency Identifying Number(s): EudraCT 2017-002664-40
Approval Date: 24-JUL-2018
Copyright 2018 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.


PPD
PPD


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 01
24-JUL-2018
Original Protocol Republishing
17-OCT-2017
Original Protocol
06-OCT-2017
Amendment 01 24-JUL-2018
Overall Rationale for the Amendment:
As described in Section 5.5.5 and Section 8.2 of this protocol,  plasma concentrations of 
the mutagenic substance 5-ABT and its metabolite NAc-5-ABT are being monitored 
throughout the study to ensure that participants remain below the threshold of 
toxicological concern (TTC) of  <120 µg/day (for up to one month of dosing) as defined 
by the ICH M7 guidance.  Following administration of  a single dose of 100 mg 
GSK2983559 in Cohort 1 of Part A, quantifiable concentrations of 5-ABT were observed 
in 4 of the 8 subjects dosed with GSK2983559.  The maximum observed 5-ABT 
concentration of 1.25 ng/mL was below the stopping criteria of 3 ng/mL.  The presence 
of quantifiable concentrations of 5-ABT in plasma is believed to be due to hydrolysis of 
the drug substance to form 5-ABT in the acidic conditions of the stomach.  It is also 
known that the drug product contains 5-ABT; however, this is being controlled to < 10 
ppm in the current synthetic route and extraction procedure. 
This amendment will change the formulation from a standard capsule (HPMC) to an 
enteric capsule (HPMCAS) to determine if an enteric formulation minimises the gastric 
conversion of drug substance to  5-ABT.  The disintergration of an enteric capsule is pH 
dependent and is expected to avoid hydrolysis in the stomach and release active 
pharmaceutical ingredient (API) in the higher pH environment in the proximal small 
intestine. The 5-ABT stopping criteria are unchanged and continue with progression in to 
Cohort 2 and if controlled will carry through Cohort 6.
PK parameters AUC and Cmax for GSK2983559 and GSK2668176 increase 
approximately linearly with increasing doses.  Draft preliminary review of blinded safety 
data indicate that there are no clinical significant safety concerns.  No SAEs or deaths 
have been reported. Cohort 2 is planned to start with a 200 mg dose and escalate to the 
top predicted dose which values will not exceed the mean GSK2668176 AUC(0-24) and 
Cmax values observed at one third of the No Observable Effect Limit (NOAEL) in 
minipig. The sample size for Cohort 2 will be increased from 8 to 12 subjects to monitor 
for 5-ABT concentrations in more subjects and to ensure at least 8 active subjects 
progress to the food effect dosing in this cohort.


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Section # 
and Name
Description of Change
Brief Rationale
Section1. 
Protocol 
Synopsis
Section 5.1. 
Overall 
Design
Section 5.2. 
Number of 
Participants
Section 5.5.3 
Anticipated 
efficacious 
dose
Section 5.5.4 
Top dose 
selection for 
Part A and B
Section 5.5.5 
Assessment 
and control of 
5-ABT
Section 7 
Treatments 
The Number of Participants has 
been raised to 12 in Cohort 2, 
which has been reflected in the 
Treatment Groups Table.
Figure 1 Study Design has been 
updated to change the number of 
subjects in Cohort 2 from 8 to 12.
Table 6 updated with number of 
participants for Cohort 2.
The text has been edited to state 
that there will be 12 subjects in 
Cohort 2 and this cohort will switch 
to the enteric capsule.
Table 6 Treatment Sequences for 
Part A – Cohort 2 updated from 8 
to 12 subjects and DL9 in treatment 
period 4 updated to remove OL and 
become an optional dose if 
required.
Updated section to reflect predicted 
pharmacological dose.  Removed 
Table 7.
Updated section and Table 8 with 
observed and predicted fold cover 
to NOAEL.
Removed Table (previously 
numbered Table 9) Predicted 
amount of 5-ABT.  
Provide rationale for enteric 
(HPMCAS) capsule for remaining 
cohorts.
Section 7.1 updated with HPMCAS 
capsule information.
Cohort 2 increase in sample size is needed 
to monitor for 5-ABT concentrations and 
ensure at least 8 active subjects progress 
to the food effect in this cohort using the 
enteric capsule.
PK and PD data are now available from 
Cohort 1 to determine predicted 
pharmacological dose.
Table not applicable since quantifiable 
concentrations of 5-ABT have been 
observed below TTC in 4 out of 8 subjects 
treated with 100 mg in Cohort 1.


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Section # 
and Name
Description of Change
Brief Rationale
Section 7.3 
Method of 
Treatment 
Assignment
Section 11.1 
Sample Size 
Determiniation
Cohort 2 and Treatment codes 
updated.
Maximum number of participants 
updated in Part A or B.
To include up to 4 dosing sequences in 
1:1:1:1 ratios.
Original planned treatment description 
updated to what has been administered in 
Cohort 1 and what is planned for Cohort 2.
Probability of an observed safety event 
changes with an increase in sample size.


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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS...............................................................................................................9
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................11
3.
INTRODUCTION....................................................................................................16
3.1.
Study Rationale ..........................................................................................16
3.2.
Background ................................................................................................16
3.3.
Benefit/Risk Assessment ............................................................................16
3.3.1.
Risk Assessment .........................................................................18
3.3.2.
Benefit Assessment.....................................................................22
3.3.3.
Overall Benefit:Risk Conclusion...................................................22
4.
OBJECTIVES AND ENDPOINTS...........................................................................23
5.
STUDY DESIGN ....................................................................................................24
5.1.
Overall Design ............................................................................................24
5.2.
Number of Participants ...............................................................................28
5.3.
Participant and Study Completion...............................................................29
5.4.
Scientific Rationale for Study Design ..........................................................29
5.5.
Dose Justification........................................................................................30
5.5.1.
Human PK prediction...................................................................30
5.5.2.
Starting dose selection for Part A.................................................30
5.5.3.
Anticipated efficacious dose ........................................................31
5.5.4.
Top dose selection for Part A.......................................................31
5.5.5.
Assessment and control of 5-ABT................................................33
6.
STUDY POPULATION...........................................................................................33
6.1.
Inclusion Criteria.........................................................................................34
6.2.
Exclusion Criteria........................................................................................35
6.3.
Lifestyle Restrictions...................................................................................37
6.3.1.
UV exposure................................................................................37
6.3.2.
Meals and Dietary Restrictions ....................................................37
6.3.3.
Fasted Conditions........................................................................37
6.3.3.1.
Part A.........................................................................37
6.3.3.2.
Part B.........................................................................38
6.3.3.3.
Fed Conditions ...........................................................38
6.3.4.
Caffeine, Alcohol, and Tobacco ...................................................38
6.3.5.
Activity .........................................................................................39
6.4.
Screen Failures...........................................................................................39
7.
TREATMENTS.......................................................................................................39
7.1.
Treatments Administered............................................................................40
7.2.
Dose Modification .......................................................................................40
7.3.
Method of Treatment Assignment ...............................................................41
7.4.
Blinding.......................................................................................................42
7.5.
Preparation/Handling/Storage/Accountability..............................................43
7.6.
Treatment Compliance................................................................................43


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7.7.
Concomitant Therapy..................................................................................43
7.8.
Treatment after the End of the Study ..........................................................44
8.
DOSE ESCALATION CRITERIA............................................................................44
8.1.
PK criteria for GSK2668176........................................................................44
8.2.
PK criteria for 5-ABT and NAc-5-ABT .........................................................44
8.3.
Safety criteria..............................................................................................45
9.
DISCONTINUATION CRITERIA.............................................................................45
9.1.
Individual Safety Stopping Criteria ..............................................................45
9.2.
Neurological/psychiatric Stopping Criteria...................................................46
9.3.
Liver Chemistry Stopping Criteria ...............................................................46
9.3.1.
Study Treatment Restart or Rechallenge .....................................47
9.4.
QTc Stopping Criteria .................................................................................47
9.5.
Withdrawal from the Study..........................................................................48
9.6.
Lost to Follow Up........................................................................................48
10. STUDY ASSESSMENTS AND PROCEDURES .....................................................48
10.1.
Adverse Events...........................................................................................49
10.1.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................49
10.1.2.
Method of Detecting AEs and SAEs.............................................50
10.1.3.
Follow-up of AEs and SAEs.........................................................50
10.1.4.
Regulatory Reporting Requirements for SAEs .............................50
10.1.5.
Pregnancy ...................................................................................51
10.2.
Treatment of Overdose...............................................................................51
10.3.
Safety Assessments ...................................................................................51
10.3.1.
Physical Examinations.................................................................51
10.3.2.
Neurological Exams.....................................................................51
10.3.3.
Vital Signs....................................................................................52
10.3.4.
Electrocardiograms......................................................................52
10.3.5.
Clinical Safety Laboratory Assessments ......................................52
10.4.
Pharmacokinetics .......................................................................................53
10.4.1.
Blood Sample Collection..............................................................53
10.4.2.
Plasma Sample Analysis .............................................................53
10.4.3.
Urine sample collection and analysis ...........................................54
10.5.
Exploratory Pharmacodynamics and Target Engagement ..........................54
10.6.
Pharmacodynamic Samples .......................................................................54
10.7.
Target Engagement (TE) Samples..............................................................54
11. STATISTICAL CONSIDERATIONS........................................................................54
11.1.
Sample Size Determination ........................................................................55
11.2.
Populations for Analyses ............................................................................56
11.3.
Statistical Analyses.....................................................................................56
11.3.1.
Safety Analyses...........................................................................56
11.3.2.
PK Analyses ................................................................................56
11.3.3.
Other Analyses ............................................................................57
11.3.4.
Interim Analyses ..........................................................................57
12. REFERENCES.......................................................................................................59
13. APPENDICES........................................................................................................60


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13.1.
Appendix 1: Abbreviations and Trademarks................................................60
13.2.
Appendix 2: Clinical Laboratory Tests.........................................................65
13.3.
Appendix 3: Study Governance Considerations..........................................67
13.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................71
13.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................76
13.6.
Appendix 6: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................79
13.7.
Appendix 7: Protocol Amendment History...................................................81


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1.
SYNOPSIS
Protocol Title: A single-centre, randomized, double-blind (sponsor open), placebo-
controlled study 
to 
evaluate the safety, 
tolerability, 
pharmacokinetics, and 
pharmacodynamics of GSK2983559, in single (in both fed and fasted states) and repeat 
oral doses in healthy participants
Short Title: GSK2983559 First time in human study
Rationale: This study is the first administration of GSK2983559, a selective receptor 
interacting protein 2 (RIP2) kinase inhibitor, to humans.  The purpose of this study is to 
evaluate 
the 
safety, 
tolerability, 
pharmacokinetics 
(PK), 
and 
exploratory 
pharmacodynamics (PD) of single (fed and fasted) and repeat oral doses of up to 14 days 
with GSK2983559 in healthy participants.  The intention of this study is to provide 
sufficient confidence in the safety of the molecule to inform progression to further repeat 
dose proof of concept studies.
Objectives and Endpoints:
Objectives
Endpoints
Primary

To assess the safety and tolerability of single (fed 
and fasted) and repeat doses of GSK2983559 in 
healthy participants.

Safety and tolerability of GSK2983559 as assessed 
by clinical monitoring and reporting of adverse 
events and serious adverse events, change in 
laboratory values, electrocardiogram (ECG), vital 
signs, physical examinations.
Secondary

To characterise the PK profile of single (fasted) 
doses of GSK2983559 and its active moiety 
GSK2668176 in healthy participants.

Derived PK parameters for GSK2983559 and 
GSK2668176 including area under the plasma drug 
concentration versus time curve (area under the 
concentration-time curve from time zero (pre-dose) 
to last time of quantifiable concentration [AUC(0-t)], 
area Under the Concentration-time curve from time 
zero to infinity [AUC(0-∞)]),
maximum observed 
plasma drug concentration (Cmax), time to maximum 
observed plasma drug concentration (tmax), and 
terminal half-life (t1/2) following single (fasted) 
doses, where data allow.

To characterise the PK profile of repeat doses of 
GSK2983559 and its active moiety GSK2668176 in 
healthy participants.

Derived PK parameters for GSK2983559 and 
GSK2668176 including area under the plasma drug 
concentration versus time curve (AUC(0-t), AUC(0-τ)), 
maximum observed plasma drug concentration 
(Cmax), time to maximum observed plasma drug 
concentration (tmax), and terminal half-life (t1/2) 
following single and repeat doses, and estimation of 
an accumulation ratio where data allow.


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Objectives
Endpoints

To assess the effect of food on the pharmacokinetics 
of GSK2983559 and its active moiety GSK2668176
in fasted and fed state in healthy participants.

Derived PK parameters for GSK2983559, and 
GSK2668176 including area under the plasma drug 
concentration versus time curve (AUC(0-t), AUC(0-∞)), 
maximum observed plasma drug concentration 
(Cmax), time to maximum observed plasma drug 
concentration (tmax), and terminal half-life (t1/2) 
following single (fed and fasted) dose, where data 
allow.
Overall Design:
This study will be a randomised, double-blind (sponsor open), placebo-controlled, two-
part study of oral administration of GSK2983559 in healthy participants. Part A will be a 
single ascending dose crossover design in two separate cohorts of participants (Cohorts 1 
and 2). In addition to the crossover treatment periods, subjects in Cohort 2 will participate 
in an additional treatment period and receive open-label GSK2983559 under fed 
conditions. Part B will be a repeat dose design in up to 4 cohorts of participants (Cohorts 
3-6). This study is planned to include approximately 62 participants.
Parts A and B of this study will be double-blind with respect to participants, investigator 
and site staff (except for the site pharmacist). Sponsor open refers only to members of the 
Dose Escalation Committee (DEC) at defined meetings. Members and requirements are 
provided in a Dose Escalation Charter. 

Part A – single ascending doses, randomized, placebo controlled, crossover.
Part A plans to explore up to 9 single ascending dose levels. This will be 2 cohorts, 
Cohort 1 (standard capsule) and Cohort 2 (enteric capsule), of 10 and 12 healthy 
participants, respectively. The total duration of Part A of the study for each participant, 
including screening and follow-up, is approximately 11 weeks.

Part B – repeat ascending dose, randomized, placebo controlled, sequential-group.
Part B will consist of up to four cohorts of 10 healthy participants. The total duration of 
Part B of the study for each participant, including screening and follow-up, is 
approximately 15 weeks. The treatment period will be 14 days.
In all cases the decision to proceed to the next dose level will be made at a DEC meeting 
(see Study Governance Considerations).


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2.
SCHEDULE OF ACTIVITIES (SOA)
The schedules of activities (SOA) for Part A and Part B are presented in Table 2 and 
Table 3, respectively.  The time points for the PK blood sample collection in Part A and 
Part B are presented in Table 2 and Table 4, respectively.
The timing and number of planned study assessments, including safety or PK 
assessments may be altered during the course of the study based on newly available data 
(e.g., to obtain data closer to the time of peak plasma concentrations) to ensure 
appropriate monitoring. 
Any changes in the timing or addition of time points for any planned study assessments 
as a result of emerging pharmacokinetic data must be documented and approved by the 
relevant study team members and then archived in the sponsor and site study files. The 
competent authority (CA) and ethics committee (EC) will be informed of any safety 
issues that constitute a substantial amendment and require alteration of the safety 
monitoring scheme or amendment of the informed consent form (ICF).  The changes will 
be approved by the CA and the EC before implementation.
There are times where the protocol requires more than one procedure to be completed at 
the same time point. In these instances the following will apply to post dose time points:
PK samples should take priority over other procedures scheduled at the same time point. 
As guidance, the preferred order of assessments is:

Electrocardiograms (ECGs)

Vital Signs

PK blood sampling (nominal time)

Other assessments e.g., physical exams, 
Electrocardiograms (ECGs) should be taken prior to vital signs when both measurements 
are scheduled at the same time point.  Other assessments, e.g., physical examinations etc, 
will be performed within the required time windows.  All safety assessments will be 
timed and performed relative to the start of dosing.


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Table 1
Screening and Follow Up SOA
Procedure
Screening
Follow-up Visit
Notes
(up to 28 days prior to Day 1)
Outpatient Visit
X
X
Follow-up Visit to occur approximately 7 days or 5 half lives (as 
determined from Part A PK data), whichever is longer, and no greater 
than 14 days after last study drug administration.
Informed Consent
X
Inclusion and Exclusion Criteria
X
Medical/medication/drug/alcohol history
X
Demographics
X
Full Physical Examination
X
Additional examinations may be performed, or brief examinations 
made full examinations, by the Investigator, as deemed necessary (e.g. 
where safety or laboratory findings indicate).
Brief Physical Examination
X
Drug/alc./cotinine screen
X
Tests include alcohol breath test, urine cotinine and drug screen.
HIV, Hep B and Hep C screen
X
Tuberculosis Test
X
Conducted as standard practice of the site.
Serum Pregnancy Test (all females)
X
FSH and estradiol (all females)
X
Hema/Chem/Urinalysis tests
X
X
Coagulation Panel
X
Lipid panel (Part B only)
X
Height and weight
X
Holter Monitoring (24-hour)
X
12-lead ECG
T
X
T= Triplicate
Vital signs
X
X
Vital signs to include heart rate, blood pressure, respiration rate and 
temperature.
Concomitant Medication Review
X
X
AE and SAE Review
X


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Table 2
Part A SOA
Notes
Day -1
Day 2 Day 3
Participants to be admitted to the unit the day before dosing (Day -1), 
and remain in house until discharge after 48-hour post-dose 
assessments (Day 3) are completed.
Pre dose 0 h 15min 30min 1 hr 1.5 hr 2 hr 2.5 hr 3 hr 3.5hr 4hr 5hr 6hr 8 hr 10 hr 12 hr 24 hr 48 hr
X
X
X
X
Additional exams./screens may be performed, or brief exams made full 
exams. by the Investigator, as deemed necessary (e.g. where safety or 
laboratory findings indicate).
X
Additional assessments may be performed at the discretion of the 
Investigator.  Tests will be conducted within site specified standards.
X
X
X
X
X
Non-fasted samples will be collected on Day -1 and at 8 hours on Day 1. 
Non-fasted chemistry only will be collected at 8 hour time point.
X
X
X
X
Continuous at least 8 hours post-dose.  Initiate at least 15 min. prior to 
dosing
X
T
X
X
X
X
X
X
X
X
X
X
X
Vital signs to include HR, BP, respiration rate and temperature.
T = Triplicate (HR and BP only) single respiration rate and temperature. 
Timings will be reviewed as cohorts progress and may be adjusted to 
ensure appropriate measurements relative to peak concentrations for 
subsequent cohorts.  
T
T
X
X
X
X
X
X
X
X
X
X
All
D
Cohort 2, fed period 
D
B
X
A minimum interval of 30 minutes will be observed between the dosing 
of the first 2 participants at each dose level.  A minimum interval of 15 
minutes will be observed between the dosing of the remaining 6 
participants.
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
The number and sampling times may be adjusted once the human PK 
data are available.
X
Participants will void bladder prior to dosing, a sample will be kept as 
control.  0-24-hr urine samples will be collected. 
X
X
X
X
X
X
 Two samples will be drawn at pre-dose.  The PD  sampling time points 
may be updated based on emerging PK data. PD samples will not be 
collected in the food efect part of the study.
X
X
X
X
X
X
TE samples will not be collected in the food effect part of the study 
See section 10.1.1 for pre-dose SAE requirements
For ECG and vital signs T=Triplicate, For Meals B=Breakfast, D=Dinner
<---------------------------------------------------------------------------------->
Prior to dosing, participants will fast for 8 hrs overnight; no food is 
allowed for at least 4 hrs post-dose.  Water is permitted with dosing and 
at all times except 1 hour pre-dose through 2-hours post-dose.  
Participants will receive standardized meals scheduled at the same time 
in each period.  
Meals
TE Blood Sample
PD Blood Sample
PK Blood Sample
Urine Collection for 
Metabolites
Study Treatment dosing
12-lead ECG
Telemetry
Vital signs
<--------------------------------------------------------------X----------------------------------------------------------------->
Adverse Event Review
Concomitant Med.
<---------------------------------------0-24 hours---------------------------------------->
Per site Schedule
<--------------------------------------------------------------X------------------------------------------------------->
Pregnancy test (all females)
Procedure
Study Day (each dosing session)
Day 1 (time relative to dose)
See Study Reference Manual for assessment time windows
Neuro. examination
Brief Physical Examination
Drug/alc./cotinine screen
Heam/Chem/Coags/Urinalysis


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Table 3
Part B SOA
Notes
-1
1
2
3 4 5 6 7 8 9 10 11 12 13
14
15
16
Participants to be discharged after the 48-hour post-dose 
assessments are completed on Day 16.
Pregnancy test (all females)
X
Brief Physical Examination
X
X
X
X
X
X
Full Physical Examination
X
Drug/alc./cotinine screen
X
Weight
X
X
X
Telemetry
X
Continuous initiating 15 min. pre-dose through at least 8 hrs 
post-dose
12-lead ECG
T
X
X X
X
X
X 
24h post 
D14 dose
Vital signs
T
X
X X X X X X X X
X
X
X
X 
24h post 
D14 dose
Hem/Chem/Coag/Urinalysis
X
X
X
X
X
X
On Days 2, 4, 7 and 10 to be drawn at pre-dose. 
Neuro. Examination
X
X
X
X
Fasting lipid panel
X
X
Fasting from at least 12:01 am.
Meals Served
X
X
X X X X X X X X
X
X
X
X
X
X
Study Treatment Dosing
X
X X X X X X X X
X
X
X
Dosing frequency (qd or bid) to be determined based on Part A 
data.
PK Blood Sample 
X 
24h post 
D1 dose
X X X X X
X
X
X 
24h post 
D14 dose
X 
48h post 
D14 dose
Pre-dose PK samples collected on Days 3 through 7, Day 10 and 
Day 12. 
PD Blood Sample
X 
24h post 
D1 dose
X 
24h post 
D14 dose
X 
48h post 
D14 dose
TE Blood Sample 
X 
24h post 
D1 dose
X 
24h post 
D14 dose
X 
48h post 
D14 dose
AE Assessment
See section 10.1.1 for pre-dose SAE requirements
Concomitant Med. Review
Procedure
Study Day(s)
<-------------------------------------------------x------------------------------------------------>
Day 2 – Day 13 readings to be performed pre-dose. 
Vital signs include HR, BP, respiration rate and temperature.
T=Triplicate;  Vitals signs Triplicate (HR and BP only) single 
respiration rate and temperature.
Please see separate SOA for D1 assessments 
Please see separate SOA for D1 
assessments 
Please see separate SOA for D14 assessments 
Please see separate SOA for 
D14 assessments 
Additional exams/screens may be performed, or brief exams 
made full exams, by the Investigator, as deemed necessary 
(e.g. where safety or laboratory findings indicate). Tests will be 
conducted within site specified standards.
<----------------------------------x------------------------------------>


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Table 4
Part B Day 1 and Day 14 SOA
Pre dose 0 15 min 30 min 1 hr 1.5 hr 2 hr 2.5 hr 3 hr 3.5 4hr 5hr 6hr 8 hr 10 hr
12 hr
12.5 h
13 h
13.5 h
14 h
14.5 h
15.5
16 h
Hema/Chem/Coag/Urinalysis
X
X
Pre-dose for Day 1 may be drawn on either Day 1 or Day -1 and 
does not include pre-dose on Day 14.  Non-fasted Chemistry 
only at 8-hour time point on Day 1.
Neuro. Examination
X
No examinations to be performed on Day 14.
12-lead ECG and vital signs
T
X
X
X
X
X
X
X
X
X
Vital signs to include HR, BP, respiration rate and temperature. 
T = Triplicate (HR and BP only) single respiration rate and 
temperature.  
Time points may be added or subtracted after review of Part A 
data.
Telemetry 
Continuous at least 8 hours post-dose.  Initiate at least 15 min. 
prior to dosing
PK Blood Sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
BID 
dosing 
only
X
BID 
dosing 
only
X
BID 
dosing 
only
X
BID 
dosing 
only
X
BID 
dosing 
only
X
BID 
dosing 
only
X
BID 
dosing 
only
The number and sampling times may be adjusted once the 
human PK data are available.
Metabolite Blood Sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
BID 
dosing 
only
X
BID 
dosing 
only
X
BID 
dosing 
only
X
BID 
dosing 
only
X
BID 
dosing 
only
X
BID 
dosing 
only
X
BID 
dosing 
only
The number and sampling times may be adjusted once the 
human PK data are available.
Urine Collection for Metabolites
X
Participants will void bladder prior to dosing, a sample will be 
kept as a control.  0-24-hr urine samples (or 0-12hr samples for 
BID dosing) will be collected. 
PD Blood Sample 
X
X
X
X
 Two samples will be drawn at pre-dose.  The PD  sampling time 
points may be updated based on emerging PK data. PD 
samples will not be collected in the food efect part of the study.
TE Blood Sample 
X
X
X
X
The TE sampling time points may be updated based on 
emerging PK data.  TE samples will not be collected in the food 
effect part of the study 
Study Treatment Dosing
X
X
BID 
dosing 
only
Dosing frequency (qd or bid) to be determined based on Part A 
data.
Meals Served
On Days 1 and 14 - participants will fast 8 hrs overnight; no 
food is allowed for at least 4 hrs post-dose.  Water permitted 
with dosing and at all times except 1 hour pre-dose through 2-
hours post-dose.  Participants will receive standardized meals 
scheduled at the same time in each period.
<-----------------------------------------X---------------------------------------->
Procedure
Notes
Days 1 and 14  (time relative to dose)
See Study Reference Manual for assessment time windows
Study Days
<---------------------------------------0-24 hours---------------------------------------->
or for BID dosing
<-----------------0-12 hours-------------->
Per site schedule


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3.
INTRODUCTION
3.1.
Study Rationale
This study is the first administration of GSK2983559, a selective RIP2 kinase inhibitor, 
to humans.  The purpose of this study is to evaluate the safety, tolerability, 
pharmacokinetics (PK), and exploratory pharmacodynamics (PD) of single (fed and 
fasted) and repeat oral doses of up to 14 days with GSK2983559 in healthy participants.  
The intention of this study is to provide sufficient confidence in the safety of the 
molecule to inform progression to further repeat dose proof of concept studies.
3.2.
Background
GSK2983559 is a novel oral first-in-class inhibitor of Receptor Interacting Protein 
Kinase-2 (RIPK2). GSK2983559 is a phosphate ester pro-drug, which breaks down 
rapidly into GSK2668176 providing an increase in solubility and exposure. GSK2668176 
is a potent, reversible, and highly-selective inhibitor of RIP2 kinase (RIPK2).
RIPK2 is a serine/threonine kinase, comprised of an N-terminal kinase domain, an 
intermediate domain, and C-terminal caspase-activation-and-recruitment (CARD) 
domain. The nucleotide-binding oligomerization domain 1 (NOD1)/RIP2 and 
NOD2/RIP2 pathways are widely expressed in both immune and non-immune cells. 
Upon activation RIP2 undergoes post-translational modifications (ubiquitination and 
autophosphorylation), which facilitate NF-κB and mitogen-activated protein kinase 
(MAPK) activation, and lead to release of multiple proinflammatory cytokines (e.g., 
tumour necrosis factor [TNF], interleukin [IL]-1, -6, -8, etc.). Properly regulated, these 
pathways play an important role in maintaining innate immune homeostasis and host 
defense. 
Dysregulation of these pathways has been linked to multiple inflammatory diseases.  
Mutations in the Leucine-rich repeat (LRR) domain of NOD2 have been linked to 
increased susceptibility to Crohn’s disease (CD). In both CD and ulcerative colitis (UC) a 
breakdown in intestinal immune homeostasis is associated with disruption of epithelial 
barrier integrity, leading to inappropriate interaction between commensal bacteria and 
mucosal immune cells, aberrant activation of pattern recognition receptors (PRRs), and 
RIPK2-dependent inflammation. Activating mutations in the nucleotide binding domain 
of NOD2 have been linked to Blau Syndrome, a rare, monogenic, autoinflammatory 
disease characterized by granulomatous inflammation affecting multiple organs, often 
presenting with the clinical trial of arthritis, uveitis, and dermatitis. RIP2-dependent 
signaling has also been implicated in additional inflammatory diseases, including 
rheumatoid arthritis, psoriasis, vasculitis, type 2 diabetes, and multiple sclerosis.
3.3.
Benefit/Risk Assessment
To date, GSK2983559 has not been administered to human participants; therefore, no 
clinical data are available.  This is the first single and repeat dose study proposed in 
human participants with GSK2983559.  GlaxoSmithKline is not aware of any compound 
targeting this pathway having previously been administered in humans.


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The risk assessment of GSK2983559 is based on the pre-clinical studies conducted to 
date.  More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of GSK2983559 can be found in the GSK2983559 
Investigator’s Brochure [GlaxoSmithKline Document Number 2016N308990_00].  
Details of these risks and the proposed strategy to mitigate/monitor these risks are 
detailed in Section 3.1 below.  The proposed risk assessment and management plan for 
the study has been developed in accordance with the tenets of European Medicines 
Agency (EMA) guideline on strategies to identify and mitigate risks for first time in 
human (FTiH) clinical trials with investigational medicinal products [European 
Medicines Evaluation Agency (EMEA)/ Committee for Medicinal Products for Human 
Use (CHMP)/SWP/28367/07].  GlaxoSmithKline (GSK) has assessed this study for any 
risks that may be posed to participants taking part.  Only healthy male and female 
participants of non-child bearing potential (NCBP) will participate in this study.


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3.3.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [e.g., GSK2983559]
Neurobehavioral effects
Non-clinical data:
Non-reproducible neurobehavioural observations in an 
acute study in rats at doses ≥15mg/kg/day (vocalisation, 
increased touch response, grip strength and body tone).
No central nervous system (CNS)-related clinical signs 
were seen in any other acute or repeat dose study in rats, 
dogs or minipigs.
Participant Selection:

Participants with known history of significant 
neurological or psychiatric disorders or suicidal 
ideation behaviour will be excluded from 
GSK2983559 clinical studies.  

Participants with potentially increased 
susceptibility for neurologic or psychiatric effects 
will be excluded based on medical history at 
screening.
Participant Monitoring:

Targeted physical examinations with 
comprehensive neurological assessments will be 
conducted at appropriate intervals throughout 
the study.

Participants will be monitored for standard CNS-
related adverse events (AEs). Common 
terminology criteria for adverse events (CTCAE)
Nervous System Stopping Criteria are included 
in the protocol.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Immunosuppression
There is a theoretical risk of immunosuppression, including 
an increase in the frequency and/or severity of infection, 
resulting from the intended pharmacologic effect of 
GSK2983559.
Participant Selection:

Participants with recurrent, chronic or active 
infections will be excluded from GSK2983559
clinical studies.

Participants will be screened for tuberculosis 
(TB), human immunodeficiency virus (HIV), and 
Hepatitis B and C, and excluded from this study.
Participant Monitoring:

Participants will be monitored for signs of 
infection.
Vaccinations
There is a theoretical risk that GSK2983559 could 
decrease a participant’s immune response to vaccines or 
allow symptoms to develop following vaccination with a live 
vaccine when administered on therapy.  Currently, there
are no preclinical or clinical data with respect to this 
potential risk.
Participant Selection:

Routine or planned attenuated or live vaccines 
should not be administered to participants for 
30 days prior to the first dose of GSK2983559, 
during study participation, and for 5 half-lives 
plus 30 days after receiving GSK2983559.

Non-live vaccines (e.g., inactivated influenza 
vaccines) may be administered while receiving 
GSK2983559.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Hepatotoxicity
Non-clinical data:
Increased mean serum glutamate dehydrogenase (GLDH) 
and alanine aminotransferase (ALT) concentrations 
correlated with mixed inflammatory cell infiltrates present 
around the bile duct regions in the liver in female rats given 
240 mg/kg/day (6-week study). These changes were not 
observed in male rats at any dose. Additional liver findings, 
including hepatocellular necrosis, have been observed in 
rats and minipigs at non-tolerated doses.
Participant Monitoring:

Clinical hematologic and chemistry laboratory 
tests are readily measurable in the clinic and will 
be monitored periodically throughout the study 
(see SoA in Section 2). 

Liver Chemistry Stopping Criteria are included in 
the clinical protocol.
Phototoxicity
Non-clinical data:
There is a potential risk that GSK2983559 can lead to 
photosensitivity responses in some people.  
In a ultraviolet/visible light (UV/VIS) spectrum for 
GSK2983559 (max abs [absorbance] 340 nm) and 
GSK2668176 (max abs 339 nm) in acetonitrile 
(ACN)/water showed an absorbance between 290-700 nm 
demonstrated a risk for potential phototoxicity effects.
Participant Selection:

Participants must agree to avoid prolonged UV 
exposure to natural sunlight or tanning beds for 
the duration of the study.

Participants should be advised to wear protective 
clothing (e.g., sun hat, long sleeves) covering 
exposed areas and use a broad spectrum 
ultraviolet A/ultraviolet B (UVA/UVB) sunscreen 
and lip balm (SPF ≥30) on exposed areas when 
outdoors for a minimum of 5 half-lives after 
receiving GSK2983559.  Participants should also 
wear sunglasses which filter UVA and UVB rays 
for a minimum of 5 half-lives after receiving 
GSK2983559.  
Participant Monitoring:

Participants should be monitored for adverse 
effects potentially related to phototoxicity.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Mutagenicity/
Genotoxicity
Non-clinical data:
5-amino-benzothiazole (5-ABT), an impurity and acid 
degradant, is mutagenic in an in vitro Ames assay.  It is 
unknown if GSK2983559 itself presents a genotoxic 
hazard to humans.
Participant Monitoring:

Plasma samples from FTIH will be analysed for 
5ABT and N-acetyl 5ABT at each dose level. 
Dose escalation will be halted if in any individual 
the Cmax of combined concentration of 5-ABT 
and n-acetyl-5-amino benzothiazole (NAc-5-
ABT) (in ng/mL equivalents 5-ABT) is > 3 ng/mL
in either the standard or enteric capsule.
Reproductive toxicity
Non-clinical data:
Animal reproductive studies have not been conducted with 
GSK2983559.  Therefore, the compound must not be 
administered to pregnant women, nursing mothers or 
women of childbearing potential.
Subject Selection:

Male and female participants of non-childbearing 
potential (WONCBP) may be included in this 
study.

Male participants must agree to use highly 
effective methods of contraception during the 
treatment period and for at least 5 half-lives plus 
an additional 90 days after the last dose of study 
treatment and refrain from donating sperm during 
this period (Appendix 5).


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3.3.2.
Benefit Assessment
The proposed study with GSK2983559 will be conducted in healthy participants.  No 
medical benefit will be derived by participants’ participation.  Participants will indirectly 
gain through their contribution to the process of developing new therapies in an area of 
unmet need.  
3.3.3.
Overall Benefit:Risk Conclusion
The known risks associated with GSK2983559 can be appropriately mitigated by the 
careful selection of study participants and the proposed safety monitoring procedures.  As 
such, the risk to potential participants is considered low.  Routine safety and tolerability 
will be evaluated from reported adverse events (AEs), scheduled physical examinations, 
vital sign measurements, cardiac rhythm monitoring, 12-lead ECGs, and clinical 
laboratory test results as well as continued observation by clinical staff.  
The study will be conducted in a hospital-based unit or unit with immediate access to 
hospital facilities for the treatment of medical emergencies.  The in-house periods as 
detailed in the SoA will allow for continuous medical monitoring for all participants 
following the first dose in each treatment group.  Participants will only be discharged 
from the unit 48 hours after their last dose of GSK2983559 if the Investigator deems it 
safe to do so.
Taking into account the measures taken to minimize risk to participants participating in 
this study, the potential risks identified in association with GSK2983559 are justified by 
the anticipated benefits that may be afforded by the future development of a new therapy 
in an area of unmet need.  


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4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To assess the safety and tolerability of single (fed 
and fasted) and repeat doses of GSK2983559 in 
healthy participants.

Safety and tolerability of GSK2983559 as 
assessed by clinical monitoring and reporting of 
adverse events and serious adverse events, 
change in laboratory values, ECG, vital signs, 
physical examinations.
Secondary

To characterise the PK profile of single (fasted) 
doses of GSK2983559 and its active moiety 
GSK2668176 in healthy participants.

Derived PK parameters for GSK2983559 and 
GSK2668176 including area under the plasma 
drug concentration versus time curve (AUC(0-t), 
AUC(0-∞)), maximum observed plasma drug 
concentration (Cmax), time to maximum observed 
plasma drug concentration (tmax), and terminal 
half-life (t1/2) following single (fasted) doses, 
where data allow.

To characterise the PK profile of repeat doses of 
GSK2983559 and its active moiety GSK2668176 
in healthy participants.

Derived PK parameters for GSK2983559 and 
GSK2668176 including area under the plasma 
drug concentration versus time curve (AUC(0-t), 
AUC(0-τ)), maximum observed plasma drug 
concentration (Cmax), time to maximum observed 
plasma drug concentration (tmax), and terminal 
half-life (t1/2) following single and repeat doses, 
and estimation of an accumulation ratio where 
data allow.

To 
assess 
the 
effect 
of 
food 
on 
the 
pharmacokinetics of GSK2983559 and its active 
moiety GSK2668176 in fasted and fed state in 
healthy participants.

Derived PK parameters for GSK2983559, and 
GSK2668176 including area under the plasma 
drug concentration versus time curve (AUC(0-t), 
AUC(0-∞)), maximum observed plasma drug 
concentration (Cmax), time to maximum observed 
plasma drug concentration (tmax), and terminal 
half-life (t1/2) following single (fed and fasted) 
dose, where data allow.
Exploratory

To determine the PD effect of single and repeat 
doses of GSK2983559 in healthy participants.

PD/biomarker endpoints may include, but not be 
limited to, assessments of pharmacologic effects 
through measurements of target engagement and 
pathway 
activation. 
These 
may 
include 
measurements of RIP-2 receptor occupancy, and 
levels of MIP1, MIP1
and TNF proteins, 
following stimulation of whole blood, as data permit.

To 
investigate 
the 
metabolic 
profile 
of 
GSK2983559 following single and/or repeat doses 
in healthy participants in blood and urine

Identification and quantitative estimates of 
GSK2983559 and its active moiety GSK2668176
and potential metabolites following single and 
repeat doses in plasma and urine.

To characterize exposure to 5-ABT and NAc-5-
ABT after single and repeated doses of 
GSK2983559 in healthy participants.

Concentration of 5-ABT and NAc-5-ABT (adjusted 
to 5-ABT concentration based on MW) and derive 
Cmax for the combined concentration curve of 5-ABT 
and MW adjusted NAc-5-ABT


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5.
STUDY DESIGN
5.1.
Overall Design
This study will be a randomised, double-blind (sponsor open), placebo-controlled, two-
part study of oral administration of GSK2983559 in healthy participants. Part A will be a 
single ascending dose crossover design in two separate cohorts of participants (Cohorts 1 
and 2). In addition to the crossover treatment periods, subjects in Cohort 2 will participate 
in an additional treatment period and receive open-label GSK2983559 under fed 
conditions. Part B will be a repeat dose design in up to 4 cohorts of participants (Cohorts 
3-6). This study is planned to include approximately 62 participants.
Parts A and B of this study will be double-blind with respect to participants, investigator 
and site staff (with the exception of the site pharmacist). Sponsor open refers only to 
members of the Dose Escalation Committee (DEC) at defined meetings. Members and 
requirements are provided in a Dose Escalation Charter. 

Part A – single ascending doses, randomized, placebo controlled, crossover.
Part A plans to explore up to 9 single ascending dose levels. This will be 2 cohorts, 
Cohort 1 (standard capsule) and Cohort 2 (enteric capsule), of 10 and 12 healthy 
participants, respectively. The total duration of Part A of the study for each participant, 
including screening and follow-up, is approximately 11 weeks.
Figure 1
Study design – Part A
Screening
(28 days prior to 1st 
dose)
Follow-up
(7-14 days post last 
dose)
DL1
N=10
8A:2P
DL2
N=10
8A:2P
DL3
N=10
8A:2P
DL4
N=10
8A:2P
DL5
N=10
8A:2P
Screening
(28 days prior to 1st 
dose)
Follow-up
(7-14 days post last 
dose)
Food effect 
(open-label)
DL6
N=12
9A:3P
DL7
N=12
9A:3P
DL8
N=12
9A:3P
DL9/TBC
N=12
9A:3P
Fed
(DL TBC)
N=12
12A
Cohort 2, N=12, 9A:3P
Dose escalation meeting
Treatment period
Single ascending dose (double-blinded)
Cohort 1, N=10, 8A:2P
Treatment period
Single ascending dose (double-blinded)
Separate participants will be enrolled into both cohorts of Part A.
The design for the 2 cohorts is as follows:


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-
Cohort 1: 5-way crossover design with the standard capsule. Each participant will 
receive single ascending oral doses of either GSK2983559 or placebo in a 4:1 ratio 
according to the randomisation schedule, in study periods 1 to 5, in a blinded manner.
-
Cohort 2: 4-way crossover design with the enteric capsule for single ascending dose, 
including an additional period for assessing GSK2983559 under fed conditions 
(period 5 – open-label).
During the blinded part, each participant will receive single ascending oral doses of 
either GSK2983559 or placebo in a 3:1 ratio according to the randomisation schedule, 
in study periods 1 to 4, in a blinded manner.
If dose levels 6-9 are not investigated, Cohort 2 will only be used for evaluating the 
effect of food. It will be an open-label 2-way crossover design.
-
Cohorts 1 and 2 will be dosed sequentially, incorporating sentinel participants: Cohort 
1 will complete all 5 dosing periods before Cohort 2 begins. 
-
Following completion of Cohort 1 and before starting Cohort 2, a GSK internal safety 
board (independent of DEC) will be reviewing the data.
-
Based on emerging PK data, all doses may not be investigated.
-
There will be a at least 48-hour washout period between each dose escalation step but 
the washout period may be extended depending on emerging data.
Treatment period
-
Cohort 1 (single dose) will be comprised of up to 5 study periods, each at least 4 days 
in duration with participants in-house for 3 nights (through 48 hours post-dose). 
During each treatment period, participants will be admitted to the unit the day before 
dosing and will be discharged after completion of the 48-hour post-dose assessments.
-
Cohort 2 (single dose) will be comprised of up to 4 study periods, each at least 4 days 
in duration with participants in-house for 3 nights (through 48 hours post-dose). 
During each treatment period, participants will be admitted to the unit the day before 
dosing and will be discharged after completion of the 48-hour post-dose assessments.
-
Participants in Cohort 2 (food effect) will participate in up to 2 additional treatment 
periods and receive a single oral dose of GSK2983559 under fasted (Period 4) and/or
fed (Period 5) conditions, dose to be determined by DEC.
If the dose level chosen for the food effect assessment was administered in:
Cohort 1: participants will receive the dose of open-label GSK2983559 under 
fasted (Period 4) and fed (Period 5).
Cohort 2: participants will only receive the dose of open-label GSK2983559 
under fed (Period 5) conditions.
-
All participants will participate in no more than 5 Treatment Periods (see Table 5 and 
Table 6).
-
Participants will have a follow-up visit at least 7 days or 5 half-lives whichever is 
longer, and no greater than 14 days after last dose of GSK2983559. If warranted, 
additional follow-up visits may be scheduled.
Dosing
-
Participants will be randomized on Day 1 followed by a single oral dose of 
GSK2983559.


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-
Sentinel dosing will be employed within each ascending dose cohort and treatment 
period (except for when investigating the food effect). On Day 1, one participant will 
receive GSK2983559 and one participant will receive matched-placebo, to evaluate 
tolerability and safety for at least 24 hours post-dose. Dosing in the remaining 8 and 
10 participants in Cohorts 1 and 2, and treatment period will occur at least 24 hours 
later after review of safety results from the initial 2 participants in a 7:1 and 4:1 ratios
(GSK2983559: placebo) for Cohorts 1 and 2, respectively
The decision to proceed to the next single dose level will be made at a DEC meeting (see 
Appendix 3: Study Governance Considerations).
Treatment sequences for Part A:
The treatment sequences for Part A are outlined below and the planned dose levels (DLs) 
are defined in Section 5.5. The dose of GSK2983559 administered with a high-fat meal 
will be a dose level already evaluated in the dose escalation part of the study and will be 
determined by DEC and based on attainment of adequate exposure and safety.
Table 5
Treatment sequences for Part A – Cohort 1
Cohort 1: 
5-way crossover design with standard capsule
Sequence
Number 
of 
participants 
(N=10)
Period 1
Period 2
Period 3
Period 4
Period 5
1
2
Placebo
DL2
DL3
DL4
DL5
2
2
DL1
Placebo
DL3
DL4
DL5
3
2
DL1
DL2
Placebo
DL4
DL5
4
2
DL1
DL2
DL3
Placebo
DL5
5
2
DL1
DL2
DL3
DL4
Placebo
Table 6
Treatment sequences for Part A – Cohort 2
Cohort 2: 
4-way crossover design + open-label period for food effect with enteric capsule
Sequence
Number 
of 
participants 
(N= 12)
Period 1
Period 2
Period 3
Period 4*
Period 5
(w/food)
1
3
Placebo
DL7
DL8
DL9
TBC
2
3
DL6
Placebo
DL8
DL9
TBC
3
3
DL6
DL7
Placebo
DL9
TBC
4
3
DL6
DL7
DL8
Placebo
TBC
* If exposure levels are lower than expected, doses higher than Period 3 (DL9), may be evaluated.  If the 
dose level chosen for the food effect period was already evaluated in Cohort 2 (i.e., DL6-8), participants will 
only receive the dose of GSK2983559 under fed (period 5) conditions.
Abbreviations: DL: dose level; BL: blinded; TBC: to be confirmed


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
Part B – repeat ascending dose, randomized, placebo controlled, sequential-group
with enteric capsule.
Part B will consist of up to four cohorts of 10 healthy participants. The total duration of 
Part B of the study for each participant, including screening and follow-up, is 
approximately 15 weeks. The treatment period will be 14 days.
Figure 2
Study design – Part B
See Section 5.5.5 for dose justification in Part B.
Separate cohorts of participants will be enrolled into Parts A and B.
Cohorts 3-6 will be dosed sequentially (i.e., Cohort 4 starts after dosing in Cohort 3 is 
completed).
The participants in each cohort will be randomised in a 4:1 ratio to receive either 
GSK2983559 or placebo (enteric capsule), according to the randomisation schedule.


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Treatment period
-
The treatment period will be 14 days. 
-
Participants will be admitted to the unit the day before dosing, will remain in the unit 
overnight, and will be discharged following completion of the assessments on Day 
16, provided there are no safety concerns. 
-
Participants will have a follow-up visit at least 7 days or 5 half-lives (as determined 
from Part A PK data) whichever is longer, and no greater than 14 days after last study 
drug administration. If warranted, additional follow-up visits may be scheduled.
Dosing
-
Once-daily (QD) dosing is planned in Part B, but twice-daily dosing (BID) may be 
considered based upon the PK profile as well as the safety and tolerability observed in 
Part A.
-
Sentinel dosing will be employed within each cohort.  On Day 1, one participant will 
receive GSK2983559 and one participant will receive matched-placebo, both 
participants will be dosed to steady state (approximately Day 2 minimum based on 
PK predictions from Part A). Dosing in the remaining 8 participants in each cohort 
will occur after review of safety results from the initial 2 participants in a 7:1 ratio 
(GSK2983559: placebo).
The decision on the dose level of GSK2983559 to be administered in Cohort 3 will be 
made at a DEC meeting based on all safety, tolerability, and PK data accumulated from 
Part A of the study. The decision to proceed to the next single dose level will be made at 
a DEC meeting (see Appendix 3: Study Governance Considerations).
5.2.
Number of Participants
Participants will be screened to ensure that a minimum of 62 are eligible to be 
randomised (10 participants into Cohort 1, 12 participants into Cohort 2, and 10 
participants into each of Cohorts 3-6), so that a minimum of evaluable participants are 
achieved in each of cohorts as described in the table below:
Randomised 
Evaluable
Part A
Cohort 1 (single dose)
10
4 out of 8 on active
Cohort 2 (single dose)
12
4 out of 9 on active
Cohort 2 (food effect)
up to 12
4 out of at least 8 
on active
Part B
Cohorts 3-6 (repeat dose)
10
4 out of 8 on active
Total
62
Participants are considered as evaluable if the following are completed:
-
Part A - Cohort 1 (single dose): screening and all 5 treatment periods.
-
Part A - Cohort 2 (single dose): screening and all 3 or 4 treatment periods.
-
Part A - Cohort 2 (food effect): screening and all 2 treatment periods (fed and fasted).
-
Part B - Cohort 3-6 (repeat dose): screening and the 14-day treatment period.


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Additional participants/cohorts may be enrolled to allow for evaluation of additional dose 
levels. No more than 10 additional participants will be allowed in a cohort either in Part 
A and/or B.  The schedule of assessments will be as for these parts and the number of 
dosing periods will not exceed those in the current cohorts.
If a participant withdraws prematurely from Part A of the study, additional participants 
may be recruited and assigned to the same treatment sequence, starting from the current 
dosing period of the early withdrawal at the discretion of the sponsor in consultation with 
the investigator.
If a participant withdraws prematurely from Part B of the study, additional participants 
may be recruited and assigned to the same repeat dose level, starting from baseline at the 
discretion of the sponsor in consultation with the investigator.
5.3.
Participant and Study Completion
A participant is considered to have completed: 
-
Part A (cohort 1) of the study if he/she has completed all the periods of Part A –
cohort 1, including the follow-up visit.
-
Part A (cohort 2 – single dose) of the study if he/she has completed all the periods of 
Part A – cohort 2 – single dose, including the follow-up visit.
-
Part A (cohort 2 – food effect) of the study if he/she has completed the 2 periods of 
Part A – cohort 2 – food effect, including the follow-up visit.
-
Part B of the study if he/she has completed all visits including the follow-up visit.
The end of the study is defined as the date of the last visit (including follow-up) of the 
last participant in the study (Part A and Part B).
5.4.
Scientific Rationale for Study Design
The current study described herein has been designed to address regulatory guidance for 
FTIH studies and in particular General Considerations for Clinical Trials [The 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use (ICH) E8/ Committee For Proprietary Medicinal Products 
(CPMP)/ICH/291/95] and Guideline on Strategies to Identify and Mitigate Risk for First-
in-Human 
Clinical 
Trials 
with 
Investigational 
Medical 
Products 
[EMEA/CHMP/SWP/28367/07] as well as pre-clinical findings for GSK2983559, 
contributing to the frequency, type and duration of safety assessment and monitoring 
during treatment periods during each cohort.
The sequential design of the single dose components (Part A) and estimated 5-hour half-
life (t1/2) will allow for dose escalation to occur after less than 6 days of washout. The 
predicted time for GSK2668176 plasma concentrations to reach the lower limit of 
quantification (LLOQ, 0.20 ng/ml) after dosing for the highest selected dose (see Section 
5.5 below) was 3 days. This will allow any adjustment needed based on emerging safety, 
tolerability, and PK information. The randomised crossover design was chosen to allow 
for treatment comparison between and within participants. Further, a food-effect 
evaluation is planned to support progression into patient studies.


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In Part B, the 14-day dosing will provide exposure to PK steady state and will also be 
informative of the likely safety and tolerability in future longer studies.
5.5.
Dose Justification
5.5.1.
Human PK prediction
GSK2983559 is a phosphate ester pro-drug which is converted into GSK2668176 (active 
moiety) primarily by the alkaline phosphatase present in the intestinal lumen. The 
systemic exposure of the prodrug GSK2983559 is predicted to be <2% in humans and is 
considered to have a negligible contribution to clinical effect and is not considered 
relevant for human dose determination.
The human pharmacokinetic (PK) profiles as well as parameters of parent drug 
GSK2668176 following oral dosing of prodrug GSK2983559 were predicted using in 
vitro to in vivo extrapolation and allometric scaling. The predicted human mean 
absorption rate constant (0.85 1/h), clearance (0.426 L/h/Kg), volume of distribution (2.8 
L/Kg), half-life (4.6 hours) and bioavailability (70%) were used to determine the blood 
PK profiles for GSK2668176 following oral administration of GSK2983559. 
As the exposures observed in preclinical species were in plasma, the predicted human PK 
estimates in blood were multiplied by a factor of 0.83 (blood/plasma ratio=1.2 for
GSK2668176) to give the corresponding human PK estimates in plasma for calculating 
the safety fold coverage to the no observable adverse effect limit (NOAEL).
5.5.2.
Starting dose selection for Part A
The predicted human PK parameters along with the human whole blood (HWB) ex vivo 
assay data (HWB:
muramyl dipepide
(MDP)/TNFα Inhibitory concentration 
(IC)90=86.67 ng/mL) were used for human PK/PD predictions at various human dose 
levels. The ‘Minimal Anticipated Biological Effect Level’ (MABEL) approach was used 
as the basis to define the starting dose for GSK2983559 monotherapy in the single 
ascending dose phase of the study. A starting dose of 2 mg was chosen, as maximum and 
minimum PD inhibition are predicted to be approximately 30% and 3% at the predicted 
mean Cmax and mimimum observed concentration (Cmin) (24 h) values, respectively. 
Mean Cmax and AUC(0-) values of GSK2668176 in human plasma are projected to be 
0.004 µg/mL and 0.038 µg.h/mL, respectively, for the starting dose of 2 mg 
GSK2983559; these human predicted exposures are 753- and 708-fold lower than plasma 
Cmax and area under the concentration-time curve from time zero to 24 hours post first 
dose [AUC(0-24)] values at the NOAEL(60 mg/kg/day) in the six-week female rat 
preclinical toxicological study and 1870 and 1338-fold lower at the NOAEL 
(120mg/kg/day) in the six-week minipig preclinical toxicology study. In addition, the 
predicted mean Cmax at the 2 mg/day human dose is 106-fold lower compared to Cmax at 
the no observable effect limit (NOEL)
(1 mg/kg) in the rat Irwin studies 
(neurobehavioural studies in male rats). Thus, a starting dose of 2 mg in human provides 
sufficient safety margins against the preclinical toxicological findings to ensure the safety 
of study participants.


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5.5.3.
Anticipated efficacious dose
The level of inhibition of ex-vivo cytokine response required for efficacy is not known.
An efficacious dose may be anticipated with  90% inhibition of cytokine response at 
trough concentration measured at the end of a dosing interval at steady state (Ctrough)
(HWB:MDP/TNFα IC90=86.67 ng/mL). A dose of 800 mg QD was originally predicted 
to provide a mean inhibition of 90% at Ctrough for 24 hours.  A similar level of inhibition 
was predicted to be achieved with 100 mg BID dosing (total dose 200 mg/day). 
Accounting for between subject variability in PK and PD (assuming 30% between-
subject variability on apparent total clearance of the drug from plasma after oral 
administration (CL/F)], V/F, absorption rate constant (Ka) and IC50 for simulations), a 
dose of 400 mg BID (total daily dose of 800 mg) was predicted to be required for 90% 
inhibition at Ctrough in approximately 90% of population.  Based on emerging 
GSK2668176 pharmacokinetic data from the current study, a dose of 400 mg QD is 
predicted to provide a mean inhibition of 90% at Ctrough for 24 hours.  Accounting for 
between subject variability in PK, a dose of 200 mg BID (total daily dose of 400 mg) is 
predicted to be required for 90% inhibition at Ctrough in approximately 90% of population.
5.5.4.
Top dose selection for Part A
The expected exposure from the anticipated efficacious dose of 200 mg BID would have 
to be tested in the single ascending dose part, thus, requiring the need for evaluating 400 
mg. Since the level of inhibition of ex-vivo cytokine response required for efficacy is not 
known, doses that produce higher than 90% cytokine inhibition should be evaluated in 
the future efficacy dose ranging study. With the highest planned single dose of 600 mg, 
predicted plasma Cmax (1.84 µg/mL) and AUC(0-) (17.3 µg.h/mL) values are expected to 
provide >1.6-fold and >1.6-fold safety margin over the female rat NOAEL in the 6-week 
study for Cmax and area under the concentation-time curve (AUC), respectively and 4.1-
fold for Cmax and 2.94-fold for AUC in minipigs. If exposure levels are lower than 
expected, doses higher than 600 mg may be evaluated. The progression from one dose 
level to another will be made based on the assessment of the available data from previous 
dose levels by the Dose Escalation Committee (See Appendix 3: Study Governance 
Considerations). Table 7 lists the predicted NOAEL cover for GSK2668176 at various 
planned GSK2983559 doses in the FTIH study. 


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Table 7
Average GSK2668176 AUC and Cmax following single oral doses of 
GSK2983559, with Fold Cover to NOAEL
Dose
(mg)
Projected 
human 
plasma 
AUC(024)
(µg.h/mL)
Fold 
cover to 
NOAEL 
Minipig1
Fold 
cover 
to 
NOAEL 
male 
Rat2
Fold 
cover 
to 
NOAEL 
female 
Rat3
Projected 
human 
plasma 
Cmax
(µg/mL)
Fold 
cover to 
NOAEL 
Minipig1
Fold 
cover 
to 
NOAEL 
male 
Rat2
Fold 
cover 
to 
NOAEL 
female 
Rat3
Mean % 
PD 
inhibition 
coverage 
at Ctrough
2*
0.095
535
815
283
0.0105
714
706
288
9
4*
0.230
221
337
117
0.026
288
285
116
21
10*
0.347
147
223
77.5
0.038
197
195
79.5
29
30*
0.812
62.6
95.3
33.1
0.094
79.8
78.8
32.1
45
100*
2.476
20.5
31.3
10.9
0.306
24.5
24.2
9.87
73
200#
4.952
10.3
15.6
5.43
0.612
12.3
12.1
4.93
84
400#
9.904
5.13
7.82
2.72
1.224
6.13
6.05
2.47
92
600#
14.86
3.42
5.21
1.81
1.836
4.08
4.04
1.64
94
Key:
1= 6 week Minipig NOAEL is 120 mg/kg/day GSK2983559: Gender-averaged Day 42 mean plasma AUC0-t
of 50.85 µg.h/mL GSK2668176 and Cmax of 7.5 g/mL GSK2668176.
2= 6-week Rat NOAEL in males is 240 mg/kg/day GSK2983559: Day 42 plasma AUC0-t of 77.4 µg.h/mL 
GSK2668176 and plasma Cmax of 7.41 µg/mL GSK2668176.
3= 6-week Rat NOAEL in females is 60 mg/kg/day GSK2983559: Day 42 plasma AUC0-t of 26.9 µg.h/mL 
GSK2668176 and plasma Cmax of 3.02 µg/mL GSK2668176.
*. Observed AUC(0-24) and Cmax.
# Predicted AUC(0-24) and Cmax based on 100 mg values and assuming linear.
Dose selection for Food Effect
An assessment of the effect of food on the exposure to GSK2983559/ GSK2668176 will 
be incorporated into the single dose part of the study (Part A). The food effect was 
predicted to be non-significant up to 300 mg dose using GastroPlus (physiologically 
based pharmacokinetic modelling (PBPK) modeling platform). Fed State Simulated 
Intestinal Fluid / Fasted State Simulated Intestinal Fluid (FeSSIF / FaSSIF) ratio for 
GSK2983559 is 1.5; therefore, a 50% increase in exposure could be anticipated relative 
to fasting state exposure. The dose to be administered with food will be selected such 
that, if there were a 50% increase in exposure it would be predicted to be within the 
safety margins.
Dose selection for Part B
Part B (repeat dose) of the study will be initiated after completion of Part A. Dose 
selection will be based upon consideration of available safety, tolerability and PK data 
from Part A and/or preceding repeat dose cohorts in Part B. Based on the observed half-
life of approximately 8 h GSK2668176 in humans, minimum accumulation is anticipated 
after BID dosing.  The dose of GSK2983559, noted as X, is anticipated to provide 90% 
inhibition at Ctrough levels of GSK2668176 in 50% of the population and will be re-
estimated based on the PK and PD data collected in the early doses in Part A. The initial 


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dose in Part B (Cohort 3, repeat dose) will be approximately half X. Dose escalation in 
the repeat dose part of the study will not exceed 2-fold between cohorts and will be 
driven by safety and PK stopping criteria (see Section 8). In addition, a dose will not be 
assessed as a repeat dose until the anticipated steady-state exposure (Cmax and AUC(0-) on 
Day 14) for that dose have been evaluated and shown not to have met safety stopping 
criteria in the single dose portion of the study (Part A). Based on current PK predictions a 
dose of 200 mg BID dosing regimen is predicted to provide 90% inhibition in 
approximately 90% of subjects. Dose levels higher than this may be explored in order to 
evaluate dose response in future phase 2 dose ranging study provided that exposure levels 
for that dose has been previously evaluated in Part A of the study.
5.5.5.
Assessment and control of 5-ABT
5-amino-benzothiazole (5-ABT), an impurity in the GSK2983559 drug substance (3-6 
parts per million (ppm) [m.2.1.S.3.2 Impurities in chemistry, manufacturing and controls 
(CMC) investigational medicinal product dossier (IMPD)], was found to be mutagenic in 
an in vitro Ames assay. In addition, 5-ABT was formed from GSK2668176 in bio
relevant media (pH 6.5 and pH 8 in FaSSIF and FeSSIF conditions), suggesting that a 
theoretical risk exists for its formation at physiological pH.  According to ICH M7 
guidance for the assessment and control of deoxyribonucleic acid (DNA) reactive 
(mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk, 5-ABT is 
classified as a Class 2 hazard (i.e. known mutagen with unknown carcinogenic potential) 
and must be controlled at or below the Threshold of Toxicological Concern (TTC) of 120 
µg/day considering the duration of treatment of ≤ 1 month..
5-ABT is not predicted to be a metabolite, and has not been observed as a metabolite in in 
vitro hepatocyte or S9 incubations. Real time analysis of plasma samples from FTIH for 
5-ABT and its metabolite N-acetyl 5-ABT will be performed to monitor exposure to 5-
ABT in healthy volunteers.
Quantifiable concentrations of 5-ABT were observed below the stopping criteria 
(combined Cmax of 5-ABT  and NAc-5-ABT of 3 ng/mL) in 4 out of 8 subjects treated 
with GSK2983559 in Cohort 1 at the 100-mg dose level.  The maximum observed 5-ABT 
concentration was 1.25 ng/mL.  An enteric capsule [Hydroxypropylmethyl Cellulose
Acetate Succinate (HPMCAS)] will be used starting in Cohort 2 and carry through to 
Cohort 6 to determine if this formulation will minimize the gastric conversion of drug 
substance to 5-ABT.  The disintergration of an enteric capsule is pH dependent and is 
expected to avoid hydrolysis of the active pharmaceutical ingredient (API) to 5-ABT in 
the acidic environment of the stomach and release API in a higher pH environment in the 
proximal small intestine.
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.


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6.1.
Inclusion Criteria
AGE
1.
Male and female participants between 18 and 65 years of age inclusive, at the 
time of signing the informed consent.
TYPE OF PARTICIPANT AND DISEASE CHARACTERISTICS
2.
Volunteers who are overtly healthy as determined by medical evaluation 
including medical and psychiatric history, physical examination, neurological 
examination, clinical laboratory tests and cardiac monitoring. 
WEIGHT
3.
Body weight 50 kg and body mass index (BMI) within the range 19-32 kg/m2 
(inclusive).
SEX
4.
Male and female participants:
a. Male participants:
A male participant must agree to use a highly effective contraception (see below) 
during the treatment period and for at least 5 half-lives plus an additional 90 days 
after the last dose of study treatment and refrain from donating sperm during this 
period.

Male participants with female partners of child-bearing potential are eligible to 
participate if they agree to ONE of the following during the protocol-defined 
time frame above: 

Are abstinent from penile-vaginal intercourse as their usual and preferred 
lifestyle (abstinent on a long term and persistent basis) and agree to remain 
abstinent 

Agree to use a male condom plus an additional method of contraception 
with a failure rate of <1% per year as described in Appendix 5 when 
having penile-vaginal intercourse with a woman of childbearing potential 

Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of 
penile penetration during the protocol-defined time frame.

Refrain from donating sperm for duration of study and for 90 days from the last 
dose.
b.  Female participants:
A female participant is eligible to participate if she is not pregnant (see 
Appendix 5), not breastfeeding, and is not a woman of childbearing potential 
(WOCBP) as defined in Appendix 5.
INFORMED CONSENT
5.
Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this 


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protocol.
6.
Participants must agree to avoid prolonged UV exposure to natural sunlight
without required UVA/UVB protection or tanning beds for the duration of the 
study.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
MEDICAL CONDITIONS
1. History or presence of/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. History or current evidence of febrile seizures, epilepsy, convulsions, significant head 
injury, or other significant neurologic conditions.
3. History of clinically significant psychiatric disorders as judged by the investigator.
4. Any history of suicidal behavior within the past 6 months or any history of attempted 
suicide in a participant’s lifetime.
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%).
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. History of GI surgery (with exception of appendectomy).
9. Average QTc > 450 msec 
NOTES:
a.
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.
b. The specific formula that will be used to determine eligibility and
discontinuation for an individual participant 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 participant and then the lowest
QTc value used to include or discontinue the participant 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).


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PRIOR/CONCOMITANT THERAPY
10. Intended use of over-the-counter or prescription medication including herbal 
medications within 7 days prior to dosing [Specific medications listed in the protocol 
may be allowed]
11. Live or attenuated vaccine(s) within 30 days of randomisation, or plans to receive 
such vaccines during the study or plans to receive a vaccine within 30 days + 5 half-
lives of the last dose of study medication.
12. Regular alcohol consumption within 6 months prior to the study defined as:
13. 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.
14. Current use or history of regular tobacco- or nicotine-containing products within 6 
months prior to screening.  Subject must have urinary cotinine levels indicative of 
non-smoking status at screening visit.
PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE
15. Exposure to more than 4 new chemical entities within 12 months prior to the first
dosing day.
16. Current enrollment or past participation within the last 30 days before signing of
consent in this or any other clinical study involving an investigational study
treatment or any other type of medical research.
DIAGNOSTIC ASSESSMENTS
17. Participants with impaired renal function defined as Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) calculation ≤60 (mL/min/1.73m2) estimated 
by the CKD-EPI equation [Snyder, 2009 and Levey, 2010].
18. An elevated C-reactive protein (CRP) outside of the normal reference range.
19. Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test 
result at screening or within 3 months prior to first dose of study treatment.  As 
potential for and magnitude of immunosuppression with this compound is unknown, 
participants with presence of hepatitis B core antibody (HBcAb) should also be 
excluded.
Participants positive for HBsAg and/or positive for anti-HBc antibody (regardless of 
anti-HBs antibody status) are excluded.
20. A positive pre-study drug/alcohol screen.
21. A positive test for HIV antibody.
22. A positive diagnostic TB test at screening defined as a positive QuantiFERON-TB 
Gold test or T-spot test.  In cases where the QuantiFERON or T-spot test is 
indeterminate, the participant may have the test repeated once, but they will not be 
eligible for the study unless the second test is negative. In cases where the 
QuantiFERON or T-spot test is positive, but a locally-read follow up chest x-ray, 


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shows no evidence of current or previous pulmonary tuberculosis, the participant may 
be eligible for the study at the discretion of the Investigator and GSK Medical 
Monitor.
OTHER EXCLUSIONS
23. Sensitivity to any of the study treatments, or components thereof, or drug or other
allergy that, in the opinion of the Investigator or GSK Medical Monitor,
contraindicates participation in the study.
24. Where participation in the study would result in donation of blood or blood products 
in excess of 500 mL within a 56-day period.
25. Part A (Food Effect) Cohort:  Participant must have no dietary restrictions (e.g., 
lactose intolerance) or inability to eat a high fat meal. 
6.3.
Lifestyle Restrictions
6.3.1.
UV exposure

Participants should be advised to wear protective clothing (e.g., sun hat, long 
sleeves) covering exposed areas and use a broad spectrum UVA/UVB sunscreen and 
lip balm (SPF ≥ 30) on exposed areas when outdoors for a minimum of 5 half-lives 
after receiving GSK2983559.  Participants should also wear sunglasses which filter 
UVA and UVB rays for a minimum of 5 half-lives after receiving GSK2983559.  
6.3.2.
Meals and Dietary Restrictions

Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit 
juice, pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices from 7 days 
prior to each first dose of study treatment in Part A up until discharge from the unit.  
In Part B, subject must refrain from consumption of red wine, Seville oranges, 
grapefruit or grapefruit juice, pomelos, exotic citrus fruits, grapefruit hybrids, or fruit 
juices from 7 days prior to the first dose of study treatment until after the final dose.
6.3.3.
Fasted Conditions
6.3.3.1.
Part A
During Part A (fasted treatment periods) participants will fast overnight from Day -1 to 
Day 1:

Water is permitted with dosing and at all times except 1 hour pre-dose through 2-
hours post-dose.

Participants must fast from all food and drink (except water) for 8 hours pre-dose 
and prior to any clinical laboratory evaluations (except repeat evaluations).

No food is allowed for at least 4 hours post-dose.


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6.3.3.2.
Part B
If once daily (QD) dosing is investigated, the following fasting conditions will be 
followed:

Water is permitted with dosing and at all times except 1 hour pre-dose through 2-
hours post-dose.

Participants must fast every night from all food and drink (except water) for 8 hours 
pre-dose and prior to any clinical laboratory evaluations (except repeat evaluations).

A schedule of meals in relation to dosing will be provided in the study reference 
manual (SRM).
If BID dosing is required, the fasted conditions will be determined on the basis of the 
data emerging from the food effect seen in Part A and will be detailed in the SRM.
6.3.3.3.
Fed Conditions
With the exception of those outlined in Section 6.3.3.1, participants will receive 
standardized meals scheduled at the same time in each period.
In the final treatment period of Cohort 2 in Part A, participants will fast from 
approximately midnight on the day prior to dosing and will receive a standard high-fat 
meal 30 minutes prior to dosing. The breakfast will be consumed steadily over 25 
minutes.  Dose administration must occur within 5 minutes of completing breakfast.  
Participants will not receive any further food until 4 hours post-dose.  Water will not be 
allowed from 1 hour before until 4 hours after dosing.
According to the European Medicines Agency – Guidelines on the Investigation of Drug 
Interaction, the high fat meal should contain 800-1000 kcal with 500-600 kcal from fat 
and 240 kcal from carbohydrates.  A typical standard high-fat meal should consist of:

Two eggs fried in butter

Two strips of bacon

Two slices of toast with butter

120 grams of hash brown potatoes cooked in butter

240 mL of whole milk
6.3.4.
Caffeine, Alcohol, and Tobacco

During each dosing session, participants will abstain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate) for 24
hours before the start of dosing untildischarge from the clinic.


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
During each dosing session, participants will abstain from alcohol for 24 hours 
before the start of dosing until after collection of the final PK and/or 
pharmacodynamic sample. 

Use of tobacco or nicotine-containing products will not be allowed from 6 months 
prior to screening until after the final follow-up visit.
6.3.5.
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 (e.g., watching television, reading).

Participants will abstain from traveling to regions of high endemic infection, as 
determined by the investigator, for the duration of the study.
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized. 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 only on approval of the GSK Medical Monitor. Rescreened 
participants should be assigned the same participant number as for the initial screening.
7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.


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7.1.
Treatments Administered
Product name:
GSK2983559
Placebo
GSK2983559
Placebo
Formulation 
description:
API filled capsule
Avicel filled capsule
API filled capsule
Avicel filled capsule
Dosage form:
HPMC Capsule
HPMC Capsule 
HPMC Capsule
HPMC Capsule 
Unit 
dose 
strength(s)/Dosage 
level(s):
2-45 mg
NA
100, 114 mg
NA
Route/
Administration/
Duration:
Oral
Oral
Oral
Oral
Dosing instructions:
Dose with water
Dose with water
Dose with water
Dose with water
Physical 
description:
Size 0 Swedish 
Orange capsule 
containing white to 
almost white solid
Size 0 Swedish 
Orange capsule 
containing white to 
almost white solid
Size 00 White 
Opaque capsule 
containing white to 
almost white solid
Size 00 White 
Opaque capsule 
containing white to 
almost white solid
Manufacturer/
source 
of 
procurement:
GlaxoSmithKline
GlaxoSmithKline
GlaxoSmithKline
GlaxoSmithKline
Method 
for 
individualizing 
dosage:
Site to assemble
Site to assemble
Site to assemble
Site to assemble
HPMC – Hydroxypropylmethyl Cellulose
Product name:
GSK2983559
Placebo
Formulation 
description:
API filled capsule
Avicel filled capsule
Dosage form:
HPMCAS Capsule
HPMCAS Capsule 
Unit 
dose 
strength(s)/Dosage 
level(s):
50-100 mg
NA
Route/
Administration/
Duration:
Oral
Oral
Dosing instructions:
Dose with water
Dose with water
Physical 
description:
Size 00 White 
Opaque capsule 
containing white to 
almost white solid
Size 00 White 
Opaque capsule 
containing white to 
almost white solid
Manufacturer/
source 
of 
procurement:
GlaxoSmithKline
GlaxoSmithKline
Method 
for 
individualizing 
dosage:
Site to assemble
Site to assemble
HPMCAS – Hydroxypropylmethyl Cellulose Acetate Succinate
7.2.
Dose Modification
This protocol allows some alteration from the currently outlined dosing schedule, but the 
maximum total daily dose will not intentionally exceed the PK stopping criteria defined 
in Section 8.  Currently, the highest planned dose is 600 mg/day of GSK2983559.


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7.3.
Method of Treatment Assignment
At screening a unique number (case report form [CRF] number) will be assigned to any 
participant who has at least one Screening procedure performed, other than signed
informed consent. The unique number will be used to identify individual participants 
during the course of the study.
Participants who meet the screening eligibility criteria will be randomised to a treatment 
group through an Interactive Response Technology (IRT). The IRT will confirm the 
participants CRF number and provide the randomisation number, where:

A randomisation number will be assigned from a randomisation schedule 
generated by Clinical Statistics, prior to the start of the study, using validated 
internal software. Once assigned, this number must not be reassigned to any other 
participant in the study.
The randomisation is centrally controlled by the IRT.
Part A
Within Cohort 1, participants will be assigned to one of 5 dosing sequences in a 1:1:1:1:1
ratio. 
Within Cohort 2, participants will be assigned to one of up to 4 dosing sequences in a 
1:1:1:1 ratio. 
Participants will be randomised to:
Cohort 1
Cohort 2
Sequence
PBCDE
APCDE
ABPDE
ABCPE
ABCDP
PGHIJ
FPHIJ
FGPIJ
FGHPJ
Where the treatment codes are as follows:
Treatment code
Original Planned 
Treatment Description
Cohort 1 Actual 
Treatment & Cohort 2 
Planned Treatment 
Description
A
2 mg GSK2983559
B
10 mg GSK2983559
4 mg GSK2983559
C
30 mg GSK2983559
10 mg GSK2983559
D
75 mg GSK2983559
30 mg GSK2983559
E
150 mg GSK2983559
100 mg GSK2983599
F
300 mg GSK2983559
200 mg GSK2983599
G
600 mg GSK2983559
400 mg GSK2983559
H
800 mg GSK2983559
600 mg GSK2983559
I
Dose TBC GSK2983559
Dose TBC GSK2983559
J
GSK2983559 Fed
GSK2983559 Fed
P
Placebo


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Part B
Within each cohort participants will be assigned to either GSK2983559 or placebo in a 
4:1 ratio. The treatments will be determined following the completion of Part A, where 
the treatment codes will be:
Treatment code
Treatment Description
K
Dose 1 GSK2983559
L
Dose 2 GSK2983559
M
Dose 3 GSK2983559
N
Dose 4 GSK2983559
P
Placebo
7.4.
Blinding
This will be a double blind (sponsor open) study with respect to allocation of 
GSK2983559 or placebo to participants. The food effect part of the study will be open-
label. 
The following will apply:

The investigator or treating physician may unblind a participant’s treatment 
assignment only in the case of an emergency OR in the event of a serious 
medical condition when knowledge of the study treatment is essential for the 
appropriate clinical management or welfare of the participant as judged by the 
investigator.

Investigators have direct access to the participant’s individual study treatment.

It is preferred (but not required) that the investigator first contacts the Medical 
Monitor or appropriate GSK study personnel to discuss options before unblinding 
the participant’s treatment assignment.

If GSK personnel are not contacted before the unblinding, the investigator must 
notify GSK as soon as possible after unblinding, but without revealing the 
treatment assignment of the unblinded participant, unless that information is 
important for the safety of participants currently in the study.

The date and reason for the unblinding must be fully documented in the CRF.

A participant will be withdrawn if the participant’s treatment code is unblinded
by
the investigator
or
treating
physician.
The
primary
reason
for
discontinuation (the event or condition which led to the unblinding) will be 
recorded in the CRF.

GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind 
the treatment assignment for any participant with an SAE. If the SAE requires
that an expedited regulatory report be sent to one or more regulatory agencies, a
copy of the report, identifying the participant’s treatment assignment, may be sent
to investigators in accordance with local regulations and/or GSK policy.

Sponsor open refers only to the DEC members involved in the review of the
unblinded safety data on an as required basis and at the dose escalation meetings,


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where no-one outside of this committee will be unblinded to the study data.
Further details of how this will be managed are included in Appendix 3.
7.5.
Preparation/Handling/Storage/Accountability

The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment.

Only participants enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment. All study treatments 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access limited 
to the investigator and authorized site staff.

The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records).

Further guidance and information for the final disposition of unused study treatment 
are provided in the Study Reference Manual.

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 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.
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 
enrollment 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


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The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
Participants must abstain from taking prescription or nonprescription drugs (including 
vitamins and dietary or herbal supplements) within 7 days (or 14 days if the drug is a 
potential enzyme inducer) or 5 half-lives (whichever is longer) before the start of study 
treatment until completion of the follow-up visit, unless, in the opinion of the investigator 
and sponsor, the medication will not interfere with the study. 
Paracetamol, at doses of 2 grams/day, is permitted for use any time during the study. 
Other concomitant medication may be considered on a case-by-case basis by the 
Investigator in consultation with the Medical Monitor if required.
7.8.
Treatment after the End of the Study
Participants will not receive any additional treatment from GSK, or with GSK2983559, 
after the completion of the study because only healthy participants are eligible for study 
participation.
8.
DOSE ESCALATION CRITERIA
8.1.
PK criteria for GSK2668176
Due to the non-tolerated high dose of 420 mg/kg/day GSK2983559 in minipigs, the PK 
stopping criteria are based on AUC(0-24) and Cmax values at 1/3rd of the NOAEL of 120 
mg/kg/day GSK2983559 (GSK2668176 AUC(0-24) 50.9 µg*h/mL, Cmax 7.5 µg/mL).  
The decision to proceed to the next dose level of GSK2983559 in each part of this study 
will be made by the DEC, based on safety, tolerability, and preliminary PK data obtained 
(through at least 24 hours post dose) with at least 4 participants having received active 
treatment (GSK2983559) at the current dose level.  The actual doses to be administered 
may be adjusted based on safety, tolerability and preliminary PK data at previous dose 
levels; these dose adjustments may involve either an increase or a decrease in the planned 
dose, but will not exceed PK criteria.  Planned doses may also be repeated.
It is planned that the predicted human mean GSK2668176 AUC(0 24) or Cmax values will 
not exceed the mean GSK2668176 AUC(0-24) and Cmax values observed at one third of the 
NOAEL in minipig (16.94 µg*h/mL and 2.5 µg/mL, respectively).  In addition, the 
predicted human maximum AUC(0 24) or Cmax values will not exceed the maximum 
observed AUC(0 24) and Cmax values at one third NOAEL (21.6 µg*h/mL and 3.25 
µg/mL).
8.2.
PK criteria for 5-ABT and NAc-5-ABT
The drug product contains an impurity (5-ABT) known to be mutagenic (with unknown 
carcinogenic potential) that is controlled in drug production to assure its level is below a 
Threshold of Toxicological Concern (TTC) per the ICH M7 guideline.  However, 
because of a possibility for 5-ABT to be formed in the body, monitoring for 5-ABT (and 
its metabolite, NAc-5-ABT) in blood plasma will be undertaken with application of the 


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same TTC (120 µg), which translates to a plasma concentration of 3 ng/mL under the 
assumption that the mutagenic impurity distributes into a volume equal to total body 
water of 42L. Based on this information, if in any individual the Cmax of combined 
concentration of 5-ABT and NAc-5-ABT (in ng/mL equivalents 5-ABT/mL) is > 3 
ng/mL, it will suggest the TTC level of 120 µg has been reached and further dose-
escalation will be stopped. During dose escalation, progression to the next dose level will 
be guided by the criteria where the maximum predicted 5-ABT amount for the next dose 
will not exceed the TTC of 120 µg.
8.3.
Safety criteria
The Principal Investigator and the GSK Medical Monitor will review the following and 
study dosing will be stopped if any of these criteria is met:

One (1) or more participants experience a serious adverse event (SAE) which has a 
reasonable possibility of relation to study drug.

Two (2) or more participants experience a severe or clinically significant non-serious 
adverse event (based upon investigator judgment) which has a reasonable possibility 
of relation to study drug.

Two (2) or more participants in a Part A cohort or 3 or more participants in a Part B 
cohort experience the same adverse event of moderate severity which has a 
reasonable possibility of relation to study drug.

Consistent Common Terminology Criteria for Adverse Events (CTCAE) Nervous 
System adverse events of any grade occur across participants that have a reasonable 
possibility of relation to study drug.
If dosing is halted and if deemed acceptable by GSK internal safety review to proceed 
with or modify dose escalation to further characterize the safety profile, a formal request 
with appropriate data and substantial amendment will be submitted to Medicines and 
Healthcare Products Regulatory Agency (MHRA) for approval.
9.
DISCONTINUATION CRITERIA
9.1.
Individual Safety Stopping Criteria

If a participant experiences a serious or severe clinically significant AE that in the 
clinical judgement of the Investigator, after consultation with the Medical 
Monitor, is possibly, probably or definitely related to investigational product.

The participant initiates treatment with any prohibited medications.

The participant develops a serious opportunistic or atypical infection.

If any of the liver chemistry stopping criteria or QTc stopping criteria are met.

The participant experiences any signs of suicidal ideation or behaviour.


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9.2.
Neurological/psychiatric Stopping Criteria
The CNS observations in the first good laboratory practice (GLP) acute neurobehavioural 
study in rats were found to be present at all single doses.  The same findings were not 
observed in a second study with overlapping doses.  The CTCAE Nervous System is a 
monitoring tool which provides the Principal Investigator the appropriate guidance for 
grading of a neurological event.  The significance of any neurological event experienced 
by a participant will be determined based on clinical judgment, characteristics of the 
event and/or based upon changes from a baseline assessment.
The Principal Investigator and the GSK Medical Monitor will review all neurological
events utilizing the CTCAE Nervous System criteria
A participant will be withdrawn from the study if any of these criteria is met:

A Grade 3 or greater CTCAE Nervous System finding (see SRM) is observed or a 
significant neurologic change from a participant’s baseline physical examination is 
observed.

Any adverse event included in the CTCAE for Nervous System, which is also 
considered to be clinically significant by the Principal Investigator, will be reviewed 
for potential participant withdrawal.
9.3.
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 food 
and drug administration [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 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:


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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
Section 13.6
9.3.1.
Study Treatment Restart or Rechallenge
During part B, study treatment restart or rechallenge after liver chemistry stopping 
criteria are met by any participant in this study is not allowed.
9.4.
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.  


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
QTc > 500 msec,

Change from baseline: QTc >60 msec increase
See the SoA for data to be collected at the time of treatment discontinuation and follow-
up and for any further evaluations that need to be completed.
9.5.
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 SoA for data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed.
9.6.
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. 
10.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA. 

Protocol waivers or exemptions are not allowed 


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
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 SoA.

The maximum amount of blood collected from each participant over the duration of 
the study, including any extra assessments that may be required, will not exceed 500
mL.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.
10.1.
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 Section 9). 
10.1.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the start of treatment until the follow-up visit at 
the time points specified in the SoA (Section 2).  However, any SAEs assessed 
as related to study participation (e.g., study treatment, protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
product will be recorded from the time a subject consents to participate in the 
study.

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.

All SAEs will be recorded and reported to the sponsor or designee within 24 
hours after becoming aware of the event, as indicated in Appendix 4. The 


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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.
10.1.2.
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. 
10.1.3.
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 9.6). Further information on follow-up procedures is given in 
Appendix 4.
10.1.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are 
met. 

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study treatment 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or 
other specific safety information (e.g., summary or listing of SAE) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the institutional
review board/independent ethics committee 
(IRB/IEC), if appropriate according to local requirements.


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10.1.5.
Pregnancy

Details of all pregnancies in female partners of male participants will be collected 
after the start of study treatment and until 30 days after the last dose.

If a pregnancy is reported, the investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Section 13.5.

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
10.2.
Treatment of Overdose
GSK does not recommend specific treatment for an overdose.  The investigator will use 
clinical judgement to treat an overdose as and when they are made aware of this.
In the event of an overdose, the investigator should:
1.
Contact the Medical Monitor immediately.
2.
Closely monitor the participant for AE/SAE and laboratory abnormalities until 
GSK2983559 can no longer be detected systemically (at least 48hours).
3.
Obtain a plasma sample for PK analysis if requested by the Medical Monitor 
(determined on a case-by-case basis).
4.
Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.
10.3.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
10.3.1.
Physical Examinations

A full physical examination will include, at a minimum, assessments of the 
Skin, Cardiovascular, Respiratory, and Gastrointestinal systems. Height and 
weight will also be measured and recorded.

A brief physical examination will include, at a minimum, assessments of the 
skin, lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
10.3.2.
Neurological Exams
Neurological examination will include, at a minimum, assessment of: mental status, gait, 
balance, coordination, cranial nerves, motor power, reflexes, and sensory system (light 


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touch and pain). Assessments will be standardized across all scheduled time points (see 
SoA).  Significant changes from the baseline or any clinically significant changes will be 
noted as part of further scheduled examinations or unscheduled examinations (if needed).  
Clinically significant abnormalities or changes in status from baseline will be:

entered as an adverse event,

may trigger increased monitoring of the subject(s),

may result in withdrawal of the subject (see Section 9.2),

may result in referral to a specialist.
10.3.3.
Vital Signs

Vital signs will be measured in a semi-supine position after 5 minutes rest in a 
quiet setting without distractions (e.g., television, cell phones) and will include 
temperature, systolic and diastolic blood pressure, and pulse and respiratory rate.

In Part A and Part B on Day 1 vital signs (to be taken before blood collection for 
laboratory tests) will consist of triplicate pulse and blood pressure measurements
only (3 consecutive blood pressure readings will be recorded at intervals of at 
least 1 minute). All 3 readings will be recorded on the CRF.
10.3.4.
Electrocardiograms

Triplicate OR Single 12-lead ECG will be obtained as outlined in the SoA using 
an ECG machine that automatically calculates the heart rate and measures PR, 
QRS, QT, and QTc intervals. Refer to Section 9.4 for QTc withdrawal criteria 
and additional QTc readings that may be necessary.

At each time point at which triplicate ECG are required, 3 individual ECG 
tracings should be obtained as closely as possible in succession, but no more
than 2 minutes apart. The full set of triplicates should be completed in less than 
4 minutes.

Continuous cardiac telemetry will be performed at time points indicated in the 
SoA (Section 2).  Full disclosures will be reviewed in detail and the review 
maintained as part of the subject’s source documents.

Holter monitoring will be performed at screening only.  This 24-hour Holter will 
be performed to eliminate participants with non-clinically overt cardiac 
arrhythmias.
10.3.5.
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 


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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 should be repeated until the values return to 
normal or baseline or are no longer considered significantly abnormal by the 
investigator or medical monitor. 

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
10.4.
Pharmacokinetics
10.4.1.
Blood Sample Collection
Blood will be collected into ethylenediaminetetraacetic acid (EDTA) tubes and processed 
to plasma for PK analysis of GSK2983559, GSK2668176, 5ABT and NAc-5ABT at the 
time points indicated in Section 2, SoA Tables. The actual date and time (24-hour clock 
time) of each blood sample collection will be recorded. The timing of PK samples may be 
altered and/or PK samples may be obtained at additional time points to ensure thorough 
PK monitoring.  
In Part B on Day 1 and Day 14, at each sampling time point an additional blood sample 
will be collected for metabolite profiling. 
Details of blood sample collection, processing, storage and shipping procedures are 
provided in the SRM. 
10.4.2.
Plasma Sample Analysis
Plasma analysis will be performed at a bioanalytical site (to be detailed in the SRM) 
under the control of Platform Technology and Science In Vitro/In Vivo Translation (PTS 
IVIVT) and Third Party Resource, GlaxoSmithKline. Concentrations of GSK2983559, 
GSK2668176, 5ABT and NAc-5ABT in plasma samples will be determined using the 
currently approved bioanalytical methodology. Raw data will be archived at the 
bioanalytical site (detailed in the SRM). 
Once the plasma sample has been analysed for GSK2983559, GSK2668176, 5ABT and 
NAc-5ABT, any remaining plasma sample may be analysed for other compound-related 
material and the results may be reported under a separate PTS-Global Spectroscopy, 
GlaxoSmithKline protocol.
Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.


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10.4.3.
Urine sample collection and analysis
Urine samples for analysis of GSK2983559 and GSK2669176 as well as any metabolites 
will be collected at the time points listed in Section 2, SoA Table.
Prior to dosing on Day 1, each subject will be instructed to void their bladder and no 
more than 40 mL of this urine sample will be retained as a control. Urine collection time 
points listed in the SoA table will begin immediately following dose administration (0 to 
24 hours). The time will be recorded for each urine sample collected as well as the 24-
hour volume of urine for each subject. In Part A only, urine obtained at the highest dose 
reached will be shipped to GSK. Results will be reported under a separate PTS-Global 
Spectroscopy, GlaxoSmithKline protocol. Processing, storage and shipping procedures 
are provided in the Study Reference Manual (SRM).
10.5.
Exploratory Pharmacodynamics and Target Engagement
Blood samples will also be collected at the time points indicated in Section 2 SOA. The 
actual date and time of these collections will be recorded. All procedures will be 
performed at the site.
10.6.
Pharmacodynamic Samples
For this assay 1 mL of blood will be drawn into TruCulture tubes containing a 
standardized amount of the NOD2 agonist, MDP.  Following a 6 hr incubation at 37°C, 
plasma cytokines (macrophage inflammatory protein 1 alpha [MIP1α], MIP1β, and TNF) 
will be quantified using the MesoScale Discovery platform. Two pre-dose baseline 
samples will be drawn to measure the maximum intrasubject inhibition via treatment with 
a tool compound with a similar chemical structure to GSK2983559. Details of the 
collection, processing, and storage of these PD samples are provided in the SRM.
10.7.
Target Engagement (TE) Samples
Two sets of samples will be used to evaluate target engagement. (1) For ex-vivo
evaluation of TE, blood will be drawn into 2 mL sodium heparin or K2 EDTA tubes. (2) 
For post-challenge evaluation of TE, an aliquot of the residual cells will be collected 
from the Truculture PD samples (described above). Cellular lysates will be prepared form 
both sets of samples and TE will be assessed using a novel competitive binding assay. 
Details of the collection, processing and storage of these TE samples are provided in the 
SRM.
11.
STATISTICAL CONSIDERATIONS
The objectives of this study are to assess the safety and tolerability of single and repeat 
ascending doses of GSK2983559 in healthy volunteers. No formal hypotheses will be 
tested.


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11.1.
Sample Size Determination
A minimum number of 18 participants (10 in cohort 1 and 8 in cohort 2) will be recruited 
into Part A, and up to 40 participants (10 in each of 4 cohorts) will be recruited into Part 
B. An additional cohort may be added to Part A of the study to allow for evaluation of 
additional dose levels or repeat an existing dose level. 
The sample size is based on feasibility considerations and no statistical techniques were 
used to calculate it. 
Safety is the primary objective of Parts A and B, where numbers of safety events are of 
interest. 
A maximum of 9 participants will receive each of the active doses in Part A or B. If 0 out 
of 9 participants with a particular safety event is observed, there is 95% certainty that the 
probability of observing a participant on active with a particular safety event will lie 
between 0.04 and 0.39.
There is no sample size re-estimation planned. 


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11.2.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Screened 

All participants who were screened for eligibility
Randomized 

All participants who were randomly assigned to treatment in the study.

This population will be based on the treatment the participant was 
randomized to.
Safety

All randomized participants who received at least one dose of study 
treatment.

This population will be based on the treatment the participant actually 
received.
Note: Participants who were not randomized but received at least one dose of 
study treatment should be listed.
PK

All participants in the Safety population who had at least 1 non-missing PK 
assessment (Non-quantifiable [NQ] values will be considered as non-
missing values).

This population will be based on the treatment the participant actually 
received.
11.3.
Statistical Analyses
11.3.1.
Safety Analyses
All safety analyses will be performed on the Safety Population. 
Endpoint
Statistical Analysis Methods
Primary
Will be presented in tabular and/or graphical format and summarised descriptively 
according to GSK's Integrated Data Standards Library standards.
11.3.2.
PK Analyses
All pharmacokinetic analyses will be performed on the Pharmacokinetic Population. 
For the secondary pharmacokinetic (PK) endpoints in this study, no formal hypotheses 
will be tested.


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Endpoint
Statistical Analysis Methods
Secondary
Plasma GSK2983559 and GSK2668176, concentration-time data will be 
analysed by non-compartmental methods. Calculations will be based on the 
actual sampling times recorded during the study.
From the plasma concentration-time data, the following pharmacokinetic 
parameters will be determined, as data permit: maximum observed plasma 
concentration (Cmax), time to Cmax (tmax), area under the plasma concentration-
time curve [AUC(0-24), AUC(0-t) and AUC(0-∞)], and apparent terminal phase half-life 
(t1/2). 
Part A (single dose): Dose proportionality will be assessed by visual inspection 
of dose normalised AUC(0 ∞) [or if not available AUC(0-t)] and Cmax values 
versus dose. Analysis of these loge-transformed parameters may be carried out, 
using the power model.
Part A (food effect): The ratio of fed state to fasted state may be assessed for 
the loge-transformed parameters AUC(0-∞) [or if not available AUC(0-t)] and Cmax.
The effect of food will be assessed utilising a mixed effects model, with fed state 
(fasted or fed) as a fixed effect and participant as a random effect.
Part B: The extent of accumulation after repeat dosing, the observed 
accumulation ratio (Ro), may be determined. The plasma steady state ratio (Rs) 
and an assessment of plasma steady state across the trough concentrations may
also be made. Dose proportionality may be assessed using similar methods to 
the single dose Part A. 
For combined 5-ABT and NAc-5-ABT (corrected to 5-ABT), observed Cmax and 
Tmax will be determined using non-compartmental methods and will be 
summarised descriptively.
Further details will be included in the RAP.
11.3.3.
Other Analyses
Pharmacodynamic, and biomarker exploratory analyses will be described in the reporting 
and analysis plan. The population PK analysis and pharmacodynamic analyses will be 
presented separately from the main clinical study report (CSR).
11.3.4.
Interim Analyses
Dose escalation meetings will occur after each period in Part A and after the completion 
of 14 days dosing of each cohort in Part B. The decision to proceed to the next cohort and 
next dose strength to be studied, will be made by DEC based on assessment of safety
(e.g., AEs, clinical laboratory results, vital signs and ECG) and plasma GSK2983559 
pharmacokinetic and 5-ABT concentrations obtained in all participants at the prior dose 
level. Individual safety data (adverse events, laboratory safety tests, ECGs and vital 


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signs) will be reviewed. This study is double blind (sponsor open), where the participant, 
investigator and site staff will remain blinded to the treatment allocation. Sponsor open 
refers only to those members of the DEC.
Following completion of Cohort 1 (Part A) and before starting Cohort 2 (Part A), a GSK 
internal safety board (independent of DEC) will be reviewing the data.
A formal interim analysis may be performed during the study on completed cohorts in 
Part A of the study to aid internal decision making only. Only the DEC members will be 
unblinded. There will be no changes to the study design or planned number of 
participants in future cohorts as a result of this interim analysis. This analysis may 
include review of individual participant data, summaries, graphical presentations and/or 
statistical analysis.
The Reporting and Analysis Plan will describe the planned interim analysis in greater 
detail.


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12.
REFERENCES
GlaxoSmithKline Document Number 2016N308990_00.  Investigator Brochure for 
GSK2983559.  Report Date 22-AUG-2017
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.
Levey AS and Stevens LA. Estimating GFR Using the CKD Epidemiology Collaboration 
(CKD-EPI) Creatinine Equation: More Accurate GFR Estimates, Lower CKD Prevalence 
Estimates and Better Risk Predictions. Am J Kidney Dis. 2010; 55:622-627.
Snyder JJ, Foley RN, and Collins AJ. Prevalence of CKD in the United States: A 
Sensitivity Analysis Using the National Health and Nutrition Examination Survey 
(NHANES) 1999-2004. Am J Kidney Dis. 2009; 53(2):218-228.


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13.
APPENDICES
13.1.
Appendix 1: Abbreviations and Trademarks
5-ABT
5-amino-benzothiazole
Abs. 
Absorbance
ACN
Acetonitrile
AE
Adverse Event
ALT
Alanine Aminotransferase 
API
Active Pharmaceutical Ingredient
AST
Aspartate Aminotransferase
AUC
Area Under the Concentration-time curve
AUC(0-24)
Area Under the Concentration-time curve from time zero to 24 
hours post first dose
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
AUC(0-τ)
AUC from 0 hours to the time of next dosing.
AUC(0-)
Area Under the Concentration-time curve from time zero to 
infinity
BID
Twice a Day
BMI
Body Mass Index
BP
Blood Pressure
BUN 
Blood Urea Nitrogen
CARD
C-terminal Caspase-activation-and-recruitment
CD
Crohn’s Disease
CFR
Code of Federal Regulations
CHMP
Committee for Medicinal Products for Human Use
CIOMS
Council for International Organizations of Medical Sciences
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CL/F
Apparent total clearance of the drug from plasma after oral 
administration
Cmax
Maximum Observed Concentration
CMC
Chemistry, Manufacturing and Controls 
Cmin
Minimum Observed Concentration 
CNS
Central Nervous System
CONSORT
Consolidated Standards of Reporting Trials
CPK
Creatine Phosphokinase
CPMP
Committee for Proprietary Medicinal Products 
CRF
Case Report Form
CRP
C-Reactive Protein


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CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
Trough concentration measured at the end of a dosing interval at 
steady state
DEC
Dose Escalation Committee
DLs
Dose Levels
DNA
Deoxyribonucleic Acid
ECG
Electrocardiogram
eCRF
Electronic Case Report Form 
EDTA
Ethylenediaminetetraacetic Acid 
EMA
European Medicines Agency
EMEA
Europe, the Middle East and Africa
FaSSIF
Fasted State Simulated Intestinal Fluid
FDA
Food and Drug Administration
FeSSIF
Fed State Simulated Intestinal Fluid
FSH
Follicle Stimulating Hormone
FTiH
First Time in Human
g
Gram 
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance 
GFR
Glomerular Filtration Rate
GI
Gastrointestinal Tract
GLDH
Glutamate Dehydrogenase 
GLP
Good Laboratory Practice
GSK
GlaxoSmithKline
Haem.
Haematology
HBcAb
Hepatitis B Core Antibody
HBsAg
Hepatitis B Surface Antigen
hCG
Human Chorionic Gonadotropin
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human Immunodeficiency Virus
HPLC
High Performance Liquid Chromatography
HPMC
Hydroxypropylmethyl Cellulose
HPMCAS
Hydroxypropylmethyl Cellulose Acetate Succinate
HR
Heart Rate
Hr/hrs/h
Hours
HRT
Hormonal replacement therapy
HWB
Human Whole Blood
IB
Investigator’s Brochure
IC
Inhibitory Concentration


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ICF
Informed Consent Form
ICH
The International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IL-
Interleukin
IMPD
Investigational Medicinal Product Dossier 
INR
International Normalized Ratio
IP
Investigational Product
IRB/IEC
The Institutional Review Board/ Independent Ethics Committee
IRT
Interactive Response Technology
IUD
Intrauterine Device
IUS 
Intrauterine Hormone-releasing System
Ka
Absorption Rate Constant
kcal
Kilocalorie 
kg 
Kilogram
L
Litre
LDH
Lactate Dehydrogenase
LLOQ
Lower Limit of Quantification
LRR
Leucine-rich Repeat
m²
Metre Squared
MABEL
Minimal Anticipated Biological Effect Level
MAPK
Mitogen-activated Protein Kinase 
MDP
Muramyl Dipeptide
mg
Milligram
MHRA
Medicines and Healthcare Products Regulatory Agency
Min/mins
Minute 
MIP1α
Macrophage Inflammatory Protein 1 Alpha
MIP1β
Macrophage Inflammatory Protein 1 Beta
mL
Millilitre
MSDS
Material Safety Data Sheet
msec.
Millisecond
NAc-5-ABT
n-acetyl-5-amino benzothiazole
NCBP
Non-Child Bearing Potential
ng
Nanogram
nm
Nanometre 
NOAEL
No Observable Adverse Effect Limit
NOD1
Nucleotide-binding Oligomerization Domain 1
NOD2
Nucleotide-binding Oligomerization Domain 2
NOEL
No Observable Effect Limit


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NQ
Non-quantifiable
PBPK
Physiologically Based Pharmacokinetic Modelling
PD
Pharmacodynamic 
PK
Pharmacokinetics
ppm
Parts Per Million
PR
Pulse Rate
PRRs
Pattern Recognition Receptors
QD
Once Daily 
QTc
Electrocardiogram QT interval corrected for heart rate
QTcB
Electrocardiogram QT interval corrected for heart rate using 
Bazett’s formula
QTcF
Electrocardiogram QT interval corrected for heart rate using 
Fridericia’s formula
RAP
Reporting and Analysis Plan
RBC
Red Blood Cell
RIP2
Receptor Interacting Protein 2
RIPK2
Receptor-interacting Serine/Threonine Protein Kinase 2
RNA
Ribonucleic Acid
Ro
Accumulation Ratio
Rs
Steady State Ratio
SAE
Serious Adverse Event
SGOT
Serum Glutamic-Oxaloacetic Transaminase
SoA
Schedule of Activities
SPF
Sun Protection Factor
SRM
Study Reference Manual
SUSAR
Suspected Unexpected Serious Adverse Events
T1/2
Half Life
TB
Tuberculosis
TE
Target Engagement 
TK
Toxicokinetic
Tmax
Time taken to maximum observed plasma drug concentration
TNF
Tumour Necrosis Factor
TNFα
Tumour Necrosis Factor Alpha
TTC
Threshold of Toxicological Concern 
UC
Ulcerative Colitis
μg
Microgram
μg.h
Microgam per hour
UK
United Kingdom
ULN
Upper Limit of Normal
UVA/UVB
Ultraviolet A/Ultraviolet B


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UV/VIS
Ultraviolet/Visible light 
WOCBP
Woman of Child Bearing Potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks 
not 
owned 
by 
the 
GlaxoSmithKline group of companies
NONE
GastroPlus
MesoScale
TruCulture


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13.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 8 will be performed by the local laboratory. 

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5.5.5 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 8
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
Red Clood Cell (RBC)
Count
Hemoglobin
Hematocrit
Clinical 
Chemistry1
Blood Urea 
Nitrogen (BUN)
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT)
Total Protein
Albumin
Gamma-Glutamyl 
transferase 
(GGT)
Glucose (fasted)2
Calcium
Alkaline 
phosphatase
C-reactive protein 
(CRP)
Total 
cholesterol2,3
Low-density 
lipoprotein 
(LDL)2,3
Triglycerides2,3
Coagulation 
Panel
Prothrombin Time (PT)
International normalized 
ratio (INR)
Partial thromboplastin 
time (PTT)


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Laboratory 
Assessments
Parameters
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood and ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only)

Alcohol breath test and urine drug screen (to include at minimum: 
amphetamines, 
barbiturates, 
cocaine, 
opiates, 
cannabinoids 
and 
benzodiazepines)

Urine Cotinine test

Serum human chorionic gonadotropin (hCG) pregnancy test for all women

Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis 
C virus antibody) 

Tuberculosis test

Estimated glomerular filtration rate (eGFR) will be calculated using the CKD-
EPI formula.
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 Section 13.6 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.
Fasted with exception of Day -1 which can be non-fasted samples. 
3.
Lipid panel to be performed in Part B only.
Laboratory results that could unblind the study will not be reported to investigative sites 
or other blinded personnel until the study has been unblinded.


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13.3.
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 (e.g., 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 code of federal regulations (CFR), ICH guidelines, the 
IRB/IEC, European regulation 536/2014 for clinical studies (if applicable), 
and all other applicable local regulations
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study. 


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
Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study 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.
Committees Structure
Dose Escalation Committee
The Dose Escalation Committee (DEC) will make the decision to proceed to the next 
dose level of GSK2983559 at the end of each single dose and repeat dose cohort; along 
with making the decision to move into Part B of the study.
The decision will be based on:
All available safety and tolerability data from a minimum of 4 participants who 
have received a dose of GSK2983559 at the current dose level and have been 
followed for at least 48 hours post dose.
All available safety and tolerability data accumulated from preceding dose 
levels.


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All available PK data (including levels of 5-ABT and NAc-5-ABT) from the 
current dose level for at least 4 participants who have been followed for at least 
24 hours, and from preceding doses levels. 
PK and safety stopping criteria will be strictly applied. Details of these criteria in Section 
8.
There will be an open and closed part to the dose escalation meeting. At the beginning of 
the meeting blinded data will be discussed in an open forum with the investigator in 
attendance. If required, the data will then be reviewed in an unblinded fashion by the 
unblinded members of the DEC. Members and requirements are provided in a separate 
Dose Escalation Charter.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
Dissemination of Clinical Study Data
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 


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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.

Data reported on the CRF or entered in the electronic case report form (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.

A study specific source documentation list will be finalised by the sponsor 
before the start of the clinical phase of the study. The document will identify 
what data should be considered source data for this study.
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study treatment development


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13.4.
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 (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., 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.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 


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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 (e.g., 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 
reporting is appropriate in other situations such as important medical events that may 


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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 (e.g., 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.


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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.


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Reporting of SAE to GSK
SAE Reporting to GSK via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the medical monitor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in Study Reference Manual.


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13.5.
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
3.
Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment.
Contraception Guidance
Male participants

Male participants with female partners of child-bearing potential are eligible to 
participate if they agree to ONE of the following during the protocol-defined 
time frame in Section 6.1: 

Are abstinent from penile-vaginal intercourse as their usual and preferred 
lifestyle (abstinent on a long term and persistent basis) and agree to remain 
abstinent 

Agree to use a male condom plus an additional method of contraception 
with a failure rate of <1% per year as described in Table 9 when having 
penile-vaginal intercourse with a woman of childbearing potential 

Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of 
penile penetration during the protocol-defined time frame.


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
Refrain from donating sperm for duration of study and for 90 days after study 
completion or from last dose.
Table 9
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulationb

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.)
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from
heterosexual intercourse during the entire period of risk associated with the study drug. The
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the participant.)
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 90 after the last dose of study treatment 


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Collection of Pregnancy Information
Male participants with partners who become pregnant

Investigator will attempt to collect pregnancy information on any male participant’s 
female partner of a male study participant who becomes pregnant while participating 
in this study. This applies only to participants who receive study treatment.

After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the partner’s 
pregnancy. 

Partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure. 


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13.6.
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

Immediately discontinue study treatment

Report the event to GSK within 24 hours

Complete the liver event CRF, and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver 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 

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 within 24 hours of 
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 


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Liver Chemistry Stopping Criteria 
liver event follow up assessments within 24-
72 hrs

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, immunoglobulin M (IgM) antibody; Hepatitis B surface antigen and Hepatitis B Core 
Antibody; Hepatitis C ribonucleic acid (RNA); Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM 
antibody (or if unavailable, obtain heterophile antibody or monospot testing); Hepatitis E IgM antibody 
4.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
PK blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM. 


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13.7.
Appendix 7: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
205021
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for GSK2983559 First time in 
human study 205021: A single-centre, randomised, double-
blind (sponsor open), placebo controlled study to evaluate the 
safety, tolerability, pharmacokinetics, and 
pharmacodynamics of GSK2983559, in single (in both fed 
and fasted states) and repeat oral doses in healthy participants
Compound Number 
:
GSK2983559
Effective Date 
:
25-NOV-2019
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 2017N322016_02. 

This RAP is intended to describe the safety, tolerability, pharmacokinetics, and 
pharmacodynamics of GSK2983559, in single (in both fed and fasted states) and 
repeat oral doses in healthy participants. 

This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverables.
RAP Author(s):
Approver
Date
Approval Method
14-Oct-2019
Author/Email
Statistics Leader (II Biostatistics)
17-Oct-2019
Email
Programming Manager (II Clinical 
Programming)
Copyright 2019 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD


CONFIDENTIAL
The GlaxoSmithKline group of companies
205021
2
RAP Team Approvals:
Approver
Date
Approval Method
14-Oct-2019
Email
Scientist Director (II Discovery Medicine)
17-Oct-2019
Email
Director (II Clinical Pharmacology Modelling & 
Simulation)
15-Oct-2019
Email
Global Clinical Development Manager (II Global 
Clinical Sciences and Delivery)
Clinical Statistics and Clinical Programming Line Approvals:
Approver
Date
Approval Method
25-Nov-2019
eSignature CARS
Senior Statistics Director (II Clinical Statistics)
22-Nov-2019
eSignature CARS
Programming Manager (II Clinical Programming)
PPD
PPD
PPD
PPD
PPD


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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 ................................................................................................8
2.4.
Statistical Hypotheses / Statistical Analyses ...............................................10
3.
PLANNED ANALYSES ..........................................................................................11
3.1.
Interim Analyses .........................................................................................11
3.2.
Final Analyses ............................................................................................11
4.
ANALYSIS POPULATIONS ...................................................................................12
4.1.
Protocol Deviations.....................................................................................12
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................13
5.1.
Study Treatment & Sub-group Display Descriptors.....................................13
5.2.
Baseline Definitions ....................................................................................13
5.3.
Multicentre Studies .....................................................................................14
5.4.
Examination of Covariates, Other Strata and Subgroups............................14
5.5.
Multiple Comparisons and Multiplicity .........................................................14
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................15
6.
STUDY POPULATION ANALYSES .......................................................................16
6.1.
Overview of Planned Study Population Analyses........................................16
7.
SAFETY ANALYSES .............................................................................................17
7.1.
Adverse Events Analyses ...........................................................................17
7.2.
Clinical Laboratory Analyses.......................................................................17
7.3.
Other Safety Analyses ................................................................................17
8.
PHARMACOKINETIC ANALYSES.........................................................................18
8.1.
Primary Pharmacokinetic Analyses.............................................................18
8.1.1.
Endpoint / Variables.....................................................................18
8.1.1.1.
Drug Concentration Measures....................................18
8.1.1.2.
Derived Pharmacokinetic Parameters.........................18
8.1.2.
Summary Measures.....................................................................19
8.1.3.
Population of Interest...................................................................19
8.1.4.
Strategy for Intercurrent (Post-Randomisation) Events ................19
8.2.
Secondary Pharmacokinetic Analyses........................................................20
8.2.1.
Endpoint / Variables.....................................................................20
8.2.1.1.
Drug Concentration Measures....................................20
8.2.2.
Summary Measure ......................................................................20
8.2.3.
Population of Interest...................................................................20
9.
PHARMACODYNAMIC ANALYSES.......................................................................21


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4
9.1.
Exploratory Pharmacodynamic Analyses....................................................21
9.1.1.
Endpoint / Variables.....................................................................21
9.1.2.
Summary Measure ......................................................................21
9.1.3.
Population of Interest...................................................................21
10. REFERENCES.......................................................................................................22
11. APPENDICES........................................................................................................23
11.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................23
11.2.
Appendix 2: Schedule of Activities ..............................................................24
11.2.1.
Protocol Defined Schedule of Events...........................................24
11.3.
Appendix 3: Assessment Windows .............................................................26
11.3.1.
Definitions of Assessment Windows for Analyses........................26
11.4.
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................27
11.4.1.
Study Phases ..............................................................................27
11.4.1.1.
Study Phases for Concomitant Medication .................27
11.4.2.
Treatment Emergent Flag for Adverse Events .............................28
11.5.
Appendix 5: Data Display Standards & Handling Conventions....................29
11.5.1.
Reporting Process .......................................................................29
11.5.2.
Reporting Standards....................................................................29
11.5.3.
Reporting Standards for Pharmacokinetic....................................30
11.6.
Appendix 6: Derived and Transformed Data ...............................................31
11.6.1.
General........................................................................................31
11.6.2.
Study Population..........................................................................31
11.6.3.
Safety ..........................................................................................31
11.7.
Appendix 7: Reporting Standards for Missing Data.....................................33
11.7.1.
Premature Withdrawals................................................................33
11.7.2.
Handling of Missing Data.............................................................33
11.7.2.1.
Handling of Missing and Partial Dates ........................33
11.8.
Appendix 8: Values of Potential Clinical Importance ...................................35
11.8.1.
Laboratory Values........................................................................35
11.8.2.
ECG.............................................................................................36
11.8.3.
Vital Signs....................................................................................36
11.9.
Appendix 9: Abbreviations & Trade Marks ..................................................37
11.9.1.
Abbreviations...............................................................................37
11.9.2.
Trademarks .................................................................................38
11.10. Appendix 10: List of Data Displays..............................................................39
11.10.1. Data Display Numbering..............................................................39
11.10.2. Mock Example Shell Referencing ................................................39
11.10.3. Deliverables.................................................................................39
11.10.4. Study Population Tables..............................................................40
11.10.5. Safety Tables...............................................................................43
11.10.6. Safety Figures .............................................................................46
11.10.7. Pharmacokinetic Tables...............................................................48
11.10.8. Pharmacokinetic Figures .............................................................50
11.10.9. PharmacodynamicTables ............................................................51
11.10.10.Pharmacodynamic Figures ..........................................................51
11.10.11.ICH Listings .................................................................................52
11.10.12.Non-ICH Listings..........................................................................55


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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 205021:
Revision Chronology:
2017N322016_00
06-OCT-2017
Original
2017N322016_01
17-OCT-2017
Original Protocol Republishing
2017N322016_02
24-JUL-2018
Formulation change to enteric capsule
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
This study was terminated during Cohort 2 of Part A. Participants in Cohort 2 received 
only 2 of 4 planned single doses.
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

Part A (single dose): Dose 
proportionality will be 
assessed by visual 
inspection of dose 
normalised AUC(0 ∞) [or if 
not available AUC(0-t)] and 
Cmax values versus dose. 
Analysis of these loge-
transformed parameters 
may be carried out, using 
the power model.

Summary of dose 
normalised PK parameters 
will be replaced by 
summary of PK parameters

No analyses of log-
transformed data will be 
conducted

Study terminated prior to 
full dose escalation 
completion

Part A (food effect): The 
ratio of fed state to fasted 
state may be assessed for 
the loge-transformed 
parameters AUC(0-∞) [or if 
not available AUC(0-t)] and 
Cmax. The effect of food 
will be assessed utilising a 
mixed effects model, with 
fed state (fasted or fed) as a 
fixed effect and participant 
as a random effect

No food effect summaries 
or statistical analyses

Study terminated prior to 
fed dosing period

Part B: The extent of 
accumulation after repeat 

No Part B summaries or 
statistical analyses

Study terminated prior to 
Part B multiple ascending 


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Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes
dosing, the observed 
accumulation ratio (Ro), 
may be determined. The 
plasma steady state ratio 
(Rs) and an assessment of 
plasma steady state across 
the trough concentrations 
may also be made. Dose 
proportionality may be 
assessed using similar 
methods to the single dose 
Part A.
dose cohorts

For combined 5-ABT and 
NAc-5-ABT (corrected to 5-
ABT), observed Cmax and 
Tmax will be determined 
using non-compartmental 
methods and will be
summarised descriptively

5-ABT and NAc-5-ABT 
(corrected to 5-ABT)
concentrations will be listed. 
No PK parameters will be 
produced

Limited number of subjects 
with quantifiable 5-ABT and 
NAc-5-ABT PK 
concentrations to warrant 
summaries or PK 
parameter derivations

To investigate the 
metabolic profile of 
GSK2983559 following 
single and/or repeat 
doses in healthy 
participants in urine

No urine data will be 
reported

Data is no longer planned 
due to study termination 
prior to urine samples being 
analysed
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To assess the safety and 
tolerability of single (fed and 
fasted) and repeat doses of 
GSK2983559 in healthy 
participants.

Safety and tolerability of GSK2983559 as 
assessed by clinical monitoring and reporting of 
adverse events and serious adverse events, 
change in laboratory values, ECG, vital signs, 
physical examinations.
Secondary Objectives
Secondary Endpoints

To characterise the PK profile 
of single (fasted) doses of 
GSK2983559 and its active 
moiety GSK2668176 in healthy 
participants.

Derived PK parameters for GSK2983559 and
GSK2668176 including area under the plasma 
drug concentration versus time curve (AUC(0-t), 
AUC(0-∞)), maximum observed plasma drug 
concentration (Cmax), time to maximum observed 
plasma drug concentration (tmax), and terminal 
half-life (t1/2) following single (fasted) doses, 
where data allow.

To characterise the PK profile 
of repeat doses of 
GSK2983559 and its active 

Derived PK parameters for GSK2983559 and 
GSK2668176 including area under the plasma 
drug concentration versus time curve (AUC(0-t), 


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Objectives
Endpoints
moiety GSK2668176 in healthy 
participants.
AUC(0-τ)), maximum observed plasma drug 
concentration (Cmax), time to maximum observed 
plasma drug concentration (tmax), and terminal 
half-life (t1/2) following single and repeat doses, 
and estimation of an accumulation ratio where 
data allow.

To assess the effect of food on 
the pharmacokinetics of 
GSK2983559 and its active 
moiety GSK2668176 in fasted 
and fed state in healthy 
participants.

Derived PK parameters for GSK2983559, and 
GSK2668176 including area under the plasma 
drug concentration versus time curve (AUC(0-t), 
AUC(0-∞)), maximum observed plasma drug 
concentration (Cmax), time to maximum observed 
plasma drug concentration (tmax), and terminal 
half-life (t1/2) following single (fed and fasted) 
dose, where data allow.
Exploratory Objectives
Exploratory Endpoints

To determine the PD effect of 
single and repeat doses of 
GSK2983559 in healthy 
participants.

PD/biomarker endpoints may include, but not be 
limited to, assessments of pharmacologic effects 
through measurements of target engagement 
and pathway activation. These may include 
measurements of RIP-2 receptor occupancy, 
and levels of MIP1, MIP1and TNF proteins, 
following stimulation of whole blood, as data 
permit.  (Cohort 1 subjects only)

To investigate the metabolic 
profile of GSK2983559 
following single and/or repeat 
doses in healthy participants in 
blood and urine

Identification and quantitative estimates of 
GSK2983559 and its active moiety GSK2668176 
and potential metabolites following single and 
repeat doses in plasma and urine.

To characterize exposure to 5-
ABT and NAc-5-ABT after 
single and repeated doses of 
GSK2983559 in healthy 
participants.

Concentration of 5-ABT and NAc-5-ABT 
(adjusted to 5-ABT concentration based on 
molecular weight (MW)) and derive Cmax for the 
combined concentration curve of 5-ABT and MW 
adjusted NAc-5-ABT


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2.3.
Study Design
Overview of Study Design and Key Features – Part A Single Ascending Dose
Design
Features

Separate participants will be enrolled into both cohorts of Part A.

Cohort 1 Standard Capsule: 5-way crossover design. Each participant will 
receive single ascending oral doses of either GSK2983559 or placebo in a 
4:1 ratio according to the randomisation schedule, in study periods 1 to 5, in 
a blinded manner.

Cohort 2 Enteric Capsule: 4-way crossover design for single ascending
dose, including an additional period for assessing GSK2983559 under fed 
conditions (period 5 – open-label).

During the blinded part, each participant will receive single ascending oral 
doses of either GSK2983559 or placebo in a 3:1 ratio according to the 
randomisation schedule, in study periods 1 to 4, in a blinded manner.

Cohorts 1 and 2 will be dosed sequentially, incorporating sentinel 
participants: Cohort 1 will complete all 5 dosing periods before Cohort 2 
begins.

Following completion of Cohort 1 and before starting Cohort 2, a GSK 
internal safety board (independent of DEC) will be reviewing the data.

Based on emerging PK data, all doses may not be investigated.

There will be a at least 48-hour washout period between each dose 
escalation step but the washout period may be extended depending on 
emerging data.
Dosing

Participants will be randomised on Day 1 followed by a single oral dose of
GSK2983559

Sentinel dosing will be employed within each ascending dose cohort and treatment 
period (except for when investigating the food effect). 

On Day 1, one participant will receive GSK2983559 and one participant will receive 
matched-placebo, to evaluate tolerability and safety for at least 24 hours post-dose. 

Dosing in the remaining 8 and 10 participants in Cohorts 1 and 2, and treatment 
period will occur at least 24 hours later after review of safety results from the initial 


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Overview of Study Design and Key Features – Part A Single Ascending Dose
2 participants in a 7:1 and 4:1 ratios (GSK2983559: placebo) for Cohorts 1 and 2, 
respectively
Time & 
Events

Refer to Appendix 2: Schedule of Activities
Treatment 
Assignmen
t

At screening a unique number (case report form [CRF] number) will be assigned to 
any participant who has at least one Screening procedure performed, other than 
signed informed consent. The unique number will be used to identify individual 
participants during the course of the study.

Participants who meet the screening eligibility criteria will be randomised to a 
treatment group through an Interactive Response Technology (IRT). The IRT will 
confirm the participants CRF number and provide the randomisation number, 
where, a randomisation number will be assigned from a randomisation schedule 
generated by Clinical Statistics, prior to the start of the study, using validated 
internal software. Once assigned, this number must not be reassigned to any other 
participant in the study.

The randomisation is centrally controlled by the IRT.
Part A
Within Cohort 1, participants will be assigned to one of 5 dosing sequences in a 1:1:1:1:1
ratio.
Within Cohort 2, participants will be assigned to one of up to 4 dosing sequences in a 1:1:1:1 
ratio.
Participants will be randomised 
to:


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Overview of Study Design and Key Features – Part A Single Ascending Dose
Interim 
Analysis

No Interim Analysis were conducted due to study termination
Overview of Study Design and Key Features – Part B Multiple Ascending Dose

Study terminated prior to Part B start, please refer to protocol for exact 
details
Treatment 
Assignment

Part B treatment codes were planned to be:
2.4.
Statistical Hypotheses / Statistical Analyses
The objectives of this study are to assess the safety and tolerability of single and repeat
ascending doses of GSK2983559 in healthy volunteers. No formal hypotheses will be
tested.


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3.
PLANNED ANALYSES
3.1.
Interim Analyses
Dose escalation meetings occurred after each period in Part A and were scheduled to 
occur following the completion of 14 days dosing of each cohort in Part B. The decision 
to proceed to the next cohort and next dose strength to be studied, was made by the Dose 
Escalation Committee (DEC) based on assessment of blinded safety (e.g., AEs, clinical 
laboratory results, vital signs and ECG), active moiety (GSK2668176) pharmacokinetic 
and 5-ABT concentrations obtained in all participants at the prior dose level. Individual 
safety data (adverse events, laboratory safety tests, ECGs and vital signs) was reviewed. 
This study was double blind (sponsor open), where the participant, investigator and site 
staff will remain blinded to the treatment allocation. Sponsor open refers only to those 
members of the DEC as required.
Following completion of Cohort 1: Part A and before starting Cohort 2: Part A, a GSK
internal safety board (independent of DEC) reviewed the emerging PK and safety data.
A formal interim analysis was due to be performed during the study on completed cohorts 
in Part A of the study to aid internal decision making only.  The study was terminated 
prior to completion of Part A.
3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
All participants have completed the study as defined in the protocol or the study is 
terminated.  
All required database cleaning activities have been completed and final database release
(DBR) and database freeze (DBF) has been declared by Data Management.
All criteria for unblinding the randomisation codes have been met. 
Randomisation codes have been distributed according to RandAll NG procedures.


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4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Screened 
All participants who were screened for eligibility
Screen Failure
Population Analysed.
Randomised
All participants who were randomly assigned to 
treatment in the study.
This population will be based on the treatment the 
participant was randomised to.
Age ranges
Safety
All randomised participants who received at least one 
dose of study treatment.
This population will be based on the treatment the 
subject actually received.
Note: Participants who were not randomised but 
received at least one dose of study treatment should 
be listed.
All other Study 
Population
Safety
Pharmacokinetic
(PK)
All participants in the Safety population who had at
least 1 non-missing PK assessment (Non-quantifiable 
[NQ] values will be considered as non-missing 
values).
This population will be based on the treatment the 
participant actually received.
PK
Refer to Appendix 10: List of Data Displays which details the population used for each display.
4.1.
Protocol Deviations
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed.
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan Version 2 (08-Feb-2018).
o Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations are captured and categorised on the protocol deviations 
dataset. 
o This dataset will be the basis for the summaries and listings of protocol 
deviations.
A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion 
page of the eCRF.


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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting 
Code
Description
Description
Order in TLF 
A
GSK2983559 single dose 1
GSK 2 mg
2
B
GSK2983559 single dose 2
GSK 4 mg
3
C
GSK2983559 single dose 3
GSK 10 mg
4
D
GSK2983559 single dose 4
GSK 30 mg
5
E
GSK2983559 single dose 5
GSK 100 mg
6
F
GSK2983559 single dose 6
GSK 200 mg E
7
G
GSK2983559 single dose 7
GSK 400 mg E
8
H
GSK2983559 single dose 8
GSK XX mg E [1]
Not used
I
GSK2983559 single dose 9
GSK XX mg E [1]
Not used
J
GSK2983559 fed single dose
Not Used
Not used
P
Placebo single dose
Placebo
1
K
GSK2983559 repeat dose 1
Not Used
Not used
L
GSK2983559 repeat dose 2
Not Used
Not used
M
GSK2983559 repeat dose 3
Not Used
Not used
N
GSK2983559 repeat dose 4
Not Used
Not used
Q
Placebo repeat dose
Not Used
Not used
1.
Dose level not required as the study was terminated prior to being utilised
5.2.
Baseline Definitions

For all endpoints (except as noted in baseline definitions) the baseline value will be 
the latest pre-dose assessment with a non-missing value, including those from 
unscheduled visits. If time is not collected, Day 1 assessments are assumed to be 
taken prior to first dose and used as baseline.

For Part A, baseline definitions defined in the table are applicable to each treatment 
period.

Unless otherwise stated, if baseline data is missing no derivation will be performed 
and baseline will be set to missing. The mean of triplicate measurements at any given 
time point will be used as the value for that time point unless otherwise stated.


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Parameter
Study Assessments Considered as Baseline
Baseline Used in 
Data Display
Screening
Day -1
Day 1 (Pre-Dose)
Safety
Clinical Chemistry/ 
Haematology/
Urinalysis
X
X
X
Day 1
12-lead ECG
X
X [1]
X [1]
Day 1
Vital Signs
X
X
X [1]
Day 1
Pharmacokinetic
PK Concentrations
X
Day 1
Pharmacodynamic
PD Blood sample
X
Day 1
Target Engagement 
sample
X
Day 1
[1]  ECG/Vital signs recordings will be performed in triplicate at visit. Use the mean of the triplicate 
measurements.
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing.
5.3.
Multicentre Studies
This is a single centre study. 
5.4.
Examination of Covariates, Other Strata and Subgroups
There are no covariates, strata or subgroups to be investigated in this study. 
5.5.
Multiple Comparisons and Multiplicity
No adjustments for multiplicity will be required. 


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5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
11.3
Appendix 3: Assessment Windows
11.4
Appendix 4: Study Phases and Treatment Emergent Adverse Events
11.5
Appendix 5: Data Display Standards & Handling Conventions
11.6
Appendix 6: Derived and Transformed Data
11.7
Appendix 7: Reporting Standards for Missing Data
11.8
Appendix 8: Values of Potential Clinical Importance


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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the “Screened” or “Randomised”
population, unless otherwise specified.
Study population analyses including analyses of subject’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure and treatment compliance will be based on GSK Core Data Standards.  
Details of the planned displays are presented in Appendix 10: List of Data Displays.


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7.
SAFETY ANALYSES
The safety analyses will be based on the “Safety” population, unless otherwise specified.
7.1.
Adverse Events Analyses
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs)
and other significant AEs will be based on GSK Core Data Standards. The details of the 
planned displays are provided in Appendix 10: List of Data Displays.
7.2.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, Hematology 
laboratory tests, Urinalysis, and liver function tests will be based on GSK Core Data 
Standards. The details of the planned displays are in Appendix 10: List of Data Displays.
7.3.
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. The details of the 
planned displays are presented in Appendix 10: List of Data Displays.


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8.
PHARMACOKINETIC ANALYSES
8.1.
Primary Pharmacokinetic Analyses
8.1.1.
Endpoint / Variables
PK plasma concentration-time data for the prodrug GSK2983559 and active moiety 
GSK2668176 will be listed, no statistical analysis will be conducted. Summary statistics 
of the prodrug GSK2983559 and active moiety GSK2668176 concentrations by nominal 
blood sampling time will be determined. 
PK data will be summarised for Parts A by randomised treatment. 
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 11.5.3
Reporting Standards for Pharmacokinetic).
Overview of Planned Pharmacokinetic Analyses
Endpoints
Untransformed 
Log-transformed 
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
Pharmacokinetic 
Plasma Drug concentration 
Y
Y[1][2]
Y[1]
Y
NOTES:

T = Table, F = Figure, L = Listings, Y = Display generated.

Summary = represents TF related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = represents FL related to any displays of individual participant observed raw data.  
1:  Linear and Semi-Log plots will be created on the same display.
2: Separate Mean (± SE) and Median plots will be generated.
PK plasma concentrations for 5-ABT and N-Ac-5-ABT (adjusted to 5-ABT concentration 
based on molecular weight (MW)) will be listed, no statistical analysis will be conducted. 
8.1.1.1.
Drug Concentration Measures
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 11.5.3
Reporting Standards for Pharmacokinetic)
8.1.1.2.
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 prodrug 
GSK2983559 and active moiety GSK2668176 concentration-time data, as data permits.


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Parameter
Parameter Description
AUC(0-t)
Area under the concentration-time curve from time zero to the time of the last quantifiable 
concentration (C(t)) will be calculated using the linear trapezoidal rule for each incremental 
trapezoid and the log trapezoidal rule for each decremental trapezoid.
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.
Tmax
Time to reach Cmax, determined directly from the concentration-time data
t1/2
Apparent terminal half-life will be calculated as: 
t½ = ln2 / lambda_z
NOTES:

Additional parameters may be included as required.
8.1.2.
Summary Measures

The pharmacokinetic profile following a single dose of GSK2983559

Derived PK parameters for GSK2983559 and active moiety GSK2668176 including 
area under the plasma drug concentration versus time curve (AUC(0-t), AUC(0-∞)), 
maximum observed plasma drug concentration (Cmax), time to maximum observed 
plasma drug concentration (tmax), and terminal half-life (t1/2) following single (fasted) 
doses, where data allow.

Descriptive statistics (n, arithmetic mean, standard deviation [SD] standard error
[SE], 95% CI, minimum, median and maximum) will be calculated by treatment for 
all PK concentrations over time and for the derived PK parameters. 

In addition, for loge-transformed PK parameter variables geometric mean, 95% CI 
and %CVb (100 * √ (exp(SD2) -1)) will be provided, where the SD is the standard 
deviation of log-transformed data.
8.1.3.
Population of Interest 
The primary pharmacokinetic analyses will be based on the “Pharmacokinetic” 
population, unless otherwise specified.
8.1.4.
Strategy for Intercurrent (Post-Randomisation) Events

Study completion (i.e. as specified in the protocol) was defined as completing all 
phases of the study including the follow-up visit.

Withdrawn participants may be replaced in the study. Replacement participants,
enrolled will be dosed with the next planned treatment of the withdrawn participant, 
and they will not receive any treatment that the withdrawn participant has already 
received with the exception of the need to increase participants numbers to obtain the
minimum number of evaluable participants required for interim decisions, and to 
obtain data in any  other treatment that is required for a valid comparison. 
Replacement participants will receive the required treatments in the same order as 
planned for the original participant.


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
All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified. 
8.2.
Secondary Pharmacokinetic Analyses
8.2.1.
Endpoint / Variables
5-ABT and NAc-5-ABT (adjusted to 5-ABT concentration based on molecular weight 
(MW)) concentrations will be listed, no statistical analysis will be conducted.
8.2.1.1.
Drug Concentration Measures 
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 11.5.3
Reporting Standards for Pharmacokinetic)
8.2.2.
Summary Measure

Listings of 5-ABT and NAc-5-ABT (adjusted to 5-ABT concentration based on 
molecular weight (MW)) will also be provided
8.2.3.
Population of Interest 
The secondary pharmacokinetic analyses will be based on the “Pharmacokinetic”
population, unless otherwise specified.


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9.
PHARMACODYNAMIC ANALYSES
9.1.
Exploratory Pharmacodynamic Analyses
9.1.1.
Endpoint / Variables
Levels of blood MIP1, MIP1and TNF proteins will be summarised and listed by 
randomised treatment for Cohort 1 only. No statistical analyses will be conducted.
9.1.2.
Summary Measure
Actual values and percentage change from baseline of blood MIP1, MIP1and TNF 
proteins will be summarised.
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.
Unless otherwise specified, endpoints / variables defined in Section 9.1.1 will be
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
9.1.3.
Population of Interest 
The secondary pharmacodynamics analyses will be based on the “Safety” population, 
unless otherwise specified.


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10.
REFERENCES
None


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11.
APPENDICES
11.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population

Protocol deviations will be tracked by the study team throughout the conduct of the 
study in accordance with the Protocol Deviation Management Plan.
o
Data will be reviewed prior to freezing the database to ensure all important 
deviations are captured and categorised on the protocol deviations dataset.
o
This dataset will be the basis for the summaries and listings of protocol 
deviations.


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11.2.
Appendix 2: Schedule of Activities
11.2.1.
Protocol Defined Schedule of Events
Screening and Follow Up SOA
Procedure
Screening
Follow-up Visit
Notes
(up to 28 days prior to Day 1)
Outpatient Visit
X
X
Follow-up Visit to occur approximately 7 days or 5 half lives (as 
determined from Part A PK data), whichever is longer, and no greater 
than 14 days after last study drug administration.
Informed Consent
X
Inclusion and Exclusion Criteria
X
Medical/medication/drug/alcohol history
X
Demographics
X
Full Physical Examination
X
Additional examinations may be performed, or brief examinations 
made full examinations, by the Investigator, as deemed necessary (e.g. 
where safety or laboratory findings indicate).
Brief Physical Examination
X
Drug/alc./cotinine screen
X
Tests include alcohol breath test, urine cotinine and drug screen.
HIV, Hep B and Hep C screen
X
Tuberculosis Test
X
Conducted as standard practice of the site.
Serum Pregnancy Test (all females)
X
FSH and estradiol (all females)
X
Hema/Chem/Urinalysis tests
X
X
Coagulation Panel
X
Lipid panel (Part B only)
X
Height and weight
X
Holter Monitoring (24-hour)
X
12-lead ECG
T
X
T= Triplicate
Vital signs
X
X
Vital signs to include heart rate, blood pressure, respiration rate and 
temperature.
Concomitant Medication Review
X
X
AE and SAE Review
X


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Part A SOA
Notes
Day -1
Day 2 Day 3
Participants to be admitted to the unit the day before dosing (Day -1), 
and remain in house until discharge after 48-hour post-dose 
assessments (Day 3) are completed.
Pre dose 0 h 15min 30min 1 hr 1.5 hr 2 hr 2.5 hr 3 hr 4hr 5hr 6hr 8 hr 10 hr 12 hr 24 hr 48 hr
X
X
X
X
Additional exams./screens may be performed, or brief exams made full 
exams. by the Investigator, as deemed necessary (e.g. where safety or 
laboratory findings indicate).
X
Additional assessments may be performed at the discretion of the 
Investigator.  Tests will be conducted within site specified standards.
X
X
X
X
X
Non-fasted samples will be collected on Day -1 and at 8 hours on Day 1. 
Non-fasted chemistry only will be collected at 8 hour time point.
X
X
X
X
Continuous at least 8 hours post-dose.  Initiate at least 15 min. prior to 
dosing
X
T
X
X
X
X
X
X
X
X
X
Vital signs to include HR, BP, respiration rate and temperature.
T = Triplicate (HR and BP only) single respiration rate and temperature. 
Timings will be reviewed as cohorts progress and may be adjusted to 
ensure appropriate measurements relative to peak concentrations for 
subsequent cohorts.  
T
T
X
X
X
X
X
X
X
X
All
D
Cohort 2, fed period 
D
B
X
A minimum interval of 30 minutes will be observed between the dosing 
of the first 2 participants at each dose level.  A minimum interval of 15 
minutes will be observed between the dosing of the remaining 6 
participants.
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
The number and sampling times may be adjusted once the human PK 
data are available.
X
Participants will void bladder prior to dosing, a sample will be kept as 
control.  0-24-hr urine samples will be collected. 
X
X
X
X
X
X
 Two samples will be drawn at pre-dose.  The PD  sampling time points 
may be updated based on emerging PK data. PD samples will not be 
collected in the food efect part of the study.
X
X
X
X
X
X
TE samples will not be collected in the food effect part of the study 
See section 10.1.1 for pre-dose SAE requirements
For ECG and vital signs T=Triplicate, For Meals B=Breakfast, D=Dinner
<---------------------------------------------------------------------------------->
Prior to dosing, participants will fast for 8 hrs overnight; no food is 
allowed for at least 4 hrs post-dose.  Water is permitted with dosing and 
at all times except 1 hour pre-dose through 2-hours post-dose.  
Participants will receive standardized meals scheduled at the same time 
in each period.  
Meals
TE Blood Sample
PD Blood Sample
PK Blood Sample
Urine Collection for 
Metabolites
Study Treatment dosing
12-lead ECG
Telemetry
Vital signs
<--------------------------------------------------------------X----------------------------------------------------------------->
Adverse Event Review
Concomitant Med.
<---------------------------------------0-24 hours---------------------------------------->
Procedure
Study Day (each dosing session)
Day 1 (time relative to dose)
See Study Reference Manual for assessment time windows
Neuro. examination
Brief Physical Examination
Drug/alc./cotinine screen
Heam/Chem/Coags/Urinalysis
Per site Schedule
<--------------------------------------------------------------X------------------------------------------------------->
Pregnancy test (all females)


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11.3.
Appendix 3: Assessment Windows
11.3.1.
Definitions of Assessment Windows for Analyses
No Assessment Windows will be defined for Analysis, and summaries and analyses will 
be based on nominal visits.


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11.4.
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events
11.4.1.
Study Phases
Assessments and events will be classified according to the time of occurrence relative to 
the start and/or stop date/time of the study treatment within the period for Part A.
Study Phase
Definition
Pre-Treatment 
Date < Study Treatment Start Date
On-Treatment
Study Treatment Start Date ≤Date ≤ Study Treatment Stop Date + 1
Post-Treatment
Date > Study Treatment Stop Date + 1
11.4.1.1.
Study Phases for Concomitant Medication
Study Phase
Definition
Prior
If medication end date is not missing and is before 28 days prior to screening visit
Concomitant
Any medication that is not a prior
NOTES: 

Please refer to Appendix 7: Reporting Standards for Missing Data for handling of missing and partial dates for
concomitant medication. Use the rules in this table if concomitant medication date is completely missing.


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11.4.2.
Treatment Emergent Flag for Adverse Events
Flag
Definition
Treatment 
Emergent

If AE onset date is on or after treatment start date & on or before treatment stop 
date +1.

Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment Stop Date + 1

For studies with greater than one treatment period (e.g., crossover study), if AE 
onset is during one period and worsens during a later period it would be counted 
in both periods. For the initial period the logic would be as above. For the later 
period the logic would use the treatment dates associated with the later period:

Treatment Period Start Date ≤ AE Worsening Date ≤ Study Treatment Stop Date 
+1 day
NOTES: 

If the study treatment stop date is missing, then the AE will be considered to be On-Treatment.

Time of study treatment dosing and start/stop time of AEs should be considered, if collected.


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11.5.
Appendix 5: Data Display Standards & Handling 
Conventions
11.5.1.
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
UK1SALX00175
HARP Compound
One reporting effort will be set up for this study \ arenv \ arprod \ gsk2983559 \
mid205021 \final_01
Analysis Datasets 

Analysis datasets will be created according to Legacy Integrated Data Standards Library (IDSL) GSK 
A&R dataset standards
Generation of RTF Files

RTF files will be generated for all tables within the final_01 reporting effort.
11.5.2.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 

Do not include subject level listings in the main body of the GSK Clinical Study Report. All subject level 
listings should be located in the modular appendices as ICH or non-ICH listings

All data displays (Tables, Figures & Listings) will use the term “Subject” which reflects CDISC and GSK 
Data Display Standards terminology.
Formats

All data will be reported according to the actual treatment the participant received, unless otherwise 
stated.

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected, unless otherwise stated.

Numeric data will be reported at the precision collected on the eCRF.

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.
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 


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Unscheduled Visits

Unscheduled visits will not be included in summary tables and/or figures.

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.
11.5.3.
Reporting Standards for Pharmacokinetic
Pharmacokinetic Concentration Data
PC Windows Non-
Linear (WNL) File
PC WNL file (CSV format) for the non compartmental analysis by Clinical 
Pharmacology Modelling and Simulation function will be created according to 
PKOne
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. 
NONMEM/Pop PK 
File
Not applicable.
NONMEM/PK/PD 
File
Not applicable
Pharmacokinetic Parameter Derivation
PK Parameter to be 
Derived by 
Programmer
Not applicable
Pharmacokinetic Parameter Data
Is NQ impacted PK 
Parameters Rule 
Being Followed
Yes, refer to Standards for Handling NQ Impacted PK Parameters.
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.
Refer to PKOne


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11.6.
Appendix 6: Derived and Transformed Data
11.6.1.
General
Multiple Measurements at One Analysis Time Point

Mean of the measurements will be calculated and used in any derivation of summary statistics but if 
listed, all data will be presented.

If there are two values within a time window (as per Section 11.3.1) the value closest to the target day
for that window will be used. If values are the same distance from the target, then the mean will be 
taken.

Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance summary 
tables.
Study Day

Calculated as the number of days from First Dose Date:

Ref Date = Missing              → Study Day = Missing 

Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date

Ref Data ≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1    
11.6.2.
Study Population
Treatment Compliance

Treatment compliance will be calculated based on the formula:  
Treatment Compliance = Number of Actual Doses / (Planned Treatment Duration in Days * 
Frequency)

Planned Treatment Duration is defined as 1 day in Part A in each period 
Extent of Exposure

Number of days of exposure to study drug will be calculated based on the formula:  
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 1

Participants who were randomised but did not report a treatment start date will be categorised as 
having zero days of exposure. 

The cumulative dose will be based on the formula:
Cumulative Dose = Sum of (Number of Days x Total Daily Dose)

If there are any treatment breaks during the study, exposure data will be adjusted accordingly.
11.6.3.
Safety
ECG Parameters
RR Interval

IF RR interval (msec) is not provided directly, then RR can be derived as:
o
If QTcF is machine read, then: 
                                     

If ECGs are manually read, the RR value preceding the measurement QT interval should be a 


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ECG Parameters
collected value THEN do not derive.
Corrected QT Intervals

When not entered directly in the eCRF, corrected QT intervals by Fridericia’s (QTcF) formulas 
will be calculated, in msec, depending on the availability of other measurements.

IF RR interval (msec) is provided then missing QTcF will be derived as: 
Laboratory Parameters 

If a laboratory value which is expected to have a numeric value for summary purposes, has a non-
detectable level reported in the database, where the numeric value is missing, but typically a 
character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the 
comment field) is present, the number of significant digits in the observed values will be used to 
determine how much to add or subtract in order to impute the corresponding numeric value. 
o
Example 1: 2 Significant Digits =  ‘< x ‘ becomes x – 0.01
o
Example 2: 1 Significant Digit   =  ‘> x’ becomes x + 0.1
o
Example 3: 0 Significant Digits = ‘< x’ becomes x – 1    


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11.7.
Appendix 7: Reporting Standards for Missing Data
11.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) was defined as all phases of 
the study including the last scheduled procedure shown in the SoA (see Appendix 2).

Withdrawn subjects may have been replaced in the study.

All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified.

Withdrawal visits will be slotted as per Appendix 3: Assessment Windows or will be
summarised as withdrawal visits.
Liver 
Chemistry 
Stopping 
Criteria

Discontinuation of study treatment for abnormal liver tests is required when:
o
in the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the investigator believes study treatment discontinuation is in 
the best interest of the participant.
o
ALT ≥ 3 x ULN.

Note: Refer to Appendix 7 of the protocol for details of the required assessments if a 
participant meets the above criteria.
QTc 
Stopping 
Criteria

A participant that meets either bulleted criterion based on the average of triplicate ECG 
readings will be withdrawn from study treatment:
o
QTcF > 500 msec
o
Change from baseline: QTcF > 60 msec
Nervous 
System 
Stopping 
Criteria

A participant will be withdrawn from the study if:
o
A Grade 3 or greater CTCAE Nervous System finding is observed or a 
significant neurologic change from a participant’s baseline physical 
examination is observed.
o
Any adverse event included in the CTCAE for Nervous System, which is also 
considered to be clinically significant by the Principal Investigator, will be 
reviewed for potential participant withdrawal.
11.7.2.
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 subject listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such.
Outliers

Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
11.7.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in subject listing displays.


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Element
Reporting Detail
Adverse 
Events

The eCRF allows for the possibility of partial dates (i.e., only month and year) to be 
recorded for AE start and end dates; that is, the day of the month may be missing. In 
such a case, the following conventions will be applied for calculating the time to onset 
and the duration of the event:
o
Missing Start Day: First of the month will be used unless this is before the start 
date of study treatment; in this case the study treatment start date will be used and 
hence the event is considered On-treatment as per Appendix 4: Study Phases
and Treatment Emergent Adverse Events.
o
Missing Stop Day: Last day of the month will be used, unless this is after the stop 
date of study treatment; in this case the study treatment stop date will be used.

Completely missing start or end dates will remain missing, with no imputation applied. 
Consequently, time to onset and duration of such events will be missing.
Concomitant 
Medications/
Medical 
History

Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will be 
used for the month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day (dependent 
on the month and year) and 'Dec' will be used for the month.

The recorded partial date will be displayed in listings.


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11.8.
Appendix 8: Values of Potential Clinical Importance
11.8.1.
Laboratory Values
Haematology
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Hematocrit 
Ratio of 
1
Male
0.54
Female
0.54
∆from BL
↓0.075
Haemoglobin 
g/L
Male
180
Female
180
∆from BL
↓25
Lymphocytes 
x109/ L
0.8
Neutrophil Count 
x109/ L
1.5
Platelet Count 
x109/ L
100
550
While Blood Cell Count (WBC)
x109/ L
3
20
Clinical Chemistry
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Albumin 
g/L
30
Calcium
mmol/L
2
2.75
Creatinine
umol/L
∆from BL
↑ 44.2
Glucose
mmol/L
3
9
Phosphorus
mmol/L
<0.8
>1.6
Potassium
mmol/L
3
5.5
Sodium
mmol/L
130
150
Liver Function
Test Analyte
Units
Category
Clinical Concern Range
ALT/SGPT 
U/L
High
2x ULN
AST/SGOT 
U/L
High
2x ULN
AlkPhos 
U/L
High
2x ULN
T Bilirubin 
µmol/L
High
1.5xULN
T. Bilirubin + ALT
µmol/L
High
1.5xULN T. Bilirubin
+
U/L
2x ULN ALT


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11.8.2.
ECG
ECG Parameter
Units
Category
Clinical Concern Range
Lower
Upper
Absolute
Absolute QTc Interval
msec
H1
> 450 
< 480 
H2
≥ 480 
500 
H3
> 500 
Absolute PR Interval
msec
L, H
< 110
> 220
Absolute QRS Interval
msec
L, H
< 75
> 110
Change from Baseline
Increase from Baseline 
QTc
msec
H1
> 30  
≤ 60
H2
> 60
Note: PCIs will be determined for QTcF.  If QTcF not available, PCIs will be determined for QTcB instead
11.8.3.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Clinical Concern Range
Lower
Upper
Systolic Blood Pressure
mmHg
< 85
> 160
Diastolic Blood Pressure
mmHg
< 45
> 100
Heart Rate
bpm
< 40
> 110
Respiratory Rate
breaths/min
                   ≤ 8
                 ≥20
Temperature
ºC
   ≤ 35.5
≥37.8
Vital Sign Parameter
(Change from Baseline)
Units
Clinical Concern Range
Decrease
Increase
Lower
Upper
Lower
Upper
Systolic Blood Pressure
mmHg
≥ 20
≥ 40
≥ 20
≥ 40
Diastolic Blood Pressure
mmHg
≥ 10
≥ 20
≥ 10
≥ 20
Heart Rate
bpm
≥ 15
≥ 30
≥ 15
≥ 30


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11.9.
Appendix 9: Abbreviations & Trade Marks
11.9.1.
Abbreviations
Abbreviation
Description
AE
Adverse Event
A&R
Analysis and Reporting 
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CPMS
Clinical Pharmacology Modelling & Simulation
CS
Clinical Statistics
CSR
Clinical Study Report
CTR
Clinical Trial Register
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
DBF
Database Freeze
DBR
Database Release
DOB
Date of Birth
DP
Decimal Places
eCRF
Electronic Case Record Form
EMA
European Medicines Agency
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
GSK
GlaxoSmithKline
IA
Interim Analysis
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
IMMS
International Modules Management System
IP
Investigational Product
ITT
Intent-To-Treat
MMRM
Mixed Model Repeated Measures
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PP
Per Protocol
PopPK
Population PK
QC
Quality Control
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RAMOS
Randomisation & Medication Ordering System 
SAC
Statistical Analysis Complete
SDSP
Study Data Standardization Plan
SDTM
Study Data Tabulation Model
SOP
Standard Operation Procedure


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Abbreviation
Description
TA
Therapeutic Area
TFL
Tables, Figures & Listings 
11.9.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
HARP
NONMEM
SAS
WinNonlin


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11.10.
Appendix 10: List of Data Displays
11.10.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.11
Efficacy
Safety
3.1 to 3.22
3.1 to 3.7
Pharmacokinetic
4.1 to 4.6
4.1 to 4.8
Population Pharmacokinetic (PopPK)
Pharmacodynamic and / or Biomarker
6.1 
6.1 
Pharmacokinetic / Pharmacodynamic
Section
Listings
ICH Listings
1 to 30
Other Listings
31 to 37
11.10.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Efficacy
EFF_Fn
EFF_Tn
EFF_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
Pharmacokinetic
PK_Fn
PK_Tn
PK_Ln
Population Pharmacokinetic (PopPK)
POPPK_Fn
POPPK_Tn
POPPK_Ln
Pharmacodynamic and / or Biomarker
PD_Fn
PD_Tn
PD_Ln
Pharmacokinetic / Pharmacodynamic
PKPD_Fn
PKPD_Tn
PK/PD_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL /  Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’
11.10.3.
Deliverables
Delivery 
Description
SAC
Final Statistical Analysis Complete
NOTES: 
1.
Indicates priority (i.e. order) in which displays will be generated for the reporting effort


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11.10.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
Safety
ES8A
Summary of Subject Status and Reason for Study Withdrawal: 
Part A
ICH E3, FDAAA, EudraCT
Add footnote: Note: “Subjects” is used 
to refer to “Participants” in all data 
displays to reflect GSK display 
standards and CDISC SDTM/ADaM 
standards.
SAC
1.2.
Safety
ES4
Summary of Subject Disposition at Each Study Epoch: Part A
ICH E3
Page by cohort, include treatment 
column for Randomised Trt Sequence 
and Total Column
SAC
1.3.
Screened
ES6
Summary of Screening Status and Reasons for Screen Failure: 
Part A
Journal Requirements
SAC
Protocol Deviation
1.4.
Safety
DV1
Summary of Important Protocol Deviations: Part A
ICH E3
SAC


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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Population Analysed
1.5.
All Subjects
SP1 
Summary of Study Populations: Part A
IDSL
Add the following footnotes:
[1] Subjects are included in the 
Randomised population if they were 
randomly assigned to treatment in the 
study.
[2] Subjects are included in the Safety 
population if they have been 
randomised and received at least one 
dose of study treatment.
[3] Subjects are included in the 
Pharmacokinetic population if they are 
in the Safety Population and a 
pharmacokinetic sample was obtained 
and analysed.
SAC
Demographic and Baseline Characteristics
1.6.
Safety
DM1
Summary of Demographic Characteristics: Part A
ICH E3, FDAAA, EudraCT
Overall and by cohort
Include treatment column for 
randomised treatment sequence and 
total column
SAC


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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.7.
Randomised
DM11
Summary of Age Ranges: Part A
EudraCT
Only include age ranges applicable to 
the study (‘Adult (18-64 years)’ and 
‘>=65-84 years’))
Please add footnote to say that 
randomised population=enrolled 
population.
Overall and by cohort
Include treatment column for 
randomised treatment sequence and 
total column
SAC
1.8.
Safety
DM5
Summary of Race and Racial Combinations: Part A
ICH E3, FDA, FDAAA, EudraCT
Overall and by cohort
Include treatment column for 
randomised treatment sequence and 
total column
SAC
Prior and Concomitant Medications
1.9.
Safety
MH4
Summary of Current/Past Medical Conditions: Part A
ICH E3
Separate summaries for Current 
& Past conditions, if collected.
SAC
1.10.
Safety
CM1
Summary of Concomitant Medications: Part A
ICH E3
SAC
Exposure and Treatment Compliance
1.11.
Safety
EX5
Summary of Exposure to Study Treatment: Part A
ICH E3
SAC


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11.10.5.
Safety Tables
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
3.1.
Safety
AE1CP 
Summary of All Adverse Events by System Organ Class and 
Preferred Term: Part A
ICH E3
SAC
3.2.
Safety
AE5A
Summary of All Adverse Events by Maximum Grade / Intensity 
by System Organ Class and Preferred Term: Part A
ICH E3
SAC
3.3.
Safety
AE5A
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term and Maximum Intensity: Part A
ICH E3
.
SAC
3.4.
Safety
AE15
Summary of Common (>=10%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Participant 
and Occurrences) : Part A
FDAAA, EudraCT
‘
SAC
Serious and Other Significant Adverse Events
3.5.
Safety
AE16
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Subjects and Occurrences) : 
Part A
FDAAA, EudraCT
SAC
3.6.
Safety
AE3
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study by 
System Organ Class and Preferred Term /by Overall Frequency: 
Part A
IDSL
SAC
Laboratory: Chemistry 
3.7.
Safety
LB1
Summary of Chemistry Changes from Baseline: Part A
ICH E3
SAC


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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.8.
Safety
LB17
Summary of Worst Case Chemistry Results by PCI Criteria 
Post-Baseline Relative to Baseline: Part A
ICH E3
SAC
Laboratory: Hematology
3.9.
Safety
LB1
Summary of Hematology Changes from Baseline: Part A
ICH E3
SAC
3.10.
Safety
LB17
Summary of Worst Case Hematology Results by PCI Criteria 
Post-Baseline Relative to Baseline: Part A
ICH E3
SAC
Laboratory: Urinalysis
3.11.
Safety
LB1
Summary of Urine Concentration Changes from Baseline: Part A
ICH E3
SAC
3.12.
Safety
UR1
Summary of Worst Case Urinalysis Results (Discrete or 
Character Values) Post-Baseline Relative to Baseline: Part A
ICH E3
Laboratory: Hepatobiliary (Liver)
3.13.
Safety
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting: Part A
IDSL
SAC
3.14.
Safety
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities: Part A
IDSL
SAC
ECG
3.15.
Safety
EG1
Summary of ECG Findings : Part A
IDSL
SAC
3.16.
Safety
EG10
Summary of Maximum QTc Values Post-Baseline Relative to 
Baseline by Category: Part A
IDSL
SAC
3.17.
Safety
EG2
Summary of Change from Baseline in ECG Values by Visit: Part 
A
IDSL
SAC
3.18.
Safety
EG11
Summary of Maximum Increase in QTc Values Post-Baseline 
Relative to Baseline by Category: Part A
IDSL
SAC


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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Vital Signs
3.19.
Safety
VS1
Summary of Change from Baseline in Vital Signs: Part A
ICH E3
SAC
3.20.
Safety
VS3 /
VS6 /
VS7
Summary of Worst Case Vital Signs Results by PCI Criteria 
Post-Baseline Relative to Baseline: Part A
IDSL
SAC
Holter
3.21.
Safety
HM1
Summary of Holter Interpretations: Part A
SAC
3.22.
Safety
HM2
Summary of Holter Abnormalities: Part A
SAC


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11.10.6.
Safety Figures
Safety: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events
3.1.
Safety
AE10
Plot of Common (>=10%) Adverse Events and Relative Risk: 
Part A
IDSL
SAC
Laboratory
3.2.
Safety
LIVER14
Scatter Plot of Maximum vs. Baseline for ALT: Part A
IDSL
SAC
3.3.
Safety
LIVER9
Scatter Plot of Maximum ALT vs. Maximum Total Bilirubin: Part 
A
IDSL
SAC
3.4.
Safety 
SAFE_01
Individual Profile Plots for Liver Function Tests : Part A
Page by liver function test (ALT, AST, 
ALKP, BILI)
Scheduled & Unscheduled Visits to be 
presented
Panel by subject 
Lower reference line ULN, High 
Reference Line PCI as y-axis allows.  
Label reference line clearly on figure or 
in legend
SAC
3.5.
Safety
SAFE_02
Box Plot of Liver Function Tests by Period: Part A
Page by liver function test (ALT, AST, 
ALKP, BILI)
Scheduled visits only
SAC


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Safety: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.6.
Safety
SAFE_01
Individual Profile Plots for Renal Function Tests: Part A
Page by renal function test (Blood Urea 
Nitrogen, Calcium, Creatinine, Gamma 
GT, Potassium, Sodium, Blood Glucose 
– fasted, Urea)
Scheduled & Unscheduled Visits to be 
presented
Panel by subject 
LLN and ULN to be included as y-axis 
allows
Label reference line clearly on figure or 
in legend
SAC
3.7.
Safety
SAFE_02
Box Plot of Liver Function Tests by Period: Part A
Page by renal function test (Blood Urea 
Nitrogen, Calcium, Creatinine, Gamma 
GT, Potassium, Sodium, Blood Glucose 
– fasted, Urea)
Scheduled Visits Only
SAC


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11.10.7.
Pharmacokinetic Tables
Pharmacokinetic: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Pharmacokinetic Concentrations
4.1.
PK
PK01
Summary of Plasma GSK2983559 Pharmacokinetic 
Concentration-Time Data: Part A
Include column for 95% CI.
SAC
4.2.
PK
PK01
Summary of Plasma GSK2668176 Pharmacokinetic 
Concentration-Time Data: Part A
Include column for 95% CI.
SAC
Pharmacokinetic Paramaters
4.3.
PK
PK03
Summary of Derived Plasma GSK2983559 Pharmacokinetic 
Parameters: Part A
Include columns for parameter, 
period, treatment, N, n, mean, 95% 
CI, standard deviation [SD], 
standard error [SE], median, 
minimum and maximum.
SAC
4.4.
PK
PK05
Summary of Log-Transformed Derived Plasma GSK2983559
Pharmacokinetic Parameters: Part A
Include columns for parameter, 
period, treatment, N, n, geometric 
mean, 95% CI of geometric mean, 
standard deviation [SD] of logged 
data and %CVb.
Do not summarise Tmax.
SAC
4.5.
PK
PK03
Summary of Derived Plasma GSK2668176 Pharmacokinetic 
Parameters: Part A
Include columns for parameter, 
period, treatment, N, n, mean, 95% 
CI, standard deviation [SD], 
standard error [SE], median, 
minimum and maximum.
SAC


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Pharmacokinetic: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
4.6.
PK
PK05
Summary of Log-Transformed Derived Plasma GSK2668176
Pharmacokinetic Parameters: Part A
Include columns for parameter, 
period, treatment, N, n, geometric 
mean, 95% CI of geometric mean, 
standard deviation [SD] of logged 
data and %CVb.
Do not summarise Tmax.
SAC


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11.10.8.
Pharmacokinetic Figures
Pharmacokinetic: Figures
No.
Population
IDSL /
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Pharmacokinetic Concentrations
4.1.
PK
PK16b
Individual Plasma GSK2983559 Concentration-Time Plots 
(Linear and Semi-log) by Subject: Part A
SAC
4.2.
PK
PK24
Individual Plasma GSK2983559 Concentration-Time Plots 
(Linear and Semi-log) by Treatment : Part A
Set Y-axis maximum value close to 
maximum concentration for each 
treatment
SAC
4.3.
PK
PK19
Mean (+ SD) Plasma GSK2983559 Concentration-Time Plots 
(Linear and Semi-log) by Treatment: Part A
One plot / cohort
SAC
4.4.
PK
PK20
Median (Range) Plasma GSK2983559 Concentration-Time 
Plots (Linear and Semi-log) by Treatment: Part A
One plot / cohort
SAC
4.5.
PK
PK16b
Individual Plasma GSK2668176 Concentration-Time Plots 
(Linear and Semi-log) by Subject: Part A
SAC
4.6.
PK
PK24
Individual Plasma GSK2668176 Concentration-Time Plots 
(Linear and Semi-log) by Treatment : Part A
SAC
4.7.
PK
PK19
Mean (+ SD) Plasma GSK2668176 Concentration-Time Plots 
(Linear and Semi-log) by Treatment: Part A
One plot / cohort
SAC
4.8.
PK
PK20
Median (Range) Plasma GSK2668176 Concentration-Time 
Plots (Linear and Semi-log) by Treatment : Part A
One plot / cohort


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11.10.9.
PharmacodynamicTables
PharmacodynamicTables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Pathway Activation
6.1.
Safety
PD_T1
Summary of Actual and Percentage Change from Baseline 
Pathway Activation Markers by Randomised Treatment
Page by TNF, MIP-1, MIP-1
SAC
11.10.10. Pharmacodynamic Figures
Pharmacodynamic: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Pathway Activation
6.1.
Safety
Mean(+-SE) of Actual and Percentage Change from Baseline 
Pathway Activation Markers by Randomised Treatment
Page by TNF, MIP-1, MIP-1
SAC


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11.10.11. ICH Listings
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.
Screened
ES7
Listing of Reasons for Screen Failure: Part A
Journal Guidelines
SAC
2.
Safety
ES3
Listing of Reasons for Study Withdrawal Part A
ICH E3
SAC
3.
Safety 
SD3
Listing of Reasons for Study Treatment Discontinuation: Part A
ICH E3
SAC
4.
Safety
BL2
Listing of Subjects for Whom the Treatment Blind was Broken: 
Part A
ICH E3
SAC
5.
Safety
TA1
Listing of Planned and Actual Treatments: Part A
IDSL
SAC
Protocol Deviations
6.
Safety
: Part A
DV2A
Listing of Important Protocol Deviations 
ICH E3
SAC
7.
Safety
: Part A
IE4
Listing of Subjects with Inclusion/Exclusion Criteria Deviations
ICH E3
SAC
Populations Analysed
8.
All Subjects 
(Part A)
SP3a
Listing of Subjects Excluded from Any Population
ICH E3
SAC
Demographic and Baseline Characteristics
9.
Safety
: Part A
DM4
Listing of Demographic Characteristics: Part A
ICH E3
Include Weight & BMI from vitals
SAC
10.
Safety
: Part A
DM10
Listing of Race: Part A
ICH E3
SAC


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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Prior and Concomitant Medications
11.
Safety
: Part A
CP_CM4
Listing of Concomitant Medications
IDSL
SAC
Exposure and Treatment Compliance
12.
Safety
: Part A
EX4
Listing of Exposure Data
ICH E3
SAC
Adverse Events
13.
Safety 
(Part A)
AE9CP
Listing of All Adverse Events: Part A
ICH E3
SAC
14.
Safety
: Part A
AE7
Listing of Subject Numbers for Individual Adverse Events: Part A
ICH E3
SAC
15.
Safety
: Part A
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text: Part A
IDSL
SAC
Serious and Other Significant Adverse Events
16.
Safety
: Part A
AE9CPa
Listing of Serious Adverse Events: Part A
ICH E3
SAC
17.
Safety 
(Part A)
AE14
Listing of Reasons for Considering as a Serious Adverse Event: 
Part A
ICH E3
SAC
18.
Safety 
(Part A)
AE9CP
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment: Part A
ICH E3
SAC
All Laboratory
19.
Safety
: Part A
LB6
Listing of All Laboratory Data for Subjects with Any Value of 
Potential Clinical Importance: Part A
ICH E3
SAC


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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
20.
Safety 
(Part A)
LB6
Listing of Laboratory Values of Potential Clinical Importance: 
Part A
SAC
21.
Safety
: Part A
LB14
Listing of Laboratory Data with Character Results
ICH E3
SAC
22.
Safety
: Part A
UR2B
Listing of Urinalysis Data for Subjects with Any Value of 
Potential Clinical Importance
ICH E3
SAC
ECG
23.
Safety
: Part A
EG4
Listing of All ECG Values for Subjects with Any Value of 
Potential Clinical Importance
IDSL
SAC
24.
Safety
: Part A
EG4
Listing of ECG Values of Potential Clinical Importance
IDSL
SAC
25.
Safety
: Part A
EG4
Listing of All ECG Changes for Subjects with Any Value of 
Potential Clinical Importance
IDSL
SAC
26.
Safety
: Part A
EG4
Listing of ECG Changes of Potential Clinical Importance
IDSL
SAC
27.
Safety 
(Part A)
EG6
Listing of All ECG Findings for Subjects with an Abnormal ECG 
Finding
IDSL
SAC
28.
Safety
: Part A
EG6
Listing of Abnormal ECG Findings
IDSL
SAC
Vital Signs
29.
Safety 
(Part A)
VS5
Listing of All Vital Signs Data for Subjects with Any Value of 
Potential Clinical Importance
IDSL
SAC


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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
30.
Safety 
(Part A)
VS5
Listing of Vital Signs of Potential Clinical Importance
IDSL
SAC
11.10.12. Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Pharmacokinetic
31.
Pharmacokinetic 
PK08
Listing of Plasma GSK2983559 Pharmacokinetic 
Concentration-Time Data: Part A
SAC
32.
Pharmacokinetic 
PK08
Listing of Plasma GSK2668176 Pharmacokinetic 
Concentration-Time Data: Part A
SAC
33.
Pharmacokinetic 
PK08
Listing of Plasma 5-ABT Pharmacokinetic Concentration-Time 
Data: Part A
SAC
34.
Pharmacokinetic 
PK08
Listing of Plasma NAc-5-ABT Pharmacokinetic Concentration-
Time Data: Part A
SAC
Pharmacodynamic
35.
Safety
Listing of Pathway Activation Markers
TNF, MIP-1, MIP-1
SAC